Abstract
Cancer related pain is prevalent among patients with a cancer diagnosis, occurring from the tumor itself or as a result of treatment. Many patients require opioid therapy to manage pain and providers must balance efficacy with side effects. Transdermal buprenorphine (TDB) has shown promise for pain management, however, the maximum dose available in the US is considered low, resulting in doubts of efficacy. This study set out to assess if the patch strengths available in the US (5–20 mcg/hour) are able to provide analgesia for patients with cancer in a palliative medicine clinic. This retrospective chart review analyzed patient charts for outpatient TDB use within a palliative medicine clinic in the United States. Patients had to have a follow up visit with the clinic in order to be included. Sixty-eight patients were included for analysis with 54 (79%) continuing at least 28 days and 37 (54%) continuing for at least 84 days. The median change in pain score was 0, though 25 (46%) of patients reported a decrease of 1 or more points at the first follow up. TDB is a viable option for cancer related pain for select patients, demonstrated by duration of use and stable reporting of pain.
Introduction
Pain is a common sequela of cancer and associated cancer therapies, with over 50% of patients experiencing pain during treatment and 40% continuing to have pain even after curative treatment (Citation1). Opioids, with a theoretical lack of analgesic ceiling, are a valuable analgesic option for cancer patients suffering from pain (Citation2). However, opioid use is associated with a variety of risks, such as respiratory depression, constipation, hyperalgesia, and potential misuse (Citation2). Buprenorphine, though also an opioid, is a partial agonist at the mu opioid receptor and thereby is associated with a lower side effect profile and decreased potential for non-medical use (Citation3). Additionally, antagonism at the kappa opioid receptor may decrease hyperalgesia (Citation3). Transdermal buprenorphine (TDB) has been utilized for chronic pain, but has not yet gained popularity among palliative care providers due to fears of the partial agonist properties contributing to an analgesic ceiling and, therefore, some providers question buprenorphine’s adequacy for providing pain relief (Citation4).
Pain relief by TDB for cancer pain has been assessed in previous studies in other countries, which utilized patch strengths not available in the United States (35–70 mcg/hr.) (Citation5, Citation6). With these patch strengths, investigators were evaluating the efficacy for moderate to severe cancer pain for which they found positive results (Citation5, Citation6). Results from these studies indicate a significant reduction in pain score from baseline (6.4 to 3.9 vs. 6.5 to 5.1 for TDB vs. long acting morphine, respectively p < 0.001), as well as improvements in sleep (Citation6). Additionally, patients receiving TDB reported lower use of rescue medications earlier in the trial period (Citation5, Citation6). In both studies, nausea and constipation were reported at lower rates in the patients using TDB compared to those patients using morphine. Neither study reported incidence of respiratory depression, though a review of studies that did report respiratory depression found that zero of 418 patients experienced this effect, which is in part due to its ceiling effect on respiratory drive that is reached prior to its ceiling effect on analgesia (Citation3). These results demonstrate the potential for TDB to be an ideal analgesic agent, especially for patients who cannot swallow or who are sensitive to opioid side effects and cannot tolerate full mu opioid agonists.
Buprenorphine has shown promise for analgesia and safety at higher dose patch strengths available internationally. Low dose TDB may provide effective cancer pain analgesia that may be safer and more effective for appropriate patients. The aim of this study was to assess if the lower patch strengths that are available in the United States (5–20 mcg/hr.) are able to provide adequate analgesia for patients in a cancer palliative medicine clinic.
Methods
This study was a single center, retrospective chart review of cancer palliative care patients who were prescribed TDB in the James Comprehensive Cancer Center, which is part of The Ohio State University Wexner Medical Center. Using the Electronic Medical Record (EPIC, Madison, WI), patient charts were screened for TDB patch prescriptions written by a palliative care provider from January 1, 2016 through September 30, 2019. Patients were included if the patch was initiated in the outpatient setting or during a hospital admission with referral to the palliative medicine clinic. Patients were excluded if they were prisoners, pregnant, less than 18 years of age, or greater than 89 years old as these patients could be easily identified by clinic personnel. Patients who did not have documented follow-up in the outpatient clinic were also excluded. Patients who passed away prior to the primary endpoint collection time point had baseline characteristics recorded, but were not included in the primary outcome. This study was approved by the Ohio State University Institutional Review Board.
