Paradoxical Reactions to Benzodiazepines

Abstract and Introduction

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.^[5,6,7] 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]

Table 1. Summary of Paradoxical Reactions in Adults ^{[2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]}
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

Table 1. Summary of Paradoxical Reactions in Adults ^{[2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17]}

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

No. of Patients	Age (yrs)	Sex	Drug, Maximum Dose	Treatment	Outcome
14^[18]	2-7	NR	Midazolam^a 0.35 mg/kg (n=4) Midazolam^a 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

Paradoxical Reactions to Benzodiazepines: Literature Review and Treatment Options

Abstract and Introduction

Abstract

Introduction

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Email This

Feedback