Abstract #1 Submission ID#1227687
Gender disparity persists in pain medicine: a cross-sectional study of chairpersons within ACGME-accredited chronic pain fellowship programs in the United States
Roderick King, M.D.a, Ryan D’Souza, M.D.b and Oludare Olatoye, M.D.b
aResident Physician, Mayo Clinic; bAssistant Professor of Anesthesiology, Mayo Clinic
Learning objectives
Upon completion, participants will be able to discuss gender disparities among leadership in academic interventional pain fellowships.
Upon completion, participants will be able to demonstrate an understanding of the importance of a diverse workforce in interventional pain medicine as it relates to patient care.
Upon completion, participants will be able to discuss the importance of diverse leadership in academic interventional pain fellowship programs in generating a diverse workforce.
Purpose
The importance of gender equity among medical providers is becoming increasingly recognized within academia. Attaining a diverse workforce in healthcare has been linked to reduced health disparities, increased trust in the healthcare system by marginalized patient groups, and increased provider comfort with diverse patient populations. While gender representation among medical students has seen significant improvements with women now representing slightly over half of all medical students, gender gaps remain a significant issue among trainees, providers and leaders of various medical specialties including pain medicine. In 2019, less than 20% of all active physicians practicing within pain medicine identified as females. More recently, a study showed roughly 30% of chronic pain medicine fellowship programs had a female program director. Despite these findings, the degree of gender disparity among leadership ranks within pain medicine, specifically departmental and divisional chairpersons, has yet to be studied.
The importance of female representation within pain medicine leadership ranks cannot be overstated. It is likely to foster an inherent attraction of talented female trainees to the field, promote interest in academia, provide a mentorship pipeline essential to success in academia, and facilitate retention of female providers within the field.
In this cross-sectional study, we sought to assess gender disparity within chairpersons of ACGME-accredited chronic pain medicine programs across the country and its associations with various demographic, academic, and program metrics. We hypothesize that female chairpersons would be under-represented and that they would have fewer academic accomplishments including less publications and lower academic rank status.
Methods
We identified all chronic pain fellowship programs that are accredited by the Accreditation Council for Graduate Medical Education (ACGME) on 4/19/2021. We queried institutional websites or contacted programs directly to identify the respective departmental/divisional program chairperson
After determining the final list of chairperson names, we utilized publicly available sources including fellowship program websites, state licensure boards, and online curriculum vitae to identify the chairperson’s age, gender, academic degree (MD, PhD, and/or MBA), academic rank (professor, associate professor, assistant professor, or instructor), number of publications and Hirsch-index (H-index), board certification status (initial or continued), and residency training specialty (anesthesiology, physical medicine and rehabilitation, neurology, psychiatry, emergency medicine). The ACGME website was queried to abstract data on the following variables: total approved and filled fellow positions, and fellowship program accreditation status.
The primary outcome included comparisons of the following demographic, academic, and program-related characteristics between female and male program chairpersons:
Demographic characteristics: age, geographic location (Midwest, Northeast, South, West). Geographic regions were determined based on the United States Census Bureau Regions and Divisions
Academic characteristics: academic rank, dual appointment as chairperson and program director, completion of MD/PhD degree, completion of MBA degree, duration of clinical practice, number of publications, H-index, board certification status, chairperson residency training specialty
Program characteristics: number of approved fellow positions, number of filled fellow positions, program accreditation status
Continuous outcomes were reported as medians with a 25–75% interquartile range (IQR), while dichotomous categorical outcomes are reported as numbers with percentages. The Mann–Whitney rank-sum test was used to compare continuous outcomes between female and male chairpersons, while the Fisher’s exact test was used to compare categorical variables between female and male chairpersons. A P-value < 0.05 was considered statistically significant.
This study was approved by the Mayo institutional review board (IRB). The requirement for written informed consent was waived.
Results
Identification and Selection of Chairperson
We identified a total of 111 ACGME-accredited chronic pain fellowship programs at the time of study initiation (4/19/21). Chairperson name was obtained from the departmental and/or institutional website for a total of 80 programs. An additional seven fellowship programs provided the chairperson name and contact information after we contacted them via e-mail and/or phone call. Twenty-four programs did not provide chairperson information as they did not respond to e-mail or phone requests.
Demographic Characteristics of Chairpersons
Our overall cohort comprised of 17 female chairpersons (19.5%) and 70 male chairpersons (80.5%). No differences in age were detected between female and male chairpersons (P = 0.645). The proportion of female and male chairpersons based on geographic location was similar.
Academic Characteristics of Chairpersons Based on Gender
When comparing academic characteristics based on gender, a higher proportion of female chairpersons (35.3%) reported an academic rank of assistant professor compared to male chairpersons (11.4%, P = 0.027). However, similar proportions of other academic rankings (senior academic rank, full professor, associate professor, and instructor position) were noted between female and male chairpersons. Male chairpersons published more peer-reviewed articles (32.0 publications, 10.0–92.0 IQR) compared to female chairpersons (10.0 publications, 2.5–17.5 IQR, P = 0.001). Concordantly, male chairpersons achieved a higher H-index score (10.0, 5.0–28.0 IQR) compared to female chairpersons (3.0, 1.0–6.0 IQR; P = 0.001). There were no differences in other academic characteristics including dual appointment as program director, academic degrees (PhD, MBA), years in clinic practice, board certification status, and primary residency training specialty.
Program-related Characteristics Based on Gender
The ACGME reported one program was assigned probationary accreditation. Six (6.9%) programs had initial ACGME accreditation status, while 80 (92.0%) had continued ACGME accreditation status. No differences in fellow positions and program accreditation status were identified when stratified by chairperson gender.
Conclusion
Female representation in pain medicine leadership and clinicians is crucial. Population-based research has demonstrated that pain prevalence is generally higher among women relative to men, and it is not uncommon for pain practices to have a greater composition of female patients Furthermore, research has demonstrated that patient-physician gender concordance may be associated with greater patient satisfaction scores Thus, female patients may be able to relate more to female providers caring for them. This association is also reflected in the leadership setting, where female program directors are more likely to have female fellows in the pain program they lead.
Our study demonstrates that this important role is currently and overwhelmingly held by males within the specialty of pain medicine with significant underrepresentation among female physicians. This disparity is also reflected in other academic metrics including number of peer-reviewed publications, H-indices, and attainment of assistant professor rank. This study highlights the need for continued measures designed to address and eliminate barriers that persistently preclude female representation from leadership positions within our specialty.
References
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Abstract #2 Submission ID#1276326
A Pilot Clinical and Pharmacokinetic Study of Δ9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) Nanoparticle Oro-Buccal Spray in Patients with Advanced Cancer Experiencing Uncontrolled Pain
Stephen Clarke, OAM MBBS MD PhD FRACP FAChPM FAHMSa, Belinda Butcher, BSc(Hons) MBiostat PhD CMPP AStatb, Andrew McLachlan, BPharm(Hons1 Medal), PhD, FPS, FACP, MCPA, MSHPAc, Jeremy Henson, PhD, MBBSd, David Rutolo, PhD, JDe, Sean Hall, MDf, Luis Vitetta, PhD, MDg
aProfessor and Medical Oncologist, The University of Sydney and GenesisCare; bDirector, Biostatistics & Medical Writing WriteSource Medical Pty Ltd and School of Medical Sciences, University of New South Wales; cProfessor and Head of School and Dean of Pharmacy, The University of Sydney; dDirector of Medical Affairs Faculty of Medicine, Prince of Wales Clinical School, University of New South Wales and Medlab Clinical; eDirector of Science, Head of US Operations, Medlab Clinical; fChief Executive Officer, Medlab Clinical; gProfessor and Director of Medical Research , The University of Sydney and Medlab Clinical
Learning Objectives
Upon completion participants will be able to articulate the possible role of a pharmaceutical grade cannabis-based medicine in the management of pain.
Upon completion participants will be able to communicate how a nanoparticle formulated cannabis-based medicine has appropriate pharmacokinetics for analgesic efficacy.
Upon completion participants will be able to identify the adverse effects that may ensue with increased cannabis dosing in an exploratory pilot study.
Purpose
Relief from chronic pain (cancer or non-cancer related) is a common condition cited by patients for the medical use of cannabis [1–3]. A recent systematic review and meta-analysis of randomized controlled trials suggests that cannabis-based-medicines could be effective for chronic pain treatment and primarily for neuropathic pain [4]. Others have reported that cannabinoid-based pharmacotherapies may serve as an effective replacement analgesic option that delays the use of opioid medications [5]. Alternatively, cannabis-based medicines may be administered as an adjunctive medicine. This pilot study aimed to assess the safety, tolerability, pharmacokinetics (PK) and exploratory analgesic effect of a novel water-soluble oro-buccal nanoparticle suspension spray of a cannabis-based medicine (MDCNS-01) in patients with advanced incurable malignancy with unrelieved pain from opioid analgesics.
Methods
The study was a non-blinded single arm 2-stage investigation that describes a pilot preliminary safety, tolerability, and PK exploratory endpoint to obtain a possible signal for efficacy of future robust studies. In the first instance, eligible patients completed the EORTC-QLQ-30 questionnaire [6] at the induction visit and subsequent visits to the hospital and the treating clinician was blinded to this process. The study consisted of two stages, namely, Stage I which was a two-day single ascending dose (SAD) and a multiple ascending dose (MAD) simple pharmacokinetic investigation of the nanoparticle Δ9-THC/CBD formulation. Five participants diagnosed with advanced incurable cancer as confirmed by the treating clinician and with controlled pain was deemed suitable for a preliminary PK assessment of the cannabis-based medicine. On day 1, all participants were administered 2.5 mg THC and 2.5 mg of CBD in 300 mL (two actuations of the pump) to the oro-buccal mucosa. On day 2 all patients administered 7.5 mg of Δ9-THC and 7.5 mg of CBD in 900 mL (six actuations of the pump [3 doses]). Blood samples were collected at 0, 30, 60, 90, 120, 150, 180, 240, 360 min and 24 h after dose administration via indwelling cannula. Stage II was the up-titrated pilot study with n = 25 eligible participants diagnosed with advanced incurable cancer and uncontrolled pain as confirmed by the treating clinician while currently being treated with opioid analgesics. The stages of malignancy were verified but related on investigator assessment. Eligible participants were invited to participate over the three phases in a 30-day period. The three phases in Stage II were divided into a dose escalation phase over days 1 to 9; a treatment phase over days 10 to 15; and a follow-up phase over days 16 to 30. Prospective participants for all Stage II phases of this pilot study attended the Royal North Shore Hospital Medical Oncology unit, in Sydney for follow-up with the study’s principal investigator.
Results
There was an overall improvement from baseline for global health status; physical functioning; emotional functioning; cognitive functioning; fatigue; pain; dyspnea and insomnia. Given the complex presentation of the cohort of patients under investigation the EORTC-QLQ-30 scores were reported for those patients with established preliminary thresholds for clinical importance. Namely, this was for patients that presented with breast and prostate cancers and diagnosed with bone metastasis as compared to the total cohort of patients in the study. During Stage I with an increased cannabis-based medicine dose, maximum observed plasma concentrations of cannabinoids were dose dependant. The water-soluble formulation in the current study resulted in a higher median (min, max) systemic exposure of D9-THC than CBD (AUC from 2.5 mg each of D9-THC and CBD, was 1.71 ng mL.h−1 (1.1, 6.6) and 0.65 ng mL.h−1 (0.49, 4.1), respectively). During stage II a subgroup of patients diagnosed with breast and prostate cancers with bone metastasis, had the highest mean pain score improvement on a numeric pain rating scale from baseline of 40% (unadjusted) and 33% (adjusted for rescue medication use). For all patients the most reported adverse events were mild or moderate drowsiness affecting 11 (44%) and 4 (6%) patients, respectively, and nausea and vomiting that affected 18 (72%) patients.
Conclusion
This study demonstrated that the administration of the investigative cannabis-based medicine (MDCNB-01) was generally safe and tolerated in a short-term exposure study in a cohort of patients with advanced incurable cancers with controlled pain (Stage I) or intractable pain (Stage II) despite opioid treatment. Moreover, results from patient-reported outcome questionnaires suggested that patient functioning improved clinically for emotional functioning, fatigue, dyspnea, insomnia, and appetite loss, especially in those patients with improved pain management with the cannabis-based medicine (i.e. breast and prostate cancers with bone metastasis) [7]. The water-soluble nanoparticle cannabis-based medicine formulation demonstrated acceptable pharmacokinetic behavior for cannabinoids consistent with safety and tolerability and preliminary analgesic benefit. There was a peak plasma concentration of less than an hour and adequate concentration to support multiple dosing every four to eight hours. The water-soluble cannabis-based medicine suspension provided acceptable bioavailability for D9-THC/CBD in advanced incurable cancers with uncontrolled pain. Furthermore, according to the prescribing oncologist in a sub-group of patients diagnosed with breast and prostate cancers with bone metastasis there was preliminary evidence of analgesic efficacy, above what the maximal pain management was already providing ([8] unpublished data currently under review).
References
[1] Boehnke KF, et al. Qualifying Conditions Of Medical Cannabis License Holders In The United States. Health Aff (Millwood). 2019;38(2):295–302
[2] Mucke M, et al. Cannabis-based medicines for chronic neuropathic pain in adults. The Cochrane database of systematic reviews. 2018;3:Cd012182.
[3] Wang L, et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomized clinical trials. BMJ 2021; Sep 8;374:n1034. doi: 10.1136/bmj.n1034.
[4] Aviram J, Samuelly-Leichtag G. Efficacy of Cannabis-Based Medicines for Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain Physician. 2017;20(6):E755-e96.
[5] Yanes JA, et al. Effects of cannabinoid administration for pain: A meta-analysis and meta-regression. Exp Clin Psychopharmacol 2019;27(4):370–82. Epub 2019/05/24.
[6] Giesinger JM, L, et al. Thresholds for clinical importance were defined for the European Organization for Research and Treatment of Cancer Computer Adaptive Testing Core-an adaptive measure of core quality of life domains in oncology clinical practice and research. J Clin Epidemiol 2020;117:117–25.
[7] Clarke S, et al. An oro-buccal nanoparticle delivered cannabis medicine for pain management in cancer: A clinical trial in progress. J of Clin Oncology 2020; DOI: 10.1200/JCO.2020.38.15_suppl.TPS12127.
[8] Clarke S, et al. Pilot Clinical and Pharmacokinetic Study of Δ9-Tetrahydrocannabinol (THC)/Cannabidiol (CBD) Nanoparticle Oro-Buccal Spray in Patients with Advanced Cancer Experiencing Uncontrolled Pain. PLOS One 2022; [Under Review].
Abstract #3 Submission ID#1277745
Selective Inhibition of NaV1.8 with VX-548 as a Targeted Treatment for Acute Pain
Jim Jones, MD, PharmD, FACEPa, Darin J. Correll, MDb, Sandra M. Lechner, PhDc, Ina Jazic, PhDd, Cong Xu, PhDd, David Shaw, PhDe, Madalina C. Chirieac, MD, MPHf, Jeremiah D. Osteen, PhDg, Brian Hare, PhDh, Alina Beaton, MDi, Todd Bertoch, MDj, Asokumar Buvanendran, MDk, Ashraf S. Habib, MDl, Lois J. Pizzi, MSN, ACNS-BC, RN-BCm, Richard A. Pollak, MDn, Scott G. Weiner, MD, MPHo, Paul Negulescu, PhDp, Paul F. White, PhD, MDq
aVP, Clinical Development, Vertex Pharmaceuticals; bClinical Development Medical Director, Vertex Pharmaceuticals; cExecutive Director, Biology,Vertex PharmaceuticalsPrincipal Biostatistician, Vertex Pharmaceuticals; dPrincipal Biostatistician, Vertex Pharmaceuticals; eMedicinal Chemist, Vertex Pharmaceuticals;fSenior Medical Director, Patient Safety, Vertex Pharmaceuticals; gPharmacology Senior Principal Research Scientist, Vertex Pharmaceuticals; hSenior Director, Modeling & Simulations, Vertex Pharmaceuticals; iMedical Director and Principal Investigator, Lotus Clinical Research, LLC; jChief Executive Officer, JBR Clinical Research; kInterim Chairperson, Department of Anesthesiology, Rush University Medical Center; lProfessor of Anesthesiology; Chief, Division of Women’s Anesthesia, Duke University School of Medicine; mClinical Nurse Specialist-Pain Management, University of Pittsburgh Medical Center; nPresident, Endeavor Clinical Trials, LLC; oMD, Department of Emergency Medicine, Brigham and Women’s Hospital; pSenior Vice President, Research, Vertex Pharmaceuticals; qDirector of Research, Department of Anesthesiology, Cedars-Sinai Medical Center
Learning Objectives
Understand the critical role of the voltage-gated sodium channel, NaV1.8, in pain signaling.
Describe the findings from two phase 2 clinical trials demonstrating that selective inhibition of NaV1.8 results in statistically significant and clinically meaningful improvements in acute pain.
Recognize that selective inhibition of NaV1.8 represents an innovative, non-opioid, targeted approach for the treatment of people with acute pain.
Purpose
Moderate-to-severe acute pain is a serious condition with significant individual and public health implications. Acute pain is often treated with opioids due to the absence of effective alternatives. Despite an urgent need for effective, non-opioid pain treatments, there has been a lack of progress in analgesic drug development in recent decades. NaV1.8 is a voltage-gated sodium channel that is preferentially expressed in peripheral nociceptive neurons and plays a critical role in pain signaling. We hypothesized that selective inhibition of NaV1.8 would effectively treat pain without the safety and tolerability concerns, including addiction, misuse, and abuse potential, associated with standard-of-care opioid therapies. VX-548, an orally bioavailable small molecule, is a highly selective inhibitor of NaV1.8. We describe the preclinical characterization of VX-548 and report the results of two phase 2 clinical trials evaluating the efficacy and safety of VX-548 for treatment of acute pain after abdominoplasty or bunionectomy.
Methods
The potency and selectivity of VX-548 was determined in vitro using patch-clamp electrophysiology techniques to quantify NaV1.8 currents in recombinant cells and dissociated human dorsal root ganglia (DRG) neurons. Two phase 2 randomized, double-blind, placebo-controlled, clinical trials evaluated VX-548 in participants with moderate or severe acute pain following abdominoplasty or bunionectomy. Following surgery, participants with moderate or severe acute pain, as determined by the Verbal Categorical Rating Scale (VRS) and pain ≥4 on the Numeric Pain Rating Scale (NPRS), were randomized to receive VX-548 (one of two doses in the abdominoplasty trial or one of three doses in the bunionectomy trial), hydrocodone bitartrate/acetaminophen (HB/APAP; opioid reference), or placebo. VX-548 was administered orally at the following doses: 100 mg first dose followed by 50 mg every 12 hours (100 mg/50 mg q12h), 60 mg first dose followed by 30 mg every 12 hours (60 mg/30 mg q12h), or 20 mg first dose followed by 10 mg every 12 hours (20 mg/10 mg q12h) with the latter dose evaluated only in the bunionectomy trial; all VX-548 doses were administered at 12, 24, and 36 hours after the first dose. HB/APAP was evaluated at a dose of 5 mg/325 mg administered orally every 6 hours (q6h) for 42 hours after the first dose. The primary endpoint was the time-weighted sum of the pain intensity difference (SPID) as recorded on a NPRS 0 to 48 hours (SPID48) after the first dose of study drug; SPID48 was assessed at rest in the abdominoplasty trial. For the primary endpoint, statistical comparisons were made to placebo only; higher SPID48 values indicate greater improvements in pain relief. Secondary efficacy endpoints included time-weighted sum of the pain intensity difference from the time of first dose to 24 hours (SPID24) as recorded on a NPRS and the proportions of subjects with ≥30%, ≥50%, and ≥70% reduction in NPRS at 48 hours after the first dose of study drug. Safety, tolerability, and pharmacokinetics were also assessed as secondary or other endpoints.
Results
VX-548 potently inhibited NaV1.8 currents in both dissociated human DRG neurons and recombinant cells with a half-maximal inhibitory concentration (IC50) of approximately 0.7 nM and was highly selective for NaV1.8 (≥31,000-fold) relative to other NaV channels in recombinant cells. In both phase 2 trials, treatment with VX-548 (100 mg/50 mg q12h) resulted in statistically significant superior pain reduction compared to placebo following abdominoplasty (SPID48 LS mean difference from placebo: 37.80, P = 0.0097) and bunionectomy (SPID48 LS mean difference from placebo: 36.79, P = 0.0251). In both trials, treatment with VX-548 (100 mg/50 mg q12h) resulted in rapid (within 1 hour) and robust pain relief that was sustained throughout the duration of assessment. Notably, treatment discontinuations due to lack of efficacy were substantially lower in participants receiving VX-548 (100 mg/50 mg q12h) compared to participants receiving placebo or HB/APAP. Results for secondary efficacy endpoints were generally supportive of results for the primary endpoint. VX-548 was generally safe and well tolerated at all doses in both trials. The majority of adverse events (AEs) were mild or moderate in severity and there were no serious adverse events (SAEs) related to VX-548. The most common AEs in ≥10% of participants in any treatment group were nausea, headache, constipation, dizziness, and vomiting in the abdominoplasty trial and nausea and headache in the bunionectomy trial. Two participants in the abdominoplasty trial discontinued VX-548 due to AEs that were not related to treatment; there were no VX-548 treatment discontinuations due to AEs in the bunionectomy trial.
Conclusion
Preclinical studies demonstrate that VX-548, a novel small molecule, is a potent and highly selective inhibitor of NaV1.8. These data translated to a statistically significant and clinically meaningful benefit in two phase 2 clinical trials in acute pain and provide initial evidence that treatment with VX-548 represents an innovative, non-opioid, targeted approach for the treatment of people with acute pain.
Abstract #4 Submission ID#1287758
Targeted Muscle Reinnervation for the Treatment of Complex Regional Pain Syndrome in the Lower Extremity
Stephanie Shin, MSa, Zoe Haffner, BSa, Brian Chang, MDb, Grant Kleiber, MDc
aMedical Student, Georgetown University School of Medicine; bPlastic Surgery Resident, Department of Plastic and Reconstructive Surgery; cAttending Physician, Department of Plastic and Reconstructive Surgery, MedStar Georgetown University Hospital
Learning Objectives
Upon completion, participant will be able to explain the risks and benefits of surgical intervention for CRPS.
Upon completion, participant will be able to outline different treatment options for CRPS intervention.
Upon completion, participant will be able to understand CRPS pathophysiology and patient burden.
Purpose
Complex regional pain syndrome (CRPS) is characterized by severe pain accompanied by vascular, motor, or trophic changes with a debilitating impact on patient quality of life. It’s varied clinical presentation and lack of treatment options make this disease a diagnostic and therapeutic challenge for physicians. Targeted muscle reinnervation (TMR) is a surgical technique that has been shown to improve phantom limb pain in lower extremity (LE) amputation, allowing for better post-amputation outcomes for patients. The objective of this case series was to characterize TMR as an adjunctive treatment for CRPS patients with LE amputation who are refractive to more conservative therapies.
Methods
Patients were included if they had a diagnosis of CRPS in an upper extremity (UE) or lower extremity (LE) and elected to undergo TMR for CRPS management. Patient demographics, operative details, and functional outcomes were collected and compared pre- and post-operatively. Previous or concurrent treatments for pain management were also noted.
Pain was evaluated using Numerical Pain Rating Scale (NRS) values, collected during pre- and post-operative evaluations. Function of the affected limb was used as a proxy for pain interference, and assessed qualitatively based on patient-reported activity. Measures of central tendency were reported for appropriate variables.
Results
There were 6 patients identified, all Caucasian women, with an average age of 32.5 ± 15.4 years and body mass index (BMI) 24.9 ± 5.0 kg/m2. CRPS was the indication for all amputations, done either before or during TMR. All patients were following with Pain Management at the time of TMR.
Patients 1 and 2 both carried a CRPS diagnosis due to LE trauma less than 1 year before TMR, for 4 and 11 months, respectively. Patient 1 had a simultaneous amputation with TMR, while patient 2 had an amputation 11 months prior. Both patients were otherwise healthy and previously tried ketamine infusions to control their CRPS. They were followed for an average of 11 ± 4.2 months after TMR procedure, and reported no change in their pain based on NRS pain assessments. Patient 1 did not have any previous nerve operations, while Patient 2 had a tibial nerve coaptation and saphenous neurectomy during amputation. At most recent follow up, Patient 1 reported complete resolution of pain and a decreased dose of their neuroleptic medication. Patient 2 continued to endorse generalized pain, but denied any resting leg pain (RLP) or phantom limb pain (PLP). Both Patients 1 and 2 were newly independently ambulatory 90 and 122 days after TMR, respectively, reporting the improvement in pain quality allowed them to tolerate a prosthetic.
The remaining four patients all carried a CRPS diagnosis due to trauma or a post-surgical etiology ranging from 3 to 8 years before TMR. They were all otherwise healthy, with exception of a Sjogren’s (patient 3) and an Ehlers Danlos diagnosis (patient 4). Both of these patients had simultaneous amputation and TMR. Patients 5 and 6 had amputations beforehand, waiting 16 and 93 months, respectively. All had tried either ketamine infusions, spinal cord stimulation, DRG stimulation, or lumbar nerve blocks before TMR. When comparing pre- and post-TMR NRS values, all reported a 2-point increase with exception of patient 5, who maintained a score of 7 both before and after TMR. At most recent follow up, all patients endorsed generalized pain. All but patient 6 continued to endorse PLP after TMR. Of note, patient 6 had multiple neuroma excisions before TMR and reported a decrease in their narcotic dosage by most recent follow up. There were no changes between pre- and post-TMR ambulation status for these patients.
Conclusion
CRPS is a debilitating condition with a variety of clinical presentations and treatment options. Operative management may be an option to control refractory CRPS pain when more conservative measures have failed. Due to high disease burden, patients should receive psychological and social support longitudinally through the disease course. The outcomes of these cases suggest that TMR may provide some benefit to reducing pain severity and improving function in patients with severe CRPS when utilized earlier in the disease course, though further prospective trials are warranted.
Abstract #5 Submission ID#1295709
Effect of outpatient provider type on the rate of emergency department visits for patients with malignant pain
Joseph J. Cammilleri, PharmDa, Janine Short, Pharm.D.b, Brittany Johnson, Pharm.D.c, Ravindra Maharaj, MDd
aClinical Pharmacist, UF Health Jacksonville; bClinical Pharmacist, UF Health Jacksonville; cClinical Pharmacist, UF Health Jacksonville; dDirector of Palliative Care, UF Health Jacksonville
Learning Objectives
Describe the outpatient management of cancer related pain.
Define which specialty had lower emergency room visit
Describe the difference in total opioid dose between specialty
Purpose
Opioids are an integral element of end-of-life care and are considered a mainstay of cancer pain (CP) management. A national decrease in morphine milligram equivalents (MME) for the treatment of CP has been associated with an increased rate of emergency department visits for pain in patients with advanced cancer. CP has historically been managed by oncologists, however the role of outpatient palliative care for symptom management has expanded. Previous studies compare prescribing trends between oncologists and all other provider types, but have failed to evaluate the potential utility of palliative care providers. This study compares CP related outcomes between oncologist and palliative care providers by determining the average MME per opioid regimen prescribed and the rate of emergency department visits for CP in cancer patients.
Methods
A retrospective chart review was performed to assess outcomes related to CP management provided by oncologists and palliative care providers. Patients included in this study were ≥18 years of age, had a diagnosis of active cancer, and received ≥75% of their prescribed opioid medications from an outpatient oncology or palliative care clinic. Patients without active cancer, or receiving buprenorphine or tramadol were excluded. The primary outcome was the incidence of patient emergency department visits related to pain per provider type. Secondary outcomes included average MME per prescribed opioid regimen and incidence of patient emergency department visits related to constipation per provider type.
Results
Overall, 80 patients were included: 40 managed by palliative care and 40 managed by oncology. Baseline characteristics including age, sex, weight, and stage of cancer were distributed equally between groups. Cancer type differed between groups at baseline. The most common cancer type for patients managed by oncology included breast (40%) whereas digestive/gastrointestinal cancer was the most common cancer type for patients managed by palliative care (35%) (p = < .01). In terms of the primary endpoint, patients managed by palliative care had a 15% lower incidence of emergency department visits related to pain compared to patients managed by oncology (10% vs 25% respectively, p = .03). Conversely, patients managed by palliative care received an average of 7.5 MMEs more per opioid regimen for the treatment of CP than patients managed by oncology (67.5 vs 60 respectively, p = < .01). Rates of patient emergency department visits for constipation did not differ between the palliative care or oncology group (5% vs 7.5% respectively, p = .50).
Conclusion
Overall, cancer patients treated for CP received higher doses of opioids and had a lower rate of emergency department visits for pain when managed by palliative care physicians rather than oncologists. Larger studies are needed to confirm the association between lower MME containing pain regimens and emergency department visits for CP and adjust for confounding factors such as cancer type.
References
[1] Care. 2013;7(2):201–206. doi:10.1097/SPC.0b013e32836103e5.
[2] Ferrell BR, Temel JS, Temin S, Alesi ER, Balboni TA, Basch EM, Firn JI, Paice JA, Peppercorn JM, Phillips T, Stovall EL, Zimmermann C, Smith TJ. Integration of Palliative Care Into Standard Oncology Care: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017 Jan;35(1):96–112. [cited 28 October 2016]. Available from: PMID: 28,034,065.[3] WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents. Geneva: World Health Organization; 2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537492/
[4] Enzinger AC, Ghosh K, Keating NL, Cutler DM, Landrum MB, Wright AA. US Trends in Opioid Access Among Patients With Poor Prognosis Cancer Near the End-of-Life. J Clin Oncol. [cited 10 September 2021] Available from: ;39(26):2948–2958. doi: 10.1200/JCO.21.00476. Epub 22 July 2021. PMID: 34,292,766; PMCID: PMC8425843.
[5] Jairam V, Yang DX, Pasha S, Soulos PR, Gross CP, Yu JB, Park HS. Temporal Trends in Opioid Prescribing Patterns Among Oncologists in the Medicare Population. J Natl Cancer Inst. [cited 1 March 2021] Available from: 113(3):274–281. doi: 10.1093/jnci/djaa110. PMID: 32,785,685; PMCID: PMC7936059.
[6] PA Harris, R Taylor, R Thielke, J Payne, N Gonzalez, JG. Conde, Research electronic data capture (REDCap) – A metadata-driven methodology and workflow process for providing translational research informatics support, J Biomed Inform. 2009 Apr;42(2):377–81.
[7] PA Harris, R Taylor, BL Minor, V Elliott, M Fernandez, L O’Neal, L McLeod, G Delacqua, F Delacqua, J Kirby, SN Duda, REDCap Consortium, The REDCap consortium: Building an international community of software partners, J Biomed Inform. [cited 9 May 2019]Available from: [doi: 10.1016/j.jbi.2019.103208].
[8] Breuer B, Chang VT, Von Roenn JH, et al. How well do medical oncologists manage chronic cancer pain? A national survey. Oncologist. 2015;20(2):202–209.
[9] Bandieri E, Sichetti D, Romero M, Fanizza C, Belfiglio M, Buonaccorso L, Artioli F, Campione F, Tognoni G, Luppi M. Impact of early access to a palliative/supportive care intervention on pain management in patients with cancer. Ann Oncol. 2012 Aug;23(8):2016–2020.
Abstract #6 Submission ID#1300004
Potent anti-inflammatory effects of an H2S-releasing naproxen (ATB-346) in a human model of inflammation
James R. Glanvillea, Parinaaz Jalalib, Julia D. Flintc, Amit A. Patelb, Alexander A. Mainic, John L. Wallaced, Ali A. Hosinc, Derek W. Gilroye
aSpeciality Registrar in Rheumatology and Clinical Research Fellow, University College London; bResearch Associate, Univeristy College London; cClinical Research Fellow, Univeristy College London; dChief Scientific Officer, Antibe Therapeutics Inc.; eProfessor of Immunology, Univeristy College London.
Learning Objectives
Upon completion, participant will be able to understand inflammation and how this is dampened by anti-inflammatory drugs.
Upon completion, participant will be able to describe the differences between naproxen and ATB-346.
Upon completion, participant will be able to describe the importance of neutrophils in inflammation, and how ATB-346 is able to reduce these and thus dampen the flames of inflammation.
Purpose
Inflammation is a protective response against infection or injury. It is commonly treated with non-steroidal anti-inflammatory drugs (NSAIDs), including naproxen. The long-term use of such drugs is limited by significant adverse effect. Of note, NSAIDs increase cardiovascular risk, as well as causing unacceptably high levels of gastrointestinal (GI) disturbance, with mucosal irritation and even ulcer formation, often leading to cessation of drug use. Such GI effects may, to an extent, be ameliorated by the co-administration of gastroprotective drugs, but given the growing problem of polypharmacy and the propensity for untoward drug interactions, clearly single agents are preferable. Thus, there is a need to develop more efficient and effective therapeutics. Further, given the ongoing opioid crisis, non-addictive, efficacious alternatives are becoming increasingly relevant.
In this regard, attention has turned to an emerging class of compounds with significant anti-inflammatory effects, the hydrogen sulfide (H2S)-releasing NSAIDs (H2S-NSAIDs). These consist of conventional NSAIDs to which an H2S-reasing moiety is covalently attached. One such H2S-NSAID, ATB-346, has shown markedly reduced GI adverse effect profile (in terms of ulceration and bleeding) in animal studies. Furthermore, it was shown that after oral administration of ATB-346, plasma levels of naproxen derived from the compound were much lower than equimolar doses of naproxen but exhibited cyclooxygenase (COX) inhibition and analgesic effects. ATB-346 is in the order of six-times more potent than naproxen in humans and is as effective at suppressing COX activity over a 24-hour period with a single dose (versus twice-daily naproxen). In a recent Phase 2b trial in healthy volunteers, the incidence of upper GI ulceration in subjects taking standard dose twice daily naproxen was over 42%; significantly greater than the rate of ulceration of only 2.5% (p < 0.001) in subjects taking an equi-effective dose of ATB-346 daily.
Using a novel model of ultraviolet (UV)-killed Escherichia coli (UV-KEc)-triggered resolving dermal acute inflammation, we set out to investigate the anti-inflammatory role of ATB-346 in humans. Comparing this to its native counterpart, naproxen, and untreated controls we aimed to evaluate whether next generation H2S-NSAIDs, whilst demonstrating lower GI adverse effect, are still able to retain their anti-inflammatory effect in humans.
Methods
Twenty-one healthy, male volunteers aged 18–50 were recruited. Volunteers were randomly allocated to one of three treatment arms in this single-blind study. Seven volunteers were assigned to the naproxen arm and took 500 mg twice daily for three days prior to UV-KEc injection. Seven volunteers were assigned to the ATB-346 arm and took 250 mg once daily (the equi-effective dose to naproxen) for three days prior to injection. Seven volunteers took no drug during the study and served as the untreated control group.
Into the forearm of each volunteer, 1.5 × 107/100 µL UV-KEc in 100 µL of 0.9% sodium chloride were injected intradermally. Inflammation was allowed to ensue for the duration of the study with clinical measurements, laser Doppler imaging and peripheral venous blood taken at pre-defined time-points representing baseline (0 hr), onset of inflammation (4 h) and resolution phases (24 h and 48 h). At each time point, peripheral blood was taken for complete blood count (CBC) and C-reactive protein (CRP). Laser Doppler imaging was used to measure vascular hyper-reactivity. The scanner emits a laser which is scattered by erythrocytes with the resulting Doppler shift dependent on the velocity and concentration of cells at the site, therefore representing blood flow and thus leucocyte trafficking, a hitherto unappreciated marker of resolution of inflammation. As a further parameter of inflammation (and thus resolution), a visual analogue score (0–10) was used to quantify the pain experienced at the site of inflammation (0 = no pain; 10 = worst pain imaginable). This was repeated for elicited tenderness with the application of a 100 g weight. Temperature was measured using an electronic thermometer both centrally (forehead) and at the site of the injection.
Inflammatory exudate was obtained from the site of the UV-KEc injection by formation of a suction blister at two time-points; 4 h and 48 h. Blister cells were incubated with an antibody cocktail along with appropriate fluorescence minus one (FMO) controls and acquired immediately using a flow cytometer. Finally, the blister supernatant was diluted and prostaglandin E2 (PGE2) quantification, by enzyme-linked immunosorbent assay (ELISA) and for interleukin-10 (IL-10) and TNF-α quantification, a customized two-plex array.
Results
There were no significant differences in age (mean 25 years) or ethnicity between treatment groups. No adverse effects were reported in any group. Approximately 20% of total volunteers complained of axillary heaviness between 4 h and 24 h, associated with linear, erythematous tracking from injection site toward the axillae; likely representing pain-free, lymphatic drainage. The mean blister volume at 4 h was 129.73 µL and 135.43 µL at 48 h. No significant differences were seen in peripheral blood.
Cell profiles were characterized using flow cytometry. Neutrophils were defined as Lineage− (Lin−: CD3, CD19, CD20 and CD56), HLA-DR−, CD16+, Siglec-8−. Mononuclear phagocytes (MP) were identified as Lin− and HLA-DR+. Classification into MP subtypes was based on expression of CD14 and CD16: classical monocytes, CM (CD14+, CD16−), intermediate monocytes, IM (CD14+, CD16+), non-classical monocytes, NCM (CD14−, CD16+) and dendritic cells (CD14−, CD16−). Lin+ cells were further divided into B cells (HLA-DR+) and T/NK cells (HLA-DR−).
ATB-346 significantly reduced neutrophil numbers at the peak of onset of inflammation (4 h). In the naproxen group, there was a significant reduction in neutrophil infiltration at 4 h compared to untreated, albeit to a lesser extent than ATB-346. At 48 h there were no significant differences in neutrophil numbers. HLA-DR− T/NK cells were significantly lower in those treated with ATB-346 compared to untreated at 48 h. CM and IM numbers were increased at 48 h. ATB-346 and naproxen caused a trend to reduced numbers of CM and IM at 48 h. At 48 h, both CM and IM exhibited significant reduction in expression of CD14 based on geometric mean fluorescence intensity in both naproxen and ATB-346 treated groups, compared to untreated. No significant changes were seen in other cell populations.
Volunteers treated with ATB-346 reported significantly lower pain and tenderness scores at the time-point of maximal neutrophil infiltration (4 h) compared to untreated; effects also observed with naproxen. Temperature at the site of inflammation followed the same course in ATB-346 and naproxen groups, peaking at 24 h and at 4 h in the untreated. Vascular hyper-reactivity peaked at 24 h in all groups declining back to similar levels seen at 4 h by 48 h. At all time-points, there was a trend toward increased hyper-reactivity in the ATB-346 group compared to naproxen and untreated.
While there was a trend toward an increase in TNF-α and reduction in IL-10 in both treatment groups, these were not significant. There was a significantly reduced concentration of PGE2 in both ATB-346- and naproxen-treated volunteers compared to untreated.
Conclusion
We have shown that ATB-346, is potently anti-inflammatory, as evidenced by a significant reduction in neutrophil numbers at 4 h compared to untreated controls. We observed a significant reduction in the expression of CD14 on CM and IM in both drug treatment groups compared to untreated controls at 48 h, which could represent a switch to a more anti-inflammatory phenotype given its role in LPS-induced monocyte activation and role in fighting infection.
Both ATB-346 and naproxen significantly reduced pain and tenderness at 4 h compared to untreated, the time-point of maximal neutrophil infiltration, suggesting a reduction in numbers of inflammatory cells mediators may contribute to the analgesic effect of both drugs.
As the opioid crisis continues in the developed world, it is imperative that we find novel, efficacious therapeutics that are agreeable to patients in terms of adverse effects and risk. Whilst more work is needed to explore the mechanisms underpinning the reduction of neutrophils seen in those treated with ATB-346, we propose it represents the next generation of H2S-NSAIDs as a viable alternative to conventional NSAIDs, showing reduced GI adverse effects, with actions through multiple potential facets of the immune system and a novel mode of action mediated through the H2S moiety.
Abstract #7 Submission ID#1300058
Update on NTM-006, a Novel Orally-Active Non-Opioid Analgesic: Molecular-Modeling Consistent with Allosteric Modulation of the Adenosine A3 Receptor
Robert B. Raffa, PhDa, Jon Swanson 3rd, PhD, PhDb, Joseph Pergolizzi Jr, MDc
aProf Emeritus; Adjunct; CSO: Co-founder; Sci AdBoard, Temple Univ; Univ AZ; Neumentum; Enalare; Advantx; bOwner, ChemModeling; cCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other
Learning Objectives
Describe the postulated mechanism of action of the non-opioid analgesic NTM-006.
Describe the use of molecular modeling to analgesics drug discovery.
Describe allosteric modulation as an analgesic mechanism of action.
Purpose
Neumentum NTM-006 emerged as a lead candidate from a Johnson & Johnson drug-discovery program seeking novel orally-active, non-opioid, non-NSAID analgesic agents having good efficacy, but absent the usual problems associated with current major classes of analgesics. Based on in vitro assay screens, the compound is non-opioid, and non-NSAID (does not inhibit COX-1 or COX-2 cyclooxygenase isozymes) at doses that produce its anti-nociceptive and anti-pyretic effects in a variety of animal models predictive of analgesic efficacy against acute pain conditions. But NTM-006’s preclinical and clinical analgesic efficacy seems to exceed that of the original target (e.g. it is active in a preclinical model of neuropathic pain). Based on radioligand binding data and the in vivo profile, we speculated that NTM-006 allosterically modulates the Adenosine A3 receptor, but had no further data to support such a mechanism of action.
Methods
A homology model of the Adenosine A3 receptor was built using tools from the YASARA molecular modeling program. The sequence of human adenosine A3 was retrieved from the UniProt Knowledge base. Structures of Adenosine receptors containing bound adenosine were downloaded from the RCSB database and used as custom templates in the model building. The final YASARA hybrid model was used for docking and molecular dynamics simulations.
NTM-006 was built using YASARA’s small molecule building tool. Docking was performed using AutoDock VINA as implemented in YASARA using default parameters. The top 16 poses were retained for each docking result. Constructing the docking cell was done by aligning the receptor homology model with receptor structures containing bound adenosine (orthosteric), MIPS521 (transmembrane) or 6FA (cytostolic) using the Smith&Waterman method. NTM-006 was then superimposed on the known ligand and the cell centered on NTM-006. For the N-terminal site, NTM-006 was placed based on interactions described for VCD171 in the A1 receptor.
Molecular Dynamics were done by constructing a membrane around the receptor, adding water and then neutralizing the cell by addition of Na and Cl ions. Parameters for NTM-006 were assigned by YASARA. Charges were assigned using the GAFF/AM1BCC method. The AMBER14 force field was used with periodic boundary conditions and an NPT ensemble (298 K and 1 atm). Simulations were run for 100 ns after an initial minimization to remove clashes.
Results
Molecular modeling studies suggest a novel combination of binding modes for NTM-006 with the AdenosineA3 receptor. The modeling to-date predicts that: (1) NTM-006 binds with low affinity to the site where endogenous Adenosine binds (Adenosine itself also binds with relatively low affinity to this ‘orthosteric’ binding site); (2) NTM-006 also binds to an N-terminal extracellular site suggested by prior molecular dynamics calculation as an ‘allosteric’ binding site; (3) NTM-006 also fits a cytostolic binding site suggested based on analogy to allosteric modulators of other G protein-coupled receptors, and (4) NTM-006 also fits a pocket in the transmembrane domain of the Adenosine-3 receptor identified in a cryo-EM structure as an allosteric binding site in the Adenosine-1 receptor. In this case NTM-006 leaves the pocket and migrates upward out of the lipid membrane. As it transits, the conformation of Adenosine in the orthosteric binding pocket changes.
Conclusion
NTM-006 was speculated to exert its primary action at Adenosine A3 receptors, possibly as an allosteric modulator. The results of the molecular modeling reported here supports this hypothesis. The combination of binding processes would be consistent with NTM-006ʹs in vitro, animal model, and clinical characteristics of broad-spectrum and pronounced analgesic efficacy, and long-duration of analgesic action.
Abstract #8 Submission ID#1300421
OTC Analgesics Knowledge, or Lack Thereof
Mark P. Garofoli, PharmD, MBA, BCGP, CPE, CTTSa, Ahmed Hanif, PhD, BSPharmb, Shafic Sraj, MD, MBAc, Summer Kuhn, MPHd
aClinical Assistant Professor & Clinical Pain Management Pharmacist,WVU Schools of Pharmacy/Medicine & WVU Medicine; bAssistant Professor, WVU School of Pharmacy; cAssociate Professor, WVU School of Medicine and WVU Medicine; dCurriculum Research Associate, WVU Health Sciences Center
Learning Objectives
Assess and compare knowledge and literacy of over-the-counter (OTC) pain medications within the West Virginia general population.
Understand over-the-counter (OTC) pain medication perceptions within the West Virginia general population.
Assess educational efforts for West Virginia High School Students in the realm of over-the-counter (OTC) pain medication knowledge.
Purpose
We are in the midst of a new wave of our ‘Opioid Crisis,’ with an American dying of a drug overdose every 6 minutes, while a baby is born dependent on opioids every 30 minutes. Yet, with countless regulations on prescription and illicit opioids, and many other substances of abuse or medications, we continue to have tens of thousands of health risks with the utilization of Over-the-Counter (OTC) pain medications. Every year in our country, approximately 50,000 people visit an emergency room (ER) due to the over-the-counter (OTC) pain medication known as acetaminophen (Tylenol).
In wild and wonderful West Virginia, colloquially known as the ‘Ground Zero’ of the ‘Opioid Crisis,’ an interprofessional team of clinicians and researchers wanted to make a difference. Not merely a publication, nor just a poster, but an actual tangible difference in the lives of our residents. A collaboration was formed between West Virginia University (WVU) clinicians and researchers teaming up with Health Sciences and Technology Academy (HSTA) Community Research Associates to educate high school students across West Virginia, and empower them to screen the lay public for knowledge regarding OTC pain medications. Fentanyl, its analogs, and heroin dominate our current death tolls, yet OTC pain medications are readily available everywhere for anyone in pharmacies, grocery stores, convenience stores, and even hotel gift shops. This availability begs the question as to whether our society needs more education on the safe and effective utilization of OTC pain medications, and perhaps if research and development of lower risk medications is also warranted.
In this project, we had two main objectives including:
1. Assess and compare knowledge and literacy of over-the-counter (OTC) pain medications within the West Virginia general population.
2. Understand over-the-counter (OTC) pain medication perceptions within the West Virginia general population.
Methods
The Health Sciences and Technology Academy (HSTA) Community Research Associates teamed up with an interprofessional research team from West Virginia University including PharmD, PhD, and MD clinicians. HSTA programs facilitate the active learning of high school students in the realm of health sciences and technology within a collaboration of actual healthcare professionals. This overall project received IRB approval from West Virginia University.
The first aim of this overall project concentrated on the education of HSTA students on over-the-counter (OTC) pain medications in respect to safety and efficacy. WVU researchers developed pre-and-post student surveys and seven informational lessons for HSTA students to complete with both didactic and active learning efforts to facilitate comprehensive learning.
The second aim of this overall project concentrated the screening and understanding of the lay public within West Virginia in respect to knowledge of the safety and efficacy of OTC pain medications including acetaminophen, ibuprofen, and naproxen. WVU researchers developed a community-based screening survey which included gauging questions involving knowledge and perceptions. Whenever a person completed the screening survey answering in the affirmative to questions demanding consultation with a healthcare professional, a recommendation was made to do just that.
The following were the ‘knowledge-based’ community screening survey questions:
What is the difference between acetaminophen and Tylenol? (No Difference)
What is the difference between ibuprofen and Motrin? (No Difference)
What is the difference between naproxen and Aleve? (No Difference)
Generally speaking, over-the-counter (OTC) pain medications (compared to pain medications requiring a prescription) are: (As effective, but with certain safety concerns)
When taking a liquid over-the-counter pain medicine, one should: (measure with an oral syringe)
If you, a family member, or a friend accidentally took too many over-the-counter pain medicines, who is the most appropriate contact? (Poison Center or 911)
What is the largest amount of over-the-counter (OTC) acetaminophen extra strength 500 mg tablets that anyone can swallow in one day before contacting a healthcare professional? (6)
What is the largest amount of over-the-counter (OTC) ibuprofen 200 mg tablets that anyone can swallow in one day before contacting a healthcare professional? (6)
What is the largest amount of over-the-counter (OTC) naproxen 220 mg tablets that anyone can swallow in one day before contacting a healthcare professional? (3)
All data was collected through HIPAA certified REDCap online data collection software. HSTA student pre/post data was analyzed to evaluate the effectiveness of the educational materials and for the specific purpose of this study, the community screening survey results were evaluated to understand the communities understanding of OTC pain medications.
Results
In the community outreach portion of this project, a total of 1,174 community members completed the screening survey. The first portion had a ‘perception’ theme, with one of the main questions being ‘Whom do you ask questions regarding any OTC pain medications?.’ Responses included people stating doctor (51%), pharmacist (45%), and family (46%). Although healthcare professionals are viewed as organic sources of this information, concern can arise when people state of relying upon mere family members for this healthcare information.
The second portion included nine (9) knowledge-based questions regarding the safety and efficacy of OTC pain medications including acetaminophen, ibuprofen, and naproxen. The overall median of knowledge-based survey questions answered correctly of the nine total was five, with a standard deviation of two. Only 2 of 1,174 people answered all nine questions correctly, while 12% answered every single question incorrectly. Overall, 85% answered 2/3rds of the questions incorrectly, while 71% answered more than half of all questions incorrectly. All results had a p-value of < 0.001 correlating to strong statistical significance.
Further analysis was conducted in respect to the demographics of sex, race, age, education level, and income level. Female respondents fared better with a mean of 3.6 correct responses compared to male respondents with 2.3 mean correct responses. In respect to race, Caucasian respondents had the most correct answers with a mean of 3.2, followed by Black (2.5), Latino (2.3), Asian (1.9), and ‘other” (1.9). In respect to age, the most correct responses belonged to the 26yo to 45yo age group with a mean of 5.1 correct answers, followed by 46yo to 64yo (4.6), at least 65yo (3.3), 18yo to 25yo (2.9), less than 18yo (2.2), and ‘prefer not to answer’ (1.5). In respect to education level, the most correct responses belonged to those with a Bachelor’s degree (Mean 5.1), followed by Master’s degree (5), high school graduate (4.4), Doctorate degree (4.3), in high school (2.4, ‘prefer not to answer’ (1.6), and some high school (1.8). In respect to income level, the most correct responses belonged to those with an income of $40,001 to $80,000 (mean 4.3), followed by $80,001 to $100,000 (4.1), $20,000 to $40,000 (3.9), greater than $100,000 (3.6), less than $20,000 (2.5), and ‘prefer not to answer’ (2.2). There was great diversity observed in these demographic results, including unexpected results (e.g. a higher education level or a higher income level, resulting in lower knowledge-based question scores).
Conclusion
This statistically significant study data protrudes the absolute need for widespread OTC pain medication safety and efficacy education. Even though these medications are available without a prescription, or in other words, without any mandated healthcare professional guidance or recommendations, each year there continues to be approximately 50,000 acetaminophen-related emergency room (ER) visits annually in the United States. Considering that this study also involved other OTC pain medications known as Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) including ibuprofen and naproxen, one can easily understand the need for more education, or perhaps even novel OTC pain medications with lower risk profiles. Considering the observed increase in OTC self-care medication use during the COVID-19 pandemic due to the lockdown of most healthcare systems, the need for more education and perhaps lower risk OTC pain medications is promulgated now more than ever, especially as more and more people are recommended or prescribed/dispensed non-opioid pain management medications. Based on the results of this study, the authors agree that future more geographically and demographically diverse studies are needed in order to understand the national, or even international, understanding of perceptions and knowledge of OTC pain medications in respect to safety and efficacy.
References
[1] https://www.getreliefresponsibly.com/
[2] Kelly T, Conn KM, Zak M. Evaluation of Over-the-Counter Medication Knowledge and Literacy in Adolescent Students. Acad Pediatr. 2018;18(5):556–562.
[3] Chambers CT, Reid GJ, McGrath PJ, Finley GA. Self-administration of over-the-counter medication for pain among adolescents. Arch Pediatr Adolesc Med. 1997;151(5):449–455. http://www.ncbi.nlm.nih.gov/pubmed/9,158,435.
[4] Abel C, Johnson K, Waller D, Abdalla M, Goldsmith C-AW. Nonprescription medication use and literacy among New Hampshire eighth graders. J Am Pharm Assoc. 2012;52(6):777–782.
[5] Gummin DD, Mowry JB, Spyker DA, Brooks DE, Osterthaler KM, Banner W. 2017 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 35th Annual Report. Clin Toxicol (Phila). December 2018:1–203. doi:10.1080/15,563,650.2018.1533727.
[6] Shehnaz SI, Agarwal AK, Khan N. A systematic review of self-medication practices among adolescents. J Adolesc Health. 2014;55(4):467–483.
[7] Wilson KM, Singh P, Blumkin AK, Dallas L, Klein JD. Knowledge Gaps and Misconceptions About Over-the-Counter Analgesics Among Adolescents Attending a Hospital-Based Clinic. Acad Pediatr. 2010;10(4):228–232.
[8] Shone LP, King JP, Doane C, Wilson KM, Wolf MS. Misunderstanding and Potential Unintended Misuse of Acetaminophen Among Adolescents and Young Adults. J Health Commun. 2011;16(sup3):256–267.
[9] Huott MA, Storrow AB. A survey of adolescents’ knowledge regarding toxicity of over-the-counter medications. Acad Emerg Med. 1997;4(3):214–218. http://www.ncbi.nlm.nih.gov/pubmed/9,063,550. 10. Myers WC, Otto TA, Harris E, Diaco D, Moreno A. Acetaminophen overdose as a suicidal gesture: a survey of adolescents’ knowledge of its potential for toxicity. J Am Acad Child Adolesc Psychiatry. 1992;31(4):686–690
Abstract #9 Submission ID#1301017
Treatment of Painful Diabetic Neuropathy (PDN): High-Frequency (10 kHz) Spinal Cord Stimulation (SCS) Provides Significant, Durable Pain Relief for PDN Patients
Erika Petersen, MDa, Thomas Stauss, MDb, James Scowcroft, MDc, Michael J. Jaasma, PhDd, Judith White, MDe, Shawn Sills, MDf, Kasra Amirdelfan, MDg, Maged Guirguis, MDh, Jijun Xu, MD, PhDi, Cong Yu, MDj, Ali Nairizi, MDk, Denis Patterson, DOl, Vincent Galan, MDm, Richard Bundschu, MDn, Neel Mehta, MDo, Dawood Sayed, MDp, Shivanand Lad, MDq, David DiBenedetto, MDr, Michael Creamer, DOs, Paul Wu, MDt, Charles Argoff, MDu, Christian Nasr, MDv, Rod Taylor, PhDw, David Caraway, MD, PhDx, Nagy Mekhail, MD, PhDy
aProfessor, University of Arkansas for Medical Sciences; bPhysician, Advanced Pain Management; cPhysician, Pain Management Associates; dPrincipal Clinical Research Scientist, Nevro Corp; eMedical Director, Accelerated Enrollment Solutions; fPhysician, Touchstone Interventional Pain Center; gFounding Partner, IPM Medical Group; hPhysician, Ochsner Clinic Foundation; iPhysician, Cleveland Clinic Foundation; jPhysician, Swedish Pain and Headache Center; kPhysician, Reno Tahoe Pain Associates; lPhysician, Nevada Advanced Pain Specialists; mPhysician, Pain CarePhysician; 1Physician Coastal Orthopedics; oPhysician, Weill Cornell Medicine; pPhysician, University of Kansas Medical Center; qPhysician, Duke University; rPhysician, Boston Pain Care; sPhysician, Central Florida Pain Relief Centers; tPhysician, Holy Cross Hospital; uPhysician, Albany Medical Center; vClinical Professor, The University of Arizona School of Medicine; wProfessor, University of Glasgow; xChief Medical Officer, Nevro Corp; yPhysician, Cleveland Clinic Foundation
Learning Objectives
Upon completion, participants will be able to discuss with their PDN patients how SCS can provide significant pain relief, with average pain relief of 82% at 24 months post-implantation.
