Chapter  125:  Manifestations and Management of Chronic Insomnia in Adults

Prevalence of Insomnia

Insomnia, or inability to sleep, is the most commonly reported sleep problem in the industrialized world.¹ Estimates suggest that between 40 and 70 million Americans are affected by either intermittent or chronic sleep problems, representing approximately 20 percent of the population.² The Sleep in America Poll, conducted by the National Sleep Foundation, revealed that almost 50 percent of people surveyed had complaints of frequent insomnia, but only 6 percent were formally diagnosed.³ Moreover, approximately, 30 to 35 percent of respondents complained of nightly insomnia.³ The most prevalent symptoms of insomnia, experienced at least a few nights a week by people with insomnia, include waking up feeling unrefreshed (34 percent) and being awake often during the night (32 percent).³ The symptoms of difficulty falling asleep and waking up too early are less common, but still experienced at least a few nights a week by about one-fourth of adults with insomnia (23 to 24 percent).³

Risk Factors for Insomnia

Although some risk factors and etiologies of insomnia have been identified, the nature of the relationships has not been fully elucidated. Some risk factors for insomnia that have emerged from data related to insomnia include female gender³ and old age.⁴ Additional risks factors include less education, unemployment, separation or divorce, and medical illness.¹ Insomnia may be primary or secondary to other sleep problems and may be associated with a number of co-morbidities. An association has been found between insomnia and psychiatric (depression and anxiety) and psychological disorders.⁴ There is increasing evidence that chronic insomnia may predispose individuals to the development of psychiatric disorders.⁵–⁶ Persistent insomnia increases the risk of depression, substance abuse, and anxiety disorders. Environmental factors such as irregular sleep schedules, use of caffeine or other stimulants, co-morbid medical conditions, and/or shift work may also predispose vulnerable individuals to insomnia.

Consequences of Insomnia

Insomnia has significant direct and indirect effects on the health and wellness of affected individuals. Insomnia has been correlated with frequent use of medical services,⁷–⁸ chronic health problems, ⁹–¹⁰ increased drug use,⁷–⁸ and perceived poor health,¹¹ and has been associated with medical problems including heart disease,¹² hypertension,¹³ and musculoskeletal problems.¹² The daytime consequences of chronic insomnia often include increased healthcare utilization, increased risk of depression,¹⁴ poor memory, reduced concentration, poor work performance, and perceived or real risk of failure at work.¹⁵ The economic implications of insomnia and associated morbidity have been described.⁷,³ The direct costs of insomnia (insomnia treatments, healthcare services, hospital and nursing home care) are estimated to be nearly $14 billion.¹⁶–¹⁷ The indirect costs of insomnia, such as time lost from work and loss of productivity, are estimated to be nearly $28 billion. A National Sleep Foundation survey found that lost productivity from insomnia alone was over $18 billion.

Management of Insomnia

Management of acute insomnia has traditionally involved pharmacotherapy. The use of such agents is common practice for both acute and chronic insomnia, despite the fact that the Food and Drug Administration (FDA) has approved none of them for chronic insomnia. Another medication, eszopiclone (Lunesta), was recently approved by the FDA for treatment of insomnia, but the duration of use is not explicitly stated. An estimated 0.5 percent of the population takes sedative medications for insomnia for more than 1 year.³ More than 1 in 10 people (11 percent) report using prescription (6 percent) and/or over-the-counter (OTC) medications (6 percent), at least a few nights a month, to help them sleep, according to a Sleep in America Poll.³ Individuals reporting symptoms of medical conditions are more likely to take sleep aids, both prescription and OTC medications. For example, 14 percent of people with symptoms of depression report using prescription medication, and 12 percent of people with symptoms of depression report using OTC sleep aids.³ Medications commonly used to treat insomnia include sedating antidepressants,¹⁸ antihistamines, anticholinergics, benzodiazepines, and non-benzodiazepine hypnotics. A side effect of all hypnotics is to reduce slow wave sleep. Other side effects of concern are possible daytime residual effects related to sedation, rebound insomnia, and tolerance, along with minor side effects specific to each drug class. Many questions and challenges related to pharmacological therapy for chronic insomnia remains, such as the appropriate treatment for different types of primary and secondary insomnia, and the long-term side effects and daytime consequences of pharmacotherapy. The evidence for management of chronic insomnia with pharmacotherapy has not been systematically evaluated.

Cognitive/behavioral therapy has been recognized as a valid and successful treatment approach for insomnia. Cognitive/ behavioral therapy can include any combination of sleep restriction, sleep hygiene, stimulus control, paradoxical intention, and cognitive restructuring. Many of these commonly used clinical tools have not undergone rigorous testing to determine their efficacy and long-term safety. The efficacy of these treatments has been evaluated in some studies,⁴,¹⁹ but differences in the definition of insomnia and outcome measures make it difficult to compare study results.

In summary, insomnia is a common complaint with significant consequences. Significant advancements have been made in sleep research over the past three decades, yet many questions related to the treatment of chronic insomnia remain. Our goal was to review the evidence and state of research in the area of chronic insomnia.

Objectives

The objectives of this report are to conduct a systematic review of (1) the prevalence, natural history, incidence, risk factors, and consequences of chronic insomnia in adults and (2) the efficacy and safety of treatments used in the management of chronic insomnia in adults. A population was considered to suffer from chronic insomnia if the sleep disturbance persisted for at least 4 weeks, regardless of severity of symptoms.

Methods

Study Selection

In the first stage of study selection, two reviewers screened the titles and abstracts of all potentially relevant articles, independently. Each reviewer noted the titles and abstracts that were potentially relevant to the review, and these articles were retrieved. In the second stage of study selection, two reviewers appraised the potentially relevant articles, independently, using pre-determined, question-specific, inclusion criteria. Disagreements between reviewers were resolved by discussion and consensus. The rate of disagreement between reviewers and the primary reason for exclusion of potentially relevant articles were noted.

Data Extraction

Data relevant to study design, population, interventions, and outcomes were extracted from studies, as appropriate, using standardized data extraction forms. A trained reviewer extracted relevant data, and a second reviewer verified the data extracted for accuracy and completeness.

Assessment of Study Quality

The quality of studies relevant to the questions on manifestations of chronic insomnia was assessed using one of three instruments; studies on prevalence and incidence were assessed using a scale designed specifically for this purpose.²⁰ All other studies relevant to manifestations of chronic insomnia were assessed using one of two Newcastle-Ottawa scales (unpublished), each scale specific to either cohort or case-control studies.

The quality of studies relevant to management of chronic insomnia was assessed using the Jadad scale.²¹ The concealment of allocation of participants to treatment groups was also assessed.²²

Data Analysis

Data relevant to manifestations of chronic insomnia were analyzed qualitatively, while data relevant to management of chronic insomnia were analyzed quantitatively.

Main Results

Factors Associated with Chronic Insomnia

Efficacy and Safety of the Six Main Categories of Interventions Identified in the Literature

The efficacy estimates are provided as mean differences (MDs) in the effect of intervention and placebo on sleep onset latency (SOL) or wakefulness after sleep onset (WASO). The safety estimates are provided as risk differences (RDs) between intervention and placebo.

• Benzodiazepines. MD (SOL): -16.5, 95% CI: (-20.5, -12.5); MD (WASO): -23.1, 95% CI: (-35.7, -10.5); RD: 0.15, 95% CI: (0.10, 0.20); number needed to harm was eight.

• Non-benzodiazepines. MD (SOL): -18.1, 95% CI: (-22.5, -13.7); MD (WASO): -12.6, 95% CI: (-23.0, -2.3); RD: 0.05, 95% CI: (0.01, 0.09); number needed to harm was 20.

• Antidepressants. MD (SOL): -7.4, 95% CI (-10.5, -4.4); MD (WASO): -11.4, 95% CI: (-16.2, -6.6); RD: 0.09, 95% CI (0.01, 0.18); number needed to harm was 12.

• L-Tryptophan. MD (SOL): -11.0, 95% CI: (-33.0, 11.1)

• Melatonin. MD (SOL): -8.3, 95% CI: (-14.5, -2.0); MD (WASO): -9.7, 95% CI: (-33.6, 14.3); RD: 0.09, 95% CI: (-0.11, 0.29)

• Valerian. MD (SOL): -1.3, 95% CI: (-21.4, 18.9); MD (WASO): -8.4, 95% CI: (-15.9, -1.0); RD: -0.06, 95% CI: (-0.48, 0.35)

• Relaxation therapy. MD (SOL): -14.6, 95% CI: (-29.3, 0.2); MD (WASO): -1.6, 95% CI: (-14.1, 10.8). No adverse event data was provided.

• Cognitive/behavioral therapy. MD (SOL): -4.6, 95% CI: (-9.8, 0.6); MD (WASO): -18.2, 95% CI: (-30.4, -6.0). No adverse event data was provided.

Most studies were of moderate or high quality.

Discussion

Efficacy and Safety of Treatments for Chronic Insomnia

The interventions for chronic insomnia that were investigated in included studies may be categorized as either benzodiazepines, non-benzodiazepines, antidepressants, complementary and alternative care (L-tryptophan, melatonin and valerian), relaxation therapy, cognitive/behavioral therapy, barbiturates, hormone therapy, alcohol, low energy emission therapy, and combination therapy. The majority of studies were classified under the first six categories of the preceding list.

The review provides evidence that benzodiazepines and non-benzodiazepines are effective treatments for chronic insomnia. There is some evidence that antidepressants are effective treatments for chronic insomnia, although more research is required in this area. The review provides some evidence that melatonin is effective in subsets of the chronic insomnia population; however, more research is required in this area. There is also evidence that relaxation therapy and cognitive/behavioral therapy are effective treatments in subsets of the chronic insomnia population. There were too few studies of L-tryptophan and valerian to draw conclusions regarding the efficacy of these treatments in the management of chronic insomnia: additional large-scale, randomized trials are needed. Additional large-scale, randomized trials are also needed in the area of relaxation therapy and cognitive/ behavioral therapy in the management of chronic insomnia to determine the efficacy of these interventions across subsets of the chronic insomnia population. The reduction in sleep onset latency by benzodiazepines and non-benzodiazepines was significantly greater than that for antidepressants and melatonin, based on indirect comparisons. However, it should be noted that there were significantly fewer studies of antidepressants and melatonin compared to benzodiazepines and non-benzodiazepines, and additional large-scale, randomized trials of the former interventions are needed before firm conclusions can be drawn regarding the relative efficacy of these interventions.

The benzodiazepines, non-benzodiazepines, and antidepressants had a significantly greater risk of harm than placebo, while melatonin did not. There were too few studies of L-tryptophan to draw conclusions regarding the safety of this intervention. Although there was no evidence that valerian poses a risk of harm, this result was based on only three studies of relatively small sample size. Therefore, more studies are needed before firm conclusions can be drawn regarding the safety of valerian. The risk for benzodiazepines was significantly greater than for non-benzodiazepines, based on indirect comparisons. Indeed, benzodiazepine use has been shown to increase the risk of injury in the elderly,⁴² and there is pharmacologic evidence that the non-benzodiazepines have a better side-effect profile than the benzodiazepines.⁴³–⁴⁴ Studies of relaxation therapy and cognitive/behavioral therapy did not provide adverse event data.

There was substantial heterogeneity in the pooled estimate for SOL for benzodiazepines, non-benzodiazepines, L-tryptophan, valerian, and relaxation therapy. Similarly, there was substantial heterogeneity in the pooled estimate for WASO for benzodiazepines, non-benzodiazepines, melatonin, and cognitive/behavioral therapy. The heterogeneity was often due to differences in the magnitude of the point estimate and confidence interval across studies, rather than differences in the directionality of the effect. The exceptions are for estimates of the efficacy of relaxation therapy with respect to SOL and the efficacy of melatonin with respect to WASO. The heterogeneity in the pooled estimates for SOL was explored in sensitivity and sub-group analyses. The results indicate that heterogeneity in the pooled estimate for SOL for relaxation therapy is at least partially due to type of relaxation therapy, length of treatment, age and gender distribution of the study population, and study quality.

There was strong evidence of publication bias in the pooled estimates for SOL for the benzodiazepine and non-benzodiazepine categories of intervention. This finding suggests that the true estimate of efficacy is lower than the estimate calculated in the current analysis.

We identified a small sample of studies examining the efficacy of combination treatments in the management of chronic insomnia; some of these studies compared a combination of treatments with placebo, while others compared them with single treatment. Many comparisons did not have data for our primary outcome, sleep onset latency, and the majority of results were non-significant. The latter finding may reflect the low power of these analyses. None of the studies provided data on adverse events. We identified only one study that compared the efficacy of a combined pharmacological and psychological treatment with these treatments administered sequentially. The research agenda for the management of chronic insomnia should include an evaluation of the efficacy and safety of combination treatments and sequential treatments.

Our results relating to relaxation therapy and cognitive/behavioral therapy are somewhat at odds with three meta-analyses reviewing the efficacy of psychological treatments in the management of chronic insomnia.⁴⁵–⁴⁷ The difference in the findings may relate to key differences in the conduct of the reviews. First, we restricted our meta-analysis to a review of placebo-controlled, randomized trials and accounted for placebo effects in our estimations of efficacy. Other meta-analyses have included non-controlled studies, and for these studies, have not accounted for placebo/control effects in their estimation of efficacy. Second, we used clearly defined criteria for chronic insomnia; however, for some studies the criteria for insomnia was not clear. Third, we separated predominantly cognitive/behavioral approaches from predominantly relaxation approaches in management of insomnia, resulting in distinct meta-analyses for each category of intervention. These interventions have been grouped under the broader heading of psychological/non-pharmacological treatments in other reviews.

Conclusions

• There is evidence that the prevalence of chronic insomnia in outpatient and clinical populations is larger than in the general population.

• There is evidence that chronic insomnia is associated with older age, female gender, present or past psychiatric illness and psychological problems, medical conditions and poor general health, increased healthcare utilization, lower quality of life and social relationships, socioeconomic status (marital separation, unemployment, poorer working conditions and lower social status), and decrements in memory, mood, and cognitive function.

• Additional studies are needed to determine the incidence and natural history of chronic insomnia in adults. Similarly, additional studies are needed to explore the relationship between chronic insomnia and race/ethnicity, shift work, absenteeism, work performance, accidents, falls in the elderly, and the direct and indirect costs of the disorder. It is necessary that longitudinal studies be undertaken to explore the risk factors and consequences of chronic insomnia.

• There is evidence that benzodiazepines and non-benzodiazepines are effective in the management of chronic insomnia. There is some evidence that antidepressants are effective in the management of chronic insomnia: more research is required in this area. There is evidence that benzodiazepines, non-benzodiazepines, and antidepressants pose a risk of harm.

• There is some evidence that melatonin is effective in the management of chronic insomnia in subsets of the chronic insomnia population, and there is no evidence that melatonin poses a risk of harm. However, more research is required in this area given that the results are based on a small number of studies. Similarly, additional large-scale, randomized trials are needed to determine the efficacy of melatonin across subsets of the chronic insomnia population. There is insufficient evidence to conclude on the efficacy and safety of L-tryptophan and valerian in the management of chronic insomnia. Additional large-scale, randomized trials are needed in these areas.

• There is evidence that relaxation therapy and cognitive/behavioral therapy are effective in the management of chronic insomnia in subsets of the chronic insomnia population. Additional large-scale, randomized trials are needed to determine their efficacy across subsets of the chronic insomnia population.

• There is evidence that benzodiazepines have a greater risk of harm than non-benzodiazepines.

• There is insufficient evidence to conclude whether there are differences between the short- and long-term efficacy and safety of the various categories of interventions in the management of chronic insomnia; additional long-term studies are needed.

• There is insufficient evidence regarding the efficacy and safety of combined treatments of pharmacological and psychological interventions, and sequential treatments, in the management of chronic insomnia; additional studies are needed in these areas.

Availability of the Full Report

The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the University of Alberta Evidence-based Practice Center, under Contract No. C400000021. It is expected to be available in June 2005. At that time, printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 125, Manifestations and Management of Chronic Insomnia in Adults. In addition, Internet users will be able to access the report and this summary online through AHRQ's Web site at www.ahrq.gov.

Suggested Citation

Buscemi N, Vandermeer B, Friesen C, Bialy L, Tubman M, Ospina M, Klassen TP, Witmans M. Manifestations and Management of Chronic Insomnia in Adults. Summary, Evidence Report/Technology Assessment No. 125. (Prepared by the University of Alberta Evidence-based Practice Center, under Contract No. C400000021.) AHRQ Publication No. 05-E021-1. Rockville, MD: Agency for Healthcare Research and Quality. June 2005.

References

1.

Sateia MJ, Doghramji K, Hauri P. et al. Evaluation of chronic insomnia. An American Academy of Sleep Medicine Review. Sleep. 2000; 23(2): 243–308. [PubMed]

2.

Trans-NIH Sleep Research Coordinating Committee. 2003 National Sleep Disorders Research Plan. US Department of Health and Human Services. National Institute of Health. http://www.nhlbisupport.com/sleep/research/research-a.htm.

3.

National Sleep Foundation. Sleep in America Poll. Data from 1997 and 2001, 2002 sleep poll. http://www.sleepfoundation.org/img/ 2002SleepInAmericaPoll.pdf.

4.

Zorick FJ, Walsh JK. In Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. 3rd Ed. Philadelphia, PA: W.B. Saunders Co; 2000. Chapter 53, Evaluation and management of insomnia.

5.

Sateia MJ, Nowell P. Insomnia. Lancet. 2004; 364: 1959–73. [PubMed]

6.

Breslau N, Roth T, Rosenthal L. et al. Sleep disturbances and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996; 39: 411–18. [PubMed]

7.

Simon GE, VonKorff M. Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry. 1997; 154(10): 1417–23. [PubMed]

8.

Leger D, Guilleminault C, Bader G. et al. Medical and socio-professional impact of insomnia. Sleep. 2002; 25(6): 625–9. [PubMed]

9.

Ohayon M. Epidemiological study on insomnia in the general population. Sleep. 1996; 19(3 Suppl): S7–15. [PubMed]

10.

Roberts RE, Shema SJ, Kaplan GA. Prospective data on sleep complaints and associated risk factors in an older cohort. Psychosom Med. 1999; 61(2): 188–96. [PubMed]

11.

Foley DJ, Monjan A, Simonsick EM. et al. Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6,800 persons over three years. Sleep. 1999; 22(Suppl 2): S366–72. [PubMed]

12.

Janson C, Lindberg E, Gislason T. et al. Insomnia in men - A 10-year prospective population based study. Sleep. 2001; 24(4): 425–30. [PubMed]

13.

Gislason T, Reynisdottir H, Kristbjarnarson H. et al. Sleep habits and sleep disturbances among the elderly—an epidemiological survey. J Int Med. 1993; 234(1): 31–9.

14.

Riemann D, Voderholzer U. Primary insomnia: a risk factor to develop depression? J Affect Disord. 2003; 76: 255–9. [PubMed]

15.

Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. 3rd Ed. Philadelphia, PA: W.B. Saunders Co; 2000.

16.

Walsh JK, Engelhardt CL. The direct economic costs of insomnia in the United States for 1995. Sleep. 1999; 22(Suppl 2): S386–93. [PubMed]

17.

Walsh JK. Clinical and socioeconomic correlates of insomnia. J Clin Psychiatry. 2004; 65 Suppl 8: 13–9. [PubMed]

18.

Walsh J. Pharmacologic management of insomnia. J Clin Psychiatry. 2004; 65(Supp 16): 41–5. [PubMed]

19.

Morin CM, Colecchi C, Stone J. et al. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. J Am Med Assoc. 1999; 281(11): 991–9.

20.

Loney PL, Chambers LW, Bennett KJ. et al. Critical appraisal of the health research literature: prevalence or incidence of a health problem (Review). Chronic Dis Can. 1988; 19(4): 170–6. [PubMed]

21.

Jadad AR, Moore RA, Carroll D. et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17: 1–12. [PubMed]

22.

Schulz KF, Chalmers I, Hayes RJ. et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. J Am Med Assoc. 1995; 273: 408–12.

23.

DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7: 177–88. [PubMed]

24.

Bailey KR. Inter-study differences: How should they influence the interpretation and analysis of results? Stat Med. 1987; 6: 351–8. [PubMed]

25.

Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11): 1539–58. [PubMed]

26.

Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey Smith G, and Altman DG. Systematic reviews in health care. 2nd ed. London, UK: BMJ Books; 2001.

27.

Light RJ, Pillemer DB. Summing up. The science of reviewing research. Cambridge, MA: Harvard University Press; 1984.

28.

Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994; 50: 1088–101. [PubMed]

29.

Egger M, Smith GD, Schneider M. et al. Bias in meta-analysis detected by a simple, graphical test. Br Med J. 1997; 315(7109): 629–34. [PubMed] [Free Full text in PMC]

30.

