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. 2000 Jan 25;162(2):225–233.

Meta-analysis of benzodiazepine use in the treatment of insomnia

A M Holbrook 1, R Crowther 1, A Lotter 1, C Cheng 1, D King 1
PMCID: PMC1232276  PMID: 10674059

Abstract

OBJECTIVE: To systematically review the benefits and risks associated with the use of benzodiazepines to treat insomnia in adults. DATA SOURCES: MEDLINE and the Cochrane Controlled Trials Registry were searched for English-language articles published from 1966 to December 1998 that described randomized controlled trials of benzodiazepines for the treatment of insomnia. Key words included "benzodiazepines" (exploded), "randomized controlled trial" and "insomnia." Bibliographies of relevant articles were reviewed for additional studies and manufacturers of benzodiazepines were asked to submit additional randomized controlled trial reports not in the literature. STUDY SELECTION: Articles were considered for the meta-analysis if they were randomized controlled trials involving patients with insomnia and compared a benzodiazepine with placebo or another active agent. Of the 89 trials originally identified, 45 met our criteria, representing a total of 2672 patients. DATA EXTRACTION: Data were extracted regarding the participants, the setting, details of the intervention, the outcomes (including adverse effects) and the methodologic quality of the studies. DATA SYNTHESIS: The meta-analyses of sleep records indicated that, when compared with placebo, benzodiazepines decreased sleep latency by 4.2 minutes (non-significant; 95% confidence interval (CI -0.7 to 9.2) and significantly increased total sleep duration by 61.8 minutes (95% CI 37.4 to 86.2). Patient-reported outcomes were more optimistic for sleep latency; those randomized to benzodiazepine treatment estimated a sleep latency decrease of 14.3 minutes (95% CI 10.6 to 18.0). Although more patients receiving benzodiazepine treatment reported adverse effects, especially daytime drowsiness and dizziness or light-headedness (common odds ratio 1.8, 95% CI 1.4 to 2.4), dropout rates for the benzodiazepine and placebo groups were similar. Cognitive function decline including memory impairment was reported in several of the studies. Zopiclone was not found to be superior to benzodiazepines on any of the outcome measures examined. INTERPRETATION: The use of benzodiazepines in the treatment of insomnia is associated with an increase in sleep duration, but this is countered by a number of adverse effects. Additional studies evaluating the efficacy of nonpharmacological interventions would be valuable.

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Selected References

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  1. Allen R. P., Mendels J., Nevins D. B., Chernik D. A., Hoddes E. Efficacy without tolerance or rebound insomnia for midazolam and temazepam after use for one to three months. J Clin Pharmacol. 1987 Oct;27(10):768–775. doi: 10.1002/j.1552-4604.1987.tb02994.x. [DOI] [PubMed] [Google Scholar]
  2. Barbone F., McMahon A. D., Davey P. G., Morris A. D., Reid I. C., McDevitt D. G., MacDonald T. M. Association of road-traffic accidents with benzodiazepine use. Lancet. 1998 Oct 24;352(9137):1331–1336. doi: 10.1016/s0140-6736(98)04087-2. [DOI] [PubMed] [Google Scholar]
  3. Bayer A. J., Bayer E. M., Pathy M. S., Stoker M. J. A double-blind controlled study of chlormethiazole and triazolam as hypnotics in the elderly. Acta Psychiatr Scand Suppl. 1986;329:104–111. doi: 10.1111/j.1600-0447.1986.tb10544.x. [DOI] [PubMed] [Google Scholar]
