Is Naltrexone Effective in Preventing Relapse to Opioid Dependence?

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 show that an injectable, once monthly extended-release 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 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 (double-blinded) 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.

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 self-reported a median of 99% of opioid-free days, compared with only 60.4% for the placebo group.

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, 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," the commentary authors noted the current study did not sufficiently look into the incidence of post-treatment 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.

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, 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 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.

HCPLive wants to know:

Do you use naltrexone (either the oral formulation or the extended-release injectable) as a treatment for opioid-dependent patients?

Is combination treatment with buprenorphine and methadone your preferred choice in patients who are seeking treatment for opioid dependence? If so, are there any circumstances under which you would consider naltrexone as an alternative treatment?

What are your thoughts on the criticism over the FDA’s decision to approve naltrexone based on seemingly sparse efficacy data?

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