Patients with a history of complicated alcohol withdrawal syndrome should be treated with a standing benzodiazepine taper during detoxification. Patients with hepatic disease, benzodiazepines that are conjugated and renally cleared (lorazepam, oxazepam, and temazepam) should be used instead of those metabolized by the liver. Symptom-triggered withdrawal protocols, in which benzodiazepines are only given after symptoms appear and reach a critical threshold, seem to perform as well as standing benzodiazepine protocols for uncomplicated alcohol withdrawal syndrome.5
γ-Hydroxybutyrate (GHB), anticonvulsants, and α2-agonists have been studied as stand-alone or adjunctive agents in the treatment of alcohol withdrawal syndrome. Although these medications are promising for mild to moderate alcohol withdrawal syndrome, there is a dearth of information about their ability to prevent or treat complicated alcohol withdrawal.
GHB. GHB, which gained notoriety as a “date rape” drug in the US during the 1990s and, more recently, as an athletic enhancement (because of its ability to stimulate growth hormone), is currently approved in Italy as an adjunctive agent for alcohol withdrawal syndrome. It has sedative and anxiolytic effects similar to those of benzodiazepines. It is a short-chain fatty acid that is structurally similar to GABA. GHB is a weak agonist at GABAB receptors, which appears to be secondary to its recently discovered higher affinity for the α4β1δ GABAA receptor.6 Exogenously administered GHB is also converted into GABA, which can serve as the natural agonist for GABAA receptors. This may explain its sedative and anxiolytic effects and point toward its role in the hypoGABAergic alcoholic brain.
At low doses, GHB was found to stimulate dopamine release from the ventral tegmental area onto the nucleus accumbens; however, high-dose GHB has an inhibitory effect on dopamine release. Although these findings are promising for future research and development, a 2010 Cochrane Review concluded that there are insufficient data to support the use of GHB in the treatment of alcohol withdrawal syndrome.7
Anticonvulsants. Although they are sometimes used clinically to treat alcohol withdrawal syndrome (especially in patients who have had a prior documented alcohol withdrawal seizure), there is inconsistent evidence for anticonvulsants in the treatment of alcohol withdrawal syndrome.8 To date, valproic acid and carbamazepine have been the most extensively studied anticonvulsants. A recent Cochrane review reported that anticonvulsants may be more effective than benzodiazepines in treating some aspects of alcohol withdrawal syndrome (ie, decreasing seizure risk).9 Findings from a retrospective cohort study of 453 patients treated with valproate and 374 patients treated with carbamazepine suggest that valproate may have more benefits because of its higher tolerability, shorter duration of treatment, and lower incidence of alcohol-withdrawal seizures.10
The anticonvulsants gabapentin and pregabalin are used primarily for neuropathic pain and partial seizure prophylaxis. Because of their effects on GABAergic neurotransmission, they are also rational medications for alcohol withdrawal syndrome. Initially, gabapentin failed as an adjunctive agent to benzodiazepines in severe alcohol withdrawal syndrome; however, it has shown efficacy in mild to moderate alcohol withdrawal syndrome.11,12
Pregabalin has been investigated for outpatient detoxification in patients with mild to moderate alcohol withdrawal syndrome. Forty alcohol-dependent patients received 250 to 400 mg of pregabalin daily during acute detoxification (up to 14 days) and reported improved symptoms of withdrawal and cravings.13 Recently, however, pregabalin was not shown to be more efficacious than placebo for alcohol withdrawal syndrome.14
α2-Agonists. Excessive activation of the sympathetic nervous system via norepinephrine may explain some of the symptoms of alcohol withdrawal (anxiety, agitation, tremor and, most importantly, increased vital sign parameters such as hypertension and tachycardia). α2-Adrenergic receptor agonists (eg, clonidine, dexmedetomidine) decrease norepinephrine release via activity on presynaptic neurons in the locus coeruleus, thereby dampening sympathetic activation, which is consistent with its mechanism of action in treating opioid withdrawal.
Several randomized controlled trials (RCTs) have demonstrated the lack of efficacy of clonidine over benzodiazepines in the treatment of alcohol withdrawal syndrome. However, several case reports indicate that dexmedetomidine may be effective as an adjunctive agent to benzodiazepines in alcohol withdrawal syndrome. Therefore, the use of adjunctive α2-agonists may be worth exploring as a strategy for alcohol withdrawal syndrome.15
Baclofen After initial case reports of efficacy in maintenance, the GABAB receptor agonist and antispastic agent baclofen has also been investigated in alcohol withdrawal syndrome. Hospitalized patients at risk for alcohol withdrawal syndrome were randomized to receive 10 mg of oral baclofen twice daily or placebo in addition to symptom-triggered lorazepam. The coadministration of baclofen decreased the use of high-dose lorazepam (as defined by more than 20 mg in the first 72 hours).16 To date, no other RCTs of baclofen have been reported for alcohol withdrawal syndrome.