1 Nonmedical use of Xtampza ER versus other oxycodone-containing products
Jody L. Green, Rebekkah Robbins, Taryn Dailey-Govoni and Stephen F. Butler
Inflexxion, an IBH Company, Irvine, CA, USA
Purpose
Opioid therapy for chronic pain remains a challenge as providers weigh the medical need for therapy with the risks of misuse, abuse and overdose. A systematic review of literature evaluated the efficacy of opioid therapy in chronic pain. Based upon 15 studies that met the inclusion criteria, opioids appear to be efficacious for treatment of non-cancer chronic pain for up to 3 months. Other published studies suggest that rates of misuse range from 21–29% and rates of addiction range from 8–12%. Prescription opioid medications with abuse-deterrent properties are products designated by the US Food and Drug Administration (FDA) as products that may meaningfully deter abuse, even if they do not fully prevent abuse. Currently marketed abuse-deterrent opioid products are intended to deter manipulation for the purpose of snorting, smoking or injecting of the active ingredient. Compared with immediate-release formulations, extended-release (ER) products contain higher amounts of the active drug ingredient, because the drug is intended to be released in the body over an extended period of time (up to 12 hours). When an ER mechanism can be defeated so that most or all of the active ingredient becomes immediately available (for example, by crushing, grinding or dissolving), the product becomes particularly attractive for abuse by injection or by oral or nasal administration.
The purpose of this study was to estimate the real-world rate of nonmedical use (NMU) of Xtampza ER (a Schedule II drug with abuse-deterrent properties introduced to the US market in Q3 2016) and comparator prescription oxycodone-containing products (other oxycodone ER products with abuse deterrent properties and oxycodone IR products) in a population of adult patients evaluated for substance abuse treatment.
Methods
A cross-sectional surveillance study design was used to examine NMU of Xtampza ER and comparator prescription oxycodone products among adults aged 18 years or older assessed for substance abuse problems and treatment planning using the Addiction Severity Index-Multimedia Version (ASI-MV®) assessment tool. The study included ASI-MV assessments completed from 01 July 2016 (Q3 2016) through 31 December 2019 (Q4 2019), representing a 3.5-year time period. Xtampza ER was added to the ASI-MV tool on 17 September 2017. The primary outcome of the study was past 30-day NMU of Xtampza ER (alone or in combination with other prescription opioids) and comparator opioids (other oxycodone ER and oxycodone IR), overall and by specific routes of administration (i.e., oral, snorting, smoking, and injecting). NMU is defined as use in any way or for any other reason than as prescribed, or use without the user’s own prescription. Rates were adjusted for volume of assessments (per 100 ASI-MV assessments) and for drug utilization (per 100,000 prescriptions dispensed; data from IQVIA).
The strengths of this data source include (1) access to a hard-to-reach, enriched population of opioid users, (2) data collection via a clinical tool used in standard work flow that captures product-specific utilization (using pictures and product names) and route of administration, (3) large sample of assessments during the study period. Limitations of this study include reliance on self-report for use and product identification, sample is obtained from sites that use ASI-MV in clinical practice and may not be representative of all individuals evaluated for substance abuse treatment or users not seeking treatment.
Results
During the study period 647 sites located in 44 states contributed 192,810 assessments to the ASI-MV network. A total of 42,279 assessments (21.9%) indicated past 30-day NMU of at least one prescription opioid. The majority of these patients were male (52.0%), ages 18 to 34 years (58.1%), and Caucasian race (77.7%). Less than 1% of those reporting prescription opioid NMU specified past 30-day use of Xtampza ER (N = 73; 0.2%). Past 30-day NMU rates of Xtampza ER per 100 ASI-MV assessments ranged from 0.01 (Q3 2017) to 0.10 (Q1 2018), oxycodone ER NMU rates ranged from 1.25 (Q4 2019) to 2.97 (Q4 2016), and oxycodone IR NMU rates ranged from 10.87 (Q4 2019) to 23.37 (Q3 2016) mentions per 100 ASI-MV assessments. All quarterly Xtampza ER NMU rates per 100 ASI-MV assessments were significantly lower than those for other oxycodone ER and oxycodone IR. Past 30-day oxycodone IR NMU quarterly rates per 100 ASI-MV assessments were significantly higher than all other groups.
When adjusting for the volume of prescriptions dispensed during the study period, past 30-day NMU of Xtampza ER was reported at rates between 4.46 (Q4 2018) and 31.10 (Q4 2017), other oxycodone ER NMU rates ranged from 38.65 (Q4 2019) to 59.94 (Q3 2016), oxycodone IR NMU rates ranged from 16.35 (Q4 2019) to 36.37 (Q3 2016) mentions per 100,000 prescriptions. Overall, Xtampza ER rates were significantly lower than quarterly rates observed for other oxycodone ER NMU but not significantly lower than oxycodone IR NMU rates.
Nonmedical users of Xtampza were less likely to report any non-oral route of administration (28.8%) compared to nonmedical users of other oxycodone ER products (57.9%) and nonmedical users of oxycodone IR products (60.1%). Specifically, snorting and injecting were reported less frequently for Xtampza ER NMU (17.8% and 6.8%, respectively) compared to other oxycodone ER NMU (31.9% reported snorting and 21.9% reported injecting) and oxycodone IR NMU (40.6% reported snorting and 15.5% reported injecting).
Conclusions
The ability to provide effective pain management therapy while reducing the risk of opioid misuse and abuse continues to be a challenge for medical professionals. Oxycodone-containing products are some of the most commonly prescribed opioids. Xtampza ER, an opioid with abuse deterrent properties, had significantly lower rates of NMU, including by non-oral routes, than other oxycodone ER products and oxycodone IR products in a population of individuals seeking substance abuse treatment. Selection of specific opioid product for mitigating the risk of NMU should be a consideration in managing patients with pain.
2 Perception of XTAMPZA® ER and other abuse-deterrent opioid formulations on the internet
Joshua Black, Zachary Margolin, Janetta Iwanicki and Richard Dart
Rocky Mountain Poison and Drug Safety, Denver, CO, USA
Purpose
Opioid abuse-deterrent formulations (ADF) were developed to impede tampering with the tablet formulation with the intention of reducing the improper use of opioids. Patient experiences and impressions among the online community can inform an understanding of the effectiveness and safety of these medications. The internet is used to communicate about use of these medications, and internet anonymity allows posters to reveal experiences that would not otherwise be captured in traditional epidemiological studies. XTAMPZA ER is an extended-release (ER), abuse-deterrent formulation of oxycodone product that uses DETERx® technology designed to reduce tampering. Past work using the Web Monitoring Program from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System has shown that sentiment of posts discussing XTAMPZA ER promote the therapeutic benefits or safe use of a drug more so than posts about other ER ADF products. The goal of this study is to build on past work and determine the manner in which web discussion promotes or discourages therapeutic use of XTAMPZA ER and comparators.
Methods
The universe of public websites on the internet (over 150,000,000 websites) was scraped to find online posts made from 2018–2019 regarding XTAMPZA ER, other extended-release (ER) ADF opioid tablet products, immediate-release (IR) oxycodone, and single-entity IR oxycodone. The other ER ADF opioid product group includes posts mentioning: OxyContin®, EMBEDA®, Hysingla® ER, MORPHABOND® ER, and ARYMO® ER. Only posts involving substantive, personal discussion were included; posts without substantive discussion (e.g., spam, news articles, and advertisements) were removed. Additionally, posts must mention 1) an explicit product name, or 2) tablet/capsule formulations along with release type to be included. This likely resulted in an undercount for ER non-ADF opioid product group, the IR oxycodone group, and the single-entity IR oxycodone group. Sentiment is defined as the dominating view or opinion of a drug within the post. Previously used qualitative research methods were used to categorize posts as negative, positive, or neutral sentiment. Positive and negative sentiments were further broken down into mutually exclusive categories of sentiment. Positive sentiment must 1) promote therapeutic benefit, 2) discourage abuse, or 3) refer to a product in a positive another way. Posts were reviewed first to determine if they promoted therapeutic benefit or discouraged abuse; if it didn’t, the post was classified as positive in another way. Negative sentiment must 1) discourage therapeutic benefit, 2) promote abuse, or 3) refer to a product in another negative way. Posts were reviewed first to determine if they discouraged therapeutic benefit or promoted abuse; if it didn’t, the post was classified as negative in another way. Neutral sentiments are when the post has no predominant opinion or the sentiment cannot be determined. All posts discussing XTAMPZA ER were coded and therefore values are exact. Due to the large volume of posts for comparators, a stratified random sample was taken prior to coding, and estimates of total numbers of posts were calculated along with 95% confidence intervals (CI).
Results
A total of 369 XTAMPZA ER posts were observed. The percentages of posts that conveyed negative sentiment (encouraging inappropriate use, ineffectiveness, or side effects) were 23.8% for XTAMPZA ER, 49.0% (CI:46.6–51.5) for ER ADF products, and 32.9% (CI: 30.7–35.1) for IR oxycodone products. The percentages of posts that conveyed positive sentiment (encouraging safe use) were 10.0% for XTAMPZA ER, 2.2% (CI: 1.5–2.9) for ER ADF products, and 9.5% (CI: 8.1–10.9) for IR oxycodone. The percentages of posts that conveyed neutral sentiment were 66.1% for XTAMPZA ER, 48.7% (CI: 46.3–51.2) for ER ADF products, and 57.6% (CI: 55.3–59.9) for IR oxycodone. There were too few posts identifying the single-entity IR oxycodone group (n = 31) to calculate percentages.
Among posts discussing XTAMPZA ER positively, 21 posts (56.8%) promoted the therapeutic benefit and 9 posts (24.3%) discouraged abuse typically by promoting the abuse deterrent properties. An example post that discourages abuse was, ‘Insurance won’t pay for Xtampza, even though the abuse-deterrent properties have been established as better than other ER oxycodone. However, insurers are seeing this, and are making the switch.’ The remainder (12 posts, or 32.4%) referenced it positively in another manner, often in an unqualified manner; an example post was, ‘Consider Xtampza if you do well with oxycodone.’ These percentages were significantly higher than analogous percentages for IR oxycodone. Among posts discussing IR oxycodone positively, 27.0% (CI: 20.2–33.8) promoted therapeutic benefit and 6.1% (CI: 2.4–9.8) discouraged abuse. There was no significant difference between proportions discussing therapeutic benefit or proportions discouraging abuse between XTAMPZA ER and other ER ADF products. Among posts discussing ER ADF products positively, 47.0% (CI: 30.7–63.3) promoted therapeutic benefit and 16.8% (CI: 4.5–29.1) discouraged abuse.
Among posts that discussed XTAMPZA ER negatively, there were no posts discouraging therapeutic benefit and only a single post (1.1%) promoted abuse. The remainder (87 posts, or 98.9%) referenced XTAMPZA ER negatively in another manner, often by referencing side effects or referring to a lack of insurance coverage. An example post referencing side effects was, ‘He switched to Xtampza, which caused extreme nausea and vomiting.’ The proportion of posts promoting abuse for XTAMPZA ER was significantly lower than IR oxycodone, 49.5% (CI: 45.4–53.6), and ER ADF products, 26.6% (CI: 23.5–29.7). Similar to XTAMPZA ER, there was little discouraging of therapeutic benefits among posts for IR oxycodone or ER ADF products (0 posts and 1 post, respectively).
Conclusions
Individuals’ stated perceptions of abuse are likely to align with their behaviors.Negative sentiment (encouraging inappropriate use, ineffectiveness, or side effects) of XTAMPZA ER was much less prevalent than for other ER ADF opioid products. Among posts discussing XTAMPZA ER negatively, there was nearly zero encouragement of abuse, unlike posts discussing ER ADF products or IR oxycodone. Conversely, there was proportionally more discussion of discouragement of abuse for XTAMPZA products than for IR oxycodone. These results could indicate that abuse of XTAMPZA ER is less desirable for abuse than other ER ADF products or IR oxycodone.
The comprehensiveness of the public web search was a key strength of this analysis. However, some websites (e.g., personal Facebook pages, Bluelight) prohibit public web scraping, and these sites could include important information not captured here. Furthermore, categorization of posts is limited to what individuals divulge, and therefore some posts might not be included in the groupings because key information (e.g., formulation) was missing.
3 Diversion and street price of XTAMPZA® ER relative to other prescription opioids
Stevan Severtsona, Zachary Margolina, Kevin Maya, Janetta Iwanickia and Richard Darta,b
aRocky Mountain Poison & Drug Safety – Denver Health and Hospital Authority, Denver, CO, USA; bUniversity of Colorado School of Medicine, Aurora, CO, USA
Purpose
Prescription opioids are a common treatment for chronic and severe pain; however, these medications have a well-documented risk of abuse. Many individuals who abuse prescription opioids obtain these medications after they are diverted from legal distribution channels. The frequency with which a particular product is diverted and the price paid in illegal markets may be indicators of the demand among individuals who abuse opioids. Both measures have been shown to be sensitive to targeted interventions intended to reduce non-medical prescription opioid abuse. XTAMPZA® ER is an abuse deterrent extended-release (ER) oxycodone product that uses DETERx® technology designed to discourage product manipulation for misuse and abuse by oral and non-oral routes. This study assesses the extent of diversion and average street price paid for XTAMPZA ER relative to other prescription opioid analgesics.
Methods
Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System Drug Diversion Program and StreetRx Program from 2018 and 2019 were used. The Drug Diversion Program obtains information on new cases of diversion reported by law enforcement and regulatory agencies in 49 states. The StreetRx Program collects black market drug price information via anonymous submissions to the StreetRx.com website. In both programs, XTAMPZA ER was compared to two groups: other abuse deterrent formulation (ADF) ER opioids, and immediate-release (IR) oxycodone. ADF ER opioids included OxyContin®, Embeda®, Hysingla® ER, Arymo® ER, and MorphaBond™ ER. With Drug Diversion Program data, rates of diversion cases were calculated per prescriptions dispensed and morphine equivalent grams dispensed and compared. Both estimates were obtained from the IQVIA® (Danbury, CT) US-Based Longitudinal Patient Data. In the StreetRx Program, the geometric mean price per milligram strength was compared between drug groups. Unadjusted geometric mean street price and geometric mean street price adjusted for tablet strength and active pharmaceutical ingredient were assessed.
Results
From 2018 through 2019, there were 737,565 (increasing by quarter) prescriptions for XTAMPZA ER, 4.8 million (decreasing by quarter) for other ADF ER opioids, and 79 million (decreasing by quarter) for IR oxycodone. There were 2,416 cases of diversion involving drug groups of interest captured in the Drug Diversion Program; 5 involved XTAMPZA ER, 128 involved other ADF ER opioids, and 2,083 involved IR oxycodone. The diversion rates per prescriptions dispensed were all statistically significantly greater for comparator drug groups relative to XTAMPZA ER. Relative to XTAMPZA ER, the IR oxycodone diversion rate was 3.7 (95% CI: 1.5–8.8, p = 0.004) times greater and the other ADF ER opioids diversion rate was 3.8 (95% CI: 1.5–9.2, p = 0.004) times greater. Adjusting for morphine equivalent grams dispensed, the IR oxycodone diversion was 5.9 (95% CI: 2.5–14.3, p < 0.001) times greater and the other ADF ER opioids diversion rate 2.8 (95% CI: 1.1–6.9, p = 0.024) times greater.
The unadjusted geometric mean price of IR oxycodone was highest ($1.04 per mg, 95% CI: $1.00–1.07), followed by XTAMPZA ER ($0.59, 95% CI: $0.50–0.69), and other ADF ER Opioids ($0.50, 95% CI: $0.46–0.53). After adjusting for tablet strength and active pharmaceutical ingredient, XTAMPZA ER had the lowest estimated price per milligram but differences with comparator drug groups were not statistically significant.
Conclusions
Diversion of XTAMPZA ER was observed though it comprised a smaller number of cases than would be expected based on prescription volume and drug potency. The appropriate comparator based on FDA guidelines is IR oxycodone. IR oxycodone had the highest number of cases. Using two different drug availability measures (prescriptions dispensed and morphine equivalent grams dispensed), diversion of IR oxycodone and other ADF ER opioids was significantly higher than XTAMPZA ER. The street price of XTAMPZA ER is lower than IR oxycodone products among individuals who abuse opioids. No differences in price per milligram were observed between XTAMPZA ER and comparator drug groups after adjusting for differences in tablet strength and active pharmaceutical ingredient. These data sources do have limitations. The Drug Diversion Program is not a representative sample and may be affected by regional differences in law enforcement efforts. Data in StreetRx are self-reported and subjective to recall and recognition biases. Though diversion of XTAMPZA ER is rare, continued monitoring is warranted to identify sources and reasons for illegal acquisition.
4 Abuse of XTAMPZA® ER relative to other opioid analgesics
Stevan Severtsona, Heather Olsena, Janetta Iwanickia and Richard Darta,b
aRocky Mountain Poison & Drug Safety – Denver Health and Hospital Authority, Denver, CO, USA; bUniversity of Colorado School of Medicine, Aurora, CO, USA
Purpose
Extended-release (ER) oxycodone products are schedule II opioid analgesics designed to provide steady pain relief over several hours. However, these products can become preferred drugs for abuse because they contain a large amount of active pharmaceutical ingredient. Some individuals who abuse ER oxycodone tamper with the medication in order to bypass the controlled-release mechanism to release the entire amount of drug in a short period of time. Products that are more difficult to manipulate may be effective at reducing abuse via tampering and/or unintended routes of administration. XTAMPZA® ER is an abuse deterrent ER oxycodone product that uses DETERx® technology designed to discourage tampering. Studies suggest that XTAMPZA ER maintains ER properties after physical manipulation and administration via the oral or nasal routes. The FDA has granted XTAMPZA ER abuse-deterrent labeling with respect to oral, nasal, and intravenous routes of administration. This study compares rates of abuse and misuse of XTAMPZA ER to other ER opioid analgesics and other forms of oxycodone.
Methods
Data collected from 2018 through 2019 were analyzed from two Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System data sources: the Poison Center Program and the Treatment Center Programs Combined. The Poison Center Program obtains information on exposures from 53 of 55 poison centers within the United States. Information obtained includes the reason for exposure, the route of administration, and the product involved in the exposure. In the Treatment Center Programs Combined, respondents entering treatment for opioid use disorders complete a questionnaire where they select the drugs they abused in the past month from a list of prescription medications. Respondents are also asked to select the routes by which they administered the product (e.g. snorted, injected). XTAMPZA® ER was compared to two groups: other abuse deterrent formulation (ADF) ER opioids and immediate-release (IR) oxycodone. ADF ER opioids included OxyContin®, Embeda®, Hysingla® ER, Arymo® ER, and MorphaBond™ ER. In the Poison Center Program, rates of intentional abuse/misuse/unknown exposures per prescriptions dispensed and morphine equivalent grams dispensed were compared between drug groups. In the Treatment Center Programs Combined, odds of past month abuse adjusted for prescriptions dispensed and morphine equivalent grams dispensed were compared between drug groups. Prescriptions dispensed and morphine equivalent grams dispensed information was obtained from the IQVIA® (Danbury, CT) US-Based Longitudinal Patient Data. The percentage of cases where product and formulation was unknown was high for both programs and different across active pharmaceutical ingredients. Ignoring missing data would lead to biased estimates of differences between drug groups. Using multiple imputation, drug group proportions within observed data were used to estimate missing values by active pharmaceutical ingredient across 50 data sets. Analyses were performed in each of the 50 data sets and estimates averaged.
Results
From 2018 through 2019, there were 737,565 (increasing by quarter) prescriptions for XTAMPZA ER, 4.8 million (decreasing by quarter) for other ADF ER opioids, and 79 million (decreasing by quarter) for IR oxycodone.
In the Poison Center Program, exposure rates per prescription dispensed for comparator opioids were all statistically significantly greater than for XTAMPZA ER. Relative to XTAMPZA ER, the rate ratio for IR oxycodone was 2.55 (95% CI: 1.43 to 4.54, p = 0.002), and other ADF ER opioids was 5.89 (95% CI: 3.25–10.67, p < 0.001). Adjusting for morphine equivalent grams dispensed, the rate ratio for IR oxycodone was 4.19 (95% CI: 2.35–7.45, p < 0.001) and other ADF ER opioids was 4.33 (95% CI: 2.39–7.84, p < 0.001). None of the 30 XTAMPZA ER exposure cases involved injection or inhalation use.
In the Treatment Center Programs Combined, the odds of a respondent endorsing other ADF ER opioids was 9.38 (95% CI: 5.99–14.71, p < 0.001) greater than for XTAMPZA ER. Odds of endorsing IR oxycodone was greater than XTAMPZA ER but the difference was not statistically significant (odds ratio (OR) = 1.37, 95% CI: 0.88–2.14, p = 0.162). Odds ratios adjusted for morphine equivalent grams dispensed for all comparator opioids were greater than for XTAMPZA ER: IR oxycodone (OR = 2.22, 95% CI: 1.42–3.48, p < 0.001) and other ADF ER opioids (OR = 6.88, 95% CI: 4.39–10.79, p < 0.001). Of the 21 cases endorsing past month abuse of XTAMPZA ER, 2 cases reported use via injection, 2 report use via inhalation in the past month. The proportion of cases reporting abuse through unintended routes was lower than comparators.
Conclusions
Abuse and misuse exposures involving XTAMPZA ER reported to poison centers and XTAMPZA ER abuse cases among individual entering treatment for opioid use disorders are infrequent relative to comparators. No abuse or misuse of XTAMPZA ER via unintended routes of administration was reported in the Poison Center Program. The proportion of cases involving use via unintended routes of administration tended to be lower for XTAMPZA ER than for comparator drug groups among individuals entering treatment for opioid use disorders. A notable limitation of these analyses is that abuse of specific products is self-reported. In the Treatment Center Programs Combined, even if false positive endorsements on the survey are rare they are more likely to disproportionately inflate estimates of less common products such as XTAMPZA ER than more commonly prescribed comparators. Noting these limitations, continued monitoring in these surveillance systems can aid in identifying changes in abuse and misuse of XTAMPXA ER and other opioid analgesics.
5 Abuse of tapentadol among individuals entering treatment for opioid use disorder
Stevan Severtsona, Heather Olsena, Janetta Iwanickia and Richard Darta,b
aRocky Mountain Poison & Drug Safety – Denver Health and Hospital Authority, Denver, CO, USA; bUniversity of Colorado School of Medicine, Aurora, CO, USA
Purpose
Tapentadol is centrally acting analgesic thought to have dual mechanisms of action: mu-receptor agonism and inhibition of norepinephrine reuptake. Tapentadol is a schedule II opioid available as an immediate-release (IR; NUCYNTA®) and extended-release (ER; NUCYNTA ER) formulation. Postmarketing surveillance studies indicate tapentadol abuse and diversion events are rare relative to other opioids. However, studies report abuse is comparable to other schedule II opioids when adjusted for drug utilization. Tapentadol is not a commonly prescribed medication relative to other opioid analgesics. In 2019 there were fewer than 250,000 tapentadol prescriptions filled compared to 19 million oxycodone prescriptions, 26 million hydrocodone prescriptions, and 12 million tramadol prescriptions. The low prescribing volume presents challenges in evaluating the abuse liability of tapentadol using general population data sources. We address this by examining abuse among adults entering treatment for opioid use disorder, a sample at high-risk for abuse of prescription analgesics. This is a descriptive study of tapentadol abuse relative to commonly prescribed opioid analgesics. We compare abuse prevalence and the frequency that each drug group is identified as the primary substance abused in the month prior to enrollment.
Methods
Data collected from 2019 are presented from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System Treatment Center Programs Combined. In the Treatment Center Programs Combined, respondents entering treatment for opioid use disorders complete a questionnaire asking about prescription medications abused in the past month. Respondents are also asked about their primary opioid drug of abuse, defined as the active pharmaceutical ingredient (API) used the most prior to entering treatment. We compared abuse and primary drug prevalence across the following APIs: total tapentadol, total tramadol, total oxycodone, and total hydrocodone endorsements. We also compared abuse prevalence across formulations: NUCYNTA (IR tapentadol), NUCYNTA ER (ER tapentadol), IR hydrocodone, IR single-entity (SE; not in combination with acetaminophen) oxycodone tablets/capsules, and IR oxycodone combination ingredient tablets/capsules. For abuse cases, unadjusted prevalence and prevalence adjusted for prescriptions dispensed are reported. Prescriptions dispensed estimates were obtained from the IQVIA® (Danbury, CT) US-Based Longitudinal Patient Data. Prescriptions dispensed adjusted prevalence values are estimated and compared at 1 million prescriptions nationally.
Results
There were 8,001 valid surveys completed; prevalence of tapentadol abuse was 0.17% (n = 14), tramadol abuse was 6.95% (n = 556), oxycodone abuse was 25.60% (n = 2,048), and hydrocodone abuse was 18.40% (n = 1,472). The prevalence of primary drug of abuse endorsements was 0.15% (n = 12) for tapentadol, 2.56% (n = 205) for tramadol, 18.87% (n = 1,510) for oxycodone, and 11.34% (n = 907) for hydrocodone.
The prescription adjusted prevalence for past month abuse was 0.80% (95% CI: 0.47% to 1.35%) for tapentadol. This was greater than tramadol (0.57%, 95% CI: 0.52% to 0.61%), similar to hydrocodone (0.72%, 95% CI: 0.68% to 0.75%), and less than oxycodone (1.36%, 95% CI: 1.30% to 1.41%). Among tapentadol abuse cases, 14.28% (n = 2) identified tapentadol as their primary drug of abuse. Among tramadol abuse cases, 22.30% (n = 124) identified tramadol was a primary drug of abuse, 47.27% (n = 968) of oxycodone abuse cases identified oxycodone as a primary drug, and 37.29% (n = 549) of hydrocodone users identified hydrocodone as a primary drug of abuse.
By formulation, NUCYNTA abuse (n = 2) and NUCYNTA ER abuse (n = 4) was indicated on less than 0.1% of surveys. IR hydrocodone abuse was indicated on 10.17% (n = 814) of surveys, IR SE oxycodone abuse on 5.52% (n = 442) of surveys, and combination ingredient IR oxycodone abuse on 914 (11.42%) of surveys. Abuse prevalence adjusted for utilization was lowest for NUCYNTA (0.19%, 95% CI: 0.05% to 0.77%), followed by IR hydrocodone (0.40%, 95% CI: 0.38 to 0.43%), NUCYNTA ER (0.56%, 95% CI: 0.21% to 1.50%), IR SE oxycodone (0.75%, 95% CI: 0.68% to 0.82%), and highest for IR combination ingredient oxycodone (1.10%, 95% CI: 1.04% to 1.17%).
Conclusions
The abuse of tapentadol is infrequent relative to other opioids among individuals entering treatment for opioid use disorders. Relative to prescribing however, tapentadol abuse is greater than tramadol, similar to hydrocodone, and lower than oxycodone. Tapentadol is less likely to be endorsed as a primary drug of abuse than tramadol, oxycodone, and hydrocodone. Among tapentadol abuse cases, the percentage of cases reporting tapentadol as a primary drug is low relative to primary drug prevalence among tramadol, oxycodone, and hydrocodone abuse cases. When examining cases involving specific products, abuse of NUCYNTA was less frequent than all comparator drug groups and abuse of NUCYNTA ER was less frequent than all drug groups except IR hydrocodone after adjusting for prescriptions dispensed. This study has limitations. Abuse estimates are based on self-report and no adjustments were made for differences between active pharmaceutical ingredients in missing data. Noting these limitations, this study provides insight into tapentadol abuse among individuals entering treatment for opioid use disorder. Specifically, abuse relative to utilization may be similar to frequently prescribed comparators although tapentadol is less likely to be identified as a preferred drug. Given low prescribing volume, continued examination into the motivations for abuse of tapentadol products is needed.
6 Acute treatment optimization influences disability and quality of life in migraine: results of the ObserVational survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME) study
Dawn Busea, Amy Kovacikb, Robert Nicholsonb, Erin Dotyb, Andre Araujoc, Sait Ashinad, Michael Reede, Robert Shapirof, Yongin Kimb and Richard Liptona
aDepartment of Neurology, Albert Einstein College of Medicine, Bronx, USA; bEli Lilly and Company, Indianapolis, USA; cFormer Eli Lilly and Company, Indianapolis, USA; dDepartment of Neurology and Department of Anesthesia, Critical Care and Pain Medicine, and Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, USA; eVedanta Research, LLC, Chapel Hill, USA; fDepartment of Neurological Sciences, Larner College of Medicine, The University of Vermont, Burlington, USA
Purpose
Assess the influence of acute treatment optimization and migraine related disability and health related quality of life (HRQoL) across monthly Migraine Headache Day (MHD) categories from the OVERCOME study. Acute treatments for migraine attacks are considered optimized when they resolve pain and restore function. Optimized acute treatment for migraine should be associated with less disability and better HRQoL in people with migraine.
Methods
OVERCOME is a web-based survey conducted in a representative US sample. The current sample, collected in Spring 2019, included 20,041 people meeting ICHD-3 criteria for migraine who completed measures of acute treatment optimization (Migraine Treatment Optimization Questionnaire [mTOQ]), disability (Migraine Disability Assessment Scale [MIDAS], and HRQoL (Migraine-Specific Quality of Life Questionnaire, Role Function – Restrictive subscale [MSQ-RFR]). This analysis examined the relationship between mTOQ, MIDAS, and MSQ-RFR across MHDs per month categories (0–3, 4–7, 8–14, ≥15 MHDs). One-way ANOVA or Chi-square test, stratified by MHD category, evaluated differences between mTOQ groups (p < .05).
Results
For the whole cohort of 20,041 respondents, mean(SD) age was 42.5(14.9) years, 74.9% were female, and 72.1% were non-Hispanic white. Among the 3,938 respondents with 4–7 MHDs per month, 60.1% of those with very poor treatment optimization had severe MIDAS disability as opposed to only 19.5% of those with maximum treatment optimization (p < .001). In this group, those with very poor treatment optimization had significantly lower MSQ-RFR scores, Mean = 32.0 (SD 22.8) relative to those with maximum treatment optimization, Mean = 63.4 (SD 20.7) (p < .001). Significant differences in MIDAS and MSQ-RFR by treatment optimization were observed across all other MHD cohorts (i.e. 0–3, 8–14, ≥15; all p < .001).
Conclusions
When acute migraine treatment is optimized, people with migraine report lower levels of disability and better health related quality of life.
7 Neuronal effects of music entrainment versus preferred music in three patients with chronic cancer pain as measured via EEG and LORETA imaging
Andrea Hunta, Jörg Fachnerb, Robert Raffac,d, Carrie Rupnow-Kidde, Clemens Maidhofb and Cheryl Dileoc
1Rowan University, Glassboro, NJ, USA. 2Anglia Ruskin University, Cambridge, United Kingdom. 3Temple University, Philadelphia, PA, USA. 4University of Arizona, Tucson, AZ, USA. 5Rutgers Behavioral Health, South Woods State Prison, Bridgeton, NJ, USA
Purpose
Treating chronic pain requires an individualized approach to account for the various biopsychosocial factors and needs of patients, particularly those that cannot be adequately addressed by available medication alone. Many patients and practitioners have turned to modalities such as music as an intervention. Though several metanalyses and systematic reviews indicate music is effective for alleviating pain and reducing opioid use, this research also lacks consideration of cognitive mechanisms underlying music as an analgesic. Music therapists use interactive and passive interventions for pain, and the cognitive mechanisms for interactive interventions have not yet been investigated with imaging. Previous studies examining EEG and LORETA in patients with chronic pain discovered an overactivation of high theta (6–9 Hz) and low beta (12–16 Hz) power in central regions. MEG studies with healthy subjects correlating evoked nociception ratings and source localization described delta and gamma changes according to two music interventions. Using similar music conditions with chronic pain patients, we examined EEG in response to two different music interventions for pain. To study this process in-depth we conducted a mixed-methods case study approach, based on three clinical cases.
Methods
Effectiveness of personalized music therapy improvisations (entrainment music-EM) versus listening to preferred music on chronic pain was examined with 16 participants. Three patients were randomly selected for follow-up EEG sessions three months post-intervention, where they listened to recordings of the music from the interventions provided during the initial research. To test the difference of EM versus preferred music, recordings were presented in a block design: silence, their own composed EM (depicting both ‘pain’ and ‘healing’), preferred (commercially available) music, and a non-participant’s EM as a control. Participants rated their pain before and after the EEG on a 1–10 scale. We conducted a detailed single case analysis to compare all conditions, as well as a group comparison of entrainment-healing condition versus preferred music condition. Power spectrum and according LORETA distributions focused on expected changes in delta, theta, beta, and gamma frequencies, particularly in sensory-motor and central regions.
Results
Intentional moment-by-moment attention on the sounds/music rather than on pain and decreased awareness of pain was experienced from one participant. Corresponding EEG analysis showed accompanying power changes in sensory-motor regions and LORETA projection pointed to insula-related changes during entrainment-pain music. LORETA also indicated involvement of visual-spatial, motor, and language/music improvisation processing in response to his own EM which may reflect active recollection of creating the EM with the therapist. Group-wide analysis showed common brain responses to personalized entrainment-healing music in theta and low beta range in right pre- and post-central gyrus.
Conclusions
We observed somatosensory changes consistent with processing pain during entrainment-healing music that were not seen during preferred music. These results may depict top-down neural processes associated with active coping for pain.
8 Spinal cord stimulation for chronic knee pain after knee replacement surgery: a case series
Andrea Wakima, Louis Nikolisa, Ann Hulmeb and Prempreet Bajajc
aLoyola University Chicago Stritch School of Medicine, Maywood, IL, USA; bLoyola Medicine MacNeal Hospital, Berwyn, IL, USA; cLoyola University Medical Center, Maywood, IL, USA
Purpose
Chronic knee pain affects 25% of adults and significantly impairs functionality.1Total knee arthroplasty (TKA) is a common treatment modality for patients with chronic knee pain unresponsive to conservative management. Although studies have shown that, on average, patients who have undergone TKA experience improved quality of life, there is considerable variation in patient outcomes.2The persistence of pain after TKA suggests that the pain is not purely mechanical, as TKA corrects underlyingmechanical dysfunction. Rather,this pain is suspected to be multifactorial in origin, including a neuropathic component.3
Treatments for chronic knee pain post-TKA include pharmacologic management, with neuropathic medications and opioid analgesics, and interventional options such as radiofrequency ablation (RFA) of the genicular nerves. Problems with medical management include efficacy and negative side effect profiles. RFA is an effective option, however, up to 48% of patients do not experience 50% or greater relief of pain from RFA.4,5As a result, patients are left with few remaining treatment options that are safe and efficacious.
Recently, spinal cord stimulation (SCS) has become an increasingly popular treatment modality for persistent pain. One case study has shown efficacy of SCS in reducing pain in a patient with chronic regional pain syndrome after TKA.6However, more evidence is needed to evaluate the efficacy of SCS in patients who have persistent chronic knee pain after TKA and multiple other interventions. Additionally, studies have not simultaneously evaluated opioid use in this population. Therefore, the goal of this case series is to evaluate the effect of SCS in patients who have persistent chronic knee pain after total knee arthroplasty (TKA) by analyzing the reduction in their daily opioid usage, subjectively reported pain and functional status.
Methods
Three patients received SCS placement for chronic knee pain following TKA. Prior to permanent SCS placement, each patient underwent medical management, diagnostic genicular nerve blocks, and possible radiofrequency ablation without improvement in their pain. Prior to permanent SCS placement, each patient underwent a one-week SCS trial, with improvement in their pain.
Patients’ charts were abstracted for demographic data, diagnoses, treatment history, and pain medications. Patients were evaluated at the following time points (when applicable): pre-SCS trial, one-week post-SCS trial, post-permanent SCS placement (short-term), and post-permanent SCS placement (long-term). Short-term was defined as a period of three months or less since permanent SCS placement, and long-term was defined as greater than three months since permanent SCS placement.
To quantify daily opioid usage, morphine milligram equivalents (MME) were determined at each of the above time points. MME were calculated by applying conversion factors to each patient’s medication list based on the Center for Disease Control and Prevention (CDC) Guidelines for MME.
Patient 1 was a 56 year old female with a 10 year history of bilateral knee osteoarthritis who underwent bilateral TKA. Her pre-operative pain failed to improve following TKA, prompting a referral to outpatient pain management. Her pain continued despite pharmacologic management and a failed diagnostic genicular nerve block.
Patient 2 was a 59 year old male with a history of bilateral knee osteoarthritis who underwent bilateral TKA. His knee pain of greater than 12 years returned two months after TKA, prompting a referral to outpatient pain management. He had significant chronic pain despite pharmacologic management, successful diagnostic genicular nerve block, and subsequent RFA.
Patient 3 was a 41 year old female with chronic knee pain secondary to pigmented villonodular synovitis since 2005 who underwent bilateral TKA and left knee revision four years later. She continued to suffer from significant pain following TKA and revision and was seeking non-operative pain reduction. Her pain continued despite pharmacologic management and multiple RFAs that became less efficacious with time.
Results
For patient 1, prior to the SCS trial, her total daily opioid use calculated to 80 MME/day. She described her pain as 10/10, required a cane for ambulation, and had difficulty getting around her house. At the end of the one-week SCS trial, the patient was not requiring any pain medications, totaling to 0 MME/day, and had substantial improvement in pain and functional status. After permanent SCS placement, in short-term assessment, the patient had a maximum of 15 MME/day. Additionally, she no longer required a cane to walk. At long-term evaluation, the patient had a maximum of 5 MME/day. Moreover, she described her pain as a 5/10 with 70% relief, and continued to ambulate independently without a cane.
For patient 2, prior to the SCS trial, his opioid use was calculated to be 30 MME/day. He described his pain as 10/10 and stated that pain was affecting his sleep and daily activities. At the end of the SCS trial, the patient was no longer taking pain medication, resulting in 0 MME/day, and noted significant functional improvements. At short-term follow-up visits, following permanent SCS placement, the patient had reduced his opioid use, totaling to 20 MME/day. He endorsed 50% relief of pain, rated his pain as 7/10, and reported that he was able to exercise and lose weight due to reduced pain. At long-term follow up visits, the patient had not changed his opioid use, yielding 20 MME/day. He rated his pain as 6/10, felt 50% relief in his pain compared to before SCS placement, was exercising, and staying active.
Prior to the SCS trial, patient 3 had to be weaned off of long-acting opioid medications, as her total daily opioid use calculated to 240 MME/day. She rated her pain as 10/10 and required a cane for ambulation. At the end of the one week trial, the patient was not taking any opioid medications and reduced to 0 MME/day, and she endorsed significant improvements in pain. Following permanent SCS placement, at short-term follow up, the patient’s daily opioid use totaled to 40 MME/day. However, she did not feel that she was having adequate coverage with the stimulator, rated her pain was 7/10, and noted trouble with stairs.
Conclusions
Prior to SCS placement, all three patients took opioids daily, reported subjective pain scores of 7–10/10, and had difficulty with ambulation and ADLs due to their pain. Following SCS placement, all three patients had lower daily MME values at short-term (<3 months) assessment, and patient 1 and patient 2 had lower MME values at long-term assessment (>3 months). Patient 1 had a reduction in MME by 93.7%, patient 2 by 33.3%, and patient 3 by 83.3%. Patient 3 had a delay in her SCS placement due to the COVID-19 pandemic and thus only has short-term data available presently. Nonetheless, all three patients reported less pain and greater functional status following SCS placement as compared to before. This case series suggests that SCS could serve as a promising treatment modality for patients with chronic knee pain after TKA. This treatment modality can help reduce daily opioid use, reduce subjective pain, and improve functionality.
9 Remote electrical neuromodulation for acute treatment of migraine in people with chronic migraine: a pooled analysis of efficacy and safety
Brian Grosberga, Tamar Linb, Maya Vizelb, Jack Schimc, Christopher O’Carrolld, Hida Nierenburge and Paul Wrighte
aHartford Healthcare Headache Center, Hartford, CT, USA; bTheranica Bio-Electronics, Netanya, Israel; cThe Neurology Center of Southern California, Carlsbad, CA, USA; dHoag Neuroscience Institute, Newport Beach, CA, USA; eNuvance Health, Poughkeepsie, NY, USA
Purpose
Remote electrical neuromodulation (REN) is a novel acute treatment for migraine headaches. The REN device (Nerivio®, Theranica Bio-Electronics LTD., Israel) is FDA-authorized for acute treatment of migraine in adults who do not have chronic migraine. REN has been studied in two studies for acute treatment in patients impacted by chronic migraine. The objective of this pooled analysis was to evaluate the efficacy and safety of Nerivio in this population.
Methods
Both trials were open-label, single-arm studies in adults aged 18–75 years who met the ICHD-3 criteria for chronic migraine, and included a 4-week treatment phase in which they were asked to treat their headaches with the device. Pain severity levels, associated symptoms and functional disability were recorded at treatment initiation, as well as 2- and 24-hours post-treatment.Efficacy endpoints included pain relief, pain-free, disappearance of associated symptoms, and improvement in function at 2 hours post-treatment. Sustained pain responses at 24 hours and within-subjects consistency were also assessed.
Results
A total of 168 participants were enrolled in both trials, of which 129 participants were included in the efficacy analyses. Pain relief and pain-freedom at 2 hours were achieved by 56.6% (73/129) and 22.5% (29/129) of participants, respectively. Pain relief response was sustained at 24 hours in 75.4% (43/57) of participants. Nausea, photophobia, and phonophobia disappeared at 2 hours in 57.1% (30/58), 39.8% (39/98), and 45.7% (37/81) of participants, respectively. 53.2% (33/62) of participants experienced improvement in functional ability at 2 hours. Furthermore, 62.1% (80/129) achieved pain relief at 2 hours in at least half of their treated migraine headaches. Two device-related adverse events were reported.
Conclusions
REN provides clinically meaningful relief of migraine pain and associated symptoms, offering asafe and effective non-pharmacological alternative for acute treatment in patients with chronic migraine.
10 Efficacy of galcanezumab in adults with treatment resistant migraine and concomitant pain disorders: post-hoc subpopulation analyses from the randomized, double-blind, placebo-controlled CONQUER study
Charles Argoffa, Yan Dongb, Lily Lib, Peter Wrightb and Meredith Baradc
aAlbany Medical College, New York, USA; bEli Lilly and Company, Indianapolis, USA; cStanford University, Stanford, USA
Purpose
Patients with migraine frequently report comorbid pain conditions. The objective of the analyses reported in this abstract was to examine the efficacy of galcanezumab (GMB) compared to placebo (PBO) in patients with treatment-resistant episodic or chronic migraine who had 1 or more concomitant pain disorders. Treatment resistance was defined as previous failure with 2 to 4 standard-of-care migraine preventive medication categories in the past 10 years due to inadequate efficacy and/or safety/tolerability reasons.
Methods
The CONQUER study was a Phase 3, randomized, double-blind, placebo-controlled study of galcanezumab in adults with treatment-resistant episodic or chronic migraine as defined by IHS ICHD-3 guidelines. In this study, patients with treatment-resistant migraine were randomized 1:1 to receive GMB 120 mg/month (with 240-mg loading dose) or PBO during a 3-month double-blind period. Subpopulation analyses were performed on patients enrolled in this study who had 1 or more concomitant pain disorders; acute pain from surgery, procedures, or fractures was excluded. Assessments of migraine and headache-related endpoints were based on headache information captured via an electronic (ePRO) diary. The following endpoints were evaluated for Months 1–3: 1) change from baseline in number of monthly migraine headache days; 2) response rates for ≥50%, ≥75%, or 100% reduction in monthly migraine headache days; 3) change from baseline in Migraine-Specific Quality of Life – Role Function Restrictive (MSQ-RFR) domain score using mixed model with repeated measures.
Results
Patients who had 1 or more pain disorders (N = 100 GMB and N = 97 PBO) showed the GMB and PBO groups had similar baseline characteristics. While the most commonly experienced pain disorders were back pain, osteoarthritis, and neck pain, the analyses included many disorders. In this subpopulation, GMB-treated patients had significantly greater mean reduction in the number of monthly migraine headache days during the double-blind treatment phase (Months 1, 2, and 3) compared to patients who received PBO (least square mean difference from placebo at Month 1: −2.37 days, p < .001, Month 2: −1.81 days, p < .05, and Month 3: −2.34 days, p < .01). GMB-treated patients had significantly higher 50% and 100% response rates compared to PBO at Month 1 (p < .001 and p < .0001, respectively) and Month 3 (p < .01 and p < .0001, respectively); these response rates were numerically higher in GMB-treated patients at Month 2, but were not statistically significant. GMB-treated patients also had numerically higher 75% response rates than PBO patients at Months 1–3; however, the difference was not statistically significant. The mean improvement from baseline in MSQ-RFR scores at Months 1, 2, and 3 was significantly greater in the GMB-treatment group compared to PBO (least square mean difference from placebo at Month 1: 11.64, p < .0001; Month 2: 10.28, p < .001, and Month 3: 12.01, p < .0001), reflecting better health status and functional improvement.
Conclusions
GMB 120 mg/month demonstrated superior efficacy to PBO for the preventive treatment of treatment-resistant migraine in patients with 1 or more concomitant pain disorders.
11 Properties of thermal analgesia in a human chronic low back pain model
Charles Chabala, Peter Dunbarb, Ian Painterc, Douglas Youngd and Darah Chabalc
aSoovu Labs Inc., Seattle, WA, USA; bSoovu Labs Inc., Seattle, WA, USA; cUniversity of Washington, Seattle, WA, USA; dNorthern California Research Inst., Sacramento, CA, USA
Purpose
For years heat has been used for comfort and analgesia and is recommended as a first line therapy in many clinical guidelines. Yet, there are questions that remain about the actual effectiveness of heat for a condition as common as chronic low back pain, and factors such as time of onset, optimal temperature, and duration of effect. Against this background the present study was designed using a chronic low back pain model. The primary hypothesis was that higher level thermal stimulation would produce better analgesia than lower temperatures in a well design placebo controlled randomized double blinded study. In addition, this study was designed to carefully document two poorly understood outcomes of thermal analgesia: 1) the onset and 2) duration of analgesia after 30 minutes of thermal stimulation.
Methods
A randomized double blinded controlled trial was designed to compare the analgesic response to heat delivered via pulses at 45°C (experimental group, N = 49) to steady heat at 37°C (control group, N = 51) in subjects with longstanding low back pain. Treatment lasted 30 minutes with follow-up out to four hours. The hypothesis was that the experimental group would experience a higher degree of analgesia compared to the control group. Time of onset and duration of effect was also measured. The study devices used were manufactured by Soovu Labs Inc. and were identical in both the experimental and control groups. Only the temperature settings differed between groups.
