Damien Léger, Markku Partinen, Max Hirshkowitz, Sudhansu Chokroverty, Jan Hedner, EQUINOX (Evaluation of daytime QUality Impairment by Nocturnal awakenings in Outpatient's eXperience) Survey Investigators
Characteristics of insomnia in a primary care setting: EQUINOX survey of 5293 insomniacs from 10 countries.
Sleep Med. 2010 Dec;11(10):987-98. doi: 10.1016/j.sleep.2010.04.019. Epub 2010 Nov 18.
Abstract/Text
OBJECTIVE: To describe the characteristics of insomnia in primary care physicians' (PCPs') practices in 10 countries and to understand how the difficulty of maintaining sleep (DMS) was or was not associated with other insomnia symptoms such as difficulty initiating sleep (DIS), early morning awakenings (EMA) or nonrestorative sleep (NRS) in PCPs patients with insomnia.
METHODS: International, noninterventional, cross-sectional, observational survey conducted in a primary care setting in subjects complaining of sleep disturbances in 10 countries. A questionnaire based on DSM-IV and ICSD criteria was administered.
RESULTS: Thirteen thousand one hundred twenty-four subjects were enrolled by 647 physicians; 5293 of them (32.6%) had insomnia and were surveyed. The population was predominantly female (63.9%) with a mean age of 47.8±15.3 years; 39.9% of these patients have already been treated for sleep difficulties. Combination of all types of insomnia symptoms (DIS+DMS+EMA+NRS) was the most frequently reported combination (38.6% of the subjects), while the percentage of subjects presenting with only one type of insomnia symptom (DIS, DMS, EMA or NRS) was very low: 3%, 1.8%, 0.9% and 1.4% respectively. DMS was on average the most commonly reported insomnia symptom (80.2%). Multiple logistic regression showed that DMS, EMA and NRS symptoms were significantly linked with each other and also to other insomnia criteria (sleep satisfaction, sleep quality, sleep duration, number of hours of sleep, frequency of insomnia symptoms, wake up rested / unrested and non restorative sleep).
CONCLUSIONS: Patients visiting PCPs with insomnia are likely to present with severe and poly-symptomatic insomnia.
Copyright © 2010 Elsevier B.V. All rights reserved.
Michael J Sateia, Peter D Nowell
Insomnia.
Lancet. 2004 Nov 27-Dec 3;364(9449):1959-73. doi: 10.1016/S0140-6736(04)17480-1.
Abstract/Text
Effective management of insomnia begins with recognition and adequate assessment. Family doctors and other health care providers such as practice nurses and psychologists should routinely enquire about sleep habits as a component of overall health assessment. Identification and treatment of primary psychiatric disorders, medical conditions, circadian disorders, or specific physiological sleep disorders--eg, sleep apnoea and periodic limb movement disorder--are essential steps in management of insomnia. Conditioned aspects of insomnia can be primary (psychophysiological insomnia) or may complicate sleep disturbance owing to other causes. Approved hypnotic drugs have clearly been shown to improve subjective and objective sleep measures in various short-term situations. Despite widespread use of standard hypnotics and sedating antidepressants for chronic insomnia, their role for this indication still remains to be further defined by research evidence. Non-pharmacological treatments, particularly stimulus control and sleep restriction, are effective for conditioned aspects of insomnia and are associated with durable long-term improvement in sleep.
Jeanne M Geiger-Brown, Valerie E Rogers, Wen Liu, Emilie M Ludeman, Katherine D Downton, Montserrat Diaz-Abad
Cognitive behavioral therapy in persons with comorbid insomnia: A meta-analysis.
Sleep Med Rev. 2015 Oct;23:54-67. doi: 10.1016/j.smrv.2014.11.007. Epub 2014 Nov 29.
Abstract/Text
Cognitive behavioral therapy for insomnia (CBT-I) is effective for treatment of primary insomnia. There has been no synthesis of studies quantifying this effect on insomnia comorbid with medical and psychiatric disorders using rigorous selection criteria. The objective of this study was to quantify the effect of CBT-I in studies including patients with medical or psychiatric disorders. Studies were identified from 1985 through February 2014 using multiple databases and bibliography searches. Inclusion was limited to randomized controlled trials of CBT-I in adult patients with insomnia diagnosed using standardized criteria, who additionally had a comorbid medical or psychiatric condition. Twenty-three studies including 1379 patients met inclusion criteria. Based on weighted mean differences, CBT-I improved subjective sleep quality post-treatment, with large treatment effects for the insomnia severity index and Pittsburgh sleep quality index. Sleep diaries showed a 20 min reduction in sleep onset latency and wake after sleep onset, 17 min improvement in total sleep time, and 9% improvement in sleep efficiency post-treatment, similar to findings of meta-analyses of CBT-I in older adults. Treatment effects were durable up to 18 mo. Results of actigraphy were similar to but of smaller magnitude than subjective measures. CBT-I is an effective, durable treatment for comorbid insomnia.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Comorbid Insomnia: Reciprocal Relationships and Medication Managementdoi:10.1016/j.jsmc.2010.08.012.
Tracy L Skaer, David A Sclar
Economic implications of sleep disorders.
Pharmacoeconomics. 2010;28(11):1015-23. doi: 10.2165/11537390-000000000-00000.
Abstract/Text
Sleep disorders such as insomnia, obstructive sleep apnoea (OSA), excessive daytime sleepiness (EDS) and fatigue, sleep deprivation and restless legs syndrome (RLS) are increasingly seen in clinical practice. Sleep is considered vital for preserving daytime cognitive function and physiological well-being. Sleep insufficiency may have deleterious effects on work-life balance, overall health and safety. The consequential economic burden at both the individual and societal levels is significant. Moreover, sleep disorders are commonly associated with other major medical problems such as chronic pain, cardiovascular disease, mental illness, dementias, gastrointestinal disorders and diabetes mellitus. Thus, in order to properly care for patients presenting with sleep-related morbidity, and to reduce the consequential economic burden, accurate screening efforts and efficacious/cost-effective treatments need to be developed and employed.
Sharon Schutte-Rodin, Lauren Broch, Daniel Buysse, Cynthia Dorsey, Michael Sateia
Clinical guideline for the evaluation and management of chronic insomnia in adults.
J Clin Sleep Med. 2008 Oct 15;4(5):487-504.
Abstract/Text
Insomnia is the most prevalent sleep disorder in the general population, and is commonly encountered in medical practices. Insomnia is defined as the subjective perception of difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate opportunity for sleep, and that results in some form of daytime impairment.1 Insomnia may present with a variety of specific complaints and etiologies, making the evaluation and management of chronic insomnia demanding on a clinician's time. The purpose of this clinical guideline is to provide clinicians with a practical framework for the assessment and disease management of chronic adult insomnia, using existing evidence-based insomnia practice parameters where available, and consensus-based recommendations to bridge areas where such parameters do not exist. Unless otherwise stated, "insomnia" refers to chronic insomnia, which is present for at least a month, as opposed to acute or transient insomnia, which may last days to weeks.
American Academy of Sleep Medicine:The international classification of sleep disorders, 2nd ed. 2005.
日本プライマリ・ケア連合学会理事長 前沢 政次、日本プライマリ・ケア連合学会広報委員長 板東 浩 編：診療ガイドダイジェスト2011 治療 2011年5月臨時増刊号.
A Chesson, K Hartse, W M Anderson, D Davila, S Johnson, M Littner, M Wise, J Rafecas
Practice parameters for the evaluation of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine.
Sleep. 2000 Mar 15;23(2):237-41.
