Abstract and Introduction
Abstract
Aims: The objective of this study was to collect preliminary data on the efficacy and safety of pregabalin in attenuating the severity of alcohol withdrawal symptoms during detoxification treatment in alcohol dependence.
Methods: Forty-two alcohol-dependent patients with an alcohol withdrawal syndrome (AWS) were included in the prospective randomized double-blind placebo-controlled trial during inpatient alcohol detoxification. For 6 days, participants either received pregabalin or placebo according to a fixed dose schedule starting with 300 mg/day. Depending on the score of the AWS Scale (AWSS), diazepam was additionally administered as a rescue medication. The primary endpoint was the total amount of diazepam required from Day 2 to 6 of detoxification treatment in each of the two groups. Secondary outcome variables were the difference in AWSS and Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores between Day 2 and 6, tolerability and safety data, drop-out rates as well as changes in the neuropsychological scales.
Results: Pregabalin and placebo were equally safe and well tolerated. However, no statistically significant difference was found comparing the total amount of additional diazepam medication required in the two study groups. Pregabalin and placebo also showed similar efficacy according to alterations of scores of the AWSS, CIWA-Ar and neuropsychological scales. The frequency of adverse events and drop-outs did not differ between the both treatment groups.
Conclusions: The study demonstrates the relative safety of pregabalin in the treatment of AWS. However, the results do not provide evidence in favor of pregabalin compared with placebo concerning its efficacy in the treatment of AWS.
Introduction
Chronic alcohol exposure causes an imbalance in excitatory and inhibitory activity of the central nervous system (Tsai and Coyle, 1998; Williams and McBride, 1998; Chen et al., 2011). Owing to the alcohol-induced increase of inhibitory neurotransmission, a counter-regulatory response is shown by reducing gamma-aminobutyric acid (GABA)ergic and increasing glutamatergic functions in the brain in order to maintain normal function (Nevo and Hamon, 1995). The decreased responsiveness of inhibitory receptors and elevated sensitivity of excitatory receptors lead to nervous system hyperactivity when chronic alcohol intake is terminated like during detoxification treatment (Tsai et al., 1995; Tsai and Coyle, 1998; De Witte et al., 2003; Amato et al., 2011). Thus, most alcohol-dependent patients develop symptoms of withdrawal such as anxiety, tremor, tachycardia, hypertension, agitation, nausea, sweating, insomnia etc. within 6–24 h after cessation of drinking (Hall and Zador, 1997; Heinz et al., 2001; Beck et al., 2009). According to the kindling hypothesis, the intensity of these symptoms becomes greater the more detoxifications a patient experiences (De Witte et al., 2003). Besides severe symptoms, potentially life-threatening complications of an alcohol withdrawal syndrome (AWS) such as withdrawal seizures and delirium tremens can occur and therefore indicate a pharmacological treatment (Amato et al., 2011). GABAergic medications like benzodiazepines are widely used to decrease and prevent symptoms of withdrawal (Ntais et al., 2005) and to encourage patients to enter further treatment programs. Several studies have demonstrated their efficacy and safety in the treatment of the AWS (Ntais et al., 2005; de Millas et al., 2010; Amato et al., 2011). However, various side effects such as liver toxicity as well as excessive sedation, memory deficits and respiratory depression in patients with pre-existing liver impairment (Leggio et al., 2008), abuse liabilities and dependence have been reported (Williams and McBride, 1998; Becker et al., 2006). Therefore, studies have started focusing on non-benzodiazepine GABAergic medications, such as carbamazepine, gabapentin and valproic acid as well as baclofen and newer anticonvulsant drugs such as levetiracetam and pregabalin as promising medications in the treatment of AWS (Malcolm et al., 2001; Becker et al., 2006; Leggio et al., 2008; Müller et al., 2010; Lyon et al., 2011). Pregabalin is a GABA analog without direct agonistic activity at GABA A and GABA B receptors (Ben-Menachem, 2004). It binds to the alpha-2-delta regulatory subunit of voltage-sensitive calcium channels, inhibiting activity-dependent calcium influx in nerve terminals and reducing the release of neurotransmitters such as glutamate and norepinephrine (Dooley et al., 2002; Fink et al., 2002; Cunningham et al., 2004; Stahl, 2004). A possible benefit of pregabalin in the treatment of the AWS can be expected due to its anticonvulsant, analgesic, anxiolytic and antidepressant effects (Field et al., 2001; André et al., 2003; Chesler et al., 2003; Feltner et al., 2003; French et al., 2003; Pande et al., 2003; Arroyo et al., 2004; Brodie, 2004; Becker et al., 2006; Stein et al., 2008; Lydiard et al., 2010; Baidya et al., 2011). Pregabalin has also been reported to improve subjective sleep quality in benzodiazepine-dependent patients during detoxification treatment (Rubio et al., 2011). Given the high prevalence of hepatic disease associated with chronic alcohol use and other comorbidities requiring pharmacological treatment, medications like pregabalin lacking hepatic metabolism as well as drug interactions and offering predictable and linear pharmacokinetics (Ben-Menachem, 2004) may be preferential substances in detoxification treatment (Becker et al., 2006).
Only a few studies have been conducted concerning the efficacy of pregabalin in the treatment of alcohol dependence. Different preclinical studies by Becker et al. (2006) showed the ability of pregabalin to reduce central nervous system hyperexcitability associated with alcohol withdrawal in mice and lead to the conclusion that pregabalin might be effective in the treatment of the AWS, in particular of withdrawal seizures, and also in blocking kindling processes.
Di Nicola et al. (2010) demonstrated the efficacy and safety of pregabalin in outpatient detoxification in a small sample of alcohol-dependent patients with a mild-to-moderate AWS, yet lacking a randomized placebo-controlled study design. A further randomized, single-blind trial compared pregabalin, tiapride and lorazepam without a placebo control in the treatment of AWS in 111 alcohol-dependent patients. It was shown that all medications significantly reduced withdrawal symptoms according to the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) over time, with a significantly better performance of pregabalin regarding the symptoms 'headache' and 'orientation' (Martinotti et al., 2010a). The same research group also presumes pregabalin to be an equally efficacious treatment to naltrexone for the prevention of alcohol relapse prior to detoxification. Furthermore, it was demonstrated that more patients treated with pregabalin stayed completely abstinent for a larger number of days, and that pregabalin was beneficial considering the reduction of symptoms of anxiety, hostility and psychoticism and showed better results in patients with comorbid psychiatric disorders. Additionally, patients receiving naltrexone showed a larger number of adverse events and thus poorer compliance (Martinotti et al., 2010b).
Based on these encouraging findings including the probable positive effects of pregabalin on withdrawal symptoms, mood disorders, anxiety and its favorable side effect profile, we conducted a prospective, randomized, double-blind and placebo-controlled trial to examine the efficacy and tolerability of pregabalin in the treatment of AWS.