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Extended-release Naltrexone: Good but not a Panacea

Lott, DC. Lancet. 2017 Nov 14.

pii: S0140-6736(17)32872-6.

doi: 10.1016/S0140-6736(17)32872-6. (Epub ahead of print)


Comment on Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial  Lee, JD, et al. Lancet. 2017 Nov 14. pii: S0140-6736(17)32812-X. doi: 10.1016/S0140-6736(17)32812-X. (Epub ahead of print)


Reproduced with permission – see Lancet full text version

Unlike other addictions, opioid-use disorder has several highly effective medication treatments available, in particular methadone, buprenorphine, and naltrexone (1–3). Methadone is the least accessible or acceptable of these in many settings, so providers and patients are often faced with a choice between buprenorphine-naloxone (BUP-NX) and extended-release naltrexone injection (XR-NTX).

Since XR-NTX became available, many providers and researchers expected it to have similar problems to oral naltrexone—difficulty starting the treatment, poor adherence, and concerns about the possibility of higher relapse and overdose compared with agonist medication (4–6). Until recently, no direct comparison trial was available to guide this treatment selection.

Two concurrent trials comparing BUP-NX with XR-NTX have now been completed, one in Norway and one in the USA. The Norwegian randomised clinical non-inferiority study (7) showed similar retention and effectiveness of both agents. In The Lancet, Joshua D Lee and colleagues (8) report on the US study, a multicentre, open-label, randomised trial. Patients (aged 18 years and older) at inpatient detoxification units were randomly assigned to receive monthly XR-NTX (n=283) intramuscular injections or daily sublingual BUP-NX (n=287) for 24 weeks in typical community outpatient settings. The study addresses several outstanding questions about use of XR-NTX in real-world settings regarding feasibility of induction, and the safety and effectiveness of the treatment (9). To balance the success potential for the two treatments, randomisation and inductions occurred at different stages in the detoxification process.

The main outcome of the study was higher relapse for XR-NTX than with BUP-NX in the intention-to-treat population (185 [65%] vs 163 [57%]; hazard ratio [HR] 1·36, 95% CI 1·10–1·68). However, this outcome was primarily due to fewer XR-NTX inductions and high relapse among induction failures. Therefore, once treatment was successfully initiated, both medications were similar in effectiveness and safety: among the 474 participants inducted to treatment, the proportion of opioid-relapse events was 52% for the XR-NTX group and 56% for the BUP-NX group (odds ratio 0·87, 95% CI 0·60–1·25; p=0·44), with no difference in the relative hazard of relapse over time (HR 0·92, 95% CI 0·71–1·18; p=0·49).

There are two main implications of these results. First, these findings add to growing scientific literature supporting the effectiveness and safety of XR-NTX. The similar performance of the two medications after successful induction is consistent with the results of the Norwegian study (7). These are the only published direct comparison trials of these two drugs, and both studies show that XR-NTX is a valid alternative to agonist therapy that should be considered among effective treatment options for opioid use disorder.

Second, the substantial induction hurdles for XR-NTX continue to present challenges, which are especially important because induction failure might lead to relapse and overdose. In fact, in this US study most XR-NTX induction failures did relapse (70 [89%] of 79), confirming the scope of this problem. Such treatment failures are even more worrisome because of the high risk of overdose with opioids and the continuing rise in overdose deaths in the USA (10). In this study, deaths were equivalent in the two groups (two for XR-NTX and three for BUP-NX). Differences in total overdoses (fatal and non-fatal) did not differ between groups, but the numbers were noteworthy—18 for XR-NTX versus ten for BUP-NX. Considering that the study was not powered to detect overdose differences, there should be continued evaluation of how failure to complete opioid detoxification and induction onto XR-NTX might increase overdose risk.

The study might be criticised for restricting inductions to acute inpatient detoxification units only. Although this does limit generalisability, it reflects a common clinical scenario, which fits with the aims of this comparative effectiveness trial.

These results offer important guidance for treatment. The common situation of choosing between XR-NTX and BUP-NX is highly complex, involving numerous factors such as patient preference, treatment history, current level of physiological opioid dependence, and access to detoxification treatment, among others. With patients who are in an opioid-dependent state, the higher chance of induction failure and subsequent relapse with XR-NTX induction attempts must be carefully considered, unless they will be in a controlled setting long enough to withdraw completely from opioids before induction. BUP-NX might be a safer initial strategy for many of these patients because of the better chance of a quick successful induction. Different outpatient withdrawal and induction procedures for XR-NTX are being investigated (11,12), but the process remains challenging and in need of further testing. However, for patients fully withdrawn from opioids, XR-NTX can now be considered a good treatment option with equivalent safety and effectiveness to BUP-NX.

Despite the induction problems with XR-NTX, many patients choose this treatment over BUP-NX for a variety of reasons, even in an outpatient setting—preference to avoid agonists, influence from family or peers, requirements from the criminal justice system, or previous failure of agonist therapy (13). Unfortunately, this choice is sometimes forced on patients because of limits on access to agonist therapy, as is the case in certain countries and other settings (5,13). Since both medications are effective, and it is not clear which one will be better for each patient, policy makers should work to make both treatment options available and avoid preferentially mandating one medication over the other. A related problem is that many treatment programmes in the USA do not offer any opioid medication treatment or sometimes even discourage medication as an inferior mode of treatment (14). This widespread misconception needs to be addressed and access to medication for opioid use disorder at all levels of the treatment delivery system needs to be improved.

Finally, these results bring attention to several important research needs. First, continuing efforts to improve the induction process for XR-NTX will help enhance the safety and availability of this treatment. Additionally, identification of the genetic and other treatment moderators by the authors in this and other studies will further guide medication selection through improved treatment matching. Last, future research should also work to identify the causes of dropout and improve retention, with medication in addition to other methods of treatment.


David C Lott

Department of Psychiatry, University of Illinois College of Medicine, Chicago, IL 60612, USA

I declare no competing interests.


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  8. Lee JD, Nunes EV, Novo P, et al. Comparative e ectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet 2017; published online Nov 14. http://dx.doi. org/10·1016/S0140–6736(17)32812-X.

  9. Lee JD, Nunes EV, Novo P, et al. NIDA Clinical Trials Network CTN-0051, extended-release naltrexone vs. buprenorphine for opioid treatment (X:BOT): study design and rationale. Contemp Clin Trials 2016; 50: 253–64.

  10. Centers for Disease Control and Prevention. Increases in drug and opioid-involved overdose deaths—United States, 2010–2015. MMWR Morb Mortal Wkly Rep 2016; 65: 1445–52.

  11. Sullivan M, Bisaga A, Pavlicova M, et al. Long-acting injectable naltrexone induction: a randomized trial of outpatient opioid detoxi cation with naltrexone versus buprenorphine. Am J Psychiatry 2017; 174: 459–67.

  12. Mannelli P, Wu LT, Peindl KS, et al. Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial. Drug Alcohol Depend 2014; 138: 83–88.

  13. Woody GE. Current progress in opioid treatment. Am J Psychiatry 2017; 174: 414–16.

  14. Knudsen HK, Abraham AJ, Roman PM. Adoption and implementation of medications in addiction treatment programs. J Addict Med 2011; 5: 21–27.

See Online/Article

See Online/Comment Published online November 14, 2017


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