To Name :
To Email :
From Name :
From Email :
Comments :

Evidence-Based Reviews

Alcohol withdrawal: When to choose an adjunctive anticonvulsant

Anticonvulsants may reduce detoxification symptoms, support recovery.

Vol. 9, No. 4 / April 2010

Discuss this article

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.

Neurobiologic rationale

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

Table 1

Alcohol withdrawal: Acute vs long-term symptoms


Alcohol withdrawal syndrome

Protracted withdrawal syndrome


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


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


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

GI: gastrointestinal

Source: Click here for a bibliography

Table 2

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

Table 3

Mechanisms of action of benzodiazepines vs 3 anticonvulsants


Mechanism of action


Activate GABAA chloride ionophore, increasing affinity of GABAA receptor for GABA and augmenting frequency of chloride channel openinga

Valproic acid

GABA modulation and possibly second messenger systems; may inhibit Na1+ and/or Ca2+ channel, thereby boosting GABA and glutamate actionb


Decreases high voltage activated Ca2+ channels; unique binding site (synaptic vesicle protein SV2A) is thought to be involved in calcium-dependent regulation of neurotransmitter vesicle exocytosisc


GABA analog; unique binding site (Ca2+ channel subunit in brain) decreases calcium influx and inhibits release of excitatory amino acids and monoaminesd

GABA: gamma-aminobutyric acid

Source: Click here for a bibliography

CASE REPORT 1: Valproic acid for alcohol overdose

After attempting suicide with an alcohol overdose, Ms. J, age 45, is transferred from the emergency room (ER) to our psychiatry consult service 10 hours after admission. Her symptoms include nausea, tremor, headaches, agitation, disorientation, and auditory hallucinations.

Medical history reveals 25 years of alcohol dependence, multiple hospitalizations for withdrawal, and many failed attempts to quit. Ms. J reports consuming an average of 16 drink equivalents (eg, 12 oz beers) daily but denies illicit drug use.

Lab values on admission include blood alcohol concentration (BAC) 290 mg/dL (0.29%), mean corpuscular volume (MCV) 96 fL, gamma-glutamyltransferase (GGT) 164 U/L, aspartate aminotransferase (AST) 43 U/L, alanine aminotransferase (ALT) 31 U/L, and alkaline phosphatase (ALP) 151 U/L. Urine drug screen, acetaminophen, salicylate, vitamin B1 (thiamine), B12 (cyanocobalamin), B9 (folate), and electrolytes (including magnesium) are normal.

We assess alcohol withdrawal severity using the CIWA-Ar (Click here to view/download a copy of this scale). Ms. J’s initial score is 17, indicating a risk of moderate alcohol withdrawal if untreated.

In the ER, Ms. J is placed on a symptom-triggered benzodiazepine detoxification protocol with lorazepam. We add IV valproic acid, 1,250 mg (based on 20 mg/kg body weight)13 divided into 2 doses over the first 24 hours, then maintain IV valproic acid at 500 mg twice daily (Table 4). Within 12 hours of starting combination therapy, Ms. J scores 7 on the CIWA-Ar—indicating mild withdrawal—with subsequent scores <5. She scores 0 with no residual withdrawal symptoms within 36 hours.

Ms. J requires lorazepam, 7 mg, during the 10 hours before valproic acid is added. She requires only 2 mg lorazepam over the next 3 days and reports no side effects related to IV valproic acid. At discharge, Ms. J begins extended-release oral valproic acid, 1,250 mg (based on 25 mg/kg body weight)13 once daily for 2 weeks, until she can obtain outpatient follow-up.

Table 4

Benzodiazepines and anticonvulsants for alcohol detoxification



Valproic acid



Loading dose


20 mg/kg of body weight, divided into 2 doses for first 24 hours

1,500 mg IV once daily

400 mg PO qid

Maintenance dose

Day 1: 2 mg tid
Day 2: 2 mg morning,
1 mg afternoon,
2 mg evening
Day 3: 1 mg tid
Day 4: 1 mg bid
Day 5: 1 mg
Day 6: none