Duval S, Tweedie R. A nonparametric “trim and fill” method of accounting for publication bias in meta-analysis. J Am Med Assoc. 2000; 95(449): 89–98.

31.

Kageyama T, Nishikido N, Kobayashi T. et al. Cross-sectional survey on risk factors for insomnia in Japanese female hospital nurses working rapidly rotating shift systems. J Hum Ergol. 2001; 30(12): 149–54.

32.

Bixler EO, Vgontzas AN, Lin HM. et al. Insomnia in Central Pennsylvania. J Psychosom Res. 2002; 53(1): 589–92. [PubMed]

33.

Riedel BW, Durrence H, Lichstein KL. et al. The Relation Between Smoking and Sleep: The Influence of Smoking Level, Health, and Psychological Variables. Behav Sleep Med. 2004; 2(1): 63–78. [PubMed]

34.

Lopes Rocha F, Guerra HL, Lima-Costa MFF. Prevalence of insomnia and associated socio-demographic factors in a Brazilian community: The Bambui study. Sleep Med. 2002; 3(2): 121–6. [PubMed]

35.

Kageyama T, Kabuto M, Nitta H. et al. A population study on risk factors for insomnia among adult Japanese women: a possible effect of road traffic volume. Sleep. 1997; 20(11): 963–71. [PubMed]

36.

Martikainen K, Partinen M, Hasan J. et al. The impact of somatic health problems on insomnia in middle age. Sleep Med. 2003; 4(3): 201–6. [PubMed]

37.

Terzano MG, Parrino L, Cirignotta F. et al. Studio Morfeo: insomnia in primary care, a survey conducted on the Italian population. Sleep Med. 2004; 5(1): 67–75. [PubMed]

38.

Zammit GK, Weiner J, Damato N. et al. Quality of life in people with insomnia. Sleep. 1999; 22(Suppl 2): S379–85. [PubMed]

39.

Shochat T, Umphress J, Israel AG. et al. Insomnia in primary care patients. Sleep. 1999; 22(Suppl 2): S359–65. [PubMed]

40.

Perlis ML, Smith MT, Orff HJ. et al. The mesograde amnesia of sleep may be attenuated in subjects with primary insomnia. Physiol Behav. 2001; 74(12): 71–6. [PubMed]

41.

Benca RM, Ancoli-Israel S, Moldofsky H. Special considerations in insomnia diagnosis and management: depressed, elderly, and chronic pain populations. J Clin Psychiatry. 2004; 65(Suppl 8): 26–35. [PubMed]

42.

Panneman MJ, Goettsch WG, Kramarz P. et al. The costs of benzodiazepine-associated hospital-treated fall Injuries in the EU: a Pharmo study. Drugs Aging. 2003; 20(11): 833–9. [PubMed]

43.

Drover DR. Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet. 2004; 43(4): 227–38. [PubMed]

44.

Roehrs T, Roth T. Hypnotics: an update. Curr Neurol Neurosci Rep. 2003; 3(2): 181–4. [PubMed]

45.

Morin CM, Culbert JP, Schwartz SM. Nonpharmacological interventions for insomnia: A meta-analysis of treatment efficacy. Am J Psychiatry. 1994; 151(8): 1172–80. [PubMed]

46.

Murtagh DRR, Greenwood KM. Identifying effective psychological treatments for insomnia: a meta-analysis. J Consult Clin Psychol. 1995; 63(1 ): 79–89. [PubMed]

47.

Smith MT, Perlis ML, Park A. et al. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry. 2002; 159: 5–11. [PubMed]

Prevalence of Insomnia

Insomnia, or inability to sleep, is the most commonly reported sleep problem in the industrialized world.¹ Estimates suggest that between 40–70 million Americans are affected by either intermittent or chronic sleep problems, representing approximately 20 percent of the population.² The Sleep in America Poll, conducted by the National Sleep Foundation, revealed that almost 50 percent of people surveyed had complaints of frequent insomnia, but only 6 percent were formally diagnosed.³ Moreover, approximately, 30–35 percent of respondents complained of nightly insomnia.³ The most prevalent symptoms of insomnia, experienced at least a few nights a week by people with insomnia, include waking up feeling un-refreshed (34 percent) and being awake often during the night (32 percent).³ The symptoms of difficulty falling asleep and waking up too early are less common, but still experienced at least a few nights a week by about one-fourth of adults with insomnia (23–24 percent).³ The reported prevalence rates of insomnia vary in epidemiological studies based on the definitions and methods used to define insomnia. Earlier studies report prevalences of 5–35 percent.¹ The prevalence rate decreases to 10–15 percent for severe insomnia, when more stringent criteria are used.¹ The duration of insomnia is often classified as being transient, short-term or chronic. Chronic insomnia implies that insomnia is either persistent or recurrent. Definitions of chronic insomnia vary, ranging from greater than one month to greater than 6 months. Unfortunately, there is no standard definition of chronic insomnia used in studies.

There is emerging evidence that short-term sleep deprivation, under strict experimental conditions, is associated with a variety of adverse physiological and cognitive effects. Decrements in memory, concentration and executive function have been reported. There is also an increased risk of injury and accidents. Physiological effects resulting from sleep deprivation include hypertension, activation of the sympathetic nervous system, altered glucose metabolism and increased inflammatory markers. Sleep deprivation is associated with excessive sleepiness. Acute insomnia, however, may not equate to sleep deprivation. There is no evidence to suggest that patients with insomnia experience similar changes. Furthermore, it is not yet clear from the evidence what the physiological consequences of chronic insomnia are or if there is a process of adaptation that occurs in individuals with chronic insomnia. Thus, further research is needed in the area of chronic insomnia to determine what impact chronic insomnia has on health.

Risk Factors for Insomnia

Although some risk factors and etiologies of insomnia have been identified, the nature of the relationships has not been fully elucidated. Some risk factors for insomnia that have emerged from data related to insomnia include female gender ³ and old age.⁴ Additional risks factors include less education, unemployment, separation or divorce and medical illness.¹ Insomnia may be primary or secondary to other sleep problems, and may be associated with a number of co-morbidities. An association has been found between insomnia and psychiatric (depression and anxiety) and psychological disorders.⁴ There is increasing evidence that chronic insomnia may predispose individuals to the development of psychiatric disorders.⁵–⁶ Persistent insomnia increases the risk of depression, substance abuse and anxiety disorders. Environmental factors such as irregular sleep schedules, use of caffeine or other stimulants, co-morbid medical conditions and/or shift-work may also predispose vulnerable individuals to insomnia. We speculate that genetic predisposition to insomnia and environmental factors are likely involved in the development and maintenance of insomnia, and differences in the relative exposure to these influences may explain differences in the manifestation of this disorder among affected individuals.

Consequences of Insomnia

Insomnia has significant direct and indirect effects on the health and wellness of affected individuals. Insomnia has been correlated with frequent use of medical services,⁷–⁸ chronic health problems,⁹–¹⁰ increased drug use,⁷–⁸ perceived poor health,¹¹ and associated with medical problems including heart disease,¹² hypertension¹³ and musculoskeletal problems.¹² One study reported associations between insomnia and medical problems, and found that individuals with insomnia were more likely to have hypertension (59 percent), night time heartburn (62 percent) and depression (74 percent).³ The daytime consequences of chronic insomnia often include increased healthcare utilization, increased risk of depression,¹⁴ poor memory, reduced concentration, poor work performance and perceived or real risk of failure at work.¹⁵ The economic implications of insomnia and associated morbidity have been described.³;⁷ The direct costs of insomnia (insomnia treatments, healthcare services, hospital and nursing home care) are estimated to be nearly $14 billion.¹⁶–¹⁷ The indirect costs of insomnia, such as time lost from work and loss of productivity, are estimated to be nearly $28 billion. A National Sleep Foundation survey found that lost productivity from insomnia, alone, was over $18 billion. Another estimate of total costs of insomnia has reported amounts totaling almost $100 billion.¹⁸ This estimate is based on a high prevalence of insomnia, in the range of 33 percent, and the costs are related to sleepiness rather than insomnia. The data related to costs of chronic insomnia cannot be fully understood because of the impact insomnia has on many aspects of life. Nevertheless, insomnia, in its various forms, does result in substantial burden for affected individuals.

Management of Insomnia

Management of acute insomnia has traditionally involved pharmacotherapy. The use of such agents is common practice for both acute and chronic insomnia, despite the fact that the Food and Drug Administration (FDA) has approved none of them for chronic insomnia. Another medication, eszopiclone (Lunesta), was recently approved by the FDA for treatment of insomnia, but the duration of use is not explicitly stated. An estimated 0.5 percent of the population takes sedative medications for insomnia for more than one year.³ More than one in ten people (11 percent) report using prescription (6 percent) and/or over-the-counter (OTC) medications (6 percent), at least a few nights a month, to help them sleep, according to a Sleep in America Poll.³ Individuals reporting symptoms of medical conditions are more likely to take sleep aids, both prescription and OTC medications. For example, 14 percent of people with symptoms of depression report using prescription medication, and 12 percent of people with symptoms of depression report using OTC sleep aids.³ Medications commonly used to treat insomnia include sedating antidepressants,¹⁹ antihistamines, anticholinergics, benzodiazepines and non-benzodiazepine hypnotics. A side effect of all hypnotics is to reduce slow wave sleep. Other side effects of concern are possible daytime residual effects related to sedation, rebound insomnia and tolerance, along with minor side effects specific to each drug class. Many questions and challenges related to pharmacological therapy for chronic insomnia remains, such as the appropriate treatment for different types of primary and secondary insomnia, and the long-term side effects and daytime consequences of pharmacotherapy. The evidence for management of chronic insomnia with pharmacotherapy has not been systematically evaluated.

Cognitive/behavioral therapy has been recognised as a valid and successful treatment approach for insomnia. Cognitive/behavioral therapy can include any combination of sleep restriction, sleep hygiene, stimulus control, paradoxical intention and cognitive restructuring. Brief descriptions of these techniques are provided here.

Sleep restriction therapy involves limiting the amount of time in bed. The affected individual spends only the amount of time in bed that he/she sleeps, thus sleep may be restricted to 6 hours for an insomniac that spends 8 hours in bed. The purpose of the exercise is to improve the sleep efficiency progressively until the desired sleep duration is achieved, without prolonged sleep latency or maintenance insomnia.

Sleep hygiene instructions or education involves addressing environmental factors and health practices that may be counterproductive to sleep. It involves education about sleep patterns and the impact of health habits related to sleep. For example, alcohol consumed in the evening may help sleep onset, but promotes sleep maintenance insomnia during the night as the alcohol level declines.

Stimulus control therapy involves instructions aimed at curtailing sleep maladaptive behaviors and altering sleep-wake schedules. The instructions include: 1) going to bed when sleepy; 2) no other activities, besides sleep and sex, should be undertaken in the bed and bedroom; 3) get out of bed when unable to sleep for 15–20 minutes and return only if sleepy; 4) the daily wake-up time should be the same irrespective of how much sleep was obtained the previous night; 5) no naps allowed during the day.

Paradoxical intention is a technique that involves having the patient with insomnia stay awake, which is the most feared activity. The premise is that performance anxiety related to sleep would be alleviated if the patient stops trying to sleep and instead genuinely attempts to stay awake.

Cognitive restructuring can involve cognitive behavioral therapy targeted at an individual's unique perpetuating factors for insomnia.

Sleep non-suppression involves allowing oneself to think about whatever comes to mind, without any restrictions, as one gets to bed. The mind is allowed to go free, without the individual attempting to control his/her thoughts. This approach is thought to counteract the negative effects of thought suppression that often accompanies insomnia.

Relaxation therapy may or may not be a part of cognitive behavioral therapy. Different forms of relaxation therapy are designed to reduce somatic tension or cognitive arousals. Relaxation therapy may focus on somatic tension such as autogenic training, progressive muscle relaxation, or biofeedback, or may focus on the cognitive component such as intrusive thoughts that prevent sleep.

Many of these commonly used clinical tools have not undergone rigorous testing to determine their efficacy and long-term safety. The efficacy of these treatments has been evaluated in some studies,⁴;²⁰ but differences in the definition of insomnia and outcome measures make it difficult to compare study results.

In summary, insomnia is a common complaint with significant consequences. Significant advancements have been made in sleep research over the past three decades, yet many questions related to the treatment of chronic insomnia remain. Our goal was to review the evidence and state of research in the area of chronic insomnia.

Objectives

To conduct a systematic review of (1) the prevalence, natural history, incidence, risk factors and consequences of chronic insomnia in adults and (2) the efficacy and safety of treatments used in the management of chronic insomnia in adults. A population was considered to suffer from chronic insomnia if the sleep disturbance persisted for at least 4 weeks, regardless of severity of symptoms.

Analytic Approach

The analytic framework outlining the approach to the review is depicted in Flow Diagram 1. The specific questions addressed in the review appear below.

Overview

The systematic review involved a number of steps:

• Literature Search

• Development of Inclusion Criteria

• Study Selection

• Data Extraction

• Assessment of Study Quality

• Data Analysis

Literature Search

Table 1

Databases searched

Table 1

Databases searched

Database	Platform	Dates of Search
MEDLINE®	Ovid Version: rel9.1.0	1966 to September Week 1 2004
EMBASE	Ovid Version: rel9.1.0	1988 to 2004 Week 37
CINAHL	Ovid Version: rel9.1.0	1982 to September Week 2 2004
Ovid MEDLINE In-Process & Other Non-Indexed Citations	Ovid Version: rel9.1.0	September 14, 2004
Ovid OLDMEDLINE(R)®	Ovid Version: rel9.1.0	1951 to 1965 - Searched September 15, 2004
PsycINFO®	Ovid Version: rel9.1.0	1872 to September Week 1 2004
EBM Reviews - Cochrane Central Register of Controlled Trials	Ovid Version: rel9.1.0	2nd Quarter 2004, Searched September 15, 2004
International Pharmaceutical Abstracts	Ovid Version: rel9.1.0	1970 to August 2004
AMED (Allied and Complementary Medicine)	Ovid Version: rel9.1.0	1985 to September 2004
HealthSTAR/Ovid Healthstar	Ovid Version: rel9.1.0	1975 to August 2004
EBM Reviews - Cochrane Database of Systematic Reviews (CDSR); ACP Journal Club (ACPJC); Database of Abstracts of Reviews of Effects (DARE)	Ovid Version: rel9.1.0	2nd Quarter 2004 (CDSR); 1991 to March/April 2004 (ACPJC); 2nd Quarter 2004 (DARE); Searched September 15, 2004
Science Citation Index Expanded®	ISI Web of Knowledge	1945-September 2004, Searched September 17, 2004
Biological Abstracts	WebSPIRS from SilverPlatter, Version 4.3	1969-September 17, 2004
Cochrane Complementary Medicine Field Registry	Reference Web Poster 2001, ISI ResearchSoft	1950-September 20, 2004
CAB Abstracts	WebSPIRS from SilverPlatter, Version 4.3	1973-September 18, 2004
SIGLE	FIZ Karlsruhe - Version Interhost 3000	1980-September 18, 2004
OCLC Proceedings First	OCLC FirstSearch	1993-September 18, 2004
Dissertation Abstracts	ProQuest	1980-September 18, 2004
Alt HealthWatch	EBSCOhost	1990-September 18, 2004
NLM Gateway	U.S. National Library of Medicine - http://gateway.nlm.nih.gov/gw/Cmd	1950-September 18, 2004
PubMed	U.S. National Library of Medicine	1950-September 20, 2004

Table 2

Subject headings and keywords used in searches

Table 2

Subject headings and keywords used in searches

Terms used for Questions 1–4	Additional Terms used for Question 4
Insomnia	Time zone change
Sleep Initiation and Maintenance Disorders	Jet lag
Sleep onset delay	-------
Sleep onset latency	-------
DIMS	-------
Disorder of initiating and maintaining sleep	-------
Early awakening	-------
Sleeplessness	-------
Agrypnia	-------
Hyposomnia	-------

For Question 1, which relates to the definition, classification, diagnosis, and etiology of chronic insomnia in adults, we searched for narrative and systematic reviews, book chapters, diagnostic manuals and standards of practice parameters, and applied English-language restrictions. For Question 2, which relates to the prevalence, natural history, incidence, and risk factors for chronic insomnia in adults, and Question 3, which relates to the consequences, morbidities, co-morbidities and public health burden associated with chronic insomnia in adults, we searched for observational studies, encompassing a range of designs including cross-sectional, case-control, and cohort studies, and applied English-language restrictions. For Question 4, which relates to the treatments for chronic insomnia in adults, and the evidence regarding their safety, efficacy, and effectiveness, we searched for randomized controlled trials, and no language restrictions were applied. We did not apply language restrictions to searches for Question 4, since a portion of this question involves a review of complementary and alternative medicine (CAM), and there is evidence to suggest that studies of some CAM topics are often initially published in non-English languages, and many of these are not published in English.²¹ We searched electronic resources that specialize in CAM, including AMED (Allied and Complementary Medicine), Alt HealthWatch, and Cochrane Complementary Medicine Field Registry. In order to systematically search for the different types of studies required for each question, it was useful to refer to: the highly sensitive search strategy for identifying reports of randomized controlled trials in MEDLINE^® from the Cochrane Reviewer's Handbook (Appendix 5b)²²; search strategies for diagnosis, etiology, natural history and morbidities from PDQ Evidence-based Principles and Practice²³; and the search strategy for systematic reviews in MEDLINE^® from the Alberta Research Centre for Child Health Evidence.²⁴ Searches were also conducted in databases that index grey literature, including SIGLE (System for Information on Grey Literature in Europe), OCLC Proceedings First, Dissertation Abstracts and the NLM Gateway (searched specifically for meeting abstracts).

No hand searching was conducted for this review, given that the key journals pertaining to chronic insomnia, such as Sleep and Sleep Medicine Reviews, are indexed in MEDLINE.

Development of Inclusion Criteria

We did not develop formal inclusion criteria for the question pertaining to the definition, classification, diagnosis and etiology of chronic insomnia, nor for the question pertaining to the future direction of insomnia-related research. The former question was answered by providing an overview of the literature, and the latter question was answered by assessing the limitations in the evidence for the other questions of the review.

Inclusion criteria were developed for three questions of the review. Question-specific inclusion criteria appear below. The questions have been numbered according the numbering system outlined in the Introduction of this report. In the interest of clarity, questions 2 and 3 will be referred to as the questions on manifestations of chronic insomnia, while question 4 will be referred to as the question on management of chronic insomnia.

1. What are the prevalence, natural history, incidence and risk factors for chronic insomnia? Specific risk factors of interest include age, gender, race/ethnicity, psychiatric illness and psychological problems, medical disease, socioeconomic status and shift-work.

A study was considered to be relevant to the portion of Question 2 pertaining to the prevalence, natural history and incidence of chronic insomnia, if it met the following criteria:

• the report was written in English

• participants were at least 15 years old

• it examined chronic insomnia

• it had a cross-sectional or cohort design

• it assessed the prevalence, natural history or incidence of chronic insomnia

A study was considered to be relevant to the portion of Question 2 pertaining to risk factors for chronic insomnia, if it met the following criteria:

• the report was written in English

• participants were at least 15 years old

• it examined chronic insomnia

• it had a cohort, case-control, or cross-sectional design

• it assessed one of the risk factors of interest

1. What are the consequences, morbidities, co-morbidities, and public health burden associated with chronic insomnia? Specific outcomes of interest include healthcare utilization, psychiatric illness, absenteeism, work performance, accidents, falls in the elderly, quality of life and social relationships, memory, cognitive function, mood, direct and indirect costs.

A study was considered to be relevant to this question of the review, if it met the following criteria:

• the report was written in English

• participants were at least 15 years old

• it examined chronic insomnia

• it had a cohort or cross-sectional design

• it assessed one of the consequences of interest

For Questions 2 and 3, a study was considered to examine chronic insomnia if this condition was defined as a sleep disturbance of four weeks or more, or the report explicitly mentioned that chronic sleep disturbance was examined.

1. What treatments are used for the management of chronic insomnia and what is the evidence regarding their safety, efficacy, and effectiveness? Specific treatments of interest include prescription medication, over the counter medication, alcohol, behavioral therapy, combination therapy and complementary and alternative care.

A study was considered to be relevant to this question of the review, if it met the following criteria.