  4. Bayer A. J., Pathy M. S., Ankier S. I. An evaluation of the short-term hypnotic efficacy of loprazolam in comparison with nitrazepam in elderly patients. Pharmatherapeutica. 1983;3(7):468–474. [PubMed] [Google Scholar]
  5. Begg E. J., Robson R. A., Frampton C. M., Campbell J. E. A comparison of efficacy and tolerance of the short acting sedatives midazolam and zopiclone. N Z Med J. 1992 Oct 28;105(944):428–429. [PubMed] [Google Scholar]
  6. Bixler E. O., Kales A., Manfredi R. L., Vgontzas A. N., Tyson K. L., Kales J. D. Next-day memory impairment with triazolam use. Lancet. 1991 Apr 6;337(8745):827–831. doi: 10.1016/0140-6736(91)92524-6. [DOI] [PubMed] [Google Scholar]
  7. Bixler E. O., Kales A., Manfredi R. L., Vgontzas A. N., Tyson K. L., Kales J. D. Next-day memory impairment with triazolam use. Lancet. 1991 Apr 6;337(8745):827–831. doi: 10.1016/0140-6736(91)92524-6. [DOI] [PubMed] [Google Scholar]
  8. Bixler E. O., Kales A., Soldatos C. R., Scharf M. B., Kales J. D. Effectiveness of temazepam with short-intermediate-, and long-term use: sleep laboratory evaluation. J Clin Pharmacol. 1978 Feb-Mar;18(2-3):110–118. doi: 10.1002/j.1552-4604.1978.tb02430.x. [DOI] [PubMed] [Google Scholar]
  9. Caplan R. D., Andrews F. M., Conway T. L., Abbey A., Abramis D. J., French J. R., Jr Social effects of diazepam use: a longitudinal field study. Soc Sci Med. 1985;21(8):887–898. doi: 10.1016/0277-9536(85)90145-5. [DOI] [PubMed] [Google Scholar]
  10. Carskadon M. A., Seidel W. F., Greenblatt D. J., Dement W. C. Daytime carryover of triazolam and flurazepam in elderly insomniacs. Sleep. 1982;5(4):361–371. doi: 10.1093/sleep/5.4.361. [DOI] [PubMed] [Google Scholar]
  11. Chaudoir P. J., Bodkin N. L., O'Donnell J., Anderson A., Holland R. L. A comparative study of zopiclone and triazolam in patients with insomnia. Int Clin Psychopharmacol. 1990 Apr;5 (Suppl 2):21–27. [PubMed] [Google Scholar]
  12. Chen D., Chernik D. A., Ellinwood E., Hauri P., Johnson L. C., Judd L. L., Kripke D. F., Linnoila M., Moskowitz H., Roth T. A multicenter study of sleep, performance, and plasma levels in chronic insomniacs during 14-day use of flurazepam and midazolam: executive summary. J Clin Psychopharmacol. 1990 Aug;10(4 Suppl):3S–4S. [PubMed] [Google Scholar]
  13. Cohn J. B., Wilcox C. S., Bremner J., Ettinger M. Hypnotic efficacy of estazolam compared with flurazepam in outpatients with insomnia. J Clin Pharmacol. 1991 Aug;31(8):747–750. doi: 10.1002/j.1552-4604.1991.tb03771.x. [DOI] [PubMed] [Google Scholar]
  14. Cordingley G. J., Dean B. C., Harris R. I. A double-blind comparison of two benzodiazepine hypnotics, flunitrazepam and triazolam, in general practice. Curr Med Res Opin. 1984;8(10):714–719. doi: 10.1185/03007998409110122. [DOI] [PubMed] [Google Scholar]
  15. Costa E Silva J. A., Acioli A., Naylor C., Jones Da Silva C., Ferreira I. Midazolam and triazolam in out-patients: a double-blind comparison of hypnotic efficacy. Br J Clin Pharmacol. 1983;16 (Suppl 1):179S–183S. doi: 10.1111/j.1365-2125.1983.tb02292.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dement W. C. Objective measurements of daytime sleepiness and performance comparing quazepam with flurazepam in two adult populations using the Multiple Sleep Latency Test. J Clin Psychiatry. 1991 Sep;52 (Suppl):31–37. [PubMed] [Google Scholar]
  17. Dement W. C. Objective measurements of daytime sleepiness and performance comparing quazepam with flurazepam in two adult populations using the Multiple Sleep Latency Test. J Clin Psychiatry. 1991 Sep;52 (Suppl):31–37. [PubMed] [Google Scholar]
