Sedative hypnotics in older people with insomnia: meta-analysis of ris
http://www.100md.com
《英国医生杂志》
1 University of Toronto, Department of Pharmaceutical Sciences, Toronto, ON, Canada M5S 2S2, 2 Centre for Addiction and Mental Health, Toronto, ON, Canada M5S 2S1, 3 Department of Psychiatry, University of Toronto, Neuroscience Research Program, Sunnybrook and Women's College Health Sciences Centre, Toronto, ON, Canada M4N 3M5, 4 Division of Geriatric Medicine, University of Toronto, Department of Medicine, Sunnybrook and Women's College Health Sciences Centre
Correspondence to: U E Busto usoa_busto@camh.net
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reviews and meta-analyses; manufacturers of newer sedative hypnotics (zaleplon, zolpidem, zopiclone) regarding unpublished studies.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.
Insomnia often affects the quality of life for older people.1-3 Acute episodes are usually treated with drugs.4 Between 5% and 33% of elderly people in North America and the United Kingdom are prescribed a benzodiazepine or a benzodiazepine receptor agonist (zolpidem, zopiclone, zaleplon) for sleep problems.5 6
Adverse events that are associated with sedative use, such as ataxia, falls, or memory impairment, are thought to be particularly detrimental for older people.7 8 Despite the widespread use of sedative hypnotics in older people, the risk-benefit relation is not known. This meta-analysis aims to study the benefits of sedative use, as determined by subjective reported changes in sleep variables, and the risks, as determined by adverse events.
Methods
Identification of studies
We searched Medline, Embase, the Cochrane clinical trials database, PubMed, and PsychLit from 1966 to 2003, using the keywords "elderly" or "aged" (Medline and Cochrane database only) and "sedatives" or "hypnotics" or "benzodiazepines" or "zolpidem" or "zaleplon" or "zopiclone" or "antihistamines" (PsychLit and Cochrane database only) or "diphenhydramine" or "sleep" (Cochrane database only) or "sleep disorders" (PsychLit and Cochrane database only). For each citation identified, we scanned titles or s, or both, to identify randomised controlled trials that excluded patients under 60 years old. If studies included some patients who were under 60 years old, the mean age of participants had to be over 60. We searched bibliographies of published reviews and meta-analyses for relevant titles and asked Servier, Canada (manufacturer of zaleplon), Sanofi-Synthelab, US (maker of zolpidem), and ICN Canada (maker of zopiclone) about unpublished studies.
Inclusion criteria
We considered published randomised controlled trials of sedative hypnotics in English that compared active treatment against placebo or another active comparator. The active treatment phases of included studies were double blind.
In the included studies, participants had a mean age of at least 60 years and met predetermined diagnostic criteria for insomnia. Any study that included diagnostic criteria that were defined a priori was accepted.
Investigators must have excluded patients with psychiatric disorders, concurrent use of drugs affecting the central nervous system, and severe or acute physical illnesses that might disrupt sleep. As outcomes were subjective reports made by patients, investigators must have deemed that participants were cognitively able to perform the assessments (for example, by reporting appropriate score on a scale such as the mini-mental state examination9). Participants must have had a washout period after previous drug treatments, and studies with crossover designs need an appropriate washout period.
Interventions were pharmacological treatments for insomnia for at least five consecutive nights. Any sedative hypnotic currently used in clinical practice was included in the search, including over the counter medications such as antihistamines and prescription medications such as benzodiazepines and zolpidem, zopiclone, and zaleplon. We excluded studies of barbiturates and chloral hydrate or chloral hydrate derivatives as these are not recommended for elderly people.4 10
Fig 1 Flowchart for identification of studies
Study selection, data ion, and assessment of quality
Articles were selected on the basis of the inclusion criteria (JG) and verified by another investigator (UEB). Studies were included if data from at least one of the outcome variables could be extracted. Three investigators rated study quality using Jadad criteria,11 of whom two were blinded with respect to authors, author affiliation, date, and source of publication. Method of randomisation and allocation concealment were evaluated at this time while assessing the quality of the study. Two investigators (JG, UEB) ed data; UEB was blind to journal, authors, and date of publication. Any discrepancies were resolved through consensus.
Outcome measures
Benefits were measured by the participants' perceived change in sleep. The variables that we considered were sleep quality (soundness or depth of sleep); total sleep time (total amount of time participants perceive that they have slept, measured in minutes); sleep onset latency (measured in minutes) or ease of getting to sleep (qualitative measure, score on questionnaire); and number of awakenings during the night. Ratings were made by patients and not an observer. All variables were analysed separately.
To measure risks, we determined the total number of adverse events for treatment and placebo (including placebo run-in phases) and then categorised them as: cognitive adverse events (memory loss, confusion, disorientation); psychomotor-type adverse events (reports of dizziness, loss of balance, or falls); and morning hangover effects (residual morning sedation). We analysed morning impairment (as measured by performance tasks such as reaction time or hand-eye coordination tasks) separately from adverse events as a risk of sedative use.
Data synthesis
As no standard accepted instrument measures sleep quality, we used effect sizes of the change in scores. The equation for Cohen's d was used to estimate effect size: M1-M2/ (where M1 = mean sleep quality score for the treatment group, M2 = mean sleep quality score for the control group, and = pooled standard deviations from either control or treatment or both groups). To minimise false positive results, we used the larger standard error, whether in the control group, treatment group, or all participants pooled. As more than one instrument had been used to measure psychomotor impairment, we also calculated effect sizes for morning-after performance. We assessed total sleep time, number of awakenings, and sleep onset latency as continuous variables.