Upon completion, participants will be able to discuss with their PDN patients how SCS can provide large, clinically meaningful reductions in pain interference with sleep and quality of life.
Upon completion, participants will be able to discuss with their PDN patients how SCS can be a safe, effective treatment option when medications are ineffective or not tolerated.
Purpose
Approximately 37 million Americans have diabetes, and 25–30% of these patients will experience painful diabetic neuropathy (PDN).1−2 PDN is characterized by chronic sensory loss, neuropathic pain, and dysesthesias that gradually progress proximally from the feet and hands in a glove-and-stocking pattern.2 PDN often results in poor quality of life, depression, anxiety, and impaired sleep.2,3 Unfortunately, conventional medical management (CMM), which includes several classes of pharmacotherapies, is ineffective or intolerable for many PDN patients.3,4 Spinal cord stimulation (SCS) has been shown to be an effective treatment for chronic lower extremity pain, and several recent studies have shown that SCS can also be effective for reducing pain associated with PDN.5−7 While low-frequency SCS (typically 40–60 Hz) has demonstrated moderate pain relief for PDN patients (responder rate of 53–68% at 6 months),5,6 it requires the use of stimulation-induced paresthesia, which may negatively affect patient comfort8 and limit therapy acceptability and success in a population that often has underlying disease-induced paresthesia symptoms.3 In contrast, high-frequency (10 kHz) SCS provides paresthesia-free treatment, and results at 12 months7 indicate that 10 kHz SCS provides greater pain relief (responder rate of 86%) than low-frequency SCS. In addition, 10 kHz SCS has been shown to provide improved neurological function and improved quality of life metrics at 12 months.7 Because PDN is a chronic condition, the long-term effectiveness of any treatment should be considered. Here we report on the durability of outcomes to 24 months for 10 kHz SCS treatment of PDN.
Methods
We conducted a prospective, multicenter, randomized, controlled trial (RCT) to evaluate 10 kHz SCS in PDN patients. Key inclusion criteria were: PDN symptoms ≥12 months refractory to at least two classes of medications, lower limb pain intensity ≥5 cm (0–10 cm visual analog scale [VAS]), hemoglobin A1c (HbA1c) ≤10%, and BMI ≤45 kg/m2. Patients were randomized 1:1 to 10 kHz SCS plus CMM (10 kHz SCS arm) or CMM alone (CMM arm), with optional crossover to the other treatment arm at 6 months (6 M). Temporary trial SCS was used to evaluate eligibility (≥50% pain relief from baseline) for a permanent SCS device implant. To date, patients assigned to the 10 kHz SCS arm have been followed for 24 M after receiving a permanent implant, and CMM-to-SCS crossover patients have been followed for 18 months post-implantation. To evaluate safety, study-related adverse events were tabulated. To evaluate effectiveness for pain-associated outcomes, results for each patient were compared to baseline values for lower limb pain (100-mm VAS), pain-associated sleep disturbance (Pain and Sleep Questionnaire three-item index, PSQ-3), and pain interference with mood and daily activities (Brief Pain Inventory, BPI-DPN). A repeated measures ANOVA was used to assess percent change (from baseline) for each outcome. To evaluate neurological function, neurologists trained investigators to perform comprehensive neurological examinations assessing lower limb motor strength, reflexes, and sensation (pin-prick, 10-g monofilament, and light-touch at 10 locations per foot). At each neurological exam, the investigator assessed if there was improvement, maintenance, or deficit in each functional category (motor strength, reflex, and sensory) relative to the baseline exam. Overall neurological improvement was noted if a patient was assessed to have improvement in at least one category without deficit in any category.
Results
We randomized 216 patients (10 kHz SCS arm: n = 113; CMM arm: n = 103). Treatment groups were well-matched for baseline characteristics. Among participants assigned to the 10 kHz SCS arm, 104 proceeded to temporary trial and 90 received a permanent device implant.
At 6 M, patients randomized to 10 kHz SCS experienced average pain relief of 76% (95%CI: 71%–82%; n = 88; p < 0.001 vs. baseline, p < 0.001 vs. CMM). In contrast, patients randomized to CMM experienced average pain increase of 2% (95%CI: 6% decrease to 10% increase; n = 95). After 6 M, 93% of eligible CMM patients elected to cross over to 10 kHz SCS, while zero 10 kHz SCS patients crossed over to CMM. The CMM-to-SCS crossover patients experienced significant pain relief after receiving 10 kHz SCS, with average pain relief of 71% (95%CI: 64%–78%; n = 59; p < 0.001 vs. baseline) after 6 M of 10 kHz SCS. Patients receiving 10 kHz SCS continued to experience significant pain relief after 6 M, with average pain relief of 82% (95%CI: 77–87%; n = 84; p < 0.001 vs. baseline) at 24 M. HbA1c remained unchanged in both groups throughout the study, supporting that SCS vs. CMM treatment effects were not due to group differences in HbA1c.
Neurological improvements were also observed with 10 kHz SCS. At 6 M, neurological improvements were observed in 62% and 3% of patients in the 10 kHz SCS and CMM arms, respectively. Then, for CMM-to-SCS crossover patients, improvements were observed in 62% of patients after 6 M of 10 kHz SCS. Neurological improvements were also durable as 72% of patients receiving 10 kHz SCS were assessed to have improvement at 24 M.
Reductions in pain-associated sleep disturbance and pain interference with mood and daily activities were consistent with pain relief. At 6 M, 10 kHz SCS provided significant reductions in these outcomes vs. CMM (p < 0.001), and the 10 kHz SCS-associated reductions were durable through 24 M. At 24 M, patients receiving 10 kHz SCS experienced a decrease of 70% (95%CI: 61–80%; n = 83; p < 0.001 vs. baseline) in pain-associated sleep disturbance and a decrease of 70% (95%CI: 63–77%; n = 84; p < 0.001 vs. baseline) in pain interference with mood and daily activities.
There were no stimulation-related neurological deficits, and no device explants due to lack of efficacy. Of the 154 patients who received an SCS implant (including 10 kHz SCS arm and CMM-to-SCS crossover patients), there were eight (5.2%) study-related infections, three of which resolved with treatment. Five devices were explanted due to infection (3.2%).
Conclusion
This is the largest RCT to date for SCS management of PDN. The 24 M results demonstrate that 10 kHz SCS provides significant, durable reductions in pain and pain-associated effects on sleep and quality of life. In addition, the observed improvements in neurological function highlight the unique disease-modifying potential of 10 kHz SCS for PDN. Infection risk can be a concern for diabetic patients. However, the infection rate of 5.2% observed in this study is within the range reported for SCS in non-diabetic patients (2.5–10%),9 indicating that SCS can be a safe treatment option for PDN patients. Taken together, the results from this study support that 10 kHz SCS can provide safe, durable pain and symptom relief for PDN patients, while offering the potential for neurological improvements.
References
[1] CDC. National Diabetes Statistics Report; [cited 2 May 2022]Available from. Pop-Busui et al. ADA Clinical Compendia Series 2022 3. <atl>Feldman et al</atl>. Nat Rev Dis Primers 2019; 5(1):41 4. Finnerup et al. Lancet Neurol 2015; 14(2):162 5. Slangen et al. Diabetes Care 2014; 37(11):3016 6. de Vos et al. Pain 2014; 155(11):2426 7. Petersen et al. Diabetes Care 2022; 45(1):e3 8. Kapural et al. Neurosurgery 2016; 79(5):667 9. Eldabe et al. Pain Med 2016; 17(2):325
Abstract #10 Submission ID#1301273
A Forgotten Cause of Bleeding and Musculoskeletal Pain: A Case Report of Contemporary Scurvy
Nirosha D. Perera, MDa, Arjun Lakshman, MBBSb, William L. Nichols, Jr., MDc, C. Christopher Hook, MDd
aResident Physician, Mayo Clinic, Department of Internal Medicine; bFellow Physician, Mayo Clinic, Division of Hematology, Department of Medicine, Department of Medical Oncology; cAttending Physician, Mayo Clinic, Division of Hematology; dAttending Physician, Mayo Clinic, Division of Hematology
Learning Objectives
Participant will be able to describe the common presentations of patients with scurvy and identify related pain manifestations.
Participant will be able to identify patients who are at risk for contemporary scurvy and begin the appropriate workup.
Participant will be able to work with interdisciplinary colleagues to address the potential complications, including pain manifestations, of scurvy.
Purpose
Initial descriptions of scurvy, or vitamin C deficiency, date back to 1500 BC, historically occurring in sailors, monks, and army men on long journeys with limited food access.1 Scurvy resulted in more sailors’ deaths than all other diseases and disasters combined between 1500 BC and 1800 AD.2 In 1747, Sir James Lind, a British naval surgeon, used lemons and oranges to treat sailors with scurvy.3 In 1931, the active substance in citrus fruits was identified as ‘hexuronic acid,’ or vitamin C, and was renamed ascorbic acid because of its role in the prevention and treatment of scurvy.4 In 1937, Hungarian biochemist Albert von Szent-Györgyi won the Nobel Prize in physiology or medicine for this discovery.5,6
With improvements in nutrition, hygiene, and preventive medicine over the last century, the incidence of scurvy decreased dramatically. Due to its rarity, scurvy is often misdiagnosed or underdiagnosed in current practice, though it continues to occur in vulnerable patient populations and is potentially fatal if left untreated.1,7 Since the constellation of symptoms commonly includes musculoskeletal pain, pain providers may be faced with patients with underlying scurvy. We describe a case with contextualization within current literature to highlight disease findings that can help clinicians astutely make this diagnosis.
A 61-year-old female presented in March 2022 for evaluation of easy bruising, bleeding, arthralgias, myalgias, fatigue, loss of appetite with weight loss, and hypotension. Her past medical history included vertical band gastroplasty for obesity in 2001 requiring re-do and Roux-en-Y bypass in 2015 complicated by anastomotic ulcer and gastrointestinal (GI) bleeding. She also had right hemicolectomy with end ileostomy for ischemic right colon in 2018, chronic anemia, atrial fibrillation, chronic kidney disease stage 4, adrenal insufficiency, fibromyalgia, and depression. She was partially dependent on percutaneous-gastrostomy tube feeds for nutrition. Her outside dermatologic and hematologic workup for bruising and bleeding (in the post-operative and spontaneous settings) had been unrevealing, and her diffuse, daily, muscle and joint pains persisted despite acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and steroid injections, resulting in as needed oxycodone-acetaminophen use, impaired mobility, and intermittent wheelchair dependence. She was a retired phlebotomist and denied alcohol/substance use.
Methods
Patient: 61-year-old woman with complex medical history including impaired nutritional and functional status
Setting: Outpatient hematology clinic
Consent: Patient provided verbal consent to use of de-identified patient information and images for medical research
Results
Vital signs were notable for blood pressure of 84/54 mmHg. Body mass index was 30 kg/m2. Physical examination showed diffuse purpura over the limbs with thin fragile skin, diffuse areas of small well-circumscribed ecchymoses in a similar distribution, and pedal edema.
Laboratory workup showed mild macrocytic anemia but otherwise normal blood counts, stable kidney function, normal electrolytes and normal liver function tests. Her comprehensive bleeding profile testing which included prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time, platelet function/aggregation testing, coagulation factors, and von Willebrand factor activity/antigen were unremarkable. We suspected scurvy as a vascular etiology of bleeding, and testing revealed low serum ascorbic acid level (0.2 mg/dL; normal range 0.4–2.0 mg/dL). Additional testing showed low zinc and low pyridoxic acid (vitamin B6). The patient was started on daily oral vitamin/mineral supplementation including ascorbic acid 1000 mg daily, with referrals placed to GI and bariatric nutrition clinics in the interim.
Our patient had poor nutritional status and experienced bleeding, fatigue, and hypotension of unclear cause, with her arthralgias/myalgias previously attributed to fibromyalgia. Her case reminds us that scurvy is an underdiagnosed condition with a wide variety of manifestations. The most common findings are bruising, arthralgias, and joint swelling.8 Other reported symptoms in the literature include weakness, fatigue, myalgias, pedal edema, oral mucosal changes (swelling/bleeding), nausea, anorexia, and vasomotor instability. If untreated, scurvy can progress to heart failure and severe infections that can lead to death.
After one month of ascorbic acid supplementation, the patient demonstrated normalization of ascorbic acid level (0.5 mg/dl). Not all of her symptoms resolved, but her arthralgias, myalgias, and pedal edema improved and her weight stabilized. Fatigue and weakness remained significant and were felt to be driven by her comorbidities including adrenal insufficiency, debility, and poor oral intake. She did not have further bleeding and was cleared for further workup including endoscopy for her complex GI issues, provided she remained replete with vitamin C. She now follows with bariatric nutrition clinic to ensure appropriate vitamin levels.
Conclusion
Scurvy occurs due to reduced dietary intake or absorption of vitamin C, thus presenting more commonly in patients with ‘fad diets,’ reduced food access, alcoholism, GI disease or poor dentition, and patients on chemotherapy suffering from nausea/diarrhea.8 Vitamin C serves a variety of functions for the human body, including in collagen, carnitine, and norepinephrine synthesis. When defective, the abnormal synthesis of these products results in blood vessel fragility and poor wound healing (collagen), myalgias (carnitine), and vasomotor instability (norepinephrine), with reports of syncope and sudden death.8 A serum level of ascorbic acid below 0.4 mg/dl suggests scurvy.9 The signs and symptoms of scurvy rapidly respond to vitamin C supplementation. Subjective improvement in fatigue, pain, and anorexia typically occurs within 24 hours. Joint swelling and ecchymoses typically improve in days to weeks. Complete recovery occurs after about 3 months of treatment.10
Given the wide spectrum of scurvy manifestations, many of which can be dismissed as nonspecific, it is important for providers of all specialties to recognize vitamin C deficiency. Given scurvy’s association with arthralgias and myalgias, pain providers can play an integral role in helping recognize scurvy and initiating appropriate therapy promptly.
References
[1] Pimentel L. Scurvy: historical review and current diagnostic approach. The American Journal of Emergency Medicine. 2003;21(4):328–332.
[2] Popovich D, McAlhany A, Adewumi AO, Barnes MM. Scurvy: forgotten but definitely not gone. J Pediatr Health Care. 2009;23(6):405–415.
[3] C.P. Stewart, D. Cuthrie. Lind’s Treatise on Scurvy. A bicentenary volume containing a reprint of the first edition of A Treatise of the Scurvy by James Lind, Edinburgh University Press, Edinburgh (1953).
[4] L.N. Magner. A History of Medicine, Marcel Dekker, New York (1992).
[5] The Nobel Prize in Physiology or Medicine 1937. NobelPrize.org. [cited 16 April 2022] Available from: https://www.nobelprize.org/prizes/medicine/1937/szent-gyorgyi/facts/.
[6] Steensma DP. Luis Walter Alvarez: Another ‘Mayo-Trained’ Nobel Laureate. Mayo Clinic Proceedings. 2006;81(2):241–244.
[7] Larson E, Jassim A, McGrann J. Sailing the Low C’s: History Repeating Itself. Consultant360. Published 23 May 2011. [cited 6 April 2022] avilable from: https://www.consultant360.com/articles/sailing-low-c-s-history-repeating-itself.
[8] Olmedo JM, Yiannias JA, Windgassen EB, Gornet MK. Scurvy: a disease almost forgotten. Int J Dermatol. 2006;45(8):909–913.
[9] Nguyen RTD, Cowley DM, Muir JB. Scurvy: a cutaneous clinical diagnosis. Australas J Dermatol. 2003;44(1):48–51. 10. Hirschmann JV, Raugi GJ. Adult scurvy. J Am Acad Dermatol. 1999;41(6):895–906; quiz 907–910.
Abstract #11 Submission ID#1301752
The Agnostic Respiratory Stimulant ENA-001 Demonstrates Preliminary Positive Results in an Animal Model of Apnea of Prematurity
Thomas Miller, PhDa, Lynn Raab, DVMb, Thomas Shaffer, PhDc, Alfred Schweikert, PhDd, Frank Diana, PhDe, Prem Fort, MDf, Joseph Pergolizzi, Jr, MDg, Robert B. Raffa, PhDh
aVP of Clinical Development, Enalare Therapeutics; bClinical Veterinarian, Thomas D Morris, InccAssociate Director, Nemours Biomedical Research; dSr Vice President of Regulatory Affairs, Enalare Therapeutics; ePresident & Principal Consultant, FJD-CMC Consulting; fNeonatology, Johns Hopkins All Children’s Hospital; gCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other; hProf Emeritus; Adjunct; CSO: Co-founder; Sci AdBoard, Temple Univ; Univ AZ; Neumentum; Enalare; Advantx
Learning Objectives
Upon completion, participant will be able to explain the meaning of ‘agnostic respiratory stimulant’.
Upon completion, participant will be able to describe apnea of prematurity.
Upon completion, participant will be able to describe the results of this study and the implications for clinical practice.
Purpose
ENA-001 is a novel selective antagonist of large-conductance BK (big potassium) channels located in glomus cells of the carotid bodies. BK channels act as important components of the chemoreception that primarily senses low arterial oxygen levels and establish a feedback loop to brainstem nuclei responsible for initiating spontaneous breathing and maintaining adequate oxygen to tissues. In a number of animal and human studies, ENA-001 successfully attenuated the respiratory depression induced by a variety of chemical agents, its effect being essentially ‘agnostic’ to the precipitating drug (e.g. opioid, benzodiazepine, alcohol, propofol). But it was never tested against respiratory depression resulting from a physiological cause, such as apnea of prematurity (AOP). This proof-of-principle study using a well described animal model of prematurity (premature lamb) was initiated to test the effectiveness of ENA-001 in the setting of an under-developed respiratory control system, similar to that in human AOP.
Methods
The protocol described one set of twin lambs to be delivered premature via Cesarian section and stabilized as previously described [1,2]. Based on experience with the model, the investigators targeted 135 ± 2 d gestational age (GA) as it was expected that the lambs would have a spontaneous respiratory drive and could be managed for four hours with continuous positive airway pressure (CPAP); i.e. not require mechanical ventilation. Once the umbilical cord was ligated and severed, the lamb was transferred to a heated surgical bed under a radiant warming lamp. An arterial catheter was connected to a transducer for pressure monitoring and a venous catheter was connected to a pump for continuous infusion of 5% dextrose in water (D5W) at a rate of 6 ml/kg/hr. The airway was suctioned and Surfactant was administered intratracheally over a period of 5 min. Lambs were to receive four mechanical breaths for lung recruitment and then started on CPAP. After a stabilization period of 15 min, the protocol called for the first lamb to be started on continuous infusion of ENA-001, with ascending dose hourly, while the second lamb was to serve as a sham (D5W) control. The ENA-001 treatment was designed to be started without a loading dose such that plasma concentrations would climb over the course of each hour and should contribute to an ascending dose effect. The first three doses have been used in human studies of efficacy, where the lower dose had minimal effect, the second dose is the intended adult therapeutic dose (following a loading dose), the third dose is the intended adult human loading dose, and the last hourly dose rate is given to support toxicology analysis in the immature tissues (10-fold the intended adult therapeutic dose). At least ten representative breaths free of artifact from motion or atypical breaths were recorded using a pulmonary function system designed for neonatal research. For each period, the rate, tidal volumes and minute ventilation were derived from an average of the ten breaths. To maintain a stable plane of anesthesia, repeat doses of fentanyl (1 µg IM) were given as needed based on blood pressure response to stimulation.
Results
Two male lambs were delivered. However, neither lamb exhibited a drive for spontaneous breathing. Each required manual ventilation, with a complete absence of spontaneous effort. Despite the poor prognosis owing to absence of ventilatory effort, continuous infusion of the first dose of ENA-001 was started 20 min following birth. The test animal continued to require manual ventilation, which was continued for an additional 10 min. The decision was made to give an intravenous bolus infusion of ENA-001 at a dose that has yielded therapeutic plasma levels in previous animal studies. Nearly instantaneously following the delivery of the IV bolus, the lamb began breathing spontaneously and never again required manual intervention for the remainder of the study. For the remainder of the four hours following the initiation of the first infusion dose, the doses were changed hourly as per the protocol.
The sham animal was delivered approximately an hour following the test animal. As with the test animal, the sham animal lacked spontaneous breathing efforts. A decision was made to manually ventilate for 30 minutes to match the course for the test animal, and if still not breathing, would be determined inviable and sacrificed for the control tissue samples. At the 30-minute timepoint, an intravenous bolus infusion of ENA-001 was delivered. Nearly instantaneously following the delivery of the IV bolus, the lamb began breathing spontaneously. After several minutes, the spontaneous breathing efforts abated, and manual ventilation was resumed. The animal was then sacrificed for tissue harvest.
Conclusion
This proof-of-principle study using a well described animal model of prematurity (premature lamb) was initiated to test the effectiveness of ENA-001 in the setting of an under-developed respiratory control system, similar to that in human AOP. We found that ENA-001 was effective in this model of prematurity. In fact, ENA-001 induced spontaneous breathing, and the lambs were then able to maintain effective spontaneous breathing without additional support. These results suggest that ENA-001 might be effective therapy alone or as comedication for the management of AOP. They further suggest that ENA-001 might have broader applications in situations of neurological ventilatory insufficiency. ENA-001 currently is undergoing further clinical testing and development for a variety of therapeutic and emergency uses.
References
[1] Wolfson MR, Wu J, Hubert TL, Gregory TJ, Mazela J, Shaffer TH. Lucinactant attenuates pulmonary inflammatory response, preserves lung structure, and improves physiologic outcomes in a preterm lamb model of RDS. Pediatr Res. 2012;72(4):375–383.
[2] Shashikant BN, Miller TL, Welch RW, Pilon AL, Shaffer TH, Wolfson MR. Dose response to rhCC10-augmented surfactant therapy in a lamb model of infant respiratory distress syndrome: physiological, inflammatory, and kinetic profiles. J Appl Physiol (1985). 2005;99(6):2204–2211.
Abstract #12 Submission ID#1302009
Posterior femoral cutaneous nerve neuropathy post marathon: a case report
Kirk Sheplay, MDa, Anthony Sheplay, MD, FAAPMR, FAAPMb
aResident, Ascension Providence; bDirector, Physician, Pain & Spine Medicine Center of the Central Coast.
Learning Objectives
Recognize the presentation and diagnose Posterior Femoral Cutaneous Nerve Neuropathy.
Manage and treat Posterior Femoral Cutaneous Nerve Neuropathy including diagnostic and/or therapeutic blocks.
Build awareness of this uncommon but potentially under-recognized pathology.
Purpose
Posterior femoral cutaneous nerve (PFCN) neuropathy is an uncommon, potentially under-recognized cause of low back, buttock, perineal, and posterior and lateral thigh pain and numbness (1). Since there is overlap with the innervation of the sciatic and pudendal nerve, pathology of the PFCN is often under-diagnosed due to the more common pathologies of these other nerves (2). Most reports of nerve injuries regarding the PFCN are caused by intramuscular injections (1), although there are also reports due to hematoma (3), tumor formation (4), prolonged cycling (4), entrapment in the facia lata (1), piriformis hypertrophy (5), operations such as an above-knee amputation from the thigh pressure cuff (6) or a posterior hip replacement (7) abnormal venous formations (8) pressure injuries against the sciatic tuberosity or the inferior margin of the gluteus maximus due to sitting on hard surfaces or falls (2) (4), and hamstring injuries due to the proximity to the origin of the hamstring muscle (9) (10). PFCN injury due to hamstring pathology have been reported, mostly due to hamstring tears as well as vaginal, pudendal and sciatic nerve surgery, childbirth, car accident, biking accident, and falls (10). However, this is the first reported case of a PFCN injury of hamstring pathology due to tendonitis caused by long-distance running.
Methods
A 42-year-old male with no relevant past medical history developed right lower buttock pain two weeks post marathon. He is an avid runner and does not recall a discrete injury. The pain was located medial and superior to the ischia tuberosity and extended distally to the right scrotum with no testicular pain. Pain was worse with flexion of right hip. On physical examination there was no sensory changes in the skin itself and no increased pain with deep pressure. The pain progressed such that he was unable to sit down or flex his hip for over a year. The patient was able to modify his car seat to a 45-degree angle to still be able to drive.
An initial MRI showed a small amount of increased T2 signal adjacent to the ischial tuberosities at the hamstring origins bilaterally suggesting hamstring tendinitis. Consults with sports medicine and hip orthopedics provided no clear diagnosis. He failed to improve with NSAIDS, physical therapy, massage, PRP injection, two Ganglion of Impar Nerve blocks, and trial of Pregabalin. The diagnosis was confirmed with temporary relief following a PFCN block. He was then advised to have the nerve resected because of failure of non-surgical treatment. Intraoperatively, the PFCN was found to be adherent to the ischial tuberosity secondary to scar tissue in the proximity of the hamstring tendonitis, which confirmed the mechanism of the injury.
Following surgical resection of the nerve, he experienced posterior buttock numbness initially which gradually resolved over a year. He progressed in sitting tolerance and was able to return to walking and running.
Results
The Posterior femoral cutaneous nerve (PFCN) arises from the ventral primary rami of S1, S2, and S3 of the lumbosacral plexus (11) and provides the sensory innervation for the inferolateral gluteal region, the superomedial aspect of the perineal region, the posterior aspect of the thigh, and the skin at the popliteal fossa (1).
PFCN neuropathy presentation varies, due to the level and location of the abnormality along the different branches. The Perineal Branch innervates the lateral perineum, proximal medial thigh, posterolateral aspect of the scrotum/labium majus, and a portion of the penis/clitoris (12). Neuropathy of the cluneal branches can cause clunealgia, which present as pain and paresthesia referred to the inferior lateral buttock area (13). Neuropathy to these nerves along with the other terminal branches of the PFCN are responsible for the common complaint of ‘pain with sitting.’ (10). Neuropathy of the Cutaneous Branch typically manifests as pain and paresthesia of the skin over the inferior buttocks, posterior thigh, and popliteal region (14).
Diagnostic assessment is currently restricted to clinical findings and a diagnostic nerve block of the PFCN. Techniques for diagnostic blocks have been reported using anatomic landmarks (14), high resolution ultrasound (1), computed tomography guidance (13), and with high-resolution magnetic resonance imaging (12). A fluoroscopic technique is difficult due to no good fluoroscopic landmarks, other than the ischium (2). The landmark recommended by Hughes to target the whole nerve is one quarter of the distance between the ischial tuberosity and the greater trochanter. To target the perineal branch, Hughes recommends directly at the ischial tuberosity (14). In contrast, Fritz recommends targeting the pathologic branches. He recommends 2 cm below the ischial tuberosity for the perineal branch, under the gluteus maximus muscle for the cluneal nerves, and between the gluteus maximus and the long head of the biceps femoris for symptoms in the posterior thigh (12). Tubbs recommends 4 cm below the ischial tuberosity for the perineal branch (16). A somatosensory-evoked potential (SSEP) evaluation of the PFCN has been used in the literature as well (15).
Initial treatment starts with conservative therapy. If this fails, selective diagnostic nerve blocks of the PFCN can be helpful to assess the location of the pathology of the nerve and to identify potential surgical targets for a surgical neurectomy (1). Cryoablation of the posterior femoral cutaneous nerve resulting in successful treatment of PFCN-mediated sitting pain has also been reported.
Conclusion
After excluding the more common etiologies of buttock pain and sitting intolerance such as: hamstring tendinitis, sacroiliac dysfunction, gluteal myofascial syndrome, piriformis syndrome, pudendal nerve impingement, ischial stress reaction, and hip pathology, practitioners should consider the rarer condition of PFCN neuropathy in runners.
References
[1] Meng S, Lieba-Samal D, Reissig LF, et al. High-resolution ultrasound of the posterior femoral cutaneous nerve: visualization and initial experience with patients. Skeletal Radiol. 2015;44(10):1421–1426.
[2] Murinova N., Krashin D., Trescot A.M. (2016) Posterior Femoral Cutaneous Nerve Entrapment: Low Back. In: Trescot A.M. (eds) Peripheral Nerve Entrapments. Springer, Champaign, Il.
[3] Gomceli YB, Kapukiran A, Kutlu G, Kurt S, Baysal AI. A case report of an uncommon neuropathy: posterior femoral cutaneous neuropathy. Acta Neurol Belg. 2005;105(1):43–45.
[4] Arnoldussen WJ, Korten JJ. Pressure neuropathy of the posterior femoral cutaneous nerve. Clin Neurol Neurosurg. 1980;82(1):57–60.
[5] Williams SE, Swetenburg J, Blackwell TA, Reynolds Z, Black AC Jr. Posterior femoral cutaneous neuropathy in piriformis syndrome: A vascular hypothesis. Med Hypotheses. 2020;144:109,924.
[6] Chang KV, Mezian K, Naňka O, et al. Ultrasound Imaging for the Cutaneous Nerves of the Extremities and Relevant Entrapment Syndromes: From Anatomy to Clinical Implications. J Clin Med. 2018;7(11):457.
[7] Schumm F, St€ohr M, Bauer HL, Eck T. Peripheral nerve injury due to total replacement of the hip-joint. Z Orthop Ihre Grenzgeb 1975; 113:1065–1069.
[8] Chutkow JG. Posterior femoral cutaneous neuralgia. Muscle Nerve. 1988;11(11):1146–1148.
[9] Chang KV, Mezian K, Naňka O, et al. Ultrasound Imaging for the Cutaneous Nerves of the Extremities and Relevant Entrapment Syndromes: From Anatomy to Clinical Implications. J Clin Med. 2018;7(11):457.
[10] Dellon AL. Pain with sitting related to injury of the posterior femoral cutaneous nerve. Microsurgery. 2015;35(6):463–468.
[11] Mobbs RJ, Szkandera B, Blum P. Posterior femoral cutaneous nerve entrapment neuropathy: operative exposure and technique. British journal of neurosurgery. 2002;16(3):309–311.
[12] Fritz J, Bizzell C, Kathuria S, et al. High-resolution magnetic resonance-guided posterior femoral cutaneous nerve blocks. Skeletal radiology. 2013;42(4):579–586.
[13] Kasper JM, Wadhwa V, Scott KM, Chhabra A. Clunealgia: CT-guided therapeutic posterior femoral cutaneous nerve block. Clin Imaging. 2014;38(4):540–542.
[14] Hughes PJ, Brown TC. An approach to posterior femoral cutaneous nerve block. Anaesth Intensive Care. 1986;14(4):350–1.
[15] Dumitru D, Nelson MR. Posterior femoral cutaneous nerve conduction. Arch Phys Med Rehabil. 1990;71(12):979–982.
[16] Tubbs RS, Miller J, Loukas M, Shoja MM, Shokouhi G, CohenGadol AA. Surgical and anatomical landmarks for the perineal branch of the posterior femoral cutaneous nerve: implications in perineal pain syndromes. Laboratory investigation. J Neurosurg. 2009;111(2):332–5.
Abstract #13 Submission ID#1302504
The Impact of an Audio-Visual Stimulation Device on Quality of Life and Clinical Symptoms in Participants with Fibromyalgia
Jeffrey Bower, Ph.D.a, Martin Cheatle, Ph.D.b, Crystal George, MSc, Richard Hanbury, MBAd
aVP Analytics, Sana Health; bAssociate Professor, Department of Psychiatry – Perelman School of Medicine, University of Pennsylvania; cVP Clinical Affairs, Sana Health; dCEO, Sana Health
Learning Objectives
Attendees will know the effectiveness of the novel audio-visual device (AVS) as studied a fully remote trial for improving fibromyalgia symptoms including general pain, sleep, anxiety, depression, and pain catastrophizing.
Attendees will learn how the theoretical mechanisms of audio-visual stimulation (AVS) apply to neuropathic pain and fibromyalgia.
Attendees will consider how the AVS devices offers a safe, effective, and accessible treatment for fibromyalgia that can be used with existing approved drugs as well as other therapies.
Purpose
In this open label fully-remote study we assessed the effectiveness a novel Audio Visual Stimulation (AVS) improving Quality of Life (QOL) and symptoms of FM in a real-world setting. Fibromyalgia (FM) is associated with widespread chronic pain as well as additional symptoms including fatigue, sleep disturbances,1 and mood disturbances.2 The inter-relation of symptoms of pain, poor quality sleep, mood disorders, and fatigue lead to poor quality of life for patients with Fibromyalgia.3
Methods
Five hundred (projected) subjects with FM used the novel AVS device for 28 days. Outcome examined were; Fibromyalgia Impact Questionnaire – Revised (FIQ-R), Patient Global Impression of Change Quality of Life (PGIC-QOL), General Anxiety Disorder 7 (GAD-7), Patient Health Questionnaire 8 (PHQ-8), Pain Catastrophizing Scale (PCS), Promis 8a (PR8A), and the Pain Enjoyment General Activity scale (PEG).
Results
From Baseline to end of treatment there were improvements FM symptom severity (FIQ-R, p < 0.001), quality of life (PGIC-QOL, p < 0.001), anxiety (GAD-7, p < 0.001), depression (PHQ-8, p < 0.001), pain catastrophizing (PSC, p = 0.013), sleep (PR8A, p < 0.001), and pain (PEG, p < 0.001).
Conclusion
FM is a common pain disorder that leads to significant suffering. This pilot study demonstrates the effectiveness of a novel, safe AVS device in improving FM symptoms, QOL, pain, sleep, depression, and anxiety.
References
[1] Clauw D. J. (2014). Fibromyalgia: a clinical review. JAMA, 311(15), 1547–1555.
[2] Brito, R., Santos, P., Oliveira, Pina, L., Antoniolli, A., Almeida, J., Picot, L. Zengin, G. & Quintans, J., Quintans-Júnior, L. (2018). Natural Products as Promising Pharmacological Tools for the Management of Fibromyalgia Symptoms – A Review. (pp. 57–78). Intech. http://dx.doi.org/10.5772/intechopen.70016.
[3] Jacobs, H., Bockaert, M., Bonte, J., D’Haese, M., Degrande, J., Descamps, L. & De Bacquer, D. (2020). The impact of a group-based multidisciplinary rehabilitation program on the quality of life in patients with fibromyalgia: results from the QUALIFIBRO Study. JCR: J of Clin Rheumatol, 26(8), 313–319.
Abstract #14 Submission ID#1303855
An epidemiological study of fibromyalgia based on real-world data in a northern city in China
Peng Mao, MDa, Yi Zhang, MDb, Yifan Li, MDc, Bifa Fan, MDd
aAssociate Chief Physician, China-Japan Friendship Hospital; bResident, China-Japan Friendship Hospital; cResident, China-Japan Friendship Hospital; dDepartment chair, China-Japan Friendship Hospital
Learning Objectives
Upon completion, participant will be able to learn the epidemiology of fibromyalgia in a northern city in China.
Upon completion, participant will be able to recognize the low rate of confirmed fibromyalgia patients in the overall population in a northern city in China.
Upon completion, participant will be able to notice the robust increase of confirmed fibromyalgia patients in a northern city in China.
Purpose
Fibromyalgia (FM) is a common chronic diffuse pain syndrome in which, in addition to multi-site pain, patients often suffer from a variety of clinical symptoms such as fatigue, sleep and mood disorders [1], and thus FM often causes a heavy socioeconomic burden. The current global prevalence of FM is about 2–4% [2]. The prevalence of FM is gradually increasing due to factors such as an aging population, increased psychological stress, and an increase in poor lifestyle habits. However, there is a general lack of awareness among clinicians in mainland China regarding this serious disease [3]. On one hand, FM guidelines have only been promulgated and updated in China since 2011, which is a relatively short period of time for promotion; on the other hand, because of the diverse clinical manifestations of FM and the lack of specific diagnostic indicators, diagnosis is difficult and most physicians lack relevant clinical experience. In line with this understanding, epidemiologically, there is a lack of systematic studies on the prevalence and trends of FM in mainland China. To promote the understanding and awareness of FM among clinicians in mainland China, this study systematically identifies patients diagnosed with FM in the region through a regional database of electronic medical records, and demonstrates the prevalence and epidemiological trends of FM through changes in the number of patients diagnosed with FM over a 10-year period from 2010 to 2020.
Methods
Tianjin is a second-tier city in the north, one of the four major municipalities in China. Tianjin Regional Health Care Big Data Platform is currently one of the best platforms in terms of data quality governance within mainland China. The platform covers a population of about 16 million and contains a majority of tertiary and secondary hospitals in the region (a total of 80 hospitals in Tianjin, including 43 tertiary hospitals and 37 secondary hospitals). This study used the electronic medical record (EMR) and health information system (HIS) data in the platform to include patients with at least one diagnosis containing ICD-10 code M79.7 (fibromyalgia) or with an exact match of the diagnosis name ‘fibromyalgia’ or ‘fibromyalgia syndrome’(‘纤维肌痛’或‘纤维肌痛综合症’或‘纤维肌痛综合征’ in Chinese) from 1 October 2010 to 30 September 2020 after the promulgation of the FM diagnostic criteria. Each patient’s socio-demographic and diagnostic information were extracted, and the unstructured text was standardized and normalized using natural language processing techniques. The final analysis data set was formed and statistically analyzed.
Results
From 1 October 2010 to 30 September 2020, in 80 hospitals in Tianjin, the total number of confirmed FM diagnosis was 981. Among them, 289 (29.5%) were male and 692 (70.5%) were female, with a male to female ratio of approximately 1:2.4. The average age of FM patients at first diagnosis was 53.34 ± 12.80 years, and 78.54% had urban medical insurance. Based on a resident population of 13,866,009 in Tianjin in 2020, the proportion of people who were diagnosed with FM in Tianjin was 7.1/100,000, which was much lower than the prevalence rate of similar populations (0.82% in Hong Kong, China [4]). The reason for this is probably related to the low rate of both consultation and diagnosis of FM in China, in addition to the geographical area. According to a survey, 24.1% of respondents in China had never been seen for chronic pain [5]. A study in a hospital in Hebei, a northern province in China, showed that the rate of misdiagnosis at the first visit was as high as 87% [6], and physicians lacked awareness to recognize FM [3]. The number of new FM patients has shown a gradual increase over the past decade. The number of new FM patients per year increased from 7 in 2011, to 40 in 2015, to 233 in 2020. With the promulgation of the first Chinese guidelines in 2011 [7], and the popularity of the FM disease concept and ICD10 diagnostic criteria began among clinicians, the number of new FM patients slowly increased each year. Wolfe [8] et al. and The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA) and the American Pain Society (APS) [9] simplified and clarified the definitions of FM and chronic pain in 2016 and 2019, respectively, causing the number of confirmed diagnoses to show a significant upward in the respective years.
Conclusion
With the popularization and optimization of diagnostic criteria, the number of confirmed FM patients in Tianjin is gradually increasing, but the proportion of confirmed FM patients in the overall population is much lower than the prevalence rates in Europe, the United States, Hong Kong and Taiwan, suggesting that the diagnosis rate of FM patients in China is low. Therefore, it is necessary to improve clinicians’ awareness of fibromyalgia as well as to popularize and standardize the related diagnostic measures.
References
[1] Zhu Qian. Chinese expert consensus on clinical diagnosis and treatment of fibromyalgia [J]. Chinese J of Pain Med,2021,27(10):721–727.
[2] Häuser W, Ablin J, Fitzcharles MA, Littlejohn G, Luciano JV, Usui C, Walitt B. Fibromyalgia. Nat Rev Dis Primers. doi: 10.1038/nrdp.2015.22.
[3] Mu R, Li C, Zhu JX, et al. National survey of rheumatologists’ knowledge, attitudes, and practices regarding fibromyalgia. int J Rheum Dis. 2013;16(3):258–263.
[4] Roger AS, Edmund KML, Rhonda JS. prevalence of fibromyalgia syndrome among Chinese in Hong Kong. j Musculoskeletal Pain. 2006;14(2):3–11.
[5] Yongjun Z, Tingjie Z, Xiaoqiu Y, et al. A survey of chronic pain in China. Libyan J Med. 2020;15(1):1,730,550.
[6] Yu G S, Zhou H H, Tang L. Analysis of 113 cases of clinical misdiagnosis of primary fibromyalgia syndrome [J]. Hebei Medicine, 2013, 19(12):1845–1846.
[7] Guidelines for the diagnosis and treatment of fibromyalgia syndrome [J]. Chinese Journal of Rheumatology,2011(08):559–561.
[8] Wolfe F, Clauw DJ, Fitzcharles MA, et al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016;46(3):319–329. [9] Arnold LM, Bennett RM, Crofford LJ, et al. Diagnostic criteria for AAPT fibromyalgia. j Pain. 2019;20(6):611–628
Abstract #15 Submission ID#1304186
A Systematic Chemical Design Strategy Leads to NTM-004/005, an Acetaminophen Structural Analog with Minimal Liver Histopathology
Robert B. Raffa, PhDa, John Carson, PhDb, Kenneth Carson, PhDc, Joseph Pergolizzi, Jr, MDd
aProf Emeritus; Adjunct; CSO: Co-founder; Sci AdBoard, Temple Univ; Univ AZ; Neumentum; Enalare; Advantx; bCo-founder, VP Chemistry, CaRafe Drug Innovation; cCEO, CaRafe Drug Innovation; dCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other
Learning Objectives
Upon completion, participant will be able to describe the major AE of acetaminophen (paracetamol).
Upon completion, participant will be able to explain the strategy used in the study.
Upon completion, participant will be able to describe the results of the study and the clinical implications.
Purpose
In accidental or intentional overdose acetaminophen (paracetamol) is metabolized by cytochrome P450 isozymes (mainly 2E1, 1A2, 3A4, and 2A6) to generate sufficient amounts of the reactive metabolite N-acetyl-p-benzoquinone imine to covalently bind to cysteine groups on proteins and produce hepatotoxicity. Separation between the therapeutic and toxic effects is a desirable goal. Unfortunately, standard drug discovery strategies to date have not been successful when applied to finding efficacious analogs of acetaminophen that have reduced hepatotoxicity, because the mechanism of action of acetaminophen is not known. Therefore, strategies such as recombinant protein expression, assay development, High-Throughput Screening (HTS), and structure-based drug discovery have thus far not led to the elucidation of a molecular target for acetaminophen. Our hypothesis is that, by using knowledge of the mechanism of toxicity of acetaminophen, and through iterative chemical modification and synthesis of analogs, that an agent with significantly less hepatotoxicity compared to acetaminophen can be developed.
Methods
We sought to undertake development of a systematic chemical design strategy that results in modification of the structure of acetaminophen that was predicted to result in the maintenance of antinociceptive efficacy, but with dramatic decrease in in vivo measures of hepatotoxicity. The design process undertaken was to test substituted, cyclized analogs of acetaminophen that were predicted to be less prone to producing reactive quinone intermediates. A U.S. Patent (#10,537,552, 2020) has been issued that covers this work. The chemical entity 5-hydroxyoxindole, which differs from acetaminophen by a single chemical bond was identified and in preliminary studies showed antinociceptive activity in the mouse acetic acid induced abdominal constriction behavior test. Subsequently, a series of analogs (currently numbering around 50) were synthesized and tested by standard techniques for antinociceptive efficacy and safety (hepatotoxicity).
Results
Our hypothesis, that by using knowledge of the mechanism of toxicity of the widely used pain reliever acetaminophen, and through iterative chemical modification and synthesis of analogs, that a compound with a superior therapeutic index compared to acetaminophen can be developed, was confirmed. The lead compound JC-29 was shown to be effective in a standard pain model and demonstrated an apparent significant safety advantage over acetaminophen when assessed for liver toxicity.
Conclusion
A systematic chemical design strategy was developed that results in modifications of the template structure of acetaminophen that, in selective compounds, results in maintenance of antinociception, but a significant decrease in in vivo measure of hepatotoxicity. NTM-004/005 currently is undergoing testing for development as a substitute for acetaminophen for a variety of therapeutic uses.
Abstract #16 Submission ID#1304194
ADV-484, a Novel Selective Inhibitor of alpha2delta-1 for the Treatment of Neuropathic Pain
Robert B. Raffa, PhDa, Carmen Almansa, PhDb, Antonio Guzmán, PhDc, Manuel Merlos, PhDd, Joseph Pergolizzi, Jr, MDe, José Miguel Vela, PhDf
aProf Emeritus; Adjunct; CSO: Co-founder; Sci AdBoard, Temple Univ; Univ AZ; Neumentum; Enalare; Advantx; bHead of Chemistry, Welab Barcelona; cHead of ADME-TOX, Welab BarcelonadHead of Pharmacology, Welab Barcelona; eCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other; fCSO, Welab Barcelona
Learning Objectives
Upon completion, participant will be able to describe what alpha2delta-1 is.
Upon completion, participant will be able to describe the relation of alpha2delta-1 to neuropathic pain.
Upon completion, participant will be able to describe the efficacy and safety profile of ADV-484.
Purpose
α2δ-1 is an auxiliary protein that, like the σ1 receptor (sigma-1 R), interacts with the NMDA subtype of glutamate receptor. It is one subunit of an alternatively-spliced proprotein transcript variant that encodes multiple isoforms linked by a disulfide bond. Importantly, α2δ-1 is expressed in the dorsal root ganglia (DRG) and dorsal horn of the spinal cord, and the α2δ-1-NMDAR heteromeric complex is greatly upregulated at both sites in neuropathic pain. a2d-1 is generally known as a voltage-activated Ca2+ channel subunit, but it was shown by Chen et al. (2018) that Cacna2d1 (the gene that encodes for α2δ-1) overexpression potentiates pre- and postsynaptic NMDAR activity of spinal dorsal horn neurons to augment pain hypersensitivity. Thus, α2δ-1 is an NMDAR-interacting protein that increases NMDAR synaptic delivery that occurs in neuropathic pain. Gabapentinoids (e.g. gabapentin, pregabalin) non-selectively bind to both α2δ subunits, α2δ-1 and α2δ-2. The blocking of α2δ-1, which is abundantly expressed in excitatory (glutamatergic) synapsis, results in inhibition of excitatory input in pain pathways. In contrast, the α2δ-2 subunit is abundant in inhibitory (GABAergic) neurons located in cerebellum (Purkinje cells) and other brain regions, thus its pharmacological blockade by gabapentinoids is undesirable, because it results in inhibition of inhibitory synapses––that is, disinhibition––and disengagement of pain inhibitory mechanisms, plus motor incoordination secondary to inhibition of GABAergic cerebellar Purkinje neurons. In contrast, ADV-484 is a novel potent and highly selective inhibitor of α2δ-1, devoid of significant activity on α2δ-2. It was identified as part of a large discovery program aimed at identifying mechanisms to overcome shortcomings of existing analgesic classes.
Methods
A drug discovery program was undertaken to identify a non-aminoacidic selective a2d-1 blocker which led to the discovery of ADV-484. In vitro receptor binding affinity for α2δ-1 and α2δ-2, as well as for other targets was measured by using radiometric techniques. Other in vitro investigations included metabolic stability in both microsomes and cryopreserved hepatocytes from several species, permeability in Caco2 cells, plasma protein and brain tissue binding, cytochrome inhibition/induction, and several safety-related tests including hERG inhibition. Its in vivo efficacy (neuropathic pain-related capsaicin model) and safety profile (rotarod, Irwin test, acute oral toxicity and in vivo genotoxicity) were investigated in mice and its pharmacokinetics were investigated in both mice and rats.
Results
ADV-484 is a non-aminoacidic small molecule with adequate physicochemical profile, good lipophilicity (LogP 2.9; LogD7.4 1.2) and solubility (kinetic and thermodynamic solubility in the mM range). The compound is a chiral piperazinylquinazolin-4-(3 H)-one derivative that can be prepared using a 6-step enantioselective route.
ADV-484 displayed high binding affinity (Ki = 27 nM) for a2d-1 and was highly selective. Affinity was at least 2 orders of magnitude higher than for other binding sites measured, including a2d-2 (Ki = 7694 nM; 285x selective vs α2δ-1) and sigma-1 R and sigma-2 R. In contrast, pregabalin showed similar affinity for both targets (a2d-1 Ki = 19 nM; a2d-2 Ki = 42 nM).
ADV-484 was tested in animal models relevant to neuropathic pain. It was active by the oral route (40 mg/kg) as well as the i.p. route (20 mg/kg), to an extent comparable or superior to pregabalin . A stark difference from pregabalin was that at equianalgesic doses pregabalin produced profound motor discoordination (Rotarod test), whereas ADV-484 was essentially devoid of an effect on motor coordination, and no effect on the safety observational battery in the Irwin behavioral screen at doses higher than those producing analgesia.
ADV-484 had a suitable PK profile with high oral bioavailability. Based on in vitro data, it has high metabolic stability in human liver microsomes and hepatocytes, and it should have low hepatic clearance in humans, good oral absorption, and large volume of distribution. Interestingly, it has good brain penetration with a brain-to-plasma AUC ratio of 1.26, significantly exceeding that of pregabalin. ADV-484 displays low potential for CYP450 inhibition-based drug-drug interactions.
There was no alert for cytotoxicity, mutagenesis, hERG blockade, or in vivo genotoxicity (mice). The maximum non-lethal dose in mice (1,000 mg/kg) far exceeds the active dose levels.
Conclusion
ADV-484 shows highly selective affinity for α2δ-1 that results in potent analgesic activity in animal models of chronic/neuropathic pain comparable to pregabalin after oral or i.p. administration. The analgesic effect of ADV-484 is not accompanied by negative behavioral markers in the Irwin test (mice) and is virtually devoid of the motor discoordination (mice) so characteristic of pregabalin even at analgesic doses. The good efficacy results that were obtained, along with the minimal pregabalin-like AEs observed, suggest that inhibition of α2δ-1 with a highly selective compound such as ADV-484 is a superior mechanistic approach for treatment of neuropathic pain. Continued investigation of the efficacy and safety of ADV-484 is underway to determine suitability for advancement to clinical trials.
References
Chen et al. (2018) Cell Reports 22(9):2307–2321.
Abstract #17 Submission ID#1304265 ADV-502
Novel Dual Sigma-1 Receptor Antagonist and Mu-Opioid Receptor Agonist for the Treatment of Pain: I. Discovery and Preclinical Evaluation
Robert B. Raffa, PhDa, Carmen Almansa, PhDb, Antonio Guzmán, PhDc, Manuel Merlos, PhDd, Joseph Pergolizzi, Jr, MDe, José Miguel Vela, PhDf
aProf Emeritus; Adjunct; CSO: Co-founder; Sci AdBoard, Temple Univ; Univ AZ; Neumentum; Enalare; Advantx; bHead of Chemistry, Welab Barcelona; cHead of ADME-TOX, Welab Barcelona; dHead of Pharmacology, Welab Barcelona; eCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other; fCSO, Welab Barcelona
Learning Objectives
Upon completion, participant will be able to explain the rationale for a novel analgesic.
Upon completion, participant will be able to describe the dual mechanism of action of ADV-502.
Upon completion, participant will be able to summarize the efficacy and safety of ADV-502 in animal models.
Purpose
As a new strategy to address the shortcomings of existing analgesic classes, a search for compounds of dual action at both the µ-opioid receptor (MOR) and the σ1 receptor (sigma-1 R) was undertaken (García et al., 2020). The rationale for seeking this particular dual action was based on the role of sigma-1 R in inhibiting augmented excitability (hyperalgesia) and activity-induced plastic changes (central sensitization) secondary to sustained afferent input in chronic pain conditions (both phenomena for which opioids are generally less effective), and the fact that sigma-1 R agonists have been reported to inhibit––and sigma-1 R antagonists to potentiate––opioid-induced analgesia (Romero et al., 2016). Potentiation of opioid analgesia but not of opioid-related adverse events by sigma-1 R blocking results in an improved safety compared to opioid monotherapy at equianalgesia (Vidal-Torres et al., 2013).
Methods
A drug discovery program was undertaken to identify a dual, bispecific drug with sigma-1 R and MOR activities using a pharmacophore merging approach, i.e. combination of the two target pharmacophores MOR and sigma-1 R in the same central core, which led to the discovery of ADV-502 through multiparameter optimization. Its chemical synthesis, in vitro receptor binding affinity and functionality, and in vitro and in vivo ADME profile were investigated. Specifically, ADV-502 in vivo efficacy and safety profile was compared with those of strong opioids.
Results
The pharmacophore-merging approach discovery process led to the identification of a lead series of 4-aryl-1-oxa-4,9-diazaspiro[5.5]-undecane derivatives. ADV-502 (EST73502//WLB-73502) emerged as an optimal candidate for the treatment of pain with the correct affinity and functionality for the primary targets. It is a bispecific, dual MOR and sigma-1 R ligand, selective against a panel of other 180 molecular targets (receptors, transporters, ion channels, and enzymes). Its receptor binding affinity (Ki) at human MOR and sigma-1 R are 64 nM and 118 nM, respectively. ADV-502 is an antagonist at the sigma-1 R and behaves as a partial MOR agonist at the G-protein pathway, with no/insignificant β-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signaling pathways.
In vivo testing revealed that, despite its partial MOR agonism, ADV-502 exerts full antinociceptive efficacy in several pain models in rodents, including acute nociceptive pain in the paw-pressure test (Randall-Selitto) and tail-flick test; visceral pain (both pain response and referred hyperalgesia); inflammatory (carrageenan); postoperative (paw incision): osteoarthritis (MIA knee injection); and neuropathic pain (partial sciatic nerve ligation and spared nerve injury). Potency of ADV-502 was superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, but superior to both morphine and oxycodone against neuropathic pain.
ADV-502 displays a good PK profile and low potential for DDIs (CYP interaction). Contrary to opioid comparators, ADV-502 exhibits reduced respiratory depression and GI (constipation and nausea and vomiting) MOR-related AEs, low physical dependence, and a safety profile (e.g. Irwin behavioral screen, acute and repeated-dose toxicology, genotoxicity, hERG (HEK cells) that supported its advancement to a Phase-1 clinical trial) [see the accompanying poster].
Conclusion
ADV-502 benefits from its bivalent sigma-1 R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy. ADV-502 shows potent analgesic activity comparable to the MOR agonist oxycodone in animal models of nociceptive, inflammatory and osteoarthritis pain, but superior to oxycodone against neuropathic pain. ADV-502 produced analgesic activity with reduced opioid-induced relevant adverse events (less inhibition of intestinal transit and respiratory depression at analgesic doses), and less naloxone-precipitated behavioral signs of opioid withdrawal. These results provide evidence that dual MOR agonism and sigma-1 R antagonism may be a useful strategy for obtaining potent and safer analgesics, and they were the basis for the selection of ADV-502 as a clinical candidate for the treatment of pain [see accompanying poster].
References
[1] García et al. (2020) J Med Chem 63:15,508–26. Vidal-Torres et al. (2013) Eur J Pharmacol 711:63–72. Romero et al. (2016). Adv Pharmacol 75:179–215.
Abstract #18 Submission ID#1304268
ADV-502, a Novel Dual Sigma-1 Receptor Antagonist and Mu-Opioid Receptor Agonist for the Treatment of Pain: II. Tolerance and Opioid-Induced Hyperalgesia
Robert B. Raffa, PhDa, Manuel Merlos, PhDb, Daniel Zamanillo, PhDc, Joseph Pergolizzi, Jr, MDd, José Miguel Vela, PhDe, Alba Vidal-Torres, PhDf
aProf Emeritus; Adjunct; CSO: Co-founder; Sci AdBoard, Temple Univ; Univ AZ; Neumentum; Enalare; Advantx; bHead of Pharmacology, Welab Barcelona; cHead, in vivo Pharmacology, Welab Barcelona; dCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other; eCSO, Welab Barcelona; fSenior Researcher, In Vivo Efficacy, WeLab Barcelona
Learning Objectives
Upon completion, participant will be able to explain the purpose for conducting the studies.
