Medication Assisted Treatment for Opioid Use Disorder: Parenteral Therapy (Part III)

Depot Intramuscular Naltrexone. Depot (extended-release) naltrexone (Vivitrol®) is given as a large volume (4 mL) monthly gluteal injection to block activity at the μ-opioid receptor. It does not control symptoms of withdrawal or reduce craving and is suitable only for highly compliant patients with a robust support system who wish to discontinue all μ-opioid receptor agonists. It is indicated for the prevention of relapse in patients who have already achieved complete abstinence and who are highly motivated to stay abstinent. Patients must first undergo opioid withdrawal for 7 days and abstain from buprenorphine and methadone, a major challenge for many. Patients can also experience withdrawal symptoms for up to two weeks after stopping their μ-opioid receptor agonist(s).

Transient LFT elevations and injection site pain have been reported with Vivitrol. The Vivitrol prescribing information does not provide additional guidance on the anatomic placement of IM injections in the buttocks (beyond “gluteal injection"). Dorsogluteal injections are no longer recommended in clinical practice, particularly for larger volumes and viscous injections due to close proximity to neurovascular structures and the inconsistent depth of adipose tissue. Inexperience with IM injection techniques and imprecise landmarking, particularly for dorsogluteal injection can result pain and sciatic nerve injury. Other IM injection-related side effects common to many drugs are granuloma, intravascular injection, abscess, tissue necrosis, hematoma, fibrosis, cellulitis, and injury to vessels, bone and nerves.

Extended-Release (Depot) Subcutaneous Buprenorphine. Depot subcutaneous buprenorphine virtually eliminates the risk of diversion and accidental poisoning and removes the burden of daily adherence observed with oromucosal buprenorphine. This provides the potential for enhanced treatment retention, reduced illicit drug use, and greater focus on psychosocial treatment and improved health care outcomes. Two depot buprenorphine formulations, Probuphine® and Sublocade® are on the market. With the recent availability of Sublocade, Probuphine must be considered an "anachronistic" treatment with little or no therapeutic justification. Probuphine was launched in 2016 as a subdermal implant of four rods (2.5 mm x 26 mm) which release buprenorphine over 6 months, followed by surgical removal and replacement with a second set of rods in the contralateral arm for a further 6 months. The prescribing information for Probuphine notes that “implants should not be used for additional treatment cycles after one insertion in each upper arm”. In other words, patients must transition back to a oromucosal buprenorphine or receive Sublocade after a maximum of 12 months of Probuphine. Additionally, Probuphine is indicated for patients with low-to-moderate oromucosal buprenorphine requirements (≤ 8 mg per day). Rare but serious complications including nerve damage and migration resulting in embolism and death from improper Probuphine implant insertion have been reported. Additional complications include local migration, protrusion and expulsion.

Sublocade® a monthly abdominal subcutaneous depot buprenorphine was launched in 2018. To initiate Sublocade, patients need to be on a stable oromucosal buprenorphine dose of 8 to 24 mg for at least seven days. Even in the setting of a pivotal 19-week Sublocade clinical trial, 90% abstinence was achieved in only 24%, and only 62% of subjects completed the study at the highest buprenorphine dose. In clinical trials, 18.9% and 13.8% receiving 300/300 and 300/100 of Sublocade, respectively reported injection site reactions of mild to moderate severity, with injection site pain, pruritus and erythema predominating. Despite these apparent limitations, Sublocade represents a major therapeutic advance for the treatment of OUD.

Summary. Although presently available MATs represent an important pharmacologic advance for the treatment of OUD, there is striking interindividual variability in the efficacy, safety, tolerability and psychic effects of MATs. Vivitrol (depot IM naltrexone) is suitable only for a limited number of highly compliant and opioid abstinent patients with a robust support system. Oral methadone has a robust evidence base for use in OUD. However, daily OTP clinic visits significantly limit methadone’s therapeutic potential. With the availability of Sublocade (depot SC buprenorphine), it is difficult to justify the continued use of Probuphine (implanted buprenorphine rods) for OUD. Sublocade should virtually eliminate the diversion observed with oromucosal buprenorphine. It also has the potential to provide improved convenience and compliance over daily oromucosal buprenorphine. While Sublocade represents a potential “game-changer” for OUD, abstinence and treatment retention rates for all MATs remain modest, underscoring the need for continued R&D into new pharmacologic modalities with improved outcomes.

We should acknowledge that none of the available MATs for OUD would have been possible without significant basic and translational research support from NIDA, highlighting the important role of the NIH in the prevention and treatment of OUD. Despite significant therapeutic gains in MAT for OUD and similar advances for SUD, there is even more work to done in view of the proliferation of synthetic opioids sold as adulterated heroin, heroin substitute and fentanyl-laced counterfeit opioid pills.

Dr. Najib Babul, PharmD, MBA.

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