ORIGINAL ARTICLE
Complex Behaviors Related to Zolpidem: An Analysis of Published Clinical Cases
from Taiwan
Ana Isabel Wu-Chou
1, Winston W. Shen
1,2 *1Department of Psychiatry, Taipei Medical University-Wan Fang Medical Center, Taipei, Taiwan 2Department of Psychiatry, TMU-School of Medicine, Taipei, Taiwan
a r t i c l e i n f o
Article history: Received: Dec 29, 2011 Revised: Jan 31, 2012 Accepted: Jan 31, 2012 KEY WORDS: adverse drug events; anterograde amnesia;sleep-related complex behaviors; sleep-related eating syndrome; sleepwalking;
zolpidem
Objective: Benzodiazepines with a unique chemical structure of three-ring diabenzine can induce the benzodiazepine-gamma aminobutyric acid A receptor complex to produce sedative, anxiolytic, muscle-relaxant, and anticonvulsant effects. But they have serious side effects such as tolerance and withdrawal, memory and performance impairments, and complex behaviors associated with amnesia.
Method: We searched zolpidem-related published papers from Taiwan from 2003 to 2011. All biblio-graphical data of original clinical reports were studied. We focused only on complex behaviors related to zolpidem and not on the symptoms of zolpidem-related addiction, tolerance, and withdrawal.
Results: The search in PubMed with the keyword“zolpidem” yielded 729 articles published from 2003 to 2011. Of these, 20 articles were written by Taiwanese author(s). There were 15 case reports andfive clinical studies. Besides the symptoms of addiction, tolerance, and withdrawal, these papers describe complex behavioral disturbances, such as performance impairments, behavioral impairment with amnesia, sleep-walking, sleep-related eating disorder, and hallucination and sensory distortion.
Conclusion: We have summarized the case reports and clinical studies of zolpidem-related adverse effects published from Taiwan and reviewed concerns about zolpidem’s safety that international researchers have been voicing out in recent years. The incidence of those zolpidem-induced complex behaviors is similar to that found in Western countries. Clinicians should therefore use more antidepressants to treat the underlying diseases that present with insomnia (such as major depressive disorder or generalized anxiety disorder).
CopyrightÓ 2012, Taipei Medical University. Published by Elsevier Taiwan LLC. All rights reserved.
1. Introduction
Zolpidem was first introduced in France in 1988 and quickly became one of the most prescribed hypnosedatives around the world. It was later marketed in the United States under the trade name of Ambien, which literally translates to“good morning” in English, i.e., a.m. meaning“morning” in Latin, and bien “good” in French. Zolpidem is now sold worldwide using 60 different brands. From 2001 to 2002, over 1.34 million tablets of zolpidem were sold across Japan, Europe, and the United States.1The exact number of zolpidem prescriptions worldwide is unknown, but speculated to be over billions of tablets per year.
1.1. Complex behaviors induced by zolpidem
Zolpidem is associated with complex behavioral disturbances which are defined in the package insert: (www.ambiencr.com):
“Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported with sedative-hypnotics, including zolpidem. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as“sleep-driving” may occur with Ambien CR alone at thera-peutic doses, the use of alcohol and other CNS depressants with Ambien CR appears to increase the risk of such behaviors, as does the use of Ambien CR at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontin-uation of Ambien CR should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with“sleep-driving,” patients usually do not remember these events. Amnesia, anxiety and other neuropsychi-atric symptoms may occur unpredictably.”
1.2. Magnitude and regulatory responses from various countries In as recent as 2008, the Therapeutic Goods Administration in Australia issued a black box with the strongest warning about
* Corresponding author. Winston W. Shen, Number 111, Hsing Long Road, Section 3, Taipei 116, Taiwan.
E-mail: Winston W. Shen <Shenwinw@gmail.com>
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adverse drug events possible without withdrawing the drug from the country (www.tga.gov.au).56Asian countries such as Japan and Taiwan quickly followed suit with similar measures in recent years. Zolpidem quickly became the most prescribed hypnotic drug in Taiwan; in 2006, it was one of the 10 most prescribed drugs according to the Taiwanese National Insurance Health Insurance, the single insurance payer on the island. About 100e300 millions pills are prescribed each year, and an extraordinary sum of at least NT$800 million (US$26.7 million) is paid by the Taiwanese National Insurance Health Insurance each year on zolpidem alone.2With its astounding popularity, news and television reports of extraordi-nary stories such as amnestic sex and rape related to zolpidem warrants further study of its pharmacological effects.
