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Zolpidem-Induced Sleepwalking, Sleep Related Eating Disorder, and Sleep-Driving: Fluorine-18-Flourodeoxyglucose Positron Emission Tomography Analysis, and a Literature Review of Other Unexpected Clinical Effects of Zolpidem

2009; American Academy of Sleep Medicine; Volume: 05; Issue: 05 Linguagem: Inglês

10.5664/jcsm.27605

1550-9397

Romy Hoque, Andrew L. Chesson,

Restless Legs Syndrome Research

Free AccessBenzodiazepinesZolpidem-Induced Sleepwalking, Sleep Related Eating Disorder, and Sleep-Driving: Fluorine-18-Flourodeoxyglucose Positron Emission Tomography Analysis, and a Literature Review of Other Unexpected Clinical Effects of Zolpidem Romy Hoque, M.D., Andrew L. Chesson, M.D Romy Hoque, M.D. Address correspondence to: Romy Hoque, M.D., Department of Neurology, Louisiana State University School of Medicine, 1501 Kings Highway, Shreveport, LA E-mail Address: [email protected] Sleep Disorders Center, Department of Neurology, Louisiana State University School of Medicine, Shreveport, LA , Andrew L. Chesson, M.D Sleep Disorders Center, Department of Neurology, Louisiana State University School of Medicine, Shreveport, LA Published Online:October 15, 2009https://doi.org/10.5664/jcsm.27605Cited by:89SectionsAbstractPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTZolpidem is a hypnotic which acts at the GABAA receptor and is indicated for short-term insomnia. Sleep related disorders including somnambulism, sleep related eating and sleep-driving have been reported with zolpidem. A 51-year-old insomniac who used zolpidem 10 mg nightly starting at 44 years of age is described. A few weeks after starting zolpidem she began walking, eating, and had one episode of driving while asleep. Episodes of sleep related eating, sleepwalking, and sleeptalking occurred 3 nights per week, 1 to 2 h after sleep onset. After her evaluation, the patient's zolpidem was gradually discontinued, and all sleep related activities immediately ceased. An 18F-FDG-PET was obtained 2 months after discontinuation of zolpidem. The following day, FDG was administered 1 h after oral administration of 10 mg zolpidem, and then a second PET was performed. We report the results and a review of the literature regarding other unintended effects seen with zolpidem use.Citation:Hoque R; Chesson AL. Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: fluorine-18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other unexpected clinical effects of zolpidem. J Clin Sleep Med 2009;5(5):471-476INTRODUCTIONSleepwalking or somnambulism, is a parasomnia consisting of a series of complex behaviors usually initiated during arousals from slow wave sleep and commonly culminate in walking with an altered state of consciousness and impaired judgment.1 Sleep related eating disorder (SRED) consists of recurrent episodes of involuntary eating during arousals from sleep.1 Parasomnias such as sleepwalking, SRED, and sleep-driving can coexist and are rare side effects of zolpidem. In a 2005 National Institutes of Health consensus statement for the treatment of chronic insomnia in adults zolpidem was considered a hypnotic with limited risk.2 Two post-marketing studies of zolpidem reported sleepwalking incidences of 7 of 1972 patients (0.3%)3 and 1 of 96 patients (1%).4 We present a patient with zolpidem-induced sleepwalking, SRED, and sleep-driving. A fluorine-18-flourodeoxyglucose positron emission tomography (18F-FDG-PET) was obtained one month after discontinuation of zolpidem. A second 18F-FDG-PET was acquired the following day, 1 h after oral administration of zolpidem 10 mg (Figure 1). The cerebral glucose metabolism rates of the 2 studies were then compared, using statistical parametric mapping analysis. We also review the literature regarding unintended effects of zolpidem use.CASE REPORTThe patient is a 51-year-old African American woman with past medical history of hypertension, mild obstructive sleep apnea, hyperlipidemia, and depression. Previous diagnostic polysomnogram revealed an apnea-hypopnea index of 10 events/h. Medications included paroxetine 20 mg once a day, extended release metoprolol 25 mg twice per day, and simvastatin 40 mg once a day. History for alcohol, tobacco, or illicit drug use was negative. The patient reported no personal or family history of sleepwalking or other parasomnias. The patient did not have a history of daytime eating disorder. At age 44 the patient was started on non-extended release zolpidem 10 mg at bedtime for insomnia. A few weeks after starting zolpidem. she began sleep related walking, eating, and one episode of driving.Episodes of sleepwalking, SRED, and sleeptalking occurred 3 nights per week, 1-2 h after sleep onset. The patient would speak incoherently