• the report was written in English

• participants were at least 15 years old, and the majority were at least 18 years old

• participants suffered from chronic insomnia

• participants were randomized to intervention or placebo

• participants and assessors were blind to treatment received

• it assessed at least one of the following outcomes, listed in order of importance in deriving conclusions of the review:

  • sleep onset latency

  • wakefulness after sleep onset

  • sleep efficiency

  • total sleep time

  • sleep quality

  • quality of life

Sleep onset latency was defined as the amount of time between the participant laying down to sleep and the onset of sleep; wakefulness after sleep onset was defined as the amount of time spent awake in bed following the attainment of sleep; sleep efficiency was defined as the amount of time spent asleep as a percentage of the total time spent in bed; and total sleep time was defined as the total time spent asleep while in bed. We used broad definitions of sleep outcomes in this review. For example, sleep onset latency could be defined as time to sleep, time to stage 1 sleep, time to stage 2 sleep or latency to persistent sleep. We believe that it was acceptable to combine studies with differing definitions of sleep onset latency in the analysis, since differences in the magnitude of estimations across definitions would be accounted for by subtraction of placebo effects from treatment effects. Although it could be argued that these definitions are significantly different, the optimal definition of sleep onset latency has not yet been determined. Nonetheless, differences between polysomnography, sleep diary and actigraphy definitions of sleep onset latency were explored indirectly through sub-group analyses.

Sleep onset latency and wakefulness after sleep onset were given the highest priority in deriving conclusions of the review, since they were considered the best indices of sleep initiation and sleep maintenance, respectively. However, sub-group analyses were conducted only on data relevant to sleep onset latency, since this outcome was the most highly reported outcome across studies.

If the majority of participants met one of the following criteria, the study population was considered to suffer from chronic insomnia:

• participants suffered from a sleep disturbance of 4 weeks or more

• participants were described as having a chronic/long-standing/persistent sleep disturbance

• participants were selected from a sleep disorders clinic

The 4-week cut-point for chronic insomnia was considered long enough to eliminate studies involving transient insomnia, and short enough to include studies involving persistent insomnia.

In the case of combination therapy, the combined treatment could be compared to either placebo or single treatment.

We acknowledged the fact that double-blinding is often not feasible in studies of psychological treatments by not requiring double-blinding in these studies for inclusion in the review. The placebo treatment for relaxation therapy and cognitive/behavioral therapy was minimal treatment, such as sleep hygiene recommendations or minimal instruction. We required a placebo control and randomization of participants to intervention groups in order to account for potential confounders in the analysis. That is, we wanted to control for potential improvements in insomnia symptoms that may occur during the natural course of observation, irrespective of treatment effects, and for systematic differences in the experimental and control groups.

Given that placebo for psychological treatment is variable and not standardized across studies, we restricted our analysis to a particular type of placebo such that our results could be put in some context i.e. the efficacy of psychological treatment could be judged against a particular type of comparator. We required that the placebo resemble the intervention of the study except that it was known to produce either no effect or only a minimal effect. Thus, component controls or attention-placebo were considered appropriate if they were thought to have at most a minimal effect. A waiting-list or measurement control was considered inadequate because no intervention was provided. A pill-placebo was considered inadequate because it did not resemble the experimental intervention, which did not involve administration of a pill.

Study Selection

The research librarian provided three databases containing the titles and abstracts of potentially relevant articles of the review; one database was relevant to the question on the definition and etiology of chronic insomnia, another database was relevant to the questions on manifestations of chronic insomnia, and another database was relevant to the question on management of chronic insomnia. In the first stage of study selection, two reviewers screened the titles and abstracts of all potentially relevant articles, independently. Each reviewer noted the titles and abstracts that were potentially relevant to the review, and these articles were retrieved. In the second stage of study selection, two reviewers appraised the potentially relevant articles, independently, using pre-determined, question-specific, inclusion criteria. Disagreements between reviewers were resolved by discussion and consensus. The rate of disagreement between reviewers and the primary reason for exclusion of potentially relevant articles were noted.

Assessment of Study Quality

The quality of studies relevant to the questions on manifestations of chronic insomnia was assessed using one of three instruments; studies on prevalence and incidence were assessed using a scale designed specifically for this purpose.²⁵ This scale assesses bias in sample selection, sampling frame, sample size, outcomes and their assessment, response rate, confidence intervals and sub-group analysis, and sample description. The maximum score is eight. A priori, it was established that a score of zero to two would be considered low quality, a score of three to five would be considered moderate quality and a score of six to eight would be considered high quality. All other studies relevant to manifestations of chronic insomnia were assessed using one of two Newcastle-Ottawa scales (unpublished), each scale specific to either cohort or case-control studies. The scale specific to cohort studies assesses bias in the selection of exposed and non-exposed cohorts, ascertainment of exposure, presence of outcomes at the start of the study, comparability of cohorts based on design or analysis, outcome assessment, and length and adequacy of follow-up. The scale specific to case-control studies assesses bias in the definition, selection, comparability, ascertainment of exposure, and non-response rate for both cases and controls, and how these groups compare on these items. The maximum score for the Newcastle-Ottawa scales is nine. A priori, it was established that a score of zero to two would be considered low quality, a score of three to five would be considered moderate quality and a score of six to nine would be considered high quality.

The quality of studies relevant to management of chronic insomnia was assessed using the Jadad scale.²⁶ This scale assesses bias in sample selection, outcome assessment, data analysis, and appropriateness of randomization and blinding methods. The maximum score is five. A priori, it was established that a score of zero to one would be considered low quality, a score of two to three would be considered moderate quality and a score of four to five would be considered high quality. The concealment of allocation of participants to treatment groups was also assessed.²⁷ Allocation was considered adequate, inadequate or unclear.

Appendix B contains the quality assessment tools used in this review.

Data Extraction

The following data were extracted for studies relevant to manifestations of chronic insomnia, as applicable: first author and year of publication, site, objectives, design, time-frame, intended sample size, response and follow-up rates, type of participants, definition of comparison groups, participants' gender, age, and ethnicity, and participants' co-morbid conditions at entry. For the question on prevalence, incidence, natural history and risk factors for chronic insomnia, additional data extracted included setting, sampling frame and method of sampling, data collection method, prevalence, incidence and natural history parameters. We did not identify studies with designs that would support the categorization of outcomes as either risk factors or consequences of chronic insomnia; therefore, data relevant to potential risk factors and potential consequences of chronic insomnia were extracted, and these outcomes were referred to as associated factors of chronic insomnia.

The following data were extracted for studies relevant to management of chronic insomnia: first author and year of publication, funding source and role of funding organization, design, whether an intent-to-treat analysis was conducted, number of participants enrolled and their distribution by gender, participants' age, number of withdrawals and reasons for withdrawal, duration of insomnia, participants' co-morbid conditions at entry, methods used to assess outcomes, details of the intervention, such as frequency and duration of treatment and timing and route of delivery, number of participants allocated to treatment groups and number analyzed in each group, length of follow-up, patient preference, and data relevant to sleep onset latency, wakefulness after sleep onset, sleep efficiency, total sleep time, sleep quality, quality of life and adverse events. A trained reviewer extracted relevant data, and a second reviewer verified the data extracted for accuracy and completeness.

Appendix B contains data extraction forms for the questions on manifestations and management of chronic insomnia.

The information gathered by data extraction was used to generate Evidence Tables. Appendix C contains these tables.

Data Analysis

Data relevant to manifestations of chronic insomnia were analyzed qualitatively, while data relevant to management of chronic insomnia were analyzed quantitatively.

Manifestations of chronic insomnia. For the questions on prevalence, natural history, incidence, risk factors and consequences of chronic insomnia, data relevant to each variable were analyzed separately, except for data relevant to potential risk factors and potential consequences of chronic insomnia, which were analyzed together as associated factors of chronic insomnia. The key features of all studies providing information on prevalence, natural history, incidence or associated factors of chronic insomnia were summarized in tables, such that data relevant to each variable appeared in a separate table. The information on prevalence was divided into three tables, one for prevalence in the general population, one for prevalence in outpatients of general practice and one for prevalence in clinical populations.

The following information was included in the tables on prevalence: first author and year of publication, study quality, study design, sampling frame, sampling method, response/follow-up rate, method of data collection, type of participants, duration of sleep complaints and definition of cases and comparison groups, gender distribution of sample, age distribution of sample, and prevalence estimates. The following information was included in the table on natural history: first author and year of publication, study quality, study design, time frame for the study, response/follow-up rate, type of participants, duration of sleep complaints, gender distribution of sample, age distribution of sample, and natural history estimates. The following information was included in the table on associated factors for chronic insomnia: author and year of publication, study quality, study design, type of participants, duration of sleep complaints, gender distribution of sample, age distribution of sample, response/follow-up rate, and a qualitative summary of the findings of the study. The qualitative summary of results was derived by consolidating information available in the results and conclusions of relevant studies. We did not identify information relevant to the incidence of chronic insomnia.

The data provided in the tables were synthesized to provide a description of the methods and results of the studies relevant to a given variable. In the analysis of prevalence of chronic insomnia, a range, median and interquartile range were provided for each population (general, outpatient and clinical), separately for high and moderate quality studies, where appropriate. In the analysis of associated factors of chronic insomnia, the qualitative summary of findings were summarized in terms of the studies that did or did not find an association between chronic insomnia and the various factors of interest.

Management of chronic insomnia. A priori, the drug interventions were categorized according to drug class i.e. benzodiazepines, non-benzodiazepines and antidepressants. It was considered acceptable to combine different drugs of the same category in a meta-analysis, based on similar mechanisms of action. For psychological interventions, it was considered acceptable to combine predominantly cognitive approaches in a meta-analysis, and also to combine predominantly relaxation approaches in a meta-analysis; however, it was considered unacceptable to combine these two types of psychological approaches in a meta-analysis, since they were considered too different in their modes of action. Relaxation techniques address somatized tension, and different forms of this type of therapy (progressive relaxation and group relaxation) were considered similar enough to be pooled. However, cognitive therapy addressing the cognitive aspects of insomnia was not thought to be equivalent to relaxation therapy because it targets different aspects of insomnia, and was considered separately. A few interventions (e.g. L-tryptophan, melatonin and valerian) were categorized under the heading of “complementary and alternative care”; however, separate meta-analyses were presented for these interventions. We did not combine these interventions in a meta-analysis, given their distinct modes of action.

For continuous outcomes (i.e. sleep onset latency, sleep efficiency), studies were combined using a Mean Difference (MD), with the exception of sleep quality and quality of life, where studies were combined using a Standardized Mean Difference (SMD). Dichotomous outcomes (i.e. safety outcomes) were combined using a Risk Difference. A number needed to harm (NNH) was also reported for any safety outcomes that were found to be statistically significant. The Inverse Variance Method²⁸ was used to weight the studies. An efficacy estimate, with corresponding 95% Confidence Interval (CI), was computed for each outcome. For interpreting estimates calculated using the SMD, we used the generalization of 0.2 as small, 0.5 as moderate, and 0.8 as large.²⁹

We were usually able to calculate the efficacy estimates for each study exactly (i.e. mean difference, standardized mean difference, risk difference), but occasionally, estimates had to be made by extracting from graphs or using medians. Standard errors of the differences were calculated exactly from available data (i.e. individual patient data or exact P-values), whenever possible. For studies with a parallel design, this calculation was usually accomplished with the standard formula for variance of difference of independent variables: var(A-B) = var(A) + var(B). For studies with a crossover design, the standard error was estimated using the formula for variance of difference of dependant variables: var(A-B) = var(A) + var(B) -2ρ(var(A)var(B))^½ and using a correlation estimate of 0.5. In cases where exact values could not be obtained, standard errors were estimated using conservative P-values (i.e. p < 0.05), ranges, inter-quartile ranges, and extracting from graphs. As a last resort, an average of standard deviations of other studies was used to impute standard deviations of a study.

For studies with a parallel design, change from baseline data were used if available, otherwise final data were used. For studies with a crossover design, final data were always used. When continuous data were presented for multiple conditions, which we wished to combine, a new mean and standard deviation were computed.

All meta-analyses were performed using a Random Effects Model. Bailey³⁰ suggests that the Random Effects Model is more appropriate when making recommendations for management and treatment of the next given patient.

For some outcomes (sleep onset latency and number of adverse events), treatment categories were compared indirectly, via their relationship to placebo. Differences of differences with 95% CI were computed. Indirect comparisons were not made between pharmacological and psychological treatments for the following reasons (1) although our inclusion criteria required blinding for drug and complementary and alternative care, this criteria was omitted for psychological treatments (2) the placebo intervention was considered to have no effect for drug and complementary and alternative treatments, while it may have had minimal effect for psychological treatments (3) the pool of participants for psychological interventions was much smaller than for either the benzodiazepines, non-benzodiazepines or antidepressants. Thus, only indirect comparisons between non-psychological intervention categories and between psychological intervention categories were made.

All estimates of efficacy were assessed for heterogeneity using the I-squared statistic.³¹ Based on this statistic, heterogeneity for each outcome was classified as negligible (I² = 0 percent), minimal (I² < 20 percent), moderate (20 percent < I² < 50 percent), or substantial (I² > 50 percent). This measure of heterogeneity describes the degree of variation in the efficacy estimates among studies. For our primary outcome (sleep onset latency), heterogeneity was explored in sub-group analyses using a number of variables. The following variables were targeted a priori and explored in sub-group analyses: treatment sub-group (i.e. type of drug or therapy), presence or absence of psychiatric illness (as defined in the study inclusion criteria), length of treatment (short-term and long-term, defined as less than or equal to 4 weeks and greater than 4 weeks, respectively), age (adult and elderly defined as the majority of patients 15–65 years or greater than 65 years, respectively) and gender (male and female). Method of measurement of sleep outcomes (polysomnography, sleep diary actigraphy) was analyzed post-hoc in a sub-group analysis based on comments from peer reviewers. Study quality (low, moderate and high quality defined as Jadad scores of 0–1, 2–3 and 4–5, respectively) was also explored in a sensitivity analysis. Deeks' chi-square statistic ³² was used to test for significant heterogeneity reduction in partitioned sub-groups.

Publication bias is the publication of studies based on the nature and direction of results. We tested for publication bias visually using the Funnel Plot³³ and quantitatively using the Rank Correlation Test,³⁴ the Graphical Test,³⁵ and the Trim and Fill Method.³⁶

Literature Review

The database searches resulted in 16,991 references of potentially relevant articles. One thousand two hundred studies were evaluated for inclusion in the review; 528 studies were potentially relevant to prevalence, natural history, incidence, risk factors and consequences of chronic insomnia, and 672 studies were potentially relevant to efficacy and safety of treatments used in the management of chronic insomnia. The application of inclusion criteria resulted in 79 studies included and 449 studies excluded for the questions on manifestations of chronic insomnia, and 116 studies included and 556 studies excluded for the question on management of chronic insomnia.

The primary reasons for exclusion of studies potentially relevant to manifestations of chronic insomnia were as follows: (1) the study was reported in a language other than English (n=9), (2) the report was a review (n=38), (3) the study was not relevant to the review topic (n=71), (4) the study was a case report (n=9), (5) the study did not have a control group (n=47), (6) the study did not examine an adult population (n=8), (7) the study population did not have chronic insomnia as defined in this report (n=208), (8) the study did not report on any of the outcomes of this review (n=58), and (9) data relevant to the study outcomes were not adequately reported (n=1). The primary reasons for exclusion of studies potentially relevant to the management of chronic insomnia were as follows: (1) the study was reported in a language other than English (n=27), (2) the report was a review/commentary/practice parameter (n=32), (3) the study report was a duplicate publication (n=3), (4) the study did not examine an adult population (n=17), (5) the study population did not suffer from chronic insomnia as defined in this report (n=221), (6) the study was not a randomized controlled trial (n=160), (7) the study did not have a placebo arm (n=48), (8) the study was not double-blind (n=15), (9) the study did not report on any of the outcomes of this review (n=16), and (10) data relevant to the study outcomes were not adequately reported (n=15).

The rate of disagreement between reviewers for inclusion/exclusion of studies was 61/528 (11.6 percent) for the questions on manifestations of chronic insomnia and 53/672 (7.9 percent) for the question on management of chronic insomnia. The primary reason for disagreement between reviewers was oversight of study details, such that reviewers erred on the side of over-inclusion. Therefore, consensus often resulted in exclusion of studies: for the questions on manifestations of chronic insomnia, 18 disagreements resulted in inclusion and 43 disagreements resulted in exclusion, and for the question on management of chronic insomnia, eight disagreements resulted in inclusion and 45 disagreements resulted in exclusion.

Flow Diagram 2 outlines study retrieval and selection for the review.

Data Synthesis

Classification of insomnia

The International Classification of Sleep Disorders Manual. A clinically relevant classification of insomnia is outlined in the ICSD-R, 2001.³⁷ According to the ICSD-R, the different categories of insomnia include: psychophysiological insomnia, sleep state misperception, idiopathic insomnia, as well as insomnia secondary to other medical conditions or sleep disorders. Acute and chronic insomnia are not classified separately; however, insomnia is considered to be chronic if the symptoms last for more than six months. A brief overview of the ICSD-R categories follows:

1. Psychophysiological insomnia, also known as conditioned or learned insomnia, is a disorder of somatized tension and learned sleep preventing associations that result in a complaint of insomnia and associated decreased functioning during wakefulness.³⁷ Continued problems in somatized tension and maladaptive learned sleep-preventing associations can worsen insomnia, creating a vicious cycle by perpetuating the initial problem. One must search for precipitating, predisposing and perpetuating factors for insomnia. A hallmark of this diagnosis is the individual's fixation with his/her sleep problem. This diagnosis cannot be made in the context of other medical or psychiatric disorders. Associated features include perceived decrement in daytime mood and functioning, without overt sleepiness. The true prevalence of psychophysiological insomnia in the general population is not known, although approximately 15 percent of patients referred to a sleep disorders clinic suffer from this type of insomnia.³⁷ Diagnostic criteria for psychophysiological insomnia include:

   • a) A combination of a complaint of insomnia and a complaint of decreased functioning during wakefulness.

   • b) Indications of learned sleep-preventing associations such as trying too hard to sleep, or increased arousal in the bedroom (concern and worry about sleep).

   • c) Evidence of somatized tension.

   • d) Polysomnography may show increased sleep latency, reduced sleep efficiency and increased number and/or duration of awakenings during the sleep period.

   • e) No other medical condition accounts for the sleep disturbance.

   The diagnosis of psychophysiological insomnia requires that criteria a) and b) are satisfied.

2. Sleep state misperception, or pseudo insomnia, is a subjective complaint of problems initiating or maintaining sleep without objective findings to support the complaint. There is no psychopathology per se associated with this disorder. The afflicted individual honestly has complaints of insomnia and decreased daytime functioning, without objective data to support the claim. Although the exact prevalence of this disorder is not known, this group accounts for approximately 5 percent of individuals with complaints of insomnia. Diagnostic criteria for sleep state misperception include:

   • a) complaint of insomnia.

   • b) sleep quality and quantity are normal.

   • c) polysomnography shows normal sleep latency, sleep duration and awakenings during the sleep period.

   The diagnosis of sleep state misperception requires that criteria a) and b) are satisfied.

3. Idiopathic Insomnia is defined as a life-long inability to obtain adequate sleep and may be related to abnormalities in the neurological systems affecting the sleep-wake cycle. The exact prevalence of this disorder is not known, but it is thought to be rare. Diagnostic criteria for idiopathic insomnia include:

   • a) Complaint of insomnia with decreased functioning.

   • b) Insomnia is life-long and may begin in early childhood.

   • c) Insomnia is relentless and does not vary.

   • d) Polysomnography shows increased sleep latency, decreased sleep efficiency and multiple awakenings during the night.

   • e) No other medical illness or disease explains the early onset of insomnia.

   The diagnosis of idiopathic insomnia requires that criteria a), b), and d) are satisfied.

Proposed classification for insomnia. A more recent article considers a novel method for classifying insomnia for research purposes.⁴⁰ The authors propose research diagnostic criteria for Insomnia Disorder, Primary Insomnia, Insomnia due to a Mental Disorder, Paradoxical Insomnia and Psychophysiological Insomnia. The main differences between this classification scheme and that of ICDS-R, 2001, is that the criteria are more precise and the duration of symptoms must be more than one month for all categories. This classification scheme does not define a subcategory of chronic insomnia. This classification scheme was developed to allow for clear categorization of insomniacs within a study population, and thus avoid the study of a heterogeneous population. Based on a review of the literature, acute, situational or transient insomnia is considered to be different from chronic insomnia. It is not clear whether there are distinct differences in the nature of insomnia that lasts for more than 1 month, but less than 6 months versus insomnia lasting for more than 6 months.

