“I Did What?” Zolpidem and the Courts
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REGULAR ARTICLE “I Did What?” Zolpidem and the Courts Christopher Daley, MD, Dale E. McNiel, PhD, and Rene´e L. Binder, MD Zolpidem is a widely prescribed nonbenzodiazepine hypnotic medication available in the United States since 1992. Attention has been drawn recently to its potential to cause sleep-related, complex behaviors such as sleepwalking and sleep driving. These automatic behaviors have led to a deluge of legal claims. To the authors’ knowledge, this is the first review in the forensic literature of the legal ramifications of zolpidem. In this article, the medical literature will be reviewed to explore the current understanding of zolpidem’s specific psychopharmacology. Case law will be explored to determine how the courts have handled the claims surrounding sleep-related, complex behaviors alleged to be caused by zolpidem. Finally, a summary of recommendations will be provided for forensic psychiatrists who are asked to be experts in these cases. J Am Acad Psychiatry Law 39:535–42, 2011 A young adult with no prior history of psychiatric bien by the French company Sanofi-Aventis. Am- illness used zolpidem once a week to fall asleep. One bien has been widely prescribed, ranking as the ninth night, she took a shower after her dose of zolpidem most prescribed medication in the United States in and went to sleep later than her usual time. She woke 2006, with more than 20 million prescriptions,2 up with a garden axe on her nightstand with no grossing nearly 2 billion dollars in sales3 that year memory of how it got there. Later she scrolled alone. In 2007, Ambien’s patent protection expired, through her text messages from the night before and and zolpidem became available as a generic medica- discovered a conversation that she had had with her tion manufactured by 13 different companies.4 Zol- partner after her shower. She had no memory of writ- pidem remains a top prescribed medication, with ing the text messages. In them, she described to her more than 28 million prescriptions written in 2008, partner hearing voices from her kitchen and seeing ranking as the 16th most prescribed generic medica- moving images out of the corner of her eye. Con- tion that year,5 with gross sales of over $700 million.6 cerned for her safety, she had gotten the axe from the These figures do not include the ongoing sales for tool shed and placed it on her nightstand. (This is a Ambien CR (controlled release), which had more composite description.) than 7 million prescriptions in 2008.7 Background Zolpidem is one of 13 hypnosedative medications approved by the FDA for treatment of insomnia,8 Zolpidem is an imidazopyridine hypnotic agent although by far it has been the most prescribed hyp- that is approved by the U.S. Food and Drug Admin- nosedative over the past decade. Its popularity is the istration (FDA) for the short-term treatment of in- 9 1 likely result of aggressive marketing and early re- somnia in the United States. It has been on the U.S. ports of low rates of daytime sedation and low abuse market since 1992, sold under the trade name Am- potential.10 However, postmarketing studies and case reports Dr. Daley is Health Sciences Assistant Clinical Professor, Dr. McNiel is Professor of Clinical Psychology, and Dr. Binder is Professor and began to show that zolpidem was associated with Interim Chair of Psychiatry, Department of Psychiatry, University of sleep-related, complex behaviors. These included California San Francisco, San Francisco, CA. Presented in part at the 41st annual meeting of The American Academy of Psychiatry and the sleep driving, sleep cooking, sleep eating, sleep con- Law, October 18–20, 2010, Tucson, Arizona. Address correspon- versations, and, rarely, sleep sex, generally accompa- dence to: Christopher Daley, MD, University of California San Fran- 8 cisco, San Francisco General Hospital, 1001 Potrero Avenue, Suite nied by anterograde amnesia for the event. As these 7M, San Francisco, CA 94110. E-mail: christopher.daley@ucsf .edu. behaviors became recognized, the FDA requested Disclosures of financial or other potential conflicts of interest: None. that specific warnings be put on all hypnosedative Volume 39, Number 4, 2011 535 Zolpidem and the Courts medications. This regulation took effect in March Medical Literature 200711 and was widely publicized. The sleep-related, complex behaviors associated Pharmacology with zolpidem have been the basis of two legal strat- Zolpidem is a member of a newer class of hyp- egies of interest in the forensic psychiatry arena: the nosedative drugs known as nonbenzodiazepine re- concept of “the pill made me do it ” and the sleep- ceptor agonists (NBRAs). NBRAs available in the walking defense. Discussions with colleagues con- United States include zolpidem, eszopiclone, and za- firm that many cases have arisen where a history of leplon. These medications bind to the same GABAA zolpidem treatment is used as a means to influence receptor complexes as the benzodiazepines, but are criminal or civil liability. Psychiatrists are frequently more selective to the ␣-1 