Results
Both groups were similar in average duration of pain (10.3 years). The primary outcome measure was pain reduction 30 minutes after the end of treatment, using a 10 points numeric pain scale. Reduction in pain was greater for the experimental group than the control group (difference in mean reduction = 0.72, 95% CI 0.15–1.29, p = 0.014). Statistically significant differences in pain levels were observed from the first measure at 5 minutes of treatment through 120 minutes after completion of treatment. Reduction with movement was greater in the active heat group than the placebo group (p = 0.04).
Conclusions
High level pulsed heat (45°C) produced significantly more analgesia as compared to steady heat at 37°C at the primary end point and for an additional 2 hours after treatment. The onset of analgesia was rapid, < 5 minutes of treatment. The results of this trial provide insight into the mechanisms and properties of thermal analgesia that are not well understood in a chronic low back pain model.
12 Thermal analgesia, exploring the boundary between pain relief and nociception
Charles Chabala, Peter Dunbarb, Douglas Youngc and Ian Painterd
aSoovu Labs Inc., Seattle, WA, USA; bSoovu labs Inc., Seattle, WA, USA; cNorthern California Research Inst., Sacramento, CA, USA; dUniversity of Washington, Seattle, WA, USA
Purpose
Humans have used heat to provide analgesia and comfort for thousands of years yet there are many aspects that remain poorly understood. There are major gaps in knowledge such as mechanism of action, optimal temperature and duration of heat. This study compared the delivery of twice the thermal energy of a previous study and examined aspects such as time of onset, analgesic effect, and duration of effect. In addition, a new safety standard and measure of thermal energy is proposed.
Methods
A randomized blinded controlled three arm trial was designed to compare the analgesic response to heat delivered via pulses at 4 pulses/minute at 45°C (N = 30) versus heat delivered via pulses at 2 pulses/minute at 45°C (N = 49) to steady heat at 37°C (N = 51) in subjects with longstanding low back pain. Treatment lasted 30 minutes with follow-up out to four hours. The hypothesis was that the highest energy group (4 pulses/minute) would receive improved analgesia compared to the other groups. Time of onset and duration of effect was also measured.
Results
The primary outcome measure was pain reduction 30 minutes after the end of treatment and used the 10 point numeric pain scale. Reduction in pain was greater for the both the experimental group in the Initial Study (2 pulses per minute) and the High Energy Study group (4pulses per minute)as compared to the control group (steady heat). The High Energy group (4 pulses per minute) reduced pain for the entire 180 minutes of post heating observation as compared to the Initial Study group (2 pulses per minute) that reduced pain for 120 minutes. The reduction in pain in the High Energy group was greater than that in the experimental group in the Initial Study but did not reach statistical significance. Both experimental groups (2 pulses per minute and 4 pulses per minute) produced significantly better analgesia when compared to the steady heat control group.
Conclusions
High level pulsed heat 45°C at 4 pulses per minute produced significantly longer analgesia as compared to the control groups of pulsed heat 45°C at 2 pulses per minute, and steady heat at 37°C. Pain relief was rapid, with an onset of analgesia < 5 minutes. The results suggest that there is a dose relationship between thermal energy delivered and duration of analgesia with the upper limit likely defined as the analgesic nociceptive boundary. In this study that boundary was not reached offering a possibility of improved analgesia as thermal energy is increased. However, increased thermal energy requires a better standardized approach to user safety. The concept of CEM43 as a measure of thermal energy and safety is introduced. The results provide insight into the mechanisms and properties of thermal analgesia that are not well understood in a chronic low back pain model.
13 Assessment of thermal safety of a new medical device using high energy pulsed heat: A novel standardized approach
Charles Chabala and Raja Sivamanib,c
aSoovu Labs Inc., Seattle, WA, USA; bUniversity of California, Davis, Sacramento, CA, USA; cIntegrative Skin Science and Research, Sacramento, CA, USA
Purpose
Local heat application has been used to help soothe stiff joints, relieve pain, relax muscles, and reduce spasms. Recent studies support that the pain relieving properties of heat may be related to a peripheral interaction with transient receptor potential vanilloid (TRPV) channels and/or small diameter peripheral nerves. Further, the analgesic response to heat may be related to the amount of thermal energy applied to the skin and underlying receptors. Parameters of thermal energy such as absolute temperature, rate of temperature rise, and duration of heating are thought to affect the number and degree of stimulation of peripheral thermal sensitive receptors. A new medical device (Soovu Labs Inc.) uses high energy pulsed heat to stimulate peripheral receptors and recent studies indicate that 30 minutes of stimulation can produce over two hours of pain relief. This novel approach of using high energy pulsed heat to stimulate and recruit receptors required the development of a standardized approach to assess thermal safety of this device. As such, this study developed a testing paradigm using objective measures to evaluate the safety of this new device.
Methods
All participants provided written informed consent prior to participation and received financial compensation. Twenty-five healthy participants were recruited and screened for eligibility at the Integrative Skin Science and Research site (Sacramento CA). The average age of the participants was 29 years old, and their ethnicities were as follows: Asian (11), White/European (7), Latino (4), Middle Eastern (3). The study was conducted over ten days and consisted of two visits.
The heating devices for this study were designed by Soovu Labs, Inc. These devices are designed for eventual commercial sales as a noninvasive, non-prescription, over-the-counter devices that provide heat to temporarily reduce muscle aches and pains. The maximum temperature of the heating device is 45°C. The device briefly pulses up to the maximum temperature 45°C for 10 seconds after which power is turned off and the temperature drifts to 40°C. In one a single 10-minute treatment cycle there are a number of pulses up to 45°C. After each treatment cycle there is a three-minute lockout period of no heating. The devices are constructed following documented ANSI/AAMI ES60601-1, ANSI/AAMI HA60601-1-11, IEC 60601-1-2, IEC 60529, ISO 10993–5, and 10993–10 safety standards.
Heating devices were applied to the following locations on each participant’s upper body: upper back, lower back, abdomen, and inner upper arms. Two devices were applied to each location for a total application of eight devices per participant. Participants underwent 25 three ten-minute treatment cycles during the first visit. Photographs of the locations, transepidermal water loss measurements, and skin colorimeter measurements were taken at the following time points: baseline, after 2 treatment cycles (30 min), after 8 treatment cycles (90 min), after 15 treatment cycles (3 hours), and at the second visit (7–10 days from the first visit). Participants were also instructed to complete a visual analog scale (VAS) assessment for pain at all the previously mentioned time points.
Results
Pain:
The average pain throughout the treatment cycles in Visit 1 was minimal and decreased over time. Average pain returned to baseline at Visit 2.
Erythema:
The average erythema increased over time in all locations during Visit 1, but returned to baseline by Visit 2 indicating that there was no prolonged erythema after the device exposure.
Lightness:
The average lightness decreased over time in all locations during Visit 1, indicating that there was a slight increase in pigmentation during the treatment cycles. However, all of the measures returned to baseline by Visit 2 indicating that there was no prolonged pigmentation after device exposure.
TEWL:
The average TEWL increased over time during Visit 1 in the following locations: right and left upper back, right and left abdomen, and right and left inner upper arms. The average TEWL decreased over time during Visit 1 in the right and left lower back. In all locations, the average TEWL returned to baseline by Visit 2.
Conclusions
It was determined that the heating devices were well tolerated with no adverse effects due to the device’s heating mechanism. There were no episodes of post-inflammatory hyperpigmentation or persistent erythema with use of the devices. While there were temporary changes in the erythema, skin lightness (pigment), and transepidermal water loss, all of these measures returned to baseline. Pain was minimal during the treatment cycles. The devices were equally safe at all tested anatomical sites: upper arm, upper back, lower back, and the lower abdomen.
The amount of thermal energy used in this experiment greatly exceeded what is anticipated in a commercial device with no evidence of skin damage at either the short term or longer term assessment. It is hypothesized that pain relief from thermal stimulation displays a ‘dose-like’ response whereas more energy delivered produces better analgesia up to a point limited by nociception or tissue injury. In this case the device delivered high temperature thermal stimulation in brief pulses producing analgesia but reducing thermal energy delivered to the skin and increasing the margin of safety. The study design offers a standardized safety testing approach and may be applied to other cutaneous heating devices whether electrical or chemical based.
14 Buprenorphine buccal film in patients with chronic low back pain: a pooled subgroup analysis of two double-blind, placebo-controlled, randomized withdrawal trials by baseline pain severity
Christine Moorea, P. Hunter Allmanb and Gary Cutterb,c
aBioDelivery Sciences International, Inc., Raleigh, NC, USA; bUniversity of Alabama at Birmingham School of Public Health, Department of Biostatistics, Birmingham, AL, USA; cPythagoras, Inc., Birmingham, AL, USA
Purpose
Buprenorphine is a Schedule III opioid with partial agonistic activity at the mu-opioid receptor, antagonist activity at the delta- and kappa-opioid receptors, and agonist activity at the opioid-receptor-like 1 (ORL-1) receptor. Buprenorphine is a unique opioid with demonstrated efficacy as an analgesic and favorable safety properties that may provide an improved risk-benefit profile relative to other opioids.
As with Schedule II long-acting opioids, buprenorphine buccal film (BELBUCA®, BioDelivery Sciences International, Inc.) is approved by the US Food and Drug Administration 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. Two previous phase 3 clinical trials established the efficacy of buprenorphine buccal film for treating chronic low back pain in opioid-naïve and opioid-experienced subjects (ClinicalTrials.gov NCT01633944 and NCT01675167, respectively). Both studies used an enriched enrollment, randomized withdrawal design that consisted of an open-label buprenorphine buccal film titration phase followed by a randomized, double-blind phase in which subjects either continued treatment with buprenorphine buccal film or were switched to placebo. After 12 weeks of double-blind treatment, results of the primary efficacy analysis showed that mean average daily pain scores increased (worsened) significantly less from baseline in subjects who continued use of buprenorphine buccal film than in those who switched to placebo. Subjects in the buprenorphine buccal film group also had significantly lower pain scores than subjects in the placebo group at week 1 and at all subsequent time points through week 12. This post hoc analysis pools data from both clinical trials to further characterize the efficacy of buprenorphine buccal film on the basis of baseline pain severity scores.
Methods
Both studies enrolled adults aged ≥18 years who had chronic low back pain as their primary source of pain for ≥6 months. To enter the open-label titration phase, subjects had to have an average pain intensity score of ≥5 on an 11-point numeric rating scale (NRS) from 0 (no pain) to 10 (worst pain imaginable) during the last week of screening. Opioid-experienced subjects with well controlled pain (average pain intensity <5) were also permitted to enroll, provided that their pain scores were at ≥5 for at least 3 consecutive days during taper of their previous opioid. After titration to their optimal buprenorphine buccal film dose during the open-label phase, eligible subjects were randomly assigned (1:1 ratio) to receive buprenorphine buccal film or placebo buccal film twice daily for 12 weeks. Subjects assigned to receive buprenorphine buccal film continued the same optimal dose established during the open-label phase.
Post hoc analyses combined data for subjects from both studies and evaluated the mean difference in average daily NRS scores from baseline (the start of double-blind treatment) in 10-day intervals through day 80. Subjects were stratified by average pain severity in the 7 days before the start of open-label titration, with mild pain defined as an average NRS of ≤4, moderate pain as an average NRS of 5 or 6, and severe pain as an average NRS ≥7. A linear mixed-effects model was used to assess differences between the groups in individual NRS pain scores. The mean pain score over time adjusted for baseline was used to assess the change in pain intensity scores from baseline to week 12. Estimates of mean treatment differences were calculated using a quadratic model that provided a conservative estimate of the difference as the model was adjusted to fit excess differential dropouts over time in the placebo arm; p values were calculated using the least squares means at each time point from the model.
Results
Across both studies, 971 subjects were randomly assigned to buprenorphine buccal film (n = 483) and placebo buccal film (n = 488). Mean (SD) pain scores before open-label titration were 7.0 (1.2) in the buprenorphine buccal film group and 6.9 (1.2) in the placebo group; scores improved to 2.9 (1.0) and 2.8 (1.1), respectively, at the start of the double-blind period. Overall, mean differences between treatment groups suggested significantly lower pain scores in the buprenorphine buccal film group than in the placebo group at every 10-day interval assessed; the greatest difference was observed at day 60 (mean difference, −0.8 [95% CI, −1.1 to −0.6]; p < 0.0001). At most time points, greater decreases in pain scores for buprenorphine buccal film than for placebo were observed in subjects with moderate pain at entry (n = 102 and 94, respectively) and severe pain at entry (n = 366 and 371) than in subjects with mild pain at entry (n = 15 and 23). For both the moderate and severe pain subgroups, mean differences between groups suggested significantly lower pain scores in the buprenorphine buccal film group than the placebo group for every 10-day interval assessed. The greatest difference in pain scores between the buprenorphine buccal film and placebo group was observed at day 50 for the moderate pain subgroup (mean difference, −1.0 [95% CI, −1.5 to −0.6]; p < 0.0001) and at day 60 and day 70 for the severe pain subgroup (mean difference for both, −0.8 [95% CI, −1.1 to −0.5]; p < 0.0001). Mean differences in pain scores between the buprenorphine buccal film group and the placebo group were the same or greater for subjects in the moderate pain subgroup than for those in the severe pain subgroup at every 10-day interval assessed.
Conclusions
Buprenorphine buccal film has demonstrated analgesic efficacy for the treatment of chronic low back pain in opioid-naïve and opioid-experienced patients. The results of this post hoc analysis indicate that treatment with buprenorphine buccal film results in greater reductions in pain than does placebo; similar reductions in pain were observed regardless of whether subjects had moderate or severe pain at study entry. Given the favorable risk-benefit profile of buprenorphine, buprenorphine buccal film should be considered a treatment option for patients who require long-term opioid treatment for which alternative treatment options are inadequate, even when their pain levels are considered severe.
15 Retrospective chart review of advanced practice pharmacist prescribing of controlled substances for pain management in veterans
Courtney Kominek
Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO, USA
Purpose
The objective of the retrospective chart review project was to identify the impact of an advanced practice pharmacist with controlled substance prescriptive authority on morphine milligram equivalent dose (MME) and compliance with opioid risk mitigation.
Methods
This was a retrospective, single-center chart review conducted in March 2020 of patients prescribed controlled substances from July 2018 – January 2020. Patients received care through the outpatient Pharmacy Pain Clinic in-person or via telephone who were enrolled at the Harry S. Truman Memorial Veterans’ Hospital in Columbia, MO or associated outlying outpatient clinics. Patients were included if referred to the Pharmacy Pain Clinic and prescribed a schedule II or III opioid medication. A two-sided t-test was conducted to compare MME and a Fisher’s exact test was used to compare compliance with opioid risk mitigation.
Results
Patients seen in Pharmacy Pain Clinic had a statistically significant reduction in MME from consult (93 MME) to discharge (31 MME) (p < 0.0001). There was also a statistically significant (p < 0.0001) improvement in use of opioid risk mitigation strategies including urine drug screen, informed consent, naloxone, prescription drug monitoring program checks, and stratification tool for opioid risk mitigation (STORM) dashboard reviews.
Conclusions
An advanced practice pharmacist with controlled substance prescriptive authority improved patient care with demonstrated statistically significant differences in MME and compliance with opioid risk mitigation from consult to discharge. Healthcare teams should look to add advanced practice pharmacists to their team as medication experts to deliver comprehensive medication management which can include controlled substance prescribing and management.
16 An Exploration of the Implications of Sequencing Order on Group Pain Interventions
David Cosio and Madison Simons
Jesse Brown VA Medical Center, Chicago, IL, USA
Purpose
As both Acceptance and Commitment Therapy (ACT) and Cognitive-Behavioral Therapy (CBT) have been found to be effective in treating chronic, non-cancer pain, there is a need to explore how to optimally apply these treatments to improve patient outcomes.The primary aim of this study was to evaluate whether a sequential approach to treatment, where acceptance based coping strategies are taught prior to problem-focused coping strategies, improves pain-related outcomes.As a basis for evaluating the effects of sequencing order, we also tested the hypothesis that Veterans receiving both treatments (ACT and CBT) would show significantly greater improvement in pain outcome measures than those receiving just one of the treatments.
Methods
A sample of 168 Veterans participated in the current study at a Midwestern Department of Veterans Affairs (VA) Medical Center between November 1, 2009 and November 30, 2012. All participants self-selected to participate in manualized ACT, CBT, or both interventions, and were administered a standard pre- and post-intervention assessment battery. The battery of measures in the current study included the Readiness Questionnaire (M. Jensen, personal communication, August 23, 2004), the Brief Pain Inventory-Short Form (BPI; Cleeland & Ryan, 1994), the Oswestry Disability Index © (ODI; Fairbank, Davies, Couper, & O’Brien, 1980), the Coping Strategies Questionnaire-Catastrophizing Scale (CSQ; Rosenstiel & Keefe, 1983), the Chronic Pain Coping Inventory-Short Form (CPCI; Jensen, Turner, Romano, & Strom, 1995), and the Brief Symptom Inventory® 18 (BSI-18; Derogatis, 1975). These measures were chosen based on their brevity and ease of administration as well as their reliability and validity in prior research.
Results
A 4 × 2 RM MANOVA did not find a significant interaction effect or a significant main effect for type of intervention. Significant univariate main effects for time were obtained for both primary measures of pain severity, F(1,152) = 5.02, p = 0.03, n2 = .03,and pain interference, F(1,152) = 7.75, p = .01, n2 = .05. In addition, significant main effects for time were noted for secondary outcome measures of illness-focused coping, F(1,152) = 4.58, p = .03, n2 = .03, global distress, F(1,152) = 16.57, p < .001, n2 = .10, and catastrophizing, F(1,152) = 18.98, p < .001, n2 = .11. There was no significant main effect for time found for wellness-focused coping, F(1,152) = 104.19, p = .27, or disability, F(1,152) = 1.01, p = .32 (see Table 2). These findings largely replicate those from a previous study (Cosio, 2015), though the significant effects in pain severity are unique to this study.
Conclusions
Participation in both groups did not produce significantly different pain-related outcomes than participation in just one group. These findings reinforce common factors theory in psychotherapy and provide insight into treatment dosage for patients with chronic pain. Considering that outcomes are similar regardless of which modality of treatment is received, providers can encourage patient collaboration in establishing a treatment plan and help them select an intervention that is most in line with their goals and values. At sites where both treatments are available, though patients may elect to receive both treatments based on personal preference, this approach may only benefit them in the sense of increasing patient-provider alliance. As treatment for chronic pain emphasizes the importance for patients of assuming an active self-management approach to their healthcare, providers should be judicious when helping patients select interventions that will be most likely to facilitate this goal as opposed to encouraging dependence on treatment.
17 The Effect of Covid-19 on the opioid epidemic: a retrospective review investigating the changes in opioid consumption in chronic pain patients unable to undergo their interventional pain procedure during the Covid-19 pandemic
David Kima,b, Seth Whitea,b, Nelson Nwannunua,b and Shantha Ganesanb
aState University of New York Downstate Medical Center, Brooklyn, NY, USA; bNYC Health + Hospitals/Kings County Hospital Center, Brooklyn, NY, USA
Purpose
The opioid epidemic is a serious national crisis that has detrimental impacts on both public health, and social and economic welfare. Therefore, any efforts to combat the opioid epidemic, including minimizing or weaning opioid prescriptions, and using other modes of analgesia when possible are undeniably necessary in this day and age. With the onset of Covid-19 pandemic, healthcare providers abruptly changed their care delivery. In-person clinic visits were changed to telemedicine, and elective cases were canceled. Due to a growing concern that chronic pain patients may have limited resources from this unprecedented time of social and economic shutdown, organizations such as American Medical Association and Drug Enforcement Administration have supported implementing measures to ensure these patients achieve adequate pain control by improving access to pain medications, but at the cost of reducing barriers and restrictions to controlled substances. Some of these policies include allowing all ‘authorized practitioners’ to prescribe controlled substances via telemedicine without first conducting an in-person examination, and removing existing barriers for patients, which includes dose, quantity, refill restrictions on controlled substances. In addition, FDA has advised patients stating the use of NSAIDs could worsen coronavirus disease.
Given the cancellation of elective interventional pain management procedures, relaxed regulations on controlled substances, and cautioned use of NSAIDs during the Covid-19 pandemic, it is reasonable to suspect a dramatic increase in opioid prescription during this time. However, to my understanding, there are no reports measuring the rate of opioid prescriptions during the pandemic although there has been numerous reports of increased rates of opioid-overdose related cases when compared to previous years.
Our study will focus on the change in opioid consumption in chronic pain patients who were unable to undergo their interventional pain procedure during the Covid-19 pandemic. By demonstrating whether or not there has been a significant increase in opioid consumption in this patient population, we can justify the efficacy of these procedures and the necessity of these elective procedures to be allowed to be performed during future pandemics.
Methods
Our study will take place at King’s County Hospital Center. It will be a retrospective study looking into the medical charts of chronic pain patients who had a scheduled interventional pain procedure to be performed in the OR, from March 1, 2020 to May 30, 2020. EPIC and QuadraMed are the EMR systems that will be used to collect data. Subjects will be classified into groups based on their canceled interventional pain procedure. For each patient, the number of opioid(s), frequency, dose, and duration of each opioid prescribed will be obtained from the visits just prior and after the notification of the canceled procedure. The secondary outcome will determine if there are any co-variates (age, gender, race/ethnicity, and number of procedures received in the past) associated with an increase in opioid consumption.
Results
This study anticipates including a total of about 100 subjects. These subjects will be further divided into their respective planned interventional pain procedures including: epidural steroid injections, facet joint injections, trigger point injections, sympathetic blocks, and radiofrequency nerve ablations. In each group, the change in opioid consumption will be quantified by calculating the change in MME. Data will be further stratified by covariates.
Conclusions
If the results do show a statistically significant increase in opioid consumption with the cancellation of interventional pain procedures, then this may justify that these procedures should be allowed to be performed during a future pandemic and to think twice before canceling all elective procedures.
18 Complex regional pain syndrome treated with combined stellate ganglion and axillary approach brachial plexus blocks – a case series
Davood Tarzi, Tadeh Setaghian and Eduard Vaynberg
Boston Medical Center – Department of Anesthesiology & Perioperative Medicine, Boston, MA, USA
Purpose
Complex regional pain syndrome (CRPS) is a taxonomic system representing two types of neuropathy. Type I CRPS represents regional sympathetic dystrophies in individuals with no proof of nerve damage. Type II CRPS represents those neuropathies in patients who have nerve damage, also termed causalgia. CRPS presents most commonly in middle-aged women with traumatic upper extremity injuries, though it can present in various ways in both children and adults of both sexes. Spontaneous CRPS is less common, though it is also possible.
CRPS is most commonly associated with a constant and severe burning-like pain located at or near the affected limb, which is out of proportion to the initial injury or event. As the condition progresses, additional symptoms may include the spread of pain to surrounding areas, fluctuation in pain sensation, fluctuation in temperature, swelling, sweating, limb weakness or tremors, as well as changes in growth of hair, skin, and nails. Unfortunately, there is currently no specific test to confirm the diagnosis of CRPS.
Chronic regional pain syndrome treatment is individualized to each patient based on his or her unique clinical presentation. Options include physical and occupational therapies, neuropathic and anti-inflammatory medications, as well as, interventional procedures, such as, nerve blocks and spinal cord stimulators. No treatment proves superior than another and some individuals may require treatments of varying frequency and modality. Based on current studies, most individuals who are diagnosed with CRPS see significant clinical improvement within the first year. Though, this is not guaranteed as the condition is highly variable and may persist despite treatment.
The purpose of this case series is to identify and follow two unique cases of CRPS. This allows us to track the progression of the disease and symptoms in tandem with varying treatment modalities. In particular, these patients required escalating care, and both combinations of stellate ganglion blocks and somatic nervous system blockade with reported improvement in pain relief. More studies are needed on the treatment options of CRPS including those exploring the viability of combined sympathetic and somatic nervous systems blockade.
Methods
Two patients identified to have chronic regional pain syndrome type I were followed in clinic over the course of one and five years, respectively. During clinic visits patients underwent routine physical examinations and were asked questions detailing the development and improvement of their symptoms. When appropriate, medical therapies were adjusted as needed.
Prior to any procedures, patients were informed of the risks and benefits in being treated with multi-modal therapies, including stellate ganglion and brachial plexus blocks. For the stellate ganglion block, patients were placed supine. The neck was sterilely prepped and draped. Under fluoroscopic guidance, a 25-gauge needle was advanced to the anterior border of C6 vertebra. Aspiration was negative confirmed with contrast AP lateral view and no intravascular intrathecal uptake was ensured. Patients were injected with a varying formulation of dexamethasone, 0.5% bupivacaine, and 1.5% lidocaine with epinephrine. After that, needle was removed.
For the axillary approach brachial plexus block, the axilla was sterilely prepped and draped in usual axillary approach and using a nerve stimulator the brachial plexus was located with a hand twitch. Once patient twitch persisted at appropriate voltage and aspiration was confirmed negative a formulation of 0.5% Marcaine, 1.5% lidocaine with epinephrine and dexamethasone was injected in divided doses. Needles were then removed, the area cleaned, and Band-Aid applied. Patients followed up at varying intervals as dependent on personal schedules, symptomatic improvement, and the outbreak of COVID-19.
Results
A 23-year-old femalewith Ehlers-Danlos and multiple joint dislocations requiring a total of 20 surgeries including, bilateral di-rotational osteotomies, open-reduction-internal-fixation-left-knee-surgery, and hardware removals presented with sensations of temperature change, skin color changes (purple), and hypersensitivity to light touch in her right leg one year after her surgery in 2013 with resolution in 2015, and reappearance in 2017 in the left leg. She was diagnosed with CRPS-I, and she failed therapeutic measures with physical therapy, medical management, and multiple lumbar plexus blocks. In August 2019, a spinal-cord-stimulator provided adequate relief, but symptoms spread to her left-upper extremity. In September 2019, a left stellate ganglion block provided symptomatic relief for 1-week. She then underwent combined stellate ganglion and axillary brachial plexus blocks withcomplete resolution with slow recurrence after one week. The blocks were repeated with diminishing efficacy three weeks later with return of lower extremity symptoms.At two-week follow-up another set of blocks was performed and her spinal cord stimulator was reprogrammed with symptomatic improvement lasting three weeks. She then underwent a cervical spinal cord stimulator trial and presented two weeks later with CRPS-like symptoms in her right upper extremity. Combined blocks were performed for her right upper extremity to slow progression of CRPS. In April 2020, patient reported spread of CRPS to right leg and both upper extremities, and she underwent right lumbar sympathetic, stellate ganglion, and brachial plexus blocks with symptomatic improvement. The patient continues to be followed.
A 31-year-old female with thoracic outlet syndrome status-post left first-rib removal and veno-lysis in February 2002, presented with worsening left-sided neck and upper-extremity pain, weakness, temperature-changes, and numbness for three months in July 2015. She was diagnosed with CRPS-I in her left upper extremity after failing therapy with a chiropractor, heat and cold, multiple physical therapy regimens, and medical management. She subsequently underwent and experienced good relief with a spinal cord stimulator and periodic brachial plexus and stellate ganglion blocks. She weaned off hydromorphone over the course of several months following several surgeries excising scar tissues developing around the original insult. Her other medical therapies included clonidine, occasional cyclobenzaprine, duloxetine, nortriptyline, and etodolac. Almost six months after her initial combination blocks, the patient underwent a repeat combination block in January 2020 with subsequent manageable pain control with spinal cord stimulator and adjustments to medical management. She eventually weaned off nortriptyline in May 2020. The patient continues to be followed.
Conclusions
Finding an algorithmic approach to treating chronic regional pain syndrome remains elusive. The complex nature of these cases require a multi-modal approach that should address both symptomatic improvement, as well as, restoration of function. Exercise and physical therapies act as foundational treatments to improve motion and strength of involved extremities.Pharmacological intervention provides pain relief to facilitate improvement in functionality. In our cases, various medications were used at varying time periods throughout treatment with fluctuating efficacy. Among the medications employed for our patients were, NSAIDs, steroids, opioids, tri-cyclic antidepressants, alpha-2-antagonists, serotonin-norepinephrine reuptake inhibitors, muscle relaxants, anti-convulsants, and anti-arrhythmics. Failure to achieve symptomatic improvement with these therapies inspires the pursuit of alternative options. In our patients, we achieved significant symptomatic improvement with spinal cord stimulation. Furthermore, where spinal cord stimulation failed, we achieved symptomatic relief with combined stellate ganglion and axillary approach brachial plexus blocks, albeit with significantly different temporal efficacy. These blocks aimed at treating the sympathetic and somatic components of the symptoms of our patients. Further case reports outlining treatment methods and course of disease may help elucidate important clues that may help in understanding the pathophysiology of CRPS and improvement in its treatment.
19 Consensus Recommendations on Dosing and Administration of Medical Cannabis to Treat Chronic Pain: Results of a Modified Delphi Process
Arun Bhaskara, Alan Bellb, Michael Boivinc, Wellington Briquesd, Matthew Browne,f, Hance Clarkeg, Claude Cyrh, Elon Eisenbergi, Ricardo Ferreira de Oliveira Silvaj, Eva Frohlichk, Peter Georgiusl, Malcolm Hoggm, Tina Ingrid Horstedn, Caroline A. MacCallumo, Kirsten R. Müller-Vahlp, Colleen O’Connellq, Robert Sealeyr, Marc Seibolts, Aaron Sihotat, Brennan K. Smithu, Dustin Sulakv, Antonio Viganow and Dwight E. Moulinx
aPain Management Center, Imperial College Healthcare NHS Trust, London, United Kingdom; bDepartment of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada; cCommPharm Consulting, Barrie, Ontario, Canada; dCanopy Growth Corp, São Paulo, Brazil; eDepartment of Pain Medicine, The Royal Marsden Hospital, London, United Kingdom; fThe Institute of Cancer Research, London, United Kingdom; gDepartment of Anesthesia and Pain Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; hDepartment of Family Medicine, McGill University, Montreal, Quebec, Canada; iInstitute of Pain Medicine, Rambam Health Care Campus, The Technion, Israel Institute of Technology, Haifa, Israel; jDirector at Vertebralis Spine Center, Rio de Janeiro, Brazil; kDepartment of Anesthesiology and Pain Management, Helen Joseph Hospital, Johannesburg, South Africa; lPain Rehab, Suite 4 Noosa Central, 6 Bottlebrush Avenue, Noosa Heads, QLD 4567, Australia; mDepartment of Anesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Australia; nRheumatology, Danish Hospital for Rheumatic Diseases, Gråsten, Denmark; oFaculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; pHannover Medical School, Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover, Germany; qDepartment of Physical Medicine and Rehabilitation, Stan Cassidy Center for Rehabilitation, Fredericton, New Brunswick, Canada; rCannabinoid Medicine Specialist, Victoria, British Columbia, Canada; sAlgesiologikum – Centers for Pain Medicine, Day Clinic for Pain Medicine, Munich, Germany; tThe University of British Columbia, Faculty of Pharmaceutical Sciences, Vancouver, British Columbia, Canada; uCTC Communications, Medical Division, Mississauga, Ontario, Canada; vIntegr8 Health, Falmouth, Maine, USA; wDepartment of Oncology, McGill University, Montreal, Ontario, Canada; xDepartments of Clinical Neurological Sciences and Oncology, Earl Russell Chair in Pain Medicine, Western University, London, Ontario, Canada
Purpose
Chronic pain affects close to two billion people worldwide and is associated with impairment in physical and emotional function, reduced participation in social and vocational activities, and lower perceived quality of life.
Medical cannabis has been used to treat chronic pain for centuries. Patient-reported data across numerous geographies indicates that chronic pain management is one of the most common reasons for medical cannabis use. In patients with chronic pain, medical cannabis treatment has been associated with an improvement in pain-related outcomes, increased quality of life, improved function, and a reduced requirement for opioid analgesia.
The number of countries in which medical cannabis use is approved has increased in recent years. Additionally, the World Health Organization has moved to consider a rescheduling of cannabis in the international drug control framework to a less stringent schedule.
Despite the storied history and increased global use of medical cannabis, systematic reviews and meta-analyses examining cannabinoids for treatment of chronic pain have reported low to moderate levels of evidence to support the use of cannabinoids for chronic pain. As a result of this evidence gap, there are limited scientific data to guide dosing and administration of medical cannabis in clinical practice.
To bridge the gap between a lack of evidence and increased use of medical cannabis, we have conducted a modified Delphi process with 20 medical cannabis leaders across nine countries to develop consensus-based recommendations for the safe and effective use of medical cannabis to treat chronic pain.
Methods
We conducted a multi-stage modified Delphi process. An initial clinical practice survey was sent out to a 20-member global task force to gain an understanding of how patients are being treated with medical cannabis across different countries. A draft of consensus questions was developed and reviewed twice by the 9-member scientific committee before being sent out to all task force members for two rounds of pre-voting.A threshold of ≥75% agreement was predetermined for declaring consensus.Following the pre-voting rounds, two virtual meetings were held to vote on the remaining key questions.
Results
There was consensus that medical cannabismay be considered for patients experiencing neuropathic, inflammatory, nociplastic, and mixed pain. Three treatment protocols were developed and categorized as: Routine, Conservative, and Rapid. The clinician and patient may choose to move between the protocols as necessary. Oral administration with oil or capsules was found to be the recommended administration format. If breakthrough pain management is necessary, dried flower vaporization was the found to be the recommended mode of administration.
The routine stream is designed for the majority of patients with chronic pain. The recommendations included:Initiate on CBD-predominant variety at a dose of 5 mg CBD twice daily. Titrate the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day clinicians may consider adding THC at 2.5 mg and titrate by 2.5 mg every 2 to 7 days until a maximum daily dose of 40 mg/day of THC. When up-titrating either cannabinoid, the total daily dose can be divided in 2–4 administrations.
The conservative protocol is recommended for patients who may be more sensitive to medical cannabis effects and who would prefer to prioritize safety. Clinically frail patients, the elderly, those with complex comorbidities, polypharmacy, and/or mental health disorders, may also be appropriate for the conservative approach. The recommendations included:Initiate on CBD-predominant variety at a dose of 5 mg once daily. Titrate the CBD-predominant dose by 10 mg every 2 to 3 days until the patient reaches their goals, or up to 40 mg/day. At a CBD-predominant dose of 40 mg/day clinicians may consider adding THC at 1 mg/day and titrate by 1 mg every 7 days until a maximum daily dose of 40 mg/day of THC.
The rapid stream was designed for individuals who require more rapid titration or earlier initiation of THC such as patients with severe pain or functional impairment, or cannabis experienced patients. The recommendations included:Initiate on a balanced THC:CBD variety at 2.5–5 mg of each cannabinoid once or twice daily. Titrate by 2.5–5 mg of each cannabinoid every 2 to 3 days until the patient reaches his/her goals or to a maximum THC dose of 40 mg/day.
Conclusions
Our modified Delphi process lead by experts in the field of medical cannabis/cannabinoid medicine resulted in the development of three protocols for the dosing and administration of medical cannabis to treat chronic pain. These results are intended to provide clinicians with safe and effective medical cannabis prescribing protocols and may be of great utility should medical cannabis be included in a patient’s treatment regimen. It is important to note that every patient is different and medical cannabis treatment, like most other therapies, should be individualized to the patient. Shared treatment decision-making with the patient is important and establishing treatment goals during the initial medical consultation may enhance patient outcomes and adherence to medical cannabis treatment. Future randomized control trials examining the safety and efficacy of medical cannabis compared against current standards of care will be required to elucidate if the developed protocols result in improved patient outcomes. The recommendations provided will be updated as new clinical trial evidence becomes available to inform on the type of dosing and mode of administration of medical cannabis for the treatment of chronic pain.
20 10 kHz Spinal Cord Stimulation for Treatment of Painful Diabetic Neuropathy – A Multicenter Randomized Controlled Trial
Erika Petersena, Thomas Staussb, James Scowcroft3, Elizabeth Brooksd, Judith Whitee, Shawn Sillsf, Kasra Amirdelfang, Maged Guirguish, Jijun Xui, Cong Yuj, Ali Nairizik, Denis Pattersonk, Vincent Galanl, Richard Bundschum, Neel Mehtan, Dawood Sayedo, Shivanand Ladp, David DiBenedettoq, Khalid Sethir, Paul Wus, Charles Argofft, Christian Nasri, Rod Tayloru, Jeyakumar Subbaroyand, Bradford Glinerd, David Carawayd and Nagy Mekhaili
aUniversity of Arkansas for Medical Sciences, Little Rock, USA; bAdvanced Pain Management, Greenfield, USA; cPain Management Associates, Lee’s Summit, USA; dNevro Corp., Redwood City, USA; eAES Compass Orlando, Orlando, USA; fTouchstone Interventional Pain Center, Medford, USA; gIPM Medical Group, Walnut Creek, USA; hOchsner Health System, New Orleans, USA; iCleveland Clinic, Cleveland, USA; jSwedish Medical Center, Seattle, USA; kNevada Advanced Pain Specialists, Reno, USA; lPain Care, Stockbridge, USA; mCoastal Orthopedics and Sports Medicine, Bradenton, USA; nWeill Cornell Medical College, New York, USA; oUniversity of Kansas Medical Center, Kansas City, USA; pDuke University, Durham, USA; qBoston PainCare, Waltham, USA; rUnited Health Services, Johnson City, USA; sHoly Cross Hospital, Fort Lauderdale, USA; tAlbany Medical Center, Albany, USA; uUniversity of Glasgow, Glasgow, United Kingdom
Purpose
The Centers for Disease Control and Prevention (CDC) estimates there are 34.2 million persons with diabetes and 88.0 million with prediabetes in the US.1 Approximately 20% will develop painful diabetic neuropathy (PDN),2 a chronic pain condition significantly impacting health-related quality of life. Neither pharmacological treatments nor low-frequency spinal cord stimulation (SCS) provides long-term relief for many of these patients;3−6 however, preliminary data suggest 10 kHz SCS relieves pain and improves sensory deficits.7
Methods
A prospective, multicenter, randomized controlled trial (SENZA-PDN) with 216 subjects assigned 1:1 to 10 kHz SCS (Nevro Corp.) combined with conventional medical management (CMM) or CMM alone. Key inclusion criteria: PDN symptoms present for ≥12 months that are refractory to medications, lower limb pain ≥ 5 cm (on 0–10 cm visual analog scale [VAS]), and appropriate candidate for SCS. Key exclusion criteria: hemoglobin A1c > 10%, daily opioid dosage > 120 mg morphine equivalents, and upper limb pain ≥ 3 cm. Outcomes include pain, neurological function, health-related quality of life, sleep, satisfaction, and cost-effectiveness. Follow-up will last 24 months.
Results
Screening 430 candidates resulted in 113 subjects randomized to 10 kHz SCS+CMM and 103 to CMM alone. Treatment arms were well matched across a variety of baseline characteristics, including hemoglobin A1c, and duration of diabetes and peripheral neuropathy. There were no reported study-related adverse events (AEs) for the CMM group and 16 study-related AEs reported in the 10 kHz SCS+CMM group up to 3 months. There were 2 procedure-related infections in the 10 kHz SCS+CMM group, representing a 1.8% infection rate.
Intention-to-treat analysis revealed 5% CMM and 79% 10 kHz SCS+CMM subjects met the primary endpoint (p < 0.001). Lower limb pain scores (mean ± SEM) in the CMM group were 7.0 ± 0.2 cm at baseline and 6.5 ± 0.2 cm at 3-month follow-up. In the 10 kHz SCS+CMM group, lower limb pain scores were 7.6 ± 0.2 cm at baseline and 1.7 ± 0.2 cm at 3 months. Analysis of the per-protocol population revealed 7% of the CMM group experienced pain relief ≥ 50% versus 89% of the 10 kHz SCS+CMM group. Investigator-assessed sensory improvements were observed in 7% of the CMM group, while 72% of the 10 kHz SCS+CMM group had such improvement compared to baseline. Similar differences between the treatment groups were observed across several quality of life and functional measures.
Conclusions
The SENZA-PDN study is the largest RCT to date of SCS management of PDN patients and will help inform the place of 10 kHz SCS in the PDN treatment continuum. The primary endpoint was met with a significant proportion of subjects responding to 10 kHz SCS. These early results are encouraging for PDN patients with symptoms refractory to conventional care.
21 Assessment of Students’ Knowledge, Skills and Attitudes after Comprehensive Pain Assessment Training
Heather Cooka, Karen Kaiserb, Kathryn Walkerc and Mary Lynn McPhersona
aUniversity of Maryland School of Pharmacy, Baltimore, Maryland, USA; bUniversity of Maryland Capitol Region Health, Baltimore, Maryland, USA; cMedstar Health, Baltimore, Maryland, USA
Purpose
A comprehensive pain assessment is the first step in safe and effective pain management. Multiple pain assessment tools are used across different health care settings and patient populations. Clinicians must be adequately trained to use various strategies and measures to optimally treat pain and improve patient outcomes. However, there is no gold standard method for the implementation of pain education. Few studies have explored pain assessment education using a variety of strategies and measures in both verbal and nonverbal patients. This can be especially challenging when teaching in an online environment. In this retrospective cohort study, students previously enrolled in University of Maryland Baltimore’s Doctor of Pharmacy (PharmD) program and Master of Science (MS) in Palliative Care program completed an 11-step multidimensional pain assessment training as part of an online pain management course. The program combined multimodal techniques to engage students through sequential worksheets, video lectures and video vignettes of standardized patients. It taught students the PQRSTA mnemonic to assess pain for verbal patients and the Pain Assessment in Advanced Dementia Scale (PAINAD) and Checklist of Nonverbal Pain Indicators (CNPI) tools to assess pain for nonverbal patients. The purpose of this study was to compare and assess the change in knowledge, attitudes and self-perceived skills regarding pain assessment in verbal and nonverbal patients before and after the training.
Methods
Students completed a pre- and post-training survey which measured self-perceived skills and attitudes surrounding pain management. The pre- and post-training survey was divided into 2 parts. Part 1 asked questions related to utilization, components and interpretation of pain measures. Part 2 of the survey asked students to rate their level of agreement on statements related to the relevance and generalizability of pain assessment strategies and measures in routine clinical practice. Additionally, students completed a series of worksheets based on the PQRSTA, PAINAD and CNPI tools to develop their knowledge of pain assessment while progressing through the videos within the training. For the steps involving pain assessment in a verbal patient, worksheets were scored based on the students’ ability to correctly identify components of the PQRSTA strategy included in the video vignette. For the steps involving pain assessment in a nonverbal patient, worksheets were scored based on students’ ability to correctly determine the numerical answer as compared to the expert defined score. The number of correct answers for each worksheet and the pain scores on the PAINAD and CNPI were recorded. Data were excluded if the worksheet was incomplete or the student did not follow the directions (e.g., provided text explanations, not scores on the PAINAD and CNPI). Wilcoxon signed-rank test and independent t-test were used to detect differences between worksheets and the pre and post survey. Attitudes and skills of pre- and post-survey were assigned to a Likert scale and analyzed using Fischer’s exact test. For change in knowledge, one-sample Wilcoxon signed-rank test was used to compare students’ answers with the expert defined score for the worksheets.
Results
One-hundred eighty-two students were included in the study. Data were collected from two sections of the Palliative Care Imperative (PharmD) course during Sep 2018- Sep 2019 (a total of 55 PharmD students). Data were also collected from six sections of the Symptom Management in Advanced Illness (MS in Palliative Care) during Jan 2018- Mar 2019 (a total of 127 interdisciplinary students). Disciplines included doctor of pharmacy students (35%), nurses (24%), physicians (11%), pharmacists (8%), social workers (5%), advanced practice nurses (4%), chaplains (3%), and other clinical and non-clinical professions.
Analysis of the survey indicated no change in attitudes in part 1 of the survey, as all components were rated as important both before and after training. For part 2 of the survey, there was a statistically significant increase in favor of using pain assessment strategies and measures for 11/13 (85%) statements indicating an improvement in attitudes.
Results showed a statistically significant improvement in 9/13 (69%) questions related to self-perceived skills in part 1 of the survey. Part 2 of the survey showed a statistically significant improvement in 11/11 (100%) statements related to self-perceived skills.
Regarding change in knowledge, congregate data showed that students could more accurately identify components of PQRSTA strategy included in the video of the verbal patient (p = 0.0028) and assess pain during movement in a nonverbal patient using the CNPI (p = 0.033) after completion of the training. A subgroup analysis comparing PharmD vs MS students showed that the MS students significantly improved in identifying the components of PQRSTA strategy included in the video of the verbal patient (p = 0.0056). PharmD students were able to more accurately assess pain during movement in a nonverbal patient using the CNPI (p = 0.026). An additional subgroup analysis removed all PharmD students’ data and divided participants into team body (physicians, pharmacists, advanced practice nurses, nurses) vs team soul (chaplains, social workers, all other disciplines). Team body improved in identifying the components of PQRSTA strategy included in the video of the verbal patient (p = 0.012), though the effect was small (Cohen’s d = 0.29). Other than these specific findings, data did not support an overall increase in accuracy of scoring or change in knowledge using PQRSTA, PAINAD or CNPI.
Conclusions
This study demonstrates that pain assessment training via video vignettes is an effective way to increase attitudes and self-perceived skills, but not consistently improve knowledge. Future pain assessment programs or research should consider training using only one non-verbal pain measure to minimize confusion. Integrating real-time feedback throughout the training may potentially improve students’ knowledge. An additional learning tactic may include incorporating bedside assessments to gain practical, real-world experience. Lastly, programs may consider adding refresher courses to reinforce concepts after completion of the program.
22 Efficacy and safety of NTM-006 in a randomized, double-blind, placebo- and active-controlled trial in moderate to severe pain after third molar extraction. Meaningful and sustained analgesia over 24 h demonstrated for a single dose (1000 mg) of NTM-006, an NCE with a novel non-opioid/non-NSAID mechanism of action
Ilona Steigerwalda, Joseph Pergolizzia,b and Charles Argoffc
aNeumentum, Inc., Palo Alto, CA, USA; bNEMA Research, Inc., Naples, FL, USA; cAlbany Medical Center – Department of Neurology, Albany, NY, USA
Purpose
NTM-006 (formerly JNJ-10,450,232) was discovered as part of a research program to identify a novel analgesic with an enhanced safety and efficacy profile vs. acetaminophen. Despite structural similarity to acetaminophen (APAP), it is notably different with respect to overall in-vitro and in-vivo pharmacologic profile, metabolism and pharmacokinetics, and the targeted lack of acetaminophen-induced hepatotoxicity. It is also targeted to positively differ from other classes of analgesics/co-analgesics like opioids, NSAIDs, cannabinoids and gabapentinoids with their shortfalls (i.e., gastrointestinal, cardiovascular, respiratory, CNS, renal safety or abuse potential). In preclinical models, NTM-006 exhibited clear antinociceptive and antipyretic effects but little inhibition of ligand binding in a panel of receptor, enzyme, ion-channel, and neurotransmitter transporters, except for a concentration-related inhibition of radio-labeled ligand at the human adenosine A3 receptor, at concentrations attained in the brain following administration of an active in vivo dose (data on file).
