Alcohol withdrawal: When to choose an adjunctive anticonvulsant

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 GABA_A 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 gabapentin^11,12 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

Table 2

How alcohol affects GABA and glutamate neurotransmitters

Table 3

Mechanisms of action of benzodiazepines vs 3 anticonvulsants

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

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

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.

Advantages of levetiracetam

Levetiracetam is FDA-approved for adjunctive treatment of adults with partial-onset seizures.²¹ Successful AWS treatment with adjunctive levetiracetam has been supported by few but promising studies.^10,20 Potential advantages of levetiracetam in detoxification include:

• a lack of GABAergic properties, which limits the risk of intoxication or respiratory insufficiency when combined with alcohol²¹
• low drug-drug interaction risk because of nonhepatic metabolism and primary renal excretion.^22,23

We selected levetiracetam for Mr. H because of his history of alcohol withdrawal seizures and acute pancreatitis. Anticonvulsants may be more effective than lorazepam in reducing the risk of alcohol withdrawal seizures,²⁴ and we felt valproic acid might not be safe for him because of its low but real risk of pancreatitis.¹³ We based our levetiracetam dosing on a small open-label trial²⁰ and product information for treating adults with partial-onset seizures.²⁵

Studies also demonstrate levetiracetam’s potential for relapse prevention during outpatient therapy. In a 10-week trial, levetiracetam decreased the number of standard drinks in alcohol-dependent patients from 5.3 to 1.7 per day.¹⁰ This was a small open trial, however, and large controlled trials support the usefulness of other, FDA-approved medications—including disulfiram, naltrexone, and acamprosate—for alcohol relapse prevention.

CASE REPORT 3: Gabapentin for acute withdrawal

Mr. B, age 38, presents to the ER after a 13-day alcohol binge. He has been drinking increasing amounts of alcohol over 6 weeks. Three months earlier, Mr. B was admitted for alcohol withdrawal treatment and received 49 mg of lorazepam over 3 days. This resulted in his transfer from the step-down unit to the intensive care unit for increased agitation, possibly caused by paradoxical disinhibition from excessive lorazepam use.²⁶

Mr. B’s medical history is significant for alcohol-induced seizures, DTs, traumatic brain injury related to craniotomy, and right arm amputation. Mr. B drinks approximately 24 beers per day. He denies tobacco use but admits to past use of cocaine, marijuana, and heroin.

On admission, Mr. B’s BAC is 360 mg/dL (0.36%), AST is elevated at 72 U/L, ALT at 42 U/L, and LDH significantly elevated at 384 U/L. Urine drug screen is negative, and his CIWA-Ar score is 23. His score of –1 on the Richmond Agitation and Sedation Scale (RASS)²⁷ correlates with very mild sedation.

Guided by Bonnet et al²⁸ and clinical experience, we start Mr. B on gabapentin, 1,200 mg tid, and IV lorazepam, 2 mg every 8 hours as needed for breakthrough withdrawal. We decrease lorazepam by 50% every other day until Mr. B is discharged. On days 2, 3, and 4, Mr. B’s CIWA-Ar scores are 6, 9, and 2, respectively. His RASS score drops from –1 on days 1 and 2 to 0 until discharge, indicating an alert and calm state.

Mr. B requires a total of 2 mg of lorazepam throughout hospitalization. He finishes alcohol detoxification on day 4 and is discharged with a prescription for gabapentin, 1,200 mg tid. Two weeks later, when he is admitted to a 28-day inpatient alcohol rehabilitation unit, Mr. B has not relapsed.

More abstinent days

Gabapentin is FDA-approved as adjunctive therapy for partial seizures. Off-label, it has been generally efficacious as an adjunct in alcohol detoxification.^29-32 We chose adjunctive anticonvulsant therapy for Mr. B because of his history of alcohol-induced seizures. We chose gabapentin instead of valproic acid because of Mr. B’s liver damage and gabapentin’s lack of hepatic metabolism.

