Injectable extended-release naltrexone for opioid dependence

Abstract

Daniel Wolfe and colleagues (April 30, p 1468)1Wolfe D Carrieri MP Dasgupta N Wodak A Newman R Bruce RD Concerns about injectable naltrexone for opioid dependence.Lancet. 2011; 377: 1468-1470Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar present a very unbalanced review of published data in an apparent effort to show that injectable extended-release naltrexone is more dangerous than agonist treatment for a disorder with a known high mortality. For example, they misrepresent the fact that all deaths in the Miotto study2Miotto K McCann MJ Rawson RA Frosch D Ling W Overdose, suicide attempts and death among a cohort of naltrexone-treated opioid addicts.Drug Alcohol Dep. 1997; 45: 131-134Summary Full Text PDF PubMed Scopus (76) Google Scholar occurred after patients stopped oral naltrexone (a problem sustained-release formulations address); ignored missing data in the Digiusto study3Digiusto E Shakeshaft A Ritter A O'Brien S Mattick R NEPOD Research GroupSerious adverse events in the Australian National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD).Addiction. 2004; 99: 450-460Crossref PubMed Scopus (85) Google Scholar that reported excess deaths after naltrexone versus methadone treatment even though 33% of naltrexone patients and 88% of agonist patients had no out-of-treatment observation time; and overlooked that Gibson and Degenhardt4Gibson A Degenhardt LJ Mortality related to pharmacotherapies for opioid dependence: a comparative analysis of coronial records.Drug Alcohol Rev. 2007; 26: 405-410Crossref PubMed Scopus (55) Google Scholar compared deaths after naltrexone versus methadone during the first 2 weeks of methadone and did not mention that deaths also increase after patients leave methadone maintenance. Relevant to the naltrexone overdose issue are data from a recently completed study5Krupitsky E, Zvartau E, Woody G. Naltrexone for opiate dependence: oral, implantable, and injectable. Presented at annual meeting of the American Association for the Treatment of Opioid Dependence; Chicago, IL, USA; Oct 23–27, 2010.Google Scholar in which 306 opioid-addicted patients were randomly assigned to a 6-month course of a naltrexone implant that blocks opioids for 2–3 months (Prodetoxon) plus oral placebo; oral naltrexone plus naltrexone implant placebo; or double placebo, all with biweekly drug counselling. Follow-ups done 6 months or more after treatment ended contacted 85% of patients or relatives for the specific purpose of finding out how many had died. Five deaths were identified: none in the implant group, one in the oral naltrexone group, and four in the placebo group. GEW collaborates with Evgeny Krupitsky on naltrexone studies. He introduced the Alkermes Medical Director to Evgeny Krupitsky and the Pavlov research team during a visit to St Petersburg in 2006 and participated in discussions about study logistics, the Pavlov team's ability to conduct high-quality randomised trials in a timely fashion, and the potential to study extended-release injectable naltrexone in Russia with an eye towards getting it approved for that indication in the USA. Fidelity Capital provided Prodetoxon at reduced price for the recent implant study; Alkermes provided Vivitrol for a study in which GEW is a co-investigator; GEW received a consulting fee from Alkermes in 2010. DSM has no conflics of interest. Injectable extended-release naltrexone for opioid dependence – Authors' replyOur concerns about the approval of injectable naltrexone (Vivitrol) for treatment of opioid dependence turned on three points. First, that the US Food and Drug Administration (FDA) accepted a single trial of injectable naltrexone in Russia, unpublished at the time,1,2 as primary evidence of efficacy. Second, that the study did not adequately assess risk of post-treatment overdose in trial participants. Third, that it was ethically questionable to do a placebo-based trial given the proven efficacy of methadone and buprenorphine and the known risk of mortality in patients offered counselling alone. Full-Text PDF