Diagnosis and assessment of insomnia. Different evaluation methods have evolved to identify individuals with insomnia. Diagnosis of insomnia is made in the context of a clinical history based on any of the aforementioned criteria or definitions. There are semi-structured or structured interviews available for diagnosing insomnia [i.e., Insomnia Interview Schedule and Duke Structured Sleep Inventory (the latter is currently being evaluated in a large-scale study)]. Sleep diaries/logs, sleep histories, actigraphy, ambulatory monitoring, and in-home polysomnography are often used to assess sleep parameters. The most commonly used measure for evaluation of insomnia is self-reported questionnaires. The use of objective tools, such as polysomnography or multiple sleep latency tests for the diagnosis of insomnia are not recommended.⁴¹–⁴³ Sleep diaries are essential for identifying sleep onset and sleep maintenance difficulties; however, the reporting of sleep onset latency by diary is subjective. Scientists have tried to evaluate more objective measures for measuring sleep disturbances in patients with insomnia, but currently available tools have limitations (polysomnography and unattended home studies), and are most commonly used to diagnose sleep disorders other than insomnia. Moreover, these methods are cumbersome and costly. Actigraph monitors are small watch-like devices that are worn on the wrist and are used to record movement; they can be useful adjuncts for gathering data from individuals with sleep complaints; however, these devices are not indicated for the routine diagnosis of any sleep disorder.³⁹ There is currently no biomarker of insomnia, which makes objective diagnosis of insomnia more difficult. Research in the area of insomnia has recently been directed towards identifying specific hormones or neurotransmitters that may be involved in this disorder.¹⁵ Various research groups are studying the link between specific electroencephalogram findings and insomnia. A less commonly used diagnostic tool for insomnia, position emission tomography imaging, has been used to evaluate brain metabolism and its role in insomnia.⁴⁴ Insomnia is a clinical diagnosis and the lack of a research model for insomnia makes it difficult to target appropriate therapy for this disorder and evaluate treatment outcomes.

Etiology of insomnia. Despite significant advances in sleep medicine over the past 50 years, much less is known about the cause of insomnia, its natural history, and its consequences than the treatments available for insomnia. Recent studies have demonstrated an increased metabolic rate in patients with insomnia,⁴⁵ suggesting that sleep difficulties may at least partially have a physiological basis. It is also speculated that patients with insomnia are more aroused than people without insomnia;⁴⁶ however, this theory is difficult to prove, given that the neurotransmitters involved in arousal are unknown. Advances in molecular genetics have shed light on the potential role of genetics in sleep disorders. Indeed, a familial etiology of this disorder has been postulated. A recent study concluded that more than 33 percent of patients with insomnia had a family history of insomnia.⁴⁷ A similar study estimated a family history of insomnia among first-degree relatives of people suffering from insomnia to be 48.8 percent, compared to 23.5 percent among first-degree relatives of people who did not suffer from insomnia.⁴⁸ The familial aggregates of insomnia have led researchers to investigate the genetic basis of insomnia, but no specific gene has been implicated.

Certain populations, including the elderly, psychiatric patients, and those suffering from chronic pain are known to have more chronic sleep maintenance problems.¹;⁴⁹ A strong link has been found between insomnia and depression.⁵⁰ The directionality of the association has not been fully elucidated, but the association appears to be strong.¹

Environmental factors, such as irregular sleep schedules, use of caffeine or other stimulants, co-morbid medical conditions, and/or shift-work may also predispose vulnerable individuals to insomnia.¹ Genetic predisposition, in addition to environmental factors, are likely involved in the development and maintenance of insomnia, and differences in the relative exposure to these influences may explain differences in the manifestation of this disorder across affected individuals.

What are the prevalence, natural history, incidence and risk factors for chronic insomnia?

What are the consequences, morbidities, co-morbidities and public health burden associated with chronic insomnia?

See answer

Table 3a

Prevalence of chronic insomnia in adults: general population (more...)

Table 3a

Prevalence of chronic insomnia in adults: general population

Author / Year	Study Design	Sampling Frame / Method	Method Of Data Collection	Participants	Duration of Sleep Complaints, Definition of Cases and Comparison Groups	Gender	Age (years)	Response Rate / Follow-up Rate	Prevalence
Quality (score)
Ancoli-Israel, S / 1999	Cross-sectional	Phone list/ random	Phone interview (non-validated)	General population	Sleep complaints on a frequent basis; population referred to as “chronic” insomniacs.	Not specified	Range: 18–65	51.2%	9% (95%CI: 7.23–10.77)
Moderate (3/8)
Bixler, EO / 1979	Cross-sectional	Census data/ random	Face-to face interview (non-validated)	General population	Current or past sleep disorders; prevalence reported for “long-term” insomniacs.	Male: 44% Female: 56%	Over 18	Not specified	Lifetime: (Current or past insomnia): 42.5% (95%CI: 39.4–45.5). Current chronic insomnia: 32.2% (95%CI: 29.3–35.0).
Moderate (3/8)
Bixler, EO / 2002	Cross-sectional	Phone list/ random	Self-reported Qu (non-validated)	General population	Sleep complaint for at least one year.	Male: 42.6% Female: 57.4%	Over 20	66.6%	Point: (Insomnia during at least 1 year): 7.5% (95%CI: 6.27–8.73).
Moderate (3/8)
Broman, JE / 1996	Cross-sectional	Population register/ random	Self-reported Qu (validated)	General population	Sleep complaints during the last three months.	Male: 46.9% Female: 53.1%	Range: 20–64	68%	Three-month: (Chronic sleep loss): 12% (95%CI: 8.8–15.2).
High (6/8)
Hajak, G / 2001	Cross-sectional and Case-Control (matched)	Census data/ random	Face-to face interview (non-validated)	Cross-sectional: General population Case-control:Cases: severe insomnia	Cross-sectional: Insomnia disorders during the previous month (DSM-III-R and DSM-IV criteria). Severe insomniacs had sleep complaints during the previous month.Case-control:Cases: Severe insomniacs as defined above.	Cross-sectional:Male: 46.8% Female: 53.1%	Over 18	Not specified	One-month: (Sleep disturbances) 45% (95%CI: 42.7–47.2). (Severe insomnia): 4% (95%CI: 3.2–4.8).
High (6/8) - cross sectional				Controls: normal sleepers	Controls: No sleep complaints.
High (7/9) - case control
Hetta, J / 1999	Cross-sectional	Not specified/ non-random (quota method)	Not clearly specified	General population	Sleep complaints over the past month (DSM-III-R criteria modified).	Not specified	Over 18	25%	One-month: 31% (95%CI: 27–35).
Low (0/8)
Hidalgo, MP / 2002	Cross-sectional	Not specified	Self-reported Qu (validated)	Medical students	Sleep complaints for at least one month during the past year.	Male: 58.2% Female: 41.8%	Range: 18–35	Not specified	One-year: (Sleep difficulties persisting for at least one month): 26% (95%CI: 21.3–30.6).
Moderate (5/8)
Kageyama, T / 1997	Cross-sectional	Residential registration information/ random sample of some districts, recruitment at block meetings in others	Self-admin Qu (non-validated)	Adult women living in urban areas	Sleep complaints for at least one month (ICD-10 and DSM-IV criteria).	All women	Range: 20–80	Varied between district 51–59%	Point: 11.2% (95% CI 10.2, 12.2)
Moderate (6/8)
Kageyama, T / 2001	Cross-sectional	Not specified	Self-admin Qu (non-validated)	Hospital nurses	Sleep complaints for at least one month.	Not specified	Range: 24–59	Not specified	Point: 29.2% (95% CI 28.7, 29.7)
Moderate (5/8)
Kawada, T / 2003	Cross-sectional	Map/ Not specified	Self-reported Qu (non-validated)	Women from the general population	Sleep complaint for at least one month (ICD-10 and DSM-IV criteria).	All female	Range: 20–80	50.4%	Point: (DSM-IV criteria for at least one month): 8.8% (95%CI: 6.6–10.9).
High (6/8)
Leger, D / 2000	Cross-sectional	Census data/ random	Face-to face interview (non-validated)	General population	Sleep complaint for at least a month (DSM-IV criteria).“Severe insomnia” considered as“chronic insomnia” if sleep complaints were over a four-month period.	Male: 47% Female: 53%	Over 18	85.2%	One-month: (Insomnia) 19% (95%CI: 18.3–19.6). (Severe/chronic insomnia): 9% (95%CI: 8.51–9.49).
High (6/8)
Martikainen, K / 2003	Cross-sectional	Not specified / random	Self-reported Qu (non-validated)	General population	Sleep complaints during the previous three months.	Male: 42.2% Female: 57.8%	Range: 41–55	52.6%	Three-month: 14% (95%CI: 11.3–16.7).
Moderate (5/8)
Millar, A / 2004	Cross sectional case-control	Not applicable	Self-reported Qu (validated), sleep laboratory investigations	Cases: remitted Bipolar I disorder subjects	Cases: DSM-IV criteria for Bipolar I disorder.	Cases:Male: 8 Female: 11	Cases: range: 26–68	Cases: 59.3% (follow-up)	Percentage of reported longstanding sleep disturbances (Sleep History Questionnaire): Cases: 100%.
High (6/9)				Controls: healthy subjects	Controls: No psychiatric disorders.	Controls:Male: 8 Female: 11	Controls: range: 27–67	Controls: Not specified	Controls: 21% (95%CI: 2.7–39.3).
Ohayon, MM / 2002	Cross-sectional	Phone list/ random	Phone interview (validated)	General population	Insomnia complaints during the last year (DSM-IV criteria).	Male: 48.2% Female: 51.8%	Over 15	89.4%	One-year: (Insomnia symptoms): 27.6% (95%CI: 26.2–28.9). (Insomnia disorder diagnoses): 7% (95%CI: 6.2–7.7).
High (8/8)
Ohayon, MM / 2002	Cross-sectional	Census data/ random	Phone interview (validated)	General population	Chronic insomnia diagnosed according to DSM-IV criteria.	Male: 48.2% Female: 51.8%	Over 18	78.2%	Point: Insomnia disorder diagnoses: 11.7%
High (8/8)
Ohayon, MM / 1997	Cross-sectional	Census data/ random	Phone interview (validated)	General population	Insomnia complaints for at least one month.	Male: 47.9% Female: 52.1%	Over 15	80.7%	Point: (Insomnia complaints lasting for at least one month): 15.3% (95%CI: 14.36–16.24)
High (8/8)
Ohayon, MM / 2003	Cross-sectional	Census data/ random	Phone interview (validated)	General population	Insomnia complaints for more than six months.	Male: 47.9% Female: 52.1%	Over 15	78.6%	Point: (Chronic insomnia lasting more than six months): 17.6% (95%CI: 16.9–18.21). (Insomnia lasting more than one month): 18.4% (95%CI: 17.78–19.02).
High (7/8)
Ohayon, MM / 2000	Cross-sectional	Census data/ random	Computer-ized phone interview (validated)	General population	Diagnoses of chronic sleep disorders according to DSM-IV criteria.	Male: 49.2% Female: 50.8%	Range: 19 –24	Not specified	Point: 5.4% (95% CI: 4.5, 6.4)
High (7/8)
Ohayon, MM / 2001	Cross-sectional	Census data/ random	Phone interview (validated)	General population	Chronic insomnia defined by both DSM-IV and ICSD criteria.	Male: 49.5% Female: 50.5%	Range: 19–24	Not specified	Point: 8.1% (95% CI: 7.4, 8.8).
High (7/8)
Ohayon, MM / 2001	Cross-sectional	Census data/ random	Telephone interview (validated)	General population	Sleep complaints for at least a month (DSM-IV criteria).	Male: 49% Female: 51%	Over 15	All countries, except Germany (68.1%) had participation rate of 80% or higher. Overall 81.0%	Point: 6.1% (95% CI 5.8, 6.4)
High (8/8)
Ohayon, MM / 2002	Cross-sectional	Phone lists/ random	Telephone interview (validated)	General population	Chronic insomnia diagnosed according to ICSD and DSM-IV criteria.	Male: 49.5% Female: 50.5%	Range: 15–90	91.4%	Point: 5% (95% CI 4.3, 5.7)
High (8/8)
Riedel, BW / 2004	Cross-sectional	Not specified/ random	Self-reported Qu (validated)	General population	Sleep complaints for at least six months (ICSD criteria).	Male: 49.3% Female: 50.7% - 390/769	Range: 20–98	43.4%	Point: 32.1% (95%CI: 28.8–35.3).
High (6/8)
Rocha, FL / 2002	Cross-sectional	Census data/ whole population studied	Face-to-face interview (validated)	Elderly from the general population	Sleep complaints during the last month.	Male: 38.9%Female: 61.1%	Over 60	87%	One-month: (Insomnia): 38.9% (95%CI: 34.6–41.3).
High (7/8)
Rocha, FL / 2002	Cross-sectional	Census data/ random	Face-to-face interview (validated)	General population	Sleep complaints in the last month.	Male: 44.3% Female: 55.7%	Over 18	87.3%	One-month: 35.4% (95%CI: 32.5–38.3).
High (7/8)
Taylor, DJ / 2003	Cross-sectional	Three-digit telephone prefixes/ random digit dialling	Sleep diaries and self-admin Qu	General population	Sleep complaints for at least six months.	Male: 49.4% Female: 50.6%	Range: 20–98	49%	Point: 19.6% (95% CI 16.8, 22.4)
High (6/8)
Yeo, BKL / 1996	Cross-sectional	House registers/ random	Face-to face interview (non-validated)	General population	Sleep complaint for the past year.	Male: 50% Female: 50%	Range: 15–55	Not specified	One-year: 15.3% (95%CI: 13.8–16.73).
Moderate (3/8)

Abbreviations: CI = confidence interval; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ICSD = International Classification of Sleep Disorders; MSK = musculoskeletal injury; Qu = questionnaire; rehab = rehabilitation; SCI = spinal cord injury; TBI = traumatic brain injury

Table 3b

Prevalence of chronic insomnia in adults: outpatients (more...)

Table 3b

Prevalence of chronic insomnia in adults: outpatients of general practice

Author / Year	Study Design	Sampling Frame / Method	Method Of Data Collection	Participants	Duration of Sleep Complaints, Definition of Cases and Comparison Groups	Gender	Age (years)	Response Rate / Follow-up Rate	Prevalence
Quality (score)
Hohagen, F / 1993	Cross-sectional	Not specified/ non-random (consecutive)	Self-reported Qu (non-validated)	Outpatients from general practices	Insomnia disorders during the last month (DSM-III-R criteria).	Male: 44.7% Female: 55.3%	Range: 18–65	97.9%.	Six-month: (Severe, moderate, and mild insomnia): 45.9% (95%CI: 44–48). (Severe): 18.7% (95%CI: 17.1–20.2).
Moderate (4/8)
Hohagen, F / 1994	Cross-sectional	Not specified / non-random (consecutive)	Self-reported Qu (non-validated)	Elderly outpatients from general practices	Sleep complaints (mild, moderate, and severe) for at least one month (DSM-III-R criteria).	Male: 28% Female: 72%	Over 65	97.5%	Point: (All DSM-III-R diagnoses of insomnia): 56.3% (95%CI: 50.9–61.6). (Severe DSM-III-R insomnia diagnosis): 23% (95%: 18.4–27.5).
Moderate (4/8)
Hohagen, F / 1994	Cross-sectional and prospective cohort	Not specified/ non-random (consecutive)	Self-reported Qu (non-validated)	Outpatients from general practices	Sleep complaints for at least one month.	Cross-sectional:Male: 44.7% Female: 55.3%	Range: 18–65	Cross-sectional: 97.9%	One-month:Cross-sectional: 31% (95%CI: 29.2–32.8). Cohort (Data after a four-month follow-up period: 86.9% (95%CI: 83.2–90.5). Remission rate: 19%–24% (for insomnia sub-groups).
Moderate (4/8)						Cohort:Male : 60.4%. Female: 39.6%		Cohort: 42.2% (follow-up)
Ishigooka, J / 1999	Cross-sectional	Not specified	Self-reported Qu (non-validated)	Outpatients from general hospitals	Long-term insomnia defined as sleep complaints for more than one month.	Male: 41.9% Female: 58.1%	Range: 15–65	88.3%	Point: (Insomnia lasting more than one month): 11.7% (95%CI: 10.9–12.4).
Moderate (5/8)
Kappler, C / 2003	Cross-sectional	Not specified	Self-reported Qu (non-validated)	Outpatients from general practices	Diagnosis of chronic insomnia (moderate and severe) according to DSM-III-R criteria.	Male: 49.9% Female: 50.1%	Range: 18–65	37.6%	Point: (DSM-III definition of severe/moderate insomnia): 27.3% (95%CI: 24.5–30.1).
Low (2/8)
Ohayon, MM / 1999	Cross-sectional	Not specified/ non-random	Face-to-face clinical interview (validated)	Outpatients from general practices	Chronic sleep disorders diagnosed according to DSM-IV criteria.	Male: 44.5% Female: 55.5%	Over 15	Not specified	Point: (Complaint of insomnia symptoms accompanied with sleep dissatisfaction): 16.0% (95%CI: 15.3–16.7).
Moderate (5/8)
Scochat, T / 1999	Cross-sectional	All patients presenting to participating family medicine clinics/ all asked to participate	Self-administration Qu (non-validated)	Patients consulting their primary care physician	Normal sleepers: no sleep complaints; Occasional insomniacs: sleep complaints on an occasional basis. Chronic insomniacs: sleep complaints on a frequent basis; chronic insomniacs defined as such.	Male: 42% Female: 58%	Range: 18–87	Not specified	Point: 19% (95% CI 14.5, 23.5)
Low (1/8)
Terzano, MG / 2004	Cross-sectional	List of general practitioner patients/ non-random	Face-to-face clinical interview (non-validated)	Patients presenting to their general practitioner for medical problems other than sleep disorders	Sleep complaints for at least one month.	Male: 39.1% Female: 60.9%	Over 18	Not specified	Point: (Sleep difficulties persisting for at least one month): 63.7% (95%CI: 62–65).
Moderate (4/8)

Abbreviations: CI = confidence interval; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ICSD = International Classification of Sleep Disorders; MSK = musculoskeletal injury; Qu = questionnaire; rehab = rehabilitation; SCI = spinal cord injury; TBI = traumatic brain injury

Table 3c

Prevalence of chronic insomnia in adults: clinical population (more...)

Table 3c

Prevalence of chronic insomnia in adults: clinical population

Author / Year	Study Design	Sampling Frame / Method	Method Of Data Collection	Participants	Duration of Sleep Complaints, Definition of Cases and Comparison Groups	Gender	Age (years)	Response Rate / Follow-up Rate	Prevalence
Quality (score)
Braga-Neto, P / 2004	Cross-sectional	Not specified/ non-random (consecutive)	Face-to-face clinical interview (non-validated)	Patients with Parkinson's Disease	Sleep complaints over the last month.	Male: 64% Female: 36%	Range: 34–86	Not specified	One-month: 53.3% (95%CI: 42.8–63.8).
Low (2/8)
Fichtenberg, NL / 2002	Cross-sectional	Patients enrolled in outpatient rehab. clinics/ non-random (consecutive)	Self-reported Qu (validated), sleep diaries, clinical interview	Rehabilitation patients (TBI, SCI, MSK)	DSM-IV criteria	TBI: Male: 56% Female: 44%.	TBI: mean±SD:36.5±14.5	100%	Point: (By DSM-IV Criteria): 30% (95% CI 27.3, 42.7) of TBI patients.
Moderate (4/8)						SCI:Male: 76% Female: 24%.	SCI: mean±SD:38.2±13.5
						MSK:Male: 20% Female: 80%	MSK: mean±SD:47.3±12.2
Han, SY / 2002	Cross-sectional	Not specified	Self-reported Qu (non-validated)	Diabetic haemodialysis patients	Sleep complaints for at least two months (DSM-IV criteria modified).	Male: 61% Female: 39%	Range: 27–78	Not specified	Point: (Sleep difficulties for at least two months): 68.2% (95%CI: 58.2–78.2).
Low (2/8)
Leppavuori, A / 2002	Cross-sectional	Not specified / non-random (consecutive)	Face-to-face clinical interview (validated)	Stroke patients	Insomnia complaints for at least one month (DSM-IV criteria).	Male: 50.9% Female: 49.1%	Range: 55–85	Not specified	Point: (DSM-IV criteria of insomnia): 37.6% (95%CI: 31.9–43.3). (Insomnia complaints): 56.7% (95%CI: 50.9–62.5).
Moderate (4/8)
Millar, A / 2004	Cross sectional case-control	Not applicable	Self-reported Qu (validated), sleep laboratory investigations	Cases: remitted Bipolar I disorder subjects	Cases: DSM-IV criteria for Bipolar I disorder.	Cases:Male: 8 Female: 11	Cases: range: 26–68	Cases: 59.3% (follow-up)	Percentage of reported longstanding sleep disturbances (Sleep History Questionnaire): Cases: 100%.
High (6/9)				Controls: healthy subjects	Controls: No psychiatric disorders.	Controls: Male: 8 Female: 11	Controls: range: 27–67	Controls: Not specified	Controls: 21% (95%CI: 2.7–39.3).
Robbins, L / 1995	Retrospective cross-sectional	Long-term patients of headache clinic/ random	Face-to-face interview	Patients with migraines	Chronic insomnia assessed by qualitative judgement of the neurologist and patient.	Male: 20.4% Female: 79.6%	Range: 18–60	100%	Point: Sleep onset insomnia: 27% (95% CI 23.1, 30.9). Sleep maintenance insomnia: 26% (95% CI 22.1, 29.9)
Moderate (4/8)
Sabbatini, M / 2002	Cross-sectional	Not specified	Face-to-face interview (non-validated)	Haemodialysis patients	Sleep complaints for at least one month.	Male: 55.5% Female: 44.5%	Mean±SD: 61.0±14.4	Not specified	Point: 45% (95%CI: 41.3–48.7).
Moderate (3/8)
Savard, J / 2001	Cross-sectional	Not specified/ non-random (consecutive)	Self-reported Qu (non-validated) and phone interview (validated)	Women with metastatic breast cancer	Insomnia symptoms, insomnia syndrome and chronic insomnia syndrome defined by sleep complaints for at least six months (DSM-IV criteria).	All female	Range: 28–90	88%	Point: (Insomnia symptoms): 51.3% (95% CI: 45.7–56.9); (Insomnia syndrome): 19% (95%CI: 14.6–23.4); (Chronic Insomnia syndrome): 17.6% (95%CI: 13.3–21.9).
Moderate (4/8)

Abbreviations: CI = confidence interval; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ICSD = International Classification of Sleep Disorders; MSK = musculoskeletal injury; Qu = questionnaire; rehab = rehabilitation; SCI = spinal cord injury; TBI = traumatic brain injury

Prevalence. A description of key features of studies relevant to prevalence of chronic insomnia is provided in Tables 3a (prevalence in general population), 3b (prevalence in outpatients of general practice) and 3c (prevalence in clinical populations), and additional information on each study is provided in Evidence Table C-1 ^♦. The evidence provided in Tables 3a, b and c is summarized here.

