Benzodiazepines are the mainstay of alcohol detoxification treatment, with extensive evidence supporting their efficacy and relative safety.1 The risk of benzodiazepine-alcohol interaction, however, and psychomotor and cognitive impairments associated with benzodiazepine use may limit early rehabilitation efforts in hospitalized patients.2 Cross-tolerance with alcohol also limits benzodiazepines’ potential benefit in outpatients with substance use disorders.
Adding anticonvulsants to acute benzodiazepine therapy has been shown to decrease alcohol withdrawal symptom severity, reduce seizure risk, and support recovery, particularly in patients with multiple alcohol withdrawal episodes. After detoxification, long-term anticonvulsant use may reduce relapse risk by decreasing post-cessation craving, without abuse liability.3
Although not all studies endorse adding anticonvulsants to benzodiazepines for managing alcohol withdrawal syndrome (AWS),4 we present 3 cases in which anticonvulsants were used successfully as adjuncts to lorazepam. Valproic acid, levetiracetam, and gabapentin offer advantages in acute and long-term therapy of alcohol dependence with efficacy in AWS, low abuse potential, benign safety profile, and mood-stabilizing properties.
AWS manifests as a cluster of clinical symptoms including delirium tremens (DTs) and seizures (Table 1). Its pathophysiology can be explained by alcohol’s agonist effect on the gamma-aminobutyric acid (GABA) system and antagonist effect on the glutamatergic system (Table 2).5
Chronic alcohol intake leads to neuroadaptation in the brain in the form of down-regulation of GABAA receptors and upregulation of N-methyl-D-aspartate receptors. During alcohol withdrawal, this neuroadaptation leads to a decrease in central GABA activity and an increase in glutamate activity, resulting in hyperexcitation, anxiety, and seizures.6
Little data exist regarding time to relapse after detoxification in alcohol-dependent patients. One theory—called “protracted withdrawal syndrome” (Table 1)—suggests that abstinent alcoholics return to drinking because of the same, but attenuated, neuroadaptations that trigger acute AWS.7
Advantages of adjunct therapy. Ntais et al8 evaluated benzodiazepines’ effectiveness and safety in treating AWS in a clinical review of 57 randomized, controlled trials totaling 4,051 patients. Benzodiazepines showed similar success rates as other drugs (relative risk [RR] 1.00) or anticonvulsants in particular (RR 0.88), as measured by changes in Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) scores at the end of treatment. Benzodiazepines also offered significant benefit for seizure control compared with nonanticonvulsants (RR 0.23), but less when compared with anti convulsants (RR 1.99).
Although the literature does not support anticonvulsant use for monotherapy in AWS, anticonvulsants show potential as adjunctive therapy. Valproic acid, levetiracetam, and gabapentin offer unique mechanisms of action (Table 3) and demonstrate advantages over benzodiazepine monotherapy for AWS. Adjunctive use of valproic acid,8,9 levetiracetam,10 and gabapentin11,12 in detoxification also has demonstrated efficacy in reducing risk of relapse and delaying relapse.
The neurobiologic rationale for using anticonvulsants in acute AWS is speculative, but these agents appear to:
- inhibit “kindling” (neuronal changes that may be associated with repeated intoxications)
- facilitate GABAergic mechanisms.9
Alcohol withdrawal: Acute vs long-term symptoms
|Alcohol withdrawal syndrome||Protracted withdrawal syndrome|
|Description||Cluster of symptoms in alcohol-dependent persons after heavy or prolonged alcohol use has lessened or ceased||Constellation of symptoms lasting weeks to months after alcohol use ends|
|Presentation||Develops during acute detoxification period and lasts 5 to 7 days||Develops after 5- to 7-day acute detoxification period and may persist for 1 year|
|Symptoms||Mild: insomnia, tremor, anxiety, GI upset, headache, diaphoresis, palpitations, anorexia |
Severe: alcoholic hallucinosis Seizures (generalized tonic-clonic) occur in up to 25% of withdrawal episodes, usually within 24 hours after alcohol cessation Delirium tremens (characterized by hallucinations, disorientation, tachycardia, hypertension, low-grade fever, agitation, and diaphoresis) occurs in up to 5% of patients undergoing withdrawal, may be delayed 4 to 5 days, and has mortality rates reaching 15%
|Sleep disruption; anxiety; depressive symptoms; irritability; increased breathing rate, body temperature, blood pressure, and pulse|
|Source: Click here for a bibliography|
How alcohol affects GABA and glutamate neurotransmitters
|GABA, the brain’s primary inhibitory neurotransmitter, renders nerve cells less sensitive to further signaling||Glutamate, the brain’s major excitatory neurotransmitter, renders nerve cells more sensitive to further signaling|
|Alcohol facilitates the inhibitory function of the GABAA receptor, allowing more GABA to traverse the receptor, and leading to alcohol’s intoxicating effects||Alcohol seems to inhibit the excitatory function of the NMDA glutamate receptor, believed to play a role in memory, learning, and generation of seizures|
|During alcohol withdrawal, brain GABA concentrations fall below normal and GABAA receptor sensitivity may be reduced||Long-term alcohol exposure produces an adaptive increase in the function of NMDA receptors and results in development of glutamate-NMDA supersensitivity|
|In the absence of alcohol, the resulting decrease in inhibitory function may contribute to symptoms of CNS hyperactivity associated with acute and protracted alcohol withdrawal||Acute alcohol withdrawal activates glutamate systems, leading to autonomic nervous system hyperactivity; alcohol withdrawal seizures are associated with increased NMDA receptor function|
|GABA: gamma-aminobutyric acid; NMDA: N-methyl-D-aspartate|
|Source: Click here for a bibliography|