Upon completion, participant will be able to describe the two major ‘take-home’ messages.
Upon completion, participant will be able to explain the clinical translational value of the results.
Purpose
Pharmacological activation of opioid receptors, particularly the µ-opioid receptor (MOR), is one of the main options for the treatment of moderate-to-severe pain. However, the use of opioids is associated with a wide range of side effects as well as opioid-induced tolerance and hyperalgesia, that result in a diminished effectiveness, potentially leading to the use of higher doses that increase the abuse potential and over-dose risk. If tolerance develops, drug potency decreases. If opioid-induced hyperalgesia (OIH) is expressed, pain sensitivity increases. Thus, tolerance and OIH are pharmacologically distinct phenomena, but both tolerance and OIH become apparent as an increased requirement of opioid dose to keep pain controlled. ADV-502 (EST73502, WLB-73502, is a bispecific, dual µ-opioid receptor (MOR) partial agonist and σ1 receptor (S1R) antagonist, selective against a panel of other 180 molecular targets (receptors, transporters, ion channels, and enzymes) (García et al., 2013). Potentiation of opioid analgesia but not of opioid-related adverse events (AEs) by S1R blocking results in an improved efficacy of ADV-502 and reduced AEs compared to opioid monotherapy [see accompanying poster]. Here we investigated the development of tolerance and hyperalgesia following administration of ADV-502 in comparison with strong opioids.
Methods
The efficacy over time and thus eventual development of pharmacodynamic tolerance was investigated following repeated administration of ADV-502 and opioid comparators in a rat model of osteoarthritis (OA) pain induced by intraarticular knee injection of monoiodoacetate (MIA) and in a rat model of bone cancer pain induced by injecting MRMT-1 rat mammary gland carcinoma cells into the intramedullar cavity of the proximal tibia. Mechanical allodynia was assessed using von Frey filaments. The presence and duration of OIH was assessed following acute administration of compounds.
Results
Systemic b.i.d. administration of SDV-502 induced a dose-dependent reduction of MIA-induced mechanical hypersensitivity. The effect of ADV-502 remained unchanged throughout the 28-d treatment period, with a slight tendency to increase efficacy over time, thus suggesting absence of tolerance to its analgesic effect after 4 weeks of repeated administration. Although morphine and oxycodone also reduced mechanical hypersensitivity, their antinociceptive effect diminished progressively throughout the treatment period (i.e. pharmacodynamic tolerance developed), the effect being almost completely lost after 3 weeks of treatment. Similar results were obtained in the bone cancer pain model: the antinociceptive effect of ADV-502 remained unchanged after daily administration for 14 days, whereas the effect of morphine did not.
With regards to OIH, single administration of fentanyl induced OIH lasting for several days. The OIH was blocked when fentanyl was co-administered with naloxone (MOR antagonist) or with S1RA, a selective S1R antagonist, indicating that OIH involves MOR activation and that S1R blocking prevents OIH. In contrast to fentanyl and other MOR agonists, including the biased MOR agonist TRV-130, all of which induced long-lasting OIH, administration of ADV-502 did not induce OIH. Interestingly, co-administration of ADV-502 with the pure S1R agonist PRE-084 did result in OIH, indicating that the bispecific ability of ADV-502 to antagonize S1R is a key distinctive mechanism to counteract MOR agonist-mediated OIH.
Conclusion
ADV-502 is a bispecific S1R antagonist/MOR partial agonist that demonstrates antinociceptive potency and efficacy comparable to, or better than (in neuropathic pain models), mono-mechanistic full MOR agonists, but unlike such drugs ADV-502 does not induce tolerance or OIH at antinociceptive doses. These results provide further evidence that dual MOR agonism and S1R antagonism may be a useful strategy for obtaining potent and safer analgesics, and they were the basis for the selection of ADV-502 as a clinical candidate for the treatment of pain [see accompanying poster].
References
[1] García et al. (2020) J Med Chem 63:15,508–26.
Abstract #19 Submission ID#1304909
At-Home Virtual Reality Program for Chronic Low Back Pain: Durability of a Randomized, Placebo-Controlled Trial to 18-months Post-Treatment
Todd Maddox, PhDa, Heidy Garcia, Esqb, Kelsey Ffrench Maddox, MSc, Roselani Maddox, BSd, Partha Krishnamurthy, PhDe, David Okhotin, MDf, Charisse Sparks, MDg, Liesl Oldstone, PhDh, Laura Garcia, PhDi, Brandon Birckhead, MDj, Josh Sackman, MBAk, Ian Mackey, BAl, Robert Louis, MDm, Vafi Salmasi, MDn, Alexis Oyao, BSo, Beth Darnall, PhDp
aVP of Research, AppliedVR; bResearch Associate, AppliedVR; cResearch Associate, AppliedVR; dResearch Associate, AppliedVR; eProfessor, University of Houston; fMedical Director, AppliedVR; gChief Medical Officer, AppliedVR; hVP of Market Access, AppliedVR; iDirector of Research, AppliedVR; jConsultant, AppliedVR; kPresident, AppliedVR; lResearch Associate, AppliedVR; mAdvisor, Hoag Hospital; nClinical Instructor, Stanford University; oResearch Associate, AppliedVR; pProfessor, Stanford University
Learning Objectives
Describe the procedure for a randomized controlled trial that examines RelieVRx, a virtual reality based chronic pain treatment.
Describe the usability and engagement associated with RelieVRx, a virtual reality based chronic pain treatment.
Describe the efficacy associated with RelieVRx, a virtual reality based chronic pain treatment, at the end of the 8 week treatment and out to 18 months post treatment.
Purpose
Chronic low back pain (CLBP) is the most prevalent chronic pain condition worldwide.1 CLBP can be disabling, costly, and confer suffering to individuals and their families. The incidence and prevalence of CLBP continue to rise despite the increasing use of pharmacological and surgical interventions.2 Pain education and cognitive behavioral therapy (CBT) are recommended as first line treatments for CLBP.3 CBT for chronic pain engages participants in active pain and symptom self-management,4,5,6 sometimes on 1-on-1 sessions and sometimes in group settings, and typically involving 8–12 two-hour treatment sessions (16–24 hours total treatment time). Although CBT is generally effective, access to care remains poor due to barriers such as few trained and available local therapists, health insurance limits, and burdens associated with travel, scheduling, and treatment time.7 There is an urgent need for effective, accessible treatments for the many people who suffer from back pain. On-demand digital therapeutics provide home-based access to pain education and skills-based pain self-management.
A recent surge of pain mitigation solutions have been developed that utilize virtual reality (VR) headsets. VR provides a unique environment comprising three-dimensional (3D) visually immersive experiences enriched with sounds, colors and scenic environments that facilitate the enhancement and activation of the central nervous system. VR broadly engages multiple pain and learning centers in the brain in synchrony. This has the potential to speed the development of behavioral skills and habits known to be effective at mitigating pain.
The purpose of the present study is to test the durability of the pain reduction to 18-months post treatment for AppliedVR’s RelieVRx solution, an 8-week, self-administered at-home behavioral skills-based therapeutic VR solution for chronic low back pain. RelieVRx includes VR modules that incorporate principles and elements drawn from CBT, mindfulness and acceptance-based treatments for chronic pain. RelieVRx was compared with an active control that utilized non-immersive VR. We conducted a placebo-controlled RCT in community-based individuals with CLBP assigned to receive therapeutic VR (RelieVRx) or Sham VR8. and found superior outcomes for RelieVRx for all baseline to post-treatment comparisons. In this study we examine durability of effect to 18-months post-treatment.
Methods
A national online convenience sample of individuals with self-reported nonmalignant low back pain ≥ 6 months duration and with average pain intensity ≥ 4/10 were enrolled and randomized 1:1 to one of two daily (56-day) VR programs: (1) RelieVRx (immersive pain relief skills VR program); or (2) Sham VR (2D nature content delivered in a VR headset).
RelieVRx is an immersive multi-modal, skills-based, pain self-management VR program that incorporates evidence-based principles of CBT, mindfulness, and pain neuroscience education. RelieVRx combines biopsychosocial education, diaphragmatic breathing training, relaxation response exercises that activate the parasympathetic nervous system, and executive functioning games to provide a mind-body approach toward pain relief. The standardized 56-day program delivers a multifaceted combination of pain relief skills training through a prescribed sequence of daily immersive experiences. Each VR experience is 2–16 minutes in length (average of 6 minutes). The VR treatment modules were designed to minimize triggers of emotional distress or cybersickness. In compliance with Virtual Reality Clinical Outcomes Research Experts (VR-CORE) clinical trial guidelines, we selected an active control that utilizes non-immersive, two-dimensional (2D) content within a VR headset as the most rigorous VR placebo.9 The Sham VR headset displayed 2D nature footage (e.g. wildlife in the savannah) with neutral music selected to be neither overly relaxing, aversive nor distracting. The experience of Sham VR is similar to viewing nature scenes on a large screen television and is not interactive. Experiences varied in length from 1:42 to 6:30 minutes.
Self-reported data were collected at pre-treatment, twice a week during the treatment, and immediately at the end of treatment. Durability of the pain treatment effect was evaluated by collecting data on pain intensity and pain-related interference with activity, stress, mood, and sleep at 1, 2, 3, 6, and 18 months post-intervention. Results for the end of treatment, 1, 2, and 3 month durability, and 6-month durability are available in these three peer-reviewed publications.10,11,12
Results
The study sample was 188 adults (female: 77%; Caucasian: 91%; at least some college education: 92%; mean age: 51.5 years, SD = 13.1; average pain intensity: 5/10, SD = 1.2; back pain duration ≥5 years: 67%). No group differences were found for any baseline variable or treatment engagement. At the end of treatment (EoT) relative to pre-treatment, and at 6 months post-treatment relative to pre-treatment, clinically meaningful reductions (i.e. those 30% or greater) in pain intensity (EoT = 42%; 6 mo = 31%), as well as pain interference with activity (EoT = 49%; 5 mo = 35%), sleep (EoT = 52%; 6 mo = 45%), mood (EoT = 56%; 6 mo = 39%), and stress (EoT = 57%; 6 mo = 43%) were observed for the RelieVRx group. These pain reductions were significantly larger than those observed in the Sham VR group for all metrics at both EoT and 6 months post-treatment (all p’s < .05).
At 18-month post-treatment relative to pre-treatment, clinically meaningful reductions in pain interference with activity (42%), sleep (38%), mood (47%), and stress (48%) were observed for the RelieVRx group. Only pain intensity (26%) did not reach the 30% threshold. These pain reductions were significantly larger than those observed in the Sham VR group for pain intensity and pain interference with activity and stress (p’s < .05).
To determine whether participants with 30%+ pain reductions at EoT showed durability at 6 or 18 months post-treatment, we computed the percentage of participants who achieved 30%+ reductions at EoT and 6 months post-treatment and the percentage of participants who achieved 30%+ reductions at EoT and 18 months post-treatment. We compared these percentages with those for participants who did not achieve 30% reductions at EoT and 6 months post-treatment and who did not achieve 30% reductions at EoT and 18 months post-treatment.
First, for RelieVRx, nearly half (45%) of participants showed 30%+ pain reductions that were durable to 6 months, whereas only 20% of Sham participants showed the same pattern. For RelieVRx, only 20% of participants do not show 30%+ pain reductions at both EoT and 6 mo, whereas 54% of Sham participants showed this pattern.
Second, for RelieVRx, 1/3rd (33%) of participants showed 30%+ pain reductions that were durable to 18 months, whereas only 6% of Sham participants showed the same pattern. For RelieVRx, only 32% of participants do not show 30%+ pain reductions at both EoT and 18 mo, whereas nearly half (48%) of Sham participants showed this pattern.
Conclusion
The observed benefit of RelieVRx at 6 months post-treatment in pain-related interference with activity, sleep, mood, and stress persisted at 18 months post-treatment. Only the reduction in pain intensity at 18 months did not persist at the clinically meaningful extent of at least 30% reduction. In addition, nearly half of RelieVRx participants showed clinically meaningful pain intensity reductions at both EoT and 6 months post-treatment, and 1/3rd of RelieVRx participants showed clinically meaningful pain intensity reductions at both EoT and 18 months post-treatment. Clinical outcomes suggest that RelieVRx helps patients develop behavioral skills and habits that are applied outside of the headset. Home-based RelieVRx is an effective, on-demand non-pharmacologic treatment for chronic low back pain with sustained durability of benefits for up to a year and a half after treatment. Future research could investigate whether a booster regimen of RelieVRx may expand the degree and duration of benefit of this novel FDA-authorized treatment for chronic low back pain.
References
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[2] Freburger JK, Holmes GM, Agans RP, Jackman AM, Darter JD, Wallace AS, et al. The rising prevalence of chronic lowback pain. Arch Intern Med 9 February 2009;169(3):251–258 [FREE Full text] [Medline:19,204,216].
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[5] Turner JA, Anderson ML, Balderson BH, Cook AJ, Sherman KJ, Cherkin DC. Mindfulness-based stress reduction andcognitive behavioral therapy for chronic low back pain: similar effects on mindfulness, catastrophizing, self-efficacy, and acceptance in a randomized controlled trial. Pain 30 November 2016;157(11):2434–2444 [FREE Full text] [doi:10.1097/j.pain.0000000000000635] [Medline: 27,257,859]
[6] Cherkin DC, Sherman KJ, Balderson BH, Cook AJ, Anderson ML, Hawkes RJ, et al. Effect of Mindfulness-Based StressReduction vs Cognitive Behavioral Therapy or Usual Care on Back Pain and Functional Limitations in Adults With ChronicLow Back Pain: A Randomized Clinical Trial. JAMA [cited 22 March 2016] Available from: 315(12):1240–1249 [Medline: 27,002,445]
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[8] Garcia LM, Darnall BD, Krishnamurthy P, Mackey IM, Sackman J, Louis R, et al. Self-Administered Behavioral Skills-BasedAt-Home Virtual Reality Therapy for Chronic Low Back Pain: Protocol for a Randomized Controlled Trial. JMIR ResProtoc 19 January 2021;10(1):e25291 [FREE Full text]
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[10] Garcia L, Birckhead B, Krishnamurthy P, Sackman J, Mackey I, Louis R, Salmasi V, Maddox T, Darnall B An 8-Week Self-Administered At-Home Behavioral Skills-Based Virtual Reality Program for Chronic Low Back Pain: Double-Blind, Randomized, Placebo-Controlled Trial Conducted During COVID-19 J Med Internet Res 2021;23(2):e26292 URL: https://www.jmir.org/2021/2/e26292 DOI: 10.2196/26,292.
[11] Garcia L, Birckhead B, Krishnamurthy P, Sackman J, Mackey I, Louis R, Salmasi V, Maddox T, Darnall B Three-month follow-up results of a double-blind, randomized placebo-controlled trial of 8-week self-administered at-home behavioral skills-based virtual reality (VR) for chronic low back pain. Journal of Pain, 23(5), 822–840.
[12] Garcia L, Birckhead B, Krishnamurthy P, Mackey I, Sackman J, Salmasi V, Louis R, Castro C, Maddox R, Maddox T, Darnall B Durability of the Treatment Effects of an 8-Week Self-administered Home-Based Virtual Reality Program for Chronic Low Back Pain: 6-Month Follow-up Study of a Randomized Clinical Trial J Med Internet Res 2022;24(5):e37480 URL: https://www.jmir.org/2022/5/e37480 DOI: 10.2196/37,480
Abstract #20 Submission ID#1305160
Exploratory Efficacy of INP104 in Migraine Patients by Prior Treatment
Tanya Bilchik, MD, FAHSa, Robert Vann, PhDb, Brett Downing, MEngc, Sutapa Ray, PhDd, Stephen B. Shrewsbury, MDe, Sheena Aurora, MDf
aAssistant Professor of Clinical Neurology, Yale University School of Medicine; bDirector, Medical Science Liaison, Impel Pharmaceuticals; cMedical Science Liaison, Impel Pharmaceuticals; dInternal Science Liaison, Impel Pharmaceuticals; eChief Medical Officer, Impel Pharmaceuticals; fVice President, Medical Affairs – Migraine, Impel Pharmaceuticals
Learning Objectives
To learn about INP104, a drug-device combination product that delivers dihydroergotamine mesylate to the upper nasal space using Precision Olfactory Delivery (POD®) technology, for the acute treatment of migraine
To learn about the exploratory efficacy of INP104 as an acute treatment for migraine over 24 weeks of treatment based on prior acute treatment history
To learn that INP104 may be an effective acute treatment option for migraine irrespective of prior acute medication used, including the commonly prescribed triptans
Purpose
Despite the availability of multiple acute treatment options for migraine, patient dissatisfaction persists as an unmet need. INP104 is a drug-device combination product that delivers dihydroergotamine mesylate to the upper nasal space using Precision Olfactory Delivery (POD®) technology and is approved for the acute treatment of migraine. Previously presented self-reported exploratory efficacy data for INP104 demonstrated that during Weeks 1–12 and Weeks 13–24, 39% and 35% of migraine attacks treated with INP104 were pain-free, and 55% and 51% were most bothersome symptom (MBS)–free at 2 hours, respectively. The objective of this post hoc analysis was to report the exploratory efficacy of INP104 over 24 weeks of treatment based on acute medications used before INP104 treatment, to determine if the efficacy of INP104 is predicated by prior acute treatment history.
Methods
STOP 301 was a pivotal phase 3, interventional, open-label, single-group assignment study that assessed the safety, tolerability, and exploratory efficacy of INP104. Patients were on their best usual care during a 28-day screening period (ie, baseline). Inclusion criteria included adult migraine patients with or without aura not qualifying as chronic migraine; having ≥2 migraine attacks per month for the previous 6 months and during the 28-day screening period; and being in general good health with no history of cardiovascular risk factors or diseases. Eligible patients continued into a 24-week treatment period and were provided with INP104 to nasally self-administer (1.45 mg in 2 sprays) with self-recognized migraine attacks. eDiaries were used to collect information, both daily and with every headache or migraine, on medication used and pain or MBS severity. This post hoc analysis assessed exploratory efficacy end points of self-reported pain and MBS freedom 2 hours post-INP104 administration based on acute therapies used before study initiation. Acute medications during the screening period included acetaminophen, barbiturates, combination analgesics, other ergotamine products, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, other medications, and triptans. STOP 301 was performed before the launch of gepants and ditans, and patients were included in a screening medication group if they used the medication during the 28-day screening period, so patients and their migraine attacks were counted in more than 1 group.
Results
In total, 354 patients self-administered ≥1 dose of INP104 over 24 weeks and were included in this analysis. Most patients used acetaminophen (n = 163), NSAIDs (n = 139), other medications (n = 121), and triptans (n = 101), followed by combination analgesics (n = 57), opioids (n = 9), barbiturates (n = 6), and other ergotamine products (n = 3) during the 28-day screening period. During Weeks 1–12 and Weeks 13–24, migraine attacks self-reported as pain-free at 2 hours were 37% and 37% among acetaminophen users, 29% and 11% among barbiturate users, 41% and 31% among combination analgesics users, 90% and 50% among other ergotamine users, 36% and 34% among NSAID users, 45% and 50% among opioid users, 39% and 36% among users of other medications, and 39% and 42% among triptan users, respectively. During Weeks 1–12 and Weeks 13–24, migraine attacks self-reported as MBS-free at 2 hours were 54% and 50% among acetaminophen users, 43% and 29% among barbiturate users, 57% and 44% among combination analgesics users, 90% and 50% among other ergotamine users, 53% and 53% among NSAID users, 55% and 66% among opioid users, 54% and 54% among users of other medications, and 55% and 59% among triptan users, respectively.
Conclusion
Pain and MBS freedom at 2 hours post-INP104 were similar at Weeks 1–12 and Weeks 13–24 for most prior acute treatment groups. Results suggest that INP104 may be an effective acute treatment option for migraine irrespective of prior acute medication, including triptans.
Abstract #21 Submission ID#1305281
Exploratory Efficacy of INP104 in Patients Using Concomitant Preventive Migraine Medications
Jihan Grant, MDa, Robert Vann, PhDb, Christopher Fitzpatrick, PhDc, Stephen B. Shrewsbury, MDd, Sheena Aurora, MDe
aDirector, Headache and Facial Pain Center, Headache and Facial Pain Center; bDepartment of Neurology, Icahn School of Medicine at Mount Sinai; cDirector, Medical Science Liaison, Impel Pharmaceuticals; dMedical Science Liaison, Impel Pharmaceuticals; eChief Medical Officer, Impel Pharmaceuticals, Vice President, Medical Affairs – Migraine, Impel Pharmaceuticals
Learning Objectives
To learn about INP104, a drug-device combination product that delivers dihydroergotamine mesylate to the upper nasal space using Precision Olfactory Delivery (POD®) technology, for the acute treatment of migraine.
To learn about the exploratory efficacy and safety of INP104 as an acute therapy for migraine in patients who concomitantly used migraine preventive medications over 24 weeks of treatment.
To learn that INP104 may be an effective and well-tolerated acute medication for migraine in patients who are concurrently using migraine preventive therapies.
Purpose
It is typical for migraine patients to concomitantly use acute and preventive therapies as part of their migraine management. INP104 is drug-device product of dihydroergotamine (DHE) mesylate and Precision Olfactory Delivery (POD®) approved for the acute treatment of migraine. The exploratory efficacy of INP104 has been assessed in a phase 3 study, but the impact of concomitant use of preventive migraine therapies on the exploratory efficacy and safety of INP104 has not been evaluated. The objective of this post hoc analysis was to investigate the exploratory efficacy and safety of INP104 in patients who did or did not use concomitant migraine preventive medications over 24 weeks of treatment.
Methods
STOP 301 was a phase 3, open-label study. Inclusion criteria included adult migraine patients with or without aura not qualifying as chronic migraine; having ≥2 migraine attacks per month for the previous 6 months and during the 28-day screening period; and being in general good health with no history of cardiovascular risk factors or diseases. Patients treated migraine attacks with their best usual care during a 28-day screening period, which was followed by a 24-week treatment period in which eligible patients self-administered INP104 (1.45 mg) for self-recognized migraine attacks. eDiaries were used to collect information, both daily and with every headache or migraine, on medication used and pain or most bothersome symptom (MBS) severity through 24 weeks. Concomitant (preventive) migraine medications were permitted during the study if stable (>30 days before screening) unless they were contraindicated for concomitant use with DHE mesylate. For this post hoc analysis, exploratory efficacy end points of self-reported pain and MBS freedom at 2 hours post-INP104 were evaluated based on concomitant preventive migraine medication groups used during the study: none, topiramate, erenumab, or other. Other included propranolol, propranolol hydrochloride, amitriptyline, onabotulinum toxin A, bupropion, Cannabis sativa, Curcuma longa, duloxetine hydrochloride, estradiol, gabapentin, ibuprofen, labetalol, lamotrigine, loratadine, magnesium, nadolol, nortriptyline, nortriptyline hydrochloride, paroxetine hydrochloride, timolol, valproate semisodium, and zonisamide. Patients who used >1 preventive medication were included under each applicable group; therefore, patients could be listed more than once. Safety outcomes based on concomitant preventive migraine medications used over 24 weeks were also evaluated.
Results
A total of 354 patients self-administered ≥1 dose of INP104 over 24 weeks and constituted the full safety set. For this post hoc analysis, 254, 31, 7, and 29 patients used none, topiramate, erenumab, or other migraine preventive medications concomitantly at Month 0 (i.e. baseline), respectively. For patients who used none, topiramate, erenumab, or other preventive medications concomitantly, the mean number of INP104-treated migraine attacks was 2.2 (n = 226), 2.0 (n = 20), 2.8 (n = 4), and 2.4 (n = 21) at Month 6 compared with 3.1 (n = 292), 3.0 (n = 32), 3.6 (n = 7), and 3.4 (n = 31) at Month 1, respectively. For patients who did not use concomitant preventive medications, self-reported pain and MBS freedom at 2 hours post-INP104 were 30.1% and 47.4% at baseline (n = 254) compared with 36.1% and 53.6% at Month 6 (n = 172), respectively. For patients who used topiramate concomitantly, self-reported pain and MBS freedom at 2 hours post-INP104 were 32.6% and 50.7% at baseline (n = 31) compared with 31.1% and 51.7% at Month 6 (n = 15), respectively. For patients who used erenumab concomitantly, self-reported pain and MBS freedom at 2 hours post-INP104 were 22.3% and 47.4% at baseline (n = 7) compared with 33.3% and 41.7% at Month 6 (n = 4), respectively. For patients who used other preventive medications concomitantly, self-reported pain and MBS freedom at 2 hours post-INP104 were 35.3% and 49.4% at baseline (n = 29) compared with 25.3% and 38.3% at Month 6 (n = 17), respectively. The incidence of treatment-emergent adverse events (TEAEs) was 73.6% (n = 215), 62.5% (n = 20), 42.9% (n = 3), and 71.0% (n = 22) for patients who used none, topiramate, erenumab, or other migraine preventive medications concomitantly over 24 weeks, respectively. The incidence of serious TEAEs was 2.1% (n = 6), 0% (n = 0), 14.3% (n = 1), and 0% (n = 0) for patients used none, topiramate, erenumab, or other migraine preventive medications concomitantly over 24 weeks, respectively. No serious TEAEs were considered related to INP104. The incidence of severe TEAEs was 4.5% (n = 13), 3.1% (n = 1), 14.3% (n = 1), and 0% (n = 0) for patients who used none, topiramate, erenumab, or other migraine preventive medications concomitantly over 24 weeks, respectively.
Conclusion
Over 24 weeks of treatment, the exploratory efficacy of INP104 demonstrated numerical improvements in self-reported pain and MBS freedom at 2 hours post-INP104 with most of the concomitant migraine preventive groups analyzed. Safety measures were similar in patients who did or did not use concomitant migraine preventive medications over the 24-week treatment period. Results from this post hoc analysis suggest that INP104 may be an effective and well-tolerated acute medication for migraine in patients who are concurrently using preventive therapies and need effective therapy for acute episodes of migraine despite being on prevention.
Abstract #22 Submission ID#1305286
Early Prediction of Response to INP104 for the Acute Treatment of Migraine
Sara Sacco, MD, FAHSa, Robert Vann, PhDb, Sutapa Ray, PhDc, Stephen B. Shrewsbury, MDd, Sheena Aurora, MDe
aPhysician, Carolinas Headache Clinic; bDirector, Medical Science Liaison, Impel Pharmaceuticals; cInternal Science Liaison, Impel Pharmaceuticals; dChief Medical Officer, Impel Pharmaceuticals; eVice President, Medical Affairs – Migraine, Impel Pharmaceuticals
Learning Objectives
To learn about INP104, a drug-device combination product that delivers dihydroergotamine mesylate to the upper nasal space using Precision Olfactory Delivery (POD®) technology, for the acute treatment of migraine
To learn that if INP104 provides pain relief for the first 2–3 migraine attacks, it is likely a patient will continue to be an INP104 responder with long-term use
To understand the importance of using predictive models of treatment response in clinical trials of acute therapies for migraine
Purpose
Understanding the early prediction of response to acute therapies for migraine may help patients and healthcare providers optimize the acute management of migraine. Predictive models have the potential to individualize choice of acute medication class for migraine attacks through a simple data-driven approach. However, future research needs to improve on predictive models and then prospectively explore if improvement in the selection of pharmacological treatment gained from such treatment-response predictors lets patients and clinicians confidently alter management plans. INP104 is an approved drug-device combination product that delivers dihydroergotamine mesylate to the upper nasal space using Precision Olfactory Delivery (POD®) technology. Previously reported data from the phase 3 STOP 301 study in migraine patients showed that INP104 was well tolerated and associated with improvements in several outcomes of exploratory efficacy for the first INP104-treated migraine attacks, as well as across multiple migraine attacks over 24 and 52 weeks of treatment. The objective of this post hoc analysis was to determine if early treatment response to INP104 could predict response over consecutive migraine attacks.
Methods
STOP 301 was a phase 3, open-label, single-group assignment study that assessed the safety, tolerability, and exploratory efficacy of INP104. Inclusion criteria included adult migraine patients with or without aura not qualifying as chronic migraine; having ≥2 migraine attacks per month for the previous 6 months and during the 28-day screening period; and being in general good health with no history of cardiovascular risk factors or diseases. The study comprised a 28-day screening period in which patients used their best usual care, a 24-week treatment period for all patients, a treatment extension to 52 weeks for a subset of the patients, and a 2-week post-treatment follow-up period for all patients. The percentage of patients who were overall ≥75% responders during Weeks 1–24 based on self-reported pain level after treatment for their first, first 2, and first 3 INP104-treated migraine attacks during Weeks 1–4 was evaluated. A ≥75% responder was defined as a patient who self-reported having at least three-quarters of their migraine attacks with mild or no pain 2 hours after INP104 over a given period. Pain levels included none, mild, moderate, or severe, and pain severity subgroups were based on the worst pain reported for a migraine attack during Weeks 1–4.
Results
A total of 360 patients were screened and enrolled into the 24-week treatment period, with 354 patients who self-administered ≥1 dose of INP104 over 24 weeks. This post hoc analysis included 188 patients who had ≥4 INP104-treated migraine attacks over 24 weeks. The ≥75% response rates for Weeks 1–24 were 72.9% (51/70), 87.2% (34/39), and 94.4% (17/18) for patients with pain of none at 2 hours post-INP104 for the first, first 2, and first 3 INP104-treated migraine attacks during Weeks 1–4, respectively. The ≥75% response rates for Weeks 1–24 were 69.2% (45/65), 75.4% (52/69), and 89.1% (41/46) for patients with pain of mild at 2 hours post-INP104 for the first, first 2, and first 3 INP104-treated migraine attacks during Weeks 1–4, respectively. The ≥75% response rates for Weeks 1–24 were 35.0% (14/40), 32.6% (14/43), and 33.3% (17/51) for patients with pain of moderate at 2 hours post-INP104 for the first, first 2, and first 3 INP104-treated migraine attacks during Weeks 1–4, respectively. The ≥75% response rates for Weeks 1–24 were 8.3% (1/12), 15.0% (3/20), and 27.8% (5/18) for patients with pain of severe at 2 hours post-INP104 for the first, first 2, and first 3 INP104-treated migraine attacks during Weeks 1–4, respectively.
Conclusion
Patients who self-report mild or no pain at 2 hours for their first 3 INP104-treated migraine attacks are extremely likely (>89%) to be a ≥ 75% responder over Weeks 1–24, and those with mild or no pain for their first 2 INP104-treated migraine attacks are likely (>75%) to be a ≥75% responder over Weeks 1–24. Results suggest that if INP104 provides pain relief for the first 2–3 migraine attacks, it is likely a patient will continue to be an INP104 responder with long-term use. This predictability of response should be able to help clinicians determine a treatment armamentarium for appropriate patients.
Abstract #23 Submission ID#1305304
Improvements in Productivity and Disability with INP104 as Assessed by the Migraine Disability Assessment Scale (MIDAS): Results from the Phase 3 STOP 301 Study
Christina Treppendahl, FNP-BC, AQH, MHDa, Dawn Buse, PhDb, Robert Vann, PhDc, Christopher Fitzpatrick, PhDd, Michelle Murphy, PhDe, Stephen B. Shrewsbury, MDf, Sheena Aurora, MDg
aFounder and Director, The Headache Center; bDepartment of Neurology, Albert Einstein College of Medicine; cDirector, Medical Science Liaison, Impel Pharmaceuticals; dMedical Science Liaison, Impel Pharmaceuticals; eMedical Science Liaison, Impel Pharmaceuticals; fChief Medical Officer, Impel Pharmaceuticals; gVice President, Medical Affairs – Migraine, Impel Pharmaceuticals
Learning Objectives
To learn about INP104, a drug-device combination product that delivers dihydroergotamine mesylate to the upper nasal space using Precision Olfactory Delivery (POD®) technology, for the acute treatment of migraine.
To learn about the impact of long-term INP104 treatment on migraine-associated disability by using the Migraine Disability Assessment Scale (MIDAS) questionnaire.
To learn that long-term INP104 use was associated with improvements in several MIDAS items of productivity and disability, which reduced overall patient burden over 24/52 weeks of treatment.
Purpose
Migraine is a highly prevalent, disabling disorder with significant patient burden. New and effective acute therapies that improve the migraine symptoms responsible for patient burden remains an unmet need. INP104 is a drug-device combination product of dihydroergotamine mesylate and Precision Olfactory Delivery (POD®) approved for the acute treatment of migraine. The safety, tolerability, and exploratory efficacy of long-term INP104 use was assessed in the phase 3 STOP 301 trial in migraine patients. As part of this study, migraine-associated disability was evaluated using the Migraine Disability Assessment Scale (MIDAS) questionnaire. Here, the scores are reported for each item of the MIDAS questionnaire following long-term treatment with INP104.
Methods
STOP 301 was a phase 3, open-label, 24-week safety and exploratory efficacy study with a 28-week extension period for a subset of patients. Inclusion criteria included adult migraine patients with or without aura not qualifying as chronic migraine; having ≥2 migraine attacks per month for the previous 6 months and during the 28-day screening period; and being in general good health with no history of cardiovascular risk factors or diseases. Following a 28-day screening period, during which patients treated migraine attacks with their best usual care, eligible patients received INP104 (1.45 mg) to self-administer nasally with self-recognized migraine attacks. The MIDAS questionnaire is a validated instrument measuring the headache-related disability affecting patients, with a grading system to categorize the degree of disability. The MIDAS questionnaire included 5 scored questions that measured the number of days in the past 3 months of limitations in daily activities at work, school, social, and leisure resulting from migraine. It was completed by patients during screening, at baseline, at Weeks 12 and 24, and if applicable, at Weeks 36 and 52. MIDAS total scores were determined based on the sum of questions 1–5 for all nonmissing data.
Results
Overall, 360 patients were screened and enrolled in the STOP 301 study, with 354 patients having self-administered ≥1 INP104 dose over 24 weeks. A total of 73 patients continued into the 52-week extension period. The MIDAS study population included 354, 283, 209, 69, and 65 patients for baseline, Week 12, Week 24, Week 36, and Week 52, respectively. The mean MIDAS total scores were 18.4, 17.4, 15.3, and 14.9 at Weeks 12, 24, 36, and 52, respectively, compared with 25.1 at baseline. The mean number of headache days in the past 3 months was 11.3, 10.1, 9.1, and 10.5 at Weeks 12, 24, 36, and 52, respectively, compared with 15.9 at baseline. The mean number of school or work days missed because of headache in the past 3 months was 1.7, 1.8, 1.5, and 1.7 at Weeks 12, 24, 36, and 52, respectively, compared with 2.4 at baseline. The mean number of school or workdays with productivity reduced by half because of headache in the past 3 months was 4.6, 3.9, 3.4, and 3.3 at Weeks 12, 24, 36, and 52, respectively, compared with 5.6 at baseline. The mean number of days of missed household work because of headache in the past 3 months was 5.2, 5.3, 4.2, and 4.4 at Weeks 12, 24, 36, and 52, respectively, compared with 7.2 at baseline. The mean number of days with productivity in household work reduced by half because of headache in the past 3 months was 4.5, 3.9, 3.5, and 3.1 at Weeks 12, 24, 36, and 52, respectively, compared with 6.5 at baseline. The mean number of days of missed family, social, or leisure activities because of headache in the past 3 months was 2.5, 2.6, 2.7, and 2.4 at Weeks 12, 24, 36, and 52, respectively, compared with 3.4 at baseline. On a scale of 1 to 10, mean headache pain intensity was 7.3, 7.0, 7.0, and 7.1 at Weeks 12, 24, 36, and 52, respectively, compared with 7.0 at baseline.
Conclusion
Long-term INP104 use was associated with improvements in scores of several individual MIDAS items of productivity and disability, as well as a decrease in the number of headache days over 24 and 52 weeks, leading to a reduction in overall patient burden.
Abstract #24 Submission ID#1305509
Opioid Prescription Dispensing Patterns Among Patients With Schizophrenia or Bipolar Disorder
Brittany D. Roy, MPHa, Jianheng Li, MPH, MBBSb, Cathy Lally, MSPHc, Sarah C. Akerma, MDd, Alkermes, Inc., Waltham, MA, USA, Maria A. Sullivan, MD, PhDe, James Fratantonio, PharmDf, W. Dana Flanders, MD, DSc, MPH, MAg, Made Wenten, PhD, MPHh
aManager, Epidemiology – Drug Safety & Pharmacovigilance, Alkermes, Inc., Waltham, MA, USA; bEpidemiologist, Epidemiologic Research & Methods, LLC, Southport, NC, USA; cSenior Epidemiologist/Data Analyst, Epidemiologic Research & Methods, LLC, Southport, NC, USA; dExecutive Medical Director, Alkermes, Inc., Waltham, MA, USA; eAssociate Professor of Clinical Psychiatry, Alkermes, Inc., Waltham MA, USA; Columbia University, New York, NY, USA; fMedical Director, Alkermes, Inc., Waltham, MA, USA; gProfessor, Epidemiologic Research & Methods, LLC, Southport, NC, USA; hSr Dir, Drug Safety & Pharmacovigilance, Alkermes, Inc., Waltham, MA, USA
Learning Objectives
To describe trends in opioid dispensing over time in patients with schizophrenia and bipolar disorder versus controls.
To understand differences in opioid dispensing rates between Commercial and Medicaid insured populations.
To understand the differences in chronic versus non-chronic opioid dispensing among patients with schizophrenia and patients with bipolar disorder.
Purpose
Patients with schizophrenia (SZ) or bipolar disorder (BD) may have an increased risk of overdose or opioid use disorder from prescribed opioids. To better understand the prevalence of opioid prescribing in these populations, we compared prescription opioid dispensing among patients with SZ or BD vs controls over 5 years (2015–2019).
Methods
This retrospective, observational study analyzed claims data from the IBM® MarketScan® Commercial and Multi-State Medicaid Databases. Individuals aged 18–64 years with ≥1 inpatient or ≥2 outpatient claims for SZ or BD diagnoses during the year preceding the analysis years 2015–2019 were included, with age- and sex-matched controls. Baseline characteristics, comorbidities, and medication use were assessed. Opioid dispensing was defined as chronic (≥70 days over a 90-day period or ≥6 prescriptions annually) or nonchronic (≥1 prescription, chronic definition not met). Results. In 2019, the Commercial and Medicaid databases contained 4773 and 30,179 patients with SZ and 52,780 and 63,455 patients with BD, respectively. Patients with SZ or BD had a higher prevalence of comorbidities, including pain, vs controls in each analysis year. From 2015 to 2019, among commercially insured patients with SZ, chronic opioid dispensing proportions decreased from 6% (controls: 3%) to 2% (controls: 1%), and, for patients with BD, from 11% (controls: 3%) to 6% (controls: 2%). Chronic opioid dispensing proportions declined in Medicaid-covered patients with SZ from 15% (controls: 15%) to 7% (controls: 6%), and, for patients with BD, from 27% (controls: 12%) to 12% (controls: 5%). Among commercially insured patients with SZ, nonchronic opioid dispensing proportions decreased from 15% (controls: 16%) to 11% (controls: 11%) and, for patients with BD, from 26% (controls: 17%) to 20% (controls: 12%). In Medicaid-covered patients with SZ, nonchronic opioid dispensing proportions declined from 23% (controls: 24%) to 15% (controls: 13%), and, for patients with BD, from 32% (controls: 26%) to 25% (controls: 14%). Conclusion From 2015 to 2019, chronic or nonchronic prescription opioid dispensing decreased for patients with SZ or BD and controls in the Commercial and Medicaid databases. The proportion of individuals dispensed chronic or nonchronic opioids each year was similar between commercially and Medicaid-insured patients with SZ vs controls but was consistently higher for patients with BD vs controls.
Abstract #25 Submission ID#1305629
Association of Oral Triptans and Other Common Oral Migraine Treatments With Cardiovascular Outcomes in Patients With a History of Cardiovascular Conditions
David W. Dodick, MDa, Matt Fisher, PharmDb, Maral DerSarkissian, PhDc, Shawn N. Murphy, MD, PhDd, Chi Gao, MS, ScDe, Rory Weiner, MDf, Louise H. Yu, MSg, Christopher Herrick, MBAh, Yichuan Grace Hsieh, PhD, RNi, Mei Sheng Duh, MPH, ScDj, Travis Wang, MSk, Greg Belsky, BSl, Azeem Banatwala, BSm, Janet Boyle-Kelly, MSN, RNn, Jennifer Costello, RNo, Marykate Murphy, RNp, Amy K. Wong, RNq, Jessica Ailani, MDr
aNeurology, Mayo Clinic, Scottsdale, AZ; bMedical Director, GlaxoSmithKline Consumer Healthcare, Warren, NJ; cVice President, Analysis Group, Inc., Boston, MA; dChief Research Information Officer, Mass General Brigham, Boston, MA; eAssociate, Analysis Group, Inc., Boston, MA; fAssociate Chief for Clinical Operations of the Cardiology Division, Mass General Brigham, Boston, MA; gSenior Analyst, Analysis Group, Inc., Boston, MA; hVice President, Research Technology, Mass General Brigham, Boston, MA; iInstructor of Medicine, Mass General Brigham, Boston, MA; jManaging Principal, Analysis Group, Inc., Boston, MA; kSenior Healthcare Analyst, Analysis Group, Inc., Boston, MA; lData Engineer, Mass General Brigham, Boston, MA; mAnalyst, Analysis Group, Inc., Boston, MA; nRegistered Nurse, Mass General Brigham, Boston, MA; oRegistered Nurse, Mass General Brigham, Boston, MA; pRegistered Nurse, Mass General Brigham, Boston, MA; qRegistered Nurse, Mass General Brigham, Boston, MA; rNeurology, Medstar Georgetown University Hospital
Learning Objectives
Describe cardiovascular risk of acute migraine treatments in patients with cardiovascular conditions.
Distinguish cardiovascular risk of triptans/sumatriptan vs opioids/butalbital and NSAIDs.
Articulate the occurrence of MACE in acute migraine treatment.
Purpose
Although US prescribing information for triptans notes history of cardiovascular (CV) disease as a contraindication for treatment, evidence is lacking on whether triptans pose greater risks of CV events in high-risk CV patients compared with other acute migraine therapies. This large, retrospective longitudinal study is the first to assess the risk of major adverse CV events (MACE) associated with oral triptans versus opioids/butalbital (O/B) and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) in migraine patients with preexisting CV conditions. A subgroup analysis assessing the risk of MACE associated with oral sumatriptan only versus O/B and non-aspirin NSAIDs was also conducted.
Methods
Adults treated with acute migraine treatment (ie, oral triptans, O/B, or non-aspirin NSAIDs) between 1/1/2006 and 12/31/2020 were identified from the Mass General Brigham Research Patient Data Registry database. The index date was defined as the date of each eligible prescription, and multiple prescriptions per patient were included. Baseline was defined as the 12-month period before index to assess patient characteristics and probability of baseline CV risk; ≥1 diagnosis of a baseline CV condition was required. Prescriptions with a cluster headache diagnosis at baseline or on index date were excluded; a washout period was set to exclude any prescriptions for acute migraine treatment 60 days before index. Nonfatal myocardial infarction (MI), nonfatal stroke, and in-facility all-cause mortality were assessed separately and together as a composite MACE-proxy (MACE) endpoint from index to earliest of treatment switch, 60 days post-index, end of clinical activity/data availability, or death. Inverse probability of treatment-weighted Cox proportional hazards models were used to estimate the adjusted risk of MACE comparing oral triptans with O/B and non-aspirin NSAIDs; subgroup analyses were conducted to compare only oral sumatriptan with O/B and non-aspirin NSAIDs.
Results
A total of 12,121 prescriptions were identified, including 4,016 (33%) oral triptans, 6,084 (50%) O/B, and 2,021 (17%) non-aspirin NSAIDs. The most frequent index treatments were sumatriptan (59%) in the oral triptan cohort, butalbital (39%) and oxycodone (27%) in the O/B cohort, and ibuprofen (62%) in the non-aspirin NSAIDs cohort. The mean ages at index were 49, 54, and 47 years for the oral triptan, O/B, and non-aspirin NSAIDs cohorts, respectively; 86%–87% of patients in each cohort were female. Compared with the oral triptan cohort (13%), the O/B and non-aspirin NSAIDs cohorts had higher baseline usage of low dose aspirin (24% and 20%, respectively) and the O/B cohort had higher baseline usage of antihyperlipidemics, including statins (38%) compared with non-aspirin NSAIDs and oral triptan cohorts (22% and 24%, respectively). MACE occurred with 1.0%, 4.5% and 3.8% of oral triptan, O/B, and nonaspirin NSAIDs prescriptions, respectively. The adjusted hazard ratios of MACE were 0.38 (95% CI: 0.22, 0.67) comparing oral triptans with O/B and 0.46 (95% CI: 0.29, 0.71) comparing oral triptans with non-aspirin NSAIDs. Adjusted comparisons for individual endpoints of nonfatal MI, nonfatal stroke, and in-facility all-cause mortality were underpowered to detect statistically significant differences between cohorts, although results from these analyses were consistent with those for MACE. Of the 4,016 oral triptan prescriptions, 2,368 sumatriptan prescriptions (59%) were identified. The mean age at index was 50 years in the sumatriptan cohort and 85% of patients were female. Similar to the oral triptan cohort, the sumatriptan cohort had lower baseline usage of low-dose aspirin (15%) compared with the O/B and non-aspirin NSAIDs cohorts (24% and 20%, respectively) and lower baseline usage of antihyperlipidemics, including statins (25%), compared with the O/B cohort (38%; non-aspirin NSAIDs cohort: 22%). MACE occurred with fewer oral sumatriptan prescriptions (1.1%) compared with O/B (4.5%) and non-aspirin NSAIDs (3.8%) prescriptions. The adjusted hazard ratios of MACE were 0.34 (95% CI: 0.21, 0.56) comparing oral sumatriptan with O/B and 0.47 (95% CI: 0.28, 0.79) comparing oral sumatriptan with non-aspirin NSAIDs.
Conclusion
Analysis of real-world data from clinical practice shows that oral triptans are associated with a significantly lower risk of MACE in migraine patients with a history of CV conditions compared with O/B and non-aspirin NSAIDs. A subgroup analysis including only oral sumatriptan showed similar results to the oral triptan cohort compared with the O/B and non-aspirin NSAIDs cohorts. The results suggest more deliberation may need to be given when considering migraine treatments for adults with CV conditions. These data should be considered in the context of all available treatment options for acute migraine relief. This study is subject to the typical limitations of observational research, including residual confounding, selection bias, and misclassification. Decreasing barriers to effective acute migraine therapy will help reduce the burden of migraine, which remains an undertreated and debilitating disease.
Abstract #26 Submission ID#1305824
Response to Treatment with Lemborexant in Older Subjects with Insomnia Disorder and Comorbid Pain at Baseline
Alan Kaplana, Jocelyn Y. Chengb, Masahiro Suzukic, Dinesh Kumard, Margaret Molinee, Elizabeth Pappadopulosf
aChair, Family Physician Airways Group of Canada; bSenior Director, Eisai Inc.; cProfessor, Department of Psychiatry, Nihon University School of Medicine; dAssociate Director of Biostatistics, Eisai Inc.; eExecutive Director, Head of Orexin Platform Clinical Development Lemborexant and E2086, Eisai Inc.fExecutive Medical Director, Global Medical Affairs, Eisai Inc.
Learning Objectives
Upon completion, participants will be able to describe the comorbid relationship between insomnia and pain.
Upon completion, participants will learn that subjects who reported pain at baseline experienced more improvement in sleep with lemborexant treatment compared with placebo.
Upon completion, participants will learn that lemborexant was well tolerated by subjects who reported pain at baseline.
Purpose
Although the prevalence of insomnia among the elderly varies globally, most reports estimate that 25–50% are affected in most countries.1 Chronic pain is also prevalent among the elderly, affecting 25%-50% of those dwelling in the community and up to 80% of those institutionalized.2 The reciprocal relationship between poor sleep and pain has been well established.3 Insomnia increases pain sensitivity and pain can interfere with sleep, thus impacting quality of life.4 Therefore, it is of critical clinical importance to evaluate whether a sleep-promoting drug such as lemborexant (LEM) can improve sleep in older patients, with both insomnia and ongoing pain. LEM is a dual orexin receptor antagonist approved in the United States, Japan, Canada, Australia and several Asian countries to treat adults with insomnia. We report here, the effects of LEM in older subjects with insomnia and comorbid pain.
Methods
Study E2006-G000-304 (Study 304; SUNRISE-1; NCT02783729) was a 1-month, double-blind, placebo (PBO)- and active-controlled study in subjects age ≥55y with insomnia disorder (full analysis set [FAS] = 1006). Subjects from the FAS who also endorsed some or extreme pain at baseline on the pain/discomfort dimension (subjects endorse one of the choices: no problems/some problems/extreme problems) of the EuroQual-5 Dimension-3 Level scale (EQ-5D-3 L)5 were eligible for inclusion in these post-hoc analyses. Medical history of pain conditions and/or ongoing therapy for pain were not required for eligibility in Study 304 or these post-hoc analyses. Exclusion criteria for Study 304 included chronic pain that, in the opinion of the investigator, could have affected the subject’s safety or interfered with the study assessments. Subjects were randomized to bedtime doses of PBO, LEM 5 mg (LEM5), 10 mg (LEM10) or zolpidem tartrate extended release 6.25 mg (not reported here). Changes from baseline (CFB) in objective sleep parameters as assessed by polysomnography (latency to persistent sleep [LPS]; wake after sleep onset [WASO]) were analyzed by mixed-effect repeated measures analyses with adjustments for relevant factors.
Results
Some or extreme pain at baseline was reported on the EQ-5D-3 L by 183/1006 or approximately 18% of subjects in the FAS (PBO = 55/1006 [5.5%]; LEM5 = 78/1006 [7.8%]; LEM10 = 50/1006 [5.0%]). For LPS, baseline median values (minutes) were 31.0, 29.4 and 42.1 for PBO, LEM5 and LEM10, respectively. Decreases (improvement) in median CFB for LPS were significantly different and larger for both LEM doses compared with PBO at the beginning of treatment (mean of Nights 1/2: +2.5; −8.4, −15.8; both P < 0.005); and at the end of treatment (mean of Nights 29/30: −7.1,-9.9, −9.0; LEM5 P = 0.031, LEM10
P = 0.054). For WASO, baseline median values (minutes) were 101.0, 103.6 and 111.1 for PBO, LEM5 and LEM10, respectively. Decreases (improvement) in median CFB for WASO were significantly different and larger (P < 0.001) for both LEM doses compared with PBO at the beginning (mean of Nights 1/2; −1.5; −41.5, −64.4) and end of treatment (mean of Nights 29/30; −1.1, −37.9, −52.5). LEM was generally well tolerated with mild/moderate treatment-related adverse events.
Conclusion
LEM treatment improved objective measures of sleep onset (LPS) and sleep maintenance (WASO) compared with PBO among older adults with insomnia and comorbid pain. The improvements from baseline in LPS were smaller compared to findings in the overall clinical trial population for Study 304 reported previously,6 but improvement for WASO was comparable. LEM was well tolerated in subjects with comorbid pain, with safety findings similar to the overall population. These data suggest LEM may effectively treat insomnia in older adults with concomitant painful conditions
This study was supported by Eisai Inc.
References
[1] Gulia KK, Kumar VM. Psychogeriatrics. 2018;18(3):155–65.
[2] Cravello L, et al. Pain Ther. 2019;8(1):53–65.
[3] Craner JR, Flegge LG. Pain Pract. 2022 Feb;22(2):171–181.
[4] Finan PH, Goodin BR, Smith MT. J Pain. 2013 Dec;14(12).
[5] EuroQol Research Foundation EQ-5D-3 L User Guide. [Cited 3 March 2022]Available from: 2018 Available online: https://euroqol.org/wp-content/uploads/2021/01/EQ-5D-3LUserguide-14-0421.pdf. 6. Rosenberg R, et al. JAMA NetwOpen. 2019;2:e1918254.
Abstract # 27 Submission ID#1305837
Efficacy of Celecoxib Oral Solution in Adults with and without Baseline Nausea: Post-Hoc Analysis of Results from Two Randomized, Double-Blind Placebo-Controlled Trials in the Acute Treatment of Migraine
Richard B.a, Daniel Serranob, Mancia Koc, Todd Kunkeld, Stewart Teppere
aNeurology, Albert Einstein College of Medicine; bNeurology, OPEN Health; cHead of Medical Affairs, Collegium Pharmaceutical; dDirector of Scientific Communications, Collegium Pharmaceutical; eProfessor of Neurology, Dartmouth-Hitchcock Medical Center
Learning Objectives
Recall that the presence of baseline nausea had no effect on the efficacy of celecoxib 120 mg oral solution at 2 hours postdose.
Explain that celecoxib 120 mg oral solution did not cause treatment-emergent nausea and may prevent treatment-emergent nausea.
Modify migraine prescribing to include celecoxib oral solution as an option in patients with a history of baseline nausea and those at risk of treatment-emergent nausea.
Purpose
In adults with migraine, nausea can influence timing and likelihood of oral medication use, as well as the probability of a positive outcome, in acute treatment of migraine. Celecoxib oral solution (Elyxyb) is a liquid formulation of the cyclooxygenase-2-selective nonsteroidal anti-inflammatory drug indicated for the acute treatment of migraine in adults. In previous research, celecoxib oral solution had a shorter Tmax than oral tablets, and a single 120 mg dose was more effective than placebo for the acute treatment of migraine. In this post-hoc analysis, we pooled data from 2 randomized, double-blind, placebo-controlled trials (NCT03009019; NCT03006276) to compare efficacy of celecoxib oral solution 120 mg with placebo in the acute treatment of migraine attacks with and without nausea at baseline.
Methods
We pooled data from 2 randomized, double-blind, placebo-controlled trials in which adults with migraine treated a single migraine attack of moderate or severe intensity with celecoxib oral solution 120 mg/4.8 mL or an identical placebo. Efficacy endpoints at 2 hours postdose included pain freedom, freedom from the most bothersome symptom, and pain relief. The population was stratified by the presence or absence of nausea at baseline. Separate regression models were fit to the data for each endpoint to evaluate if treatment efficacy differed across nausea subgroups (nausea at baseline vs no nausea at baseline) as tested by a treatment-by-nausea interaction. In addition, a regression model was fit to subjects with no nausea at baseline to evaluate treatment-emergent nausea at 2 hours postdose.
Results
The study population (N = 1075) had a mean age of 40.5 years; 86.4% of subjects were female. The analysis groups were demographically balanced at baseline (Table). Nausea was present in 20.2% (111/550) of subjects treated with celecoxib oral solution and 19.6% (103/525) of subjects treated with placebo. At 2 hours postdose, celecoxib oral solution 120 mg was superior to placebo for pain freedom in subjects with baseline nausea (22% vs 15%, P < .001) and without baseline nausea (37% vs 25%, P < .001); freedom from the most bothersome symptom in subjects with baseline nausea (53% vs 40%, P < .001) and without baseline nausea (59% vs 44%, P < .001); and pain relief in subjects with baseline nausea (63% vs 51%, P < .001) and without baseline nausea (74%% vs 60%, P < .001). Across all 3 regression models, none of the treatment-by-nausea interaction terms was significant, reflecting treatment efficacy in both nausea subgroups. Among subjects without nausea at baseline, the incidence of treatment-emergent nausea at 2 hours postdose was numerically higher with placebo than celecoxib oral solution, but the difference was not statistically significant (32.3% vs 23.7%, P = .065).
