Although a recent study found naltrexone compared favorably to placebo in treating patients for opioid dependence, critics have questioned the results.
Study results published in the April 2011 issue of The Lancet (http://HCP.LV/kBLPuZ) show that an injectable, once monthly extendedrelease formulation of the opioid antagonist naltrexone is safe and effective for the treatment of opioid dependence following detoxification treatment. However, critics of the study have raised questions about the safety of using maltrexone in this patent population and the strength of the data used to justify FDA approval.
Naltrexone was approved by the FDA in 2010 (http://HCP.LV/kmo8tB) to treat and prevent relapse in patients with opioid dependence who have undergone detoxification treatment.
In the 24-week study, 250 patients with opioid dependence disorder were randomized to receive either 380 mg injections of naltrexone or placebo. All participants in the trial were age 18 years or older and “30 days or less of inpatient detoxification and 7 days or more off all opioids.” All patients also receive 12 biweekly counseling sessions. The primary endpoint of the study was percentage of opioid-free weeks in the final 20 (doubleblinded) weeks of the study, as assessed by urine drug tests and self reported non-use. Secondary endpoints were “self-reported opioid-free days, opioid craving scores, number of days of retention, and relapse to physiological opioid dependence.”
More information on the design of this trial is available at ClinicalTrials.gov (http://HCP.LV/ kEKjOV).
The authors reported a median proportion of weeks of confirmed abstinence of 90% in the naltrexone group, versus 35% in the placebo group. The naltrexone group also selfreported a median of 99% of opioid-free days, compared with only 60.4% for the placebo group.
The authors of a review titled “Oral Naltrexone Maintenance Treatment for Opioid Dependence,” published in April 2011 in the Cochrane database of systematic reviews (http://HCP.LV/kv0t2W), searched the Cochrane Central Register of Controlled Trials for “randomised controlled clinical trials which focus on the use of naltrexone maintenance treatment versus placebo, or other treatments to reach sustained abstinence from opiate drugs.” They identified 13 clinical studies that met their criteria, involving nearly 1,200 patients. They looked at a variety of factors and outcomes, including the effect of treatment with naltrexone on rates of re-incarceration. Based on their analysis of these studies, they reported that “oral naltrexone did not perform better than treatment with placebo or no pharmacological agent with respect to the number of participants re-incarcerated during the study period. If oral naltrexone is compared with other pharmacological treatments such as benzodiazepine and buprenorphine, no statistically significant difference was found.” They concluded that “the studies conducted have not allowed an adequate evaluation of oral naltrexone treatment in the field of opioid dependence. Consequently, maintenance therapy with naltrexone cannot yet be considered a treatment which has been scientifically proved to be superior to other kinds of treatment.”
Opioid craving scores, measured using patients’ response on a validated Visual Analog Scale during several weekly visits (a score of 0 represented “no craving;” a score of 100 represented “highest possible craving”), decreased by 10 points in the treatment group, versus a small (0.7) increase in the placebo group. Retention scores were also more favorable for the naltrexone group (median of 168 days vs. 96 days for the placebo group). Seventeen patients in the placebo group relapsed to physiologic opioid dependence (measured via “naloxone challenge test” in which patients were injected with the opioid antagonist naloxone); only one patient in the treatment arm relapsed. Adverse events sufficient to cause discontinuation of treatment were reported in two patients in each study arm.
Based on these results, the authors concluded that once-monthly extended release naltrexone is “superior to placebo with respect to the endpoints of confirmed abstinence, craving for opioids, retention, and prevention of relapse to opioid dependence.” They wrote that naltrexone in conjunction with psychosocial treatment and counseling “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.”
Concerns over the safety of naltrexone
Although these results seem to offer promising news for patients suffering from opioid dependence, the study has been criticized in several quarters. Of note, three of the six authors of the article (including the senior author) are employees of Alkermes Inc, maker of naltrexone (marketed under the brand name Vivitrol). A commentary written by Daniel Wolfe, PhD, et al, published in the same issue of The Lancet (http://HCP.LV/ kXa7QL), questioned the safety of naltrexone and the design of the study, suggesting that rather than compare naltrexone to placebo, the authors should have compared it to substitution treatment with buprenorphine and methadone. Because some studies have suggested the risk of heroin overdose is “significantly elevated after naltrexone treatment as a result of reduced tolerance” (http://HCP.LV/kV8dLG), the commentary authors noted the current study did not sufficiently look into the incidence of posttreatment opioid overdose, claiming that previous studies have shown that patients taking oral naltrexone are up to three times more likely to overdose compared to patients on buprenorphine and methadone.
An article published in 2010 in the European Journal of Clinical Pharmacology (http://HCP. LV/miBB3Z) reviewed “opioid detoxification treatments, methadone and buprenorphine maintenance and other modes of agonist substitution,” and “consider[ed] newer strategies of relapse prevention with opioid antagonists.” The authors concluded that “treatments such as naltrexone implants and depot injections that prevent relapse for a limited time need further evaluation.” Proclaiming that “Opioid maintenance drugs, naltrexone, or future vaccines alone are largely insufficient as long as poly-drug use is not addressed,” the authors wrote that combination treatment with pharmacotherapies and psychosocial support strategies, though “demanding and costly,” are “the most thorough approach to facilitate the long-term behaviour change that is necessary to treat opioid addiction effectively.”
They claimed this study raised several questions “about the FDA’s approval processes and clinical trial ethics,” and identified several factors that they said required additional scrutiny, including “paucity of efficacy data, adequacy of risk assessment (particularly of overdose risk in treatment dropouts), and the questionable ethics of a placebo-controlled trial when an accepted standard of treatment exists.” They called on the FDA to “justify why it has lowered the scientific, regulatory, and ethical standards in approving depot naltrexone for opioid dependence.” As reported by Medscape (http://HCP.LV/mk8lPR), naltrexone for the treatment of opioid addiction was recommended for approval in 2010 by the FDA Psychopharmacologic Drugs Advisory Committee. Although the committee agreed that the data presented demonstrated that naltexone was safe and effective for the treatment of opioid dependence, several committee members raised concerns that the efficacy data came from only a single study that was conducted in Russia.
As additional questions emerge regarding the use of naltrexone for the treatment of opioid-dependent patients (for example, this article http://HCP.LV/lYzO5y notes that the Lancet study featured a surprisingly high placebo response rate and a retention rate of only 50% after six months, which is markedly lower than rates achieved using buprenorphine and methadone), it is likely that critics will continue to call for additional studies to establish whether naltrexone is truly effective in this patient population.