The development program comprised two phase 1 studies with NTM-006 apart from the reported phase 2a study: In a first-in-human double-blind study exploring SD and MD kinetics, NTM-006 administered up to 6000 mg as a single dose and up to 2500 mg twice daily (5000 mg/day) for eight days was well tolerated by 102 healthy male subjects (Gelotte et al, TBC).
An open-label, multiple-dose, safety, and pharmacokinetics study assessed the tolerability of NTM-006 under a 10 days MD treatment regimen (500 mg bid) in male and female volunteers (Vakil et al, TBC)
Since the original target profile for NTM-006 was as an OTC analgesic with APAP as a comparator, dose strengths selected for the reported phase 2a study (ie 250 mg and 1000 mg) were targeted to assess the potentially lowest and comparably effective single doses of NTM-006 vs .1000 mg APAP (relating to the maximum daily dose of APAP of 4000 mg).The current development of NTM-006 as a prescription analgesic for moderate to severe acute and chronic pain indications (including neuropathic pain) aims to explore a wider dose range and more potent comparators from other classes of analgesics including opioids and gabapentinoids.
NTM-006 was licensed to Neumentum, Inc. in October. 2019, for further development.
Methods
This was a single-center, randomized, double-blind, placebo- and active-controlled, parallel group study to evaluate the efficacy, safety and pharmacokinetic profile of a single dose of NTM-006, over a 24-hour on-site period in moderate to severe pain after third molar extractions in up to 280 male subjects.
Extraction of a minimum of three third-molars was required:
Mandibular extractions without a trauma rating of ‘severe’ (on a scale of mild, moderate, severe) including a) Two full or partial bony impactions or b) One full bony impaction in combination with a partial bony or soft tissue impaction.
Maxillary third molar extraction regardless of impaction level
Subjects meeting criteria (post-surgical pain of moderate or severe intensity on the 4-point categorical pain scale, and at least a score of 5 on the 11-point [0–10] pain intensity numerical rating scale [PI-NRS] at baseline within 4.5 hours after the last surgical stitch) were randomized 1:1:1:1 to four treatment groups: NTM-006 250 mg, NTM-006 1000 mg, acetaminophen 1000 mg, or placebo.
Efficacy Endpoints:
Primary: Analgesic efficacy 0–6 h after dosing using the time-weighted sum of pain intensity difference (SPID 0–6).
Secondary/Tertiary
· Pain intensity difference from baseline (PID) scores and pain relief (PAR) scores at each time point
· Duration of pain relief after dosing (time to rescue medication)
Pain intensity/pain relief were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, hourly up to 12, 16, 24 hours post-dose and at time of first rescue medication.
· Subject Global Evaluation
· Time-weighted SPID/TOTPAR at 0–4, 0–8, 0–12, 0–24 hours
· Times to confirmed first perceptible and meaningful pain relief (2-stopwatch technique)
· Amount of rescue medication (oral ibuprofen) at all evaluation time intervals.
Safety:Assessed by results from ECGs, vital signs, clinical laboratory, additional hepatic aminotransferase/bilirubin measurements and subject-reported adverse events.
A follow-up phone call was scheduled within 7 days after surgery.
Pharmacokineticsamples were taken linked to population pharmacokinetic model development and analysis.
Statistical Methods:A sample size of 66 subjects by treatment group was needed to detect a treatment difference at an alpha level of 0.05 (two-sided) with approximately 90% power, assuming an effect size of 0.57 for SPID 0–6.
Results
Population/Demographics
Overall, 269 subjects were randomized to IMP: 66 (NTM-006 1000 mg), 69 (NTM-006 250 mg), 67 (acetaminophen 1000 mg), and 67 (placebo).
Three subjects withdrew from the study, one for personal reasons, two for AEs.
Demographic/baseline characteristics were comparable among treatment groups: All male, average age 19.1 years, 251 (93.3%) Caucasian.
At baseline, 51.3% (138/269) reported severe pain (mean PI-NRS score of 7.6).
Efficacy
Primary efficacy endpoint: SPID 0–6 was significantly greater (p < 0.001) for subjects treated with 1000 mg NTM-006 (20.56) and acetaminophen 1000 mg (20.75) but not 250 mg NTM-006 (8.95) when compared with placebo (4.37).
Secondary endpoints: statistically significantly greater PID and PAR scores were observed for both 1000 mg NTM-006 and acetaminophen compared to placebo beginning at 45 min and 30 min, respectively, while continuing through 24 h on a stable level for NTM-006 and only 7 h for acetaminophen.
Accordingly, for both SPID 0–12 and 0–24, 1000 mg NTM-006 had statistically significantly greater scores than 1000 mg acetaminophen while SPID 0–4 and 0–8 were similar between these treatment groups (and also TOTPAR for these periods.)
The median time to first perceptible pain relief was 45.2 and 28.3 minutes for the 1000 mg NTM-006 and acetaminophen groups, respectively;
Over the 24 h study period, less subjects treated with NTM-006 1000 mg rescued (45.45%) compared with those treated with NTM-006 250 mg (73.53%), acetaminophen (72.73%), or placebo (71.86%).
The median time to rescue was not estimable for the NTM-006 1000 mg group, since fewer than 50% of subjects rescued. It was 109.0/129.0/468.5 minutes for placebo/NTM-006 250 mg/acetaminophen groups, statistically significant vs placebo for NTM-006 1000 mg and acetaminophen (p ≤ 0.042) and for NTM-006 1000 mg vs. acetaminophen (p</ = 0.006)
Safety
Overall, 13.4% of subjects reported AEs with similar incidences among treatment groups: 7 (10.6%) – 1000 mg NTM-006, 7 (10.1%) – 250 mg NTM-006, 10 (14.9%) – acetaminophen, and 12 (17.9%) placebo. No serious AEs or deaths were reported. Two subjects withdrew from the study due to AEs (one with pyrexia under placebo and one NTM-006 250 mg-treated subject with nausea, dizziness, and headache exacerbation, not rated as related to IMP). The most common AE was increased bilirubin reported by 5.9% of subjects. All AEs were of mild or moderate intensity with the exception of one case of syncope considered severe, not related to IMP (placebo). There were no clinically relevant differences among groups for vital signs and ECGs.
Conclusions
NTM-006, an analgesic NCE with a novel mechanism of action (non-opioid, non-NSAID) provided sustained pain relief throughout a 24 h time interval in moderate to severe pain following third molar extraction with a single oral dose of 1000 mg. It exerted significantlysuperior efficacy over 1000 mg of acetaminophen after 7 h and decreased use of rescue medication over the observation period.NTM-006 appeared overall safe and well-tolerated.
The natural properties of NTM-006 with sustained efficacy may qualify it further as an important asset for the treatment of chronic in addition to acute pain. The full analgesic potential of NTM-006 has yet to be explored, in more severe pain conditions, at different doses, vs. opioids or gabapentinoids in chronic and neuropathic pain. Being devoid of opioid-related side effects (CNS, GI, respiratory), apparent abuse potential as well as potentially serious NSAID-related side effects (GI, cardiovascular, renal) and considering a favorable metabolic profile, NTM-006 may work as a monotherapy and also become a suitable combination partner in multimodal analgesic regimens.
These opportunities will be explored during the continued development of NTM-006 in moderate to severe acute and chronic pain indications including musculoskeletal and neuropathic pain.
23 Symptomatically severe secondary fibromyalgia, tertiary fibromyalgia, therapeutic clinical resistance & PTSD
James Figueroa
Harrington Memorial Hospital, Southbridge, MA, USA; UMass, Memorial Healthcare Systems, Clinton Hospital, Clinton, MA, USA
Purpose
There exists a symptomatically severe form of secondary fibromyalgia (SF) that I found to be present in all patients referred to me with musculoskeletal pain who also had ‘post traumatic stress disorder’(PTSD).
These patient’s SF shared certain common clinical features with PTSD:
1. ) sleep disturbance
2. ) musculoskeletal pain
3. ) mood disturbance (anxiety and/or depression).
Given the severity of the SF, treatment using conventional fibromyalgia medications tended not to be effective (ie. an NSAID plus a tricyclic or an FDA approved drug). SF, I found, will respond to a combination of tramadol, tizanidine, tapentadol and modafinil which I described in my abstracts at PAINWeek 2015 & 2017. If SF is ignored and/or not successfully treated, it can influence the primary disease, PTSD – SF appears to aggravate those clinical features shared with the primary disease thus resulting in ‘therapeutic clinical resistance’, which will symptomatically worsen the PTSD as well as contribute to prolonging it.
Correctly recognizing SF and not casually disregarding it is critical and will allow for more effective psychiatric treatment and permit an improved outcome for the PTSD. My treatment method seeksto modulate tender point pain and augment restorative sleep.
Methods
Initially I do screening bloodwork for fibromyalgia – ESR, CBC, chem-profile, uric acid, TSH, rheumatoid factor, ANA, and any other historically relevant testing, i.e. thyroid autoantibodies, Lyme disease testing etc. Search for sources of chronic ongoing pain that would corrupt sleep – such as obesity with pes planus and associated chronically painful bursitis (anserine, trochanteric), tarsal sinus syndrome and SI joint strain, etc.
My treatment method evolved over a decade and a half with national and international presentations/publications, including the NIH. These are the dosing schedules described in my 2015 & 2017 PAINWeek abstracts:
A combination of tramadol 50–100 mg TID and tizanidine capsules 4–8 mg QHS. The tender point exam is repeated at each visit documenting any physical manifestation of improvement. The patient needs to achieve at least 6 hours of uninterrupted sleep, feeling rested on awakening. Non PTSD patients typically respond to the aforementioned, PTSD patients do not. Occasionally I use the FIQR, to assess for benefit. For PTSD patients, I add tapentadol 50 mg PO QHS for 2 nights, observe if benefit is achieved, if not increase the dose to 100 mg – subsequent dose increases only as appropriate if necessary. Finally if mental clarity remains an issue, the addition of modafinil 100–200 mg PO QAM can be beneficial. Also the patient should be assessed for ulterior sources of pain at each visit – bursitis, tendonitis, plantar fasciitis etc., which could ulteriorly disrupt sleep. At each visit it is necessary to discuss with the patient as to whether or not additional stressors physical or emotional have arisen, offering appropriate treatment suggestions that facilitate their resolution. Sustained collaboration with a psychiatrist is a must.
I established the patients fibromyalgia diagnosis – consistent with 1990 ACR fibromyalgia diagnostic criteria. As a rheumatology fellow, I participated in the 1990 ACR Northeast Fibromyalgia Diagnostic Criteria Committee proceedings and was chosen as 1 of 8 physicians to teach the fibrositic tender point exam. I provided all patient follow up visits in this series.
PTSD was diagnostically established by independent, community psychiatric services – at that time DSM -IV diagnostic criteria was used.
Results
In 40 out of 41(97.5%) consecutive patients there was observed a gradual symptomatic improvement in the SF. Subsequently there followed a global, symptomatic improvement in the features of the PTSD.
Initially as these 40 patients experienced a near total reduction in their tender point pain contemporaneously their ability to sleep improved to approximately 6 hours/night without awakenings and feeling less fatigue on awakening. They became better able to memorize, concentrate, accomplish mental and physical tasks – they expressed less sadness/anxiety. Subsequently they were able to improve numerous personal issues – impaired personal relationships, hold a job or return to some form of educational activity. None of this reportedly was possible prior to my treatment. Notably, there were no suicides. Only 1 patient claimed no benefit.
Conclusions
Currently there appears to be no appreciation of the clinical concept of SF nor that of the associated ‘therapeutic resistance’. An accurate diagnosis and treatment of SF lends to a successful psychiatric treatment of PTSD. This awareness can enable a single physician, working with a community psychiatrist, the possibility to render effective therapy for an otherwise therapeutically resistant PTSD patient. In those patients I treated, the previous lack of appreciation of the proper diagnosis/treatment of SF resulted in the prolongation of the PTSD for years/decades. Of interest, in this series of patients, SF tends to be a constant feature of PTSD. SF tends not to respond to traditional fibrositic therapy and can act to both aggravate and prolong the PTSD. SF can respond to the 4 medications I described but not to traditional fibrositic therapeutics. I would therefore suggest that it would be of significant clinical benefit if SF associated with PTSD was designated with a separate identity such that a better diagnostic awareness and that more effective therapy is required. I would therefore submit the name of ‘tertiary fibromyalgia’ for that the recalcitrant form of SF associated with PTSD.
24 Clinically meaningful results with voltaren® arthritis pain (Topical diclofenac sodium 1%), a non-surgical treatment option for osteoarthritis of the knee
Jeffrey Fudina, Gilbert Shangab and Richard Petruschkeb
aRemitigate Therapeutics, Delmar, NY, USA; bGSK Consumer Healthcare, Warren, NJ, USA
Purpose
With osteoarthritis (OA) affecting 1 in 7 adults living in the United States, it is crucial to find effective and well tolerated ways to manage pain associated with OA.1,2 Topical nonsteroidal anti-inflammatory drugs (NSAIDs) act locally and are strongly recommended for patients with knee osteoarthritis as a pharmacologic approach to pain management.3 Further, it is recommended that topical NSAIDs be used prior to the use of oral NSAIDs to minimize systemic exposure.3 Diclofenac sodium gel 1% (DSG 1%), a topical NSAID, provided better pain relief than vehicle alone for patients with knee OA in 3 clinical trials.4−6 A post-hoc meta-analysis of these trials was conducted to determine the percentage of patients achieving a minimal clinically important improvement (MCII) in pain and other symptoms of OA to gain insight into the clinical impact of the benefits of DSG 1% for patients. The MCII is defined as the smallest improvement in symptoms viewed as clinically meaningful for patients.7 Thus, the MCII represents an improvement of relevance in a clinical trial and the minimal meaningful change at an individual level.
Methods
All 3 studies pooled for this analysis wereconducted in US centers, and were 12-week, prospective, randomized, double-blind, multi-center, parallel group studies with similar endpoints comparing DSG 1% with vehicle in subjects with knee OA.4−6 An MCII responder was defined as a patient who had an improvement of ≥20% relative to baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function, or stiffness or in pain on movement (POM), a definition consistent with theOsteoarthritis Research Society International(OARSI)-Outcome Measures in Rheumatology(OMERACT) responder criteria.8,9 The percentage of MCII responders was analyzed using the Cochran-Mantel-Haenszel test stratified by study. Time to MCII response was analyzed using the log-rank test stratified by study. Heterogeneity of treatment effect across studies was investigated using the Breslow-Day test.
Results
The pooled analysis included 719 DSG 1%-treated patients and 705 vehicle only-treated patients (ITT Efficacy population, N = 1426). By Week 1, there was a significant difference in the number of subjects reaching MCII for all endpoints (DSG 1% vs vehicle): WOMAC pain, 67.9% vs 57.2% (P < .0001); POM, 65.8% vs 51.6% (P < .0001); WOMAC function, 58.3% vs 47.8% (P < .0001); WOMAC stiffness, 64.5% vs 53.3% (P < .0001). Mean time to first MCII was shorter with DSG 1% vs vehicle for all measures: WOMAC pain, 25.5 vs 32.2 days (P < .0001); POM, 26.6 vs 34.9 days (P < .0001); WOMAC function, 30.5 vs 38.8 days (P < .0001); WOMAC stiffness, 28.0 vs 35.2 days (P = .0001). Significant differences in the percentage of patients with an MCII between groups were still evident at Week 12 for all endpoints.No evidence of heterogeneity of treatment effect was found between studies, indicating the results from this meta-analysis were robust and reliable.
Conclusions
MCII signifies an improvement of relevance in a clinical trial by taking the patient’s perception into account. As applied to this post-hoc meta-analysis, the majority of DSG 1%-treated patients achieved clinically meaningful relief from OA pain and other symptoms within 1 week. Responses sustained over 12 weeks further suggested the clinical relevance of the meaningful patient benefits observed in the 3 original studies. Topical DSG 1%, which limits systemic NSAID exposure, was also generally well-tolerated in the original studies. It provides patients with an alternative to oral NSAIDs.4,10
1. Arthritis Foundation. Arthritis By the Numbers. 2019; v3; 4100.17.10445.
2. US Bone and Joint Initiative. The Burden of Musculoskeletal Diseases in the United States (BMUS). https://www.boneandjointburden.org/fourth¬edition/iiib10/osteoarthritis. Accessed 6/30/20
3. Kolasinski et al. Arthritis Rheum.2020;72(2):220–33.
4. Baraf et al. Phys Sportsmed.2010;38(2):19–28.
5. Barthel et al. Semin Arthritis Rheum. 2009;39(3):203–12.
6. Data on File. GSK Consumer Health, Inc.
7. Kvien et al. Ann Rheum Dis. 2007;66 Suppl 3:iii40-1.
8. Tubach et al. Arthritis Care Res (Hoboken). 2012;64(11):1699–707.
9. McAlindon et al. Osteoarthritis Cartilage.2014;22(3):363–88.
10. Kienzler, Gold, Nollevaux. J Clin Pharmacol. 2010;50(1):50–61.
25 Reductions in pain, increased function, and improved quality of life after use of a topical analgesic pain relieving patch: results from the RELIEF study
Jeffrey Gudina, Derek Dietzeb and Peter Hurwitzc
aEnglewood Hospital, Englewood, NJ, USA; bMetrics for Learning, Queen Creek, AZ, USA; cClarity Science LLC, Narragansett, RI, USA
Purpose
Pain is the most common reason patients consult primary care providers. There is evidence that relying on opioids for pain control may lead to worse clinical outcomes. There are also well-known risks associated with oral medications including opioids, NSAIDs and even acetaminophen. Therefore, alternative evidence-based therapies are needed to support an opioid-sparing multimodal approach to pain management. Numerous guidelines including CDC recommend topical analgesics for a variety of painful conditions. They can play an important role in the management of acute and chronic, mild to moderate pain syndromes including soft tissue injuries, musculoskeletal pain, and various neuropathic pain disorders.
Evaluation of effective treatments for pain relief, including topical analgesic patches, is critical to identify safer opioid-sparing approaches to pain treatment. We therefore undertook an IRB-approved observational study to evaluate patients with mild to moderate acute and chronic pain. The purpose of the study was to evaluate perceptions of pain treatment and associated symptoms with the use of a topical pain-relieving patch (Salonpas Pain Relieving Patch) via subject and clinician reported surveys over the course of two weeks.
Methods
This IRB-approved study evaluated the efficacy of a topical pain-relieving patch containing methyl salicylate 10%, menthol 6% and camphor 3.1% in reducing Brief Pain Inventory (BPI) scores in patients experiencing mild/moderate acute pain. 152 adult patients (100 females, 52 males) with acute arthritic, neurologic or musculoskeletal pain received patches for 14 days. A control group of an additional 47 patients (27 females, 20 males) did not receive a patch. After 14 days, 34 Patients from the control group crossed over to treatment and were treated with the pain patch, increasing the total treatment group to 186 patients. Surveys were administered to all patients at baseline and 14 days to assess changes in pain severity and interference by BPI Short Form. Changes in oral pain medication use, side effects and satisfaction with patch use were also assessed.
Results
Treatment group paired data were collected in both active and control groups. Over 14 days, treatment group (n = 186) mean BPI Severity score decreased 49% (4.9 to 2.5/10;P < .001, 95% CI [2.09, 2.58]) and mean BPI Interference score decreased 58% (4.3 to 1.8/10;P < .001, 95% CI [2.33, 2.82]). Decreases in mean BPI Severity and Interference scores were significantly less in the control group (13%, 15% respectively). Treatment group patients showed a 36.4% decrease in usage of other oral pain medications. No side effects of treatment were reported. At day 14, 61% of the treatment group were using concomitant oral pain medications ‘a lot less’ then when they started using the patch. 90% were very/extremely satisfied with the patch. Results also showed Quality of Life (QoL) improvements with the treatment group.
Conclusions
Results indicate that this topical analgesic pain-relieving patch can reduce BPI pain severity and interference scores and related pain for adult patients with arthritic, neurologic and musculoskeletal pain and should be considered first-line therapy for patients experiencing mild to moderate pain.
26 The crisis within the crisis: fentanyl abuse and COVID-19
Jeffrey Gudina, Justin Nilesb, Jeff Radcliffb and Harvey Kaufmanb
aRutgers NJ Medical School, Newark, NJ, USA; bQuest Diagnostics, Secaucus, NJ, USA
Purpose
More than 750,000 people in the U.S. have died from a drug overdose since 1999, with nearly 400,000 deaths involving prescribed or illicit opioids. The 12-month rolling count of provisional overdose deaths associated with non-methadone synthetic opioids (likely fentanyl) has increased every month since January 2015 (5,766) through December 2019 (36,509). Although overall overdose deaths began to plateau or even decrease in recent years, the COVID-19 pandemic appears to be reversing these trends. To help prevent the spread of COVID-19, there was widespread adoption of virtual telemedicine visits and recommendations to postpone preventive medical services during stay-in-place orders. During that time, overdose-related deaths progressively increased, especially related to illicit synthetic opioids and heroin: nationally, suspected overdose submissions to the Overdose Mapping Application Program (ODMAP) in 2020 rose by 18% in March, 29% in April, and 42% in May, based on a 30-day rolling mean comparison to these months in 2019. Tracking national laboratory drug monitoring data can help yield early signals to our country’s reemerging drug abuse problem. To better understand how the drug epidemic is interacting with the COVID-19 pandemic, we investigated changes in the results of prescription drug monitoring fentanyl tests after large-scale implementation of stay-at-home measures in the United States during the COVID-19 pandemic.
Methods
We analyzed changes in prescription urine drug monitoring testing patterns and results at a national reference clinical laboratory, comparing data for fentanyl positivity obtained before and during the pandemic. De-identified results from all medMATCH specimens with clinician-provided prescribed drug information performed from January 1, 2019 through May 16, 2020 were selected for potential inclusion. medMATCH reports indicated whether the prescribed drug(s) specified by the ordering provider, or other drugs, were detected in a specimen. The pre-pandemic ‘baseline’ time period included specimens tested January 1, 2019, through March 14, 2020. The ‘during COVID-19’ time period included specimens tested March 15 to May 16, 2020; the week starting March 15 was the first full week after a national emergency was declared on March 13.
Positivity for fentanyl was defined as the presence of a positive result for any fentanyl product not listed as prescribed by the ordering clinician. Analysis of all UDT results included either presumptive immunoassay screening tests, with confirmation of positive results by quantitative definitive mass spectrometry, or tests performed directly by quantitative definitive mass spectrometry. Quantitative confirmation analysis was performed to rule out false-positive presumptive screening results.
Results
Clinical drug monitoring declined rapidly during stay-at-home orders, starting the week beginning March 15, 2020. There were 310,709 specimens in this study. The weekly clinical drug monitoring test volume fell approximately 71% from the mean during the baseline period to the trough (the week starting April 5), and then rose in subsequent weeks. Test volume in the final week of the study had doubled from the trough but was still 42% below the mean baseline weekly test volume.
During COVID-19, positivity for non-prescribed fentanyl increased (by 35%; P < 0.01) compared to the baseline period. Significant increases in non-prescribed fentanyl positivity were demonstrated for males, females, and all age groups 25 years and above. The increase in non-prescribed fentanyl positivity during COVID-19 remained significant in a multivariable model controlling for various independent risk factors (AOR 1.55, 95% CI 1.43–1.67). Specimens from substance use disorder (SUD) facilities (adjusted odds ratio [AOR] 4.90, 95% CI 4.55–5.27) and medication assisted treatment (MAT) patients (AOR 4.33, 95% CI 4.08–4.59) had the strongest associations with non-prescribed fentanyl positivity. The combination of non-prescribed fentanyl with other drugs also increased during the pandemic. Specifically, positivity for non-prescribed fentanyl increased by 89% among patients positive for amphetamines (P < 0.01); 48% for benzodiazepines (P < 0.01); 34% for cocaine (P < 0.01); 39% for opiates (P < 0.01); and 4% for heroin.
Conclusions
Our findings indicate that not only has drug testing decreased since the start of the pandemic, non-prescribed positivity for fentanyl, one of the drugs most responsible for the overdose epidemic in recent years, has greatly increased. Perhaps even more troubling, the data suggest that use of fentanyl drug combinations is increasing as well. The COVID-19 pandemic appears to have created an environment of increased risk for those prone to drug misuse, which includes increased stress, isolation, removal of access to treatment, and a decrease in clinical drug monitoring. In these times of crises, we must maintain extra vigilance and not lose ground in our continued efforts to combat our nation’s drug abuse crisis. We need to continue employ opioid abuse risk management strategies including drug testing, the only objective measure of what drugs or substances a patient is taking.
27 Effects of induction and maintenance ketamine infusions in CRPS patients
Jennifer Dinga, Faye Weinsteinb, Doerte U. Junghaenelc, Steven Richeimerb and Talin Evazyand
aKeck School of Medicine, Los Angeles, CA, USA; bKeck Medical Center of University of Southern California, Department of Anesthesiology and Psychiatry, Los Angeles, CA, USA; cUniversity of Southern California Dornsife Center for Self-Report Science & Center for Economic and Social Research, Los Angeles, CA, USA; dKeck Medical Center of University of Southern California, Department of Anesthesiology, Los Angeles, CA, USA
Purpose
Complex regional pain syndrome (CRPS) is a painful and debilitating condition characterized by abnormal sensory, motor, sudomotor, vasomotor, edema, and/or trophic findings seemingly disproportionate in time or degree to an initial trauma. Many patients progress from an acute phase of peripheral nervous system inflammation to a chronic phase of central nervous sensitization involving activation and proliferation of NMDA receptors. Ketamine is an NMDA-receptor antagonist that has been used with increasing frequency over the past two decades to treat chronic pain. There is moderate evidence supporting serial ketamine infusions at a sub-anesthetic level over a 10-day induction period to provide reductions in pain that persist for up to 12 weeks in CRPS patients. The goal of this study was to observe and evaluate the results of induction and maintenance ketamine infusions on the treatment and longer-term symptom experience of complex regional pain syndrome in an outpatient clinic.
Methods
This is a single-center, retrospective, observational chart review. Patients were included if they had a primary diagnosis of CRPS, received induction and maintenance ketamine infusions between July 2014 and December 2019, and completed a CRPS Severity Score (CSS) survey at the first infusion visit and at a subsequent visit about one year later. The CSS17 is a quantitative index with three parts: a subjective patient-reported section indicating presence or absence of common signs and symptoms of CRPS; an observed provider-reported section indicating presence or absence assessment of CRPS signs; patient-reported lowest, highest, and average pain scores over the last 7 days. We used descriptive analysis to evaluate all information in this study.
Results
16 patients met inclusion criteria and were included in this study. Patients received an average of 79 (SD = 42.05, range = 34 to 188) infusions over the course of about one year. 11 patients (69%) rated their pain intensity as low to moderate at baseline and 5 patients (31%) rated their pain as high at baseline; there was no significant difference between the two groups in the number of infusions received. Number of ketamine infusions was positively correlated with reduction in CSS scores from baseline to one-year follow-up. Specifically, the more ketamine infusions a patient received, the greater the reduction in CSS observed scores (r = 0.543, p = 0.03) and in CSS total scores (r = 0.646, p = 0.007), indicating an improvement in CRPS signs. Although the pattern of results was similar for subjective, patient-perceived changes in CSS scores (r = 0.314), the results were not significant. Similarly, although more ketamine infusions were associated with less average pain at follow-up (r = −0.311) and a greater reduction in average pain from baseline to follow-up (r = 0.344), these findings did not reach statistical significance.
Conclusions
The results of this pilot study suggest that long-term ketamine infusions at sub-anesthetic doses given over a one-year period significantly reduced observed CRPS signs but did not significantly change subjective symptoms or pain. Further studies are needed with a larger sample size to determine whether ketamine is an effective therapeutic modality for CRPS considering the significant financial and time costs associated with the treatment and the need to achieve patient-perceived improvement in symptom experience.
28 The use of external neuromodulation in a community chronic pain service
Johanna Theron
Kent Community Health NHS Foundation Trust, Maidstone, Kent, United Kingdom
Purpose
To assess whether External Neuromodulation (ENM) offers a demonstrable and unique benefit for patients with difficult-to-treat neurological conditions, in order to inform the decision whether to continue offering the modality to such patients as part of their treatment pathway in a multi-disciplinary community-based chronic pain management service.
Background
ENM is a noninvasive modality that could be utilized for patients with localized neuropathic pain. An external nerve mapping probe connected to an impulse generator, of the type commonly used in operating theater for nerve blocks, is used to apply electrical stimulation to the nerves covering distribution of the painful area, or targeting the epicenter of the painful area directly. The amplitude is adjusted to achieve acceptable paresthesia in the painful area. Three to 4 treatments are considered a trial.
If helpful, then onwards referral for percutaneous or implanted stimulation could be considered. Those with medium term relief may choose to have repeated treatments instead. Self-treatment is an option but few patients can afford the cost of the machines. Repeated treatment sessions cost clinician time and running self-treatment clinics in-house is a logistical burden for a multi-site service. There was concern that neither option would lead to long term self-management or discharge.
Methods
Retrospective data interrogation was used. With the help of the health trust’s IT department, the last 50 patients who received the treatment prior to July 2018 were identified in the electronic data system. A clinician then reviewed each patient’s notes, making use of Excel spreadsheets. Data extracted included all treatment specifics and outcomes recorded on the service’s ENM treatment template, whether patients also had TENS and/or acupuncture for the same problem, and whether medication was reduced following treatment. Contemporaneous clinic notes, discharge letters and discharge coding were reviewed too.
Results
A wide variety of causes for neuropathic symptoms were represented, with the largest group being lumbosacral radiculopathy (18%).
Just under half (48%) of patients had some positive response. Of those, 42% had 100% pain relief following a treatment, 75% had more than 50% pain relief. Trial period pain relief lasted from 12–24 hours, to more than one week after a single treatment. 42% of those with a positive response could reduce their pain medication. Seven of the responders continued to self-treatment, of which 3 patients bought the machines and 4 others could maintain the effect with another electronic device. Three patients were referred onwards for spinal cord stimulation.
24% had 4 treatments and 44% had more than 4 treatments by a clinician, averaging 7.6 treatments. Those having less than 4 treatments, were where the treatment caused pain or no effect.
Acupuncture and TENS each had similar overall success rates where trialed. However, individual patients did not respond in the same way to the different modalities and they thus did not seem interchangeable.
Two thirds of patients were discharged with completed pathways following ENM.
Conclusions
Team discussion considered an overall independently beneficial modality. The service would continue providing ENM in a protocol similar to how we offer acupuncture (goal-orientated and a fixed maximum number). Alternative lower cost stimulators would also be explored.
29 A retrospective comparison of postpartum oral morphine equivalent (OME) requirements in pregnant individuals treated with buprenorphine or methadone for opioid use disorder (OUD)
Mariya Kotova, Lyndsey Chitty, Kristen Vanderhoef, Joseph Cammilleri, Jeniffer DelaCruz and Brittany Johnson
UF Health Jacksonville, Jacksonville, FL, USA
Purpose
Buprenorphine and methadone are currently recommended as medication-assisted therapy for pregnant individuals with opioid use disorder (OUD). Limited evidence exists surrounding peripartum use of methadone and buprenorphine on postpartum oral morphine equivalent (OME) requirements.
Methods
This single-center, retrospective, IRB-approved review included pregnant individuals with OUD receiving oral buprenorphine or oral methadone upon admission who delivered a neonate from October 2015 to August 2019. The primary outcome was to determine the impact of buprenorphine and methadone on 48-hour postpartum OME requirements. Secondary outcomes included 48-hour postpartum pain scores, and Neonatal Abstinence Syndrome (NAS) outcomes.
Results
There were 53 pregnant individuals on buprenorphine (median dose 16 mg) and 212 on methadone (median dose 95 mg). Buprenorphine-maintained pregnant individuals, compared to methadone, had lower 48-hour postpartum total median OME requirements (12.5 vs 68.9, p = 0.001) and 48-hour postpartum median pain scores (3.0 vs 4.0, p = 0.003). Both methadone and buprenorphine patients undergoing vaginal delivery required lower OME (5.5 vs 34.2, p = 0.009) than patients undergoing cesarean delivery (138.5 vs 128.9, p > 0.05). Neonates born to buprenorphine mothers had higher birthweight (3090 mg vs 2830 mg, p = 0.03) and head circumference (33.9 cm vs 33.0 cm, p = 0.002) compared to methadone-maintained mothers. NAS incidence and duration of treatment was similar amongst both groups – (23 vs 90 neonates, p = 0.90) and (11.8 days vs 15.0 days, p = 0.12), respectively.
Conclusions
Pregnant individuals on buprenorphine for OUD may require lower postpartum opioids, especially following vaginal delivery, compared to methadone-maintained pregnant individuals. Neonates with in-utero exposure to buprenorphine may have higher head circumference and birthweight.
30 Nonpharmaceutical fentanyl analogs in the illicit drug trade: where are we heading?
Joseph Pergolizzia, Robert Raffab,c, Peter Magnussond,e, Jo Ann LeQuanga, Charles Wollmutha, Robert Taylora, Rohit Nalamasuf, Robert Coluccig, Kailyn Mitchella, Maninder Choprah, Giustino Varrassii and Frank Brevej
aNEMA Research, Inc., Naples, FL, USA; bTemple University School of Pharmacy, Philadelphia, PA, USA; cUniversity of Arizona College of Pharmacy, Tucson, AZ, USA; dUppsala University, Gavleborg, Gavle, Sweden; eKarolinska Institutet, Stockholm, Sweden; fUniversity of Nebraska Medical Center, Omaha, NE, USA; gColucci and Associates, Newton, CT, USA; hDecision Alternatives, LLC, Frederick, MD, USA; iPaolo Procacci Foundation, Rome, Italy; jTemple University Department of Pharmacy Practice, Philadelphia, PA, USA
Purpose
In 2018, 67% of all opioid-related deaths in the United States traced back to synthetic opioids, mainly fentanyl.1 Synthetic drugs are made for any number of reasons, including superior pharmacological attributes, but drugs with abuse potential such as opioids may result in synthetic products to appeal specifically to the illicit market. So ubiquitous are illicit fentanyl analogs that they are collectively termed ‘nonpharmaceutical fentanyl’ (NPF) to distinguish them from pharmaceutical-grade fentanyl, a powerful anesthetic and analgesic drug. NPFs were first observed in street drugs from 2005 to 2007, all traced back to a single clandestine laboratory; when the lab was closed in 2007, NPF trade stopped, but not until more than 1,000 NPF-related deaths had occurred.2 Since that time, more clandestine laboratories have opened and NPF reappeared in the street-drug stream in 2010 as an additive to heroin and cocaine, as a product on its own, or as the active ingredient in counterfeit opioid analgesic tablets or counterfeit benzodiazepines. While the first fentanyl analog (AMF) was produced by Janssen Pharmaceutica in the 1960s, today numerous fentanyl products are on the market or being developed. The original analogs of fentanyl were developed for specific uses, such as veterinary medicine for large animals (carfentanil).3
Each novel agent represents a major new challenge to drug enforcement as the specific formulation may not be known to medicine or law enforcement, may not technically be illegal or scheduled as a controlled substance, and may not be testable using available testing options. The purpose of our review was to revisit an important topic relevant to the opioid overdose crisis.
Methods
This was a literature review using the PubMed database of medical journals using the search terms ‘fentanyl analogs’ and ‘illicit fentanyl.’ We also searched the websites of the Centers for Disease Control and Prevention, the Drug Enforcement Agency, and the Food and Drug Administration. A narrative review of the materials with an emphasis on newest findings was presented.
Results
Fentanyl has been and remains the driver of the increased opioid-overdose mortality in the United States and it appears that fentanyl is likewise driving such mortality trends in Europe as well.4 While fentanyl-related overdose deaths are increasing markedly, it is likely they are under-reported as many NPF drugs go undetected either because there is no currently available test for them or the decedent has taken other drugs which are blamed for the death. Street drug users are often unaware that the drugs sold to them as cocaine, heroin, benzodiazepines, or prescription oxycodone tablets are laced with NPF.
NPF is not used to ‘cut’ or ‘stretch’ drugs like heroin, because NPF is highly potent, in fact, often many times more potent than morphine. Instead, heroin may first be cut with some other substance such as sugar, baking soda, or even laundry detergent or rat poison to increase the quantity.5 Small amounts of fentanyl are added to boost the psychoactive effects. The economics behind this are clear: it can cost upward of $65,000 to produce one kilogram of heroin but just $3,500 for the same amount of fentanyl.6,7 The intrusion of fentanyl into the nation’s heroin supply tends to be geographically limited to areas east of the Mississippi River where white heroin is more common than the West Coast’s black tar heroin.8
Fentanyl analogs have a unique chemical composition and as new agents, they are not necessarily controlled substances. As early as 1986, Congress passed the U.S. Federal Analogue Act, an addendum to the U.S. controlled Substances Act which allowed for ‘substantially similar’ Schedule I and II agents to be treated as such, but this has not always been well supported in the courts. 3
As a result, analog NPF drugs can enter the street drug trade with a quasi-legal status. They are not detectable until they are identified and appropriate tests are developed. Furthermore, it seems that novel fentanyl analogs are produced very rapidly, introduced into the street trade, and then supplanted by newer products once the older versions are discovered.
Conclusions
The rapid development and proliferation of highly potent and dangerous fentanyl analogs poses an ongoing international public health crisis. Improved methods are needed to rapidly identify these agents and develop tests for them. Better education is needed for harm reduction among those who use illicit drugs, as NPF can be added to products without the knowledge or consent of the buyer. More readily available and accessible testing is needed so that the opioid-overdose mortality attributable to NPF analogs can be better quantified and, in that way, more effectively addressed.
31 What is the role of buprenorphine in the era of abuse deterrent formulations?
Joseph Pergolizzia, Peter Magnussonb,c, Jo Ann LeQuanga, Charles Wollmutha, Robert Taylora, Rohit Nalamasud, Kailyn Mitchella, Frank Brevee and Giustino Varrassif
aNEMA Research, Inc., Naples, FL, USA; bKarolinska Institutet, Stockholm, Sweden; cUppssala University, Gavle, Sweden; dUniversity of Nebraska Medical Center, Omaha, NE, USA; eTemple University School of Pharmacy, Philadelphia, PA, USA; fPaolo Procacci Foundation, Rome, Italy
Purpose
The role of opioids in chronic pain management is controversial. Opioids are associated with a number of potentially treatment-limiting adverse effects, such as opioid-induced constipation and somnolence; can cause dependence; and may lead to use disorder in certain individuals. Nevertheless, they are effective analgesics. To help reduce opioid use disorder and related morbidity and mortality, abuse-deterrent formulations (ADFs) have been introduced to the market along with other measures to reduce opioid use disorder while still providing analgesic benefits. The Food and Drug Administration (FDA) has specifically advocated for the development of ADFs and issued guidance to pharmaceutical companies.1,2 Yet ADFs have failed to gain widespread acceptance, possibly because they are more expensive than generic opioid analgesic and are not always reimbursed.
Buprenorphine was developed in 1966 in England by John Lewis a chemist working for Reckitt & Colman, a home products company. During the 1980s, buprenorphine was offered as a safe, effective pharmacologic therapy for heroin addiction, and the injectable and the sublingual form of the drug were widely used for analgesic purposes by the mid-1980s. In the mid-1990s, countries started approving buprenorphine for the treatment of opioid dependence, starting with France. Subutex® and Suboxone® were approved in 2002 by the FDA for the treatment of opioid addiction. However, buprenorphine is also an effective analgesic and certain buprenorphine products have been approved for pain indications.3
In fact, the use of buprenorphine as an analgesic agent offers some interesting advantages. Unlike most strong opioids, which are Schedule II controlled substances, buprenorphine is a Schedule III agent. It has a ceiling effect for respiratory depression and is not as well ‘liked’ by people who seek the psychoactive effects of opioids as other agents, such as oxycodone or hydromorphone. Its available in a transdermal delivery system makes it relatively difficult to tamper with the drug for misuse.
The authors sought to investigate the role of buprenorphine in the context of ADFs.
Methods
This is a narrative review, so the authors searched keywords such as ‘buprenorphine chronic pain,’ ‘buprenorphine abuse’ and ‘buprenorphine abuse-deterrent formulations.’ The authors include many who have published on buprenorphine previously, and their expertise as well as clinical opinions were sought. The bibliographies of key articles were also used.
Results
There are numerous studies reporting on the analgesic effectiveness and safety of buprenorphine in the context of chronic noncancer pain. It has been effective in treating musculoskeletal pain4,5 and low back pain.6 In a four-arm multicenter study comparing morphine, transdermal fentanyl, transdermal buprenorphine, and oxycodone in 520 cancer pain patients, all agents were similarly effective in controlling pain.7 Transdermal buprenorphine was found noninferior to tramadol for postoperative pain control in spinal fusion patients8 and was likewise noninferior to co-codamol for osteoarthritis pain9 and was similarly effective to hydrocodone/acetaminophen for osteoarthritis pain management.10
Yet buprenorphine is not frequently prescribed for pain control. Its development, marketing, promotion, and the breadth of clinical experience with buprenorphine has ‘type-cast’ this agent in the role of a medication to manage opioid use disorder rather than as a pain reliever. Prescribers may be unaware that it is indicated and available for pain control and may be under the impression that in the United States they need a so-called ‘X-waiver’ for substance abuse treatment in order to prescribe buprenorphine in any context, including for pain. Buprenorphine prescribing for pain is regulated by the Drug Enforcement Agency (DEA) in the same manner as oxycodone or morphine prescribing.
An important advantage in the use of buprenorphine is that it has a proposed ceiling effect for respiratory depression but no ceiling effect for analgesia.11,12 Although buprenorphine is sometimes described as a ‘partial agonist’ of the μ-opioid receptors, it may be considered a full agonist in terms of analgesic effect.3
A further drawback to the use of buprenorphine for treating pain is that it may not be reimbursed as a first-line drug, causing prescribers to select higher-risk Schedule II substances, such as oxycodone, first. If a patient fails on these Schedule II substances, it may be permitted to have the Schedule III buprenorphine product reimbursed, but this requires the exposure of a patient to the Schedule II substance before buprenorphine can be considered.
Buprenorphine is effective in the treatment of pain and is less well ‘liked’ by those who seek the psychoactive effects of pain relievers.13 It is time to re-imagine and reevaluate buprenorphine as a pain reliever and to allow it to join the ADFs and other products that may help resist or deter opioid use disorder.
Conclusions
Buprenorphine has become so well-known and valued for its role in medication-assisted therapy for opioid use disorder that it obscures the fact that it is also a safe, effective pain reliever. Certain buprenorphine products have been approved for pain indications. The role of buprenorphine for pain may be overlooked, but could be of vital importance. As an opioid, buprenorphine is not as well ‘liked’ as other opioids by those who seeks the psychoactive effects of opioids. It has a proposed ceiling for respiratory depression and tolerability and safety profiles similar to other opioids. It is a Schedule III controlled substance, rather than Schedule II. In clinical trials, buprenorphine has been effective in managing cancer pain as well as chronic noncancer pain. As the FDA encourages the development of ADF opioid products, it is time to reevaluate buprenorphine and expand its reimbursement so that it can be more widely prescribed to appropriate pain patients.
32 Exploring the connections between sleep and cluster headache
Joseph Pergolizzia, Peter Magnussonb,c, Jo Ann LeQuanga, Charles Wollmutha, Robert Taylora, Rohit Nalamasud, Kailyn Mitchella, Frank Brevee and Giustino Varrassif
aNEMA Research, Inc., Naples, FL, USA; bUppsala University, Gavle, Sweden; cKarolinska Institutete, Stockholm, Sweden; dUniversity of Nebraska Medical Center, Omaha, NE, USA; eTemple University School of Pharmacy Practice, Philadelphia, PA, USA; fPaolo Procacci Foundation, Rome, Italy
Purpose
The International Classification of Sleep Disorders recognizes four types of headaches related to sleep: cluster headache, hypnic headache, chronic paroxysmal hemicrania, and migraine.1 The prevalence of cluster headaches is 0.1% and its etiology is unknown.2 More men than women suffer from cluster headaches and patients typically exhibit wakefulness, agitation, and a desire to pace during paroxysmal bouts which are characterized by multiple headaches that remit and recur over the course of several hours or days.3,4 Typically, a headache would last from 15 minutes to 3 hours, resolve spontaneously, and then recur, giving the condition its name of ‘cluster’ headache. Cluster attacks are excruciatingly painful and differ from other types of headache in that the pain is periorbital, unilateral, and the episodes typically involve rhinitis, drooping eyelids, and lacrimation. People experiencing a cluster headache find no relief in sleep and may even prefer to pace or stand up.
Unlike other sleep-related headaches, cluster headaches have a clear diurnal relationship (many patients arise with the headache) and seasonality, such that patients may have months of remission.5 Some patients develop chronic cluster headaches which do not have such periods of remission. Headaches in general are associated with poor quality sleep,6 but the association is quite pronounced in cluster headaches. People who suffer from any types of headache are also more likely to report symptoms associated with poor sleep, such as daytime fatigue and insomnia.7,8 It has been speculated that cluster headaches may be a manifestation of a sleep disorder or that more complex sleep-related mechanisms are involved.9
The purpose of this review is to examine the literature on cluster headaches and their relationship to sleep to present the current understanding by the medical community.
Methods
The authors searched the National Institutes of Medicine database, PubMed, for peer-reviewed medical literature on the subject by searching keywords: ‘sleep headache,’ ‘sleep-disordered headache,’ ‘sleep cluster headache,’ and ‘cluster headache.’ The articles were then evaluated to find those which offered insight into the relationship of sleep to cluster headache. In some cases, the bibliographies of relevant articles were searched for supplemental material. The result is a narrative review of the topic.
