P-018 - Safety and Tolerability of Schedule III Buprenorphine and Oral Schedule II Opioid Treatment in Chronic Low Back Pain Patients: A Retrospective US Medicare 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 Medicare Claims Analysis

Background: Chronic low-back pain (cLBP) is a common healthcare condition among older adults affecting their daily activities, diminishing quality of life and imposing great challenges on healthcare providers and decision makers.^1,2
American Geriatric Society recommends acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) as the first choice to cope with chronic pain in the elderly.^3,4 Since NSAIDs cannot control the chronic pain of higher severity and may have gastrointestinal and cardiovascular consequences, schedule II (CII) opioids are commonly prescribed to ensure around-the-clock analgesia.⁴ Although CII opioids are an effective treatment option, there is no ideal dose among older cLBP patients, and it should be carefully titrated to fit individual needs.^4,5 In addition, CII opioids may increase the risk of falls and other drug-related adverse events in opioid-naïve elderly patients during treatment initiation or the use of long-acting opioids.^5,6
Buprenorphine, a Schedule III (CIII) opioid is also a treatment option for long-term chronic pain management, with an improved risk-benefit profile compared to other CII opioids.^6,7 The bioavailability of oral formulations is limited due to the high first-pass metabolism in gastrointestinal tract. Therefore, buccal and transdermal buprenorphine formulations were developed to avoid extensive first-pass metabolism and improve bioavailability.⁸

Purpose/Objectives: A previous real-world evidence study conducted among the commercially insured population diagnosed with cLBP demonstrated a better safety and tolerability profile of CIII buprenorphine over oral CII opioids.⁹ There were only 3 out of 44 serious treatment-emergent adverse events (TEAEs) that occurred more frequently in CIII buprenorphine cohort, while 15 of 44 investigated TEAEs were more common in CII opioid cohort.⁹ Therefore, the assessment of safety characteristics of CIII buprenorphine and CII opioids among elderly cLBP patients will provide significant benefits to the decision makers, especially considering patients’ characteristics and medication overburden in this population.
The objective of this retrospective study among Medicare cLBP patients was to evaluate and compare safety and tolerability of CIII buprenorphine and oral CII opioids. The safety outcomes were also assessed particularly within cLBP patients treated with Belbuca^® (buprenorphine buccal formulation) and compared to oral CII opioids and transdermal buprenorphine formulations.

Methods: This retrospective study was conducted on Merative MarketScan^® database of Medicare patients from January 2018 to December 2021. The first date of CIII buprenorphine or oral CII opioid medication prescription identified via the most relevant national drug codes was defined as index date. Observation consisted of 6-month pre-index period and post-index period that lasted until the end of index treatment or the end continuous healthcare coverage. Two low back pain diagnoses during the pre-index and continuous coverage during observational period were required. Additionally, patients assigned to opioid cohort had no prior or concomitant buprenorphine patch or buccal film prescriptions, while concomitant CII opioid treatment during the post-index period was allowed for buprenorphine patients.
The main outcomes were serious TEAE rates reported as incidence rate ratios (IRR). Only events requiring emergency department or hospitalization management were considered serious. For TEAEs that occurred in one cohort, the rates were compared using absolute incidence rate difference (IRD) per 1,000 person-years. The primary analysis compared oral CII opioids and CIII buprenorphine (Belbuca^® and transdermal patch), while sub-analyses assessed differences between Belbuca^® and oral CII opioids, as well as between Belbuca^® and buprenorphine patches. Propensity-score matching (PSM) was performed to balance differences in patients’ characteristics.

