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Primary Care Companion to The Journal of Clinical Psychiatry logoLink to Primary Care Companion to The Journal of Clinical Psychiatry
. 2007;9(1):25–31. doi: 10.4088/pcc.v09n0105

Update on the Safety Considerations in the Management of Insomnia With Hypnotics: Incorporating Modified-Release Formulations Into Primary Care

Joseph A Lieberman III 1,✉
PMCID: PMC1894851  PMID: 17599165

Abstract

Objective: From a safety perspective, several issues require assessment when a decision is made to prescribe a sleep medication, including next-day residual effects, the potential for abuse, tolerance, and dependence. This article aims to provide an update of the safety profile of agents commonly used in the management of insomnia, with an emphasis on newly approved hypnotics.

Data Sources: Publications relevant to the subject of this review were identified by a PubMed search (conducted without date restrictions; search terms: insomnia WITH safety OR tolerability OR side effects OR tolerance OR dependence OR abuse OR residual effects AND benzodiazepines OR non-benzodiazepines OR zolpidem OR eszopiclone OR zaleplon OR ramelteon OR melatonin OR trazodone OR antihistamines OR alcohol OR alternative therapies), and additional articles (selected by the author on the basis of his experience) were included.

Study Selection and Data Extraction: Publications relevant to the objective of this article were obtained, and the key safety data relating to adverse events, next-day residual effects, tolerance, and withdrawal were summarized.

Data Synthesis: The non-benzodiazepines (eszopiclone, zolpidem, zolpidem extended-release, and zaleplon), which have largely replaced the benzodiazepines for insomnia treatment, have a lower risk of tolerance, dependence, abuse, and residual effects compared with benzodiazepines. The modified-release formulation of zolpidem demonstrates a comparable safety profile to that of original zolpidem but has an additional sleep maintenance benefit. Ramelteon, a novel melatonin receptor agonist, is indicated for sleep-onset difficulties and is not scheduled. Over-the-counter agents, alternative therapies, and the prescription of off-label drugs, such as trazodone, have a lack of controlled clinical efficacy and safety studies in the treatment of insomnia and as a result should be used with caution.

Conclusions: Overall, published studies report that the safety of insomnia treatments has improved considerably over the past 10 years with the introduction of agents that provide improved safety, particularly with regard to next-day residual effects and abuse liability.

Even with advances in therapy for sleep disorders and the recognition that insomnia has a significant impact on patient health and quality of life, the majority of patients with insomnia remain undiagnosed or are not treated appropriately. In the 2005 Sleep in America Poll, the National Sleep Foundation found that less than one third of patients with insomnia were asked about their sleep during physician visits.1 Furthermore, epidemiologic studies suggest that only 27% to 45% of individuals with disrupted sleep discuss their problems proactively during a physician visit,2,3 and many patients with insomnia visit their physician only after unsuccessful self-medication with over-the-counter (OTC) treatments. These studies highlight the need for improved physician-patient communication regarding sleep quality.

Insomnia may consist of 1 or more of the following features: difficulty in initiating sleep, difficulty in maintaining sleep, and waking up too early.4 DSM-IV classification also includes nonrestorative sleep and requires that the insomnia must also cause difficulty in the person's social, work, or other significant area of life.5 It is common for patients to experience more than one symptom of insomnia and for symptoms to change over time, often unpredictably.6 Insomnia may be transient (occurring a few nights a week for up to a month) or chronic (occurring most nights for a period longer than a month), both of which are associated with next-day consequences.

It has been estimated that 10% to 15% of the general population suffers from insomnia.7 The 2005 National Sleep Foundation poll reported that 54% of those surveyed experienced at least 1 symptom of insomnia (the definition of insomnia in that study also included snoring, restless leg syndrome, and pauses in breathing) for at least a few nights a week within the previous year.1 The poll also found that 33% experienced at least 1 symptom of insomnia every night, or almost every night, during the previous year.

The economic burden of insomnia remains largely unknown, and the direct and indirect medical costs and potential societal benefits from the effective treatment of insomnia also require further investigation.

The National Institutes of Health (NIH) recently released a state-of-the-science conference statement on the treatment of chronic insomnia.4 The statement summarized the treatment options available as of June 2005 and highlighted the need for clinical studies to support the safety and efficacy of agents currently used in the treatment of insomnia, especially those used off-label that at present have few data to support their efficacy in insomnia.

The most commonly used treatments for insomnia patients are OTC antihistamines, self-medication with alcohol, and prescription medications (used both on- and off-label). Other treatments include melatonin and the alternative therapies, such as valerian, kava kava, and l-tryptophan.1,8 Evaluation of the benefit/risk profile of insomnia treatment options reveals a number of important safety issues that require assessment, including the potential for effects on next-day performance (such as next-day cognitive and psychomotor performance) and drug-drug interactions, as well as possible abuse potential.