If means were reported without variances, estimates were obtained from studies with similar methodology and patient population and a similar or smaller sample size.12 If the study did not have a placebo arm but did have a placebo run-in period, we used the run-in period as the control to preserve as much raw data as possible.
We obtained common odds ratios for all adverse events. All results used random effects models and 95% confidence intervals. We used 2 analysis to test heterogeneity for all combined results.
We calculated numbers needed to treat and to harm by using the inverse of the absolute risk reduction (efficacy data) and the absolute risk increase (adverse event data).13 14
To assess publication bias and heterogeneity, we used funnel plots and Begg and Mazumdars' rank correlation test for all primary outcomes.15 16 If publication bias was detected, we used the "trim and fill" method to adjust the funnel plot and recalculated the results.17
Results
Of 120 studies identified, 20 satisfied inclusion and exclusion criteria and had extractable subjective data.18-37 Four further studies reported on adverse events only and have been included in the assessment of risk (fig 1).38-41
A total of 830 participants were treated with a benzodiazepine, 106 with zopiclone, 384 with zolpidem, 609 with zaleplon, 14 with diphenhydramine, and 468 with placebo (not including placebo run-ins) (table 1).
Characteristics of included studies
Quality of sleep
Number needed to treat was derived from four studies that in which participants reported any improvement in sleep quality (considered "successes") compared with no improvement or a worsening in sleep quality ("failures"). On the basis of four studies (1072 participants), the number of patients who would need to be treated with a sedative (zaleplon, brotizolam or nitrazepam, or loprazolam) for one to have an improvement in sleep quality is 13 (95% confidence interval 6.7 to 62.9).18 20 25 37
Eight studies (719 participants) had extractable sleep quality score data (means and standard deviations) for any sedative versus placebo, and we used these to determine the magnitude of effect.19 21 23 25 26 32 36 37 Reported sleep quality was significantly better with sedative use (mean effect size 0.14, 0.05 to 0.23; P < 0.005, fig 2). This effect size indicates a difference in mean scores on sleep quality for sedative versus placebo groups of 0.11. In the most heavily weighted study in the analysis,25 this would correspond to mean scores of 3.8 in the placebo group and 3.7 in the sedative group on a seven point scale.
Fig 2 Mean effect size (95% confidence intervals) for subjective improvements in sleep quality with any sedative treatment and benzodiazepines only compared with placebo for at least five nights in people aged 60 or older with insomnia
Seven studies (277 participants) were combined to see the effect of benzodiazepines only versus placebo on sleep quality measures.19 21 23 26 32 36 37 A significant improvement in sleep quality improved significantly (mean effect size 0.37, 0.01 to 0.73; fig 2). This effect size corresponds to a difference of 0.46 between the treatment means—scores of 2.7 for placebo and 3.1 for drug, on the five point scale used by the most heavily weighted study in this analysis.37
Three studies (339 participants) comparing benzodiazepines with benzodiazepine receptor agonists (zaleplon, zolpidem, and zopiclone) found no significant difference in sleep quality (mean effect size 0.04, -1.11 to 1.19; test for heterogeneity P = 1.0).23 26 36
Two studies (116 participants) that reported sleep quality data for zopiclone versus placebo had a magnitude of effect of 0.41 (-0.76 to 1.58; test for heterogeneity P = 0.98).23 26 Data for zolpidem or zaleplon versus placebo were insufficient for inclusion.
Amount of sleep
In eight studies (601 participants) with extractable data, the increase in total sleep time with any sedatives compared with placebo was 25.2 minutes (12.8 to 37.8 minutes; P = 0.001; test for heterogeneity P = 0.10).20 21 27-29 31 34 37 In eight studies (524 participants) that compared benzodiazepines with placebo, the increase in total sleep time was 34.2 minutes (16.2 to 52.8 minutes, P < 0.01; test for heterogeneity P = 0.13).20 21 27-29 31 34 37
Data were insufficient to analyse sleep onset latency or ease of getting to sleep.
Number of awakenings
In six studies (441 participants) with extractable data, the mean number of awakenings decreased by 0.63 (-0.48 to -0.77, P < 0.0001; test for heterogeneity P = 0.71).20 22 27 29 34 36 In six studies with benzodiazepines versus placebo (296 participants) the mean number of awakenings decreased by 0.60 (-0.41 to -0.78, P < 0.0001; test for heterogeneity P = 0.58).20 22 27 29 34 36
Adverse events
On the basis of all adverse events reported in 16 studies (2220 participants), the number needed to harm for sedative hypnotics compared with placebo is 6 (4.7 to 7.1).18-28 30 34 37 39-41 The most common adverse events were drowsiness or fatigue, headache, nightmares, and nausea or gastrointestinal disturbances. As severity of adverse events was reported in only one study, pooled estimates could not be determined.