using short phrases with her eyes closed and would then open her eyes when questioned by her husband. She would also leave her bedroom to go to her kitchen where she would eat a loaf of bread, cold cereal, or leftover food. The following morning she would have abdominal fullness, find her kitchen messy, and have complete amnesia for the event. The patient would also leave her home and walk on her front porch or on her front lawn. As a preventive measure, she installed nocturnal alarms on her doors to wake her or her family from sleep if she opened one. Other reported events included one occasion of urination in the hallway, and one episode when the patient drove her automobile 10 miles from her home and was found asleep behind the wheel by police. She had a vague recollection of this event, but thought that she was dreaming. After her evaluation, the patient's zolpidem was gradually withdrawn; all sleep related activities immediately ceased and have not recurred during 6 months of follow-up.18F-FDG-PET AnalysisThe first PET study in our patient was performed after discontinuation of zolpidem for 2 months. A second PET study FDG was administered 1 h after the administration of 10 mg zolpidem. The patient was asleep in the scanner during both PET studies. Statistical parametric mapping comparison between our patient's 2 studies demonstrated no significant differences (Figure 1).Figure 1 18-fluorine-flourodeoxyglucose-positron emission tomography (18F-FDG-PET) of a patient with zolpidem induced sleepwalking, sleep related eating disorder, and sleep-driving. A: 18F-FDG-PET off zolpidem. B: 18F-FDG-PET on zolpidem. FDG was administered to patient 1 h after ingestion of 10 mg zolpidem. Statistical parametric mapping comparison of the 2 sequences shows no significant differences.Download FigureDISCUSSIONZolpidem is an imidazopyridine drug indicated for short-term insomnia at a dosage usually ranging from 5 to 10 mg per day.5 Though considered a non-benzodiazepine since its imidazopyridine structure differs from benzodiazepine fusion of benzene and diazepine, zolpidem is a benzodiazepine receptor agonist with high binding affinity for the GABAA (gamma-amino butyric acid type A) receptor expressing the α1 subunit. Benzodiazepines and benzodiazepine receptor agonists like zolpidem bind to the GABAA receptor at sites that are distinct from the GABA binding site, thereby allosterically affecting the activity of the ligand-operated chloride channel.GABA is the main inhibitory neurotransmitters in the mammalian central nervous system (CNS). GABAA receptors exist as pentameric protein complexes, assembled from a combination of at least 19 subunits from 7 distinct gene families (α, β, γ, δ, ϵ, θ, and π). Synaptic GABAA receptors are responsible for modulating benzodiazepine sensitivity and typically contain α1, 2, 3, or 5, β2 or 3, and the γ2 subunits.6 GABAA receptor sensitivity to benzodiazepines is mediated through α subunits. Benzodiazepines bind to synaptic GABAA receptors containing α1, α2, α3, or α5 subunits with comparable affinity. The GABAA receptor expressing the α1 subunit corresponds to the benzodiazepine ω1 receptor.7 GABAA receptors containing the α1, α2, α3, or α5 subunits correspond to ω2 benzodiazepine receptors. The ω3 benzodiazepine receptor is not related to the GABAA receptor. Extrasynaptic GABAA receptors are primarily composed of α4-6 subunits in combination with δ subunits, and are insensitive to benzodiazepines. The current benzodiazepine receptor nomenclature (ω1, ω2, and ω3) replaced the previous anatomical localization classification (central benzodiazepine receptor type 1, central BZ-1; central benzodiazepine receptor type 2, central BZ-2; and peripheral benzodiazepine receptor type 3, BZ3) because of the existence of "central" benzodiazepine receptors with peripheral localization, and "peripheral" benzodiazepine receptors with central localization.Zolpidem was developed as a drug with a structure different from benzodiazepines, allowing affinity for only a given subset of central benzodiazepine receptors resulting in hypnotic properties without additional anticonvulsant and myorelaxant properties of benzodiazepines. In contrast to benzodiazepines like clonazepam, diazepam and flunitrazepam, which lack selectivity for the ω1, ω2, or ω3 benzodiazepine receptor subtypes; zolpidem has a high affinity for ω1.8A possible explanation for zolpidem-induced nocturnal events is that after an arousal from sleep into wakefulness, nocturnal activity (i.e., walking, eating, or driving) occurred and was subsequently not recalled after returning to sleep because of the sedation-mediated amnestic properties of zolpidem. Another possibility is that an arousal occurred out of slow wave sleep with the parasomnia occurring