Here, I review safety profiles of those agents commonly used in the management of insomnia, with an emphasis on newly approved hypnotics. Publications relevant to the subject of this review were identified by a PubMed search (conducted without date restrictions; search terms: insomnia WITH safety OR tolerability OR side effects OR tolerance OR dependence OR abuse OR residual effects AND benzodiazepines OR non-benzodiazepines OR zolpidem OR eszopiclone OR zaleplon OR ramelteon OR melatonin OR trazodone OR antihistamines OR alcohol OR alternative therapies), and additional articles (selected by the author on the basis of his experience) were included.

BENZODIAZEPINE RECEPTOR AGONISTS

Benzodiazepine Derivatives

Benzodiazepines were the cornerstone of insomnia treatment prior to the 1990s, as supported by extensive studies and their relative safety in short-term use (in comparison to other agents available at the time). They are still prescribed for the treatment of insomnia; however, their use has significantly decreased due to concerns over abuse, dependence, cognitive and psychomotor impairments, and residual effects (“hangover”).9–11

Benzodiazepines bind to and mediate the activity of the γ-aminobutyric acid–A (GABAA) receptor complex, which consists of 5 protein subunits (formed from the coassembly of at least 19 different subunits from at least 7 subunit families: α, β, γ, δ, ε, θ, ρ).12 This diversity of subunits allows the expression of a vast number of structurally unique GABAA receptor subtypes with distinct characteristics. There are 6 α subunit subtypes (α1–6); the α1 subunit is thought to be located predominantly in areas of the brain that are involved in sleep-wake mechanisms, sedation, and memory.12,13 GABAA receptor complexes containing the α2, α3, or α5 subunit appear to be most highly concentrated in areas responsible for cognitive and psychomotor functions, along with anticonvulsant and anxiolytic activity.12 Benzodiazepines act at multiple GABAA receptor subtypes (containing the α subunit subtypes 1, 2, 3, and 5), which may account for their hypnotic effects as well as undesirable effects such as impaired cognitive and psychomotor function.14

Benzodiazepines can be classified according to their pharmacokinetic profile: short half-life (e.g., triazolam), intermediate half-life (e.g., temazepam), or long half-life (e.g., flurazepam) (Table 1). The use of benzodiazepines can cause alteration of sleep architecture, in addition to tolerance to the hypnosedative effect over time, pharmacologic dependence, rebound insomnia and withdrawal reactions at discontinuation, anterograde amnesia, cognitive and psychomotor impairment, misuse episodes, and respiratory depression.15,16 Withdrawal symptoms occur more rapidly and more frequently with the short-acting benzodiazepines (characterized by a half-life of < 4 hours) compared with the longer-acting benzodiaz-epines.17 Next-day residual deficits (“hangover”) occur most frequently with long-acting benzodiazepines (characterized by a half-life > 24 hours and pharmacologically active metabolites), although they are also observed following the administration of intermediate-acting agents (characterized by a half-life of 4–24 hours and few active metabolites).18,19

Table 1.

Overview of Compounds Approved in the United States for the Treatment of Insomnia

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Non-Benzodiazepines

The next generation of sleep aids, with a more sleep-focused mechanism of action, the non-benzodiazepines, were introduced in the 1990s. These benzodiazepine receptor agonists are as effective as benzodiazepines in the promotion of sleep, but have a reduced risk of abuse and fewer side effects compared with benzodiazepines.20,21

Like the benzodiazepines, non-benzodiazepines are agonists at the GABAA receptor complex. However, non-benzodiazepines preferentially bind to the sleep-mediating α1 subunit subtype GABAA receptor complexes and were developed, in part, to improve on the safety profile of benzodiazepines while retaining their sleep-promoting effects.22,23 GABAA receptor complexes with α1 subunit subtype are also thought to be primarily located in areas of the brain responsible for memory; therefore, both benzodiazepines and non-benzodiazepines have the potential to adversely affect this area of functioning.24 Additionally, compared with the majority of benzodiazepines, non-benzodiazepines are relatively short-acting, with half-lives ranging from ultra-short (zaleplon, 1 hour) to intermediate (eszopiclone, 6–9 hours).

Zolpidem extended-release and zolpidem

Zolpidem extended-release,25 a modified-release formulation of original zolpidem, has recently been approved by the U.S. Food and Drug Administration (FDA) and was developed to improve on the efficacy profile of original zolpidem while retaining the low risk for next-day functional impairments. Zolpidem extended-release is a 2-layer tablet with a biphasic absorption property; approximately 60% is released immediately while the remainder is released at a slower rate. Zolpidem extended-release has a rapid onset of action and a short half-life, similar to original zolpidem; however, zolpidem plasma levels are maintained beyond 3 hours with zolpidem extended-release.