  18. Ehsanullah R. S., Galloway D. B., Gusterson F. R., Kingsbury A. W. A double-blind crossover study of diazepam rectal suppositories, 5 mg and 10 mg, for sedation in patients with advanced malignant disease. Pharmatherapeutica. 1982;3(3):215–220. [PubMed] [Google Scholar]
  19. Elie R., Deschenes J. P. Efficacy and tolerance of zopiclone in insomniac geriatric patients. Int Pharmacopsychiatry. 1982;17 (Suppl 2):179–187. [PubMed] [Google Scholar]
  20. 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 Apr;5 (Suppl 2):39–46. [PubMed] [Google Scholar]
  21. Elie R., Lavoie G., Bourgouin J., Le Morvan P. Zopiclone versus flurazepam in insomnia: prolonged administration and withdrawal. Int Clin Psychopharmacol. 1990 Oct;5(4):279–286. doi: 10.1097/00004850-199010000-00005. [DOI] [PubMed] [Google Scholar]
  22. Fillingim J. M. Double-blind evaluation of the efficacy and safety of temazepam in outpatients with insomnia. Br J Clin Pharmacol. 1979;8(1):73S–77S. doi: 10.1111/j.1365-2125.1979.tb00461.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Fischbach R. Efficacy and safety of midazolam and vesparax in treatment of sleep disorders. Br J Clin Pharmacol. 1983;16 (Suppl 1):167S–171S. doi: 10.1111/j.1365-2125.1983.tb02290.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Fisher R. J., Dean B. C. A multi-centre, double-blind trial in general practice comparing the hypnotic efficacy and event profiles of flunitrazepam and temazepam. Pharmatherapeutica. 1985;4(4):231–235. [PubMed] [Google Scholar]
  25. Fleming J. A., McClure D. J., Mayes C., Phillips R., Bourgouin J. A comparison of the efficacy, safety and withdrawal effects of zopiclone and triazolam in the treatment of insomnia. Int Clin Psychopharmacol. 1990 Apr;5 (Suppl 2):29–37. [PubMed] [Google Scholar]
  26. Fontaine R., Beaudry P., Le Morvan P., Beauclair L., Chouinard G. Zopiclone and triazolam in insomnia associated with generalized anxiety disorder: a placebo-controlled evaluation of efficacy and daytime anxiety. Int Clin Psychopharmacol. 1990 Jul;5(3):173–183. doi: 10.1097/00004850-199007000-00002. [DOI] [PubMed] [Google Scholar]
  27. Ford D. E., Kamerow D. B. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA. 1989 Sep 15;262(11):1479–1484. doi: 10.1001/jama.262.11.1479. [DOI] [PubMed] [Google Scholar]
  28. Goetzke E., Findeisen P., Welbers I. B. Comparative study on the efficacy of and the tolerance to the triazolodiazepines, triazolam and brotizolam. Br J Clin Pharmacol. 1983;16 (Suppl 2):407S–412S. doi: 10.1111/j.1365-2125.1983.tb02318.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Grad R., Tamblyn R., Holbrook A. M., Hurley J., Feightner J., Gayton D. Risk of a new benzodiazepine prescription in relation to recent hospitalization. J Am Geriatr Soc. 1999 Feb;47(2):184–188. doi: 10.1111/j.1532-5415.1999.tb04576.x. [DOI] [PubMed] [Google Scholar]
  30. Greenblatt D. J., Harmatz J. S., Shapiro L., Engelhardt N., Gouthro T. A., Shader R. I. Sensitivity to triazolam in the elderly. N Engl J Med. 1991 Jun 13;324(24):1691–1698. doi: 10.1056/NEJM199106133242403. [DOI] [PubMed] [Google Scholar]
  31. Greenblatt D. J., Harmatz J. S., Zinny M. A., Shader R. I. Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam. N Engl J Med. 1987 Sep 17;317(12):722–728. doi: 10.1056/NEJM198709173171202. [DOI] [PubMed] [Google Scholar]
  32. Gringras M., Beaumont G., Ankier S. I. A comparison of the hypnotic activity of loprazolam, temazepam and placebo in general practice. J Int Med Res. 1984;12(1):10–16. doi: 10.1177/030006058401200102. [DOI] [PubMed] [Google Scholar]
