Clinical Therapeutics/Volume 36, Number 11, 2014

Hypnotics in Insomnia: The Experience of Zolpidem James MacFarlane, PhD1; Charles M. Morin, PhD2; and Jacques Montplaisir, MD, PhD3,4 1

Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; MedSleep (Network of Clinics) Toronto, Canada; 2School of Psychology, Universite´ Laval, and Sleep Research Center, Institut Universitaire en Sante´ Mentale de Que´bec, Montreal, Que´bec, Canada; 3Department of Psychiatry, Universite´ de Montre´al, Montreal, Que´bec, Canada; and 4Center for Advanced Research in Sleep Medicine (CARMS), Sacre´-Coeur Hospital, Montreal, Que´bec, Canada ABSTRACT Purpose: One of the most commonly prescribed medications to treat insomnia is zolpidem, a nonbenzodiazepine compound that is available as an immediate-release oral tablet formulation, an extended-release oral formulation, an oral spray formulation, and as sublingual formulations. The purpose of this review was to summarize the data currently available on the efficacy and safety of zolpidem in the treatment of insomnia among adults. Methods: Published studies on the use of zolpidem in the treatment of insomnia were identified by using combinations of relevant search terms in PubMed and Google Scholar. Studies were included if they were placebo- or active comparator–controlled studies, with the exception of trials on the long-term use of zolpidem. Studies were limited to those conducted in adults. Studies were not included if the patient population was small, if the study was not designed or powered to assess the efficacy or safety of zolpidem, if insomniac patients had a medical condition in addition to insomnia (with the exception of comorbid depression or anxiety for studies on comorbid insomnia), or if zolpidem was given concomitantly with any other therapy (with the exception of selective serotonin reuptake inhibitors for studies on comorbid insomnia). Findings: Twenty-five studies designed to evaluate the efficacy of zolpidem in insomnia and 51 studies reporting the safety of zolpidem in insomnia were included in this review. Implications: The studies discussed in this review report the efficacy and safety of zolpidem in both young adults and the elderly. It can be used for either bedtime or middle-of-the-night administration, over the short or long term, with minimal risk of withdrawal or abuse. The use of zolpidem is associated

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with rebound insomnia, complex sleep-related behaviors, and next-day residual effects (after middle-of-thenight dosing) on driving ability, memory, and psychomotor performance. (Clin Ther. 2014;36:1676–1701) & 2014 Elsevier HS Journals, Inc. All rights reserved. Key Words: chronic insomnia, primary insomnia, secondary insomnia, zolpidem.

INTRODUCTION The central features of insomnia, as identified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, are dissatisfaction with sleep quantity or quality accompanied by complaints of difficulty initiating or maintaining sleep that result in clinically significant distress or impairment in social, occupational, or other important areas of functioning.1 Insomnia may occur during the course of another medical condition or mental disorder (comorbid insomnia), or it may occur independently (primary insomnia).2 The standard approach to treating comorbid insomnia used to be to treat the primary disorder, and the resolution of insomnia was expected to follow once the primary disorder achieved remission.3 In recent years, there has been a shift in the approach to treating comorbid insomnia. Comorbid insomnia is increasingly recognized as a separate disorder that requires treatment either on its own or in conjunction with the primary condition.4 Improving quantitative and qualitative aspects of sleep, improving daytime function, and reducing the distress and anxiety associated with poor sleep are the Accepted for publication September 24, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.09.017 0149-2918/$ - see front matter & 2014 Elsevier HS Journals, Inc. All rights reserved.

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J. MacFarlane et al. main goals of treatment.5 Current treatment options for insomnia can be broadly categorized into nonpharmacologic and pharmacologic approaches. Nonpharmacologic treatment options include cognitive-behavioral therapy, which involves various behavioral interventions (eg, stimulus control therapy, relaxation training, sleep restriction therapy, sleep hygiene, paradoxical intention therapy).6–11 Pharmacologic treatment options, indicated or off-label, include benzodiazepine receptor agonists, melatonin receptor agonists, sedating antidepressants, atypical antipsychotics, sedating antihistamines, and unregulated substances (eg, valerian, melatonin).12–16 Patients also try self-help strategies including reading and relaxation, home remedies such as alcohol, and herbal therapies.17 One of the most commonly prescribed medications to treat insomnia is zolpidem, a nonbenzodiazepine compound that acts by modulating the binding of γaminobutyric acid (GABA) at the benzodiazepinebinding site on the GABAA receptor complex.18 In 1992, the immediate-release oral tablet formulation of zolpidem was approved in the United States for the treatment of patients with insomnia.19 In 2005, an extended-release formulation was approved for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.20,21 In 2008, an oral spray formulation of zolpidem was approved for the treatment of insomnia characterized by difficulty with sleep initiation.22 More recently, sublingual formulations of zolpidem have been approved, one a sublingual tablet approved for bedtime administration, and the other a sublingual lozenge specifically approved for middle-of-the-night (MOTN) awakening and difficulty returning to sleep.19,23–25 The present review details the evidence supporting zolpidem as a current therapy for the treatment of insomnia, with a focus on its efficacy in treating sleep onset and maintenance; primary, comorbid, and chronic insomnia; and its benefits with regard to next-day residual effects, long-term use, “as-needed” use, and risk of abuse.

MATERIALS AND METHODS Published studies on the use of zolpidem in the treatment of insomnia were identified by using PubMed and Google Scholar. Searches were conducted for articles that contained combinations of

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the following terms: abuse, adverse events, as needed, chronic, comorbid, complex behaviors, dependence, efficacy, elderly, gender, guidelines, induction, insomnia, intermittent, latency, long-term, maintenance, middle-of-the-night, next-day, onset, parasomnia, pregnancy, primary, rebound, residual, safety, secondary, side effects, sleep, withdrawal, and zolpidem. The literature search was limited to English language, with no restrictions regarding year of publication. Studies were included in this review if they were placebo- or active comparator–controlled trials, with the exception of studies on the long-term use of zolpidem that typically followed up patients taking zolpidem over extended periods and thus did not have a placebo or active comparator group. Studies were limited to those conducted in adults. Studies were not included if the patient population was small, if the study was not designed or powered to assess the efficacy or safety of zolpidem, if insomniac patients had a medical condition in addition to insomnia (with the exception of comorbid depression or anxiety for studies on comorbid insomnia), or if zolpidem was given concomitantly with any other therapy (with the exception of selective serotonin reuptake inhibitors for studies on comorbid insomnia). Studies supporting the efficacy of zolpidem that are discussed in detail in this review are listed in the Table.

EFFICACY OF ZOLPIDEM Zolpidem in Primary Insomnia Zolpidem is effective in treating primary insomnia in adults by improving the induction, maintenance, and duration of sleep (Table). In one study designed to subjectively evaluate the efficacy and safety of a nightly dose of zolpidem 10 mg in patients with primary insomnia, patients receiving zolpidem reported significantly longer total sleep time (422.2 [11.0] vs 389.0 [10.1] minutes, respectively; P = 0.054), fewer awakenings after sleep onset (0.8 [0.1] vs 1.2 [0.1]; P = 0.014), shorter time spent awake after sleep onset (18.1 [3.4] vs 34.6 [4.8] minutes; P = 0.001), shorter sleep latency (43.2 [6.9] vs 64.0 [7.7] minutes; P = 0.001), greater ease of falling asleep (34.8 [2.2] vs 45.2 [2.3]; P = 0.004; measured on a Visual Analog Scale where 0 = very easy and 100 = not at all easy), and better quality of sleep (2.2 [0.1] vs 2.5 [0.01]; P = 0.007; measured on a Likert Scale where 1 = excellent and 4 = poor) compared with patients receiving placebo.26 Similarly, the efficacy of

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Study

Design

Zolpidem in primary insomnia Randomized, double-blind, placebo-controlled Dockhorn study of zolpidem 10 mg and placebo given and Dockhorn, for 7–10 days 199626

Walsh et al, 199829

Randomized, placebo-controlled, parallel-group, double-blind, 14-day comparison of trazodone 50 mg and zolpidem 10 mg

Roth et al, 200627 Randomized, double-blind, placebo-controlled, parallel-group, multicenter study of modifiedrelease zolpidem 12.5 mg and placebo over 3 weeks Randomized, double-blind, placebo-controlled, Walsh et al, parallel-group, multicenter study of extended200828 release zolpidem 6.25 mg or placebo over 3 weeks

Patients

Conclusion

Patients with primary Patients rated that falling asleep was easier with insomnia zolpidem than with placebo. Compared with patients receiving placebo, patients in the N ¼ 68 zolpidem zolpidem group reported reduced latency to N ¼ 66 placebo sleep on all nights of treatment, longer total sleep time, fewer awakenings after sleep onset, shorter wake time after sleep onset, greater ease of falling asleep, and better quality of sleep. Patients with primary Both zolpidem and trazodone significantly insomnia improved sleep latency and sleep duration compared with placebo during the first week. N ¼ 100 zolpidem During the second week, only patients in the N ¼ 98 trazodone zolpidem group had significantly improved sleep N ¼ 103 placebo latency and sleep duration compared with placebo. Patients with primary Compared with placebo, zolpidem improved wake insomnia after sleep onset, latency to persistent sleep, and N ¼ 93 zolpidem sleep efficiency. N ¼ 99 placebo Patients with primary Compared with placebo, zolpidem significantly insomnia decreased wake time after sleep onset, reduced N ¼ 94 zolpidem latency to persistent sleep, and increased total N ¼ 104 placebo sleep time, both at nights 1/2 and 15/16. Sleep efficiency improved only on nights 1/2.

