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 with rebound insomnia, complex sleep-related behaviors,
and next-day residual effects (after middle-of-the-night dosing) on driving ability,
memory, and psychomotor performance.
Key Words
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References
- Fifth Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Press, Washington, DC2013
- Diagnostic and Statistical Manual of Mental Disorders.Fourth edition, Text Revision. American Psychiatric Association, Washington, DC2000
- Emerging research on the treatment and etiology of secondary or comorbid insomnia.Sleep Med Rev. 2006; 10: 7-18
- Current and new thinking in the management of comorbid insomnia.Am J Manag Care. 2009; 15: S24-S32
- Clinical guideline for the evaluation and management of chronic insomnia in adults.J Clin Sleep Med. 2008; 4: 487-504
- Psychological and behavioral treatment of insomnia: update of the recent evidence (1998-2004).Sleep. 2006; 29: 1398-1414
- Chronic insomnia.Lancet. 2012; 379: 1129-1141
- Non-pharmacological treatment of insomnia.Neurotherapeutics. 2012; 9: 717-727
- A comparison between acupuncture versus zolpidem in the treatment of primary insomnia.Asian J Psychiatr. 2012; 5: 231-235
- Non-pharmacological management of insomnia.Br J Med Pract. 2013; 6: a623
- Cognitive behavioral treatment of insomnia.Chest. 2013; 143: 554-565
- Insomnia.JAMA. 2013; 309: 706-716
- Pharacological treatments of insomnia.in: Attarian H.P. Viola-Saltzman M. Sleep Disorders in Women: A Guide to Practical Management. Humana Press, New York, NY2013: 121-134
- Pharmacotherapy of insomnia.Expert Opin Pharmacother. 2012; 13: 1243-1260
- Pharmacological treatment of insomnia.in: Attarian H.P. Schuman C.S. Clinical Handbook of Insomnia. Humana Press, New York, NY2010: 297-316
- Drugs for insomnia.Expert Opin Emerg Drugs. 2012; 17: 299-317
- Prevalence of insomnia and its treatment in Canada.Can J Psychiatry. 2011; 56: 540-548
- The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents.CNS Drugs. 2004; 18: 9-15
- Zolpidem for insomnia.Expert Opin Pharmacother. 2012; 13: 879-893
- Zolpidem extended-release: a single insomnia treatment option for sleep induction and sleep maintenance symptoms.Am J Ther. 2007; 14: 299-305
- Zolpidem extended-release.CNS Drugs. 2006; 20: 419-426
- ZolpiMist: a new formulation of zolpidem tartrate for the short-term treatment of insomnia in the US.Nat Sci Sleep. 2010; 2: 79-84
- Sublingual zolpidem tartrate lozenge for the treatment of insomnia.Expert Rev Clin Pharmacol. 2009; 2: 333-337
- A new sublingual formulation of zolpidem for the treatment of sleep-onset insomnia.Expert Rev Neurother. 2012; 12: 141-153
- Sublingual zolpidem (Edluar; Sublinox).CNS Drugs. 2012; 26: 1003-1010
- Zolpidem in the treatment of short-term insomnia: a randomized, double-blind, placebo-controlled clinical trial.Clin Neuropharmacol. 1996; 19: 333-340
- Efficacy and safety of zolpidem-MR: a double-blind, placebo-controlled study in adults with primary insomnia.Sleep Med. 2006; 7: 397-406
- Efficacy and safety of zolpidem extended release in elderly primary insomnia patients.Am J Geriatr Psychiatry. 2008; 16: 44-57
- Subjective hypnotic efficacy of trazodone and zolpidem in DSMIII-R primary insomnia.Hum Psychopharmacol. 1998; 13: 191-198
- Zolpidem in the treatment of transient insomnia: a double-blind, randomized comparison with placebo.Sleep. 1995; 18: 246-251
- Comparative efficacy of zolpidem and temazepam in transient insomnia.Hum Psychopharmacol. 2001; 16: 169-176
- A double-blind comparative study of zolpidem versus zopiclone in the treatment of chronic primary insomnia.J Int Med Res. 2001; 29: 163-177
- A double-blind, randomized, comparative study to evaluate the efficacy and safety of zaleplon versus zolpidem in shortening sleep latency in primary insomnia.Chang Gung Med J. 2011; 34: 50-56
- Sublingual zolpidem is more effective than oral zolpidem in initiating early onset of sleep in the post-nap model of transient insomnia: a polysomnographic study.Sleep Med. 2009; 10: 616-620
