Nalmefene and alcohol dependence: A new approach or the same old unacceptable marketing?

Abstract

Dear editor “A great deal of intelligence can be invested in ignorance when the need for illusion is deep”. Saul Bellow Paille and Martini’s review on nalmefene for alcohol dependence deserves some comment.1 First, the authors stated no conflict of interest despite both repeatedly received money from Lundbeck laboratories, the company marketing nalmefene (eg, http://www.lundbeck.com/fr/a-propos-de-lundbeck/transparence-des-liens and https://www.transparence.sante.gouv.fr/flow/main?execution=e2s1). We recently challenged such unprofessional behavior in a French journal where authors also masked their conflicts of interest and provided an inaccurate analysis.2 Second, the data analysis is flawed and failed to discuss the limitations. a. Nalmefene [17-N-cyclopropylmethyl-3,14-dihydroxy-4,5-beta-alpha-epoxy-6 methylenemorphinan hydrochloride (10365 NIH)], is a simple 6-methyl derivative of naltrexone. Its origin goes back to early 1980. Naltrexone is a drug that had a marketing authorization on validated and rigorous criteria (abstinence) and all the related numerous independent trials using a solid methodology are consistent.3,4 Instead, nalmefene is characterized by a dystocia. In 1998, Contral Pharma tried to develop nalmefene against alcohol use disorders. The trials in this indication like in other more anecdotal conditions (eating behavior, memory disorder, bronchospasm, pruritus, cystitis …) have been unsuccessful, the results failing to reach statistical significance. The Lundbeck laboratory acquired the patent for this somewhat forgotten molecule and tried to relaunch its development. b. “If you torture the data enough, nature will Always confess”. Ronald Coase. All three trials (Sense 1, 2 and 3) exhibit poor results, which may explain why these have not been published in the core clinical journals unlike the pivotal trials of acamprosate or naltrexone.4–6 Sense 1 and 2 trials were pooled to provide a basis for the marketing authorization with a post hoc analysis of a subgroup of patients – representing only ¼ of the cohort, this is far from an intention to treat analysis.7,8 There were too many missing data and too many patients were lost to follow-up.9 Sense 3 study is not significant regarding the 4 endpoint measures (both primary and secondary).10 But the authors underlined significant results for endpoints at the 13th month despite this was not in the original protocol of the study. Last, there is a significant bias of attrition, only 61% of patients in the nalmefene group completing the study against 67% in the placebo group. c. The endpoint (consumption of alcohol) was on a declarative basis and no objective measures commonly used in the tests were retained: alcohol, CDT (carbohydrate deficient transferrin) or ethyl glucuronide (hair or urine).11 d. The endpoint was not validated. The decrease in consumption is a surrogate endpoint and so far no study has shown it could reduce hospitalization, morbidity, or mortality rates. A decrease in consumption could be a temporary solution to develop the therapeutic alliance when a patient is not ready for abstinence. However, considering this endpoint as a success is nothing but hype or a hoax. The paradigm of reducing risks is well established for the risk of infection with a drug addict. Reducing risk by reducing consumption remains a myth. It goes back to 1973, but the extended follow-up of the cohort has shown that this concept was inappropriate.12 All studies testing a decrease in consumption failed to show evidence for effectiveness.13 What would we say if a drug against morbid obesity had a marketing authorization without data on weight or morbidity because it allows patients to refrain from eating one slice of pizza per day?14 The marketing authorization from the European Medicines Agency relied on a “white paper” on accepting the decrease in consumption as a surrogate endpoint. This position is not accepted by the FDA. The “white paper” was authored by van den Brink who has received fees from Lundbeck, as all investigators publishing nalmefene trials.7,8,10 Sense 3 was also published in a journal where the two publishers were also paid by Lundbeck and failed to respond to a request to publish a brief critical analysis of the trial (A Braillon, personal communication, 2015).10 e. It was neither scientific nor ethical not to compare nalmefene to a validated treatment that received a marketing authorization. Helsinki declaration (1964) stated that any experimental maneuver was to be compared to the best available care as a comparator (Article II.2). It was possible to build such comparative tests. Third, independent evaluations are negative. a. The independent drug bulletin Prescrire concluded: “In both trials, patients taking nalmefene declared two “heavy drinking days” per month less than patients in the placebo groups. Daily consumption of alcohol was 5–9 grams lower with nalmefene than with placebo. The most common side effects are insomnia, dizziness, headache and nausea, which were severe in more than 10% of patients. Other serious but less common side effects include confusion, hallucination and dissociation, usually at the beginning of the treatment. These side effects have affected about 3% of patients treated with nalmefene, a figure three times higher than in the placebo groups. The consequences of nalmefene mixed with large amounts of alcohol are not known. In practice, the clinical relevance of nalmefene in alcohol-dependent patients seeking to reduce or abstain is questionable. The impact of nalmefene on alcohol dependence complications is not known. The crucial first step in the management of alcohol-dependent patients is to establish a relationship based on trust and to provide psychological and social support. When drugs are considered, it is best to choose acamprosate or naltrexone, drugs that are only moderately effective but better evaluated”.15 b. The Drug Evaluation German Agency (IQWIG) made its conclusion on December 1: “Nalmefene for alcohol dependence: no benefit evidenced” (https://www.iqwig.de/en/press/press-releases/press-releases/nalmefene-for-alcohol-dependence-added-benefit-not-proven.6458.html). c. The French Health Authority concluded that nalmefene trials showed little evidence for an improvement in actual benefit when compared to existing treatments (rating =4, on a scale of 5 to 1, the highest). The agency advised to restrict prescription to addiction specialists considering the major importance of psycho-social care, a difficult condition to achieve in general practice. Such restriction is rarely used by the Commission (http://www.has-sante.fr/portail/jcms/c_1737894/en/selincroenct12915english-version). d. The Swedish Agency for health assessment concluded (March 31, 2015) to the lack of interest of nalmefene compared to existing treatments and did not recommend its reimbursement (http://www.tlv.se/beslut/beslut-lakemedel/avslag-uteslutningar/Selincro-ingar-inte-i-hogkostnadsskyddet/). Fourth, who will benefit from nalmefene? Monthly cost for nalmefene in France is €101.34 vs €36.07 for naltrexone. The psychosocial support, a key element in the care of patients with addiction but it is not reimbursed by the health care scheme. Accordingly, this money could have been better used to cover two monthly psychologist visits. Fifth, on June 19, 2013, the European Commission imposed a €93.8 million fine to Lundbeck for having offered payments and other bribes to other companies who accepted to delay the marketing of their cheaper generic of citalopram. The Vice-President of the Commission Joaquín Almunia said: “Agreements of this type (breach of EU antitrust rules. Article 101 of the Treaty on the Functioning of the European Union) directly affect patients and national health systems, which are already subject to strict budget constraints” (http://www.europeanvoice.com/article/almunia-fines-lundbeck-and-rivals-for-fudging-competition-on-medicines/).