On the basis of 10 studies (712 participants), cognitive effects were significantly more common with sedative use than with placebo (odds ratio 4.78, 1.47 to 15.47, P < 0.01; test for heterogeneity P = 0.35, fig 3).21 23 24 26 27 30 36 39-41
Fig 3 Cognitive and psychomotor adverse events, odds ratios, z scores, and test for heterogeneity for any sedative hypnotics taken for at least five nights in people aged 60 or older with insomnia
Psychomotor-type side effects such as reported dizziness or loss of balance were reported in 13 studies (1016 participants) and were more common after treatment with a sedative, but this result did not reach significance (odds ratio 2.25, 0.93 to 5.41, P = 0.07; test for heterogeneity P = 0.08, fig 3).20-24 26-28 30 36 39-41 Of the 59 psychomotor effects that were reported, seven were serious events (six falls and one motor vehicle crash). Three resulted in broken bones: a fall resulting in a broken hip after five nights of 15 mg temazepam,30 a fall resulting in a broken femur after 0.125 mg triazolam,38 and one case of hip fracture while taking placebo.28 A motor vehicle crash after a single dose of temazepam 15 mg was reported.28
There were significantly more subjective reports of morning or daytime fatigue (seven studies, 829 participants) after treatment than after placebo (odds ratio 3.82, 1.88 to 7.80, P < 0.001).20 21 26 28 30 36 38
Impairment on performance tasks the morning after sedative use (four studies, 251 participants) was significantly greater than after placebo (d = 0.14, 0.11 to 0.16; test for heterogeneity P = 0.57).20 21 24 29
Six studies (648 participants) that compared benzodiazepine receptor agonists and benzodiazepine reported little difference in numbers of adverse events (odds ratio 1.11, 0.59 to 2.07, P = 0.75; test for heterogeneity P = 0.07).22 23 26 28 36 40 Studies of zaleplon, zopiclone and zolpidem (combined) versus benzodiazepines found no significant difference in cognitive adverse events (four studies, 268 participants; odds ratio 1.12, 0.16 to 7.76, P = 0.91; test for heterogeneity P = 0.35)23 26 36 40 or psychomotor-type adverse events (six studies, 625 participants; odds ratio 1.48, 0.75 to 2.93; test for heterogeneity P = 0.46).22 23 26 28 36 40
Publication bias
Funnel plot analyses indicated a possible publication bias on outcomes of sleep quality and total sleep time favouring positive results (rs = 0.78, P 0.05). The mean effect size did not change after "trim and fill" to correct estimates of effect size, and the result was still significant in favour of sedatives (d = 0.14, P 0.05 for sleep quality; mean increase in total sleep time = 15 minutes, P 0.05).
Discussion
Brostrom A, Stromberg A, Dahlstrom U, Fridlund B. Sleep difficulties, daytime sleepiness, and health-related quality of life in patients with chronic heart failure. J Cardiovasc Nurs 2004;19: 234-42.
Byles JE, Mishra GD, Harris MA, Nair K. The problems of sleep for older women: changes in health outcomes. Age Ageing 2003;32: 154-63.
Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 2002;6: 97-111.
Holbrook AM, Crowther R, Lotter A, Cheng C, King D. The diagnosis and management of insomnia in clinical practice: a practical evidence-based approach. CMAJ 2000;162: 206-10.
Aparasu RR, Mort JR, Brandt H. Psychotropic prescription use by community-dwelling elderly in the United States. J Am Geriatr Soc 2003;51: 671-7.
Craig D, Passmore AP, Fullerton KJ, Beringer TR, Gilmore DH, Crawford VL, et al. Factors influencing prescription of CNS medications in different elderly populations. Pharmacoepidemiol Drug Saf 2003;12: 383-7.
Barbone F, McMahon AD, Davey PG, Morris AD, Reid IC, McDevitt DG, et al. Association of road-traffic accidents with benzodiazepine use. Lancet 1998;352: 1331-6.
Neutel CI, Perry S, Maxwell C. Medication use and risk of falls. Pharmacoepidemiol Drug Saf 2002;11: 97-104.
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12: 189-98.
Fleming JAE. Insomnia. In: Gray J, ed. Therapeutic choices. Ottawa: Canadian Pharmacists Association, 2003: 54-62.
Jadad A, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17: 1-12.
Holbrook A, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ 2000;162: 225-33.
McAlister FA, Straus SE, Guyatt GH, Haynes RB. Users' guides to the medical literature. XX. Integrating research evidence with the care of the individual patient. Evidence-Based Medicine Working Group. JAMA 2000;283: 2829-36.
De Craen AJ, Vickers AJ, Tijssen JG, Kleijnen J. Number-needed-to-treat and placebo-controlled trials. Lancet 1998;351: 310.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50: 1088-101.
Cochrane collaboration open learning material. Module 15. 2002. www-cochrane-net.org/openlearning/HTML/mod15/htm (accessed Mar 2004).
Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56: 455-63.
Ancoli-Israel S, Walsh JK, Mangano RM, Fujimori M. Zaleplon A. Novel nonbenzodiazepine hypnotic, effectively treats insomnia in elderly patients without causing rebound effects. Prim Care Companion J Clin Psychiatry 1999;1: 114-20.
Bayer AJ, Pathy MS, Ankier SI. An evaluation of the short-term hypnotic efficacy of loprazolam in comparison with nitrazepam in elderly patients. Pharmatherapeutica 1983;3: 468-74.
Bayer A, Pathy MSJ. Clinical and psychometric evaluation of 2 doses of loprazolam and placebo in geriatric patients. Curr Med Res Opinion 1986;10: 17-24.
Dehlin O, Bjornson J. Triazolam as a hypnotic for geriatric patients. Act Psychiatr Scand 1983;67: 290-6.
Dehlin O, Rubin B, Rundgren A. Double-blind comparison of zopiclone and flunitrazepam in elderly insomniacs with special focus on residual effects. Curr Med Res Opinion 1995;13: 317-24.
Elie R, Frenay M, Le Morvan P, Bourgouin J. Efficacy and safety of zopiclone and triazolam in the treatment of geriatric insomniacs. Int Clin Psychopharmacol 1990;5(suppl 2): 39-46.
