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Comparative Tolerability of Newer Agents for Insomnia

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Abstract

Newer treatment options for insomnia include the non-benzodiazepine hypnotics zolpidem, zolpidem-controlled release, zaleplon, zopiclone, eszopiclone and the melatonin receptor agonist, ramelteon. These compounds are generally well tolerated and present favourable safety profiles in comparison with the older benzodiazepines and barbiturates. Commonly cited impairments of memory formation and decrements in psychomotor performance are related to the mechanism of action of hypnotics, and are both dose- and time-dependent. These effects typically are minimal on the morning following night-time administration. The non-benzodiazepines are associated with some risk for dependence and abuse. However, concerns regarding such risks appear to be greater than warranted by empirical evidence. The appropriate therapeutic use of hypnotics is generally not associated with physiological responses that are commonly thought to lead to dependence, such as tolerance or discontinuation effects. Former substance abusers and psychiatric patients appear to be at greatest risk. The labelling of hypnotics was recently updated to incorporate warnings about very rare, but serious adverse events that have been identified in postmarketing surveillance. These events include anaphylaxis (severe allergic reaction); angio-oedema (severe facial swelling); and complex sleep-related behaviours, which may include sleep-driving, making phone calls and preparing and eating food. This article will review the adverse event profiles of these newer sedative hypnotics, their effects on memory and psychomotor performance, abuse liability concerns and the most recent information about the rare adverse effects that prompted the recent revision to the labelling of drugs in the hypnotic class.

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References

  1. Lahmeyer H, Wilcox CS, Kann J, et al. Subjective efficacy of zolpidem in outpatients with chronic insomnia: a double-blind comparison with placebo. Clin Drug Invest 1997; 13(3): 134–44

    Article  CAS  Google Scholar 

  2. Scharf MB, Roth T, Vogel GW, et al. A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia. J Clin Psychiatry 1994 May; 55(5): 192–9

    PubMed  CAS  Google Scholar 

  3. Maarek L, Cramer P, Attali P, et al. The safety and efficacy of zolpidem in insomniac patients: a long-term open study in general practice. J Int Med Res 1992 Apr; 20(2): 162–70

    PubMed  CAS  Google Scholar 

  4. Roger M, Attali P, Coquelin JP. Multicenter, double-blind, controlled comparison of zolpidem and triazolam in elderly patients with insomnia. Clin Ther 1993 Jan–Feb; 15(1): 127–36

    PubMed  CAS  Google Scholar 

  5. Shaw SH, Curson H, Coquelin JP. A double-blind, comparative study of zolpidem and placebo in the treatment of insomnia in elderly psychiatric in-patients. J Int Med Res 1992 Apr; 20(2): 150–61

    PubMed  CAS  Google Scholar 

  6. Kryger MH, Steljes D, Pouliot Z, et al. Subjective versus objective evaluation of hypnotic efficacy: experience with zolpidem. Sleep 1991 Oct; 14(5): 399–407

    PubMed  CAS  Google Scholar 

  7. Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry 1999 Oct; 60(10): 668–76

    Article  PubMed  CAS  Google Scholar 

  8. Roehrs T, Merlotti L, Zorick F, et al. Sedative, memory, and performance effects of hypnotics. Psychopharmacology (Berl) 1994 Oct; 116(2): 130–4

    Article  CAS  Google Scholar 

  9. Walsh JK, Erman M, Erwin CW, et al. Subjective hypnotic efficacy of trazodone and zolpidem in DSMIII-R primary insomnia. Hum Psychopharmacol 1998; 13(3): 191–8

    Article  CAS  Google Scholar 

  10. Dockhorn RJ, Dockhorn DW. Zolpidem in the treatment of short-term insomnia: a randomized, double-blind, placebo-controlled clinical trial. Clin Neuropharmacol 1996 Aug; 19(4): 333–40 744

    Article  PubMed  CAS  Google Scholar 

  11. Physicians’ desk reference. 60th ed. Montvale (NJ): Thomson PDR, 2006

  12. Hajak G, Bandelow B. Safety and tolerance of zolpidem in the treatment of disturbed sleep: a post-marketing surveillance of 16944 cases. Int Clin Psychopharmacol 1998 Jul; 13(4): 157–67