Zolpidem is a member of the imidazopyridine class of hypnotics, with selective affinity for the α1 subunit GABAA receptor subtype, and does not have anticonvulsant or myorelaxant properties at recommended doses. Unlike original zolpidem, zolpidem extended-release is indicated for both sleep onset and sleep maintenance insomnia and can be prescribed as long as medically necessary.25

In healthy volunteers, zolpidem extended-release had a longer duration of sedation compared with zolpidem (measured by a biomarker of sedation: relative electroencephalogram beta frequency band amplitude).26 In 2 additional studies in healthy volunteers, zolpidem extended-release in adults (12.5 mg) and the elderly (6.25 mg and 12.5 mg [double the recommended dose in the elderly]) did not impair objective and subjective measurements of psychomotor and cognitive performance measured 8 hours postdose.27,28 This is similar to findings that zolpidem did not have an adverse effect on memory or cognitive function the morning after nighttime administration in healthy volunteers29–32 or in patients with insomnia.33

Zolpidem extended-release was well tolerated in clinical studies, with the most commonly occurring adverse events being headache, somnolence, and dizziness.25

There is an abundance of information regarding the safety of zolpidem in the treatment of insomnia. In a large postmarketing surveillance database involving 16,944 patients, only 182 patients (1.1%) reported an adverse event after zolpidem treatment.34 The risk of abuse and tolerance with zolpidem is low when used as directed.20,31,35 No significant withdrawal effects have been reported following discontinuation of zolpidem.20,34,36

As with other non-benzodiazepines, a brief (first-night) rebound effect, in which insomnia symptoms are worse than the initially presented insomnia, has been reported following discontinuation of zolpidem extended-release37,38 or zolpidem.39–41

Eszopiclone

Eszopiclone is a non-benzodiazepine recently approved for the treatment of insomnia. Eszopiclone is an S(+)-enantiomer of zopiclone, a cyclopyrrolone hypnotic that binds to a site close to the benzodiazepine receptor on the GABAA receptor complex.42 Eszopiclone has a half-life of 5 to 6 hours in adults and has shown minimal evidence of residual drug effects 9.5 and 12 hours after drug administration.43,44 However, in elderly patients, the half-life increases to 9 hours.45 A 2-week safety and efficacy study in elderly patients showed that eszopiclone did not affect morning sleepiness, daytime alertness, or daily ability to function compared with placebo when measured by a questionnaire completed by patients upon waking.46

The safety and tolerability of eszopiclone (1–3.5 mg) have been shown to be similar to placebo, with an unpleasant taste being the most frequent dose-related adverse event,45 reported more often in eszopiclone-treated patients than in the placebo-treated group. Other adverse events included somnolence, headache, dizziness, and unpleasant dreams.45,47,48 Dependence on eszopiclone has not been reported, although it is classified as a schedule IV medication by federal regulation, and no evidence of serious withdrawal syndrome was reported. Tolerance, as assessed over 6 and 12 months, was not observed.47,48 As described before with other non-benzodiazepines, rebound insomnia was observed with eszopiclone 2 mg on the first night after discontinuation.44

Zaleplon

Zaleplon49 has a pyrazolopyrimidine structure that binds to both the α1 and α2 subunit GABAA receptor subtypes, but with preferentiality for the α1 subtype.49 Zaleplon is a very short acting drug with a half-life of 1 hour that has demonstrated efficacy for sleep induction but does not improve sleep maintenance nor total sleep time. The ultra-short half-life contributes to the low propensity toward next-day effects on memory in healthy individuals50,51 and in those with insomnia.52

Compared with placebo, zaleplon did not impair performance in various psychometric tests 8 to 12 hours after dosing.53 No significant evidence of rebound insomnia or serious withdrawal reactions has been documented.41 Zaleplon has a favorable safety profile and is well tolerated. The incidence of adverse events is comparable with placebo in most studies, with headache being the most commonly reported adverse event, which appears to be dose-dependent. Other commonly reported adverse events include dizziness, nausea, abdominal pain, and somnolence.41 After 4 weeks of zaleplon treatment, withdrawal effects are not evident upon discontinuation.41

MELATONIN RECEPTOR AGONISTS

Ramelteon belongs to a new class of drugs with a novel mechanism of action that specifically targets the melatonin type-1 and type-2 (MT1 and MT2) receptors in the brain, which are believed to be involved in the regulation of the body's sleep-wake cycle.54 Ramelteon is the first prescription hypnotic approved by the FDA that is not classified as a controlled substance. While ramelteon has demonstrated efficacy for sleep induction, it does not improve sleep maintenance.

At doses up to 20 times the recommended dose, no differences in subjective responses indicative of abuse potential were seen between ramelteon and placebo in preclinical studies.55 No next-day residual effects were seen after 2 nights of ramelteon administration. In a 35-night double-blind study that measured next-day residual effects at 3 timepoints, small differences were observed between the ramelteon (8 mg) and placebo groups at weeks 1 and 3, but not at week 5.56

In a crossover study, ramelteon (5 treatment periods consisting of 2 nights of ramelteon treatment at doses of 4, 8 [recommended dose], 16, and 32 mg, separated by a 5- to 12-day washout period) was found to have similar withdrawal effects to placebo, and there was also no evidence of rebound insomnia.57 The most commonly reported adverse events were headache, somnolence, and sore throat. In an evaluation of the effect of ramelteon on endocrine function, no significant abnormalities were reported in either the thyroid or adrenal axis; however, abnormalities were noted within the reproductive axis. Decreased testosterone levels and increased prolactin levels (32% of ramelteon-treated patients reported increased prolactin levels, compared with 19% of placebo patients) have been associated with the use of ramelteon.56 As a result, patients are advised to seek medical attention if they experience cessation of menses or galactorrhea (females), decreased libido, or problems with fertility.

