Safety and Tolerability of Schedule III Buprenorphine and Oral Schedule II Opioid Treatment in Chronic Low Back Pain Patients: A Retrospective US Commercial Claims Analysis

Abstract Title: Safety and Tolerability of Schedule III Buprenorphine and Oral Schedule II Opioid Treatment in Chronic Low Back Pain Patients: A Retrospective US Commercial Claims Analysis

Background:

Chronic pain that requires long-term around-the-clock analgesia represents a great challenge in terms of disease burden and clinical management. It is estimated that 20.0% of the US population suffers from chronic pain, with 13.1% of US patients diagnosed with chronic low back pain (cLBP).¹ Due to a great impact on quality of life, cLBP patients are usually heavily treated, leading to a high economic burden from the payer’s perspective.

Schedule II (CII) opioids are commonly prescribed medications to cope with chronic pain in clinical practice, especially for patients who do not respond to non-opioid and other therapies.² Although CII opioids are an effective treatment option, their frequent use is usually followed by severe and serious adverse events.³ In addition, to these risks, CII opioids also have the potential for diversion and nonmedical use among persons not prescribed the medication.

Buprenorphine, a Schedule 3 (CIII) opioid is also a treatment option for long-term chronic pain management, and appears to exhibit efficacy and safety characteristics to result in an improved risk-benefit profile compared to other opioids. The bioavailability of per-os buprenorphine is very low (10-15%) as it undergoes extensive first-pass metabolism in the gastrointestinal mucosa and liver.⁴ Hence, transdermal, and buccal formulations of buprenorphine were designed to overcome absorption issues of oral administration and bypass gastrointestinal and hepatic metabolism improving the drug’s bioavailability.

Purpose/Objectives:

The objective of this retrospective study was to evaluate and compare the safety and tolerability of CIII buprenorphine and oral CII opioids in the treatment of cLBP. Furthermore, the safety profile of Belbuca® (buprenorphine buccal formulation) was particularly assessed and compared with oral CII opioids and transdermal buprenorphine formulations.

Method:

This retrospective study was conducted on the Merative MarketScan® database of commercially-insured patients from January 2018 to December 2021. The index date was set to be first date of CIII buprenorphine (Belbuca® or buprenorphine patch) or oral CII opioid prescription. Medications were identified based on the most relevant national drug codes. Based on index medication prescription, patients were assigned to CIII buprenorphine or CII opioid cohort. The observational period consisted of 6-month pre-index period and post-index period that lasted until the end of index treatment or continuous healthcare coverage.

Treatment-naïve cLBP adults were included in the analysis. Two LBP diagnoses and a lack of buprenorphine and opioid treatment during the pre-index period were required. Patients with gap in continuous healthcare coverage during observational period were excluded. Additionally, patients assigned to CII opioid cohort were required to be without CIII buprenorphine treatment, while patients in CIII buprenorphine cohort were allowed to have concomitant CII opioid treatment during the post-index period.

Demographic characteristics were assessed on the index date, while clinical characteristics were observed during the pre-index period. The main study outcomes were rates of serious treatment-emergent adverse events (TEAEs) reported as incidence rate ratios (IRR). For TEAEs that occurred only in one cohort, the rates were compared using absolute incidence rate difference (IRD). IRR less than one and negative IRD values imply that TEAE rates were higher in CII opioid or buprenorphine patch cohorts.

Relevant TEAEs were identified based on the published literature. Event occurrence was observed during the treatment period (calculated as a sum of index medication supplies during the follow-up) and captured using diagnostic codes. Only events that required emergency department or hospitalization management were considered serious TEAEs. Subgroup analyses were performed to compare study outcomes between Belbuca® vs. CII opioids, and Belbuca® vs. buprenorphine patch.

Continuous variables were analyzed with an independent sample t-test and categorical variables were analyzed with the chi-square test of independence. IRR test was used to compare TEAE rates between study cohorts. Propensity-score matching (PSM) analysis using the nearest-neighbor algorithm was performed to minimize the selection bias, and balance observed differences in patients’ characteristics.
 


Results: There were 213,195 patients identified in non-matched sample, with 781 CIII buprenorphine cohort (380 in Belbuca® and 401 buprenorphine patch) and 212,414 CII opioid cohort. After performing PSM analysis, 2,737 patients were matched (711 patients in CIII buprenorphine cohort and 2,020 in CII opioid cohort). Further subgroup analysis yielded 352 Belbuca® patients matched to 1,630 CII opioid-treated patients, and 239 Belbuca® patients matched to 239 buprenorphine patch patients.

