Monthly naltrexone intramuscular injections to manage opioid dependence may be as effective as daily buprenorphine/naloxone tablets for treatment retention and opioid abstinence but may increase the risk of withdrawal-related adverse events
EBM Focus - Volume 12, Issue 44
- Once-monthly naltrexone intramuscular injections as maintenance therapy for opioid dependence is effective compared to placebo, but evidence compared to buprenorphine/naloxone is lacking.
- In an open-label 12-week randomized trial in Norway, 159 adults with opioid dependence completed a detoxification program and were randomized to extended-release naltrexone 380 mg intramuscular injection once every 4 weeks vs. combination buprenorphine/naloxone oral tablets once daily.
- Naltrexone was noninferior to buprenorphine/naloxone for treatment retention and opioid-negative urine tests, but had an increased risk of withdrawal-related adverse events.
Medication-based maintenance therapy is recommended for patients with opioid dependence, and the specific choice of medication and regimen should be a shared decision between physician and patient taking into account individual preferences as well as the clinical situation (ASAM guidelines 2015). Established options include opioid agonist-based therapies with buprenorphine/naloxone or methadone, but they require frequent administrations and have some risk of physiological dependence. The opioid antagonist naltrexone, on the other hand, can be administered as once-monthly intramuscular injections and does not carry the risk of physiological dependence. It is more effective than placebo (Lancet 2011) but has not been directly compared to agonist therapy. In a recent open-label 12-week trial conducted in Norway, 159 adults with opioid dependence who completed a minimum 7-day detoxification program were randomized to extended-release naltrexone 380 mg intramuscular injection (Vivitrol) once every 4 weeks vs. combination buprenorphine/naloxone oral tablets (Suboxone) once daily. The buprenorphine/naloxone dose was started at buprenorphine 4 mg/day and titrated up as needed. Both regimens were administered in controlled settings. Patients had weekly urine tests (a missed test was considered to be opioid-positive) and were asked about substance use and cravings at monthly visits. Naltrexone efficacy was assessed using noninferiority analyses adjusted for age, sex, and other variables. The noninferiority margins were 20% for the difference in 12-week treatment retention rates and 20% for the difference in mean percentage of opioid-negative urine tests.
At baseline, the mean self-reported number of days using illicit opioids during the 30 days before the trial was lower among patients allocated to naltrexone compared to buprenorphine/naloxone (7.6 vs. 12 days for heroin; 8.2 vs. 14.5 days for other opioids; statistical comparisons not reported). At the end of the 12-week trial, naltrexone met noninferiority criteria for both treatment retention (in 79% with naltrexone vs. 68% with buprenorphine/naloxone, 95% CI for adjusted difference -10% to 20%) and mean percentage of opioid-negative urine tests (90% vs. 80%, 95% CI for adjusted difference -4% to 20%). Patients on naltrexone also reported fewer days using opioids during the final 28 days of the trial in per-protocol analyses: mean 1.1 vs. 4.1 days for heroin (p = 0.003) and 2 vs. 4.4 days for other opioids (p = 0.06). However, adverse events were more common with naltrexone (in 69% vs. 34.7% of all randomized patients, NNH 3), including opioid-withdrawal related events such as nausea, diarrhea, and chills (in 39.4% vs. 13.9%, NNH 4) and serious adverse events (in 8.5% vs. 4.2%, not significant). No patients died during the trial, and 1 overdose (from the buprenorphine/naloxone group) was reported. There were no significant differences in self-reported mean number of days using other illicit substances such as amphetamines or cocaine.
This trial demonstrated that monthly naltrexone intramuscular injections may be as effective as daily buprenorphine/naloxone tablets for treatment retention and opioid abstinence over 12 weeks in adults with opioid dependence, but they may also be accompanied by more withdrawal-related adverse events. One limitation of this study is that the choices of noninferiority margins were not explained, raising the question of whether or not the 95% CI for difference in treatment retention rates includes clinically significant differences in favor of buprenorphine/naloxone. Another limitation is that patients in the naltrexone group had lower self-reported rates of opioid use at baseline, which could contribute to the apparent effectiveness of naltrexone. In addition, the patients in this trial appear to be highly motivated: only patients who successfully completed a minimum 7-day detoxification program were included, only 1 overdose was reported, and an additional 51 patients met inclusion criteria but declined to participate. These results may not generalize to less motivated patients, or to countries with less supportive policies and services than Norway. Finally, while positive results over 12 weeks are encouraging, longer-term effects of naltrexone compared to other therapies need to be determined. When published, results from a 24-week trial in the United States comparing naltrexone intramuscular injections to buprenorphine/naloxone tablets may address questions regarding longer-term efficacy and efficacy in a non-Norwegian country (Contemp Clin Trials 2016). In the meantime, the current trial provides evidence that once-monthly naltrexone intramuscular injections should be considered along with opioid agonist therapies when discussing different options for treating opioid dependence.