Concerns about injectable naltrexone for opioid dependence
In The Lancet, Evgeny Krupitsky and colleagues1 report on Adverse Event Reporting System includes 51 reports the use of injectable naltrexone for treatment of opioid of deaths associated with depot naltrexone between dependence. Their report comes some months after the 2006 and 2010.5 Serious unlabelled adverse events US Food and Drug Administration (FDA) approved use of this magnitude have triggered black-box warnings of the preparation for opioid-dependent patients on for other drugs.6 Although it is not clear whether the the basis of the same findings. The study by Krupitsky approximately 45 000 patients that the manufacturer and colleagues suggests the strong potential of a once- reports to have received depot naltrexone were all monthly, extended-release formulation of injectable being treated for alcoholism, prescription of the drug naltrexone for opioid addiction—the median proportion for opioid dependence raises the question of whether of weeks of confirmed abstinence was 90·0% in the injectable naltrexone might inadvertently increase risk Published Online
depot naltrexone group compared with 35·0% in the of fatal overdose. Detoxified opioid-dependent patients April 28, 2011
placebo group (treatment effect 55% [95% CI 15·9–76·1], are vulnerable to overdose in the event of relapse, 6736(10)62056-9
p=0·0002). The study is also striking, however, for the including relapse after treatment with naltrexone.7 The See Online/Articles
questions it raises about the FDA’s approval processes need for careful scrutiny of mortality after treatment DOI:10.1016/S0140-
and clinical trial ethics. Factors requiring scrutiny include with injectable naltrexone is further underscored by paucity of efficacy data, adequacy of risk assessment the lack of deaths reported in placebo-treated patients (particularly of overdose risk in treatment dropouts), in Krupitsky and colleagues’ study, which is in stark and the questionable ethics of a placebo-controlled trial contrast to other trials of opioid-dependent participants when an accepted standard of treatment exists.
with placebo controls in whom multiple deaths have The FDA’s assessment of depot naltrexone’s efficacy been reported.8,9 was based on then-unpublished evidence from this trial Experience with oral naltrexone highlights the in Russia, in which 250 eligible patients at 13 sites were importance of adequate investigation of overdose randomly assigned to receive 380 mg depot naltrexone risk following treatment with depot naltrexone. or placebo.2,3 This single study, in which 54% of patients Risk of overdose for detoxified heroin-dependent did not complete the protocol and just over half of those patients receiving oral naltrexone treatment is well on naltrexone received the full treatment course,1,2 was documented.10 A review of 13 trials of pharmacotherapies judged sufficient proof by the FDA.
for opioid dependence in Australia showed that the For evidence on safety, the FDA accepted data from the heroin overdose rates were more than trebled (at Russian study and another in the USA in patients with 6·8 per 100 person-years) for patients on oral naltrexone alcohol or opioid dependence, or both.2 Strikingly, neither treatment compared with those receiving opioid the materials provided to the FDA advisory committee agonist treatment (1·9 per 100 person-years). Patients nor the Lancet study make clear what fol ow-up was on naltrexone were as much as six times more likely to done to evaluate post-treatment opioid overdose in the experience a heroin overdose once out of treatment than participants in the Russian trial. Data from the US study while receiving medication, and patients who stopped are similarly vague on post-treatment adverse events.
naltrexone were 7·6 times more likely than patients The FDA sometimes requires only a single clinical trial on opioid agonist to experience an overdose after for new indications of an already approved drug. A single treatment cessation.7 Retrospective analysis based on trial is not justified, however, when there are questions coronial records and prescription data also found high about the safety of the drug as it will be prescribed or mortality rates (22·1 per 100 person-years) for those recommended.4 Although voluntary reporting captures prescribed naltrexone who subsequently stopped.11only a small portion of serious adverse events that occur An additional question, particularly in light of once a drug enters the marketplace, approval of depot earlier research that showed oral naltrexone to be less naltrexone for alcoholism treatment has been followed effective in the treatment of opioid dependence than by reports to the manufacturer of 19 fatalities, some buprenorphine,12 is why researchers and institutional tied to suicidal ideation or opioid overdose.2 The FDA’s review boards deemed it ethically acceptable to expose www.thelancet.com Published online April 28, 2011 DOI:10.1016/S0140-6736(10)62056-9
some study participants to placebo. The Declaration of ND and RDB received an honorarium for speaking at an event sponsored by Reckitt Helsinki, which sets standards for all medical research Benckiser. ND has participated in advisory boards for and received honoraria from King Pharmaceuticals and Covidien. AW has received support from Mundipharma on human beings, states clearly that the benefits, risks, to train general practitioners on prescription opioids and pain relief. burdens, and effectiveness of a new drug should be 1 Krupitsky E, Nunes EV, Ling W, Il eperuma A, Gastfriend DR, Silverman BL. tested against best available treatment, and authorises a Injectable extended-release naltrexone for opioid dependence: a double-blind, placebo-control ed, multicentre randomised trial. placebo group only when there is no accepted standard Lancet 2011; published online April 28. DOI:10.1016/S0140-6736(11)60358-9.
