Paradoxical Reactions to Benzodiazepines: Literature Review and Treatment Options

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


Pharmacotherapy. 2004;24(9) 

Abstract and Introduction


Benzodiazepines frequently are administered to patients to induce sedation. Paradoxical reactions to benzodiazepines, characterized by increased talkativeness, emotional release, excitement, and excessive movement, are relatively uncommon and occur in less than 1% of patients. The exact mechanism of paradoxical reactions remains unclear. Most cases are idiosyncratic; however, some evidence suggests that these reactions may occur secondary to a genetic link, history of alcohol abuse, or psychological disturbances. This review evaluates the numerous cases of paradoxical reactions to benzodiazepines in adult and pediatric patients that have been reported in the biomedical literature. It also explores the advantages and disadvantages of the various available treatment options.


Benzodiazepines are used primarily in the treatment of generalized anxiety and panic disorders, as sedative hypnotics, muscle relaxants, and anticonvulsants. These agents exert their pharmacologic action by binding to benzodiazepine-γ-aminobutyric acid (GABA)-type A-chloride receptors in the central nervous system.[1] This action results in increased inhibitory action of GABA, producing a state of relaxation and inducing anterograde amnesia.

Benzodiazepines commonly are given alone or in combination with anesthetics to induce sedation. Unfortunately, some patients experience paradoxical reactions to these agents.[1] These reactions are characterized by increased talkativeness, emotional release, excitement, excessive movement, and even hostility and rage. The pathophysiologic mechanisms underlying these reactions are unclear; however, several predisposing risk factors have been identified. These include young and advanced age, genetic predisposition, alcoholism, and psychiatric and/or personality disorders. Children and elderly patients may be more predisposed than other patients to paradoxical reactions with benzodiazepines. It has been theorized that these subgroups of patients have alterations in the pharmacodynamic response to benzodiazepines; however, the exact differences have not been specifically characterized in the literature.[2] Some patients may have a genetic variability in the benzodiazepine-GABA-chloride receptor that results in an abnormal pharmacodynamic response.[3] Multiple allelic forms of genetically determined benzodiazepine receptors exist, resulting in differing affinity for benzodiazepines among patients.

Patients who are alcoholic may be at increased risk of adverse reactions from benzodiazepines due to an alteration of the neuroregulatory mechanisms of the brain.[4] Alcoholics are believed to have decreased synthesis and functioning of GABA, resulting in less inhibitory action of the neurotransmitter. Finally, patients with psychiatric and/or personality disorders have an increased risk of paradoxical reactions to benzodiazepines.[5,6,7] In this group of patients, the highest risk is experienced by those with psychiatric histories of anger and aggressive behavior. The exact mechanism of paradoxical reaction development in these patients is unclear.[4]