Ramelteon has a highly variable intersubject pharmacokinetic profile. The major cytochrome P450 (CYP) isoenzyme involved in the metabolism of ramelteon is CYP1A2, and, to a lesser degree, the CYP2C subfamily and CYP3A4 isoenzymes are also involved. Therefore, the use of alcohol and strong inhibitors of these isoenzymes, in particular fluvoxamine (CYP1A2 inhibitor), rifampin, ketoconazole, and fluconazole, should be avoided with ramelteon.56

OFF-LABEL PRESCRIPTION DRUGS

In the United States, the antidepressant trazodone is one of the most commonly prescribed medications for the treatment of insomnia.4 Although there are no long-term studies on the use of trazodone in the treatment of insomnia, reports of sedation, dizziness, psychomotor impairment, and tolerance related to its use are of concern. The efficacy of trazodone use in the treatment of insomnia beyond 2 weeks is also unknown, and this lack of controlled clinical studies regarding efficacy and safety in the treatment of insomnia is seen across a range of antidepressants (e.g., amitriptyline, doxepin, mirtazapine). Two studies on the safety of sedating antidepressants in patients with primary insomnia found that these medications used in this context had more frequent and more serious safety concerns compared with benzodiazepines.58,59 In 1 investigation, 2 of 4 patients with primary insomnia in the doxepin-treatment group who withdrew from the study cited significant adverse events as the reason for discontinuation (leukopenia, thrombopenia, and increased levels of liver enzymes).58

Most information on the sedative properties of antide-pressants comes from experience in patients with depression60; therefore, a dose-response relationship needs to be established for safe prescription of these drugs in the treatment of insomnia in nondepressed patients.

Other prescription medications have been used off-label in the treatment of insomnia, including antipsychotics (e.g., quetiapine, olanzapine). There are, however, limited studies to demonstrate the usefulness of these medications for either short- or long-term treatment of insomnia. In addition, these agents have significant risks, and, therefore, their use in the treatment of chronic insomnia was not recommended by the NIH State of the Science Conference Panel.4

NONPRESCRIPTION DRUGS

Over-the-Counter Drugs

Antihistamines are well known for their sedative effects. Patients may, however, also experience adverse events such as urinary retention, confusion, and delirium and side effects including daytime sleepiness, dizziness, drunken movements, blurred vision, and dry mouth and throat.61

Diphenhydramine is the most commonly used antihistamine OTC product for sleep. It has an elimination half-life of approximately 9 hours in adults.62,63 Commonly used drugs may simply contain diphenhydramine alone (Nytol, Sleep-Eez, Sominex) or combinations of diphen-hydramine with pain relievers (Anacin P.M., Excedrin PM, Tylenol PM). Sedating antihistamines can have next-day residual effects64 and may not be very effective in providing restful sleep. There is also the potential for drug-drug interaction, often increasing the sedative effects of other medications, which is especially common in the elderly who are often taking a number of prescription medications simultaneously.65

Alternative Therapies

A number of herbal and alternative therapies, including melatonin, valerian, camomile, kava kava, and 5-hydroxy-tryptophan, are used for the treatment of insomnia,8 although available clinical data suggest minimal to no efficacy for these agents, and there are few data on safety to warrant recommendation of use.4 The FDA does not regulate these agents, and thus preparations vary in content and purity. While some alternatives, such as melatonin, may be safe for short-term use,66 others may have significant risks.4 For example, there have been case reports of hepatotoxicity with the use of valerian-based remedies.8

Alcohol is well known for its sedative properties and is a common form of self-medication for insomnia.67 However, in addition to serious side effects, including dependence and tolerance, and despite the initial sedative effect, alcohol is associated with an increased number of awakenings and sleep-stage changes.68 Use of alcohol in combination with hypnotics is contraindicated and can significantly increase the risk of serious drug interactions.

DISCUSSION

It is the role of the physician to ensure that all sleep medications are taken appropriately. Patients should be informed that all sleep medications should be taken strictly as prescribed, never with alcohol, and always immediately before the patient intends to get into bed, with the exception of ramelteon, which should be taken 30 minutes prior to going to bed, after which patients should confine their activities to those necessary to prepare for bed. Drug-drug interactions should be considered prior to the prescription of sleep medications, especially with the use of cough and cold medications and sedating antihistamines used for an alternative indication.