Results
Cluster headaches have three distinct pathophysiological stages: first, chronobiological aberrations impair the sympathetic nervous system.5 Induction is stage two which is promoted by persistent dysfunction of the chemoreceptors accompanied by hypoxia, which may be caused by sleep apnea, vasodilatation, or some other cause. The third and final phase occurs with the signs and symptoms of the attack, resulting in trigeminal nerve stimulation with parasympathetic response. Thus, a neurological process starts the cascade of events that triggers the vasodilatation leading to the painful headache, with vasodilatation the result rather than the cause of trigeminal activation.5
Most cluster headache patients report sleep as a headache trigger,10,11 and they usually start about 90 minutes into a sleep cycle although the connection between a cluster headache and rapid-eye-movement sleep has been speculated but never established.
Cluster headaches often occur more frequently around summer and winter solstices, and it is speculated that the natural dark/light cycle may play a role as the differences are most pronounced at these times of year.
Hypothalamic activation has been observed in brain scans of cluster headache patients during an attack.12,13 Magnetic resonance imaging has shown that cluster headache patients have asymmetry of the hypothalamus gland and these patients have more gray matter in the hypothalamus than control patients. The hypothalamus produced hypocretin (a neuropeptide) which is significantly lower in people with cluster headache than controls. Furthermore, melatonin which is produced by the pineal gland and secreted into the hypothalamus to promote sleep is not produced as much in cluster headache patients as others, particularly during attacks.14
Finally, a study of sleep found that a healthy individual rouses out of sleep 7 to 15 times per hour although sleepers are rarely aware of these momentary arousals.11 People with cluster headaches have fewer arousals during sleep, which has been suggested to be caused by reduced hypothalamic activity.
Sleep-disordered breathing has been linked to certain headaches, but may not play a role in cluster headaches.15 Apnea contributes to many forms of sleep-related headaches, but its association specifically to cluster headaches is unclear.
Most people with cluster headaches do not get adequate treatment and many are never diagnosed at all.16 In a survey, half of cluster headache patients said they would not tell their employer about their headache history for fear of losing their job.17
Conclusions
The relationship between sleep and cluster headache has been well known for decades but remains to be more fully elucidated. It is tempting to see sleep as a cluster headache trigger, but the circadian and circannual periodicity of these headaches deserves special consideration. It appears as if cluster headaches involve an intricate synchronization of multiple factors: hypothalamic function in the brain, the light/dark cycle, sleep architecture, trigeminal inflammation, and the response of the autonomic nervous system. Since many people with cluster headache report getting them in their sleep and have a headache upon arising which is not relieved with sleep, cluster headaches were thought to be a form of sleep-related headache, such as migraine. However, evidence seems to suggest that cluster headaches are more likely a brain disorder than a problem with sleep or sleep-disordered breathing.
33 Medication-assisted therapy for opioid use disorder: a review of established treatments and new directions
Rohit Nalamasua, Charles Wollmuthb, Joseph Pergolizzib, Jo Ann LeQuangb, Dean J. Marianoc, Robert Taylorb, Frank Breved, Kailyn Mitchellb, Giustino Varrassie and Peter Magnussonf,g
aUniversity of Nebraska Medical Center, Omaha, NE, USA; bNEMA Research, Inc., Naples, FL, USA; cMariano Medical Pain/Addiction Consultants, West Hartford, Connecticut, USA; dTemple University School of Pharmacy Practice, Philadelphia, PA, USA; ePaolo Procacci Foundation, Rome, Italy; fUppsala University, Gavle, Sweden; gKarolinska Institutet, Stockholm, Sweden
Purpose
Opioid use disorder (OUD) is a global public health concern associated with substantial morbidity and mortality.1 OUD places a burden on the healthcare system, legal system, economy, and society in general that is vast but difficult to assess.2 OUD exists on a spectrum and at the extreme involves compulsive use of the drug even when the user recognizes its adverse effects, neuroplastic brain changes, and intense cravings for the drug. In this extreme form, OUD can interfere with a person’s ability to hold a responsible job, participate in family life, or maintain strong positive relationships. At the other extreme, OUD may involve occasional, opportunistic misuse of the drug or occasional recreational use (‘chipping’). The brain changes associated with prolonged opioid use can alter the brain’s reward circuits and may have negative effects on executive function, reactions to stress, and self-control. While OUD is treatable and many overcome the condition, it is characterized by relapse.3
People with OUD often intersect with the healthcare system as they are susceptible not only to opioid-associated respiratory distress but infections and other conditions. They also intersect with the legal system either because they were arrested for illicit drug use or they committed unrelated crimes but happen to also use drugs. It has been estimated that in the United States, about 200,000 people with active heroin use disorder are incarcerated every year.4 Prisons are often ill-equipped to manage the complex issues of opioid rehabilitation. Likewise hospitals find treating patients with active OUD increases the complexity of care.
Medication-assisted treatment (MAT) is an approach to opioid rehabilitation that involves combining certain medications with counseling and behavioral therapy to help an individual overcome OUD. MAT may involve methadone or buprenorphine, opioid agents that help prevent withdrawal symptoms and blunt opioid cravings.5,6 Other pharmacological approaches have been proposed as well. Counseling and therapy help the individual recognize the nature of the OUD and develop coping strategies. Our purpose is to call attention to OUD and present a narrative review of current treatment options and future directions.
Methods
This is a narrative review. The authors conducted a literature search on ‘medication-assisted therapy,’ ‘medication-assisted treatment,’ ‘buprenorphine,’ ‘methadone,’ and ‘opioid use disorder.’ Several of the authors have expertise and clinical experience in the management of OUD and provided their expertise as well.
Results
In the United States, both methadone and buprenorphine, are approved for the treatment of OUD.7 These agents must be dispensed by specially trained and licensed physicians within the scope of a rehabilitation program that includes a counseling component. The main criticism of these two approaches is that they simply substitute one opioid for another. On the other hand, buprenorphine and methadone rehabilitation programs have been successful for many individuals.8
It is not clear whether methadone or buprenorphine is the preferred agent for OUD rehabilitation. A recent study of 1,267 OUD patients found methadone was associated with better retention in drug treatment programs compared to buprenorphine and buprenorphine was associated with a greater use of concomitant illicit drugs than methadone.9 The Starting Treatment with Agonist Replacement Therapies (START) study found buprenorphine and methadone similarly effective in maintenance treatment.10 Buprenorphine offers a good safety profile but its broader use is limited by the fact that physicians must have special licensure to provide buprenorphine maintenance therapy.11
Antagonist therapy involves these of a μ-opioid-receptor antagonist which competes with an opioid for the receptors. Extended-release (ER) naltrexone can be injected once a month and is thought to prevent relapse because patients are blocked from the psychoactive effects of opioids. Antagonist therapy requires detoxification, that is, the patient must be taken off opioids before antagonist therapy can be administered. In a study of incarcerated volunteers (n = 153) over 78 weeks, relapse to opioid addiction was lower among patients in the ER naltrexone groups and significantly fewer overdose events occurred compared to the usual-treatment group (0 vs. 7 events, respectively, p = 0.02).12
Promising new vaccines are in development which could be administered and then essentially negate the psychoactive effects of opioids.13 Novel delivery systems are being proposed such as subcutaneous depot injections of buprenorphine or subdermal implants that can facilitate treatment and promote adherence.14 Dopamine has been implicated in OUD as part of the brain’s reward circuits. In fact, molecular imaging suggests that genetic polymorphisms may be associated with particular individual vulnerabilities to OUD.15 Antagonists of the dopamine D3 receptors are being explored as a treatment strategy for OUD.16
Conclusions
OUD is a prevalent and serious condition that poses numerous challenges for safe, long-term treatment. While some patients overcome OUD by willpower or formal and informal support groups, MAT is a treatment option that may be more effective for certain patients. Unfortunately, a shortage of licensed prescribers means that not everyone who seeks MAT can get it. Antagonist therapy requires detoxification but has been shown effective. Newer strategies including a vaccine and dopamine 3 receptor antagonism are being explored as are novel delivery systems to facilitate patient adherence. There is no simple ‘one size fits all’ to opioid rehabilitation and providers must consider each patient individually. For instance, age, comorbid conditions including mental health status, severity and duration of OUD, and patient’s attitudes and objectives may all play a role in selecting the optimal course of treatment. OUD is characterized by relapse so providers and patients must be aware that the course of recovery often includes disappointing setbacks. While some have criticized MAT approaches as merely switching one substance for another, MAT often enables patients to resume relatively normal and productive lives and to pursue counseling to better understand their drug use and ways to avoid future setbacks.
34 COVID-19 and NSAIDs: knowns and unknowns
Joseph Pergolizzia, Giustino Varrassib, Peter Magnussonc,d, Jo Ann LeQuanga, Robert Taylora, Charles Wollmutha, Frank Brevee, Kailyn Mitchella, Maninder Chopraf and Paul J. Christog
aNEMA Research, Inc., Naples, FL, USA; bPaolo Procacci Foundation, Rome, Italy; cUppsala University, Gavle, Sweden; dKarolinska Institutet, Stockholm, Sweden; eTemple University School of Pharmacy Practice, Philadelphia, PA, USA; fDecision Alternatives, LLC, Frederick, MD, USA; gJohns Hopkins School of Medicine, Baltimore, Maryland, USA
Purpose
Concern about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 have been raised. The viral point of entry is the angiotensin-converting enzyme (ACE)2 receptor and it has been speculated that some NSAIDs, in particular ibuprofen, may upregulate ACE2 receptors and that NSAIDs may also have certain immunosuppressive effects. Two specific questions have been raised: do NSAIDs increase the risk of contracting COVID-19 and, in infected persons, do NSAIDs worsen outcomes? While NSAIDs represent a well-known drug class, there are considerable variations among NSAIDs, such as selective and nonselective NSAIDs. It is unknown if such differences are clinically important in COVID-19 patients. The purpose of this research is to provide an overview of what is currently known – and what is not known – about the use of NSAIDs in the setting of COVID-19.
Methods
The body of literature is large and new reports, case studies, clinical studies, and commentaries appear daily. The authors used the PubMed database of the National Institutes of Medicine to search for keywords ‘COVID’ plus ‘NSAID,’ ‘ibuprofen,’ and ‘naproxen.’ Some of our authors are frontline clinicians in and outside of the United States who brought their expertise to the discussion. Selected articles were obtained and their bibliographies searched for other relevant material. Content was synthesized but it must be noted that there are no large randomized clinical trials investigating the question of NSAIDs but there are emerging reports. Information about COVID-19 is changing rapidly, even daily. This was a qualitative narrative review. The content was reviewed, discussed among the authors, and synthesized.
Results
The inflammatory cascade or cytokine storm, known to play a role in worse outcomes in influenza,1 is associated in COVID-19 with tissue injury, morbidity, and mortality.2
In diseases associated with coronaviruses, such as Middle Eastern Respiratory Syndrome (MERS) or Severe Acute Respiratory Syndrome (SARS), the marked increase in inflammatory cytokines parallels a rapid replication of the virus resulting in lung injury and potentially life-threatening acute respiratory distress syndrome.3 Early evaluations of COVID-19 patients suggest similarly high levels of pro-inflammatory cytokines along the lines of MERS and SARS.3 As cytokine storm likely plays a major role in adverse outcomes of severely ill COVID-19 patients, the role of anti-inflammatories ranging from NSAIDs to glucocorticoids to hydroxychloroquine and others would seem beneficial in an effort to reduce inflammation before it overwhelms the body’s systems.
The role of NSAIDs in viral infections of other kinds has been controversial.4 Anti-inflammatory therapy for influenza may be associated with certain drawbacks. The use of an anti-inflammatory might potentially slow viral elimination and elevate the risk of a secondary infection. While an anti-inflammatory can reduce inflammation, it may have limited or poorly understood effect on cytokine storm, which involves multiple cytokines and complex interactions. One argument against the use of NSAIDs and also acetaminophen is that these are antipyretic drugs that may mask a rising fever associated with COVID-19 and thus delay diagnosis and rapid management of the infection.5
There is no evidence that the occasional use of an oral, over-the-counter NSAID for a few days by a person with suspected or diagnosed mild COVID-19 infection will exacerbate the infection. Second, there is no reason to think that patients taking prescribed NSAIDs for a chronic painful condition should stop taking this drug for fear it might increase their risk of contracting COVID-19 or exacerbate it if they get it.6 The confusion about NSAIDs arises mainly because prostaglandin production is complex and can both promote and inhibit inflammatory processes. As with other analgesics, there are considerations with NSAIDs which should be taken at the lowest effective doses for the shortest periods of time. The Expert Working Group of the Commission on Human Medicines in the United Kingdom has issued a statement that there is ‘currently insufficient evidence to establish a link between the use of ibuprofen and susceptible to contracting COVID-19 or the worsening of its symptoms.’7
Conclusions
To date there is no evidence in favor or disputing the use of NSAIDs in COVID-19. Indeed, any blanket ‘for’ or ‘against’ statement on this topic would not be clinically realistic or prudent.
35 Four pandemics: lessons learned, lessons lost
Joseph Pergolizzia, Jo Ann LeQuanga, Giustino Varrassib, Paul J. Christoc, Robert Taylora, Frank Breved, Maninder Choprae, Charles Wollmutha, Megan Nalamachua, Kailyn Mitchella and Peter Magnussonf,g
aNEMA Research, Inc., Naples, FL, USA; bPaolo Procacci Foundation, Rome, Italy; cJohns Hopkins University School of Medicine, Baltimore, MD, USA; dTemple University School of Pharmacy Practice, Philadelphia, PA, USA; eDecision Alternatives, LLC, Frederick, MD, USA; fUppsala University, Gavle, Sweden; gKarolinska Institutet, Stockholm, Sweden
Purpose
In the past hundred years, the world has faced four distinctly different pandemics: the Spanish flu of 1918–1919, the SARS pandemic of 2003, the H1N1 or ‘swine flu’ pandemic of 2012, and the ongoing COVID-19 pandemic. Each public health crisis exposed specific systemic shortfalls and provided public health lessons for future events. The Spanish flu revealed a nursing shortage and led to a great appreciation of nursing as a profession. SARS showed the importance of having frontline clinicians be able to work with regulators and those producing guidelines. H1N1 raised questions about the nature of a global organization such as the World Health Organization (WHO) in terms of the benefits and potential disadvantages of leading the fight against a long-term global public health threat. In the era of COVID-19, it seems apparent that we are learning about both the blessing and curse of social media. The authors did not include the Middle Eastern Respiratory Syndrome (MERS) among the pandemics although it is sometimes described as a pandemic. It began in 2014 and cases have been reported every year since then, but usually in a geographically limited area and never more than 500 per year.
Methods
This was a commentary. The authors used the PubMed database to search for keywords relating to Spanish flu, SARS, H1N1, and COVID-19 and reviewed primarily articles that discussed the management and public health ramifications of these pandemics. The information was synthesized and presented in light of what was learned in each pandemic that carried forward or failed to carry forward to aid us in future crises.
Results
Each pandemic brought to light deficiencies and shortfalls in the healthcare system and the opportunity to create better systems to manage these emerging illnesses.
Following the Spanish flu pandemic, educational pathways in the United States were set up to allow people to become licensed as a practical nurse and the clinical role of nurses was better defined.
One lesson learned in SARS was the life-saving role of extracorporeal membrane oxygenation (ECMO) for patients with severe respiratory illness. In 2007, the International Health Regulations had gone into effect, which was an official attempt to codify lessons learned from SARS in terms of connecting front-line clinicians with politicians, regulators, and other public health authorities.
The H1N1 pandemic highlighted limitations with the capabilities and authority of the WHO. While WHO has demonstrated great ability and dexterity in managing short-term health crises, the long-term management of a severe pandemic may exceed the competence and financial strength of any global organization.
COVID-19 occurred in the post-television era where most people obtain news from online platforms. On one hand, social media allowed rapid dissemination of basic strategies to prevent COVID-19, however, misleading and false information also emerged. WHO labeled it an ‘infodemic’ that paralleled the pandemic.
Conclusions
Each of these four pandemics has had a devastating effect but has also left us with lessons to learn that may blunt or even prevent future disasters. The Spanish flu exposed a shortage of trained nurses that has since been largely remedied. The SARS epidemic drove home the fact that ECMO could be lifesaving in selected cases. Guidance is often urgently needed not just from experts but from front-line clinicians. In the H1N1 pandemic, the role of WHO in pandemic care was highlighted and certain key questions emerged about how well one global organization can manage a long-term pandemic. Today, in COVID-19 the role of ‘viral’ media in the context of a viral pandemic will no doubt fuel many later studies.
36 Ibuprofen safety: a look back on 50 years
Giustino Varrassia, Joseph Pergolizzib, Rohit Nalamasuc, Jo Ann LeQuangb, Robert Coluccid, Frank Brevee, Peter Magnussonf,g, Dean Marianoh and Paul J. Christoi
aPaolo Procacci Foundation, Rome, Italy; bNEMA Research, Inc., Naples, FL, USA; cUniversity of Nebraska Medical Center, Omaha, NE, USA; dColucci & Associates, Newtown, CA, USA; eTemple University School of Pharmacy Practice, Philadelphia, PA, USA; fUniversity of Uppsala, Gavle, Sweden; gKarolinska Institutet, Stockholm, Sweden; hMariano Medical Pain/Addiction Specialists, West Hartford, CA, USA; iJohns Hopkins University School of Medicine, Baltimore, MD, USA
Purpose
Ibuprofen is nearing its golden anniversary (50 years) and remains among the most widely prescribed and frequently taken over-the-counter analgesic in the world. First developed in the United Kingdom by Boots Pure Drug Company, Limited,1 the drug evolved when scientist Stewart Adams sought to elucidate the anti-inflammatory effects of aspirin which seemed to him to be a clear advantage over acetaminophen.2 Adams and his colleague John Nicholson developed over 200 compounds and brought four to clinical trials with disappointing results. It was the fifth drug they tried that succeeded and came to market in 1969 in the United Kingdom and in 1974 in the United States.3 An anecdote told by Adams himself said that he took the first dose of the new drug himself to treat a hangover.1
Despite lengthy clinical experience with ibuprofen, new safety concerns had been raised about its role in infections4 and its safety for COVID-19 patients.5 Ibuprofen is unique in the NSAID family in that it appears to block both cyclooxygenase (COX) 1 and COX 2 enzymes. The COX enzymes synthesize prostaglandins which are associated with the inflammatory cascade. Safety concerns related to COX-1 inhibition mainly involved gastrointestinal adverse events; the introduction of selective COX-2 inhibitors or coxibs likewise raised safety concerns, in particular relating to cardiovascular events. Almost all NSAIDS may be associated with elevating blood pressure but the safety profiles of various NSAIDs are unique. Ibuprofen’s position of balance ‘middle of the road’ position as being neither strongly selective for COX-1 or COX-2 has afforded it a strong safety and tolerability profile.
The authors sought to review safety data on ibuprofen at the half-century mark and to consider the advantages and disadvantages of this versatile and popular analgesic.
Methods
Articles were obtained via PubMed search in June of 2019 through the searching various keywords. ‘Ibuprofen safety gastrointestinal’ resulted 223, ‘ibuprofen safety cardiovascular’ resulted 122, ‘ibuprofen safety renal’ resulted 111, ‘ibuprofen safety infection’ resulted 35, and ‘ibuprofen Streptococcus’ resulted 35. Bibliographies of certain articles were also searched. Cost-effectiveness studies, and non-safety aspect of analgesia studies were excluded along with studies exclusively on pediatric, geriatric, or special populations like patent ductus arteriosus patients were excluded. Non-English studies without full text translation were also excluded. Articles focusing on major safety concerns of ibuprofen were kept including meta-analyses, safety, and safety and efficacy studies. Studies published in the last ten years were emphasized. In addition, among the authors are several physicians with relevant clinical experience with analgesics whose expertise contributed to the project.
Results
Ibuprofen is an analgesic and antipyretic. Its Tmax is 1.9 ± 1.4 hours in healthy subjects with a half-life of about 2.2 ± 0.4 hours. (1.4 hours).6 In safety studies, ibuprofen was found in the Paracetamol, Aspirin, and Ibuprofen New Tolerability (PAIN) study to have similar rates of adverse events as acetaminophen (paracetamol) at doses of ≤ 1200 mg/day and significantly fewer adverse events compared to ≤ 3000 mg/day of aspirin.7,8 The PRECISION trials of osteoarthritis and rheumatoid arthritis patients found that in long-term follow-up NSAID toxicity occurred in 5.3% of ibuprofen patients compared to 4.1% of celecoxib and 4.8% of naproxen patients.9 A meta-analysis (n = 2187 patients) found that ibuprofen was associated with a numerical frequency of adverse events similar or lower than placebo patients.10 In the Ibuprofen Paracetamol Study in Osteoarthritis (IPSO), 222 patients were randomized to receive 400 mg ibuprofen three times a day or acetaminophen (paracetamol) 1000 mg three times a day; ibuprofen was the more effective pain reliever with a similar risk of gastrointestinal adverse events as paracetamol over the 14-day study.11
The association of ibuprofen to infections is complex because in some cases, it confers a benefit (cystic fibrosis) but in others, it appears to exacerbate the infection. Ibuprofen was not found to be associated with increased bleeding risk following surgery.12 Hypersensitivity reactions in various NSAIDs have been reported but are so rare there are insufficient data to compare individual agents.
Conclusions
After 50 years, new evidence continues to emerge regarding the safety profile of ibuprofen. Taken as directed in the therapeutic dose range, ibuprofen is associated with significant anti-inflammatory action, effective analgesia, and a comparatively low risk of GI, CV, renal, hepatic, or infectious side effects. Ibuprofen, with its favorable safety profile, may be considered the safest of all NSAIDs pain relievers. Risks for GI, CV, renal, and hepatic side effects are lower than other NSAIDS. Prescribers must always balance benefit against risk with any medication and NSAIDs should only be taken at the lowest effective dose for the shortest amount of time. Ibuprofen may not be appropriate for all patients, but its safety profile makes it an attractive first line for many acute and chronic pain conditions., Clinicians should evaluate the evidence and safety when making prescribing choices or recommending OTC products to their patients.
37 Clinically meaningful responses to fremanezumab in migraine patients with medication overuse and documented inadequate response to 2–4 migraine preventive medications in the randomized, placebo-controlled FOCUS study
Sait Ashinaa, Verena Ramirez Camposb, Joshua M. Cohenb, Lindsay Jankab and Egilius L.H. Spieringsc
aBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; bTeva Pharmaceuticals Industries, West Chester, PA, USA; cBoston Headache Institute, Boston PainCare, Waltham, MA, USA
Purpose
Patients who overuse acute medications for migraine generally experience a greater disease burden, including more migraine days, more severe pain intensity, and greater disability. The FOCUS study of fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with chronic migraine (CM) or episodic migraine (EM) and documented inadequate response to 2 to 4 classes of migraine preventive medications. We aimed to evaluate responder rates in a subgroup of patients with medication overuse (use of any acute medication on ≥15 days/month or use of triptans, ergots, or combination medications on ≥10 days/month) at baseline.
Methods
For 12 weeks of double-blind treatment in the randomized, double-blind, placebo-controlled period of the phase 3b FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab (months 1/2/3: 675 mg/placebo/placebo), monthly fremanezumab (months 1/2/3: 225 mg [EM],675 mg [CM]/225 mg/225 mg), or matched monthly placebo. Proportions of patients with ≥50% and ≥75% reductions from baseline in the monthly average number of migraine days at 4 weeks and during 12 weeks were compared using logistic regression.
Results
Of 838 randomized patients, 435 had medication overuse. During 12 weeks of double-blind treatment, a significantly greater proportion of patients achieved ≥50% reduction in the monthly average number of migraine days with quarterly fremanezumab (25%) and monthly fremanezumab (33%) versus placebo (7%; P ≤ 0.0001). A significantly greater proportion of patients also achieved ≥75% reduction in the monthly average number of migraine days with monthly fremanezumab (11%) versus placebo (1%; P = 0.0040) during 12 weeks of treatment; differences between quarterly fremanezumab (5%) and placebo were not statistically significant. At 4 weeks, significantly greater proportions of patients achieved ≥50% and ≥75% reduction in the monthly average number of migraine days with both fremanezumab dosing regimen versus placebo (P ≤ 0.0125).
Conclusions
In migraine patients with medication overuse and documented inadequate response to 2 to 4 classes of migraine preventive medication classes, significantly more patients treated with fremanezumab achieved ≥50% and 75% reductions in the monthly average number of migraine days versus placebo. Fremanezumab provided early and sustained clinically meaningful results in this subgroup, suggesting medication overuse is not an impediment to effective preventive treatment with this antibody.
38 Impact of fremanezumab on any acute headache medication use in migraine patients with medication overuse and documented inadequate response to 2–4 migraine preventive medication classes in the multicenter, randomized, placebo-controlled FOCUS study
Lawrence Newmana, Joshua M. Cohenb, Verena Ramirez Camposb, Lindsay Jankab and Hans-Christoph Dienerc
aDepartment of Neurology, Headache Division, NYU Langone Medical Center, New York, NY, USA; bTeva Pharmaceuticals Industries, West Chester, PA, USA; cFaculty of Medicine, University Duisburg-Essen, Essen, Germany
Purpose
Patients who overuse acute medications for migraine generally experience a greater disease burden, including more migraine days, more severe pain intensity, and greater disability. The FOCUS study of fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with either chronic migraine (CM) or episodic migraine (EM) and documented inadequate response to 2 to 4 classes of migraine preventive medication classes. Changes in use of any acute headache medication were evaluated in a subgroup of patients with medication overuse (use of any acute medication on ≥15 days/month or use of triptans, ergots, or combination medications on ≥10 days/month) at baseline.
Methods
For 12 weeks of double-blind treatment in the randomized, double-blind, placebo-controlled period of the phase 3b FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab (month 1: 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: CM, 675 mg; EM, 225 mg; months 2 and 3: 225 mg), or matched monthly placebo. Changes from baseline in the monthly average number of days with acute headache medication use at 4 and 8 weeks and during the 12 weeks after the first dose were compared using mixed-effects model for repeated measures.
Results
Of 838 randomized patients, 435 had medication overuse. Reductions from baseline in monthly average days of any acute headache medication use were significantly greater with fremanezumab versus placebo at 4 weeks (least-squares mean [standard error] change: quarterly fremanezumab, −4.2 [0.60]; monthly fremanezumab, −5.0 [0.54] vs placebo, −0.3 [0.60]; P < 0.0001) and 8 weeks (quarterly fremanezumab, −3.8 [0.70]; monthly fremanezumab, −4.9 [0.63] vs placebo, −1.1 [0.71]; P ≤ 0.0016). Reductions from baseline in monthly average days of use of any acute headache medication were also significantly greater with fremanezumab versus placebo during the 12 weeks after the first study drug dose (quarterly fremanezumab, −3.9 [0.61]; monthly fremanezumab, −4.9 [0.55] vs placebo, −0.8 [0.61]; P < 0.0001).
Conclusions
Fremanezumab provided early and consistent reductions in the use of any acute headache medication versus placebo in migraine patients with medication overuse at baseline and documented inadequate response to 2 to 4 classes of migraine preventive medications.
39 Early onset of efficacy with fremanezumab in patients with medication overuse and documented inadequate response to 2–4 classes of migraine preventive treatments: subgroup analysis of the randomized, double-blind FOCUS study
Zaza Katsaravaa, Martina Machkovab, Verena Ramirez Camposc, Joshua M. Cohenc, Lindsay Jankac and Egilius L.H. Spieringsd
aDepartment of Neurology, University of Duisburg-Essen, Essen, Germany; bCCR Czech Prague, Prague, Czech Republic; cTeva Pharmaceuticals Industries, West Chester, PA, USA; dBoston Headache Institute, Boston PainCare, Waltham, MA, USA
Purpose
The overuse of acute medications for migraine is often associated with a greater disease burden, including a greater number of migraine days, more severe pain intensity, and greater disability. The FOCUS study of fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with either chronic migraine (CM) or episodic migraine (EM) and documented inadequate response to 2 to 4 classes of migraine preventive medications. Early response was evaluated in a subgroup of patients with CM or EM and medication overuse (use of any acute medication ≥15 days/month or use of triptans, ergots, or combination medications ≥10 days/month) at baseline.
Methods
In the randomized, double-blind, placebo-controlled period of the phase 3b FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab (Month 1: 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: EM, 225 mg; CM, 675 mg; months 2 and 3: 225 mg), or matched monthly placebo for 12 weeks. At weeks 1 to 3, changes from baseline in the weekly average number of migraine days and weekly average number of headache days of at least moderate severity were evaluated using mixed-effects models for repeated measures, and responder rates (≥50% reduction in the weekly average number of migraine days) were evaluated using logistic regression.
Results
Of 838 randomized patients, 435 had medication overuse. Reductions from baseline in weekly migraine days were significantly greater with fremanezumab versus placebo by Week 1 (least-squares mean [standard error] change from baseline: quarterly fremanezumab, −0.9 [0.20]; monthly fremanezumab, −1.2 [0.18] vs placebo, −0.1 [0.21]; P ≤ 0.0018), as were reductions in weekly headache days of at least moderate severity (quarterly fremanezumab, −1.0 [0.20]; monthly fremanezumab, −1.4 [0.18] vs placebo, −0.1 [0.20]; P ≤ 0.0003). Significantly higher proportions of patients achieved ≥50% reductions in migraine days with fremanezumab versus placebo at Week 1 (quarterly fremanezumab, 39%; monthly fremanezumab, 38% vs placebo, 14%; P < 0.0001). Significant differences were maintained through Weeks 2 and 3 (all P ≤ 0.0004).
Conclusions
Both quarterly andmonthlyfremanezumab demonstrated early onset of action, with greater response rates within 1 week and significantly greater reductions in weekly migraine days and headache days as early as week 1 versus placebo, in migraine patients with medication overuse and documented inadequate response to 2 to 4 classes of migraine preventive medications.
40 Efficacy of fremanezumab in migraine patients with medication overuse and documented inadequate response to 2–4 migraine preventive medication classes: subgroup analysis of the randomized, placebo-controlled FOCUS study
Stephen Silbersteina, Joshua M. Cohenb, Verena Ramirez Camposb, Ronghua Yangb, Maja Galicc, Xiaoping Ningb and Adelene Jannd
aJefferson Headache Center, Philadelphia, PA, USA; bTeva Branded Pharmaceutical Products R&D, Inc., West Chester, PA, USA; cTeva Pharmaceuticals, Amsterdam, Netherlands; dNYU Langone Health, New York, NY, USA
Purpose
Patients who overuse acute medicationsfor migraine generally experience more migraine days, greater disability, and more severe pain intensity. The FOCUS study of fremanezumab, a fully-humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with both chronic migraine (CM) and episodic migraine (EM) and documented inadequate response to 2 to 4 classes of migraine preventive medications.This subgroup analysis of the FOCUS study evaluated the efficacy of fremanezumab in patients with baseline medication overuse (use of any acute medication on ≥15 days/month or use of triptans, ergots, or combination medications on ≥10 days/month).
Methods
In the randomized, double-blind, placebo-controlled period of the phase 3b FOCUS study, patients were randomized (1:1:1) to quarterly fremanezumab (month 1: 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: CM, 675 mg; EM, 225 mg; months 2 and 3: 225 mg), or matched monthly placebo for 12 weeks. Changes from baseline in the monthly average number of migraine days and monthly average number of headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were compared using a mixed-effect model for repeated measures.
Results
Of 838 randomized patients, 435 had baseline medication overuse. Reductions from baseline in the monthly average number of migraine days were significantly greater with quarterly fremanezumab (least-squares mean [standard error (SE)] change, −3.3 [0.61]) and monthly fremanezumab (−4.6 [0.55]) versus placebo (−0.5 [0.62]; both P ≤ 0.0001) during 12 weeks of treatment. Reductions from baseline in the monthly average number of headache days of at least moderate severity were also significantly greater with quarterly fremanezumab (least-squares mean [SE] change, −4.0 [0.61]) and monthly fremanezumab (−5.1 [0.54]) versus placebo (−0.8, [0.61]; both P < 0.0001) during 12 weeks of treatment. At 4 weeks of double-blind treatment, changes from baseline in the monthly average number of migraine days and monthly average number of headache days of at least moderate severity were also significantly greater with both dosing regimens of fremanezumab versus placebo (all P < 0.0001).
Conclusions
Quarterly and monthly fremanezumab provided early and sustained reductions in monthly migraine and monthly headache days of at least moderate severity versus placebo in migraine patients with medication overuse and documented inadequate response to 2 to 4 classes of migraine preventive medications.
41 Characterizing patients after opioid taper in a VA Medical Center
Kathryn Muzzioa, Lisa Dragica, Michael Chandlera and Jacob Paintera,b
aCentral Arkansas Veterans Healthcare System, Little Rock, AR, USA; bUniversity of Arkansas for Medical Sciences, Little Rock, AR, USA
Purpose
The purpose of this project was to identify potential areas for intervention by describing the types of follow-up care and resources utilized by patients and gain insight on current practice who are tapered to 0 morphine equivalent daily doses (MEDD) through the Pharmacy Pain E-Consult at a Veterans Healthcare System.
Methods
This project was a retrospective chart review of Veterans with non-cancer pain on chronic-opioid therapy consulted to the pharmacy e-consult service from October 1, 2017 to September 30, 2018 who were tapered to 0 MEDD. Descriptive statistics were collected one year pre-taper and one year post-taper.
Results
A total of 60 patients met inclusion criteria. One year post-taper, approximately one-third of the patients were re-started on opioid therapy. However, average MEDD overall was lower at one year post-taper compared to pre-taper. Reduction in pain scores was not significant pre-taper compared to post-taper. Adjuvant medications generally increased post-taper. Follow-up with mental health and pain management clinical pharmacy specialists decreased post-taper.
Conclusions
Tapering to 0 MEDD did not lead to a significant decrease in pain one-year post-taper. Approximately 33% of patients were re-started on opioids within one year post-taper. Average MEDD scores decreased post-taper. Continued follow-up with patients who are tapered to 0 MEDD is required in order to improve outcomes.
42 Long-term treatment with capsaicin 8% patches: a subgroup analysis in patients with postherpetic neuralgia from an open-label study
Christopher Ghariboa, Marielle Eerdekensb, Sylvia Engelenb and Lizandra Marcondesc
aNYU Langone Health, New York, NY, USA; bGrünenthal GmbH, Aachen, Germany; cGrünenthal Inc., Morristown, NJ, USA
Purpose
Painful neuropathy or peripheral neuropathic pain (PNP) is a common neurological condition estimated to affect ~7–8% of the general population in Europe. Managing patients with PNP is challenging; it often becomes chronic and can have a significant impact on quality of life. According to the revised International Association for the Study of Pain (IASP) recommendations for ICD11, PNP is considered to be a distinct chronic pain condition (Scholz et al., 2019)1. Postherpetic neuralgia (PHN) following shingles infection, has specifically been named as one of the PNP conditions. High concentration 8% capsaicin patch (HCCP) is commonly recommended as a second line therapy for PHN. HCCP is indicated for the treatment of peripheral neuropathic pain (PNP) in the EU and for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and for neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet in the US. Capsaicin is a highly selective, potent and high-affinity exogenous agonist for the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors which, through a combination of activities, defunctionalizes nociceptor fibers and reduces cutaneous hypersensitivity. As a result, capsaicin is an attractive peripherally acting treatment to control localized pain, hyperalgesia, or allodynia (Anand and Bley, 2011)2. The HCCP delivers the drug effectively and directly to the skin while limiting the risk of systemic effects and drug interactions. Whilst controlled trials have demonstrated the safety and effectiveness of capsaicin patches, the STRIDE study was designed to investigate the long-term safety of repeated patch administration in patients with non-diabetic neuropathic pain (Gálvez et al., 2017)3. The present analysis considers the effect on treatment outcomes among a subgroup of patients with PHN included in the STRIDE study.
Methods
The STRIDE study was an open-label, multicenter, 52-week observational trial conducted in Europe. A diagnosis of PHN was based on pain persisting since shingles vesicle crusting, for a minimum of 3 months. Prior treatment with capsaicin patches and a history of diabetes were among the exclusion criteria. Patients received up to 6 capsaicin 640 g/cm2 (8% weight for weight) HCCP treatments at 9- to 12-week intervals. At each application visit, a maximum of 4 patches equivalent to an area of up to 1120 cm2 were applied for 60 minutes. HCCP retreatment was at the investigator’s discretion and according to patient feedback. Long-term tolerability and safety were the primary objectives of the study. In addition, areas of spontaneous pain and allodynia were monitored, and various scales were used to assess pain, quality of life and overall treatment outcome at each retreatment assessment timepoint. Descriptive statistics (including means and standard deviations) are presented; missing observations were not imputed.
Results
Of the 107 PHN patients included in the study, 66 completed the trial. The reason for withdrawal was lack of efficacy (14.95%), adverse events in (4.67%) and other reasons (18.69%). HCCP was applied once in 22 patients, twice in 26, three times in 24 and ≥4 times in 35. All but 1 patient used preapplication topical anesthesia during the study, and 79.4% used concomitant medications for neuropathic pain.
73% of patients experienced possible or probable drug-related adverse events, mostly associated with transient application site reactions (57.9%). The maximum severity was mild or moderate in 57% of cases, and only 1 drug-related event required treatment discontinuation.
The average daily pain score was reduced from a baseline value of 6.6 (SD, 1.46) to 5.0 (1.99) after 6 months and 4.6 (2.18) after 12 months. The overall change in mean daily pain intensity by the end of study was approximately −1.7. The proportion of responders (≥30% decrease from baseline on a Numerical Pain Rating Scale) progressively increased during the study, to 22.7% after 3 months, and 33.3% and 39.7% after 6 and 12 months, respectively. Over 50% of patients showed at least minimal improvement according to the assessment of their condition by the end of study. The area of allodynia/hyperplasia and the extent of spontaneous pain (reported in most patients at baseline, mainly on the torso) decreased during the study by just over 20%.
Conclusions
HCCP repeat application over 12 months in patients with PHN was well tolerated, with mostly transient local adverse events directly linked to the site of application. Progressive and sustained reduction in pain intensity was achieved, as well as reductions in the area of allodynia and spontaneous pain. Overall, the findings from this study demonstrate that repeated HCCP application is a well-tolerated and effective long-term treatment option in patients with PHN.
43 Treatment outcomes in patients with postherpetic neuralgia: a controlled trial of capsaicin 8% patch versus oral pregabalin
Charles Argoffa, Marielle Eerdekensb, Sylvia Engelenb and Lizandra Marcondesc
aAlbany Medical Center, New York, NY, USA; bGrünenthal GmbH, Aachen, Germany; cGrünenthal Inc., Morristown, NJ, USA
Purpose
Postherpetic neuralgia (PHN) is the most common complication of shingles. It continues to be a prevalent peripheral neuropathic pain (PNP) condition, despite the availability of a variety of pharmacological interventions (Hadley et al., 2016)1. In addition to pain, the disorder is associated with impaired functionality and quality of life. Pregabalin (PRE) is one of the established first line treatments for use in PHN whereas the high concentration 8% capsaicin patch (HCCP) is commonly recommended as a second line therapy. HCCP is indicated for the treatment of peripheral neuropathic pain (PNP) in the EU and for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and for neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet in the US. The goal of this investigation was to compare treatment outcomes of HCCP and PRE in a subgroup of patients with PHN from ELEVATE (primary data and safety/tolerability data have been presented previously by Haanpää et al., 2016)2.
Methods
The ELEVATE study was an open-label, randomized, multicenter, non-inferiority trial. Eligible patients with PHN had pain persisting for at least 6 months after shingles vesicle crusting, and were either naïve to, or, in the opinion of the investigator had not received adequate pain relief with, gabapentin or pregabalin. The study participants were randomly assigned 1:1 to a single treatment with the HCCP (179 mg (8% w/w)) or to optimized daily treatment with pregabalin (75 mg capsules), the study lasted 8 weeks.
Subjects were assessed at baseline and predefined times throughout the study using the following rating scales: Numeric Pain Rating Scale (NPRS); maximum Neuropathic Pain Symptom Inventory (NPSI) subscales [burning (superficial) spontaneous pain, pressing (deep) spontaneous pain, paroxysmal pain, evoked pain, paresthesia/dysesthesia]; Treatment Satisfaction Questionnaire for Medication (TSQM); EuroQol-5D (EQ-5D); Patient Global Impression of Change (PGIC); and Medical Outcomes Study-6 item questionnaire for cognitive function and sleep (MOS). The area of dynamic mechanical allodynia (ADMA) was measured, and adverse events were monitored.
The primary efficacy parameter was defined as a ≥ 30% reduction from baseline in the average pain score over a 24-hour period based on the NPRS score. The optimal therapeutic effect was defined as no change in concomitant chronic pain medication, no discontinuation of the HCCP application or trial medication due to lack of efficacy or tolerability prior to the end of study (EoS), ≥30% reduction in NPRS pain score for ≥4 consecutive days between baseline and EoS, and no moderate or serious adverse reactions during the stable treatment period. Post hoc analyses with logistic regression models were used, with baseline observation carried forward (BOCF) analyses to account for missing data.
Results
In the ELEVATE study 136 patients had PHN and were randomized to each group, 63 participants received treatment with HCCP and 73 received oral pregabalin.
In the two different treatment groups, 71.4% of patients were responders in the HCCP group compared with 76.7% in the pregabalin group (difference: −5.3%, 95% CI: −20.1%, +9.5%). In terms of the optimal response, the numbers were 71.4% versus 63.0%, respectively (difference: +8.4%, 95%: −7.3%, +24.1%).
The secondary efficacy assessments evaluated for the two treatment groups included: NPRS pain responses, NPSI subscale responses, patient satisfaction with treatment (TSQM), quality of life (EQ-5D), and the Patient Global Impression of Change (PGIC). Specifically, the total NPSI score decreased with a mean (SD) of −56.4 (40.48) and −47.0 (42.47) for HCCP and PRE, respectively. On the TSQM scale, outcomes were generally similar between the two treatment groups with the exception of the side effects scale where scores were higher favoring HCCP (91.6) over PRE (78.8) with a LS Mean Difference of 12.8 (95% Cl: 5.2, 20.4). The EQ-5D-5 L scores increased with an absolute mean (SD) change of 17.2 (19.65) and 13.7 (19.75) for HCCP and PRE, respectively. On the PGIC, 69.8% vs 57.7% patients reported to be very much or much improved with HCCP and PRE, respectively. The mean (SD) change on the MOS scale was 5.4 (9.87) versus 0.7 (10.70) for HCCP and PRE respectively with a LS mean difference (95% Cl) of 5.7 (2.8, 8.6). The mean (SD) reduction of area of dynamic mechanical allodynia was −162.9 (213.93) cm2and −73.2 (269.7) cm2 with HCCP and PRE, respectively. In total, the % days (mean (SD)) free from any treatment emergent adverse events (TEAEs) were 89.1 (23.04) % and 74.8 (35.18) % with HCCP and PRE, respectively.
Approximately two-thirds of patients achieved pain relief within 7 days with HCCP, versus only one-third of patients with PRE. TSQM scale outcomes were generally similar between the two treatments, with the exception of the side effects scale which showed better patient satisfaction in the HCCP treatment group. Furthermore, HCCP provided an optimal therapeutic response in more patients than PRE, and it produced better outcomes on the MOS 6 item questionnaire for cognitive function and sleep, as well as the response to ADMA.
Conclusions
PHN is a complex disorder that can significantly impact patient functioning and quality of life. In this randomized controlled trial, HCCP treatment outcomes compared favorably with PRE in patients with PHN. The proportion of patients with a ≥ 30% reduction in NPRS score (primary response) was equivalent between treatments, whilst more patients had an optimal response in the HCCP group. The mean TSQM side effects score was better with the HCCP, and fewer patients discontinued treatment because of treatment-related adverse events. In addition, the onset of pain relief was quicker and there was a greater reduction in ADMA. Treatment with the HCCP provided an optimal therapeutic effect in more patients, led to better outcomes on the MOS cognitive functioning scale, provided a quicker onset of pain relief and more prominently reduced the ADMA with improved tolerability (higher % of days free from TEAEs) than treatment with PRE. The outcomes of this head-to-head study show that the HCCP has non-inferior efficacy to oral PRE, allowing for patient preference and involvement when selecting single or combined therapies for chronic PNP conditions.
44 Treatment outcomes in patients with Post-Surgical Neuropathic Pain (PSNP): data from a randomized controlled clinical trial comparing high concentration capsaicin patch with pregabalin
Mayank Guptaa, Marielle Eerdekensb, Sylvia Engelenb and Lizandra Marcondesc
aKansas Pain Management, Overland Park, KS, USA; bGrünenthal GmbH, Aachen, Germany; cGrünenthal Inc., Morristown, NJ, USA
Purpose
Post-surgical neuropathic pain (PSNP) is peripheral neuropathic pain (PNP) following surgery. Managing patients with PNP is challenging as it often becomes chronic, with marked long-term reductions in health-related quality of life, decreased individual productivity and increased patient and healthcare expenditure. Etiologies range from mechanical and inflammatory diseases to injury and nerve compression. A key pathophysiological mechanism is neuronal hyperexcitability, both within the axon and cell body as well as at the peripheral nociceptors. This allows for single or combined therapies targeting one or more sites within the neuron.Treatments for PNP include systemic and local treatments such as pregabalin (PRE) or the high concentration 8% capsaicin patch (HCCP). PRE reduces neuronal excitability in the central nervous system by reversibly binding alpha-2-delta subunits of the Ca++ channels, thus reducing synaptic neurotransmitter release. Locally applied HCCP for 60-min rapidly delivers capsaicin into the skin directly targeting the nociceptor leading to its defunctionalization. HCCP is indicated for the treatment of peripheral neuropathic pain (PNP) in the EU and for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and for neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet in the US.PSNP is a common yet underdiagnosed PNP condition with a high growing need for symptomatic treatments. In a recent placebo-controlled trial in patients with post-traumatic neuropathic pain (including patients with PSNP), pregabalin failed to meet the primary endpoint (change from baseline to week 15 on the numeric pain rating scale (NPRS) whereas key secondary endpoints yielded positive result (Markman et al. 2018)1.To date, no direct comparison of the efficacy of the HCCP and PRE in PSNP have been reported. In this post-hoc analysis in a subgroup of patients with PSNP from ELEVATE, treatment outcomes of HCCP and PRE are compared (primary and safety/tolerability data published in Haanpää et al., 2016)2.
