Paradoxical Reactions to Benzodiazepines: Literature Review and Treatment Options

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


Pharmacotherapy. 2004;24(9) 


Reports of paradoxical reactions to midazolam are a recent development in the medical literature. Midazolam, which has sedative effects, is commonly prescribed before short surgical procedures.

While participating in a study to evaluate benzodiazepine potency, 28-year-old healthy, identical twin men experienced similar paradoxical reactions.[3] On three separate occasions, the men received various dosages of midazolam and diazepam. After receiving intravenous midazolam 5 mg, one of the twins became sedated with restlessness and heightened motor responses of his extremities. An additional dose of midazolam 5 mg heightened these responses. On the second occasion, one of the men became unconscious after receiving intravenous midazolam 12 mg. When he awoke, he was extremely restless and agitated. Administration of intravenous diazepam 10 mg resulted in similar but less intensive sedation and motor responses. The second twin displayed the same responses. Neither man had any recollection of the events. The authors stated that the intensity of the behaviors was so strong that if this had been an actual procedure and not an experiment, the procedure would have had to be discontinued. These cases demonstrate that paradoxical reactions to benzodiazepines may be genetically linked.

Another case report describes aggressive behaviors in a patient with anger management difficulties.[7] A 31-year-old man was hospitalized for an endogastric-duodenoscopy to evaluate recent complaints of epigastric pain with fever. Before the procedure, the man received midazolam 5 mg intravenously. Soon thereafter, he became verbally and physically threatening to an extent that necessitated restraint. The behaviors ceased after he received an intramuscular injection of sodium amobarbital 200 mg. The authors did not mention if the procedure was reattempted at a later time.

Paradoxical reactions to midazolam occurred during surgical removal of impacted molars in a 22-year-old woman with a history of anger management problems and alcohol abuse sufficient to require rehabilitation.[4] The patient was enrolled in a multicenter clinical trial to evaluate the safety and efficacy of intravenous sedatives. The study protocol randomly assigned participants to one of five groups to receive various combinations of midazolam, fentanyl, and methohexital. The dosage of midazolam was titrated to slurred speech and ptosis, with a maximum dose not to exceed 25 mg. After receiving midazolam 18 mg over 18 minutes, the woman became belligerent and verbally abusive, with disruptive movement of her extremities. The dental procedure was terminated due to these extreme behaviors, which continued for the next 24 hours. Afterward, the woman had no recollection of the events. Based on this case, the authors suggested that a history of alcohol abuse may predispose patients to paradoxical reactions with benzodiazepines.

Other authors described a case of agitation secondary to midazolam successfully managed with haloperidol.[12] A 50-year-old man with a medical history of hypercholesterolemia was hospitalized for coronary artery bypass grafting (CABG) surgery after presenting with chest pain consistent with myocardial infarction and 90% occlusion of the coronary artery. The patient received intravenous midazolam before placement of the arterial catheter. After a total dose of 6 mg was administered, the man developed worsening anxiety and agitation. The physician chose to treat the paradoxical reaction with haloperidol 10 mg delivered intravenously over 2 minutes. The patient calmed, the CABG procedure was completed, and amnesia was retained. The authors concluded that haloperidol may be a safe and effective agent for treating paradoxical reactions of benzodiazepines.

Several reports indicate that the benzodiazepine antagonist flumazenil may be useful in the treatment of paradoxical reactions to midazolam. Flumazenil should be considered if these types of reactions are suspected.

A 49-year-old healthy woman experienced a paradoxical reaction while under conscious sedation during insertion of breast implants.[13] Midazolam was started before the procedure and administered throughout the procedure, in varying doses as needed, until adequate sedation was attained. Vital signs were monitored and remained within normal limits during the surgery. In general, every time the woman moved during the procedure, additional midazolam was delivered. This pattern was repeated several times, and she received a total dose of midazolam 12 mg intravenously over 70 minutes. Fluma-zenil 0.5 mg was administered intravenously when her movements became very aggressive and required force to control. Her aggressiveness ceased after receiving flumazenil; however, she remained sedated and amnesia was retained.

In another report, a 71-year-old man with a 1-year history of episodes of increased anger, jealousy, and paranoid ideation, experienced paradoxical reactions to midazolam before an endoscopy.[14] One month earlier, the patient had undergone an uneventful endoscopy procedure. On this occasion, after receiving midazolam 4 mg intravenously over 14 minutes, he became sedated and delirious, requiring restraint for increased movement of his extremities. The behaviors were reversed after administration of intravenous flumazenil 0.2 mg. The man did not remember the events. This case illustrates that elderly patients, as well as those with psychiatric disturbances, may be at increased risk for paradoxical reactions to benzodiazepines.

One case report indicated that patients without psychiatric disorders also may experience paradoxical reactions with benzodiazepines.[15] A 27-year-old man received a total dose of midazolam 7 mg intravenously before cystoscopy and laser ablation of a meatal condyloma. The surgery was completed despite his agitated and restless behavior. Vital signs remained within normal limits and the patient denied pain. Postoperatively, he received lorazepam 4 mg intravenously with no change in behavior. The agitation ceased after administration of flumazenil 0.3 mg (total dose), and amnesia was retained.

Flumazenil effectively reversed paradoxical reactions of midazolam in three patients undergoing endoscopy procedures.[16] The first patient, a 62-year old man with a long history of alcohol abuse, experienced movement of the extremities with head shaking after receiving midazolam 5 mg intravenously. The second patient, a 58-year-old woman, also with a history of alcohol abuse, became restless and agitated after receiving midazolam 7.5 mg intravenously. The last patient, a healthy 26-year-old man, had violent movements after receiving midazolam 10 mg intravenously. In all three patients, the paradoxical reactions were reversed by intravenous flumazenil 0.5 mg. Sedation was maintained, the procedures were completed, and no patient had any recollection of the unusual behaviors.

A case series of patients who underwent minor to medium lower body surgical procedures addressed the development of paradoxical reactions to midazolam.[2] All patients were given spinal or epidural anesthesia and incremental injections of midazolam 1.5 mg intravenously to induce sedation. Six of 58 patients experienced paradoxical reactions to midazolam. The authors compared these patients with six matched control subjects who received midazolam uneventfully. The paradoxical reactions were characterized as flailing of the arms, writhing on the examination table, and attempting to speak during the surgical procedures. All six patients were delirious and needed to be physically restrained due to their aggressive behavior. The mean ± SD total dose of midazolam was 7.3 ± 2.8 mg, which was similar in the six matched controls (8.8 ± 3.2 mg). Flumazenil was administered in all six patients, with total doses ranging from 0.3-0.5 mg. The paradoxical reactions ceased after administration of flumazenil, and all patients completed the surgical procedure and were discharged successfully.

The most recent report described two cases of paradoxical reactions in patients given midazolam for dental procedures.[17] An anxious 19-year-old woman requested sedation before molar extraction. After receiving midazolam 5 mg intravenously over 7 minutes, she became uncooperative and began crying, yet denied pain. A 21-year-old woman displayed a similar response after receiving midazolam 7 mg intravenously over 10 minutes. In both cases, the women calmed and ceased crying after receiving flumazenil 0.2-0.4 mg intravenously. Neither patient had any memory of the events.