What is the best medication, lacosamide, levetiracetam (Keppra), phenobarbital, or fosphenytoin (Cerebyx), for managing alcohol withdrawal in a patient with a history of one seizure?

From the Guidelines

For alcohol withdrawal with a history of one seizure, benzodiazepines remain the first-line treatment rather than antiepileptic drugs. The most recent and highest quality study, 1, supports the use of benzodiazepines as the primary treatment for alcohol withdrawal seizures. Lorazepam (1-2mg IV/PO every 1-4 hours as needed) or diazepam (5-10mg IV/PO every 1-4 hours as needed) should be used initially, with dosing based on withdrawal severity using a validated scale like CIWA-Ar.

Among the antiepileptic options listed, phenobarbital would be the most appropriate adjunctive therapy if benzodiazepines alone are insufficient, typically starting at 130-260mg IV/IM, then 60-130mg every 4-6 hours as needed. Phenobarbital works on GABA receptors similarly to alcohol and benzodiazepines.

• Levetiracetam, lacosamide, and fosphenytoin are not recommended for alcohol withdrawal seizures as they don't address the underlying pathophysiology of withdrawal.
• The patient should receive thiamine 100mg IV/IM daily for 3-5 days, followed by oral supplementation, adequate hydration, and electrolyte replacement (particularly magnesium and potassium) to prevent complications like Wernicke's encephalopathy and further seizures.
• The use of benzodiazepines is supported by multiple studies, including 1, 1, and 1, which emphasize the importance of benzodiazepines in managing alcohol withdrawal symptoms and preventing seizures and delirium.
• However, the most recent study, 1, provides the strongest evidence for the use of benzodiazepines as the first-line treatment for alcohol withdrawal seizures.

From the FDA Drug Label

The lethal dose of a barbiturate is far less if alcohol is also ingested. The symptoms of barbiturate withdrawal can be severe and may cause death. Minor withdrawal symptoms may appear 8 to 12 hours after the last dose of a barbiturate These symptoms usually appear in the following order: anxiety, muscle twitching, tremor of hands and fingers, progressive weakness, dizziness, distortion in visual perception, nausea, vomiting, insomnia and orthostatic hypotension. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of these drugs Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Individuals susceptible to barbiturate abuse and dependence include alcoholics and opiate abusers, as well as other sedative-hypnotic and amphetamine abusers Drug dependence to barbiturates arises from repeated administration of a barbiturate or agent with barbiturate-like effect on a continuous basis, generally in amounts exceeding therapeutic dose levels The characteristics of drug dependence to barbiturates include: (a) a strong desire or need to continue taking the drug, (b) a tendency to increase the dose, (c) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects and (d) a physical dependence on the effects of the drug requiring its presence for maintenance of homeostasis and resulting in a definite, characteristic and self-limited abstinence syndrome when the drug is withdrawn. Individuals subject to barbiturate abuse and dependence include alcoholics and opiate abusers as well as other sedative-hypnotics and amphetamine abusers. Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. In all cases, withdrawal takes an extended period of time. One method involves substituting a 30 mg dose of phenobarbital for each 100 to 200 mg dose of barbiturate that the patient has been taking The total daily amount of phenobarbital is then administered in 3 to 4 divided doses, not to exceed 600 mg daily. Should signs of withdrawal occur on the first day of treatment, a loading dose of 100 to 200 mg of phenobarbital may be administered IM in addition to the oral dose After stabilization on phenobarbital, the total daily dose is decreased by 30 mg a day as long as withdrawal is proceeding smoothly. If withdrawal symptoms appear, dosage is maintained at that level or increased slightly until symptoms disappear A modification of this regimen involves initiating treatment at the patient’s regular dosage level and decreasing the daily dosage by 10 percent if tolerated by the patient. The symptoms of withdrawal can be severe and may cause death. Minor withdrawal symptoms (e.g., anxiety, muscle twitching, tremors, nausea, etc.) may appear 8-12 hours after the last dose of a barbiturate. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to five days after abrupt cessation of the barbiturate. The intensity of withdrawal symptoms gradually declines over a period of two weeks. Infants physically dependent on barbiturates may be given phenobarbital 3 to 10 mg/kg/day After withdrawal symptoms (hyperactivity, disturbed sleep, tremors, hyperreflexia) are relieved, the dosage of phenobarbital should be gradually decreased and completely withdrawn over a 2-week period.

Phenobarbital is the best option for alcohol withdrawal and history of one seizure, as it can be used for the treatment of barbiturate dependence and withdrawal, and it has a long history of use for this purpose 2.

• Key points:
  • Phenobarbital can be used to treat barbiturate dependence and withdrawal.
  • It has a long history of use for this purpose.
  • The dosage of phenobarbital should be gradually decreased and completely withdrawn over a period of time to minimize the risk of withdrawal symptoms.
  • Phenobarbital may be administered in divided doses, not to exceed 600 mg daily.
  • A loading dose of 100 to 200 mg of phenobarbital may be administered IM in addition to the oral dose if signs of withdrawal occur on the first day of treatment.

Note: The other options, lacosamide and levetiracetam, are not mentioned in the provided drug labels as being used for alcohol withdrawal and history of one seizure. Fosphenytoin is not mentioned in the provided drug labels at all.

From the Research

Treatment Options for Alcohol Withdrawal and History of One Seizure

• The treatment of alcohol withdrawal syndrome (AWS) with benzodiazepines is limited by risk of abuse, intoxication, respiratory problems, and liver toxicity 3.
• Levetiracetam has been investigated as an alternative to benzodiazepines for the treatment of AWS, but the results did not support an additional effect of levetiracetam on the reduction of alcohol withdrawal symptoms 3.
• For patients with a history of one seizure, the treatment options for alcohol withdrawal include levetiracetam, fosphenytoin, and phenobarbital 4, 5, 6, 7.

Efficacy of Treatment Options

• Levetiracetam has been shown to be effective in treating toxin-related seizures, including those caused by alcohol withdrawal, with a treatment success rate of 100% in one study 5.
• Fosphenytoin has also been shown to be effective in treating toxin-related seizures, including those caused by alcohol withdrawal, with a treatment success rate of 50% in one study 5.
• Phenobarbital has been shown to be effective in managing symptoms of alcohol withdrawal, with similar primary and secondary treatment outcomes to benzodiazepines in one study 7.

Safety and Tolerability

• Levetiracetam has a favorable pharmacokinetic profile and good tolerability, with a lack of sedating effects 4.
• Fosphenytoin has been associated with life-threatening hypotension in one patient who used cocaine and an opioid 5.
• Phenobarbital has been shown to be safe and effective in managing symptoms of alcohol withdrawal, with similar medication-related adverse events to benzodiazepines in one study 7.