500 mg IV bid

Either 500 mg IV tid or 1,000 mg PO bid after 2 to 3 days of treatment

1,200 mg PO tid

Side effects

Impaired consciousness,
respiratory depression,

hair loss/thinning,
nausea, tremor,
weight gain

coordination difficulties

ataxia, fatigue

Drug interactions

↑ BZ: cimetidine, oral contraceptives, ethanol (acute), disulfiram, isoniazid, propranolol ↓ BZ: rifampin, ethanol (chronic)

↑ VPA: aspirin, felbamate, fluoxetine, isoniazid ↓ VPA: carbamazepine, lamotrigine, phenobarbital, phenytoin, ritonavir


↓ GBP 20%: antacids

BZ: benzodiazepine; GBP: gabapentin; PO: per os (by mouth); VPA: valproic acid

Source: Click here for a bibliography

Less lorazepam needed

Adjunctive anticonvulsants can reduce the amount of lorazepam required during detoxification.14,15 Compared with benzodiazepine monotherapy, the advantages of combination therapy—particularly in outpatient alcohol withdrawal treatment and relapse prevention—include:

  • minimal interaction with alcohol (avoiding increased psychomotor deficits, cognitive impairment, and intoxication)15
  • lower abuse potential
  • possible efficacy in mood stabilization before, during, and after withdrawal (Table 5).16

Given the risk of seizures during AWS, anticonvulsants seem to make empirical sense. One study reported a 1% incidence of withdrawal-related seizures in 545 alcohol-dependent inpatients treated with valproic acid.17 Another case series of 37 patients found no acute sequelae when valproic acid was used for AWS.18

Anticonvulsants such as valproic acid may reduce the frequency and severity of alcohol relapse, whereas benzodiazepines may increase relapse risk.19 During a 6-week trial, patients receiving valproic acid maintenance therapy had greater abstinence rates and improved drinking outcomes compared with detoxification-only groups.9

One disadvantage of valproic acid is potential hepatotoxicity, an important consideration in patients with liver damage. Fortunately, Ms. J’s AST and ALT values remained within normal limits during valproic acid treatment.

Table 5

Pharmacologic profiles of benzodiazepines vs 3 anticonvulsants



Valproic acid




CYP 2C19: diazepam
CYP 3A3/4: alprazolam,
triazolam Phase II only: lorazepam,

>95% hepatic, of which <20% occurs via CYP isoenzymes

Not extensively metabolized;
renal clearance;
not involved with hepatic CYP isoenzymes

Not metabolized;
secreted via kidneys as unchanged drug


Mild to moderate

Mild to moderate

Mild to moderate

Moderate to severe

Synergistic effects with alcohol





Paradoxical disinhibition





Risk of addiction in outpatient therapy





CYP: cytochrome P450

Source: Click here for a bibliography

CASE REPORT 2: Levetiracetam for withdrawal seizures

Mr. H, age 42, presents to the ER after suffering a seizure. His medical history includes hypertension, alcohol dependence, and seizures during alcohol withdrawal. He denies a history of psychiatric illness, and his family history is unknown. He is noncompliant with hypertension treatment, which includes clonidine. Mr. H reports his usual alcohol consumption as a 6-pack of beer nightly during the week and a 12-pack nightly on weekends. He says his last drink was 4 days before admission.

Mr. H scores 19 on the CIWA-Ar, placing him at risk for moderate withdrawal. Head CT shows diffuse atrophy, without evidence of an acute intracranial process. BAC is zero on admission, and urine drug screen is negative. Amylase, lipase, and lactate dehydrogenase (LDH) levels suggest acute pancreatitis. AST is elevated to 131 U/L, ALT is elevated to 42 U/L, but MCV is within normal limits.

The psychiatric service is consulted on day 2 of admission, and we prescribe levetiracetam, 500 mg IV every 8 hours.20 IV lorazepam also is available as needed: 1 mg every 8 hours for the first 2 days, then 1 mg every 12 hours for 2 days, then 1 mg every 24 hours. The patient’s CIWA-Ar score is 9 on days 2 and 3 of admission, followed by scores consistently between 2 and 3 after scheduled levetiracetam administration. Mr. H requires 3 mg of lorazepam the remainder of his hospitalization. He is discharged on day 7 with a CIWA-Ar score of 2, and reports no adverse effects related to levetiracetam. He leaves the hospital with a 2-week prescription for oral levetiracetam, 500 mg tid.

Did you miss this content?
Botulinum toxin for depression? An idea that’s raising some eyebrows