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Zolpidem in sleep onset Healthy volunteers Roth et al, 199530 Randomized, placebo-controlled, single-night, double-blind study of zolpidem 5, 7.5, 10, 15, N ¼ 52 zolpidem and 20 mg in a model of transient insomnia 5 mg N ¼ 102 zolpidem 7.5 mg

This study focused on the efficacy of zolpidem 7.5 mg and 10 mg compared with placebo. Zolpidem 7.5 mg and 10 mg were effective in this model of transient insomnia; zolpidem decreased sleep latency and increased sleep duration and maintenance. (continued)

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Table. Studies supporting the efficacy of zolpidem in the treatment of insomnia

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Table. (continued). Study

Erman et al, 200131

Tsutsui, 200132

Staner et al, 200934

Staner et al, 201036

Design

Patients

Conclusion

(continued)

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N ¼ 104 zolpidem 10 mg N ¼ 51 zolpidem 15 mg N ¼ 51 zolpidem 20 mg N ¼ 102 placebo Randomized, placebo-controlled, single-night Healthy volunteers Both zolpidem and temazepam improved sleep laboratory-based, double-blind study of N ¼ 269 zolpidem latency. There was no difference between zolpidem 10 mg and temazepam 15 mg N ¼ 272 temazepam zolpidem and temazepam. N ¼ 89 placebo Randomized, double-blind comparison of Patients with chronic Compared with zopiclone, zolpidem improved zolpidem 10 mg and zopiclone 7.5 mg primary insomnia sleep-onset latency in significantly more patients. Significantly fewer patients in the zolpidem group N ¼ 209 zolpidem showed longer sleep-onset latency relative to N ¼ 219 zopiclone baseline at follow-up. Randomized, 3-period, crossover, single-center, Healthy volunteers Sublingual zolpidem 10 mg was effective in open study of sublingual zolpidem 5 and 10 N ¼ 18 total, number producing significantly earlier sleep initiation mg versus oral zolpidem 10 mg in a postnap per treatment group compared with oral zolpidem 10 mg. model of transient insomnia not specified in article Randomized, double-blind, 2-period, crossover Patients with primary Sublingual zolpidem 10 mg was superior to oral multicenter study comparing sublingual insomnia zolpidem 10 mg in improving sleep onset. zolpidem 10 mg versus oral zolpidem 10 mg N ¼ 70 sublingual zolpidem 10 mg N ¼ 70 oral zolpidem 10 mg

Study

Design

Patients

Conclusion

Randomized, double-blind, active-controlled, Patients with primary Compared with baseline, both zaleplon and double-dummy, comparative study of zolpidem insomnia zolpidem significantly improved sleep latency. 10 mg and zaleplon 10 mg N ¼ 24 zolpidem No significant difference was observed between N ¼ 24 zaleplon zaleplon and zolpidem. Randomized, double-blind, double-dummy, Health volunteers Sublingual zolpidem at both 5 mg and 10 mg Valente et al, controlled, open study comparing sublingual N ¼ 19 sublingual induced earlier sleep onset than oral zolpidem 201335 zolpidem 5 and 10 mg versus oral zolpidem zolpidem 5 mg 10 mg. 10 mg in a model of transient insomnia N ¼ 20 sublingual Subjective perception of earlier sleep onset was zolpidem 10 mg reported by subjects receiving sublingual zolpidem N ¼ 19 oral zolpidem 10 mg. 10 mg Zolpidem in chronic insomnia Multicenter, single-blind study of 12 weeks of Patients with chronic Compared with baseline, changes in patients' Scharf et al, nightly treatment with zolpidem 15 mg primary insomnia subjective assessments of sleep latency, total 199448 N ¼ 229 patients; 155 sleep time, number of awakenings, and sleep completed 12 weeks quality during the course of the study were of treatment significantly improved after 12 weeks. Randomized, double-blind, placebo-controlled, Patients with chronic Leppik et al, Zolpidem and temazepam, but not triazolam, parallel group, multicenter study comparing 199747 primary insomnia produced significantly shorter self-reported zolpidem 5 mg, triazolam 0.125 mg, and N ¼ 82 zolpidem 5 mg sleep latency after 4 weeks of treatment temazepam 15 mg N ¼ 85 triazolam compared with placebo. 0.125 mg N ¼ 84 temazepam 15 mg N ¼ 84 placebo Randomized, double-blind comparison of Patients with chronic Zolpidem and zopiclone were equally effective in Tsutsui, 200132 zolpidem 10 mg and zopiclone 7.5 mg primary insomnia achieving ratings of “moderately improved” sleep. N ¼ 209 zolpidem Sleep-onset latency improved significantly in N ¼ 219 zopiclone more patients in the zolpidem group than in the zopiclone group. Huang et al, 201133

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(continued)

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Table. (continued).

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Table. (continued). Study

Design

Krystal et al, 200849

Randomized, double-blind, placebo-controlled, parallel-group, multicenter study of zolpidem extended-release 12.5 mg or placebo 3 to 7 nights/week for 6 months

Randall et al, 201250

Randomized, double-blind, placebo-controlled study of nightly zolpidem 10 mg (5 mg for patients aged 460 years) or placebo 30 minutes before bedtime for 8 months

Zolpidem use as needed Randomized, double-blind, placebo-controlled, Walsh et al, parallel group, multicenter study of zolpidem 200055 10 mg or placebo 3 to 5 nights/week for 8 weeks Randomized, double-blind, placebo-controlled, ZOLDIS, Allain multicenter study of zolpidem10 mg or et al, 200157 placebo over 3 weeks; patients were asked to use as few tablets as possible

Patients with chronic primary insomnia N ¼ 669 zolpidem extended-release 12.5 mg N ¼ 349 placebo Patients with chronic primary insomnia N ¼ 60 zolpidem N ¼ 65 placebo

Patients with primary insomnia N ¼ 63 zolpidem N ¼ 71 placebo Patients with primary insomnia N ¼ 124 zolpidem N ¼ 121 placebo

Patients with chronic primary insomnia N ¼ 388 nightly zolpidem N ¼ 408 nonnightly zolpidem

Conclusion Patients receiving zolpidem reported significant improvements in sleep onset and sleep maintenance, as well as sustained improvement in morning sleepiness and ability to concentrate compared with placebo. Patients in the zolpidem group experienced significantly increased overall total sleep time and sleep efficiency, as well as reduced sleep latency and wake after sleep onset, compared with the patients in the placebo group at months 1 and 8. Zolpidem was significantly better than placebo in initiating and maintaining sleep on nights taken, and significantly reduced insomnia severity throughout the study. Total sleep time during the last week of the study relative to baseline did not differ between the 2 groups. Zolpidem was significantly more effective than placebo in improving sleep quality and quality of life, and was associated with less daytime drowsiness. Both nightly and nonnightly use of zolpidem improved sleep and quality of life in patients with insomnia.

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(continued)

J. MacFarlane et al.

STILINT II, Hajak Randomized, double-blind, pan-European, multicenter study comparing nightly and et al, 200253 nonnightly zolpidem 10 mg over 2 weeks

Patients

Study

Design

INSOMNIA 2000 Prospective, observational, multicenter, open study of zolpidem 10 mg, taken for a maximum Hajak et al, 52 of 5 nights/week for 3 weeks 2002 Perlis et al, 200454 Randomized, double-blind, placebo-controlled, parallel-group, multicenter study of zolpidem 10 mg or placebo 3 to 5 nights/week for 12 weeks Levy et al, 200460 Open, noncomparative, multicenter study of zolpidem 10 mg (5 mg for patients aged 460 years) up to 7 nights/per week over 3 weeks

Patients

Conclusion

Patients with chronic primary insomnia N ¼ 2690 zolpidem Patients with primary insomnia N ¼ 98 zolpidem N ¼ 101 placebo Patients with primary insomnia N ¼ 1734 zolpidem

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At the end of the study, the time to sleep onset was significantly reduced, and total sleep time was significantly improved. Compared with placebo, zolpidem was significantly better in improving sleep latency, number of awakenings, wake time after sleep onset, and total sleep time. Ninety percent of patients showed moderate to very marked improvement on CGI scales. Other sleep quality and clinical improvement parameters indicated overall satisfaction. Roth et al, 201359 Randomized, double-blind, placebo-controlled, Patients with primary Zolpidem significantly reduced latency to return parallel-group, multicenter study of sublingual insomnia and to sleep compared with placebo. Sleep quality zolpidem 3.5 mg or placebo, taken after difficulty returning to was improved, and morning sleepiness/ middle-of-the-night awakening sleep after middle-ofalertness scores also improved with zolpidem the-night awakenings compared with placebo. N ¼ 150 zolpidem N ¼ 144 placebo Zolpidem in comorbid insomnia Asnis et al, 199963 Randomized, double-blind, parallel-group study Patients with insomnia Compared with placebo, the zolpidem group had of zolpidem 10 mg or placebo over 4 weeks and depression under significantly longer sleep times, better sleep treatment with an quality, and reduced wake after sleep onset, SSRI along with feeling significantly more refreshed, N ¼ 94 zolpidem less sleepy, and more able to concentrate. N ¼ 96 placebo Fava et al, 200962 Randomized, double-blind, placebo-controlled, Patients with insomnia At all time points assessed, and at the end of the parallel-group study of extended-release and comorbid study, there was a significant improvement in zolpidem 12.5 mg or placebo over 8 weeks generalized anxiety the zolpidem/escitalopram group compared disorder under with the placebo/escitalopram group in total treatment with sleep time, sleep-onset latency, wake time after escitalopram sleep onset, number of awakenings, and N ¼ 191 zolpidem quality of sleep. N ¼ 190 placebo (continued)

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Table. (continued).

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CGI ¼ Clinical Global Impressions; SSRI ¼ selective serotonin reuptake inhibitor; INSOMNIA 2000 = Insomnia patients treated in the year 2000 study; STILINT II = STILnox INTermittent II study; ZOLDIS = ZOLpidem DIScontinuous study.

Compared with placebo, extended-release zolpidem administered concomitantly with escitalopram significantly improved sleep onset, sleep maintenance, and total sleep time. Zolpidem did not significantly augment the antidepressive effect of escitalopram. Patients with insomnia and comorbid depression N ¼ 93 zolpidem/ escitalopram N ¼ 94 placebo/ escitalopram Fava et al, 201164 Randomized, double-blind, placebo-controlled, 2-phase, parallel-group study of extendedrelease zolpidem 12.5 mg or placebo concomitant to escitalopram 10 mg over 24 weeks

Study

Table. (continued).