Gabapentin may reduce alcohol consumption and craving in alcohol-dependent patients. By increasing the number of abstinent days, gabapentin may help patients maintain abstinence.³³ Gabapentin does not appear to interact clinically with alcohol, causing neither sedation nor synergistic effects.³⁴ Its relative lack of abuse potential may be valuable in outpatient alcohol withdrawal treatment and in maintaining alcohol abstinence after detoxification.

Related resource

• Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification. J Fam Pract. 2004;53(7):545-554. www.jfponline.com/Pages.asp?AID=1730.

Drug brand names

• Acamprosate • Campral
• Alprazolam • Xanax
• Carbamazepine • Carbatrol
• Cimetidine • Tagamet
• Clonazepam • Klonopin
• Clonidine • Catapres
• Diazepam • Valium
• Disulfiram • Antabuse
• Felbamate • Felbatol
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Isoniazid • Nydrazid
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lorazepam • Ativan
• Naltrexone • ReVia, Vivitrol
• Oxazepam • Serax
• Phenobarbital • Luminal
• Phenytoin • Dilantin
• Propranolol • Inderal
• Rifampin • Rifadin
• Ritonavir • Norvir
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakote, Depakene

Disclosures

Dr. Spiegel is a speaker for Pfizer Inc. and GlaxoSmithKline.

Dr. Radac reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The authors thank Rishi Laroia, MD, Robert Swanson, MD, and Adam W. Coe, MD for their contributions to this article.

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 GABA_A 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 gabapentin^11,12 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

Table 2

How alcohol affects GABA and glutamate neurotransmitters

Table 3

Mechanisms of action of benzodiazepines vs 3 anticonvulsants

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

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

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.

Advantages of levetiracetam

Levetiracetam is FDA-approved for adjunctive treatment of adults with partial-onset seizures.²¹ Successful AWS treatment with adjunctive levetiracetam has been supported by few but promising studies.^10,20 Potential advantages of levetiracetam in detoxification include:

• a lack of GABAergic properties, which limits the risk of intoxication or respiratory insufficiency when combined with alcohol²¹
• low drug-drug interaction risk because of nonhepatic metabolism and primary renal excretion.^22,23

We selected levetiracetam for Mr. H because of his history of alcohol withdrawal seizures and acute pancreatitis. Anticonvulsants may be more effective than lorazepam in reducing the risk of alcohol withdrawal seizures,²⁴ and we felt valproic acid might not be safe for him because of its low but real risk of pancreatitis.¹³ We based our levetiracetam dosing on a small open-label trial²⁰ and product information for treating adults with partial-onset seizures.²⁵

Studies also demonstrate levetiracetam’s potential for relapse prevention during outpatient therapy. In a 10-week trial, levetiracetam decreased the number of standard drinks in alcohol-dependent patients from 5.3 to 1.7 per day.¹⁰ This was a small open trial, however, and large controlled trials support the usefulness of other, FDA-approved medications—including disulfiram, naltrexone, and acamprosate—for alcohol relapse prevention.

CASE REPORT 3: Gabapentin for acute withdrawal

Mr. B, age 38, presents to the ER after a 13-day alcohol binge. He has been drinking increasing amounts of alcohol over 6 weeks. Three months earlier, Mr. B was admitted for alcohol withdrawal treatment and received 49 mg of lorazepam over 3 days. This resulted in his transfer from the step-down unit to the intensive care unit for increased agitation, possibly caused by paradoxical disinhibition from excessive lorazepam use.²⁶

Mr. B’s medical history is significant for alcohol-induced seizures, DTs, traumatic brain injury related to craniotomy, and right arm amputation. Mr. B drinks approximately 24 beers per day. He denies tobacco use but admits to past use of cocaine, marijuana, and heroin.

On admission, Mr. B’s BAC is 360 mg/dL (0.36%), AST is elevated at 72 U/L, ALT at 42 U/L, and LDH significantly elevated at 384 U/L. Urine drug screen is negative, and his CIWA-Ar score is 23. His score of –1 on the Richmond Agitation and Sedation Scale (RASS)²⁷ correlates with very mild sedation.