Conclusion
Celecoxib oral solution 120 mg was equally effective on pain freedom, freedom from the most bothersome symptom, and pain relief at 2 hours postdose in patients with or without nausea at baseline. Celecoxib oral solution did not cause treatment-emergent nausea, and a nonsignificant trend suggested that it may prevent treatment-emergent nausea.
Abstract #28 Submission ID#1306542
A Comparison of Definitive Urine Drug Test Results for Illicit Drugs in a Sample of People with Chronic Pain Prescribed Opioids to Those Not Prescribed Opioids
Monika Holbeina, Maria Guevarab, Penn Whitleyc, Eric Dawsond, John Colemane, Steven D.f
aAssistant Professor of Medicine, Penn State Health; bClinical Science Liaison, Millennium Health; cSenior Director, Bioinformatics, Millennium Health; dVP, Clinical Affairs, Millennium Health; eAssistant Administrator (Retired), US Drug Enforcement Administration; fVP, Scientific Affairs, Millenium Health
Learning Objectives
Demonstrate an understanding of UDT results for illicit drugs reflecting drug use by people with chronic pain prescribed opioid medications compared with those not prescribed opioids.
Debate the impact of policies that have led to dramatic decreases in opioid prescribing.
Consider alternative approaches to patients who are exposed to opioids to maximize safety of such exposures.
Purpose
Opioid prescribing has decreased dramatically over the past decade, and yet drug overdose deaths continue to climb.1,2 Changing views about management of chronic pain with opioids have been reflected in shifting guidelines, policy and rules, and are driven by a desire to reckon with the societal problems of opioid misuse, addiction, diversion, overdose and death. In part, sparing people with chronic pain exposure to opioids is motivated by a desire to protect vulnerable people from the possibility of setting in motion misuse or unhealthy use of opioids and/or addiction. Whether these policies have been a success or failure is a matter of debate; in any event, the number of people with chronic pain treated with opioids has decreased to levels unseen since the early 1990s.1
We set out to compare urine drug test (UDT) results from people with chronic pain not prescribed opioids to those prescribed opioids. We examined a large sample of people treated in pain management practices who underwent UDT with liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology. We eliminated sub-groups of subjects who, it may be argued, might be best treated without opioids, while safer alternatives are trialed (e.g. patients with a history of substance use disorder), to drill down to the group in whom the reasons for foregoing opioids may be less obvious and more a reflection of present policy. Describing the influence of opioid prescribing on the frequency of UDT findings for illicit drugs may help those interested in understanding whether present policies are indeed protecting people with chronic pain from opioid misuse or whether it is resulting in dangerous self-treatment at a time when the drug supply of illicit and counterfeit opioids are tainted with lethal fentanyl, fentanyl analogues, and other excipients that can cause harm. People who think they are purchasing a legal opioid with which they are familiar from an illicit source might well be purchasing a lethal dose of fentanyl.
Methods
This retrospective study of UDT results examined specimens obtained between 1 January 2019 and 30 September 2021, from patients receiving treatment in pain management practices. The study used a sample of 231,932 unique specimens, from Millennium Health’s proprietary UDT database. Specimens included in the study had been tested using LC-MS/MS for each analyte ordered based on clinician determination of medical necessity. The study protocol was approved by the Aspire Independent Review Board and includes a waiver of consent for the use of deidentified data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
We first determined those in the population who were reported to be prescribed opioids, using eight commonly prescribed opioids. Out of the 231,932 total urine specimens, 170,992 (73.7%) were from patients who were prescribed at least one of the following drugs at the time of the sampling: fentanyl, codeine, hydrocodone, hydromorphone, oxymorphone, morphine, oxycodone, and tramadol.
We then evaluated positivity in the 231,932 specimens for four illicit substances; these were chosen because they are the four drugs known to contribute most to overdose deaths2. The following drugs and/or drug classes were tested based on the ordering clinician’s determination of medical necessity (drug and metabolites tested in parentheses): cocaine (benzoylecgonine), fentanyl (fentanyl, norfentanyl), heroin (6-monoacetylmorphine), and methamphetamine. If any parent analyte or metabolite was detected, the drug of interest was considered positive for that specimen. We excluded positive results for medications that contained these active ingredients that were reported by clinicians to be currently prescribed to patients (ie, if Desoxyn® was prescribed, we did not count them for methamphetamine positivity).
Additional characteristics for each specimen included the patient’s sex, age, diagnosis code, collection year and county of health care provider were also collected. The source of payment for the UDT was also included as a covariate in regression models.
We examined the crude prevalence of illicit drug positivity for the first collected specimen for each patient in each study year. Clopper-Pearson 95% binomial confidence intervals, Fisher’s exact test, and Poisson generalized estimating equations were used to further analyze the sample.
Results
60,000 patients contributed the 231,932 total specimens, a mean of 3.9 specimens per patient. The population was mostly female (58.6%). The median patient age was 57 years old at collection and 58.3% were 55 years or older. The specimens were relatively evenly distributed for each collection year (31.0%-38.1%). 61.7% of patient specimens were collected in the East North Central, South Atlantic or Mountain divisions. 73.7% of patients were reported to be prescribed at least one of the eight opioids at the time of their first specimen, most commonly hydrocodone (31.5%) and oxycodone (32.5%). ICD-10 diagnosis codes associated with Substance Use Disorders (SUD) were found in 11.4% of the patients. A Fisher’s exact test demonstrated a significant negative association between SUD codes and opioid prescribing (OR = 0.52[0.51–0.53], p < 2.2e-22) suggesting that opioid prescribing is reduced in the pain clinic population with an SUD diagnosis. Methadone (2.2%) and buprenorphine (7.5%) were found in the medication listings provided by the ordering physician. SUD diagnosis codes were positively associated with both methadone (OR = 1.88[1.75–2.02], p < 2.2e-06) and buprenorphine (OR = 3.39[3.27–3.51], p < 2.2e-06).
From 2019 to 2021, illicit positivity rates for heroin, fentanyl, cocaine and methamphetamine were lower in the population prescribed an opioid compared to those not prescribed an opioid. When patients with SUD and patients prescribed buprenorphine or methadone were removed from the analysis, those prescribed an opioid were 47% less likely to be positive for illicit fentanyl, 52% less likely to be positive for heroin, 63% less likely to be positive for methamphetamine, and 32% less likely to be positive for cocaine (all significant at p < 0.001).
Conclusion
The results of this study suggest that people with chronic pain who are not prescribed opioid medications are more likely to have UDT results positive for illicit drugs, than were those prescribed opioid medications. It is unclear what the actual clinical circumstances and motives of people with pain who use illegally obtained drugs are from a database such as this one. Is their use of these drugs the result of desperation to relieve pain and other symptoms? Or is their unsanctioned use a manifestation of a substance use disorder? Based on our analysis, avoiding opioid prescribing does not automatically translate to less drug use on the part of people with chronic pain – at a time when self-medication using street opioids has perhaps never been more dangerous. Instead, safe opioid prescribing processes might be preferred wherein the hope would be that adequate comfort and pain management with needed safeguards might help a subset of people with chronic pain avoid desperate and dangerous attempts to self-treat.
References
[1] American Medical Association. 2021 Overdose Epidemic Report: Physicians’ actions to help end the nation’s drug-related overdose and death epidemic – and what still needs to be done. Available from: https://www.ama-assn.org/system/files/ama-overdose-epidemic-report.pdf. [cited July 2022].
[2] Provisional Drug Overdose Death Counts. National Center for Health Statistics. Centers for Disease Control and Prevention Website. Available from. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm. [Cited November 2021]..
Abstract #29 Submission ID#1307295
A Rapid Review of Noninvasive Electromagnetic Devices for the Treatment of Pain
Robert N. Bilkovskia, Melanie Rosenblattb, Joseph Pergolizzic
aChief Scientific Officer, President, other, Qualis Innovations Inc., RNB Ventures Consulting Inc; bCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other; cOwner, Pain Managament Strategies
Learning Objectives
Upon completion, participants will gain information on additional therapeutic modalities for the management of pain.
Upon completion, participant will be able to list four treatment modalities that deliver wave-based energy for treatment of musculoskeletal injuries.
Upon completion, participant will be able to identify future clinical studies where these technologies may offer meaningful patient impact.
Purpose
Acute pain conditions are in continual search for complimentary therapies that reduce reliance on opiates and/or interventional procedures that are painful and costly. Non-interventional complimentary therapies are continually being developed that attempt to address this goal. One area of interest is the delivery of wave-based therapy leveraging ultrasound or electromagnetic waves for the purpose of providing pain relief. A rapid review of the literature and regulatory databases was conducted to illustrate relevant technology.
Methods
A rapid review was conducted of PubMed and the FDA 510k database to identify relevant technologies that are a) in current use clinically, b) have received a premarket authorization from the FDA via a 510(k), c) deliver variants of wave-based therapy that could be ultrasound, radiofrequency or electromagnetic and d) have an indication of pain-relief or treatment of soft-tissue injuries.
Results
Four technologies were identified that met the above search criteria. Pulsed electromagnetic field therapy (PEMF) has been on market since 1979. The therapeutic effects of PEMF aim at the cellular and molecular level of very low frequency (<30 Hz) and low energy (<400 micro-Tesla) to impart biologic effects. PEMF is indicated for temporary relief of minor muscle and joint aches and pain associated with overextension, strains, sprains and arthritis. Multiple RCT and meta-analysis show favorable effects in knee and finger osteoarthritis.
Combined electrochemical therapy (CET) combines two principles for the treatment of peripheral neuropathy: electrical cell signaling treatment (EST) and administration of local anesthetic to the target tissue. The mechanism of action is that the target tissue will experience increased blood flow and oxygen delivery, increased regenerative tissue effects and chemically blocking of pain fibers. EST is delivered via a sequence of varying frequencies of radiofrequency signals which include: 1) slow frequency (1–4 Hz) for nerve stimulation, 2) slightly faster (10 Hz) to produce local vasoconstriction, 3) fast stimulation (100 Hz) to produce local vasodilatation and 4) very fast (>2 MHz) which fall within the cell membrane refractory period to inhibit action impulse capability resulting in sustained cell membrane depolarization.
Extracorporeal shockwave therapy (ESWT) is an extension of shockwave lithotripsy that is used for renal calculi. ESWT delivers high frequency acoustic impulses to the target tissue. This technology was first FDA cleared in 2000 for the treatment of plantar fasciitis. ESWT waves are uniphasic and higher pressure (500 bars) or 1000× stronger than ultrasound. Clinical utility has been shown in multiple RCTs for conditions including but not limited to plantar fasciitis, lateral epicondylitis, patellar tendinopathy, Achilles tendinopathy and nonunion of long-bone fractures.
Short wave diathermy (SWD) delivers deep tissue heating via electromagnetic waves delivered to the tissue at 27.12 MHz. SWD devices have been FDA cleared for decades but often used bulky drums applicators that hinder targeted localization of thermal effects. Modern designs created hand-held applicators that improve tissue targeting of SWD. Many SWD devices deliver the thermal effects by way of biomagnetic induction that results in heat to deeper tissue layers (4 cm below the dermis). SWD is indicated for pain relief of acute musculoskeletal injuries such as but not limited to muscle spasms, joint arthropathies and tendinopathies. The mechanism of action focuses on increasing blood flow, increasing the extensibility of collagen fibers and facilitating local inflammatory effects.
Conclusion
Multiple complimentary noninvasive modalities are currently available for clinical use to augment the treatment of painful musculoskeletal conditions and this review article illustrates four – Pulsed electromagnetic field therapy, Combined electrochemical therapy, Extracorporeal shockwave therapy and Short wave diathermy. More ongoing clinical studies are needed to help expand where the above technologies may be of use as a standalone or in concert with other modalities.
References
Odell, R. H., & Chaya, Z. (2016). Clinical outcomes utilizing the Combined Electrochemical Treatment for peripheral neuropathy: a retrospective study from a western clinic. Gavin J Anesthesiol, 2016, 1–7. Auersperg, Vinzenz, and Klemens Trieb. ‘Extracorporeal shock wave therapy: an update.’ EFORT Open Reviews 5, no. 10 (2020): 584–592.
Abstract #30 Submission ID#1307356
Atogepant for the preventive treatment of chronic migraine: results from the PROGRESS phase 3 trial
Patricia Pozo-Rosicha, Jessica Ailanib, Messoud Ashinac, Peter J. Goadsbyd, Richard Be, Uwe Reuterf, Hua Guog, Brittany Schwefelg, Ramesh Boinpallyg, Emily McCuskerg, Sung Yun Yug, Michelle Finnegang, Joel M. Trugmang
aNeurology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Research, Universitat Autonoma de Barcelona, Sung Yun Yu, Michelle Finnegan; bNeurology, Medstar Georgetown University Hospital; cNeurology, Danish Headache Center, Rigshospitalet Glostrup, University of Copenhagen; dNeurology, NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London; University of California, Los Angeles, CA; eNeurology, Albert Einstein College of Medicine; fNeurology, Charité – Universitätsmedizin Berlin; Universitätsmedizin Greifswald; gNeurology, AbbVie
Learning Objectives
Upon completion, participant will be able to describe the design of the phase 3 randomized, double-blind, placebo-controlled PROGRESS trial of atogepant in people with chronic migraine.
Upon completion, participant will be able to summarize the efficacy of atogepant compared with placebo in the PROGRESS trial.
Upon completion, participant will be able to articulate the safety and tolerability of atogepant in people with chronic migraine.
Purpose
The objective of this study was to evaluate the efficacy, safety, and tolerability of atogepant 30 mg twice daily (BID) and atogepant 60 mg once daily (QD) for the preventive treatment of chronic migraine. Atogepant is an oral, small-molecule calcitonin gene–related peptide receptor antagonist approved in the United States for the preventive treatment of episodic migraine.
Methods
PROGRESS (NCT03855137) was a randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial conducted across North America, Europe, and East Asia. Participants were adults (18–80 years) with a history of chronic migraine (≥1 year) who had ≥15 headache days per month in the 3 months prior to screening and ≥15 headache days, of which ≥8 were migraine days, during the 4-week baseline screening period. Participants were randomized 1:1:1 to atogepant 30 mg BID, atogepant 60 mg QD, or placebo for 12 weeks. The primary efficacy endpoint was change from baseline in mean monthly migraine days (MMDs) across the 12-week treatment period. A key secondary endpoint was the proportion of participants with ≥50% reduction in the 3-month average of MMDs.
Results
There were 778 participants randomized (89.2% completed the double-blind treatment period); 773 were included in the safety population and 755 in the modified intent-to-treat (mITT) population. Participants in the safety population were on average 42.1 years old with a mean body mass index of 25.5 kg/m2; the majority were female (87.6%), 59.4% were White, and 36.4% were Asian. Based on the mITT population, baseline mean MMDs ranged from 18.6–19.2 across groups. The mean change from baseline across the 12-week treatment period was −7.5 days with atogepant 30 mg BID, −6.9 days with atogepant 60 mg QD, and −5.1 days with placebo (atogepant 30 mg BID vs placebo, P < 0.0001; atogepant 60 mg QD vs placebo, P = 0.0009; adjusted for multiple comparisons). A reduction of ≥50% in the 3-month average of MMDs was achieved by 42.7% (108/253) of participants in the atogepant 30 mg BID group, 41.0% (105/256) in the atogepant 60 mg QD group, and 26.0% (64/246) in the placebo group (30 mg BID vs placebo, P = 0.0003; 60 mg QD vs placebo, P = 0.0009; adjusted for multiple comparisons). Statistically significant improvements were also achieved across all other secondary endpoints with atogepant 30 mg BID and 60 mg QD. Treatment-emergent adverse events (TEAEs) were reported by 56.4% receiving atogepant 30 mg BID, 63.2% receiving atogepant 60 mg QD, and 49.4% receiving placebo. The most frequently reported TEAEs (≥5% in any group) were constipation (10.9% atogepant 30 mg BID, 10.0% atogepant 60 mg QD, 3.1% placebo) and nausea (7.8% atogepant 30 mg BID, 9.6% atogepant 60 mg QD, 3.5% placebo). Treatment-emergent serious adverse events were reported by 1.6% receiving atogepant 30 mg BID, 2.7% receiving atogepant 60 mg QD, and 1.2% receiving placebo; none were considered treatment related.
Conclusion
Atogepant 30 mg BID and 60 mg QD demonstrated statistically significant reductions in mean MMDs among participants with chronic migraine. Atogepant was safe and generally well tolerated, consistent with the known safety profile of atogepant.
Abstract #31 Submission ID#1307450
Bibliometric Analysis of Camphor and Menthol Containing Topical Anesthetics
Don Hoanga, Ashley Wongb, Robert Olympiac
aMedical Student, Pennsylvania State University College of Medicine; bMedical Student, Pennsylvania State University College of Medicine; cEmergency Medicine Physician, Penn State Milton S. Hershey Medical Center
Learning Objectives
Describe the importance of alternative pain management options.
Assess the clinical utility of Tiger Balm and comparable topical compounds.
Interpret trends in research pertaining to Tiger Balm.
Purpose
In the United States, there are more than 25 millions adults living with chronic pain.1 With opioids responsible for significant healthcare, social, and economic burdens, there is an urgent need for alternative pain management treatments.2 However, currently, options are limited for non-opioid options that are both safe and efficacious in relieving pain.2 One alternative pain management includes topical analgesics, which tend to be safer, have lower risk of addiction, and are more accessible than oral and parenteral therapies.3,4 Examples of topicals commonly seen in literature include compounds containing capsaicin, lidocaine, topical antidepressants, ketamine, clonidine, gabapentin, baclofen, phenytoin, and/or NSAIDs.4 It is evident that more studies are needed for elucidation of the role of topical analgesics and their effects, especially when combined with other treatments.4
Given the demonstrated efficacy of topical agents in relieving pain, the authors were interested in looking for other possible topical agents. One agent, in particular, stood out: Tiger Balm. Tiger Balm and other compounds containing menthol and camphor have deep roots in eastern medicine, and have historically been used for alleviating pain, cold symptoms, and pruritus in various cultures. However, unlike many of the other analgesic treatments, these compounds are not nearly as recognized in the literature. Consequently, the purpose of this bibliometric study was to analyze current clinical research regarding Tiger Balm and similar topical agents.
Methods
This study involved a bibliometric analysis of English, peer-reviewed articles indexed in PubMed from 2010 to 2022 using the search term: ‘“Tiger Balm” OR (“Menthol” AND “Camphor”).’ We identified the journal (and the journal impact factor score), year of publication, study design, clinical relevance, and study topic of each of the resulting articles and discerned underlying trends and themes regarding research on Tiger Balm and Tiger Balm-like compounds.
Results
The PubMed search resulted in 106 articles, of which 28 (26.4%) articles were deemed clinically relevant research by the authors based on resulting clinical applications. Of all articles, Molecules, Nat Prod Res, and Pest Manag Sci were the most represented, with 4 articles each. Of the clinically relevant articles, each article was published in a unique journal, including Molecules and Nat Prod Res. In regard to Journal Impact Factor (based on Journal Citation Reports), the range for all articles was 0.684 to 14.553, with an average of 3.90, and the range for clinically relevant articles was 0.684 to 8.262, with an average of 3.26. The publication count per year for all articles and for clinically relevant articles demonstrated no obvious trend, with a maximum of 14 total articles in 2021 and a maximum of 4 clinically relevant articles in 2013, 2014, and 2017. Of the clinically relevant articles, study designs included 12 basic science studies, 6 clinical trials, 6 reviews, 1 case series, 1 prospective case control study, 1 retrospective cohort study, and 1 case report. And, of the clinically relevant articles, pain was discussed in only 5 articles, antimicrobial activity in 8 articles, adverse effects in 5 articles, pharmacology in 5 articles, inflammation in 4 articles, pruritus in 4 articles, cold symptoms in 3 articles, circulation effects in 2 articles, and antineoplastic activity in 1 article.
Overall, Tiger Balm and Tiger Balm-like substances have been documented for their topical use for acute and chronic pain, antimicrobial purposes, and cold symptoms relief. Proposed analgesic mechanisms for acute and chronic pain such as knee osteoarthritis,5 myalgias, neuralgias6 include anti-inflammatory effects7,8 reduction in pain perception,9−13 and improvement in blood circulation.14,15
Other benefits of Tiger Balm and similar products include relieving nasal congestion and reducing nighttime cough frequency and severity, improving sleep for both the child and parents.16−18 Additionally, antimicrobial properties were observed against Streptococcus pyogenes and Candida albicans,19 fluconazole-resistant Candida species,20 A. gypsicola,21 multidrug-resistant Staphylococcus aureus,22 Bacillus subtilis, Proteus mirabilis, Listeria monocytogenes, Bacillus subtilis, Escherichia coli, leishmania major,23 onychomycosis,24 and Origanum vulgare.25
Potential side effects these topical agents include contact dermatitis,26 allergic reactions, skin irritation,27 accidental ingestion,28 and thiamine deficiency.29
Conclusion
Based on existing literature, Tiger Balm and other compounds containing menthol and camphor are potentially effective for pain relief in addition to alleviating cold symptoms, relieving pruritus, and functioning as an antimicrobial. However, given the limited number of studies, a definitive, evidence-based recommendation cannot be made in regard to the use of these agents. As such, given the promising results of earlier studies, the authors recommend that more research be done into the clinical application of Tiger Balm and Tiger Balm-like substances as it pertains to pain management, amongst other uses. Specifically, given its popularity in eastern cultures, a literature review of eastern journals that have been published in their native language would be beneficial.
References
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[2] Coussens, N. P., Sittampalam, G. S., Jonson, S. G., Hall, M. D., Gorby, H. E., Tamiz, A. P., McManus, O. B., Felder, C. C., & Rasmussen, K. (2019). The Opioid Crisis and the Future of Addiction and Pain Therapeutics. JPET, 371(2), 396–408. doi: 10.1124/jpet.119.259408
[3] Leppert, W., Malec-Milewska, M., Zajaczkowska, R., & Wordliczek, J. (2018). Transdermal and Topical Drug Administration in the Treatment of Pain. Molecules, 23(3), 681.
[4] Knezevic, N. N., Tverdohleb, T., Nikibin, F., Knezevic, I., & Candido, K. D. (2017). Management of chronic neuropathic pain with single and compounded topical analgesics. Pain management, 7(6), 537–558.
[5] Rodriguez-Merchan E. C. (2018). Topical therapies for knee osteoarthritis. Postgrad med, 130(7), 607–612.
[6] Nawaz, A., Sheikh, Z. A., Feroz, M., Alam, K., Nazar, H., & Usmanghani, K. (2015). Clinical efficacy of polyherbal formulation Eezpain spray for muscular pain relief. Pak J Pharm Sci., 28(1), 43–47.
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[10] Selescu, T., Ciobanu, A. C., Dobre, C., Reid, G., & Babes, A. (2013). Camphor activates and sensitizes transient receptor potential melastatin 8 (TRPM8) to cooling and icilin. Chemical senses, 38(7), 563–575.
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[12] Alpizar, Y. A., Gees, M., Sanchez, A., Apetrei, A., Voets, T., Nilius, B., & Talavera, K. (2013). Bimodal effects of cinnamaldehyde and camphor on mouse TRPA1. Pflugers Archiv, 465(6), 853–864.
[13] Danial, C., Adeduntan, R., Gorell, E. S., Lucky, A. W., Paller, A. S., Bruckner, A. L., Pope, E., Morel, K. D., Levy, M. L., Li, S., Gilmore, E. S., & Lane, A. T. (2015). Evaluation of Treatments for Pruritus in Epidermolysis Bullosa. Pediatr dermatol, 32(5), 628–634.
[14] Kotaka, T., Kimura, S., Kashiwayanagi, M., & Iwamoto, J. (2014). Camphor induces cold and warm sensations with increases in skin and muscle blood flow in human. Biol & pharm bull, 37(12), 1913–1918.
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[16] DeGeorge, K. C., Ring, D. J., & Dalrymple, S. N. (2019). Treatment of the Common Cold. Am fam physician, 100(5), 281–289.
[17] Allan, G. M., & Arroll, B. (2014). Prevention and treatment of the common cold: making sense of the evidence. CMAJ, 186(3), 190–199
[18] Paul I. M. (2012). Therapeutic options for acute cough due to upper respiratory infections in children. Lung, 190(1), 41–44
[19] Ghavam M. (2022). In vitro biological potential of the essential oil of some aromatic species used in Iranian traditional medicine. Inflammopharmacology, 30(3), 855–874.
[20] Iraji, A., Yazdanpanah, S., Alizadeh, F., Mirzamohammadi, S., Ghasemi, Y., Pakshir, K., Yang, Y., & Zomorodian, K. (2020). Screening the antifungal activities of monoterpenes and their isomers against Candida species. J appl microbiol, 129(6), 1541–1551.
[21] Akif Açıkgöz M. (2019). Evaluation of Phytochemical Compositions and Biological Properties of Achillea gypsicola at Different Phenological Stages. Chemistry & biodiversity, 16(12), e1900373
[22] Kot, B., Wierzchowska, K., Piechota, M., Czerniewicz, P., & Chrzanowski, G. (2019). Antimicrobial activity of five essential oils from lamiaceae against multidrug-resistant Staphylococcus aureus. Nat prod res, 33(24), 3587–3591
[23] Bouyahya, A., Et-Touys, A., Bakri, Y., Talbaui, A., Fellah, H., Abrini, J., & Dakka, N. (2017). Chemical composition of Mentha pulegium and Rosmarinus officinalis essential oils and their antileishmanial, antibacterial and antioxidant activities. Microb pathog, 111, 41–49. doi: 10.1016/j.micpath.2017.08.015
[24] Derby, R., Rohal, P., Jackson, C., Beutler, A., & Olsen, C. (2011). Novel treatment of onychomycosis using over-the-counter mentholated ointment: a clinical case series. J Am Board Fam Med, 24(1), 69–74.
[25] Soković, M., Glamočlija, J., Marin, P. D., Brkić, D., & van Griensven, L. J. (2010). Antibacterial effects of the essential oils of commonly consumed medicinal herbs using an in vitro model. Molecules, 15(11), 7532–7546.
[26] Noiles, K., & Pratt, M. (2010). Contact dermatitis to Vicks VapoRub. Dermatitis, 21(3), 167–169. [27] Antonelli, M., Donelli, D., & Valussi, M. (2020). Efficacy, safety and tolerability of Tiger Balm® ointments: A systematic review and a meta-analysis of prevalence. Journal of Pharmacy & Pharmacognosy Research, 8(1), 1–17.
[28] Bazzano, A. N., Var, C., Grossman, F., & Oberhelman, R. A. (2017). Use of Camphor and Essential Oil Balms for Infants in Cambodia. J trop pediatr, 63(1), 65–69.
[29] Keating, E. M., Nget, P., Kea, S., Kuong, S., Daly, L., Phearom, S., Enders, F., Cheryk, L. A., Topazian, M., Fischer, P. R., & Kumar, V. (2015). Thiamine deficiency in tachypneic Cambodian infants. Pediatr int child health, 35(4), 312–318.
Abstract #32 Submission ID#1307609
Prescription Opioid Nonmedical Use via Oral Manipulation: An Under-Recognized Risk
Jody L. Greena, Taryn Dailey-Govonib, Suzanne K. Vosburgc
aChief Scientific Officer, Inflexxion/Uprise Health; bSenior Epidemiologist, Inflexxion/Uprise Health; cAssociate Research Director, Inflexxion/Uprise Health
Learing Objectives
Define nonmedical use of prescription opioids and the routes of administration used, including oral intact, oral manipulation, and non-oral routes.
Describe differences in patient characteristics and behaviors of those who report nonmedical use of prescription opioids via oral intact versus oral manipulation versus nonoral routes of administration.
Describe the reasons why nonmedical use of prescription opioids via oral manipulation should be considered high risk behavior in your patient population.
Purpose
While overdose deaths involving prescription opioid medications are decreasing, the latest data regarding overall substance abuse in the United States are daunting, exacerbated by the collision of the opioid epidemic and the COVID-19 pandemic. Recent studies have focused on closing the knowledge gap regarding the substance use pathways and behavioral profiles contributing to this ongoing public health crisis. The increased risk of prescription opioid abuse via non-oral routes of administration has been studied, suggesting the relative risk of an exposure resulting in a life-threatening event or death was 2.43 (95% CI 1.97, 2.99) if non-oral routes were reported compared to exposures involving oral route only. The increased risk associated with non-oral routes of administration of a prescription opioid is important, however, the majority of prescription opioid use occurs via the oral route of administration. Oral route of administration includes ingesting an intact tablet or capsule (‘oral intact’), as well as manipulation of prescription opioid products prior to ingestion (chewing, crushing or dissolving) for the purpose of changing the user experience, for example, to increase the speed and intensity of a psychotropic effect (‘oral manipulation’). Regardless of intent, oral manipulation is considered nonmedical use (NMU), meaning that the prescription medication is being used in a different way or for a different purpose than intended, whether it be for therapeutic reasons (misuse) or for psychotropic effect such as to get high (abuse). It is unknown whether those who engage in prescription opioid oral manipulation are at an increased risk of also using illicit drugs or engaging in even higher risk non-oral routes of administration.
The purpose of this study was to utilize data from a general population study in the United States (US) to compare biopsychosocial and behavioral characteristics among those reporting prescription opioid NMU via oral intact route only, oral manipulation, and non-oral routes of administration.
Methods
This was an observational study conducted with a nationally representative sample of the general adult US population. Participants were recruited via e-mail through YouGov, a survey panel company that has an established participant registry as well as a validated sampling methodology to ensure representativeness of the research. The study used a self-administered online survey drawn from the opt-in panelists using sample-matching methods to represent a target population of US adults ages 18–49 years. Inclusion criteria was a history of prescription opioid NMU. Four mutually exclusive groups were studied: (1) those who only reported prescription opioid NMU via oral intact route of administration, (2) those who reported oral manipulation but no non-oral routes of administration, (3) those who reported non-oral route of administration but no oral manipulation, and (4) those who reported both oral manipulation and non-oral routes of administration. Prescription opioid NMU via oral intact route of administration may have also been reported in groups 2, 3, and 4. Data were collected on demographics (age, sex, race, ethnicity, education, college enrollment, employment, etc.), select co-morbidities (diagnosis of anxiety, depression, alcohol use disorder, substance use disorder, etc.), routes of administration, sources of drug procurement, primary reason for use, factors influencing use of non-oral routes of administration, and concomitant use of other substances with prescription opioid NMU. Prescription opioid product names, active ingredients, and photos were used to aid in selection of substances used. Prescription opioid NMU included ANY of the following: (1) use for any reason, even once, without your own prescription, (2) use in ways other than prescribed (such as taking more than prescribed, more often than prescribed, or for any other reason or way than prescribed), and (3) use for the feeling or experience the medication caused (such as a feeling of being high, enhancement of other drugs, prevention or treatment of withdrawal symptoms, or other feelings). The route referenced as oral manipulation was defined as physical alteration of a prescription medication, such as chewing, crushing, cutting, or dissolving, prior to ingestion.
Results
Of the 24,000 study participants, 4,590 reported a history of prescription opioid NMU and met inclusion criteria for analysis: 3,477 (75.8%) reported prescription opioid NMU via oral intact only; 438 (9.5%) reported oral manipulation but no non-oral routes of administration; 390 (8.5%) reported non-oral routes of administration but no oral manipulation; and 285 (6.2%) reported both oral manipulation and non-oral route of administration. Compared to oral intact only users, those who reported oral manipulation and/or non-oral routes were more likely to be male, younger in age, and cover healthcare costs through Medicare and/or Medicaid. They were also more likely to have been arrested compared to oral intact only users. Those who reported oral manipulation (with or without non-oral routes) were more likely to be currently enrolled in a college or university than those who reported prescription opioid NMU via oral intact route only. The prevalence of lifetime diagnosis of select behavioral and mental health comorbidities was significantly higher among all oral manipulation and non-oral route study groups compared to the oral intact only group. The prevalence of anxiety, ADHD, bipolar, and alcohol use disorder was similar between those who reported prescription opioid NMU via oral manipulation and those who reported non-oral routes. The prevalence of substance use disorder significantly increased from the oral manipulation group to the non-oral route group to the oral manipulation plus non-oral route group. The age of initiation for most substances was younger among those in the oral manipulation and non-oral route groups compared to the oral intact only group. In relation to polysubstance use, the prevalence of concomitant use of tobacco, alcohol, marijuana, cocaine, sedatives, methamphetamine, prescription stimulants, heroin, and street fentanyl was significantly higher for those reporting prescription opioid NMU via oral manipulation and those reporting any non-oral route of administration compared to the oral intact only group. The prevalence of use to treat or prevent opioid-related withdrawal was similar between those who reported prescription opioid NMU via oral manipulation only (11.9) and non-oral routes only (13.6), yet over 3 times that (42.5) for those who reported both oral manipulation and non-oral routes of administration. Interestingly, those who reported oral manipulation were significantly more likely to do so to treat pain, for energy/stimulation, or to enhance the effect of other drugs than those who reported prescription opioid NMU via non-oral routes.
Conclusion
This study illustrates that biopsychosocial characteristics and behaviors of individuals that engage in prescription opioid NMU via oral manipulation are more similar to those that engage in non-oral routes of administration than with those that engage in oral intact route only. Hence, oral manipulation cannot be presumed as benign or insignificant. While this study did not allow for determination of causation, the data suggest a greater likelihood of high-risk behaviors in those who engage in prescription opioid NMU via oral manipulation than oral intact. These conclusions may be surprising to clinicians who view non-oral (intranasal or intravenous) use as the first sign of concerning behavior. Overall, these findings have significant implications for clinicians and the greater research community as they highlight why oral manipulation (chewing, crushing, dissolving prior to ingestion) of a prescription opioid medication is not to be ignored and should be as concerning as non-oral use: both oral manipulated and non-oral routes suggest a significant potential for prescription opioid misuse, abuse and diversion, and related consequences such as overdose and death.
References
[1] Ciccarone D (2021). The rise of illicit fentanyls, stimulants and the fourth wave of the opioid overdose crisis. Curr Opin Psychiatry. 34, 344–350.
[2] Jones CM, Bekheet F, Park JN, Alexander GC (2020). The evolving overdose epidemic: synthetic opioids and rising stimulant-related harms. Epidemiol Rev. 42, 154–166.
[3] Green JL, Bucher Bartelson B, Le Lait MC, Roland CL, Masters ET, Mardekian J, Bailey JE, Dart RC (2017). Medical outcomes associated with prescription opioid abuse via oral and non-oral routes of administration. Drug Alc Dependence. 175, 140–145.
Abstract #33 Submission ID#1307993
Effectiveness of Battlefield Acupuncture on Pain Outcomes at the Carl Vinson VA Medical Center
Nieka Jacksona, Rachel Barrb
aPain Clinical Pharmacist Practitioner, Carl Vinson VA Medical Center; bClinical Pharmacist Practitioner, Carl Vinson VA Medical Center
Learning Objectives
Define Battlefield Acupuncture and its theoretical mechanism in pain management.
Understand the potential role of Battlefield Acupuncture in chronic pain management.
Identify the effectiveness of battlefield acupuncture on pain outcomes in a rural Veteran population.
Purpose
Over 50% of Veterans currently suffer from chronic pain in the United States. Battlefield acupuncture is a type of auricular acupuncture that is offered to Veterans as an alternative or adjunctive option to pain medications to reduce chronic pain. The theoretical mechanism involves semi-permanent, gold-plated needles being placed in the ear and interfering with pain in the central nervous system. This project’s purpose is to further analyze battlefield acupuncture’s effectiveness in managing chronic pain and decreasing the number of pain medications needed. Methods
This quality improvement project was approved by the P&T committee in September 2021. Assessment of effectiveness of battlefield acupuncture will include two parts – one being a retrospective chart review and the other a standardized questionnaire. Patients were included if they have completed at least one session of battlefield acupuncture from March 2021 to August 2021. Patients were excluded if they had an allergy to gold, refused therapy, had an aversion to needles, or were currently pregnant. This yielded a total of 293 patients.
Data collected through retrospective chart reviews included age, race, gender, and chronic pain indication. In addition to the retrospective chart review, standardized questionnaires were given via telephone or through face to face visit to assess Veteran perceived effectiveness. Questions asked assessed how effective patients have found BFA to be in alleviating their pain as well as how long pain relief lasted, any side effects of treatment, and if they would like to continue battlefield acupuncture in the future. If a participant did not desire to continue with treatment, they were asked the reason for discontinuation.
Results
The average age of patients was 55.5 years old. 69.3% of patients were male, and the majority of patients were either African American (55.5%) or Caucasian (41.6%). A variety of pain indications were seen, with the most common being back, knee, shoulder, and neck pain, as well as headache/migraine. 19.7% of patients had just one pain indication, 29.5% had two indications, and 50.7% of patients had three or more indications for BFA. 68% of patients found BFA to be beneficial in treating their chronic pain, with length of benefit most often being less than 2 weeks. Veterans who discontinued BFA most often did so due to ineffectiveness, with adverse effects being the second most common reason. The most common adverse effects involved external trauma to the ears.
Conclusion
Battlefield acupuncture performed at the Carl Vinson VA Medical Center from 1 March 2021 to 31 August 2021 provided benefit to over half of Veterans regarding pain reduction. Shorter follow-up visits may lead to improved outcomes, as Veterans most often reported pain relief lasting less than two weeks after receiving battlefield acupuncture. Adverse effects often involved external trauma to the ears. However, most adverse effects could likely be presumed as mild, as only 19% of Veterans who discontinued BFA did so because of this.
Further research should be done on the potential differences in effect among race, sex, and age. Further research should also be done to determine BFA’s effect on potential reduction of opioids and other pain medications.
Abstract #34 Submission ID#1308008
Cross-sectional Study of Tampering in an Abuse-Deterrent Formulation of an Extended-Release Opioid in a Treatment Center Population
Jennifer S. Jewella, Joshua Blackb, Matthew Ellisc, Heather Olsend, Janetta Iwanickie, Richard Dart
aAssistant Research Scientist, Rocky Mountain Poison and Drug Safety; bSenior Research Scientist, Rocky Mountain Poison and Drug Safety; cInstructor, Washington University in St. Louis; dBiostatistics Manager, Rocky Mountain Poison and Drug Safety; eScientific Director, Rocky Mountain Poison and Drug Safety; fDirector, Rocky Mountain Poison and Drug Safety
Learning Objectives
Describe the real-world utility of an ADF opioid (oxycodone myristate) in a treatment center population.
Understand how the tampering rates in a treatment center population differ among different formulations of opioids.
Make educated decisions about the most appropriate opioid to prescribe for their patients.
Purpose
Opioid use disorders continue to plague many individuals even as misuse and abuse of prescription opioids has decreased [1]. Though prescription opioid abuse in general remains high among those with opioid use disorder (OUD) [2], abuse of immediate-release (IR) and extended release (ER) formulations does not occur equally. Among individuals with OUD, use of IR formulations was preferred over ER formulations, where ease of manipulation was cited as a chief reason for preferring the IR products [3]. Though IR formulations have had higher rates of abuse, ER formulations have historically been physically tampered with and used via unintended methods (e.g. chewing, smoking, snorting, or injecting) [4]. In response to this abuse, pharmaceutical companies have developed abuse deterrent formulations (ADFs) for extended-release opioids. These formulations are designed to reduce a person’s ability to easily tamper with a drug, and they present a barrier against the person using in a manner not intended by the drug manufacturer, which has been shown to dissuade some individuals from transitioning from oral use to non-oral use [4]. While all ER oxycodone drugs now utilize ADFs to reduce tampering, there is still information to be gathered about their real-world utility [5]. The chemical formulation for XTAMPZA ER’s ADF is oxycodone myristate, which keeps its extended-release properties even with tampering to the drug. To test the effectiveness of oxycodone myristate, its rate of tampering in a treatment center population was compared to immediate release (IR) single entity (SE) oxycodone, other ER oxycodone opioids, and ER oxymorphone.
Methods
This cross-sectional study utilized data from the Treatment Center Programs Combined, which are included in the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System. The RADARS® System is a mosaic of programs that collect and report on trends in drug use throughout the US [6]. These data were collected between the third quarter of 2018 and the third quarter of 2021 from individuals upon entry into opioid treatment programs, and it included basic demographic data as well as drug history. The 163 treatment centers participating in the study are nationally distributed throughout 46 states and the District of Columbia. Both privately funded clinics and publicly funded opioid treatment programs participate. Surveys are self-administered and anonymous. Participants are asked about which drug products they used ‘to get high’ in the past month and the route they used. For the purposes of these analyses, tampering was defined as chewing, smoking, snorting, or injecting an opioid. They were able to select as many opioids and routes of use as necessary. As a result, participants could have used more than one drug group during the study period. The analyses for this study investigated the relationship between oxycodone myristate tampering and three comparators: 1) IR SE oxycodone, 2) other ER oxycodone, and 3) ER oxymorphone. IR SE oxycodone was selected because IR formulations are more frequently prescribed than ER formulations [1], making them generally more available for abuse than ER formulations. No IR oxycodone formulation currently has abuse-deterrent labeling. Other ER oxycodone was selected because all current formulations are labeled as abuse-deterrent, presenting a contrast to a similar drug. Finally, ER oxymorphone was selected because it has high abuse potential via manipulation and manipulation has produced adverse health events historically. Logistic regression was used to estimate odds of manipulating oxycodone myristate compared to each drug comparator.
Results
The participants in this study were 57.6% male and predominantly white (78.4%). The mean age was 36.7 (SD = 9.9). Of the 2,273 participants, 35.2% had previously overdosed on an opioid, and 33.9% had never previously been in a substance abuse treatment program. Health care professionals made up 5.6% of the sample, and 3.1% were former active-duty armed forces personnel. The highest percent of manipulation was seen in IR SE oxycodone (72.5%, 95% CI: 69.9, 74.9). ER oxymorphone had the next highest rate at 66.7% (95% CI: 62.1, 71.2), followed by ER oxycodone with 56.4% (95% CI: 53.9, 58.8) and oxycodone myristate with the lowest manipulation rate at 38.5% (95% CI: 23.4, 55.4). Overlap among the categories of drug manipulation was high. Only 16 individuals (< 1%) tampered with oxycodone myristate alone, while 1,066 individuals (42%) tampered with ER oxycodone alone. Those that tampered with both IR SE oxycodone and other ER oxycodone made up 14% (N = 357) of the sample. Logistic regression analyses found that oxycodone myristate had lower odds of manipulation when compared to both IR SE oxycodone (OR = 0.23 [0.11, 0.50], p = 0.0002) and ER oxymorphone (OR = 0.30 [0.14, 0.67], p = 0.0038). Oxycodone myristate was not significantly different from other ER oxycodone opioids (OR = 0.5 [0.24, 1.03], p = 0.0612). These findings did not change when the estimates were adjusted for age and gender.
Conclusion
The results of this study provide community-based, real-world evidence of the abuse deterrence of the oxycodone myristate formulation. These findings demonstrate that, in a sample of individuals entering a treatment program, oxycodone myristate is less likely to be manipulated than IR SE oxycodone and ER oxymorphone but was statistically no different than other abuse-deterrent oxycodone drugs. As seen by Severtson et al. [7], the reduction in tampering seen in this study may also extend to other real-world settings, such as those abusing, but not seeking treatment. These findings also provide additional post-market evidence of the real-world utility of ADF opioids [8, 9]. Though the estimated odds ratio was notable, no significant difference was observed between the two types of abuse-deterrent oxycodone products. This suggests that individual abuse-deterrent technologies could result in different reductions in abuse, but, due to the rarity of manipulation of oxycodone myristate, this study was insufficiently powered to detect smaller effects. This finding highlights a need to evaluate each individual ADF technology separately. Disseminating information and research into ADF technology and outcomes, particularly among clinicians managing chronic pain, would add to the range of options clinicians have to combat misuse, abuse, and opioid use disorder.
References
[1] Iwanicki, J.L., et al., Abuse and Diversion of Immediate Release Opioid Analgesics as Compared to Extended Release Formulations in the United States. PLOS ONE, 2016. 11(12): p. e0167499.
[2] Cicero, T.J., M.S. Ellis, and Z.A. Kasper, Polysubstance Use: A Broader Understanding of Substance Use During the Opioid Crisis. Am J Public Health, 2020. 110(2): p. 244–250.
[3] Cicero, T.J., M.S. Ellis, and Z.A. Kasper, Relative preferences in the abuse of immediate-release versus extended-release opioids in a sample of treatment-seeking opioid abusers. Pharmacoepidemiol Drug Saf, 2017. 26(1): p. 56–62.
[4] Katz, N., et al., Tampering with prescription opioids: nature and extent of the problem, health consequences, and solutions. Am J Drug Alcohol Abuse, 2011. 37(4): p. 205–17.
[5] Larance, B., et al., The effect of a potentially tamper-resistant oxycodone formulation on opioid use and harm: main findings of the National Opioid Medications Abuse Deterrence (NOMAD) study. The Lancet Psychiatry, 2018. 5(2): p. 155–166.
[6] Dart, R.C., et al., Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med, 2015. 372(3): p. 241–8.
[7] Severtson, S.G., et al., Postmarketing Analysis of Misuse, Abuse, and Diversion of Xtampza ER. Pain Med, 2020. 21(12): p. 3660–3668.
[8] Salwan, A.J., N.E. Hagemeier, and S. Harirforoosh, Abuse-Deterrent Opioid Formulations: A Key Ingredient in the Recipe to Prevent Opioid Disasters? Clinical Drug Investigation, 2018. 38(7): p. 573–577.
[9] Brown Jr, M.D.F.R.E., Abuse-deterrent formulations of opioids: Many questions still to answer. Journal of Opioid Management, 2017. 13(6): p. 353–356.
Abstract #35 Submission ID#1308102
Cocaethylene: When Cocaine Meets Alcohol
Joseph Pergolizzia, Frank Breveb, Jo Ann LeQuangc, Morgan Wagnerd, Giustino Varrassie
aCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other; bConsultant, Mid-Atlantic PharmaTech Consultants, LLC.; cWriter, NEMA Research, Inc.; dChief of Staff, NEMA Research; ePresident, Paolo Procacci Foundation (FPP), Rome
Learning Objectives
Upon completion, participants will be able to identify the psychoactive metabolite produced by concurrent ingestion of ethanol and cocaine.
Upon completion, participants will be able to describe the potential clinical ramifications of treating cocaine toxicity when the patient has ingested alcohol.
Upon completion, participants will be able to explain how ethanol alters the metabolic pathway of cocaine.
Purpose
Polysubstance drug use may be more the norm than taking individual recreational substances and a common pairing is cocaine with alcohol. Even among users, it is not widely appreciated that cocaine and alcohol interact together in important and potentially dangerous ways. When cocaine and ethanol are taken together, a psychoactive metabolite known as cocaethylene is produced which as similar pharmacological and psychoactive properties as cocaine, but it is more toxic to the cardiovascular and hepatic systems and has a longer plasma elimination half-life. For those consuming alcohol plus cocaine, it is often not possible to predict the serum concentration of cocaethylene in the body because the timing of ingestion of alcohol and cocaine as well as relative quantities play a role.
While cocaethylene is frequently encountered by first responders and emergency medical professionals, it has not been thoroughly studied and many clinicians are not aware of it, its role in overdose toxicity, cocaine-induced heart disease, and driving under the influence. The purpose of our poster is to describe cocaethylene and its role in complicating overdose care.
Methods
This is a narrative review of the literature intended to raise awareness about cocaethylene and its possible effects on clinical outcomes of cocaine-using patients. Using cocaethylene as the keyword, the PubMed database was searched (473 results) and further articles were obtained using the ‘similar features’ option in PubMed. When results were narrowed to the past five years, there were 63 total results. We searched Embase (542 results), Web of Science (2 results), and Cochrane Library (17 meta-analyses). We reviewed all of these materials in order to present a comprehensive overview of what cocaethylene is, how it occurs, and why clinicians need to consider it when treating patients who may have overdosed on cocaine.
Results
Taking ethanol alters the metabolic pathway of cocaine; instead of hydrolysis with water, the cocaine undergoes transesterification with ethanol and produced cocaethylene. This is the only known situation in which a novel psychoactive substance is created entirely within the body. The overall effects of cocaethylene are like those of cocaine and the two molecules are structurally and chemically similar.
Consuming cocaine and ethanol together reduces clearance of both substances by about 20%.1 Cocaethylene, like the parent drug, blocks dopamine reuptake and reinforces the stimulating effects of dopamine, contributing to the feelings of energy and focus. While cocaethylene and cocaine are equipotent in terms of producing the feelings of excitement and focus, cocaethylene has a much longer half-life ands its effects persist longer. While cocaine appears to block serotonin reuptake, cocaethylene is more selective for dopamine reuptake inhibition.
Cocaethylene increases blood pressure and heart rate to a greater extent than cocaine and is considered ten times as cardiotoxic.2 Cocaethylene worsens outcomes for trauma patients because of its deleterious hemodynamic and systemic effects.3,4
The popularity of alcohol plus cocaine may be due to the fact that alcohol seems to prolong cocaine’s psychoactive effects. The phenomenon of polysubstance abuse is not well studied.
The clinical implications are concerning. When clinicians treat patients with cocaine intoxication, they should ask about alcohol use and consider that there may be a potent and potentially cardiotoxic metabolite. A patient who is still experiencing psychoactive effects long after consumption of cocaine may be experiencing the effects of cocaethylene, with a half-life about double that of the parent drug. Greater education is needed for substance users, even recreational drug users, as well as families, friends, and clinicians.
Conclusion
Cocaethylene is the only psychoactive substance produced entirely in the human body and it occurs when ethanol and cocaine are taken together. Considered far more cardiotoxic than cocaine and with a much longer half-life, cocaethylene is an important clinical consideration when treating patients with cocaine intoxication. While the psychoactive effects of cocaine and cocaethylene are similar (focus, energy, enthusiasm), cocaethylene is a more selective dopamine reuptake inhibitor. Greater awareness is needed among recreational drug users and clinicians. Clinicians may sometimes treat patients who appear to be under the influence of cocaine long after they have consumed it; such patients may be experiencing the prolonged and potentially dangerous effects of cocaethylene.
References
[1] SC, Mandrell T, Gades NM, Parker RB. Cocaethylene metabolism and interaction with cocaine and ethanol: role of carboxylesterases. Drug Metab Dispos. 2003;31(1):16–20.
[2] Wilson LD, Jeromin J, Garvey L, Dorbandt A. Cocaine, ethanol, and cocaethylene cardiotoxity in an animal model of cocaine and ethanol abuse. Acad Emerg Med. 2001;8(3):211–222.
[3] Brotto V, Lee G. Substance use and its implications for the critical care nurses: a literature review. Intensive Crit Care Nurs. 2007;23(2):64–70.
[4] Oliveira KD, Fraga GP, Baracat ECE, et al. Prevalence of cocaine and derivatives in blood and urine samples of trauma patients and correlation with injury severity: a prospective observational study. Eur J Trauma Emerg Surg. 2019;45(1):159–165.
Abstract #36 Submission ID#1308131
The Heat is On: When Hot Weather Hurts
Joseph Pergolizzia, Jo Ann LeQuangb, Morgan Wagnerc, Giustino Varrassid
aCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other; bWriter, NEMA Research, Inc.; cChief of Staff, NEMA Research; dPresident, Paolo Procacci Foundation (FPP), Rome
Learning Objectives
Upon completion, participants will be able to explain how the ‘heat index’ is a more reliable indicator of heat threat to patients than air temperature.
Upon completion, participants will be able to describe symptoms and steps to take if a person appears to be experiencing heat stroke.
Upon completion, participants will be able to name at least one medication (or type of medication) that can adversely affect the body’s cooling system.
Purpose
Both meteorologists and the Farmer’s Almanac predict an unusually hot summer in 2022. From 2018 to 2020, the Centers for Disease Control and Prevention (CDC) reported 3,066 heat-related deaths. According to the CDC, the most affected age group for heat mortality are those between the ages of 55 to 64. The body maintains a core temperature of around 104° Fahrenheit; perspiration combined with vascular efforts to migrate overheated blood to the periphery is the body’s compensatory mechanism to cool down. Humid weather impairs this adaptive function and has given rise to the ‘heat index,’ a combination metric that provides a ‘feels like’ temperature using heat plus humidity. When the body becomes overheated, cellular damage can occur and lead to a potentially fatal physiologic cascade to organ failure. Besides heat-related illnesses such as heat exhaustion and heat stroke, heat can have adverse consequences on those with preexisting chronic conditions. The purpose of this poster is to describe how heat affects us all and how heat affects people with chronic pain in particular. Methods This is a narrative review based on authoritative websites and a literature search using the Medline databases of the National Institutes of Medicine. There is a paucity of research on the impact of heat on preexisting condition.
Results
Heat-related conditions can occur in people of all ages with all different degrees of heath. These include sunburn, heat rash, heat cramps, heat exhaustion, and the life-threatening emergency of heat stroke. People who work or exercise outdoors in the heat for prolonged periods of time are particularly vulnerable.
People with cardiovascular deficits may be at elevated risk for heat-related problems because part of the body’s compensatory cooling system involves moving blood from the core to the periphery for cooling. Vascular compromise can make this difficult.
Not often reported is the role of medication in heat-related illness. Drugs that help regulate the balance of salt and water in the body, such as hypertension medications, can adversely affect how the body responds to heat.
Dehydration can cause painful symptoms, particularly headache and muscle aches. Drinking alcohol or caffeine can have dehydrating effects.
Bright sunlight is a frequently reported trigger for migraine headaches. Even those who are not migraineurs may experience headache with prolonged exposure to the heat and bright light.
Heat can also cause muscle spasms which can exacerbate the pain experienced by those with chronic back pain or other chronic musculoskeletal conditions. Heat may exacerbate inflammation, which can intensify the chronic pain associated with many diseases such as chronic pelvic pain, gout, or pain associated with an infection.
Finally, high temperatures can interfere with restorative sleep. For chronic pain patients already struggling to sleep, this can intensify their pain and heighten their discomfort. For those with mood disorders, frequently comorbid with chronic pain, the uncomfortable feelings of being too hot can intensity irritability and distress.
Many chronic pain patients depend on exercise to manage their pain, at least in part. High temperatures can limit the activities of those who walk, cycle, or exercise outside and may promote sedentariness. For many chronic pain patients, this will over time exacerbate pain. Water exercises can be helpful in the hot summer months, particularly for those with joint pain.
Topical analgesic products can be combined with sunscreen for outdoor use. The best protections against heat-related pain are obvious: stay in the shade as much as possible, cool down (or go inside a cool place) when you feel overheated, drink lots of water, and wear loose light-colored clothing.
Note that heat exhaustion is characterized by profuse perspiration, clammy skin, and dizziness; sometimes people also get nauseous and have muscle cramps. Call for emergency help at once if a person has heat stroke, characterized by hot, dry skin, a high body temperature, and symptoms of nausea, headache, confusion, and disorientation. Heat stroke can be fatal.
Conclusion
The summer of 2022 will be abnormally hot and this means there is a greater-than-average risk for heat-related illnesses and even mortality. For people with preexisting painful conditions or preexisting disorders such as heart disease, heat can pose special problems. Bright sunlight and high temperatures can trigger headaches; hot weather and a high heat index can cause muscle cramps. Heat may also exacerbate inflammatory conditions, interfere with good sleep, and reduce the ability to exercise outdoors. As much as possible, everyone should avoid extreme heat, keep well hydrated, and stay in the shade when possible.