Design

Patients

Conclusion

J. MacFarlane et al. extended-release zolpidem 12.5 mg was investigated in patients with primary insomnia.27 Compared with placebo, patients receiving zolpidem reported significant improvements in wake after sleep onset (41:26 [33:17] vs 21:27 [20:33] minutes; P ¼ 0.0001), latency to persistent sleep (30:29 [30:36] vs 22:10 [21:43] minutes; P ¼ 0.0338), and sleep efficiency (0.800 [0.096] vs 0.839 [0.091]; P ¼ 0.0172). In elderly patients with primary insomnia, zolpidem significantly improved both sleep maintenance and sleep induction during 3 weeks of administration.28 Patients who were given zolpidem experienced reduced wake time after sleep onset, measured by using polysomnography (PSG), compared with placebo during the first 2 days of treatment (35:23 [26.41] vs 62:31 [30:41] minutes; P o 0.0001) and after 2 weeks of treatment (49:43 [36.21] vs 62:45 [31:28] minutes; P ¼ 0.0042). In addition, latency to persistent sleep during the first 2 days of treatment (19:23 [20:11] vs 29:06 [24:15] minutes; P ¼ 0.0001) and after 2 weeks of treatment (22:24 [20:01] vs 27:40 [22:36] minutes; P ¼ 0.0255) was also significantly improved in the zolpidem group compared with the placebo group, measured according to overnight PSG. Sleep efficiency measured by using PSG was significantly improved only during the first 2 days of treatment (0.729 [0.091] for the placebo group vs 0.802 [0.092] for the zolpidem group; P ¼ 0.0001) and not after 2 weeks of treatment (0.734 [0.104] for the placebo group vs 0.758 [0.112] for the zolpidem group; P ¼ 0.0509). The efficacy of zolpidem 10 mg was compared with that of trazodone 50 mg in improving self-reported sleep latency and sleep duration over 14 days in patients with primary insomnia.29 During the first week, both zolpidem and trazodone produced significantly shorter self-reported sleep latencies than placebo (by 35% and 22%, respectively). Patients treated with zolpidem reported a significantly shorter mean sleep latency (48.2 [2.7] minutes) than patients treated with trazodone (57.7 [4.0] minutes, P o 0.037). During the second week, only patients in the zolpidem group maintained significantly shorter sleep latency than placebo (48.1 [3.1] vs 64.7 [4.6] minutes, respectively; P o 0.005). Both zolpidem and trazodone produced significantly longer self-reported sleep durations (378.8 [5.3] minutes and 366.4 [6.4] minutes) than placebo (344.6 [5.3] minutes) during the first week. During the second week, only patients in

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Clinical Therapeutics the zolpidem group maintained significantly shorter sleep latency (P o 0.005) and significantly longer sleep duration (P o 0.02) than the placebo group. Zolpidem has also been studied for its efficacy in decreasing time to sleep onset in patients with primary insomnia, its efficacy in patients with chronic primary insomnia, and its efficacy when used nonnightly or as needed.

Zolpidem in Sleep Onset One of the main features of insomnia is difficulty initiating sleep, defined as subjective sleep latency 420 to 30 minutes.1 Studies with healthy volunteers suggest that zolpidem significantly reduces sleep-onset latency (Table). In a placebo-controlled, double-blind, parallel-group study using a model of transient insomnia in 462 healthy volunteers, Roth et al30 reported that zolpidem reduced sleep latency and improved duration and maintenance, measured by using PSG, without a significant effect on next-day psychomotor performance. Subjects experienced significantly shorter sleep latency with zolpidem 7.5 mg (17.0 [1.4] minutes) and 10 mg (17.4 [1.6] minutes) compared with placebo (27.1 [2.6] minutes; P o 0.001 for both). PSG recordings showed that sleep maintenance was improved in terms of number of awakenings with zolpidem 7.5 mg (5.0 [0.3]) and zolpidem 10 mg (5.3 [0.4]) compared with placebo (6.7 [0.4], P ¼ 0.004 and P ¼ 0.014, respectively) and in terms of wake time after sleep onset with zolpidem 7.5 mg (21.2 [2.4] minutes) and zolpidem 10 mg (21.4 [2.4] minutes) compared with placebo (31.4 [3.1] minutes; P ¼ 0.004 and P ¼ 0.005, respectively). Zolpidem also reduces latency to sleep onset in patients with insomnia (Table). Erman et al31 compared the efficacy of zolpidem and temazepam at reducing latency to sleep onset measured by using PSG in a phase advance model of transient insomnia, in which patients were asked to go to bed 2 hours earlier than their usual bedtime in a sleep laboratory. In this study, healthy volunteers were given zolpidem 10 mg, temazepam 15 mg, or placebo. Of the 630 subjects who completed the study, subjective latency to persistent sleep was significantly longer for the placebo group (35.0 [3.9] minutes) than for either the zolpidem (23.0 [1.3] minutes) or temazepam (23.9 [1.2] minutes) groups (P o 0.01 vs placebo for both). No significant difference was observed between the 2 active treatment groups. Studies suggest that zolpidem is at least as effective as

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zopiclone in initiating sleep onset in patients with chronic primary insomnia.32 Zolpidem 10 mg and zopiclone 7.5 mg were administered at night for 14 days, with a 1-week follow-up, and patient diaries were used to assess sleep and sleep-associated parameters. After 14 days, sleep-onset latency improved in significantly more patients in the zolpidem group compared with the zopiclone group (85.8% vs 77.5%; P ¼ 0.041). At follow-up, significantly fewer patients in the zolpidem group experienced worsened sleep-onset latency compared with baseline than patients in the zopiclone group (4.5% vs 15.4%; P ¼ 0.005). In a study using patients’ sleep diaries to compare the efficacy of zolpidem and zaleplon in reducing sleep latency in patients with primary insomnia, zolpidem was not significantly different from zaleplon.33 Patients received zolpidem 10 mg or zaleplon 10 mg over a 2week period. At the end of the study, patients in both the zolpidem and zaleplon arms reported a significant decrease in sleep latency compared with baseline. In the zolpidem group, sleep latency decreased from 61.9 (44.7) minutes at baseline to 30.0 (31.1) minutes at the end of the study (P o 0.05), whereas sleep latency decreased from 63.0 (34.5) minutes at baseline to 31.6 (20.5) minutes at the end of the study in the zaleplon group (P o 0.05). This improvement was noted by day 7 of the study in both groups. There was no significant difference noted between the 2 groups in sleep latency. More recently, studies with sublingual zolpidem have reported better efficacy than oral zolpidem in initiating early onset of sleep in both healthy volunteers and patients with insomnia. The efficacy of single doses of sublingual zolpidem 5 mg and 10 mg versus oral zolpidem 10 mg in healthy volunteers was compared by using PSG in a postnap model of transient insomnia.34 Treatment with sublingual zolpidem 10 mg resulted in significantly shorter sleep-onset latency compared with oral zolpidem (14.17 [7.65] vs 19.97 [11.16] minutes, respectively; P ¼ 0.024). There was no difference in latency between sublingual zolpidem 5 mg and oral zolpidem. A subsequent study comparing sublingual zolpidem with oral zolpidem in healthy volunteers reported shorter sleep-onset latencies at lower doses of sublingual zolpidem.35 The latter study was conducted in 58 healthy volunteers who were given sublingual zolpidem 5 mg or 10 mg or oral zolpidem 10 mg before PSG. Subjects receiving sublingual zolpidem 5 mg and 10 mg had significantly earlier sleep onset

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J. MacFarlane et al. than subjects receiving oral zolpidem (12.09 [7.67], 9.96 [5.62], and 21.02 [15.07] minutes for sublingual zolpidem 5 mg and 10 mg and oral zolpidem 10 mg, respectively). In patients with primary insomnia, the efficacy of sublingual zolpidem 10 mg was compared with that of oral zolpidem 10 mg by using PSG in a study by Staner et al.36 Treatment with sublingual zolpidem resulted in significantly shorter sleep-onset latency compared with oral zolpidem (17.66 [13.37] vs 26.31 [22.72] minutes).

Zolpidem in Chronic Insomnia Evidence from the literature suggests that 50% of patients with insomnia continue to have symptoms for Z1 year, with many patients reporting duration of symptoms lasting several years.37–39 Patients with chronic insomnia typically experience irritability, labile mood, fatigue, and cognitive impairment.40 In addition, chronic sleep deprivation is associated with increased risk of various diseases, including cardiovascular disease, diabetes, and cancer.41–45 In a meta-analysis of 1894 patients with chronic insomnia, zolpidem as well as benzodiazepines produced reliable improvements in quantitative and qualitative subjective measures of sleep.46 Studies investigating the efficacy of zolpidem in the treatment of chronic insomnia are listed in the Table. Evidence from the literature suggests that zolpidem 10 mg is at least as effective as zopiclone 7.5 mg in improving sleep in patients with chronic primary insomnia over 14 days, with a 1-week follow-up.32 Of the 209 patients in the zolpidem group, 142 (67.9%) were rated at least “moderately improved” by investigators using a modified Clinical Global Impressions scale compared with 135 (61.6%) of 219 patients in the zopiclone group. In addition, sleep-onset latency improved in significantly more patients in the zolpidem group compared with the zopiclone group (85.8% vs 77.5%; P ¼ 0.041). At follow-up, significantly fewer patients in the zolpidem group experienced worsened sleep-onset latency compared with baseline than patients in the zopiclone group (4.5% vs 15.4%; P ¼ 0.005). In addition, zolpidem was associated with significantly less rebound insomnia when discontinued. Compared with placebo, zolpidem produced significantly shorter self-reported sleep latency in elderly patients with chronic insomnia, as reported in a study conducted by Leppik et al.47 This study compared the

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efficacy of zolpidem 5 mg, triazolam 0.125 mg, temazepam 15 mg, or placebo over 28 days, followed by a 4-day placebo withdrawal period, in decreasing sleep latency in elderly patients with chronic insomnia. Compared with placebo, only zolpidem produced significantly shorter sleep latency over all 4 weeks of the study period. After 4 weeks of treatment, sleep latency was 57.9 (5.6) minutes for the placebo group, 40.5 (3.1) minutes for the zolpidem group (P o 0.05 compared with placebo), 47.7 (3.5) minutes for the triazolam group, and 38.0 (3.0) minutes for the temazepam group (P o 0.05 compared with placebo). Because patients with chronic insomnia take medication for long periods of time, several studies have investigated the long-term use of zolpidem in this patient population. Scharf et al48 assessed the efficacy of zolpidem 15 mg (with dose reduction to 10 mg permitted if adverse events developed) over 12 weeks in patients with chronic insomnia. Patients were given placebo for an additional week to assess maintenance of improvement after discontinuation of zolpidem. At the end of the study, there were significant improvements in patients’ subjective assessments of sleep latency, total sleep time, number of awakenings, and sleep quality compared with baseline. Although patients experienced a partial return to baseline values during the placebo week (week 13), 35% to 50% of the improvement achieved in week 12 was maintained through to the end of the placebo week. Krystal et al49 investigated the safety and efficacy of zolpidem extended-release tablets for up to 6 months in patients with chronic primary insomnia. In this study, patients with chronic insomnia were given extended-release zolpidem 12.5 mg or placebo over 24 weeks. Patients were instructed to self-administer either zolpidem or placebo for a minimum of 3 nights per week to a maximum of 7 nights per week over the course of the study. At week 12, significantly more patients in the zolpidem group reported that their treatment “helped me sleep” than patients in the placebo group (89.8% vs 51.4%, respectively). This difference maintained significance up to week 24 (92.3% for zolpidem vs 59.7% for placebo). Zolpidem was also significantly superior to placebo throughout the study for all patient-reported measures of sleep onset and sleep maintenance, with improved next-day concentration and reduced morning sleepiness. There was no evidence of rebound insomnia during the first 3 nights after discontinuation.