Alkermes, Inc. FDA Psychopharmacologic drugs advisory committee of care.13 This is not the case for opioid dependence. meeting: Vivitrol (naltrexone for extended-release injectable suspension), The fact that Russia does not permit methadone or NDA 21-897. Sept 16, 2010. http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ buprenorphine treatment does not excuse the use PsychopharmacologicDrugsAdvisoryCommittee/UCM225664.pdf of placebo, but rather raises the question of why 3 Krupitsky E, Zvartau E, Woody G. Use of naltrexone to treat opioid investigators chose that country to test a drug for which addiction in a country in which methadone and buprenorphine are not available. Curr Psychiatry Rep 2010; 12: 448–53.
US approval would be sought. The testing of depot 4 US Food and Drug Administration. CFR—Code of Federal Regulations naltrexone in Russia is akin to finding a location with no Title 21. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?fr=314.125 (accessed April 1, 2011).
access to antiretrovirals and then testing a new HIV drug 5 US Food and Drug Administration. Quarterly data from FDA Adverse Event against placebo.
Reporting System, 2006–10. http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Surveillance/ The FDA should justify why it has lowered the AdverseDrugEffects/default.htm (accessed April 22, 2011).
scientific, regulatory, and ethical standards in approving 6 Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH. Timing of new black box warnings and withdrawals for prescription depot naltrexone for treatment of opioid dependence. medications. JAMA 2002; 287: 2215–20.
Digiusto E, Shakeshaft A, Ritter A, O’Brien S, Mattick RP. Serious adverse Although there is public demand and a market for new events in the Australian National Evaluation of Pharmacotherapies for treatments for opioid dependence, approval in this Opioid Dependence (NEPOD). Addiction 2004; 99: 450–60.
Gunne LM, Gronbladh L. The Swedish methadone maintenance program: instance might endanger patients, and sets a precedent a controlled study. Drug Alcohol Depend 1981; 7: 249–56.
that unjustifiably degrades standards for all treatment 9 Kakko J, Svanborg KD, Kreek MJ, Heilig M. 1-year retention and social function after buprenorphine-assisted relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Lancet 2003; 361: 662–68.
10 Miotto K, McCann MJ, Rawson RA, Frosch D, Ling W. Overdose, suicide *Daniel Wolfe, M Patrizia Carrieri, Nabarun Dasgupta, attempts and death among a cohort of naltrexone-treated opioid addicts. Drug Alcohol Depend 1997; 45: 131–34.
Alex Wodak, Robert Newman, R Douglas Bruce 11 Gibson AE, Degenhardt LJ. Mortality related to pharmacotherapies Open Society Institute, International Harm Reduction for opioid dependence: a comparative analysis of coronial records. Development Program, New York, NY 10019, USA (DW); INSERM, Drug Alcohol Rev 2007; 26: 405–10.
12 Schottenfeld RS, Chawarski MC, Mazlan M. Maintenance treatment with U912 (SE4S), Marseil e, France (MPC); ORS PACA, Marseil e, France buprenorphine and naltrexone for heroin dependence in Malaysia: (MPC); Université Aix Marseil e, IRD, UMR-S912, Marseil e, France a randomised, double-blind, placebo-controlled trial. Lancet 2008; (MPC); Department of Epidemiology, Gil ings School of Global 371: 2192–200.
13 Lewis JA, Jonsson B, Kreutz G, Sampaio C, van Zwieten-Boot B. Public Health, University of North Carolina, Chapel Hil , NC, USA Placebo-controlled trials and the Declaration of Helsinki. Lancet 2002; (ND); Alcohol and Drug Service, St Vincent’s Hospital, Darlinghurst, 359: 1337–40.
NSW, Australia (AW); Baron Edmond de Rothschild Chemical Dependency Institute, Beth Israel Medical Center, NY, USA (RN); and Yale University AIDS Programme, New Haven, CT, USA (RDB) dwolfe@sorosny.org www.thelancet.com Published online April 28, 2011 DOI:10.1016/S0140-6736(10)62056-9

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