1.3. Objectives of this analysis
Given the magnitude of the problems that result from zolpidem use, our objective was to review published clinical reports from Taiwan, and to familiarize physicians with the behavioral and performance impairments, hallucinations, and amnesia associated with zolpidem. Then we reviewed the relevant clinical psycho-pharmacology in an attempt to help elucidate zolpidem-related complex behavioral problems.
2. Method
We searched zolpidem-related published papers from Taiwan from 2003 to 2011.
AIWC, thefirst author of this article, did a PubMed (www.ncbi. nlm.nih.gov/pubmed) search with the keyword “zolpidem.” All bibliographical data of original clinical reports were studied. After the initial screening, she identified all published articles written by author(s) from Taiwan. Attention was focused on the description of complex behaviorsdcomplex behavioral disturbances such as performance impairments, behavioral impairment with amnesia, sleepwalking, sleep-related eating disorder, and hallucination and sensory distortion.
3. Results
The search in PubMed using the keyword“zolpidem” yielded 729 articles. Of these, 20 articles were written by Taiwanese author(s). We found that many patients in Taiwan took zolpidem for longer-than-recommended periods and at higher than therapeutic doses.
This inappropriate use of medications often resulted in potential adverse drug events.3Then, we divided zolpidem-related papers into two (15 case reports and 5 clinical studies) categories.
Table 1lists 15 case reports4e15describing patients abusing and developing addiction-related tolerance/withdrawal symptoms and neuropsychiatric complications in Taiwan from 2003 to 2011. This should raise cautionary measures among all prescribing physicians since every reported patient is probably accompanied by hundreds of unreported cases in clinical practice.Table 2 summarizesfive clinical drug trials16e20involving zolpidem’s side effects conducted in Taiwan.
As shown in Table 1, the most striking finding was that all reported cases of zolpidem-induced addiction problems in Taiwan involved female patients, and that many of them took higher-than-therapeutic dose of zolpidem for a long period. Nine out of 15 patients took zolpidem in the daytime. Seven out of 15 patients took high daily doses:five patients taking daily doses in the hundreds of milligrams (160e600 mg/day), one taking 1000 mg/day, and the other one taking 20 mg/day. All high daily dose patients showed physiological symptoms and signs of drug addiction reflected by tolerance and withdrawal, whereas the development of zolpidem-related complex behavior happened both in therapeutic and high doses of zolpidem.
4. Discussion
4.1. Clinical description of zolpidem-related complex behavioral disturbances
One of the most strikingfindings in our review was learning the term “complex behavioral disturbances” (www.ambiencr.com).
Table 1 Clinical case reports of zolpidem-related side effects from Taiwan (N¼ 15) No. References Age (y) Sex Highest daily
dose (mg/d) Intake during daytime Tolerance/withdrawal Dependence on other substance Neuropsychiatric complications 1 Tsai et al 20034 23 F 5e10 () n/a () (þ)
2 Chang and Lin 20035 24 F 10 (IV) n/a n/a n/a n/a
3 Chang and Wang 20116 40 F 1000 (þ) (þ)/(þ) (þ) (þ)
4 Chen et al 20117 53 F 160 (þ) (þ)/(þ) (þ) þ
5 Hsieh et al 20118 27 F 200 (þ) (þ)/(þ) () (þ)
6 Huang et al 20079 35 F 500 (þ) (þ)/(þ) n/a (þ)
7 Wang et al 201110 43 F 400 (þ) (þ)/(þ) n/a (þ)
8 Kao et al 200411 59 F 600 (þ) (þ)/(þ) (þ) n/a
9 Tsai et al 200912 65 F 5e10 (þ) Accidental n/a () (þ) TGA-like Sx
10 Chen et al 200913 34 F 2000 (þ) (þ)/(þ) () n/a
11 Chu et al 200814 28 F 400e500 (þ) (þ)/(þ) (þ) (þ)
12 Tsai et al 200715 34 F 5e10 () () n/a (þ)
13 Tsai et al 200715 40 F 10e15 () () n/a (þ)
14 Tsai et al 200715 50 F 10 () () n/a (þ)
15 Tsai et al 20034 23 F 5e10 () n/a n/a (þ)
References were obtained from a PubMed (www.ncbi.nlm.nih.gov/pubmed) search with the key word“zolpidem.” A total of729 published articles was found. Fifteen articles were found to be clinical case reports describing zolpidem-related side effects written by authors from Taiwan.