It is also advisable that sleep medications, in particular those with a longer duration of action, should only be taken when the patient has enough time for a full night's sleep (7–8 hours). With regard to this point, half-life is an important consideration, as drugs with longer half-lives may impair next-day performance and some agents (like eszopiclone) have significant pharmacokinetic changes in older patients. The newer non-benzodiazepines and melatonin agonists have the best data to support lack of residual effects, but not all clinical trials measured next-day functioning during the time when patients are likely to be starting their day. For example, the zolpidem extended-release efficacy studies37,38 measured morning performance within 30 minutes of awakening (8.5 hours postdose), whereas eszopiclone studies measured performance 9.5 hours postdose or when the patient naturally awoke.43,44

The NIH has emphasized the move toward thinking of insomnia as a chronic disorder that needs to be treated over the long term, rather than a short-term condition with a short-term solution, making safety an even more important consideration. This certainly corroborates the findings from the 2002 National Sleep Foundation poll that reported 15% of respondents continually used (at least a few nights per month) either a prescription sleep medication (8%) and/or an OTC sleep aid (10%) to help them sleep over the past year.69 This shift in thinking has also led the FDA to approve 3 new drugs in 2005 without recommended limitations on duration of use: eszopiclone, ramelteon, and zolpidem extended-release. This is a significant change from previous FDA decisions, when hypnotics were approved only for short-term treatment of insomnia. Now, with over a decade of clinical experience in the United States with non-benzodiazepines such as zolpidem and the recognition of insomnia as a chronic condition, the approval for the short-term use of previously approved insomnia drugs is being revisited.

CONCLUSIONS

The safety of insomnia treatments has improved considerably over the past 10 years with the introduction and development of new treatment options that provide improved safety, especially with regard to next-day effects and abuse liability. Despite a lack of demonstrated efficacy and safety, use of OTC agents, alternative therapies, and off-label prescription medications in patients with insomnia remains high. A recent statement produced by an independent panel assembled by the NIH to advise physicians recommends the use of only those treatments studied in clinical trials that have been shown to be safe and effective for the treatment of insomnia.4 According to the NIH findings, the non-benzodiazepine hypnotics have a superior safety profile compared to the older benzodiazepines.

In 2005, 3 new agents were approved for the treatment of insomnia without any recommendations for limiting the duration of use. These were zolpidem extended-release (a modified-release formulation of zolpidem), eszopiclone (a novel non-benzodiazepine), and ramelteon (a melatonin receptor agonist). Zolpidem extended-release was designed to extend the duration of action through the middle-of-the-night, thus improving sleep maintenance while retaining the sleep initiation benefits and the established safety profile of original zolpidem.

Drug names: estazolam (ProSom and others), eszopiclone (Lunesta), fluconazole (Diflucan and others), flurazepam (Dalmane and others), ketoconazole (Ketozole and others), mirtazapine (Remeron and others), olanzapine (Zyprexa), quazepam (Doral), quetiapine (Seroquel), ramelteon (Rozerem), rifampin (Rimactane and others), temazepam (Restoril and others), triazolam (Halcion and others), zaleplon (Sonata), zolpidem (Ambien).

Footnotes

The author would like to thank Megan Bridges, M.Sc., Medicus International, London, U.K., for her editorial assistance. Editorial support was funded by sanofi-aventis.

The author has the following financial relationships, which have not in any way impacted on this manuscript: He has participated in advisory boards for Ortho-McNeil, Pfizer, sanofi-aventis, Takeda, and AstraZeneca and has been a speaker for Takeda and AstraZeneca.

