Escaping the daily grind: Non-oral buprenorphine options for opioid use disorder management

Opioid use disorder (OUD) is a complex, chronic condition that imparts tragic consequences on the lives of Canadians who use opioids, their families and communities. The COVID-19 pandemic has exacerbated the negative outcomes associated with OUD, including increased morbidity and mortality across Canada.1,2 Although numerous opioid stewardship actions have shown to be helpful in mitigating OUD, none match the life-saving capability of opioid agonist therapy (OAT), which is considered first-line treatment for OUD.3 Prompt access to OAT agents, such as buprenorphine-naloxone (BUP-NAL) and methadone, reduces mortality associated with opioid overdose; it also reduces the incidence of HIV and hepatitis C in this population, and has several other benefits.4 Although methadone is effective and may be more appropriate for some patient populations, BUP-NAL sublingual tablets are considered first-line for most patients due to their favourable safety profile.3 A notable limitation of these agents is their requirement for daily—and often observed—ingestion, which may deter long-term adherence and treatment success. To mitigate this, alternatives to daily dosing are making their way to the forefront of OUD care. Longer-acting buprenorphine formulations, including a once-monthly subcutaneous injection (Sublocade) and a six-month subdermal implant (Probuphine), are becoming preferred long-term treatment approaches for some individuals. Buprenorphine: A refresher Regardless of the formulation, the effect of buprenorphine in the body is the same. As a partial mu opioid agonist, it reduces the withdrawal symptoms and opioid cravings associated with OUD. Buprenorphine binds with high affinity to these receptors, contributing to long-lasting craving reduction (> 24 hours) and reduces the rewarding impact of any other opioids that may be used at the same time.4 Furthermore, early evidence highlights buprenorphine’s anxiolytic and antidepressant properties, likely due (at least in part) to its antagonist properties at kappa opioid receptors.5 From a safety perspective, compared with other opioid agonists, buprenorphine carries a reduced risk of respiratory depression and associated overdose, with a ceiling effect on respiratory depression at doses beyond 32 mg daily.4,6 Monthly dosing option: Subcutaneous buprenorphine For many individuals, daily (or near daily) supervised doses of BUP-NAL are a challenge. Unsurprisingly, evidence favours extended-release subcutaneous buprenorphine depot (BUP-SC) over sublingual BUP-NAL across several key endpoints, including reduced concomitant use of illicit opioids and overall patient satisfaction.6-8 In addition to therapy adherence, the BUP-SC formulation addresses other critical issues, such as diversion and accidental pediatric exposure. The monthly BUP-SC abdominal injection, administered by an eligible healthcare provider possessing administration certification, is only available to individuals stabilized on a daily sublingual BUP-NAL dose of 8–24 mg for at least seven days. In several provinces (AB, SK, MB, NS, NL), and with varying legislative provisions, pharmacists are permitted to administer BUP-SC injections, increasing the accessibility of this life-saving therapy. Twice a year: Too good to pass up, or too good to be true? Buprenorphine subdermal implant (BUP-IMP) consists of four small rods (320 mg total buprenorphine HCl) implanted subdermally, releasing drug continuously to provide stable plasma levels for the six-month placement.6 With the clear benefit of monthly BUP-SC, it would be a fair supposition that an option for bi-annual administration with BUP-IMP may further improve clinical outcomes and reduce access challenges. Unfortunately, current evidence does not demonstrate this consistently. However, some trials suffer from significant limitations (e.g., high attrition, use of supplemental buprenorphine, missing urine drug screen data), so evidence needs to be interpreted cautiously.6,9-12 Furthermore, available efficacy studies only provide comparative data against placebo or BUP-NAL, not BUP-SC. Current evidence suggests superiority to placebo and non-inferiority to BUP-NAL, across key clinical endpoints.9,10 In addition to the limitations of current evidence, the practical utility of this agent is important to consider. At present, only those who are stable on < 8 mg of sublingual buprenorphine for at least three months are eligible for BUP-IMP treatment, excluding those requiring moderate to high doses. As well, current recommendations support a duration of use of one year (two six-month cycles), as clinical experience beyond two cycles is limited.4,6 Finally, access to BUP-IMP could be challenging, as advanced certification is a requirement for healthcare providers to offer this office-based procedure. Nevertheless, BUP-IMP remains an OAT option that may be particularly suited for those who demonstrate early adherence issues or where concerns regarding misuse or diversion exist.12 Additional research and clinical experience will provide greater insight into the role of BUP-IMP in the management of OUD. Table 1 includes additional product and dosing details for BUP-SC and