F¼ female; IV ¼ intravenous; n/a ¼ not available; Sx ¼ symptoms; TGA ¼ transient global amnesia.
Table 2 Clinical studies on zolpidem from Taiwan (N¼ 5)
Study name Year Type of study No. of participants Huang et al16 2010 Cross-sectional pilot study 125
Yang et al17 2010 Retrospective study TNIHD
Wang et al18 2010 Retrospective study TNIHD
Huang et al19 2011 Double-blind, randomized,
comparative study
48 Tsai et al20 2009 Retrospective study 255
References were obtained from a PubMed (www.ncbi.nlm.nih.gov/pubmed) search with the key word“zolpidem.” A total of729 published articles was found. Five articles were found to be clinical studies describing zolpidem-related side effects written by authors from Taiwan.
Therefore, we willfirst discuss all those symptoms and signs to familiarize the readers with the most important types of those zolpidem-related problems.
4.1.1. Performance impairments
The effects of acute ingestion of zolpidem typically peak at 45 minutese2.5 hours and are associated with impaired performance as measured by a battery of tests. A large-scale retrospective study using the Taiwanese National Insurance Health Database (Table 2) showed that use of zolpidem is associated with an increased risk of motor vehicle accidents in the following day (odds ratio¼ 1.74; 95% confidence interval ¼ 1.25e2.43).17 The acute
performance-impairing effects of zolpidem are comparable to those of benzo-diazepines (BZDs), despite using different sample populations, methods of study, and different comparison drugs.21 At doses as low as 7.5 mg in non-elderly participants, zolpidem has shown comparable dose- and time-dependent impairment in learning, recall, and performance.22
Leufkens et al23showed that zolpidem at a middle-of-the-night dose of 10 mg significantly impairs performance in all tests of a series of highway driving tests in the morning after bedtime administration, and that increased effort did not overcome perfor-mance impairment.23Moreover, tolerance does not develop in acute performance impairments, including psychomotor function, atten-tion, working memory, and episodic memory. A double-blind, placebo-controlled study showed that performance is significantly impaired during nighttime awakening even after 1 month of nightly zolpidem administration, and that these impairments could signif-icantly affect safety during nighttime awakening.24
4.1.2. Behavioral impairments with amnesia
Acute ingestion of zolpidem is associated with complex behaviors that usually start during arousals from slow-wave sleep (SWS) and terminate in walking or eating within an altered state of consciousness and judgment. In descending order of frequency, these behaviors include the following: sleep eating, sleepwalking with manipulation of objects (e.g., cooking, cleaning), sleep talking (on the phone or in person), sleep driving, sleep sex, and sleep shopping.25
Traditional BZDs have been associated with amnesia and those with stronger gamma aminobutyric acid A (GABAA)-complex
binding have greater potential (e.g., triazolam). Similarly, zolpidem has been reported to have comparable memory impairments to those of triazolam and other BZDs.26It has also been proposed that zolpidem may have greater risks of producing amnestic complex behaviors than other Z-drugs (zopiclone and zaleplon) because of its higher affinity and selectivity to
a
1-GABAAreceptors which arefound in lesser amounts in the hippocampus, an important struc-ture in memory consolidation. The amnestic nastruc-ture of the complex behaviors is dose-dependent and dependent on route of adminis-tration.27It has also been suggested that zolpidem’s anterograde amnesia is related to disruption of long-term memory consolida-tion through the shortening of sleep latency.28
4.1.3. Sleepwalking
In 1994, Mendelson29was thefirst to describe the case of a man
sleepwalking after taking zolpidem. The patient had gotten up and began walking around during stage 4 on polysommnography while feeling asleep subjectively. The patient had woken up the next day without memory of this event. Since then, several more reports have been described in the literature.30,31Although post-marketing studies reported low incidences of sleepwalking (0.3e1%),31they can be dangerous to patients.32,33
The incidence reported in Taiwan is considerably higher (5.1%)20 as shown in one retrospective study listed inTable 2. The authors
suggested that amnesia of these events appear to be dose-dependent, and that it occurred more frequently at doses higher than 15 mg. Another study by Hwang et al19also gave a similar conclusion (Table 2).