Abstract/Text
Chronic insomnia is the most common sleep complaint which health care practitioners must confront. Most insomnia patients are not, however, seen by sleep physicians but rather by a variety of primary care physicians. There is little agreement concerning methods for effective assessment and subsequent differential diagnosis of this pervasive problem. The most common basis for diagnosis and subsequent treatment has been the practitioner's clinical impression from an unstructured interview. No systematic, evidence-based guidelines for diagnosis exist for chronic insomnia. This practice parameter paper presents recommendations for the evaluation of chronic insomnia based on the evidence in the accompanying review paper. We recommend use of these parameters by the sleep community, but even more importantly, hope the large number of primary care physicians providing this care can benefit from their use. Conclusions reached in these practice parameters include the following recommendations for the evaluation of chronic insomnia. Since the complaint of insomnia is so widespread and since patients may overlook the impact of poor sleep quality on daily functioning, the health care practitioner should screen for a history of sleep difficulty. This evaluation should include a sleep history focused on common sleep disorders to identify primary and secondary insomnias. Polysomnography, and the Multiple Sleep Latency Test (MSLT) should not be routinely used to screen or diagnose patients with insomnia complaints. However, the complaint of insomnia does not preclude the appropriate use of these tests for diagnosis of specific sleep disorders such as obstructive sleep apnea, periodic limb movement disorder, and narcolepsy that may be present in patients with insomnia. There is insufficient evidence to suggest whether portable sleep studies, actigraphy, or other alternative assessment measures including static charge beds are effective in the evaluation of insomnia complaints. Instruments such as sleep logs, self-administered questionnaires, symptom checklist, or psychological screening tests may be of benefit to discriminate insomnia patients from normals, but these instruments have not been shown to differentiate subtypes of insomnia complaints.
D E Ford, D B Kamerow
Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention?
JAMA. 1989 Sep 15;262(11):1479-84.
Abstract/Text
As part of the National Institute of Mental Health Epidemiologic Catchment Area study, 7954 respondents were questioned at baseline and 1 year later about sleep complaints and psychiatric symptoms using the Diagnostic Interview Schedule. Of this community sample, 10.2% and 3.2% noted insomnia and hypersomnia, respectively, at the first interview. Forty percent of those with insomnia and 46.5% of those with hypersomnia had a psychiatric disorder compared with 16.4% of those with no sleep complaints. The risk of developing new major depression was much higher in those who had insomnia at both interviews compared with those without insomnia (odds ratio, 39.8; 95% confidence interval, 19.8 to 80.0). The risk of developing new major depression was much less for those who had insomnia that had resolved by the second visit (odds ratio, 1.6; 95% confidence interval, 0.5 to 5.3). Further research is needed to determine if early recognition and treatment of sleep disturbances can prevent future psychiatric disorders.
Maurice M Ohayon, Thomas Roth
Place of chronic insomnia in the course of depressive and anxiety disorders.
J Psychiatr Res. 2003 Jan-Feb;37(1):9-15.
Abstract/Text
BACKGROUND: Insomnia is frequent in the general population and is often related to a psychiatric illness. However, little is known about how the chronicity of insomnia affects this relation and how often subjects with chronic insomnia have antecedents of psychiatric disorders.
METHODS: A total of 14,915 subjects aged from 15 to 100 years representative of the general population of the United Kingdom, Germany, Italy, and Portugal were interviewed by telephone using the Sleep-EVAL system. The questionnaire assessed current psychiatric disorders according to the DSM-IV classification and a series of questions assessed the psychiatric history. Insomnia was considered as chronic when it lasted for 6 months or more.
RESULTS: The prevalence for insomnia accompanied with impaired daytime functioning was 19.1% and significantly increased with age. More than 90% of these subjects had a chronic insomnia. About 28% of subjects with insomnia had a current diagnosis of mental disorders and 25.6% had a psychiatric history. A DSM-IV insomnia disorder was found in 6.6% of the sample. Presence of severe insomnia, diagnosis of primary insomnia or insomnia related to a medical condition, and insomnia that lasted more than one year were predictors of a psychiatric history. In most cases of mood disorders, insomnia appeared before (> 40%) or in the same time (> 22%) than mood disorder symptoms. When anxiety disorders were involved, insomnia appeared mostly in the same time (>38%) or after (> 34%) the anxiety disorder.
CONCLUSIONS: The study shows that psychiatric history is closely related to the severity and chronicity of current insomnia. Moreover, chronic insomnia can be a residual symptom of a previous mental disorder and put these subjects to a higher risk of relapse.
Bruce Arroll, Natalie Khin, Ngaire Kerse
Screening for depression in primary care with two verbally asked questions: cross sectional study.
BMJ. 2003 Nov 15;327(7424):1144-6. doi: 10.1136/bmj.327.7424.1144.
Abstract/Text
OBJECTIVE: To determine the diagnostic accuracy of two verbally asked questions for screening for depression.
DESIGN: Cross sectional criterion standard validation study.
SETTING: 15 general practices in New Zealand.
PARTICIPANTS: 421 consecutive patients not taking psychotropic drugs.
MAIN OUTCOME MEASURES: Sensitivity, specificity, and likelihood ratios of the two questions compared with the computerised composite international diagnostic interview.
RESULTS: The two screening questions showed a sensitivity and specificity of 97% (95% confidence interval, 83% to 99%) and 67% (62% to 72%), respectively. The likelihood ratio for a positive test was 2.9 (2.5 to 3.4) and the likelihood ratio for a negative test was 0.05 (0.01 to 0.35). Overall, 37% (157/421) of the patients screened positive for depression.
CONCLUSION: Two verbally asked questions for screening for depression would detect most cases of depression in general practice. The questions have the advantage of brevity. As treatment is more likely when doctors make the diagnosis, these questions may have even greater utility.
Kumar Budur, Carlos Rodriguez, Nancy Foldvary-Schaefer
Advances in treating insomnia.
Cleve Clin J Med. 2007 Apr;74(4):251-2, 255-8, 261-2 passim.
Abstract/Text
Too often, insomnia is treated as a symptom without investigation of the cause. Insomnia may be a condition unto itself (primary insomnia), or it may be associated with a medical or psychiatric condition (comorbid insomnia), and it may be acute or chronic. Inadequate treatment often leads to significant frustration and lost productivity. We review the classification, pathophysiology, and treatment of insomnia and discuss how we can minimize its adverse consequences.
Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians.
Ann Intern Med. 2016 Jul 19;165(2). doi: 10.7326/P16-9016. Epub 2016 May 3.
Abstract/Text
三島和夫：睡眠薬の適正使用・休薬ガイドライン．じほう，東京，2014: 表4.
P Montgomery, J Dennis
Physical exercise for sleep problems in adults aged 60+.
Cochrane Database Syst Rev. 2002;(4):CD003404. doi: 10.1002/14651858.CD003404.
Abstract/Text
BACKGROUND: The prevalence of sleep problems in adulthood increases with age. While not all sleep changes are pathological in later life, severe disturbances may lead to depression, cognitive impairments, deterioration of quality of life, significant stresses for carers and increased healthcare costs. The most common treatment for sleep disorders (particularly insomnia) is pharmacological. The efficacy of non-drug interventions has been suggested to be slower than pharmacological methods, but with no risk of drug-related tolerance or dependency. Physical exercise, taken regularly, may promote relaxation and raise core body temperature in ways that are beneficial to initiating and maintaining sleep.
OBJECTIVES: To assess the efficacy of physical exercise amongst older adults (aged 60 and above).
SEARCH STRATEGY: We searched: MEDLINE (1966 - October 2001); EMBASE (1980 - January 2002), CINAHL ( 1982 - January 2002; PsychINFO 1887 to 2002; The Cochrane Library (Issue 1, 2002); National Research Register (NRR [2002]). Bibliographies of existing reviews in the area, as well as of all trial reports obtained, were searched. Experts in the field were consulted.
