Paradoxical Reactions to Benzodiazepines: Literature Review and Treatment Options

Carissa E. Mancuso, PharmD; Maria G. Tanzi, PharmD; Michael Gabay, PharmD

Disclosures

Pharmacotherapy. 2004;24(9) 

Treatment Options

Treatment of paradoxical reactions secondary to benzodiazepines is supportive, with airway and blood pressure management. In addition, a limited number of case studies report the use of physostigmine, flumazenil, and haloperidol.

Physostigmine was the first agent used to manage paradoxical reactions to benzodiazepines.[23] Physostigmine is an acetylcholinesterase inhibitor that readily crosses the blood-brain barrier and is associated with various adverse effects, including nausea, vomiting, epigastric pain, miosis, bradycardia, salivation, and dyspnea. Once in the central nervous system, the drug increases cholinergic stimulation and may reverse drug-induced central nervous system depression. It is thought that its role in benzodiazepine reversal is due to a nonspecific analeptic effect. Reversal of paradoxical reactions has not been consistent; therefore, physostigmine is generally not recommended in the management of paradoxical reactions to benzodiazepines.[14,23,24,25,26]

Flumazenil is an imidazobenzodiazepine compound used clinically as a benzodiazepine antagonist.[27] It is an intravenous agent that competitively antagonizes GABA-benzodiazepine receptors in the central nervous system. The drug displays dose-independent pharmacokinetics. It distributes rapidly into the body with a quick onset of action of 1-2 minutes and has an elimination half-life of 0.7-1.3 hours. Flumazenil has a large volume of distribution (0.95 L/kg) and is only 50% bound to plasma proteins. The drug is completely metabolized through hepatic pathways.

Flumazenil is indicated for reversal of benzodiazepine sedation. Clinically, it has been given before administration of benzodiazepines to modify their effects. Administration of flumazenil in adults is accomplished by intravenous titration with a bolus of 0.5 mg followed by 0.1 mg until a desired response is achieved. Doses of 0.3-0.5 mg have been used successfully in the reversal of paradoxical reactions while maintaining sedation and retaining amnesia. Sedative reversal in pediatric patients at least 1 year old may be achieved with a starting dose of flumazenil 0.01 mg/kg (up to 0.2 mg) intravenously over 15 seconds.[28] Additional doses of 0.01 mg/kg (up to 0.2 mg) may be repeated to achieve the desired level of consciousness. The maximum recommended dose of flumazenil in children is 0.05 mg/kg or 1.0 mg, whichever is lower. For most pediatric cases, successful management of paradoxical reactions with flumazenil has been attained with doses of 0.01 mg/kg.[21,22]

Haloperidol may be a safe alternative to flumazenil for treating paradoxical reactions to benzodiazepines.[12] The drug is a butyrophenone-derivative antipsychotic agent clinically used in the treatment of psychiatric disorders, Tourette's syndrome, delirium, and in children with attention-deficit-hyperactivity disorder.[29] Haloperidol is metabolized in the liver, is 92% bound to plasma proteins, and has a half-life of 20 hours. Although the exact mechanism is unknown, it is thought that haloperidol's action on dopaminergic receptors in the central nervous system results in a calming effect.[12] Haloperidol may be beneficial in patients with severe coronary artery disease because it avoids the adverse effects of increased left ventricular end diastolic pressure, hypertension, and tachycardia, all of which are sometimes seen with flumazenil and may lead to myocardial infarction in patients with coronary artery disease. The most trouble-some adverse effects associated with haloperidol are extrapyramidal reactions. A total dose of haloperidol 10 mg intravenously, delivered in two divided doses, has been used to treat benzo-diazepine-induced paradoxical reactions in adults.

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