    Article  PubMed  CAS  Google Scholar 

  13. Roth T, Soubrane C, Titeux L, et al. Efficacy and safety of zolpidem-MR: a double-blind, placebo-controlled study in adults with primary insomnia. Sleep Med 2006 Aug; 7(5): 397–406

    Article  PubMed  Google Scholar 

  14. Krystal AD, Erman M, Zammit GK, et al. Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Sleep 2008 Jan 1; 31(1): 79–90

    PubMed  Google Scholar 

  15. Elie R, Ruther E, Farr I, et al. Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. Zaleplon Clinical Study Group. J Clin Psychiatry 1999 Aug; 60(8): 536–44

    Article  PubMed  CAS  Google Scholar 

  16. Walsh JK, Vogel GW, Scharf M, et al. A five week, polysomnographic assessment of zaleplon 10 mg for the treatment of primary insomnia. Sleep Med 2000 Feb 1; 1(1): 41–9

    Article  PubMed  Google Scholar 

  17. Allain H, Delahaye C, Le Coz F, et al. Postmarketing surveillance of zopiclone in insomnia: analysis of 20,513 cases. Sleep 1991 Oct; 14(5): 408–13

    PubMed  CAS  Google Scholar 

  18. Zammit GK, McNabb LJ, Caron J, et al. Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia. Curr Med Res Opin 2004 Dec; 20(12): 1979–91

    Article  PubMed  CAS  Google Scholar 

  19. McCall WV, Erman M, Krystal AD, et al. A polysomnography study of eszopiclone in elderly patients with insomnia. Curr Med Res Opin 2006 Sep; 22(9): 1633–42

    Article  PubMed  CAS  Google Scholar 

  20. Lunesta® (eszopiclone) tablets 1 mg, 2 mg and 3 mg: prescribing information [online]. Available from URL: http://www.lunesta.com/PostedApprovedLabelingText.pdf [Accessed 2009 Jun 17]

  21. Zammit G, Erman M, Wang-Weigand S, et al. Evaluation of the efficacy and safety of ramelton in subjects with chronic insomnia. J Clin Sleep Med 2007; 3(5): 495–504

    PubMed  Google Scholar 

  22. Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-response study of ramelteon in patients with chronic primary insomnia. Sleep Med 2006 Jan; 7(1): 17–24

    Article  PubMed  Google Scholar 

  23. Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med 2006 Jun; 7(4): 312–8

    Article  PubMed  Google Scholar 

  24. Roth T, Seiden D, Wang-Weigand S, et al. A 2-night, 3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin 2007 May; 23(5): 1005–14

    Article  PubMed  CAS  Google Scholar 

  25. Salva P, Costa J. Clinical pharmacokinetics and pharmacodynamics of zolpidem: therapeutic implications. Clin Pharmacokinet 1995 Sep; 29(3): 142–53

    Article  PubMed  CAS  Google Scholar 

  26. Darcourt G, Pringuey D, Salliere D, et al. The safety and tolerability of zolpidem: an update. J Psychopharmacol 1999; 13(1): 81–93

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  28. Dujardin K, Guieu JD, Leconte-Lambert C, et al. Comparison of the effects of zolpidem and flunitrazepam on sleep structure and daytime cognitive functions: a study of untreated unsomniacs. Pharmacopsychiatry 1998 Jan; 31(1): 14–8

    Article  PubMed  CAS  Google Scholar 

  29. Fairweather DB, Kerr JS, Hindmarch I. The effects of acute and repeated doses of zolpidem on subjective sleep, psychomotor performance and cognitive function in elderly volunteers. Eur J Clin Pharmacol 1992; 43(6): 597–601

    Article  PubMed  CAS  Google Scholar 

  30. Frattola L, Maggioni M, Cesana B, et al. Double blind comparison of zolpidem 20 mg versus flunitrazepam 2 mg in insomniac in-patients. Drugs Exp Clin Res 1990; 16(7): 371–6

    PubMed  CAS  Google Scholar 

  31. Holm KJ, Goa KL. Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 2000 Apr; 59(4): 865–89

    Article  PubMed  CAS  Google Scholar 

  32. Scharf MB, Mayleben DW, Kaffeman M, et al. Dose response effects of zolpidem in normal geriatric subjects. J Clin Psychiatry 1991 Feb; 52(2): 77–83

    PubMed  CAS  Google Scholar 

  33. Unden M, Roth-Schechter B. Next day effects after nighttime treatment with zolpidem: a review. Eur Psychiatry 1996; 11 Suppl. 1: 21–30S