receptor subtype.8,12 Six consulted by attorneys to assess the credibility of different ␣-receptor subtypes are currently known. these allegations. Agonism of the ␣-1 receptor type is believed to result To the authors’ knowledge, this is the first pub- in sedation and amnesia. The other receptor types lished review in the forensic psychiatry literature of have anxiolytic, anticonvulsant, and muscle relaxant the legal ramifications of zolpidem use. In this article, properties.8 The selectivity of zolpidem for the ␣-1 we review the medical literature that describes the subtype was believed to confer more specific sedative pharmacologic properties specific to zolpidem that properties along with less memory impairment and are associated with its potential to cause sleep-related, less residual daytime sedation, when compared with complex behaviors. We examine appellate level cases benzodiazepines.13 Clinical studies of zolpidem have involving zolpidem, to illustrate how the courts have shown significant impairments in memory and psy- applied the current scientific knowledge in contem- chomotor performances at one and four hours after porary cases. We use these examples to formulate ingestion.14 recommendations to assist experts who are consulted Zolpidem is rapidly absorbed in the gastrointesti- on such cases. nal tract, with onset of action of approximately 30 minutes and average peak concentration at 90 min- Methods utes. When compared with most hypnosedatives, it A PubMed search was conducted using the key- has a short half-life, two to three hours. It is metab- word zolpidem, along with complex behaviors, sleep- olized by hepatic metabolism by CYP 3A4 enzymes. walking, driving, eating, parasomnias, memory, fo- Drug-drug interactions are possible with medica- rensic, legal, amnesia, violence, and aggression. The tions that affect 3A4 enzymes such as ketoconazole.1 search returned dozens of articles. Representative ar- When compared with other hypnosedatives, zolpi- ticles were selected for review. The search included dem has a high binding affinity for the GABAA re- articles through January 2010. ceptor. This property is similar to that of triazolam,8 A Lexis-Nexis search was conducted using the key- a benzodiazepine that gained notoriety in the early word zolpidem or Ambien, along with involuntary 1990s because of its association with aberrant behav- intoxication, voluntary intoxication, criminal re- iors, culminating with its removal from European sponsibility, negligence, and malpractice. The search markets and a successful product liability suit in the included cases through January 2010. An additional United States (Freeman v. Upjohn Co., No. 89- Lexis-Nexis search was performed to explore benzo- 09648-A (Tex. Dist. Ct. 1992)).15 diazepines for comparison cases using the keywords benzodiazepine, clonazepam, Klonopin, diazepam, Adverse Drug Reactions Valium, alprazolam, Xanax, triazolam, or Ambien, The FDA’s prescribing information for zolpidem along with criminal responsibility, voluntary intoxi- lists a variety of abnormal thinking and behavioral cation, involuntary intoxication, negligence, and changes that can be associated with it and other hyp- malpractice. The Lexis-Nexis database contains fed- nosedatives. These include disinhibition (extrover- eral district court, appellate, and Supreme Court sion or aggressiveness that seem out of character), cases. The database also covers state and appellate depersonalization, hallucinations, and alterations in level and Supreme Court cases. State level district mood. Anterograde amnesia is also frequently re- court cases are not included in the database and were ported with zolpidem. Complex, parasomnia-like not reviewed for this article. behaviors have also been reported, such as driving, 536 The Journal of the American Academy of Psychiatry and the Law Daley, McNiel, and Binder talking, eating, and engaging in sex.1 Postmarketing Etiology studies of zolpidem found the incidence of complex It is helpful to conceptualize distinct mechanisms behaviors to be low, occurring in less than one per- to explain these abnormal behaviors. A patient may cent of cases, although a recent case series found it inadvertently (or intentionally) remain awake after higher, at five percent.16 The incidence of hallucina- taking zolpidem and begin to experience disinhibi- tions with zolpidem is reported to occur in less than tion or hallucinations with associated anterograde one percent of patients.1 Because these behaviors are amnesia. These patients typically retain the ability to accompanied by amnesia, it is likely that they are speak in short, coherent phrases.14 Le Bon and underreported. Neu24 reported a case of a woman who had a conver- sation with her boyfriend about their relationship 45 Sleep-Related Eating minutes after ingesting 10 mg of zolpidem. She had Sleep-related eating behavior has been associated no recollection of the conversation the next day. The with zolpidem. A case series from the Mayo Clinic boyfriend reported that she had a linear conversation described five patients who exhibited new-onset or with him, although she appeared disinhibited.