SELECTION CRITERIA: Randomised controlled trials of physical exercise for primary insomnia where 80% or more of participants were over the age of 60. Participants must have been screened to exclude those with dementia and/or depression.
DATA COLLECTION AND ANALYSIS: Abstracts of studies identified in searches of electronic databases were read and assessed to determine whether they might meet the inclusion criteria. Data were analysed separately depending on whether results had been obtained subjectively or objectively.
MAIN RESULTS: One trial, including 43 participants with insomnia, examined the effectiveness of exercise in a population within an elderly population. At post-treatment, sleep onset latency improved slightly for both men and women. Total sleep duration, sleep onset latency and scores on a scale of global sleep quality showed significant improvement. Improvements in sleep efficiency were not significant. In some cases improvements indicated falls to below what are usually considered pathological levels but the wide confidence intervals and small sample size indicate that these findings must be interpreted with caution.
REVIEWER'S CONCLUSIONS: When the possible side-effects of standard treatment (hypnotics) are considered, there is an argument to be made for clinical use of alternative treatments in the elderly. Exercise, though not appropriate for all in this population, may enhance sleep and contribute to an increased quality of life. Research involving exercise programmes designed with the elderly in mind is needed.
A C King, R F Oman, G S Brassington, D L Bliwise, W L Haskell
Moderate-intensity exercise and self-rated quality of sleep in older adults. A randomized controlled trial.
JAMA. 1997 Jan 1;277(1):32-7.
Abstract/Text
OBJECTIVE: To determine the effects of moderate-intensity exercise training on self-rated (subjective) sleep quality among healthy, sedentary older adults reporting moderate sleep complaints.
DESIGN: Randomized controlled trial of 16 weeks' duration.
SETTING: General community.
PARTICIPANTS: Volunteer sample of 29 women and 14 men (of 67 eligible subjects) aged 50 to 76 years who were sedentary, free of cardiovascular disease, and reported moderate sleep complaints. No participant was withdrawn for adverse effects.
INTERVENTION: Randomized to 16 weeks of community-based, moderate-intensity exercise training or to a wait-listed control condition. Exercise consisted primarily of four 30- to 40-minute endurance training sessions (low-impact aerobics; brisk walking) prescribed per week at 60% to 75% of heart rate reserve based on peak treadmill exercise heart rate.
MAIN OUTCOME MEASURE: Pittsburgh Sleep Quality Index (PSQI).
RESULTS: Compared with controls (C), subjects in the exercise training condition (E) showed significant improvement in the PSQI global sleep score at 16 weeks (baseline and posttest values in mean [SD] for C=8.93 [3.1] and 8.8 [2.6]; baseline and posttest values for E=8.7 [3.0] and 5.4 [2.8]; mean posttest difference between conditions=3.4; P<.001; 95% confidence interval, 1.9-5.4), as well as in the sleep parameters of rated sleep quality, sleep-onset latency (baseline and posttest values for C=26.1 [20.0] and 23.8 [15.3]; for E=28.4 [20.2] and 14.6 [13.0]; net improvement=11.5 minutes), and sleep duration baseline and posttest scores for C=5.8 [1.1] and 6.0 [1.0]; for E=6.0 [1.1] and 6.8 [1.2]; net improvement=42 minutes) assessed via PSQI and sleep diaries (P=.05).
CONCLUSIONS: Older adults with moderate sleep complaints can improve self-rated sleep quality by initiating a regular moderate-intensity exercise program.
P Montgomery, J Dennis
Cognitive behavioural interventions for sleep problems in adults aged 60+.
Cochrane Database Syst Rev. 2002;(2):CD003161. doi: 10.1002/14651858.CD003161.
Abstract/Text
BACKGROUND: The prevalence of sleep problems in adulthood increases with age. While not all sleep changes are pathological in later life, severe disturbances may lead to depression, cognitive impairments, deterioration of quality of life, significant stresses for carers and increased healthcare costs. The most common treatment for sleep disorders (particularly insomnia) is pharmacological. The efficacy of non-drug interventions has been suggested to be slower than pharmacological methods, but with no risk of drug-related tolerance or dependency. Cognitive and behavioural treatments for sleep problems aim to improve sleep by changing poor sleep habits, promoting better sleep hygiene practices and by challenging negative thoughts, attitudes and beliefs about sleep.
OBJECTIVES: To assess the efficacy of cognitive-behavioural interventions in improving sleep quality, duration and efficiency amongst older adults (aged 60 and above).
SEARCH STRATEGY: The following databases were searched: MEDLINE (1966 - October 2001); EMBASE (1980 - January 2002), CINAHL ( 1982 - January 2002; PsychINFO 1887 to 2002; The Cochrane Library (Issue 1, 2002); National Research Register (NRR [2002]). Bibliographies of existing reviews in the area, as well as of all trial reports obtained, were searched. Experts in the field were consulted.
SELECTION CRITERIA: Randomised controlled trials of cognitive behavioural treatments for primary insomnia where 80% or more of participants were over 60. Participants must have been screened to exclude those with dementia and/or depression.
DATA COLLECTION AND ANALYSIS: Abstracts of studies identified in searches of electronic databases were read and assessed to determine whether they might meet the inclusion criteria. Data were analysed separately depending on whether results had been obtained subjectively or objectively.
MAIN RESULTS: Six trials, including 282 participants with insomnia, examined the effectiveness of cognitive-behavioural treatments (CBT) for sleep problems in this population. The final total of participants included in the meta-analysis was 224. The data suggest a mild effect of CBT for sleep problems in older adults, best demonstrated for sleep maintenance insomnia.
REVIEWER'S CONCLUSIONS: When the possible side-effects of standard treatment (hypnotics) are considered, there is an argument to be made for clinical use of cognitive-behavioural treatments. Research is needed to establish the likely predictors of success with such treatments. As it may well be the case that the treatment efficacy of cognitive-behavioural therapy itself is not durable, the provision of "top-up" sessions of CBT training to improve durability of effect are worthy of investigation.
Bootzin RR: Stimulus control treatment for insomnia. Proceedings, 80th Annual Convention American Psychological Association, 395-396, 1972.
Jacobson E. Progressive Relaxation. Chicago: University of ChicagoPress, 1974.
A J Spielman, P Saskin, M J Thorpy
Treatment of chronic insomnia by restriction of time in bed.
Sleep. 1987 Feb;10(1):45-56.
Abstract/Text
A treatment of chronic insomnia is described that is based on the recognition that excessive time spent in bed is one of the important factors that perpetuates insomnia. Thirty-five patients, with a mean age of 46 years and a mean history of insomnia of 15.4 years, were treated initially by marked restriction of time available for sleep, followed by an extension of time in bed contingent upon improved sleep efficiency. At the end of the 8-week treatment program, patients reported an increase in total sleep time (p less than 0.05) as well as improvement in sleep latency, total wake time, sleep efficiency, and subjective assessment of their insomnia (all p less than 0.0001). Improvement remained significant for all sleep parameters at a mean of 36 weeks after treatment in 23 subjects participating in a follow-up assessment. Although compliance with the restricted schedule is difficult for some patients, sleep restriction therapy is an effective treatment for common forms of chronic insomnia.
C Guilleminault, A Clerk, J Black, M Labanowski, R Pelayo, D Claman
Nondrug treatment trials in psychophysiologic insomnia.
Arch Intern Med. 1995 Apr 24;155(8):838-44.
Abstract/Text
BACKGROUND: Due to a variety of potential problems with long-term hypnotic use, patients and treating physicians often try to avoid drugs in the treatment of psychophysiologic insomnia and to use nondrug treatment strategies, but these treatments must bring relief within a limited amount of time to be acceptable to patients.