  33. Götestam K. G., Oppöyen F., Berntzen D. Treatment of insomnia with two benzodiazepines: a double-blind crossover study. Eur J Clin Pharmacol. 1991;41(2):137–140. doi: 10.1007/BF00265906. [DOI] [PubMed] [Google Scholar]
  34. Hanlon J. T., Horner R. D., Schmader K. E., Fillenbaum G. G., Lewis I. K., Wall W. E., Jr, Landerman L. R., Pieper C. F., Blazer D. G., Cohen H. J. Benzodiazepine use and cognitive function among community-dwelling elderly. Clin Pharmacol Ther. 1998 Dec;64(6):684–692. doi: 10.1016/S0009-9236(98)90059-5. [DOI] [PubMed] [Google Scholar]
  35. Heffron W. A., Roth P. Double-blind evaluation of the safety and hypnotic efficacy of temazepam in insomniac outpatients. Br J Clin Pharmacol. 1979;8(1):69S–72S. doi: 10.1111/j.1365-2125.1979.tb00460.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hegelbach-Feller D. A., Tschopp J. M., Christeller S., Fabre J. Comparison of the short-acting benzodiazepines midazolam and triazolam with placebo. Arzneimittelforschung. 1988 Mar;38(3):387–392. [PubMed] [Google Scholar]
  37. Herings R. M., Stricker B. H., de Boer A., Bakker A., Sturmans F. Benzodiazepines and the risk of falling leading to femur fractures. Dosage more important than elimination half-life. Arch Intern Med. 1995 Sep 11;155(16):1801–1807. [PubMed] [Google Scholar]
  38. Hindmarch I., Ott H. Sleep, benzodiazepines and performance: issues and comments. Psychopharmacology Suppl. 1984;1:194–202. doi: 10.1007/978-3-642-69659-6_17. [DOI] [PubMed] [Google Scholar]
  39. Hindmarch I. Psychopharmacological aspects of idiopathic and transient insomnia. Acta Psychiatr Scand Suppl. 1986;332:47–54. doi: 10.1111/j.1600-0447.1986.tb08980.x. [DOI] [PubMed] [Google Scholar]
  40. Holbrook A. M., Crowther R., Lotter A., Cheng C., King D. Diagnosis and management of acute alcohol withdrawal. CMAJ. 1999 Mar 9;160(5):675–680. [PMC free article] [PubMed] [Google Scholar]
  41. Holbrook A. M., Crowther R., Lotter A., Cheng C., King D. Meta-analysis of benzodiazepine use in the treatment of acute alcohol withdrawal. CMAJ. 1999 Mar 9;160(5):649–655. [PMC free article] [PubMed] [Google Scholar]
  42. Holbrook A. M., Crowther R., Lotter A., Cheng C., King D. The diagnosis and management of insomnia in clinical practice: a practical evidence-based approach. CMAJ. 2000 Jan 25;162(2):216–220. [PMC free article] [PubMed] [Google Scholar]
  43. Jadad A. R., Moore R. A., Carroll D., Jenkinson C., Reynolds D. J., Gavaghan D. J., McQuay H. J. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996 Feb;17(1):1–12. doi: 10.1016/0197-2456(95)00134-4. [DOI] [PubMed] [Google Scholar]
  44. Jovanovic U. J., Dreyfus J. F. Polygraphical sleep recordings in insomniac patients under zopiclone or nitrazepam. Pharmacology. 1983;27 (Suppl 2):136–145. doi: 10.1159/000137920. [DOI] [PubMed] [Google Scholar]
  45. Judd L. L., Ellinwood E., McAdams L. A. Cognitive performance and mood in patients with chronic insomnia during 14-day use of flurazepam and midazolam. J Clin Psychopharmacol. 1990 Aug;10(4 Suppl):56S–67S. [PubMed] [Google Scholar]
  46. Kales A., Allen C., Scharf M. B., Kales J. D. Hypnotic drugs and their effectiveness. All-night EEG studies of insomniac subjects. Arch Gen Psychiatry. 1970 Sep;23(3):226–232. doi: 10.1001/archpsyc.1970.01750030034006. [DOI] [PubMed] [Google Scholar]
  47. Kales A., Bixler E. O., Scharf M., Kales J. D. Sleep laboratory studies of flurazepam: a model for evaluating hypnotic drugs. Clin Pharmacol Ther. 1976 May;19(5 Pt 1):576–583. doi: 10.1002/cpt1976195part1576. [DOI] [PubMed] [Google Scholar]