Guided by Bonnet et al²⁸ and clinical experience, we start Mr. B on gabapentin, 1,200 mg tid, and IV lorazepam, 2 mg every 8 hours as needed for breakthrough withdrawal. We decrease lorazepam by 50% every other day until Mr. B is discharged. On days 2, 3, and 4, Mr. B’s CIWA-Ar scores are 6, 9, and 2, respectively. His RASS score drops from –1 on days 1 and 2 to 0 until discharge, indicating an alert and calm state.

Mr. B requires a total of 2 mg of lorazepam throughout hospitalization. He finishes alcohol detoxification on day 4 and is discharged with a prescription for gabapentin, 1,200 mg tid. Two weeks later, when he is admitted to a 28-day inpatient alcohol rehabilitation unit, Mr. B has not relapsed.

More abstinent days

Gabapentin is FDA-approved as adjunctive therapy for partial seizures. Off-label, it has been generally efficacious as an adjunct in alcohol detoxification.^29-32 We chose adjunctive anticonvulsant therapy for Mr. B because of his history of alcohol-induced seizures. We chose gabapentin instead of valproic acid because of Mr. B’s liver damage and gabapentin’s lack of hepatic metabolism.

Gabapentin may reduce alcohol consumption and craving in alcohol-dependent patients. By increasing the number of abstinent days, gabapentin may help patients maintain abstinence.³³ Gabapentin does not appear to interact clinically with alcohol, causing neither sedation nor synergistic effects.³⁴ Its relative lack of abuse potential may be valuable in outpatient alcohol withdrawal treatment and in maintaining alcohol abstinence after detoxification.

Related resource

• Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification. J Fam Pract. 2004;53(7):545-554. www.jfponline.com/Pages.asp?AID=1730.

Drug brand names

• Acamprosate • Campral
• Alprazolam • Xanax
• Carbamazepine • Carbatrol
• Cimetidine • Tagamet
• Clonazepam • Klonopin
• Clonidine • Catapres
• Diazepam • Valium
• Disulfiram • Antabuse
• Felbamate • Felbatol
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Isoniazid • Nydrazid
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lorazepam • Ativan
• Naltrexone • ReVia, Vivitrol
• Oxazepam • Serax
• Phenobarbital • Luminal
• Phenytoin • Dilantin
• Propranolol • Inderal
• Rifampin • Rifadin
• Ritonavir • Norvir
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakote, Depakene

Disclosures

Dr. Spiegel is a speaker for Pfizer Inc. and GlaxoSmithKline.

Dr. Radac reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The authors thank Rishi Laroia, MD, Robert Swanson, MD, and Adam W. Coe, MD for their contributions to this article.

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 GABA_A 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 gabapentin^11,12 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

Table 2

How alcohol affects GABA and glutamate neurotransmitters

Table 3

Mechanisms of action of benzodiazepines vs 3 anticonvulsants

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

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

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.

Advantages of levetiracetam

Levetiracetam is FDA-approved for adjunctive treatment of adults with partial-onset seizures.²¹ Successful AWS treatment with adjunctive levetiracetam has been supported by few but promising studies.^10,20 Potential advantages of levetiracetam in detoxification include:

• a lack of GABAergic properties, which limits the risk of intoxication or respiratory insufficiency when combined with alcohol²¹
• low drug-drug interaction risk because of nonhepatic metabolism and primary renal excretion.^22,23

We selected levetiracetam for Mr. H because of his history of alcohol withdrawal seizures and acute pancreatitis. Anticonvulsants may be more effective than lorazepam in reducing the risk of alcohol withdrawal seizures,²⁴ and we felt valproic acid might not be safe for him because of its low but real risk of pancreatitis.¹³ We based our levetiracetam dosing on a small open-label trial²⁰ and product information for treating adults with partial-onset seizures.²⁵

Studies also demonstrate levetiracetam’s potential for relapse prevention during outpatient therapy. In a 10-week trial, levetiracetam decreased the number of standard drinks in alcohol-dependent patients from 5.3 to 1.7 per day.¹⁰ This was a small open trial, however, and large controlled trials support the usefulness of other, FDA-approved medications—including disulfiram, naltrexone, and acamprosate—for alcohol relapse prevention.