Methods
In an eight-week open-label, randomized, multicenter, non-inferiority trial eligible patients with PSNP were randomly assigned 1:1 to a single treatment of the HCCP (179 mg (8% w/w)) or to optimized daily treatment of pregabalin (75 mg capsules), the study lasted 8 weeks. Efficacy assessments included the Numeric Pain Rating Scale (NPRS), Neuropathic Pain Symptom Scale (NPSI), Treatment satisfaction Questionnaire for Medication (TSQM), EQ-5D, Patient Global Impression of Change (PGIC), Area of Dynamic Mechanical Allodynia (ADMA). The proportion of patients in each arm who achieved ≥30% decrease in the ‘average pain for the past 24 hours’ NPRS score was assessed from baseline to Week 8. The results pertain to a post-hoc analysis using analysis of covariance models, and Least Square means are presented. Baseline observation carried forward (BOCF) analyses were used to account for missing data. Secondary endpoints included optimal therapeutic effect (OTE), time-to-onset of pain relief and treatment satisfaction.
Results
In the ELEVATE study 145 patients had PSNP and were randomized to each group, 78 participants received treatment with HCCP and 67 received oral pregabalin. At the end of week 8, respectively 48.7% and 31.3% were responders (≥30% decrease in NPRS from baseline) and 46.2% versus 22.6% were very much or much improved on the PGIC. HCCP treatment scored higher than PRE on TQSM (68.7 versus 43.8 on global satisfaction). The total NPSI score decreased (−35.1 and −27.0 for HCCP and PRE, respectively) whereas the EQ-5D-5 L scores increased (15.3 and 4.3, respectively). The ADMA was reduced by 78.9 cm2and 63.5 cm2, respectively.
Conclusions
A single treatment with HCCP compared favorably with daily oral pregabalin in PSNP patients considering responder rates, patient assessment of improvement, patient satisfaction and reduction of ADMA.
45 Is repeat treatment with high concentration capsaicin patch beneficial in patients with peripheral neuropathic pain who did not respond after a first treatment?
Rainer Freynhagena, Marielle Eerdekensb, Sylvia Engelenb and Lizandra Marcondesc
aBenedictus Hospital Tutzing, Tutzing, Germany; bGrünenthal GmbH, Aachen, Germany; cGrünenthal Inc, Morristown, NJ, USA
Purpose
High concentration capsaicin patch (179 mg or 8% w/w) (HCCP) is indicated for the treatment of peripheral neuropathic pain (PNP) in the EU and for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and for neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet in the US. HCCP can be administered in adults as a monotherapy or in combination with other medicinal products for the treatment of chronic neuropathic pain. The rapid and sustained pain relief from a single application of HCCP has been shown to be maintained for up to 12 weeks in multiple randomized controlled clinical trials. HCCP treatment can be repeated approximately every 3 months. Repeated treatments with HCCP have been investigated in open label extension trials following randomized controlled clinical trials and in two larger stand-alone clinical trials.
A previous investigation of repeated applications of HCCP in a randomized controlled clinical trial with a duration of 52 weeks in patients with painful diabetic peripheral neuropathy (PDPN) has shown that HCCP demonstrated greater efficacy than standard of care, and the magnitude of the differential treatment effect increased over time from the first to the last patch application (PACE published by Vinik A. et al., 2019).
Likewise, in a 52-week trial in non-diabetic PNP, the subset of patients who received 4 consecutive HCCP treatments (n = 100), displayed a reduction in average daily pain scores. This observation was recorded after each successive HCCP treatment, and in addition, pain relief was sustained between treatments (STRIDE published by Gálvez R. et al., 2017).
Available data and literature do not provide detailed insights regarding responder rates beyond the first application of HCCP. In particular, the question whether patients deemed as non-responders following the first application could become responders after a second or third application remains unknown.
To investigate this question, we conducted a post hoc analysis of the two 52-week trials mentioned previously, considering a subset of subjects defined as initial non-responders. Safety/tolerability data of the two trials included in this analysis have been previously published (Vinik A. et al., 2016 and Gálvez R. et al., 2017).
Methods
In the two selected trials of 52-week duration, HCCP was applied 30 min to the feet or 60 mins to other body areas. All patients were diagnosed with PNP (i.e. PDNP in PACE and non-diabetic PNP in STRIDE) and had an average daily pain score ≥4 on the question 5 of the Brief Pain Inventory or the Brief Pain Inventory-Diabetic Neuropathy scale. In the STRIDE study repeat treatment was allowed every 9–12 weeks, whereas in PACE, repeat treatment was allowed after an interval of at least 8 weeks. Initial non-responders were defined as patients having a < 30% decrease on the Numeric Pain Rating Scale (NPRS) from baseline to 3 months post-baseline. Responders were defined as patients who achieved a ≥ 30% decrease on the NPRS at predefined timepoints (month 6, 9 and 12).
Results
In the STRIDE study at month 3, 76.6% of patients having received an initial treatment with HCCP (n = 306) did not meet the responder criteria. A total of 168non-responders had a repeat treatment and 115 patients (68%) were still enrolled in the trial at 12 months. In comparison, from the total trial population (responders and non-responders), 174 patients (56.9%) were still enrolled in the trial at month 12. Of the initial non-responders who were still in the trial at 12 months (n = 115), 57.4% received at least 4 applications of HCCP and, 33.9% had become responders to HCCP treatment whereas of the total population 43.7% could be classified as responders.
In the PACE study at month 3, 54% of patients who received an initial treatment with HCCP (n = 313) did not meet the responder criteria (n = 152). Of the 152 patients, 127 (i.e. 83.5%) were still enrolled in the trial at 12 months whereas from the total population (responders and non-responders), 250 patients (78.9%) were still enrolled in the trial. Of the initial non-responders receiving repeat applications, 80.2% had received at least 4 applications at month 12. In addition, of the initial non-responders who were still in the trial at 12 months (n = 127), 45.7% had become responders to HCCP treatment whereas of the total population 58% could be classified as responders.
Conclusions
Repeat treatment with HCCP over 52 weeks in patients with various types of peripheral neuropathic pain etiologies was well tolerated. Importantly, repeated application in initial non-responders provides additional benefit to patients. As observed across trials, more than one third of initial non-responders converted into responders with continued repeated treatment with HCCP. Although at month 12, the responder rates in patients who did not initially respond to HCCP were approximately 10% lower than in the overall population, the substantial increase in responder rates (≥30% decrease on NPRS) justifies a repeat treatment with the HCCP.
46 Ketamine metabolites in the treatment of neuropathic pain
Lucas Stollea,b, Joseph P. Pergolizzia and Irving W. Wainera
aSpirify Pharma, Naples, FL, USA; bUniversity of Oxford, Oxford, Oxfordshire, United Kingdom
Purpose
(R,S)-Ketamine is effective in the treatment of peripheral and central pain and is particularly active in neuropathic pain, such as complex regional pain syndrome and treatment resistant migraine headaches. (R,S)-Ketamine is rapidly and extensively metabolized into a wide variety of compounds including hydroxynorketamine (HNK). Initial studies employing multiple murine pain models demonstrated that HNK is a potent analgesic [1]. We demonstrated that a key pharmacological effect of HNK is decreased D-serine concentrations. D-Serine is an essential co-agonist of the NMDA receptor and reduced D-serine production results in reduced NMDA receptor hyper-activation and associated neurotoxicity. We have demonstrated that gabapentin and pregabalin also reduce the cellular production of D-serine [2]. We here report the results of a study designed to create a molecular template for the design of new analgesics using HNK as the model compound [3]. The goal is the optimized attenuation of D-serine production and the introduction of a new paradigm for the treatment of neuropathic pain.
Methods
The test compounds were (R)-ketamine, (S)-ketamine, (2 R,6 R)-HNK, (2S,6S)-HNK, (2 R,6S)-HNK, (2S,6 R)-HNK, (R)-norketamine, (S)-norketamine, (R)-dehydronorketamine, and (S)-dehydronorketamine. The model system was the PC-12 neuronal cell line maintained in vitro using standard techniques. The test compounds were added to the incubation media in escalating concentrations in order to determine the ability of the compounds to reduce intracellular D-serine production, expressed as IC50 values. Intracellular D-serine concentrations were measured usingcapillary electrophoresis-laser induced fluorescence (CE-LIF) and extra cellular D-serine concentrations were determined using liquid chromatography with mass spectrometric detection. The data was analyzed using Comparative Molecular Field Analysis (CoMFA) employing the molecular structure of the test compounds and the corresponding IC50 values associated with their effect on D-serine concentrations.The models were aligned using 2-chlorobenzyl moiety as a common substructure and steric and electronic molecular fields were sampled on the grid lattice surrounding each structure. The pICvalues presenting effects on the intracellular D-serine levels in PC-12 cells of ketamine metabolites were also subjected to 3D-QSAR modeling
Results
The intracellular D-serine concentrations were reduced by all of the studied compounds, except for (S)-ketamine. The concentrations were reduced by >30%, and (2S,6S)-HNK and (2 R,6 R)-HNK were the most potent with IC50 values of 0.18 nM and 0.68 nM, respectively. Incubation with (S)-Ketamine increased intracellular D-serine concentration which is consistent with our previous study demonstrating that (S)-ketamine selectively inhibits the ASCT2 transporter, which mediates D-serine cellular export [4]. Incubation with (2S,6S)-HNK, a (S)-ketamine metabolite reduced both intracellular and extra cellular D-serine concentrations indicating that the compound does not affect ASCT2 transport. COMFA and QSAR modeling identified a relationship between molecular structure and effect on D-serine production. The study indicated that the C2 and C6 positions were key interaction points on the cyclohexanone ring of HNK and that hydrophobic and hydrogen bonding capabilities at C2 and hydrogen bonding at C6 are associated with the observed pharmacological activity.
Conclusions
The study demonstrated that HNK is a template for new drug development aimed at the optimized treatment of neuropathic pain. The computational models developed in our study have been applied to the design of new chemical entities that are under investigation.
References
[1] Kroin JS, et al. Efficacy of ketamine metabolite (2 R,6 R)-hydroxynorketamine in mice models of pain. Reg Anesth Pain Med. 2018;44:111–117.
[2] Singh NS, et al., Gabapentin and (S)-pregabalin decrease intracellular D-serine in PC-12 cells. Neuroscience Letters. 2013;535: 90–94.
[3] Singh NS et al. Ketamine metabolites enantioselectively decrease intracellular D-serine concentgrations in PC-12 cells. PloS One. 2016;11: e0149499.
[4] Singh NS et al. Enantioselective inhibition of D-serine transport by (S)-ketamine. Br J Pharmacol. 2015;172: 4546–4559.
47 Reductions in all-cause mortality associated with the use of methylnaltrexone for opioid-induced bowel disorders: a pooled analysis
Lynn R. Webstera, Darren Brennerb, Robert J. Israelc, Nancy Stamblerd and Neal E. Slatkine
aPRA Health Sciences, Salt Lake City, UT, USA; bNorthwestern University Feinberg School of Medicine, Chicago, IL, USA; cBausch Health US, LLC, Bridgewater, NJ, USA; dProgenics Pharmaceuticals, Inc, New York, NY, USA; eSalix Pharmaceuticals, Bridgewater, NJ, USA
Purpose
Opioids are often associated with the development of delays in gastrointestinal motility and associated conditions. Preclinical and clinical studies have suggested that activation of the µ-opioid receptor may reduce overall survival and increase the risk for all-cause mortality in patients with cancer and noncancer pain.1−4Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, has demonstrated efficacy for the treatment of bowel disorders.5,6This analysis evaluated if all-cause mortality was impacted by methylnaltrexone use.
Methods
A retrospective analysis of 12 phase 2 to 4 randomized, double-blind, placebo-controlled studies of methylnaltrexone for the treatment of opioid-induced bowel disorders in patients with advanced illness or noncancer pain was conducted. The risk of all-cause mortality, defined as the number of patients who died within 30 days after the last dose of study medication during the double-blind phase of each study, was compared between methylnaltrexone and placebo groups. The data were also stratified by cancer vs noncancer, age, gender, and acute vs chronic diagnosis.
Results
The analysis was based on 2526 patients who received methylnaltrexone and 1192 patients who received placebo, from which there were 33 deaths in the methylnaltrexone group and 35 deaths in the placebo group. Based on the number of deaths in each group, the mortality rate was 17.8 deaths/100 person-years of exposure in the methylnaltrexone group, and 49.5 deaths/100 person-years of exposure for the placebo group. The all-cause mortality risk was significantly lower among patients receiving methylnaltrexone (hazard ratio 0.399; 95% confidence interval 0.25–0.64; P = 0.0002) compared with patients receiving placebo, corresponding to a 60% reduction in risk. Significant risk reductions were observed for those receiving methylnaltrexone who had cancer (hazard ratio 0.470; 95% confidence interval 0.27–0.83, P = 0.009) or chronic illness (hazard ratio 0.315; 95% confidence interval 0.19–0.54, P < 0.0001). Methylnaltrexone-treated patients had a significantly reduced mortality risk compared with placebo regardless of age or gender.
Conclusions
A substantial reduction in all-cause mortality was observed among methylnaltrexone-treated patients pooled from phase 2–4 studies. Significant reductions were also observed for those receiving methylnaltrexone regardless of age or gender and who had cancer or a chronic illness. We hypothesize that methylnaltrexone µ-opioid receptor antagonism may provide protective benefit against the additional mortality risk associated with opioid treatment in patients with chronic illnesses.
References
1. Janku F, et al. Treatment with methylnaltrexone is associated with increased survival in patients with advanced cancer. Ann Oncol.2016;27(11):2032–2038.
2. Zylla D, et al. Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer. Cancer.2013;119(23):4103–4110.
3. Ray WA, et al. Prescription of long-acting opioids and mortality in patients with chronic noncancer pain. JAMA.2016;315(22):2415–2423.
4. Lennon FE, et al. The mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and epithelial mesenchymal transition in human lung cancer. PLoS One.2014;9(3):e91577.
5. Thomas J, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med.2008;328(22):2332–2343.
6. Rauck R, et al. Randomized, double-blind trial of oral methylnaltrexone for the treatment of opioid-induced constipation in patients with chronic noncancer pain. Pain Pract.2017;17(6):820–828.
48 Benefit of buprenorphine buccal film versus oral oxycodone hydrochloride on respiratory drive: a phase 1 placebo-controlled trial
Lynn Webstera, Jacqueline Catera and Thomas Smithb
aPRA Health Sciences, Salt Lake City, UT, USA; bBioDelivery Sciences International, Inc., Raleigh, NC, USA
Purpose
Respiratory depression is the primary cause of death related to opioid overdose. Buprenorphine is a partial μ-opioid receptor agonist that, unlike full μ-opioid receptor agonists (eg, morphine, oxycodone, fentanyl), has been shown to exhibit a ceiling effect for respiratory depression. Partial agonism refers to receptor-level activity and not analgesic efficacy, as buprenorphine has analgesic efficacy comparable to that of full μ-opioid receptor agonists. This partial agonism at the μ-opioid receptor, together with antagonism at the κ and δ opioid receptors, and agonism at opioid-receptor like 1 may play a role in limiting common opioid-related adverse events such as respiratory depression. Respiratory depression is caused in part by inhibition of respiratory drive (ie, the ability of neuronal respiratory centers to control and regulate ventilation). The goal of this study was to compare the effects of buprenorphine buccal film (BELBUCA®) and oral oxycodone (immediate release) on respiratory drive to distinguish the impact of a partial μ-opioid receptor agonist from that of a full μ-opioid receptor agonist.
Methods
The effect of buprenorphine buccal film and oxycodone (immediate release) on respiratory drive was assessed in healthy subjects (N = 19) who self-identified as recreational opioid users and were not dependent on opioids (confirmed via a naloxone challenge test at day – 1). The study had a single-center, double-blind, double-dummy, 6-treatment, 6-period, placebo-controlled, randomized crossover design. Treatments were 300 μg, 600 μg, and 900 μg buprenorphine buccal film; 30 mg and 60 mg oral oxycodone; and placebo. Each subject received every treatment once, following a computer-generated randomization treatment sequence, and all treatments were separated by a minimum 7-day washout period to avoid any potential carryover effects. This study design was chosen to minimize variability by allowing each subject to serve as their own control. Respiratory drive was evaluated by measuring the ventilatory response to hypercapnia through assessment of the maximum decrease in minute ventilation (Emax) after administration of each study drug (primary endpoint). Mean minute ventilation was measured pre-dose and at 0.5, 1, 2, 3, and 4 hours post-dose. Throughout the study, from the first dose up to 7 ± 2 days after the last study dose was administered, patients were monitored for adverse events (AEs), which were recorded. Statistical analyses were performed using a linear mixed-effects model with treatment, period, and sequence as fixed effects and subject nested within sequence as a random effect; Emax was defined as the maximum effect for each subject after each study medication was administered. Least squares (LS) mean differences between each treatment were calculated, along with differences in LS means with 95% CIs and P values. A similar model was used to assess the difference between each treatment and placebo at each post-baseline timepoint (where the model also included a fixed effect term for timepoint).
Results
The difference between buprenorphine buccal film and placebo for minute ventilation at Emax (L/minute) was not significantly different for the 300 μg dose (+1.24 versus placebo, P = 0.529), 600 μg dose (+0.23, P = 0.908), or 900 μg dose (+0.93, P = 0.637). In contrast, 30 mg oxycodone numerically reduced minute ventilation at Emax versus placebo (−0.79, P = 0.687), and 60 mg oxycodone led to a significantly greater decrease in minute ventilation at Emax than did placebo (−5.23, P = 0.010).
Oxycodone 30 mg produced a significantly greater decrease in mean minute ventilation than did placebo at the 1 hour post-dose timepoint (P = 0.007), and oxycodone 60 mg led to significantly greater decreases than placebo did at 1 hour (P < 0.001), 2 hours (P < 0.05), and 4 hours (P < 0.05) post-dose. Mean minute ventilation was similar for placebo and buprenorphine buccal film for all doses and timepoints.
No deaths or serious AEs were reported in this study. The most common treatment-emergent AEs with buprenorphine buccal film and oxycodone were nausea, vomiting, somnolence, euphoric mood, and pruritus; dizziness was also a common AE with buprenorphine buccal film. Only 1 subject discontinued owing to an AE likely related to the study drug (buprenorphine buccal film 600 µg, idioventricular rhythm).
Conclusions
Buprenorphine buccal film did not significantly reduce respiratory drive at any dose compared with placebo. Administration of oxycodone resulted in a significant dose-dependent decrease in respiratory drive. The tolerability profiles of both drugs were similar. No AEs related to respiratory depression have been reported in previous clinical studies of buprenorphine buccal film. Data from this study show that buprenorphine buccal film is well tolerated, and results from previous studies suggest that buprenorphine buccal film provides effective analgesia and may be a safer treatment option than a full μ-opioid receptor agonist for patients with chronic pain.
49 The pharmacodynamics and pharmacokinetics of buprenorphine buccal film versus oral oxycodone hydrochloride: results of a phase 1 placebo-controlled trial
Lynn Webstera, Jacqueline Catera and Thomas Smithb
aPRA Health Sciences, Salt Lake City, UT, USA; bBioDelivery Sciences International, Inc., Raleigh, NC, USA
Purpose
Buprenorphine is a Schedule III atypical opioid that functions by binding to various opioid receptors located throughout the central nervous system to elicit analgesia. Buprenorphine acts as a partial agonist with high binding affinity at the mu-opioid receptor, an antagonist with high binding affinity at the delta- and kappa-opioid receptors, and an agonist with low binding affinity at opioid receptor-like 1. Unlike full mu-opioid receptor agonists (eg, fentanyl, morphine, oxycodone), buprenorphine has been shown to have a ceiling effect on respiratory depression, which is attributed to its unique pharmacodynamic and pharmacokinetic properties. Recently, a phase 1 placebo-controlled study compared the pharmacologic properties of buprenorphine buccal film (BELBUCA®, BioDelivery Sciences International, Inc.), a US Food and Drug Administration–approved treatment for chronic pain, with those of the full mu-opioid receptor agonist oxycodone hydrochloride (clinicaltrials.gov, NCT03996694). This study found that buprenorphine buccal film did not significantly impact various pharmacodynamic measures of respiratory drive, including the maximum decrease in minute ventilation as well as changes in minute ventilation and peak expiratory flow rates over time; whereas oxycodone decreased each of these parameters relative to placebo. Pharmacokinetic properties, including maximum observed plasma concentration (Cmax), time to attain maximum observed plasma concentration (Tmax), area under the plasma concentration versus time curve from 0 to the last measurable concentration (AUC0-last), and the abuse quotient (AQ; the ratio of Cmax to Tmax), were also assessed for buprenorphine buccal film and oxycodone.
Methods
This was a randomized, double-blind, double-dummy, 6-period, 6-treatment, placebo-controlled, crossover study, which compared the effects of buprenorphine buccal film (300, 600, or 900 μg) with those of oral immediate-release oxycodone hydrochloride (30 or 60 mg) and matching placebo on respiratory drive in recreational opioid users. Each treatment was separated by a 7-day washout period to avoid any unintentional carryover effects. Before randomization, subjects were determined not to be dependent on opioids via a Naloxone Challenge Test. Pharmacokinetic assessments were evaluated using blood samples collected pre-dose and at 0.5, 1, 2, 3, 4, and 6 hours post-dose to obtain Cmax, Tmax, AUC0-last, and AQ. These parameters were calculated using non-compartmental methods.
Results
A total of 19 subjects (18 [94.7%] men, 1 [5.3%] woman) were enrolled, and 15 (78.9%) completed the study. After the administration of 300, 600, or 900 µg of buprenorphine buccal film, Cmax increased proportionally with dose, with mean (SD) values of 0.4 (0.2), 0.8 (0.9), and 1.1 (0.4) ng/mL, respectively. The Cmax of immediate-release oxycodone also increased proportionally with dose, with mean (SD) values of 65.8 (19.1) ng/mL for 30 mg and 132 (46.2) ng/mL for 60 mg. The buccal film formulation of buprenorphine exhibited rapid absorption across all dosage strengths. For 300, 600, and 900 µg of buprenorphine buccal film, the median (minimum, maximum) Tmax values were similar at 2.2 (2.1, 3.2), 3.1 (1.1, 6.0), and 2.2 (2.1, 6.0) hours, respectively. The Tmax for immediate-release oxycodone was also similar between doses; the median (minimum, maximum) was 1.2 (0.6, 3.2) hours for the 30-mg dose and 1.2 (0.7, 6.0) hours for the 60-mg dose, suggesting faster absorption than buprenorphine buccal film. For both study drugs, AUC0-last increased proportionally with dose; the mean (SD) was 1.8 (1.2), 2.9 (2.5), and 4.0 (1.0) h*ng/mL for buprenorphine buccal film 300, 600, and 900 µg, respectively, and 216 (49.4) and 435 (141) h*ng/mL for immediate-release oxycodone 30 and 60 mg, respectively. AQ was low and similar among all doses of buprenorphine buccal film, with mean (SD) values of 0.2 (0.1) for 300 µg, 0.3 (0.2) for 600 µg, and 0.4 (0.1) for 900 µg. For immediate-release oxycodone, the AQ was higher than for buprenorphine buccal film, with mean (SD) values of 67.4 (39.2) for oxycodone 30 mg and 110 (75.3) for oxycodone 60 mg.
Conclusions
The unique pharmacokinetic properties of buprenorphine buccal film resulted in a slower absorption and lower AQ than immediate-release oral oxycodone. As higher AQ is associated with greater drug liking and abuse potential, these data could aid clinicians in proper medication and dose selection for patients who have been determined by risk-benefit analysis to be candidates for use of opioids in the management of chronic pain. Opioids are commonly used recreationally and carry a high risk of diversion; therefore, choosing a medication with less drug liking and abuse potential is imperative during the current opioid crisis. Taken together, these data further support the safety of buprenorphine buccal film over full mu-opioid receptor agonists for the treatment of chronic pain.
50 Secondary Outcomes of a Phase 1 Placebo-Controlled Trial Comparing the Effects of Buprenorphine Buccal Film and Oral Oxycodone Hydrochloride on Respiratory Drive
Lynn Webstera, Jacqueline Catera and Thomas Smithb
aPRA Health Sciences, Salt Lake City, UT, USA; bBioDelivery Sciences International, Inc, Raleigh, NC, USA
Purpose
Buprenorphine is a Schedule III atypical opioid with partial mu-opioid receptor agonist activity, which is thought to contribute to its decreased risk of respiratory depression relative to that of full mu-opioid receptor agonists (eg, fentanyl, morphine, oxycodone). Buprenorphine also has functions at other opioid receptors, including antagonism at the delta- and kappa-opioid receptors and agonism at opioid receptor-like 1. The unique receptor activation profile of buprenorphine translates to effective analgesia and potentially greater safety than Schedule II opioids for the management of chronic pain. As the primary cause of opioid-related death is suppression of respiratory drive, leading to respiratory depression, this phase 1 study was conducted to directly compare the effects of buprenorphine buccal film (BELBUCA®, BioDelivery Sciences International, Inc.) and the full mu-opioid receptor agonist oxycodone hydrochloride (immediate release) on respiratory drive (clinicaltrials.gov, NCT03996694). The primary outcome of the study evaluated respiratory drive by observing the maximum decrease in minute ventilation after the administration of each study drug via the ventilatory response to hypercapnia and showed that buprenorphine buccal film did not impact respiratory drive at any of the doses tested relative to placebo, whereas oxycodone did in a dose-dependent fashion. Presented here are additional secondary outcomes that were assessed throughout the study, including changes in minute ventilation, peak expiratory flow rate, and oxygen saturation over time.
Methods
This study was a randomized, double-blind, double-dummy, 6-period, 6-treatment, placebo-controlled, crossover trial that compared the effects of 300, 600, and 900 μg buprenorphine buccal film; 30 and 60 mg oral immediate-release oxycodone hydrochloride; and matching placebo on respiratory drive in recreational opioid users. Before randomization, subjects were determined not to be dependent on opioids with a Naloxone Challenge Test. Each subject received every treatment and acted as their own control, and the treatments were separated by 7-day washout periods to avoid any potential carryover effects. During the ventilatory response to hypercapnia test, minute ventilation, peak expiratory flow rate, and oxygen saturation were observed at each specific post-dose time point. These parameters were continuously recorded as the hypercapnic gas mixture (72% N2, 21% O2, and 7% CO2) was administered. For minute ventilation, least-squares (LS) mean differences were calculated for each treatment, and statistical analysis was performed using a linear mixed-effects model with treatment, period, sequence, and time point as fixed effects and subject as a random effect. For peak expiratory flow rate, statistical analysis was performed using a linear mixed-effects model with treatment, period, and sequence as fixed effects and timepoint and treatment-by-timepoint interaction as repeated fixed effects. These analyses compared each study drug to placebo at each post-dose time point. Other endpoints of the study included assessments of pupil diameter, change in the ratio of minute ventilation over end-tidal CO2, vital signs, the number of reported adverse events, and results from 12-lead electrocardiograms and laboratory safety tests. Any observed clinically significant abnormalities were also reported.
Results
A total of 19 subjects were enrolled (18 [94.7%] men, 1 [5.3%] woman), and 15 (78.9%) completed the study. For all doses of buprenorphine buccal film (300, 600, and 900 μg) across all time points (0.5, 1, 2, 3, and 4 hours), mean minute ventilation remained similar to that seen with placebo. However, oxycodone 30 mg resulted in a significant LS mean (95% CI) decrease (–4.9 [–8.6, – 1.2] L/min; P < 0.05) in minute ventilation at 1-hour post-dose relative to placebo. Oxycodone 60 mg resulted in the largest overall decrease in minute ventilation, including significant LS mean (95% CI) decreases at hours 1, 2, and 4 (–6.5 [–10.3, – 2.8], – 4.0 [–7.6, – 0.3], and – 4.5 [–8.1, – 0.8] L/min, respectively; P < 0.05 for each time point) relative to placebo. Oxycodone 60 mg also caused the largest sustained decrease in peak expiratory flow rate, with a maximum and significant LS mean (95% CI) decrease relative to placebo at 1-hour post-dose (–18.6 [–29.5, – 7.7]; P < 0.05). Oxycodone 30 mg resulted in an initial LS mean (95% CI) decrease in peak expiratory flow rate, which was significant at 1-hour post-dose (–14.9 [–25.8, – 4.0]; P < 0.05), whereas rates for buprenorphine buccal film remained similar to that of placebo throughout all post-dose time points. Mean oxygen saturation levels remained fairly stable (≥95%) after treatment with each study drug. However, one subject had an oxygen saturation level of 86% approximately 1.5 hours after receiving oxycodone 60 mg, which was considered by the investigator as a moderate adverse event likely related to the study drug.
Conclusions
None of the buprenorphine buccal film doses (300, 600, or 900 μg) decreased minute ventilation or peak expiratory flow rate over time or caused an adverse reaction related to a decrease in oxygen saturation levels, whereas oxycodone did. These secondary outcomes further support the primary results of this study by confirming the enhanced safety profile of buprenorphine buccal film compared with that of the full mu-opioid receptor agonist oxycodone. Overall, buprenorphine buccal film may be a safer treatment option and should be considered before the use of a full mu-opioid receptor agonist for the management of chronic pain.
51 Buprenorphine buccal film and oral oxycodone hydrochloride effects on pupillometry in a phase i placebo-controlled trial
Lynn Webstera, Jacqueline Catera and Thomas Smithb
aPRA Health Sciences, Salt Lake City, UT, USA; bBioDelivery Sciences International, Inc., Raleigh, NC, USA
Purpose
Opioid overdose is a serious health issue, with approximately 450,000 deaths from overdose of prescription and illicit opioids reported in the US between 1999 and 2018. Owing to the rising number of opioid overdoses, the safety of these drugs has been increasingly scrutinized. Of particular concern is the abuse liability of opioids, which can lead to accidental overdose. However, whether in the context of misuse and abuse or legitimate prescription use of these drugs, most opioid-related deaths are caused by respiratory depression.
Buprenorphine is a partial μ-opioid receptor agonist analgesic that has been shown to have a limited effect on respiratory drive when compared with full μ-opioid agonists. In previous studies, a ceiling effect on respiratory depression has been demonstrated with intravenous buprenorphine. Buprenorphine may induce euphoria in subjects who are not physically dependent on opioids and may be positively reinforcing; however, buprenorphine is considered to have lower abuse potential than full μ-opioid agonists and is therefore classified as a Schedule III drug.
A phase 1 placebo-controlled study was recently conducted to compare the effects of buprenorphine buccal film on respiratory drive with those of oxycodone hydrochloride (a full μ-opioid receptor agonist). In addition, since previous opioid studies have demonstrated a relationship between drug ‘liking’ and pupil diameter, we also compared the effects of buprenorphine buccal film and oxycodone on pupil diameter. Both buprenorphine buccal film and oxycodone would have pupillary-constricting effects, with oxycodone having more prominent effects.
Methods
Subjects were healthy individuals who self-identified as recreational opioid users, which was confirmed with a Naloxone Challenge Test. Study treatments were placebo; 300 μg, 600 μg, and 900 μg buprenorphine buccal film; and 30 mg and 60 mg oxycodone. Each treatment was separated by a 7-day washout period to avoid any potential carryover effects. The effect of each treatment on respiratory drive and pupil diameter was assessed using a double-blind, double-dummy, 6-treatment, 6-period, placebo-controlled, randomized crossover design. Respiratory drive was evaluated by measuring the ventilatory response to hypercapnia through assessment of the maximum decrease in minute ventilation (Emax). Pupil diameter was determined with standard pupillometry at the following time points: pre-dose, and 0.5, 1, 1.5, 2, 2.5, 3, and 4 hours post-dose. Statistical analyses were performed using a mixed-effects model with treatment, period, and sequence as fixed effects, and time point and treatment by time point interaction as repeated fixed effects.
Results
A total of 19 subjects were enrolled, and 15 subjects completed the study. Of the 19 subjects enrolled, there were 18 men and 1 woman, ranging in age from 27 to 41 years. Most (73.7%) of the subjects were white. For the measurement of respiratory depression, only oxycodone 60 mg significantly decreased Emax minute ventilation relative to placebo. For pupillometry, statistically significant miosis was slower to develop with buprenorphine buccal film than with oxycodone. The initial onset of miosis that was significant relative to that seen with placebo occurred at 2 hours, 1.5 hours, and 1 hour after dosing with buprenorphine buccal film 300 μg, 600 μg, and 900 μg, respectively; and at 0.5 hours after dosing with oxycodone 30 mg or 60 mg. In addition, the miosis observed with buprenorphine buccal film 300 μg was significantly less than that seen with oxycodone 30 mg (at all time points except 4 hours post-dose) and oxycodone 60 mg (at all time points). Compared with both oxycodone doses (30 mg and 60 mg), administration of buprenorphine buccal film 600 μg resulted in significantly less miosis for up to 2 hours post-dose. Similarly, buprenorphine buccal film 900 μg led to significantly less miosis than either oxycodone doses did, for up to 1.5 hours post-dose.
Conclusions
In this study involving healthy volunteers, administration of oxycodone resulted in respiratory depression in a dose-dependent manner, whereas buprenorphine buccal film (at all doses) did not. In addition, the decrease in pupil diameter that is typically associated with opioid administration, occurred earlier after oxycodone use than after buprenorphine buccal film use. Since previous studies have shown a relationship between pupil constriction and opioid drug liking, the delayed miosis found with buprenorphine buccal film, relative to that seen with oxycodone, may be indicative of a lower risk of drug liking and abuse potential, at least in the time period immediately following drug administration. This is also in agreement with the abuse quotient (Cmax/Tmax) for buprenorphine buccal film, which is much lower than that for oral oxycodone. Together, these results suggest that buprenorphine buccal film, at these doses, may be a safer treatment option than full μ-opioid agonists for the treatment of chronic pain.
52 Can the implementation of the CDC’s opioid guidelines by providers decrease opioid misuse among patients in 2 months?
Mariel Cunamay
Brandman University, Irvine, CA, USA
Purpose
The purpose of this project is to decrease the misuse of opioids in the clinic by utilizing the recommended CDC’s Opioid Guidelinesand to demonstrate that its use can influenceclinician behavior and decrease opioids prescribed by primary care providers.
Methods
This quantitative research project utilized the paired samples t-test to compare the
urine drug screen tests of participants at their first visit against their last visit to detect for opioid misuse. Pain levels were assessed using the Wong-Bakers Faces pain rating scale to evaluate the effectiveness of opioid management and pain control.
Results
Utilizing the paired samples t-test, results of the UDS pre – implementation(M = 27.93 SD = 4.93)and post- implementation of opioid guidelines(M = 26.14 SD = 4.11) t(29) = 2.05, p = .047, p < .05, show statistically significant decrease of opioid misuse in the clinical setting.
Conclusions
Results show clinical significance in practice by offering insight on certain risk factors predisposes an individual to opioid misuse, it effectively managed pain among patients, decreased the rate of opioids prescribed, and increased the use of UDS testing and pharmacy drug monitoring programs.
53 Assessing conversion to transdermal fentanyl (TDF) or methadone during transition on hospice admission
Sulgi Chaea, Kathryn Walkerb and Mary Lynn McPhersona
aUniversity of Maryland School of Pharmacy, Baltimore, MD, USA; bMedStar Health Palliative Care Medicine, Baltimore, MD, USA
Purpose
This study determined if TDF/methadone dose transitions are done appropriately in the week prior to transition from hospital to hospice setting
Methods
Patients were retrospectively identified for inclusion into the study by reviewing patients who discharged by death from Seasons Hospice between July 1 2015 – June 30 2019. Each eligible patient was screened and ultimately admitted into the review if they have met the inclusion/exclusion criteria. Research investigator also obtained the previous inpatient hospitalization’s oral morphine equivalent (OME) and time exposure from MedStar Health electronic health record to help guide the analysis in determining the appropriate drug initiation or titration. A standardized algorithm was created and approved by research investigators prior to data collection. This study is IRB exempt.
Results
Baseline characteristics include hospice admission diagnosis (68%), male (52%), hospice setting of home (68%), and average age of 71. Only 5 patients (26%) of all methadone and TDF initiation/titration were done appropriately in our findings.
Conclusions
More than half of initiation or titration of the two high-risk opioids were deemed inappropriate by our criteria. TDF initiation made up the majority of inappropriate dose changes in patients who discharged on hospice. Medication changes made with palliative care pharmacist involvement were more likely to be appropriate.
54 Delphi study of opioid stewardship programs in hospice setting
Sul Gi Chaea, Kathryn Walkerb and Mary Lynn McPhersona
aUniversity of Maryland School of Pharmacy, Baltimore, MD, USA; bbMedStar Health Palliative Care Medicine, Baltimore, MD, USA
Purpose
Perform a Delphi study to characterize which National Quality Forum (NQF) recommendations have the highest utility in implementation in hospice practice.
Methods
Delphi survey of 13 experts will be conducted to reach a consensus. The inputs will be anonymous to the rest of the expert panel. The questionnaire will include the additional questions regarding the experts’ clinical experience. The panel will be asked to 1) rate the utility of each NQF recommendation on 0–5 Likert scale and 2) list top ten recommendations as ‘top contenders’ that were considered most important in hospice practice. In this research, ‘utility’ was defined as relevance; 2) ability to set metrics and measure outcomes; 3) importance; 4) ease of operationalization in hospice care. Experts will also be encouraged to provide literature, data, and rationale of their responses, which will be distributed back to the group anonymously. In the second round of Delphi, the experts were asked to repeat the utility rating listing the top ten recommendations as ‘top contenders.’ The experts were also asked to propose possible metrics to measure the ‘top contenders’ recommendations, which will be explored further in a separate study.
Results
In the first round of Delphi, 18 NQF recommendations averaged higher than 3 on the utility Likert scale and received >25% consensus as the highest priority/importance in hospice setting. The rest of NQF recommendations were excluded from the second round.
In the second round of Delphi, the top ten contending recommendations averaged 4.413 on the utility Likert scale. The top ten recommendations, in descending order, 1) Require ongoing clinician training, education, and engagement to support effective pain management and opioid stewardship for prescribers and care teams 2) Develop core competencies in pain management for members of the interdisciplinary team, including clinicians responsible for and engaged in opioid stewardship 3) Support consistent use of prescription drug monitoring programs (PDMPs) for all prescribers 4) Implement organizational leadership accountability for: Developing processes to address clinicians whose prescribing practices are outliers amongst their peers Developing systems to support the safety of clinicians, patients, and family caregivers around safe storage and disposal of opioids Monitoring for healthcare worker drug diversion and holding staff accountable per organizational policies (e.g., compliance with controlled substance waste procedures) Treating and providing support for healthcare workers who exhibit signs of opioid use disorder (OUD) or drug diversion 5) Engage patients and family caregivers as partners in setting pain management goals based on realistic expectations for safe and effective pain relief and functional outcomes 6) Invest in staff education on appropriate pain management strategies, opioid stewardship, and effective patient communication techniques 7) Invest in staff education on appropriate pain management strategies, opioid stewardship, and effective patient communication techniques 8) Ensure patients’ pain needs are being adequately addressed and clinicians are not discharging or avoiding patients due to complexities involved in pain management 9) When prescribing opioids, promote patient and family caregiver education and awareness of: Drug interactions and side effects, including signs of withdrawal and overdose Safe drug storage and disposal Risks and signs of drug diversion Risks of dependence with opioid therapy – Naloxone availability, indications, and use and 10) Develop and promote the use of standardized risk assessment tools, while understanding their limits in predictive accuracy, to identify vulnerable or at-risk patients prior to prescribing opioids.
Conclusions
The results of this two round Delphi panel showed that the experts found a wide spectrum of NQF recommendations that is most appropriate in hospice practice, ranging all the way from staff education to hospital leadership. Most recommendations that received highest consensus included strong emphasis on staff/patient education, utilization of PDMP, and organizational leadership’s role in establishing site-specific protocols for safe drug disposal and drug diversion prevention.
55 Opioid stewardship MATters: addressing opioid use disorder across the continuum of care
Michelle Busch and Todd Walroth
Eskenazi Health, Indianapolis, IN, USA
Purpose
More than 2 million patients suffer from opioid use disorder in the United States resulting in a vulnerable population in need of targeted treatment efforts. Our health-system has addressed this need by implementing opioid stewardship efforts related to medication assisted treatment (MAT) led by an oversight committee and clinical pharmacist. A clinical pharmacist position dedicated to pain and opioid stewardship initiatives was created in March 2019 with the main objective to implement an opioid stewardship program across inpatient and outpatient services. Alongside developing a new service, this pharmacist focuses on process improvement activities related to opioids, maintaining regulatory readiness, tracking and reporting various metrics related to opioid prescribing and pain management, policy and procedure development, leveraging the electronic health record to support pain management and opioid use, ensuring legal compliance, and the development of a controlled substance diversion detection and prevention program. This pharmacist also serves as the cochair for a newly formed interdisciplinary pain management oversight committee for the institution. Led by the oversight committee, strategies for addressing pain management in patients receiving MAT have been designed and implemented, such as: policy development, implementation of assessment tools, electronic order sets, patient and provider education, and alignment of treatment agreements for controlled substances and buprenorphine across specialties.
Methods
In October 2019, process mapping was completed by the pain management oversight committee to identify gaps and needs in current clinical pathways and workflows related to treatment and access for opioid use disorder across the continuum of care. This gap-analysis reviewed opioid use disorder from all perspectives of patient interactions (i.e., ED, inpatient, PCP, OB, teen, MAT, transitions, etc.) from initial presentation through follow-up. A questionnaire was distributed to interdisciplinary committee members from various departments, both inpatient and outpatient, to outline baseline screening, treatment, and referral practices for patients with opioid use disorder prior to the discussion. Responses were recorded and distributed to committee members to facilitate discussion. Current state processes were analyzed in order to develop inefficiencies and variation in practice, in order to develop a more streamlined future state process that would meet the needs of the multiple service lines involved. Following this work, updates needed for various order sets, policies, screening tools, and education were identified.
Results
Results from this gap-analysis led to the identification and prioritization of various projects related to opioid use disorder and its treatment at our organization. In early 2020, a formalized clinical opiate withdrawal scale (COWS) assessment was implemented in combination with an inpatient MAT initiation electronic order set to facilitate appropriate dosing and monitoring of buprenorphine/naloxone. Prior to this, a discrete order for a COWS assessment did not exist in the electronic health record (EHR) and could only be ordered through a generic nursing communication order. MAT initiation was at the discretion of the ordering provider with no direction or dosing support in the EHR. This effort required collaboration between inpatient hospitalists, pharmacists, information services (IS) support, nurses, and clinical education team members. Specialty-specific education was created for providers, nurses, and pharmacists prior to the COWS and MAT order set implementation. Providers were given an hour of live continuing education (CE) to review opioid use disorder, associated stigma, MAT options, COWS assessment, and EHR changes. Pharmacists were provided similar live education while nurses completed education electronically. After all clinical education was complete, the COWS assessment and MAT order set went live in February 2020 and its use in the first month was evaluated. From 02/11/2020 to 03/08/2020, the new order set was utilized for 79 individual orders on 13 unique patients. We are working with our informatics team to obtain necessary data to conduct a pre and post implementation analysis; endpoints collected will be inpatient buprenorphine/naloxone prescribing, orders for COWS assessment, and nursing documentation related to COWS. Results from the initial walkthrough also prompted the creation of a website with provider access to answers to frequently asked questions about opioid use disorder and associated treatment to be prioritized. Pain recommendations before, during, and after surgery concentrated on guidance for surgeons managing acute pain in patients receiving MAT have been developed. Additional projects that were identified for future initiatives include educational materials for MAT products and naloxone, targeted education to providers and nurses, naloxone access and supply, identification of metrics specific to MAT, assessment of the referral process, and inpatient consult services.
Conclusions
A pain management oversight committee and clinical pharmacy specialist dedicated to opioid stewardship play integral roles in the prioritization of initiatives to address identified gaps in workflows related to opioid use disorder and MAT. Oversight committees promote interdisciplinary collaboration across the organization. Other health-systems are encouraged to evaluate their own processes in order to identify opportunities for improvement in caring for these patients across the continuum of care.
56 Efficacy of subcutaneous tanezumab for the treatment of osteoarthritis across body mass index groups: a subgroup analysis of pooled data from two randomized, placebo-controlled trials
Francis Berenbauma, Bill McCarbergb, Iris Zinkc, Claudia Rivera-Salasc, Jerry Halld, Mojgan Sadrarhamie and Ruoyong Yange
aSorbonne Université, INSERM, AP-HP Hospital Saint Antoine, Paris, France; bUniversity of California, San Diego, CA, USA; cLansing Rheumatology, East Lansing, MI, USA; dEli Lilly and Company, Indianapolis, IN, USA; ePfizer Inc., New York, NY, USA
Purpose
Tanezumab is a monoclonal antibody against nerve growth factor with efficacy in the treatment of osteoarthritis (OA). Higher body mass index (BMI) can reduce the effectiveness of some drugs. This pooled, post-hoc, subgroup analysis explored the efficacy of subcutaneous tanezumab in patients with OA and differing BMI.
Methods
A pooled exploratory analysis of patient level data from two randomized, placebo-controlled, Phase 3 trials (NCT02697773 and NCT02709486) of subcutaneous tanezumab (2.5 mg or 5 mg every 8 weeks for 16 or 24 weeks) in patients aged ≥18 years with moderate-to-severe knee or hip OA. In one trial, tanezumab was titrated from 2.5 mg at baseline to 5 mg at Week 8. This data is included in the pooled 5 mg group. Co-primary endpoints were change from baseline in Western Ontario and McMaster Universities OA Index (WOMAC) Pain (0 to 10; increasing pain), WOMAC Physical Function (0 to 10; increasing difficulty), and Patient Global Assessment of OA (PGA-OA; 1 to 5; poorer assessment) scores. Results are presented as LS mean change from baseline versus placebo at Week 16 with 95% confidence interval. This exploratory post-hoc analysis was not part of the pre-specified hypothesis testing plan or included in any sample size calculations (leading to possibly low or uneven n); therefore, comparisons between treatment or BMI subgroups (<25; 25–30, 30 – <35, and ≥35 kg/m2) should be conducted with caution.