Forty-one studies provided evidence regarding the prevalence of chronic insomnia in adults; 38/41 studies were cross-sectional studies, one study was a cross-sectional case-control study and compared the prevalence of chronic insomnia in bipolar subjects and healthy controls,⁵¹ one study had both cross-sectional and case-control components,⁵² and one study had both cross-sectional and cohort components.⁵³ Seventeen studies were considered of high quality, 19 studies were considered of moderate quality and five studies were considered of low quality.

Twenty-four studies described the sampling frame; most studies used census data, phone lists or patients presenting to a health clinic. Thirty-four studies described the sampling method; 21 studies used a random method, while the majority of the remaining studies used a non-random method, and a minority of studies investigated entire populations. Twenty-seven studies provided a response or follow-up rate. The rate ranged from 25–100 percent; slightly more than half of the studies had a rate greater than 80 percent. All studies except one ⁵⁴ clearly described the method of data collection; 19 studies used self-reported questionnaires, 12 studies used face-to-face interviews and 10 studies used phone interviews. One of these studies ⁵⁵ used both self-reported questionnaires and phone interviews. Of the studies that described the method of data collection, slightly more than half used a validated method. The criteria used to establish the duration of chronic insomnia ranged from one month to one year; most of the studies required that participants suffer from insomnia symptoms for at least one month. Most studies reported the gender distribution of the population; the majority of studies used mixed gender populations and a minority of studies used all-female populations. All studies provided an estimate of the age of the population; the age of the populations ranged from 18 to 98 years, based on studies that provided a range.

Twenty-six studies investigated general populations (Table 3a), eight studies investigated populations of outpatients from general practice (Table 3b), and eight studies investigated clinical populations (Table 3c). For high quality studies investigating general populations, the prevalence of chronic insomnia ranged from 5–45 percent, and the median was 17.6 percent. The interquartile range was 8.5–24.3 percent. For moderate quality studies investigating general populations, the prevalence of chronic insomnia ranged from 7.5–42.5 percent, and the median was 15.3. The interquartile range was 11.2–29.2 percent.

We did not identify any high quality studies investigating the prevalence of chronic insomnia in outpatients of general practice. For moderate quality studies investigating this population, the prevalence of chronic insomnia ranged from 11.7–63.7 percent, and the median was 38.4 percent. The interquartile range was 19.8–53.7 percent.

We identified only one high quality study investigating clinical populations, and it compared the prevalence of chronic insomnia in patients with Bipolar I disorder and a non-psychiatric population.⁵⁶ One hundred percent of participants in the psychiatric group reported a long-standing sleep disturbance, while 21 percent of participants in the non-psychiatric group reported such a disorder. For moderate quality studies investigating clinical populations, the prevalence of chronic insomnia ranged from 26–51.3 percent, with a median of 33.5 percent. The interquartile range was 27.8–43 percent. The disorders of the clinical populations investigated were Parkinson's Disease, brain injury, diabetes, stroke, Bipolar I disorder, migraines, blood disorders and metastatic breast cancer.

Table 4

Natural history of chronic insomnia in adults

Table 4

Natural history of chronic insomnia in adults

Author/Year	Study Design	Time Frame	Response Rate / Follow-up Rate	Participants	Duration Of Sleep Complaints	Gender	Age (years)	Natural History
Quality (Score)
Hohagen, F / 1994	Cross-sectional and prospective cohort	Four months	Response rate (cross-sectional): 97.9%	Outpatients from general practices	Sleep complaints for at least one month	Cross-sectional:Male: 44.7% Female: 55.3%	Range:18–65	Cross-sectional: One-month prevalence: 31% (95%CI: 29.2–32.8).
Moderate (4/8)			Follow-up rate (cohort): 42.2%			Cohort:Male: 60.4% Female: 39.6%.		Cohort: Once-month prevalence within insomniac group identified in cross-sectional study, after four months: 86.9% (95%CI: 83.2–90.5).

Abbreviations: CI = confidence interval

Natural history. A description of key features of the study relevant to natural history is provided in Table 4, and additional information on this study is provided in Evidence Table C-1. The evidence provided in Table 4 is summarized here.

Only one study was identified that provided evidence regarding the natural history of chronic insomnia,⁵³ and it was of moderate quality. In this prospective cohort study, the participants consisted of outpatients from general hospitals with sleep complaints lasting for at least one month. The population was of mixed gender and had an age range of 18–65 years. At a four-month follow-up, the prevalence of chronic insomnia was reduced from 100 percent to 86.9 percent, providing a remission rate of 13.1 percent. The follow-up rate was 42.2 percent.

Incidence. We did not identify any studies that provided evidence on the incidence of chronic insomnia in adults.

Associated factors. The majority of studies identified did not have designs that would support the categorization of an associated factor of chronic insomnia as either a risk factor or consequence of the disorder, such as longitudinal cohort studies. Most studies that examined the risk factors and consequences of interest were either of a cross-sectional or cross-sectional case-control design. Thus, we do not report on risk factors and consequences of chronic insomnia per se, rather we report on associated factors. For simplicity, we separate the results relevant to the various factors according to their categorization in the relevant question of the review, such that potential risk factors are reported separately from potential consequences.

Table 5

Factors associated with chronic insomnia in adults

Table 5

Factors associated with chronic insomnia in adults

Author / Year	Study Design	Participants	Duration of Sleep Complaints	Gender	Age (years)	Response / Follow-up Rate	Summary of Findings
Quality (Score)
Bastien, CH / 2003	Cross- sectional case-control(unmatched)	Cases: chronic insomniacs	Cases: insomnia complaint for at least six months (ICSD-10 and DSM-IV criteria combined)	Cases: chronic insomniacs using benzodiazepines: Male: 10, Female: 10. Drug-free insomniacs: Male: 9, Female: 11	Cases and controls: Over 55	Not specified	Insomnia associated with anxiety and depression.
Moderate (5/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 11, Female: 9.
Bixler, EO / 2002	Cross- sectional	General population	Insomnia complaint for at least one year	Male: 42.6% Female: 57.4%	Over 20	66.6%	Insomnia associated with female gender, non-Caucasian minority, depression and medical conditions.
Moderate (3/8)							No association between age and insomnia was found.
Bixler, EO / 1979	Cross- sectional	General population	Current or past sleep disorders; results provided for chronic insomniacs	Male: 44% Female: 56%	Over 18	Not specified	Insomnia associated with general health problems, hospitalizations, tension, depression, and loneliness.
Moderate (3/8)
Bliwise, NG / 1992	Cross-sectional case-control (unmatched)	Cases: poor sleepers	Cases: sleep complaint for at least five years	All women	Cases: mean ± SD: 68.4 ± 8.7, range: 49–82	Not specified	Insomnia associated with psychological problems (anxiety, paranoid ideation, psychoticism, obsessive compulsiveness and depression).
Low (1/9)		Controls: good sleepers	Controls: no sleep complaints		Controls: mean ± SD: 67.5 ± 9.9, range: 52–95
Bonnet, MH / 1995	Cross- sectional case-control(matched)	Cases: chronic insomniacs	Cases: sleep complaints for at least one year	Not specified	Cases: range: 18–50	Cases: 50%	Insomnia associated with hyperarousal and degraded mood.
High (7/9)		Controls: normal sleepers	Controls: no sleep complaints		Controls: range: 18–50	Controls: 50%	No association between cognitive function (vigilance and proof-reading) and insomnia were found.
Braga-Neto, P / 2004	Cross- sectional	Parkinson's Disease patients	Sleep complaints over the last month	Male: 64% Female: 36%	Range: 34–86	Not specified	No associations between age or disease duration and insomnia were found.
Low (2/8)
Broman, JE / 1996	Cross- sectional	General population	Sleep complaints during the last three months	Male: 46.9% Female: 53.1%	Range: 20–64	68%	Insomnia associated with higher dysphoric mood, somatic symptoms, and cognitive/behavioral fatigue.
High (6/8)							No association between gender and insomnia was found.
Broman, JE / 1992	Cross- sectional case-control(matched)	Cases: persistent primary insomniacs	Cases: persistent sleep complaints	Cases:Male: 5, Female: 15	Cases: mean ± SD: 45.8 ± 11.5	Not specified	Insomnia associated with anxiety.
Moderate (5/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 5, Female: 15	Controls: mean ± SD: 45.0 ± 10.2		No association between cognitive performance (reaction time, memory, motor performance), tension, excitement, stress, concentration, or a measure of behavior, and insomnia was found.
Chambers, MJ / 1993	Cross-sectional case-control(unmatched)	Cases: chronic insomniacs referred to a sleep clinic	Cases: sleep complaints for at least six months (ASDA criteria)	Cases:Male: 35.5%, Female: 64.5%	Cases: mean ± SD: 47.5 ± 10.9	Not specified	Insomnia associated with anxiety.
Low (1/9)		Controls: good sleepers	Controls: no sleep complaints	Controls:Male: 40%, Female: 60%	Controls: mean ± SD: 45.9 ± 16.0
Coursey, RD / 1975	Cross- sectional case-control(matched)	Cases: chronic insomniacs	Cases: sleep complaints for at least two years	Cases:Male: 13, Female: 5	Cases and controls: mean ± SD: 44.7 ± 16.8	Not specified	Insomnia associated with depression, anxiety, lower cognitive function (sensory-reduced, lower perceptual-motor skills), obsessive worrying, and hypochondriacal concerns.
High (7/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 13, Female: 5
Crenshaw, MC / 1999	Cross-sectional case-control(age-matched)	Cases: insomniacs	Cases: history of insomnia complaints for ≥ 6 months	Cases:Male: 50% Female: 50%	Cases: mean ± SD: 67.7 ± 4.8	Not specified	No association between cognitive function (reaction time) and insomnia was found.
Moderate (3/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 50%, Female: 50%	Controls: mean ± SD: 67.5 ± 5.7
Dorsey, CM / 1997	Cross- sectional case-control(unmatched)	Cases: chronic insomniacs (subjective and objective)	Cases: sleep complaints > 6 months	Male: 17 Female: 14	Cases and controls: range: 18–25	Not specified	Insomnia associated with neuroticism (subjective insomniacs) and introversion (objective insomniacs).
Low (2/9)		Controls: normal sleepers	Controls: no sleep complaints				No association between gender and insomnia was found.
Edinger, JD / 2000	Cross- sectional case-control(matched)	Cases: persistent primary insomniacs	Cases: sleep complaints > 6 months (DSM-IV criteria)	Cases:Male: 32, Female: 32	Cases and controls: range: 40–79	Cases: 100% (64/64);	No association between mood or anxiety and insomnia was found.
High (8/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 30, Female: 31		Controls: 95.3% (61/64)
Edinger, JD / 2000	Cross-sectional case-control(age and gender-matched)	Cases: insomniacs	Cases: history of insomnia complaints for ≥ 6 months	Cases:Male: 44.4%, Female: 55.6%	Cases and controls: range: 40–79	Cases: 84.4%	No association for most measures of cognitive performance and insomnia.
Moderate (4/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 48.4% Female: 51.6%		Controls: 96.9%
Hajak, G / 2001	Cross- sectional and case-control(matched)	Cross-sectional: General population Case-control:	Cross-sectional: Insomnia disorders during the previous month (DSM-III-R and DSM-IV criteria). Severe insomnia: Sleep complaints during the previous month.	Cross-sectional:Male: 46.8% Female: 53.1%	Over 18	Not specified	Insomnia associated with impaired vitality/energy/activity level.
High (6/8)- cross-sectional		Cases: severe insomniacs	Case-control:Cases: severe insomnia as defined above				Severe insomnia associated with higher healthcare utilization, female gender, and separation/divorce.
High (7/9)- case control		Controls: normal sleepers	Controls: no sleep complaints				Age not associated with severe insomnia.
Han, SY / 2002	Cross- sectional	Diabetic haemo-dialysis patients	Sleep complaints for at least two months (DSM-IV criteria modified)	Male: 61% Female: 39%	Range: 27–78	Not specified	Insomnia associated with increased age and depression.
Low (2/8)							No association was found between gender, education, or pain and insomnia.
Harvey, AG / 2003	Cross-sectional case-control(unmatched)	Cases: insomniacs	Cases: sleep complaints for at least one month (DSM-IV criteria)	Cases:Male: 40% Female: 60%	Cases: mean ± SD: 20.4 ± 4.7	Not specified	Insomnia associated with worry.
Moderate (3/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 36.7% Female: 63.3%	Controls: mean ± SD: 22.3 ± 8.9
Hauri, PJ / 1997	Cross- sectional case-control(matched)	Cases: chronic insomniacs	Cases: sleep complaints for at least six months	Cases:Male: 7, Female: 19	Cases and controls: mean ± SD: 47.7 ± 11.8	Not specified	Insomnia associated with impaired cognitive function for some cognitive parameters (reaction time).
High (7/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 7, Female: 19			No association between some cognitive parameters (divided attention, recent memory and auditory/verbal patterns) and insomnia was found.
Healey, ES / 1981	Cross- sectional case-control(matched)	Cases: chronic insomniacs	Cases: sleep complaints within the previous eight years; defined as “chronic” insomniacs	Cases:Male: 9, Female: 22	Cases: range: 19–63	Not specified	Insomnia associated with more stressful life events preceding sleep problem, more health problems and tendency to somatize and internalize stress, lower self-concept, less satisfaction with life.
High (8/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 9, Female: 22	Controls: range: 18–63
Hidalgo, MP / 2002	Cross- sectional	Medical students	Sleep complaints for at least one month during the past year	Male: 58.2% Female: 41.8%	Range: 18–35	Not specified	Insomnia associated with minor psychiatric disorders.
Moderate (5/8)
Hohagen, F / 1994	Cross- sectional	Elderly outpatients from general practices	Sleep complaints for at least one month (DSM-III-R criteria)	Male: 28% Female: 72%	Over 65	97.5%	Insomnia associated with psychiatric disorders such as depression.
Moderate (4/8)							No association between age and insomnia was found.
Hohagen, F / 1993	Cross- sectional	Outpatients from general practices	Sleep complaints during the past month (DSM-III-R criteria)	Male: 44.7% Female: 55.3%	Range: 18–65	97.9%.	Moderate and severe insomnia associated with psychiatric disorders.
Moderate (4/8)							No association between mild insomnia and psychiatric problems was found.
Ishigooka, J / 1999	Cross- sectional	Outpatients from general hospitals	Sleep complaints for more than 1 month	Male: 41.9% Female: 58.1%	Range: 15–65	88.3%	Insomnia associated with old age, female gender and visits to neurology and psychiatric departments.
Moderate (5/8)
Kageyama, T / 2001	Cross-sectional	Hospital nurses	Sleep complaints for at least one month	Not specified	Range: 24–59	Not specified	Insomnia associated with being 24 or less years old, having three or less night shifts per month within last three months, receiving less support form colleagues, and taking care of severely ill patients.
Moderate (5/8)							Insomnia not associated with marital status, having a young child, undergoing medical treatment, recent major life events or work stress.
Kageyama, T / 1997	Cross-sectional	Adult women living in urban areas	Sleep complaints for at least one month (ICD-10 and DSM-IV criteria)	All women	Range: 20–80	Varied between district 51–59%	Insomnia associated with being age 70 or older, living with young children, undergoing medical treatment, experiencing one or more major life events within the past six months, having an irregular bedtime, and having sleep apnea-like symptoms.
High (6/8)							No association between marital status, job status or medical disease and insomnia was found.
Kales, JD / 1984	Cross-sectional case-control(unmatched)	Cases: 100 patients with sleep com-plaints for at least one year, + 114 insomniacs (appropriate data was available)	Cases: sleep complaints for at least one year	Cases:Male: 41.1% Female: 58.9%	Cases: mean: 43.1	Cases: not specified	Insomnia associated with tension, anxiety, worry, depression and poor mental and physical health.
Low (1/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 41% Female: 59%	Controls: mean ± SD: 48.2 ± 1.5 range: 24–80	Controls: 94%
Kales, AK / 1983	Cross-sectional case-control	Cases: chronic insomniacs	Cases: defined as “chronic” insomniacs	Cases:Male: 41% Female: 59%	Cases: mean ± SD: 43.1 ± 0.9 range: 18–84	Cases: 93%	Insomnia associated with depression, rumination and anxiety.
Moderate (4/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 41%. Female: 59%	Controls: mean ± SD: 40.9 ± 1.5 range: 19–74	Controls: 97%
Kales, A / 1982	Cross- sectional case-control(unmatched)	Cases: chronic insomniacs	Cases: sleep complaints > 6 months	Cases:Male: 82, Female: 118	Cases: range: 18–78	Not specified	Insomnia associated with psychopathology.
Low (2/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 41, Female: 59	Controls: range: 18–74
Kappler, C / 2003	Cross- sectional	Outpatients from general practices	Insomnia disorders diagnosed according to DSM-III-R criteria	Male: 49.9% Female: 50.1%	Range: 18–65	37.6%	Insomnia associated with increased age, conflicts with relatives, work and housekeeping stress, psychiatric disorders, medical illness or surgery in relatives and social status..
Low (2/8)							No association between gender and insomnia was found
Kawada, T / 2003	Cross- sectional	Women from the general population	Sleep complaints for at least one month (ICD-10 and DSM-IV criteria)	All female	Range: 20–80	50.4%	Insomnia associated with major life events, poor health, and depression.
High (6/8)
Leger, D / 2000	Cross- sectional	General population	Sleep complaints for at least one month (DSM-IV criteria).	Male: 47% Female: 53%	Over 18	85.2%	Insomnia associated with female gender and with being 24–34 years old (but not older). Severe insomnia associated with older age.
High (6/8)			Sleep complaints over a four-month period was considered “severe insomnia”.				No association between employment or marital status and insomnia was found.
Leppavuori, A / 2002	Cross- sectional	Stroke patients	Insomnia complaints for at least one month (DSM-IV criteria)	Male: 50.9% Female: 49.1%	Range: 55–85	Not specified	Insomnia associated with female gender, older age, psychological stress, anxiety, depression, health problems (including migraine), and impaired psychosocial function.
Moderate (4/8)							No association between sleep apnea and insomnia was found.
Levitt, H / 2004	Cross-sectional and case-control(age-matched)	Cases: insomniacs	Cases: primary insomnia diagnosed according to DSM-IV criteria	Cases:Male: 14.3% Female: 85.7%	Cases: mean ± SD: 24.1 ± 3.4 range: 20–30	100%	Insomnia associated with decreased cognitive function (concentration), fatigue, lower mood and lower ability to complete tasks.
Low (2/9)- case control		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 12.5% Female: 87.5%	Controls: mean ± SD: 23.3 ± 1.9 range: 20–30
Low (0/9)- cross sectional
Lichstein, KL / 2001	Cross- sectional case-control(unmatched)	Cases: primary or secondary insomniacs	Cases: sleep complaints of at least six months (ASDA criteria)	Cases: Primary insomnia: Male: 24, Female: 58 Secondary insomnia: Male: 23, Female: 23	Cases and controls: Over 58	Not specified	Insomnia associated with anxiety and depression.
Moderate (5/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 26, Female: 35			No association between gender and insomnia was found.
Linzmayer, L / 2002	Cross-sectional case-control(unmatched)	Cases: non-organic insomniacs associated with different mental disorders	Cases: Group A: nonorganic insomnia: ICSD classification of psychophysiological insomnia, DSM-IV classification of primary insomnia. All other cases had insomnia plus a concomitant mental disorder.	Cases:Female: 51.1% Male: 48.9%	Range: 22–63	Not specified	Insomnia not associated with lower intelligence.
Low (1/9)		Controls: normal sleepers	Controls: no sleep complaints				Insomnia associated with lower memory and wakefulness.
Lundh, LG / 1997	Cross- sectional case-control(matched)	Cases: persistent insomnia	Cases: long-standing problems with insomnia	Cases:Male: 4, Female: 16	Cases and controls: range: 20–65Cases mean ± SD: 46.5 ± 11.3	Not specified	Insomnia associated with depression and lower verbal ability.
Moderate (5/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 4, Female: 16	Controls mean ± SD: 45.5 ± 11.1		No association between anxiety or memory and insomnia was found.
Martikainen, K / 2003	Cross- sectional	General population	Sleep complaints during the previous three months	Male: 42.2% Female: 57.8%	Range: 41–55	52.6%	Insomnia associated with poorer working conditions, worry, nervousness, and tension.
Moderate (5/8)							No association between marital status or shift-work and insomnia was found.
Mendelson, WB / 1984	Cross- sectional case-control(matched)	Cases: insomniacs	Cases: sleep complaints for at least one year	Cases:Male: 1, Female: 9	Cases and controls: range: 22–44	Not specified	Insomnia associated with decreased memory for some parameters, distress, depression and introversion.
Moderate (4/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 1, Female: 9			No association between psychomotor performance and insomnia was found.
Niemcewicz, S / 2001	Case-control(matched for gender, age, and education)	Cases: primary insomniacs recruited from sleep disorder clinic.	Cases: primary insomnia diagnosed according to DSM-IV criteria	Cases:Male: 44%, Female: 56%	Mean ± SD: 40.8 ± 11.3Range: 21–55	100%	Insomnia associated with hypochondria, depression, hysteria, psychasthenia, hyperarousal, impaired memory, and impaired cognitive function (reaction time).
Low (2/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 44%, Female: 56%
Ohayon, MM / 2003	Cross- sectional	General population	Sleep complaints > 6 months	Male: 47.9% Female: 52.1%	Over 15	78.6%	Insomnia associated with past psychiatric illness such as anxiety and/or mood disorders.
High (7/8)
Ohayon, MM / 2002	Cross- sectional	General population	Chronic insomnia diagnosed according to ICSD and DSM-IV criteria	Male: 49.5% Female: 50.5%	Range: 15–90	91.4%	Insomnia associated with being elderly.
High (8/8)							No association between gender and insomnia was found.
Ohayon, MM / 2002	Cross- sectional	General population	Sleep complaints during the past year (DSM-IV criteria)	Male: 48.2% Female: 51.8%	Over 15	89.4%	Insomnia associated with female gender.
High (8/8)
Ohayon, MM / 2001	Cross- sectional	General population	Chronic Insomnia diagnosed according to DSM-IV criteria	Male: 47.9% Female: 52.1%	Over 15	78%	Insomnia associated with inactivity, dissatisfaction with social life, and the presence of organic diseases and mental disorders.
High (8/8)							No association between increased age and insomnia was found.
Pallesen, S / 2002	Cross- sectional case-control(matched)	Cases: chronic primary insomniacs	Cases: chronic primary insomnia diagnosed according to DSM-IV criteria	Cases:Male: 11, Female: 49.	Cases: range: 60–84	Cases: not specified	Insomnia associated with higher levels of psychological distress, depression, worry, somatization, and obsessive-compulsiveness.
High (7/9)		Controls:1) normal sleepers, 2) community sample	Controls: 1) no sleep complaints, 2) community sample	Controls: Good sleepers: Male: 9, Female: 32 Community: Male: 19, Female: 41	Controls: Good sleepers: 63–83; Community: 60–86	Controls: Good sleepers: not specified Community: 82.6%.	No association between number of life events or their subjective impact or recent life events and insomnia.
Pavlova, M / 2001	Cross- sectional case-control(unmatched)	Cases: primary insomniacs	Cases: primary Insomnia diagnosed according to DSM-IV criteria	Not specified	Cases: mean ± SD: 45.9 ± 14	Not specified	Insomnia associated with hyperarousal and introspectiveness.
Moderate (4/9)		Controls: normal sleepers	Controls: no sleep complaints		Controls: mean ± SD: 44.6 ± 15
Perlis, ML / 2001	Cross-sectional case-control(matched for age, sex, and body mass)	Cases: insomniacs	Cases: psychophysiologic insomnia for ≥ 6 months (ICSD criteria)	Cases:Male: 50%, Female: 50%	Cases: mean ± SD: 30.6 ± 8.9	Not specified	Insomnia associated with better memory of presentations made at sleep onset.
Moderate (5/9)		Controls: good sleepers	Controls: no sleep complaints	Controls:Male: 40%, Female: 60%	Controls: mean ± SD: 32.3 ± 11.5		No association between some measures of cognitive function (reaction time, words heard and repeated during stimuli presentation, free recall) and insomnia was found.
Riedel, BW / 2004	Cross- sectional	General population	Sleep complaints for at least six months (ICSD criteria)	Male: 49.3% Female: 50.7%	Range: 20–98	43.4%	Insomnia associated with being white, having a medical condition, depression and anxiety.
High (6/8)							Insomnia not significantly associated with age, gender, and neurological problems.
Rocha, FL / 2002	Cross- sectional	Elderly from the general population	Sleep complaint during the last 30 days	Male: 38.9% Female: 61.1%	Over 60	87%	Insomnia associated with female gender and poor health.
High (7/8)							No association between lower education or age and insomnia was found.
Rocha, FL / 2002	Cross- sectional	General population	Sleep complaints in the last month	Male: 44.3% Female: 55.7%	Over 18	87.3%	Insomnia associated with female gender, increased age and less education.
High (7/8)							No association between ethnicity, marital status and insomnia was found.
Roth, T / 1999	Cross- sectional	General population	Sleep complaints on a frequent basis; defined as “chronic” insomniacs	Not specified	Range: 18–65	51.2%	Insomnia associated with lower quality of life: impaired concentration, decreased ability to accomplish tasks, decreased enjoyment of interpersonal relationships, and decrements in perceived mood and wellness.
Moderate (3/8)
Sabbatini, M / 2002	Cross- sectional	Haemo-dialysis patients	Sleep complaints for at least one month	Male: 55.5% Female: 44.5%	Mean ± SD: 61.0 ± 14.4	Not specified	Insomnia associated with anxiety, pruritis, more time spent on dialysis.
Moderate (3/8)							No association between, pain, depression or tremors and insomnia was found.
Saletu-Zyhlarz, G / 1997	Cross-sectional case-control(unmatched)	Cases: non-organic insomniacs with concomitant generalized anxiety disorder (ICD-10)	Cases: sleep complaint for at least one month	Cases:Male: 43.2%, Female: 56.8%	Cases: mean ± SD: 43.2 ±11.7 range: 24–65	Cases: 100%	Insomnia associated with decreased psychomotor performance.
Low (1/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 45.5%, Female: 54.5%	Controls: mean ± SD: 43.0 ±11.7 range: 24–65	Controls: 77.3%	No association between alertness, concentration or memory and insomnia was found.
Savard, J / 2001	Cross- sectional	Women with metastatic breast cancer	Insomnia symptoms, insomnia syndrome and chronic insomnia syndrome with sleep complaints for at least six months (DSM-IV criteria)	All female	Range: 28–90	88%	Insomnia associated with being unemployed, separated, widowed, as well as chemotherapy, lumpectomy and higher education.
Moderate (4/8)							No association between psychological co-morbidity, or hormone therapy and insomnia was found.
Schneider-Helmert, D / 1987	Cross- sectional case-control(matched)	Cases: chronic insomniacs referred to a sleep clinic	Cases: persistent psychophysiological insomnia diagnosed by ASDC criteria	Cases:Male: 7, Female: 9	Cases: range: 32–61	Not specified	A difference in personality traits between insomniacs and controls was found.
High (7/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 7, Female: 9	Controls: range: 28–61
Shochat, T / 1999	Cross- sectional	Patients consulting their primary care physician	Occasional-insomniacs: sleep complaints on an occasional basis	Male: 42% Female: 58%	Range: 18–87	Not specified	Insomnia associated with poor daytime functioning on a variety of measures: impaired quality of life, mood, memory, concentration, quality of relationship with spouse and ability to accomplish tasks in the day.
Low (1/8)			Chronic insomniacs: sleep complaints on a frequent basis; defined as “chronic” insomniacs
			Normal Sleepers: no sleep complaints
Seidel, WF / 1984	Cross- sectional case-control(matched)	Cases: chronic insomniacs	Cases: sleep complaints for at least three months (ASDC criteria)	Cases:Male: 15, Female: 23	Cases and controls: mean ± SD: 29 ± 5	Not specified	No association between personality traits or mood and insomnia was found.
High (6/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 15, Female: 23
Sharpley, AL / 1997	Cross-sectional case-control(gender matched)	Cases: insomniacs	Cases: primary insomnia diagnosed according to DSM-II-R diagnosis	Cases:Male: 50% Female: 50%	Cases: mean ± SD: 54.7 ± 40–69	100% both groups	Insomnia associated with a past psychiatric illness.
Moderate (5/9)		Controls: normal sleepers	Controls: no sleep complaint	Controls:Male: 50% Female: 50%	Controls: mean ± SD: 53.9 ± 40–68
Shaver, JLF / 2002	Cross-sectional case-control(unmatched)	Cases: Psycho physiologic-type insomniacs and subjective-only type insomniacs	Cases: sleep complaints for at least three months	All women	Cases: PP-type insomnia: mean ± SD: 46.7 ± 3.3, SO-type insomnia: mean ± SD: 46.1 ± 4.4	Not specified	Insomnia associated with higher psychological distress.
High (6/9)		Controls: normal sleepers	Controls: no sleep complaints		Controls: mean ± SD: 44.4 ± 3.5		No association between stress exposure over the past year and insomnia was found.
Sugerman, JL / 1985	Cross- sectional case-control(matched)	Cases: insomniacs	Cases: sleep complaints for at least six months	Cases: 1) Objective insomnia: Male: 2, Female: 62) Subjective insomnia: Male: 2, Female: 6	Cases and controls: range: 21–55	Not specified	Insomnia associated with impaired waking performance in subjective insomniacs, but not in objective insomniacs.
High (6/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 2, Female: 6			No association between mood (depression, tension, fatigue, and confusion) and insomnia was found.
Taylor, DJ / 2003	Cross-sectional	Community volunteers	Sleep complaints for at least six months	Male: 49.4% Female: 50.6%	Range: 20–98	49%	Insomnia associated with female gender, older age, medical conditions, anxiety and depression.
High (6/8)
Terzano, MG / 2004	Cross- sectional	Patients presenting to their GP for medical problems other than sleep disorders	Sleep complaints for at least one month	Male: 39.1% Female: 60.9%	Over 18	Not specified	Insomnia associated with female gender, older age, lower education, depression, medical conditions (cardiovascular condition most common), absenteeism, increased healthcare utilization, and lower quality of life.
Moderate (4/8)
Vgontzas, AN / 1995	Cross-sectional case-control(unmatched)	Cases: insomniacs from the community and a sleep clinic	Cases: sleep complaints for more than six months	Cases:Male: 49.9% Female: 50.1%	Cases: range: 18–86	Not specified	No association between sleep apnea or nocturnal myoclonus and insomnia was found.
Low (2/9)		Controls: normal sleepers from the community	Controls: no sleep complaints	Controls:Male: 41.3% Female: 58.7%	Controls: range: 16–80
Vignola, A / 2000	Cross- sectional case-control(unmatched)	Cases: chronic insomniacs (using or not benzo-diazepines)	Cases: sleep complaints > 6 months	Cases: Chronic insomnia using benzodiazepines: Male: 10, Female: 10. Drug-free insomnia: Male: 9, Female: 11	Cases and Controls: Over 55	Not specified	Insomnia associated with decreased attention, concentration, fatigue, tension, alertness and energy.
Moderate (5/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 11, Female: 9			No association between some cognitive function parameters (visual and verbal memory, psychomotor speed, executive functions) and insomnia was found.
Vincent, NK / 2000	Cross-sectional case-control(unmatched)	Cases: chronic insomniacs from the community	Cases: sleep complaints for at least the previous six months (DSM-IV criteria)	Cases:Male: 28%, Female: 72%	Cases: mean ± SD: 46.91±10.04	Not specified	Insomnia associated with a tendency for maladaptive perfectionism and worry.
Moderate (4/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls: Not specified	Controls: mean ± SD: 39.64±11.49
Wang, W / 2001	Cross- sectional case-control(unmatched)	Cases: chronic primary insomniacs.	Cases: diagnosis of chronic primary insomnia according to DSM-IV criteria	Cases:Male: 11, Female: 12	Cases: mean ± SD: 30.2 ± 7.0	Cases: 100%	Insomnia associated with depression, anxiety, neuroticism, impulsivity and lower thrill and adventure-seeking behavior.
Moderate (4/9)		Controls: Normal sleepers	Controls: no sleep complaints	Controls:Male: 9, Female: 19	Controls: mean ± SD: 27.2 ± 5.0	Controls: 89.2%
Yeo, BKL / 1996	Cross- sectional	General population	Sleep complaints for the past year	Male: 50% Female: 50%	Range: 15–55	Not specified	Insomnia associated with female gender, increased stress level, phobia, depression and anxiety.
Moderate (3/8)							No association found between education level and insomnia.
Zammit, GK / 1999	Cross- sectional case-control(unmatched)	Cases: primary insomniacs	Cases: sleep complaints for at least one month	Cases:Male: 104, Female: 157	Cases: mean ± SD: 44.1 ± 14.04	Not specified	Insomnia associated with more health concerns and poorer general health, bodily pain, less vitality, more emotional problems, depression, anxiety, decreased cognitive function (attention, concentration, mental acuity, reasoning and problem-solving ability, mental reactivity), impaired occupational functioning, increased absenteeism from work.
Moderate (4/9)		Controls: normal sleepers	Controls: no sleep complaints	Controls:Male: 38, Female: 63	Controls: mean ± SD: 37.1 ± 12.7