METHOD: Thirty patients participated in the study. All had, for a minimum of 6 months, the complaint of less than 6 hours total sleep time per night in conjunction with either: (1) spending more than 30 minutes in bed before falling asleep, or (2) awakening during the night within 2 hours of sleep onset with difficulty returning to sleep. All subjects had the associated complaint of daytime impairment and none had used hypnotics for at least 3 months. Patients were randomly assigned to three parallel treatment groups: structured sleep hygiene, structured sleep hygiene with late afternoon moderate exercise, and structured sleep hygiene with early morning light therapy. Patients responded to questionnaires and filled out sleep logs. In addition, they underwent clinical evaluation, structured interviews, nocturnal monitoring, and actigraphy. The analyzed variables before and at the end of treatment were those derived from sleep logs and actigraphy.
RESULTS: All subjects showed a trend toward improvement, independent of the treatment received, but only the "structured sleep hygiene with light treatment" showed statistically significant improvement at the end of the trial.
CONCLUSIONS: Patients with chronic psychophysiologic insomnia may benefit from a nondrug treatment approach. Light therapy appears particularly promising.
Nina Buscemi, Ben Vandermeer, Carol Friesen, Liza Bialy, Michelle Tubman, Maria Ospina, Terry P Klassen, Manisha Witmans
The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-analysis of RCTs.
J Gen Intern Med. 2007 Sep;22(9):1335-50. doi: 10.1007/s11606-007-0251-z. Epub 2007 Jul 10.
Abstract/Text
BACKGROUND: Hypnotics have a role in the management of acute insomnia; however, the efficacy and safety of pharmacological interventions in the management of chronic insomnia is unclear.
OBJECTIVE: The objective of this paper is to conduct a systematic review of the efficacy and safety of drug treatments for chronic insomnia in adults.
DATA SOURCES: Twenty-one electronic databases were searched, up to July 2006.
STUDY SELECTION: Randomized double-blind, placebo-controlled trials were eligible. Quality was assessed using the Jadad scale. Data were pooled using the random effects model.
DATA SYNTHESIS: One hundred and five studies were included in the review. Sleep onset latency, as measured by polysomnography, was significantly decreased for benzodiazepines (BDZ), (weighted mean difference: -10.0 minutes; 95% CI: -16.6, -3.4), non-benzodiazepines (non-BDZ) (-12.8 minutes; 95% CI: -16.9, -8.8) and antidepressants (ADP) (-7.0 minutes; 95% CI: -10.7, -3.3). Sleep onset latency assessed by sleep diaries was also improved (BDZ: -19.6 minutes; 95% CI: -23.9, -15.3; non-BDZ: -17.0 minutes; 95% CI: -20.0, -14.0; ADP: -12.2 minutes; 95% CI: -22.3, -2.2). Indirect comparisons between drug categories suggest BDZ and non-BDZ have a similar effect. All drug groups had a statistically significant higher risk of harm compared to placebo (BDZ: risk difference [RD]: 0.15; non-BDZ RD: 0.07; and ADP RD: 0.09), although the most commonly reported adverse events were minor. Indirect comparisons suggest that non-BDZ are safer than BDZ.
CONCLUSIONS: Benzodiazepines and non-benzodiazepines are effective treatments in the management of chronic insomnia, although they pose a risk of harm. There is also some evidence that antidepressants are effective and that they pose a risk of harm.
Susanne Rösner, Christian Englbrecht, Renate Wehrle, Göran Hajak, Michael Soyka
Eszopiclone for insomnia.
Cochrane Database Syst Rev. 2018 Oct 10;10:CD010703. doi: 10.1002/14651858.CD010703.pub2. Epub 2018 Oct 10.
Abstract/Text
BACKGROUND: Insomnia is a major public health issue affecting between 6% to 10% of the adult population in Western countries. Eszopiclone is a hypnotic drug belonging to a newer group of hypnotic agents, known as new generation hypnotics, which was marketed as being just as effective as benzodiazepines for this condition, while being safer and having a lower risk for abuse and dependence. It is the aim of the review to integrate evidence from randomised controlled trials and to draw conclusions on eszopiclone's efficacy and safety profile, while taking methodological features and bias risks into consideration.
OBJECTIVES: To assess the efficacy and safety of eszopiclone for the treatment of insomnia compared to placebo or active control.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled trials (CENTRAL), MEDLINE, Embase, PsycINFO, PSYNDEX and registry databases (WHO trials portal, ClinicalTrials.gov) with results incorporated from searches to 10 February 2016. To identify trials not registered in electronic databases, we contacted key informants and searched reference lists of identified studies. We ran an update search (21 February 2018) and have placed studies of interest in awaiting classification/ongoing studies. These will be incorporated into the next version of the review, as appropriate.
SELECTION CRITERIA: Parallel group randomised controlled trials (RCTs) comparing eszopiclone with either placebo or active control were included in the review. Participants were adults with insomnia, as diagnosed with a standardised diagnostic system, including primary insomnia and comorbid insomnia.
DATA COLLECTION AND ANALYSIS: Two authors independently extracted outcome data; one reviewer assessed trial quality and the second author cross-checked it.
MAIN RESULTS: A total of 14 RCTs, with 4732 participants, were included in this review covering short-term (≤ 4 weeks; 6 studies), medium-term (> 4 weeks ≤ 6 months; 6 studies) and long-term treatment (> 6 months; 2 studies) with eszopiclone. Most RCTs included in the review included participants aged between 18 and 64 years, three RCTs only included elderly participants (64 to 85 years) and one RCT included participants with a broader age range (35 to 85 years). Seven studies considered primary insomnia; the remaining studies considered secondary insomnia comorbid with depression (2), generalised anxiety (1), back pain (1), Parkinson's disease (1), rheumatoid arthritis (1) and menopausal transition (1).Meta-analytic integrations of participant-reported data on sleep efficacy outcomes demonstrated better results for eszopiclone compared to placebo: a 12-minute decrease of sleep onset latency (mean difference (MD) -11.94 min, 95% confidence interval (CI) -16.03 to -7.86; 9 studies, 2890 participants, moderate quality evidence), a 17-minute decrease of wake time after sleep onset (MD -17.02 min, 95% CI -24.89 to -9.15; 8 studies, 2295 participants, moderate quality evidence) and a 28-minute increase of total sleep time (MD 27.70 min, 95% CI 20.30 to 35.09; 10 studies, 2965 participants, moderate quality evidence). There were no significant changes from baseline to the first three nights after drug discontinuation for sleep onset latency (MD 17.00 min, 95% CI -4.29 to 38.29; 1 study, 291 participants, low quality evidence) and wake time after sleep onset (MD -6.71 min, 95% CI -21.25 to 7.83; 1 study, 291 participants, low quality evidence). Adverse events during treatment that were documented more frequently under eszopiclone compared to placebo included unpleasant taste (risk difference (RD) 0.18, 95% CI 0.14 to 0.21; 9 studies, 3787 participants), dry mouth (RD 0.04, 95% CI 0.02 to 0.06; 6 studies, 2802 participants), somnolence (RD 0.04, 95% CI 0.02 to 0.06; 8 studies, 3532 participants) and dizziness (RD 0.03, 95% CI 0.01 to 0.05; 7 studies, 2933 participants). According to the GRADE criteria, evidence was rated as being of moderate quality for sleep efficacy outcomes and adverse events and of low quality for rebound effects and next-day functioning.
AUTHORS' CONCLUSIONS: Eszopiclone appears to be an efficient drug with moderate effects on sleep onset and maintenance. There was no or little evidence of harm if taken as recommended. However, as certain patient subgroups were underrepresented in RCTs included in the review, findings might not have displayed the entire spectrum of possible adverse events. Further, increased caution is required in elderly individuals with cognitive and motor impairments and individuals who are at increased risk of using eszopiclone in a non-recommended way.