Results
In the overall pooled population, comprising patients of all BMIs, both tanezumab doses were associated with improved WOMAC Pain, WOMAC Physical Function, and PGA-OA scores at Week 16 compared with placebo (all p < 0.05).Similar improvements vs placebo were observed for allthree outcomes, irrespective of BMI(grouped as<25 [placebo n = 51; 2.5 mg n = 72; 5 mg n = 64], 25─<30 [165; 162; 169], 30─<35 [167; 172; 183], and≥35 [130; 107; 101]).In the pooled population, change in LS mean WOMAC Pain score over placebo (n = 513) was −0.7 (−0.95, −0.37) and −0.7 (−0.99, −0.41) in the 2.5 mg (n = 513) and 5 mg (n = 517) tanezumab groups, respectively.In the BMI subgroups, change over placebo ranged from −0.6 to −0.9 for both tanezumab doses (all p < 0.05 [unadjusted] except for 5 mg in the <25 kg/m2 subgroup and both doses in the≥35 kg/m2 subgroup).In the pooled population, change in LS mean WOMAC physical function score over placebo was −0.7 (−1.00, −0.42) and −0.8 (−1.08, −0.50) in the 2.5 mg and 5 mg tanezumab groups. In the BMI subgroups, change in over placebo ranged from −0.6 to −0.9 for both tanezumab doses (all p < 0.05 [unadjusted] except for 5 mg in the <25 kg/m2 subgroup). In the pooled population, change in LS mean PGA-OA score over placebo was −0.2 (−0.30, −0.09) and −0.3 (−0.36, −0.15) in the 2.5 mg and 5 mg tanezumab groups. In the BMI subgroups, change over placebo ranged from −0.1 to −0.3 for both tanezumab doses (p > 0.05 [unadjusted] except for 5 mg in the 25─30 kg/m2 and≥35 kg/m2 subgroups).
Conclusions
This exploratory analysis indicates that patient BMI does not influence the improvements in OA associated with short-term subcutaneous tanezumab use.
57 Not another opioid crisis: assessing pharmacists’ knowledge and attitudes about opioid use for pain management and palliative care
Natalie Malonea, Andrea Wetshteina,b, Jessica Geigera and Abigail Beneckea
aOhioHealth, Columbus, OH, USA; bCleveland Clinic Fairview Hospital, Cleveland, OH, USA
Purpose
Will targeted education regarding safe opioid prescribing practices and pharmacokinetics increase knowledge and confidence among hospital pharmacists?
Although pain is one of the most common reasons for visiting a provider, few health care professionals report adequate training on appropriate pain management.1−3
Many pharmacists, especially in the community setting, express low confidence in promoting safe opioid use due to lack of time and training.Limited literature has been published assessing these same parameters for hospital-based pharmacists.2
At our institution, system-wide opioid comfort orders are based on pharmacokinetic properties, such as half-life and time to peak serum concentration (effect).
Objectives of this study were to assess health-system pharmacists’ baseline knowledge and attitude scores regarding opioid medications and prescribing habits and determine if education about opioids would improve knowledge and attitude scores.
Methods
Pre/post observational study evaluating change in pharmacists’ knowledge and comfort with opioid verification and opioid recommendations to providers following a virtual competency program
Survey questions were developed both from the literature and through collaboration with OhioHealth pharmacists.3
Competency program reviewed pharmacology of opioids, opioid equivalency tables, definition of tolerance and naïve, and opioid conversions.
Results
Overall knowledge scores increased significantly from the pre-education group (M = 3.98 ± 1.51) to the post-education group (M = 5.63 ± 1.26;p < 0.001).
A significantly larger proportion of participants in the post-education group gave a correct answer for 5 of the 9 knowledge questions.
A significantly smaller proportion of participants in the post-education group disagreed with the question ‘I feel I have received adequate training regarding opioids and pain management throughout my career’ (p = 0.007).
Conclusions
A virtual education program increased health-system pharmacist knowledge about the pharmacology of opioids. Attitudes toward common prescribing practices surrounding opioids also changed. Opioids are a high-risk medication and the education provided surrounding this project has been added to an annual competency for pharmacists at OhioHealth. Future directions may include an evaluation of new pharmacy graduates to evaluate their knowledge and attitudes surrounding opioids as well as their exposure to education surrounding opioids.
58 Cumulative laxation response with methylnaltrexone: implications for hospitalized patients with advanced illness and opioid-induced constipation
David Farchardia, Neal E. Slatkinb,c, Nancy Stamblerd, Robert J. Israele and Michael Matusa
aLoma Linda University Medical Center, Loma Linda, CA, USA; bUniversity of California Riverside, School of Medicine, Riverside, CA, USA; cSalix Pharmaceuticals, Bridgewater, NJ, USA; dProgenics Pharmaceuticals, New York, NY, USA; eBausch Health US, LLC, Bridgewater, NJ, USA
Purpose
Hospitalized patients with advanced illness often encounter constipation when receiving opioid treatment for pain. Methylnaltrexone (MNTX) is a peripherally acting μ-opioid receptor antagonist used to treat opioid-induced constipation (OIC), which does not affect opioid central analgesia. This post hoc analysis evaluated cumulative laxation response rates with repeated doses of MNTX in adults with advanced illness and laxative refractory OIC who had varying levels of baseline functional status.
Methods
Data were pooled from 2 randomized, double-blind, placebo-controlled studies. Patients received subcutaneous MNTX 0.15 mg/kg or placebo (study 302; NCT00402038) or subcutaneous MNTX 8 mg (38–<62 kg), 12 mg (≥62 kg), or placebo (study 4000; NCT00672477) every other day for 2 weeks. Baseline assessments included demographics and patient characteristics (eg, primary diagnosis, functional status, laxative use). Endpoints were rescue-free laxation (RFL) within 4 or 24 hours after the first dose, cumulative laxation rates after the first and second doses, and after the first, second, and third doses. RFL response rates were also analyzed when patients were stratified by baseline functional status (assessed by the World Health Organization [WHO] or the Eastern Cooperative Oncology Group [ECOG] performance status scales). Other endpoints included time to RFL, pain intensity, and treatment-emergent adverse events.
Results
The analysis included 364 patients (MNTX = 179; placebo = 185). The median age was 66 years in each group. Approximately 52% were women; 94% were white. The primary diagnosis was cancer (63.4%), followed by cardiovascular disorders (11.3%) and pulmonary disease (7.4%), among others. Cumulative RFL responses with MNTX increased from 62.4% within 4 hours of the first dose to 80.9% within 4 hours of the third dose compared with 16.8% and 35.1%, respectively, with placebo. Cumulative RFL responses among MNTX-treated patients with baseline WHO/ECOG performance status of >2 at baseline increased from 59.0% within 4 hours after the first dose to 81.0% within 4 hours of the third dose compared with 12.4% and 32.4%, respectively, with placebo. Similar findings were observed among patients with baseline WHO/ECOG performance status of ≤2. Median time to RFL was significantly shorter with MNTX than with placebo, at the 4- and 24-hour time points following initial dosing (4 hours: 1.11 vs >4 hours; 24 hours: 1.11 vs 23.58 hours; P < 0.0001 for both comparisons). Similar results from the Kaplan-Meier analysis were observed when patients were stratified by baseline WHO/ECOG performance status. Regardless of baseline WHO/ECOG status, no significant differences vs placebo were observed in current and worst pain intensity scores. Treatment-emergent adverse events were mostly gastrointestinal in nature (ie, nausea, abdominal pain, flatulence).
Conclusions
In a diverse population of laxative-treated advanced-illness patients with OIC, MNTX significantly improved RFL responses 4 hours after the first dose vs placebo; the cumulative response continued after the second and third doses and was maintained regardless of baseline WHO/ECOG status, indicating that MNTX efficacy was not impacted by functional performance status. Opioid analgesia was maintained, and side effects were generally reflective of effective laxation. These findings have implications for hospitalized advanced-illness patients with OIC.
59 Kyphoplasty and vertebroplasty: a systematic review of 26 clinical studies for height restoration in osteoporotic vertebral compression fractures.
Nimesh Patela, Lakshmi Nerusub, Marissa Tandronb, Jessin Johna, William Daileyb, Ricardo Ayalaa, Mark Pahutaa, Jason Schwalba, David Jacobsa, Patrick Forresta, Nabil Sibaia and Rohit Aiyera
aHenry Ford Health System, Detroit, MI, USA; bWayne State Medical School, Detroit, MI, USA
Purpose
Osteoporotic vertebral compression fractures (OVCF) are a major source of chronic and acute low back pain, with over 700,000 cases reported in the US annually. In addition to the human suffering caused by OVCF, this condition also leads to enormous economic and productivity losses in the US, with an estimated 149 million days of lost work per year and productivity losses of $100-200 billion annually. Occurring mainly in older adults with osteoporosis, OVCF are usually treated with conservative management, such as lumbosacral orthotic compressor brace/belts, calcitonin, physical therapy, bed rest, and short-duration narcotics; however, conservative approaches are ineffective for many patients. Therefore, it is crucial to know which treatments are most successful in relieving pain and restoring function for patients who are refractory to conventional treatment.
Kyphoplasty and vertebroplasty are vertebral augmentation therapies that can restore bone height, which is a major factor in alleviating the morbidity due to OVCF. While both procedures involve injection of a polymer cement into sites of fracture, kyphoplasty involves using an inflatable balloon to first make space for polymer injection. These minimally invasive procedures are recommended for patients who have OVCF but are refractory to conventional therapies. Additionally, 2017 guidelines identify other patients who may benefit from vertebral augmentation, such as those with benign bone tumors or traumatic acute vertebral compression fractures with a local kyphotic angle greater than 15 degrees.
While kyphoplasty and vertebroplasty have both been assessed in clinical trials, there is no comprehensive review comparing the two procedures that takes into consideration all clinical results. Our aim was to perform a thorough systematic review to identify the overall effectiveness of these two methods to better inform the medical community regarding which strategy would best benefit OVCF patients. Because restoration of vertebral height is a key factor associated with pain relief, we chose to assess height restoration as a primary indicator of therapeutic success. Additionally, we used restoration of function and pain relief as secondary outcomes in order to provide a comprehensive picture on how these two procedures compare.
Methods
Our systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Protocols Statement issued in 2015. A literature search was performed to identify relevant studies using electronic databases, PubMed/MEDLINE (1954 to March 2020), Embase (1974 to March 2020), Web of Science (1954 to March 2020), Cochrane Library (including Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (1970 to March 2020), ClinicalTrials.gov (2008 to March 2020), and CINAHL (1937 to March 2020) to retrieve randomized controlled trials (RCTs).
Regarding data extraction and quality assessment, only RCTs were included. The Harden model was used to break down studies into different levels of review. Only level II studies were included, which is ‘One or more well powered randomized, controlled trials.’
For study selection, inclusion criteria included: patient over the age 18, studies written in English, study population of vertebral osteoporotic compression fractures, active comparator (placebo or treatment) and RCTs that had an outcome measure of height restoration with statistical significance. If the study included height restoration, we also included secondary outcomes of pain relief and functionality.
Exclusion criteria included: omitting systematic review, observational studies, case reports, editorials, case series, non-human (animal) studies, cadaver models, non-English studies, inclusion of patients with vertebral compression fractures other than osteoporosis, and studies of kyphoplasty and/or vertebroplasty that did not look at outcome measures of vertebral height restoration.
A total of 1752 articles were identified and duplicates were removed, resulting in 1248 articles. Titles and abstracts were screened, resulting in 48 articles. The full-text of these 48 articles were then assessed for eligibility, and all studies apart from RCTs for osteoporotic vertebral compression fractures without statistical analysis were removed. This resulted in a final number of 26 articles that were included in the study, with 4 of the studies specifically comparing kyphoplasty to vertebroplasty.
Results
A total of 26 RCTs were viewed. Of the 26 studies, 19 reviewed kyphoplasty, 11 reviewed vertebroplasty, and there was overlap within 4 studies that performed head-to-head comparisons of kyphoplasty and vertebroplasty.
Vertebral Height Restoration:
A. Of 11 studies that investigated vertebroplasty, 2 showed less height loss after vertebroplasty, 1 showed no improvement after vertebroplasty as measured by Becks index, 4 showed improvements as percent change ratio, and all 4 studies that measured absolute vertebral height gain showed improvements.
B. Of 19 studies that assessed vertebral height restoration with kyphoplasty, none reported vertebral height loss, 10 reported vertebral height restoration, and 9 reported absolute restored vertebral height.
C. Of the few studies that compared kyphoplasty head-to-head with vertebroplasty, 1 study did not show significant anterior height restoration ratio post-operatively at 3 months for either procedure, 1 study showed significantly more vertebral body height restoration from kyphoplasty, and 1 did not find any significant increase in vertebral body height for either procedure.
Wedge, Kyphosis, and Cobbs Angle Restoration:
A. Of the 4 studies that investigated wedge angle after vertebroplasty, all showed significant post-operative improvement. One study that measured kyphoplasty showed improved but not statistically significant post-operative wedge angle.
B. While there were no studies that directly compared kyphoplasty to vertebroplasty regarding kyphosis angle restoration, 1 study reported significant improvement from vertebroplasty, and 7 studies showed improvement from kyphoplasty.
C. For Cobbs angle restoration, there were no reports that assessed with this vertebroplasty, but 7 studies of kyphoplasty showed significantly improved Cobbs angle, some with lasting changes up to 3 years.
Pain Reduction:
A. Of 9 studies that looked at preoperative and postoperative VAS scores for patients who received vertebroplasty, 7 studies reported all patients having had reduced postoperative pain scores.
B. Of 19 studies that measured kyphoplasty, all patients had reduced postoperative pain scores, with long-term follow-up showing sustained reductions in pain at 12 months and 24 months.
C. Of the 4 studies that directly compared kyphoplasty and vertebroplasty, all reported statistically significant sustained reduction in pain, with no difference between the procedures.
Restoration Of Functionality:
A. Functionality was assessed by the Oswestry Disability Index (ODI) in most studies. Of the 5 studies that looked at pre- and post-operative ODI after vertebroplasty, all showed improved functionality. For kyphoplasty, 13 of the 19 studies showed improved functionality. Only 1 study measured functionality as a comparison of both procedures and showed that all patients improved.
Conclusions
Our systematic review found evidence to support both kyphoplasty and vertebroplasty as effective treatments for OVCF. Each therapy was shown to restore some vertebral body height, reduce kyphosis angle, improve Cobbs angle, and improve the wedge angle. Importantly, both treatments also showed similar benefits for pain reduction and improved patient-reported functionality. Although fracture type and age of fracture may be important parameters influencing outcomes from kyphoplasty versus vertebroplasty, there was insufficient evidence available to make any associations between fracture type and height restoration. Also, there is a possibility that the occurrence of cement leakage, which can lead to negative outcomes, may be higher for kyphoplasty. Overall, while clinical studies have revealed multiple benefits from both methods, it was not possible to conclude whether one approach was superior to the other. However, we conclude that our results are extremely encouraging for clinicians, since both kyphoplasty and vertebroplasty are effective, viable options for treating OVCF patients who have not benefited from traditional therapies.
60 Concern about addiction is associated with lower quality of life in patients with osteoarthritis: an observational data analysis
Louis P Garrison Jra, Patricia Schepmanb, Andrew B Bushmakinb, Rebecca L Robinsonc, Leslie Tiveb, Jerry Hallc, Mendy Dzinginab, James Jacksond, Mia Berryd and Joseph C Cappellerib
aUniversity of Washington, Seattle, WA, USA; bPfizer Inc, New York, NY, USA; cEli Lilly and Company, Indianapolis, IN, USA; dAdelphi Real World, Bollington, United Kingdom
Purpose
Osteoarthritis (OA) pain is one of the most common and economically burdensome conditions in the United States, affecting approximately 20% of adults and resulting in high healthcare costs and lost work productivity. Clinical guidelines recommend a multimodal approach to treating OA, combining physical therapies with pharmacological intervention, such as acetaminophen, NSAIDs, opioids, and other medicines. According to a prior US treatment preference study of a hypothetical pharmacological treatment that would prevent OA from worsening, patients with OA would be willing to accept some degree of risk for adverse events (Fraenkel et al., 2014). In a more recent study of OA patient preferences, Turk et al. (2020) showed that control of OA pain and symptoms and reduced treatment-related risk of physical dependency would be the two most important attributes of a new medicine for adult patients with moderate to severe OA and inadequate response to pain treatment. Several different measurement instruments could be helpful in weighing these impacts on patient quality of life (QoL). One of the most widely used disease-specific measure of OA symptoms is the Western Ontario and McMaster Universities of Osteoarthritis Index (WOMAC). While the WOMAC is commonly used in clinical studies, it is not suitable for direct use in conventional economic evaluation because WOMAC scores provide neither a cardinal nor a preference-based index scale. And generic instruments used to measure patient QoL for economic analysis, such as the EQ-5D, are infrequently included in clinical studies. Therefore, economic evaluations sometimes rely on a mapping from WOMAC to predict the EQ-5D. Several studies, including Cappelleri et al. (2016), have a demonstrated consistent statistical relationship between the two with demonstrated goodness of fit. In the current research, we aim to evaluate the relationship between self-reported concerns about becoming addicted to a medicine (for this condition, opioids) and individual patient QoL measured alternatively by (a) the EQ-5D-5 L Index score and (b) the EQ-5D Visual Analogue Scale (VAS) in patients with OA.
Methods
This unique, non-trial observational study used patient-level cross-sectional surveydata collected from February-May 2017 from the US Adelphi Disease Specific Programme (DSP), which provides a holistic assessment for illnesses by gathering descriptive data on how diseases are managed in clinical practices based on both physician and patient perspectives. The Adelphi DSP for OA selected 153 physicians (primary care, rheumatology, and orthopedic surgeons) identified from publicly available lists of healthcare professionals. Physicians completed an on-line survey and an electronic patient record form collecting de-identified data (including patient demographics, medical history, treatment patterns) on their next 9 adult (18 years+) patients with OA. Each patient was invited to complete a self-completion survey relevant to the disease area.
The question of interest for this analysis was about a ‘concerns of medication addiction’ as reflected in the following Likert-scale question based on the level of agreement (from completely disagree [1] to completely agree[5]) with the statement ‘I am concerned about becoming addicted to my medicine’ (CAA). A set of ordinary least squares (OLS) regressions using QoL measures (EQ-5D Index score and EQ-5D VAS) as outcomes and CAA as a continuous predictor were estimated, including models with CAA as a categorical predictor as a sensitivity analysis. The relationship between EQ-5D utility score as a predictor and EQ-5D VAS as the outcome was also studied. Finally, treating the EQ-5D VAS as the more general indicator of QoL, an OLS regression with the EQ-5D VAS as an outcome and with the EQ-5D-5 L Index score and the CAA as two independent continuous predictors was estimated in this sample. Correlations between the measures were also assessed.
Results
A total of866 OA patients completed the survey with the majority beingfemale (61.2%), white (77.7%) and with mean age of 64.2 years (Standard deviation 11.7). 835 patients completed the single item: ‘I am concerned about becoming addicted to my medicine’. The responses were well distributed with sizable representation for each category: about one-third of the patients responded that they ‘agree’ (18%) or ‘completely agree’ (11%), while 27% responded ‘completely disagree’ and 20% ‘disagree’. The relationship between CAA as a continuous predictor and the EQ-5D Index score revealed that a one-category increase in CAA score is associated with a 0.029 reduction in the EQ-5D Index score, equivalent to 0.14 in terms of the standardized effect sizes (ES), which can be interpreted ‘trivial-to-small’ effect. The difference in means between the lowest category (‘Completely disagree’) and the highest category (‘Completely agree’) corresponds to value of 0.11 (p < 0.0001) in the EQ-5D Index score (a ‘medium’ 0.57 ES). Correlation between CAA and the EQ-5D Index score is 0.19 (p-value<0.0001). The relationship between CAA and the EQ-5D VAS showed that a one-category increase in CAA score was associated with a 2.6 points reduction in the EQ-5D VAS (0.15 ES). The difference in means between the lowest and the highest category is 10.5 (p < 0.0001) representing ‘medium’ ES of 0.59. Correlation between CAA and the EQ-5D VAS is 0.20 (p-value<0.0001). Using CAA as a categorical predictor indicated that a linear approximation is appropriate in both models. A significant and robust relationship between EQ-5D VAS as an outcome and EQ-5D Index score as a predictor was observed (slope 60.7; p value<0.0001). Correlation between EQ-5D Index score and the EQ-5D VAS is substantial 0.69 (p-value<0.0001). Using EQ-5D Index score as a categorical predictor indicated that a linear approximation is appropriate. When both EQ-5D Index score and CAA scores where used simultaneously as predictors of EQ-5D VAS, the effect of CAA (after adjusting for EQ-5D utility) was still significant (slope −0.97, p = 0.0071). In this case, the difference between the CAA lowest and highest categories is 3.89 and the associated effect size is 0.22, which would be regarded as ‘small’ statistically. This is equivalent to −0.039 on a utility scale of 0–1.0, which would be regarded as significant in utility and economic terms.
Conclusions
This study found that patients with a diagnosis of OA who have concerns about medication addiction – as reflected in self-reported concern about addiction – have significantly and meaningfully different EQ-5D utility and EQ-5D VAS scores compared with patients who do not have this concern. Furthermore, concern about addiction has an additional negative impact – of potential clinical and economic importance – that is not fully captured in EQ-5D utility. Health technology assessment authorities who rely on the EQ-5D may underestimate the value of products that reduce concerns about opioid dependency. It is well-accepted that the EQ-5D works better for some diseases than others. One work-around or adjustment that is sometimes used is to include a ‘bolt-on’ question for patients in trials. In this case, it would be worthwhile to consider a bolt-on question for inclusion (after successful psychometric validation) about these concerns in an assessment of the impact of new interventions on OA patients. To our knowledge, this study is the first to use rigorous methodologies to estimate the disutility impact of concern about opioid addiction on patient quality of life in OA. Further research is needed to evaluate direction and magnitude of effect by severity for this disease.
61 Treatment patterns of patients with moderate-to-severe osteoarthritis in the United States
Ryan Hansena, Patricia Schepmanb, Sheena Thakkarb, Rebecca Robinsonc, Craig Beckd, Deepa Malhotrab and Birol Emirb
aUniversity of Washington, Seattle, WA, USA; bPfizer Inc, New York, NY, USA; cEli Lilly and Co, Indianapolis, IN, USA; dPfizer Ltd, Surrey, United Kingdom
Purpose
Chronic pain is typically defined as pain that lasts for more than 3 to 6 months and can be the result of a wide array of issues, including underlying medical conditions or disease such as osteoarthritis (OA). OA is a degenerative joint disease involving the cartilage and surrounding tissues that impacts approximately 32.5 million adults in the United States (US). Two of the most commonly affected OA joints are the hips and the knees (it can also affect the hands, facet joints, and feet). The current standard of care for OA focuses on symptomatic pain management and improving joint movement. Pain management options are classified into non-pharmacological and pharmacological management, and joint surgery.Pharmacological treatment options for OA pain commence with the use of oral analgesics, followed by topical/oral non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. A number of studies have assessed the relative effectiveness and safety of OA pain medications. A literature review conducted by Costa et al (2014) assessed the effectiveness of opioids (oral and transdermal) for the treatment of hip and knee OA (vs placebo or no intervention) and found a limited effect of opioids on pain and functional outcomes. For safety outcomes, adverse events and substance abuse could potentially limit the use of opioids for OA pain management. Although the American College of Rheumatology’s clinical practice guideline conditionally recommends the use of tramadol and conditionally recommends against the use of non-tramadol opioids for patients with OA, opioids continue to be prescribed. The aim of this study was to characterize the demographics of patients who received treatment for moderate-to-severe OA pain, and to compare them to the non-moderate-to-severe OA pain cohort.
Methods
This was a retrospective cohort study using data from the 2013–2018 IBM® MarketScan®Commercial and Medicare Supplemental Database (integrated US commercial claims database that contains patient-level demographic, diagnosis, inpatient, outpatient, procedure, prescription and payment information). Patients aged ≥45 years, with at least one diagnosis of hip and/or knee OA (ICD9/10) or unspecified diagnosis of OA plus a diagnosis of pain in the hip or knee within 3 months during the study period were included. The date of the first OA diagnosis was defined as the index date. Patients who presented with at least one of the following criteria: a visit to a specialist within 3 months post-index date, a surgical or non-surgical invasive procedure relating to OA treatment within 12 months post-index period, had ≥2 prescriptions for various NSAIDs within 3 months post-index date, ≥2 prescriptions for any opioids within 3 months post-index date, or an Emergency Room (ER) visit for hip or knee OA within 12 months post-index date, with a subsequent primary care physician visit within 14 days were classified as having moderate-to-severe OA pain. To minimize selection bias, moderate-to-severe OA pain patients were propensity-score matched 1:1 with patients with an OA diagnosis to non-moderate-to-severe pain (controls) using age, sex, Charlson Comorbidity Index (CCI) score, type of health plan, obesity, anxiety, depression, and geographical region. Descriptive analyses were performed to gain a better understanding of the data used in this study and of the characteristics of the study populations. Binary and categorical variables were summarized as counts and proportions of the total study populations, and by subgroups where appropriate. Continuous variables were reported as means (standard deviations) or median and ranges, where appropriate. Bivariate analyses were conducted to identify significant demographic/clinical characteristics between the treatment/outcome groups and to identify potential covariates for inclusion in multivariable models. For dichotomous and categorical measures, Chi-squared tests or Fisher’s exact tests were used to test for differences between groups. For continuous measures, t-tests or Wilcoxon rank-sum tests were utilized to test for differences for two-sample comparisons and one-way analysis of variance in the case of multi-sample comparisons.
Results
A total of 546,254 patients with OA were eligible for the study; after propensity score matching, the final cohort count was 186,374 in each group. Overall, 65.6% of patients were aged 45–65 years and 34.4% were ≥65 years and there were more females (61.0%) than males in both cohorts. More than half of patients within the moderate-to-severe cohort were on a Preferred Provider Organization (PPO) healthcare plan (51.0%) and most were from the Southern and North-Central regions of the US. Prior to matching, patients in the moderate-to-severe cohort had a lower mean CCI score (0.95) compared with the non-moderate-to-severe cohort (1.11; P < 0.0001). Comorbidities of interest were reported for 37.6% of patients (moderate-to-severe) vs 32.6% (non-moderate-to-severe) with the majority being sleep-related (16.8% vs 14.0%, respectively; P < 0.0001).After propensity score matching, overall pain medication use was greater in the moderate-to-severe pain cohort 12-months (89.6% vs 76.1%) and 24-months’ post-index (94.0% vs 85.0%) vs the non-moderate-to-severe cohort (P < 0.0001).The three most commonly prescribed medications at baseline were NSAIDs (39.5% vs 32.3%), non-tramadol opioids (41.2 vs 28.6%) and antidepressants (28.3% vs 21.7%) in the moderate-to-severe vs non-moderate-to-severe cohorts, respectively (all P < 0.0001). In the 12-month follow-up period, prescriptions for non-tramadol opioids, tramadol and intra-articular injections of corticosteroids increased (38.6%, 54.6% and 133.6%, respectively) in the moderate-to-severe cohort, while prescriptions for non-tramadol opioids, tramadol and intra-articular injections of corticosteroids increased by smaller rates (2.6%, 16.4% and 88.5%, respectively) in the non-moderate-to-severe group over the same period. In the 24-month follow-up period, prescriptions for non-tramadol opioids, tramadol and intra-articular injections of corticosteroids also increased (66.4%, 101.8% and 185.3% in the moderate-to-severe cohort, and 44.9%, 51.0%, and 35.8% in the non-moderate-to-severe group) over the same period.
Conclusions
This study provides valuable information on the characteristics of patients with moderate-to-severe OA pain of the hip and/or knee. In this study, most patients with moderate-to-severe OA pain were female, from the Southern and North-Central regions of the US, aged 45–65 years, and on a PPO healthcare plan.A greater proportion of patients with moderate-to-severe OA pain reported comorbidities of interest and greater use of pain medication that those with non-moderate-to-severe OA pain.This study also provides insights into current treatment paradigms and showed that patients with moderate-to-severe OA pain had a substantial increase in prescriptions for non-tramadol opioids, tramadol and intra-articular injections of corticosteroids 12 months from baseline, while those with non-moderate-to-severe OA pain received smaller increases for the same medications over the same time period. Moreover, greater increases in prescriptions for non-tramadol opioids, tramadol and intra-articular injections of corticosteroids were noted 24 months from baseline in the moderate-to-severe group than the non-moderate-to-severe group.Data are limited as causal relationship between factors and outcomes cannot be inferred; however, these data demonstrate potential areas for further exploration in improving patient outcomes.
62 The impact of pain severity on treatment patterns, adherence and healthcare resource utilization among individuals with osteoarthritis in the United States.
Patricia Schepmana, Sheena Thakkara, Rebecca Robinsonb, Craig Beckc, Deepa Malhotraa and Birol Emira
aPfizer Inc, New York, NY, USA; bEli Lilly and Co, Indianapolis, IN, USA; cPfizer Inc, Surrey, United Kingdom
Purpose
Chronic pain impacts approximately 100 million patients in the United States (US), accounting for an estimated $560 to $635 billion per year (2010 dollars) in direct and indirect health care costs, including workplace productivity. Osteoarthritis (OA) is one of the most common causes of chronic pain and a leading cause of disability in the US. Furthermore, increased pain severity in patients with OA is associated with a poorer overall health-related quality of life (HRQoL), increased healthcare resource utilization (HCRU) and costs.Using survey data of individuals with OA from the Kantar 2019 US National Health and Wellness Survey (NHWS), we have previously shown that respondents with moderate-to-severe pain due to OA had more comorbidities, a higher rate of obesity, lower work productivity (longer disability leave, greater activity and work productivity impairment, absenteeism and presenteeism) and decreased HRQoL than those with mild OA pain. However, the extent to which pain severity among patients with OA differentially affects treatment patterns and adherence to pain medications has yet to be addressed. The objective of this study was to compare treatment patterns, medication adherence and HCRU of respondents with mild vs moderate-to-severe OA pain in a real-word setting.
Methods
This cross-sectional, observational study assessed data from the NHWS (Jan 2019-Dec 2019); a self-reported, internet-based survey containing data from 74,994 respondents, representative of the US population. Potential respondents were primarily identified via opt-in online survey panels, with stratified random sampling to ensure representativeness of age and gender. Adults ≥18 years who responded to the NHWS with patient-reported physician-diagnosed OA were included in the study. Respondents who reported experience with OA pain were included in the pain module of this study (N = 6,851). These respondents were excluded if they reported cancer pain, did not report OA pain, or reported that the only joint affected by OA was the back, shoulder or neck. Data were available for 5,836 respondents. Self-reported data were collected for OA pain severity, OA pain treatment, adherence to pain medication (current and past) and HCRU. Patients were stratified into OA pain severity cohorts based on responses to the Short Form-McGill Pain Questionnaire visual analog scale (SF-MPQ-VAS) (mild: 1–34, moderate: 35–74, severe: ≥75, moderate-to-severe: combination of moderate and severe cohorts). Respondents who had a pain score of 0 were excluded from the study. The type of OA pain medication prescribed, number of pain drugs received, duration (length of time) and frequency of medication (maximum number of days taken in prior month) taken by respondents were recorded. Adherence was assessed using the simple version of the Medication Adherence Rating Scale (MARS), for which respondents provided an estimate of how much (%) of their prescribed pain medication they had taken in the last 4 weeks. Medication satisfaction was measured using a Likert scale of 1–7, with a score of 1 being extremely dissatisfied and a score of 7 being extremely satisfied. HCRU was assessed by the presence or absence of a visit during the 6 months prior to the survey, as well as recording the number of outpatient visits, emergency room (ER) or urgent care visits, and all-cause hospitalizations. Total population and cohorts were analyzed using descriptive analyses. Univariate analysis was performed to examine differences in treatment patterns and HCRU between mild and moderate-to-severe OA pain respondents.
Results
Overall, 5,836 respondents were included and stratified into cohorts with mild (n = 2,038) or moderate-to-severe (n = 3,798) OA pain. The majority of respondents across both mild vs moderate-to-severe cohorts were ≥55 years (55–64 years: 26.2% vs 31.3%; ≥65 years: 56.6% vs 45.2%), white (86.6% vs 82.3%), female (57.3% vs 69.4%), and had knee OA (72.5% vs 79.5%), respectively. Most respondents had a body mass index (BMI) that classified them as overweight (BMI 25–29 kg/m2: 34.5% vs 26.0%) or obese (BMI ≥30 kg/m2: 40.5% vs 53.0%), (both P < 0.0001) respectively. While approximately half of mild and moderate-to-severe respondents were retired (52.4% vs 47.0%), significantly more respondents with mild OA pain were employed full-time (21.0% vs 16.6%) and reported an income ≥$75,000 (42.1% vs 26.4%), (all P < 0.0001) respectively. Compared with mild OA pain respondents, significantly more moderate-to-severe OA pain respondents had self-reported diagnoses of sleep disturbance (7.8% vs 16.4%), insomnia (12.2% vs 25.3%), depression (23.6% vs 41.6%) and general anxiety disorder (10.2% vs 19.1%), (all P < 0.0001) respectively. Furthermore, frequency of daily OA and joint pain was higher for the moderate-to-severe OA pain cohort (P < 0.0001). Compared to those with mild OA pain, moderate-to-severe OA pain respondents received a greater proportion of pain drugs overall (31.7% vs 92.4%), especially NSAIDs (8.7% vs 21.8%) and strong opioids (4.0% vs 15.2%), (all P < 0.0001) respectively. The most commonly taken over-the-counter drugs by both cohorts included acetaminophen and ibuprofen; and more mild OA pain respondents took ibuprofen (35.0% vs 29.9%) and less took acetaminophen (32.2% vs 36.9%) than moderate-to-severe OA pain respondents (both P < 0.01). Compared with mild OA pain respondents, those with moderate-to-severe OA pain took pain medication for longer (94.2 vs 106.8 months) and at a higher medication frequency (21.1 vs 22.7 days during prior month; P < 0.05). However, moderate-to-severe OA respondents reported lower overall satisfaction with their pain medication (4.8) vs mild OA pain respondents (5.2; P < 0.0001), specifically NSAIDs and opioids (P < 0.0001). Despite this, moderate-to-severe OA pain respondents were more adherent to their pain medication (76.4%) than those with mild OA pain (65.2%; P < 0.0001). HCRU analyses showed that the number of outpatient visits (94.3% vs 95.8%, p < 0.05), ER visits (11.5% vs 18.9%, p < 0.0001) and hospitalizations (8.1% vs 10.8%, p < 0.01) 6 months prior to the survey were greater in the moderate-to-severe OA pain cohort vs the mild OA pain cohort.
Conclusions
This real-world study captured a large amount of information on the impact of pain severity in 5,836 respondents with OA and their current treatments. Compared with those with mild OA pain, respondents with moderate-to-severe OA pain received significantly more pain medication, more frequently and showed greater adherence; however, this cohort was also significantly more dissatisfied with their current pain medication. Comparisons across both cohorts showed that respondents with moderate-to-severe OA pain reported greater HCRU, including outpatient visits, ER visits and hospitalization 6 months prior to participation in the survey. While these data are limited to self-reported pain assessed cross-sectionally over the past 4 weeks and applied to self-reported medical history, these findings were consistent with other studies that assessed treated populations and may be expanded to understand the relationship of OA pain severity, HCRU and treatment patterns at a national level. Understanding the clinical and economic burden of patients with moderate-to-severe OA pain may help to direct future changes in clinical practice settings and inform stakeholders to provide effective pain treatment in patients with moderate-to-severe OA pain.
63 Long-term cardiovascular safety of lasmiditan for the acute treatment of migraine for up to one year: interim results of an open-label phase 3 study (GLADIATOR)
Noah Rosena, Paul Mathewb, Andrew Buchananc, Simin Bayganic, Helen Hochstetlerc and Rashna Khannac
aDonald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hofstra University, Hempstead, USA; bHarvard Medical School, Boston, USA; cEli Lilly and Company, Indianapolis, USA
Purpose
Lasmiditan, a selective serotonin (5-HT) 1 F receptor agonist, lacks the vasoconstrictive activity of other acute migraine treatments. Previous studies of lasmiditan for the acute treatment of a single migraine attack demonstrated that the drug has a low risk of associated cardiovascular (CV) treatment-emergent adverse events (TEAEs), with no difference in the frequency of CV TEAEs between subjects with and without CV risk factors. The long-term CV safety of lasmiditan for the acute treatment of migraine for up to 1 year was assessed by analyzing interim results from the Phase 3 study GLADIATOR.
Methods
In GLADIATOR (NCT02565186), patients who previously participated in Phase 3, placebo-controlled, single-attack lasmiditan studies (SAMURAI, NCT02439320; SPARTAN, NCT02605174) were randomized 1:1 to open-label lasmiditan 100 or 200 mg taken as one dose (within 4 hours of the onset of moderate or severe pain) or, if needed, two doses (within 2–24 hours of each other). Both SAMURAI and SPARTAN allowed enrollment of patients with CV risk factors (e.g., hypertension, hypercholesterolemia, smoking, obesity, diabetes), and SPARTAN also included patients with coronary artery disease (CAD), arrhythmia, and uncontrolled hypertension. In GLADIATOR, CV adverse event rates (incident and recurrent events, defined using relevant Standardized MedDRA Queries) were calculated for 3 time periods – treatment-emergent (<48 hours postdose), intermediate (48 hours–1 week postdose), and remote (>1 week postdose) – as it is possible some CV events were not reported as treatment emergent or were identified at a later date. Consequently, CV events occurring beyond 48 hours of dosing were also analyzed to determine whether such events increased in the treatment-emergent or intermediate periods compared with the remote period.
Results
At data cutoff for this interim analysis, 1978 patients had received ≥1 dose of lasmiditan (963 received 100 mg, 1015 received 200 mg) and 19,058 migraine attacks had been treated in GLADIATOR. Median duration in the study was 288 days. Eighty-one percent of patients had ≥1 CV risk factor, 0.3% had CAD, and 35.0% had low high-density lipoprotein cholesterol. No vasoconstriction-related CV events (e.g. angina) occurred in the treatment-emergent period, and such events were rarely observed in general (absolute number ranged from 1 to 3, all in remote period, limiting clinical interpretation). As expected, treatment-related CV events (palpitations and tachycardia) were more frequent in the treatment-emergent period than in the intermediate and remote periods.
Conclusions
In an interim analysis of the long-term GLADIATOR study, no vasoconstriction-related CV events occurred during the treatment-emergent period. The CV safety of lasmiditan was generally consistent with data from single-attack studies.
64 A prospective evaluation of clinical and psychologic factors on extended postoperative opioid use after primary total joint arthroplasty.
Dhiren S. Shetha, Robert S. Nambaa, Peggy D. Zilla, Jose R. Piob, Ngoc J. Hob and Stephanie Tovarb
aKaiser Permanente, Irvine, CA, USA; bKaiser Permanente, Pasadena, CA, USA
Purpose
Anxiety, depression and pain catastrophizing have been implicated for increase in postoperative opioid use. The purpose of the study was to identify clinical and psychological risk factors associated with extended postoperative opioid use following primary joint replacement (TJR).
Methods
During preoperative visit patients were asked to fill out PHQ9, PCS (pain catastrophizing scale), opioid risk tool (ORT) and either KOOS-JR or HOOS-JR. Patient with opioid prescription dispensed after 90 days were considered as extended users. Enrollment was limited to primary TJR patients and data was collected in prospective fashion
Logistic regressions were used for univariate and multivariable modelings and create receiver operating characteristic (ROC) curves.A backward stepwise regression analysis was used to select significant factors in the multivariable model.
Results
The study included 258 patients (163 TKR, 95 THR) with average age of 68.2 years (range 23–91), 58% (151) were females, average BMI of 30.21 (range 19.26–43.13), 49.22% were obese (BMI >30) and 19% had total PHQ-9 score > 10. The average length of stay was 1.41 days. 23.6% patients had associated back pain. 29.84% were on pre-operative opioids and the majority of which (81.78%) were taking opioids for reasons other than index primary joint pain.
14% (37 out of 258) of patients had opioids dispensed after 90 days (extended users). In univariate analysis, age < 65, associated back pain, chronic pain or fibromyalgia, previous use of opioids, drug potency of more than 10 morphine equivalent and total score on ORT of more than 7, were associated with extended use. In multivariable analysis, age < 65, associated back pain, chronic pain and preoperative use of opioids were significant risk factors for extended use (combine AUC = 0.83). Pre-op Opioid Use had the highest AUC = 0.72 (p = 0.0005). None of the psychological profile tests either as continuous variable of total score or accepted cut off predicted extended use.
Conclusions
In our prospective study, preoperative opioid use was the strongest predictor of extended opioid use after primary THR and TKR. Neither total nor accepted cut off scores of the psychological profile tests assessing depression, pain catastrophizing or opioid addiction risk corelated with extended use of opioids.
65 Tolperisone 100 and 200 mg three times daily (TID) for acute muscle spasm of the back: a double-blind, randomized, placebo-controlled, multicenter phase 3 study
Randall Kayea, Henry Riordanb, Srinivas Nalamachuc, Joseph Pergolizzid and Sanam Ara Vaughna
aNeurana Pharmaceuticals, Inc., San Diego, CA, USA; bWorldwide Clinical Trials, Morrisville, NC, USA; cMid America PolyClinic, Overland Park, KS, USA; dNEMA Research, Naples, FL, USA
Purpose
Back pain, one of the most common reasons for a physician visit and a leading cause of disability worldwide, is typically due to acute musculoskeletal spasm. Skeletal muscle relaxants (SMRs) can be an effective treatment for the relief of pain due to acute muscle spasm. However, there are barriers to prescribing SMRs, including side effects such as somnolence and cognitive function impairment. Tolperisone, a centrally acting, nonopioid SMR in clinical development in the United States, does not have these untoward effects. The recently completed dose-ranging phase 2 STAR study (NCT03802565) evaluated tolperisone administered at 50, 100, 150, and 200 mg TID for 14 days in subjects with acute muscle spasm of the back. Tolperisone was effective for the relief of pain, with the greatest efficacy seen in the highest dose (200 mg TID). The primary efficacy endpoint, subject-rated pain ‘right now’ using a numerical rating scale (NRS) on day 14, was significantly lower (p = 0.0040) in the tolperisone 200 mg TID group compared with the placebo group. Although the study was not sufficiently powered, a number of secondary efficacy endpoints also trended toward statistical significance at the tolperisone 200 mg TID dose. Tolperisone was well tolerated and its treatment-related adverse events (AEs) were similar to those of placebo; the most common AEs were headache (7.1%) and diarrhea (2.4%). Importantly, the incidence of somnolence was comparable between subjects treated with tolperisone versus placebo (0%, 3.4%, 0%, and 1.2% of subjects in the tolperisone 50 mg TID, 100 mg TID, 150 mg TID, and 200 mg TID dose groups, respectively, compared with 2.6% of those in the placebo group). Based on the design of the phase 2 STAR study, the safety and efficacy demonstrated by tolperisone, and an earlier phase 1 driving simulation study, a pivotal phase 3 study has recently been launched to evaluate the safety and efficacy of tolperisone (100 and 200 mg TID) for the relief of pain due to acute muscle spasm of the back.
Methods
This is a double-blind, randomized, placebo-controlled, parallel-group, multicenter phase 3 study of tolperisone (100 and 200 mg TID) in subjects experiencing pain due to acute muscle spasm of the back. Subjects are randomized 1:1:1 to tolperisone 100 mg TID or tolperisone 200 mg TID or placebo for 14 days. Male or female subjects aged 18–64 years with current back pain and/or stiffness due to acute and painful muscle spasm starting within 7 days prior to study entry and at least 8 weeks after the last episode of back pain are eligible for enrollment. Eligible subjects must also have a subject-rated ‘pain right now’ NRS score of ≥4 at baseline. Subjects can receive acetaminophen 500 mg TID as rescue medication, with use documented daily through day 14. The primary efficacy endpoint is subject-rated pain ‘right now’ using NRS score (0 = no pain to 10 = worst possible pain) on day 14. Secondary endpoints include onset of action, time to relief, Clinician’s and Patient’s Global Impression of Change, and the Oswestry Disability Index questionnaire. Use of rescue medication and subject responses to the satisfaction questions ‘Would you take this medication again?’ and ‘Were you able to resume your usual activities?’ are exploratory efficacy endpoints. Safety assessments include AEs, a visual analog scale for subject-reported sleepiness, the Epworth Sleepiness Scale, and the Columbia-Suicide Severity Rating Scale. The study will be approved by an institutional review board at each site.
Results
Approximately 750 subjects will be enrolled at about 60 clinical sites in the United States, and the first subject is expected to be enrolled in October 2020. A second replicate phase 3 study will be initiated at a later date.
Conclusions
Pain due to acute muscle spasm of the back represents a common and disabling condition. Given the widespread clinical use of SMRs for acute muscle spasm of the back, physicians and patients must have a safe and effective alternative option that is not associated with somnolence or cognitive function impairment. In studies to date, tolperisone does not exhibit the CNS effects typically seen with currently available SMRs and is both effective and well tolerated with somnolence rates comparable to placebo-treated subjects. This pivotal phase 3 study is based on the promising results from the STAR phase 2 study and is sponsored by Neurana Pharmaceuticals, Inc. The phase 3 study will be conducted in a similar patient population as the phase 2 STAR study, and is designed to confirm the safety and efficacy of tolperisone for the management of acute muscle spasm of the back in a registration setting.
66 Adverse events associated with analgesics used for osteoarthritis pain: analysis of post-marketing data
Raveendhara Bannurua, Mo Dimbilb, Wenhui Weic, Susan Colillad, Clotilde Huyghues-Despointesc, Joanne Nettleshipd and Ravi Iyerd
aTufts Medical Center, Boston, MA, USA; bAdvera Health Analytics, Santa Rosa, CA, USA; cRegeneron Pharmaceuticals, Tarrytown, NY, USA; dTeva Pharmaceutical Industries, Frazer, PA, USA
Purpose
Several pharmacological interventions are available for treating patients with osteoarthritis (OA) pain. Whilst each of these therapies is associated with potential adverse events (AEs), those risks have not been comprehensively quantified in the real-world setting. Real-world data for AEs associated with OA analgesics may be useful to patients and healthcare providers to better assess treatment risk when considered within the context of an individual’s medical history and existing comorbidities. The aim of this study was to analyze post-marketing data for AEs associated with analgesics most commonly used for OA pain.