Abbreviations: ASDA = American Sleep Disorders Association; ASDC = Association of Sleep Disorders Centers; DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; GP = general practitioner; ICD-10 = International Classification for Disease Version 10; PP = psychophysiologic; SD = standard deviation; SO = subjective only

A description of key features of the studies relevant to associated factors is provided in Table 5, and additional information for each study is provided in Evidence Table C-1. The evidence provided in Table 5 is summarized here.

Sixty-seven studies provided evidence regarding the association between various factors and chronic insomnia in adults; 30/67 studies were cross-sectional studies and 37/67 studies were cross-sectional case-control studies. The cross-sectional case-control studies compared chronic insomniacs (cases) and normal sleepers (control) on various factors to determine whether these factors are associated with chronic insomnia. Similarly, the cross-sectional studies examined the relationship of various factors and chronic insomnia by comparing chronic insomniacs and normal sleepers within a given population. Twenty-three studies were considered of high quality, 30 studies were considered of moderate quality and 14 studies were considered of low quality.

The criteria for chronic insomnia varied widely across studies and it was explicitly reported for most studies. The duration of sleep disturbance required to meet the criteria for chronic insomnia ranged from one month to 5 years, although the majority of studies required symptoms to be present for one or 6 months. Most studies reported the gender distribution of the population; the majority of populations were of mixed gender, and a minority of populations were all-female. The age of participants was reported for most studies, and ranged from 18 to 98 years, based on studies that provided a range. A number of studies (37/67) did not report the response/follow-up rate for the study. Of those that reported the response/follow-up rate, it ranged from 37.6–100 percent. The majority of studies had a rate of 80 percent or more.

Benzodiazepines

Figure 1. Meta graph: Sleep onset latency: benzodiazepines (more...)

   Figure 1. Meta graph: Sleep onset latency: benzodiazepines versus placebo

Sleep onset latency. Meta-analysis of the 32 studies that compared the effects of benzodiazepines and placebo on sleep onset latency (SOL) showed a statistically significant, albeit modest, difference of 16.5 minutes in favour of benzodiazepines (Figure 1). While there was substantial heterogeneity among the studies, all but two studies had a point estimate that favoured benzodiazepines. The heterogeneity was due more to different estimates of how effective the drugs were than as to whether or not they were superior to placebo. The study estimates ranged from about 65 minutes improvement in SOL to no difference.

Table 6

Sleep onset latency: benzodiazepines versus placebo (more...)

Table 6

Sleep onset latency: benzodiazepines versus placebo

Categorization	Sub-group	No. of studies	No. of Participants		Point Estimate (min.)	95% Confidence Interval (min.)	Heterogeneity	Deeks' Chi-Square P-value
			Tr.	Pl.
	All Studies	32	1345	961	-16.5	(-20.5,-12.5)	Substantial (I2: 72.4%)	NA
Drug Type (*)	Brotizolam	5	101	92	-10.5	(-16.2,-4.8)	Negligible (I2: 0%)	< 0.001
	Estazolam	3	235	125	-10.2	(-14.5,-5.9)	Negligible (I2: 0%)
	Flunitrazepam	2	49	30	-23.6	(-62.8, 15.6)	Substantial (I2: 74.4%)
	Flurazepam	10	317	215	-23.2	(-34.3,-12.2)	Substantial (I2: 51.8%)
	Lormetazepam	4	137	112	-14.8	(-21.8,-7.7)	Minimal (I2: 7.7%)
	Nitrazepam	1	37	19	-47.4	(-76.6,-18.2)	NA
	Quazepam	3	51	41	-14.2	(-23.7,-4.6)	Negligible (I2: 0%)
	Temazepam	4	128	78	-11.6	(-23.6, 0.4)	Substantial (I2: 84.0%)
	Triazolam	8	290	249	-19.7	(-28.4,-11.0)	Substantial (I2: 69.2%)
Psychiatric Illness	Absent	28	1147	803	-15.4	(-19.5,-11.2)	Substantial (I2: 70.7%)	0.001
	Present	4	198	158	-25.8	(-41.7,-9.8)	Substantial (I2: 72.3%)
Length of Treatment	Short Term	30	1275	898	-16.5	(-20.5,-12.4)	Substantial (I2: 74.1%)	0.53
	Long Term	2	70	63	-18.5	(-51.3, 14.4)	Negligible (I2: 0%)
Age	Adult	26	999	775	-15.4	(-19.9,-10.9)	Substantial (I2: 75.2%)	0.001
	Elderly	6	346	186	-19.2	(-26.6,-11.7)	Moderate (I2: 32.4%)
Gender	Male	3	43	43	-17.0	(-29.5,-4.5)	Negligible (I2: 0%)	0.14
	Female	1	6	6	-10.0	(-19.4,-0.6)	NA
	Mixed	28	1296	912	-16.9	(-21.2,-12.6)	Substantial (I2: 74.5%)
Method of Measurement (*)	PSG	9	181	170	-7.1	(-12.5,-1.7)	Substantial (I2: 57.8%)	< 0.001
	Sleep Diary	25	1216	842	-18.3	(-22.0,-12.4)	Moderate (I2: 41.2%)
Study Quality	Moderate	18	648	400	-13.5	(-18.7,-8.3)	Substantial (I2: 62.8%)	< 0.001
	High	14	697	561	-19.2	(-24.7,-13.7)	Substantial (I2: 68.1%)

Abbreviations: min. = minutes; NA = not applicable; No. = number; Pl. = placebo group; PSG = polysomnography; Tr. = treatment group

*

Sum of studies in each group is greater than total studies because some studies are included in multiple groups.

Table 6 lists all of the sub-group analyses conducted for sleep onset latency. Nine different types of benzodiazepines were examined by the studies. With the exception of nitrazolam (which had a significantly higher estimate than all other drugs except flunitrazepam, flurazepam, and triazolam, but was examined by only one study) all drug types had SOL estimates between 24 and 10 minutes. The four studies that examined patients with a psychiatric illness showed a mean SOL difference of about 26 minutes, 10 minutes more than the remainder of the studies that had patients without a psychiatric illness (not statistically significant). The two studies that had results for long-term treatment showed a nearly identical estimate to those with results for short-term treatment. Similarly, age had little impact on SOL, with a 19-minute difference for elderly patients compared to a 15-minute difference for adult patients. There were only three studies that examined solely male patients and only one study that examined solely female patients. These studies were not very different from each other or the remaining studies. Finally, subdividing the studies by method of measurement of outcomes showed that those studies that used a sleep diary to measure SOL had a significantly greater efficacy estimate than those that used polysomnography (about 18 minutes compared to 7 minutes). The sub-groups of drug type, psychiatric illness, age and method of measurement had a Deeks' chi-square P-value less than 0.05, indicating that heterogeneity was significantly reduced by the sub-group.

Analysis of the studies by quality revealed that the high quality studies showed a slightly stronger estimate of SOL difference (19 minutes) than the moderate quality studies (14 minutes) (there were no low quality studies). Although the difference is not statistically significant, Deeks' chi-square shows that this sub-grouping significantly reduced heterogeneity.