REFERENCES CITED

  1. National Sleep Foundation. National Sleep Foundation 2005 Sleep in America Poll [online]. Available at: www.sleepfoundation.org. Accessed January 2006. [Google Scholar]
  2. Ohayon MM.. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev. 2002;6:97–111. doi: 10.1053/smrv.2002.0186. [DOI] [PubMed] [Google Scholar]
  3. Ohayon MM, Shapiro CM.. Tenses of insomnia epidemiology. J Psychosom Res. 2002;53:525–527. doi: 10.1016/s0022-3999(02)00442-7. [DOI] [PubMed] [Google Scholar]
  4. National Institutes of Health. National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults. Sleep. 2005;28:1049–1057. doi: 10.1093/sleep/28.9.1049. [DOI] [PubMed] [Google Scholar]
  5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association. 2002 [Google Scholar]
  6. Buysse DJ, Finn L, and Young T. Onset, remission, persistence, and consistency of insomnia symptoms over 10 years: longitudinal results from the Wisconsin Sleep Cohort Study (WSCS). Sleep. 2004 27:A268. Abstract 602. [Google Scholar]
  7. Drake CL, Roehrs T, Roth T.. Insomnia causes, consequences, and therapeutics: an overview. Depress Anxiety. 2003;18:163–176. doi: 10.1002/da.10151. [DOI] [PubMed] [Google Scholar]
  8. Wheatley D.. Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability. J Psychopharmacol. 2005;19:414–421. doi: 10.1177/0269881105053309. [DOI] [PubMed] [Google Scholar]
  9. Kales A, Scharf MB, and Kales JD. et al. Rebound insomnia: a potential hazard following withdrawal of certain benzodiazepines. JAMA. 1979 241:1692–1695. [DOI] [PubMed] [Google Scholar]
  10. Kales A, Bixler EO, and Soldatos CR. et al. Quazepam and flurazepam: long-term use and extended withdrawal. Clin Pharmacol Ther. 1982 32:781–788. [DOI] [PubMed] [Google Scholar]
  11. Tansella CZ, Tansella M, Lader M.. A comparison of the clinical and psychological effects of diazepam and amylobarbitone in anxious patients. Br J Clin Pharmacol. 1979;7:605–611. doi: 10.1111/j.1365-2125.1979.tb04650.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Rudolph U, Crestani F, and Benke D. et al. Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature. 1999 401:796–800. [DOI] [PubMed] [Google Scholar]
  13. McKernan RM, Rosahl TW, and Reynolds DS. et al. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha 1 subtype. Nat Neurosci. 2000 3:587–592. [DOI] [PubMed] [Google Scholar]
  14. Korpi ER, Mattila MJ, and Wisden W. et al. GABA(A)-receptor subtypes: clinical efficacy and selectivity of benzodiazepine site ligands. Ann Med. 1997 29:275–282. [DOI] [PubMed] [Google Scholar]
  15. Ashton H.. Guidelines for the rational use of benzodiazepines: when and what to use. Drugs. 1994;48:25–40. doi: 10.2165/00003495-199448010-00004. [DOI] [PubMed] [Google Scholar]
  16. Vgontzas AN, Kales A, Bixler EO.. Benzodiazepine side effects: role of pharmacokinetics and pharmacodynamics. Pharmacology. 1995;51:205–223. doi: 10.1159/000139363. [DOI] [PubMed] [Google Scholar]
  17. Monti JM.. Sleep laboratory and clinical studies of the effects of triazolam, flunitrazepam and flurazepam in insomniac patients. Methods Find Exp Clin Pharmacol. 1981;3:303–326. [PubMed] [Google Scholar]
  18. Nicholson AN.. The use of short- and long-acting hypnotics in clinical medicine. Br J Clin Pharmacol. 1981;11:61S–69S. doi: 10.1111/j.1365-2125.1981.tb01841.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gorenstein C, Gentil V.. Residual and acute effects of flurazepam and triazolam in normal subjects. Psychopharmacology (Berl) 1983;80:376–379. doi: 10.1007/BF00432125. [DOI] [PubMed] [Google Scholar]
  20. Monti JM, Attali P, and Monti D. et al. Zolpidem and rebound insomnia—a double-blind, controlled polysomnographic study in chronic insomniac patients. Pharmacopsychiatry. 1994 27:166–175. [DOI] [PubMed] [Google Scholar]
  21. Voderholzer U, Riemann D, and Hornyak M. et al. A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects. Eur Arch Psychiatry Clin Neurosci. 2001 251:117–123. [DOI] [PubMed] [Google Scholar]
  22. Sanger DJ, Zivkovic B.. Differential development of tolerance to the depressant effects of benzodiazepine and non-benzodiazepine agonists at the omega (BZ) modulatory sites of GABAA receptors. Neuropharmacology. 1992;31:693–700. doi: 10.1016/0028-3908(92)90148-i. [DOI] [PubMed] [Google Scholar]
  23. Sanger DJ, Benavides J, and Perrault G. et al. Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes. Neurosci Biobehav Rev. 1994 18:355–372. [DOI] [PubMed] [Google Scholar]
  24. Savic MM, Obradovic DI, and Ugresic ND. et al. Memory effects of benzodiazepines: memory stages and types versus binding-site subtypes. Neural Plast. 2005 12:289–298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ambien-CR [prescribing information]. Paris, France: sanofiaventis. Available at: http://products.sanofiaventis.us/ambien_cr/ambien_cr.pdf. Accessed November 2006. [Google Scholar]
