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Zolpidem and anoxic encephalopathy: Prolonged treatment response

Kenneth R. Kaufman, MD, MRCPsych

Departments of Psychiatry, Neurology, Anesthesiology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

Issa P. Bagayogo, MD, PhD

Department of Psychiatry, Office of Global Health, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

Irving H. Kaufman, MD

Department of Family Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

Arvind Das, MD

Department of Internal Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

KEYWORDS: zolpidem, anoxic encephalopathy, paradoxical arousal, dosing strategy, longitudinal treatment, health care economics and ethics



Zolpidem, an omega-1-specific indirect γ-aminobutyric acid agonist, is a nonbenzodiazepine sedative hypnotic approved by the FDA and the European Medicines Agency for treating insomnia.1,2 Recent literature reports the paradoxical arousal effect of low-dose zolpidem in patients suffering from vegetative states and anoxic brain injuries.2-7 Further, zolpidem has been therapeutic in neurologic disorders including Parkinson’s disease, spinocerebellar ataxia, aphasia, spasticity, and dementia.8-12 Because of zolpidem’s short half-life (2.4 hours), patients return to a vegetative state or have recurrent neurologic symptoms after 4 hours, leading to patient-specific dosing strategies to maintain arousal.2-4,9 These reports are limited, and often reflect immediate response. To our knowledge, only 1 case series (3 patients) reported prolonged effect.2 This case report further defines the prolonged effects of zolpidem in treating anoxic encephalopathy with a patient-specific dosing strategy. Ethical and health care economic issues also are addressed.

Case report

Mr. N, age 25, has polysubstance dependence and bipolar disorder (BD) diagnosed by DSM-IV criteria.13 He experienced anoxic encephalopathy after a “speedball” overdose (IV heroin and cocaine) and his hospital course was complicated by rhabdomyolysis and myocardial infarction. Sequelae included paraparesis, limited verbal responsiveness, dysphagia, drooling, and inability to read. These features persisted for 4 years until Mr. N’s primary care physician attempted to organize the patient’s sleep cycle with zolpidem, 10 mg, after a failed modafinil trial. Mr. N experienced significant arousal with zolpidem, and gained the ability to eat foods alone, dial a telephone (he spoke with his parents for the first time in 4 years after his first zolpidem dose and continues to communicate with his family by telephone), and walk with a walker. However, 4 hours after the zolpidem dose, Mr. N returned to baseline. Zolpidem was titrated to 10 mg, 3 times a day, with prolonged treatment response (>9 years) consisting of significant verbal interaction, spontaneous speech, improved long-term memory although he had deficits in short-term recall, independent eating, and the ability to read signs, walk with assistance, use a computer, and play Wii games. Mr. N’s family reported that after he took zolpidem, 20 mg as a single dose, he walked unassisted with a steady gait. Mr. N has shown marked improvement in quality of life after initiating zolpidem, and has not required long-term placement in a health care institution.

Mr. N’s BD is stable on lamotrigine, 25 mg, 3 times a day, and citalopram, 5 mg/d. Mr. N is maintained on amantadine, 250 mg/d. His polysubstance dependence is in chronic remission.


This case supports the arousing effect of zolpidem in patients with anoxic encephalopathy, initiation of effective treatment an extended time (4 years) after brain insult, and, uniquely, prolonged treatment response (>9 years) without habituation. Although low-dose zolpidem has been reported to be effective in these patients, Mr. N’s family reported that after he took zolpidem, 20 mg, as a single dose, he walked unassisted, but with a 10-mg dose he required assistance. The short half-life of zolpidem permitted case-controlled, on-off-on observation with 3-times-daily dosing for maximal efficacy. These findings are consistent with the literature; in Parkinson’s disease, improvement in different symptoms with zolpidem may be time- and dose-dependent.9

In our clinical case, no interventions were pursued to determine mechanism of action for zolpidem arousal; however, a research case report combining neuroimaging (ie, single photon emission tomography, magnetic resonance spectroscopy, MRI) and clinical neurophysiology (magnetoencephalography) addressed the mechanism by which zolpidem improves neurologic deficits in a patient after a stroke, which is through increased perfusion and suppression of pathological slow wave activity.5

As noted in Mr. N’s case and the literature cited, zolpidem may be effective for several neurologic conditions2-12; however, the use of chronic and potentially high-dose zolpidem has 2 key considerations: 1) the possibility of drug dependence, especially in patients with a history of drug abuse, and 2) the need to consider potential withdrawal from chronic zolpidem use.14-16

Zolpidem arousal from anoxic encephalopathy and vegetative states raises an unusual but important ethical issue: can a health care proxy terminate life support based on a living will before the patient has been challenged with zolpidem? A twist in our current health care climate concerns the refusal by some insurance companies to authorize payment for zolpidem in 3 times a day or 4 times a day dosing when treating anoxic encephalopathy and other neurologic conditions (even though such treatment may significantly reduce overall health care costs and decrease the need for long-term placement in a health care institution). In Mr. N’s case, this problem required several insurance appeals. Although cost-effectiveness is beyond the scope of this article, budgetary impact analysis from the perspective of the patient, the family, and the health care system is warranted. In 1994, the estimated total cost for treating American patients in persistent vegetative states was between $1 and $7 billion annually.17

Limitations to Mr. N’s case include:

  • As a single case, our findings cannot be generalized.

  • Zolpidem blood levels were not assessed so that a specific dose-concentration response cannot be determined.

  • Neither functional neuroimaging nor clinical neurophysiologic studies were performed that could have associated specific improvement in symptoms with dose and physiologic response.

  • Pre/post/serial neuropsychological testing was not performed, which would have validated improvements noted by clinicians and permitted assessment of longitudinal changes.

  • Alternative dosing schedules—such as 5 to 10 mg every 6 hours—and the use of zolpidem extended-release formulations were not assessed.

  • Mr. N was maintained on lamotrigine and amantadine, which have been reported to promote behavioral responsiveness in patients with disorders of consciousness, possibly confounding our findings.18,19

Zolpidem may be an effective treatment for anoxic encephalopathy. In this case, maximum zolpidem treatment response was noted with 3-times-daily dosing with efficacy persisting for >9 years. Controlled research is needed to further elucidate the efficacy of zolpidem for treating anoxic encephalopathy, vegetative states, and other neurologic disorders with emphasis on dose-dependent response, dosing regimen, ethics, health care economics, and mechanism of action.

DISCLOSURE: The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

ACKNOWLEDGEMENT: Presented in part at the Third Meeting of the West European Societies of Biological Psychiatry, Berlin, Germany, June 2-4, 2010.


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CORRESPONDENCE: Kenneth R. Kaufman, MD, Departments of Psychiatry, Neurology, and Anesthesiology, Rutgers Robert Wood Johnson Medical School, 125 Paterson Street, Suite #2200, New Brunswick, NJ 08901, USA; E-MAIL: kaufmakr@rwjms.rutgers.edu; adamskaufman@verizon.net