All benzodiazepines treat symptoms of anxiety, and some shorter-acting ones are useful hypnotic agents.66 Benzodiazepines, such as chlordiazepoxide, have long proved useful in treating delirium, especially when associated with alcohol withdrawal. Some patients with epilepsy experience an aura resembling a panic attack (predominantly anxiety and fear),60 and anxiety frequently accompanies depression in persons with epilepsy,32 so many patients take benzodiazepines for both conditions.

Medications acting at the benzodiazepine-GABAA receptor site have overlapping effectiveness in the treatment of insomnia, delirium, and epilepsy.64 In patients with primary generalized seizures or myoclonus, clonazepam is the most commonly used benzodiazepine, clorazepate is occasionally used as adjunctive treatment for complex partial seizures, and parenteral diazepam, lorazepam, and midazolam are used to treat status epilepticus.64,65

Adverse reactions to this class of drug are similar, regardless of the underlying condition being treated. Benzodiazepines, like barbiturates, can cause irritability or aggression in some children with attention deficit disorder or mental retardation.60

Abrupt or rapid withdrawal from benzodiazepines, especially after chronic use and high dosages, can cause seizures, but usually they are brief and require no treatment.12,15,67–70 Many dually dependent patients (those with a psychiatric illness and substance abuse) insist on renewing their benzodiazepine prescription (often clonazepam) because of previous seizures during withdrawal. They may self-medicate to obtain relief from withdrawal symptoms of anxiety and, possibly, delirium,60 just as alcoholic patients occasionally request long-term therapy with benzodiazepines after undergoing detoxification from the alcohol.12,68 If benzodiazepines are used chronically, they are best supervised by psychiatrists or behavioral medicine specialists. In patients genuinely fearful of withdrawal seizures, even with careful, prolonged tapering, it may be useful for them to keep the rectal gel form of diazepam on hand in case of generalized seizure.71 Enzyme-inducing AEDs (e.g., phenytoin, carbamazepine) can lower benzodiazepine levels, rarely precipitating withdrawal seizures.56 (See Table: Anxiolytic drugs and their metabolizing enzymes.)

Benzodiazepine levels are increased to varying degrees by:

  • antidepressants: nefazodone, fluoxetine, and fluvoxamine
  • histamine-2 blocker: cimetidine
  • antibiotics: erythromycin and disulfan53

Benzodiazepine overdose is not associated with seizures, however.

Reversing benzodiazepine effects with the antagonist flumazenil is not recommended in patients at risk of seizures.16,72 When benzodiazepine effects are reversed by flumazenil, other drug toxicities may be unmasked in patients with mixed overdoses (e.g., suicide attempts, drug abuses), and flumazenil is ineffective against opiate overdose.72

Hypnotics and seizure risk

Sleep deprivation increases the risk for most types of seizures, so restoring normal sleep patterns may be an important part of treatment. The chronic use of hypnotics is not advisable, however. Searching for the cause of sleep disruption may reveal unrecognized nocturnal seizures or adverse effects of medications.36,37

Short-acting benzodiazepines, such as temazepam, flurazepam, and estazolam, are useful as hypnotics. Newer, even shorter-acting benzodiazepines, such as zolpidem and zaleplon, act at the central benzodiazepine omega-1 (type 1) site of the GABAA receptor complex; their effect on seizure threshold is unknown.

Antihistamines, which are the main active ingredient in over-the-counter sleeping aids, lower seizure threshold and should therefore be avoided, although the magnitude of this risk is not known. In one series, overdosage with diphenhydramine was the third leading cause of seizures.5

Adapted from: Koppel BS. Contribution of drugs and drug interactions (prescribed, over the counter, and illicit) to seizures and epilepsy. In: Ettinger AB and Devinsky O, eds. Managing epilepsy and co-existing disorders. Boston: Butterworth-Heinemann; 2002;155–173. With permission from Elsevier (www.elsevier.com).

Authored By: 
Barbara S. Koppel MD
I<
Reviewed By: 
Steven C. Schachter MD
on: 
Monday, March 1, 2004