Abstract #37 Submission ID#1308138
Real-World Effectiveness of Ubrogepant for the Acute Treatment of Migraine in Combination with OnabotulinumtoxinA Preventive: Results from the COURAGE Study
Richard Ba, Ella Engstromb, Daniel Serranob, Linda Davisc, Katherine Sommerd, Janette Contreras-De Lamad, Susan Hutchinsone
aNeurology, Albert Einstein College of Medicine; bNeurology, OPEN Health; cNeurology, Kolvita Family Medical Group; dNeurology, AbbVie; eNeurology, Orange County Migraine and Headache Center
Learning Objectives
Upon completion, participant will be able to describe the design of the prospective, observational, app-based COURAGE study.
Upon completion, participant will be able to discuss the real-world use of acute and preventive treatment in people with migraine.
Upon completion, participant will be able to summarize the real-world effectiveness of ubrogepant when used as an acute treatment in combination with onabotulinumtoxinA preventive treatment for migraine.
Purpose
Ubrogepant is an oral calcitonin gene–related peptide (CGRP) receptor antagonist approved for the acute treatment of migraine and may be used to treat breakthrough attacks by individuals using preventive medications. This analysis evaluated the real-world effectiveness of ubrogepant when used in combination with onabotulinumtoxinA.
Methods
Using data collected via the Migraine Buddy application, this prospective, observational study evaluated real-world acute treatment effectiveness in people taking preventive treatment and ubrogepant 50 mg or 100 mg for acute treatment of migraine. Eligible participants were adults who reported ≥3 migraine attacks in the last 30 days, had treated ≥3 prior attacks with ubrogepant, and were concurrently taking an anti-CGRP monoclonal antibody (mAb), onabotulinumtoxinA, or both as migraine preventive treatment. Self-reported assessments were collected daily for approximately 30 days. Daily assessments included meaningful pain relief (MPR), defined as a reduction of headache pain to a meaningful degree or remaining pain free if no pain was reported at ubrogepant dosing, and return to normal function (RNF) after dosing. This analysis reports results from the first ubrogepant-treated attack and first 10 ubrogepant-treated attacks in the ubrogepant plus onabotulinumtoxinA group. The repeated attack endpoints were modeled via logistic generalized estimating equations to account for the correlated nature of the repeated attacks.
Results
A total of 122 participants reported using ubrogepant as acute treatment in combination with onabotulinumtoxinA (without an anti-CGRP mAb) as migraine preventive treatment. A median of 9 attacks (IQR, 6–12) per respondent were recorded. The mean age of participants was 40.4 years, and the majority of participants were female (95.9%) and White (92.2%); 86.9% of respondents had severe or very severe disability as measured by the Migraine Disability Assessment (MIDAS), 84.2% were triptan insufficient responders, 55.7% used ubrogepant 100 mg, and most participants (82.5%) took a single dose of ubrogepant to treat an attack. For the first ubrogepant-treated attack at 2 and 4 hours post-dose, MPR was achieved in 53.3% and 76.2% of participants, respectively. RNF was achieved by 25.4% and 45.9% of ubrogepant-treated participants at 2 and 4 hours post-dose, respectively. For the first 10 ubrogepant-treated attacks, MPR was achieved in 44.8% and 72.9% of attacks at 2 and 4 hours post-dose, respectively. RNF was achieved by 30.1% and 52.1% at 2 and 4 hours post-dose, respectively, for the first 10 ubrogepant-treated attacks.
Conclusion
These findings support the real-world effectiveness of ubrogepant as an acute treatment in combination with onabotulinumtoxinA, providing evidence for a common treatment pattern. These results also demonstrate the feasibility of using a novel, app-based design to evaluate the real-world effectiveness of migraine treatment. Evaluating the real-world effectiveness of ubrogepant in combination with other preventive treatments is an area of future research consideration.
Abstract #38 Submission ID#1308152
When an Old Drug Brings New Challenges: Nitazenes
Joseph Pergolizzia, Frank Breveb, Jo Ann LeQuangc, Morgan Wagnerd, Giustino Varrassie
aCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other; bMid-Atlantic PharmaTech Consultants, LLC; cWriter, NEMA Research, Inc.; dChief of Staff, NEMA Research; ePresident, Paolo Procacci Foundation (FPP), Rome
Learning Objectives
Upon completion, participants will be able to briefly give a short history of nitazenes in the United States.
Upon completion, participants will be able to explain how and why nitazenes are being detected in the recreational drug supply.
Upon completion, participants will be able to name the main challenge nitazenes and their analogs pose to the Drug Enforcement Administration.
Purpose
In the late 1950s, the synthesis of 2-benzylbenzimidazole opioids led the development of several new synthetic opioid analgesics, none of which were cleared or market release. These nitazenes were extremely potent agents and older medical literature documented their chemistry. Recently, toxicology reports have documented the emergence of nitazenes in the recreational drug stream. Illicit nitazenes, manufactured in clandestine labs, have entered the street drug trade with alarming consequences.
The public health crisis of opioid use disorder has caused considerable financial impact to the healthcare system and our society at large. This cost is so large it is difficult to estimate fairly. In 2017–2018, the U.S > spent $2 billion just on treating opioid overdoses. An out-of-hospital successful opioid rescue cost an estimated $3000 per event.1 Over dose deaths are a main cause of death for Americans aged 25 to 64 years,2 (and nonfatal overdoses can be associated with prolonged and costly opioid-related morbidity. The emergence of new and highly potent synthetic opioids is alarming.
Our aim was to report on nitazenes as the latest new synthetic opioid family and the clinical implications of their arrival on the recreational drug scene.
Methods This is a narrative review and was based on recent literature about the reemergence of nitazenes. Medline and Google Scholar databases were used along with authoritative websites, particularly government-run sites reporting on this as news. There is very little recent material available about nitazenes.
Results
Nitazenes are potent mu-opioid receptor agonists with psychoactive effects similar to heroin. There are several of these agents, the best known of which is isotonitazene (street name Iso or Tony), which was first identified in Europe in 2019. Metonitazene was identified in North America in 2020. The creation of numerous analogs is possible and technically not an obstacle. Some, but not all, nitazenes are as potent or more potent than fentanyl. Metonitazene was confirmed to be present in 20 forensic autopsies and in most cases was used in combination with other drugs.3 A 2021 analysis in Tennessee found metonitazene and fentanyl as a combination occurred in 26 overdose deaths.4
Nitazenes are sometimes mixed with other drugs to add potency, and consumers are not necessarily aware of nitazene additives. Counterfeit pharmaceutical products such as counterfeit hydromorphone tablets have been identified. In this case, inert material is mixed with nitazenes and formed to resemble a pharmaceutical product using a pill press.5 (Pill presses are available for sale on Google.)
Some of these ‘new, old’ nitazenes fall outside the Drug Enforcement Administration’s schedule of controlled substances, giving them a murky legal status. Their manufacture in clandestine labs assures that there are no purity, quality, or manufacturing standards. Each new agent brings with it its own toxicity and specific challenges.
The clinical implications are profound because first responders and many emergency clinicians are not aware of nitazenes and many drug users take them without knowing it. Most labs do not routinely test for nitazenes so their presence in the recreational drug stream may be underreported.
Conclusion
Nitazenes are infiltrating the recreational drug market with potentially devastating consequences. These potent synthetic opioids may be mixed in with other drugs or taken in polysubstance abuse and have been associated with overdose mortality. Greater awareness of nitazenes are needed in both the clinical and first-responder communities. The mechanics of nitazene-induced respiratory depression are not elucidated, and rescue protocols should be developed. Nitazene-associated respiratory depression and distress can be challenging to treat.
References
[1] LaPointe J. Opioid overdose care totals $1.94B in annual hospital costs. Revcycle intelligence. Practice management news Web site. Published 2019. [cited 6 June 2022]. Available from: https://revcycleintelligence.com/news/opioid-overdose-care-totals-1.94b-in-annual-hospital-costs.
[2] Dezfulian C, Orkin AM, Maron BA, et al. Opioid-Associated Out-of-Hospital Cardiac Arrest: Distinctive Clinical Features and Implications for Health Care and Public Responses: A Scientific Statement From the American Heart Association. Circulation. 2021;143(16):e836-e870.
[3] Krotulski AJ, Papsun DM, Walton SE, Logan BK. Metonitazene in the United States – Forensic toxicology assessment of a potent new synthetic opioid using liquid chromatography mass spectrometry. Drug test and anal, 2021–10, Vol13 (10), p1697-1711. 2021.
[4] Trecki J, Gerona RR, Ellison R, Thomas C, Mileusnic-Polchan D. Notes from the Field: Increased Incidence of Fentanyl-Related Deaths Involving Para-fluorofentanyl or Metonitazene – Knox County, Tennessee, November 2020-August 2021. MMWR Morb Mortal Wkly Rep. 2022;71(4):153–155. 5. Ujváry In, Christie R, Evans-Brown M, et al. DARK Classics in Chemical Neuroscience: Etonitazene and Related Benzimidazoles. ACS chem neurosci, 2021–04-07, Vol12 (7), p1072-1092. 2021.
Abstract #39 Submission ID#1308286
Mobile Health Technology & Pain Management
Lynn R. Webstera, Scott Cashonb, Jeff Gudinc, Charles Argoffd
aChief Medical Officer [email protected] Painnscript; bCTO, PainScript; cProfessor, Consultant, U of Miami Dept Anesthesiology, Periop Med and Pain Mangement; dPhysician, Albany Medical Center
Learning Objectives
Understand how M-Health technology can improve physician -patient communication.
Understand how treatment plan adherence can be improved with M-Health technology.
Understand how M-Health technology can provide safeguards against legal liability.
Purpose
Chronic pain imposes a significant burden on individuals and society. Patient adherence is important for safety and treatment effectiveness. Like many chronic illnesses, more frequent Health Care Professional (HCP) interaction with chronic pain patients would benefit the provider’s ability to monitor treatment response to enhance patient safety as well as the efficacy of the treatment. Unfortunately, practical and payor limitations limit this approach, with much care reliant on delayed visits or suboptimal communication through telephone messages. This operational issue/work-flow problem leads to delayed care and unreported changes in clinical status especially including adverse events. In addition, documentation is lacking to justify the need for intervention or prescription changes with opioids as well as other medications. Current health record practices reduce the ability to track clinical data outside of direct face-to-face care, resulting in insufficient documented evidence to support practice treatment decisions and potentially provide litigation protection.
A mobile health (mHealth) technology platform has been developed (PainScript) that enhances communication between clinic staff and patients to improve outcomes. The PainScript platform is innovative in its focus on physician practice management, providing a patient-monitoring capability to support adherence with treatments (pharmacologic and nonpharmacologic) and provide early detection of adverse/serious adverse events.
An mHealth intervention is particularly timely now that the Covid-19 pandemic has increased telehealth utilization, changing the delivery of healthcare. Telehealth is a new and proven communication approach, focused on clinical information for improving care; different modalities, recognized by the AMA CPT, include remote Patient Monitoring (RPM), Digital Evaluation & Management (D E&M), Chronic Care Management (CCM), and Remote Therapeutic Monitoring (RTM). Specific examples identified for medication management include clinical questioning, dynamic text messages, smart pill containers/dispensers,1 interactive mobile apps,2 and support over the phone.
The majority of pain apps introduced in recent years have focused on the physical characteristics of pain, and few have supported clinician or staff access to real-time pain data and patient adherence.3 Furthermore, few available mHealth products for patients with chronic pain have the clinical evidence of improved patient outcomes needed for mHealth adoption and engagement. Here we review the PainScript platform as evaluated by clinicians and patients with chronic pain.
Methods
The PainScript patient app provides a HIPAA-compliant and accessible connection between patients and providers. It is integrated into the practice electronic health record (EHR). Patients are enrolled using a smartphone and a digital telehealth app. Once enrolled, patients will provide clinical information, guided by their physician through text messaging, with 3 daily clinically validated questions. The platform is also able to send patients medication reminders and assesses side effects and changes in clinically important measures of outcome. The responses to the questions are then reviewed by the practice via a secure HIPAA-compliant private clinical dashboard. A designated qualified healthcare provider evaluates the triaged responses which lie outside the normative range set by the provider. If required, the results will be elevated to the appropriate level of provider for decision-making.
Medication adherence is self-assessed by patients reporting metrics such as when they (1) take all meds as prescribed and (2) are not taking meds that are not prescribed. Assessment questions, direct and indirect, occur on a 14-day cycle to limit repetition of questions yet recur frequently enough to allow for sufficient sampling of clinical measurements. By the end of each 14-day cycle, the proposed National Chronic Pain Surveillance questions may also be covered.
Data collection began in November 2021 and has continued to the present. In this Abstract, all patients were reviewed for clinical responses over their first 12 weeks on the system. Note that regardless of when an individual response was collected, the data normalizes to when the patient answered the question relative to when they enrolled (for example, all Pain Scale answers from the first 2 weeks, week 3, week 4, etc.). We report here on experiences and data analysis from the platform.
Results
Through 30 June 2022, patients provided more than 55,000 individual daily clinical responses to their physicians in diverse locations across the United States.
Based on initial observational data across all those patients from baseline through 12 weeks on the PainScript platform, there was a 5.5% improvement in average reported levels of pain, 13% improvement in reported levels of fatigue, 17% improvement in reported levels of depression, 28% improvement in reported levels of anxiety, and 28% improvement reported levels of cravings. No patient data was excluded from the observation. Through 12 weeks, patients achieved a 99.8% adherence to their prescribed medication regime – including taking/not taking prescription and non-prescription medications as directed.
In nine previous peer-reviewed and published trials, almost all co-funded by the NIH or NIMH, of the PainScript Medi-eXpert system (2003−2016), Care Plan Adherence results are as follows: 98% satisfaction among caregivers, 95% care plan adherence rate in patients with heart disease (p = 0.002), 90% care plan adherence rate in senior citizens with diabetes, heart failure and fifth- and sixth-grade education levels, and 92% care plan adherence rates in patients with diabetes HbA1c, which was reduced by 8.5% in three months (p < 0.002). In addition, medication adherence results are as follows: 94% medication adherence rate in patients with heart disease, 89% medication adherence rate in patients with HIV, substance-use disorder (SUD), mental illnesses, and homelessness, and 95% medication adherence rate in patients with schizophrenia. Conclusion
The modernization of healthcare will be equally important to all clinicians, especially those who treat patients with chronic pain. Preliminary data suggests that PainScript telehealth technology can improve patient care, treatment plan adherence, and medication adherence. The platform bridges a treatment gap that occurs between visits and has been shown to improve clinically important outcomes. Improving physician-patient communication and patient monitoring may reduce the risk of opioid misuse and addiction and provide clinicians with information that can help differentiate addiction from tolerance and physical dependence.4 It may also provide the practice a means to be compensated by the Centers for Medicare & Medicaid Services and many other payors for the time and expertise of providing daily contact with patients, as well as safeguard against legal liability due to enhanced communication and affirmative documentation.
References
[1] Schuman-Olivier Z, Borodovsky JT, Steinkamp J, et al. MySafeRx: a mobile technology platform integrating motivational coaching, adherence monitoring, and electronic pill dispensing for enhancing buprenorphine/naloxone adherence during opioid use disorder treatment: a pilot study. Addict Sci Clin Pract. 2018;13(1):21.
[2] Guarino H, Acosta M, Marsch LA, Xie H, Aponte-Melendez Y. A mixed-methods evaluation of the feasibility, acceptability, and preliminary efficacy of a mobile intervention for methadone maintenance clients. Psychol Addict Behav. 2016;30(1):1–11.
[3] Zhao P, Yoo I, Lancey R, Varghese E. Mobile applications for pain management: an app analysis for clinical usage. BMC Medical Informatics and Decision Making. 2019;19(1):106.
[4] Volkow ND, McLellan AT. Opioid Abuse in Chronic Pain – Misconceptions and Mitigation Strategies. New England Journal of Medicine. 2016;374(13):1253–1263.
Abstract #40 Submission ID#1308303
Ultrasound-guided transversus abdominis plane block with liposomal bupivacaine in patients undergoing elective cesarean section via spinal anesthesia
Renee E. Marchegiania, Bryan E. Hierlmeierb
aInterventional Pain Fellow, University of Mississippi Medical Center; bProgram Director, University of Mississippi Medical Center
Learning Objectives
Learning how regional anesthesia can decrease opioid consumption in patients while in the hospital.
Learning how regional anesthesia can decrease pain scores while inpatient.
Learning how regional anesthesia can potentially help decrease patient pain scores even in the outpatient setting.
Purpose
Cesarean section surgery is a very common surgery in the United States and can affect women negatively during their recovery period. Many women experience moderate to severe post-cesarean pain post-operatively (1). Pain after cesarean section is caused from somatic pain due to abdominal wall incision as well as visceral pain from the uterus incision. Several previous studies have used a multimodal pain approach to better improve post-operative pain as well as to decrease the potential of opioid misuse with the current on-going opioid epidemic in the United States. A retrospective health claims study including 201,662 patients who underwent cesarean delivery determined that these women have a 28% increased risk for chronic opioid use compared with those not undergoing a surgery (2).
Multimodal pain approaches typically include a combination of nonsteroidal anti-inflammatory drugs, acetaminophen, systemic opioids, intrathecal opioids, local infiltration around surgical site, and/or various anesthesia regional blocks. Various combinations of these help to control both somatic and visceral pain from cesarean section as well as decrease opioid consumption and their potential side effects. One study illustrated that in cesarean delivery, intra-incisional infiltration of liposomal bupivacaine after completion of surgery had shown to reduce opioid consumption when compared with usual care (3). Enhanced recovery after surgery protocols (ERAS) programs that include transversus abdominis plane blocks are instituted across the country and in multiple specialties of medicine. One study illustrated the analgesic efficacy of the US-guided TAP block after Cesarean delivery have opioid-sparing effects, reduced antiemetic use, and improved satisfaction with pain relief while inpatient (4).
We compared the effects of TAP block with liposomal Bupivacaine in patients undergoing elective cesarean section via spinal anesthesia to those who did not receive the TAP block. We focused on opioid consumption while inpatient, pain scores, length of hospital stays, and patient satisfaction. Previous studies have illustrated that TAP blocks decrease opioid consumption while inpatient; however, there does not appear to be studies that look at patient’s opioid consumption outpatient. We also focused on opioid consumption and pain scores in the outpatient setting at their two-week follow-up.
Methods
This single-center prospective study was approved by the University of Mississippi Medical Center Institutional Review Board. We recruited 30 patients (age 18–45 years) who were scheduled for elective cesarean section under spinal anesthesia from 1 January 2022 to 30 June 2022. The exclusion criteria were: Emergent cesarean section, Pre-Eclampsia, COVID undergoing cesarean section, under 18 years, and/or allergies to the pain medications used. Patients were offered the TAP block versus no TAP block post-cesarean section. Patients who chose TAP block were placed in the experimental group while the patients who did not want a TAP block were placed in the control group. All study participants received a spinal containing Bupivacaine 0.75% (1.4 cc < 5 feet tall or 1.6cc > 5 feet tall), Fentanyl 10 mcg, Morphine 150 mcg, and Epinephrine 100 mcg for elective cesarean section. When surgery was complete, the experimental group patients received bilateral TAP blocks with liposomal Bupivacaine under SonoSite ultrasound guidance before leaving the operating room. The dose of liposomal Bupivacaine administered was 266 mg total which was diluted with normal saline to equal 60 ml. Patients received 30 ml liposomal Bupivacaine/Normal saline mixture bilaterally.
For pain assessment, the patients were asked to rate their pain at rest on a 0 to 10 pain scale (0 = no pain; 10 = imaginable pain) before leaving the operating room and the post-operation recovery room. All participants were then transferred to the inpatient floor for further recovery. All patients received oral Ibuprofen 800 mg TID, Tylenol 1 g TID, and Oxycodone 5 mg q4h PRN while inpatient. Patient’s pain with ambulation was re-assessed at 24 hours, 48 hours, and at time of discharge using the numeric 0 to 10 pain scale. Patients were discharged with a prescription of Percocet 5 mg q6h PRN (20 tablets) and Ibuprofen 800 mg q8h PRN.
Data was obtained from operative note, nursing notes and medicine administration times from EPIC. Patients were followed up at two weeks post-operation for pain scores, opioid consumptions, and satisfaction scores.
Results
There were 31 patients total with 19 being in the experimental (TAP block group) and 12 in the control group (No TAP block). At time of OR discharge, both groups had zero pain scores which is what we used for a baseline. Pain scores at time of PACU discharge, 24 hours, and at 48 hours were decreased in the TAP block group on average when compared to the control group. The time to first supplemental analgesia on average was increase to about 10 hours in the TAP group. In the control group, they typically received supplemental analgesia within 1.5 hours. Morphine equivalents that were consumed at 24 hours, 48 hours, and at time of discharge were decreased in the TAP group. At two weeks follow, pain scores in the TAP group were less than the control group; however, there was no difference in opioid consumption. Length of hospital stay and patient satisfaction scores between the two groups were the same.
Conclusion
Patients who received ultrasounds guided TAP block with liposomal Bupivacaine after elective cesarean section surgery illustrated lower pain scores and decreased opioid consumption while inpatient. At the two-week follow-up, the patients who received the TAP block had lower pain scores then the control group; however, there did not appear to be a difference in opioid consumption. Also, there was no difference in hospital stay or patient satisfaction scores.
References
[1] Pan PH, Tonidandel AM, Aschenbrenner CA, Houle TT, Harris LC, Eisenach JC. Predicting acute pain after cesarean delivery using three simple questions. Anesthesiology. 2013;118(5):1170–1179.
[2] Sun EC, Darnall BD, Baker LC, Mackey S. Incidence of and risk factors for chronic opioid use among opioid-naïve patients in the post-operative period. JAMA Intern Med. 2016; 176(9):1286–1293.
[3] Parikh P, Sunesara I, Singh Multani S, Patterson B, Lutz E, Martin JN Jr. Intra-incisional liposomal bupivacaine and its impact on postcesarean analgesia: a retrospective study. J Matern Fetal Neonatal Med. 7 November 2017; Epub.
[4] Belavy D, Cowlishaw PJ, Howes M, Phillips F. Ultrasound-guided transverse abdominis plane block for analgesia after Cesarean delivery. Br J Anaesth. 2009;103:726–30.
Abstract #41 Submission ID#1308386
Capsaicin 8% Topical System combined with Electric cell-Signaling Treatment (EcST) for the treatment of Painful Diabetic Peripheral Neuropathy (PDPN) of the feet: a case series
Jennifer Martina, David L Salyerb
aDNP, APRN, FNP-C, Neuropathy Treatment Clinic of Oklahoma; bPhD,Averitas Pharma, Morristown, NJ
Learning Objectives
Painful conditions such as PDPN often require multimodal therapy to achieve adequate long-term pain relief.
In this case series capsaicin 8% topical system was combined with Electric cell-Signaling Treatment in patients with PDPN, and after 3 months pain levels were reduced by almost 70%.
The combination of capsaicin 8% topical system with Electric cell-Signaling Treatment also reduced symptoms such as tingling, burning and numbness by 40–58% in patients with PDPN after 3 months.
Purpose
Painful diabetic peripheral neuropathy (PDPN) effects approximately 5.6 million people in the US.1 Although a variety of treatments are available, many patients continue to suffer from a lack of adequate pain control and require multiple modalities to sufficiently reduce the symptoms of PDPN.2 This case series examines the effects of two combined modalities, capsaicin 8% topical system* followed by Electric cell-Signaling Treatment (EcST), for the reduction of painful DPN symptoms.
Methods
Six adult patients naïve to both treatments were selected for this retrospective case series at the Neuropathy Treatment Clinic of Oklahoma. Each patient had type 2 diabetes (T2D) with good glycemic control, and unresolved clinically diagnosed PDPN of the feet. On Day 0, patients were treated with capsaicin 8% topical system on their feet for 30 min. On Day 7, patients began a prescribed 3 months (24 treatment sessions) of EcST. Baseline data were collected for pain as well as other symptoms reported by patients (burning, tingling, numbness, tightness, stabbing, throbbing) on Day 0 with subsequent data collection on Days 7, 30, 60 and 90. Percent pain reduction was compared to baseline at each timepoint. All other symptoms were measured on a numeric pain rating scale (NPRS; 0–10) at each of the time points.
Results
Two females and four males with an age range from 72 to 90 year old and a mean age of 79.8 years old were included in the case series. On average, patients had painful DPN for 9.5 years and T2D for 15.3 years (mean baseline HbA1C 6.47%). Common comorbidities included hypertension (n = 3), hyperlipidemia (n = 3), atrial fibrillation (n = 3), bilateral lower extremity edema (n = 3), and hypothyroidism (n = 2). Results showed mean reductions in pain from baseline at each time point (Day 7: 43.3%, Day 30: 48.4%, Day 60: 62.5%, and Day 90: 68.3%). The most prevalent patient-reported symptoms included tingling (n = 6), burning (n = 5), and numbness (n = 4), which were also reduced from baseline to Day 90 by 40%, 49%, and 58%, respectively. No serious adverse events were reported; however, all patients experienced mild and transient erythema of the treatment area following application of the capsaicin 8% topical system.
Conclusion
Multimodal treatment is often employed for adequate pain relief. In this case series, six adults with painful DPN were treated with capsaicin 8% topical system followed by EcST. The results showed a clinically meaningful effect with regard to pain relief, burning, tingling, and numbness. The capsaicin 8% topical system works as a neurolytic de-innervation agent and it has been shown to reduce epidermal nerve fiber density significantly after 1 week.3 EcST acts through multiple biochemical, biomechanical, and other physiological mechanisms to stimulate nerve regeneration.4 This case series suggests that combining these two treatment modalities may reduce the symptoms of painful DPN; however, more data are needed to understand these effects more accurately.
* QUTENZA® (capsaicin) 8% topical system is indicated in adults for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and for neuropathic pain associated with painful diabetic peripheral neuropathy (PDPN) of the feet.
References
[1] International Diabetes Federation. IDF diabetes atlas, ninth edition. 2019 2. Iqbal Z, et al. Clin Ther. 2018;40(6):828–850 3. Kennedy WR, et al. J Pain. 2010;11(6):579–587 4. Odell RH Jr, Pain Phys. 2008;11:891–907
Abstract #42 Submission ID#1308435
Efficacy of Methylnaltrexone in Patients with Advanced Illness and Opioid-Induced Constipation Refractory to Conventional Laxatives: Impact of Baseline Laxative Use
Gregory S. Sayuka, Rowe B. Brookfieldb, Nancy Stamblerc, Robert J. Israeld
aProfessor of Medicine and Psychiatry, Washington University School of Medicine; bAssociate Director, Medical Affairs, Salix Pharmaceuticals; cVice President, Biometrics and Data Management, Progenics Pharmaceuticals, Inc., a subsidiary of Lantheus Holdings, Inc.; dSenior Vice President Clinical and Medical Affairs, Bausch Health US, LLC
Learning Objectives
Describe the overall efficacy of methylnaltrexone for treatment of opioid-induced constipation.
Compare the efficacy of methylnaltrexone for treatment of opioid-induced constipation in patient subgroups stratified by baseline use of laxatives, including stimulants, osmotic agents, stool softeners, or combinations thereof.
Describe the safety of methylnaltrexone treatment.
Purpose
Methylnaltrexone (MNTX) is a peripherally acting µ-opioid receptor antagonist indicated for opioid-induced constipation (OIC). We evaluated whether baseline use of laxatives, including stimulants, osmotic agents, stool softeners, or combinations thereof affects the efficacy and safety of MNTX.
Methods
This post hoc analysis included pooled data from 2 multicenter, randomized, double-blind, placebo (PBO)-controlled, institutional review board–approved clinical studies in adult patients with OIC and advanced illness. Study 302 (NCT00402038) compared subcutaneous (SC) MNTX 0.15 mg/kg versus PBO and study 4000 (NCT00672477) compared body weight‒based SC MNTX 8 mg (38–< 62 kg) or 12 mg (≥62 kg) versus PBO. Patients were stratified according to baseline laxative regimen (stimulant laxative, stool softener, and/or osmotic laxatives), which were permitted to continue during the studies. Efficacy endpoints included the proportion of patients with rescue-free laxation (RFL) within 4 or 24 hours of ≥2 of the first 4 doses and median time to RFL. Treatment group comparisons were performed using Chi-square tests. Treatment-emergent adverse events (TEAEs) were summarized by patient subgroup.
Results
The pooled population included 358 patients (MNTX, 175; PBO, 183). More than 98% of patients in both treatment groups were receiving a laxative regimen at baseline, and the distribution of laxative use was similar in patients treated with MNTX and PBO (stimulants only, 20.6% and 17.5%; osmotic agents only, 12.0% and 8.2%; stool softener only, 6.3% and 7.1%; stimulants + osmotic agents, 13.1% and 19.7%; stimulants + stool softeners, 22.9% and 29.5%; osmotic agents + stool softeners, 2.3% and 2.2%; stimulants + osmotic agents + stool softeners, 21.1% and 14.8%; no laxatives, 1.7% and 1.1%). Patients receiving MNTX were more likely to have RFL within 4 hours of ≥ 2 of the first 4 doses, regardless of baseline laxative regimen (stimulants only, 52.8% vs 15.6%; osmotic agents only, 57.1% vs 13.3%; stool softener only, 54.5% vs 0.0%; stimulants + osmotic agents, 60.9% vs 8.3%; stimulants + stool softeners, 57.5% vs 3.7%; osmotic agents + stool softeners, 75.0% vs 0.0%; stimulants + osmotic agents + stool softeners, 62.2% vs 7.4%; no laxatives, 33.3% vs 0.0%); treatment differences were significant (P < 0.05) in every subgroup except the no laxatives group. In the 24-hour interval after ≥ 2 of the first 4 doses, patients receiving MNTX were more likely to have an RFL as well (stimulants only, 72.2% vs 43.8%; osmotic agents only, 76.2% vs 53.3%; stool softener only, 90.9% vs 38.5%; stimulants + osmotic agents, 73.9% vs 47.2%; stimulants + stool softeners, 82.5% vs 46.3%; osmotic agents + stool softeners, 75.0% vs 50.0%; stimulants + osmotic agents + stool softeners, 73.0% vs 59.3%; no laxatives, 100.0% vs 50.0%) with differences reaching statistical significance in the stimulants, stool softeners, stimulants + osmotic agents, and stimulants + stool softeners groups. Overall, most patients reported TEAEs (MNTX, 80.0%; PBO, 69.4%), which were more frequent with MNTX vs PBO in all subgroups except the stimulants + stool softeners and osmotic agents + stool softeners groups. Consistent with prior reports, the most common TEAEs were gastrointestinal in nature, and no new or unusual safety signals were observed in any subgroup.
Conclusion
In patients with advanced illness and OIC refractory to conventional laxative treatments, MNTX significantly increased the proportion of patients who experienced RFL (laxation within 4 hours without the use of a rescue laxative), regardless of baseline laxative regimen.
Abstract #43 Submission ID#1308449
Impact of Patient Subgroups on the Efficacy of Methylnaltrexone for Opioid-Induced Constipation in Patients with Advanced Illness
Neel Mehtaa, Eric D. Shahb, Robert J. Israelc, Nancy Stamblerd
aPhysician, Weill Cornell Medicine; bAssistant Professor of Medicine, Assistant Professor of The Dartmouth Institute, Dartmouth Hitchcock Medical Center; cSenior Vice President Clinical and Medical Affairs, Bausch Health US, LLC; dVice President, Biometrics and Data Management, Progenics Pharmaceuticals, Inc., a subsidiary of Lantheus Holdings, Inc.
Learning Objectives
Understand the overall efficacy of methylnaltrexone for treatment of opioid-induced constipation.
Understand the efficacy of methylnaltrexone for treatment of opioid-induced constipation in patient subgroups stratified by age, Eastern Cooperative Oncology Group (ECOG) performance status, cancer status, and oral morphine equivalent dose.
Understand the most important safety features of methylnaltrexone treatment.
Purpose
Constipation is a leading adverse event of opioid use and is associated with reduced quality of life and lowered adherence to opioid treatment. Methylnaltrexone (MNTX) is a peripherally acting µ-opioid receptor antagonist indicated for opioid-induced constipation (OIC) in patients with advanced illness who are receiving palliative care and in patients with chronic noncancer pain.1 MNTX relieves constipation without diminishing the effects of opioid analgesia. We investigated whether baseline patient characteristics, including age, Eastern Cooperative Oncology Group (ECOG) performance status, cancer status, and oral morphine equivalent dose, impact the efficacy of MNTX in patients with advanced illness and OIC.
Methods
This post hoc analysis included pooled data from 2 randomized, double-blind, placebo (PBO)-controlled studies (study 302 [NCT00402038]2 and study 4000 [NCT00672477]3) involving patients with advanced illness, including cancer. Study 302 included 133 patients with advanced illness randomized to receive subcutaneous (SC) MNTX 0.15 mg/kg or PBO every other day (QOD) for 2 weeks, with possible dose escalation to 0.30 mg/kg in the second week.2 Study 4000 included 230 patients with advanced illness receiving SC MNTX 8 mg or 12 mg QOD in patients weighing 38 kg to < 62 kg or ≥ 62 kg, respectively, or PBO for 2 weeks.3 The proportion of patients who achieved a rescue-free laxation (RFL) within 4 hours after the first dose of study drug was assessed in patient subgroups stratified by baseline age (< 65 vs ≥ 65), performance status (ECOG ≤ 2 vs ECOG > 2), cancer status, and oral morphine equivalent dose (< 80 mg/day, 80 to < 150 mg/day, and ≥ 150 mg/day). Institutional review board approval was obtained for these studies.
Results
Overall, 363 patients were included in the pooled analysis (MNTX = 178; PBO = 185). Mean age was 67.8 years in the MNTX group and 66.7 years in the PBO group; 46.8% were men across all treatment groups. Overall, a significantly greater proportion of patients receiving MNTX achieved RFL within 4 hours (n = 111/178 [62.4%] vs n = 31/185 [16.8%], P < 0.0001). When stratified by baseline characteristics, a significantly greater proportion of patients in the MNTX group (P < 0.0001 for all comparisons MNTX vs PBO) achieved RFL within 4 hours after the first dose versus PBO, regardless of baseline age (< 65 years: 63.9% vs 14.6%; ≥ 65 years: 61.1% vs 18.8%), performance status (ECOG ≤ 2: 66.7% vs 22.5%; ECOG > 2: 59.0% vs 12.4%), cancer status (cancer: 63.8% vs 14.9%; no-cancer: 59.7% vs 19.7%), and oral morphine equivalent dose (< 80 mg: 57.1% vs 12.3%; 80 to < 150 mg: 61.5% vs 19.0%; ≥ 150 mg: 64.9% vs 18.6%). Most adverse events associated with MNTX were gastrointestinal in nature and included abdominal pain and nausea.
Conclusion
Across the range of patient characteristics, including age, ECOG performance status, cancer status, and oral morphine equivalent dose, treatment with MNTX was superior to PBO in achieving RFL within 4 hours after the first dose.
References
[1] Relistor [package insert]. Bridgewater, NJ: Salix Pharmaceuticals, Inc. 2020.
[2] Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;358(22):2332–2343.
[3] Bull J, Wellman CV, Israel RJ, et al. Fixed-dose subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation: results of a randomized, placebo-controlled study and open-label extension. J Palliat Med. 2015;18(7):593–600.
Abstract #44 Submission ID#1308450
Celecoxib-tramadol Hydrochloride Co-crystal Safety, Tolerability, and Differential Pharmacokinetics: A Summary of Five Phase 1 Randomized Clinical Trials
Craig Sponsellera, Jesús Cebrecosb, Gregorio Encinac, Neus Gascónd, Adelaida Mortee, Carlos Plata-Salamánf, Artur Sansg, Mariano Susth, Anna Vaquéi, Sebastián Videlaj
aChief Medical Officer, Kowa Pharmaceuticals America, Inc.; bClinical Investigation Physician, ESTEVE Pharmaceuticals S.A.; cHead of Bioanalysis and Drug Metabolism/Pharmacokinetics, Esteve Pharmaceuticals S.A.; dGlobal Drug Safety & PV Head EU QPPV, ESTEVE Pharmaceuticals S.A.; eClinical Investigation Physician, ESTEVE Pharmaceuticals S.A.; fExternal Advisor, ESTEVE Pharmaceuticals S.A.; gClinical Trial Monitor, ESTEVE Pharmaceuticals S.A.; hBiostatistician, ESTEVE Pharmaceuticals S.A.; iMedical Drug Safety Officer & back up EUQPPV ESTEVE Pharmaceuticals S.A.; jClinical Research Physician, ESTEVE Pharmaceuticals S.A.
Learning Objectives
Describe the differential pharmacokinetics of celecoxib-tramadol hydrochloride co-crystal compared with concomitant administration of reference products.
Outline the ways in which the pharmacokinetics of celecoxib-tramadol hydrochloride co-crystal are improved compared with reference products.
Detail the clinical implications of the improved pharmacokinetics of celecoxib-tramadol hydrochloride co crystal compared with concomitant administration of reference celecoxib and tramadol hydrochloride, including that these are not substitutable.
Purpose
Celecoxib and tramadol hydrochloride (Seglentis®; CTC) is the first co-crystal analgesic for acute pain. Seglentis® received US Food and Drug Administration approval in October 2021.1 Phase 1 pharmacokinetic (PK) and safety data are summarized.
Methods
Of five randomized, open-label studies,2–6 three evaluated single-2,3,6 and multi-dose3 CTC 200 mg (88 mg tramadol hydrochloride/112 mg celecoxib) versus individual or concomitant US6/EU2–5 reference products (immediate-release tramadol hydrochloride 100 mg and celecoxib 100 mg). One study assessed CTC bioavailability under fed/fasting conditions;4 another compared PK in Japanese and white healthy volunteers.5 Data reported include cumulative area under the plasma concentration–time curve (AUC0–T), maximum plasma concentration (Cmax), and time to Cmax (Tmax). Cmax and AUC0–T values are arithmetic mean (% coefficient of variation [%CV]), Tmax values are median (minimum–maximum [min–max]).
Results
For tramadol, Cmax was lower, AUC0–T similar, and Tmax longer with CTC versus tramadol hydrochloride alone or concomitantly with celecoxib. In the study that compared CTC to US reference products, mean (%CV) Cmax for tramadol was 214 (29), 305 (23), and 312 (22) ng/mL, for CTC, tramadol hydrochloride alone, and for concomitant administration of tramadol hydrochloride and celecoxib, respectively. Mean (%CV) tramadol AUC0–T was 2507 (36), 2709 (34), and 2888 (34) ng∙h/mL, for the same groups. Median (min–max) tramadol Tmax was 3.0 (1.25–8.0), 2.0 (0.75–3.0), and 1.9 (1.0–6.0) hours, for CTC, tramadol hydrochloride alone, and concomitant administration of tramadol hydrochloride and celecoxib, respectively.6
For celecoxib, Cmax and AUC0–T were reduced and Tmax shorter with CTC versus celecoxib alone. Higher Cmax, shorter Tmax, and similar AUC0–T were observed with CTC compared with concomitant administration of tramadol hydrochloride and celecoxib. For the study that evaluated CTC versus US reference products, mean (%CV) Cmax for celecoxib was 259 (34), 318 (47), 165 (46) ng/mL, from CTC, celecoxib alone, and concomitant celecoxib and tramadol hydrochloride administration, respectively. AUC0–T was 1930 (41), 2348 (40), and 1929 (38) ng∙h/mL, for the same groups. Tmax was 1.5 (0.75–6.0), 3.0 (1.25–8.0), and 2.5 (1.0–12.0) hours, for CTC, celecoxib alone, and concomitant celecoxib and tramadol hydrochloride administration, respectively.6
As for the reference product, food increased celecoxib bioavailability from CTC; tramadol was unaffected. Differences were not suggestive of requirements for dose adjustment/recommendations related to meal times. Differences between Japanese and white healthy volunteers were also not suggestive of a need for dose adjustment.
Safety was consistent with that of reference products, with similar types of adverse events and no serious adverse events or deaths.
Conclusion
PK improved with CTC versus tramadol hydrochloride and celecoxib alone or concomitantly. The clear interaction between concomitant tramadol hydrochloride and celecoxib, resulting in reduced celecoxib absorption, was minimized with CTC. Overall, results were consistent across Phase 1 studies and indicate that CTC has differential PK, showing that CTC is not substitutable by concomitant US/EU tramadol hydrochloride and celecoxib.
References
[1] Seglentis® (celecoxib and tramadol hydrochloride) US prescribing information (last updated Oct 2021)
[2] Videla S et al. Br J Clin Pharmacol 2017;83:2718–28
[3] Videla S et al. Br J Clin Pharmacol 2018;84:64–78
[4] Encina G et al. Clin Drug Investig 2018;38:819–27
[5] Dooner H et al. Eur J Drug Metab Pharmacokinet 2019;44:63–75
[6] Cebrecos J et al. Clin Ther 2021;43:1051–65
Abstract #45 Submission ID#1308455
Naloxegol Provides Clinically Meaningful Healthcare Related Quality of Life (HR-QOL) Improvement in Patients with Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Global Phase 3 Studies of Naloxegol
Charles McLeskeya, Brooks Cashb, Theresa Mallick-Searlec, Mansi Jamindard, Carol Rockette, Enoch Borteyf, Darren Brennerg
aVice President, Global Affairs, RedHill Biopharma Inc – Raleigh, NC; bChief of the Division of Gastroenterology, Hepatology, and Nutrition, University of Texas Health Science Center at Houston; cNurse Practitioner–Pain Medicine, Sanford Pain Management; dMedical Director, RedHill Biopharma; eAssociate Vice President, Medical Affairs, RedHill Biopharma; fFounder, Pharmaceutical Development Strategies LLC; gAssociate Professor of Associate Professor of Medicine (Gastroenterology and Hepatology) and Surgery Northwestern Medicine
Learning Objectives
Describe the significant impact that opioid-induced constipation has on patients’ quality of life.
Understand naloxegol efficacy in providing rapid and clinically meaningful, constipation-related quality of life improvement in patients with opioid-induced constipation.
Provide holistic patient management including assessment and treatment of opioid-induced constipation.
Purpose
The American Gastroenterological Association (AGA) reported that OIC affects 40–80% of patients taking chronic opioid therapy1 which negatively impacts patients’ healthcare related quality of life (HR-QOL).2 Naloxegol (Movantik®) is a peripherally acting mu-opioid receptor antagonist (PAMORA) which targets the GI tract to decrease the constipating effects of opioids. It was shown to be effective in treating OIC in adult subjects with non-cancer related pain in two pivotal Phase 3 Studies (KODIAC 4/5: NCT01309841/NCT01323790).3 This study reports a pooled analysis of these two randomized, placebo-controlled trials which evaluates the efficacy of naloxegol in providing clinically meaningful HR-QOL improvements by utilizing the validated Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL). Methods Patient-reported scores from the PAC-QOL questionnaire were collected during KODIAC 4 and 5 as supportive efficacy measures of OIC HR-QOL improvement. Scoring ranged from 0 (absence of symptoms) to 4 (very severe) for each domain (Physical Discomfort, Psychosocial Discomfort, Worries/Concerns, and Satisfaction). Two Minimal Clinically Important Difference (MCID) thresholds were used to identify responders and non-responders. PAC-QOL MCID threshold of 0.5 is based on literature4 and naloxegol real-world studies in cancer patients with OIC.5,6 MCID threshold of 0.8 is based on anchor method analysis of naloxegol phase 3 clinical trial data.
Results
This pooled analysis included 1337 patients treated once daily with naloxegol (25 mg, 12.5 mg) or placebo (PBO). The overall baseline values for PAC-QOL Total, Physical Discomfort, Psychosocial Discomfort, Worries/Concerns, and Satisfaction scores were 2.0, 2.1, 1.3, 2.0, and 3.3, respectively.
For MCID ≥0.5, treatment with naloxegol 25 mg and 12.5 mg demonstrated a rapid, statically significant, and clinically meaningful improvement in HR-QOL vs. PBO (Proportion of PAC-QOL Responders 25 mg: 63.9%; 12.5 mg: 66.2; PBO:57.3%) at week 4. Odds ratios (ORs) at week 4 were 1.4 (p = 0.038) for 25 mg and 1.5 (p = 0.013) for naloxegol 12.5 mg vs. PBO. At week 12 there was a significantly higher proportion of PAC-QOL responders observed for naloxegol (25 mg: 66.1%; 12.5 mg: 68.5%) vs. PBO (59.0%). ORs at week 12 were 1.4 (p = 0.047) for 25 mg and 1.5 (p = 0.017) for 12.5 mg vs. PBO.
For MCID ≥0.8, treatment with naloxegol 25 mg and 12.5 mg demonstrated a rapid, statically significant, and clinically meaningful HR-QOL improvement vs. PBO (Proportion of PAC-QOL Responders 25 mg: 50.4%; 12.5 mg: 48.8; PBO: 39.7%) at week 4. Odds ratios (ORs) at week 4 were 1.7 (p = 0.001) for 25 mg and 1.4 (p = 0.017) for naloxegol 12.5 mg vs PBO. At 12 weeks, higher proportions of PAC-QOL responders were also observed for naloxegol (25 mg: 52.7%; 12.5 mg: 56.2%) vs. PBO (45.7%). ORs at 12 weeks were 1.4. (p = 0.068) for 25 mg and 1.5 (p = 0.010) for 12.5 mg vs. PBO.
ORs were generally consistent between MCID ≥0.8 and 0.5. At 4 weeks for both MCID thresholds, patients receiving naloxegol 25 mg and 12.5 mg were 40–70% more likely to achieve clinically meaningful symptom improvement than with PBO. At 12 weeks for both MCID thresholds, patients receiving naloxegol 12.5 mg were 40–50% more likely to achieve clinically meaningful symptom improvement than with PBO.
A significantly greater proportion of patients receiving naloxegol 25 mg and 12.5 mg vs. PBO achieved clinically meaningful improvement in the PAC-QOL Satisfaction subdomain for both MCID thresholds at 12 weeks (p < 0.05 for both doses). Other subdomains also showed statistically significant and numerical improvements with naloxegol (25 mg, 12.5 mg) vs. PBO. Conclusion These data highlight the significant impact OIC has on patients’ quality of life. In this pooled analysis of two phase 3 clinical trials, naloxegol 12.5 mg and 25 mg demonstrated rapid and clinically meaningful, constipation-related HR-QOL improvement in patients with OIC across MCID thresholds. Patient satisfaction appeared to drive these improvements, consistent with the known effects of PAMORAs. Such HR-QOL improvement may be an important clinical consideration in improving OIC management.
References
[1] AGA Institute Clinical Guidelines Committee. AGA Institute Guideline on the Medical Management of Opioid-Induced Constipation. Gastroenterology. 2019;156(1):218–226
[2] Varrassi G et al. Impact and Consequences of Opioid-Induced Constipation: a Survey of Patients. Pain Med 2021 Dec;10(2):1139–1153
[3] Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014;370(25):2387–96.
[4] Marquis P, De La Loge C, Dubois D, et al. Development and validation of the patient assessment of constipation quality of life questionnaire. Scand J Gastroenterol 2005;40:54
[5] Lemaire A. et al. Effectiveness of naloxegol in patients with cancer pain suffering from opioid-induced constipation. Supportive care in Cancer. 2021 29:7577–7586
[6] Cobo Dols M, et al. One-year efficacy and safety of naloxegol on symptoms and quality of life related to opioid-induced constipation in patients with cancer: KYONAL study. BMJ Supportive & Palliative Care 2021;0:1–9
Abstract #46 Submission ID#1308460
Celecoxib-Tramadol Hydrochloride Co-crystal in Patients with Moderate-to-Severe Pain Following Bunionectomy with Osteotomy: Secondary Analyses of a Phase 3, Randomized, Double-Blind, Factorial, Active- and Placebo-Controlled Trial
Eugene R.a, Oscar de Leon-Casasolab, Craig Sponsellerc, Jesús Cebrecosd, Adam Jacobse, Adelaida Mortef, Esther Ortizg, Mariano Susth, Anna Vaquéi, Ira Gottliebj, Stephen Danielsk, Derek Musel, Michael E. Kussm, Sebastián Videlan, Neus Gascóno, Carlos Plata-Salamánp
aProfessor of Anesthesiology, Chief of Pain Medicine, and Director, Acute Pain Management, Sidney Kimmel Medical College of Thomas Jefferson University; bSenior VC/Prof. of Anesthesiology and Medicine/Chief, Div of Pain Medicine and Prof. of Oncology, University of Buffalo/Roswell Park Cancer Institute; cChief Medical Officer, Kowa Pharmaceuticals America, Inc.; dClinical Investigation Physician, ESTEVE Pharmaceuticals S.A.; eSenior Director, Biostatistics, Premier Research; fClinical Investigation Physician; gESTEVE Pharmaceuticals S.A.; hClinical Trial Coordinator & Monitor, ESTEVE Pharmaceuticals S.A.; iClinical Biostatistician, ESTEVE Pharmaceuticals S.A.; jMedical Drug Safety Officer & back up EUQPPV, ESTEVE Pharmaceuticals S.A.; kPrincipal Investigator and Medical Director, Chesapeake Research Group LLC; lDirector of Medical Operations (retired)Optimal Research LLC; mDoctor of Medicine, JBR Clinical Research; nVice President: Analgesia, Premier Research; oClinical Research Physician, ESTEVE Pharmaceuticals S.A.; pGlobal Drug Safety & PV Head EU QPPV, ESTEVE Pharmaceuticals S.A.External Advisor, ESTEVE Pharmaceuticals S.A.
Learning Objectives
Describe the differences in rescue medication requirements for patients with acute moderate-to-severe pain following bunionectomy with osteotomy receiving celecoxib tramadol hydrochloride co-crystal versus those receiving reference products alone.
Outline the differential adverse event profile of celecoxib-tramadol hydrochloride co-crystal versus that of tramadol hydrochloride or celecoxib.
Understand the benefit/risk profile of celecoxib-tramadol hydrochloride co-crystal versus reference products alone in acute pain management, both in patients under 65 years and in those 65 years and older.
Purpose
Celecoxib and tramadol hydrochloride (Seglentis®; CTC) is the first co-crystal analgesic for acute pain and received US Food and Drug Administration approval in October 2021.1 CTC provided greater analgesia than comparable doses of tramadol hydrochloride or celecoxib in the Phase 3 SUSA-301 trial (NCT03108482).2 Here, we present post hoc secondary analyses.
Methods
SUSA-301 was a randomized, double-blind, factorial trial conducted at six US clinical research centers. Adults with acute moderate-to-severe pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [88 mg tramadol hydrochloride/112 mg celecoxib] every 12 hours [q12h]; n = 184), tramadol hydrochloride (50 mg every 6 hours; n = 183), celecoxib (100 mg q12h; n = 181), or placebo (n = 89) for 48 hours. Rescue medication use was permitted. First-line rescue medication was 1 g of intravenous acetaminophen every 4–6 hours as needed, up to 4 g in 24 hours. Second-line rescue medication was 5 mg of immediate-release oral oxycodone every 4–6 hours as needed, up to 30 mg in 24 hours. Rescue medication use was analyzed via two-sided Pearson chi-square test.
Results
Significantly lower proportions of patients in the CTC group, versus other groups, used rescue pain medication within 4 hours post-dose (CTC: 91 [49.5%]; tramadol hydrochloride: 113 [61.7%]; celecoxib: 118 [65.2%]; placebo: 67 [75.3%]; P = 0.0178, P = 0.0024, and P = 0.0001 vs tramadol hydrochloride, celecoxib, and placebo, respectively), including oxycodone (CTC: 27 [14.7%]; tramadol hydrochloride: 48 [26.2%]; celecoxib: 61 [33.7%]; placebo: 31 [34.8%]; P = 0.0061, P < 0.0001, and P = 0.0001 vs tramadol hydrochloride, celecoxib, and placebo, respectively). A similar pattern occurred within 48 hours, irrespective of baseline pain intensity.
Among patients who used rescue medication, fewer in the CTC group required ≥3 doses, irrespective of baseline pain intensity. For patients with moderate baseline pain, 29.2%, 51.1%, 54.6%, and 57.2% of those in the CTC, tramadol hydrochloride, celecoxib, and placebo groups, respectively, required ≥3 doses of rescue medication. For patients with severe baseline pain, this was 40.0%, 60.3%, 66.3%, and 70.2%, respectively.
Adverse event (AE) incidence by age (< 65 vs ≥ 65 years) differed between groups. In those aged < 65 years, treatment-emergent AEs (TEAEs) occurred in 63.4%, 62.9%, 53.6%, and 57.3% of those taking CTC, tramadol hydrochloride, celecoxib, and placebo, respectively. For those aged ≥65 years, TEAE incidence was 63.6%, 66.7%, 37.5%, and 57.1%, for CTC, tramadol hydrochloride, celecoxib, and placebo, respectively. The incidence of TEAEs related to study drug was highest for tramadol hydrochloride in both age groups. TEAEs of special interest (confusion, constipation, difficulty with urination, dizziness, dry mouth, fatigue, headache, inability to concentrate, itching, nausea, somnolence, vertigo, and vomiting) were also highest for tramadol hydrochloride in both age groups. AE incidence was generally unaffected by the use of rescue or antiemetic medication.
Conclusion
CTC is associated with less rescue medication use than tramadol hydrochloride or celecoxib alone in acute moderate-to-severe pain, and is well tolerated by adults under 65 years and those 65 years and older.
References
[1] Seglentis® (celecoxib and tramadol hydrochloride) US prescribing information (last updated Oct 2021).
[2] Viscusi ER et al. Pain Pract 10 June 2022. Epub ahead of print. doi:10.1111/papr.13136.
Abstract #47 Submission ID#1308462
Naloxegol Provides Clinically Meaningful Symptom Improvement in Patients with Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Global Phase 3 Studies of Naloxegol
Charles McLeskeya, Brooks Cashb, Theresa Mallick-Searlec, Mansi Jamindar, PharmDd, Carol Rockette, Enoch Borteyf, Darren Brennerg
aVice President, Global Affairs, RedHill Biopharma Inc – Raleigh, NCChief of the Division of Gastroenterology, Hepatology, and Nutrition, University of Texas Health Science Center at Houston; bNurse Practitioner–Pain Medicine; cSanford Pain Management; dMedical Director, RedHill Biopharma; eAssociate Vice President, Medical Affairs, RedHill Biopharma; fFounder, Pharmaceutical Development Strategies LLC; gMedicine (Gastroenterology and Hepatology) and Surgery, Northwestern Medicine
Learning Objectives
Describe the high symptom burden experienced by patients with opioid-induced constipation.
Understand naloxegol efficacy in providing clinically meaningful, constipation-related symptom improvement in patients with opioid-induced constipation.
Provide holistic patient management including assessment and treatment of opioid-induced constipation.
Purpose
The American Gastroenterological Association (AGA) reported that OIC affects 40–80% of patients taking chronic opioid therapy1 and 58% of patients with OIC reported at least one severe or very severe constipation-related symptom.2 Naloxegol (Movantik®) is a peripherally acting mu-opioid receptor antagonist (PAMORA) which targets the GI tract to decrease the constipating effects of opioids. It has demonstrated a rapid and predictable response and relief of OIC symptoms in patients treated with opioids for non-cancer pain in two phase 3 clinical trials (KODIAC 4/5: NCT01309841/NCT01323790).3,4 This study reports a pooled analysis of these two randomized, placebo-controlled trials which evaluates the efficacy of naloxegol in providing clinically meaningful symptom improvement through utilizing the validated Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM). Methods Data were pooled from the KODIAC 4 and 5 intent-to-treat population. PAC-SYM scores were collected during KODIAC 4/5 as supportive efficacy measures. Scores range from 0 (absence of symptoms) to 4 (very severe) for each domain (abdominal, rectal, and stool symptoms). Two Minimal Clinically Important Difference (MCID) thresholds were used to identify responders and non-responders. PAC-SYM MCID threshold of 0.5 is based on literature5,6 and naloxegol real-world studies in cancer patients with OIC.7,8 MCID threshold of 0.8 is based on anchor method analysis of naloxegol phase 3 clinical trial data.
