An Article published Online First and in an upcoming Lancet shows that a once-monthly injection of extended-release naltrexone (XR-NTX) is an effective treatment for opioid dependence when compared with placebo. This is, say the authors, especially important in countries that, for whatever reason (political or financial), don't have access to other therapies. But in a linked Comment written by an international team of six authors, the study is criticised, as is the US Food and Drug Administration (FDA) for having approved this treatment for use in heroin and prescription opioid addiction in October 2010. The Article is by Professor Evgeny Krupitsky, Department of Addictions, St Petersburg Bekhterev Psychoneurological Research Institute, Russia, and colleagues.
Naltrexone (whether normal release or extended release) is an opioid receptor antagonist, meaning that it blocks absorption of heroin into cell receptors by 'competing' with the heroin molecules for those receptors. This blocks the euphoria associated with heroin use. Other treatments such as methadone and buprenorphine act as agonists, signaling a measured amount of opioid activity via those same receptors themselves and therefore decreasing the craving for heroin (often called maintenance therapy). XR-NTX has already been approved for use in alcohol addiction; in this study the authors assessed the effects of XR-NTX for treatment of patients with opioid dependence after detoxification.
The placebo-controlled, randomised, 24-week trial incuded 250 patients with opioid dependence disorder. Patients aged 18 years or over who had 30 days or less of inpatient detoxification and 7 days or more off all opioids were enrolled at 13 clinical sites in Russia. Patients were randomly assigned to either 380 mg XR-NTX (126 patients) or placebo (124) Participants also received 12 bi-weekly counselling sessions. The primary endpoint was the response profile for confirmed abstinence during weeks 5, assessed by urine drug tests and self report of non-use. Secondary endpoints were self-reported opioid free days, opioid craving scores, number of days of retention in the study, and relapse to physiological opioid dependence.
The researchers found that the median proportion of weeks of confirmed abstinence was 90•0% in the XR-NTX group compared with 35•0% in the placebo group. Patients in the XR-NTX group self-reported a median of 99% opioid-free days compared with 60% for the placebo group. The mean change in craving (on a 100 point scale) was in the XR-NTX group compared with +1 in the placebo group. Median retention was over 168 days in the XR-NTX group compared with 96 days in the placebo group. Naloxone challenge* confirmed relapse to physiological opioid dependence in 17 patients in the placebo group compared with one in the XR-NTX group. XR-NTX was well tolerated. Two patients in each group discontinued owing to adverse events. No XR-NTX-treated patients died, overdosed, or discontinued owing to severe adverse events.
The authors note that systematic reviews have proven the beneficial effects of opioid substitution treatment (buprenorphine and methadone) in treating opioid dependence, but that such treatments are restricted or unavailable in many countries (eg, Russia) and might not be suitable for all patients. They conclude: "In this study, once-monthly extended release naltrexone (XR-NTX) was superior to placebo with respect to the endpoints of confirmed abstinence, craving for opioids, retention, and prevention of relapse to opioid dependence. XR-NTX offers a new treatment option without risk of physical dependence or illegal diversion. This approach might aid community and cultural acceptance of opioid dependence pharmacotherapy."
The Comment authors, who include Daniel Wolfe (Open Society Foundation, International Harm Reduction Development Program, New York, NY, USA), Dr. M. Patrizia Carrieri (Institut National de la Santé et de la Recherche Médicale, Marseilles, France), and Dr Alex Wodak (Alcohol and Drug Service, St Vincent's Hospital, Sydney, Australia), refer to the Helsinki Convention, whicht states that the benefits, risks, burdens, and effectiveness of a new medicine should be tested against best available treatment, and authorises a placebo group only when there is no accepted standard of care. They say: "This is not the case for heroin dependence. The fact that Russia does not permit methadone or buprenorphine treatment does not excuse the use of placebo, but rather raises the question of why investigators chose that country to test a drug for which US approval would be sought. The testing of depot** naltrexone in Russia is akin to finding a location with no access to antiretrovirals and then testing a new HIV drug against placebo."
They also raise concern that the data submitted to the FDA on injectable naltrexone did not adequately investigate risk of post-treatment opioid overdose. Past studies on the oral formulation of the drug show that patients have three times the risk of overdose compared with those receiving methadone and buprenorphine treatment, and that oral naltrexone participants were about six times more likely to experience a heroin overdose once out of treatment than during treatment. The Comment authors contend that the FDA's approval of injectable naltrexone on the basis of this single study was imprudent and unwarranted.
They conclude: "The FDA should justify why it has lowered the scientific, regulatory, and ethical standards in approving depot naltrexone for opioid dependence. Although there is public demand and a market for new treatments for opioid dependence, approval in this instance might endanger patients, and sets a precedent that unjustifiably degrades standards for all treatment of opioid dependence."
Professor Evgeny Krupitsky, Department of Addictions, St Petersburg Bekhterev Psychoneurological Research Institute, Russia. Contact via Kathryn Morris, The Yates Network, USA. T) +1 914-204-6412 E) kathryn@theyatesnetwork.com
Daniel Wolfe, Open Society Foundations, International Harm Reduction Development Program, New York, NY, USA. T) +1 212 548-0195 /+11 917 969 7139 E) dwolfe@sorosny.org
Dr Alex Wodak (Alcohol and Drug Service, St Vincent's Hospital, Sydney, Australia. T) +61416143823 /+61293618012 E) awodak@stvincents.com.au
Journal
The Lancet