Figure 2. Funnel Plot: Sleep onset latency: benzodiazepines versus (more...)

   Figure 2. Funnel Plot: Sleep onset latency: benzodiazepines versus placebo

Although both Begg's (P-value = 0.81) and Duval's (no studies added) tests indicated no publication bias non-parametrically, Egger's test (p-value < 0.001) showed significant asymmetry in the funnel plot. This finding is also confirmed by a visual inspection of the funnel plot (Figure 2). The finding may indicate that the efficacy estimate given by the meta-analysis may in fact overestimate true efficacy, due to possible unpublished studies with non-significant results.

Figure 3. Meta graph: Wakefulness After Sleep Onset: benzodiazepines (more...)

   Figure 3. Meta graph: Wakefulness After Sleep Onset: benzodiazepines versus placebo

Wakefulness after sleep onset. Only eight benzodiazepine studies reported data on wakefulness after sleep onset (WASO). They revealed an average 23-minute improvement in WASO in the benzodiazepine patients as compared to the placebo patients (Figure 3). This result was statistically significant. Although there was substantial heterogeneity in this estimate, seven of the eight studies showed a point estimate that favoured treatment.

Table 7

Other outcomes: benzodiazepines versus placebo

Table 7

Other outcomes: benzodiazepines versus placebo

Outcome (units)	Comparison	No. of studies	No. of Participants		Point Estimate (min.)	95% Confidence Interval	Heterogeneity
			Tr.	Pl.
Efficacy Outcomes
Wakefulness After Sleep Onset (min.)	Mean Difference	8	153	137	-23.1	(-35.7,-10.5)	Substantial (I2: 51.4%)
Sleep Efficiency (%)	Mean Difference	10	187	168	6.3	(4.7, 8.0)	Negligible (I2: 0%)
Total Sleep Time (min.)	Mean Difference	17	416	404	39.1	(27.2, 51.0)	Substantial (I2: 66.9%)
Sleep Quality (SD)	Standardized Mean Difference	24	1243	857	0.80	(0.66, 0.94)	Moderate (I2: 47.6%)
Safety Outcomes
Adverse Events	Risk Difference	34	2566	1595	0.15	(0.10, 0.20)	Substantial (I2: 69.6%)

Abbreviations: min.= minutes; No. = number; Pl. = placebo group; SD = standard deviation; Tr. = treatment group

Other efficacy outcomes. Three other estimates of efficacy were measured, and the results can be viewed in Table 7. All outcomes showed statistically significant results that favoured benzodiazepines over placebo. Benzodiazepines increased sleep efficiency over placebo by an average of 6.3 percent and increased total sleep time by an average of 39 minutes. Sleep quality also showed a large difference between the groups with the benzodiazepines group having a standard mean difference (SMD) that was 0.8 standard deviations larger than placebo. Heterogeneity was negligible for sleep efficiency, substantial for total sleep time, and moderate for sleep quality.

Safety. The benzodiazepines showed a significantly greater proportion of adverse events than did placebo, although the meta-analysis showed substantial heterogeneity (Table 7). The risk difference estimates had a range of (0.01, 0.30) and an interquartile range of (0.08, 0.22) across interventions. The pooled risk-difference of 0.15 translates into a number needed to harm of seven patients (95% CI: 5, 10).

The most commonly reported adverse events of benzodiazepine use were somnolence (n=27 studies), headache (n=18), dizziness (n=16), nausea (n=11) and fatigue (n=11). There were no reports of falls, injury or death.

Non-benzodiazepines

Figure 4. Meta graph: Sleep Onset Latency: non-benzodiazepines versus (more...)

   Figure 4. Meta graph: Sleep Onset Latency: non-benzodiazepines versus placebo

Sleep onset latency. Twenty-nine studies on non-benzodiazepines showed a statistically significant difference of about 18 minutes in sleep onset latency compared to placebo (Figure 4). This difference is similar to the one reported for benzodiazepines. Again, similar to benzodiazepines, there was substantial heterogeneity among the studies, but all studies had a point estimate that favoured non-benzodiazepines. The study estimates ranged from about 67 minutes improvement to 4 minutes improvement in SOL.

Table 8

Sleep onset latency: non-benzodiazepines versus placebo (more...)

Table 8

Sleep onset latency: non-benzodiazepines versus placebo

Categorization	Sub-group	No. of studies	No. of Participants		Point Estimate (min.)	95% Confidence Interval (min.)	Heterogeneity	Deeks' Chi-Square P-value
			Tr.	Pl.
	All Studies	29	2913	1614	-18.1	(-22.5,-13.7)	Substantial (I2: 67.2%)	NA
Drug Type (*)	Eszopiclone	1	593	195	-16.7	(-29.4,-4.0)	NA	0.02
	Zaleplon	8	1145	433	-20.1	(-29.8,-10.5)	Substantial (I2: 85.7%)
	Zolpidem	17	997	808	-12.8	(-16.4,-9.1)	Minimal (I2: 4.5%)
	Zopiclone	5	178	178	-30.9	(-49.4,-12.4)	Substantial (I2: 73.9%)
Psychiatric Illness	Absent	28	2837	1534	-18.7	(-23.2,-14.2)	Substantial (I2: 67.0%)	0.06
	Present	1	76	80	-3.7	(-16.1, 8.7)	NA
Length of Treatment (*)	Short Term	24	2591	1338	-18.4	(-23.4,-13.4)	Substantial (I2: 71.0%)	0.79
	Long Term	6	915	471	-16.8	(-25.1,-8.6)	Moderate (I2: 37.2%)
Age	Adult	26	2520	1355	-18.7	(-23.9,-13.5)	Substantial (I2: 70.2%)	0.75
	Elderly	3	393	259	-16.1	(-21.2,-10.9)	Negligible (I2: 0%)
Gender	Male	1	12	12	-10.3	(-36.6, 16.0)	NA	0.69
	Female	1	6	6	-34.8	(-84.6, 15.0)	NA
	Mixed	27	2895	1596	-18.2	(-22.7,-13.6)	Substantial (I2: 69.1%)
Method of Measurement (*)	PSG	9	278	185	-16.7	(-24.3,-9.0)	Moderate (I2: 40.7%)	0.21
	Sleep Diary	24	2809	1543	-18.5	(-23.4,-13.6)	Substantial (I2: 68.6%)
Study Quality	Moderate	20	2462	1219	-14.1	(-16.9,-11.3)	Negligible (I2: 0%)	0.29
	High	9	451	395	-29.7	(-43.7,-15.6)	Substantial (I2: 88.8%)

Abbreviations: min. = minutes; NA = not applicable; No. = number; Pl. = placebo group; PSG = polysomnography; Tr. = treatment group

*

Sum of studies in each group is greater than total studies because some studies are included in multiple groups.

The results for the sub-group analyses for sleep onset latency can be viewed in Table 8. Four different types of non-benzodiazepines were examined by the studies. The four different drugs examined ranged in their efficacy from a 31-minute improvement (zopiclone) to a 13-minute improvement (zolpidem). Deeks' chi-square test showed that this sub-grouping resulted in a significant reduction in heterogeneity. All of the other sub-groups examined did not show significant reductions in heterogeneity. For psychiatric illness, only one study had patients with such an illness, and that study showed a significantly shorter improvement in SOL. For length of treatment, the short-term and long-term studies had nearly identical improvements, as did the studies for adult and elderly patients. For gender, there was one study that examined an all-male population and one study that examined an all-female population. Although the results differed from the overall average (less effective for males and much more effective for females), there was not enough data to draw any firm conclusions (no statistically significant differences). Finally, the studies that used polysomnography to estimate sleep onset latency were not different from those that used a sleep diary.

The high quality studies had an SOL estimate (30 minutes) that was significantly greater than the estimate for moderate quality studies (14 minutes) (there were no low quality studies), as was the case with the benzodiazepines. However, this sub-grouping did not significantly reduce heterogeneity.

Figure 5. Funnel Plot: Sleep Onset Latency: non-benzodiazepines versus (more...)

   Figure 5. Funnel Plot: Sleep Onset Latency: non-benzodiazepines versus placebo

Only Duval's test (no studies added in the trim and fill) showed no evidence of publication bias. Begg's (P-value = 0.01) and Egger's (P-value = 0.01) tests both showed evidence of funnel plot asymmetry, as did a visual examination of the plot (Figure 5). This finding suggests a possible overestimation of the efficacy in terms of SOL of non-benzodiazepines in our meta-analysis.

Figure 6. Meta graph: Wakefulness After Sleep Onset: non-benzodiazepines (more...)

   Figure 6. Meta graph: Wakefulness After Sleep Onset: non-benzodiazepines versus placebo

Wakefulness after sleep onset. Nine studies reported on WASO comparing non-benzodiazepines to placebo. The studies found that non-benzodiazepines decreased WASO by an average of about 13 minutes, which was statistically significant. Heterogeneity was substantial, caused mostly by one study, whose estimate was very different from the others (Figure 6).

Table 9

Other outcomes: non-benzodiazepines versus placebo

Table 9

Other outcomes: non-benzodiazepines versus placebo

Outcome (units)	Comparison	No. of studies	No. of Participants		Point Estimate	95% Confidence Interval	Heterogeneity
			Tr.	Pl.
Efficacy Outcomes
Wakefulness After Sleep Onset (min.)	Mean Difference	9	950	552	-12.6	(-23.0,-2.3)	Substantial (I2: 64.6%)
Sleep Efficiency (%)	Mean Difference	7	172	115	5.9	(3.7, 8.0)	Negligible (I2: 0%)
Total Sleep Time (min.)	Mean Difference	23	2505	1247	28.0	(21.3, 34.6)	Moderate (I2: 44.3%)
Sleep Quality (SD)	Standardized Mean Difference	20	2818	1554	0.48	(0.37, 0.59)	Substantial (I2: 56.1%)
Quality of Life (SD)	Standardized Mean Difference	1	231	227	0.45	(0.27, 0.64)	NA
Safety Outcomes
Adverse Events	Risk Difference	21	3718	1951	0.05	(0.01, 0.09)	Substantial (I2: 57.6%)

Abbreviations: min. = minutes; NA = not applicable; No. = number; Pl. = placebo group; SD = standard deviation; Tr. = treatment group

Other efficacy outcomes. Four other estimates of efficacy were measured, and their results can be viewed in Table 9. All outcomes showed statistically significant results that favoured non-benzodiazepines over placebo. Sleep efficiency was increased in non-benzodiazepines by about 6 percent, while total sleep time was increased by about 28 minutes. Both sleep quality and quality of life showed moderate improvements in non-benzodiazepines compared to placebo with SMDs of 0.48 and 0.45, respectively. Heterogeneity was negligible for sleep efficiency, moderate for total sleep time, and substantial for sleep quality.

Safety. The non-benzodiazepines showed a significantly greater proportion of adverse events than did placebo, although the meta-analysis showed substantial heterogeneity (Table 9). The risk-difference had a range of (0.00, 0.15) and an interquartile range of (0.05, 0.08) across interventions. The pooled risk-difference of 0.05 translates into a number needed to harm of 20 patients (95% CI: 11, 100).

The most commonly reported adverse events of non-benzodiazepine use were headache (n=16 studies), dizziness (n=14), nausea (n=13) and somnolence (n=13). Accidental injury was reported in only one study, although there was no difference in the frequency of this event between experimental and control groups.

Antidepressants

Figure 7. Meta graph: Sleep Onset Latency: antidepressants (more...)

   Figure 7. Meta graph: Sleep Onset Latency: antidepressants versus placebo

Sleep onset latency. There were six studies that examined the effect of antidepressants (doxepin, pivagabine, trazodone and trimipramine) on sleep onset latency. They showed a small but statistically significant difference of about 7 minutes in sleep onset latency compared to placebo (Figure 7). The heterogeneity in this estimate was minimal and all six studies had an estimate that favoured the drug. The study estimates ranged from about 17 minutes improvement in SOL to no difference.

Table 10

Sleep onset latency: antidepressants versus placebo (more...)

Table 10

Sleep onset latency: antidepressants versus placebo

Categorization	Sub-group	No. of studies	No. of Participants		Point Estimate (min.)	95% Confidence Interval (min.)	Heterogeneity	Deeks' Chi-Square P-value
			Tr.	Pl.
	All Studies	6	159	166	-7.4	(-10.5,-4.4)	Minimal (I2: 4.5%)	NA
Drug Type	Doxepin	3	40	40	-6.7	(-10.7,-2.6)	Moderate (I2: 49.3%)	0.45
	Trazodone	2	100	108	-12.2	(-22.3,-2.2)	Negligible (I2: 0%)
	Trimipramine	1	19	18	-15.4	(-36.8, 6.0)	NA
Psychiatric Illness	Absent	5	152	159	-7.2	(-10.3,-4.1)	Minimal (I2: 17.6%)	0.30
	Present	1	7	7	-17.4	(-36.8, 2.0)	NA
Length of Treatment (*)	Short Term	6	159	166	-7.8	(-10.2,-5.4)	Negligible (I2: 0%)	0.11
	Long Term	1	10	10	-4.4	(-7.7,-1.1)	NA
Method of Measurement	PSG	4	59	59	-7.0	(-10.7,-3.3)	Moderate (I2: 34.1%)	0.32
	Sleep Diary	2	100	108	-12.2	(-22.3,-2.2)	Negligible (I2: 0%)
Study Quality	Moderate	5	152	159	-7.2	(-10.3,-4.1)	Minimal (I2: 17.6%)	0.30
	High	1	7	7	-17.4	(-36.8, 2.0)	NA

Abbreviations: min. = minutes; NA = not applicable; No. = number; Pl. = placebo group; PSG = polysomnography; Tr. = treatment group

*

Sum of studies in each group is greater than total studies because some studies are included in multiple groups.

The results of sub-group analyses for sleep onset latency can be viewed in Table 10. All six studies were of mixed gender and featured only adults, so no sub-group analysis on gender or age was performed. Of the comparisons that were made, none significantly reduced heterogeneity, despite some marked differences in point estimates. This finding was mainly due to the low number of studies: most categories had a sub-group of only one study and method of measurement had a sub-group of only two studies. None of the differences in point estimates were statistically significant.

The one high quality study had an SOL estimate (17 minutes) that was higher than the estimate for the moderate quality studies (7 minutes) (there were no low quality studies). This sub-grouping did not significantly reduce heterogeneity, and the difference between estimates was not significant.

Since only six studies were included in this analysis, there were too few studies to perform any meaningful tests of publication bias.

Figure 8. Meta graph: Wakefulness After Sleep Onset: antidepressants (more...)

   Figure 8. Meta graph: Wakefulness After Sleep Onset: antidepressants versus placebo

Wakefulness after sleep onset. Three studies reported on WASO comparing antidepressants (doxepin and trazodone) to placebo. The studies found that antidepressants decreased WASO by an average of about 11 minutes, which was statistically significant. Heterogeneity was negligible (Figure 8).

Table 11

Other outcomes: antidepressants versus placebo

Table 11

Other outcomes: antidepressants versus placebo

Outcome (units)	Comparison	No. of studies	No. of Participants		Point Estimate	95% Confidence Interval	Heterogeneity
			Tr.	Pl.
Efficacy Outcomes
Wakefulness After Sleep Onset (min.)	Mean Difference	3	123	131	-11.4	(-16.2, -6.6)	Negligible (I2: 0%)
Sleep Efficiency (%)	Mean Difference	4	59	58	13.8	(9.6, 18.0)	Negligible (I2: 0%)
Total Sleep Time (min.)	Mean Difference	5	66	65	53.1	(2.8, 103.5)	Substantial (I2: 85.4%)
Sleep Quality (SD)	Standardized Mean Difference	3	162	169	0.63	(0.27, 0.99)	Substantial (I2: 52.6%)
Safety Outcomes
Adverse Events	Risk Difference	3	143	145	0.09	(0.01, 0.18)	Negligible (I2: 0%)

Abbreviations: min. = minutes; No. = number; Pl. = placebo group; SD = standard deviations; Tr. = treatment group

Other efficacy outcomes. Three other estimates of efficacy were measured (no studies included an analysis of quality of life), and their results can be viewed in Table 11. All outcomes showed statistically significant results that favoured antidepressants over placebo. Sleep efficiency was increased in the antidepressant group by about 13.8 percent, while total sleep time was increased by about 53.1 minutes. Sleep quality showed a moderate increase for antidepressants of about 0.63 on the SMD scale. Heterogeneity was negligible for sleep efficiency and substantial for both total sleep time and sleep quality.

Safety. The antidepressants showed a significantly greater proportion of adverse events than placebo, and the meta-analysis showed negligible heterogeneity (Table 11). The risk-difference had a range of (-0.07, 0.13) and an interquartile range of (0.01, 0.11). The pooled risk-difference of 0.09 translates into a number needed to harm of 11 patients (95% CI: 6, 100).

The most commonly reported adverse events with antidepressant use were somnolence (n=4), headache (n=3), dizziness (n=3), and nausea (n=3). There were no reports of falls, injury or death.

Complementary and alternative care

There were three different types of complementary and alternative therapies observed in our included studies: L-tryptophan, melatonin, and valerian. These three substances were considered too different clinically to combine, and thus their results will be considered separately.

L-tryptophan

Figure 9. Meta graph: Sleep Onset Latency: complementary (more...)

   Figure 9. Meta graph: Sleep Onset Latency: complementary and alternative care versus placebo

Table 12

All outcomes: L-trytophan versus placebo

Table 12

All outcomes: L-trytophan versus placebo

Outcome (units)	Comparison	No. of studies	No. of Participants		Point Estimate	95% Confidence Interval	Heterogeneity
			Tr.	Pl.
Efficacy Outcomes
Sleep Onset Latency (min.)	Mean Difference	2	47	41	-11.0	(-33.0, 11.1)	Substantial (I2: 61.5%)

Abbreviations: min. = minutes; No. = number; Pl. = placebo group; Tr. = treatment group

Sleep onset latency. Only two studies reported data for l-trytophan versus placebo and the results for sleep onset latency can be seen in Figure 9. The two studies showed an average reduction in SOL of 11 minutes, but the result was not significant, and the heterogeneity between the two studies was substantial. There were too few studies to do any meaningful tests for publication bias. No other outcomes of interest were reported for L-tryptophan (Table 12). The two studies used different methods to measure sleep onset latency. The study that used polysomnography showed a significant effect of L-tryptophan (-20.1 minutes; 95% CI: -33.6, -6.6), while the study that used sleep diary did not (2.9 minutes; 95% CI: -21.6, 27.4). However, the difference between the two studies was not statistically significant.

Melatonin

Sleep onset latency. There were 8 studies on melatonin that examined sleep onset latency. Similar to the antidepressants, this category of intervention showed a small but statistically significant difference of about 8 minutes in sleep onset latency compared to placebo (Figure 9). The heterogeneity in this estimate was moderate, and all but two of the studies had an estimate that favoured the drug. The study estimates ranged from about 20 minutes improvement in SOL to 10 minutes detriment. When the eight studies were grouped by method of measurement, some differences in efficacy estimates were observed among the groups. The estimate for polysomnography (-3.6 minutes; 95% CI: -8.8, 1.6) was significantly different from the estimate for actigraphy (-16.7 minutes; 95% CI: -25.0, -8.3). Neither estimate was significantly different from the estimate for sleep diary (5.1 minutes; 95% CI: -20.0, 30.2).

Figure 10. Funnel Plot: Sleep Onset Latency: melatonin (more...)

   Figure 10. Funnel Plot: Sleep Onset Latency: melatonin versus placebo

No publication bias was immediately apparent from the funnel plot (Figure 10), and both Begg's test (P-value = 0.90) and Egger's test (P-value = 0.21) did not show significant asymmetry. However, Duval's trim and fill test did add one study to the meta-analysis and slightly increased the efficacy estimate (-8.7 minutes; 95% CI: -14.9, -2.5).

Figure 11. Meta graph: Wakefulness After Sleep Onset: complementary (more...)

   Figure 11. Meta graph: Wakefulness After Sleep Onset: complementary and alternative care versus placebo

Wakefulness after sleep onset. Five studies reported on WASO comparing melatonin to placebo. The studies found that melatonin decreased WASO by an average of about 10 minutes, but this difference was not statistically significant. Heterogeneity was substantial, with two studies indicating a significant effect in favour of melatonin, while the other three studies all had estimates on the side of the null favouring placebo (Figure 11).