    Article  Google Scholar 

  34. Allain H, Patat A, Lieury A, et al. Comparative study of the effects of zopiclone (7.5mg), zolpidem, flunitrazepam and a placebo on nocturnal cognitive performance in healthy subjects, in relation to pharmacokinetics. Eur Psychiatry 1995; 10 Suppl. 3: 129–35S

    Article  Google Scholar 

  35. Danjou P, Paty I, Fruncillo R, et al. A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 h before awakening. Br J Clin Pharmacol 1999 Sep; 48(3): 367–74

    Article  PubMed  CAS  Google Scholar 

  36. Drover D, Lemmens H, Naidu S, et al. Pharmacokinetics, pharmacodynamics, and relative pharmacokinetic/ pharmacodynamic profiles of zaleplon and zolpidem. Clin Ther 2000 Dec; 22(12): 1443–61

    Article  PubMed  CAS  Google Scholar 

  37. Mintzer MZ, Griffiths RR. Triazolam and zolpidem: effects on human memory and attentional processes. Psychopharmacology (Berl) 1999 May; 144(1): 8–19

    Article  CAS  Google Scholar 

  38. Mintzer MZ, Griffiths RR. Selective effects of zolpidem on human memory functions. J Psychopharmacol 1999; 13(1): 18–31

    Article  PubMed  CAS  Google Scholar 

  39. Rush CR, Baker RW. Zolpidem and triazolam interact differentially with a delay interval on a digit-enterand-recall task. Hum Psychopharmacol 2001 Mar; 16(2): 147–57

    Article  PubMed  CAS  Google Scholar 

  40. Rush CR, Griffiths RR. Zolpidem, triazolam, and temazepam: behavioral and subject-rated effects in normal volunteers. J Clin Psychopharmacol 1996 Apr; 16(2): 146–57

    Article  PubMed  CAS  Google Scholar 

  41. Troy SM, Lucki I, Unruh MA, et al. Comparison of the effects of zaleplon, zolpidem, and triazolam on memory, learning, and psychomotor performance. J Clin Psychopharmacol 2000 Jun; 20(3): 328–37

    Article  PubMed  CAS  Google Scholar 

  42. Blin O, Micallef J, Audebert C, et al. A double-blind, placebo- and flurazepam-controlled investigation of the residual psychomotor and cognitive effects of modified release zolpidem in young healthy volunteers. J Clin Psychopharmacol 2006 Jun; 26(3): 284–9 745

    Article  PubMed  CAS  Google Scholar 

  43. Hindmarch I, Legangneux E, Stanley N, et al. A double-blind, placebo-controlled investigation of the residual psychomotor and cognitive effects of zolpidem-MR in healthy elderly volunteers. Br J Clin Pharmacol 2006 Nov; 62(5): 538–45

    Article  PubMed  CAS  Google Scholar 

  44. Greenblatt DJ, Legangneux E, Harmatz JS, et al. Dynamics and kinetics of a modified-release formulation of zolpidem: comparison with immediate-release standard zolpidem and placebo. J Clin Pharmacol 2006 Dec; 46(12): 1469–80

    Article  PubMed  CAS  Google Scholar 

  45. Greenblatt DJ, Harmatz JS, von Moltke LL, et al. Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo. Clin Pharmacol Ther 1998 Nov; 64(5): 553–61

    Article  PubMed  CAS  Google Scholar 

  46. Terzano MG, Rossi M, Palomba V, et al. New drugs for insomnia: comparative tolerability of zopiclone, zolpidem and zaleplon. Drug Saf 2003; 26(4): 261–82

    Article  PubMed  CAS  Google Scholar 

  47. Goa KL, Heel RC. Zopiclone. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy as an hypnotic. Drugs 1986 Jul; 32(1): 48–65

    Article  PubMed  CAS  Google Scholar 

  48. Griffiths AN, Jones DM, Richens A. Zopiclone produces effects on human performance similar to flurazepam, lormetazepam and triazolam. Br J Clin Pharmacol 1986 Jun; 21(6): 647–53

    Article  PubMed  CAS  Google Scholar 

  49. Isawa S, Suzuki M, Uchiumi M, et al. The effect of zolpidem and zopiclone on memory. Nihon Shinkei Seishin Yakurigaku Zasshi 2000 May; 20(2): 61–9

