WORSENING HEPATIC ENCEPHALOPATHY
SECONDARY TO ZOLPIDEM
Adam Clark

OBJECTIVE: To report a case of worsening hepatic encephalopathy secondary to ingestion of zolpidem.

CASE SUMMARY: A 41-year-old white man had postoperative complications 11 months after liver transplantation. Complications included narrowing of the choledochal anastomosis site, cyclosporine nephrotoxicity, and recurrent hepatitis C. Approximately seven months after transplantation, the patient experienced elevations in liver enzyme concentrations, lethargy, ascites, fever, chills, and nausea. Examination of a biopsy sample revealed recurrent hepatitis C. The patient's condition did not resolve despite administration of interferon alfa-2b, and his mental status began to deteriorate secondary to hepatic encephalopathy. One day before admission, the patient was given zolpidem 5 mg for sleep; one hour after taking zolpidem, he awoke in a stupor and was not oriented to place or time. When he became increasingly incoherent and verbally abusive, family members brought him to the emergency department. Although the patient exhibited mental status deterioration before receiving zolpidem, considering the strong temporal relationship, his rapidly worsening state may be attributable to the drug. The patient subsequently required a second liver transplant in addition to a kidney transplant as a result of cyclosporine nephrotoxicity. The patient was not rechallenged with zolpidem nor given flumazenil.

DISCUSSION: One pathophysiologic explanation for hepatic encephalopathy implicates endogenously produced benzodiazepine agonists. In patients with portal–systemic shunting, psychoactive compounds escape metabolism and are subsequently free to cross the blood–brain barrier. This mechanism is supported by reports of successful treatment of patients who have encephalopathy with flumazenil, a benzodiazepine antagonist. Hence, it follows that a benzodiazepine agonist could potentially exacerbate encephalopathic symptomatology. Zolpidem, although structurally unrelated to benzodiazepines, is a benzodiazepine agonist that binds preferentially to the benzodiazepine₁w₁ subtype of the g-aminobutyric acid (GABA_A) receptor complex. Therefore, administration of zolpidem to patients with encephalopathy may worsen the condition by contributing to the accumulation of benzodiazepine agonists within the central nervous system.

CONCLUSIONS: Although this patient's worsening mental status could be explained by a naturally evolving encephalopathic state, it is possible that zolpidem exacerbated his decline. Existing evidence supports this view. First, an endogenously produced, benzodiazepine-related mechanism of hepatic encephalopathy is described in the literature. Second, benzodiazepine-like substances have been detected in the serum of patients with encephalopathy who have not received benzodiazepine therapy. Finally, clinical evidence supports the use of flumazenil in encephalopathic patients. Thus, it is likely that administration of zolpidem hastened the mental decline of this patient.

J Pharm Technol 1999;15:139-41.