Among CIII buprenorphine and CII opioid matched cLBP patients, CIII buprenorphine cohort treatment was associated with significantly greater rate of serious opioid abuse/dependence (IRR 3.13, p=0.004) (influenced by buprenorphine patch subgroup (no difference between Belbuca® and CII opioid patients)), significantly greater rate of dizziness (IRR 2.44, p=0.011) (influenced by Belbuca® subgroup), and cholecystitis (CIII buprenorphine vs. CII opioids IRD 20.25 per 1,000 person-years, p=0.044). However, CIII buprenorphine cohort experienced significantly less frequent serious TEAEs: coronary artery disease, osteoarthritis, urinary discomfort, respiratory depression, pneumonia, sleep disturbances, constipation, dehydration, abdominal pain and nausea/vomiting (IRRs 0.05, 0.05, 0.08, 0.18, 0.32, 0.34, 0.35, 0.37, 0.45, and 0.57 respectively; p< 0.05). CIII buprenorphine cohort also experienced significantly lower incidence of serious TEAEs: seizures, hot flushes, opioid poisoning, pruritis, and rash (CIII buprenorphine vs. CII opioids IRDs -39.88, -34.89, -29.91, -19.94, and -19.94 per 1,000 person-years, respectively; p< 0.05).

Belbuca® vs. CII opioids analysis identified dizziness as the only serious TEAE significantly associated with Belbuca® treatment (IRR 3.17, p=0.024), while serious syncope, pneumonia, nausea/vomiting, constipation, abdominal pain, fatigue, and dehydration were more common in CII opioid cohort (IRRs 0.12, 0.20, 0.29, 0.32, 0.32, 0.34, and 0.35 respectively; p< 0.05). Belbuca® was associated with significantly lower rates of serious respiratory depression, atrial fibrillation, osteoarthritis, seizures, sleep disturbances, and urinary discomfort (Belbuca® vs. CII opioids IRDs -134.63, -87.51, -74.05, -60.59, -53.85, and -47.12 per 1,000 person-years, respectively; p< 0.05), with no rate difference in serious opioid abuse/dependence (24.60 vs. 26.93, p=0.921).

Comparison of Belbuca® vs. buprenorphine patch observed suicidal ideation (related to major depressive disorder in one outlier hospitalized patient) and cholecystitis as serious TEAEs significantly more common in Belbuca® cohort (Belbuca® vs. buprenorphine patch IRDs 156.50 and 52.17 per 1,000 person-years, respectively; both p< 0.05). However, Belbuca® patients had less frequent dizziness and opioid abuse/dependence (both IRRs 0.04, p< 0.001), while atrial fibrillation, QT prolongation, and respiratory depression occurred only in buprenorphine patch cohort (Belbuca® vs. buprenorphine patch IRDs -163.86, -117.04, and -58.52 per 1,000 person-years, respectively; p< 0.05).

Conclusions: This study demonstrated the wide spectrum of serious TEAEs captured during the CIII buprenorphine and CII opioid treatment among cLBP patients.

More granularly, Belbuca® demonstrated the potential of being well tolerated as compared to CII opioids, with lower rates of many serious TEAEs including atrial fibrillation, seizures, syncope, sleep disturbances, fatigue, dehydration, nausea and vomiting, constipation, abdominal pain, osteoarthritis, respiratory depression, pneumonia, and urinary discomfort. Only serious dizziness had a significantly higher rate in Belbuca® patients.

Additionally, Belbuca® as compared to the buprenorphine patch showed significantly lower rate of serious opioid abuse and dependence, dizziness, atrial fibrillation, QT prolongation, and respiratory depression.

References: [1] Dahlhamer J, Lucas J, Zelaya C, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults - United States, 2016. MMWR Morb Mortal Wkly Rep. Sep 14 2018;67(36):1001-1006. doi:10.15585/mmwr.mm6736a2.
[2] Fine PG, Mahajan G, McPherson ML. Long-acting opioids and short-acting opioids: appropriate use in chronic pain management. Pain Med. Jul 2009;10 Suppl 2:S79-88. doi:10.1111/j.1526-4637.2009.00666.x.
[3] Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. Feb 17 2015;162(4):276-86. doi:10.7326/m14-2559.
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