  48. Kales A., Bixler E. O., Soldatos C. R., Vela-Bueno A., Jacoby J. A., Kales J. D. Quazepam and temazepam: effects of short- and intermediate-term use and withdrawal. Clin Pharmacol Ther. 1986 Mar;39(3):345–352. doi: 10.1038/clpt.1986.51. [DOI] [PubMed] [Google Scholar]
  49. Kales A., Bixler E. O., Soldatos C. R., Vela-Bueno A., Jacoby J., Kales J. D. Quazepam and flurazepam: long-term use and extended withdrawal. Clin Pharmacol Ther. 1982 Dec;32(6):781–788. doi: 10.1038/clpt.1982.236. [DOI] [PubMed] [Google Scholar]
  50. Kales A., Kales J. D., Bixler E. O., Scharf M. B., Russek E. Hypnotic efficacy of triazolam: sleep laboratory evaluation of intermediate-term effectiveness. J Clin Pharmacol. 1976 Aug-Sep;16(8-9):399–406. doi: 10.1002/j.1552-4604.1976.tb02414.x. [DOI] [PubMed] [Google Scholar]
  51. Kales A., Manfredi R. L., Vgontzas A. N., Bixler E. O., Vela-Bueno A., Fee E. C. Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines. Clin Pharmacol Ther. 1991 Apr;49(4):468–476. doi: 10.1038/clpt.1991.55. [DOI] [PubMed] [Google Scholar]
  52. Kales A., Soldatos C. R., Bixler E. O., Goff P. J., Vela-Bueno A. Midazolam: dose-response studies of effectiveness and rebound insomnia. Pharmacology. 1983;26(3):138–149. doi: 10.1159/000137795. [DOI] [PubMed] [Google Scholar]
  53. Kales A., Soldatos C. R., Bixler E. O., Kales J. D. Early morning insomnia with rapidly eliminated benzodiazepines. Science. 1983 Apr 1;220(4592):95–97. doi: 10.1126/science.6131538. [DOI] [PubMed] [Google Scholar]
  54. Keeney R. L. Decisions about life-threatening risks. N Engl J Med. 1994 Jul 21;331(3):193–196. doi: 10.1056/NEJM199407213310311. [DOI] [PubMed] [Google Scholar]
  55. Klimm H. D., Dreyfus J. F., Delmotte M. Zopiclone versus nitrazepam: a double-blind comparative study of efficacy and tolerance in elderly patients with chronic insomnia. Sleep. 1987;10 (Suppl 1):73–78. doi: 10.1093/sleep/10.suppl_1.73. [DOI] [PubMed] [Google Scholar]
  56. Kripke D. F., Hauri P., Ancoli-Israel S., Roth T. Sleep evaluation in chronic insomniacs during 14-day use of flurazepam and midazolam. J Clin Psychopharmacol. 1990 Aug;10(4 Suppl):32S–43S. [PubMed] [Google Scholar]
  57. Lachnit K. S., Proszowski E., Rieder L. Midazolam in the treatment of sleep disorders in geriatric patients. Br J Clin Pharmacol. 1983;16 (Suppl 1):173S–177S. doi: 10.1111/j.1365-2125.1983.tb02291.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Lingjaerde O., Bratlid T. Triazolam (Halcion) versus flunitrazepam (Rohypnol) against midwinter insomnia in Northern Norway. Acta Psychiatr Scand. 1981 Sep;64(3):260–269. doi: 10.1111/j.1600-0447.1981.tb00782.x. [DOI] [PubMed] [Google Scholar]
  59. Lingjaerde O., Bratlid T., Westby O. C., Gordeladze J. O. Effect of midazolam, flunitrazepam, and placebo against midwinter insomnia in northern Norway. Acta Psychiatr Scand. 1983 Feb;67(2):118–129. doi: 10.1111/j.1600-0447.1983.tb06731.x. [DOI] [PubMed] [Google Scholar]
  60. Linnoila M., Viukari M., Lamminsivu U., Auvinen J. Efficacy and side effects of lorazepam, oxazepam, and temazepam as sleeping aids in psychogeriatric inpatients. Int Pharmacopsychiatry. 1980;15(2):129–135. doi: 10.1159/000468424. [DOI] [PubMed] [Google Scholar]
  61. Loew F., Pawlak C., Benaroyo L., Junod J. P. Comparison of midazolam and oxazepam as hypnotics in elderly hospitalized patients. A double-blind clinical trial. Arzneimittelforschung. 1988 Apr;38(4):563–567. [PubMed] [Google Scholar]
