Journal of Pain and Symptom Management
Volume 36, Issue 5 , Pages e5-e6, November 2008

Midazolam-Induced Extrapyramidal Side Effects

Division of Hematology, Oncology, Palliative Care, Mayo Clinic, Scottsdale, Arizona, USA

published online 27 August 2008.

Article Outline

 

To the Editor:

In response to the letter by Brown and colleagues,1 I would like to comment on the extrapyramidal side effects (EPS) induced by midazolam hydrochloride and the possible mechanisms behind their production. Midazolam is a short-acting, water-soluble benzodiazepine used for induction and maintenance of general anesthesia and for sedation in palliative care. Its use has been associated with several types of untoward reactions, including agitation, mental confusion, and uncooperativeness. Reported motor disturbances include dystonic extrapyramidal reactions,2 muscle tremor,3 myoclonus,4 athetosis,3 and laryngospasm.5 In the case described by Brown et al., EPS occurred after administration of midazolam 5mg over 24 hours via syringe driver.

Several reports suggest that these adverse motor effects can be reversed with the γ-aminobutyric acid (GABA) antagonist flumazenil.6 GABA is the major inhibitory neurotransmitter in the central nervous system (CNS) of mammals. Two major classes of GABA receptors have been identified in the CNS: 1) GABAA receptors, which are ligand-gated chloride channels that mediate the fast hyperpolarizing actions of GABA and 2) G-protein-coupled GABAB receptors.7 Research has led to the recognition of GABAA diversity throughout the CNS. Seven subunit families comprising at least 18 subunits in the CNS (α1–6, β1–3, γ1–3, δ,ɛ θ, ρ1–3) indicate the extraordinary structural heterogeneity of the GABAA receptors.7

Known clinical correlations between GABA receptor subtypes and the clinical effects of benzodiazepines include the relationship of α1GABAA receptors with sedation and of α2GABAA receptors with the mediation of anxiolysis. Motoric phenomena may be another manifestation of the effect of GABA receptor subtypes, in this case, α3-containing GABAA receptors. The dopaminergic system is under GABAergic inhibitory control mainly by α3-containing GABAA receptors.8 In fact, although it is common to link a basal ganglia disease, such as Parkinson's disease, to dopamine deficiency, Parkinson's disease is also a disease of GABA. GABA agonists, such as benzodiazepines, worsen motor function in patients with basal ganglia disorders and inhibit cell firing in the substantia nigra. In both open-label and controlled trials, GABA antagonists, such as flumazenil, have been shown to improve movement in patients with Parkinson's disease.9, 10 Possible mechanisms of flumazenil activity in Parkinson's disease include: 1) inhibition of GABA effects to the pediculopontine nucleus and thalamus, which improves output from the basal ganglia; 2) an increase in dopamine turnover and release; 3) direct stimulation of the cortex; and 4) hypothetically, an increase in dopamine receptor density.

Midazolam is a potent ligand for GABA receptors and a strong α3-containing GABAA receptor agonist; similar to other benzodiazepines, it inhibits substantia nigra firing, resulting in EPS.11 Brown et al. are correct in linking the adverse EPS of GABA and midazolam to basal ganglia activity. The recognition of EPS might prompt us to consider altering the dose of midazolam or using flumazenil to reverse the effect of midazolam that results in EPS.

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References 

  1. Brown DJF, McArthur D, Moulsdale H. Subcutaneous midazolam as a cause of extrapyramidal side effects in a patient with prostate cancer. J Pain Symptom Manage. 2007;34(2):111–113
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  8. Fritschy JM, Mohler H. GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J Comp Neurol. 1995;359(1):154–194
  9. Ondo WG, Hunter C. Flumazenil, a GABA antagonist, may improve features of Parkinson's disease. Mov Disord. 2003;18(6):683–685
  10. Ondo WG, Silay YS. Intravenous flumazenil for Parkinson's disease: a single dose, double blind, placebo controlled, cross-over trial. Mov Disord. 2006;21(10):1614–1617
  11. Kilpatrick GJ, McIntyre MS, Cox RF, et al. CNS 7056: a novel ultra-short-acting Benzodiazepine. Anesthesiology. 2007;107(1):60–66

PII: S0885-3924(08)00437-5

doi:10.1016/j.jpainsymman.2008.06.002

Journal of Pain and Symptom Management
Volume 36, Issue 5 , Pages e5-e6, November 2008

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