    PubMed  CAS  Google Scholar 

  50. Vermeeren A, Danjou PE, O’Hanlon JF. Residual effects of evening and middle-of-the-night administration of zaleplon 10 and 20 mg on memory and actual driving performance. Hum Psychopharmacol 1998; 13 Suppl. 2: S98–107

    Article  CAS  Google Scholar 

  51. Vermeeren A, Riedel WJ, van Boxtel MP, et al. Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol. Sleep 2002 Mar 15; 25(2): 224–31

    PubMed  Google Scholar 

  52. Boyle J, Trick L, Johnsen S, et al. Next-day cognition, psychomotor function, and driving-related skills following nighttime administration of eszopiclone. Hum Psychopharmacol 2008 Jul; 23(5): 385–97

    Article  PubMed  Google Scholar 

  53. Eszopiclone (Lunesta), a new hypnotic. Med Lett Drugs Ther 2005 Feb 28; 47(1203): 17–9

    Google Scholar 

  54. Griffiths RR, Johnson MW. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry 2005; 66 Suppl. 9: 31–41

    Google Scholar 

  55. Bensimon G, Foret J, Warot D, et al. Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo. Br J Clin Pharmacol 1990 Sep; 30(3): 463–9

    Article  PubMed  CAS  Google Scholar 

  56. Erman MK, Erwin CW, Gengo FM, et al. Comparative efficacy of zolpidem and temazepam in transient insomnia. Hum Psychopharmacol 2001 Mar; 16(2): 169–76

    Article  PubMed  CAS  Google Scholar 

  57. Fleming J, Scharf MB, Moldofsky H, et al. Comparison of residual effects and efficacy of zolpidem, flurazepam and placebo in patients with chronic insomnia. Clin Drug Invest 1995; 9(6): 303–13

    Article  Google Scholar 

  58. Gieschke R, Cluydts R, Dingemanse J, et al. Effects of bretazenil versus zolpidem and placebo on experimentally induced sleep disturbance in healthy volunteers. Methods Find Exp Clin Pharmacol 1994 Nov; 16(9): 667–5

    PubMed  CAS  Google Scholar 

  59. Morgan PJ, Chapados R, Chung FF, et al. Evaluation of zolpidem, triazolam, and placebo as hypnotic drugs the night before surgery. J Clin Anesth 1997 Mar; 9(2): 97–102

    Article  PubMed  CAS  Google Scholar 

  60. Richens A, Mercer AJ, Jones DM, et al. Effects of zolpidem on saccadic eye movements and psychomotor performance: a double-blind, placebo controlled study in healthy volunteers. Br J Clin Pharmacol 1993 Jul; 36(1): 61–5

    Article  PubMed  CAS  Google Scholar 

  61. Roth T, Roehrs T, Vogel G. Zolpidem in the treatment of transient insomnia: a double-blind, randomized comparison with placebo. Sleep 1995 May; 18(4): 246–51

    PubMed  CAS  Google Scholar 

  62. Sicard BA, Trocherie S, Moreau J, et al. Evaluation of zolpidem on alertness and psychomotor abilities among aviation ground personnel and pilots. Aviat Space Environ Med 1993 May; 64(5): 371–5

    PubMed  CAS  Google Scholar 

  63. Mintzer MZ, Frey JM, Yingling JE, et al. Triazolam and zolpidem: a comparison of their psychomotor, cognitive, and subjective effects in healthy volunteers. Behav Pharmacol 1997 Nov; 8(6–7): 561–74

    Article  PubMed  CAS  Google Scholar 

  64. McCall WV. Sleep in the elderly: burden, diagnosis, and treatment. Prim Care Companion J Clin Psychiatry 2004; 6(1): 9–20

    Article  PubMed  Google Scholar 

  65. Bocca ML, Le Doze F, Etard O, et al. Residual effect of zolpidem 10 mg and zopiclone 7.5 mg versus flunitrazepam 1 mg and placebo on driving performance and ocular saccades. Psychopharmacology (Berl) 1999 Apr; 143(4): 373–9

    Article  CAS  Google Scholar 

  66. Vermeeren A, O’Hanlon JF, Declerck A, et al. Acute effects of zolpidem and flunitrazepam on sleep, memory and driving performance, compared to those of partial sleep deprivation and placebo. Acta Ther 1995; 21: 47–64

