Extended-release injectable naltrexone (XR-NTX)

Abstract

We appreciate the letter by Brewer and Streel expanding on clinical issues reported in our recent review on extended-release injectable naltrexone (XR-NTX).1 As stated in our methods, we intentionally focused on studies using XR-NTX and did not consider studies on other long-acting NTX formulations. Induction procedures for other long-acting NTX formulations, if more successful than those described in our review, could be investigated for their utility in increasing XR-NTX induction. However, the authors’ claim that 100% intent-to-treat induction rates for implantable NTX have been routinely achieved for thousands of patients is not supported by the cited reports. Two of these reported induction onto oral NTX.2,3 The other4 was a retrospective report of two cohorts, which were both comprised of patients who had previously received implantable NTX; induction rates were not reported. We described induction procedures as “rapid” because these involved XR-NTX administration before the manufacturer-recommended 7 to 10 days of opioid abstinence.5 In our search, we did not identify any published studies investigating shorter XR-NTX inductions within 24 hours. The suggestion by Brewer and Streel that induction to XR-NTX can routinely be easy and rapid is out of touch with broad experience to the contrary. For example, a recent multisite clinical trial6 that was included in our review from the U.S. National Drug Abuse Treatment Clinical Trials This article is protected by copyright. All rights reserved. Network referred to the relative difficulty of beginning XR-NTX versus sublingual buprenorphine-naloxone (significant at p < .0001) as “a substantial induction hurdle.” Regarding our decision to report urinalysis data, we agree that, while guidelines are available,7 there is no single standard for the selection of primary outcome measures for clinical trials evaluating medications for opioid use disorder.8 We chose to measure opioid use as the percentage of urine samples negative for opioids because this is nearly universally collected in clinical trials and provides an objective measures of recent opioid use. Several of the clinical trials included in our review used other opioid use outcomes (e.g., relapse, self-reported opioid-free days). We reported these findings and considered them in our conclusions on XR-NTX’s efficacy and effectiveness. Brewer and Streel’s statement that opioid use during XR-NTX blockade might constitute a “neuropharmacological abstinence” is valid but of unclear relevance. When adhered to, XR-NTX affords protection from overdose and agonist effects that might interfere with normal activities (e.g., driving, working, taking care of children), but opioid use can still have considerable negative impacts when taken under XR-NTX blockade (e.g., spread of HIV/HCV, infection, exposure to legal consequences, financial problems). These consequences should be emphasized, even if further evidence confirms an extinction-based mechanism for XR-NTX’s effectiveness.9 Our statement that XR-NTX’s therapeutic effects on opioid use do not persist once discontinued was based on a large 24-week multi-site randomized controlled trial with follow up at 52 and 78 weeks.10 This finding and our statement are consistent with the chronic, relapsing nature of opioid use disorder and mirror the much larger literature on the effects of adherence to methadone and buprenorphine on opioid use.11 Rather than obscuring the clinical effects of XR-NTX, as suggested by Brewer and Streel, we believe this finding highlights the critical role that medication adherence and treatment retention play in promoting long-term remission and preventing relapse to opioid use.