Mechanisms of action of benzodiazepines vs 3 anticonvulsants
|Agent||Mechanism of action|
|Benzodiazepines||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|
|Levetiracetam||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|
|Gabapentin||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.
Benzodiazepines and anticonvulsants for alcohol detoxification
|Loading dose||None||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, |
|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||None||↓ 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.