Sleepwalking is a disorder of arousal that often initiates during SWS and is purposeless in nature.34Zolpidem increases SWS espe-cially in young adults, and this effect is not seen with other BZDs. In fact, conventional BZDs (e.g., clonazepam) have, in turn, been useful in treating these parasomnias.34Thus, zolpidem-medicated patients have a predominance of non-REM sleep, so when the drug action is weaning down, the patient is still in non-REM sleep.
Several authors have suggested an interesting theory on the cause of somnambulism involving theoretical cerebral pattern generators (CPGs).34CPGs are neuronal collections in the brain,
brainstem, and spinal cord that are thought to control innate motor behaviors that are crucial for living, such as feeding and locomo-tion. Diffuse binding of zolpidem in the central nervous system (CNS) elicits CPGs-associated evolutionarily preserved actions such as walking and eating, leading to sleepwalking and sleep-related eating disorders. CPGs that reside in cortical areas release over-learned behaviors such as driving.
4.1.4. Sleep-related eating disorder
Strunkard et alfirst described the syndrome of night eating in obese patients back in 1955.35Since then, many more detailed cases of patients presenting with partial or full amnesia of nocturnal eating behavior have been reported in the literature.35e37 Collectively
known as sleep-related eating syndrome (SRED), the spectrum encompasses many abnormal behaviors that are characterized by nocturnal eating episodes in a partially aroused state and conse-quent morning anorexia/bloating, feelings of guilt, and weight gain. Patients often describe these experiences as“automatic” penchants to eat and suffering from the inability to return to sleep unless they have completed this act. Patients may exhibit nocturnal eating only after initiation of zolpidem, while other patients may continue their preexisting nocturnal eating problem but with increased frequency and newly onset amnesia of events.
Once the medication was discontinued, the unusual behavior stopped in most of the reported cases. Najjar38in 2007 observed two types of patients with preexisting eating disorders: (1) patients who experience nocturnal eating as a symptom of a diurnal eating disorder, and (2) those who exhibit nocturnal eating as a result of an eating disorder that presents predominantly during sleep. The second group often complains of insomnia, and the patients are fully awake during their nocturnal eating episode. An association exists between somnambulism and SRED.39,40 The ingested substances can be either ordinary or unusual and are typically of high-calorie content.
The precise pathological mechanism of SRED is unclear, but is thought to be related to dysregulation of the dopaminergic system in the CNS. This is supported by evidence of increased prevalence of SRED in patients with restless legs syndrome, periodic limb movement disorder, and the improvement of SRED to dopamine agonists. Other conditions that cause fragmented sleep (e.g., obstructive apnea, withdrawal from nicotine, alcohol, opiates, and cocaine) are also known to be associated with SRED.41
Although zolpidem was marketed as weight-neutral, most conventional BZDs have been shown to induce hyperphagia in mammals.42 Given the recent reports about zolpidem-related SRED, the effect of zolpidem on appetite and weight control in humans warrants further reassessment.