  62. Lohmann H., von Delbrück O., Findeisen P. Comparative studies on the efficacy of brotizolam and nitrazepam: a multi-centre study. Br J Clin Pharmacol. 1983;16 (Suppl 2):403S–406S. doi: 10.1111/j.1365-2125.1983.tb02317.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Lorizio A., Salsa F. The effectiveness of oral midazolam as a hypnotic compared with lorazepam. Pharmatherapeutica. 1986;4(7):463–471. [PubMed] [Google Scholar]
  64. Maczaj M. Pharmacological treatment of insomnia. Drugs. 1993 Jan;45(1):44–55. doi: 10.2165/00003495-199345010-00005. [DOI] [PubMed] [Google Scholar]
  65. 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 Psychopharmacol. 1989 Aug;9(4):260–267. [PubMed] [Google Scholar]
  66. McClure D. J., Walsh J., Chang H., Olah A., Wilson R., Pecknold J. C. Comparison of lorazepam and flurazepam as hypnotic agents in chronic insomniacs. J Clin Pharmacol. 1988 Jan;28(1):52–63. doi: 10.1002/j.1552-4604.1988.tb03101.x. [DOI] [PubMed] [Google Scholar]
  67. McClusky H. Y., Milby J. B., Switzer P. K., Williams V., Wooten V. Efficacy of behavioral versus triazolam treatment in persistent sleep-onset insomnia. Am J Psychiatry. 1991 Jan;148(1):121–126. doi: 10.1176/ajp.148.1.121. [DOI] [PubMed] [Google Scholar]
  68. Mellinger G. D., Balter M. B., Uhlenhuth E. H. Insomnia and its treatment. Prevalence and correlates. Arch Gen Psychiatry. 1985 Mar;42(3):225–232. doi: 10.1001/archpsyc.1985.01790260019002. [DOI] [PubMed] [Google Scholar]
  69. Meuleman J. R., Nelson R. C., Clark R. L., Jr Evaluation of temazepam and diphenhydramine as hypnotics in a nursing-home population. Drug Intell Clin Pharm. 1987 Sep;21(9):716–720. doi: 10.1177/106002808702100908. [DOI] [PubMed] [Google Scholar]
  70. Mitler M. M., Browman C. P., Menn S. J., Gujavarty K., Timms R. M. Nocturnal myoclonus: treatment efficacy of clonazepam and temazepam. Sleep. 1986;9(3):385–392. doi: 10.1093/sleep/9.3.385. [DOI] [PubMed] [Google Scholar]
  71. Monti J. M., Alterwain P., Debellis J., Altier H., Pellejero T., Monti D. Short-term sleep laboratory evaluation of midazolam in chronic insomniacs. Preliminary results. Arzneimittelforschung. 1987 Jan;37(1):54–57. [PubMed] [Google Scholar]
  72. Morgan K., Oswald I. Anxiety caused by a short-life hypnotic. Br Med J (Clin Res Ed) 1982 Mar 27;284(6320):942–942. doi: 10.1136/bmj.284.6320.942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Morin C. M., Colecchi C., Brink D., Astruc M., Mercer J., Remsberg S. How "blind" are double-blind placebo-controlled trials of benzodiazepine hypnotics? Sleep. 1995 May;18(4):240–245. doi: 10.1093/sleep/18.4.240. [DOI] [PubMed] [Google Scholar]
  74. Morin C. M., Colecchi C., Stone J., Sood R., Brink D. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA. 1999 Mar 17;281(11):991–999. doi: 10.1001/jama.281.11.991. [DOI] [PubMed] [Google Scholar]
  75. Morin C. M., Culbert J. P., Schwartz S. M. Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry. 1994 Aug;151(8):1172–1180. doi: 10.1176/ajp.151.8.1172. [DOI] [PubMed] [Google Scholar]
  76. Murtagh D. R., Greenwood K. M. Identifying effective psychological treatments for insomnia: a meta-analysis. J Consult Clin Psychol. 1995 Feb;63(1):79–89. doi: 10.1037//0022-006x.63.1.79. [DOI] [PubMed] [Google Scholar]
  77. Nair N. P., Schwartz G., Dimitri R., Le Morvan P., Thavundayil J. X. A dose-range finding study of zopiclone in insomniac patients. Int Clin Psychopharmacol. 1990 Apr;5 (Suppl 2):1–10. [PubMed] [Google Scholar]
  78. Ngen C. C., Hassan R. A double-blind placebo-controlled trial of zopiclone 7.5 mg and temazepam 20 mg in insomnia. Int Clin Psychopharmacol. 1990 Jul;5(3):165–171. doi: 10.1097/00004850-199007000-00001. [DOI] [PubMed] [Google Scholar]
