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) 

 

Abstract

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.

Introduction

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.[5-7] 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]

 
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Table 1.  Summary of Paradoxical Reactions in Adults [2-17]
Age (yrs),
Sex		 Daily Drug Dose Treatment Outcome Concomitant Psychiatric
or Medical Conditions
67, M[2] Midazolam 15 mg i.v. Flumazenil 0.5 mg i.v. Restlessness resolved Coronary artery disease, atrial fibrillation
66, M[2] Midazolam 3 mg i.v. Flumazenil 0.3 mg i.v. Restlessness resolved Obstructive lung disease, alcoholism
65, M[2] Midazolam 18 mg i.v. Flumazenil 0.4 mg i.v. Body rocking resolved None noted
73, M[2] Midazolam 6 mg i.v. Flumazenil 0.4 mg i.v. Restlessness resolved Diabetes mellitus
70, M[2] Midazolam 6 mg i.v. Flumazenil 0.3 mg i.v. Restlessness, vocalizations resolved Diabetes mellitus, coronary artery disease
76, M[2] Midazolam 9 mg i.v. Flumazenil 0.3 mg i.v. Restlessness, vocalizations resolved Diabetes mellitus, atrial fibrillation
28, M
(twins)[3] 		Midazolam 12 mg i.v. None Restlessness resolved and retained amnesia None noted
  Diazepam 10 mg p.o. None Restlessness resolved and retained amnesia None noted
22, F[4] Midazolam 18 mg i.v. None Abusive, belligerent behavior ceased within 24 hrs Alcoholism, anger management issues
32, F[5] Alprazolam 1.5 mg p.o. Discontinued Racing thoughts, increased energy resolved in 48-72 hrs Depressive bipolar disease
34, M[5] Alprazolam 3 mg p.o. Discontinued Racing thoughts, paranoid feelings resolved in 72 hrs Anxiety, panic attacks
32, F[5] Alprazolam 1 mg p.o. Discontinued Racing thoughts and insomnia resolved in 48 hours Panic attacks
37, M[6] Clonazepam 12 mg p.o. Discontinued Aggressive behavior ceased Bipolar affective disorder
25, M[6] Clonazepam 4.5 mg p.o. Discontinued Hyperactivity, belligerence ceased Bipolar affective disorder
19, M[6] Clonazepam 4 mg p.o. Discontinued Agitation ceased Borderline personality disorder
31, M[7] Midazolam 5 mg i.v. Sodium amobarbital
200 mg i.m.		 Combative, verbally threatening behavior ceased Anger management issues
22, F[8] Lorazepam 3 mg p.o. Discontinued Hostile behavior resolved Phobia of elevators and escalators
28, F[9] Diazepam 20 mg p.o. Discontinued Improvement of hostile, physical abuse in 48-72 hrs Depression, anxiety
30, F[10] Temazepam 30 mg p.o. at bedtime Discontinued Anger and enraged behavior ceased Manic-depression
30, M[10] Temazepam 30 mg p.o. at bedtime Discontinued Anger and agitation resolved, no recollection of events Chronic insomnia
37, M[10] Temazepam 30 mg p.o. at bedtime Discontinued Anger resolved Schizophrenia
39, F[10] Temazepam 15-30 mg p.o. at bedtime Discontinued Agitation and restlessness resolved Obsessive-compulsive symptoms
75, F[10] Triazolam 0.5 mg p.o. every other night Discontinued Agitation and nervousness resolved Chronic insomnia
40, M[10] Triazolam 1-1.5 mg p.o. at bedtime Discontinued Anger, panic, visual hallucinations ceased Chronic insomnia
60, F[10] Triazolam 0.5-1 mg p.o. at bedtime Discontinued Anger and argumentative behaviors ceased Chronic insomnia
29, F[10] Triazolam 0.5 mg p.o. at bedtime Discontinued Anxiety and agitation resolved Chronic insomnia
64, F[10] Triazolam 0.5 mg p.o. at bedtime Discontinued Bizarre behaviors ceased Chronic insomnia
56, F[10] Triazolam 0.5 mg p.o. at bedtime Discontinued Agitation ceased over 2 days Chronic insomnia
37, M[11] Clonazepam 8 mg p.o. Discontinued Irritability, hyperactivity ceased Manic episodes, panic attacks
50, M[12] Midazolam 6 mg i.v. Haloperidol 10 mg i.v. Patient calmed, retained amnesia Coronary artery disease
49, F[13] Midazolam 12 mg i.v. Flumazenil 0.5 mg i.v. Aggressive behavior ceased, retained amnesia None noted
71, M[14] Midazolam 4 mg i.v. Flumazenil 0.2 mg i.v. Patient calmed, retained amnesia Anger management issues
27, M[15] Midazolam 7 mg i.v. Flumazenil 0.3 mg i.v. Patient calmed, retained amnesia None noted
62, M[16] Midazolam 5 mg i.v. Flumazenil 0.5 mg i.v. Patient calmed, retained amnesia Alcoholism
58, F[16] Midazolam 7.5 mg i.v. Flumazenil 0.5 mg i.v. Patient calmed, retained amnesia Alcoholism
26, M[16] Midazolam 10 mg i.v. Flumazenil 0.5 mg i.v. Patient calmed, retained amnesia None noted
19, F[17] Midazolam 5 mg i.v. Flumazenil 0.2 mg i.v. Crying ceased, retained amnesia None noted
21, F[17] Midazolam 7 mg i.v. Flumazenil 0.4 mg i.v. Crying ceased, retained amnesia None noted
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Table 2.  Summary of Paradoxical Reactions in Pediatric Patients [18-22]
No. of
Patients		 Age
(yrs)		 Sex Drug, Maximum Dose Treatment Outcome
14[18] 2-7 NR Midazolama 0.35 mg/kg (n=4)
Midazolama 0.45 mg/kg (n=10)		 None Agitation, restlessness resolved
1[19] 26 mos F Midazolam 0.5 mg/kg p.o. Morphine sulfate 0.1 mg/kg i.v. Calmed, ceased crying
1[20] 11 M Midazolam 17.5 mg p.o. Flumazenil 0.15 mg i.v. Confusion, screaming ceased, amnesia retained
36[21] 1-17 19 M
17 F		 Midazolam 0.1-0.5 mg/kg i.v.
Meperidine 1-2 mg/kg i.v.		 Flumazenil 0.01 mg/kg i.v. (n=30)
Physostigmine i.v. (dose unknown, n=6)		 Inconsolable crying, restlessness resolved
25[22] 2.5-18 NR Midazolam 0.1-0.3 mg/kg i.v.
Meperidine 1-2 mg/kg i.v.		 Flumazenil 0.01 mg/kg i.v. i.v. (n=2) Agitation resolved

 

NR = not reported.
aRoute of administration was per rectum.

 

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Authors and Disclosures

Carissa E. Mancuso, PharmD, Maria G. Tanzi, PharmD, and Michael Gabay, PharmD, Department of Pharmacy Practice, College of Pharmacy, University of Illinois, Chicago, Illinois

 

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