in electroencephalographically verifiable sleep. We felt our patient experienced the later, given her incoherent interactions with her husband during her nocturnal events. Patients who do not recall waking events on zolpidem are typically cognitively functional, and retain the ability to speak in coherent short phrases.9Sleepwalking is a relatively common condition affecting 10% of adults.1 Recently hotels across the United Kingdom reported an increase in the number of hotel guests found to be sleepwalking.10 Though the incidence of zolpidem induced sleepwalking has been reported to be low, it is possible that many cases of unexplained sleepwalking may be secondary to zolpidem given its widespread use.3,4Along with sleepwalking, SRED, and sleep-driving parasomnias, zolpidem has been anecdotally reported to produce a range of unexpected beneficial effects. These include improvement in the following conditions: post-stroke Broca's aphasia; blepharospasm; quadriparesis of central pontine myelinolysis; catatonia of schizoaffective disorder; dementia with apraxia; post-anoxic minimally conscious states; bradykinesia, akinesia, and dystonia in Parkinson disease; post-levodopa dyskinesias in Parkinson disease; vertical saccadic eye movements and parkinsonism in progressive supranuclear palsy; restless legs syndrome; post-anoxic spasticity; and spinocerebellar ataxia (Table S1 summarizes the available reports of improvement in varied neurological conditions with zolpidem use). Effects were usually noted within 30 min of ingestion of the non-extended release formulation and lasted for 2 to 4 h, corresponding with a time to peak plasma contraction of approximately 1.2 h and a half-life of approximately 2.5 h.Zolpidem effects might be mediated through its anti-anxiety effects, its benzodiazepine receptor agonist properties, its GABAergic activity, or some combination of all three. For example, symptoms of Parkinson disease worsen with anxiety. The improvement noted in Parkinson disease with zolpidem use may be secondary to its anxiolytic effect through a GABAergic effect on the limbic system or elsewhere. The improvement seen in blepharospasm, catatonia, and restless legs syndrome may be caused by the benzodiazepine ω1 receptor agonist activity of zolpidem. However, opposing this theory of purely benzodiazepine agonist mediated effects, is that parasomnias like sleepwalking are often treated with benzodiazepines like clonazepam; yet zolpidem seems to induce parasomnias in a susceptible subpopulation.The action of zolpidem via synaptic GABAA receptors with α1 subunits may produce different clinical responses depending upon regional distribution of receptor subtypes. Benzodiazepines bind to all the synaptic GABAA receptors, which are expressed throughout the nervous system. Even though zolpidem is a preferred α1 agonist, α1 subunits are expressed widely throughout the CNS.11 Benzodiazepine-insensitive extrasynaptic GABAA receptors containing α4-6 subunits show much more regional specificity than benzodiazepine-sensitive synaptic GABAA receptors containing α1, 2, 3, or 5.Zolpidem has a less recognized but limited binding affinity to ω2 benzodiazepine receptors. ω1 and ω2 receptors are also widely expressed throughout the human brain.12 At higher doses these lower binding affinities may be expressed resulting in unexpected clinical outcomes. For example, anecdotally there appears to be differential efficacy of high dose zolpidem (70 mg/d) for blepharospasm, and low dose zolpidem (5-10 mg/d) for parkinsonian features. (Surprisingly at the high doses used by Garretto et. al for blepharospasm and Evidente for early onset Parkinson disease, 5 of 6 patients reported no somnolence, and only one patient had to discontinue the medication secondary to drug-induced diarrhea.13,14 Somnolence was overcome with slow dose titration.)The potential clinical significance of preferred GABAA α1 subunit/ω1 receptor activation is unclear. For example, it was previously thought that zolpidem did not possess significant myorelaxant properties similar to benzodiazepines. However, anecdotal reports of efficacy for zolpidem in post-anoxic spasticity, parkinsonian dyskinesias/tremors, blepharospasm, and restless legs syndrome provides anecdotal evidence to the contrary. Zolpidem may affect many neurological diseases through binding at a variety of locations simultaneously (Figure 2). Zolpidem binding at one anatomical location is unlikely to explain all of its myriad effects. Also, electrophysiological studies suggest that different GABA subunit combinations may mediate different physiological and pharmacological properties of the ligand-operated ion channel.11 Therefore, even though zolpidem has a high affinity for GABAA receptors with the α1 