Fairweather DB, Kerr JS, Hindmarch I. The effects of acute and repeated doses of zolpidem on subjective sleep, psychomotor performance and cognitive function in elderly volunteers. Eur J Clin Pharmacol 1992;43: 597-601.
Hedner J, Yaeche R, Emilien G, Farr I, Salinas E. Zaleplon shortens subjective sleep latency and improves subjective sleep quality in elderly patients with insomnia. The Zaleplon Clinical Investigator Study Group. Int J Geriatr Psychiatry 2000;15: 704-12.
Klimm H, Dreyfus JF, Delmotte M. Zopiclone vs. nitrazepam: a double-blind comparative study of efficacy and tolerance in elderly patients with chronic insomnia. Sleep 1987;10: 73-8.
Lachnit K, Proszolowski E, Rieder L. Midazolam in the treatment of sleep disorders in geriatric patients. Br J Clin Pharmac 1983;16 (suppl): 173-7S.
Leppik I, Roth-Schecheter GB, Gray GW, Cohn MA, Owens D. Double-blind, placebo-controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia. Drug Dev Res 1997;40: 230-8.
Mamelak M, Csima A, Buck L, Price V. A comparative study on the effects of brotizolam and flurazepam on sleep and performance in the elderly. J Clin Psychopharm 1989;9: 260-7.
Meuleman JR, Nelson RC, Clark RL Jr. Evaluation of temazepam and diphenhydramine as hypnotics in a nursing-home population. Drug Intell Clin Pharm 1987;21: 716-20.
Morin C, Colecchi C, Stone J, Sood R, Brink D. Behavioural and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA 1999;281: 991-9.
Murphy P, Hindmarch I, Hyland CM. Aspects of short-term use of two benzodiazepine hypnotics in the elderly. Age Ageing 1982;11: 222-8.
Overstall P, Oldman PN. A comparative study of lormetazepam and chlormethiazole in elderly in-patients. Age Ageing 1987;16: 45-51.
Reeves R. Comparison of triazolam, flurazepam, and placebo as hypnotics in geriatric patients with insomnia. J Clin Pharmacol 1977;17: 319-23.
Richards HH, Valle-Jones CJ. A double-blind comparison of two lormetazepam doses in elderly insomniacs. Curr Med Res Opin 1988;11: 48-55.
Roger M, Attali R, Coquelin JP. Multicentre, double-blind, controlled comparison of zolpidem and triazolam in elderly patients with insomnia. Clin Therapeutics 1993;15: 127-36.
Viukari M, Vartio T, Verho E. Low doses of brotizolam and nitrazepam as hypnotics in the elderly. Neuropsychobiol 1984;12: 130-3.
Bayer A, Bayer EM, Pathy MSJ, Stoker MJ. A double-blind controlled study of chlomethiazole and triazolam as hypnotics in the elderly. Acta Psychiatr Scand 1986;73: 104-11.
Caldwell JR. Short-term quazepam treatment of insomnia in geriatric patients. Pharmatherapeutica 1982;3: 278-82.
Mouret J, Ruel D, Maillard F, Bianchi M. Zopiclone versus triazolam in insomniac geriatric patients: a specific increase in delta sleep with zopiclone. Int Clin Psychopharmacol 1990;5(suppl 2): 47-55.
Roth T, Roehrs TA, Ksohorek GL, Greenblatt DJ, Rosenthal LD. Hypnotic effects of low doses of quazepam in older insomniacs. J Clin Psychopharmacol 1997;17: 401-6.
Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Earlbaum, 1988.
Nowell PM, Mazumdar S, Buysse DJ, Dew MA, Reynolds CF 3rd, Kupfer DJ. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997;278: 2170-7.
Smith MT, Perlis ML, Park A, Smith MS, Pennington J, Giles DE, et al. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry 2002;159: 5-11.
Wysowski D, Barash D. Adverse behavioural reactions attibuted to triazolam in the Food and Drug Administration's spontaneous reporting system. Arch Intern Med 1991;151: 3003-8.
American Sleep Disorders Association. International classification of sleep disorders diagnostics and coding manual. Rochester, MN: ASDA, 1990.
Mort JR, Aparasu RR. Prescribing of psychotropics in the elderly: why is it so often inappropriate? CNS Drugs 2002;16: 99-109.
Kallin K, Jensen J, Olsson LL, Nyberg L, Gustafson Y. Why the elderly fall in residential care facilities, and suggested remedies. J Fam Pract 2004;53: 41-52.
Greenblatt D, Harmatz JS, Shapiro L, Engelhardt N, Gouthro TA, Shader RI. Sensitivity to triazolam in the elderly. N Engl J Med 1991;324: 1691-8.
Greenblatt D, Shader RI, Harmatz JS. Implications of altered drug disposition in the elderly: studies of benzodiazepines. J Clin Pharmacol 1989;29: 866-72.
Greenblatt DJ, Harmatz JS, von Moltke LL, Wright CE, Shader RI. Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate. Clin Pharmacol Ther 2004;76: 467-79.
Hemmelgarn B, Suissa S, Huang A, Boivin J, Pinard G. Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA 1997;278: 27-31.
Ray W. Safety and mobility of the older driver. JAMA 1997;278: 66.
Kripke DF, Hauri P, Ancoli-Israel S, Roth T. Sleep evaluation in chronic insomniacs during 14-day use of flurazepam and midazolam. J Clin Psychopharmacol 1990;10(suppl): 32-43S.
Morin C, Culbert JP, Schwartz SM. Nonpharmacological interventions for insomnia: a meta-analysis of treatement efficacy. Am J Psychiatry 1994;151: 1172-80.
