Paradoxical Reactions to Benzodiazepines: Literature Review and Treatment Options

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


Pharmacotherapy. 2004;24(9) 

Literature Evaluation: Children

Paradoxical reactions to benzodiazepines in children have been described in both case reports and in clinical trials involving midazolam. Table 2 [18,19,20,21,22] summarizes these findings.

A randomized, double-blind, placebo-controlled study assessed the efficacy of rectal midazolam for sedation in children undergoing dental surgery.[18] Participants were 80 healthy children, aged 2-7 years. Exclusion criteria were past hypersensitivity to benzodiazepines, current treatment with psychotropic agents, and diagnosis of myasthenia gravis. Each child was assigned to one of four treatment groups: placebo or rectal midazolam 0.25 mg/kg, 0.35 mg/kg, or 0.45 mg/kg. The drug was administered 30 minutes before the procedure. Vital signs, hemodynamic parameters, sedation, and pain levels were assessed at various intervals during surgery. Adverse effects were observed in 14 children in the groups receiving the highest doses of midazolam: 0.35 mg/kg and 0.45 mg/kg. Of these reactions, agitation, restlessness, and excitement were the most common. This study illustrates that paradoxical reactions to benzodiazepines in children may be dose related.

A case report described unusual behavior in a healthy 26-month-old girl who was brought to the emergency department after suffering a facial dog bite.[19] Before suture placement, the girl was playful yet anxious. Therefore, oral midazolam 0.5 mg/kg was administered and the sutures were placed uneventfully. During the procedure, vital signs were monitored and remained within normal limits. After discharge to home, the child became agitated and upset. Her parents brought her back to the emergency department to be reevaluated. Mental evaluation showed no evidence of head trauma, but the child remained in the fetal position, crying and screaming. She calmed and ceased crying after receiving morphine sulfate 0.1 mg/kg intravenously; after leaving the hospital she was playful and interactive. The authors of the report eliminated other possible causes of delirium in this patient, such as administration of other drugs or the possibility of an illicit drug ingestion.

In another case report, flumazenil was effective in reversing a paradoxical reaction in a normally quiet 11-year-old boy with nephrotic syndrome.[20] After ingesting oral midazolam 17.5 mg, the child experienced an abrupt change in behavior. During this episode, the boy became uncontrollable and confused and started screaming and kicking. The behaviors ceased after he received flumazenil 0.15 mg intravenously; the boy had no recollection of his adverse reaction. This case suggests that flumazenil may be an effective option for treating paradoxical reactions to benzodiazepines in children.

The frequency of paradoxical reactions to benzodiazepines in children requiring emergent endoscopy was prospectively evaluated in a 48-month study.[21] Of the 2617 children aged 1-17 years who received midazolam and meperidine before undergoing endoscopy, 36 children (1.4%) experienced paradoxical reactions, including tachycardia, inconsolable crying, restlessness with agitation, dysphoria, and disorientation. The total doses of meperidine and midazolam were 1-2 mg/kg and 0.1-0.5 mg/kg, respectively, and the mean time to onset of adverse effect was 17 minutes after administration of the sedatives. Reversal of the behaviors was successful with intravenous physostigmine (dose not reported, six patients) and intravenous flumazenil 0.01 mg/kg (30 patients). The onset and duration of these reactions and time to recovery did not correlate with patients' age. Of note, three of the 36 patients received meperidine alone for additional endoscopy procedures; there were no behavioral changes or adverse effects reported. Limitations of this study include its nonrandomized design as well as the use of both agents for sedation. However, based on previous reports, the authors concluded that midazolam is the more likely cause of the paradoxical reactions.

A research group described their experiences with midazolam for conscious sedation in 222 children aged 2.5-18 years undergoing endoscopic procedures.[22] Twenty-five of the children experienced a paradoxical reaction after receiving meperidine 1-2 mg/kg and midazolam 0.1-0.3 mg/kg. The reactions were classified as agitation, refusing intubation, head shaking, restlessness, and tachycardia. In 23 instances the procedures were continued despite these behaviors. In two cases, the procedures were stopped but resumed after administration of flumazenil 0.01 mg/kg intravenously.