Results
This pooled analysis included 1337 patients treated once daily with naloxegol (25 mg, 12.5 mg) or placebo (PBO). The overall mean baseline values for PAC-SYM total, abdominal, rectal, and stool symptoms scores were 1.8, 1.7, 1.3, and 2.3, respectively, and were similar across groups.
For MCID ≥0.5, treatment with naloxegol 25 mg demonstrated a rapid, statically significant, and clinically meaningful improvement in symptoms vs. PBO (Proportion of PAC-SYM Responders 25 mg: 65.6%; PBO: 57.3%) at week 4. Odds ratios (OR) at week 4 were 1.5 (p = 0.006) for 25 mg vs. PBO. At week 12, there was a significantly higher proportion of PAC-SYM responders with both naloxegol doses (25 mg: 69.5%; 12.5 mg: 65.6%) vs. PBO (57.7%). ORs at week 12 were 1.8 (p = 0.001) for 25 mg and 1.5 (p = 0.014) for 12.5 mg vs. PBO.
For MCID ≥0.8, higher proportions of PAC-SYM responders were also observed for both naloxegol doses (25 mg: 53.5%; 12.5 mg: 45.7%) vs. PBO (42.3%) at week 12. ORs at week 12 were 1.7 (p = 0.002) for 25 mg and 1.2 (p = 0.237) for 12.5 mg vs. PBO.
ORs were generally consistent between MCID ≥0.8 and 0.5. At 12 weeks for both MCID thresholds, patients receiving naloxegol 25 mg were 70–80% more likely to achieve clinically meaningful symptom improvement in the PAC-SYM total score than with PBO.
Subdomain analyses revealed dose-dependent responses. At week 12, significant and clinically meaningful improvement in PAC-SYM rectal (ORs: MCID 0.5 = 1.7; MCID 0.8 = 1.9) and stool symptoms (ORs: MCID 0.5 = 2.0; MCID 0.8 = 2.0) subdomains were achieved for naloxegol 25 mg vs. PBO (p < 0.05) at both MCID thresholds.
Conclusion
These data reinforce the high symptom burden at baseline experienced by patients with OIC. Naloxegol demonstrated clinically meaningful, constipation-related symptom improvement in patients with OIC. These improvements were dose dependent, with significant gains demonstrated for naloxegol 25 mg at both MCID thresholds. Rectal and stool symptoms appear to drive these improvements, consistent with the known effects of PAMORAs. Such symptom improvement may be an important clinical consideration in improving OIC management and patient satisfaction.
References
[1] AGA Institute Clinical Guidelines Committee. AGA Institute Guideline on the Medical Management of Opioid-Induced Constipation. Gastroenterology. 2019;156(1):218–226
[2] Varrassi G et al. Impact and Consequences of Opioid-Induced Constipation: a Survey of Patients. Pain Med 2021 Dec;10(2):1139–1153
[3] Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014;370(25):2387–96.
[4] Chey WD, Rockett CB, Bortey E, Almenoff J. Poster Presentation (Sa058): Rapid Onset of Time to First Spontaneous Bowel Movement (SBM) and Predictable Efficacy of Naloxegol: Pooled Analysis of Two Global Randomized Controlled Trials. Digestive Disease Week, May 21–23, 2021.
[5] Frank L, Kleinman L, Farup C, et al. Psychometric validation of a constipation symptom assessment questionnaire. Scand J Gastroenterol 1999;34:870–7.
[6] Yiannakou Y, Tack J, Piessevaux H et al. The PAC-SYM questionnaire for chronic constipation: defining the minimal important difference. Aliment Pharmacol Ther. 2017; 46(11–12):1103–1111.
[7] Lemaire A. et al. Effectiveness of naloxegol in patients with cancer pain suffering from opioid-induced constipation. Supportive care in Cancer. 2021 29:7577–7586 8.
Cobo Dols M, et al. One-year efficacy and safety of naloxegol on symptoms and quality of life related to opioid-induced constipation in patients with cancer: KYONAL study. BMJ Supportive & Palliative Care 2021;0:1–9
Abstract #48 Submission ID#1308527
Development of Machine Learning Algorithms Using EEG Features to Detect Presence of Chronic Pain Submission Type: Scientific Abstracts Submission Category: Submission Status: Complete/Locked Submitter: Skylar Jacobs – PainQx, Inc
Jonathan Millera, Joseph Lovelaceb, Skylar Jacobsc, Federica Portad, Frank Minellae, William Koppesf
aLead Algorithm Engineer, PainQx, Inc; bVP Research & Development, PainQx, Inc; cVP Business Development & Operations, PainQx, Inc; dEEG Algorithm Engineer, PainQx, Inc; eFounder & CEO, PainQx, Inc; fVP Regulatory, PainQx, Inc
Learning Objectives
Upon completion, participant will be able to understand the potential use of EEG for purposes of characterizing chronic pain states.
Upon completion, participant will be able to understand machine learning techniques and approaches for purposes of pain assessment.
Upon completion, participant will be able to question the integration of an EEG technology for pain assessment in chronic pain clinical practice.
Purpose
The current standard of care for assessing pain intensity is a subjective patient self-report using the Numeric Rating Scale (NRS) or the Visual Analog Scale (VAS). Subjective pain measurement may lead to a non-replicable, unreliable assessment of a patient’s pain state, leading to inappropriate treatment and ultimately poorly managed pain.
The purpose of PainQx’s research was to develop a technology to assess an individual’s pain state objectively and empirically. With support from a National Institutes on Drug Abuse SBIR grant, PainQx conducted Phase I of a multi-site research study and developed algorithms using quantitative electroencephalography (qEEG) derived neural activity to objectively classify chronic pain patients as ‘in pain’ or ‘not in pain.’ Through this research effort, PainQx developed a large database of chronic pain patients and controls, EEG processing modules for quality control, artifact removal, and epoch selection, and a machine learning (ML) pipeline for EEG based chronic pain classification algorithm development.
Development of a chronic pain biomarker that is linked to pain intensity has long been recognized as a valuable goal in the clinical community and has received increasing attention among qEEG researchers in the last two decades. PainQx sought to ensure our findings regarding neurological differences between pain patients and healthy controls were congruent with domain knowledge and the published literature on qEEG and pain.
Ultimately, the use of EEG to detect a chronic pain state will provide clinicians and patients an empirical, additional data point in their determination of appropriate treatment paths. Additionally, an EEG-based biomarker for chronic pain would have significant value for future research on pain mechanisms and therapeutic development. It is PainQx’s goal to further pain research and improve outcomes for the millions of patients currently suffering from chronic pain.
Methods
In the first phase of the project, a multi-site clinical study was conducted to collect EEG and clinical data from a healthy control cohort and a pain patient cohort. Male and female participants ages 18–80 were included in the study, and pain subjects were required to meet the IASP definition of chronic pain. Subjects with neurological disorders or other conditions affecting neurological patterns were excluded from the study. Additionally, patients who may have had a reason to misrepresent their pain (e.g. patients on workers compensation) were also excluded. Participant data collected during the study included fifteen minutes of eyes closed, resting EEG data and clinical information relating to the subject’s pain history, functional impairment, and mental state.
During and following the clinical study, EEG data was sent to the PainQx cloud computing platform, where it was processed by a set of core modules. The first module assessed the quality of the EEG files to insure they met several standards. If an EEG file met these quality criteria, it was processed by automatic artifactor software that identified and removed any distortions in the EEG data caused by signals not originating from the brain. The output was a collection of EEG segments called epochs. Epoch selection algorithms were used to assemble an optimal set of EEG segments that were then passed to the feature extractor module. Over nine thousand unique EEG features were extracted and calculated from each EEG recording, such as signal power within a frequency range on an electrode and signal coherence within a frequency range between pairs of electrodes. Complex features such as Granger Causality and Cross Frequency Coupling were also computed.
PainQx took the resulting qEEG features and participant reported NRS scores as inputs to develop an algorithm to predict chronic pain. The algorithm is a binary classifier generated utilizing Machine Learning (ML) best practices. Several methodologies, including Elastic Net (ENET) and Support-Vector Machine were used during development. Algorithms were developed solely on a train/test set (60% of the data), with performance evaluated on the remaining data to insure against overtraining of the algorithm.
Results
There was a total of 386 participants in the study, 93 healthy controls and 293 chronic pain patients. The data from 235 subjects were used for algorithm development and is referred to as Train/Test (TT) data set. The remaining 151 participants is referred to as Hold Out (HO) and used for performance evaluation. Participants were assigned to either the TT or HO dataset randomly, but stratified for gender, age, and pain intensity.
Using the TT data, multiple Pain vs No Pain binary classifiers were created. After utilizing several machine learning methodologies in algorithm development, ENET was the most successful in correct classification of Pain vs. No Pain.
Performance was evaluated for both the TT and HO datasets. The TT performance was derived from 20 repetitions of 10-fold cross-validation, in which the TT set is partitioned at random into a Train interval and Test interval and results are aggregated, whereas the HO performance was a single application of the TT-developed classifier applied to the HO dataset.
The performance of the classifier was assessed using multiple metrics. Area Under the Curve (AUC) is the preferred metric as it is independent of a specific operating point, which can be set to optimize sensitivity and specificity. The following results utilize an operating point that provides an equal emphasis on both sensitivity and specificity.
The AUC was 0.941 for TT and 0.903 for HO. Sensitivity/specificity was 0.886/0.874 for TT and 0.841/0.878 for HO. Accuracy was 0.883 for TT and 0.841 for HO. Using a pain prevalence model developed by PainQx, the Negative Predictive Value/Positive Predictive Value was 0.291/0.993 for TT and 0.238/0.984 for HO.
Using ENET, each qEEG feature received a weight, with heavily weighted features indicating that feature’s relevance to the classification of Pain vs No Pain. There were several features that were heavily weighted in PainQx’s algorithm that are consistent with previously reported results. For example, an increase in theta-band activity in chronic pain patients has been reported in multiple publications [Mussigmann et al. 2022]. Additionally, a recent paper found five measures of EEG connectivity were the most predictive for identifying severe chronic pain vs pain-free controls [Ploner et al. 2019], which is also consistent with our results. The consistency of these features across multiple studies supports that the ML analysis has captured fundamental underlying physiology related to chronic pain, and not spurious anomalies present by chance in our training data.
Conclusion
The research effort successfully demonstrated that machine learning based algorithms utilizing EEG data can be used to classify healthy controls in no pain versus chronic pain patients in pain. Several EEG features identified with the machine learning pipeline are congruent with domain knowledge identified by previous chronic pain and EEG studies. The ability to empirically differentiate patients in pain from those not in pain has several clinical use cases, including determination of proper opioid dispensing practices or validation of chronic pain state in legal cases.
Even with the success of this research, limitations in the performance achieved indicates that additional research is needed to refine the technology. Areas of future research opportunities include conducting additional studies to increase the training database or combining EEG with other physiological data sources (such as heart rate or blood-based biomarkers) to further improve the technology and its pain intensity prediction capabilities.
References
[1]Mussigmann, Thibaut, et al. ‘Resting-State Electroencephalography (EEG) Biomarkers of Chronic Neuropathic Pain. A Systematic Review.’ NeuroImage, vol. 258, 2022, p. 119,351., https://doi.org/10.1016/j.neuroimage.2022.119351
[2] Ta Dinh S, Nickel MM, Tiemann L, May ES, Heitmann H, Hohn VD, Edenharter G, Utpadel-Fischler D, Tölle TR, Sauseng P, Gross J, Ploner M. Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography. Pain. 2019 Dec;160(12):2751–2765.
[3]Erratum in: Pain. 1 July 2020;161(7):1684. PMID: 31,356,455; PMCID: PMC7195856.
Abstract #49 Submission ID#1308560
A call for implementation of transitional pain services within the perioperative setting: Using a commercial digital telehealth platform to overcome barriers Submission Type: Scientific Abstracts Submission Category: Submission Status: Complete/Locked Submitter: Maryam Hussain – Lucid Lane
Maryam Hussaina, Beau Norgeotb, Ahmed Zaafranc, Barrett LarsondT. Kyle Harrisone
aClinical Research, Lucid Lane; bChief Data Officer, Lucid Lane; cChief Medical Officer, Lucid Lane; dSenior VP of Clinical Product, Lucid Lane; eClinical Professor, Staff Physician, Stanford, Palo Alto VA
Learning Objectives
Upon completion, participants will be able to summarize the the current literature on the role of transitional pain services in the perioperative setting.
Upon completion, participants will be able to discuss preliminary findings connected to virtual transitional pain services in the perioperative setting.
Upon completion, participants will be able to identify if their patient population could benefit from virtual transitional pain services.
Purpose
Pain is a prevalent condition amongst U.S. adults, with estimates ranging from 11% to 40%.1 Pain patients often seek surgical intervention to relieve their pain2; however, 80% continue to experience postoperative chronic pain,3 which can have subsequent complications, such as dependence on opioids, restrictions in mobility and daily living activities, anxiety and depression.4 Although these population-estimates provide rationale for more pain-related services, there is limited understanding of who will go on to develop chronic pain.5 Thus, necessary pain-related services may be reaching perioperative patients too late.
One promising program called transitional pain services (TPS) aims to identify perioperative patients at risk of developing chronic pain and subsequent complications and provides continuity of care through the surgical journey.6 During TPS, the patients receive preoperative preparation (e.g. anxiety reduction, surgical expectations) and postoperative pain management, particularly focusing on pain resolution, improvement of quality of life, and tapering off postoperative opioids.7 Additionally, patients experience secondary benefits, such as improved mood (e.g. reduction in anxiety and depression symptoms) and lower cost of care (e.g. hospital visits and opioid-related costs).8,9
Despite awareness of the positive impact that TPS has on. chronic pain reduction and associated opioid use, hospitals seem slow to implement such services.10 Although TPS staffing models can widely range as needed, the upfront and yearly costs associated with personnel to effectively deliver this care (~$2 million to ~$7 million) can be a deterrent.9,10 Furthermore, patients may experience personal barriers to engaging with TPS appointments, such as transportation to appointments and pain-related mobility issues.11,12
With the advent of telehealth platforms, one solution to incorporating TPS widely may be to provide it digitally through a commercial digital platform that specializes in virtual-TPS (vTPS).13 This would shift the financial incentives and barriers for the hospital to the commercial platform, and allow patients who are otherwise limited by physical accessibility to maintain appointments from the safety and comfort of their own homes. Therefore, we provide recommendations on vTPS methodology delivered through a commercial digital platform, and provide preliminary data highlighting how these recommendations are being practically implemented.
Methods
The methodology from the commercial digital platform focuses on three main recommendations: the staffing model, the interventions employed, and the duration and content of the patient engagement and experience. The commercial vTPS staffing model consists of the anesthesiologists involved in the patient’s surgery, addiction medicine physicians, clinicians with experience in pain management, licensed therapists and/or psychologists, and patient advocates that coordinate care. These multidisciplinary providers should integratively deliver comprehensive pain management surgical patients at risk for chronic pain and opioid use after surgery.
vTPS engagement should occur during three phases of perioperative care: (1) preoperative period up to 1 month before surgery, (2) surgical hospitalization, and (3) postoperative period up to 3 months. Preoperatively, we suggest that patient eligibility and risk for chronic pain and chronic opioid dependency after surgery be established through digital risk calculator. The risk calculator will consider the relative risk of chronic Preoperative content should comprise virtual patient education on surgery preparedness, reduction of patient anxiety, and preparation for opioid use and management after surgery. During hospitalization, the patient advocate should virtually communicate with the patient and provide care coordination. Postoperatively, the patient should receive regularly scheduled virtual interventions by licensed therapists or psychologists for the acute recovery period of 4 weeks, and then receive virtual maintenance interventions for the longer recovery period for at least up to 3 months. This timeline allows for ongoing support until the patient is completely off opioids, their pain is adequately controlled, and there are no behavioral health issues complicating postoperative recovery.
Throughout the vTPS journey, both pharmacological and non-pharmacological interventions should be supported and used. Pharmacological interventional support should focus on the conscientious inclusion of the patient in the opioid weaning process before and/or after surgery. Non-pharmacological interventions should include digital health applications to monitor pain and other behavioral health signals, sensory therapies (visual, distraction, and relaxation techniques), and cognitive behavioral therapies including psychotherapy and counseling. Furthermore, non-pharmacological interventions should augment the direct pharmacological interventions prescribed by the surgeons.
Results
We delivered vTPS to a veteran patient population at a major VA hospital. We present preliminary findings on three veterans who completed the vTPS journey. Patients were opioid naive (i.e. no opioid exposure 30-days prior to consent and until surgery).
The patients were recruited from a cohort of total joint arthroplasty (TJA) patients receiving surgical care at a VA hospital. Around 44% of TJA patients experience pain postoperatively, with around 15% reporting severe or extremely severe pain14,15. After consent, patients were matched with licensed therapists associated with the vTPS program. Patients received surgery preparedness care using cognitive behavioral therapy protocols for anxiety for 4 weeks preoperatively. Furthermore, patients were informed that they would be guided in tapering off postoperatively prescribed opioids with their matched therapist. After the TJA, patients received psychological pain management care using cognitive behavioral therapy protocols for pain for 4 weeks after the TJA. Patient also engaged in a 90-day postoperative follow-up. Patients received cognitive and behavioral tools to employ at home in the duration between the acute and longer recovery periods. During the preoperative and postoperative care, and follow-up appointment, patients also responded to validated surveys on depression (PHQ-9), anxiety (GAD-7), pain (KOOS-Pain), quality of life (KOOS-QoL), pain catastrophizing (PCS), and reported overall opioid use.
During the preoperative period, on average, patients reported minimal depression (PHQ-9 = 3) and anxiety (GAD-7 = 3.5) symptoms. On the KOOS surveys (ranging from 0 to 100, with 0 representing extreme problems and 100 representing no problem), patients reported moderately high pain (KOOS-Pain = 44.5%) and poor QoL (KOOS-QoL = 31.5%). On average, patients reported above average, but not clinically significant, pain catastrophizing (PCS = 25). Because all patients were opioid naive, there were no opioid dosages to report.
After surgery, patients reported use of postoperative prescribed opioids ranging from 15 MME to 30 MME. At the end of the postoperative vTPS journey, on average, patients reported no depression (PHQ-9 = 0) or anxiety (GAD-7 = 0) symptoms. On the KOOS surveys, patients reported no pain (KOOS-Pain = 100%) and moderate problems with QoL (KOOS-QoL = 56%). On average, patients reported no pain catastrophizing (PCS = 0). All patients reported no opioid use (0 MME). Thus, patients experienced a 100% reduction in depression and anxiety symptoms, 124% improvement in pain symptoms, 78% improvement in QoL, and 100% reduction in pain catastrophizing.
Conclusion Initial findings from the implementation of a commercial telehealth platform to deliver vTPS to veterans from a major VA hospital indicate that patients experience complete reduction in opioid use, pain, pain catastrophizing, and anxiety and depression symptoms, along with improved QoL. These results indicate that a vTPS program is feasible for providing care for patients who are at increased risk for developing chronic postoperative pain and persistent postoperative opioid use. With more data supporting the need for healthcare systems to offer enhanced perioperative care through a high-quality pain management program, we urge a concerted and organized effort by clinicians, patients, and other stakeholders to prioritize TPS and vTPS to deliver perioperative care.
References
[1] Zelaya CE, Dahlhamer JM, Lucas JW, Connor EM. Chronic pain and high-impact chronic pain among US adults, 2019. NCHS Data Brief, No. 390. 2020 Nov; No. 390
[2] Huang A, Azam A, Segal S, Pivovarov K, Katznelson G, Ladak SS, Mu A, Weinrib A, Katz J, Clarke H. Chronic postsurgical pain and persistent opioid use following surgery: the need for a transitional pain service. Pain management. 2016 Oct;6(5):435–43.
[3] Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J pain res. 2017;10:2287.
[4] Dahlhamer J, Lucas J, Zelaya C, Nahin R, Mackey S, DeBar L, Kerns R, Von Korff M, Porter L, Helmick C. Prevalence of chronic pain and high-impact chronic pain among adults – United States, 2016. Morb Mortal Wkly Rep. 9 September 2018;67(36):1001.
[5] Interagency Pain Research Coordinating Committee. National pain strategy: a comprehensive population health-level strategy for pain. Washington, DC: US Department of Health and Human Services, National Institutes of Health; 2016.
[6] Huang A, Azam A, Segal S, Pivovarov K, Katznelson G, Ladak SS, Mu A, Weinrib A, Katz J, Clarke H. Chronic postsurgical pain and persistent opioid use following surgery: the need for a transitional pain service. Pain Manag. 2016;6(5):435–43.
[7] Katz J, Weinrib AZ, Clarke H. Chronic postsurgical pain: from risk factor identification to multidisciplinary management at the Toronto General Hospital Transitional Pain Service. Canadian J Pain. 15 July 2019;3(2):49–58.
[8] Buys MJ, Bayless K, Romesser J, Anderson Z, Patel S, Zhang C, Presson AP, Brooke BS. Opioid use among veterans undergoing major joint surgery managed by a multidisciplinary transitional pain service. Reg Anesth & Pain Med. 1 November 2020;45(11):847–52.
[9] Sun EC, Mariano ER, Narouze S, Gabriel RA, Elsharkawy H, Gulur P, Merrick SK, Harrison TK, Clark JD. Making a business plan for starting a transitional pain service within the US healthcare system. Reg Anesth & Pain Med. 1 August 2021;46(8):727–31.
[10] Rosenquist RW, Mariano ER. The Future of Pain Medicine. ASA Monitor. 2021 Oct;85(S10):35–7.
[11] Odonkor CA, Christiansen S, Chen Y, Sathiyakumar A, Chaudhry H, Cinquegrana D, Lange J, He C, Cohen SP. Factors associated with missed appointments at an academic pain treatment center: a prospective year-long longitudinal study. Anesth & Analg. 1 August 2017;125(2):562–70.
[12] Brown EE, Schwartz M, Shi C, Carter T, Shea JA, Grande D, Chaiyachati KH. Understanding why urban, low-income patients miss primary care appointments: insights from qualitative interviews of West Philadelphians. J Ambul Care Manage. 1 January 2020;43(1):30–40.
[13] Hunter OO, Mariano ER, Harrison TK. Leveraging video telehealth for the transitional pain service in response to COVID-19. Regional Anesthesia & Pain Medicine. 1 May 2021;46(5):460–1. 14. Goesling J, Moser SE, Zaidi B, Hassett AL, Hilliard P, Hallstrom B, Clauw DJ, Brummett CM. Trends and predictors of opioid use following total knee and total hip arthroplasty. Pain. 2016 Jun;157(6):1259.
[15] Piscitelli P, Iolascon G, Innocenti M, Civinini R, Rubinacci A, Muratore M, D’Arienzo M, Leali PT, Carossino AM, Brandi ML. Painful prosthesis: approaching the patient with persistent pain following total hip and knee arthroplasty. Clin Cases in Miner and Bone Metab. 2013 May;10(2):97.
Abstract #50 Submission ID#1308710
The Role of Over-the-Counter Pain Relivers for Self-Care in America’s Changing Healthcare Landscape Submission Type: Scientific Abstracts Submission Category: Submission Status: Complete/Locked Submitter: Kathleen Boyle – Johnson & Johnson Consumer Inc
Chrystine Zacheraua, Jonathan Johnsonb
aSenior Director, APCO Insight; bResearch Manager, APCO Worldwide
Learning Objectives
Upon completion, participants will be able to list the types of over-the-counter medicines that survey participants reported having in their homes for self care.
Upon completion, participants will be able to describe why survey participants viewed over-the-counter availability of acetaminophen as important to them.
Upon completion, participants will be able to list 3 reasons survey participants agreed were important for acetaminophen to be available OTC.
Purpose
The COVID-19 pandemic triggered dramatic changes in daily life in the United States (US) and globally. The pandemic also exacerbated existing inequitable access to health care and accelerated changes in the delivery of health care, influencing individuals to take more responsibility for their own care (self-care). Review of published literature confirms changes in healthcare access, delivery and seeking brought on by the pandemic.1,2 However, a gap exists regarding patients’ perceptions of the value of over-the-counter (OTC) medicines for appropriate self-care at home. In this context, the current study aimed to understand patients’ attitudes about OTC pain relievers, particularly acetaminophen, and its role in the at-home health care toolkit.
Methods
APCO Insight, a stakeholder research consultancy that has particular expertise in conducting qualitative and quantitative research in the health sector, identified and refined key concepts to develop a consumer-focused questionnaire in partnership with medical experts (e.g. medical doctors) and academically credentialed survey methodologists. The main survey focused on 4 distinct sets of questions to capture the current public health context and view of OTCs: demographics, health history/access, views toward OTC medicines, and the value and impact of current acetaminophen options. APCO partnered with YouGov, an internationally-recognized data collection platform and analytics group, to conduct a 400-person pilot study of the questionnaire to ensure target populations understood the survey language and questions had meaningful differentiation. Pilot study results and open-end responses from participants about the survey quality and ease of use for both Spanish and English speakers were reviewed to improve quality. APCO and YouGov then conducted a 20-minute, nationally representative online survey in both English and Spanish from January 26 to 9 February 2022 among 2,499 US adults, including oversamples for key subpopulations. The survey monitored national demographics by gender, age, race, and geography: 48% of participants were male, 51% female, 51% under 50-years-old, 49% older than 50 and 23% older than 65. The majority were white (64%), with 12% self-identifying as Black/African American, 15% as Hispanic/Latino and 10% as part of another group; 48% lived in suburban areas, 28% in urban, and 24% in rural areas.
The data were examined descriptively. Oversampling was implemented for two key subpopulations (African Americans and low-income households) to ensure large enough sample sizes for statistical analysis. Survey results were weighted to be representative of the US adult population. The margin of error for the survey is ±2% overall; though the margin of error is higher when opinion is more divided.
Results
51% reported using OTC medicines, 60% prescription medicines and 68% daily vitamins/nutritional supplements during the previous week. OTC medicines that ≥50% reported having in their homes included pain relievers (85%), cold/cough (75%), allergy relief (61%), antibiotic ointment (58%) and antacids (56%). Among those with a pain reliever in their home, acetaminophen (76%) and ibuprofen (77%) were reported most commonly.
Ibuprofen and acetaminophen were most often preferred for common ailments, except cold/flu. Acetaminophen was most preferred for fever, seen as satisfactory in treating multiple common conditions and used occasionally (73% reported use ≥few times over previous 6 months). During the previous 6 months, 3 of 4 participants experienced aches and pains (85%), headache (79%), and back pain (73%); ≥3 of 10 also had cold/flu (49%), pain from injury (43%), arthritis pain (41%), or fever (31%). Ibuprofen was preferred to acetaminophen for treating aches and pains (50% and 40%, respectively), back pain (40% and 32%, respectively), and arthritis pain (24% and 20%, respectively). Acetaminophen was preferred to ibuprofen to treat fever (46% and 34%, respectively). Multiple ingredient cold treatments were most preferred for cold/flu (66%).
Acetaminophen is seen as important to have OTC; has preferred existing dosing options; is viewed as efficacious, accessible, and safe; helps people manage pain to engage in regular activities; and satisfactorily relieves common ailments. Similar percentages of respondents preferred regular strength (650 mg) and extra strength (1000 mg) acetaminophen (43% and 42%, respectively). Among 81% who reported ability to get acetaminophen as an OTC medicine was very (53%) or somewhat (28%) important, efficacy (46%) and accessibility (38%) were the most common open-ended reasons. A majority strongly or somewhat agreed that acetaminophen was important to be available OTC because it was accessible without a prescription (88%), affordable (83%), effective (76%), tolerable (77%), non-addictive (75%), and safer than other pain relief options (60%). Regarding how acetaminophen helped with their regular activities, 52% reported that acetaminophen aided them in getting a full night’s sleep through pain relief. Approximately 40% said acetaminophen helped them with daily living tasks like showering and dressing (40%), spending quality time with loved ones (40%) and typical movement activities (48%). 41% reported relying on acetaminophen for pain relief so that they were able to participate in activities that required extra effort (e.g. swimming, hiking). For headaches (66%), aches and pains (63%), and fever (61%) over 6 in 10 participants were satisfied with acetaminophen; < 5% were unsatisfied.
Conclusion
This nationally representative survey of adults in the US showed strong reported use of various self-care options. Half of participants reported using OTC medicines. Pain relievers were the most commonly reported OTC medicines in participants’ homes and acetaminophen and ibuprofen were the analgesics most commonly used to manage aches and pains, back pain, arthritis pain, and fever. Nearly 3 of 4 participants (73%) reported using acetaminophen at least a few times over the previous 6 months. When asked to focus on acetaminophen, survey participants cited efficaciousness, availability, and affordability of acetaminophen as top reasons for it to be available as an OTC medicine. Moreover, participants confirmed that OTC acetaminophen enabled them to be active in a variety of activities of daily living. Survey results suggest that the accessibility and effectiveness of OTC acetaminophen allows individuals to appropriately self-manage their health and quality of life.
References
[1] Nana-Sinkham et al. 2021. 2. Centers for Disease Control and Prevention. 2022.
Abstract #51 Submission ID#1309223
Celecoxib Oral Solution in the Acute Treatment of Migraine: Pooled Efficacy and Safety Results From 2 Randomized Placebo-controlled Trials Submission Type: Scientific Abstracts Submission Category: Submission Status: Complete/Locked Submitter: Todd Kunkel – Collegium Pharmaceutical, Inc.
Stewart Teppera, Harvey Kushnerb, Mancia Koc, Richard B. Liptone, Todd Kunkeld
aProfessor of Neurology, Dartmouth-Hitchcock Medical Center; bDirector of Biometrics, Biomedical Computer Research Institute Corp.; cHead of Medical Affairs, Collegium Pharmaceutical; dDirector of Scientific Communications, Collegium Pharmaceutical; eNeurology, Albert Einstein College of Medicine
Learning Objectives
Describe celecoxib oral solution as a fast-acting selective cyclo-oxygenase (COX)-2 inhibitor that provides unique pharmacokinetic benefits via its formulation.
List co-primary efficacy endpoints of this pooled analysis, including freedom from migraine headache pain and freedom from most bothersome symptoms.
Describe the co-primary efficacy endpoints, where celecoxib oral solution exhibited significantly higher efficacy over placebo.
Purpose
Nonsteroidal anti-inflammatory drugs (NSAIDs) have established efficacy and are commonly used in acute treatment of migraine headache. Celecoxib oral solution (Elyxyb) is a selective cyclo-oxygenase (COX)-2 inhibitor that provides unique pharmacokinetic benefits by employing a self-microemulsifying drug delivery system (SMEDDS) technology, making it a rapidly absorbed oral solution formulation (Tmax = 42 min) that may be beneficial for patients seeking immediate migraine relief. Two recently published phase 3 clinical trials have established the safety and efficacy of celecoxib oral solution, leading to the US Food and Drug Administration approval of celecoxib oral solution for the acute treatment of migraine headache with or without aura. The purpose of this pooled analysis is to assess the co-primary efficacy outcomes from these 2 clinical trials that compare celecoxib oral solution and placebo for acute treatment of migraine in adults with or without aura.
Methods
Adults with 2 to 8 migraine attacks per month of moderate to severe pain intensity were enrolled in these 2 identical, randomized, double-blind, placebo-controlled clinical trials (ClinicalTrials.gov identifiers: NCT03006276 and NCT03009019). Subjects were randomized (1:1) and administered either celecoxib oral solution (120 mg) or placebo within 1 hour of migraine onset. The patient-reported co-primary efficacy outcomes at 2 hours postdose comprised freedom from headache pain (2hPF) and most bothersome symptom (2hMBS-F), which were recorded in an eDiary. Freedom from headache pain was defined as a reduction from predose moderate (grade 2) or severe (grade 3) pain to none (grade 0). Freedom from most bothersome symptom is defined as a reduction of the subjects’ most bothersome symptom (chosen among nausea, photophobia, or phonophobia at screening) from predose moderate (grade 2) or severe (grade 3) to none (grade 0). The safety population included all dosed patients with recorded data. Pooled results from participants in the intent-to-treat full-analysis set populations of both studies were used to calculate odds ratios (ORs) with 95% Wald confidence intervals (CIs) for the 2-hour time point and all preceding time points.
Results
Both co-primary efficacy outcomes achieved statistical significance: 2hPF (34.3% celecoxib oral solution vs 24.0% placebo; p = 0.0002; OR, 1.66; 95% CI, 1.28–2.16; n = 1112) and 2hMBS-F (57.3% celecoxib oral solution vs 43.7% placebo; p < 0.0001; OR, 1.73; 95% CI, 1.35–2.20; n = 1060). For most bothersome symptom freedom, significant improvement was first observed at 45 minutes postdose (28.7% celecoxib oral solution vs 22.4% placebo; p = 0.023; OR, 1.39; 95% CI, 1.05–1.84; n = 1034) and at all time points thereafter through 2 hours postdose. Freedom from headache pain first achieved significance at 1 hour postdose (18.2% celecoxib oral solution vs 12.5% placebo; p = 0.0095; OR, 1.56; 95% CI, 1.11–2.17; n = 1095). Sensitivity and subgroup analyses showed no significant differences by sex, race, age, or moderate vs severe predose pain. Extensive safety analyses identified no safety concerns in either clinical trial. Conclusion
This pooled analysis of 2 identical placebo-controlled clinical trials illustrated that significantly more subjects experienced freedom from headache pain and freedom from the most bothersome symptoms following celecoxib oral solution (120 mg) administration, compared with placebo at 2 hours postdose. Post hoc analysis showed significantly improved ORs and 95% CIs at 45 minutes postdose for freedom from most bothersome symptom and at 1 hour postdose for freedom from headache pain in subjects receiving celecoxib oral solution. These findings support the hypothesis that the rapid absorption of celecoxib oral solution facilitated by the use of SMEDDS technology, and the liquid formulation translates into fast onset of migraine-related pain relief with a favorable safety and tolerability profile for the acute treatment of migraine in adults.
Abstract #52 Submission ID#1309321
Application of Musculoskeletal Ultrasonogram for Same Day Diagnosis and Interventions in the Setting of a Physiatrist’s Office – A Rewarding Experience in Chronic Pain Management.
Jai Shanthini Singarama, Ayyoub Baqerb, Salah AlShalahic
aSpecialist in Physical Medicine and Rehabilitation, Department of Physical Medicine and Rehabilitation, Al Farwaniya Hospital, Kuwait; bConsultant in Physical Medicine and Rehabilitation, Department of Physical Medicine and Rehabilitation, Farwaniya Hospital, Kuwait; cSr Registrar, Physical Medicine and Rehabilitation, Department of Physical Medicine and Rehabilitation, Farwaniya Hospital, Kuwait
Learning Objectives
Demonstrate knowledge about the use of ultrasonogram in musculoskeletal pain.
Approach patients with chronic musculoskeletal pain with a new perspective.
Refer suitable patients with musculoskeletal pain for ultrasound guided procedures.
Purpose
Management of chronic musculoskeletal pain is complex. Accurate diagnosis and injection procedures of focal pain can be beneficial. We explored the possibility of using Musculoskeletal Ultrasonogram for same day evaluation, diagnosis and ultrasound guided injection procedures in our clinic and found the experience rewarding. This is a preliminary report of a retrospective descriptive study of 61 patients who were referred to our weekly Musculoskeletal Pain clinic in Physical Medicine Department in Al Farwaniya Hospital, Kuwait, during May–June 2022.
Methods
Medical records of all adult patients who consulted in our weekly Musculoskeletal Pain clinic were scrutinized for the period from May to June 2022. Data was collected with regards to demography, referral diagnosis, reason for referral, Ultrasonogram findings, and final treatment given. Numerical Rating Pain scores on first visit and on follow up visit after four weeks, were noted. Patients with inflammatory arthritis were excluded.
Results
Total number of patients = 61. 21 were male and 40 were female. Mean age = 57.45 years. Of the joints evaluated, knee constituted 47.5% and shoulder, 36%. In 80.32% of patients, in addition to the primary referral diagnosis, new additional diagnosis was confirmed after performing Ultrasound examination. In 78.6% patients, this additional diagnosis was the main source of pain and treatment plan was modified based on the new findings. 60.6% patients underwent ultrasound guided injection procedures including soft tissue and joint injection procedures such as Xylocaine, Steroids and Platelet Rich Plasma either in the same visit or by appointment. In all these patients who received injections, pain medications were tapered or stopped. The Mean pain score in the patients who underwent intervention was 8.37 on first visit and 3.86 on follow up visit. Mean difference was 4.38. p value calculated using Wilcoxon Signed – Rank Test was 0.00001 which was statistically significant.
Conclusion
Ultrasonogram is an important diagnostic and therapeutic office tool in Musculoskeletal pain clinic. When used as an extension of clinical examination by a trained Physiatrist, it improves diagnosis and helps in guiding joint and soft tissue injection procedures resulting in a significant improvement in pain scores, a mutually rewarding experience for both the patients and the Physiatrist.
References
[1] Sahoo RK, H. Peng PW. Role of ultrasound in chronic pain management. Indian J Pain 2020;34:151–9 2. Daniels EW, Cole D, Jacobs B, Phillips SF. Existing Evidence on Ultrasound-Guided Injections in Sports Medicine. Orthop J Sports Med. 22 February 2018;6(2):2,325,967,118,756,576. PMID: 29,511,701; PMCID: PMC5826008.
Abstract #53 Submission ID#1309367
Brucellosis Bursitis: A not so Uncommon yet so Easily Missed Differential Diagnosis of Knee Pain – A Unique Case Report of Symptomatic Dual Knee Bursitis
Jai Shanthini Singarama, Ayyoub Baqerb, Salah AlShalahic
aSpecialist in Physical Medicine and Rehabilitation, Department of Physical Medicine and Rehabilitation, Al Farwaniya Hospital, Kuwait; bConsultant in Physical Medicine and Rehabilitation, Department of Physical Medicine and Rehabilitation, Farwaniya Hospital, Kuwait; cSr Registrar, Physical Medicine and Rehabilitation, Department of Physical Medicine and Rehabilitation, Farwaniya Hospital, Kuwait
Learning Objectives
Demonstrate knowledge about joint involvement in Brucellosis
Demonstrate knowledge about the differential diagnosis of non traumatic knee pain in young individuals
Define the importance of careful history taking in the management of joint pain
Purpose
Osteoarticular manifestations are not uncommon in Brucellosis. Here we present the report of a patient who was referred to Physical Medicine Department for knee pain management with a diagnosis of medial meniscus degeneration; however the cause of knee pain was found to be Brucellosis bursitis Methods Report: 25 years old Arab male attended Physical Medicine Department for the first time with complaints of knee pain, stiffness and difficulty in walking. Detailed history revealed the following: History of first episode of knee pain with swelling 2 months earlier for which he had been treated in a private clinic symptomatically and improved partially. No history of trauma or sports injury. MRI then had showed medial meniscus Gr I changes with mild joint effusion. 2 weeks after this, he had been admitted to the Medical ward of regional hospital with gastro enteritis and fever. Blood test for Brucella antibody was positive and he was started on a course of antibiotics including Doxycycline and Rifampicin. Subsequently, Streptomycin had also been added. He recovered well and he was referred to our department for knee pain management with the diagnosis of medial meniscus degeneration. Patient gave history of handling camels as part of family business. Clinical examination of knee showed tenderness over the lateral suprapatellar and infrapatellar regions. Knee flexion was painful and restricted to 120 degrees. Patient walked with a mild limp. Ultrasonogram examination was done in the same visit in our clinic and it revealed anechoic fluid in the suprapatellar pouch and in the deep infrapatellar bursa. A diagnosis of suprapatellar and deep infrapatellar bursitis due to Brucellosis was made. Management: The patient was assured that his knee pain was due to Brucella bursitis and he was advised to continue his antibiotics course, avoid any strenuous activities and perform simple knee exercises at home. Low Level Laser therapy was initiated. After 3 weeks, follow up Ultrasonogram showed no fluid in the infrapatellar bursa and very minimal fluid in the suprapatellar bursa. There was no tenderness in the knee, range of motion was full and gait was normal.
Results
Discussion: Prepatellar bursitis is the most common presentation when knee joint is affected. Our patient presented with suprapatellar and deep infrapatellar bursitis. Management of bursitis is strict regimen of antibiotics. Our patient was well managed with 3 weeks of Streptomycin and is still continuing the 12 weeks course of Doxycycline and Rifampicin.
Conclusion Conclusion: Ours is a unique report of dual knee bursitis in Brucellosis . It is important to have a high index of suspicion in endemic places when a young patient presents with non traumatic joint pain and effusion. Musculoskeletal Ultrasonogram is useful for diagnosis, follow up and monitoring bursitis in Brucellosis.
References
[1] Traboulsi, R., Uthman, I. & Kanj, S.S. Prepatellar Brucella melitensis bursitis: case report and literature review. Clin Rheumatol 26, 1941–1942 (2007).
[2] Arkun R, Mete BD. Musculoskeletal brucellosis. Semin Musculoskelet Radiol. 2011 Nov;15(5):470–9. doi: 10.1055/s-0031-1,293,493. [Cited 11 November 2011] Available from: PMID: 22,081,282.
Abstract #54 Submission ID#1309413
Impact of Celecoxib Oral Solution on Symptomatic Improvements in the Acute Treatment of Migraine
Stewart Teppera, Harvey Kushnerb, Mancia Koc, Todd Kunkeld
aProfessor of Neurology, Dartmouth-Hitchcock Medical Center; bDirector of Biometrics, Biomedical Computer Research Institute Corp.; cHead of Medical Affairs, Collegium Pharmaceutical; dDirector of Scientific Communications, Collegium Pharmaceutical
Learning Objectives
Describe celecoxib oral solution as a fast-acting selective cyclo-oxygenase (COX)-2 inhibitor that may provide improved gastrointestinal safety and rapid efficacy in the acute treatment of migraine.
List the secondary efficacy endpoints analyzed in these 2 studies including the proportion of participants experiencing headache pain relief and freedom from nausea, phonophobia, and photophobia at 2 hours postdose.
Describe the additional evidence illustrating the efficacy of celecoxib oral solution for treatment of acute treatment of migraine, that is, achievement of improved secondary endpoints listed in objective 2.
Purpose
Nonsteroidal anti-inflammatory drugs (NSAIDs) have established efficacy and are commonly used in acute treatment of migraine headache as standard-of-care therapy. Many NSAIDS are associated with adverse gastrointestinal effects and slow absorption, illustrating the need for alternative acute treatments for migraine. Celecoxib oral solution (Elyxyb) is a selective cyclo-oxygenase (COX)-2 inhibitor in a well-tolerated and rapidly available formulation (Tmax = 42 min) that may improve gastrointestinal safety and tolerability while providing rapid effect onset. Two recently published phase 3 clinical trials have established the safety and efficacy of celecoxib oral solution (ClinicalTrials.gov identifiers: NCT03006276 and NCT03009019). Based on evidence from these trials, the US Food and Drug Administration has approved celecoxib oral solution for the acute treatment of migraine. Pooled analysis from the first treatment period of these 2 studies supported the efficacy and safety of celecoxib oral solution by achieving significance for the coprimary efficacy endpoints of freedom from pain and freedom from the most bothersome symptom (MBS) at 2 hours postdose with no safety concerns observed (see our these results in the abstract ‘Celecoxib Oral Solution in the Acute Treatment of Migraine: Pooled Efficacy and Safety Results From 2 Randomized Placebo-controlled Trials’). This pooled analysis evaluates secondary efficacy outcomes from 2 identical clinical trials comparing celecoxib oral solution and placebo for the acute treatment of migraine headache with or without aura.
Methods
Participants reporting 2 to 8 migraine attacks per month of moderate to severe pain intensity were enrolled in these identical multicenter, randomized, double-blind, placebo-controlled clinical trials. The studies included more than 1200 total subjects at approximately 90 centers. Subjects were randomized (1:1) and administered either celecoxib oral solution (120 mg) or placebo within 1 hour of migraine onset. Participants recorded their responses to efficacy assessments in an eDiary. Secondary efficacy outcomes assessed at 2 hours postdose included the proportion of participants achieving headache pain relief and freedom from nausea, phonophobia, and photophobia. Only results pooled from the first double-blind period (DB1) were analyzed. Secondary outcomes from the pooled intent-to-treat full-analysis set population (n = 1130) were tested for statistical significance using Fisher’s exact test. Odds ratios (ORs) with 95% confidence intervals (CIs) were also calculated.
Results
Significantly more subjects administered celecoxib oral solution vs placebo reported 2-hour postdose headache pain relief (403 [71.3%] vs 317 [58.15%], respectively, p < 0.0001), freedom from predose phonophobia (238 [60.1%] vs 209 [50.6%], p = 0.0072), and freedom from photophobia (283 [58.1%] vs 212 [43.4%], p < 0.0001) in this pooled analysis. Freedom from nausea and allodynia did not achieve significance 2 hours postdose. ORs (95% CI) comparing celecoxib oral solution and placebo were 1.8 (1.4–2.3) for headache pain relief, 1.5 (1.1–1.9) for freedom from phonophobia, and 1.8 (1.4–2.3) for freedom from photophobia.
Conclusion
This pooled analysis of 2 identical clinical trials revealed that administration of celecoxib oral solution helped significantly more patients to achieve key secondary efficacy endpoints at 2 hours postdose (during treatment period 1). These outcomes included headache pain relief, freedom from photophobia, and freedom from phonophobia. These secondary endpoint results support the co-primary efficacy endpoint results, where significantly more subjects achieved 2-hour postdose pain freedom and 2-hour postdose freedom from the MBS following administration of celecoxib oral solution, compared with placebo. The findings presented here provide additional evidence for the efficacy of celecoxib oral solution in the acute treatment of migraine headache in adults with or without aura.
Abstract #55 Submission ID#1309666
Comparison of Radiation Dosages for Lumbar Epidural Injections using Midline and Transforminal Approaches.
Vijayasree Arvinda, Lisa Patinob, Kavya Arvindc, Ezra Aguilar, Studentd, Anup Arvinde
aPhysician Owner, Cardinal Pain Center; bLVN and Research Coordinator, Cardinal Pain Center; cMedical Student, Cardinal Pain Center; dStudent Researcher, Cardinal Pain Center; eMedical Student Researcher, Cardinal Pain Center
Learning Objectives
Choose interventional pain procedures and take radiation precautions to protect physician and patient.
Take protective measures during interventional procedures.
Aware of radiation limits for various organs of the body and improve radiation safety.
Purpose
Interventional Pain Management involves routine use of fluoroscopy to promote accuracy of needle placement, delivery of medications to appropriate locations and enhance patient safety using multimodal views of fluoroscopy to minimize complications. Fluoroscopy has become mandatory for most procedures based either on the definition of the procedure or the requirement of insurance companies.
The most commonly used fluoroscopy in interventional pain management is with C-arm fluoroscopes with image intensification. Fluoroscopic exposure to radiation causes enhanced risk to physicians, medical personnel assisting during procedures and patients alike. Hence keen awareness and efforts to minimize radiation exposure is mandatory.
We compared the radiation dosages and fluoroscopy duration in most common interventional pain procedures such as lumbar translaminar epidural steroid injections and lumbar transforaminal epidural Steroid injections. Bilateral single level or unilateral two level transforaminal epidural steroid injections were compared to single level translaminar epidural steroid injection. The cases were performed in a 3 month period by one physician in a private practice setting, thereby limiting the variability in doses due to physician expertise or performance method.
Fluoroscopy doses and times were compared in 25 patients each of patient categories, who underwent translaminar and transforaminal lumbar epidural steroid injections
Methods
The data was reviewed from the fluoroscopy machine from January 2022 to April 2022 in the procedure suite. Mean fluoroscopy time (FT), mean radiation dose per procedure, and utilization of pulsed fluoroscopy were analyzed.
Results
Data of a total of 25 cases of translaminar epidural steroid injections were collected. The average fluoroscopy exposure time for translaminar lumbar epidural steroid injection was 0.115 minute and the transforaminal approach average time was 0.24 minutes.
The average radiation dose for lumbar translaminar approach was 5.51 mGy and for the trasnsforaminal approach was 9.59mGy.
he data was analyzed using a two-sample independent t-test for statistical significance. There was sufficient evidence to suggest that there is a statistically significant difference between both the radiation doses and radiation times between the transforaminal and translaminar approaches to lumbar epidural steroid injections since the p-value of the t-test was less than 0.05. The transforaminal approach had a statistically significant greater average radiation dose and delivery time.
Conclusion
Since the transforaminal approach involved higher radiation doses and times incurred both by the patients and physician, every effort should be taken to judiciously limit exposure. Risk and benefits of choosing different approaches for interventional procedures need to be carefully evaluated.
In particular, clinicians or medical staff that use fluoroscopic imaging outside of dedicated radiology or interventional departments have low adherence and training to radiation safety guidelines. As radiation exposure becomes more prevalent, a thorough understanding of radiation exposure risks and dose reduction techniques will be of utmost importance.
The image intensifier or x-ray plate should be as close to the patient as possible, with the x-ray tube positioned as far away as possible. Utilization pulsed fluoroscopy also reduce the radiation exposure significantly. Scattered radiation can be reduced by one fourth if the staff members double the distance from the source. Since scattered radiation follow the inverse square law distance plays a pivotal role in exposure.
References
[1] Radiation Exposure to the Physician in Interventional Pain Management Laxmaiah Manchikanti, MD*, Kim A. Cash, RT, Tammy L. Moss, RT, and Vidyasagar Pampati, MSc
Abstract #56 Submission ID#1309775
Evaluating the Literacy Levels of Opioid Agreements Submission Type: Scientific Abstracts
Canyon Lohnasa, Aimee Morewoodb, Stephanie Pocklc, Corinne Layne-StuartdRenee Nicholson, MFAe, Monika Holbeinf
aProgram Specialist, College of Applied Human Sciences, West Virginia University; bProfessor Literacy Education, College of Applied Human Sciences, West Virginia University; cGeriatrics Fellow, College of Health Sciences, West Virginia University; dAssistant Professor of Anesthesia, College of Health Sciences, West Virginia University; eDirector of the Humanities Center West Virginia University and Director at Programs for Multi- and I, Eberly College, West Virginia University; fAssistant Professor of Medicine, Penn State Health
Learning Objectives
Upon completion, participants will be able to describe two different literacy evaluation tools.
Upon completion, participants will be able to identify three key components that increase or decrease the reading level of a document.
Upon completion, participants will be able to outline three themes of opioid agreements and describe them to patients using non medical jargon.
Purpose
Readability formulas are often used to determine reading levels, however, these formulas may not be capturing the realities of the content within the documents. Given that healthcare professionals are taught throughout their training to use nonmedical language to increase patient understanding, it is important to look closely at the language and themes portrayed in medical documents. This research focused specifically on opioid agreements.
Every step in patient care should help the patient achieve their goals in a safe and effective manner; the opioid agreement should not be an exception. Opioid agreements are part of risk mitigation and in some instances a requirement for prescription. The worry about these agreements is that in their current form, they may not be easily understood and thus not patient centered. The hypothesis was that the opioid agreements were not written at a literacy level that could easily be understood. This led to the formation of a working group that spanned different colleges within the university.
The university’s Humanities Center brings together this interdisciplinary team of researchers from the field of education and medicine to evaluate the literacy levels of opioid agreements. Also known as opioid contracts, these documents inform patients of the risks and expectations of the use of opioids for pain management. The reading difficulty of these documents have a significant impact on a patient’s ability to comprehend the associated risks, benefits, and expectations of this treatment plan. This research focused on one university hospital system serving an Appalachian population and consisted of two phases: (1) a review of the readability levels and (2) a content analysis of the university’s Non-Chronic Pain Contract for Use of Opioid Medications (Pain Contract) and the university’s Consent to Treat with Opioid Medications (Consent Form). Two readability formulas were used; the Fleisch-Kincaid Grade Level (FK) formula and the Simple Measure of Gobbledygook (SMOG).
The research questions that guided this study were:
1. How are readability formulas used to evaluate the reading difficulty of opioid agreements?
2. What themes emerged during a content analysis of an opioid agreement?
Methods
Using a case study approach (Yin, 2009) the readability levels of the university’s opioid documents were first analyzed using three easily accessible and (presumably) free tools (e.g. Microsoft Word, Readabilityformulas.com, and Textcompare.org) to evaluate the reading grade levels of the document. The reading scores are reported using the grade level and month within the grade (e.g. a score of 12.9 is the equivalent of reading abilities typical of someone in the ninth month of twelfth grade).
The documents had different total numbers of words; the Pain Contract had 915 words and the Consent Form had 446 words. To control for consistency in assessing the reading levels of the documents, the exact number of words were used from the beginning of each document to calculate the individual reading levels and then the documents were combined (1361 total words) to determine an overall reading grade level.
Each document and then both together were entered into each of the three readability tools and scored using the FK formula and the SMOG. The FK was selected because this is often used in educational settings and the SMOG was selected because this is typically used by the medical field.
Content analysis was used in the second phase to look more closely at the meaningful language units within each of the documents. This social science approach includes a critical examination of text, an interpretation of the texts through either an emerging or a priori lens, and an understanding that socially constructed perspectives are brought to the text during analysis.
Initially, codes emerged from both of the university documents. Then, to more clearly see the emerging code patterns, the educational team members separated the documents and the codes. After this separation, the codes from both documents were merged and color coded to establish one code list. The code list was shared with the medical team researchers, so that they could use their specific disciplinary knowledge to categorize the codes. The categorization groups were then titled by the collective team members to capture the codes within each of these groups.
Results
The evaluation of the opioid agreements using multiple readability formulas and tools led to several insights regarding the reading difficulty of the documents. The opioid medication agreement documentation at WVU Medicine is 1,361 words. The document was entered into the readability calculators to evaluate the reading difficulty of the documents. An evaluation using the FK formula yielded three grade level scores: 12.9 (Microsoft Word), 12.2 (readabilityformulas.com), and 12.9 (text compare.org). An evaluation using the SMOG index yielded two scores (Microsoft Word does not calculate SMOG score): 12 (readabilityformulas.com) and 15.61 (textcompare.org).
Regardless of the readability formula used, there is variation in readability scores. This raises questions about the accuracy of the formulas and calculators. These readability scores are higher than expected by the researchers and call for further consideration of the reading difficulty of opioid agreements.
The content analysis identified several pieces of text within the document. Forty-two unique codes were identified and classified into seven categories within three themes. By coding the documents and placing the codes into categories, researchers were able to identify and describe the most meaningful elements of the documents and capture the purpose and significance of the document.
Expectations
Acknowledgments
Agree to conditions
Consent
Patients understands document
Patient Responsibility statement
Risk acknowledgment
Start/End date
Administration
Directions for completing contract
Introduction
Patient signature
Pharmacy name
Practitioner signature
Prescription authorization
Questions answered
Read to me
Witness signature
Objective Medication Information
Dosage/Frequency
Medication schedule/refill
Pill counts
Quantity
Types of medications
Other treatments
(i)Other possible treatment options
Punitive Consequences
Disclaimer on prescription duration
Expiration of consent/termination of medication
Reference local, state, federal law
Termination of medication
Termination of provider-patient relationship
Rules
Attend scheduled appointments
Illegal/illicit drugs
Notification of other medications
Prescriptor
Random drug screenings
Responsibility for tracking prescription
Specimen tampering
(2) Risks
a. Adverse outcomes
(i) Addiction
(ii) Anticipated risks
(iii) No guarantee
(iv) Physical dependency
(v) Potential to worsen conditions
(vi) Precautions
(vii) Side effects
(3) Benefits
a. Benefits of opioid prescription
b. Benefits of other treatment options
Through the content analysis, meaningful elements were identified within the document and revealed a stronger emphasis on the risks associated with opioid medication rather than the benefits.