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Clinical Therapeutics Randall et al50 conducted a clinical trial that evaluated the efficacy of zolpidem 10 mg (5 mg for patients aged 460 years) nightly over 8 months in adults with chronic primary insomnia. Patients in the zolpidem group experienced significantly increased overall total sleep time and sleep efficiency, reduced sleep latency, and wake after sleep onset measured by PSG compared with patients in the placebo group when assessed after 1 month and 8 months. After 1 month of treatment, mean total sleep time was 382.73 (56.2) minutes for the placebo group and 418.23 (37.9) minutes for the zolpidem group (P ¼ 0.0001), sleep efficiency was 79.78% (9.8%) for the placebo group and 86.30% (8.2%) for the zolpidem group (P ¼ 0.001), latency to sleep onset was 30.76 (21.5) minutes for the placebo group and 12.65 (8.8) minutes for the zolpidem group (P ¼ 0.001), and wake after sleep onset was 78.12 (45.9) minutes for the placebo group and 58.17 (41.1) minutes for the zolpidem group (P ¼ 0.033). After 8 months of treatment, total sleep time was 371.36 (65.1) minutes for the placebo group and 411.00 (32.7) minutes for the zolpidem group (P ¼ 0.0001), sleep efficiency was 78.88% (10.4%) for the placebo group and 85.71% (6.5%) for the zolpidem group (P ¼ 0.001), latency to sleep onset was 29.76 (26.9) minutes for the placebo group and 14.2 (12.2) minutes for the zolpidem group (P ¼ 0.001), and wake after sleep onset was 84.30 (45.2) minutes for the placebo group and 58.25 (32.7) minutes for the zolpidem group (P ¼ 0.002). For patients with chronic insomnia, less-thannightly administration of medication is often recommended.51 Several studies have investigated the efficacy of zolpidem when administered intermittently or as needed. Results from these studies suggest that efficacy is comparable whether the drug is administered every night or intermittently in patients with chronic insomnia.52–55

Zolpidem Use As Needed Typically, patients with insomnia do not experience sleep difficulty on a nightly basis.56 Early studies with zolpidem given on an as-needed basis revealed that it was both safe and efficacious when used in this manner (Table). The ZOLDIS (ZOLpidem DIScontinuous) study, a French study conducted in 245 patients with primary insomnia, evaluated the safety and efficacy of zolpidem administered at

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bedtime on an as-needed basis over a 4-week period, compared with placebo.57 At the end of the study, patient-reported increased total sleep time was not significantly different between the 2 groups (74.6 [77.7] minutes for zolpidem vs 63.2 [69.9] minutes for placebo). There was a significant difference in patient-reported total sleep time between the 2 groups during the nights in which medication was taken (82.7 [80.4] minutes for zolpidem vs 62.8 [77.2] minutes for placebo; P o 0.05). Compared with placebo, patients in the zolpidem group reported significant improvements with respect to sleep quality (14.1 [17.4] vs 20.6 [22.3], respectively; P ¼ 0.01), daytime drowsiness (–1.8 [12.6] vs –5.3 [14.9]; P ¼ 0.048), quality of life (3.0 [4.4] vs 5.4 [5.4]; P ¼ 0.0004), and scores on the Clinical Global Impressions scales (P ¼ 0.002 for all 6 measures of severity of illness, P o 0.0001 for all 3 measures of global improvement, and P ¼ 0.0004 for all 3 measures of efficacy index). The safety of zolpidem, measured as treatment-emergent adverse events, was similar to that of placebo (19% in the zolpidem group vs 15% in the placebo group). There was no difference between the 2 groups in the frequency of tablet intake. The results of the study suggest that zolpidem when used as needed is safe and efficacious, and it did not lead to any drug-seeking behavior. The STILINT II (STILnox INTermittent II) and INSOMNIA 2000 (Insomnia patients treated in the year 2000) studies studied the efficacy of zolpidem on an as-needed basis to treat chronic insomnia.53,58 STILINT II was a Pan-European study in 796 patients with insomnia who were given either continuous treatment with zolpidem 10 mg, or treatment alternating zolpidem 10 mg with placebo in random order, at bedtime over 2 weeks.53 There were no significant differences between the 2 treatment arms with respect to patient-reported sleep-onset latency (25.9 [21.9] minutes in the continuous treatment group and 33.9 [32.8] minutes in the discontinuous treatment group) and patient-reported total sleep time (6.5 [1.2] hours in the continuous treatment group and 6.3 [1.2] hours in the discontinuous treatment group). The INSOMNIA 2000 study was a German trial involving 2690 patients with chronic insomnia.52,53 In this study, patients could take zolpidem 10 mg at bedtime as needed over 3 weeks but were asked to stay in the range of 3 to 5 treatment nights per week. On the drug-free nights, patients had the choice of using

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J. MacFarlane et al. behavioral therapy (stimulus control). At the end of the study, as-needed use over 3 weeks resulted in a 30% decrease in the number of tablets taken without any significant impact on the treatment efficacy. In addition, subjective latency to sleep onset decreased significantly from 74.4 to 27.0 minutes (P o 0.00001), and subjective total sleep time increased significantly from 5.0 to 6.8 hours (P o 0.00001). Similar findings have been reported in a study with sublingual zolpidem as-needed MOTN dosing.59 This study was conducted in 295 patients with primary insomnia characterized by difficulty returning to sleep after MOTN awakenings. Patients were randomized to as-needed MOTN dosing with either sublingual zolpidem 3.5 mg or placebo for 4 weeks. Over the course of the study, patients in the zolpidem group reported significantly decreased subjective latency to sleep onset (38.2 vs 68.1 minutes at baseline) compared with patients in the placebo group (56.4 vs 69.4 minutes at baseline). In addition, patients in the zolpidem group reported significantly higher subjective ratings of morning alertness on nights when the medication was taken but not on other nights (5.59 [0.088] for zolpidem vs 5.24 [0.089] for placebo; P ¼ 0.0041). There was no difference between the 2 groups in the frequency of pill taking, with patients in the zolpidem group taking study drug on 62% of nights and patients in the placebo arm taking study drug on 64% of nights. Together, these studies suggest that as-needed dosing of zolpidem is efficacious and that pill taking did not increase with the active treatment. The use of zolpidem on an as-needed basis over longer periods (8 and 12 weeks) has not been associated with increases in pill-taking frequency. In 1 study in 163 patients with chronic primary insomnia, Walsh et al55 reported that zolpidem 10 mg taken as needed at bedtime over 8 weeks was efficacious and safe, with minimal evidence of rebound insomnia and no increase in pill-taking behavior. The mean number of nights on which study medication was taken was 7.7 (0.2) for the placebo group and 7.8 (0.2) for the zolpidem group during weeks 1 and 2 (P ¼ 0.54), 7.8 (0.2) for the placebo group and 7.6 (0.2) for the zolpidem group during weeks 3 and 4 (P ¼ 0.40), 7.7 (0.2) for the placebo group and 7.8 (0.2) for the zolpidem group during weeks 5 and 6, and 7.6 (0.2) for the placebo group and 7.9 (0.2) for the zolpidem group during weeks 7 and 8 (P ¼ 0.19). Not only

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were there no differences in the frequency of pill taking between the groups at any point during the study, the frequency of pill taking did not change significantly across the study period for either group. Another study compared zolpidem 10 mg with placebo over 12 weeks in 199 patients with primary insomnia who were told to take no fewer than 3 and no more than 5 pills per week at bedtime.54 Patients in the zolpidem group achieved significant improvements in several subjective sleep measures, including sleep latency (42% decrease), number of awakenings (51% decrease), wake time after sleep onset (55% decrease), and total sleep time (27% increase). Moreover, these clinical gains were not associated with increases in pill-taking frequency. The mean number of doses per 2-week increments across the 12-week study were similar to those observed by Walsh et al. Zolpidem was not associated with rebound insomnia between nights of treatment and drug-free nights. In a study designed to evaluate zolpidem consumption and evolution of its use in routine general practice, 1938 patients with insomnia were instructed to take zolpidem 10 mg (5 mg for patients aged 465 years) as needed at bedtime over 3 weeks.60 Over the course of the study, mean zolpidem consumption decreased steadily from 5.1 (1.9) doses per week in week 1 to 3.7 (2.5) doses per week during week 3. At the end of the study, 90% of patients reported moderate to very marked improvement, suggesting that zolpidem as-needed administration allows patients to adapt treatment to their needs and to the evolution of their insomnia.

