Review of: Shulman M et al, JAMA Netw Open 2024;7(5):e249744

Study Type: Prospective randomized clinical trial

Long-acting injectable naltrexone (XR-NTX, brand name Vivitrol) is an FDA-approved treatment for opioid use disorder (OUD). Though safe and effective, it can be tricky to start. Before receiving the first dose of XR-NTX, patients must stop all opioid use and remain completely abstinent from opioids for a full 7–10 days (www.tinyurl.com/3dfezwrv). If it is given too soon, a very uncomfortable precipitated withdrawal can result. This abstinence period is a substantial barrier and limits its real-world utility in the clinic (Lee JD et al, Lancet 2018;391(10118):309–318). In an effort to shorten this requirement, researchers developed a novel rapid procedure (RP) for starting XR-NTX that lasts just 5–7 days. 

Researchers compared the standard initiation procedure (SP) of 7–10 days with their RP by enrolling 415 participants receiving inpatient treatment for OUD across 6 sites. In the SP group (n=190), participants started with several days of buprenorphine, followed by an opioid-free washout period of 7–10 days, then received an injection of 380 mg of XR-NTX. In the RP group (n=225), participants got just enough buprenorphine to curb withdrawal symptoms on the first day, followed by an opioid-free washout day, then several days of a low-dose oral naltrexone titration and aggressive oral hydration (see the “Timeline of Standard and Rapid Procedures” table). All participants in the RP group received adjunctive medications like clonidine, clonazepam, and antiemetics, whereas adjunctive medications differed depending on site in the SP group. The primary endpoint was receipt of XR-NTX, and participants were followed for two months afterwards.

In the RP group, 62.7% of participants received XR-NTX, compared to only 35.8% in the SP group (odds ratio=3.60, 95% confidence interval=02.12–6.10). Both procedures were well tolerated, though side effects were a bit more common in the RP group; 5.3% of participants in the RP group had a side effect compared to 2.1% in the SP group during the period leading up to the first administration. Both groups had similarly poor rates of subsequent treatment adherence, with less than half receiving two more injections in the eight-week follow-up period. 

Investigators showed that RP has the upper hand when it comes to successful XR-NTX initiation, at least in an inpatient setting. One drawback is that the aggressive oral hydration, frequent adjunctive medication administration, and compounding of low-dose oral naltrexone makes RP more labor intensive for staff. Implementing RP in the real world would require a well-trained inpatient staff with the ability to monitor patients closely and treat them quickly. The researchers also chose to stabilize all participants on buprenorphine, which is not required to start XR-NTX, potentially exaggerating the time advantage of RP over SP.

Carlat Take 

The period of abstinence required prior to starting XR-NTX can be a significant barrier. This new, faster procedure shortens the abstinence time and increases the likelihood of receiving the medication, though it is more labor intensive, has only been studied for inpatients, and ultimately does not improve long-term adherence. Though not a magic bullet, the protocol is worth considering for inpatients who struggle with starting XR-NTX.