  26. Greenblatt DJ, Zammit G, and Rice KM. et al. Zolpidem modified-release formulation has greater pharmacologic and pharmacodynamic activity than standard zolpidem in the period 3–6 hours postdose. Sleep. 2005 28:A245. Abstract 0730. [Google Scholar]
  27. Blin O, Micallef-Roll J, and Audebert C. et al. 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. [DOI] [PubMed] [Google Scholar]
  28. Hindmarch I, Legangneux E, and Stanley N. et al. 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Fairweather DB, Kerr JS, Hindmarch I.. 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. doi: 10.1007/BF02284957. [DOI] [PubMed] [Google Scholar]
  30. Berlin I, Warot D, and Hergueta T. et al. Comparison of the effects of zolpidem and triazolam on memory functions, psychomotor performances, and postural sway in healthy subjects. J Clin Psychopharmacol. 1993 13:100–106. [PubMed] [Google Scholar]
  31. Scharf MB, Roth T, and Vogel GW. et al. A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia. J Clin Psychiatry. 1994 55:192–199. [PubMed] [Google Scholar]
  32. Wesensten NJ, Balkin TJ, Belenky GL.. Effects of daytime administration of zolpidem versus triazolam on memory. Eur J Clin Pharmacol. 1995;48:115–122. doi: 10.1007/BF00192735. [DOI] [PubMed] [Google Scholar]
  33. Monti JM.. Effect of zolpidem on sleep in insomniac patients. Eur J Clin Pharmacol. 1989;36:461–466. doi: 10.1007/BF00558070. [DOI] [PubMed] [Google Scholar]
  34. Hajak G, Bandelow B.. 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. doi: 10.1097/00004850-199807000-00002. [DOI] [PubMed] [Google Scholar]
  35. Monti JM, Monti D, and Estevez F. et al. Sleep in patients with chronic primary insomnia during long-term zolpidem administration and after its withdrawal. Int Clin Psychopharmacol. 1996 11:255–263. [DOI] [PubMed] [Google Scholar]
  36. Herrmann WM, Kubicki ST, and Boden S. et al. Pilot controlled double-blind study of the hypnotic effects of zolpidem in patients with chronic ‘learned’ insomnia: psychometric and polysomnographic evaluation. J Int Med Res. 1993 21:306–322. [DOI] [PubMed] [Google Scholar]
  37. Roehrs T, Soubrane C, and Walsh J. et al. Zolpidem modified-release objectively and subjectively improves sleep maintenance and retains the characteristics of standard zolpidem on sleep initiation and duration in elderly patients with primary insomnia. Sleep. 2005 28:A244. Abstract 0725. [Google Scholar]
  38. Roth T, Soubrane C, and Titeux L. et al. Efficacy and safety of zolpidem MR: a double-blind, placebo-controlled study in adults with primary insomnia. Sleep Med. 2006 7:397–406. [DOI] [PubMed] [Google Scholar]
  39. Fry J, Scharf MB, Berkowitz DV.. A phase III, 28 day, multi-center, randomized, double-blind, comparator and placebo-controlled, parallel-group safety, tolerability, and efficacy study of 5, 10, and 20 mg of zaleplon, compared with 10 mg of zolpidem or placebo in adult outpatients with insomnia [abstract] Sleep. 1998;21:262. [Google Scholar]
  40. Ancoli-Israel S, Roth T.. Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation Survey, 1. Sleep. 1999;22:S347–S353. [PubMed] [Google Scholar]
  41. Elie R, Ruther E, and Farr I. et al. Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. Zaleplon Clinical Study Group. J Clin Psychiatry. 1999 60:536–544. [DOI] [PubMed] [Google Scholar]
  42. Trifiletti RR, Snyder SH.. Anxiolytic cyclopyrrolones zopiclone and suriclone bind to a novel site linked allosterically to benzodiazepine receptors. Mol Pharmacol. 1984;26:458–469. [PubMed] [Google Scholar]
  43. Leese P, Maier G, and Vaickus L. Eszopiclone: pharmacokinetic and pharmacodynamic effects of a novel sedative hypnotic after daytime administration in healthy subjects. Sleep. 2002 25Abstract A45. [Google Scholar]
  44. Lunesta [prescribing information]. Malborough, Mass: Sepracor Inc. Available at: http://www.lunesta.com/lunestaOverview/LunestaPPI.pdf. Accessed November 2006. [Google Scholar]
  45. Rosenberg R, Caron J, and Roth T. et al. An assessment of the efficacy and safety of eszopiclone in the treatment of transient insomnia in healthy adults. Sleep Med. 2005 6:15–22. [DOI] [PubMed] [Google Scholar]
  46. Scharf MB, Erman M, and Rosenberg J. et al. A 2-week efficacy and safety study of eszopiclone in elderly patients with primary insomnia. Sleep. 2005 28:720–727. [DOI] [PubMed] [Google Scholar]
  47. Krystal AD, Walsh JK, and Laska E. et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep. 2003 26:793–799. [DOI] [PubMed] [Google Scholar]
  48. Roth T, Walsh JK, and Krystal A. et al. An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Med. 2005 6:487–495. [DOI] [PubMed] [Google Scholar]
  49. Sonata [prescribing information]. Bristol, Tenn: King Pharmaceuticals; 2003. Available at: http://www.kingpharm.com/uploads/pdf_inserts/Sonata_Web_PI.pdf. Accessed May 2006. [Google Scholar]
  50. Beer B, Ieni JR, and Wu WH. et al. A placebo-controlled evaluation of single, escalating doses of CL 284,846, a non-benzodiazepine hypnotic. J Clin Pharmacol. 1994 34:335–344. [DOI] [PubMed] [Google Scholar]