Zolpidem in Comorbid Insomnia Insomnia is a primary symptom in 30% to 90% of psychiatric disorders, and anxiety and depression account for 40% to 50% of all cases of chronic insomnia.4,61 The current approach to treating comorbid insomnia is to treat insomnia in addition to treating the primary disorder.1 Concurrent zolpidem and escitalopram significantly improved insomnia in patients with comorbid insomnia and generalized anxiety disorder.62 In this study by Fava et al, zolpidem 12.5 mg or placebo was coadministered with escitalopram 10 mg over 8 weeks in 383 patients with comorbid insomnia and generalized anxiety disorder. At the end of the trial, and at all time points studied, patients who received concurrent zolpidem and escitalopram reported

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Clinical Therapeutics significantly greater total sleep time than patients who received placebo and escitalopram (106.0 vs 68.2 minutes, respectively; P o 0.0001). Moreover, improvements in subjective sleep measures including sleep onset latency, number of awakenings, wake time after sleep onset, quality of sleep, and sleep-related nextday symptoms (morning energy, morning concentration, and impact of sleep on daily activities), also significantly favored zolpidem at most visits. Mean Hamilton Rating Scale for Anxiety scores improved for both groups throughout the study (reductions of –13.3 for zolpidem plus escitalopram and –12.5 for placebo plus escitalopram), although there was no difference between the 2 treatment arms (P ¼ 0.4095). These results suggest that concomitant administration of zolpidem and escitalopram significantly improves insomnia and sleep-related next-day symptoms, without affecting anxiety symptoms, in patients with comorbid insomnia and generalized anxiety disorder. In patients with comorbid insomnia and depression, coadministration of zolpidem with a selective serotonin reuptake inhibitor has been associated with improvements in sleep-related measures. Asnis et al63 investigated the benefits of zolpidem 10 mg or placebo over 4 weeks in 190 patients who were being treated for depression with fluoxetine, sertraline, or paroxetine. Over the course of the study, patients in the zolpidem group reported significantly longer sleep times at weeks 1 through 4 compared with the placebo group, with a mean difference of 26 minutes (P o 0.05). Patients in the zolpidem group also reported significantly better sleep quality, with an 18% improvement over 4 weeks compared with an improvement of 9% for the placebo group (P o 0.05). In addition, patients in the zolpidem group reported significantly reduced wake after sleep onset at weeks 1, 2, and 4. The mean change in subjective wake after sleep onset from baseline was 30 minutes for the zolpidem group and 11 minutes for the placebo group (P o 0.05). Patients in the zolpidem group also reported feeling significantly more refreshed, less sleepy, and more able to concentrate. Fava et al64 reported that zolpidem given concomitantly with escitalopram to patients with comorbid insomnia and depression led to significant improvement in subjective sleep onset, sleep maintenance, and total sleep time. In this study, all 385 patients received open-label escitalopram 10 mg/d for the duration of the study. In phase 1, patients with depression were

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randomized to receive zolpidem 12.5 mg or placebo for 8 weeks. Patients whose depression improved (measured as a Z50% decrease in Hamilton Depression Rating Scale score) continued an additional 16 weeks of treatment, for a total of 24 weeks. Throughout phase 1, patients in the zolpidem group reported significantly greater improvements in total sleep time (P o 0.0001), wake time after sleep onset (P o 0.001), sleep-onset latency (P o 0.001), number of awakenings (P o 0.001), and sleep quality (P o 0.001) than patients in the placebo group. In addition, patients in the zolpidem group reported significant improvements in measures of sleep-related next-day functioning. However, there were no differences in depressive symptoms or quality of life in the zolpidem group compared with the placebo group. During phase 2, significant improvements in subjective total sleep time were maintained at weeks 12 and 16 in the zolpidem group (P o 0.05) but not at weeks 20 and 24. Patients in the zolpidem group maintained significant improvements in patient-reported number of awakenings and sleep quality through week 24 (P r 0.001 for both), in subjective wake time and sleep onset at weeks 16 and 20 (P o 0.05 for both), and in subjective measures of sleep-related next-day functioning through week 24 (P o 0.05). As in phase 1, there were no differences in depressive symptoms or quality of life in phase 2 between the 2 groups. The results of this study suggest that zolpidem administered concomitantly with escitalopram for up to 24 weeks is associated with significant sleep benefits compared with escitalopram monotherapy. Zolpidem, however, did not augment the antidepressive effects of escitalopram.

SAFETY OF ZOLPIDEM By 1998, a total of 13 postmarketing studies including 461,000 patients with various types of insomnia had been published and concluded that zolpidem is generally considered to be safe when administered according to labeling instructions.65,66 Zolpidem does not have any adverse effects on liver, cardiovascular, or renal function. Evidence indicates that rebound insomnia and withdrawal symptoms do not seem to be a significant problem, and zolpidem is not associated with significant dependence or abuse risks. It is currently recommended that the use of zolpidem should be avoided during pregnancy.67 It is believed that infants born to mothers taking sedative-hypnotic drugs such as zolpidem may be at

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J. MacFarlane et al. risk for physical dependence and withdrawal symptoms during the postnatal period. In addition, the pharmacologic action of zolpidem may cause hypothermia and moderate respiratory depression in the neonate, as well as neonatal flaccidity. There have been reports of severe neonatal respiratory depression among infants born to mothers who took zolpidem at the end of pregnancy, especially when taken along with other central nervous system depressants.67 To date, several studies have examined adverse outcomes among pregnant women taking zolpidem. Juric et al68 compared the rates of preterm delivery and low birth weight between a group of women taking zolpidem during pregnancy and a group of matched control subjects. The study investigators found that more women taking zolpidem experienced a preterm delivery than matched comparators (26.7% vs 13.3%), and more infants born to mothers taking zolpidem than infants born to matched comparators had low birth weight (15.6% vs 4.4%). In addition, zolpidem could be detected in umbilical cord blood, with the ratio of umbilical cord to maternal plasma zolpidem concentrations ranging from 0.48 to 2.75. A larger study was conducted more recently among 2497 mothers who received zolpidem treatment during pregnancy and 12,485 randomly selected mothers who did not receive the drug.69 The authors reported that mothers who took zolpidem had a higher incidence of delivery of lowbirth-weight infants (7.61% vs 5.19%; odds ratio [OR], 1.39 [95% CI, 1.17–1.64]; P o 0.001), preterm deliveries (10.01% vs 6.30%; OR, 1.49 [95% CI, 1.28–1.74]; P o 0.001), delivery of small-forgestational-age infants (19.94% vs 15.06%; OR, 1.34 [95% CI, 1.20–1.49]; P o 0.001), and cesarean deliveries (46.86% vs 33.46%; OR, 1.74 [95% CI, 1.59–1.90]; P o 0.001). Wikner and Källén70 compared the presence of congenital malformations among 1341 infants born to mothers who reported the use of zolpidem, zopiclone, or zaleplon in early pregnancy versus 1,125,734 infants born to mothers who did not. When the data were analyzed for specific malformations, there were significantly more infants born with intestinal malformations (other than atresia/ stenosis) among the mothers taking zolpidem compared with mothers not taking zolpidem (relative risk, 5.06 [95% CI, 1.38–13.0]). Taken together, these data support the recommendation that zolpidem should not be used during pregnancy.

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One of the largest postmarketing studies, including data from 16,994 patients with insomnia, was published by Hajak and Bandelow.66 Overall, 182 (1.1%) patients reported 268 adverse events, of which 113 cases reported 1 adverse event, 53 cases reported 2 adverse events, and 16 cases reported 42 adverse events. Of the patients reporting an adverse event, 118 (64.8% [0.006% of all participating patients]) discontinued treatment due to the adverse event. The most common adverse events were nausea (n ¼ 36), dizziness (n ¼ 35), malaise (n ¼ 23), nightmares (n ¼ 20), agitation (n ¼ 19), and headache (n ¼ 18). There were no life-threatening adverse events reported among the study population. This study, in addition to the 12 studies reviewed by Allain and Monti,65 support the findings of clinical studies assessing the safety of zolpidem in patients with insomnia. The most common adverse events (related to the central nervous system) can to a great extent be avoided by following the recommended doses and prescription rules.

Rebound Insomnia An issue of concern to clinicians is the occurrence of rebound insomnia after the discontinuation of zolpidem. There is conflicting evidence as to whether zolpidem is associated with rebound insomnia. In a meta-analysis of studies with short-acting hypnotic agents up to 1997, Soldatos et al71 reported that zolpidem was associated with minimal rebound symptoms, measured as a nonsignificant difference in total sleep time (–2.4 minutes [95% CI, –11.4 to 6.6]), but a significantly prolonged sleep-onset latency (13.0 minutes [95% CI, 4.3 to 21.7]) (P o 0.01) during the first night after discontinuing zolpidem. Results from studies designed to assess rebound insomnia reported no report signs of this condition after discontinuing zolpidem after 2 to 4 weeks, and up to 24 weeks of treatment.49,72–75 Two studies reported the occurrence of rebound insomnia, identified as at least 1 night with worse total sleep time of sleep latency after cessation of 3 or 4 weeks of zolpidem that was not worse than at baseline.27,76 One of these studies reported a 25.7% prevalence of rebound insomnia on the first night after discontinuing zolpidem that progressively decreased to 10.6% on night 7 after discontinuation.76 Rebound insomnia has been reported in elderly patients with insomnia during the first night after withdrawal of zolpidem (significantly longer subjective sleep latency by 16 minutes compared with placebo [P o 0.01] and

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Clinical Therapeutics significantly shorter subjective total sleep time by 17.5 minutes compared with placebo [P o 0.001]),77 although minimal or no evidence to support these findings were found in other studies28,47,78 in the same population.

Complex Sleep-Related Behaviors Another concern to clinicians is the occurrence of complex sleep-related behaviors (CSBs). CSBs are categorized as “parasomnias” in the International Classification of Sleep Disorders, Second Edition, defined as sleep disturbances characterized by undesirable physical events or experiences that occur during entry into sleep, within sleep, or during arousal from sleep.79 The use of zolpidem has been associated with certain CSBs, including sleepwalking with object manipulation (eg, cooking, cleaning), sleep conversations (on the telephone or in person), sleep eating, sleep driving, sleep shopping, and sleep sex.80 CSBs have also been described with other nonbenzodiazepine receptor agonists (zopiclone and zaleplon), as well as with benzodiazepines (triazolam and alprazolam) and drugs with a GABAergic mechanism of action. To date, zolpidem-associated CSBs are rare and have been documented mostly in case studies.80–84 Evaluation of individual reports revealed that many patients took large doses of zolpidem, had underlying psychiatric diseases, had medical diseases, or experienced drug–drug interactions.19 Patients who experience CSBs after taking zolpidem were significantly more likely to have taken a higher dose of zolpidem (410 mg/d; P o 0.001), to be younger (P ¼ 0.023), to be female (P ¼ 0.011), and to not go to sleep immediately after taking zolpidem (P ¼ 0.047).85 The only risk factor that predicted the occurrence of zolpidem-related CSBs was a higher dose of zolpidem (410 mg/d). In 2007, the US Food and Drug Administration (FDA) called for revisions to the Warnings and Precautions section of the product labels for 13 insomnia medications, including zolpidem, to include CSBs.19 Aside from rebound insomnia and CSBs, the dangers related to next-day residual effects, withdrawal, and abuse, as well as the safety of long-term use of zolpidem, have been studied.