Results: Non-matched sample consisted of 26,995 patients, with 1,020 patients in CIII buprenorphine cohort (203 in Belbuca^® and 817 buprenorphine transdermal patch) and 25,975 patients in CII opioid cohort. After PSM analysis, 1,496 patients were matched in the primary analysis (545 patients in CIII buprenorphine and 951 in CII opioid cohort). Sub-analyses yielded 124 Belbuca^® patients matched to 297 CII opioid patients, and 62 Belbuca^® patients matched to 62 buprenorphine transdermal patch patients.
Compared to CII opioid cohort, CIII buprenorphine treatment was associated with significantly lower rate of confusion (IRR 0.07, p< 0.001), syncope (IRR 0.08, p< 0.001), headache (IRR 0.11, p=0.002), urinary discomfort (IRR 0.16, p< 0.001), constipation (IRR 0.17, p< 0.001), cerebrovascular accident (IRR 0.18, p=0.003), atrial fibrillation (IRR 0.19, p=0.001), osteoarthritis (IRR 0.28, p=0.029), cellulitis (IRR 0.29, p=0.004), pneumonia (IRR 0.34, p=0.001), and abdominal pain (IRR 0.45, p=0.029). CIII buprenorphine patients also experienced significantly lower incidence of sleep disturbances (IRD -91.85 per 1,000 person-years, p< 0.001) and hypotension (IRD -30.62 per 1,000 person-years, p=0.036). However, CIII buprenorphine cohort more frequently experienced bone fractures (IRR 5.90, p=0.044) than patients treated with oral CII opioids.
The sub-analysis comparing Belbuca^® and CII opioids identified constipation (IRR 0.12, p=0.035) and fatigue (IRR 0.20, p=0.043) as more common serious TEAEs in CII opioid cohort. Significantly lower incidence of osteoarthritis (IRD -340.08 per 1,000 person-years, p=0.001) and urinary discomfort (IRD -194.33 per 1,000 person-years, p=0.010) were observed among Belbuca^® patients. There were no serious TEAEs that occurred more frequently in Belbuca^® than CII opioids.
The other sub-analysis comparing Belbuca^® and buprenorphine transdermal patch demonstrated greater incidence of osteoarthritis and confusion in the Belbuca^® cohort (IRDs 867.30 and 462.56 per 1,000 person-years, respectively; both p< 0.05). However, Belbuca^® patients experienced dehydration (IRR 0.08, p=0.002) and pneumonia less frequently (IRR 0.12, p=0.016). Also, opioid abuse and dependence, abdominal pain, and loss of appetite occurred only in buprenorphine transdermal patch cohort (IRDs -806.84, -496.52, and -372.39 per 1,000 person-years, respectively; all p< 0.05).

Conclusions/Implications for future research and/or clinical care: This study demonstrated a higher occurrence of serious TEAEs in the CII opioid cohort vs. the buprenorphine cohort including confusion, syncope, headache, urinary discomfort, constipation, cerebrovascular accident, atrial fibrillation, osteoarthritis, cellulitis, pneumonia, abdominal pain, sleep disturbances, and hypotension. In general, CIII buprenorphine also seems better tolerated among the Medicare population than CII opioids, with exception of the higher rate of serious bone fractures.
Based on the real-world retrospective claims, Belbuca^® demonstrated better safety and tolerability than CII opioids, with lower rates of serious TEAEs including fatigue, constipation, osteoarthritis, and urinary discomfort. No serious TEAEs were significantly more common in Belbuca^® than CII opioids.
Additionally, Belbuca^® showed significantly lower rates of serious TEAEs of opioid abuse and dependence, abdominal pain, loss of appetite, dehydration, and pneumonia compared to the buprenorphine patch. Only the higher rates of confusion and osteoarthritis were observed more frequently in Medicare Belbuca^®-treated cLBP patients.

References: [1] de Souza IMB, Sakaguchi TF, Yuan SLK, et al. Prevalence of low back pain in the elderly population: a systematic review. Clinics (Sao Paulo). 2019; 74:e789. doi: 10.6061/clinics/2019/e789.

[2] 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.

[3] 2023 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023; 71(7): 2052-2081. doi:10.1111/jgs.18372.

[4] Wong AYL, Karppinen J, Samartzis D. Low back pain in older adults: risk factors, management options and future directions. Scoliosis Spinal Disord. 2017 Apr 18;12:14. doi: 10.1186/s13013-017-0121-3.

[5] 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.

[6] Vadivelu N, Hines RL. Management of chronic pain in the elderly: focus on transdermal buprenorphine. Clin Interv Aging. 2008;3(3):421-30. doi: 10.2147/cia.s1880.

[7] Webster L, Gudin J, Raffa RB, et al. Understanding Buprenorphine for Use in Chronic Pain: Expert Opinion. Pain Med. Apr 1 2020;21(4):714-723. doi:10.1093/pm/pnz356.

[8] Gudin J, Fudin J. A Narrative Pharmacological Review of Buprenorphine: A Unique Opioid for the Treatment of Chronic Pain. Pain Ther. Jun 2020;9(1):41-54. doi:10.1007/s40122-019-00143-6.

[9] Zah V, Stanicic F, Kunkel T, Vukicevic D, Grbic D. 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. The 17th Annual National Conference on Pain for Healthcare Professionals (PAINWeek 2023); September 5-8, 2023; Las Vegas, NV.