Gary Zammit, Sherry Wang-Weigand, Murray Rosenthal, Xuejun Peng
Effect of ramelteon on middle-of-the-night balance in older adults with chronic insomnia.
J Clin Sleep Med. 2009 Feb 15;5(1):34-40.
Abstract/Text
STUDY OBJECTIVES: To evaluate the effect of ramelteon on middle-of-the-night balance, mobility, and memory in older insomniacs.
METHODS: Thirty-three older adults (age > or = 65 years) with insomnia were enrolled in a single-dose, 3-way crossover study of balance after bedtime administration of ramelteon, 8 mg; zolpidem, 10 mg (positive control); or placebo. Subjects were administered study medication 30 minutes before bedtime and were awakened 2 hours after dosing to evaluate balance (Sensory Organization Test), turning speed and stability, memory (immediate and delayed word recall), and adverse events. There was a 4- to 10-day washout between treatments.
RESULTS: Ramelteon or zolpidem (positive control) was compared with placebo. There were no differences between placebo and ramelteon on the Sensory Organization Test (p = 0.837), turn time (p = 0.776), or turn sway (p = 0.982). The positive control (zolpidem) did reveal significant impairments on the Sensory Organization Test, turn time, and turn sway (p < 0.001, all). Immediate and delayed memory recall were not significantly different with ramelteon (p = 0.683 and p = 0.650, respectively). Immediate recall declined significantly with zolpidem (p = 0.002). Adverse events were infrequent (ramelteon, n = 7; placebo, n = 7; zolpidem, n = 13); none were serious.
CONCLUSION: In older adults, ramelteon did not impair middle-of-the night balance, mobility, or memory relative to placebo.
Akira Kuriyama, Michitaka Honda, Yasuaki Hayashino
Ramelteon for the treatment of insomnia in adults: a systematic review and meta-analysis.
Sleep Med. 2014 Apr;15(4):385-92. doi: 10.1016/j.sleep.2013.11.788. Epub 2014 Feb 8.
Abstract/Text
Ramelteon is the first selective melatonin receptor agonist and currently is approved in the United States and Japan for the treatment of insomnia. Our meta-analysis assessed the efficacy and safety of ramelteon for the treatment of insomnia in adults. We included both published and unpublished data from randomized placebo-controlled trials evaluating the efficacy of ramelteon in adults with insomnia in the analysis. Our primary outcomes were sleep quality, subjective sleep latency (sSL), and subjective total sleep time (sTST). Secondary outcomes included latency to persistent sleep (LPS), total sleep time (TST), sleep efficiency (SE), proportion of rapid eye movement (REM) sleep, wakefulness after sleep onset (WASO), subjective WASO, number of nighttime awakenings (NAW), subjective NAW, and adverse events. Thirteen trials involving 5812 patients with insomnia or insomnia symptoms with a mean study duration of 38 days were pooled. Ramelteon was associated with reduced sSL (weighted mean difference [WMD], -4.30 min [95% confidence interval {CI}, -7.01 to -1.58]) and improved sleep quality (standardized mean differences, -0.074 [95% CI, -0.13 to -0.02]) but was not associated with increased sTST. Ramelteon also was associated with improvement in LPS, SE, and TST. The only significant adverse event was somnolence. Short-term use of ramelteon was associated with improvement in some sleep parameters in patients with insomnia, but its clinical impact is small. Long-term trials are needed before solid conclusions can be established.
Copyright © 2014 Elsevier B.V. All rights reserved.
David Michelson, Ellen Snyder, Erin Paradis, Mary Chengan-Liu, Duane B Snavely, Jill Hutzelmann, James K Walsh, Andrew D Krystal, Ruth M Benca, Martin Cohn, Christopher Lines, Thomas Roth, W Joseph Herring
Safety and efficacy of suvorexant during 1-year treatment of insomnia with subsequent abrupt treatment discontinuation: a phase 3 randomised, double-blind, placebo-controlled trial.
Lancet Neurol. 2014 May;13(5):461-71. doi: 10.1016/S1474-4422(14)70053-5. Epub 2014 Mar 27.
Abstract/Text
BACKGROUND: Suvorexant (MK-4305) is an orexin receptor antagonist shown to be efficacious for insomnia over 3 months. We aimed to assess its clinical profile during and after 1 year of treatment.
METHODS: We did a randomised, placebo-controlled, parallel-group trial at 106 investigational centres in the Americas, Australia, Europe, and South Africa from December, 2009, to August, 2011. Patients aged 18 years or older with primary insomnia by DSM-IV-TR criteria were assigned using a computer-generated randomised allocation schedule to receive nightly suvorexant (40 mg for patients younger than 65 years, 30 mg for patients aged 65 years or older) or placebo at a 2:1 ratio for 1 year with a subsequent 2-month randomised discontinuation phase in which patients on suvorexant either continued suvorexant or were abruptly switched to placebo while patients on placebo remained on placebo. Treatment assignment was masked from patients and investigators. The primary objective was to assess the safety and tolerability of suvorexant for up to 1 year. Secondary objectives were to assess the efficacy of suvorexant for improving patient-reported subjective total sleep time (sTST) and time to sleep onset (sTSO) over the first month of treatment. Efficacy endpoints over the first month were assessed with a mixed model with terms for baseline value of the response variable, age, sex, region, treatment, time, and treatment by time interaction. This trial is registered with ClinicalTrials.gov, number NCT01021813.
FINDINGS: 322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p<0·0001) and sTSO (-18·0 min vs -8·4 min, difference -9·5, -14·6 to -4·5; p=0·0002).
INTERPRETATION: Our findings show that suvorexant was generally safe and well tolerated over 1 year of nightly treatment in patients with insomnia, with efficacy noted for subjective measures of sleep onset and maintenance.
FUNDING: Merck & Co Inc.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Russell Rosenberg, Patricia Murphy, Gary Zammit, David Mayleben, Dinesh Kumar, Shobha Dhadda, Gleb Filippov, Antonia LoPresti, Margaret Moline
Comparison of Lemborexant With Placebo and Zolpidem Tartrate Extended Release for the Treatment of Older Adults With Insomnia Disorder: A Phase 3 Randomized Clinical Trial.
JAMA Netw Open. 2019 Dec 2;2(12):e1918254. doi: 10.1001/jamanetworkopen.2019.18254. Epub 2019 Dec 2.
Abstract/Text
Importance: Insomnia disorder is prevalent and associated with health risks in older adults; however, efficacy and safety issues with existing treatments create significant unmet needs in this patient population.
Objective: To compare treatment with the orexin receptor antagonist lemborexant with placebo and zolpidem tartrate extended release in participants with insomnia disorder.
Design, Setting, and Participants: The Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older With Insomnia Disorder (SUNRISE 1) clinical trial was a global randomized double-blind parallel-group placebo-controlled active-comparator phase 3 study conducted at 67 sites in North America and Europe from May 31, 2016, to January 30, 2018. Data analyses were conducted from January 31, 2018, to September 10, 2018. Participants were 55 years and older with insomnia disorder characterized by reported sleep maintenance difficulties and confirmed by sleep history, sleep diary, and polysomnography. Participants could have also had sleep onset difficulties.
Interventions: Participants received placebo, zolpidem tartrate extended release (6.25 mg), or lemborexant (5 mg or 10 mg) for 1 month at bedtime.
Main Outcomes and Measures: Paired polysomnograms were collected at baseline, the first 2 nights, and the last 2 nights of treatment. The primary end point was the change from baseline in latency to persistent sleep for lemborexant therapy vs placebo. Key secondary end points were changes from baseline in sleep efficiency and wake-after-sleep onset compared with placebo, and wake-after-sleep onset in the second half of the night compared with zolpidem therapy.