Next-Day Residual Effects Zolpidem has been associated with next-day residual effects, although these effects appear to occur after

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MOTN administration and not after administration at bedtime.86–88 Because driving a car is a common yet potentially dangerous daily activity, the next-day residual effects on driving performance are of particular interest. These studies highlight the importance of allowing 8.5 hours before the desired arise time, although it has been suggested by clinicians that a full 9 hours is preferable.20 This dosing approach coincides with the lowest serum levels of zolpidem occurring at the desired arise time.67 Based on findings from recent studies, Health Canada and the FDA have recommended that the starting dose of zolpidem be lowered to 5 mg to minimize the risk of next-day residual effects.89,90 One study in 16 healthy volunteers investigated the residual effects of zolpidem 10 mg, zopiclone 7.5 mg, and flunitrazepam 1 mg on driving performance at 9:00 AM and 11:00 AM the morning after bedtime (11:00 PM) administration.91 At both 9:00 AM and 11:00 AM, zolpidem had no significant residual effects on driving performance compared with placebo (measured as variance of the lateral position during a simulated driving test), whereas both zopiclone and flunitrazepam impaired driving performance at 9:00 AM compared with placebo (P o 0.001 for both). There were no effects on driving performance at the 11:00 AM time point. In a similarly designed study investigating the residual effects of zolpidem on collision anticipation capacities the next morning, Berthelon et al92 also observed no residual effects in the zolpidem group. Blin et al93 conducted a study to measure the residual psychomotor and cognitive effects of zolpidem 12.5 mg or flurazepam 30 mg in 18 healthy young adults. Eight hours after bedtime dosing, subjects in the flurazepam group (but not subjects in the zolpidem group) were significantly impaired on critical flicker fusion frequency test (29.1 [0.5] Hz for the placebo group; 29.0 [0.6] Hz for the zolpidem group [P ¼ 0.6375 vs placebo]; and 28.2 [0.6] Hz for the flurazepam group [P ¼ 0.0066 vs placebo]), choice reaction time (619 [19] milliseconds for the placebo group; 635 [16] milliseconds for the zolpidem group [P ¼ 0.1837 vs placebo]; and 662 [17] milliseconds for the flurazepam group [P ¼ 0.0009 vs placebo]), immediate word recall (13.2 [0.8] for the placebo group; 12.7 [0.6] for the zolpidem group [P ¼ 0.5455 vs placebo]; and 10.7 [0.7] for the flurazepam group [P ¼ 0.0045 vs placebo]), and delayed word recall (10.3 [0.8] for

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J. MacFarlane et al. the placebo group; 8.9 [0.8] for the zolpidem group [P ¼ 0.1451 vs placebo]; and 5.9 [0.8] for the flurazepam group [P ¼ 0.0001 vs placebo]), compared with subjects in the placebo group. A recent study compared zolpidem and the antihistamines ketotifen and diphenhydramine in next-day residual effects in healthy adults after bedtime dosing.94 No difference was observed between the zolpidem group and the placebo group, whereas ketotifen and diphenhydramine were significantly associated with sleepiness (P o 0.05 using a visual analog scale to assess subjective sleepiness, and the multiple sleep latency test and alpha attenuation test to assess objective sleepiness) and psychomotor performance decline (P o 0.05 using the n-back test, 3 different tasks to measure reaction time to a stimulus, and the Digit Symbol Substitution Test [DSST]). In conclusion, these studies suggest a lack of next-day impairment of zolpidem in young, healthy adults. Next-day residual effects of zolpidem administered at bedtime in elderly, healthy volunteers have also been studied. Fairweather et al95 conducted a study in 24 elderly, healthy volunteers with a perceived sleep onset of at least 30 minutes. Subjects were given zolpidem 5 mg, zolpidem 10 mg, or placebo for 7 days at bedtime. On days 1 and 7, there were no differences between subjects in the zolpidem groups compared with the placebo group on choice reaction time, tracking, critical flicker fusion threshold, memory scanning, and word recognition. Hindmarch et al96 investigated the residual effects of zolpidem 6.25 mg, zolpidem 12.5 mg, and flurazepam 30 mg, given at bedtime, in 24 elderly, healthy volunteers. Eight hours after treatment, subjects in the flurazepam group, but not subjects in either zolpidem group, had significantly impaired psychometric performance on choice reaction times (842 [23] milliseconds for placebo, 841 [25] milliseconds for zolpidem 6.25 mg, 851 [25] milliseconds for zolpidem 12.5 mg, and 890 [28] milliseconds for flurazepam [the only significant difference was between flurazepam and placebo, P ¼ 0.005]), immediate word recall (9.2 [0.5] for placebo, 8.8 [0.6] for zolpidem 6.25 mg, 8.5 [0.7] for zolpidem 12.5 mg, and 6.4 [0.4] for flurazepam [the only significant difference was between flurazepam and placebo, P ¼ 0.0001]), delayed word recall (6.0 [0.7] for placebo, 5.9 [0.6] for zolpidem 6.25 mg, 4.9 [0.8] for zolpidem 12.5 mg, and 3.0 [0.5] for flurazepam [the only significant difference was

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between flurazepam and placebo, P ¼ 0.0001]), and continuous tracking test mean response time (655 [31] milliseconds for placebo, 635 [27] milliseconds for zolpidem 6.25 mg, 697 [53] milliseconds for zolpidem 12.5 mg, and 768 [60] milliseconds for flurazepam [the only significant difference was between flurazepam and placebo, P ¼ 0.0198]). Although the results of these 2 studies in elderly patients agree with results obtained in young, healthy adults, one study suggests that zolpidem is associated with next-day driving impairment when subjects are asked to perform a monotonous driving performance task.97 In this study, 16 elderly, healthy subjects were given zolpidem 10 mg, zopiclone 7.5 mg, or flunitrazepam 1 mg at bedtime and then asked the following morning to drive in a simulated monotonous (no traffic, repetitive landscape) driving environment for 1 hour. In this study, both zolpidem and zopiclone (compared with placebo) equivalently and significantly impaired the subjects’ ability to maintain a lateral position on the road and to maintain a speed of 110 km/h. The ability to maintain a lateral position on the road, measured as the SD of lateral position, was 0.48 (0.09) meter for placebo, 0.57 (0.14) meter for zolpidem (P ¼ 0.00002 vs placebo), 0.56 (0.14) meter for zopiclone (P ¼ 0.00004 vs placebo), and 0.52 (0.14) meter for flunitrazepam (P ¼ NS vs placebo). The ability to maintain a lateral position on the road, measured as the number of road exits, was 4.50 (4.3) for placebo, 27.5 (49.3) for zolpidem (P ¼ 0.02 vs placebo), 25.00 (43.3) for zopiclone (P ¼ 0.02 vs placebo), and 19.50 (42.3) for flunitrazepam (P ¼ NS vs placebo). The ability to maintain a speed of 110 km/h, measured as the SD of speed, was 2.96 (2.65) km/h for placebo, 4.67 (4.32) km/h for zolpidem (P ¼ 0.009 vs placebo), 4.70 (3.67) km/h for zopiclone (P ¼ 0.008 vs placebo), and 3.70 (2.97) km/h for flunitrazepam (P ¼ NS vs placebo). This study was the first to reveal residual effects of zolpidem on driving performance in elderly subjects. Several published studies have examined whether the results of studies with zolpidem given at bedtime in healthy volunteers could be generalized to patients with insomnia. Vermeeren et al98 investigated nextday residual effects in patients with insomnia, comparing single doses of zolpidem 10 mg and flunitrazepam 2 mg administered at bedtime. Results of psychometric tests conducted the following morning revealed that flunitrazepam, but not zolpidem, caused

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Clinical Therapeutics significant memory impairment. Results of driving performance tests suggest that neither flunitrazepam nor zolpidem had an effect compared with placebo. Staner et al99 conducted a study in 23 patients with primary insomnia who were given zolpidem 10 mg, zopiclone 7.5 mg, or lormetazepam 1 mg at bedtime, and driving tests were performed 9 to 11 hours later. Zolpidem was not different from placebo with regard to driving abilities, measured as ability to maintain the set speed of 130 km/h (123.7 [14.6] km/h for placebo vs 123.3 [8.2] km/h for zolpidem), lateral deviation from the ideal route (0.18 [0.3] meter for placebo vs 0.17 [0.4] meter for zolpidem), deviation from the speed limit (4.6 [13.2] km/h for placebo vs 5.7 [8.2] km/h for zolpidem), and number of collisions (0.21 [0.6] for placebo vs 0.15 [0.4] for zolpidem). Conversely, zopiclone increased the number of collisions (0.66 [1.9] vs 0.21 [0.6] for placebo; P o 0.01) and lormetazepam increased deviation from speed limit (3.0 [10.8] km/h vs 4.6 [13.2] km/h for placebo; P o 0.05) and deviation from absolute speed (127.2 [11.6] km/h vs 124.6 [15.4] km/h for placebo; P o 0.05). These studies corroborate the findings of studies conducted in healthy volunteers reporting that zolpidem does not increase residual effects in young, healthy adults. In contrast to studies using bedtime dosing of zolpidem, studies administering zolpidem for MOTN wakening have reported the occurrence of significant residual effects. Verster et al100 assessed the effects of MOTN administration of zolpidem 10 mg or 20 mg on driving ability, memory, and psychomotor performance in healthy volunteers. Driving ability was measured 4 hours after administration, and memory and psychomotor performance were measured 6 hours after administration. At the 10-mg dose, patients in the zolpidem group experienced significant impairment in driving ability, measured as elevated weaving over 100 kilometers on a 2-lane primary highway in real traffic (21.3 [6.7] vs 17.5 [4.2] cm for placebo; P o 0.005). There were no effects on memory and psychomotor test performance at this dose of zolpidem. At the 20-mg dose, zolpidem significantly increased weaving (28.1 [11.9] vs 17.5 [4.2] cm for placebo; P o 0.001) and speed variability (3.08 [1.30] vs 2.25 [0.67] km/h for placebo; P o 0.001) over the same driving test. In addition, zolpidem 20 mg significantly impaired performance on all psychomotor tests (P o 0.001 for the DSST, the critical tracking test, and the divided attention test