Murtagh D, Greenwood KM. Identifying effective psychological treatments for insomnia: a meta-analysis. J Consult Clin Psychol 1995;63: 79-89.(Jennifer Glass, PhD candidate1, Krista L)
Correspondence to: U E Busto usoa_busto@camh.net
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.
Insomnia often affects the quality of life for older people.1-3 Acute episodes are usually treated with drugs.4 Between 5% and 33% of elderly people in North America and the United Kingdom are prescribed a benzodiazepine or a benzodiazepine receptor agonist (zolpidem, zopiclone, zaleplon) for sleep problems.5 6
Adverse events that are associated with sedative use, such as ataxia, falls, or memory impairment, are thought to be particularly detrimental for older people.7 8 Despite the widespread use of sedative hypnotics in older people, the risk-benefit relation is not known. This meta-analysis aims to study the benefits of sedative use, as determined by subjective reported changes in sleep variables, and the risks, as determined by adverse events.
Methods
Identification of studies
We searched Medline, Embase, the Cochrane clinical trials database, PubMed, and PsychLit from 1966 to 2003, using the keywords "elderly" or "aged" (Medline and Cochrane database only) and "sedatives" or "hypnotics" or "benzodiazepines" or "zolpidem" or "zaleplon" or "zopiclone" or "antihistamines" (PsychLit and Cochrane database only) or "diphenhydramine" or "sleep" (Cochrane database only) or "sleep disorders" (PsychLit and Cochrane database only). For each citation identified, we scanned titles or s, or both, to identify randomised controlled trials that excluded patients under 60 years old. If studies included some patients who were under 60 years old, the mean age of participants had to be over 60. We searched bibliographies of published reviews and meta-analyses for relevant titles and asked Servier, Canada (manufacturer of zaleplon), Sanofi-Synthelab, US (maker of zolpidem), and ICN Canada (maker of zopiclone) about unpublished studies.
Inclusion criteria
We considered published randomised controlled trials of sedative hypnotics in English that compared active treatment against placebo or another active comparator. The active treatment phases of included studies were double blind.
In the included studies, participants had a mean age of at least 60 years and met predetermined diagnostic criteria for insomnia. Any study that included diagnostic criteria that were defined a priori was accepted.
Investigators must have excluded patients with psychiatric disorders, concurrent use of drugs affecting the central nervous system, and severe or acute physical illnesses that might disrupt sleep. As outcomes were subjective reports made by patients, investigators must have deemed that participants were cognitively able to perform the assessments (for example, by reporting appropriate score on a scale such as the mini-mental state examination9). Participants must have had a washout period after previous drug treatments, and studies with crossover designs need an appropriate washout period.
Interventions were pharmacological treatments for insomnia for at least five consecutive nights. Any sedative hypnotic currently used in clinical practice was included in the search, including over the counter medications such as antihistamines and prescription medications such as benzodiazepines and zolpidem, zopiclone, and zaleplon. We excluded studies of barbiturates and chloral hydrate or chloral hydrate derivatives as these are not recommended for elderly people.4 10
Fig 1 Flowchart for identification of studies
Study selection, data ion, and assessment of quality
Articles were selected on the basis of the inclusion criteria (JG) and verified by another investigator (UEB). Studies were included if data from at least one of the outcome variables could be extracted. Three investigators rated study quality using Jadad criteria,11 of whom two were blinded with respect to authors, author affiliation, date, and source of publication. Method of randomisation and allocation concealment were evaluated at this time while assessing the quality of the study. Two investigators (JG, UEB) ed data; UEB was blind to journal, authors, and date of publication. Any discrepancies were resolved through consensus.
Outcome measures
Benefits were measured by the participants' perceived change in sleep. The variables that we considered were sleep quality (soundness or depth of sleep); total sleep time (total amount of time participants perceive that they have slept, measured in minutes); sleep onset latency (measured in minutes) or ease of getting to sleep (qualitative measure, score on questionnaire); and number of awakenings during the night. Ratings were made by patients and not an observer. All variables were analysed separately.
To measure risks, we determined the total number of adverse events for treatment and placebo (including placebo run-in phases) and then categorised them as: cognitive adverse events (memory loss, confusion, disorientation); psychomotor-type adverse events (reports of dizziness, loss of balance, or falls); and morning hangover effects (residual morning sedation). We analysed morning impairment (as measured by performance tasks such as reaction time or hand-eye coordination tasks) separately from adverse events as a risk of sedative use.
Data synthesis
As no standard accepted instrument measures sleep quality, we used effect sizes of the change in scores. The equation for Cohen's d was used to estimate effect size: M1-M2/ (where M1 = mean sleep quality score for the treatment group, M2 = mean sleep quality score for the control group, and = pooled standard deviations from either control or treatment or both groups). To minimise false positive results, we used the larger standard error, whether in the control group, treatment group, or all participants pooled. As more than one instrument had been used to measure psychomotor impairment, we also calculated effect sizes for morning-after performance. We assessed total sleep time, number of awakenings, and sleep onset latency as continuous variables.
If means were reported without variances, estimates were obtained from studies with similar methodology and patient population and a similar or smaller sample size.12 If the study did not have a placebo arm but did have a placebo run-in period, we used the run-in period as the control to preserve as much raw data as possible.
We obtained common odds ratios for all adverse events. All results used random effects models and 95% confidence intervals. We used 2 analysis to test heterogeneity for all combined results.
