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Resident and Fellow Corner

Paradoxical Reactions from Benzodiazepines – A Review of the Literature

Dr. BurgerBy Becky Burger, MD
Section Editor

Background
Paradoxical reactions have been reported following the administration of benzodiazepines.  The first publication of such phenomena was published in 1960 by Ingram and Timbury regarding paradoxical reaction after administration of chlordiazepoxide.3   In defining paradoxical reactions, Hall and Zisook referred to DiMascio & Shader's definition of behavioral toxicity:  pharmacological reactions to a drug that alter "perceptual and cognitive functions, psychomotor performance, motivation, mood, interpersonal relationships or intrapsychic processes of an individual to the degree that they interfere with, or limit the capacity of the individual to function ... or constitute a hazard to his physical well-being.”1 They characterized paradoxical reactions as appearing abruptly or insidiously in patients not thought to be predisposed to behavioral conditions.1 They further categorized paradoxical reactions as one of the following:

  1. Depression,
  2. Gross behavioral disturbance or
  3. Hostility, aggression and rage.1 Most publications cite an incidence for paradoxical reactions following benzodiazepine administration of approximately one percent.

Sedation from benzodiazepines is mediated by brainstem GABA receptors. Benzodiazepines also act on GABA receptors located in the septum, amygdala and hippocampus, areas that are related to emotional regulation.  Catecholamine uptake is down-regulated, serotonin metabolism is slowed and acetylcholine availability is modified by benzodiazepines as well.  All of these effects of benzodiazepines are thought to be related to its ability to produce paradoxical agitation but also have led to investigations of ways to combat the paradoxical agitation.  The majority of case reports and studies of paradoxical agitation have been in adults, however most cite extremes of age as a risk factor for a paradoxical reaction.4,7  Other risk factors reported include history of mental illness, alcohol abuse, administration of higher doses of benzodiazepines, and being female (though newer studies show equal distribution among males and females).4,6,7

Treatment

1) Physostigmine
The first drug to be studied to treat a paradoxical reaction from a benzodiazepine was physostigmine in the late 1970s. It was thought that central anti-cholinergic symptoms such as coma, delirium and hallucinations were related to the paradoxical reaction and therefore physostigmine as an acetylcholinesterase inhibitor could reverse the paradoxical reaction.11  

Physostigmine was only partially successful in most cases and led to significant bradycardia, as well as nausea, vomiting and dyspnea, causing it to lose favor.4 It is no longer recommended for reversal of paradoxical reactions.

2) Flumazenil
Flumazenil is a GABA receptor antagonist and competitively inhibits benzodiazepines. It has been show to reverse paradoxical reactions from benzodiazepines.9 Massanari studied 2617 pediatric patients undergoing endoscopy using midazolam and meperidine and found that 36 (1.4%) experienced a paradoxical reaction with a mean onset time of 17 minutes (+/- 14 minutes).6  Thirty of these 36 patients received flumazenil (0.01mg/kg) with a mean recovery time of 14 minutes (+/-12 minutes).6  

The total dose for reversing paradoxical agitation reported in the literature has ranged from is 0.1-0.5 mg IV for adults with an onset of action of 1-2 minutes and duration of 0.7-1.3 hours.8  For pediatric patients, an initial dose of 0.01 mg/kg (up to 0.2mg)  with subsequent doses of 0.1mg/kg (up to 0.2mg) up to a total of 0.05mg/kg or 1mg maximum has been shown to be effective.5  Subsequent doses of flumazenil may be necessary for longer acting benzodiazepines if symptoms of a paradoxical reaction recur.  Adult patients have reported amnesia to paradoxical reactions reversed with flumazenil, therefore it appears the amnestic property of benzodiazepines are maintained despite flumazenil use.7  Flumazenil should be used with caution in patients with a seizure history as it can precipitate seizures and in patients with heart disease as it can also cause cardiac arrhythmia.4 

