Zolpidem for postanoxic spasticity.

Abstract: A 28-year-old male sustained anoxic brain damage following aborted cardiac arrest, and subsequently developed severe muscular rigidity and spasticity involving all extremities. The spasticity was refractory to the standard regimens used for spastic hypertonia. Zolpidem dramatically inhibited muscular rigidity, spasticity, and dystonic posturing in a dose-dependent manner, resulting in a sustained improvement of his global performance over four years. The authors postulate a central mechanism of action by selective inhibition of GABAergic inhibitory neurons, and suggest a controlled clinical study to investigate the potential efficacy of zolpidem in relieving spasticity related to postanoxic brain injury.

Key Words: encephalopathy, [gamma]-aminobutyric acid, spasticity, zolpidem

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Severe spasticity produces disability by interfering with posture, motor capacity, and activities of daily living. An important part of treatment includes pharmacotherapy. (1) This approach relies on drugs that decrease spinal reflex excitability by reducing the release of excitatory neurotransmitters, or by potentiating the activity of inhibitory inputs. (1-3) Zolpidem is a short-acting hypnotic GABAergic compound that has been shown to improve rigidity and spasticity in progressive supranuclear palsy and in Parkinson disease. (2-6) This has been attributed to a selective agonist effect on the benzodiazepine subtype receptor BZ([.sub.1]) in the basal ganglia, and in particular in the ventral globus pallidus and the substantia nigra pars reticulata. (5)

Case Reports

We observed a 28-year-old Native American male who sustained anoxic brain damage following aborted cardiac arrest. He developed severe muscular rigidity and spasticity involving all extremities. Concurrent flexor and extensor posturing was evident with difficulty in bringing any of the limbs into a neutral position. Electroencephalogram showed muscle spasm artifacts. He became completely dependent for his activities of daily living. The spasticity was refractory to the standard regimens used for spastic hypertonia, (1-4) such as baclofen and benzodiazepines, and it did not respond to multiple injections of Clostridium botulinum toxin (Botox, Allergan Inc., Irvine, CA) or phenol. Botox was not satisfactory due to widespread involvement of spasticity, thus requiring large doses and multiple injection sites. Zolpidem given at 10 mg orally every four hours dramatically inhibited muscular rigidity, spasticity, and dystonic posturing. Beneficial effects were detectable 40 to 60 minutes after administration, and lasted 2 to 4 hours. The effect of zolpidem was dose-dependent. Adverse effects, if any, were mild drowsiness and mild postural instability observed only at doses above 10 mg. We have since followed this patient for approximately four years. His spasticity and global performance has markedly improved, and he has been maintained effectively at a dose of 2.5 mg taken orally every four hours without evidence of either toxicity or tolerance.

Discussion

A severely debilitating spasticity caused by anoxic encephalopathy in this patient was clearly resistant to the standard pharmacological treatment options. (1-4) Zolpidem produced a remarkable improvement in motor capacity, posture, and performance of the activities of daily living. We postulate a central mechanism of action by selective inhibition of GABAergic inhibitory neurons. Zolpidem-mediated inhibition of GABAergic neurons in the globus pallidus and substantia nigra pars reticulata has been suggested as a possible mechanism by which it may activate the thalamus and cerebral cortex. (4-6)

Conclusion

A controlled clinical study to examine the potential efficacy of zolpidem in relieving spasticity related to postanoxic encephalopathy should be considered.

First have something to say, say it as briefly as possible, and stop
when you have said it.
--John Shaw Billings

Accepted November 12, 2003.

References

1. Abbruzzese G. The medical management of spasticity. Eur J Neurol 2002;suppl 1:30-34; discussion 53-61.

2. Elovic E. Principles of pharmaceutical management of spastic hypertonia. Phys Med Rehabil Clin N Am 2001;Nov;12:793-816.

3. Francisco GE, Kothari S, Huls C. GABA agonists and gabapentin for spastic hypertonia. Phys Med Rehabil Clin N Am 2001;Nov;12:875-888.

4. Daniele A, Albanese A, Gainotti G, et al. Zolpidem in Parkinson's disease. Lancet 1997;349:1222-1223.

5. Langer SZ, Arbilla S, Scatton BV, et al. Receptors involved in the mechanism of action of zolpidem, in Sauvanet JP, Langer SZ, Morselli PL (eds): Imidazopyridines in sleep disorders: a novel experimental therapeutic approach. New York, Raven Press, 1988, pp 55-70.

6. Daniele A, Moro E, Bentivoglio AR. Zolpidem in progressive supranuclear palsy. New Engl J Med 1999;341:543-544.

RELATED ARTICLE: Key Points

* Zolpidem inhibited muscular rigidity, spasticity, and dystonic posturing.

* Zolpidem resulted in a sustained improvement of the patient's global performance.

* A central mechanism of action by selective inhibition of GABAergic neurons is postulated.

Farhad F. Shadan, MD, PHD, J. Steven Poceta, MD, and Lawrence E. Kline, DO, FACP 

From the Divisions of Molecular and Experimental Medicine, Hospital Medicine, Neurology, and Chest Medicine, Scripps Clinic Sleep Center, La Jolla, CA.

Support for this report was provided by Scripps Clinic Academic Affairs.

Reprint requests to Farhad F. Shadan, MD, PhD, 403C, 10666 North Torrey Pines Road, Scripps Clinic, La Jolla, CA 92037. E-mail: [e-mail]