4.1.5. Hallucinations/sensory distortion
Since Ansseau et al43 in 1992 first reported two patients with zolpidem-induced visual hallucinations and amnesia, stories of
patients with similar neuropsychiatric conditions (Table 1) have repeatedly been reported in Taiwan4,12 and around the world. Zolpidem-induced hallucinations are mostly of the visual kind and often occur when patients are falling asleep or waking up. Although the mechanism is unclear, hallucinations are thought of result from GABAergic abnormalities.4
Zolpidem-related hallucinations should raise awareness in clinicians since even at therapeutic levels, it can be associated with transient cognitive and behavioral complications43,44 that can result in patients self-harm.45Common characteristics among the described patients include: female sex, a dose-dependent reaction, the symptoms appearing around 20e30 minutes after zolpidem ingestion, and the spontaneous clearance of the cognitive/behav-ioral symptoms without need of treatment several hours later or after discontinuation of zolpidem use. In most severe cases, patients even develop delirium.44,46
Toner et al40suggested four variables that should be considered when prescribing zolpidem in order to avoid these neuropsychiatric complications: (1) female sex is associated with higher serum drug levels; (2) zolpidem dose, hallucinations occurred at higher doses and were dose-dependent; (3) zolpidem-related hallucinations are more severe in patients suffering from malnutrition or hypo-albuminemia, because zolpidem has high protein binding affinity. Some antidepressants with high-protein binding properties may also displace zolpidem from carrying proteins and increasing the amount of zolpidem; and (4) medications that inhibit CYP3A4 hepatic izoenzyme may interfere with the metabolism of zolpidem. Besides taking into account these four factors, individual variations in pharmacodynamics sensitivity and neuroanatomical differences need also to be considered when prescribing zolpidem.46
4.2. Why zolpidem is more likely to elicit complex behavior compared to other BZDs and other Z-drugs
The Food and Drug Administration issued a warning about hypnosedative-related complex behaviors on 13 types of hyp-nosedatives in as recent as March 2007 (www.fda.gov). Besides being the most prescribed hypnotic in Taiwan, the focus on zolpi-dem was chosen because side effects such as amnesia, confusion, and even psychosis have already been well documented in the literature for many decades, whereas zolpidem-induced complex behaviors are still relatively understudied despite its popularity as a prescription drug. Even though the remaining Z-drugs (zopiclone and zaleplon) have also been linked to complex behaviors, zolpi-dem is the drug most frequently reported.24It is unclear whether this phenomenon is because of an increased risk for complex behaviors in zolpidem or simply because it is more frequently prescribed. After documenting zolpidem-related pharmacoepi-demiology in Taiwan, clinical descriptions, and magnitude of its use and associated side effects, we have made an attempt to explain why zolpidem-induced side effects are better known compared to other BZDs or BZD-receptor agonists.
4.2.1. Mechanisms of action of BZDs and Z-drugs
Figure 1summarizes BZD and BZD-receptor agonists (Z-drugs). All of them exert similar pharmacologic properties that include anxiolytic, hypnotic, anticonvulsant, and muscle relaxant effects, but they have several side effectsdamnesia, hyperphagia, and parasomniadas described previously. GABA exerts inhibitory effects in the CNS by binding to GABAAreceptors and causing an influx of chloride ions
into neurons. BZDs and Z-drugs bind to GABAAreceptors at a site
near the GABA binding site and enhance the effects of GABA. In the absence of GABA, hypnotics cannot exert their effects.47
The BZDeGABAAechloride ion channel complex has a trans-membrane pentameric structure with subunits chosen from eight
polypeptide classes:
a
,b
,g
,d
,ε,p
,r
, ands
. Thea
subunits dictate the pharmacology of the BZD receptor site. Activation of thea
1subunit results in sedative, amnesic, and motor impairments but not in anxiolytic, myorelaxant, or alcohol-potentiating effects. The latter effects are due to actions on the
a
2,a
3, anda
5subunits.42Cooper42suggested that hyperphagia is medicated by the
a
2anda
3subunits. Variations in GABAAreceptor subunits among patientsmay partly explain the differences in the pharmacodynamic effects of zolpidem.44
4.2.2. Hypothesized pathological mechanisms of complex behavior and amnesia
4.2.2.1.
a
1-Agonist activity. BZDs with higher affinity to alphasubunits, such as triazolam, tend to produce more amnesia and complex behaviors.48,49According to this theory, zolpidem may have greater risks for these side effects because it has the strongest binding affinity for alpha and greater in vitro intrinsic activity than the rest of the Z-drugs.50,51 Originally, zolpidem was thought to have less amnesia than the other BZDs because of its selectivity to
a
-GABAAreceptors and the relative lack of these receptors in thehippocampus. However, memory impairments of zolpidem are comparable to those of triazolam.52Theoretically, zolpidem loses its selectivity for
a
1subunits at higher concentrations and showssimilar pharmacological effects to those of traditional BZDs. It is therefore not surprising that zolpidem has been associated with complex behaviors previously reported with BZDs. This phenom-enon results in amnesia of events experienced while a person is conscious.