3) Caffeine
Given the similarity of paradoxical reactions to symptoms of ADHD, Rubin et. al. studied oral versus intravenous caffeine use for treatment of paradoxical reaction from benzodiazepine use.10  Their paradoxical reaction rate was 1.8%.10  They found that only intravenous caffeine was effective at treating a paradoxical reaction with a mean recovery time of 33 minutes (+/- 23 minutes).10

4) Haloperidol
Khan and Lustik published a case report of a 50 year-old man with a myocardial infarction who received two doses of midazolam prior to coronary artery bypass graft surgery and developed a paradoxical reaction.4 They decided not to use flumazenil due to concern for increase in left ventricular end diastolic pressure.4  Haloperidol can reverse the paradoxical reaction, though its mechanism is unknown, and it causes further sedation which can allow the procedure to continue.  Use Haloperidol with caution as it can cause extra-pyramidal side effects, prolonged QT interval and torsades de pointes.4

Conclusion
Paradoxical reactions to benzodiazepines are rare and unpredictable.  They are more common in extremes of age and in patients with pre-existing mental illness or alcohol abuse who receive a high dose of benzodiazepine.  Paradoxical reactions can be treated with flumazenil 0.1-0.5mg in adults or for children 0.01-0.05mg/kg (max 1mg total).  However, use of flumazenil or other agents is somewhat controversial due to the self-limited, relatively brief duration of most paradoxical reactions, especially those that are due to short acting benzodiazepines such as midazolam. Caffeine (IV) may be an alternative treatment option for severe paradoxical reactions from benzodiazepines in children.  There is insufficient evidence for use of haloperidol given its potential toxicity and long duration of action.  Future areas of research could examine predictors, prevention strategies, and optimal treatment of paradoxical reactions.

References

  1. Hall RC, Zisook S. Paradoxical Reactions to Benzodiazepines. BrJClinPharmacol. 1981, 11: 99S-104S.
  2. Heller M, Hayes CM, Krejei NC.  Paradoxical Reaction to Midazolam Reversed with Flumazenil in a Patient Undergoing Tumescent Liposuction. Dermatol Surg.  2009, 35(7): 1144-6.
  3. Ingram IM, Timbry GD.  Side Effects of Librium.  Lancet.  1960; 2: 766-775.
  4. Khan L, Lustik SJ. Treatment of a Paradoxical Reaction to Midazolam with Haloperidol. Anesth Analg.  1997, 85: 213-5.
  5. Mancuso CE, Tanzi MG, Gabay M. Paradoxical Reactions to Benzodiazepines: Literature Review and Treatment Options.  Pharmacotherapy.  2004, 24(9): 1177-85.
  6. Massanari M, Novitsky J, Reinstein LJ.  Paradoxical Reactions in Children Associated with Midazolam Use During Endoscopy.  Clin Padiatr. 1997 Dec, 36:681-4.
  7. McKenzie WS, Rosenberg M.  Paradoxical Reaction Following Administration of a Benzodiazepine. J Oral Maxillofac Surg. 2010, 68: 3034-6.
  8. Robin C, Trieger N. Paradoxical Reactions to Benzodiazepines in IV Sedation: A Report of 2 Cases and a Review of the Literature.  Anesth Prog. 2002, 49:128-32.
  9. Rodrigo CR. Flumazenil Reverses Paradoxical Reactions with Midazolam. Anesth Prog. 1991, 38:65-68.
  10.  Rubin JT, et. al. Oral and Intravenous Caffeine for Treatment of Children with Post-Sedation Paradoxical Hyperactivity.  Pediatric Radiol.  2004, 34: 980-4.
  11. Van der Bijl P, Roelofse JA. Disinhibitory Reactions to Benzodiazepines: A Review. J Oral Maxillofac Surg. 1991, 49: 519-523.
  12. Weinbroum AA, Szold O, Ogorek D, Flaishon R.  The Midazolam-Induced Paradox Phenomenon is reversible by Flumazenil.  Epidemiology, Patient Characteristics and Review of the Literature.  Europe J Anaesthesiol. 2001 Dec, 18(12): 789-97.

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