Evidence Backing Approval of Drug for Alcohol Misuse 'Weak'

Megan Brooks

June 10, 2016

Evidence supporting the effectiveness of nalmefene (Selincro, H. Lundbeck A/S) for alcohol dependence is weak, uncertain, and could be biased, conclude UK researchers, who took an in-depth look at the data.

Approved in Europe in 2013 and subsequently recommended by the UK National Institute for Health and Care Excellence (NICE), nalmefene is licensed for use in conjunction with psychosocial support to reduce alcohol consumption in adults with mild to moderate alcohol dependencies who have a high drinking risk level, who are without physical withdrawal symptoms, and who do not require immediate detoxification.

On the basis of the analysis, Niamh Fitzgerald, PharmD, of the University of Stirling, and colleagues conclude that the evidence for the efficacy of nalmefene in reducing alcohol consumption is, "at best, modest, and of uncertain significance to individual patients." They note that any possible effect of nalmefene hovers at a rate of reduction of 1 drink per day on average.

In the United States, nalmefene is approved for use in the treatment of opioid overdose but not for alcohol dependence.

The study was published online June 5 in Addiction.

Dilemma for Docs

Dr Fitzgerald's team notes that the European Medicines Agency's (EMA's) assessment of nalmefene was based largely on three studies sponsored by the manufacturer and that the data may be biased "due to lack of specification of a priori outcome measures and sensitivity analyses, use of post-hoc sample refinement and the use of inappropriate comparators."

Their data analysis also found that patients taking nalmefene generally had more side effects and were more apt to drop out of the clinical trials than those taking placebo. The researchers also note that nalmefene is more expensive than similar drugs on the market and that no comparison with alternative drugs for the treatment of alcohol dependence, such as naltrexone (multiple brands), was made.

"We were interested in nalmefene because it is licensed for use in people with mild to moderate dependence on alcohol, a group in which psychosocial treatment (counseling) would usually be the first approach tried," Dr Fitzgerald told Medscape Medical News. "We were also interested that the company expected it to be prescribed mostly in primary care, despite a long history of difficulty persuading primary care clinicians to intervene on alcohol problems.

"There is no evidence at present that nalmefene offers superior benefits to naltrexone or optimally delivered psychosocial interventions," Dr Fitzgerald said.

"It's vitally important that we know that prescribed drugs are effective in treating the intended problem," she added in a university-issued news release. "In this case, we found problems with the registration, design, analysis, and reporting of these clinical trials which did not prevent the drug being licensed or recommended for use.

"We believe this creates a difficulty for doctors trying to treat alcohol dependence and throws up critical questions for regulators around why a drug was licensed without a bank of high- quality, reliable evidence," she said.

Commenting on the findings for Medscape Medical News, Prof Carole Longson, director of the NICE Centre for Health Technology Evaluation, said: "Nalmefene was recommended within its marketing authorization by the regulator in 2013, where the EMA rigorously reviewed its safety and efficacy before approval ― as it does with all medicines under evaluation.

"Our appraisal process for nalmefene," she added, "thoroughly interrogated the evidence base and, as is the standard with all our appraisals, we engaged with and took into account submissions from a multitude of stakeholders. When presented with the evidence, including the analysis of the clinical studies, the independent committee concluded that there was sufficient evidence to recommend nalmefene in specific circumstances."

"Bad Medicine"

Also reached for comment, Florian Naudet, MD, PhD, from the Meta-research Innovation Center at Stanford University (METRICS), in Palo Alto, California, said this is a "very interesting paper about a very important problem that might go beyond the evaluation of nalmefene. Nevertheless, in the nalmefene case, the points [the authors] made are valid, and indeed, we cannot be sure whether nalmefene is a useful drug or not."

Dr Naudet noted that the points made by Dr Fitzgerald and colleagues are "directly in line" with a recent letter in the BMJ titled, Bad Medicine: Nalmefene in Alcohol Misuse.

The new analysis also supports a systematic review and meta-analysis Dr Naudet and colleagues published in PLOS Medicine in which they conclude that "the value of nalmefene for treatment of alcohol addiction is not established. At best, nalmefene has limited efficacy in reducing alcohol consumption."

"Evidence from nalmefene randomized controlled trials cannot be interpreted as confirmatory because of the use of a posteriori subgroup analyses, because there was a lot of withdrawals (including more in the nalmefene groups), because the interest was focused on consumption outcomes, while interest of patients and clinicians is focused on health outcomes. Also, naltrexone should have been used as a comparator. At last, the clinical relevance of these small reductions in alcohol consumption is very doubtful," Dr Naudet told Medscape Medical News.

"All of these problems lead to persistent uncertainty and to difficult and controversial decisions for clinicians and health authorities," he concluded.

The study received no funding. The authors have disclosed no relevant financial relationships.

Addiction. Published online June 5, 2016. Abstract

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