BUP-IMP. The pharmacist’s role Pharmacists have an important role in improving access to OAT and reducing barriers to care.15-18 For example, a 2021 study demonstrated the impact of community pharmacists that assumed the role for monitoring individuals on stable doses of buprenorphine.19 No reported safety events, high treatment retention (89%) and high stakeholder (patient, pharmacist, physician) satisfaction underscore the added value that pharmacists can bring to the team-based management of OUD and OAT.19 In community practice, pharmacists have frequent (often daily) interactions with those taking BUP-NAL for OUD. As a result, pharmacists are positioned to discuss OAT challenges with these individuals, potentially identifying those who may benefit from a non-oral OAT option. Given the superiority of and patient preference for BUP-SC, this option could be discussed with nearly all individuals stable on BUP-NAL, as many are unaware of this alternative. Involving patients in care decisions and addressing potential therapy challenges before they contribute to nonadherence are two ways for pharmacists to make positive impacts on treatment outcomes for OUD. Table 1 Buprenorphine for Opioid Use Disorder: Non-Oral Formulations11-14 Brand name Route (location) Supplied As Dosing for Opioid Use Disorder Additional Comments Sublocade Subcutaneous injection (abdomen) PFS: 100 mg/0.5 mL & 300 mg/1.5 mL Induction: 300 mg monthly x 1–2 months Maintenance: 100 mg monthly (300 mg monthly if cravings persist on 100 mg dose or if BUP-NAL dose was 20–24 mg/day) - Patients must be stable on 8–24 mg/day BUP-NAL for > 7 days prior to injection - Rotate injection sites each month Probuphine Subdermal implants (inner aspect of upper arm) Four rods (26 mm x 2.5 mm), each containing 80 mg buprenorphine HCl - Inserted 12–24 hours after last BUP-NAL dose - Four rods (= 320 mg buprenorphine HCl) inserted subdermally on inner aspect of upper arm - Remove rods after 6 months; if second cycle given, insert in opposite arm - Recommendations suggest no more than two cycles (one year) of treatment - Patients must be stable on 3 months prior to insertion - Insertion procedure requires advanced training - Insertion takes ~30 minutes - Some may require supplemental BUP-NAL (2/0.5 mg) tablets ongoing for breakthrough craving management.11 PFS–prefilled syringe; BUP-NAL–buprenorphine and naloxone sublingual tablets References Gomes T, Kitchen SA, Murray R. Measuring the burden of opioid-related mortality in Ontario, Canada, during the COVID-19 pandemic. JAMA Netw Open 2021;4(5):e2112865. Green TC, Bratberg J, Finnell DS. Opioid use disorder and the COVID 19 pandemic: a call to sustain regulatory easements and further expand access to treatment. Subst Abus 2020;41(2):147-9. Bruneau J, Ahamad K, Goyer MÈ, et al; CIHR Canadian Research Initiative in Substance Misuse. Management of opioid use disorders: a national clinical practice guideline. CMAJ 2018;190:E247-57. doi: 10.1503/cmaj.170958. Substance Abuse and Mental Health Services Administration. TIP 63: Medications for opioid use disorder. Updated 2021. https://store.samhsa.gov/sites/default/files/SAMHSA_Digital_Download/PEP21-02-01-002.pdf (accessed August 31, 2022). Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry 2016;173:499-508. doi: 10.1176/appi.ajp.2015.15070921. Harricharan S, Farah K. Buprenorphine formulations for the treatment of opioid use disorders: a review of comparative clinical effectiveness, cost-effectiveness and guidelines. CADTH rapid response report: summary with critical appraisal. Ottawa: CADTH; July 2017. https://www.ncbi.nlm.nih.gov/books/NBK525042/ (accessed August 31, 2022). Lintzeris N, Dunlop AJ, Haber PS, et al. Patient-reported outcomes of treatment of opioid dependence with weekly and monthly subcutaneous depot vs daily sublingual buprenorphine: a randomized clinical trial. JAMA Netw Open 2021;4(5):e219041. doi: 10.1001/jamanetworkopen.2021.9041. Institute for Clinical and Economic Review. Extended-release opioid agonists and antagonist medications for addiction treatment (MAT) in patients with opioid use disorder: effectiveness and value. 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Sublocade (buprenorphine extended release) product monograph. Toronto, ON; January 2020. Bach P, Hartung D. Leveraging the role of community pharmacists in the prevention, surveillance, and treatment of opioid use disorders. Addict Sci Clin Pract 2019;14(1):30. McCarty D, Bougatsos C, Chan B, et al. Office-based methadone treatment for opioid use disorder and pharmacy dispensing: a scoping review. Am J Psychiatry 2021;178:804–17. Peckham AM, Ball J, Colvard MD, et al. Leveraging pharmacists to maintain and extend buprenorphine supply for opioid use disorder amid COVID-19 pandemic. Am J Health Syst Pharm 2021;78:613-8. Chiarello E. Pharmacists should treat patients who have opioid use disorders, not police them. J Am Pharm Assoc 2021;61(6):e14-e19. doi: 10.1016/j.japh.2021.06.019. Wu LT, John WS, Ghitza UE, et al. 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Escaping the daily grind: Non-oral buprenorphine options for opioid use disorder management

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Dana Turcotte

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