- Lower doses of sublingual zolpidem are more effective than oral zolpidem to anticipate sleep onset in healthy volunteers.Sleep Med. 2013; 14: 20-23
- Sublingual zolpidem in early onset of sleep compared to oral zolpidem: polysomnographic study in patients with primary insomnia.Curr Med Res Opin. 2010; 26: 1423-1431
- The natural history of insomnia: a population-based 3-year longitudinal study.Arch Intern Med. 2009; 169: 447-453
- Prevalence, course, and comorbidity of insomnia and depression in young adults.Sleep. 2008; 31: 473-480
- Epidemiology of insomnia: a longitudinal study in a UK population.Sleep. 2007; 30: 274-280
- Chronic insomnia.Am J Psychiatry. 2008; 165: 678-686
- A prospective study of self-reported sleep duration and incident diabetes in women.Diabetes Care. 2003; 26: 380-384
- A prospective study of sleep duration and coronary heart disease in women.Arch Intern Med. 2003; 163: 205-209
- A prospective study of sleep duration and mortality risk in women.Sleep. 2004; 27: 440-444
- Rotating night shifts and risk of breast cancer in women participating in the Nurses’ Health Study.J Natl Cancer Inst. 2001; 93: 1563-1568
- Night-shift work and risk of colorectal cancer in the Nurses’ Health Study.J Natl Cancer Inst. 2003; 95: 825-828
- Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy.JAMA. 1997; 278: 2170-2177
- Double-blind, placebo-controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia.Drug Dev Res. 1997; 40: 230-238
- A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia.J Clin Psychiatry. 1994; 55: 192-199
- Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study.Sleep. 2008; 31: 79-90
- Efficacy of eight months of nightly zolpidem: a prospective placebo-controlled study.Sleep. 2012; 35: 1551-1557
- Consensus on drug treatment, definition and diagnosis for insomnia.Clin Drug Investig. 2003; 23: 351-385
- “As needed” pharmacotherapy combined with stimulus control treatment in chronic insomnia—assessment of a novel intervention strategy in a primary care setting.Ann Clin Psychiatry. 2002; 14: 1-7
- Zolpidem “as needed” versus continuous administration: pan-European study results.Sleep Med Rev. 2002; 6: S21-S28
- Long-term, non-nightly administration of zolpidem in the treatment of patients with primary insomnia.J Clin Psychiatry. 2004; 65: 1128-1137
- Eight weeks of non-nightly use of zolpidem for primary insomnia.Sleep. 2000; 23: 1087-1096
- Behaviour of insomniacs and implication for their management.Sleep Med Rev. 2002; 6: S3-S6
- Efficacy and safety of zolpidem administered “as needed” in primary insomnia.Clin Drug Investig. 2001; 21: 391-400
- Experience with zolpidem ‘as needed’ in primary care settings.CNS Drugs. 2004; 18: 35-40
- Novel sublingual low-dose zolpidem tablet reduces latency to sleep onset following spontaneous middle-of-the-night awakening in insomnia in a randomized, double-blind, placebo-controlled, outpatient study.Sleep. 2013; 36: 189-196
- ‘As-needed’ prescription of zolpidem for insomnia in routine general practice.Clin Drug Investig. 2004; 24: 625-632
- Treatment of sleep dysfunction and psychiatric disorders.Curr Treat Options Neurol. 2009; 11: 349-357
- Zolpidem extended-release improves sleep and next-day symptoms in comorbid insomnia and generalized anxiety disorder.J Clin Psychopharmacol. 2009; 29: 222-230
- Zolpidem for persistent insomnia in SSRI-treated depressed patients.J Clin Psychiatry. 1999; 60: 668-676
- Improved insomnia symptoms and sleep-related next-day functioning in patients with comorbid major depressive disorder and insomnia following concomitant zolpidem extended-release 12.5 mg and escitalopram treatment: a randomized controlled trial.J Clin Psychiatry. 2011; 72: 914-928
- General safety profile of zolpidem: safety in elderly, overdose and rebound effects.Eur Psychiatry. 1997; 12: 21-29
- Safety and tolerance of zolpidem in the treatment of disturbed sleep: a post-marketing surveillance of 16944 cases.Int Clin Psychopharmacol. 1998; 13: 157-167
Meda Valeant Pharma Canada Inc. Sublinox (Zolpidem Tartrate) Product Monograph. www.hc-sc.gc.ca. Accessed December 11, 2013.