Results: Among 1006 participants randomized (placebo, n = 208; zolpidem, n = 263; lemborexant 5 mg, n = 266; and lemborexant 10 mg, n = 269), 869 (86.4%) were women and the median age was 63 years (range, 55-88 years). Both doses of lemborexant therapy demonstrated statistically significant greater changes from baseline on objective sleep onset as assessed by latency to persistent sleep (log transformed) that was measured using polysomnography at the end of 1 month of treatment (nights 29 and 30) compared with placebo (primary end point for least squares geometric means treatment ratio vs placebo: for lemborexant 5 mg, 0.77; 95% CI, 0.67-0.89; P < .001; for lemborexant 10 mg, 0.72; 95% CI, 0.63-0.83; P < .001). For nights 29 and 30, as measured using polysomnography, the mean change from baseline in sleep efficiency (LSM treatment difference vs placebo for lemborexant 5 mg, 7.1%; 95% CI, 5.6%-8.5%; P < .001 and for lemborexant 10 mg, 8.0%; 95% CI, 6.6%-9.5%; P < .001) and wake-after-sleep onset (least squares mean treatment ratio vs placebo for lemborexant 5 mg, -24.0 min; 95% CI, -30.0 to -18.0 min; P < .001 and for lemborexant 10 mg, -25.4 min; 95% CI, -31.4 to -19.3 min; P < .001) were significantly greater for both doses of lemborexant therapy compared with placebo. Also, for nights 29 and 30, wake-after-sleep onset in the second half of the night (least squares mean treatment difference vs zolpidem for lemborexant 5 mg, -6.7 min; 95% CI, -11.2 to -2.2 min; P = .004 and for lemborexant 10 mg, -8.0 min; 95% CI, -12.5 to -3.5 min; P < .001) was significantly greater for both doses of lemborexant therapy compared with zolpidem therapy measured using polysomnography. Six participants (4 in the zolpidem group and 2 in the lemborexant 5 mg group) reported serious adverse events; none were treatment-related. Other adverse events were mostly mild or moderate in severity.
Conclusions and Relevance: In this randomized clinical trial, lemborexant therapy significantly improved both sleep onset and sleep maintenance, including in the second half of the night, compared with both placebo and zolpidem measured objectively using polysomnography. Lemborexant therapy was well tolerated.
Trial Registrations: ClinicalTrials.gov identifier: NCT02783729; EudraCT identifier: 2015-001463-39.
Akira Kuriyama, Hiromitsu Tabata
Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis.
Sleep Med Rev. 2017 Oct;35:1-7. doi: 10.1016/j.smrv.2016.09.004. Epub 2016 Oct 28.
Abstract/Text
Suvorexant is a dual orexin receptor agonist and is currently approved for the treatment of insomnia in the United States and Japan. We conducted a systematic review and meta-analysis to assess the efficacy and safety of suvorexant for the treatment of primary insomnia. We searched PubMed, EMBASE, and the Cochrane central register of controlled trials, contacted a relevant pharmaceutical company, and accessed websites of the U.S. Food and Drug Administration (FDA) and Pharmaceuticals and Medical Devices Agency (PMDA) for published and unpublished data. A total of four randomized trials involving 3076 patients with primary insomnia were included in our analysis. Our analysis suggested that suvorexant was associated with significant improvements in subjective time to sleep onset, subjective total sleep time, and subjective quality of sleep at 1 mo and 3 mo. Somnolence, fatigue, and abnormal dreams were the most common adverse effects. We concluded that suvorexant was associated with improvement in some sleep parameters and some adverse effects. To determine the place of suvorexant in the treatment of insomnia, comparative effectiveness trials are needed.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Shelly L Gray, Andrea Z LaCroix, Joseph T Hanlon, Brenda W J H Penninx, David K Blough, Suzanne G Leveille, Margaret B Artz, Jack M Guralnik, Dave M Buchner
Benzodiazepine use and physical disability in community-dwelling older adults.
J Am Geriatr Soc. 2006 Feb;54(2):224-30. doi: 10.1111/j.1532-5415.2005.00571.x.
Abstract/Text
OBJECTIVES: To determine whether benzodiazepine use is associated with incident disability in mobility and activities of daily living (ADLs) in older individuals.
DESIGN: A prospective cohort study.
SETTING: Four sites of the Established Populations for Epidemiologic Studies of the Elderly.
PARTICIPANTS: This study included 9,093 subjects (aged > or =65) who were not disabled in mobility or ADLs at baseline.
MEASUREMENTS: Mobility disability was defined as inability to walk half a mile or climb one flight of stairs. ADL disability was defined as inability to perform one or more basic ADLs (bathing, eating, dressing, transferring from a bed to a chair, using the toilet, or walking across a small room). Trained interviewers assessed outcomes annually.
RESULTS: At baseline, 5.5% of subjects reported benzodiazepine use. In multivariable models, benzodiazepine users were 1.23 times as likely as nonusers (95% confidence interval (CI) = 1.09-1.39) to develop mobility disability and 1.28 times as likely (95% CI = 1.09-1.52) to develop ADL disability. Risk for incident mobility was increased with short- (hazard ratio (HR) = 1.27, 95% CI = 1.08-1.50) and long-acting benzodiazepines (HR = 1.20, 95% CI = 1.03-1.39) and no use. Risk for ADL disability was greater with short- (HR = 1.58, 95% CI = 1.25-2.01) but not long-acting (HR = 1.11, 95% CI = 0.89-1.39) agents than for no use.
CONCLUSION: Older adults taking benzodiazepines have a greater risk for incident mobility and ADL disability. Use of short-acting agents does not appear to confer any safety benefits over long-acting agents.
Jennifer Glass, Krista L Lanctôt, Nathan Herrmann, Beth A Sproule, Usoa E Busto
Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits.
BMJ. 2005 Nov 19;331(7526):1169. doi: 10.1136/bmj.38623.768588.47. Epub 2005 Nov 11.
Abstract/Text
OBJECTIVES: To quantify and compare potential benefits (subjective reports of sleep variables) and risks (adverse events and morning-after psychomotor impairment) of short term treatment with sedative hypnotics in older people with insomnia.
DATA SOURCES: Medline, Embase, the Cochrane clinical trials database, PubMed, and PsychLit, 1966 to 2003; bibliographies of published reviews and meta-analyses; manufacturers of newer sedative hypnotics (zaleplon, zolpidem, zopiclone) regarding unpublished studies.
SELECTION CRITERIA: Randomised controlled trials of any pharmacological treatment for insomnia for at least five consecutive nights in people aged 60 or over with insomnia and otherwise free of psychiatric or psychological disorders.
RESULTS: 24 studies (involving 2417 participants) with extractable data met inclusion and exclusion criteria. Sleep quality improved (effect size 0.14, P < 0.05), total sleep time increased (mean 25.2 minutes, P < 0.001), and the number of night time awakenings decreased (0.63, P < 0.001) with sedative use compared with placebo. Adverse events were more common with sedatives than with placebo: adverse cognitive events were 4.78 times more common (95% confidence interval 1.47 to 15.47, P < 0.01); adverse psychomotor events were 2.61 times more common (1.12 to 6.09, P > 0.05), and reports of daytime fatigue were 3.82 times more common (1.88 to 7.80, P < 0.001) in people using any sedative compared with placebo.
CONCLUSIONS: Improvements in sleep with sedative use are statistically significant, but the magnitude of effect is small. The increased risk of adverse events is statistically significant and potentially clinically relevant in older people at risk of falls and cognitive impairment. In people over 60, the benefits of these drugs may not justify the increased risk, particularly if the patient has additional risk factors for cognitive or psychomotor adverse events.
Anita K Wagner, Fang Zhang, Stephen B Soumerai, Alexander M Walker, Jerry H Gurwitz, Robert J Glynn, Dennis Ross-Degnan
Benzodiazepine use and hip fractures in the elderly: who is at greatest risk?