CASE REPORT 3: Gabapentin for acute withdrawal

Mr. B, age 38, presents to the ER after a 13-day alcohol binge. He has been drinking increasing amounts of alcohol over 6 weeks. Three months earlier, Mr. B was admitted for alcohol withdrawal treatment and received 49 mg of lorazepam over 3 days. This resulted in his transfer from the step-down unit to the intensive care unit for increased agitation, possibly caused by paradoxical disinhibition from excessive lorazepam use.²⁶

Mr. B’s medical history is significant for alcohol-induced seizures, DTs, traumatic brain injury related to craniotomy, and right arm amputation. Mr. B drinks approximately 24 beers per day. He denies tobacco use but admits to past use of cocaine, marijuana, and heroin.

On admission, Mr. B’s BAC is 360 mg/dL (0.36%), AST is elevated at 72 U/L, ALT at 42 U/L, and LDH significantly elevated at 384 U/L. Urine drug screen is negative, and his CIWA-Ar score is 23. His score of –1 on the Richmond Agitation and Sedation Scale (RASS)²⁷ correlates with very mild sedation.

Guided by Bonnet et al²⁸ and clinical experience, we start Mr. B on gabapentin, 1,200 mg tid, and IV lorazepam, 2 mg every 8 hours as needed for breakthrough withdrawal. We decrease lorazepam by 50% every other day until Mr. B is discharged. On days 2, 3, and 4, Mr. B’s CIWA-Ar scores are 6, 9, and 2, respectively. His RASS score drops from –1 on days 1 and 2 to 0 until discharge, indicating an alert and calm state.

Mr. B requires a total of 2 mg of lorazepam throughout hospitalization. He finishes alcohol detoxification on day 4 and is discharged with a prescription for gabapentin, 1,200 mg tid. Two weeks later, when he is admitted to a 28-day inpatient alcohol rehabilitation unit, Mr. B has not relapsed.

More abstinent days

Gabapentin is FDA-approved as adjunctive therapy for partial seizures. Off-label, it has been generally efficacious as an adjunct in alcohol detoxification.^29-32 We chose adjunctive anticonvulsant therapy for Mr. B because of his history of alcohol-induced seizures. We chose gabapentin instead of valproic acid because of Mr. B’s liver damage and gabapentin’s lack of hepatic metabolism.

Gabapentin may reduce alcohol consumption and craving in alcohol-dependent patients. By increasing the number of abstinent days, gabapentin may help patients maintain abstinence.³³ Gabapentin does not appear to interact clinically with alcohol, causing neither sedation nor synergistic effects.³⁴ Its relative lack of abuse potential may be valuable in outpatient alcohol withdrawal treatment and in maintaining alcohol abstinence after detoxification.

Related resource

• Asplund CA, Aaronson JW, Aaronson HE. 3 regimens for alcohol withdrawal and detoxification. J Fam Pract. 2004;53(7):545-554. www.jfponline.com/Pages.asp?AID=1730.

Drug brand names

• Acamprosate • Campral
• Alprazolam • Xanax
• Carbamazepine • Carbatrol
• Cimetidine • Tagamet
• Clonazepam • Klonopin
• Clonidine • Catapres
• Diazepam • Valium
• Disulfiram • Antabuse
• Felbamate • Felbatol
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Isoniazid • Nydrazid
• Lamotrigine • Lamictal
• Levetiracetam • Keppra
• Lorazepam • Ativan
• Naltrexone • ReVia, Vivitrol
• Oxazepam • Serax
• Phenobarbital • Luminal
• Phenytoin • Dilantin
• Propranolol • Inderal
• Rifampin • Rifadin
• Ritonavir • Norvir
• Temazepam • Restoril
• Triazolam • Halcion
• Valproic acid • Depakote, Depakene

Disclosures

Dr. Spiegel is a speaker for Pfizer Inc. and GlaxoSmithKline.

Dr. Radac reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The authors thank Rishi Laroia, MD, Robert Swanson, MD, and Adam W. Coe, MD for their contributions to this article.