Conclusion
A cross-disciplinary approach to this research allowed for a critical examination of the reading levels of these documents. While there was variance across the individual tools, they all produced upper grade level scores. This suggests that closer attention to the reading difficulty of opioid agreements is necessary to increase patients’ understanding of the documents associated with opioid medication. More accurate measures of readability could assist those crafting these documents and ensure an appropriate reading difficulty, which could lead to better understanding of the agreements by the patient. Additionally, a call for greater consistency among readability formulas and tools is also needed.
Further, the content analysis demonstrated that increased attention to the potential benefits of opioid medication is needed given that this data suggested a stronger emphasis on the associated risks. Patients having a better understanding of the benefits could improve patient care.
The findings from this study will be used to improve the readability of this institution’s opioid agreement documentation. Future cross-curricular research also involves continuing to focus on the language used in this institution’s opioid documents and expanding the research to include other US university medical center’s documents to better understand the readability levels and the content.
References
[1] Krippendorff, Klaus. (2004). Content analysis: An introduction to its methodology. Thousand Oaks, CA: Sage Publishing. Yin, R. K. (2009). Case study research: Design and method (4th ed.). Thousand Oaks, CA: Sage. Dowell, Deborah, Tamara M. Haegerich, and Roger Chou. ‘CDC guideline for prescribing opioids for chronic pain – United States, 2016.’ Jama 315.15 (2016): 1624–1645.
[2] McAuliffe Staehler, Tuesday M., and Laura C. Palombi. ‘Beneficial opioid management strategies: A review of the evidence for the use of opioid treatment agreements.’ Substance abuse 41.2 (2020): 208–215.
Abstract #57 Submission ID#1309783 ADV-502
Novel Dual Sigma-1 Receptor Antagonist and Mu-Opioid Receptor Agonist for the Treatment of Pain: III. Phase-1 Study
Joseph Pergolizzia, Anna Vaquéb, Mariano Sustc, Soledad Casalsd, Josep-Maria Cendróse, Anna Cabotf, Gregorio Encinag, Begoña Fernándezh, Robert B. Raffai, Ukrike Lorchj
aCo-founder, CEO, other, NEMA, Neumentum, Enalare, Advantx, other; bMedical Drug Safety Officer & back up EUQPPV, ESTEVE Pharmaceuticals S.A.; bClinical Biostatistician, ESTEVE Pharmaceuticals S.A.; dClinical Trials & Monitors Coordinator, Esteve Pharmaceuticals; eDrug Discovery & Preclinical Development Center, WeLab Barcelona; fDrug Discovery & Preclinical Development CenterWeLab Barcelona; gHead of Bioanalysis and Drug Metabolism/Pharmacokinetics, Esteve Pharmaceuticals S.A.; hDrug Discovery & Preclinical Development Center, WeLab Barcelona; iProf Emeritus; Adjunct; CSO: Co-founder; Sci AdBoard, Temple Univ; Univ AZ; Neumentum; Enalare; Advantx; jCo-founder & Medical Director, Richmond Pharmacology Ltd
Learning Objectives
Upon completion, participant will be able to explain the importance of a proof-of-principle clinical trial of a novel MOR/S-1 R analgesic.
Upon completion, participant will be able to describe the efficacy results of the trial.
Upon completion, participant will be able to describe the safety results of the trial.
Purpose
ADV-502 was identified in a discovery program aimed at overcoming shortcomings of existing analgesic classes. The process employed a new strategy (pharmacophore-merging) to identify compounds having dual action at both the µ-opioid receptor (MOR) and the s1 receptor (sigma-1 R). The rationale was the role of sigma-1 R antagonists in inhibiting central sensitization (in which opioids are not completely satisfactory) and the enhancement of opioid-induced analgesia by sigma-1 R antagonists. ADV-502 (EST73502//WLB-73502) emerged as a novel compound of particular interest (García et al., 2020). It has binding affinity for both MOR and sigma-1 R and behaves as a partial MOR agonist and sigma-1 R antagonist. Efficacy in vivo revealed antinociceptive effects in animal models of acute pain, visceral pain, and chronic/neuropathic pain. ADV-502 displays good selectivity over other binding sites, has a good PK profile and a balanced metabolism. It also displays less respiratory and gastrointestinal (GI) MOR-related AEs, low development of tolerance and physical dependence, and a safety profile [see the accompanying poster for the Preclinical summary] that supported advancement to a Phase-1 clinical trial, summarized here. Methods This was an exploratory, randomized, double-blinded, placebo- and active-therapy-controlled phase I study of ADV-502 using an adaptive integrated design which assessed the safety tolerability, food effect, PK and PD of single ascending doses (SAD) and multiple doses (MD). The participants were healthy Caucasians 18–45 yrs. Sixty-two participants were analyzed for safety and tolerability and were sampled for PK analysis, and 51 underwent intensive cardiac assessment. ADV-502, placebo, or oxycodone were administered by oral capsules. Primary endpoints included safety and tolerability as measured by the incidence of treatment emergent adverse events (TEAEs), proportion of subjects with clinically significant changes in laboratory values, ECG, or vital signs. Secondary endpoints included PK and some ADME measures. Some exploratory endpoints (e.g. PK/PD relationship, PD effects of ADV-502 and oxycodone IR on pupil size and gastrointestinal function and symptoms) were also included. Results
A total of 62 healthy volunteers were enrolled and dosed in the study. None withdrew from the study. Overall, single and multiple administrations of ADV-502 were well tolerated, no serious adverse event (SAEs) occurred during the study, and no participant was discontinued due to a TEAE. In Part I (SAD), ADV-502 demonstrated a clear dose response as the incidence of TEAEs increased with increasing single oral doses from 2.5 mg up to 30 mg, and most notably in the 20 and 30 mg doses. In Part II (food effect), the safety profile of ADV-502 was generally comparable in the fed and fasted state; however, the frequency of dizziness and headache was higher in the fed than fasted state, despite no clear relationship was observed with individual PK data. In Part III (5 mg MD), the small number of subjects who received oxycodone IR translated to a relatively limited comparison with ADV-502. Despite this, the limited data showed a relatively comparable safety profile for a 5 mg dose of both oxycodone IR and EST73502 administered QID for 7 consecutive days (and a morning dose on Day 8). The most common TEAEs included somnolence, headache, nausea, euphoric mood, and dizziness, more commonly in the oxycodone and ADV-502 groups than in the placebo group. There were no ADV-502-related or clinically-significant changes in vital signs, clinical lab tests, or ECG, and no evidence of respiratory depression. QTc prolongation occurred at the highest dose (30 mg). A rapid PD effect was demonstrated by pupillometry. PK/PD relationship between reduction of pupil size and exposure to ADV-502 was observed after single oral administration of ADV-502 at dose levels equal or higher than 5 mg. In the 5 mg MD administration, QID regimen, the limited data obtained for 5 mg oxycodone IR suggested similar potency to reduce pupil size to that of ADV-502. There was a PD effect on bowel function but less than oxycodone. There was a dose-related increase in drug-liking compared to placebo. Established PK/PD models of ADV-502 predict that analgesia, measured by its potency to produce miosis, appeared at lower ADV-502 concentrations than neurological performance, measured by drug-related relative VAS.
Conclusion
ADV-502 shows dual MOR-agonism and sigma-1 R antagonism that results in potent analgesic activity comparable to the MOR agonist oxycodone in animal models of pain including chronic/neuropathic pain after single and repeated administration [see accompanying poster]. These efficacy results, and reduced MOR-like AEs provided evidence that dual MOR-agonism and sigma-1 R antagonism appeared to be a useful strategy for obtaining potent and safer analgesics, and were the basis for the selection of ADV-502 as a clinical candidate for the treatment of pain. This Phase-1 study explored a range of ADV-502 doses that encompass the potential anticipated therapeutic dose range. The dose of 5 mg QID seemed adequate to maintain the required plasma concentration above the predicted therapeutic threshold. Continued investigation of efficacy and safety is needed. Due to the low number of participants in the oxycodone arm, no comparative conclusions could be drawn, but the results aligned with preclinical data that showed a trend to better GI tolerability. Based on the overall results of this study (and perhaps depending on some extent of accumulation factor with dosing), the potential analgesic effect of ADV-502 appears to be achievable at the 5 mg dose without exceeding the PK and safety limits and no QT-prolongation concerns.
References
[1] García et al. (2020) J Med Chem 63:15,508–26
Abstract #58 Submission ID#1310205
Non-Medical Use of XTAMPZA ER: Motivation, Methods, and Perceptions of Tampering
Joshua Blacka, Karilynn Rockhillb, Geoff Severtsonc, Richard Dartd
aSenior Research Scientist, Rocky Mountain Poison and Drug Safety; bBiostatistician III, Rocky Mountain Poison and Drug Safety; cAssociate Research Scientist, Rocky Mountain Poison and Drug Safety; dDirector, Rocky Mountain Poison and Drug Safety
Learning Objectives
List reasons for non-medical use of Xtampza ER
Describe differences between non-medical use of Xtampza ER and similar drugs.
List methods for tampering with Xtampza ER.
Purpose
Opioid abuse-deterrent formulations (ADF) were developed to impede manipulation with the intention of reducing the improper use of opioids. XTAMPZA ER® is an extended-release (ER), abuse-deterrent formulation oxycodone product that uses DETERx® technology designed to reduce manipulation. The effectiveness of XTAMPZA ER at reducing improper use has been studied in preclinical and clinical settings, and results from real world contexts are growing. Among poison center calls, XTAMPZA ER intentional drug exposures rates were shown to be lower than other ADF products and immediate release (IR) oxycodone (1). In addition, the odds of past-month abuse of XTAMPZA ER among entrants to opioid treatment facilities were lower than for other ADF products (1). Relatively little is known about why drug users choose to non-medically use ADF products, how effective ADF products are in preventing tampering in the real world, and perceived risks of using ADF products. The goal of this study was to assess the motivations, methods, and perceptions of tampering with XTAMPZA ER with the intention of non-medically using the tampered product.
Methods
The Survey of Non-Medical Use of Prescription Drugs (NMURx) Program is an online general population survey from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System. A repeated cross-sectional survey about drug use was administered in two survey waves in 3rd quarter 2021 and 1st quarter 2022 to a commercial online panel, which is a convenience sample of the national adult population. Participants who reported non-medical use (NMU) of XTAMPZA ER, other extended-release abuse-deterrent opioids (other ER-ADF opioids); and immediate release, single entity oxycodone (IR-SE oxycodone) were included in the analysis. The ER-ADF opioids included were OxyContin®, Hysingla®, and generic forms of ER oxycodone or hydrocodone. NMU of a drug was defined as ‘used < drug > in a way not directed by your healthcare provider’ in the last 12 months.
Participants who met these criteria were given a follow-up survey with detailed questions about whether they tampered with the pills. Participants were asked if they tampered in the following ways: chew, crush, heat or melt, dissolve in mouth, dissolve in liquid, or combine with another drug. For each, they were asked if they tampered for the following reasons: to inject, to smoke or vape, to snort, to increase a high feeling, to improve pain relief, or to feel effects more quickly.
Descriptive percentages of methods and reasons for tampering and motivations for each drug group are reported. Race and ethnicity were asked where Hispanic ethnicity was a separate question, and participants could select any of the following races: White, Black, Asian, American Indian or Alaskan Native, Native Hawaiian or Pacific Islander, or something else.
Results
A total of 10,896 participants were invited to the study in 3rd quarter 2021 and 931 have provided completed questionnaires. The sample of invited participants was 52.9% female, 69.4% non-Hispanic White, 6.4% non-Hispanic Black, 10.1% Hispanic, 12.8% another non-Hispanic race, 3.0% multiple non-Hispanic races, and had a median age of 55 years (interquartile range: 41-67).
NMU of XTAMPZA ER was uncommon relative to other drugs. Among adults who reported use of XTAMPZA ER, 67 (9.8%) reported NMU of XTAMPZA ER; comparatively, 289 (42.3%) reported NMU of other ER-ADF opioids and 247 (36.2%) reported NMU of IR-SE oxycodone. However, among those who non-medically used, similar percentages reported tampering across drug groups. Among adults reporting NMU of XTAMPZA ER, 36 (53.7%) reported tampering; analogously, 123 (42.6%) reported tampering of other ER-ADF opioids and 108 (43.7%) reported tampering of IR-SE oxycodone.
There was little difference between tampering methods across drug groups. Among those tampering with XTAMPZA ER, methods of tampering ranged from 14 (38.9%) reporting heated or melted the drug while 22 (61.1%) reported taking the drug with another drug. Similarly for those tampering with other ER-ADF opioids, 35 (28.5%) reported heating or melting the drug while 68 (55.3%) reported taking the drug with another drug. For those tampering with IR-SE oxycodone, 22 (20.4%) reported heating or melting the drug while 64 (59.3%) reported taking the drug with another drug.
There was little difference in the reasons for tampering or the reported success in achieving the reason for tampering. Among those tampering with XTAMPZA ER, reasons for tampering ranged from 20 (55.6%) reported seeking to inject the pill; while 30 (83.3%) reported tampering to feel the effects of the pill more quickly. Similarly for those tampering with other ER-ADF opioids, 41 (33.3%) reported seeking to smoke or vape while 88 (71.5%) reported tampering to feel the effects of the pill more quickly. Across all adult and reason combinations, a large majority reported accomplishing the reason they sought to tamper. A total of 89 (84.0%) reported reasons for tampering with XTAMPZA ER accomplished the reason while 263 (90.7%) and 205 (88.7%) reasons for tampering accomplished the reason for other ER-ADF opioids and IR-SE oxycodone, respectively.
Conclusion
In a real-world setting, the abuse-deterrence properties of a drug like XTAMPZA ER may be deterring individuals from using it for NMU, while those who are persistent enough to tamper with an ADF product will have the skill to accomplish the goals they seek. Despite increasing availability, NMU of XTAMPZA ER is relatively infrequent compared to other similarly indicated drugs. However, those who do tamper with XTAMPZA ER report effective tampering. These individuals who NMU could be those experienced with tampering, and therefore have higher rates of accomplishing the effect they are seeking. Notably, studies have shown that crushing and chewing XTAMPZA ER do not affect the pharmacokinetic profile. Those who are seeking to crush or chew for the reason of increasing the effect may be experiencing a placebo effect where they are expecting a certain feeling from tampering, and they feel that effect regardless of the actual drug effect.
References
[1] Severtson GS, Kreider SED, Amioka EC, Margolin ZR, Iwanicki JL, Dart RC. Postmarketing Analysis of Misuse, Abuse, and Diversion of Xtampza ER. Pain Med. 2020;21(12):3660–3668.
Abstract #59 Submission ID#1310221
Differences in the severity of medical outcomes of exposures reported to poison centers involving XTAMPZA® ER and other opioid analgesics
Geoff Severtsona, Joshua Blackb, Janetta Iwanickic,Richard Dartd
aAssociate Research Scientist, Rocky Mountain Poison and Drug Safety; bSenior Research Scientist, Rocky Mountain Poison and Drug Safety; cPhysician, Denver Health and Hospital Authority; dDirector, Rocky Mountain Poison and Drug Safety
Learning Objectives
Understand potential medical consequences from non-medically using Xtampza ER.
Describe differences in medical outcomes between non-medical use of Xtampza ER and simliar drugs.
Describe exposures to Xtampza ER that results in calls to a poison control center system.
Purpose
Opioids are a frequently used treatment for acute and chronic pain in the United States. Misuse of these medications is also common and places the individual at significant risk of overdose and death. The development of abuse deterrent formulations (ADFs) is one approach prioritized by the U.S. Food and Drug Administration (FDA) to reduce the harms of prescription opioid misuse. In a guidance to pharmaceutical manufacturers, the FDA outlined four categories for evaluating the effectiveness of ADFs with the fourth category being demonstrated reduced abuse, misuse, and related adverse outcomes such as overdose and death in the post-approval, real-world setting. As of 2022, no opioid has met category four labeling requirements. XTAMPZA® ER (Collegium Pharmaceutical, Stoughton, MA) is an oxycodone analgesic with properties intended to discourage tampering. XTAMPZA ER was granted abuse-deterrent labeling with respect to oral, nasal and intravenous routes of administration based on premarket studies. It was first dispensed to patients in 2016. Post-marketing studies of XTAMPZA ER are consistent with the aim of reduced abuse and tampering. However, it is unclear whether these changes correspond with meaningful reductions in adverse outcomes associated with misuse and abuse such as overdose and death. Poison centers are a useful data source to assess medical outcomes such as overdose and death related to misuse of pharmaceuticals. We assessed the number of XTAMPZA ER exposures reported to poison centers and whether they are less likely to be classified as intentional (e.g. abuse, misuse, or suspected suicidal) than exposures involving other opioid analgesics. We examined whether the severity of outcomes for exposures involving XTAMPZA ER were less severe than exposures involving other opioids. Finally, we assessed whether XTAMPZA ER corresponded to less severe outcomes among intentional exposures.
Methods
Data collected between 1st quarter 2016 through 4th quarter 2021 from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System Poison Center Program were used. Data from cases involving 1) XTAMPZA ER, 2) immediate-release (IR) single-entity (SE) oxycodone 3) other ADF extended-release (ER) opioids, 4) non-ADF ER opioids 5) unspecified oxycodone, and 6) unspecified morphine were analyzed. Analyses were restricted to cases where the exposure was followed to a known outcome of either no effect, minor effect, moderate effect, major effect, or death and to instances where the route of administration was known to involve ingestion, inhalation, or injection. Multinomial logistic regression was used to compare the proportion of XTAMPZA ER exposures that were either abuse/misuse/unknown or suspected suicidal to other opioids. Medical outcome was treated as an ordinal variable, from no effect to death. We compared medical outcome of XTAMPZA ER to other drug groups for all exposures and for intentional exposures. To compare severity of medical outcome between drug groups we used nonparametric Kruskal-Wallis test. If there was a statistically significant difference between drug groups based on the Kruskal-Wallis test, we conducted the Dunn test to compare differences between XTAMPZA ER to each comparator. Multiple comparisons were adjusted for using the false discovery rate. A lower mean rank of medical outcomes was interpreted as cases being less severe on average than comparator groups.
Results
From 2016 through 2021 there were 161 exposures involving XTAMPZA ER that were followed to a known outcome. Of these, 16 (9.9%) were intentional misuse/abuse/unknown exposures, and 47 (29.2%) were suspected suicidal exposures. The percentage of XTAMPZA ER exposures that were either abuse/misuse/unknown or suspected suicidal were statistically significantly less than for other drug groups. We compared the distribution of medical outcomes within each drug group. The results of the Kruskal-Wallis test indicated a statistically significant difference in the distribution of medical outcomes (Χ2 = 350.80, df = 5, p < 0.001). Results of the Dunn Test showed that the rank order for XTAMPZA ER was significantly lower than other drug groups, indicating that, on average, a case involving XTAMPZA ER is likely to be a less severe outcome relative to other comparators. We examined whether intentional exposures involving XTAMPZA ER were less likely to result in severe outcomes than comparators. Results of the Kruskal-Wallis test were statistically significant (Χ2 = 15.2, df = 5, p = 0.010), but XTAMPZA ER values were not statistically significantly different from any comparator based on the Dunn test.
Conclusion
We observed that a smaller percentage of XTAMPZA ER exposures reported to poison centers are categorized as either intentional misuse/abuse/unknown intentional or suspected suicidal compared to other opioids. Both the lower number of intentional exposures and lack of manipulation may explain the lower severity of medical outcomes for XTAMPZA ER across all exposures. Among intentional exposures involving XTAMPZA ER, no differences relative to other opioids were observed. For all drug groups, most intentional exposures involved multiple substances or the intent was self-harm. In these instances, XTAMPZA ER outcomes were no different than comparators, though no formal statistical tests were conducted. Overall, these findings are consistent with reduced abuse related outcomes in the post marketing setting. However, additional efforts are needed to reduce the burden of prescription opioid misuse, including effective identification and treatment of mental health conditions, increased naloxone access, and treatment for polysubstance use disorders.
Abstract #60 Submission ID#1310239
Association between per capita prescribing and abuse of tapentadol and other opioids among individuals entering treatment for opioid use disorders
Geoff Severtsona, Annika Czizikb, Matthew Ellisc, Joshua Blacked, Janetta Iwanickie, Richard Dartf
aAssociate Research Scientist, Rocky Mountain Poison and Drug Safety; bBiostatistician I, Rocky Mountain Poison and Drug Safety; cInstructor, Washington University in St. Louis; dSenior Research Scientist, Rocky Mountain Poison and Drug Safety; ePhysician, Denver Health and Hospital Authority; fDirector, Rocky Mountain Poison and Drug Safety
Learning Objectives
Describe the relationship between tapentadol dispensing and abuse among those entering treatment.
Compare the odds of abuse of tapentadol to other opioids drugs used to treat pain.
List other studies that describe tapentadol abuse relative to other opioids.
Purpose
Tapentadol is a schedule II atypical opioid analgesic thought to have dual mechanisms of action: mu-receptor agonism and inhibition of norepinephrine reuptake. Scheduling was based on clinical studies where tapentadol had rewarding and reinforcing effects similar to morphine and drug liking scores similar to comparable potencies of hydromorphone. However, in post-marketing surveillance studies, tapentadol has consistently been found to have lower abuse, misuse, and diversion rates than conventional schedule II opioids. Among individuals assessed for substance use disorders, tapentadol abuse has been lower than other schedule II opioids after adjusting for utilization. Drug utilization-adjusted estimates are important adjustments when comparing tapentadol to other drug products given the different degrees of exposure to prescription opioid products. These adjustments allow for comparisons of odds of past month abuse at equivalent levels of exposure. However, in previous studies of treatment-seeking populations, utilization adjustments are performed with prescribing values aggregated for a particular time-period or geographic region. These studies are useful in assessing overall cases relative to prescriptions but may be limited because they do not examine an individual respondents’ odds of using a particular drug based on prescribing within their community. The goal of this study was to compare differences in an individuals’ odds of reporting past month abuse of tapentadol to other opioid analgesics using prescriptions per capita in each respondents three-digit ZIP code as the exposure variable. Methods Data collected from 2019 through 2021 from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System’s Treatment Center Programs Combined (Opioid Treatment Program and the Survey of Key Informants’ Patients Program) are included. The data were collected from 2019 through 2021 from individuals enrolling for treatment for opioid use disorder who endorsed abuse of at least one substance. An abuse case was defined as a respondent who endorsed past month use of one or more products within the drug groups of interest to get high. We use the term abuse because the type of use asked about on this survey is nontherapeutic and for psychotropic effects. This is distinct from other forms of non-medical use (e.g. self-treating pain without a prescription) and may be of greater risk to the respondent. Odds of abuse of tapentadol were compared to hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone, and tramadol. Information on prescriptions dispensed was obtained from the IQVIA® (Danbury, CT) US-Based Longitudinal Prescription Data database. Per capita prescribing was calculated by dividing quarterly prescriptions dispensed value for each three-digit ZIP code by the estimated population in that ZIP code. A generalized linear mixed model was performed with a binary outcome indicating past month abuse or not of each drug group. A random intercept was included to account for within subject responses. In each model the predictor was the natural log of prescriptions dispensed per person within a respondents’ three-digit ZIP code. Comparisons of odds of abuse were conducted at the median prescriptions per capita value for tapentadol.
Results
The association between prescriptions dispensed per capita within a respondents’ three-digit ZIP code and odds of past month abuse was not statistically significant for tapentadol (OR = 1.05, p = 0.793). The association between prescriptions dispensed per capita within a respondents’ three-digit ZIP code was statistically significantly greater for oxycodone (p < 0.001), hydrocodone (p = 0.001), hydromorphone (p < 0.001), and tramadol (p < 0.001) than for tapentadol. Drug groups were compared at the median per capita prescribing value of tapentadol. The odds a respondent abused oxycodone (OR = 13.8, 95% CI: 8.4–22.9, p < 0.001), hydrocodone (OR = 2.4, 95% CI:1.4–4.1, p = 0.001), hydromorphone (OR = 26.1, 95% CI: 18.4–37.1, p < 0.001), morphine (OR = 28.2, 95% CI:18.1–44.0, p < 0.001), oxymorphone (OR = 40.9, 95% CI: 29.8–56.2, p < 0.001), and tramadol (OR = 3.1, 95% CI: 1.4–7.1, p = 0.006) were each greater than odds of abuse of tapentadol.
Conclusion
These findings are consistent with other published studies that, among individual seeking treatment for opioid use disorders, abuse of tapentadol is less frequent than other schedule II opioid analgesics after adjusting for prescribing volume. This study is unique in the adjustment for exposure to prescription opioids. Notably, we examined an individuals’ risk of abuse relative to prescriptions dispensed per person in their residential ZIP code. Our findings indicate that tapentadol abuse is less common than tramadol when accounting for different levels of prescribing. This study adds to several years of post-marketing surveillance finding that tapentadol abuse is infrequent relative to conventional opioids. Though additional surveillance and research are needed to fully understand the motivations and risks to individuals who abuse tapentadol, our findings suggest that tapentadol may be an option for pain management with lower abuse potential than other Schedule II opioids.
Abstract #61 Submission ID#1310390
Drug Positivity and Trends in Clinical Inquiries from a National Drug Monitoring Laboratory
Jeff Gudina, Jack Kainb, john Aroc, Emily Schindlerd
aConsultant, U of Miami Dept Anesthesiology, Periop Med and Pain Mangement; bDirector, MSL, Quest Diagnostics; cHealth Informatics Analyst, Quest Diagnostics; dMedical Advisor, Quest Diagnostics
Learning Objectives
Gain insights into the most common drug tests ordered by clinicians.
Describe the drugs most frequently positive on drug testing.
Describe the most frequently asked questions/topics of toxicologists when calling in to a laboratory hot-line.
Purpose
The CDC Guideline for Prescribing Opioids recommends drug testing before starting opioid therapy, as well as consideration of drug testing at least annually during therapy. Clinical drug monitoring detects the presence of prescribed or illicit drugs or alcohol and has become an integral component of risk management when treating chronic pain and substance use disorders. When introducing drug monitoring into their practice clinicians often seek guidance regarding type and frequency of testing, as well as on the interpretation of (often complex) results. Clinician inquiries to our reference laboratory are triaged by dedicated drug monitoring client services representatives and escalated to subject matter experts in toxicology, pathology, or pharmacology as appropriate. We sought to characterize the frequency of test ordering and rates of positivity for drug testing as well as the volume and scope of inquiries requiring escalation to a subject matter expert. This data should be useful to clinicians when considering which drugs are most relevant to test for, as well as to provide educational support surrounding the most frequently asked questions drug monitoring. Methods To determine frequency of testing and drug positivity data, we analyzed de-identified quantitative, definitive urine drug tests (UDT) performed at Quest Diagnostics over a 12-month time frame from all categories of providers. UDT included either presumptive immunoassay screening tests with confirmation of positive results by quantitative definitive mass spectrometry, or direct quantitative definitive mass spectrometry. Mass-spectrometry methods were validated using National Institute of Standards and Technology (NIST)-traceable reference materials. Results were considered positive when a drug (or appropriate metabolite) was identified at a concentration equal to or greater than its cutoff. Tests were available as individual drugs or as part of predefined or custom panels. Not all specimens were tested for all drug classes as ordering patterns vary among clinicians. To evaluate the most frequently asked questions, all inquiries recorded for a 12-month time frame were reviewed. Only inquiries that were escalated to the Medical Advisor Team and resolved by a toxicologist, pathologist, or pharmacist were included in the analysis. Over 1,330 of these unique toxicology consultation records were identified. Inquiries were cataloged by drug class based on test code, test name, and free text associated with the interaction record. Free text fields containing inquiry and resolution information were sorted into categories based on subject matter.
Results
Over the 12-month study period, the tests most ordered (at least 90% of the time) by frequency were for the drugs/ classes: opiates, benzodiazepines, cocaine, amphetamines, and oxycodone. The highest positivity rates were for buprenorphine products presumably prescribed for opioid use disorder (43% with naloxone, 28% without), followed by marijuana (28%), gabapentin (22%), opiates (12%), benzodiazepine (12%), alcohol (11%), and fentanyl (11%).
Of the 1,330 inquiries, those most frequently escalated to subject matter experts regarded unexpected positive results (432; 32%). The next most common inquiry regarded an explanation of drug analytes and their metabolites (336; 25%). There were inquiries regarding correlation of the quantitative results of a drug test result to the dose of the drug taken (124; 9%), as well as whether drug results were consistent with new use versus terminal elimination following cessation (121; 9%). In order of decreasing frequency, the other categories of inquiries received included test selection, comparison of results obtained by different methods, unexpected negative results for a prescribed medication, interpretation of a result of ‘interference,’ determination of therapeutic or toxic levels, and detection window of a substance. When analyzed by drug class, inquiries regarding opioids were the most frequently escalated to a subject matter expert (446; 36%), with almost half of the opioid queries involving fentanyl. Amphetamine inquiries accounted for 10% of the inquiries, benzodiazepines 9%, buprenorphine 8%, marijuana 8%, alcohol 7%, and cocaine 4%.
Conclusion
When analyzing test frequency, the most common urine drug tests ordered included opiates, benzodiazepines, cocaine, amphetamines, and oxycodone. From a positivity standpoint, samples for buprenorphine, opiates, marijuana, and gabapentin were positive at least 20% of the time. These specific tests were also among the most frequently asked questions posed to our toxicologists. Those drugs with a lower incidence of positivity (e.g. MDMA, Barbiturates, Mitragynine, PCP) required less consultation.
Utilizing drug positivity data in conjunction with frequency of testing and call-center data can provide clinicians with insights into what drugs/classes are most relevant to test for and which are most likely to be impacting their patients. These data may factor into test selection by clinicians as well as recommendations in drug monitoring guidelines.
References
[1] Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain- US, 2016. MMWR Recomm Rep 2016;65(No. RR-1):1–49.
Abstract #62 Submission ID#1310404
Cebranopadol, a Novel Potent Analgesic: Binding Affinity to Opioid Receptors and In Vitro Activity
David Fama, Marc Lesnickb, James Hackworthc
aDirector, Medical Communications and Publications, Tris Pharma, Inc.; bCo-Founder, Chief Development Officer & Board Member, Park Therapeutics, Inc.; cPresident, Brand Division, Tris Pharma, Inc.
Learning Objectives
Upon completion, participant will be able to describe the mechanism of action of cebranopadol.
Upon completion, participant will be able to describe the binding affinity of cebranopadol to nociceptin/orphanin FQ peptide (NOP), μ-opioid, κ-opioid, or δ-opioid receptors.
Upon completion, participant will be able to describe the agonistic efficacy efficacy of cebranopadol on nociceptin/orphanin FQ peptide (NOP), μ-opioid, κ-opioid, or δ-opioid receptors.
Purpose
Cebranopadol is a novel, highly potent, and centrally active opioid receptor agonist with high affinity for the μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors and lesser affinity for κ-opioid receptors and δ-opioid receptors. This study investigated binding affinity of cebranopadol in human NOP, μ-opioid, κ-opioid, or δ-opioid receptor binding assays. Methods
Human μ-opioid, κ-opioid, δ-opioid, and NOP receptor binding assays were run in microtiter plates with preparations of cells transfected with the human μ-opioid receptor, the human δ-opioid receptor, the human κ-opioid receptor, or the human NOP receptor. After short mixing with radio-labeled ligands, the assays were incubated at room temperature for 60 to 90 minutes then centrifuged for 20 minutes. Half-maximal inhibitory concentration (IC50) values reflecting 50% displacement of ligand-specific receptor binding were calculated by nonlinear regression analysis.
The agonistic activity of cebranopadol at the human NOP, μ-opioid, κ-opioid, or δ-opioid receptors was tested in [35S]GTPgS binding assays with membranes from cells expressing the respective recombinant human receptors. The potency and efficacy of cebranopadol were compared with the functional activity of the selective NOP receptor agonist nociceptin/orphanin FQ, the μ-opioid receptor-selective enkephalin DAMGO, the κ-opioid receptor-selective agonist U69,593, and the δ-opioid receptor-selective agonist SNC 80.
Results
Cebranopadol binds with high affinity to NOP and opioid receptors. Cebranopadol showed the most pronounced binding affinities at human NOP and μ-opioid receptors with subnanomolar inhibitory constants. In addition, cebranopadol showed a 3- to 4-fold weaker binding affinity in a human κ-opioid receptor binding assay, and an ∼20-to 26-fold lower affinity in a human δ-opioid receptor binding assay.
Cebranopadol showed full agonistic efficacy at the human μ-opioid and δ-opioid receptors, almost full efficacy at the human NOP receptor, and partial agonism at the human κ-opioid receptor.
Conclusion
Cebranopadol combines μ-opioid and NOP receptor agonism in a single molecule which may contribute functionally to its safety and analgesic activity. Ongoing clinical investigations will assist in determining the role of cebranopadol in pain therapy.
References
[1] Linz K, Christoph T, Tzschentke TM, et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014;349(3):535–548.
[2] Data on File, Tris Pharma, Inc. MP34 • Data on File, Tris Pharma, Inc. MP39 • Data on File, Tris Pharma, Inc. MP60
Abstract #63 Submission ID#1310471
A Review of Current Evidence-Based Recommendations of Tramadol for Neuropathic Pain in Adults
Devin Reeda, Clayton Newelb, Anesh Rugnathc
aResident, University of Mississippi Medical Center; bInterventional Pain Management Fellow, University of Mississippi Medical Center; cInterventional Pain Management Attending, University of Mississippi Medical Center
Learning Objectives
Understand the mechanism of action of tramadol and its treatment efficacy in neuropathic pain.
Understand treatment goals and treatment escalation for neuropathic pain.
Understand potential side effects of tramadol use.
Purpose
The World Health Organization (WHO) reports that the leading cause of disability is pain, which has been the case since 1990. Chronic pain is often multifactorial, with the International Association for Study of Pain (IASP) accounting for neuropathic pain to affect as many as 1 in 30 across the adult population, with some demographics having a higher incidence. Given such high incidence and overall public health costs, the analytic study of efficacious treatment is pertinent in neuropathic pain.
Tramadol is a centrally acting synthetic opioid analgesic. It is available as a racemic mixture, metabolizing by demethylation to an active metabolite. The (+) enantiomer has a low affinity to mu receptors and inhibits serotonin reuptake, while the (-) enantiomer inhibits norepinephrine reuptake. Despite fitting into Step 2 of the WHO analgesic ladder and being listed as a second-tier treatment option for neuropathic pain by multiple international pain societies: IASP, Canadian Pain Society, NICE (UK National Institute for Health Care Excellence), and EFNS (European Federation of Neurological Societies), the most recent Cochran study in 2017 found low to very low quality of evidence to support the use of tramadol in the treatment of neuropathic pain.
This literary review aims to delve into the most current evidence to assess the analgesic efficacy of tramadol for chronic neuropathic pain in adults to understand the best practice better.
Methods
The World Health Organization (WHO) reports that the leading cause of disability is pain, which has been the case since 1990. Chronic pain is often multifactorial, with the International Association for Study of Pain (IASP) accounting for neuropathic pain to affect as many as 1 in 30 across the adult population, with some demographics having a higher incidence. Given such high incidence and overall public health costs, the analytic study of efficacious treatment is pertinent in neuropathic pain.
Tramadol is a centrally acting synthetic opioid analgesic. It is available as a racemic mixture, metabolizing by demethylation to an active metabolite. The (+) enantiomer has a low affinity to mu receptors and inhibits serotonin reuptake, while the (-) enantiomer inhibits norepinephrine reuptake. Despite fitting into Step 2 of the WHO analgesic ladder and being listed as a second-tier treatment option for neuropathic pain by multiple international pain societies: IASP, Canadian Pain Society, NICE (UK National Institute for Health Care Excellence), and EFNS (European Federation of Neurological Societies), the most recent Cochran study in 2017 found low to very low quality of evidence to support the use of tramadol in the treatment of neuropathic pain.
This literary review aims to delve into the most current evidence to assess the analgesic efficacy of tramadol for chronic neuropathic pain in adults to understand the best practice better.
Results
Three systematic reviews comprising 26 randomized trials and meta-analyses were identified, evaluating the utilization of tramadol of 100 mg daily and increased to as much as 400 mg daily over at least 4–6 weeks of treatment. Across studies, patients had experienced neuropathic pain symptoms for at least three months. Patient populations were an approximately equal mix of gender.
Not all studies reported measurable pain reduction outcomes, with some focusing on patient satisfaction, safety margins, and adverse drug reactions of tramadol therapy for chronic neuropathic pain.
A reduction of pain intensity by at least fifty percent was elucidated in 7 of 16 studies with tramadol therapy. Tramadol was consistently shown to provide more significant relief than placebo but not always of statistical significance. Tramadol was not shown to have a more significant pain intensity reduction than other active therapies, such as NSAIDs or duloxetine, but not less pain relief either statistical significance.
Treatment with tramadol resulted in higher adverse events than placebo in those studies reporting adversity; however, none were deemed critical, and no deaths resultant. No statistical significance between adverse outcomes of tramadol to other opioids or non-narcotic treatments was observed in the two studies.
Conclusion
A fair body of information has developed to evaluate the use of tramadol in neuropathic pain. However, most of these are small single-center studies. Heterogeneity among the study population, differing outcome measures, lack of transparency of pain reduction scores, and a variety of therapeutic intervention arms make random-effect analysis challenging as one takes the body of evidence into greater perspective. Risks for potential bias may magnify the apparent benefits of tramadol.
However, tramadol consistently outperforms placebo in pain reduction >50% and patient satisfaction through 6–12wks of therapy. This research suggests tramadol has consistent therapeutic efficacy in neuropathic pain. Tramadol also provides pain reduction similar to other modal agents in chronic neuropathic pain relief.
Given the potential for adverse symptomology and the low risk of addiction with tramadol therapy, evidence suggests similar therapeutic pain relief can be achieved with other modal agents. This research aligns with many international criteria, despite the most recent Cochrane study in which tramadol doses were used for refractory pain rescue therapy in shorter courses.
There is still ample room for further study of tramadol’s effect on neuropathic pain relief. Larger population studies with tramadol versus tramadol + Tier 1 therapy (such as gabapentin or duloxetine) may help illuminate any multi-modal effects or additive or supra-additive benefits while minimizing bias and other confounding factors. Such data could help further support practicing guidelines on an international basis, as well as help, optimize patients’ neuropathic pain relief.
References
[1] Barakat, A. Revisiting Tramadol: A Multi-Modal Agent for Pain Management. CNS Drugs 33, 481–501 (2019). Cruccu, G., Truini, A. A review of Neuropathic Pain: From Guidelines to Clinical Practice. Pain Ther 6, 35–42 (2017).
[2] Duehmke RM, Derry S, Wiffen PJ, Bell RF, Aldington D, Moore RA. Tramadol for neuropathic pain in adults. Cochrane Database Syst Rev. 2017;6:CD003726.
[3] Jung SY, Jang EJ, Nam SW, et al. Comparative effectiveness of oral pharmacologic interventions for knee osteoarthritis: a network meta-analysis. Mod Rheumatol. 2018: 1–8.
[4] Stella Chen and Charlene Argáez. Tramadol for the Management of Pain in Adult Patients: A Review of Clinical Effectiveness – An Update. CADTH Rapid Response Report: Summary with Critical Appraisal. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2018.
[5] Vos T, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016; 388(10,053):1545.
Abstract #64 Submission ID#1310511
Cebranopadol, a Novel Potent Analgesic: Limitations in Physical Dependence Using Short- and Long-term Rodent Studies
David Fama, Marc Lesnickb, James Hackworthc
aDirector, Medical Communications and Publications, Tris Pharma, Inc.; bCo-Founder, Chief Development Officer & Board Member, Park Therapeutics, Inc.; cPresident, Brand Division, Tris Pharma, Inc.
Learning Objectives
Upon completion, participant will be able to describe the interaction of nociceptin/orphanin FQ opioid peptide (NOP) receptor agonism and mu-opioid receptor agonism as it relates to the development of dependence.
Upon completion, participant will be able to compare the physical dependence observed in rodents between cebranopadol and morphine following abrupt discontinuation.
Upon completion, participant will be able to compare the physical dependence observed in rodents between cebranopadol and morphine following the administration of naloxone.
Purpose
Cebranopadol is a novel, highly potent, and centrally active opioid receptor agonist with high affinity for the μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors and lesser affinity for κ-opioid receptors and δ-opioid receptors. Agonism of the NOP receptor has been associated with a reduction in adverse events related to the agonism of the µ-opioid receptor including respiratory depression, euphoria, sedation and physical dependence. These studies evaluate the development of physical dependence in response to use of cebranopadol in mice and rats. Methods
In a short-term study in mice, cebranopadol was administered in seven escalating doses over two days. The first three administrations were given in an escalating dose scheme. The remaining doses were maintained at the level of the third dose. There were 5 dosing groups (1.0–100 μg/kg) with 12 mice each. Withdrawal was precipitated by administration of naloxone 2 hours after the last administration of cebranopadol. The mice were placed in glass jars immediately after administration of naloxone and the number of jumps (all 4 paws off the bottom surface) were recorded over 15 minutes. Withdrawal was quantified from the number of jumps occurring 0–10 min after administration of naloxone. The number of animals with a jumping frequency of more than 10 jumps/10 min were rated as withdrawal positive.
During the long-term study in rats, cebranopadol was administered twice daily at three different doses: 16 μg/kg/day, 160 μg/kg/day and 400 μg/kg/day. A placebo group served as negative control. One group with morphine administered via the drinking fluid (targeted dose of 80 mg/kg/day) served as positive control with a respective placebo group (water as drinking fluid) served as a negative control. The study drug was administered over a period of 4 weeks, followed by a week of spontaneous withdrawal and observation, followed by another week of drug administration, followed by forced withdrawal with naloxone. Endpoints measured include body weight, food and fluid intake, locomotor activity (H-maze test). Changes in body weight and withdrawal signs and symptoms were monitored to determine withdrawal.
Results
In the short-term study, across the 5 dosing groups that were evaluated, 4 mice demonstrated withdrawal symptoms in the two highest doses: 1 in the 46.4 μg/kg group and 3 in the 100 μg/kg group demonstrating a dose-dependent increase. In the dosages 1.0, 4.64 and 10.0 μg/kg no withdrawal was detectable.
During the long-term study in rats, both cebranopadol and morphine led to reduced body weight. Cebranopadol generally reduced food and fluid intake compared to placebo, whereas the effects of morphine on food and fluid intake were transient. Cebranopadol reduced locomotor activity compared to the respective placebo group; morphine had no significant effect on this parameter.
Following spontaneous withdrawal, rats in the morphine and cebranopadol groups experienced weight loss. The maximal body weight loss was 1.2–2.0% in the cebranopadol groups and 11.3% in the morphine group. Limited signs of withdrawal were observed in the 16 μg/kg/day cebranopadol group with no symptoms observed at the higher doses, but significant signs of withdrawal following cessation of morphine were observed.
Naloxone-induced withdrawal led to more pronounced weight loss in the cebranopadol group with the maximal weight loss being 4.4–5.3%. No other significant withdrawal symptoms were observed. Alternatively in the morphine group the maximal weight loss following naloxone induced drug withdrawal was 11.6% with significant withdrawal symptoms observed. Conclusion Cebranopadol is a highly potent analgesic with efficacy demonstrated across a variety of pain types and animal models at effective doses (ED50) ranging from 0.5 to 5.6 μg/kg. Spontaneous and precipitated withdrawal following cebranopadol administration was limited demonstrating a low potential for cebranopadol to lead to physical dependence in rodents despite supratherapeutic doses. Clinical studies have demonstrated consistent results in humans. Further studies to understand the application of these findings in humans are ongoing.
References
[1]Linz K, Christoph T, Tzschentke TM, et al. Cebranopadol: a novel potent analgesic nociceptin/orphanin FQ peptide and opioid receptor agonist. J Pharmacol Exp Ther. 2014;349(3):535–548.
[2] Toll L, Bruchas MR, Calo’ G, Cox BM, Zaveri NT. Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. Pharmacol Rev. 2016;68(2):419–457.
[3] Tzschentke TM, Kögel BY, Frosch S, Linz K. Limited potential of cebranopadol to produce opioid-type physical dependence in rodents. Addict Biol. 2018;23(5):1010–1019.
[4] Data on file. Tris Pharma, Inc. PH665. • Data on file. Tris Pharma, Inc. PH704.
Abstract #65 Submission ID#1310517
Treatment Effects of Celecoxib Oral Solution in Migraine With Aura and Without Aura: Post-Hoc Analysis of Results From Two Randomized, Double-Blind Placebo-Controlled Trials
Stewart Teppera, Daniel Serranob, Mancia Koc, Todd Kunkeld
aProfessor of Neurology, Dartmouth-Hitchcock Medical Center; bNeurology, OPEN Health; cHead of Medical Affairs, Collegium Pharmaceutical; cDirector of Scientific Communications, Collegium Pharmaceutical; dNeurology, Albert Einstein College of Medicine
Learning Objectives
Remember that attacks of migraine with aura can reduce the effectiveness of some migraine medications.
Describe the similar efficacy of celecoxib 120 mg oral solution in the treatment of attacks of migraine with aura or migraine without aura.
Consider celecoxib oral solution as an alternative when developing acute treatment plans for patients who have migraine with aura or migraine without aura.
Purpose
Some acute treatments, including sumatriptan, work less well for migraine with aura than for migraine without aura. Celecoxib oral solution (Elyxyb) is a liquid formulation of the cyclooxygenase-2-selective nonsteroidal anti-inflammatory drug indicated for the acute treatment of migraine in adults. In previous research, celecoxib oral solution had a shorter Tmax than oral tablets, and a single 120 mg dose was more effective than placebo for the acute treatment of migraine. The objective of this post-hoc analysis was to use pooled data from two randomized, double-blind, placebo-controlled trials (NCT03009019; NCT03006276) to compare efficacy of celecoxib oral solution 120 mg with placebo in acute treatment of migraine with and without aura.
Methods
This was a post-hoc analysis of pooled data from two randomized, double-blind, placebo-controlled trials in which adults with migraine treated a single migraine attack of moderate or severe intensity with celecoxib oral solution 120 mg/4.8 mL or an identical placebo. Eligible subjects took a dose of study medication and had a 2-hour assessment for either pain or associated symptoms (ie, nausea, photophobia, phonophobia). Efficacy endpoints included pain freedom, freedom from most bothersome symptom (MBS), and pain relief at 2 hours postdose. Separate regression models were fit to the data for each endpoint to evaluate if treatment efficacy differed across aura subgroups (history of aura vs no history of aura) as tested by a treatment-by-aura interaction.
Results
The study population (N = 1075) had a mean age of 44.5 years; 86.4% of subjects were female. As the Table shows, the analysis groups were demographically balanced at baseline. At 2 hours postdose, celecoxib oral solution 120 mg was more effective than placebo for pain freedom in subjects with aura (31% vs 21%, P < .001) and without aura (36% vs 25%, P < .001); freedom from MBS in subjects with aura (58% vs 44%, P < .001) and without aura (57% vs 43%, P < .001); and pain relief in subjects with aura (68% vs 56%, P < .001) and without aura (74% vs 61%, P < .001). None of the treatment-by-aura interaction terms were significant, reflecting treatment efficacy in both aura subgroups.
Conclusion Pooled data from two randomized, double-blind, placebo-controlled trials indicate that celecoxib oral solution 120 mg was more effective than placebo whether subjects treating attacks in trial had a history of aura or not. Interaction models suggest that the magnitude of the treatment effect relative to placebo did not differ by aura status.
Abstract #66 Submission ID#1310522
LX9211 A Novel Therapeutic Approach to Treatment of Neuropathic Pain
Suma Gopinathana, Walter Kostichb, Brian Hammanc, Phillip Kramerd, Suman Wasone, Alan Mainf
aSenior Director, Lexicon Pharmaceuticals; bDirector, Bristol-Myers Squibb; cExecutive Director, Lexicon Pharmaceuticals; dProfessor, Biomedical Sciences, Texas A&M University College of Dentistry; eVP, Clinical Development, Lexicon Pharmaceuticals; fEVP Innovation and Chemical Sciences, Lexicon Pharmaceuticals
Learning Objectives
Upon completion, the participant will be able to describe a potential novel mechanism to treat neuropathic pain.
Upon completion, the participant will be able to describe a potential new treatment option for neuropathic pain.
Upon completion, the participant will be able to describe limitations of current standard of care for neuropathic pain.
Purpose
Neuropathic pain is a debilitating, chronic condition affecting millions of people. It is associated with several disease conditions including painful diabetic neuropathy (PDN) and post-herpetic neuralgia (PHN). The current standard of care (SOC) provides modest relief with less than half of the patients reporting ≥50% improvement. Additionally, the current SOC is associated with undesirable side effects, including sedation and cognitive impairment.
We have identified and developed LX9211, an orally acting inhibitor of a novel target, adaptor-associated protein kinase 1 (AAK1), for the treatment of neuropathic pain. LX9211, taken once daily, demonstrated statistically significant reduction in average daily pain score (ADPS) compared to placebo in a Phase 2 clinical trial for PDN. Here, we present the mechanism of action (MOA) of this novel target and results from preclinical models of neuropathic pain.
Methods
Mice deficient in the AAK1 gene were tested for their response to neuropathic pain in the formalin model and spinal nerve ligation model. LX9211 was evaluated in a streptozotocin-induced PDN model in rats and a varicella-zoster virus (VZV) model of PHN in rats.
Mechanistic studies were conducted exploring the need for orally-administered AAK1 inhibitors to cross into the CNS tissue to achieve analgesic effect. The effect of AAK1 inhibitors on neural activity in pain-related circuits at spinal level were explored in a chronic constriction injury (CCI) model in the rat. Combination studies of AAK1 inhibitors with opioid antagonist (naloxone) and alpha-2 adrenergic antagonists (yohimbine and idazoxan) in preclinical models of neuropathic pain were conducted.
Results
Mice deficient in the AAK1 gene were resistant to development of neuropathic pain. Oral administration of LX9211 led to robust reduction in pain in the preclinical models of PDN and PHN. The MOA required CNS distribution of the AAK1 inhibitor and resulted in reduced spontaneous firing in the dorsal horn neurons of the spinal cord. Importantly, the MOA does not involve the opioid pathway. It works via the alpha-2 adrenergic receptor pathway without directly modulating the alpha-2 adrenoreceptors.
Conclusion
We have identified a novel target and an associated drug candidate for the treatment of neuropathic pain. The results from preclinical models have recently been bolstered by encouraging topline results from a Phase 2 clinical trial in patients who suffer with PDN and need better therapeutic options than those currently available.
Abstract #67 Submission ID#1310575
Consistency of Response to Liquid Celecoxib in Adults With Migraine: Post Hoc Analysis of Results From Two Randomized, Placebo-Controlled Studies
Daniel Serranoa, Stewart Tepperb, Mancia Koc, Todd Kunkeld, Richard Be
aNeurology, OPEN Health; bProfessor of Neurology, Dartmouth-Hitchcock Medical Center; cHead of Medical Affairs, Collegium Pharmaceutical; dDirector of Scientific Communications, Collegium Pharmaceutical; eNeurology, Albert Einstein College of Medicine
Learning Objectives
Explain that the most widely prescribed medications for the acute treatment of migraine, triptans, are not consistently effective over time.
Clarify that celecoxib 120 mg oral solution was an effective acute treatment across multiple migraine attacks in the same population of patients.
Include celecoxib oral solution as an option in patients whose current acute treatment does not provide consistent relief.
Purpose
In the acute treatment of migraine, patients rate consistent efficacy among the most prized attributes of medication; inconsistent efficacy ranks among the most common reasons for dissatisfaction. Yet outcomes with oral formulations can be unpredictable, mainly due to variable absorption over multiple attacks. Celecoxib oral solution (Elyxyb) is an oral liquid formulation of the cyclooxygenase-2 (COX-2)–selective nonsteroidal anti-inflammatory drug indicated for the acute treatment of migraine in adults. In previous research, celecoxib oral solution had a shorter Tmax than oral tablets, and a single 120 mg dose was more effective than placebo the acute treatment of migraine. The objective of this post hoc analysis was to evaluate pooled data from two randomized, double-blind, placebo-controlled trials to compare the consistency of treatment response of celecoxib oral solution 120 mg with placebo in adults with migraine.
Methods
This was a post-hoc analysis of pooled data from two randomized, double-blind, placebo-controlled trials in which adults with migraine completed two double-blind randomizations and treatment periods. During the first double-blind period, subjects used celecoxib oral solution to treat a single migraine attack as soon as they experienced moderate to severe headache pain intensity. Within 2 to 7 days of treating the first attack (i.e. ≥48 hours of pain and symptom freedom), subjects who remained eligible were rerandomized into a second double-blind period and instructed to treat a single migraine attack of any headache pain intensity. The present analysis included randomized subjects who took ≥1 dose of study drug and had ≥1 postbaseline efficacy assessment for either pain or associated symptoms (i.e. nausea, photophobia, phonophobia) in both double blind periods and who received study medication or placebo in both double-blind periods. Subjects who treated an attack with mild headache pain intensity in the second double-blind period were excluded. Efficacy endpoints included pain freedom, freedom from the most bothersome symptoms (MBS), and pain relief at 2 hours postdose. Consistent responders were defined as subjects who achieved treatment success in each of the 2 double-blind periods. A separate regression model was fit to the data for each endpoint. Risk rates (proportions) were presented and significance evaluated using relative risk models.
Results
Altogether, 1253 subjects were randomized in the first double-blind period, and 1080 (86%) were independently rerandomized to celecoxib (n = 521) or placebo (n = 517) in the second double-blind period. Mean age was 40.7 years; 85.7% of subjects were female. Rates of consistent endpoint achievement at 2 hours postdose between celecoxib oral solution 120 mg and placebo across pain freedom, MBS freedom, and pain relief were, respectively, 18% vs 11%, P = .016; 40% vs 32%, P = .033; and 54% vs 45%, P = .012.
Conclusion
Across multiple attacks in adults with migraine, response to treatment with celecoxib oral solution was consistent on the clinically meaningful endpoints of pain freedom, freedom from the most bothersome symptom, and pain relief at 2 hours postdose.
Abstract #68 Submission ID#1310588
Cebranopadol, a Novel Potent Analgesic: Review of Clinical Studies Conducted Across Multiple Types of Pain including Chronic Lower Back Bain, Acute Pain, Diabetic Peripheral Neuropathy, and Cancer Pain
David Fama, Antonio Pardob, James Hackworthc
aDirector, Medical Communications and Publications, Tris Pharma, Inc.; bDirector, Clinical Development, Tris Pharma, Inc.; cPresident, Brand Division, Tris Pharma, Inc.
Learning Objectives
Upon completion, participant will be able to describe the clinical studies used to study the efficacy and safety of cebranopadol.
Upon completion, participant will be able to identify the pain types that cebranopadol has demonstrated efficacy in patients.
Upon completion, participant will be able to describe the safety of cebranopadol in patients.
Purpose
Cebranopadol is a novel, highly potent analgesic with high affinity for nociceptin/orphanin FQ peptide (NOP) and opioid receptors. It is highly effective in animal models of acute pain, visceral, inflammatory, chronic mono-and poly-neuropathic, and bone cancer pain.
In order to understand its clinical efficacy in humans, seven Phase 2 and one Phase 3 trials were conducted across multiple types of pain including chronic pain due to osteoarthritis, acute pain following bunionectomy, diabetic peripheral neuropathy, chronic lower back pain, and cancer pain.
Methods A descriptive analysis utilized trial data from 8 pain trials conducted with cebranopadol: 2 osteoarthritis pain, 1 acute pain (bunionectomy), 3 diabetic peripheral neuropathy (DPN), 1 chronic lower back pain (cLBP), and 1 chronic cancer pain trial. Across the 8 trials, patients were randomized to receive 25–1000 μg/day of cebranopadol by mouth or a control including, placebo, morphine sulfate sustained release (SR), tapentadol prolonged release (PR), morphine sulfate PR, pregabalin, or oxycodone controlled release (CR), for a duration of 2 days to 15 weeks.