Arch Intern Med. 2004 Jul 26;164(14):1567-72. doi: 10.1001/archinte.164.14.1567.
Abstract/Text
BACKGROUND: It remains unclear whether benzodiazepine use increases hip fracture incidence. We studied this relationship in a large cohort, controlling for multiple potential confounders.
METHODS: We analyzed 42 months of New Jersey Medicaid health care claims data for all enrollees. Each eligible person-day was assigned to categories of benzodiazepine exposure and categories of other predictors, based on prior and current medication dispensing and diagnosis information. Hip fractures were identified based on hospital claims with primary discharge diagnosis International Classification of Diseases, Ninth Revision (ICD-9) codes 820.xx.
RESULTS: Cohort members (n = 125 203) contributed 194 071 person-years and had 2312 eligible hip fractures. After adjustment for age, sex, race, Medicaid nursing home residence, exposure to other psychoactive medications, including antiparkinsonian medications, diagnoses of epilepsy and dementia, and hospitalization in the previous 6 months, the incidence rate of hip fracture was significantly higher compared with no benzodiazepine use for exposure to any benzodiazepine (incidence rate ratio [IRR], 1.24; 95% confidence interval [CI], 1.06-1.44), to a short half-life, high-potency benzodiazepine (IRR, 1.27; 95% CI, 1.01-1.59), during the first 2 weeks after starting a benzodiazepine (IRR, 2.05; 95% CI, 1.28-3.28), during the second 2 weeks after starting a benzodiazepine (IRR, 1.88; 95% CI, 1.15-3.07), and for continued use (IRR, 1.18; 95% CI, 1.03-1.35).
CONCLUSIONS: The incidence of hip fracture appears to be associated with benzodiazepine use. Contrary to several previous studies, short half-life benzodiazepines are not safer than long half-life benzodiazepines. Hip fracture risk is highest during the first 2 weeks after starting a benzodiazepine and declines thereafter.
S R Cummings, M C Nevitt, W S Browner, K Stone, K M Fox, K E Ensrud, J Cauley, D Black, T M Vogt
Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.
N Engl J Med. 1995 Mar 23;332(12):767-73. doi: 10.1056/NEJM199503233321202.
Abstract/Text
BACKGROUND: Many risk factors for hip fractures have been suggested but have not been evaluated in a comprehensive prospective study.
METHODS: We assessed potential risk factors, including bone mass, in 9516 white women 65 years of age or older who had had no previous hip fracture. We then followed these women at 4-month intervals for an average of 4.1 years to determine the frequency of hip fracture. All reports of hip fractures were validated by review of x-ray films.
RESULTS: During the follow-up period, 192 women had first hip fractures not due to motor vehicle accidents. In multivariable age-adjusted analyses, a maternal history of hip fracture doubled the risk of hip fracture (relative risk, 2.0; 95 percent confidence interval, 1.4 to 2.9), and the increase in risk remained significant after adjustment for bone density. Women who had gained weight since the age of 25 had a lower risk. The risk was higher among women who had previous fractures of any type after the age of 50, were tall at the age of 25, rated their own health as fair or poor, had previous hyperthyroidism, had been treated with long-acting benzodiazepines or anticonvulsant drugs, ingested greater amounts of caffeine, or spent four hours a day or less on their feet. Examination findings associated with an increased risk included the inability to rise from a chair without using one's arms, poor depth perception, poor contrast sensitivity, and tachycardia at rest. Low calcaneal bone density was also an independent risk factor. The incidence of hip fracture ranged from 1.1 (95 percent confidence interval, 0.5 to 1.6) per 1,000 woman-years among women with no more than two risk factors and normal calcaneal bone density for their age to 27 (95 percent confidence interval, 20 to 34) per 1,000 woman-years among those with five or more risk factors and bone density in the lowest third for their age.
CONCLUSIONS: Women with multiple risk factors and low bone density have an especially high risk of hip fracture. Maintaining body weight, walking for exercise, avoiding long-acting benzodiazepines, minimizing caffeine intake, and treating impaired visual function are among the steps that may decrease the risk.
W A Ray, P B Thapa, P Gideon
Benzodiazepines and the risk of falls in nursing home residents.
J Am Geriatr Soc. 2000 Jun;48(6):682-5.
Abstract/Text
CONTEXT: For nursing home residents who require a benzodiazepine, short-acting agents are recommended, primarily to avoid increased risk of falls and other injuries associated with the long-acting agents. However, much of the data for the clinical outcomes of falls and injuries comes from community-dwelling older people.
OBJECTIVE: To quantify the rate of falls among nursing home residents taking benzodiazepines and how this varies with drug elimination half-life.
DESIGN: Historical cohort study.
POPULATION: A total of 2510 residents of 53 Tennessee nursing homes, classified according to benzodiazepine use on each day of follow-up.
OUTCOME MEASURES: Falls occurring during study follow-up.
RESULTS: After adjustment for differences in resident characteristics, benzodiazepine users had a 44% increased rate of falls (adjusted rate ratio 1.44 [95% confidence interval, 1.33-1.56]). The adjusted rate ratio increased from 1.30 (1.12-1.52) for a dose equivalent to < or = 2 mg of diazepam, to 2.21 (1.89-2.60, P < .001) for a dose of > 8 mg. The rate of falls was greatest in the 7 days after the benzodiazepine was started (rate ratio of 2.96 [2.33-3.75]) but remained elevated (1.30 [1.17-1.44]) after the first 30 days of therapy. Drugs with elimination half-lives of <12, 12-23, and > or = 24 hours had adjusted rate ratios of 1.15 (0.94-1.40), 1.45 (1.33-1.59), and 1.73 (1.40-2.14), respectively. Users of hypnotics with elimination half-lives <12 hours had an increased rate of falls occurring during the night (adjusted rate ratio 2.82 [2.02-3.94]).
CONCLUSIONS: Although the risk of falls among nursing home residents receiving short-acting benzodiazepines is less than that for the long-acting agents, these drugs are associated with a materially increased risk of nocturnal falls.
D Xing, X L Ma, J X Ma, J Wang, Y Yang, Y Chen
Association between use of benzodiazepines and risk of fractures: a meta-analysis.
Osteoporos Int. 2014 Jan;25(1):105-20. doi: 10.1007/s00198-013-2446-y. Epub 2013 Sep 7.
Abstract/Text
UNLABELLED: Benzodiazepines (BZDs) are some of the most commonly prescribed drugs in the world. It has been shown that BZD use could be associated with increased fracture risk. However, studies on the use of BZDs and fracture risk have yielded inconsistent results. Results from the present meta-analysis show that BZD use is associated with a moderate and clinically significant increase in the risk of fractures.
INTRODUCTION: The relationship between the use of BZDs and fracture risk has been neither well identified nor summarized. This meta-analysis reports on the use of BZDs, especially short-acting BZDs, and their correlation with a moderate and clinically significant increase in fracture risk. This analysis will provide evidence for clinicians to consider fracture risk when prescribing BZDs among the elderly population. This study was conducted to determine whether people who take BZDs are at an increased fracture risk.
METHODS: A systematic search of studies published through January 2013 was conducted using MEDLINE, EMBASE, OVID, and ScienceDirect. Case-control and cohort studies that assessed the relationship between BZD use and the risk of fractures were identified. Literature searches, study selections, methodological assessments, and data mining were independently conducted by two reviewers. Disagreements were resolved by consensus. STATA 12.0 software was used for the meta-analysis. Random effects models were used for pooled analysis due to heterogeneity among the studies.
