ALARMING SIGNALS OF RISK WITH USE OF BACLOFEN FOR ALCOHOL WITHDRAWAL

The French medicines agency has now limited the dose of baclofen (LIORESAL, generics) for off-label use in alcohol withdrawal to a maximum of 80 mg a day (1). The reason for this is an observational study (2) based on French insurance data which the agency had a part in generating. In the period between 2009 and 2015, during which off-label use increased greatly, there was a clear rise in hospital admissions and deaths particularly with high doses of baclofen compared to licenced medicines for alcohol withdrawal such as acamprosate (CAMPRAL; a-t 2002; 33: 73) (2).

A total of 47,614 patients aged 18-70 years who had been newly started with off-label baclofen, had had at least two prescriptions filled, were not suffering from any severe co-morbidities and had not had any prior severe alcohol-related complications were included in the study and compared with 117,720 new users of acamprosate, naltrexone (ADEPEND, generics; a-t 2004; 35: 33 and 2011; 42: 4, 13) or nalmefene (SELINCRO; a-t 2014; 45: 81-3) who were selected according to the same criteria. Age (median of 48 and 47 years, respectively) and co-morbidities were similar in the two groups. There were fewer men in the baclofen group (56% vs. 69%). In addition, baclofen users were more likely to live in well-to-do residential areas than socially disadvantaged ones, had lower use of psychotropic drugs and were less likely to have been hospitalised in the past due to alcohol use (13% vs. 24%) (2).

In comparison to established withdrawal medicines, the relative risk of hospital admission increased to 1.09 (adjusted hazard ratio (HR); 95% confidence interval [CI] 1.03-1.15) with a baclofen dose of less than 30 mg/day and to 1.46 with a daily dose of 180 mg or more (95% CI 1.28-1.65). Particularly noteworthy is that neurological hospital admissions, including seizures, increased more than twofold in total (HR 2.54; 95% CI 2.13-3.03) and more than threefold with a daily dose of 180 mg or more (HR 3.31; 95% CI 1.96-5.61). The number of deaths (total HR 1.31; 95% CI 1.08-1.60) increased from a daily dose of 30 mg (HR 1.41; 95% CI 1.09-1.84). With a daily dose of 180 mg or more, the risk of death increased by more than twofold (HR 2.27; 95% CI 1.27-4.07). In this context, deaths from unexplained causes were particularly striking, with an almost fivefold risk with a high dose of at least 180 mg daily (HR 4.90; 95% CI 1.13-21.3). Assuming a causal relationship, the authors calculate that with regard to the off-label use of baclofen for alcohol withdrawal for individuals under 70 years without significant co-morbidities, there are a total of 3 additional deaths and 33 hospital admissions per 1,000 patients per year, and with doses over 180 mg per day, these numbers rise to 10 additional deaths and 116 hospital admissions (2).

Because of the observational design, these findings must be interpreted with caution, but they do comprise a clear signal of risk. Given that there is not even clear evidence of benefit with baclofen compared to placebo for alcohol withdrawal (a-t 2016; 47: 29 and 2017; 48: 63), let alone in comparison to licenced withdrawal medicines, in light of these risk data, there is an urgent need to advise against off-label use, -Ed.

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