subunit, different pharmacological responses may results from different subunit combinations with the α1 subunit. As a result, clinical efficacy in a given disease is difficult to correlate with binding and receptor activation at a single GABAA/benzodiazepine receptor type, at a single anatomic site, or at a single dose.Figure 2 Regional distribution of zolpidem binding, and the potential clinical consequences. Zolpidem is a benzodiazepine receptor agonist with high binding affinity for the GABAA (gamma-amino butyric acid type A) receptor expressing the α1 subunit. Benzodiazepines and benzodiazepine receptor agonists like zolpidem bind to the GABAA receptor at sites that are distinct from the GABA binding site, thereby allosterically affecting the channel. GABAA receptor sensitivity to benzodiazepines is mediated through α subunits. Zolpidem's action via synaptic GABAA receptors with α1 subunits may produce different clinical responses depending upon regional distribution of receptor subtypes. Benzodiazepines bind to all the synaptic GABAA receptors, which are expressed throughout the nervous system. Even though zolpidem is a preferred α1 agonist, α1 subunits are expressed widely throughout the CNS. Given zolpidem's many binding sites, the improvement noted across a range of neurological disorders are difficult to localize to binding at a single anatomic location. GABAA α1 subunits/ω1 benzodiazepine receptors are widely distributed throughout the central nervous system, in many more areas than indicated in this simple schematic figure.Download FigureAn intriguing theory on the etiology of sleepwalking and SRED concerns the presence of theoretical cerebral pattern generators (CPGs).15,16 CPG are thought to be neuronal collections in the brain, brainstem or spinal cord that can potentially control innate motor behaviors essential for survival like feeding and locomotion. Diffuse zolpidem cortical binding may cause release of CPGs associated with evolutionarily conserved motor patterns such as walking and eating, leading to subsequent disorders of arousal like somnambulism and SRED. Since some CPGs may reside in the cortex, zolpidem use also release cortical patterns associated with overlearned behaviors, such as driving.In an attempt to identify zolpidem-induced changes in cerebral glucose metabolic rates, an 18F-FDG-PET was performed in our patient on and off zolpidem. Gillin et al. compared the effects of 10 mg zolpidem and placebo on cerebral glucose metabolic rates in 12 young normal volunteers (mean age: 22.5 y) using 18F-FDG-PET.17 In that study FDG was administered about 1 h after oral administration of zolpidem while the patient was in electroencephalographically (EEG) verifiable stage 2 sleep and at a time of expected zolpidem peak concentrations (1.2 ± 0.2 h) in plasma (and presumably brain). Gillin et al. found that across all cortical areas glucose metabolic rates were not significantly different on placebo versus zolpidem. Our patient's results were similar to those seen in Gillin's normal volunteers.Compared to wake, whole brain cortical glucose metabolic rates decrease in NREM and REM stage sleep.18 One would expect a decline in cortical glucose metabolic rate with the use of sleep-inducing hypnotics like zolpidem. However, our results, along with those of Gillin show otherwise. The reasons for this are unknown.One possible explanation may be that PET is too insensitive a tool to detect subtle localized or generalized glucose metabolic rate differences on and off zolpidem in the normal brain. If such differences could be identified, then patients who are susceptible to developing parasomnias could be identified prior to use. More importantly, this may also provide insight into other extraordinary anecdotal effects of zolpidem.A limitation of our PET analysis was that the scan was not performed in EEG verified slow wave sleep (SWS), when parasomnias are thought to emerge. Future 18F-FDG-PET studies in patients with zolpidem induced parasomnias could be attempted during EEG verified SWS on and off zolpidem to identify differences in glucose metabolic rates not seen in our analysis. However, this may prove to be difficult given the variable presence of SWS and the need to wait 1 h after FDG injection prior to the PET scan. By the time the patient receives the FDG injection and the scan is performed, the patient may no longer be in SWS. And though parasomnias tend to emerge in SWS, they can potentially arise from any NREM stage.Temporal resolution is not a major limitation of PET studies in that in order to scan a brain the cortical area is divided into thirds and scanned in 3 successive 5-min sessions that are then compiled together to form an entire cortical scan. As a result, the PET findings in any particular