  79. Nowell P. D., Mazumdar S., Buysse D. J., Dew M. A., Reynolds C. F., 3rd, Kupfer D. J. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA. 1997 Dec 24;278(24):2170–2177. [PubMed] [Google Scholar]
  80. Ponciano E., Freitas F., Camara J., Faria M., Barreto M., Hindmarch I. A comparison of the efficacy, tolerance and residual effects of zopiclone, flurazepam and placebo in insomniac outpatients. Int Clin Psychopharmacol. 1990 Apr;5 (Suppl 2):69–77. [PubMed] [Google Scholar]
  81. Post G. L., Patrick R. O., Crowder J. E., Houston J., Ferguson J. M., Bielski R. J., Bailey L., Pearlman H. G., Shu V. S., Pierce M. W. Estazolam treatment of insomnia in generalized anxiety disorder: a placebo-controlled study. J Clin Psychopharmacol. 1991 Aug;11(4):249–253. [PubMed] [Google Scholar]
  82. Pull C. B., Dreyfus J. F., Brun J. P. Comparison of nitrazepam and zopiclone in psychiatric patients. Int Pharmacopsychiatry. 1982;17 (Suppl 2):205–209. [PubMed] [Google Scholar]
  83. Radecki S. E., Brunton S. A. Management of insomnia in office-based practice. National prevalence and therapeutic patterns. Arch Fam Med. 1993 Nov;2(11):1129–1134. doi: 10.1001/archfami.2.11.1129. [DOI] [PubMed] [Google Scholar]
  84. Reeves R. L. Comparison of triazolam, flurazepam, and placebo as hypnotics in geriatric patients with insomnia. J Clin Pharmacol. 1977 May-Jun;17(5-6):319–323. doi: 10.1002/j.1552-4604.1977.tb04611.x. [DOI] [PubMed] [Google Scholar]
  85. Ried L. D., Johnson R. E., Gettman D. A. Benzodiazepine exposure and functional status in older people. J Am Geriatr Soc. 1998 Jan;46(1):71–76. doi: 10.1111/j.1532-5415.1998.tb01016.x. [DOI] [PubMed] [Google Scholar]
  86. Roehrs T., Merlotti L., Zorick F., Roth T. Rebound insomnia and hypnotic self administration. Psychopharmacology (Berl) 1992;107(4):480–484. doi: 10.1007/BF02245259. [DOI] [PubMed] [Google Scholar]
  87. Roehrs T., Merlotti L., Zorick F., Roth T. Rebound insomnia in normals and patients with insomnia after abrupt and tapered discontinuation. Psychopharmacology (Berl) 1992;108(1-2):67–71. doi: 10.1007/BF02245287. [DOI] [PubMed] [Google Scholar]
  88. Roehrs T., Vogel G., Sterling W., Roth T. Dose effects of temazepam in transient insomnia. Arzneimittelforschung. 1990 Aug;40(8):859–862. [PubMed] [Google Scholar]
  89. Roger M., Attali P., Coquelin J. P. Multicenter, double-blind, controlled comparison of zolpidem and triazolam in elderly patients with insomnia. Clin Ther. 1993 Jan-Feb;15(1):127–136. [PubMed] [Google Scholar]
  90. Sateia M. J., Hauri P., Kripke D., Roehrs T. Clinical safety of flurazepam and midazolam during 14-day use in chronic insomniacs. J Clin Psychopharmacol. 1990 Aug;10(4 Suppl):28S–31S. [PubMed] [Google Scholar]
  91. Scharf M. B. Feasibility of an every-other-night regimen in insomniac patients: subjective hypnotic effectiveness of quazepam, triazolam, and placebo. J Clin Psychiatry. 1993 Jan;54(1):33–38. [PubMed] [Google Scholar]
  92. Scharf M. B., Fletcher K., Graham J. P. Comparative amnestic effects of benzodiazepine hypnotic agents. J Clin Psychiatry. 1988 Apr;49(4):134–137. [PubMed] [Google Scholar]
  93. Scharf M. B., Fletcher K., Graham J. P. Comparative amnestic effects of benzodiazepine hypnotic agents. J Clin Psychiatry. 1988 Apr;49(4):134–137. [PubMed] [Google Scholar]
  94. Scharf M. B., Roth P. B., Dominguez R. A., Ware J. C. Estazolam and flurazepam: a multicenter, placebo-controlled comparative study in outpatients with insomnia. J Clin Pharmacol. 1990 May;30(5):461–467. doi: 10.1002/j.1552-4604.1990.tb03486.x. [DOI] [PubMed] [Google Scholar]