Table 13

All outcomes: melatonin versus placebo

Table 13

All outcomes: melatonin versus placebo

Outcome (units)	Comparison	No. of studies	No. of Participants		Point Estimate	95% Confidence Interval	Heterogeneity
			Tr.	Pl.
Efficacy Outcomes
Sleep Onset Latency (min.)	Mean Difference	8	103	103	-8.3	(-14.5, -2.0)	Moderate (I2: 44.2%)
Wakefulness After Sleep Onset (min.)	Mean Difference	5	68	68	-9.7	(-33.6, 14.3)	Substantial (I2: 89.8%)
Sleep Efficiency (%)	Mean Difference	8	121	121	3.3	(-0.4, 6.9)	Substantial (I2: 81.2%)
Total Sleep Time (min.)	Mean Difference	7	95	95	5.8	(-13.2, 24.8)	Substantial (I2: 72.3%)
Sleep Quality (SD)	Standardized Mean Difference	3	35	35	0.25	(-0.22, 0.73)	Negligible (I2: 0%)
Safety Outcomes
Adverse Events	Risk Difference	2	27	27	0.09	(-0.11, 0.29)	Moderate (I2: 30.0%)

Abbreviations: min. = minutes; No. = number; Pl. = placebo group; SD = standard deviation; Tr. = treatment group

Other efficacy outcomes. Three other estimates of efficacy were measured for melatonin versus placebo (no studies included an analysis of quality of life), and their results can be viewed in Table 13. None of the three outcomes showed statistically significant results. The point estimates for sleep efficiency and total sleep time were 3 percent and 6 minutes, respectively. Sleep quality had a small efficacy difference of 0.3 standard deviations. Heterogeneity was substantial for both sleep efficiency and total sleep time, while it was negligible for sleep quality.

Safety. The melatonin studies did not show any significant difference in number of adverse events versus placebo (Table 13), with an estimated risk difference of 0.09. Heterogeneity among studies was moderate.

Valerian

Sleep onset latency. There were three studies on valerian that examined sleep onset latency. The studies showed a small average difference between valerian and placebo (1 minute), which was not statistically significant (Figure 9). The heterogeneity in this estimate was substantial with two studies favouring valerian and the third being well on the side of placebo. The study estimates ranged from about 17 minutes improvement in SOL to 23 minutes detriment. There were too few studies to do any meaningful tests for publication bias. When the studies were grouped by method of measurement, differences among groups were observed. The estimate for polysomnography (9.5 minutes; -11.3, 30.3) was significantly different from the estimate for sleep diary (-16.0 minutes; 95% CI: -29.5, -2.5).

Wakefulness after sleep onset. Only one study reported on WASO comparing melatonin to placebo, but it did find a difference of 8 minutes between the groups, which favoured valerian and was statistically significant (Figure 11).

Table 14

All outcomes: valerian versus placebo

Table 14

All outcomes: valerian versus placebo

Outcome (units)	Comparison	No. of studies	No. of Participants		Point Estimate	95% Confidence Interval	Heterogeneity
			Tr.	Pl.
Efficacy Outcomes
Sleep Onset Latency (min.)	Mean Difference	3	51	50	-1.3	(-21.4, 18.9)	Substantial (I2: 77.6%)
Wakefulness After Sleep Onset (min.)	Mean Difference	1	10	9	-8.4	(-15.9, -1.0)	NA
Sleep Efficiency (%)	Mean Difference	2	26	25	-0.1	(-3.4, 3.2)	Negligible (I2: 0%)
Total Sleep Time (min.)	Mean Difference	1	10	9	0.8	(-50.6, 52.2)	NA
Sleep Quality (SD)	Standardized Mean Difference	3	50	49	1.38	(-0.49, 3.25)	Substantial (I2: 93.1%)
Safety Outcomes
Adverse Events	Risk Difference	3	51	50	-0.06	(-0.48, 0.35)	Substantial (I2: 90.3%)

Abbreviations: min. = minutes; NA = not applicable; No. = number; Pl. = placebo group; SD = standard deviation; Tr. = treatment group

Other efficacy outcomes. Three other estimates of efficacy were measured for valerian versus placebo (no studies included an analysis of quality of life), and their results can be viewed in Table 14. None of the three outcomes showed statistically significant results. The point estimates for sleep efficiency and sleep onset latency were very small at 0.1 percent and 1 minute, respectively. Sleep quality had a large efficacy difference of 1.38 standard deviations, but, as mentioned, it was not statistically significant. Heterogeneity was negligible for sleep efficiency and substantial for sleep quality.

Safety. The valerian studies did not show any significant difference in number of adverse events versus placebo (Table 14), with an estimated risk difference of -0.06, which actually favoured valerian. Heterogeneity among studies was substantial.

Relaxation therapy

Figure 12. Meta graph: Sleep Onset Latency: relaxation (more...)

   Figure 12. Meta graph: Sleep Onset Latency: relaxation therapy versus placebo

Sleep onset latency. There were 13 studies on relaxation therapy that examined sleep onset latency. Meta-analysis showed a pooled difference of 15 minutes favouring therapy over placebo (Figure 12). This result was not statistically significant. The heterogeneity in this estimate was extremely high (I²: 96 percent), although all but three of the studies had an estimate that favoured the drug. The study estimates ranged from about 60 minutes improvement in SOL to 14 minutes detriment.

Table 15

Sleep onset latency: relaxation therapy versus placebo (more...)

Table 15

Sleep onset latency: relaxation therapy versus placebo

Categorization	Sub-group	No. of studies	No. of Participants		Point Estimate (min.)	95% Confidence Interval (min.)	Heterogeneity	Deeks' Chi-Square P-value
			Tr.	Pl.
	All Studies	13	199	185	-14.6	(-29.3, 0.2)	Substantial (I2: 96.1%)	NA
Relaxation Description(*)	Autogenic Training	1	8	4	-27.0	(-126.2, 72.2)	NA	< 0.001
	Breathing Training	1	23	23	-60.0	(-64.5, -55.5)	NA
	EMG Feedback Training	3	27	27	-5.3	(-28.4, 17.8)	Substantial (I2: 62.3%)
	Group	1	14	14	-5.5	(-10.8, -0.2)	NA
	Hypnotic	1	15	15	-16.3	(-24.3, -8.3)	NA
	Progressive	5	61	55	-15.7	(-39.2, 7.8)	Moderate (I2: 49.0%)
	Relaxation	4	51	47	-5.3	(-17.3, 6.8)	Substantial (I2: 67.7%)
Length of Treatment	Short Term	9	124	114	-22.0	(-41.0, -2.9)	Substantial (I2: 97.3%)	< 0.001
	Long Term	4	75	71	1.9	(-6.7, 10.6)	Minimal (I2: 11.7%)
Age	Adult	12	172	162	-15.9	(-31.5, -0.3)	Substantial (I2: 96.2%)	< 0.001
	Elderly	1	27	23	-0.2	(-10.4, 10.0)	NA
Gender	Female	1	14	14	-5.5	(-10.8, -0.2)	NA	< 0.001
	Mixed	12	185	171	-15.5	(-32.0, 0.9)	Substantial (I2: 95.9%)
Study Quality	Low	8	101	94	-9.1	(-16.0, -2.2)	Substantial (I2: 58.4%)	< 0.001
	Moderate	5	98	91	-17.6	(-54.2, 19.0)	Substantial (I2: 97.2%)

Abbreviations: EMG = electromyographic; min. = minutes; NA = not applicable; No. = number; Pl. = placebo group; Tr. = treatment group;

*

Sum of studies in each group is greater than total studies because some studies are included in multiple groups.

The results for sub-group analyses for sleep onset latency in relaxation therapy can be viewed in Table 15. All 13 studies analysed patients without psychiatric illnesses and used sleep diary to measure SOL, so no sub-group analyses on these variables were performed. The other four sub-groups examined yielded highly significant reductions in heterogeneity. Despite this finding, many of the individual sub-groups had very high heterogeneity. Subdividing by type of relaxation therapy, efficacy estimates ranged from 60 minutes improvement to 5 minutes improvement. Only breathing training, group relaxation, and hypnotic relaxation showed statistically significant efficacy despite each sub-group containing only one trial. The short-term effects of relaxation therapy on SOL proved significantly greater than the long-term effects (22 minutes improvement versus 2 minutes detriment). There was only one study of elderly patients, and it showed no improvement in sleep onset latency compared to the studies on adults, which showed an improvement of 16 minutes. This difference was not significant. Finally, one study had only female participants (there were no studies of all-male populations), and it had a lower efficacy than the remainder of the studies (6 minutes compared to 16 minutes). This difference was non-significant.

The moderate quality studies had a slightly higher (but not significantly higher) efficacy estimate than the low quality studies (18 minutes compared to 9 minutes) (there were no high quality studies). This sub-grouping significantly reduced heterogeneity.

Figure 13. Funnel Plot: Sleep Onset Latency: relaxation (more...)

   Figure 13. Funnel Plot: Sleep Onset Latency: relaxation therapy versus placebo

No publication bias was immediately apparent from the funnel plot (Figure 13). Both Egger's test (P-value = 0.49) and Duval's trim and fill (no studies added) did not show significant asymmetry. However, Begg's test did show some evidence of asymmetry (P-value = 0.004). This finding is somewhat surprising considering that Begg's test is usually the most conservative test (i.e. it is unusual to have a significant Begg P-value and a non-significant Egger P-value).

Figure 14. Meta graph: Wakefulness After Sleep Onset: (more...)

   Figure 14. Meta graph: Wakefulness After Sleep Onset: relaxation therapy versus placebo

Wakefulness after sleep onset. Only three studies reported on WASO comparing relaxation therapy to placebo. Their combined efficacy estimate was very small (-2 minutes) and favoured relaxation therapy (Figure 14). The result was not statistically significant. Heterogeneity was minimal.

Table 16

Other outcomes: relaxation therapy versus placebo

Table 16

Other outcomes: relaxation therapy versus placebo

Outcome (units)	Comparison	No. of studies	No. of Participants		Point Estimate	95% Confidence Interval	Heterogeneity
			Tr.	Pl.
Efficacy Outcomes
Wakefulness After Sleep Onset (min.)	Mean Difference	3	60	57	-1.6	(-14.1, 10.8)	Minimal (I2: 0.2%)
Sleep Efficiency (%)	Mean Difference	2	50	47	0.4	(-3.7, 4.6)	Negligible (I2: 0%)
Total Sleep Time (min.)	Mean Difference	3	60	57	23.0	(2.7, 43.4)	Negligible (I2: 0%)
Sleep Quality (SD)	Standardized Mean Difference	3	50	47	0.37	(-0.49, 1.24)	Substantial (I2: 79.2%)

Abbreviations: min. = minutes; No. = number; Pl. = placebo group; SD = standard deviation; Tr. = treatment group

Other efficacy outcomes. Three other estimates of efficacy were measured for relaxation therapy versus placebo (no studies included an analysis of quality of life), and their results can be viewed in Table 16. Only total sleep time showed a statistically significant result, with an average improvement in the relaxation group of 23 minutes. Sleep efficiency had an estimate of 0.4 percent, while sleep quality showed a small estimate of 0.4 standard deviations. Neither estimate was statistically significant. Heterogeneity was negligible for sleep efficiency and total sleep time, but was substantial for sleep quality.

Safety. None of the trials of this category reported on adverse events.

Cognitive/behavioral therapy

Figure 15. Meta graph: Sleep Onset Latency: cognitive/behavioral therapy (more...)

   Figure 15. Meta graph: Sleep Onset Latency: cognitive/behavioral therapy versus placebo

Sleep onset latency. There were nine studies on cognitive/behavioral therapy (CBT) that examined sleep onset latency. Meta-analysis showed a pooled difference of 5 minutes favouring therapy over placebo (Figure 15). This result was not statistically significant. The heterogeneity in this estimate was minimal, although three of the nine studies had an estimate that favoured placebo. The study estimates ranged from about 30 minutes improvement in SOL to 19 minutes detriment.

Table 17

Sleep onset latency: cognitive/behavioral therapy versus placebo (more...)

Table 17

Sleep onset latency: cognitive/behavioral therapy versus placebo

Categorization	Sub-group	No. of studies	No. of Participants		Point Estimate (min.)	95% Confidence Interval (min.)	Heterogeneity	Deeks' Chi-Square P-value
			Tr.	Pl.
	All Studies	9	152	124	-4.6	(-9.8, 0.6)	Minimal (I2: 12.5%)	NA
Cognitive Behavioral Therapy Type (*)	Multi-component CBT	2	20	19	-2.6	(-15.4, 10.2)	Moderate (I2: 49.0%)	0.65
	Paradoxical Intention	3	37	23	-3.7	(-28.7, 21.3)	Moderate (I2: 38.0%)
	Sleep Compression	1	24	23	-0.8	(-13.7, 12.1)	NA
	Stimulus Control	4	58	46	-7.3	(-18.3, 3.7)	Moderate (I2: 31.6%)
	Non-Suppression	1	13	13	-9.7	(-24.2, 4.8)	NA
Length of Treatment	Short Term	7	99	87	-4.3	(-10.4, 1.8)	Minimal (I2: 19.9%)	0.84
	Long Term	2	53	37	-8.5	(-24.7, 7.8)	Moderate (I2: 24.2%)
Age	Adult	8	128	101	-5.3	(-11.4, 0.7)	Minimal (I2: 19.0%)	0.58
	Elderly	1	24	23	-0.8	(-13.7, 12.1)	NA
Study Quality	Low	5	60	62	-8.1	(-14.6, -1.6)	Negligible (I2: 0%)	0.12
	Moderate	4	92	62	-1.2	(-7.8, 5.5)	Minimal (I2: 4.4%)

Abbreviations: min. = minutes; NA = not applicable; No. = number; Pl. = placebo group; Tr. = treatment group

*

Sum of studies in each group is greater than total studies because some studies are included in multiple groups.

The results of sub-group analyses for sleep onset latency in CBT can be viewed in Table 17. All nine studies were of mixed gender, analysed patients without psychiatric illnesses and used sleep diary to measure SOL, so no sub-group analyses on gender, psychiatric illness or method of measurement were performed. Of the three sub-groups examined, none showed significant reduction in heterogeneity. Subdividing by type of intervention, stimulus control and thought non-suppression had slightly higher estimates than multi-component CBT, paradoxical intention, and sleep compression, but the differences were not significant. Similarly, the short-term and long- term differences were comparable. There was only one study that examined elderly participants, and its efficacy estimate was not very different from the adult studies.

The low quality studies had a slightly higher efficacy estimate than the moderate quality studies (8 minutes compared to 1 minute), but the difference was not statistically significant (there were no high quality studies). This sub-grouping did not significantly reduce heterogeneity.

Figure 16. Funnel Plot: Sleep Onset Latency: cognitive/behavioral therapy (more...)

   Figure 16. Funnel Plot: Sleep Onset Latency: cognitive/behavioral therapy versus placebo

There was no evidence of publication bias. The funnel plot did not appear to be asymmetric (Figure 16), and Begg's (P-value = 0.53), Egger's (P-value = 0.37) and Duval's (no studies added) tests all confirmed this finding.

Figure 17. Meta graph: Wakefulness After Sleep Onset: cognitive/behavioral (more...)

   Figure 17. Meta graph: Wakefulness After Sleep Onset: cognitive/behavioral therapy versus placebo

Wakefulness after sleep onset. Eight studies reported on WASO comparing CBT to placebo. Their combined efficacy estimate showed that CBT improved WASO by an average of 18 minutes (Figure 17). The result was statistically significant, although heterogeneity was substantial. Despite the high heterogeneity, all but one study showed a result that favoured CBT.

Table 18

Other outcomes: cognitive/behavioral therapy versus placebo (more...)

Table 18

Other outcomes: cognitive/behavioral therapy versus placebo

Outcome (units)	Comparison	No. of studies	No. of Participants		Point Estimate	95% Confidence Interval	Heterogeneity
			Tr.	Pl.
Efficacy Outcomes
Wakefulness After Sleep Onset (min.)	Mean Difference	8	128	120	-18.2	(-30.4, -6.0)	Substantial (I2: 52.9%)
Sleep Efficiency (%)	Mean Difference	4	75	74	5.5	(1.2, 9.9)	Substantial (I2: 57.9%)
Total Sleep Time (min.)	Mean Difference	5	85	84	0.7	(-28.1, 29.5)	Substantial (I2: 65.6%)
Sleep Quality (SD)	Standardized Mean Difference	6	94	95	0.38	(0.09, 0.67)	Negligible (I2: 0%)

Abbreviations: min. = minutes; No. = number; Pl. = placebo group; SD = standard deviation; Tr. = treatment group

Other efficacy outcomes. Three other estimates of efficacy were measured for CBT versus placebo (no studies included an analysis of quality of life), and their results can be viewed in Table 18. Both sleep efficiency and sleep quality showed statistically significant improvements for CBT over placebo. Sleep efficiency improved by an average of 6 percent, while sleep quality showed an improvement of 0.38 standard deviations. Total sleep time showed no difference. Heterogeneity was negligible for sleep quality, but substantial for both the sleep efficiency and total sleep time estimates.

Safety. None of the CBT trials reported on adverse events.

Indirect comparisons

Table 19

Sleep onset latency: indirect comparisons of main pharmacological treatment (more...)

Table 19

Sleep onset latency: indirect comparisons of main pharmacological treatment categories

Comparison	Difference in SOL (min.)	95% Confidence Interval (min.)	Difference Favours:	Significant Difference(Yes or No)
BNZ versus NBNZ	1.6	(-4.3, 7.5)	NBNZ	No
BNZ versus ADP	-9.1	(-14.1, -4.1)	BNZ	Yes
BNZ versus LT	-5.5	(-28.0, 17.0)	BNZ	No
BNZ versus MLT	-8.2	(-15.7, -0.7)	BNZ	Yes
BNZ versus VAL	-15.2	(-35.8, 5.4)	BNZ	No
NBNZ versus ADP	-10.7	(-16.0, -5.4)	NBNZ	Yes
NBNZ versus LT	-7.1	(-29.6, 15.4)	NBNZ	No
NBNZ versus MLT	-9.8	(-17.5, -2.1)	NBNZ	Yes
NBNZ versus VAL	-16.8	(-37.5, 3.9)	NBNZ	No
ADP versus LT	3.6	(-18.7, 25.9)	LT	No
ADP versus MLT	0.9	(-6.1, 7.9)	MLT	No
ADP versus VAL	-6.1	(-26.5, 14.3)	ADP	No
LT versus MLT	-2.7	(-25.7, 20.3)	LT	No
LT versus VAL	-9.7	(-39.6, 20.2)	LT	No
MLT versus VAL	-7.0	(-28.2, 14.2)	MLT	No

Abbreviations: ADP = antidepressants; BNZ = benzodiazepines; LT = L-tryptophan; min. = minutes; MLT = melatonin; NBNZ = non-benzodiazepines; SOL = sleep onset latency; VAL = valerian

Efficacy. Table 19 shows the results of the pair-wise indirect comparisons of sleep onset latency for each of the four pharmacological treatment categories: benzodiazepines, non-benzodiazepines, antidepressants, and complementary and alternative care, the latter divided into L-tryptophan, melatonin, and valerian. Both benzodiazepines and non-benzodiazepines proved significantly more efficacious than antidepressants and melatonin. None of the other comparisons showed significant differences. Comparing the two non-pharmacological treatment categories (relaxation therapy and cognitive/behavioral therapy) also showed no significant difference (-10 min.; 95% CI: -25.7, 5.7).

Table 20

Adverse events: indirect comparisons of main pharmacological treatment (more...)

Table 20

Adverse events: indirect comparisons of main pharmacological treatment categories

Comparison	Difference in risk difference	95% Confidence Interval	Difference Favors:	Significant Difference (Yes or No)
BNZ versus NBNZ	0.10	(0.04, 0.16)	NBNZ	Yes
BNZ versus ADP	0.06	(-0.04, 0.16)	ADP	No
BNZ versus MLT	0.06	(-0.15, 0.27)	MLT	No
BNZ versus VAL	0.21	(-0.20, 0.62)	VAL	No
NBNZ versus ADP	-0.04	(-0.14, 0.06)	NBNZ	No
NBNZ versus MLT	-0.04	(-0.24, 0.16)	NBNZ	No
NBNZ versus VAL	0.11	(-0.30, 0.52)	VAL	No
ADP versus MLT	0.00	(-0.22, 0.22)	neither	No
ADP versus VAL	0.15	(-0.27, 0.57)	VAL	No
MLT versus VAL	0.15	(-0.31, 0.61)	VAL	No

Abbreviations: ADP = antidepressants; BNZ = benzodiazepines; MLT = melatonin; NBNZ = non-benzodiazepines; VAL = valerian

Safety. Table 20 shows the results of indirect comparisons of adverse events for the four main pharmacological treatment categories that provided relevant data: benzodiazepines, non-benzodiazepines, antidepressants and complementary and alternative care, the latter divided into melatonin and valerian (there was no safety data for L-tryptophan). The only significant comparison is that of benzodiazepines and non-benzodiazepines, where the latter treatment category was found to be significantly safer than the former in terms of number of adverse events. Note that despite the fact that valerian had the lowest point estimate, the larger confidence interval prevented a meaningful comparison of its safety relative to the other treatment categories.