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[DAT]) and on all memory tests (P o 0.001 for delayed free word recall, relative word recall, and recognition reaction time). In a second study conducted in 28 healthy volunteers, a MOTN dose (4:00 AM) of zolpidem 10 mg was given and effects on cognition and psychomotor performance were assessed between 7:30 AM and 8:30 AM and on driving between 9:00 AM and 10:00 AM.101 Treatment with sublingual zolpidem resulted in significantly shorter sleep-onset latency compared with oral zolpidem (17.66 [13.37] vs 26.31 [22.72] minutes; P o 0.01). Compared with placebo, there was a significant difference in the ability to maintain a lateral position with zolpidem (17.79 [0.57] vs 21.09 [0.84] cm, respectively; P r 0.001), a significant difference in the deviation in constant speed (1.66 [0.09] vs 1.91 [0.12] km/h; P o 0.0001), and significant impairment on the DAT average tracking error (15.87 [0.87] vs 20.03 [0.91] mm; P o 0.0001), the DAT target reaction time (1745 [64] vs 1929 [58] ms; P ¼ 0.0119), the DSST (80.4 [2.6] vs 73.9 [2.3] correct encodings; P o 0.0001), delayed free word recall (11.0 [0.7] vs 8.7 [0.6], respectively; P o 0.0001), and recognition reaction time (716 [20] vs 809 [25] ms; P o 0.0002). The mean increase in weaving during the driving test between 5 and 6 hours after administration was 3.5 cm, corresponding closely to the increase of 3.8 cm reported between 4 and 5 hours after MOTN administration in the study by Verster et al.100 Similar observations have been made in patients with insomnia undergoing MOTN dosing with zolpidem. In a study designed to assess the residual effects of zolpidem 10 mg or zaleplon 10 mg, 37 adults with insomnia received a MOTN dose of drug or placebo and were assessed for residual sedation 4 to 7 hours later.102 Self-reported measures of concentration were significantly lower with zolpidem than with placebo at 4, 5, and 6 hours (P o 0.05 for all), as were measures of alertness at 4 hours (P ¼ 0.005) and DSST scores at 4 and 5 hours (P o 0.001 for both). These results confirm that MOTN dosing with zolpidem is associated with next-day residual effects. However, in a study conducted in 18 women with insomnia, Partinen et al103 observed differences between zolpidem and placebo on some, but not all, measures of impairment the following morning. In this study, the effects of zolpidem 10 mg and temazepam 20 mg administered MOTN (2:00 AM) were investigated 5.5 hours later (7:30 AM) on driving performance and psychomotor

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J. MacFarlane et al. skills. Study investigators observed no difference between treatments for mean time to collision, speed deviation, or reaction time to tasks. However, a significant increase in lane position deviation was observed after administration of zolpidem (1.37 [0.39] meters; P ¼ 0.025 vs placebo) compared with both temazepam (1.23 [0.26] meters; P ¼ 0.05 vs placebo) and placebo (1.26 [0.24] meters). Investigators also noted that some patients exhibited more susceptibility to drug effects than others; for example, 2 patients had a high number of collisions. These results not only confirm the importance of instructing patients to take zolpidem only if they will be able to have 8 hours’ sleep but also advocating against the late intake of hypnotic drugs if patients intend to drive a car early the next morning.104 One strategy to avoid next-day residual effects might be the use of low-dose sublingual zolpidem for MOTN insomnia. In contrast to oral zolpidem, lowdose sublingual zolpidem 1.75 and 3.5 mg do not cause next-morning impairment on the DSST or ratings of sleepiness.105

Withdrawal and Abuse Drug history is a major determinant of the reinforcing effects of benzodiazepines.106,107 Studies in volunteers with drug histories have reported more “drugliking” with zolpidem compared with other hypnotic drugs. Evans et al108 compared zolpidem 15, 30, and 45 mg with triazolam 0.25, 0.5, and 0.75 mg in 15 healthy male volunteers with histories of sedative drug abuse. Although both zolpidem and triazolam produced an increase in a variety of subjective measures believed to be desirable to people who abuse sedatives, zolpidem, but not triazolam, increased ratings of easy-going/ mellow, increased ratings of good effects, and increased ratings of estimated street value (P r 0.05 for all). In a similar study, Rush et al109 compared zolpidem 15, 30, and 45 mg, trazodone 100, 200, and 300 mg, and triazolam 0.25, 0.5, and 0.75 mg in 10 healthy male volunteers with histories of alcohol and drug abuse. At the highest doses, zolpidem and triazolam increased ratings of “willing to take again” (P r 0.05 for both), whereas only zolpidem increased ratings of “like drug, happy, good effects, friendly, elated, and carefree” (P r 0.05 for all). A postmarketing study analyzing data obtained from 297 patients admitted to 3 addiction treatment centers in the United Kingdom revealed that the abuse liability of nonbenzodiazepine hypnotic drugs such as zolpidem

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and zopiclone is similar to that of sedating antidepressants such as amitriptyline, fluoxetine, and trazodone and less than that of benzodiazepines such as diazepam, nitrazepam, and temazepam.110 These findings support the likelihood of abuse of zolpidem in subjects with a history of alcohol or drug abuse. Studies in healthy volunteers with no history of drug or alcohol abuse suggest that zolpidem has only a modest abuse potential. Wilkinson111 studied volunteers with a history of social use of alcohol and drugs who were given 0, 10, or 15 mg of zolpidem with either alcohol or placebo beverage, and measured abuse liability. After administration of zolpidem, subjects reported both positive and negative effects compared with placebo. Zolpidem significantly increased drug strength perception (P o 0.001), drug liking (P o 0.05), and sedation/intoxication (P o 0.05), while also increasing drug disliking (P o 0.05) and dysphoria/fear scores (P o 0.05) at the higher dose. Zolpidem was rated less favorably than placebo on measures of mood states at both doses, scored by using the following bipolar mood scales: elated–depressed, agreeable– hostile, clearheaded–confused, confident–unsure, energetic–tired, and composed–anxious (P o 0.05 for all). In addition, alcohol had no additive effects on the subjective ratings for zolpidem. Similar results were reported by Rush and Griffiths112 and Rush et al113 in healthy, non–drug-abusing subjects who did not experience abuse-related effects. More recently, Licata et al114 reported the results of a double-blind, placebocontrolled, crossover pilot study investigating the subjective effects of zolpidem in drug-naive female subjects. Compared with placebo, zolpidem produced subjective effects characteristic of hypnotic drugs, while also reducing ratings of drug liking, willing to take again, and willing to pay for (P o 0.05 for all). Similarly, healthy subjects with no history of drug abuse were not inclined to choose zolpidem when presented with an alternative reinforcer (eg, money) in a withinsubject, double-blind study designed to assess the subjective effects of multiple doses of zolpidem (0, 5, 10, or 20 mg).115 Although subjects rated zolpidem with positive abuse-like effects such as “high,” “like,” and “good effects” at the highest doses, none chose zolpidem at any dose over money. These results suggest that zolpidem at therapeutic doses has limited potential for misuse among this population. Despite the evidence that zolpidem is not associated with abuse in the general population, a number of case

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Clinical Therapeutics reports documenting abuse and physical dependence accompanied by serious withdrawal symptoms have been published in the literature.116–121 Patients increased their dose of zolpidem to attain supratherapeutic doses ranging from 60 to 2000 mg daily. In some cases, patients reported using zolpidem to reduce daytime anxiety. A systematic review of the literature for the years 1966 to 2002 identified 36 case reports for abuse and dependence of zolpidem, and concluded that, although zolpidem is a safe drug, patients with a history of abuse or dependence and those with psychiatric diseases seem to be at increased risk of abuse.122 The French Centre for Evaluation and Information on Pharmacodependence network conducted an official inquiry regarding the abuse potential of zolpidem, analyzing French data collected during zolpidem’s postmarketing period from 1993 to 2002.123 Based on the findings of the inquiry, the center network concluded that zolpidem may have the potential for abuse and dependence at therapeutic doses, both in subjects with and without risk factors for abuse. Consequently, the French drug monograph was modified by the French health authorities in 2004 to reflect the abuse potential of zolpidem.