RESULTS: There were 25 studies, including 19 case-control studies and 6 cohort studies, that met the inclusion criteria. Overall, the results of the meta-analysis indicated that BZD use was associated with a significantly increased fracture risk (relative risk (RR) = 1.25; 95% confidence intervals (CI), 1.17-1.34; p < 0.001). Increased fracture risk associated with BZD use was observed in participants aged ≥65 years old (RR = 1.26; 95% CI, 1.15-1.38; p < 0.001). When only hip fractures were included as the outcome measure, the RR increased to 1.35. However, subgroup meta-analyses showed that there was no significant association between BZD use and fracture risk in Eastern countries (RR = 1.27; 95% CI, 0.76-2.14; p = 0.362) as well as between long-acting BZD use and risk of fractures (RR = 1.21; 95% CI, 0.95-1.54; p = 0.12). After accounting for publication bias, we observed that the overall association between BZD use and fracture risk to be slightly weaker (RR = 1.21; 95% CI, 1.13-1.30) but still significant.
CONCLUSION: The results of this meta-analysis demonstrate that the use of BZD, especially short-acting BZD, is associated with a moderate and clinically significant increase in fracture risk. However, large prospective studies that minimize selection bias are necessary to determine a more accurate fracture risk associated with BZD use.
Hiroyuki Tamiya, Hideo Yasunaga, Hiroki Matusi, Kiyohide Fushimi, Sumito Ogawa, Masahiro Akishita
Hypnotics and the Occurrence of Bone Fractures in Hospitalized Dementia Patients: A Matched Case-Control Study Using a National Inpatient Database.
PLoS One. 2015;10(6):e0129366. doi: 10.1371/journal.pone.0129366. Epub 2015 Jun 10.
Abstract/Text
BACKGROUND: Preventing falls and bone fractures in hospital care is an important issue in geriatric medicine. Use of hypnotics is a potential risk factor for falls and bone fractures in older patients. However, data are lacking on the association between use of hypnotics and the occurrence of bone fracture.
METHODS: We used a national inpatient database including 1,057 hospitals in Japan and included dementia patients aged 50 years or older who were hospitalized during a period of 12 months between April 2012 and March 2013. The primary outcome was the occurrence of bone fracture during hospitalization. Use of hypnotics was compared between patients with and without bone fracture in this matched case-control study.
RESULTS: Of 140,494 patients, 830 patients suffered from in-hospital fracture. A 1:4 matching with age, sex and hospital created 817 cases with fracture and 3,158 matched patients without fracture. With adjustment for the Charlson comorbidity index, emergent admission, activities of daily living, and scores for level walking, a higher occurrence of fractures were seen with short-acting benzodiazepine hypnotics (odds ratio, 1.43; 95% confidence interval, 1.19-1.73; P<0.001), ultrashort-acting non-benzodiazepine hypnotics (1.66; 1.37-2.01; P<0.001), hydroxyzine (1.45; 1.15-1.82, P=0.001), risperidone and perospirone (1.37; 1.08-1.73; P=0.010). Other drug groups were not significantly associated with the occurrence of in-hospital fracture.
CONCLUSIONS: Short-acting benzodiazepine hypnotics and ultrashort-acting non-benzodiazepine hypnotics may increase risk of bone fracture in hospitalized dementia patients.
Jill N Reynoldson, Ellie Elliott, Leigh Anne Nelson
Ramelteon: a novel approach in the treatment of insomnia.
Ann Pharmacother. 2008 Sep;42(9):1262-71. doi: 10.1345/aph.1K676. Epub 2008 Jul 23.
Abstract/Text
OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of ramelteon in the treatment of primary insomnia in adults, including elderly adults.
DATA SOURCES: MEDLINE (1966-July 2008) and PsycINFO (1985-July 2008) literature searches were conducted to identify clinical data involving ramelteon. The manufacturer provided a summary of clinical data and abstracts of unpublished studies.
STUDY SELECTION AND DATA EXTRACTION: All primary literature, including abstracts, focusing on the pharmacology and pharmacokinetics of ramelteon and clinical trials evaluating its use was reviewed. Information deemed most relevant was incorporated. Our search revealed 5 controlled trials evaluating the short-term efficacy and safety of ramelteon in the treatment of primary insomnia: 3 in adults and 2 in geriatric patients. Additionally, 2 studies in abstract form that evaluated the long-term effects of ramelteon were included.
DATA SYNTHESIS: Ramelteon is the first selective melatonin receptor agonist approved by the Food and Drug Administration. It has no affinity for the gamma-aminobutyric acid receptor complex or for receptors that bind acetylcholine, cytokines, dopamine, norepinephrine, neuropeptides, opiates, and serotonin. In the only published Phase 3 trial in adults, investigators found that latency to persistent sleep decreased with ramelteon to 31.5 +/- 2.91 minutes with 8 mg and 29.5 +/- 2.96 minutes with 16 mg compared with 42.5 +/- 2.97 minutes with placebo (p = 0.007 and p = 0.002, respectively). Total sleep time was not significantly different from that with placebo. Safety data from short-term studies showed advantages of ramelteon over other sleep agents including no potential for abuse, no rebound insomnia, and lack of effect on motor and cognitive function. The adverse effects seen most frequently in ramelteon clinical trials were headache, somnolence, fatigue, nausea, dizziness, and insomnia. The overall incidence was similar to that of placebo.
CONCLUSIONS: Ramelteon offers a novel mechanism of action for the treatment of insomnia. Studies support its short- and long-term use in adults and elderly adults for the treatment of primary insomnia characterized by difficulty with sleep initiation. Efficacy studies comparing ramelteon with other sleep agents are needed to further solidify the role of ramelteon in the treatment of insomnia.
Sherry Wang-Weigand, Maggie McCue, Francis Ogrinc, Louis Mini
Effects of ramelteon 8 mg on objective sleep latency in adults with chronic insomnia on nights 1 and 2: pooled analysis.
Curr Med Res Opin. 2009 May;25(5):1209-13. doi: 10.1185/03007990902858527.
Abstract/Text
OBJECTIVE: Ramelteon is an MT(1)/MT(2) melatonin receptor agonist indicated for the treatment of insomnia characterized by difficulty with sleep onset. In previous clinical studies, ramelteon reduced latency to persistent sleep (LPS) in subjects with chronic insomnia. The goal of the current analysis was to determine the average reduction in LPS and overall adverse event profile for subjects taking ramelteon 8 mg.
RESEARCH DESIGN AND METHODS: This pooled analysis examined four randomized, double-blind, placebo-controlled clinical trials of ramelteon in subjects with chronic insomnia. The analysis included adults (age 18-83 years) with chronic insomnia who took ramelteon 8 mg or placebo. The primary endpoint of each trial was mean LPS, measured by polysomnography (PSG) on nights 1 and 2. Adverse events were collected for all subjects for the duration of each trial.
RESULTS: Efficacy data were available for 566 subjects who took ramelteon 8 mg (mean age 46.7 years) and 556 subjects who took placebo (mean age 47.8 years). Mean LPS at baseline was 66.6 min for the placebo group and 66.9 min for the ramelteon group. At nights 1 and 2, mean LPS for the ramelteon 8 mg group (30.2 min) was significantly less than the mean LPS for the placebo group (43.3 min). The least squares mean difference from placebo was -13.1 min (p < 0.001). Headache (8.9% ramelteon 8 mg, 8.8% placebo) and somnolence (3.5% ramelteon 8 mg, 0.7% placebo) were the most common adverse events.
CONCLUSIONS: Ramelteon 8 mg, on average, reduced LPS by approximately 13 min more than placebo on nights 1 and 2 of treatment in adults with chronic insomnia. Ramelteon was well tolerated with a low incidence of adverse events. This mean reduction in LPS versus placebo is similar to what has been reported for other classes of insomnia medications. However, these results reflect nights 1 and 2 of treatment and may not be representative of longer treatments.