4.2.2.2. Inhibition of memory consolidation. The risk of zolpidem-induced complex behaviors may not be completely explained by actions on the
a
1subunit. Decreasing sleep latency may increasethe risk of complex behaviors because it interferes with the transferring of memory from short-term memory to long-term storage, otherwise known as memory consolidation. This phenom-enon results in amnesia of events experienced while a person is conscious.
Zolpidem decreases sleep latency more than other BZDs because of its faster onset of action.
4.2.2.3. Other considerations. Another noteworthy factor is zolpi-dem’s potential for abuse and dependence. Zolpidem was first marketed as a safe hypnotic and free of abuse and dependence liability,53,54but the number of case reports in the literature that proves otherwise is overwhelming.8,55These case reports describe patients developing long-term dependence and withdrawal symptoms, and rebound insomnia may develop even within ther-apeutic doses.53To the best of our knowledge, there is only one randomized, double-blind, comparative study conducted in Taiwan that evaluated zolpidem’s safety in the treatment of insomnia.15
This study showed that zolpidem is more significantly effective in reducing sleep latency, from a baseline of 61.9 44.7 to 30.0 31.1 minutes (p< 0.05), and observed no rebound insomnia. However, the participants in the study were treated with zolpidem for only 2 weeks, a significantly shorter period than the several months and even years seen in clinical practice.
4.2.2.4. Summary of the hypothesis. Several hypotheses have been proposed to explain the occurrence of zolpidem-induced complex behavior. While no single postulate complete explains the phenomenon, the combined data suggest that the risks are higher with high doses of zolpidem. To note, the conclusion of this review is hypothetical as there is a lack of head-to-head trials comparing complex behavior elicited by zolpidem compared to that of BZDs and other Z-drugs.
4.3. Clinical suggestion for zolpidem use in clinical practice While zolpidem is clinically effective in treating insomnia, it carries the same risks as conventional BZDs. Besides its addictive potential, zolpidem was reported to have higher odds for parasomnia, amnesia, hallucinations, and perhaps suicidality compared to other hypnotics.57 Table 1 shows that development of zolpidem-withdrawal symptoms and tolerance tended to occur in patients taking zolpidem at the dose level higher than therapeutic dose levels (>100 mg daily), while neuropsychiatric complications occurred at doses of as low as 5 mg daily. Patients taking large daily doses corresponded to those diagnosed with zolpidem depen-dence, whereas patients who developed neuropsychiatric compli-cations did not necessarily have addiction problems. To note, all reported cases in Table 1 were female patients and confirmed previous suggestions that female patients are more susceptible to the side effects of zolpidem.18Although they are small in number, there have been clinical studies conducted in Taiwan (seeTable 2) that challenges the previously assumed safety of zolpidem. Management strategies for zolpidem-related side effects include discontinuing the use of this drug, switching to another hypnotic, or using nonpharmacological treatments such as relaxation tech-niques and encouraging sleep hygiene. Interestingly, patients should be advised against using excessive caffeinated beverages to counteract the acute ingestion effects of zolpidem as a recent
studied has shown that up to four cups of coffee can only partially reverse the performance-impairing effects of zolpidem.57
The constellation of zolpidem-related adverse drug events can often be overlooked in clinical practice when physicians let their guard down while prescribing this drug in the hopes that the latest introduced hypnotic in the 21stcentury is the best and the safest. We advocate that zolpidem be used judiciously by following the Taiwan and U.S. Food and Drug Administration warnings, and with the same caution usually reserved for all traditional BZDs: at the lowest possible effective dose and for the shortest duration possible. The clinicians should prescribe more antidepressants to treat the underlying diseases with clinical presentation with insomnia (such as major depressive disorder or generalized anxiety disorder).58
Conflict of interest
The authors declare no conflict of interest in all the drugs mentioned in this article.
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