We calculated numbers needed to treat and to harm by using the inverse of the absolute risk reduction (efficacy data) and the absolute risk increase (adverse event data).13 14
To assess publication bias and heterogeneity, we used funnel plots and Begg and Mazumdars' rank correlation test for all primary outcomes.15 16 If publication bias was detected, we used the "trim and fill" method to adjust the funnel plot and recalculated the results.17
Results
Of 120 studies identified, 20 satisfied inclusion and exclusion criteria and had extractable subjective data.18-37 Four further studies reported on adverse events only and have been included in the assessment of risk (fig 1).38-41
A total of 830 participants were treated with a benzodiazepine, 106 with zopiclone, 384 with zolpidem, 609 with zaleplon, 14 with diphenhydramine, and 468 with placebo (not including placebo run-ins) (table 1).
Characteristics of included studies
Quality of sleep
Number needed to treat was derived from four studies that in which participants reported any improvement in sleep quality (considered "successes") compared with no improvement or a worsening in sleep quality ("failures"). On the basis of four studies (1072 participants), the number of patients who would need to be treated with a sedative (zaleplon, brotizolam or nitrazepam, or loprazolam) for one to have an improvement in sleep quality is 13 (95% confidence interval 6.7 to 62.9).18 20 25 37
Eight studies (719 participants) had extractable sleep quality score data (means and standard deviations) for any sedative versus placebo, and we used these to determine the magnitude of effect.19 21 23 25 26 32 36 37 Reported sleep quality was significantly better with sedative use (mean effect size 0.14, 0.05 to 0.23; P < 0.005, fig 2). This effect size indicates a difference in mean scores on sleep quality for sedative versus placebo groups of 0.11. In the most heavily weighted study in the analysis,25 this would correspond to mean scores of 3.8 in the placebo group and 3.7 in the sedative group on a seven point scale.
Fig 2 Mean effect size (95% confidence intervals) for subjective improvements in sleep quality with any sedative treatment and benzodiazepines only compared with placebo for at least five nights in people aged 60 or older with insomnia
Seven studies (277 participants) were combined to see the effect of benzodiazepines only versus placebo on sleep quality measures.19 21 23 26 32 36 37 A significant improvement in sleep quality improved significantly (mean effect size 0.37, 0.01 to 0.73; fig 2). This effect size corresponds to a difference of 0.46 between the treatment means—scores of 2.7 for placebo and 3.1 for drug, on the five point scale used by the most heavily weighted study in this analysis.37
Three studies (339 participants) comparing benzodiazepines with benzodiazepine receptor agonists (zaleplon, zolpidem, and zopiclone) found no significant difference in sleep quality (mean effect size 0.04, -1.11 to 1.19; test for heterogeneity P = 1.0).23 26 36
Two studies (116 participants) that reported sleep quality data for zopiclone versus placebo had a magnitude of effect of 0.41 (-0.76 to 1.58; test for heterogeneity P = 0.98).23 26 Data for zolpidem or zaleplon versus placebo were insufficient for inclusion.
Amount of sleep
In eight studies (601 participants) with extractable data, the increase in total sleep time with any sedatives compared with placebo was 25.2 minutes (12.8 to 37.8 minutes; P = 0.001; test for heterogeneity P = 0.10).20 21 27-29 31 34 37 In eight studies (524 participants) that compared benzodiazepines with placebo, the increase in total sleep time was 34.2 minutes (16.2 to 52.8 minutes, P < 0.01; test for heterogeneity P = 0.13).20 21 27-29 31 34 37
Data were insufficient to analyse sleep onset latency or ease of getting to sleep.
Number of awakenings
In six studies (441 participants) with extractable data, the mean number of awakenings decreased by 0.63 (-0.48 to -0.77, P < 0.0001; test for heterogeneity P = 0.71).20 22 27 29 34 36 In six studies with benzodiazepines versus placebo (296 participants) the mean number of awakenings decreased by 0.60 (-0.41 to -0.78, P < 0.0001; test for heterogeneity P = 0.58).20 22 27 29 34 36
Adverse events
On the basis of all adverse events reported in 16 studies (2220 participants), the number needed to harm for sedative hypnotics compared with placebo is 6 (4.7 to 7.1).18-28 30 34 37 39-41 The most common adverse events were drowsiness or fatigue, headache, nightmares, and nausea or gastrointestinal disturbances. As severity of adverse events was reported in only one study, pooled estimates could not be determined.