- Zolpidem (Ambien) in pregnancy: placental passage and outcome.Arch Womens Ment Health. 2009; 12: 441-446
- Increased risk of adverse pregnancy outcomes in women receiving zolpidem during pregnancy.Clin Pharmacol Ther. 2010; 88: 369-374
- Are hypnotic benzodiazepine receptor agonists teratogenic in humans?.J Clin Psychopharmacol. 2011; 31: 356-359
- Tolerance and rebound insomnia with rapidly eliminated hypnotics: a meta-analysis of sleep laboratory studies.Int Clin Psychopharmacol. 1999; 14: 287-303
- A polysomnographic placebo-controlled evaluation of the efficacy and safety of eszopiclone relative to placebo and zolpidem in the treatment of primary insomnia.J Clin Sleep Med. 2008; 4: 229-234
- Zolpidem and rebound insomnia—a double-blind, controlled polysomnographic study in chronic insomniac patients.Pharmacopsychiatry. 1994; 27: 166-175
- Rebound insomnia after abrupt discontinuation of hypnotic treatment: double-blind randomized comparison of zolpidem versus triazolam.Hum Psychopharmacol. 1996; 11: 225-233
- Minimal rebound insomnia after treatment with 10-mg zolpidem.Clin Neuropharmacol. 1997; 20: 116-125
- Zolpidem is not superior to temazepam with respect to rebound insomnia: a controlled study.Eur Neuropsychopharmacol. 2004; 14: 301-306
- a novel nonbenzodiazepine hypnotic, effectively treats insomnia in elderly patients without causing rebound effects.Prim Care Companion J Clin Psychiatry. 1999; 1: 114-120
- double-blind, controlled comparison of zolpidem and triazolam in elderly patients with insomnia.Clin Ther. 1993; 15: 127-136
- International Classification of Sleep Disorders: Diagnostic and Coding Manual.Second ed. American Academy of Sleep Medicine, Chicago, IL2005
- Hypnosedative-induced complex behaviours: incidence, mechanisms and management.CNS Drugs. 2008; 22: 1021-1036
- 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: 471-476
- Sleep driving: sleepwalking variant or misuse of z-drugs?.Sleep Med Rev. 2011; 15: 285-292
- Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series.J Clin Sleep Med. 2011; 7: 632-638
- Spontaneous adverse event reports associated with zolpidem in Australia 2001-2008.J Sleep Res. 2011; 20: 559-568
- Risk predictors for hypnosedative-related complex sleep behaviors: a retrospective, cross-sectional pilot study.J Clin Psychiatry. 2010; 71: 1331-1335
- Residual effects of hypnotics: epidemiology and clinical implications.CNS Drugs. 2004; 18: 297-328
- Residual effects of sleep medication on driving ability.Sleep Med Rev. 2004; 8: 309-325
- New approaches in the treatment of short term and middle of the night insomnia: emerging evidence for a role for sublingual zolpidem tablets.Nat Sci Sleep. 2010; 2: 63-69
United States Food and Drug Administration. Zolpidem Containing Products: Drug Safety Communication, FDA Requires Lower Recommended Doses. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm334738.htm. Accessed October 30, 2013.
Health Canada. Sublinox (zolpidem tartrate), New Dosage Recommendations to Minimize Risk of Next-Day Impairment in Both Women and Men. www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2014/37415a-eng.php. Accessed January 28, 2014.
- Residual effect of zolpidem 10 mg and zopiclone 7.5 mg versus flunitrazepam 1 mg and placebo on driving performance and ocular saccades.Psychopharmacology (Berl). 1999; 143: 373-379
- Do zopiclone, zolpidem and flunitrazepam have residual effects on simulated task of collision anticipation?.J Psychopharmacol. 2003; 17: 324-331
- A double-blind, placebo- and flurazepam-controlled investigation of the residual psychomotor and cognitive effects of modified release zolpidem in young healthy volunteers.J Clin Psychopharmacol. 2006; 26: 284-289
- Carryover effect on next-day sleepiness and psychomotor performance of nighttime administered antihistaminic drugs: a randomized controlled trial.Hum Psychopharmacol. 2012; 27: 428-436
- The effects of acute and repeated doses of zolpidem on subjective sleep, psychomotor performance and cognitive function in elderly volunteers.Eur J Clin Pharmacol. 1992; 43: 597-601
- A double-blind, placebo-controlled investigation of the residual psychomotor and cognitive effects of zolpidem-MR in healthy elderly volunteers.Br J Clin Pharmacol. 2006; 62: 538-545
- Zolpidem and zopiclone impair similarly monotonous driving performance after a single nighttime intake in aged subjects.Psychopharmacology (Berl). 2011; 214: 699-706
- Acute effects of zolpidem and flunitrazepam on sleep, memory and driving performance, compared to those of partial sleep deprivation and placebo.Acta Ther. 1995; 21: 47-64
- Next-day residual effects of hypnotics in DSM-IV primary insomnia: a driving simulator study with simultaneous electroencephalogram monitoring.Psychopharmacology (Berl). 2005; 181: 790-798
- Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance.J Clin Psychopharmacol. 2002; 22: 576-583
- Highway driving performance and cognitive functioning the morning after bedtime and middle-of-the-night use of gaboxadol, zopiclone and zolpidem.J Sleep Res. 2009; 18: 387-396