Results
Analysis included study design, sample size, basic patient demographics, dosing of cebranopadol and comparator agents and outcome measures including efficacy and safety.
Conclusion
Cebranopadol has demonstrated efficacy across a variety of pain types, and when considered along with safety and abuse potential data may serve as a much-needed treatment option for patients with moderate to severe pain.
References
[1] Christoph A, Eerdekens MH, Kok M, Volkers G, Freynhagen R. Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial. Pain. 2017;158(9):1813–1824.
[2] Bothmer J, Scholz A, Höschen K, Daniels S. Cebranopadol, A Novel First-in-Class Analgesic: Results From a Study in Patients With Moderate to Severe Pain Following Bunionectomy. Presented at PAINWeek 2016; September 6–10, 2016; Las Vegas, NV.
[3] Eerdekens MH, Dietlind Koch E, Kok, M, Sohns M, Forst T. Cebranopadol, A Novel First-in-Class Analgesic: Efficacy, Safety, Tolerability in Patients With Pain Due to Diabetic Peripheral Neuropathy (DPN). Presented at PAINWeek 2016; September 6–10, 2016; Las Vegas, NV.
[4] Eerdekens MH, Kapanadze S, Dietlind Koch E, Kralidis G, Volkers G, Meißner W. Cebranopadol, A Novel First-in-Class Analgesic: Efficacy, Safety, Tolerability in Patients With Cancer Related Chronic Pain. Presented at the International Association for the Study of Pain 2016 World Congress on Pain. September 26–30, 2016; Yokohama, Japan.
[5] Toll L, Bruchas MR, Calo’ G, Cox BM, Zaveri NT. Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. Pharmacol Rev. 2016;68(2):419–457.
[6] Data on file. Tris Pharma, Inc. IB12ed.
Abstract #69 Submission ID#1310730
Cebranopadol, a Novel Potent Analgesic: Pooled Analysis of Clinical Opiate Withdrawal Scales
David Fama, Antonio PardobJames Hackworthc
aDirector, Medical Communications and Publications, Tris Pharma, Inc.; bDirector, Clinical Development, Tris Pharma, Inc.; cPresident, Brand Division, Tris Pharma, Inc.
Learning Objectives
Upon completion, participant will be able to describe how the development of dependence was monitored during clinical studies with cebranopadol.
Upon completion, participant will be able to describe the physical dependence observed in patients on cebranopadol vs patients taking comparators including placebo, tapentadol prolonged release, pregabalin, and oxycodone controlled release.
Upon completion, participant will be able to describe the clinical studies used to study the safety and efficacy of cebranopadol across a variety of pain types.
Purpose
Cebranopadol is a novel, highly potent, and centrally active opioid receptor agonist with high affinity for the μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors and lesser affinity for κ-opioid receptors and δ-opioid receptors. Agonism of the NOP receptor has been associated with a reduction in adverse events related to the agonism of the µ-opioid. receptor including respiratory depression, euphoria, sedation and physical dependence. Animal studies with cebranopadol have demonstrated a limited potential for the development of physical dependence.
During clinical trials, patients were monitored for the development of physical dependence and withdrawal. This descriptive analysis explores the development of physical dependence by evaluating the evidence of withdrawal in patients following discontinuation of cebranopadol.
Methods
Nine phase 2/3 clinical trials were conducted with cebranopadol across multiple pain types. In 5 studies during which patients received at least 4 weeks of treatment, investigators also administered the clinical opiate withdrawal scale (COWS), measuring the signs and symptoms of withdrawal. An analysis of the adverse events reported as well as an analysis of the COWS from the safety populations across these studies was conducted. Results A total of 1,068 patients received treatment with cebranopadol with daily doses ranging from 25 to 800 μg. Comparator agents included placebo (n = 404), tapentadol prolonged release (PR) 200 mg twice daily (BID) (n = 126), pregabalin 300 mg BID (N = 65), or oxycodone controlled release (CR) 10–50 mg BID (n = 155), for a duration of 4 to 12 weeks. In contrast to standard clinical practice with opioids, all study drugs were discontinued abruptly at the end of each trial with the exception of pregabalin which was tapered over one week. The overall incidence of the treatment emergent adverse event (TEAE) drug withdrawal syndrome was similar between cebranopadol and placebo with higher rates observed in the oxycodone and tapentadol arms within the respective studies. Additionally, when evaluating COWS, incidences of mild withdrawal were similar for cebranopadol across studies and lower than oxycodone CR or tapentadol PR in the respective studies. The incidences of moderate withdrawal were lower in the cebranopadol group than in the oxycodone CR or tapentadol PR groups during the respective studies.
Conclusion
Cebranopadol has demonstrated limited physical dependence across a wide range of doses including the high dose of 800 μg which is greater than double the highest therapeutic dose that is expected to be used for pain in phase 3 trials. Considering its safety across a wide range of doses, cebranopadol may serve as a much-needed treatment option for patients with moderate to severe pain.
References
[1] Toll L, Bruchas MR, Calo’ G, Cox BM, Zaveri NT. Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems. Pharmacol Rev. 2016;68(2):419–457.
[2] Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003;35(2):253–259.
[3] Data on file. Tris Pharma, Inc. IB12ed.
Abstract #70 Submission ID#1310732
Enkephalin as a Novel Analgesic: Efficacy and Safety in Pre-Clinical Models
Jeff Gudina, Ijeoma Uchegbub, Sheila matthiasc
aProfessor, Consultant, U of Miami Dept Anesthesiology, Periop Med and Pain Mangement; bChief Scientific Officer, Nanomerics; cChief Scientific Officer, Virpax Pharmaceuticals
Learning Objectives.
Define types of enkephalin peptides.
Describe preclinical studies of a novel enkephalin formulation.
Demonstrate the potential of this product to be a novel analgesic of the future.
Purpose
Enkephalin is an endogenous peptide with central analgesic properties that binds to the delta opioid receptor and has been shown to spare typical mu-opioid toxicities. There are 2 main forms of the molecule, methionine- and leucine-enkephain (M-ENK and L-ENK). Unfortunately, enkephalins are subject to rapid metabolism and degradation and to date have not been successfully developed for use as analgesics. Using a novel encapsulation method known as Molecular Envelope Technology (MET), we have developed a ‘protected’ form of leucine enkephalin. MET is composed of a modified chitosan derivative also known as GCPQ (N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-Oglycolchitosan). Delivered intranasally, MET promotes L-ENK delivery through the olfactory nerve, across the blood brain barrier, and into the CNS. We were awarded a cooperative research and development agreement (CRADA) with the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH) to support Good Manufacturing Practices (GMP) production of drug substance and drug product, as well as to support Good Laboratory Practices (GLP) toxicology, safety studies and preclinical efficacy studies. Our goal was to characterize the safety and efficacy of the MET-LENK formulation.
Methods
A range of pharmacologic, toxicology and efficacy studies were carried out. Using a rat model, we assessed the distribution of MET and L-ENK in the blood, cerebrum, cerebellum olfactory bulb, nasal cavity, and systemic organs following intranasal administration. Following MET/L-ENK dosing, rats were sacrificed at 0, 2, 10, 20, 30, 45, 60, 120, or 240 minutes, and blood, cerebrum and olfactory bulb were harvested for LENK biodistribution using LC-MS/MS. 14-day dose range toxicity studies were performed in both rats and dogs. Anti-hyperalgesic efficacy assessments in rats were performed using a chronic pain spared spinal nerve ligation (SNL) model.
Results Dose range finding (DRF) studies were performed in rats and dogs, with no treatment related clinical signs or mortality noted. Analysis of L-ENK concentrations in plasma showed peak levels at 10 minutes post-dosing, after which LENK values began to plateau at 20–30 minutes. L-ENK concentrations in the olfactory bulb were highest at 45 minutes post-dosing. In preclinical efficacy studies, animals dosed with MET-LENK showed a strong anti-nociceptive response versus control in multiple assays of evoked pain. A dose-response with intranasal MET-LENK was noted in a Complete Freund’s Adjuvant (CFA) anti-hyperalgesia model versus intranasal placebo and subcutaneous morphine. No analgesic tolerance was noted.
Conclusion
There is a significant unmet need for effective analgesics with limited or no abuse potential. We sought to investigate the preclinical safety and efficacy of a novel L-ENK formulation. No significant safety signals were noted, and data suggests an analgesic response when the MET/L-ENK formulation was delivered intranasally. This compound warrants additional investigation and advancement through further clinical trials. If data confirms analgesic benefit without respiratory depression or addiction, this enkephalin formulation may represent a potential broad-spectrum molecule to treat multiple types of acute and chronic pain and potentially other CNS disorders.
References
[1] Godfrey L, Iannitelli A, Garrett NL, Moger J, Imbert I, King T, Porreca F, Soundararajan R, Lalatsa A, Schätzlein AG, Uchegbu IF. Nanoparticulate peptide delivery exclusively to the brain produces tolerance free analgesia. J Control Release. 28 January 2018;270:135–144.
Abstract #71 Submission ID#1310745
Budget Impact Analysis of Xtampza® ER (oxycodone extended-release) for the Treatment of Chronic Pain from a Managed Care Perspective
Alan G. Whitea, Todd Kunkelb, Mancia Koc, Hongjue Wangd
aManaging Principal, Analysis Group, Inc.; bDirector of Scientific Communications, Collegium Pharmaceutical; cHead of Medical Affairs, Collegium Pharmaceutical; dAnalysis Group, Inc.
Learning Objectives
Understand the key drivers that impact a health plan’s budget as it contemplates making a formulary switch among available oxycodone products available on the market.
Understand medical costs that are associated with abuse/misuse of opioids.
Describe abuse-deterrent properties of opioids.
Purpose
Xtampza® ER (oxycodone) is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. The development of abuse-deterrent opioids (ADO) of prescription opioids (RxO) is an important step toward deterring inappropriate use of these medications. Xtampza® ER is an extended-release (ER) oxycodone tablet formulated with physiochemical properties to deter misuse/abuse via oral, intranasal (IN), and intravenous (IV) routes of administration. Previous studies have demonstrated that Xtampza® ER has reduced drug liking (take drug again) relative to oxycodone IR for oral and IN administration. However, abuse of Xtampza® ER by oral, IN and IV administration is still possible. The objective of the model is to estimate the potential financial impact to a hypothetical health plan of 1 million members 2 years after adding Xtampza® ER to the health plan drug formulary or changing its formulary status.
Methods
The model estimates incremental healthcare resource use (HCRU) and costs associated with RxO misuse/abuse based on a health plan’s RxO formulary coverage and utilization. RxO misuse/abuse rates, incremental HCRU and costs were informed by the 2020 National Survey on Drug Use and Health, an analysis of claims from Optum Health Care Solutions, Inc. and published literature. Proportions of RxO abuse cases attributable to oxycodone ER by route of administration were obtained from ASI-MV data. In the base case analysis, RxO formulary shares were based on 2021–2022 IQVIA prescription data. After being added to the health plan’s formulary, Xtampza® ER was assumed to account for 50% market share of oxycodone ER in year 1 (taking 50% from branded and 50% from generic oxycodone ER) and an additional 10% from branded and generic oxycodone ER in year 2 after formulary adoption. Wholesale acquisition costs without discounts/rebates were used for RxO prices. The proportion of misuse/abuse cases deterred by Xtampza® ER due to its abuse-deterrent properties was assumed to be 80% for oral, IN, and IV routes of administration. Sensitivity analyses were performed to evaluate changes in model outcomes, based on changes in various model inputs.
Results
In the base case analysis, adding Xtampza® ER to the drug formulary decreased abuse-related healthcare costs for a health plan of 1 million members by -$18,108,481 over two years (−$0.75452 per-member-per month [PMPM]). In one-way sensitivity analyses on Xtampza® ER’s abuse-deterrent properties, lowering IN abuse reduction to 30% resulted in cost savings of – $0.65985 PMPM. When IN abuse reduction was lowered to 20%, the total budget continued to show cost savings (-$0.63992PMPM).
Conclusion
The budget impact model provides a framework to estimate the financial impact of including Xtampza® ER on a drug formulary. Placing Xtampza® ER on a health plan’s drug formulary has the potential to result in cost differences to health plans and those who pay their premiums, depending on Xtampza® ER’s market share and its effectiveness in deterring opioid misuse/abuse.
Abstract #72 Submission ID#1310831
Clinical Value and Utilization of Pharmacologic, Nonpharmacologic and Self-Healing Therapies: A Pilot Study
Jeff Gudina, Evan Peskinb, Peter Staatsc
aU of Miami Dept Anesthesiology, Periop Med and Pain Mangement; bFellow, University of Miami; cPresident, WIP
Learning Objectives
Describe the pharmacological and nonpharmacological analgesic modalities frequently utilized for pain treatment
Highlight which therapies are perceived as most effective
Assess perceptions of self-healing concepts to augment human biology and relieve pain
Purpose
Both pharmacologic and non-drug therapies are essential components of a multimodal analgesic treatment strategy and best practice dictates that pain treatments need to be tailored to individual patients. Although the use of nonpharmacological therapies for pain management are supported by treatment guidelines, they are often underutilized for perceived lack of knowledge, efficacy, or access. We sought to gain insights from practicing clinicians regarding perceived analgesic effectiveness and understand their utilization patterns of select pharmacologic, complementary and self-healing analgesic therapies.
Methods
A survey was sent to pain clinicians across various geographies in the US and results stratified by title (attending, resident, etc.), specialty (anesthesia, PM&R, etc.) and years of experience. Respondents were queried on their perceptions about how effective individual modalities were for chronic pain using a numeric scale; we also queried frequency of use out of 100 most recently treated patients at their practice. Modalities included pharmacologic (NSAIDS, opioids, etc.), nonpharmacologic (yoga, pain psychology, etc.), and interventional (nerve blocks, stimulators). Clinicians were asked to rate agreement with singular statements including benefit of sleep on pain, use of nonpharmacologic devices, and validity of cognitive behavioral and self-healing strategies to reduce pain.
Results
A variety of clinicians responded, including Pain Management, Anesthesiology, Primary Care, Physical Medicine and Rehabilitation, and Orthopedic Surgery, although 90% of respondents were anesthesia or PM&R trained. Responses in general favored NSAIDS and acetaminophen, as well as joint and spine injection procedures. Respondents were divided for topical analgesics and the use of devices to modulate pain (through electricity, magnetism, direct contact, or similar mechanisms). They were generally not supportive of acupuncture, yoga, benzodiazepines and opioids, although only 10% of respondents did not prescribe opioids within their last 100 treated patients. Spinal and joint injections had the highest perceived efficacy for pain (8/10) while benzodiazepines had the lowest (3/10). Most agreed that sleep quality and quantity are directly related to pain, that use of mind:body medicine techniques significantly lowers patient perception of pain, and that patients have an innate ability to promote ‘self-healing’ through diet, exercise and cognitive behavioral strategies to reduce perception of pain. On a 0–10 scale, 70% of clinicians responded ≥8/10 that humans have an innate ability to promote self-healing through diet, exercise and cognitive behavioral strategies.
Conclusion
In our sample of clinicians who treat patients with pain, it appears that pharmacologic therapies like acetaminophen and NSAIDs, as well as interventional therapies such as joint and spine injection remain first-line preferred treatment options; respondents find only moderate utility for topical and nonpharmacologic therapies. Although clinicians agree with the concepts of improved sleep, mind:body medicine and innate self-healing abilities, traditional pharmacological and interventional approaches still prevail. Our data suggests an unmet need for further exploration of self-healing and nonpharmacological therapies to augment our innate biology and promote analgesia. If effective, provider and payer education will likely be required to include these modalities as part of a comprehensive pain treatment plan.
Abstract #73 Submission ID#1310850
Evaluation of Ketamine Infusions in Chronic Pain Patients at TVHS
Justin Petwaya, Courtney L. Clarkeb, Meredith Crumbc, Timothy Atkinsone
aPGY-2 Pain and Palliative Care Pharmacy Resident, Veteran Affairs, Tennessee Valley Healthcare System; bPGY-2 Ambulatory Care Pharmacy Resident, Veterans Affairs, Tennessee Valley Healthcare System; cClinical Pharmacy Specialist, Pain Management, Veterans Affairs, Tennessee Valley Healthcare System; eClinical Pharmacy Specialist, Pain Management, Veterans Affairs, Tennessee Valley Healthcare System
Learning Objectives
Upon completion, participant will be able to list pain categories where ketamine infusions may be beneficial for chronic-pain.
Upon completion, participant will be able to identify possible ADRs associated with ketamine infusions.
Upon completion, participant will be able to understand additional benefits of ketamine infusions.
Purpose
Due to the high prevalence of chronic pain conditions in the Veteran population and the recent emphasis on finding alternatives to commonly misused pain medications, the VA is an ideal location to assess the use and impact of ketamine infusions for those suffering with chronic pain conditions. As one of the most well-established ketamine infusion programs for pain in the VA system this is an opportunity to investigate gaps in current literature related to the long term effectiveness of ketamine infusions for chronic pain conditions. The primary objective of this project was to evaluate the efficacy of ketamine infusions for chronic pain long-term (12–15 months), overall and by pain category (neuropathic, spinal discogenic, and musculoskeletal pain. The secondary objectives of this project were to assess dropout rates due to adverse events and the effects of benzodiazepine pre-medication on dropout rates, daily morphine milliequivalents – before infusion vs. long-term (12–15 months), and mental health comorbidities.
Methods
This was a single-center, retrospective, observational cohort study conducted at the VA Tennessee Valley Healthcare System (TVHS). Veterans had to be diagnosed with chronic pain (lasting at least three months or longer) and have received ketamine infusions for chronic pain. Initial data were provided through the VA data warehouse and further data were extracted via manual chart review. The primary endpoints were measured using the Numerical Pain Rating Scale (NRS), before infusion (baseline) and at intervals (about every 3 months) until the primary end point of 12–15 months. The secondary endpoints were measured as (n/%) for dropout rates, MEDD change as (%). Data were then analyzed using appropriate statistical methods, (Wilcoxon paired rank sign and Fischer’s exact) for determining statistical significance for respective endpoints. Demographic data were analyzed utilizing descriptive statistics.
Results
The primary endpoint of ketamine infusions was shown to reduce pain long-term (12–15 months) which was statistically significant, with a (−28.5% reduction in pain overall, for neuropathic pain and musculoskeletal pain categories) and Spinal discogenic pathology had a clinically significant reduction in pain (−39%, p = 0.0152) at the primary endpoint of 12–15 months after ketamine induction. Additionally, with respect to secondary endpoints the dropout rate between those pre-treated and those not with benzodiazepines was not statistically significant (24.3% vs. 29.7%, p = 0.4730). The mean MEDD was 76.88 mg and decreased to 26.18 mg, a 50.1% reduction. The effect of benzodiazepine pre-medication also had an impact on MEDD reduction compared to those who were not pre-medicated. The impact was statistically significant with a mean reduction of 75.6% vs. 5.2% (p = 0.0001), further showing the benefit of pre-medication in this population.
Conclusion
This study demonstrates the potential for ketamine infusions as a viable option for refractory chronic pain treatment long-term, however further studies need to be conducted to determine in more detail which specific pain diagnoses would benefit from ketamine infusions. Furthermore, while pre-medication with benzodiazepines does not have a statistically significant effect on dropout rates, it did have a significant effect on rate of adverse events and MEDD reduction over the course of treatment. Lastly, as previously demonstrated ketamine was shown to attenuate opioid use, which is demonstrated by the reduction of MEDD before and after ketamine infusions in this study.
Abstract #74 Submission ID#1310907
Determining the Representativeness of Participants in a Whole Health Interdisciplinary Chronic Pain Program (PREVAIL) in a VA Medical Center: Who Did We Reach?
Natalie Hicksa, Samantha Hardenb, Kris Ann Ourslerc, Rena E. Courtneyd
aPsychologist, Salem VA Medical Cente; bAssociate Professor & Exercise Specialist, Virginia Tech; cDirector, Geriatric Research and Education, Salem VA Medical Center, Virginia Tech Carilion School of Medicine; dPREVAIL Program Director; Clinical Psychologist, Salem VA Medical Center; Virginia Tech Carilion School of Medicine
Learning Objectives
Explain the importance of implementing a biopsychosocial model in an interdisciplinary format.
Compare populations who engage in interdisciplinary pain rehabilitation programming (IPRP) versus those engaging in patient-centered, self-management focused interventions.
Describe a model program for patient-centered, Whole Health pain care.
Purpose
Chronic pain is a leading cause of disability and healthcare costs worldwide; however, chronic pain is known to be more prevalent in the Veteran and Appalachian populations. Interdisciplinary teams (IDTs) are the gold standard treatment, but there is significant variability in the delivery of services by IDTs. Most IDTs either involve several weeks of programming (Interdisciplinary Pain Rehabilitation Program; IPRP) or use a consultative model that lacks follow-up with patients. A model program that reduces patient and healthcare system burden, but still accounts for the interplay of biological, psychological, and social factors is needed. The Salem VA Medical Center developed an innovative approach to IDT, called PREVAIL, in which Veterans initially meet with a team of five providers of varying disciplines (interventional pain, psychology, pharmacy, physical therapy, and nutrition) to develop a patient-centered treatment plan based on the biopsychosocial model with a heavy emphasis on active self-management strategies and the Whole Health framework. Following the initial meeting with the IDT, Veterans engage in 6 months of follow-up calls, agreed upon pain treatments (psychotherapy, physical therapy, kinesiotherapy, acupuncture, chiropractic care, injections, etc.), and patient-driven goals for use of self-management strategies. Veterans are reevaluated after 6 months by the IDT team to discuss progress. Seeing that the prescription of opioids is more prevalent in rural areas and the PREVAIL IDT program emphasizes nonpharmacological and self-management strategies for pain, Veterans’ willingness to participate in this type of programming needs to be explored. The purpose of this work is to understand the characteristics of Veterans who were willing to engage in this new type of intervention.
Methods
This was a retrospective study which involved reviewing electronic medical records for Veterans who participated in PREVAIL IDT during the first six months of pilot testing, in addition to reviewing clinically ascertained self-report data which are administered as part of the PREVAIL IDT process. Any Veteran with chronic pain who attended an initial individual IDT appointment at the Salem VA Medical Center was eligible for chart review. Self-report measures were collected using two methods: paper-pencil (PROMIS-29, Pain Catastrophizing Scale (PCS)) and electronically (sent to Veterans via text and e-mail using the Behavioral Health Touch Lab system within VHA; PEG, Pain Stages of Change Questionnaire (PSOCQ)). The following variables were obtained from the electronic medical record (EMR) and explored using descriptive statistics: gender, age, prescribed opioid use, and frequency of emergency service utilization due to pain in the year prior to IDT evaluation. General comparisons were made between proportions of various characteristics in the chronic pain and Veteran populations, particularly those participating in IPRP’s, with those in the PREVAIL program.
Results
The study sample comprised of 34 Veterans with chronic pain who attended an initial individual IDT appointment within the first 5 months of the program’s inception (i.e. 01/05/2022 to 06/01/2022). Paper-pencil measures were completed by 50% of Veterans (PROMIS-29 and PCS; N = 17) whereas 76.4% completed the electronically administered measures (PSOCQ, PEG; N = 27). The mean age of participants was 56.85 years (SD = 12.35) and the majority of participants were male (79.4%; N = 27). Data from the EMR in all Veterans (N = 34) showed that 79.4% were not prescribed an opioid pain medication at the time of their initial IDT appointment, but most (58.8%) had sought emergency services for pain at least once in the year prior to their initial IDT appointment (range = 0–12 pain-related emergency department visits). Participants’ ratings tended to suggest severe intensity of pain that had a significant impact on their lives (PEG median = 7, SD = 1.73, range = 2–10; PROMIS-29 Pain Intensity T-score median = 6, SD = 1.46; PROMIS-29 Pain Interference T-score median = 66.60, SD = 5.01) in addition to moderate difficulties with physical functioning (PROMIS-29 Physical Functioning T-score median = 35.60; SD = 2.67). Participants’ average quality of life was wide ranging (ACPA QOL Scale; range = 1–9), though the average score of 4 suggests Veterans were able to complete simple chores around the home and participate in minimal activities outside the home two days per week. Regarding mental health participants, on average, reported moderate anxiety (PROMIS-29 Anxiety T-score median = 63.40; SD = 9.60) and depression (PROMIS-29 T-score median = 60.50; SD = 10.23). Nearly half of respondents (46%) scored above the clinical cutoff for significant pain catastrophizing (PCS median = 26.00, SD = 12.56). Results indicated Veterans were in a wide range of stages of change, indicating variable levels of motivation to engage in self-management of pain (PSOCQ; Precontemplation = 23.5%, Contemplation = 14.7%, Action = 26.5%, Maintenance = 11.8%).
Conclusion
Veterans reached by the initial PREVAIL IDT evaluation tended to be similar to those who engaged in civilian IPRP’s in their age, severe pain, high pain interference, ER visits, moderate pain catastrophizing, and wide-ranging readiness to engagement in pain self-management. However, participants in PREVAIL tended to have more significant mental health symptoms, which is consistent with the literature on the prevalence of mental health concerns in Veterans with chronic pain. Surprisingly few PREVAIL participants were being prescribed opioid medication when seen by the IDT and most were at least contemplating or working toward pain self-management. Given that opioids tend to be prescribed more frequently in rural populations, it is possible that PREVAIL attracts Veterans who are more interested in a nonpharmacological approach and that further outreach may be needed for Veterans currently being prescribed opioids. Since patient-centered approaches are often associated with higher motivation to engage in treatment and higher motivation leads to better IDT outcomes, understanding the impact of PREVAIL on motivation to self-manage pain is essential. Additionally, administration of self-report measures via the BHL system may be a more effective method in the future since this method resulted in a higher completion rate (26%) than paper-pencil method.
References
[1] Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet. 29 May 2021;397(10289):2082–97.
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[6] Katz L, Patterson L, Zacharias R. Evaluation of an interdisciplinary chronic pain program and predictors of readiness for change. Canadian Journal of Pain. 1 January 2019;3(1):70–8.
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[8] Krejci LP, Carter K, Gaudet T. Whole health: the vision and implementation of personalized, proactive, patient-driven health care for veterans. Medical care. 1 December 2014;52:S5-8.
[9] García MC, Heilig CM, Lee SH, Faul M, Guy G, Iademarco MF, Hempstead K, Raymond D, Gray J. Opioid prescribing rates in nonmetropolitan and metropolitan counties among primary care providers using an electronic health record system – United States, 2014–2017. Morb and Mortal Wkly Rep. 1 January 2019;68(2):25.
[10] Nahin RL. Severe pain in veterans: the effect of age and sex, and comparisons with the general population. J Pain. 1 March 2017;18(3):247–54.
[11] Watrous JR, McCabe CT, Jones G, Farrokhi S, Mazzone B, Clouser MC, Galarneau MR. Low back pain, mental health symptoms, and quality of life among injured service members. Health Psychol. 2020 Jul;39(7):549.
Abstract #75 Submission ID#1310942
PREVAIL: Development of a Whole Health Interdisciplinary Evaluation of Chronic Pain in a Rural VA Medical Center
Francis Cannizzoa, Brian P. Dezzuttib, Beth Darnallc, Diane Elmored, Samantha Hardene
aChief of Staff, Salem VA Medical Center, bPREVAIL Medical Director, Salem VA Medical Center, cProfessor, Stanford University, dDesignated Learning Officer, Salem VA Medical Center, eAssociate Professor & Exercise Specialist, Virginia Tech
Learning Objectives
Describe the components of the VHA Whole Health framework in relation to the biopsychosocial model of pain.
Identify the contributions of various disciplines/roles to interdisciplinary care for chronic pain (interventional pain, psychology, dietitian, pharmacy, physical therapy).
Explain the importance of involving various stakeholders (i.e. patients, administration) when developing and implementing a novel clinical program.
Purpose
The Joint Commission and Veterans Health Administration (VHA) require VA Medical Centers to offer interdisciplinary (IDT) evaluations of chronic pain, which are associated with improvements in provider and staff satisfaction, decreased ER visits, increased quality of life, lower overutilization of healthcare services, decreased disability related to pain and impact of pain, decrease symptoms mental health difficulties (i.e. anxiety, depression, stress), and increased self-efficacy for patients. However, there is significant variability in models of programming and no evidence-based implementation strategies have been studied. Many VAs, including Salem VAMC, adopted a consultative model of IDT which typically involve one appointment with multiple providers (typically interventional pain, psychology, physical therapy, and pharmacy) who make chart recommendations before the patients return to their PCP. This model does not include follow-up appointments and follow-through with recommendations from the IDT team are not guaranteed once they return to their referring provider. At the other end of the spectrum, each region in VHA is expected to offer a Commission on Accreditation of Rehabilitation Facilities (CARF) accredited Interdisciplinary Pain Rehabilitation Program (IPRP), which typically involves patient participation in programming for approximately forty hours per week for six weeks (i.e. over 100 hours of provider-led service). Given the staffing shortages related to the COVID pandemic and the amount of effort required by patients, implementing the IPRP model can be challenging. To overcome these patient and provider barriers to effective pain management, the PREVAIL Program for Chronic Pain was developed and implemented at the Salem VAMC, which serves primarily rural Veterans. PREVAIL utilizes the VHA’s Whole Health framework to develop patient-centered, biopsychosocial treatment plans tailored to Veteran preferences. These plans emphasize active self-management of chronic pain, nonpharmacological strategies, involve low burden for patients and the healthcare system, and allow the Veteran to choose three of the following Whole Health self-care areas to focus on during their 6-month participation in PREVAIL: Power of the Mind, Recharge, Surroundings, Moving the Body, Family, Friends, and Coworkers, Food and Drink, Spirit and Soul, and Personal Development. This work describes the phases of development and implementation of PREVAIL.
Methods
A multiphase approach was used to iteratively assess and refine the PREVAIL program. Participants were thirty-six Veterans with chronic pain who had completed at least half of six pain education classes offered by the pain department at the Salem VA Medical Center. The a priori aims of the IDT process adaptations were to increase the efficiency of care/decrease patient burden (number of appointments needed by Veterans to establish a biopsychosocial treatment plan for chronic pain), lower healthcare system burden (number of minutes spent by PCP’s placing pain consults, number of scheduling calls needed), and increase access to care (wait time for first pain intervention). Implementation was conducted through 3 phases that included varying lengths of the IDT appointment and inclusion of Complementary and Integrative Health (CIH) modalities. During the preparation phase, a psychologist who was not part of the original IDT program (i.e. third party interview) who was trained in sound qualitative methodologies interviewed 5 providers who had placed referrals to the previous consultative model of IDT at the Salem VAMC. During phase 1 of the new IDT rollout, 9 Veterans completed a 4-hour appointment which included participation in a 1 hour shared IDT appointment (interventional pain, psychology, dietary, pharmacy, physical therapy) and 3 hours of CIH modalities. Using feedback from stakeholders, Phase 2 of the IDT rollout included 27 Veterans who completed a 90-minute shared appointment with the IDT team (aforementioned five disciplines). Stakeholder feedback led to the third phase of IDT rollout, which included a 60-minute shared appointment with the IDT (5 disciplines aforementioned). Each phase also included Veterans receiving monthly phone calls with a whole health coach who used motivational interviewing (MI) techniques to discuss successes, resolve barriers, and establish new goals. A 6-month follow up appointment with the IDT team assessed progress toward their initial goals and changes over time in self-reported measures. Measures were the number of Veterans appointments, time PCPs spent placing consults, number of scheduling calls, wait time for interventions, the three areas of self-care Veterans elected to focus on their participation in the program, and a program-specific patient satisfaction survey.
Results
Referring providers were satisfied with the following elements of the previous consultative model that was used prior to PREVAIL: Medication recommendations from Pharmacy and Pain MD, inclusion of a face-to-face physical examination, provision of an individualized treatment plan, good follow through from interventional pain, provision of suboxone prescriptions, and involvement of mental health on IDT team. Referring providers were dissatisfied with the lack of communication and follow through of recommendations resulting from the consultative model of IDT. They also noted confusion about the goals of the consultative model, concern about lack of patient buy-in for non-pharmacological strategies to manage pain, and a strong preference for the pain department to prescribe opioid medication. Stakeholder feedback (i.e. patient, administration, PREVAIL providers) were incorporated between phases of PREVAIL implementation. While patients often stated their favorite aspect of the appointment was time with the IDT team, converting to a 60-minute model based on administration preference for reduced use of resources did not decrease patient satisfaction. PREVAIL led to a number of improvements in outcomes of interest. The implementation of PREVAIL IDT decreased the number of appointments needed by Veterans to establish a biopsychosocial treatment plan for chronic pain decreased from 5 to 1, decreased the number of minutes spent by PCP’s placing pain-related consults reduced from 10 to 2, decreased the number of scheduling calls needed reduced from 5 to 1, and wait time for first pain intervention decreased from 55 days to 14 days. Results of satisfaction surveys from both Veterans and caregivers were as follows: 100% reported ‘providers treated me with respect and courtesy,’ 100% agreed or strongly agreed they understood their role in actively self-managing pain, 100% stated the IDT evaluation was a valuable use of their time, and 100% would recommend the IDT evaluation to a friend. The average overall satisfaction for the IDT evaluation was 9/10. The majority of patients chose to focus on Power of the Mind (thoughts and emotional health; 72%) and Moving the Body (exercise and movement; 67%) as one of their top 3 areas of Whole Health framework to focus on, while 25% preferred to focus on Food and Drink (dietary changes).
Conclusion
This study provides preliminary evidence that the implementation of PREVAIL IDT decreased the burden to patients and the healthcare system, as well as access to care. These preliminary results suggest IDT models that offer follow-up appointments to patients may not require the healthcare and patient burden of weeks of programming (i.e. IPRP), as PREVAIL was acceptable to both providers and Veterans. Regarding lessons learned, eliciting feedback from patients, referring providers, treating providers, and administrators was crucial in creating a rich clinical experience that wisely utilized limited resources in the midst of a pandemic. Furthermore, while traditional IDT models do not include a dietitian, this study provides evidence that Veterans with chronic pain at the Salem VAMC have an interest in follow-up nutrition services and report a high level of satisfaction with the service when dietitians are included on the IDT. Future studies should examine the efficacy of PREVAIL on physical functioning and mental health symptoms compared to established models (IPRP’s, consultative models), the cost effectiveness of PREVAIL, and longitudinal outcomes associated with participation in PREVAIL.
References
[1] Department of Veterans Affairs. VHA Directive 2009–053: Pain Management. Washington, DC. 2009.
[2]Gatchel RJ, McGeary DD, McGeary CA, Lippe B. Interdisciplinary chronic pain management: past, present, and future. Am psychol. 2014 Feb;69(2):119.
[3] Clark T, Wakim JC, Noe C. Getting ‘unstuck’: A multi-site evaluation of the efficacy of an interdisciplinary pain intervention program for chronic low back pain. InHealthcare Jun 14 (Vol. 4, No. 2, p. 33). MDPI.
[4] Gatchel RJ, Peng YB, Peters ML, Fuchs PN, Turk DC. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol bull. 2007 Jul;133(4):581.
[5] Krejci LP, Carter K, Gaudet T. Whole health: the vision and implementation of personalized, proactive, patient-driven health care for veterans. Med care. 1 December 2014;52:S5-8.
Abstract #76 Submission ID#1311023
Does Current Pain Research Reflect Our Diverse Population?
M. Denise Daley
Adjunct Assistant Professor, University of Texas Medical Branch
Learning Objectives
Describe the importance of reporting sociodemographic factors in clinical pain studies.
List the frequencies of reporting various sociodemographic factors in recent clinical pain studies.
Describe the potential need to improve the representation of Hispanic/Latino individuals in clinical pain studies.
Purpose
As awareness of the effects of sociodemographic factors on health and disease continue to expand, there is growing recognition of the need to increase the diversity of participants in clinical studies. This may be particularly important in the field of pain medicine, given the complex nature of pain, as well as increasing evidence of the role of various sociodemographic factors in the prevalence and severity of pain. This study was conducted to examine the reporting of sociodemographic factors in recently published clinical research studies in the pain medicine literature.
Methods
This study evaluated original clinical research studies published from January 2022 to June 2022 in two well-known pain medicine journals, Pain Medicine and Pain. All randomized clinical trials (RCTs), nonrandomized trials, and observational studies published during this time period were included. Case reports, case series, review articles, and meta-analyses were excluded. The reporting of these sociodemographic characteristics of study participants was recorded for each study: age, sex, race, ethnicity, income/socioeconomic status, education level, and urban/rural living status.
Results
A total of 127 studies were evaluated, 46 from Pain Medicine and 81 from Pain. The studies consisted of 30 RCTs and 97 non-RCTs. Six studies (4.7%) specifically focused on diversity-related issues (e.g. sex differences, racial disparities, underserved populations). Age and sex were reported in 124 of the 127 studies (97.6%). Overall, the age and sex distributions in each study appeared to reflect the objectives of the specific study.
Race was reported in 39 of the 127 studies (30.7%), and ethnicity was reported in 12 of the 127 studies (9.4%). White was the most common race, accounting for a median of 76.8% of patients (range, 21.4–100%) in each study. Ethnicity was primarily reported as Hispanic/Latino versus non-Hispanic/Latino, with Hispanic/Latino accounting for a median of 7.6% of patients (range, 1.0–26.3%) in each study. For comparison, the United States census figures from 2021 estimated that 75.8% of the population were White and 18.9% were of Hispanic/Latino ethnicity (https://www.census.gov/quickfacts/fact/table/US/RHI825221).
Income/socioeconomic status was reported in 19 of the 127 studies (15.0%). It was usually reported as annual family income, but some studies reported socioeconomic status or economic ‘hardship.’ Education level was reported in 32 of the 114 non-pediatric studies (28.1%), and urban/rural living was reported in 4 of the 127 studies (3.2%).
Conclusion
This study revealed that current clinical studies in the field of pain medicine almost always reported age and sex of study participants, a commendable finding. However, other sociodemographic factors were reported in only 3.2–30.7% of studies. When potentially important sociodemographic information is not provided, it is difficult for clinicians to know whether the results will be applicable for a specific patient. Not surprisingly, there was considerable variation in the percentages of specific races and ethnic groups included in the studies. However, the low median Hispanic/Latino percentage suggests that this ethnic group may be underrepresented in recent clinical studies. References
Abstract #77 Submission ID#1311025
18 Month Outcomes from Multicenter RCT: Spinal Cord Stimulation at 10 kHz for Non-Surgical Refractory Back Pain
Leonardo Kapurala, Jessica Jamesonb, Naresh Patelc, Curtis Johnsond, Daniel klostere, Aaron Calodneyf, Peter Kosekg, Julie Pilitsish, Markus Bendelgi, Erika Petersenj, Shivanand Ladk, Chengyuan Wul, Cong Yum, Taissa Cherryn, Dawood Sayedo, Rose Azaldep, David Carawayq
aDirector, Pain Management, Carolina’s Pain Institute; bDirector, Founder, Axis Spine Center; cNeurosurgeon, Mayo Clinic Pheonix; dPain Medicon, KC Pain Centers, LLC; ePain Management Physician, Crimson Pain Management; fPain Management, Precision Spine Care; gPain Management, PeaceHealth; hDean, VP Medical Affairs, Charles E. Schmidt College of Medicine; iAnesthesiologist, Mayo Clinic; jUniversity of Arkansas for Medical Sciences; kPhysician, Duke University; lNeurosurgeon, Thomas Jefferson University Medical Center; mPhysician, Swedish Pain and Headache Center; nPain Management Physician, Kaiser Permanente; oProfessor Anesthesiology Pain, Kansas University Medical center; pPrincipal Clinical Scientist, Nevro Corp.; qChief Medical Officer, Nevro Corp
Learning Objectives
Define nonsurgical back pain.
For this study, how was the patient determined to not be a surgical candidate?
List the important clinical efficacy outcomes for this study.
Purpose
Patients with moderate to severe chronic back pain even after exhausting nonsurgical therapies (such as medications, physical therapy, nerve blocks, and RFA) are left with very few options if surgical assessment indicates they are not candidates for surgery. If these patients have not had previous spine surgery, they have often been refused authorization for spinal cord stimulation (SCS) by medical payers because of the limited clinical evidence for SCS in this patient population.1 Eighteen-month results are reported here from a randomized clinical trial that was designed to provide the evidence of clinical and cost effectiveness of 10 kHz SCS to treat non-surgical refractory back pain (NSRBP).
Methods
NSRBP patients were enrolled if ineligible for surgery based on surgical consultation.2 Subjects were randomized 1:1 to either 10 kHz SCS plus conventional medical management (CMM) or CMM alone. Subjects randomized to 10 kHz SCS underwent permanent implantation if ≥50% pain relief was achieved during a temporary trial. Both groups received CMM per standard of care. Appropriate interventional procedures were tried prior to enrollment and continued if provided benefit, as needed. Both groups had the option of crossing over at 6 months if satisfactory pain relief was not achieved. In addition, all subjects had the option of consenting to a study extension to 24-months. We present pain relief reported on the visual analog scale (VAS), Oswestry Disability Index (ODI), and quality-of-life (EQ-5D-5 L) at 18 months for all implanted patients (original 10 kHz SCS arm and the crossover group). Last Observation Carried Forward imputation is used for missing values in the case of withdrawal, missed visits, and not consenting to study extension.
Results
There were 159 patients randomized to either CMM alone (n = 75) or to 10 kHz SCS in addition to CMM (n = 83), with similar baseline characteristics. All primary and secondary study endpoints were met at 3 and 6 months (p < 0.001) comparing CMM to 10 kHz group in terms of pain relief, disability, quality of life, and opioid reduction.3 At 6 months none of the 69 implanted patients in the 10 kHz SCS arm chose to crossover to CMM arm, while 74.7% (56/75) in the CMM arm crossed over, resulting in 125 total implanted patients. The reported pain relief was stable in all implanted patients at 6, 12, and 18 months with an average VAS of 2.2 ± 2.2 cm, 2.2 ± 2.1 cm, and 2.1 ± 2.1 cm, respectively, compared to a mean baseline of 7.4 ± 1.1 cm (p < 0.001 for all comparisons to baseline). The average reduction in ODI score was 20.6 ± 15.3, 20.7 ± 15.9, and 22.5 ± 17.0 for 6, 12, and 18 months, respectively, approximately 2X the minimum clinically important difference (MCID) of 10 pts.4 At 18 months 74% of patients reported clinically significant disability improvement on the ODI with 40% moving from severe/moderate disability to minimal disability. The significant improvement in quality of life was also stable to 18 months with an average utility index increase of 0.185 ± 0.149 at 18 months, more than 2X the MCID.5 A total of 5/125 (4%) explants occurred during 18-month follow-up, two due to dissatisfaction with therapy and three to infection (two of which were replaced). Conclusion This large, multicenter study demonstrates that the addition of 10 kHz SCS to CMM results in profound and durable improvements in pain relief, function, and quality of life in these NSRBP patients who have been deemed not surgical candidates and exhausted all available appropriate nonoperative medical management.
References
[1] Eckermann JM, Pilitsis JG, Vannaboutathong C, Wagner BJ, Province-Azalde R, Bendel MA. Systematic Literature Review of Spinal Cord Stimulation in Patients With Chronic Back Pain Without Prior Spine Surgery. Neuromodulation. 18 August 2021.
[2] Patel N, Calodney A, Kapural L, Province-Azalde R, Lad SP, Pilitsis J, Wu C, Cherry T, Subbaroyan J, Gliner B, Caraway D. High-Frequency Spinal Cord Stimulation at 10 kHz for the Treatment of Nonsurgical Refractory Back Pain: Design of a Pragmatic, Multicenter, Randomized Controlled Trial. Pain Practice: the official journal of World Institute of Pain 2021;21(2): 171–83.
[3] Kapural L, Jameson J, Johnson C, et al. Treatment of nonsurgical refractory back pain with high-frequency spinal cord stimulation at 10 kHz: 12-month results of a pragmatic, multicenter, randomized controlled trial. J Neurosurg Spine.
[4] Hagg O, Fritzell P, Nordwall A, Swedish Lumbar Spine Study G. The clinical importance of changes in outcome scores after treatment for chronic low back pain. Eur Spine J. Feb 2003;12(1):12–20.
[5] McClure NS, Sayah FA, Xie F, Luo N, Johnson JA. Instrument-Defined Estimates of the Minimally Important Difference for EQ-5D-5 L Index Scores. Value Health. Apr 2017;20(4):644–650.
Abstract #78 Submission ID#1311748
Patterns of Urine Drug Screen Inconsistency in Patients Referred to Establish Care for Chronic Pain: Why Are Many Patients Positive for Buprenorphine?
Luc Frenettea, David Hardinb
aPhysician, Samford University; bPhysician, Preferred Pain Associates
Learning Objectives
Understand common causes of UDS inconsistency within chronic pain patients
Understand methodologies for descriptive analysis in a pain patient population
Determine areas of chronic care surveillance that may be a needed addition to current chronic pain practices.
Purpose
It is estimated that approximately 1 in 5 U.S. adults had chronic 105 pain in 2019, and approximately 1 in 14 adults experienced ‘high-impact’ chronic pain, defined as 106 having pain most days or every day in the past three months that limited life or work activities (Zelaya, 107 Dahlhamer, Lucas, & Connor, 2020). Pain, especially chronic pain, can impact almost every aspect of a patient’s life, leading to impaired physical functioning, poor mental health, and reduced quality of life, and contributes to substantial morbidity each year (U.S. Department of Health and Human Services, 110 2019b).
Chronic pain has led to a growing opioid abuse problem, with public health officials have called the current opioid epidemic the worst drug crisis in American history, killing approximately 90,000 people in 2021 [1].
Unfortunately, many patients struggle with self-medication and illicit substance use prior to establishing care with a specialized clinic. This study is a retrospective analysis of chronic pain patients who were evaluated to establish care in a single pain management clinic providing opioid management, interventional pain procedures, and opioid dependence treatment. The clinic accepts most commercial and public insurance providers. To improve this chronic pain and opiate crisis, a first step is to gather basic information describing the characteristics of our patients, investigating patterns of illicit substance use and self-medication within the chronic pain population. These details are particularly important for those where illicit drug use or other activities impede the success in a chronic pain treatment program [2].
Methods
The study design is a retrospective analysis of new chronic pain patients who presented for initial evaluation for care in a single clinic. All patients within the sample had been referred to the clinic from outside clinicians in specialties such as primary care, orthopedics, and other spine specialists. Prior to scheduling an office visit, full chart reviews were performed including physician notes, current pain treatment regimen, and imaging. In addition to evaluation and management, each patient had urine drug screen (UDS) performed via immunoassay at the first visit. From a population of 360 total new patients from June 2021 to May 2022, 34 patients were found to have UDS results that were inconsistent with the prescribed regimen [3]. Descriptive statistics were gathered on this population to explore trends that may prompt further investigation.
Results
Within the data studied, 9.4% of patients were found to have an inconsistent UDS at the initial visit. The most common reason for inconsistency was non-prescribed buprenorphine at 17 of the 34 patients (50%). While buprenorphine had an outsized representation in the sample, other substances were found in the following numbers: 6 patients positive for cocaine (17.6%), 4 patients positive for benzodiazepines (11.8%), 3 patients negative for prescribed medications (8.8%), and 1 patient each tested positive for amphetamines, oxycodone, or gabapentin. Additionally, 1 patient provided a commercial urine substitute in an attempt to subvert accurate testing.
On secondary data analysis, 4 of 17 patients positive for non-prescribed buprenorphine were also found to have concomitant amphetamines. The mean age of patients in the study population was 50.8 years, ranging from 31 to 73 years. The population consisted of 22 females (64.7%) and 12 males (35.3%).
Conclusion
The data appears to signify a concerning trend of illicit buprenorphine widely available to patients seeking treatment for chronic pain. Given the nature of buprenorphine manufacturing, much of this illicit medication seems to be diverted from patients with seemingly legitimate prescriptions through other clinics [3]. In particular, cash-only clinics have been shown to increase risk of prescription diversion. Conversely, in previous studies, chronic pain patients who elected into buprenorphine therapy have shown a positive trend toward improvement in pain and quality of life without concern for diversion issues. Given concerning diversion trends in the geographic area surrounding the study center, widespread UDS monitoring via immunoassay and other high-complexity methods may be useful for surrounding clinics to ensure lower levels of diverted medication.
References
[1] Dowell D, et al. CDC Clinical Practice Guideline for Prescribing Opioids–United States, 2022 – draft. Centers for Disease Control. 2022. https://www.regulations.gov/document/CDC-2022-0024-0002
[2] Heit HA, Gourlay DL. Urine Drug Testing in Pain Medicine. The Journal of Pain and Symptom Management. 2004; 27(3):260–267.
[3] Daniulaityte, Raminta & Falck, Russel & Carlson, Robert. (2011). Illicit Use of Buprenorphine in a Community Sample of Young Adult Non-Medical Users of Pharmaceutical Opioids. Drug and alcohol dependence. 122. 201–7. 10.1016/j.drugalcdep.2011.09.029.
[4] Rigg KK, March SJ, Inciardi JA. Prescription Drug Abuse & Diversion: Role of the Pain Clinic. J Drug Issues. 2010;40(3):681–702. doi: 10.1177/002204261004000307. PMID: 21278927; PMCID: PMC3030470.
Abstract # 79
High energy pulsed heat for the treatment of rib fracture pain in critically ill ICU patients
Paul Bhallaa, Christopher Barnesb Adrienne Jamesc Charles Chabald Peter Dunbare
aAssistant Professor, University of Washington; bActing Assistant Professor, University of Washington; cResearch Coordinator, University of Washington; dPhysician, Consultation; eChief Science Officer, University of Washington
Learning Objectives
Upon completion, participant will be able to better understand the complexity of pain management in patients with rib fractures.
Upon completion, participant will be able to better understand factors related to outcomes in patients with fracture ribs such as inspiratory volumes, reported pain and the PIC scale
Upon completion, participant will be able to better understand how early pilot data indicates that high energy pulsed heat may relieve pain in patients with fractured ribs.
Purpose
A noninvasive medical device was developed that uses brief pulses of high energy heat delivered transcutaneously to reduce pain. The mechanism of action is thought to be stimulation and defunctionalization of TRPV-1 channels located on peripheral pain nerves. While developed for the treatment of chronic pain, anecdotal evidence from four case studies suggested that the device also reduces pain from acute rib fractures. Pain from rib fractures is associated with chest wall splinting and increased risk of hypoventilation, atelectasis, and pneumonia, yet it is notoriously difficult to manage. A pilot study was therefore designed to explore the effectiveness of this device in the treatment of pain in a group of critically ill patients in the Intensive Care Unit (ICU) of a university trauma center. The study was funded through a grant to the University of Washington (UW) Anesthesiology and Pain Medicine Department and no company officials met any patient, ICU personnel, or collected any data.
Methods
This study was approved by the UW Institutional Review Board (UW ID STUDY00012759. All patients admitted to the trauma ICU at Harborview Medical Center were screened daily by a study coordinator and approached for consent if they met the following inclusion criteria: 18 years old or older; primarily English speaking; 1–10 unilateral rib fractures with pain affecting their subjective ability to breath; Glasgow Coma Score (GCS) of 15; PIC score of 4–8. A PIC score is a serial assessment of Pain, Inspiratory capacity and Cough developed at by Wellspan York Hospital, York, Pennsylvania, USA, and used at Harborview Medical Center since 2014.
Exclusion criteria included a head injury with reduced level of consciousness (GCS < 15); inability to communicate or understand the study; history of chronic pain (>50 mg Morphine Equivalent Dose (MED) per day) or substance use disorder; major distracting injuries; current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, immunologic, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebrovascular, or psychiatric disease; epidural or peripheral nerve catheter placement; neuropathy or underlying condition that would prevent the subject perceiving heat or pain.
The experimental device (Soovu Labs) consists of two separate heating pods (1-inch2 area) attached to the skin via adhesive rings. The pods are controlled by a cellphone app and linked by Bluetooth. The maximum temperature of the pods, duration of heating and number of heat pulses per minute are controlled by the app.
After consent, subjects had two heating pods placed over the area of maximal pain on the side of the chest with rib fractures. The pods were set to deliver 30 minutes of heat, with maximum pulse temperature of 45°C and 2.5 heat pulses per minute. Prior to initiation of the thermal treatment a baseline pain assessment was performed using a 0–10 numerical rating score and a maximal inspiratory capacity was measured by volumetric incentive spirometry. A PIC score was also measured. After 15 minutes of thermal treatment and 30 minutes after completion of treatment both variables were again measured. Subjects received a single thirty minute treatment session only.
Results
Nine subjects were recruited and completed the study. There were no study dropouts. The mean age was 68 years with a range from 52 to 91 years. There were 6 females and 3 males. All subjects were receiving opiates prior to the study with a mean 24-hour MED of 81 mg.
The data were analyzed by an outside independent statistical consultant using an R Core Team package (2021) and the lmerTest package for R. Contrasts are calculated using the emmeans package for R with comparisons and the adjusted p-values (for multiple comparisons) using the Tukey method.
The mean pain ratings at baseline were 6.0 ± 0.602, after 15 minutes of treatment 4.4 ± 0.602, and 30 minutes after treatment 5.0 ± 0.602. The pain reduction from baseline to 15 minutes of treatment was significantly reduced (p = 0.043) The reported pain 30 minutes after treatment is not significantly different from baseline (p = 0.2344) nor the 15 minutes rating (p = 0.6199), though it is empirically lower than baseline and higher than the 15-minute reporting. The mean PIC scores were 6.44 ± 0.36 at baseline, 7.66 ± 0.36 at 15 minutes of treatment and 7.33 ± 0.36 30 minutes after the end of treatment. The PIC scores were significantly improved over baseline at both 15 minutes of treatment (p = 0.002) and 30 minutes after treatment (p = 0.014). The mean inspiratory volumes were 1250cc ± 169cc at baseline, 1416.66cc ± 169cc after 15 minutes of treatment and 1350cc ± 169cc 30 minutes after the end of treatment. Inspiratory capacity was significantly improved at 15 minutes compared to baseline (p = 0.009) but not at 30 minutes after treatment (p = 0.091).
Conclusion
In this pilot study high energy pulsed heat treatment for 30 minutes significantly reduced pain in subjects with multiple rib fractures after 15 minutes of treatment but not significantly 30 minutes after cessation of therapy. PIC scores were significantly improved at both 15 minutes and 30 minutes after treatment cessation. Inspiratory capacity, an objective measure of respiratory function, was significantly improved after 15 minutes of therapy. The study demonstrated positive results during active treatment with a gradual return toward baseline 30 minutes after completion of treatment.
The study was undertaken to follow-up anecdotal uses of the Soovu thermal device for the treatment of rib fracture pain. The results in this group of older multiple trauma subjects who were failing conventional noninvasive pain management strategies is encouraging as alternative pain management strategies are often complex. This initial exploratory study was undertaken due to the severity of injuries and complicated status of multiple trauma subjects. It’s anticipated that these results will lead to a larger more comprehensive prospective randomized study with longer treatment sessions.
References
[1] Duch P, Moller MH. Epidural analgesia in patients with traumatic rib fractures: a systematic review of randomized controlled trials. Acta Anaesthesiol Scand. 2015;59(6):698–709.
[2] Chapman BC, Herbert B, Rodil M, et al. RibScore: A novel radiographic score based on fracture pattern that predicts pneumonia, respiratory failure, and tracheostomy. J Trauma- Injury, Infection, and Crit Care. 2016;80(1):95–101.
[3] Russell V. Lenth (2021). emmeans: Estimated Marginal Means, aka Least-Squares Means. R package version 1.6.3. https://CRAN.R-project.org/package=emmeans