Data collected included the primary cancer diagnosis, age at time of patch initiation, gender, race, and comorbidities, specifically chronic kidney disease, hepatic impairment, substance use disorder, and chronic nonmalignant pain. Palliative care provider notes were reviewed for rationale for using TDB, oral morphine equivalents (OME) prescribed for breakthrough pain at all study time points, patient reported side effects if cause for discontinuation, patient reported withdrawal symptoms if present, and reason for patch discontinuation. Patients’ previous 24-hour opioid use in OME was collected based on provider documentation in the outpatient setting and determined by electronic medication record if inpatient. Buprenorphine information collected included the strength of TDB patch prescribed at initiation and discontinuation, any dose escalations, and duration of use. If TDB was initiated in the hospital, the initiation date was considered the hospital discharge date. Any adjuvant analgesics (scheduled acetaminophen or non-steroidal anti-inflammatory drugs, steroids, duloxetine, venlafaxine, tricyclic antidepressants, gabapentin, pregabalin, or topical agents) prescribed to the patient were collected, with their date of initiation noted as being prior to buprenorphine initiation, simultaneously with buprenorphine, or after buprenorphine.
The primary outcome was to assess the efficacy of TDB for cancer related pain, defined as no increase in pain score at 28 days of use compared to reported pain score at initiation. Baseline characteristics were recorded at patch initiation. The first palliative medicine office visit provider note that was at least 28 days after patch initiation was utilized for the primary outcome and was given the term “first follow up”. The number of touchpoints (telephone encounters, office visits) prior to this first follow up visit were also documented. The second follow up was defined as the office visit immediately after this, regardless of the time frame elapsed since the first visit. Data was collected at each of these two office visits. Secondary endpoints included percent of patients achieving a 2-point reduction in pain using an eleven point numeric rating scale (0–10), use of rescue medications while using buprenorphine transdermal patches, as determined by allowed daily doses of rescue medication, incidence of withdrawal effects if switched from a full agonist, long term use of buprenorphine at 12 weeks, and associations between baseline characteristics and successful buprenorphine treatment.
Data analysis
The goal of this retrospective, observational study is descriptive in nature and data analysis focused on summarizing demographic and baseline clinical characteristics, as well as success of transdermal buprenorphine treatment for pain control using appropriate descriptive statistics (e.g. means, standard deviations for continuous variables and frequencies, percentages for categorical variables). A limited number of formal comparisons were performed, focusing on baseline characteristics vs. success of buprenorphine treatment for pain control; all p-values from these comparisons were considered exploratory. Demographic and baseline characteristics as well as clinical outcomes were summarized overall and by duration of TBD use (less than 84 days vs greater or equal to 84 days and less than 28 days vs greater or equal to 28 days) using descriptive statistics. Data were reported as means/standard deviations or medians/interquartile range for continuous variables and frequencies and percentages for categorical variables. Comparisons between duration cohorts were run with a two sample t-test/Wilcoxon Rank Sum test or a Chi-square test/Fisher’s Exact test, where appropriate. All data analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC).
Results
An EPIC query for patients electronically prescribed TDB by palliative care providers yielded a total of 130 patient charts. Of these, sixty-eight patients met inclusion criteria. The majority of excluded patients had no clinic follow up (n = 29) or were not initiated on TDB (n = 20). Eleven patients were not initiated due to cost barrier or lack of insurance coverage of TDB. Of the included patents, 59 (87%) were initiated on TDB in the outpatient clinic setting and 48 (71%) patients had active cancer. See for additional demographic data. TDB was most commonly initiated for patients with low opioid requirements who still required a long acting agent or had a sensitivity to low doses of full agonist opioids (n = 28). The remaining rationales for initiation can be found in .
Table 1. Demographic summary by 84 day duration.
Table 2. Rationale for use by 84 day duration.
There were 14 (21%) patients who discontinued TDB prior to 28 days of use and 54 (79%) patients who continued TDB until the first follow up. Those who discontinued prior to the 28-day follow up did so because of side effects (n = 9), lack of efficacy (n = 4), and withdrawal symptoms (n = 1). The patient who reported withdrawal symptoms did not disclose true opioid intake prior to TDB initiation, which was later discovered to be significantly higher than initially reported. Withdrawal symptoms were thought to be related to overall reduction in available opioids and not because of TDB. An additional 7 patients discontinued at the first follow-up for the following reasons: lack of efficacy (n = 2), no longer being seen by the clinic (n = 2), side effects (n = 2), and other (n = 1). Of the patients who continued until first follow-up, 25 (46%) reported a decrease in pain and 15 (28%) reported no change in pain. 16 patients (30%) reported at least a 2-point reduction in pain. Additional pain score data can be found in . Patient reported best pain score and worst pain score was documented at variable rates as reflected in .
Table 3. Changes in pain scores of those continuing until the first follow-up.
There were 50 patients who used adjuvant medications prior to TDB initiation. Gabapentinoids were the most frequently used adjuvant; additional adjuvant breakdown can be found in . When TDB was initiated, 44 (65%) patients were prescribed a full mu-opioid concomitantly agonist for breakthrough pain. The breakdown of opioid medications prescribed as well as oral morphine equivalents can be found in .
Table 4. Additional medication use.