- Sleep and residual sedation after administration of zaleplon, zolpidem, and placebo during experimental middle-of-the-night awakening.J Clin Sleep Med. 2006; 2: 417-423
- Effects of after-midnight intake of zolpidem and temazepam on driving ability in women with non-organic insomnia.Sleep Med. 2003; 4: 553-561
- Zolpidem and traffic safety—the importance of treatment compliance.Curr Drug Saf. 2007; 2: 220-226
- Low-dose sublingual zolpidem tartrate is associated with dose-related improvement in sleep onset and duration in insomnia characterized by middle-of-the-night (MOTN) awakenings.Sleep. 2008; 31: 1277-1284
- Benzodiazepine self-administration in humans and laboratory animals—implications for problems of long-term use and abuse.Psychopharmacology (Berl). 1997; 134: 1-37
- Benzodiazepines: use, abuse, and consequences.Pharmacol Rev. 1992; 44: 151-347
- Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability.J Pharmacol Exp Ther. 1990; 255: 1246-1255
- Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans.Psychopharmacology (Berl). 1999; 144: 220-233
- A postmarketing study of relative abuse liability of hypnotic sedative drugs.Addiction. 2004; 99: 165-173
- The abuse potential of zolpidem administered alone and with alcohol.Pharmacol Biochem Behav. 1998; 60: 193-202
- Zolpidem, triazolam, and temazepam: behavioral and subject-rated effects in normal volunteers.J Clin Psychopharmacol. 1996; 16: 146-157
- Benzodiazepine-receptor ligands in humans: acute performance-impairing, subject-rated and observer-rated effects.J Clin Psychopharmacol. 1998; 18: 154-165
- A therapeutic dose of zolpidem has limited abuse-like effects in drug-naive females: a pilot study.Eur J Pharmacol. 2008; 598: 64-67
- Modest abuse-related subjective effects of zolpidem in drug-naive volunteers.Behav Pharmacol. 2011; 22: 160-166
- Seizure following sudden zolpidem withdrawal.Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31: 539-540
- Seizure after withdrawal from supratherapeutic doses of zolpidem tartrate, a selective omega I benzodiazepine receptor agonist.J Pain Symptom Manage. 1997; 14: 118-120
- Dependence on zolpidem.Psychiatry Clin Neurosci. 2007; 61: 207-208
- High-dose zolpidem dependence in a patient with chronic facial pain.Ann Pharmacother. 2005; 39: 773-774
- Zolpidem dependence case series: possible neurobiological mechanisms and clinical management.J Psychopharmacol. 2003; 17: 131-135
- Extensive craving in high dose zolpidem dependency.Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 591-592
- Abuse and dependence potential for the non-ben;zodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data.Addiction. 2003; 98: 1371-1378
- Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey.Br J Clin Pharmacol. 2007; 64: 198-209
- Patients with treatment-resistant insomnia taking nightly prescription medications for sleep: a retrospective assessment of diagnostic and treatment variables.Prim Care Companion J Clin Psychiatry. 2010; : 12
- Persistent insomnia in chronic hypnotic users presenting to a sleep medical center: a retrospective chart review of 137 consecutive patients.J Nerv Ment Dis. 2010; 198: 734-741
- Long-term follow-up of patients with insomnia.Proc (Bayl Univ Med Cent). 2008; 21: 264-265
- Twelve months of nightly zolpidem does not lead to dose escalation: a prospective placebo-controlled study.Sleep. 2011; 34: 207-212
- Twelve months of nightly zolpidem does not lead to rebound insomnia or withdrawal symptoms: a prospective placebo-controlled study.J Psychopharmacol. 2012; 26: 1088-1095
- Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: evaluation of sex-dependent differences.J Pharmacol Exp Ther. 2000; 293: 435-443
- Pharmacokinetic properties of zolpidem in elderly and young adults: possible modulation by testosterone in men.Br J Clin Pharmacol. 2003; 56: 297-304
- Gender differences in highway driving performance after administration of sleep medication: a review of the literature.Traffic Inj Prev. 2012; 13: 286-292
United States Food and Drug Administration. Ambien (Zolpidem Tartrate) Tablets. Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER). http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm351817.htm. Accessed October 30, 2013.
- Management of over-the-counter insomnia complaints in Australian community pharmacies: a standardized patient study.Int J Pharm Pract. 2014; 22: 125-134
- How do pharmacists respond to complaints of acute insomnia? A simulated patient study.Int J Clin Pharm. 2011; 33: 237-245
- Patients’ needs may get ignored with newer insomnia treatments, pharmacist says.Am J Health Syst Pharm. 2008; 65: 1006
- Withdrawing benzodiazepines in primary care.CNS Drugs. 2009; 23: 19-34
- A novel, pharmacist-led strategy to reduce the prescribing of benzodiazepines in Paisley.Pharmaceutical Journal. 2006; 276: 136-138
Article info
Publication history
Accepted:
September 24,
2014
Identification
Copyright
© 2014 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