  95. Schulz K. F., Chalmers I., Hayes R. J., Altman D. G. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995 Feb 1;273(5):408–412. doi: 10.1001/jama.273.5.408. [DOI] [PubMed] [Google Scholar]
  96. Schulz K. F. Unbiased research and the human spirit: the challenges of randomized controlled trials. CMAJ. 1995 Sep 15;153(6):783–786. [PMC free article] [PubMed] [Google Scholar]
  97. Sunshine A. Comparison of the hypnotic activity of triazolam, flurazepam hydrochloride, and placebo. Clin Pharmacol Ther. 1975 May;17(5):573–577. doi: 10.1002/cpt1975175573. [DOI] [PubMed] [Google Scholar]
  98. Tamminen T., Hansen P. P. Chronic administration of zopiclone and nitrazepam in the treatment of insomnia. Sleep. 1987;10 (Suppl 1):63–72. [PubMed] [Google Scholar]
  99. Tham T. C., Brown H., Taggart H. M. Temazepam withdrawal in elderly hospitalized patients: a double blind randomised trial comparing abrupt versus gradual withdrawal. Ir J Med Sci. 1989 Dec;158(12):294–299. doi: 10.1007/BF02942077. [DOI] [PubMed] [Google Scholar]
  100. Thomas R. E. Benzodiazepine use and motor vehicle accidents. Systematic review of reported association. Can Fam Physician. 1998 Apr;44:799–808. [PMC free article] [PubMed] [Google Scholar]
  101. Tilleard-Cole R. R. A placebo-controlled, dose-ranging study comparing 0.5 mg, 1 mg and 2 mg flunitrazepam in out-patients. Curr Med Res Opin. 1983;8(8):543–546. doi: 10.1185/03007998309109795. [DOI] [PubMed] [Google Scholar]
  102. Turner J. A., Deyo R. A., Loeser J. D., Von Korff M., Fordyce W. E. The importance of placebo effects in pain treatment and research. JAMA. 1994 May 25;271(20):1609–1614. [PubMed] [Google Scholar]
  103. Viukari M., Jaatinen P., Kylmämaa T. Flunitrazepam and nitrazepam as hypnotics in psychogeriatric inpatients. Clin Ther. 1983;5(6):662–670. [PubMed] [Google Scholar]
  104. Viukari M., Miettinen P. Diazepam, promethazine and propiomazine as hypnotics in elderly inpatients. Neuropsychobiology. 1984;12(2-3):134–137. doi: 10.1159/000118126. [DOI] [PubMed] [Google Scholar]
  105. Viukari M., Vartio T., Verho E. Low doses of brotizolam and nitrazepam as hypnotics in the elderly. Neuropsychobiology. 1984;12(2-3):130–133. doi: 10.1159/000118125. [DOI] [PubMed] [Google Scholar]
  106. Vogel G. W., Morris D. The effects of estazolam on sleep, performance, and memory: a long-term sleep laboratory study of elderly insomniacs. J Clin Pharmacol. 1992 Jul;32(7):647–651. doi: 10.1002/j.1552-4604.1992.tb05776.x. [DOI] [PubMed] [Google Scholar]
  107. Wheatley D. Studies in general practice with brotizolam. Br J Clin Pharmacol. 1983;16 (Suppl 2):415S–416S. doi: 10.1111/j.1365-2125.1983.tb02320.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Wheatley D. Zopiclone: a non-benzodiazepine hypnotic. Controlled comparison to temazepam in insomnia. Br J Psychiatry. 1985 Mar;146:312–314. doi: 10.1192/bjp.146.3.312. [DOI] [PubMed] [Google Scholar]
  109. Wysowski D. K., Baum C. Outpatient use of prescription sedative-hypnotic drugs in the United States, 1970 through 1989. Arch Intern Med. 1991 Sep;151(9):1779–1783. [PubMed] [Google Scholar]
  110. de Jonghe F., Ameling E. H., Jonkers F., Folkers C., Schwarz R. V. Flurazepam and temazepam in the treatment of insomnia in a general hospital population. Pharmacopsychiatry. 1984 Jul;17(4):133–135. doi: 10.1055/s-2007-1017423. [DOI] [PubMed] [Google Scholar]

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