On the basis of 10 studies (712 participants), cognitive effects were significantly more common with sedative use than with placebo (odds ratio 4.78, 1.47 to 15.47, P < 0.01; test for heterogeneity P = 0.35, fig 3).21 23 24 26 27 30 36 39-41
Fig 3 Cognitive and psychomotor adverse events, odds ratios, z scores, and test for heterogeneity for any sedative hypnotics taken for at least five nights in people aged 60 or older with insomnia
Psychomotor-type side effects such as reported dizziness or loss of balance were reported in 13 studies (1016 participants) and were more common after treatment with a sedative, but this result did not reach significance (odds ratio 2.25, 0.93 to 5.41, P = 0.07; test for heterogeneity P = 0.08, fig 3).20-24 26-28 30 36 39-41 Of the 59 psychomotor effects that were reported, seven were serious events (six falls and one motor vehicle crash). Three resulted in broken bones: a fall resulting in a broken hip after five nights of 15 mg temazepam,30 a fall resulting in a broken femur after 0.125 mg triazolam,38 and one case of hip fracture while taking placebo.28 A motor vehicle crash after a single dose of temazepam 15 mg was reported.28
There were significantly more subjective reports of morning or daytime fatigue (seven studies, 829 participants) after treatment than after placebo (odds ratio 3.82, 1.88 to 7.80, P < 0.001).20 21 26 28 30 36 38
Impairment on performance tasks the morning after sedative use (four studies, 251 participants) was significantly greater than after placebo (d = 0.14, 0.11 to 0.16; test for heterogeneity P = 0.57).20 21 24 29
Six studies (648 participants) that compared benzodiazepine receptor agonists and benzodiazepine reported little difference in numbers of adverse events (odds ratio 1.11, 0.59 to 2.07, P = 0.75; test for heterogeneity P = 0.07).22 23 26 28 36 40 Studies of zaleplon, zopiclone and zolpidem (combined) versus benzodiazepines found no significant difference in cognitive adverse events (four studies, 268 participants; odds ratio 1.12, 0.16 to 7.76, P = 0.91; test for heterogeneity P = 0.35)23 26 36 40 or psychomotor-type adverse events (six studies, 625 participants; odds ratio 1.48, 0.75 to 2.93; test for heterogeneity P = 0.46).22 23 26 28 36 40
Publication bias
Funnel plot analyses indicated a possible publication bias on outcomes of sleep quality and total sleep time favouring positive results (rs = 0.78, P 0.05). The mean effect size did not change after "trim and fill" to correct estimates of effect size, and the result was still significant in favour of sedatives (d = 0.14, P 0.05 for sleep quality; mean increase in total sleep time = 15 minutes, P 0.05).
Discussion
Brostrom A, Stromberg A, Dahlstrom U, Fridlund B. Sleep difficulties, daytime sleepiness, and health-related quality of life in patients with chronic heart failure. J Cardiovasc Nurs 2004;19: 234-42.
Byles JE, Mishra GD, Harris MA, Nair K. The problems of sleep for older women: changes in health outcomes. Age Ageing 2003;32: 154-63.
Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 2002;6: 97-111.
Holbrook AM, Crowther R, Lotter A, Cheng C, King D. The diagnosis and management of insomnia in clinical practice: a practical evidence-based approach. CMAJ 2000;162: 206-10.
Aparasu RR, Mort JR, Brandt H. Psychotropic prescription use by community-dwelling elderly in the United States. J Am Geriatr Soc 2003;51: 671-7.
Craig D, Passmore AP, Fullerton KJ, Beringer TR, Gilmore DH, Crawford VL, et al. Factors influencing prescription of CNS medications in different elderly populations. Pharmacoepidemiol Drug Saf 2003;12: 383-7.
Barbone F, McMahon AD, Davey PG, Morris AD, Reid IC, McDevitt DG, et al. Association of road-traffic accidents with benzodiazepine use. Lancet 1998;352: 1331-6.
Neutel CI, Perry S, Maxwell C. Medication use and risk of falls. Pharmacoepidemiol Drug Saf 2002;11: 97-104.
Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12: 189-98.
Fleming JAE. Insomnia. In: Gray J, ed. Therapeutic choices. Ottawa: Canadian Pharmacists Association, 2003: 54-62.
Jadad A, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17: 1-12.
Holbrook A, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ 2000;162: 225-33.
McAlister FA, Straus SE, Guyatt GH, Haynes RB. Users' guides to the medical literature. XX. Integrating research evidence with the care of the individual patient. Evidence-Based Medicine Working Group. JAMA 2000;283: 2829-36.
De Craen AJ, Vickers AJ, Tijssen JG, Kleijnen J. Number-needed-to-treat and placebo-controlled trials. Lancet 1998;351: 310.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50: 1088-101.
Cochrane collaboration open learning material. Module 15. 2002. www-cochrane-net.org/openlearning/HTML/mod15/htm (accessed Mar 2004).
Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56: 455-63.
Ancoli-Israel S, Walsh JK, Mangano RM, Fujimori M. Zaleplon A. Novel nonbenzodiazepine hypnotic, effectively treats insomnia in elderly patients without causing rebound effects. Prim Care Companion J Clin Psychiatry 1999;1: 114-20.
Bayer AJ, Pathy MS, Ankier SI. An evaluation of the short-term hypnotic efficacy of loprazolam in comparison with nitrazepam in elderly patients. Pharmatherapeutica 1983;3: 468-74.
Bayer A, Pathy MSJ. Clinical and psychometric evaluation of 2 doses of loprazolam and placebo in geriatric patients. Curr Med Res Opinion 1986;10: 17-24.
Dehlin O, Bjornson J. Triazolam as a hypnotic for geriatric patients. Act Psychiatr Scand 1983;67: 290-6.
Dehlin O, Rubin B, Rundgren A. Double-blind comparison of zopiclone and flunitrazepam in elderly insomniacs with special focus on residual effects. Curr Med Res Opinion 1995;13: 317-24.
Elie R, Frenay M, Le Morvan P, Bourgouin J. Efficacy and safety of zopiclone and triazolam in the treatment of geriatric insomniacs. Int Clin Psychopharmacol 1990;5(suppl 2): 39-46.
Fairweather DB, Kerr JS, Hindmarch I. The effects of acute and repeated doses of zolpidem on subjective sleep, psychomotor performance and cognitive function in elderly volunteers. Eur J Clin Pharmacol 1992;43: 597-601.
Hedner J, Yaeche R, Emilien G, Farr I, Salinas E. Zaleplon shortens subjective sleep latency and improves subjective sleep quality in elderly patients with insomnia. The Zaleplon Clinical Investigator Study Group. Int J Geriatr Psychiatry 2000;15: 704-12.