Long-Term Use and Safety Many insomnia patients take prescription hypnotic drugs longer than the indicated 2 to 4 weeks; these patients often suffer from chronic insomnia that persists despite nightly use of medication.124,125 In 1 survey of 58 patients who had received treatment at a sleep clinic 3 to 5 years earlier, 43 (74%) continued to experience difficulty initiating and/or maintaining sleep, and 31 (53%) continued to take prescription medication for their insomnia.126 The majority of these patients identified zolpidem or eszopiclone as their primary medication. Several studies, ranging from 12 weeks to 12 months of treatment, have investigated the long-term safety and the effects of withdrawal of zolpidem. Scharf et al48 conducted a study in adult patients with chronic insomnia who were given placebo for 4 to 7 nights, followed by zolpidem 15 mg nightly for 12 weeks, and then given placebo for 1 withdrawal week. Patients could reduce the dose to 10 mg if adverse events occurred. A total of 155 patients completed all 12 weeks of treatment; 33 patients had their dose decreased from 15 mg to 10 mg. Only 8% of initially enrolled patients withdrew from the study due to adverse effects. At the end of

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the study, there was no evidence of drug tolerance (measured as sustained improvement in subjective sleep latency, total sleep time, number of awakenings, and sleep quality at weeks 8 and 12 compared with week 1) or rebound insomnia, suggesting that zolpidem use over 12 weeks is safe. Krystal et al49 investigated the safety of 6 months of zolpidem extended-release tablets in patients with chronic primary insomnia. In this study, patients were given extended-release zolpidem 12.5 mg or placebo over 24 weeks, and instructed to self-administer study drug for a minimum of 3 nights per week to a maximum of 7 nights per week over the course of the study. At the end of 6 months, there was no evidence of rebound insomnia during the first 3 nights after discontinuation. On night 1 after discontinuation, subjective wake after sleep onset and total sleep time were significantly better for the placebo group compared with the zolpidem group (P o 0.001 and P o 0.0001, respectively). These differences were not observed on nights 2 and 3 after discontinuation. On nights 2 and 3, subjective wake after sleep onset improved by 31 to 38 minutes and total sleep time improved by 42 to 55 minutes for the zolpidem group. Zolpidem did not lead to dose escalation over 12 months of nightly use, as reported in a study in which patients with primary insomnia were allowed to self-administer zolpidem at 3 time points during the study.127 In this study, patients were given either zolpidem 10 mg (5 mg for those aged 460 years) or placebo nightly for 12 months. During months 1, 4, and 12, patients returned to the sleep laboratory for 1-week zolpidem versus placebo self-administration assessments. On days 1 and 2 of the weeklong assessment, patients were allowed to sample colorcoded placebo or zolpidem capsules, and then on days 3 to 7, were allowed to choose 1, 2, or 3 color-coded zolpidem or placebo (5-mg each) capsules each night. Overall, zolpidem was preferred over placebo, as shown by it being chosen Z3 of the 5 nights, in 16 of 17 patients in month 1; 13 of 17 in month 4; and 17 of 17 in month 12. In addition, more zolpidem capsules than placebo were self-administered, resulting in an average nightly self-administered dose of 9.3 mg. Despite zolpidem being preferred over placebo, dose escalation was not observed over the course of the study: the number of nights that zolpidem was chosen, the total number of self-administered zolpidem

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J. MacFarlane et al. capsules, and the nightly self-administration rate of zolpidem did not change over the 12 months. Zolpidem also does not lead to rebound insomnia or withdrawal symptoms after 12 months of nightly use. In a study by Roehrs et al,128 patients with primary insomnia were given either zolpidem 10 mg (5 mg for those aged 460 years) or placebo nightly for 12 months. During the study, patients returned to the sleep laboratory for a 1-week placebo discontinuation period in months 1, 4, and 12 to assess rebound insomnia by using PSG. During that week, patients spent 2 consecutive nights in the sleep laboratory, followed by 4 nights at home and a final night in the sleep laboratory. Although 30% to 40% of patients had rebound insomnia, the percentage did not differ between the 2 treatment arms and did not increase over 12 months. There were no clinically significant withdrawal symptoms observed on the placebo discontinuation nights over the 12month period. These findings suggest that zolpidem use over 12 months is not associated with rebound insomnia or withdrawal symptoms.

GENDER DIFFERENCES Gender significantly influences the pharmacokinetics of zolpidem. Women have lower clearance of zolpidem compared with men, resulting in higher AUC values at any given dose.129,130 This difference is most striking in adults aged o60 years. Although the differences can be partly explained by differences in weight between men and women, they persist when clearance values or AUC values are normalized for weight.129 The mechanism underlying the lower clearance of zolpidem in women is currently unknown. Although gender differences are not associated with a higher incidence of adverse reactions in women, they are associated with significant drowsiness and impairment in driving performance among women the morning after MOTN administration of zolpidem.131 This discovery led to an announcement by the FDA on January 10, 2013, recommending that the dosage of zolpidem for women be decreased by one half from 10 mg to 5 mg for immediate-release formulations and from 12.5 mg to 6.25 mg for extended-release formulations.89 In addition, the FDA recommended that the new dosage decreases be extended to men as well, as the mechanism underlying the gender differences remains unknown. In April 2013, the FDA approved label changes specifying these new dosage recom-

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mendations for zolpidem products based on concerns regarding next-morning impairment.132

THE ROLE OF THE PHARMACIST Pharmacists, in collaboration with physicians, are in an optimal position to assist the many patients who experience insomnia and its associated impaired daytime functioning. In a study conducted in Australian community pharmacies, 30% of all direct product requests for insomnia, and 18% of all symptom-based requests for insomnia, were handled entirely by the pharmacist.133 Pharmacy staff, including but not limited to pharmacists, recommended medicated products 38% of the time, herbal products 78% of the time, and nonpharmacologic techniques 18% of the time. In another study conducted in Australia and designed to investigate how community pharmacists react to complaints of acute insomnia, many pharmacists responded appropriately to complaints of sleeplessness by eliciting information on insomnia type and counseling about medicine use.134 Overall, 96% of pharmacists in this study supplied an over-the-counter product (ie, sedating antihistamines or herbal sleeppromoting medicines), and 4% referred to a physician. Pharmacists are also well positioned to monitor the use of hypnotic drugs and assist patients in reducing the number of pills taken. One nonprofit pharmacy benefits management company in the United States, RegenceRx (Portland, Oregon), developed 2 recommendations for its members: (1) limit automatic coverage of sedative-hypnotic agents to 14 doses per month; and (2) offer members educational outreach with assistance from a health coach.135 Over a 2-year period, the monthly dispensing rate for clients who adopted the recommendations averaged 15 to 16 doses, compared with an average of 31 monthly doses for members who did not adopt the recommendations. This strategy is supported by proponents of reducing the usage of hypnotic drugs to avoid problems associated with abuse. Lader et al136 support the role of pharmacists in monitoring the use of benzodiazepines, stating that this approach may help avoid the need for specialist services such as psychiatrists, home care, and addiction and alcohol misuse treatment facilities. The benefit of pharmacists monitoring prescriptions for benzodiazepines was reported in a prescribing intervention study in 369 patients aged o70 years with a repeat prescription for benzodiazepines.137 The intervention policy, arranged by a pharmacist,

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Clinical Therapeutics consisted of sending a letter to the patient inviting him or her to an appointment with a general practitioner to discuss the patient’s drug usage. Overall, 96 patients had their prescriptions inactivated because they had not been filled for 3 months, 206 patients were invited for an appointment, and 151 patients attended their appointments and received information on how to reduce their benzodiazepine usage. At the end of the 3-year study, only 23% of patients remained on a repeat prescription, the number of benzodiazepine tablets prescribed was reduced by 64%, and the benzodiazepine-prescribing rate decreased by 67%. This simple intervention provided by pharmacists proved to be a quick and effective method of reducing the usage of benzodiazepines.

CONCLUSIONS Zolpidem is efficacious for the treatment of primary insomnia in adults and improves the induction, maintenance, and duration of sleep. Studies specifically investigating zolpidem for the reduction of sleep-onset latency suggest that zolpidem is efficacious, with sublingual zolpidem resulting in even shorter sleep-onset latency than oral zolpidem. In patients with chronic insomnia, zolpidem improves both quantitative and qualitative subjective measures of sleep. Zolpidem is also efficacious when used as needed or intermittently to treat insomnia, thus offering patients the choice and flexibility to use the drug only when necessary. For patients who have insomnia comorbidly with anxiety or depression, zolpidem can be coadministered with selective serotonin reuptake inhibitors to improve sleep. Zolpidem is safe when used according to labeling instructions. It is not recommended for use in pregnant women. Infants born to mothers taking zolpidem may suffer physical dependence, withdrawal symptoms, severe neonatal respiratory depression, and congenital abnormalities. Zolpidem is associated with complications during pregnancy that include preterm delivery, delivery of low-birth-weight infants, delivery of smallfor-gestational-age infants, and cesarean deliveries. There is currently no consensus in the literature as to whether zolpidem is associated with rebound insomnia; some studies report such an association, whereas others do not. The use of zolpidem is associated with CSBs, and well-designed clinical trials investigating this association are lacking. Zolpidem is also associated with nextday residual effects, which appear to be worse after MOTN administration. Zolpidem is generally

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considered to have a modest abuse potential, although there are a number of cases documenting abuse and physical dependence accompanied by serious withdrawal symptoms. Current recommendations made by Health Canada and the FDA state that all patients should be started at an initial dose of 5 mg. Zolpidem can be used in young adult patients with insomnia and in elderly patients with insomnia. It can be used for either bedtime or MOTN administration, over the short or long term, with minimal risk of withdrawal or abuse.

ACKNOWLEDGMENT Dr. MacFarlane is director of the Canadian Research Chair in Sleep Medicine. This article was funded by Valeant Canada. The article sponsor had no direct involvement in the article development, in the collection, analysis, or interpretation of data, in the writing of the manuscript, or in the decision to submit the manuscript for publication. Writing and editorial support was provided by Elsevier Canada. Manuscript writing was aided by Angela Styhler, an independent medical writer funded by Elsevier Canada. Ms. Styhler worked under the direction of the authors and not Elsevier Canada. All authors contributed equally to the article design, collection, analysis, and interpretation of data, as well as the writing of the manuscript.

CONFLICTS OF INTEREST Dr. MacFarlane has served as an advisor for Merck, Servier, Valeant Pharmaceuticals, Jazz Pharmaceuticals, and Sanofi-Aventis, and he has received honoraria for speaking engagements from Valeant and Servier. Dr. Morin has consulted for Valeant, Novartis, and Merck; has received research funding from Merck, Novartis, the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the National Institutes of Health, Fonds de Recherche en Santé du Québec; and has received speaking honoraria from Valeant and Merck. Dr. Montplaisir has received research grants from the Canadian Institutes of Health Research, the Canadian Foundation for Innovation, the W. Garfield Weston Foundation, Merck, and GlaxoSmithKline; has served as an advisor for Merck, Servier, Valeant, Impax Laboratories, Jazz Pharmaceuticals, Sanofi-Aventis, GlaxoSmithKline, and UCB Canada; and has received honoraria for speaking engagements from Valeant and Otsuka Pharmaceutical.

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Address correspondence to: James MacFarlane, PhD, 586 Eglinton Avenue East, Suite 507, Toronto, Ontario, Canada M4P 1P2. E-mail: [email protected]

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