Methods
Data were obtained from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database between January 1, 2001, and June 30, 2019. We identified the known labeled risks associated with nonsteroidal anti-inflammatory drugs (NSAIDs), Drug Enforcement Administration (DEA) class II/III opioids, tramadol, and acetaminophen from theboxed warning, warnings, precautions, and adverse reactions sections of the drug labels for these agents. Based on this research, lists of custom Medical Dictionary for Regulatory Activities query searches were developed to identify AE cases. Cumulative case counts on primary suspect outcomes(i.e., cases in which the reporter listed the specified drug as the primary suspect cause associated with the AE) were calculated, and all cases were required to have OA as a reported condition. The reporting odds ratio (ROR) approach was used to compute a measure akin to the odds ratio to quantify the strength of the association between the specific aforementioned analgesic classes and AEs reported in a post-marketing safety database such as FAERS. RORs were calculated by dividing the odds of a specific AE occurring with the specific analgesic used for OA pain by the odds of that AE occurring with all drug classes (non-stratified) or only drug classes with OA as a reported condition (stratified). RORs greater than 1 indicated an elevated association between the specific drug class and the AE compared with the other drug classes, whereas RORs below 1 indicated lack of such an association. The limits of the 95% confidence intervals of ROR were obtained via an approximation of the normal distribution. The lower limit of this distribution (ROR05) was calculated and reported for both the non-stratified and stratified RORs, providing 95% certainty that the true mean of the population was at or above the number reported.
Results
During the study period in the FAERS database, the cumulative primary suspect case counts, with OA being a reported condition, were as follows: 7,128 for NSAIDs, 938 for DEA class II/III opioids, 296 for tramadol, and 149 for acetaminophen. For primary suspect AE cases overall, non-stratified ROR05s were greater than 1 (indicative of higher odds of AEs compared with the other drug classes) for 13 of the 16 expected safety issues for NSAIDs, 7 of the 18 for DEA class II/III opioids, 4 of the 18 for tramadol, and 1 of the 16 for acetaminophen. ROR05s were the highest for gastrointestinal (GI) ulceration/perforation (9.67), GI bleeding (8.24), and myocardial infarction (3.09) for NSAIDs; withdrawal symptoms (9.43), sedation (4.58), and drug abuse/dependence (2.13) for DEA class II/III opioids; withdrawal symptoms (2.92), GI obstruction (1.73), and drug overdose (1.22) for tramadol; and hepatotoxicity (7.37) for acetaminophen. Stratified ROR05 results showed similar trends but with different magnitudes. For primary suspect AE cases, when comparing to other drugs with OA as a reported condition, stratified ROR05s for NSAIDs were 2.72 for GI ulceration/perforation and 2.28 for GI bleeding. For DEA class II/III opioids, stratified ROR05s were 10.79 for withdrawal symptoms, 6.38 for sedation, and 2.56 for drug abuse/dependence. For tramadol, an association was demonstrated for seizures (1.42) when comparing to other drug classes with OA as a reported condition, which was not apparent in the non-stratified results. For acetaminophen, the stratified ROR05 was 6.58 for hepatotoxicity. Of all studied primary suspect cases with OA as a reported condition, serious AE cases (defined as death, life-threatening AEs, hospitalization, disability/permanent damage, congenital anomalies/birth defects, AEs requiring intervention to prevent permanent impairment/damage, or other serious AEs) comprised 55.7% (83/149) of all studied AEs with acetaminophen, 63.8% (598/938) with DEA class II/III opioids, 75.4%, (5,371/7,128) with NSAIDs, and 90.5% (268/296) with tramadol.
Conclusions
This study provides a comprehensive and quantitative evaluation of the safety issues with drugs used to treat patients with OA pain in the real-world setting. The results of our study demonstrate that the most commonly used OA analgesics are associated with elevated risks for certain AEs compared with the other drug classes, underscoring the need for new and safer therapies for OA pain. These data will help patients and healthcare providers to better assess the benefit-risk profiles of these analgesics before incorporating them into treatment regimens. This study was limited by the lack of control for other confounding factors and the potential for use of multiple medications in individual patients. Further research is required to evaluate the downstream effects of the studied AEs (e.g., medical costs) and to benchmark these AEs against the safety profiles for the evaluated analgesics reported in randomized clinical trials.
67 Creation and validation of algorithms to identify patients with moderate-to-severe osteoarthritis of the hip and/or knee and inadequate/intolerable response to multiple pain medications
Ariel Bergera, Rebecca L. Robinsonb, Yi Lua, Anthony J. Zagarb, Ann Yuea, Patricia Shepmanc, Marielle Bassela, Beth Johnstonb, May Slima, Sheena Thakkarc and Craig Hartrickd
aEvidera, Waltham, MA, USA; bEli Lilly and Company, Indianapolis, IN, USA; cPfizer Inc., New York, NY, USA; dAlgosunesis, LLC, Longboat Key, FL, USA
Purpose
Osteoarthritis (OA) is a degenerative joint disease involving the cartilage and surrounding tissuesthat impacts approximately 32.5 million US adults.1While its etiology is multifactorial, risk increases with advancing age – 2.1%, 19.8%, and 39.7% of persons aged 15–49 years, 50–69 years, and ≥70 years, respectively, are reported to have OA.2 Two of the most commonly affected sites are the hips and the knees (it also can occur in hands, facet joints, and feet).3OA is typically associated with pain, stiffness, and swelling, which collectively result in increasing levels of disability over time. Levels of disability can in fact preclude employment, with OA patients almost twice as likely as those without this condition to be unable to gain employment.4In addition to its deleterious physical and psychologic impacts, OA is associated with substantial societal and economic burden. One relatively recent study estimated annual mean total costs of OA to be approximately $16,1455 (expressed in 2019 US dollars), of which direct and indirect costs represent 71% and 29%, respectively.
While the deleterious impacts of OA are substantial, they are experienced disproportionately among those with moderate-to-severe disease and/or with relatively high levels of pain.3,6 Quantification of the burden among this subgroup would increase knowledge about OA that could in turn help inform development of new analgesic therapeutics. The most cost-efficient and timely means to undertake such examinations would be a retrospective cohort study based on analyses of large electronic healthcare databases. However, these databases typically lack the clinical information required to identify disease severity/progression, pain levels, and related measures. Conversely, while patients’ medical records typically contain the clinical information necessary to ascertain disease severity and pain levels, they lack cost data and may not offer ‘complete’ capture of utilization of healthcare services, as they are site/physician-specific. Thus, we undertook a limited pilot study to determine whether case-selection algorithms can be developed for use in electronic healthcare databases to identify with reasonably good accuracy patients with moderate-to-severe OA of the hip and/or knee and inadequate/intolerable response to ≥2 pain-related medications, using data sources that contained both electronic healthcare data and medical records.
Methods
We used data from the Reliant Medical Group (‘Reliant’). Reliant is a large, private, multispecialty group practice (>250 physicians in >20 locations) in central Massachusetts, with >1 million patient visits annually. For subgroups in the system, administrative data and curated electronic medical record data are available, as is the ability to conduct chart review. Institutional Review Board approval was obtained before information from patients’ charts was abstracted and analyses of their electronic health data was undertaken.
This pilot study comprised 14 adults (i.e., aged≥18 years), including 10 (71.4%) with at least one claim consistent with OA of hip or knee (defined as either≥1 medical claims resulting in diagnosis codes for OA of hip or knee, or≥1 medical claims for total/partial/revision of hip or knee arthroplasty); 2 (14.3%) with claims consistent with joint or back pain but without diagnosis codes for OA of hip or knee; and 2 (14.3%) without any claims that resulted in diagnosis codes for OA (any site), evidence of administration of hyaluronic (HA) acid or intra-articular (IA) steroids, or evidence of hip or knee arthroplasty. All criteria were assessed between January 1, 2014 and December 31, 2019 (‘study period’).
We used literature review and expert opinion to develop case-selection algorithms, limited to measures expected in electronic healthcare databases (specifically, claims), to identify patients with moderate-to-severe disease and inadequate/intolerable response to ≥2 pain-related medications. Patient allocation via algorithm was compared against information obtained from medical charts, which were considered the gold standard for patients’ ‘true status’. We assessed algorithm performance based on sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy.
Results
Mean age was 69.1 years and 78.6% were women. Most (78.6% of the study sample) were Caucasian; 14.3% and 7.1% were Hispanic and unknown race/ethnicity, respectively. Median (interquartile range) body mass index was 32.6 (26.5–40.0) kg/m2.
While several different pain and disease severity scales were assessed in patients’ charts, among those selected for the pilot test, the former was limited to numeric or verbal rating scales. Similarly, OA-specific severity assessment scales (e.g., Western Ontario and McMaster Universities Arthritis Index [WOMAC]) were not commonly recorded in patients’ medical charts. Patients averaged 6.1 pain assessments during the study period, albeit of varying frequency (range: weekly to once every two years). Functional disability was recorded in medical notes for 6 patients (42.9% of the study sample); information on degree of disability was often missing.
Chart review determined that 11 patients (78.6% of the study sample) had confirmatory evidence of OA of hip and/or knee. Among patients with ‘true’ OA of the hip/knee, 7 (63.6%) had confirmatory evidence of moderate-to-severe disease. Among those with ‘true’ moderate-to-severe disease, 5 (71.4%; 50.0% of patients with claims consistent with OA of the hip/knee; and 35.7% of the study sample) had confirmatory evidence of inadequate/intolerable response to≥2 pain-related medications.
PPV of our a priori algorithms for identifying patients with moderate-to-severe OA of the hip and/knee and inadequate/intolerable response to ≥2 pain-related medications ranged from 40.0% (≥2 medical encounters [inpatient or outpatient] with diagnoses of OA of the hip/knee within a 6-month period, ≥2 different opioids within a 90-day period) (2 of the 5 patients identified with this algorithm were ‘true positives’) to 100.0% (≥1 encounters with diagnoses of OA of the hip/knee, ≥1 mobility aids received within 30 days of an OA diagnosis [any site], ≥2 prescriptions for topical NSAIDs within 90 days of an OA diagnosis, and receipt of knee/hip arthroplasty [partial, complete, or revision]) (the single patient identified with this algorithm was a true positive). Estimates of sensitivity, specificity, and NPV for the algorithm with relatively low PPV were 40.0%, 66.7%, and 66.7%, respectively; corresponding estimates for the algorithm with relatively high PPV were 20.0%, 100.0%, and 69.2%, respectively. Overall accuracy ranged from 57.1% for the algorithm with relatively low PPV to 71.4% for the algorithm with relatively high PPV. Total true cases identified by any single algorithm ranged from 0 to 3.
Conclusions
While maximally efficient in terms of time and budget, electronic healthcare databases lack the necessary clinical detail to readily identify severity and pain associated with OA of the hip and/or knee. Nearly all patients in our pilot study were readily and accurately identified as having OA of the hip and/or knee using the a priori algorithms developed based on literature review and expert opinion; however, these algorithms were much less accurate in their ability to further differentiate by disease severity and/or pain levels. Moreover, no one algorithm identified more than 60% of total true cases. Classification of disease severity and pain levels was somewhat problematic as information required to inform these decisions was not consistently captured in patients’ medical records. Collectively, our findings suggest that potentially coupling detailed information from patients’ electronic records with their healthcare claims and/or using techniques of machine learning are needed to enable use of large, geographically representative healthcare data sources in the identification of this important subgroup of patients with OA of the hip and/or knee and subsequent quantification of burden of illness and levels of unmet need associated with current standard of care.
68 Ubrogepant is effective in the acute treatment of migraine with mild pain
Richard Liptona,b, David Dodickc, Peter Goadsbyd, Rami Bursteine, Aubrey Adamsf, Jeff Laig, Sung Yug, Michelle Finnegang and Joel Trugmang
aAlbert Einstein College of Medicine, Bronx, NY, United States Minor Outlying Islands; bMontefiore Headache Center, Bronx, NY, United States Minor Outlying Islands; cMayo Clinic, Phoenix, AZ, United States Minor Outlying Islands; dNIHR-Wellcome Trust King’s Clinical Research Facility, London, United Kingdom; eHarvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, United States Minor Outlying Islands; fAbbVie, Irvine, CA, United States Minor Outlying Islands. 7AbbVie, Madison, NJ, United States Minor Outlying Islands
Purpose
Ubrogepant, approved for the acute treatment of migraine in adults with/without aura, demonstrated efficacy in treating migraine with moderate/severe pain. Clinical guidance recommends treatment when pain is mild, a strategy studied herein for ubrogepant.
Methods
Phase 3, open-label, 52-week extension trial (NCT02873221). Adults with migraine with/without aura, randomized 1:1:1 to usual care, or in blinded fashion to ubrogepant-50 mg or −100 mg, treated up to 8 migraine attacks of any pain severity every 4 weeks. Efficacy measures, collected only for ubrogepant, included 2-hour pain freedom and absence of migraine-associated symptoms. Data were analyzed by first treated attack and all treated attacks (averaged for each participant and then across participants; individuals weighted equally).
Results
Data for 21,454 treated attacks (n = 808 participants) are included. Across all treated attacks, pain freedom was achieved in a higher proportion of attacks treated with mild vs moderate/severe pain for ubrogepant-50 mg (39% vs 19%; p < 0.0001) and ubrogepant-100 mg (43% vs 21%; p < 0.0001). Absence of photophobia was achieved in an average of 55% vs 34% (both doses; p < 0.0001) of attacks with mild vs moderate/severe pain, respectively. Absence of phonophobia was achieved in an average of 64% vs 42% (ubrogepant-50 mg; p < 0.0001) and 70% vs 45% (ubrogepant-100 mg; p < 0.0001) of attacks with mild vs moderate/severe pain, respectively. Absence of nausea was achieved in an average of 83% vs 67% (ubrogepant-50 mg; p < 0.0001) and 82% vs 68% (ubrogepant-100 mg; p < 0.0001) of attacks with mild vs moderate/severe pain, respectively. First treated attack data were similar. Overall, 10% of participants reported treatment-related adverse events; one considered serious (exacerbation of sinus tachycardia).
Conclusions
Treating migraine patients with ubrogepant when headaches are mild rather than moderate/severe increases the likelihood of rendering them free of pain and associated symptoms.
69 Summary of the preclinical pharmacology of NTM-006 (formerly JNJ-10450232): a novel orally-active non-opioid analgesic
Robert Raffaa,b,c, Joseph Pergolizzid,e, John Carsonf, Ellen Coddg,h and James McNallyi
aNeumentum, Tucson, AZ, USA; bUniv. of AZ, Tucson, AZ, USA; cTemple Univ., Philadelphia, PA, USA; dNeumentum, Naples, FL, USA; eNEMA, Naples, FL, USA; fCaRafe Drug Innovation, Princeton, NJ, USA; gCodd Consulting, Blue Bell, PA, USA; hOxfendazole Develop Group, Blue Bell, PA, USA; iAbzena, Bristol, PA, USA
Purpose
JNJ-10450232, a structural analog of acetaminophen, was designed to retain the good analgesic efficacy, but not have the usual liabilities, associated with opioid and other classes of analgesics (i.e., gastrointestinal, cardiovascular, respiratory and hepatic safety – or the abuse potential). Its clinical analgesic efficacy was demonstrated recently in a dental pain model, and its full potential in terms of efficacy and possible therapeutic use in chronic/neuropathic pain continues in development as NTM-006. We summarize here its basic preclinical pharmacology.
Methods
JNJ-10450232was screened in standard in vitro radioligand binding assays and in in vivoanimal models of acute pain, thermal hyperalgesia induced by an intraplantar injection of either carrageenan or Complete Freund’s Adjuvant, a postsurgical model with tactile allodynia, and it was tested for antipyresis. In vivo safety pharmacology studies were conducted in several species and in in vitroassays for toxicity.
Results
JNJ-10450232 had no significant affinity at more than four-dozen receptor types and subtypes (including opioid MOP, DOP, KOP; CB1 and CB2); enzymes (e.g., kinases and COX-1 and COX-2), or neurotransmitter reuptake site (norepinephrine). It did display concentration-related effect on binding at adenosine A3 receptors (A3R). It demonstrated antinociceptive, anti-hyperalgesic, and antipyretic activity in animal models suggestive of clinical efficacy in acute and possibly chronic/neuropathic pain conditions.
Conclusions
JNJ-10450232 demonstrated oral non-opioid, non-NSAID antinociceptive and antipyretic activity in several animal models predictive of analgesic efficacy against acute and chronic pain.Although structurally similar to APAP, it was different with respect to toxicology (little or no hepatotoxicity, as designed), metabolism (Phase-II), pharmacokinetics (much longer duration), as well as its overall in vitro and in vivo pharmacology profile.Based on in vitro assay screens, the compound is non-opioid, non-cannabinoid and non-NSAID (does not inhibit COX-1 or −2 cyclooxygenase isozymes) at doses that produce its antinociceptive and antipyretic effects. This preclinical pharmacologic profile is consistent with its efficacy and safety demonstrated in clinical testing. Future work as NTM-006 is aimed at elucidation of its full efficacy potential and possible use for chronic/neuropathic pain conditions with/without an inflammatory component.
70 Identifying barriers to care-seeking, diagnosis, and preventive medication among those with migraine: results of the OVERCOME study
Sait Ashinaa, Robert Nicholsonb, Karen Samaanb, Anthony Zagarb, Yongin Kimb, Eric Pearlmanb, Bert Vargasb, Dawn Busec, Michael Reedd, Susan Hutchinsone and Richard Liptonc,f
aDepartment of Neurology and Department of Anesthesia, Critical Care and Pain Medicine, and Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, USA; bEli Lilly and Company, Indianapolis, USA; cDepartment of Neurology, Albert Einstein College of Medicine, Bronx, USA; dVedanta Research, LLC, Chapel Hill, USA; eOrange County Migraine and Headache Center, Irvine, USA; fMontefiore Medical Center, Bronx, USA
Purpose
Understanding the patient path to receiving evidence-based preventive treatment for migraine may help identify barriers to effective treatment. The objectives were: 1) identify the proportion of those with migraine who are seeking care, have a migraine diagnosis, and are receiving recommended preventive medications and 2) compare individuals at each step regarding sociodemographic features, migraine-related characteristics, and migraine care-seeking location.
Methods
Data were obtained in the fall of 2018 from OVERCOME, a web-based survey conducted in a representative US sample. The study identified persons with migraine based on either ICHD-3 criteria (94% of the sample) assessed with a validated diagnostic screener or self-reported healthcare provider migraine diagnosis (61% of the sample). Candidates for recommended preventive treatment were defined as having ≥4 monthly headache days (MHDs) and at least moderate headache-related disability (MIDAS≥11). Respondents were categorized by MHD group (4–7, 8–14, ≥15). T-test or Chi-square test, across all respondents and stratified by MHD group, evaluated differences between groups at each step (p < 0.05).
Results
We identified 5,873 (27.8% of OVERCOME respondents) as candidates for preventive treatment. The mean age was 40.9 years, 79.7% female, and 74.1% Non-Hispanic white, 5.5% Non-Hispanic black, 9.9% Hispanic, 1.6% Asian, and 9.0% other (Table). Only 69% of the total population sought care and of those, 79.4% were diagnosed. Among those who sought care and were diagnosed, only 28.0% received recommended preventive treatment (Figure). Overall, only 15.4% of the total population went through all three steps. This ranged by MHD categories from 11.7% for those with 4–7 MHDs to 20.3% for those with ≥15 MHDs. Seeking care was associated with being male (Seeking = 21.8% vs Not Seeking = 16.9%, p < 0.001), having health insurance (Seeking = 89.4% vs Not Seeking = 80.1%, p < 0.001), and having severe (MIDAS ≥21) headache disability (Seeking = 74.2% vs Not Seeking = 63.1%, p < 0.001). Migraine diagnosis was associated with being female (Diagnosed = 79.5% vs Not Diagnosed = 73.4%, p < 0.001) and having severe headache disability (Diagnosed = 75.4% vs Not Diagnosed = 69.6%, p < 0.001). Being prescribed recommended preventive medication was associated with having health insurance (Prescribed = 94.5% vs Not Prescribed = 87.7%, p < 0.001) and having severe headache disability (Prescribed = 80.6% vs Not Prescribed = 73.4%, p < 0.001). Notably, seeking care exclusively at an ED/Urgent Care/Retail Clinic was associated with lack of diagnosis (Diagnosed = 7.8% vs Not Diagnosed = 12.9%, p < 0.001) and not receiving recommended preventive treatments (Prescribed = 2.2% vs Not Prescribed = 9.9%, p < 0.001).
Conclusions
Less than 1 in every 5 individuals with ≥4 MHDs and at least moderate disability traverse the steps to receiving recommended preventive migraine medication. Having health insurance, and higher levels of disability make this outcome more likely, whereas seeking care only at an ED, Urgent Care, or Retail Clinic makes it unlikely. These findings demonstrate the ongoing high level of barriers and opportunities for improvement in diagnosis and management of migraine given current availability of novel preventive therapies.
71 Real-world outcomes from high-dose transcutaneous electrical nerve stimulation in individuals with chronic knee pain
Shai Gozani and Xuan Kong
NeuroMetrix, Inc., Woburn, MA, USA
Purpose
About one-quarter of adults suffer from frequent knee pain, which limits function, decreases mobility and impacts quality of life. Osteoarthritis, affecting 30 million adults in the U.S., is the most common cause. Patients with chronic knee pain may be managed with opioids and non-steroidal anti-inflammatory drugs. However, these medications are not uniformly effective, have side effects and, in the case of opioids, may cause addition. Total knee arthroplasty (TKA) is a surgical option for some patients, however it has a long recovery time, is a costly procedure and may require prolonged post-operative pain management. For these reasons, there is a need for non-pharmacological analgesic options for chronic knee pain.
Transcutaneous electrical nerve stimulation (TENS) is a noninvasive treatment for chronic pain. Conventional TENS is delivered through surface electrodes, placed near the site of pain, to generate a strong paresthesia. The resulting stimulation of large diameter, deep tissue afferents produces transient analgesia. A possible mechanism of action is a reduction in central excitability and enhanced descending pain inhibition. TENS has been prescribed for chronic knee pain for several decades. However, recent meta-analyses on its clinical benefits are inconclusive. A likely contributor to the variability in study results is under dosing. TENS devices are generally designed for stimulation anywhere on the body through wired electrodes. This methodology can be cumbersome and complicate use during daily activities and sleep. In most studies, TENS use has been limited to 30–60 minutes per day, several times a week. Furthermore, objective compliance monitoring has rarely been utilized which creates further uncertainty on study fidelity. Recently, wearable TENS devices have been developed for extended use that do not interfere with daytime activity and sleep. These devices provide high-dose TENS, which may be defined as regular (i.e., at least 3–4 days week) stimulation for several hours. The purpose of the present study was to assess outcomes following up to 10-weeks of high-dose TENS use in individuals with chronic knee pain.
Methods
This retrospective, real-world study evaluated users of a wearable TENS device (Quell®, NeuroMetrix, Woburn, MA). The device is placed on the upper calf and provides semi-continuous nerve stimulation (60 minutes every other hour) at an intensity that is calibrated to a strong, nonpainful sensation. The device and a companion mobile app collect demographics, pain characteristics, pain measures and usage data provided by users who opt-in to research participation. The data is uploaded to a cloud database. Data analyses are performed on an anonymized version of the database.
Eligible users were those that provided demographic, clinical and pain data prior to initiating therapy. A subset meeting the following criteria were included: a) pain duration greater than 3 months, b) pain frequency at least several times a week, c) baseline pain intensity at least 4 on an 11-point numerical rating scale (NRS), d) self-reported knee pain and e) stimulation on at least half of the 70-days following the start of TENS.
The study evaluated two outcomes measures. Pain intensity was assessed on an 11-point NRS. Functional impairment was assessed with a subset of the BPI-SF pain interference domain. The sleep, general activity and mood items were averaged to form a composite functional impairment indicator between 0 and 10. The pain intensity and pain interference ratings were provided voluntarily at the user’s discretion and reflected overall pain rather than for a specific anatomical site. Both outcome measures were assessed at baseline and as close to 70-days following the start of TENS as available, using an intention-to-treat analysis. The baseline pain and functional impairment ratings occurred on the first day of device use or within the prior 6 days (latest one used). The follow-up rating was taken as that closest available to day 70. If there was no follow-up rating then the value was imputed using the baseline observation carried forward method. The changes in pain intensity and functional impairment were defined as the baseline subtracted from the follow-up. The mean group change was calculated across all participants and compared to the null hypothesis of no change using the one-sample t-test.
Results
A total of 1136 device users met the inclusion criteria. Study participants had a mean age of 58 (SD 13) years, 61.1% were female and the mean BMI was 31 (SD 8) kg/m2. Participants self-reported a mean of 5.7 (SD 2.6) pain sites and 4.4 (SD 2.5) painful health conditions. The most common self-reported conditions were arthritis (73%), prior leg injury (45%) and prior back injury (46%). Among those reporting arthritis, 62% specified osteoarthritis. Most participants (77%) reported chronic pain duration of at least 4 years. At baseline, the mean pain intensity was 6.8 (SD 1.6). Mean pain interference with sleep, activity and mood were 5.9 (SD 2.8), 7.3 (SD 2.1) and 6.5 (SD 2.5), respectively, which yielded a functional impairment score of 6.5 (SD 2.0). Pain sensitivity to weather was reported by 73% of participants.
Study participants used wearable TENS on 58 (SD 11) of the 70-day assessment period at an average of 7.0 (SD 2.6) hours per day. The average follow-up period was 50 (SD 29) days. A follow-up rating was imputed for 88 (8%) participants who only had a baseline rating. The follow-up pain rating was less than 30 days for 220 (19%) participants. The mean group change from baseline to follow-up was −1.0 (SD 2.3) for pain intensity and −1.4 (SD 2.5) for functional impairment, both p < 0.001.
Conclusions
Consistent with earlier epidemiological studies of knee pain, the participants in this study were older adults, more likely to be female, tended to be overweight or obese, and had moderate to severe pain and substantial functional impairment. Knee pain was not an isolated symptom, as most participants reported additional pain in other body locations. The key study finding was that in an intention-to-treat population with chronic knee pain, high-dose TENS was associated with clinically meaningful group changes (i.e., 1-point or greater) in pain intensity and functional impairment.
Study strengths included the large, real-world sample which supports generalizability of the findings, the use of an intention-to-treat population to reduce bias from participants who stopped therapy early, and objective compliance monitoring to improve study fidelity. The study was limited by the lack of a control group against which to compare the change in pain measures. As a result, the relative contributions of specific effects from high-dose TENS and nonspecific contributions from placebo and regression to the mean cannot be determined. Another limitation was that because the pain measures were not site-specific, the outcomes cannot necessarily be attributed to changes in knee pain.
72 Telehealth in Pain Medicine: Lessons Learned During the COVID-19 Pandemic
Sharon Weinstein
University of Utah, Salt Lake City, UT, USA; VASLCHCS, Salt Lake City, UT, USA
Purpose
Three selected cases of Pain Medicine clinical encounters are presented to illustrate three lessons learned during the conversion of face to face care to telehealth care (via video and telephone) mandated during the COVID-19 pandemic emergency situation. These lessons are described in three general categories. Those are: 1) care processes, 2) clinical impact, and 3) administrative to include costs. Lessons learned are important for improving clinical outcomes, conveying new information to clinicians planning to implement telehealth, conveying new information to clinicians utilizing telehealth, conveying new information to administrators promoting the use of telehealth and payers considering reimbursement for telehealth services. Care processes involve patient, staff, clinician and administrative perspectives.
Methods
Experience implementing telehealth services in three different health care systems in the state of Utah are the source of material to be described. Since the onset of the COVID-19 pandemic in the United States, different health systems have had different approaches to the implementation and acceleration of telehealth services. This senior Pain Medicine clinician has been practicing in these health systems for over twenty years and has made observations of the different approaches to implementing telehealth particularly since the COVID-19 pandemic hit the state of Utah. Three cases are chosen to illustrate the lessons learned from this experience. She has engaged with patients, other clinicians, and other administrators to share their observations of the impact of telehealth services on pain medicine care.
Results
There are differences in the outcomes of telehealth pain medicine services that depend on multiple factors. These factors can be divided into patient related, clinician related, technical and systems related factors. Some of the outcomes are positive and some may be negative.
Some of the positive outcomes of telehealth pain medicine were surprising.
The illustrative case reports are chosen to highlight both the positive and negative aspects of delivering telehealth pain medicine services.
Conclusions
Given the uncertainty of the COVID-19 pandemic in terms of changes to health care in the United States and the duration of the pandemic, we can expect to be using telehealth pain medicine in our care of patients well into the future.
The lessons illustrated in these cases categorized by care processes, clinical impact and administrative issues will be very important to carry going forward. Additional lessons will likely be learned as we continue to provide telehealth pain medicine services
73 A long term, open label study of Safety and Tolerability Of Precision olfactory delivery of DHE in acute migraine (STOP 301): clinical results
Sheena Aurora, Maria Jeleva, Jasna Hocevar-Trnka, John Hoekman and Stephen Shrewsbury
Impel NeuroPharma, Seattle, WA, USA
Purpose
Introduction: Migraine is a common neurological disease impacting at least12% of the United States population. Despite several recent approvals of novel abortive treatments, a high unmet need and patient dissatisfaction remains for early onset of effect, sustainable pain relief, and reduced recurrence of migraine attacks. Systemic dihydroergotamine (DHE) mesylate has a rapid onset and sustained effect, and we have previously reported similar plasma levels of DHE mesylate from 20 minutes achieved with INP104 in our Phase 1, STOP 101 trial. INP104 is a novel drug-device combination product that targets delivery of DHE mesylate to the upper nasal space, a previously unexplored route of administration, using a Precision Olfactory Delivery (I123 POD®) device.
Objective: Toreport the safety, tolerability, patient acceptability and exploratory efficacy of INP104 for migraine from the pivotal, Phase 3 STOP 301 trial.
Methods
STOP 301 was a multicenter, open-label, 24-week safety, tolerability, patient acceptability and exploratory efficacy study, with a subset entering a 28-week extension period (52-week treatment); (NCT0355733). Patients were required to complete a daily diary and a migraine diary with every attack during screening period and on treatment. After a 28-day screening period where patients used their ‘best usual care’ to treat migraine attacks, patients were allowed to self administer up to 3 doses/week of INP104 nasally with self-recognized migraine attacks (1.45 mg in 2 puffs through the POD device). The primary objective of this study assessed safety and tolerability, with specific focus on change in nasal mucosa and olfactory function.Exploratory objectives included efficacy assessments of migraine measures compared to best usual care, patient acceptability by a questionnaire (PAQ), and healthcare utilization and quality of life measures (MIDAS and HIT-6) were also collected.
Results
360 patients entered the 24-week treatment period, with 185 and 354 patients in the Primary Safety Set (PSS) and Full Safety Sets (FSS) respectively, while 55 and 73 patients composed the respective 52-week data sets. 36.7% of patients reported AEs, with 6.8% of patients discontinuing due to AEs (FSS). No significant olfactory mucosal integrity issues or functional disturbance was found by upper nasal endoscopy, nasal related TEAEs, and University of Pennsylvania Smell Identification Test (UPSIT) scores. Most common TEAEs were nasal congestion (15.0%), nausea (6.8%), nasal discomfort and unpleasant taste (5.1% each) with all other TEAEs being report by < 3%. There were no treatment related Serious AEs, no cardiac TEAEs and no deaths. A total of 4,515 migraines were treated with INP104 during the 24-week treatment period (FSS). 33.1% and 49.1% of patients reported pain- and most bothersome symptom-freedom at 2 hours post-INP104 nasal delivery (Weeks 21–24, PSS) compared to 26.2% and 43.9% on best usual care at baseline, respectively. Sustained pain freedom through 24 hours was also reported in the majority of patients, as 98.4% of patients were relapse-free of their migraine after using INP104 (Weeks 21–24) compared to 93.2% using best usual care at baseline (PSS).The PAQ demonstrated that the majority of patients agreed or strongly agreed that they found INP104 easy to use (~84%) and preferred it over their current therapy(FSS).
Conclusions
INP104 has the potential to deliver well tolerated, rapid and effective symptom relief, predictably and consistently, without injection. No new safety signals were observed following delivery to the upper nasal space. These data, along with reported patient acceptability questionnaire results, suggest INP104 may be a promising acute treatment for patients suffering from migraine.
74 A case report of pain management in calciphylaxis associated with end stage renal disease
Shuo Qiua,b and Charles Lambb
aCarilion Clinic, Roanoke, VA, USA; bSalem VA Medial Center, Salem, VA, USA
Purpose
Current estimate for prevalence of calciphylaxis is 3.5 new cases/1000 patient-years.1 Risk factors include obesity, female sex, diabetes, and ESRD on dialysis.2 Development of calciphylaxis is thought to be due to decreased expression of calcification inhibitors which in term increases precipitation of calcium phosphate in microvessels, leading to infarctions in the subcutaneous adipose tissue and dermis.3,4 The resulting presentation is an overlying necrotic skin tissue with frequent development of painful lesions.4 The necrotic skin tissue can be further complicated by sepsis. Other associated symptoms include depression, anorexia, skeletal myopathy, intestinal bleeding, and visual impairment. Mortality is much higher if patient has ESRD with 1-year mortality rate of 45–80% than those without ESRD (25–45%).
The gold standard diagnostic test is skin biopsy. Key diagnostic features are stippled calcifications of media layer of capillaries or peri-eccrine glands, pauci-inflammatory intravascular thrombi, fibrointimal hyperplasia or thrombosis in the capillaries.4,5 However, the pathognomonic presentation of painful ulcer with eschar in the setting of ESRD may not warrant a biopsy for diagnosis.4 Although calcium plays a central role in the pathophysiology, its serum level can be variable and is not a diagnostic feature in calciphylaxis.
Since calciphylaxis affects multiple organ systems, an interdisciplinary approach composed of dermatology, nephrology, nutrition, pain, and plastic surgery can achieve the best patient care.3 PTH should be maintained in normal range. Excess calcium and vitamins D supplements should be stopped. Reports regarding cinacalcet in reducing incidences of calciphylaxis are emerging and warrant further studies. Cinacalcet is described in multiple studies to be helpful in treating skin lesions.3,6 Warfarin can increase risk of calciphylaxis while vitamin K1 is being studied for efficacy to slow down progression of calciphylaxis by halting the calcification process. Sodium thiosulfate has shown to be promising in improvements in ulcers in calciphylaxis. Possible mechanisms of sodium thiosulfate action include vasodilatory properties and inhibiting the calcification process.
Pain management can be challenging due to pain severity, especially during removal of necrotic tissues. Often a combination of acetaminophen, topical anesthetics, opioids, gabapentin, ketamine, and/or spinal anesthetic agents are needed.4,7
Methods
The patient is a 61-year-old male with history of diabetes, ESRD with kidney transplant on chronic steroids, coronary artery disease status-post myocardial infarction and percutaneous coronary intervention, and peripheral arterial disease (PAD). The diagnosis of calciphylaxis was explored when the patient continued to experience pain despite improvement in perfusion of his PAD. The diagnosis was confirmed by pathology report and radiologic imaging including CT and XR. Patient’s lab showed a calcium level of 9.1 mg/dL and phosphate level of 4.2 mg/dL.
For treatment, patient withheld calcium and vitamin D supplement. He underwent IV sodium thiosulfate treatment and took cinacalcet 30 mg daily. However, neither thiosulfate nor calcitonin prevented subsequent attacks or alleviated pain.
The patient continued to have intermittent ischemic events in his hands and feet leading to gangrene and osteomyelitis. As a result of tissue destruction, there were multiple limb-conservation procedures required, including amputations of portions of his right index and middle finger, as well as the distal portion of the left middle finger. He also had transphalangeal amputation of the left hallux and open transmetatarsal amputation of left toes two through five. During inpatient admissions, his pain was managed using combinations of varied opioid and non-opioid medications. For opioids, he initially received oxycodone 7.5 mg five times daily plus oxycodone 5 mg four times which was effective for five admissions. He then had to be rotated to tramadol 50 mg every 12 hours for one admission and finally onto hydromorphone up to 2 mg every four hours as needed. Depending on the pain severity, he received additional pain medications, including gabapentin 300 mg three times daily or pregabalin 50 mg three times a week, diclofenac 1% gel four times daily, and/or topical lidocaine patches daily as needed. He received diazepam 2 mg daily as needed and trazodone 50 mg nightly for anxiety and insomnia. He is currently taking hydromorphone 6 mg every 6 hours as needed and mirtazapine 15 mg nightly for insomnia. He reported good pain relief on a follow up appointment four months after his last admission. He continued to live alone and was able to perform activities of daily living independently.
Results
Opioid choice can partly depend on renal function of patients who often have impaired GFR. Codeine and its main active metabolite morphine are renally excreted and accumulate over time in patients undergoing hemodialysis.8 Morphine metabolites can accumulate in renally impaired patients and can cause respiratory depression and seizures.8,9 Although its metabolite can be dialyzed, it’s slow to diffuse from CNS to circulation. Hydrocodone and its metabolites can accumulate in renal failure.9 Meperidine metabolites can accumulate during renal failure and cause seizures. Because of these characteristics, they are not recommended for use if a patient develops ESRD.
The three opioids our patient has used are tramadol, oxycodone and hydromorphone. Tramadol is used frequently in CKD patients as it’s not nephrotoxic. Although its metabolite is renally excreted, it can be used in lower doses even in patients undergoing dialysis.10 It should be noted that it can cause serotonin syndrome when combined with other serotonergic agents such as SSRI.11 Oxycodone is dialyzable based on the fact it’s hydrophilic; Studies show plasma oxycodone and noroxycodone concentration decrease during dialysis.12Hydromorphone is also hydrophilic but its metabolite 3-glucuronide metabolite can accumulate in dialysis.8,9 It is still recommended that dosage be adjusted/reduced when using tramadol, oxycodone and hydromorphone in ESRD.9–11
Other opioids to consider using in renally impaired patients are methadone, fentanyl and buprenorphine. Methadone can be safely used in ESRD patients as the parent compound and its metabolites are excreted through the GI system.8,9Fentanyl is interesting in that its metabolites are inactive and the parent compound maybe adsorbed onto the dialysis filter itself.8 Buprenorphine is excreted through the liver.13 It also appears buprenorphine does not accumulate in ESRD.14 Furthermore, it’s not removed by dialysis so redosing is not necessary post dialysis. Currently, opinions are divided whether methadone dose needs to be adjusted in ESRD.8 However, buprenorphine and fentanyl appear to not need dose adjustment with studies demonstrating safety in high doses up to 70mcg/hour for buprenorphine and 500mcg/hour for fentanyl in ESRD.14,15
Conclusions
Although literature shows promise with disease-modifying medications such as calcitonin and sodium thiosulfate, our patient continued to experience calciphylaxis episodes with severe pain. It is thought that the pain in calciphylaxis is of neurogenic origin with nerve inflammation.16,17 Our patient found temporary relief with gabapentin and pregabalin. Complications of opioids in the setting of renal impairment include hyperactive delirium. Benzodiazepines are used for treatment of agitation, delirium and briefly for sleep disturbances.9 Though oral NSAIDS are contraindicated in renal dysfunction, topical NSAIDs can be used due to limited systemic absorption. Diclofenac 1% gel had 5–17 fold lower systemic exposure than oral tablets.18
Our patient’s pain was treated using combinations of non-opioids and opioids during his 8 inpatient hospitalizations spanning 2 years. His pain was eventually controlled with hydromorphone alone. It is possible that oxycodone and tramadol were very effective but he developed tolerance to them. In the future, he can rotate opioids, especially methadone and buprenorphine. Our patient’s pain episodes are frequently accompanied by PAD which also causes ischemia evidenced by low transcutaneous oxygen tension. The ischemia causes poor wound healing which further exacerbates pain. Further studies may be needed to understand the association between PAD and calciphylaxis.
75 Tolperisone for acute muscle spasm: dose-ranging STAR study
Srinivas Nalamachua, Randall Kayeb and Joseph Pergolizzic
aMid America PolyClinic, Overland Park, KS, USA; bNeurana Pharmaceuticals, Inc., San Diego, CA, USA; cNEMA Research, Naples, FL, USA
Purpose
Back pain is common and mostly attributed to acute musculoskeletal spasm with no apparent underlying cause. Skeletal muscle relaxants (SMRs) are effective for the treatment of back pain due to acute muscle spasm but are typically not preferred because of adverse central nervous system effects, such as somnolence. Tolperisone, a centrally acting, nonopioid SMR in clinical development in the United States, does not seem to exhibit the central nervous system effects seen with other available treatments. The objective of this study was to assess the safety and efficacy of tolperisone50, 100, 150, and 200 mg three times daily (TID)compared with placebo in patients with acute muscle spasm of the back.
Methods
STAR (ClinicalTrials.gov, NCT03802565) was a double-blind, randomized, placebo-controlled, phase 2 study. Eligible patients were aged 18–65 years with current back pain or stiffness due to acute muscle spasm starting ≤7 days before study entry and lasting for >8 weeks after the last episode of back pain. Patients were randomly assigned 1:1:1:1:1 to receive tolperisone 50, 100, 150, or 200 mg TID or placebo for 14 days. Patients could receive acetaminophen 500 mg TID as rescue medication. The primary efficacy end point was subject-rated pain ‘right now’ using a numeric rating scale (NRS; 0 = no pain to 10 = worst possible pain) on day 14. Secondary end points included onset of action, duration of relief, use of rescue medication, and safety. The study was approved by the institutional review board at each site.
Results
Patients (N = 415) were enrolled at 38 US sites (tolperisone,n = 337;placebo, n = 78). Tolperisone was well tolerated, and most patients completed 14 days of treatment (92.6% tolperisone; 88.5% placebo). Adverse events (AEs) occurred in 18.1% vs 14.1% of patients receiving tolperisone or placebo, respectively; headache (7.1%) and diarrhea (2.4%) werethe most frequent AEs in tolperisone-treated patients vs 3.8% and 0%, respectively, in placebo-treated patients. Somnolence was reported in 1.2% and 2.6% of patients treated with tolperisone or placebo, respectively.The visual analog scale for subject-reported sleepiness on day 4 was similar in all treatment groups, including placebo.No serious AEs or deaths occurred. Day 14 mean change from baseline in NRS rating of pain ‘right now’ was −3.5 for placebo vs −4.2, −4.0, −3.7, and −4.4 for tolperisone 50, 100, 150, and 200 mg TID, respectively. The linear test of trend on the least squares mean differences (treatment-placebo) approached statistical significance (p = 0.0539).In an analysis of pairwise estimates (treatment-placebo), the greatest numerical difference and significance was observed for tolperisone 200 mg TID (p = 0.0040). Two key secondary end points – patient rating of medication helpfulness and patient’s global impression of change – trended toward significance for the tolperisone 200 mg TID group vs placebo (p = 0.0656 and p = 0.0526, respectively). Certain subcategories of the Oswestry Pain and Disability Index (ie, personal care, walking, and social life) trended toward significance for comparison of tolperisone 200 mg TID vs placebo at day 14.
Conclusions
Tolperisonewas well tolerated and effective in patients withacute muscle spasm of the back and was associated withlow rates of somnolence. Tolperisone 200 mg TID may be a promising treatment for the management of acute muscle spasm, without the somnolence that typically occurs with SMRs.
76 Efficacy of subcutaneous tanezumab for the treatment of osteoarthritis across age groups: a subgroup analysis of pooled data from two randomized, placebo-controlled trials
Yvonne D’Arcya, Alan Kivitzb, Bill McCarbergc, Jerry Halld, Zahid Bajwad, Stephanie Duenche and Ruoyong Yange
aIndependent Nurse Practitioner, Ponte Vedra Beach, FL, USA; bAltoona Center for Clinical Research, Duncansville, PA, USA; cUniversity of California, San Diego, CA, USA; dEli Lilly and Company, Indianapolis, IN, USA; ePfizer Inc., New York, NY, USA
Purpose
Tanezumab is a monoclonal antibody that binds nerve growth factor and stops it reaching its receptors. In patients with osteoarthritis (OA), subcutaneous tanezumab significantly improves pain, physical function, and patient’s global assessment of OA. The purpose of this pooled, post-hoc subgroup analysis, was to explore the efficacy of subcutaneous tanezumab in patients with OA of different ages.
Methods
A pooled exploratory analysis of patient level datafrom two randomized, placebo-controlled, Phase 3 trials (NCT02697773 and NCT02709486) of subcutaneous tanezumab (2.5 mg or 5 mg every 8 weeks for 16 or 24 weeks) in patients aged ≥18 years with moderate-to-severe knee or hip OA. In one trial, tanezumab was titrated from 2.5 mg at baseline to 5 mg at Week 8. This data is included in the pooled 5 mg group. Co-primary endpoints were change from baseline in Western Ontario and McMaster Universities OA Index (WOMAC) Pain (0 to 10; increasing pain), WOMAC Physical Function (0 to 10; increasing difficulty), and Patient Global Assessment of OA (PGA-OA; 1 to 5; increasingly poorer assessment) scores. Efficacy results are presented for the overall pooled population and age subgroups (<65, ≥65, <75 and ≥75 years) as the LS mean change from baseline to Week 16 versus placebo with 95% confidence interval.
Results
In the overall pooled population comprising patients of all ages, both doses of tanezumab were associated with significantly improved WOMAC Pain, WOMAC Physical Function, and PGA-OA scores at Week 16 compared to placebo (p < 0.05). Somewhat similar improvements were observed in all age subgroups (grouped as <65 years [placebo n = 293; 2.5 mg n = 286; 5 mg n = 265], ≥65 years [220; 227; 252], <75 years [455; 457; 453], and ≥75 years [58; 56; 64]). In the pooled population, change in LS mean WOMAC Pain score over placebo (n = 513) was −0.7 (−0.95, −0.37) and −0.7 (−0.99, −0.41) in the 2.5 mg (n = 513) and 5 mg (n = 517) tanezumab groups, respectively. In the age subgroups, change over placebo ranged from −0.5 to −1.1 for both tanezumab doses. In the pooled population, change in LS mean WOMAC physical function score over placebo was −0.7 (−1.00, −0.42) and −0.8 (−1.08, −0.50) in the 2.5 mg and 5 mg tanezumab groups. In the age subgroups, change in over placebo ranged from −0.5 to −1.1 for both tanezumab doses. In the pooled population, change in LS mean PGA-OA score over placebo was −0.2 (−0.30, −0.09) and −0.3 (−0.36, −0.15) in the 2.5 mg and 5 mg tanezumab groups. In the age subgroups, change over placebo ranged from −0.2 to −0.4 for both tanezumab doses. Changes observed for the three outcomes were statistically significant compared to placebo (p < 0.05 unadjusted) for all age and dose combinations except 2.5 mg in the ≥75 years subgroup, possibly due to low n. However, this exploratory post-hoc analysis was not part of the pre-specified hypothesis testing plan or included in any sample size calculations; therefore, comparisons between treatment or age subgroup should be conducted with caution.