Discussion
Overall, patients initiated on TDB maintained stable pain scores throughout the study period. Many patients who were maintained on TDB had active cancer diagnoses. Often, active cancer complicates the measurement of pain due to the variable nature of the disease as well as difficult courses of treatment and procedures. In this study, the majority of patients were prescribed at least one adjuvant medication, with many taking several medications to improve pain control.
Though many patients reported no change in pain score, over half of the patients included continued TDB for 3 months or longer. Pain has historically proven to be a difficult symptom to assess, with many tools, such as the numeric rating scale, offering only one dimension of pain assessment (Citation7). More comprehensive tools are often needed to fully assess pain and benefits of medications, such as improvements in sleep and functional abilities (Citation7). With this prolonged duration of therapy, it is possible to consider that patients were obtaining functional benefits from TDB, even as they reported the same pain score at previous visits. Though our study showed no change in pain scores, future prospective studies should consider using a more comprehensive, multidimensional methodology for pain assessment that evaluates changes in functional capacity. Previous studies have shown mixed benefit of TDB for cancer pain (Citation8). A recent study that used higher doses of TDB (>20 mcg/hr.) showed similar benefit to oral morphine for severe cancer pain and a significant difference in tolerability favoring TDB (Citation5). Notably, as a prospective study, the investigators were able to achieve adequate pain relief within 4 weeks with frequent titrations. Given these results, it may be reasonable that many patients can achieve acceptable pain control with titration of TDB.
A portion of patients maintained a similar pain score throughout the study period with no additional opioids prescribed for breakthrough pain. The National Comprehensive Cancer Network recommends to use long acting analgesics in combination with short acting analgesics for persistent cancer pain (Citation9). The authors state that TDB may be used for opioid naive patients (Citation9). There is a misconception that patients will not derive benefit from full agonist opioids while using TDB due to buprenorphine’s affinity for the mu opioid receptor, however, there is evidence that patients may benefit from low-dose immediate release opioids for breakthrough pain while on TDB (Citation10). Silverman and colleagues studied a different patient population than the patients in this current study (Citation10). Even though patients may experience additional pain relief with full opioids, many patients in this study were initiated on TDB due to intolerances of full mu-opioid receptor agonists, concerns for respiratory compromise, or past behaviors that indicated concerns for abuse or diversion of medications. In these situations, prescribing of full mu-opioid receptor agonists may have been unsafe. Our study shows that TDB can be an effective long acting analgesic in conjunction with adjuvants with or without short acting opioids.
The median duration of TDB was 94 days for all patients. For the subset of patients who did not discontinue prior to first follow-up, the median duration was 123 days. Due to a limited sample size, duration of use of TDB was not associated to any patient-specific factors, though patients with a past medical history significant for substance use disorder tended to stop TDB sooner. Additionally, patients who stopped TDB sooner than 84 days appeared to be on fewer adjuvant therapy. Failure of TDB could be indicative of higher opioid requirements due to advancing cancer, past non-medical opioid use, or multimodal techniques not being used to their full potential, leading to treatment failure. Future studies should evaluate patient characteristics and rates of success with TDB that help guide appropriate use of this formulation of buprenorphine.
The number of patients that stopped therapy with TDB was slightly higher than what has been reported in the literature for extended-release morphine of around 7% (Citation11). However, some patients who initiated TDB may have been at higher risk for adverse effects due to an increased sensitivity to opioids. It is reasonable to expect reports of side effects from patients who have already failed full agonist opioids due to side effects even though we expect a lower incidence with use of a partial opioid agonist. Additionally, several patients were started on TDB in order to complete their taper off of opioids and their discontinuation was expected.
This study is not without limitations; one limitation is the study’s retrospective nature. Previous prospective trials were able to titrate patch strengths at timely intervals and achieve pain relief whereas retrospectively, there was no intervention for titration of the patch and therefore, more time may have been needed to see the impact of TDB after titration. Chart review also limits the data that can be extracted from patient interviews about pain scores and additional improvements in overall well-being. There were also many patients who were excluded due to never initiating TDB, thus limiting the sample size. It is important to consider insurance payment of TDB, as many insurance providers may not approve TDB initially, or require additional steps such as prior authorizations. Some of the patients who were excluded due to never starting TDB were unable to as a result of the medication not being covered or having high co-pays.
Conclusion
Transdermal buprenorphine is a viable option for cancer pain as demonstrated by its ability to maintain reported pain scores and longevity of use at an academic, comprehensive cancer center. In order to determine transdermal buprenorphine’s true benefit at doses available in the U.S., a prospective study is needed to assess not only pain scores, but also perform a comprehensive symptom assessment.
Authorship confirmation statement
All listed authors contributed to the contents of this research in a meaningful manner. All authors attest to its contents and are satisfied with the final manuscript.
Author disclosure statement
There is no conflict of interests or disclosures to report for all authors. There was no funding for this research.
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