cortical area are an estimation of glucose metabolic rate over a five minute time window. Despite this small time window, 18F-FDG-PET findings would be difficult to correlate with a particular arousal in a period of SWS. Similar studies may be performed on and off medication in NREM and REM to assess differences in brain cortical glucose metabolic rates, though the procedural limitations described above would still apply.Single photon emission computed tomography (SPECT) studies have been used successfully to show increased cerebral blood flow in a range of cortical areas after zolpidem administration despite a more limited spatial resolution than PET. SPECT has been used to show increased regional blood flow in the frontal cortex in Broca aphasia, the cerebellum in spinocerebellar ataxia, and the contralateral hemisphere in hemiparetic patients.19–21 In normal baboon models, SPECT has been used to demonstrate that zolpidem does not cause changes in regional cerebral blood flow in normal baboons. However, in baboons with cortical injuries, zolpidem increased blood flow to the injured areas.22 Zolpidem mediated increase in regional cerebral blood flow to injured cortical areas on SPECT was attenuated by the use of flumazenil, a benzodiazepine receptor antagonist.23 The baboon studies correlate to the case report of Brefel-Courbon et al. of a patient in a post-anoxic minimally conscious state showing arousal on clinical exam and increased cerebral glucose metabolism on 18F-FDG-PET in the bilateral post-rolandic territories and frontal lobes after zolpidem administration.24 The normal baboon SPECT study findings also correlate with the 18F-FDG-PET findings in our neurologically intact patient and Gillin's normal volunteer cohort.17To date no large scale randomized controlled trials exist assessing the efficacy of zolpidem for aphasia, blepharospasm, catatonia, central pontine myelinolysis, dementia with apraxia, Parkinson disease, progressive supranuclear palsy, restless legs syndrome, post-anoxic spasticity, or spinocerebellar ataxia. The clinical benefit of zolpidem for patients in minimally conscious states is currently being explored in clinical trials.25 These results may also help to further understand sleep-wake mechanisms and the function of hypnotics.The anecdotal benefits of zolpidem have provided hope that damage to brain tissue after strokes anoxic insults previously thought to be permanent may actually be reversible. Zolpidem may reactivate cortical areas that have undergone injury-induced dormancy, or there may be more redundancy built into our brains than previously believed, e.g. CPGs. GABAergic hypnotics like zolpidem through diffuse cortical binding may somehow unmask this redundancy.Future studies may also shed light on whether different susceptibilities to zolpidem induced parasomnias and its other effects may depend upon the formulation used. For example, Chiang et al. reported 2 patients who experienced zolpidem induced sleepwalking and SRED on only the extended release formulation and not the non-extended release formulation.26 Validation of these anecdotal findings and investigations into the new sublingual formulation of zolpidem may provide insight into how formulation dependent pharmacokinetics may influence an individual's susceptibility to zolpidem-induced parasomnias.27Investigations into the mechanisms of action of GABAergic induced parasomnias may overturn therapeutic nihilism for a variety of neurological disease. Capitalizing upon zolpidem's myriad anecdotal serendipitous effects, basic science research using animal models of non–sleep-wake related neurological disorders may provide us with a of understanding how the brain reorganizes itself after injury. Also genetic analysis of individual patients may also provide insight into potentially identifiable pharmacogenetic vulnerabilities/susceptibilities. These exciting and unexplored avenues of research may be used in the treatment of disease previously thought untreatable.DISCLOSURE STATEMENTThis was not an industry supported study. The authors have indicated no financial conflicts of interest.REFERENCES1 American Academy of Sleep MedicineThe international classification of sleep disorders: diagnostic – coding manual20052nd edWestchester, ILAmerican Academy of Sleep MedicineGoogle Scholar2 National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005Sleep200528104957, 16268373Google Scholar3 Ganzoni ESantoni JPChevillard VSebille MMathy BZolpidem in insomnia: a 3-year post-marketing surveillance study in SwitzerlandJ Int Med Res1995236173, 7774760CrossrefGoogle Scholar4 Sauvanet JPMaarek LRoger MRenaudin JLouvel EOrofiamma BOpen long-term trials with zolpidem in insomnia. 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