Conclusions
When considering short-term use of subcutaneous tanezumab for the treatment of OA in specific patients, age does not appear to influence improvements in pain, function, and PGA-OA.
77 Patient acceptability of a novel upper nasal delivery system for dhe – using the precision olfactory delivery (POD®) device (INP104)
Stephen Shrewsbury, Sheena Aurora, John Hoekman and Maria Jeleva
Impel NeuroPharma, Seattle, WA, USA
Purpose
Introduction:DHE is an effective acute treatment for episodic migraine, but from 1946–1996 was only available as an injection. Nasal DHE (Migranal®) introduced in 1996 as a much desired needle-free alternative has shown variable efficacy which may be due to loss of the drug product out of the nose onto the upper lip, or down the throat, leading to inconsistent absorption of the remaining drug from the lower/anterior nasal space. Delivery of drugs to the upper nasal space may provide greater, more consistent absorption, reduce response variability and provide more reliable relief similarly without the need for an injection. Assessing the safety and tolerability of delivery to this previously unexplored area is important – but so too is understanding how acceptable patients find drug delivery to this space with the POD device.
Objective:To assess patient acceptability of INP104 (POD DHE) over 24/52 weeks in the pivotal STOP 301, safety trial.
Methods
In an open label, Phase 3 safety study of INP104 (STOP 301), conducted at 38 centers in the US, patients were asked to complete a questionnaire (PAQ) at the end of 24/52 weeks after using the INP104 product, a self-administered, single use, propellant-enabled device delivering a previously approved formulation of DHE mesylate as required for self-recognized migraine. Subjects were asked to score Strongly Disagree; Disagree; Neutral; Agree; Strongly Agree to the following series of 6 questions once they had completed the study: (1) Study drug is easy to carry, (2) Study drug allows me to return to normal faster, (3) Study drug more consistently treats my migraine, (4) Study drug works faster than previous treatment, (5) Study drug keeps my migraine from coming back and (6) Study drug is easy to use.
Results
324 subjects who entered the 24-week treatment period completed the PAQ. Results are presented in a tabular format. Neutral, Agree or Strongly Agree was noted by: 65% that the device was easy to carry; 78% that it allowed them to return to normal activities faster than previous medication; 76% that it worked more consistently than their previous best usual care; 77% that it worked faster than their previous best usual care; 82% that it kept their migraine from coming back; and 94% that it was easy to use.
Conclusions
The results suggest DHE delivered to the upper nasal space with POD may provide an effective, well tolerated alternative to acute oral treatments for migraine. The majority of study subjects reported INP104 was easy to carry and use, faster and more consistently provided benefit with longer lasting relief and allowed them to return to normal activities faster than previous medications they had used.
78 Investigating for baclofen pump failure in a case of severe rhabdomyolysis
Steven Tijmes
Memorial Healthcare System, Hollywood, FL, USA
Purpose
Baclofen withdrawal is a very serious risk for anyone on intrathecal baclofen therapy through a baclofen pump. Severe cases of withdrawal have been known to lead to rhabdomyolysis which is potentially life-threatening. When a practitioner is concerned about withdrawal symptoms in a patient, it is vital to perform a comprehensive workup to find what is causing the disruption of therapy. Rarely, a cause is not found despite a thorough workup. Here we discuss a case of suspected baclofen withdrawal in a 22 year old male with spastic dystonic quadriplegia secondary to cerebral palsy with an intrathecal baclofen pump. We will also discuss the troubleshooting that takes place as each step of the workup fails to uncover a cause.
Methods
A 22 year old male with a history of cerebral palsy with spastic dystonic quadriplegia initially had a baclofen pump placed in 2013. He recently underwent pump replacement for end of life battery replacement and had the intrathecal baclofen transferred from the old pump to the new pump with no dose change. The patient was doing well in follow up, however about 20 days after the pump replacement, he woke up shaking with headache and tachycardia, which progressed to bruxism, anorexia, neck posturing, and he became lethargic. He was admitted to an outside hospital ICU with fever and tachycardia. He was found to be in rhabdomyolysis with elevated CK of 86,230, Creatinine 4.1, WBC at 28, NA at 158, AST 1,034, ALT 203, lactic acid of 12.8, and also had elevated troponin at 1.56. EEG was unremarkable and a comprehensive infectious workup was negative. His baclofen pump was evaluated and found no malfunction and he was placed on enteral baclofen, IV fluids, and broad spectrum antibiotics. He was then transferred to our hospital for further management. On admission, his CK level was 735, his CRP was 1.3, and he also had leukocytosis at 13.7. We performed a catheter dye study which revealed no obstruction of flow. MRI of the thoracic spine did not reveal any evidence of granuloma at the catheter tip, stenosis in the thoracic intrathecal space, or other evidence of blockage. Repeat catheter dye study was negative as well as negative CT myelogram. Patient’s CK and troponin trended down with IV fluids and his condition stabilized and he was discharged home. He followed up in clinic and enteral baclofen dosing was decreased from every 6 hours to every 8 hours, and eventually to every 12 hours.
Results
This patient’s symptoms of headache, tachycardia, shaking, and neck posturing in the setting of recent baclofen pump replacement raised concern for pump failure and baclofen withdrawal. Typically, signs of baclofen withdrawal appear within hours to a few days following interruption of therapy. In rare cases, the resulting spasticity and rigidity from baclofen withdrawal can lead to rhabdomyolysis. It is very important to rule out other underlying causes which may present with similar symptoms. These include autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis. When it comes to investigating for pump failure, there are three common causes to consider: catheter malfunction/disconnection, low volume in the pump reservoir, and end of pump battery life. The catheter dye study we performed was to evaluate for any leakage or interruption of flow through the catheter, which we did not find. The MRI of the thoracic spine was done to look for any intrathecal mass at the tip of the catheter which could also obstruct the medication flow. The pump was interrogated which noted a flex dose periodic bolus schedule and calculated 15.2 mL in the reservoir and the low battery alarm was engaged and not activated. The patient’s pump had been replaced only 20 days prior to the onset of his symptoms, so the pump battery was unlikely to be the issue. In general, if troubleshooting has revealed pump failure and the issue is addressed, the suggested treatment is the restoration of intrathecal baclofen at or near the same dosage as before the therapy was interrupted. If it is not possible to restore the administration of intrathecal baclofen in a timely manner, patients may be treated with oral GABA-ergic agonist medications such as oral or enteral baclofen or benzodiazepines. It is very important to not delay the administration of either of these medications in cases of baclofen withdrawal as these patients are prone to seizures. Other medications for spasticity such as dantrolene may improve the spasticity but will not counteract the CNS withdrawal symptoms such as seizures and autonomic instability.
Conclusions
Baclofen withdrawal syndrome poses a very serious threat to the health of the patient. Educating patients and family about the signs of withdrawal and keeping frequent visits for pump checkups may decrease the incidence of injury to the patient. If, however, withdrawal is suspected and evaluation of pump function finds no malfunction, it is vital to rule out other causes of the patient’s symptoms and to control the spasticity with oral baclofen or benzodiazepines.
79 Limited utility of benzodiazepines in chronic pain management
Steven Wrighta and Terri Schrieberb
aAlliance for Benzodiazepine Best Practices, Portland, OR, USA; bThe Schreiber Research Group, Denver, CO, USA
Purpose
To provide a narrative review of the literature to identify the evidence base for the use of benzodiazepines for chronic pain conditions and provide guidance for the use of these agents in these conditions by clinicians.
Methods
A search for relevant studies regarding benzodiazepine analgesic efficacy and adverse outcomes for 111 pain conditions took place January-February 2020. The search was performed within the PubMed electronic database, reference lists of relevant articles, published guidelines, and the author’s personal files. Inclusion criteria: clinical trials, reviews, meta-analyses that compared benzodiazepines with placebo or other medications. Exclusion criteria: research involving fewer than 20 study subjects or research that addressed acute pain, analgoanesthesia, intrathecal administration, or pediatric populations.
Results
A total of 9838 pain-related, citations related to pain were retrieved. Abstracts and full-text articles of relevant titles were reviewed if available and in English. From these, 189 related to chronic pain and met inclusion criteria. There was sufficient and clear evidence supporting the use of benzodiazepines for analgesic purposes for only 2 of 111 pain conditions examined: stiff person syndrome and burning mouth syndrome. For the other 109 pain conditions the following was found with respect to benzodiazepine analgesia: 1) Absence of evidence, 2) Insufficient evidence, 3) Inconclusive or mixed evidence,4) Poor risk/benefit ratio, or 5) Ineffective.
Conclusions
Of 111 pain conditions examined, there was evidence supporting the use of benzodiazepines for analgesia in stiff person syndrome and burning mouth syndrome. Recommendations for benzodiazepine prescribing in pain management include limited initiation and duration (2–4 weeks), as well as to encourage, support, and assist patients in a slow (perhaps more than one year) tapering process for those on these agents for greater than one month.
80 A close association of pain freedom with freedom from most bothersome symptom and from migraine-related functional disability in lasmiditan studies SAMURAI and SPARTAN
Li Shen Looa, Richard Liptonb, Stewart Tepperc, Raghavendra Vasudevaa, Simin Baygania, Eric Pearlmana, Paula Haucka and John Kregea
aEli Lilly and Company, Indianapolis, USA; bDepartment of Neurology, Albert Einstein College of Medicine, Bronx, USA; cGeisel School of Medicine at Dartmouth, Hanover, USA
Purpose
Lasmiditan is a selective 5-hydroxytryptamine 1 F receptor agonist for the acute treatment of migraine. Lasmiditan has been shown to be superior to placebo on freedom from pain and freedom from most-bothersome symptom (MBS) in 2 Phase 3 studies, SAMURAI (NCT02439320) and SPARTAN (NCT02605174).
Methods
This post-hoc analysis assessed whether the outcomes of pain freedom (reduction in pain severity from moderate or severe at baseline to none) or mildpain (reduction in pain severity from moderate or severe at baseline to mild were associated with the outcomes of MBS freedom or functional disability freedom in 2 hour pooled data from SAMURAI and SPARTAN (modified intent-to-treat population with moderate or severe pain, MBS and functional disability recorded at time of dosing). MBS freedom is defined as absence of the self-identified MBS [either nausea, phonophobia or photophobia]. Patients who recorded no symptoms present at time of dosing were excluded from the analysis. Functional disability was assessed with the question ‘How much is your migraine interfering with your normal activities.’ Response options were ‘not at all’ (functional disability freedom), ‘mild interference,’ ‘marked interference,’ ‘need complete bed rest.’ Patients who recorded ‘Not at all’ at time of dosing were excluded from the analysis. Patients treated with lasmiditan 200 mg with MBS and functional disability recorded at the time of dosing were assessed at 2 hours postdose. The coexistence of MBS freedom and functional disability freedom was examined in patients with pain freedom or mildpain.
Results
Patients withpain freedom (N = 324) frequently also experienced MBS freedom (91.4%) and functional disability freedom (81.8%). In contrast, patients who experienced mildpain(N = 220) showed lower rates of MBS freedom (45.0%; p = <0.001) and functional disability freedom (12.7%; p = <0.001) than pain-free patients In addition, more patients who were painfree experienced both MBS freedom and functional disability freedom (78.7%) compared to those with mildpain (10.0%; p = <0.001). Furthermore, 5.6% of patients experienced painfreedomwithout achieving MBS freedom or functional disability freedom compared with 52.3% of patients who experienced mildpainalone.
Conclusions
Achieving painfreedomwith lasmiditan was frequently associated with MBS freedom and a return to normal activities.
81 Prescribing NSAIDs/COX-2s in patients having osteoarthritis is associated with both negative clinical outcomes and higher costs
Stuart Silvermana,b, Patricia Schepmanc, Alan G. Whited, Nguyen Led, Michael Sommad, Craig G. Becke, Rebecca L. Robinsonf and J. Bradford Riced
aCedars-Sinai Medical Center, Los Angeles, CA, USA; bDavid Geffen School of Medicine of University of California Los Angeles, Los Angeles, CA, USA; cPfizer, New York, NY, USA; dAnalysis Group, Boston, MA, USA; ePfizer, London, United Kingdom; fEli Lilly, Indianapolis, IN, USA
Purpose
Osteoarthritis (OA) is a degenerative joint disease involving cartilage and many of its surrounding tissues and afflicts over 30 million US adults with hip and knees as the most commonly affected sites. Pharmacological treatment options for OA pain commence with the use of oral analgesics, followed by topical/oral non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. NSAIDs (including oral COX-1 and COX-2 inhibitors) are one of the most commonly prescribed pain medications in the world and although recommended by clinical guidelines as the primary pharmacological treatment of choice for management of OA, NSAIDs require risk mitigation for their safe use especially in the elderly and in patients with preexisting conditions. Much is known about the potential clinical harms associated with NSAIDs use for the management of OA in the short or intermediate term, however, less is known about the extent to which these clinical outcomes and costs are pervasive and problematic in real-world settings in specific patient populations, such as those diagnosed with hip and/or knee OA. Therefore, the goal of this research is to estimate the potential clinical and economic burden of commercially insured patients diagnosed with OA of the hip and/or knee before and after being prescribed NSAIDs, in a large, national database.
Methods
This study used de-identified administrative claims records fromOptum Healthcare Solutions, Inc., a database containing healthcare and prescription drug utilization records for approximately 19 million privately insured lives from over 84 large self-insured US-based companies, spanning from January 1, 2012 to March 31, 2017 (study period). Patients included were ≥ 18 years old with ≥2 diagnoses of hip and/or knee OA, and ≥90 days supply of oral NSAIDs during the three-year period from first prescription (index date) after their first OA diagnosis. Patients were required to be continuously enrolled during the six months before (baseline period) and 36 months after (follow-up period) the index date. Selected clinical outcomes such as gastrointestinal (GI) issues, cardiovascular (CV) events, and renal toxicity were compared between the baseline and follow-up periods. All-cause healthcare costs and healthcare resource use were normalized to account for differential duration in analytic time periods. All costs were converted to and reported in 2017 US dollars using the medical care component of the Consumer Price Index. All analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC). Statistical significance was assessed using McNemar test for categorical variables and Wilcoxon signed-rank test for continuous variables.
Results
Between January 1, 2014 and March 31, 2017, there were 176,431 patients with at least two diagnoses of OA of the hip/and or knee that had at least one prescription for an NSAID. A total of 34,697 OA patients had continuous eligibility during the 6-month baseline and 36-month follow-up periods. Among patients meeting the eligibility requirements, 22,435 had at least a 90 days’ supply of NSAIDs during the follow-up period and were included in this analysis. More than half of the patients were female (60.8%), had a mean age of 61.5 years and a mean Charlson Comorbidity Index of 0.4. 13.8% of patients had OA of the hip only, while 57.5% had OA of the knee only. Negative clinical outcomes associated with GI issues increased by 393% (1.5% v 7.4%, p < 0.01), driven by a 667% (0.3% v 2.3%, p < 0.01) increase in acute GI hemorrhages. Iron-deficiency anemia also increased 400% (1.1% to 5.5%, p < 0.01). Additionally, negative clinical outcomes associated with CV events increased by 74% (40.7% v 70.7%, p < 0.01), largely due to a 600% (0.3% v 2.1% p < 0.01) increase in acute myocardial infarction. Hypertension experienced the largest absolute increase (40.1% to 69.6%). Lastly, negative clinical outcomes associated with renal toxicity increased by 433% (1.5% v 8.0%, p < 0.01), with a 740% (0.5% v 4.2%, p < 0.01) increase in acute renal failure being the largest increase.
From the baseline period to follow-up period, all-cause total healthcare costs increased by 32% ($32,682 up to $43,024, p < 0.01) with prescription costs increasing by 205% ($3,306 to $10,093, p < 0.01) and hospitalization costs increasing by 21% ($12,330 to $14,916, p < 0.01), respectively. All-cause inpatient admissions increased 293% (13.7% to 53.9%, p < 0.01), and emergency department visits increased 236% (14.8% to 49.7%, p < 0.01).
Conclusions
This study found that patients with knee/hip OA who were prescribed NSAIDs experienced an increase in negative clinical outcomes and costs. These findings suggest that there is a need for newer treatments with improved clinical outcomes and less costs to patients with OA of the hip and/or knee.
82 Seeking care, diagnosis, and acute prescription for migraine among those with headache-related disability: results of the OVERCOME study
Susan Hutchinsona, Robert Nicholsonb, Bert Vargasb, Karen Saamanb, Anthony Zagarb, Yongin Kimb, Eric Pearlmanb, Dawn Busec, Michael Reedd, Sait Ashinae,f and Richard Liptonc,g
aOrange County Migraine and Headache Center, Irvine, USA; bEli Lilly and Company, Indianapolis, USA; cDepartment of Neurology, Albert Einstein College of Medicine, Bronx, USA; dVedanta Research, LLC, Chapel Hill, USA; eDepartment of Neurology and Department of Anesthesia, Critical Care and Pain Medicine, and Harvard Medical School, Boston, USA; fBeth Israel Deaconess Medical Center, Boston, USA; gMontefiore Medical Center, Bronx, USA
Purpose
The journey to effective acute prescription treatment for migraine among those with associated disability includes at least three steps: consulting a healthcare professional, receiving an accurate diagnosis and taking a recommended acute prescription. Objectives were: 1) Determine the proportion of people with migraine and associated disability who traverse each of these steps, and 2) Compare individuals at each step on sociodemographic features, migraine-related characteristics, and healthcare utilization for migraine.
Methods
Data were obtained in the fall of 2018 from OVERCOME, a web-based survey conducted in a representative US sample. The study identified persons with migraine based on either ICHD-3 criteria (94% of the sample) assessed with a validated diagnostic screener or self-reported healthcare provider migraine diagnosis (61% of the sample). Those with headache-related disability (MIDAS ≥6) were included. Results are presented by total and categorized by monthly headache day (MHD) groups (0–3, 4–7, 8–14, ≥15). T-test or Chi-square test, for total respondents and stratified by MHD category, evaluated differences between groups at each step (p < 0.05).
Results
Of the 21,143 participants with migraine, 12,212 (57.8%) had headache-related disability. The mean age was 40.3 years, 77.1% female, and 70.2% Non-Hispanic white, 7.8% Non-Hispanic black, 11.1% Hispanic, 2.3% Asian, and 8.6% other. Only 63% of the total population sought care and of those, 75.4% were diagnosed with migraine. Among those who sought care and were diagnosed, only 58.6% were taking a recommended acute prescription for migraine (ie, non-opioid acute prescription with level A or B effectiveness per AHS 2015 guidelines). Overall, only 27.9% of the total sample had gone through all these steps. This ranges by MHD group from 22.6% for those with 0–3 MHDs to 35.0% for those with ≥15 MHDs. For care seeking, there were differences for nearly all factors assessed (p < 0.001), including having health insurance (Seeking = 89.0% vs Not Seeking = 80.4%, p < 0.001). Overall, 10.6% of those who sought care did so only at an Emergency Department and/or Urgent Care and/or Retail Clinic (a clinic located in a pharmacy or retail store) (ED/UC/Retail). Factors differentiating diagnosis included being female (Diagnosed = 76.8% vs Not Diagnosed = 70.2%, p < 0.001), and having sought care at ED/UC/Retail only (Diagnosed = 9.1% vs Not Diagnosed = 15.3%, p < 0.001). Factors differentiating receiving a recommended acute prescription for migraine included having severe (MIDAS≥21) headache-related disability (Prescribed = 55.5% vs Not Prescribed = 49.6%, p < 0.001), and having sought care at ED/UC/Retail only (Prescribed = 5.7% vs Not Prescribed = 13.9%, p < 0.001). These findings varied across MHD groups.
Conclusions
Only a small proportion of those with headache-related disability traverse all steps to receiving recommended acute prescription for migraine. Having health insurance and more severe disability influenced outcomes. A consistent theme is that seeking care in an Emergency Department/Urgent Care/Retail Clinic only is unlikely to lead to receiving appropriate acute medications. These findings highlight the ongoing unmet needs across MHD groups and care delivery settings.
83 Impact of inpatient pain pharmacist e-consults on post-discharge morphine equivalent daily doses
Thien Phama, Derek Joea and Rajkumar Sevakb
aVA Long Beach Healthcare System, Long Beach, CA, USA; bUniversity of the Pacific, Stockton, CA, USA
Purpose
Overuse of opioids has shown to be particularly challenging in hospitals with no dedicated interdisciplinary pain team.1,2In the inpatient setting, studies suggest that more than 60% of inpatients experience incomplete or inadequate pain relief,despite extensive use of opioids.1,2 Several studies have showed the benefit of pain pharmacist E-consult services at various VA institutions.3,4
Between 2004–2012, the prevalence of opioid prescriptions among Veterans increased from 18.9% to 33.4%.5 In 2013, the Veterans Affairs Opioid Safety Initiative (OSI) was launched. Its goal was to help decrease opioid prescribing practices associated with adverse outcomes.6 In 2015, an outpatient pain clinic was established at the VA Long Beach Healthcare System (VALBHS), which comprised of a pain physician and pain pharmacist. However, there was no dedicated pain service in the inpatient setting. Inpatient pain management was primarily managed by Internal Medicine teams with consults to specialty services, and palliative care was at times inappropriately consulted for pain management for noncancer cases.
In 2018, the Joint Commission published updated recommendations regarding the use of opioids – suggesting that hospitals create and implement policies and procedures for review of pain regimens by pain specialists.7 In response to the Joint Commission mandates, the VALBHS established an Inpatient Pain Pharmacist electronic consult (E-consult) Service to address inappropriate acute care opioid prescribing. Its goal was to review patients’ electronic medical records and provide strategies to reduce high-dose opioid analgesics and recommendations for complex patient pain management cases. There are no set criteria required to submit an inpatient pain pharmacist E-consult. Although the recommendations made in the consult were available for providers to view, it was at the providers’ discretion as to whether the recommendations were accepted or rejected. This study was designed to describe the inpatient pain pharmacist E-consult service and evaluate its impact on changes inmorphine equivalent daily dose (MEDD) at discharge and 90-days post-discharge from the VALBHS.
Methods
This study has two objectives: 1) to describe the inpatient pain pharmacist E-consults services at the VALBHS, and 2) to evaluate the clinical outcomes (therapy change, MEDD change) between patients who received an inpatient pain pharmacist E-consult and patients who did not.
This retrospective chart review study evaluated patients who received an inpatient pain pharmacist E-consult from January 1, 2018 to August 31, 2019. For the first objective, all patients who received an inpatient pain pharmacist E-consult (n = 75) during the pre-specified index period were included in the analysis. For the second objective, patients who received an inpatient pain pharmacist E-consult (n = 65) were matched to a cohort of patients receiving LA/ER opioids (fentanyl transdermal system, morphine sustained-release, methadone) who did not receive an E-consult (n = 69) within the same time frame. These patients were included if they received at least one dose of LA/ER opioid during an inpatient hospitalization. These patients were excluded if they passed away within 90 days post-discharge, transferred their outpatient care to a facility other than VALBHS, or if they were continued on a LA/ER opioid initiated by a non-VA provider. Statistical analysis was performed using t-tests and Chi-Square tests for demographic variables. A two-factor repeated-measures ANOVA was conducted to evaluate MEDD difference from the admission, with Group (E-consult, Control) as the between-subjects factor and Time (discharge, 90-day post-discharge) as the within-subjects factor.
Results
A total of 75 patients received an inpatient pain pharmacist E-consult. 372 pharmacologic and 56 non-pharmacologic recommendations were made, with acceptance rates of 51.3% and 41.1%, respectively. The most common opioid therapy changes accepted by inpatient providers were as follows: IR opioid taper (76.2%), IR opioid titration (50%); and IR opioid initiation (46.2%). The most common non-opioid therapy changes were for NSAID discontinuation (71.4%), anticonvulsant initiation (67.5%), and topical analgesic initiation (61.3%). Pharmacologic recommendations not commonly accepted included antidepressant taper/discontinuation (0%), APAP/tramadol taper/discontinuation (0%), and NSAID initiation (25%). The top accepted recommendations for referrals were to Substance Abuse (84.6%) and Outpatient Pain Clinic (75%). Recommendations made to the following services were not commonly accepted: Physical Therapy (11.1%), Palliative Care (14.3%), and Psychiatry/Mental Health (20.0%).
After exclusion criteria, 65 patients in the E-consult group were randomly matched to a cohort of 69 patients in the Non E-consult group. The average MEDD for E-consult was 70.5 (at admission), 65.2 (at discharge), and 50.1 (at 90 days post-discharge), while the average MEDD for Non E-consult was 68.8 (at admission), 70.0 (at discharge), and 63.1 (at 90 days post-discharge).The outcomes from the two-factor repeated-measures ANOVA showed the significant main effect of Group (F1,132 = 9.88, p = 0.002), Time (F1,132 = 12.23, p = 0.001), but not Group X Time interaction (F1,132 = 1.70, p = 0.19). These results indicate that regardless of the time point (discharge or 90 days post-discharge), the E-consult group showed significantly greater reduction in MEDD from admission. The average MEDD differences from admission for E-consult was −5.3 mg at discharge and −20.4 at 90-days post-discharge, whereas those for the control group were +1.2 mg at discharge and −5.8 at 90-days post-discharge.There were larger percentage increasesin non-opioid prescriptions in the E-consult group for anticonvulsants, antidepressants, topical analgesics, and APAP/tramadol by discharge and 90-days post-discharge.
Conclusions
Inpatient pain pharmacist E-consult services resulted in an acceptance rate of 51.3% of pharmacologic recommendations. The most common opioid therapy changes included IR opioid taper, titration, and initiation, and the most common non-opioid therapy changes included NSAID discontinuation, anticonvulsant initiation, and topical analgesic initiation. Furthermore, this study showed significant reductions in MEDD at hospital discharge and post-discharge in patients who received inpatient E-consult services compared to the patients who did not receive the E-consult services.In the future, a dedicated inpatient pain pharmacy team should be constituted and the impact of their interventions on post-surgical opioids requirements should be evaluated.
84 General safety and tolerability of subcutaneous tanezumab for the treatment of osteoarthritis: a pooled analysis of randomized, placebo-controlled trials
Thomas Schnitzera, Francis Berenbaumb, Alan Kivitzc, Lars Viktrupd, Anne Hickmane, Glenn Pixtone, Mark Brownf, Isabelle Davignonf and Christine Westf
aNorthwestern University Feinberg School of Medicine, Chicago, IL, USA; bSorbonne Université, INSERM, AP-HP Hospital Saint Antoine, Paris, France; cAltoona Center for Clinical Research, Duncansville, PA, USA; dEli Lilly and Company, Indianapolis, IN, USA; ePfizer Inc, New York, NY, USA; fPfizer Inc, Groton, CT, USA
Purpose
Tanezumab, a monoclonal antibody against nerve growth factor, is in development for the treatment of signs and symptoms of osteoarthritis (OA).The purpose of this study was to assess the safety and tolerability of subcutaneous (SC) tanezumab in patients with OA.
Methods
Data were derived from 3 randomized placebo-controlled OA trials. SC treatment (every 8 weeks for 16–24 weeks with 8–24 week follow-up) included placebo, tanezumab 2.5 mg, tanezumab 2.5/5 mg (2.5 mg at day 1 and 5 mg at week 8), and tanezumab 5 mg. Overall treatment-emergent adverse events (TEAEs) and TEAEs of abnormal peripheral sensation were pooled from all 3 trials (placebo N = 586; tanezumab: 2.5 mg N = 602, 2.5/5 mg N = 219, 5 mg N = 347).Pre-specified TEAEs potentially associated with sympathetic neuropathy (anhidrosis, bradycardia, hypohidrosis, orthostatic hypotension, or syncope) and pre-specified joint events (primary osteonecrosis, rapidly progressive OA [RPOA] type 1 or type 2, subchondral insufficiency fracture, or pathological fracture; adjudicated by an independent committee of experts) were pooled from the 2 trials that included prospective evaluation of sympathetic and joint safety (placebo N = 514; tanezumab: 2.5 mg N = 528, 2.5/5 mg N = 219, 5 mg N = 284).TEAEs are presented for the treatment period; joint safety is presented for the full study (treatment plus follow up) period.
Results
Patient demographics (80.7% white, 66.8% female, mean age ≈ 63 years) and clinical characteristics were similar across groups. TEAE rates were: placebo = 51.7%, tanezumab 2.5 mg = 52.3%, tanezumab 2.5/5 mg = 47.0%, and tanezumab 5 mg = 54.8%. Of TEAEs occurring in ≥2% of patients in any group, only edema peripheral, joint stiffness, and paresthesia had a higher incidence(95% confidence interval excluded 0) in any tanezumab group relative to placebo. Serious TEAE rates were: placebo = 1.5%, tanezumab 2.5 mg = 2.2%, tanezumab 2.5/5 mg = 1.4%, and tanezumab 5 mg = 2.6%. Rates of treatment and/or study discontinuation due to TEAEs were: placebo = 2.2%, tanezumab 2.5 mg = 1.8%, tanezumab 2.5/5 mg = 0.5%, and tanezumab 5 mg = 1.4%. Only arthralgia and OA led to discontinuation in >1 patient in any group. TEAEs of abnormal peripheral sensation rates were: placebo = 2.2%, tanezumab 2.5 mg = 5.1%, tanezumab 2.5/5 mg = 3.2%, and tanezumab 5 mg = 6.1%. Paresthesia and hypoaesthesia were the most common events. Potential sympathetic neuropathy TEAE rates were: placebo = 0.8%, tanezumab 2.5 mg = 1.5%, tanezumab 2.5/5 mg = 0.5%, and tanezumab 5 mg = 2.8%; exposure-adjusted rates were not statistically different between any tanezumab group and placebo. Bradycardia and orthostatic hypotension were the most common events. No patient was considered to have a sympathetic neuropathy. TEAEs of abnormal peripheral sensation and potential sympathetic neuropathy were mostly mild and resolved. Joint safety event rates were statistically different for tanezumab 5 mg (3.2%), but not 2.5 mg (1.9%) or 2.5/5 mg (0.5%), compared to placebo (0%). RPOA type-1 was the most common event. Total joint replacement rates were: placebo = 4.5%, tanezumab 2.5 mg = 5.9%, tanezumab 2.5/5 mg = 6.8%, and tanezumab 5 mg = 7.0%; rates were not statistically different between any tanezumab group and placebo.
Conclusions
Tanezumab was generally safe and well tolerated in most patients, with rates of overall TEAEs and treatment/study discontinuations similar to placebo and no evidence of a sympathetic safety signal. TEAEs of abnormal peripheral sensation and joint safety events were infrequent but more common with tanezumab than placebo.
85 Peripherally induced reconditioning of the central nervous system: proposed mechanisms for sustained relief of chronic pain with percutaneous peripheral nerve stimulation
Timothy Deera, Sam Eldabeb, Steven Falowskic, Marc Huntoond, Peter Staatse, Isaac Cassarf, Nathan Crosbyf and Joseph Boggsf
aThe Spine and Nerve Center of the Virginias, Charleston, WV, USA; bThe James Cook University Hospital, Middlesbrough, United Kingdom; cNeurosurgical Associates of Lancaster, Lancaster, PA, USA; dVirginia Commonwealth University Medical Center, Richmond, VA, USA; ePremier Pain Centers, Shrewsbury, NJ, USA; fSPR Therapeutics, Cleveland, OH, USA
Purpose
Chronic pain is associated with peripheral and central sensitization processes that result in abnormal pain processing and hypersensitivity throughout pain pathways in the periphery and CNS. Supraspinal circuits play a major role in the processing of pain and have been implicated in centrally mediated chronic pain. Specifically in the somatosensory cortex, which encodes the sensory-discriminative aspects of pain, the nociceptive representational zones exhibit a sensitized state characterized by expansion and/or shifting of pain representations, reduced GABAergic inhibition, and stronger response to activation, while non-nociceptive representational zones may diminish in size and response to activation. These maladaptive shifts in the balance of sensory processing are likely due to activity-dependent cortical remapping caused by the relative increases in nociceptive and decreases in non-nociceptive information coming from the region of pain.
Peripheral nerve stimulation (PNS) can be an effective tool for the treatment of chronic pain, though its utilization has previously been limited by available technology. Recent years have seen the advancement of various PNS features and techniques intended to overcome many of the limitations of conventional neurostimulation. Several key advances have enabled the development and adoption of improved neurostimulation systems designed specifically for use in the periphery including the development of minimally-invasive percutaneous implantation techniques, advancements in ultrasound imaging to guide lead placement, renewed focus on non-opioid treatment alternatives for pain, observation of long term efficacy when a temporary percutaneously implanted lead is employed without an implanted pulse generator or receiver, and the incorporation of open coil leads designed to enable more secure percutaneous peripheral placement with lower rates of infection. Recent clinical evidence suggests significant and sustained reductions in pain often persist well beyond the stimulation period following short-term (up to 60-day) PNS treatments, outcomes which have not previously been observed with conventional permanently implanted neurostimulation devices. This review summarizes the potential mechanisms by which selective large diameter afferent fiber activation may reverse maladaptive CNS changes associated with chronic pain to induce a prolonged reduction in pain.
Methods
This review is based on searches of published literature on PubMed, Google Scholar, and Web of Science and the authors’ familiarity with the published literature in their respective fields, including preclinical and clinical articles related to chronic pain, neurostimulation, peripheral nerve stimulation, and cortical plasticity.
Results
The somatotopic representation map in the primary somatosensory cortex (S1) is dynamic and can substantially change as a result of shifts in afferent input, with expansion of regions that experience stronger and more frequent input than those around them and contraction of regions that have reduced inputs. Activity-dependent cortical remapping requires that the peripheral input to the cortex be robust, since sufficient signal strength is needed to drive the plasticity, and that it is focally derived from within a specific region, since functional plasticity also requires a low level of relative activity in surrounding cortical regions. Preclinical and clinical studies suggest that conventional PNS is limited by the use of small electrodes placed in close contact with target neural structures, resulting in a narrow therapeutic window that prevents selective, robust, and/or focal activation of large diameter fibers.
It has been hypothesized that one way to overcome the limitations of conventional, ‘intimate’ electrode placement is to use percutaneous PNS systems designed to enable remote selective targeting. The goal of remote selective targeting is to activate a greater proportion of large diameter fibers while avoiding the unwanted activation of nociceptive afferents to produce a robust non-nociceptive peripheral signal. The relationships between stimulation strength, electrode characteristics, electrode-fiber distance, and fiber diameter are predicted to result in a greater separation of activation thresholds between large and small diameter fibers when using a PNS system designed to enable electrode placement up to several centimeters away (e.g., 0.5–3 cm) and deliver stimulation at therapeutic parameters more selective for large diameter fibers. Leads designed for remote selective targeting have large monopolar electrodes such that the generated electric fields, which decay exponentially across distance, are broad and relatively homogeneous at remote distances and have the potential to activate large diameter fibers throughout the entire cross-section of a nerve while avoiding activation of smaller fibers. Remote selective targeting may enable more robust activation of large diameter fibers (i.e., a larger proportion of targeted fibers) while avoiding small diameter fibers by optimizing the strength-distance and strength-diameter relationships that govern the activation of nerve fibers. It is theorized that activation of non-nociceptive, large diameter afferent fibers via percutaneous PNS with remote selective targeting could widen the therapeutic window for both focal and robust activation of Aα/β fibers to optimally recondition the S1 cortex and produce pain relief that long outlasts a temporary (e.g., up to 60-day) PNS treatment.
Conclusions
Advancements in imaging and neurostimulation technology have enabled innovation in PNS for pain relief in recent years. Studies of percutaneous PNS systems utilizing remote selective targeting have suggested the ability to produce clinically meaningful sustained reductions in pain following temporary (up to 60-day) treatment periods across a variety of chronic pain conditions. Mechanistically, it is theorized that these results may be the result of a widened therapeutic window for stimulation that enables robust and selective activation of Aα/βfibers focally from the region of pain, leading to multiple analgesic mechanisms from the periphery to the dorsal horn and cortex. These diverse effects may be explained in a new neuromodulation theory of pain management, Peripherally Induced Reconditioning of the CNS, involving stimulation-evoked reversal of the central sensitized state that contributed to the chronic pain.
86 Randomized, controlled trial of lasmiditan over four migraine attacks: first attack findings
Judith Krikke-Workela, John Kregea, Messoud Ashinab,c, Timothy Smithd, Qun Lina, Suzanne Klisea, Sonja Bragga, Erin Dotya, Sherie Dowsetta and Uwe Reutere
aEli Lilly and Company, Indianapolis, USA; bDanish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Copenhagen, Denmark; cUniversity of Copenhagen, Copenhagen, Denmark; eStudyMetrix Research, St Peters, USA; eDepartment of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany
Purpose
Lasmiditan is a novel, selective 5-HT1F receptor agonist,approved by the FDA for the acute treatment of migraine, with or without aura, in adults. We present findings from themulticenter, placebo-controlled, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy, including consistency of response, and safety of lasmiditan in the acute treatment of migraine across 4 attacks.
Methods
Patients were randomized 1:1:1 to one of 3 treatment groups 1) lasmiditan 200 mg; 2) lasmiditan 100 mg; or 3) a control group which received placebo for 3 attacks and lasmiditan 50 mg for either the third or fourth attack (1:1). The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in at least 2 out of 3 attacks. Statistical testing used a logistic regression model and graphical multiplicity methodology to preserve overall type I error at 1-sided alpha level of 0.025.
Results
1613 patients were randomized, and 1471 patients (mean age 41 years; 84% female; 76% Europe, 12% N. America, 12% Asia; MIDAS mean score 31.6) treated ≥1 migraine attack with study drug (control, n = 500; lasmiditan 100 mg, n = 485, lasmiditan 200 mg, n = 486). All primary and gated secondary endpoints were met (p < 0.001 in all cases).Here we present efficacy findings for the first attack; consistency findings across multiple attacks will be reported elsewhere. Pain freedom rates at 2 h (primary endpoint) were for placebo, 8.4%; lasmiditan 100 mg, 25.8% (Odds ratio vs placebo,3.8 [2.6, 5.7], with a therapeutic gain of ~17%); lasmiditan 200 mg, 29.3% (OR 4.6 [3.1, 6.8]; therapeutic gain ~21%). Both doses of lasmiditan were significantly better than placebo for pain freedom at 1 h, and for pain relief at 2 h with significant separation from placebo beginning at 30 minutes in the 200 mg group and 1 hour in the 100 mg group. Additional statistically significant differences between lasmiditan and placebo included migraine-related disability freedom at 2 h, much/very much better on the Patient Global Impression of Change at 2 h, most bothersome symptom freedom at 2 h, need for rescue medication, and sustained pain freedom at 24 and 48 h. In a predefined subset of patients who were triptan insufficient responders, lasmiditan was significantly superior to placebo for pain freedom at 2 h. Across the study, the incidence of treatment emergent serious adverse events was similar across treatment groups – control, n = 2 (0.4%) (both after treatment with placebo); lasmiditan 100 mg, n = 1 (0.2%), lasmiditan 200 mg, n = 2 (0.4%); there were no major cardiovascular events consistent with ischemia. The most frequent treatment emergent adverse events with lasmiditan (≥2% in either dose group in the first attack) were dizziness, paresthesia, fatigue, nausea, vertigo, somnolence, hypoesthesia, muscle weakness, asthenia, and feeling abnormal.
Conclusions
The CENTURION study had a modified parallel design enabling a comparison of the consistency of effect of two doses of lasmiditan to placebo.Lasmiditan was superior to placebo for all gated endpoints and its overall safety and tolerability was generally consistent with that observed in previous Phase 3 lasmiditan studies. During the first attack, lasmiditan was significantly superior to placebo for pain freedom and pain relief beginning at 1 h, and for sustained pain freedom at 24 and 48 h. Lasmiditan was also efficacious in triptan insufficient responders. These results confirm the early and sustained efficacy of lasmiditan.
87 Enhanced recovery after surgery in a veteran population
Vada Campbell
Charles George VA Medical Center, Asheville, NC, USA
Purpose
To show the effectsof ERAS protocols on decreasing opioid use, prescribing and post op complications in Total Knee Arthroplasty cases at the Charles George VA Medical Center in Asheville, NC.
Methods
ERAS Protocols were implemented with a multidisciplinary team. The protocols included multi-modal pain management techniques, blocks, pre-op optimization and whole health coaching, minimal fasting, pre-op extensive education with education booklet, avoidance of tubes and drains, cryotherapy, early PT and mobilization, and integrative therapies. Data collected over the course of one year for post op ERAS patients who had total knee arthroplasty was compared to the prior year’s data.
Results
There was a 72% decrease in opioids used by the Veterans in the ERAS group. Incidentally there was a decrease of 87% in anti-emetics used. Length of stay decreased by 1.43 days which computed to an annual savings of $1,458,000 for one facility. Overall opioids were reduced by 21% in the facility. ERAS protocols were then put in place for all orthopedic procedures, as well as general surgery.
Conclusions
ERAS protocols can save significant revenues, as well as decrease opioid use, length of stay and complications. Overall decreases in opioid prescribing after discharge were documented as well which contributed to NO post op overdoses after ERAS protocols were put into place.
88 Standing in the (pain) gap–why you need a clinical social worker in your primary care/rural health/rheumatology clinic
Wenona Andress
Lubbock, Texas, USA
Purpose
‘If you don’t shut the gate, all the animals get out.’ – This is the long-standing premise of the Gate Theory of pain development (Mezack & Wall, 1965).The sooner one can close the gate, pain is decreased. But who mans the gate? The patient, of course! How does the patient obtain the knowledge, tools, commitment, and experience to do it effectively? Enter the Multidisciplinary Pain Team – Intheory. In actuality, little of this is happening in the US,is targeted to special populations or urban areas,and few physicians employ Clinical Social Workers. This paper will discuss the critical issues primary care and other physicians face with chronic pain patients, gaps in service, and how employing a Clinical Social Worker may improve patient outcomes and clinic success.
WHY IS THIS NEEDED?
There are two main considerations: Quality of Care and Retention: Pain patients can be difficult to work with. Their condition isbio-psychosocialin nature:
Physiologicallythe experience of pain is like a fire alarm that never stops. It is overwhelming and all-consuming. Driven by the human need to ‘avoid pain’, thepsychecreates elaborate measures to attempt to cope – based on experience, resiliency, and learned behavior. Socially, the pain patient is too distracted to engage effectively at work, with family, or in the community. And yet the pain patient is not an island; everything and everyone they touch is impacted by their pain. Some support systems help, others are detrimental.
Pain patients need quality care that addresses every issue. According to Margaret Caudill, MD, PhD, MPH (2016), it is important for patients, specifically chronic pain patients, tocease looking for a cure,but rather,manage pain.
When patients believe their needs are not being met by their physician, they will shop elsewhere. Often this is interpreted as ‘Dr. shopping/med-seeking’; or they are seen as non-compliant. Retentionoccurs when patients believe their physicians ‘really care’ about them. According to Caudill, it’s important for a behavioral health provider in clinics to teach patients toevaluate their expectations of their physiciansand tolearn to communicate effectivelywith their treatment team.
Methods
The author searched the American College of Rheumatology database for a sample of rheumatology clinics/hospitals in the state of Texas. Searches on the Commission for Accreditation of Rehabilitation Facilities, the Joint Commission on Accreditation of Healthcare Facilities, and Substance Abuse and Mental Health Services Association were also retrieved, using the term ‘Multidisciplinary Pain Clinics’.
Content was researched from the PubMed database related to Fibromyalgia, Lupus and connection to childhood trauma.
The author also retrieved information from the United States Health and Human Services Pain Task Force,the NASW response to the task force, USA Jobs and VA careers. Additional references were sought from PAINWEEK Journal (Vol.8, 2020) and ‘Managing Pain Before It Manages You–Fourth Edition’ by Margaret Caudill, MD, PhD, PH (2016)
Results
The author identifies the following services to be provided by the primary care/rural or rheumatology clinic:
Screening of all patients for Substance Use Disorders using ASAM criteria
Screening for ACE: Adverse Childhood Experiences, anxiety and depression
Primary Pain Screening Tools (FABQ, Pain Catastrophizing Scale, etc.)
Assessment for psychiatric emergency and referral
Brief crisis counseling, PRN
Individual Counseling utilizing Acceptance and Commitment Therapy, Cognitive Behavioral Therapy, Mindfulness and Meditation and Motivational Interviewing. Enhanced trauma therapies could include EMDR, hypnosis, EFT, and other experiential therapies
Pain management support groups/family education
Case Management and community referral to CAM, social services and specialized mental health (chemical dependency treatment, neuropsychological testing, etc)
WHY AN LCSW AND NOT ANOTHER DISCIPLINE?
On March 26, 2019, the National Association of Social Workers submitted their response to the draft produced by the Pain Management Task Force: ‘3.3.3 Workforce.NASW supports expanding nonphysician,behavioral health specialists in pain care, particularly clinical social workers who have the skills and expertise to treat pain from a holistic approach.(Gap 1, Recommendation 1 c).’
Social Workers work with special populations such as indigenous persons, refugees, child welfare, geriatric care, veterans and military, homeless, etc. This is why there are certain payors/systems that actuallyprefer and require clinicians to be Social Workers. The VA and Medicare reimburses Social Workers and Psychologists only. A physician hiring a Clinical Social Worker with experience inchemical dependenceorchronic paincounseling will be ahead of the game. ForRural providers, having an LCSW on the team meets one of the major gaps stated by the Pain Management Task Force.
A Clinical Social Worker can be credentialed by many insurance providers.
Given the preference by the VA and Medicare or Medicaid, the Clinical Social Worker will meet the need forveterans, seniors and disabled. Clinical Social Workers can provideTele-for healthseverely disabled patients, or those with transportation issues. If office space is a barrier, services can be provided through Tele-health; the only exception would be pre-service screenings, group or family work. The LCSW may be trained and credentialed throughWorkman’s Compensation,as well asEAP services.
Conclusions
There are too many gaps in services to our pain patients. Physicians wanting to provide quality pain management are burdened by managed care, federal regulations, the opiate crisis, an aging population, liability and many other issues. Interdisciplinary pain management seems like an impossibility. A good first step would be to add a Clinical Social Worker to the practice. Social Work training is not one ofpsychopathology,but ratherstrengths-based. They study family systems, role theory, culture, ethnicity, race, gender, sexual orientation, age, disability, religion, socioeconomic and other social systems.
Social Workers are trained to be gatekeepers and connectors. Theymake connectionsto community resources where another type of behavioral health provider may say ‘You might want to look for a support group’. A Clinical Social Worker will help” shut the gate” before the ‘animals get out’ … and everyone’s pain is out of control.