  51. Rosen AS, Fournie P, and Darwish M. et al. Zaleplon pharmacokinetics and absolute bioavailability. Biopharm Drug Dispos. 1999 20:171–175. [DOI] [PubMed] [Google Scholar]
  52. Walsh JK, Pollak CP, and Scharf MB. et al. Lack of residual sedation following middle-of-the-night zaleplon administration in sleep maintenance insomnia. Clin Neuropharmacol. 2000 23:17–21. [DOI] [PubMed] [Google Scholar]
  53. Dietrich B, Emilien G, Salinas E.. Zaleplon does not produce residual sedation in a phase-advance model of transient insomnia [abstract] J Sleep Res. 1998;21:67. [Google Scholar]
  54. Hirai K, Kato K, Nishikawa H.. TAK-375 and its metabolites are selective agonists at ML-1 receptors [abstract] Sleep. 2003;26:A79. [Google Scholar]
  55. Miyamoto M, Nishikawa H, and Ota H. et al. Behavioral pharmacology of TAK-375 in small mammals [abstract]. Ann Neurol. 2003 54:S46. 12891653 [Google Scholar]
  56. Rozerem [prescribing information]. Deerfield, Ill: Takeda Pharmaceuticals North America, Inc. Available at: http://www.rozerem.com/PI_1.aspx. Accessed January 2006. [Google Scholar]
  57. Erman M, Seiden D, and Zammit G. et al. An efficacy, safety, and dose-response study of ramelteon in patients with chronic primary insomnia. Sleep Med. 2006 7:17–24. [DOI] [PubMed] [Google Scholar]
  58. Hajak G, Rodenbeck A, and Voderholzer U. et al. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry. 2001 62:453–463. [DOI] [PubMed] [Google Scholar]
  59. Riemann D, Voderholzer U, and Cohrs S. et al. Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study. Pharmacopsychiatry. 2002 35:165–174. [DOI] [PubMed] [Google Scholar]
  60. Mendelson WB.. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry. 2005;66:469–476. doi: 10.4088/jcp.v66n0409. [DOI] [PubMed] [Google Scholar]
  61. Estelle F, Simons R.. H1-receptor antagonists: safety issues. Ann Allergy Asthma Immunol. 1999;83:481–488. doi: 10.1016/s1081-1206(10)62855-4. [DOI] [PubMed] [Google Scholar]
  62. Ringdahl EN, Pereira SL, Delzell JE Jr. Treatment of primary insomnia. J Am Board Fam Pract. 2004;17:212–219. doi: 10.3122/jabfm.17.3.212. [DOI] [PubMed] [Google Scholar]
  63. Simons KJ, Watson WT, and Martin TJ. et al. Diphenhydramine: pharmaco-kinetics and pharmacodynamics in elderly adults, young adults, and children. J Clin Pharmacol. 1990 30:665–771. [DOI] [PubMed] [Google Scholar]
  64. Kay GG.. The effects of antihistamines on cognition and performance. J Allergy Clin Immunol. 2000;105:S622–S627. doi: 10.1067/mai.2000.106153. [DOI] [PubMed] [Google Scholar]
  65. Sproule BA, Busto UE, and Buckle C. et al. The use of non-prescription sleep products in the elderly. Int J Geriatr Psychiatry. 1999 14:851–857. [PubMed] [Google Scholar]
  66. Zhdanova IV.. Melatonin as a hypnotic: pro. Sleep Med Rev. 2005;9:51–65. doi: 10.1016/j.smrv.2004.04.003. [DOI] [PubMed] [Google Scholar]
  67. Roth T. Prevalence, associated risks, and treatment patterns of insomnia. J Clin Psychiatry. 2005 66suppl 9. 10–13.quiz 42–43. [PubMed] [Google Scholar]
  68. Roth T, Roehrs T, and Zorick F. et al. Pharmacological effects of sedative-hypnotics, narcotic analgesics, and alcohol during sleep. Med Clin North Am. 1985 69:1281–1288. [DOI] [PubMed] [Google Scholar]
  69. National Sleep Foundation. Sleep in America Poll. Data from 1997–2001, 2002 sleep poll. Available at: http://www.sleepfoundation.org/_content/hottopics/2002SleepInAmericaPoll.pdf. Accessibility verified January 11, 2007. [Google Scholar]
  70. Halcion [prescribing information]. New York, NY: Pfizer Inc. Available at: http://www.pfizer.com/pfizer/download/uspi_halcion.pdf. Accessed November 2006. [Google Scholar]
  71. Mendelson WB. Hypnotic medications: mechanisms of action and pharmacologic effects. In: Kryger M, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia, Pa: Elsevier. 2005 444–451. [Google Scholar]
  72. Restoril [prescribing information]. St. Louis, Mo: Mallinckrodt Pharmaceuticals. Available at: http://www.restoril.com/pdf/restoril_prod_pi.pdf. Accessed November 2006. [Google Scholar]
  73. ProSom [prescribing information]. Abbott Park, Ill: Abbott Laboratories. Available at: http://www.fda.gov/Medwatch/SAFETY/2004/jun_PI/Prosom_PI.pdf. Accessed November 2006. [Google Scholar]
  74. Doral [prescribing information]. Union City, Calif: Questcor Pharmaceuticals. Available at: http://www.questcor.com/pdf/doral_PI.pdf. Accessed November 2006. [Google Scholar]
  75. Dalmane [prescribing information]. Aliso Viejo, Calif: Valeant Pharmaceuticals International. Available at: http://www.valeant.com/fileRepository/products/PI/Dalmane_Capsule_15-30mg_PI_Sep01.pdf. Accessibility verified January 11, 2007. [Google Scholar]
  76. Ambien [prescribing information]. Paris, France: sanofi-aventis. Available at: http://www.ambien.com/consumer/utility/ambienPatient.pdf. Accessed November 2006. [Google Scholar]

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