Buprenorphine saves the lives of people with opioid use disorder (OUD). Not only does it decrease fatal drug overdoses, but its use is associated with lower risk of death from suicide, cancer, cardiovascular conditions, and alcohol. But these benefits are lost if a patient stops taking the medication; mortality increases six-fold in the first month after discontinuation and indefinitely remains twice that of patients who continue taking buprenorphine (Santo T Jr et al, JAMA Psychiatry 2021;78(9):979–993). Long-acting formulations have therefore been developed to enhance adherence, with a subcutaneous injectable called ­Sublocade leading the pack. Let’s take a closer look.

Why long-acting buprenorphine?

Two long-acting formulations of buprenorphine have been brought to market, and more are in the works (see CATR July/August 2020). The first available formulation was an implantable device called Probuphine, which had several serious shortcomings (invasive placement procedure, low serum levels, inflexible dosing, unable to be used longer than two years) and is no longer available in the United States. This leaves the subcutaneous long-acting injectable buprenorphine (XR-Bup) as the only long-acting formulation currently available.

XR-Bup (Sublocade) is a monthly, flexibly dosed, long-acting injection (LAI) that was approved by the FDA at the end of 2017. Its flexible dosing and ability to be used indefinitely made it an appealing alternative to the Probuphine implants; however, relatively few efficacy data were available at the time of approval. Now, with several years of experience under our belts, we can discuss XR-Bup’s “real world” use and provide tips to help you decide whether it is right for your practice.

How effective is it?

At present, there haven’t been any direct head-to-head comparisons of XR-Bup and sublingual buprenorphine, though studies are underway. Nonetheless, some promising data have emerged in just the past year. Recent studies have demonstrated a high level of treatment retention and treatment satisfaction among patients on XR-Bup, including those who started it in jail prior to release (Farrell M et al, Int J Drug Policy 2022;100:103492; Lee JD et al, JAMA Netw Open 2021;4(9):e2123032; see CATR Sept/Oct 2022).

Data for other LAIs might provide additional insight when considering which patients may benefit most from XR-Bup. Studies comparing oral and LAI antipsychotics suggest that treatment adherence and outcomes are improved when the medication is administered as an LAI (Kishimoto T et al, Schizophr Bull 2018;44(3):603–619). LAI naltrexone is associated with improved outcomes related to treatment retention and relapse prevention in OUD (Sullivan MA et al, Am J Psychiatry 2019;176(2):129–137) and increases time to relapse in alcohol use disorder compared to oral naltrexone (Leighty AE et al, Ment Health Clin 2019;9(6):392–396).

Using XR-Bup

XR-Bup’s slow-release technology is a bit different than other LAIs. Buprenorphine is combined with a biodegradable polymer that is injected subcutaneously into the abdomen. There, it solidifies into a depot that slowly releases medication over time (Sublocade package insert. Richmond, VA: Indivior Pharmaceuticals; 2017). Administration does not require special technique; the needle is inserted at a 45-degree angle to avoid accidental intradermal or intramuscular injection, and the medication is slowly administered. It is quite viscous, so the injection itself can last a minute or so. Since the depot is subcutaneous (most LAIs are intramuscular), warn patients that they may see or feel the depot just below the skin. Tell patients not to scratch at the injection site and not to wear clothing that is tight across the injection area.

Each dose comes as a prefilled syringe that must stay refrigerated before use and be warmed up to room temperature before administration. A dose is stable for up to seven days once it’s at room temperature, but it cannot be cooled back down—once it’s out of the fridge, the medication needs to be used within a week or discarded.

Before starting XR-Bup, patients should have at least a seven-day trial of sublingual buprenorphine to ensure tolerability and determine the most effective dose. The effective sublingual dose determines the loading schedule. Two doses of XR-Bup are available: 100 mg and 300 mg. Patients stabilized on 8–18 mg of sublingual buprenorphine should receive a single 300 mg dose and 100 mg monthly thereafter, while patients on 20–24 mg should receive two monthly doses of 300 mg and then 100 mg monthly.

Serum levels peak 24 hours after injection, so once XR-Bup is administered, sublingual buprenorphine can be discontinued. Some patients may experience minor withdrawal for a few days, which can be treated with small sublingual doses. Although designed to be given monthly, XR-Bup‘s long half-life (43–60 days) means there is leeway in injection timing; intervals of 26–42 days are fine and do not require adjustments in treatment. In fact, patients who are stable on 100 mg monthly have the option to receive a 300 mg dose every two months instead.

Shortcomings

One downside to XR-Bup is its high cost: nearly $2,000 per dose. Medicare typically covers it, as do some commercial and various state Medicaid plans, but cost can be a barrier for uninsured patients. In addition, patients must present in person for their doses. Telemedicine visits will not suffice, as providing doses to patients for self-administration is prohibited. Lack of access can also be a significant barrier. Be sure the patient has access to ongoing treatment before you start XR-Bup, especially if you are not going to be the patient’s long-term provider (if the patient is being discharged from an inpatient unit or released from jail, for example).

The clinic that administers the medication and the pharmacy that dispenses it must both be registered in a risk evaluation and mitigation strategy (REMS) program. Individual prescribers do not have to register. If you are thinking of prescribing XR-Bup yourself, you can review the requirements at www.sublocaderems.com.

XR-Bup’s side effects are essentially the same as sublingual buprenorphine, plus injection site reactions. Administration can be painful, which is a deterrent for some. In addition, there are case reports of skin necrosis at the injection site, but its incidence is very rare (Crouse E et al, J Addict Med 2022;16(2):242–245). Advise patients to seek medical attention if they develop worsening pain, redness, or erythema.

Special circumstances

You may encounter scenarios that are not covered in XR-Bup’s package insert. Most commonly, patients may have opioid cravings or withdrawal symptoms on the 100 mg maintenance dose. For these patients, it is reasonable to continue 300 mg indefinitely. If patients note cravings or withdrawal symptoms only at certain times of the month (typically just prior to their injection), you can reduce the dosing interval to as little as 26 days or add low-dose sublingual buprenorphine (2–4 mg).

Before making these adjustments, consider factors that might be causing the symptoms. For example, CYP3A4 inducers can boost buprenorphine metabolism—carbamazepine, antibiotics (rifabutin, rifampin), and antiretrovirals are common culprits. Certain disease states (eg, flu or other viral illnesses) or anxiety disorders can mimic minor withdrawal symptoms as well.

Non-standard initiation is another area where uncertainty arises. There are various reasons that you or your patient might want to skip the seven-day sublingual trial period. If this is the case, and your patient has tolerated buprenorphine in the past, you can consider giving up to 24 mg of sublingual buprenorphine and a 300 mg dose of XR-Bup in a single day, followed by a second 300 mg loading dose one month later and 100 mg monthly thereafter. This is not an approved dosing strategy, but it did work well in a small case series of five patients (Mariani JJ et al, Am J Addict 2021;30(5):470–476).

Treatment discontinuation is usually straightforward. Due to its long half-life, XR-Bup tapers itself with little to no intervention needed. In fact, single doses of XR-Bup have been used to facilitate a taper of sublingual buprenorphine, though evidence for this strategy is anecdotal. If transitioning from XR-Bup back to sublingual buprenorphine, use cravings and withdrawal symptoms to guide sublingual dosing.

Carlat Verdict

XR-Bup presents a life-saving option for patients with OUD who have difficulty adhering to sublingual formulations. Administration is relatively straightforward and can be customized to each patient's needs, but high cost and lack of access remain major barriers.