Klimm H, Dreyfus JF, Delmotte M. Zopiclone vs. nitrazepam: a double-blind comparative study of efficacy and tolerance in elderly patients with chronic insomnia. Sleep 1987;10: 73-8.
Lachnit K, Proszolowski E, Rieder L. Midazolam in the treatment of sleep disorders in geriatric patients. Br J Clin Pharmac 1983;16 (suppl): 173-7S.
Leppik I, Roth-Schecheter GB, Gray GW, Cohn MA, Owens D. Double-blind, placebo-controlled comparison of zolpidem, triazolam, and temazepam in elderly patients with insomnia. Drug Dev Res 1997;40: 230-8.
Mamelak M, Csima A, Buck L, Price V. A comparative study on the effects of brotizolam and flurazepam on sleep and performance in the elderly. J Clin Psychopharm 1989;9: 260-7.
Meuleman JR, Nelson RC, Clark RL Jr. Evaluation of temazepam and diphenhydramine as hypnotics in a nursing-home population. Drug Intell Clin Pharm 1987;21: 716-20.
Morin C, Colecchi C, Stone J, Sood R, Brink D. Behavioural and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA 1999;281: 991-9.
Murphy P, Hindmarch I, Hyland CM. Aspects of short-term use of two benzodiazepine hypnotics in the elderly. Age Ageing 1982;11: 222-8.
Overstall P, Oldman PN. A comparative study of lormetazepam and chlormethiazole in elderly in-patients. Age Ageing 1987;16: 45-51.
Reeves R. Comparison of triazolam, flurazepam, and placebo as hypnotics in geriatric patients with insomnia. J Clin Pharmacol 1977;17: 319-23.
Richards HH, Valle-Jones CJ. A double-blind comparison of two lormetazepam doses in elderly insomniacs. Curr Med Res Opin 1988;11: 48-55.
Roger M, Attali R, Coquelin JP. Multicentre, double-blind, controlled comparison of zolpidem and triazolam in elderly patients with insomnia. Clin Therapeutics 1993;15: 127-36.
Viukari M, Vartio T, Verho E. Low doses of brotizolam and nitrazepam as hypnotics in the elderly. Neuropsychobiol 1984;12: 130-3.
Bayer A, Bayer EM, Pathy MSJ, Stoker MJ. A double-blind controlled study of chlomethiazole and triazolam as hypnotics in the elderly. Acta Psychiatr Scand 1986;73: 104-11.
Caldwell JR. Short-term quazepam treatment of insomnia in geriatric patients. Pharmatherapeutica 1982;3: 278-82.
Mouret J, Ruel D, Maillard F, Bianchi M. Zopiclone versus triazolam in insomniac geriatric patients: a specific increase in delta sleep with zopiclone. Int Clin Psychopharmacol 1990;5(suppl 2): 47-55.
Roth T, Roehrs TA, Ksohorek GL, Greenblatt DJ, Rosenthal LD. Hypnotic effects of low doses of quazepam in older insomniacs. J Clin Psychopharmacol 1997;17: 401-6.
Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Earlbaum, 1988.
Nowell PM, Mazumdar S, Buysse DJ, Dew MA, Reynolds CF 3rd, Kupfer DJ. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997;278: 2170-7.
Smith MT, Perlis ML, Park A, Smith MS, Pennington J, Giles DE, et al. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry 2002;159: 5-11.
Wysowski D, Barash D. Adverse behavioural reactions attibuted to triazolam in the Food and Drug Administration's spontaneous reporting system. Arch Intern Med 1991;151: 3003-8.
American Sleep Disorders Association. International classification of sleep disorders diagnostics and coding manual. Rochester, MN: ASDA, 1990.
Mort JR, Aparasu RR. Prescribing of psychotropics in the elderly: why is it so often inappropriate? CNS Drugs 2002;16: 99-109.
Kallin K, Jensen J, Olsson LL, Nyberg L, Gustafson Y. Why the elderly fall in residential care facilities, and suggested remedies. J Fam Pract 2004;53: 41-52.
Greenblatt D, Harmatz JS, Shapiro L, Engelhardt N, Gouthro TA, Shader RI. Sensitivity to triazolam in the elderly. N Engl J Med 1991;324: 1691-8.
Greenblatt D, Shader RI, Harmatz JS. Implications of altered drug disposition in the elderly: studies of benzodiazepines. J Clin Pharmacol 1989;29: 866-72.
Greenblatt DJ, Harmatz JS, von Moltke LL, Wright CE, Shader RI. Age and gender effects on the pharmacokinetics and pharmacodynamics of triazolam, a cytochrome P450 3A substrate. Clin Pharmacol Ther 2004;76: 467-79.
Hemmelgarn B, Suissa S, Huang A, Boivin J, Pinard G. Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA 1997;278: 27-31.
Ray W. Safety and mobility of the older driver. JAMA 1997;278: 66.
Kripke DF, Hauri P, Ancoli-Israel S, Roth T. Sleep evaluation in chronic insomniacs during 14-day use of flurazepam and midazolam. J Clin Psychopharmacol 1990;10(suppl): 32-43S.
Morin C, Culbert JP, Schwartz SM. Nonpharmacological interventions for insomnia: a meta-analysis of treatement efficacy. Am J Psychiatry 1994;151: 1172-80.
Murtagh D, Greenwood KM. Identifying effective psychological treatments for insomnia: a meta-analysis. J Consult Clin Psychol 1995;63: 79-89.(Jennifer Glass, PhD candidate1, Krista L)