    Google Scholar 

  67. Verster JC, Volkerts ER, Schreuder AH, et al. Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. J Clin Psychopharmacol 2002 Dec; 22(6): 576–83

    Article  PubMed  CAS  Google Scholar 

  68. Drake CL, Roehrs TA, Mangano RM, et al. Dose-response effects of zaleplon as compared with triazolam (0.25 mg) and placebo in chronic primary insomnia. Hum Psychopharmacol 2000 Dec; 15(8): 595–604

    Article  PubMed  CAS  Google Scholar 

  69. Beaumont M, Batejat D, Coste O, et al. Effects of zolpidem and zaleplon on sleep, respiratory patterns and performance at a simulated altitude of 4,000 m. Neuropsychobiology 2004; 49(3): 154–62

    Article  PubMed  CAS  Google Scholar 

  70. Walsh JK, Pollak CP, Scharf MB, et al. Lack of residual sedation following middle-of-the-night zaleplon administration in sleep maintenance insomnia. Clin Neuropharmacol 2000 Jan–Feb; 23(1): 17–21

    Article  PubMed  CAS  Google Scholar 

  71. Hindmarch I, Patat A, Stanley N, et al. Residual effects of zaleplon and zolpidem following middle of the night administration five hours to one hour before awakening. Hum Psychopharmacol 2001 Mar; 16(2): 159–67

    Article  PubMed  CAS  Google Scholar 

  72. Rush CR, Frey JM, Griffiths RR. Zaleplon and triazolam in humans: acute behavioral effects and abuse potential. Psychopharmacology (Berl) 1999 Jul; 145(1): 39–51

    Article  CAS  Google Scholar 

  73. Verster JC, Veldhuijzen DS, Patat A, et al. Hypnotics and driving safety: meta-analyses of randomized controlled trials applying the on-the-road driving test. Curr Drug Saf 2006 Jan; 1(1): 63–71 746

    Article  PubMed  CAS  Google Scholar 

  74. Warot D, Bensimon G, Danjou P, et al. Comparative effects of zopiclone, triazolam and placebo on memory and psychomotor performance in healthy volunteers. Fundam Clin Pharmacol 1987; 1(2): 145–52

    Article  PubMed  CAS  Google Scholar 

  75. Uchiumi M, Isawa S, Suzuki M, et al. The effects of zolpidem and zopiclone on daytime sleepiness and psychomotor performance. Nihon Shinkei Seishin Yakurigaku Zasshi 2000 Aug; 20(3): 123–30

    PubMed  CAS  Google Scholar 

  76. Tamminen T, Hansen PP. Chronic administration of zopiclone and nitrazepam in the treatment of insomnia. Sleep 1987; 10 Suppl. 1: 63–72

    Google Scholar 

  77. Ngen CC, 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): 165–71

    Article  PubMed  CAS  Google Scholar 

  78. Ponciano E, Freitas F, Camara J, et al. 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

    Google Scholar 

  79. Elie R, Lavoie G, Bourgouin J, et al. Zopiclone versus flurazepam in insomnia: prolonged administration and withdrawal. Int Clin Psychopharmacol 1990 Oct; 5(4): 279–86

    Article  PubMed  CAS  Google Scholar 

  80. Rosenberg R, Caron J, Roth T, et al. An assessment of the efficacy and safety of eszopiclone in the treatment of transient insomnia in healthy adults. Sleep Med 2005 Jan; 6(1): 15–22

    Article  PubMed  Google Scholar 

  81. Gary M, Rubens R, Amato D. Pharmacokinetic (PK) and pharmacodynamic (PD) effects of eszopiclone: a comparison of healthy non-elderly and elderly adults [abstract]. Sleep 2004; 27 Suppl.: A56

    Google Scholar 

  82. Roth T, Stubbs C, Walsh JK. Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep 2005 Mar 1; 28(3): 303–7

    PubMed  Google Scholar 

  83. Wang-Weigand S, Zammit G, Peng X. Effect of ramelteon on middle-of-the-night balance, mobility, and memory performance in older adults [abstract]. Sleep 2007; 30 Suppl.: A244

    Google Scholar 

  84. Hajak G, Ebrahim I, Hibberd M, et al. Ramelteon, unlike zopiclone, has no effect on body sway at peak plasma levels in insomnia patients [abstract]. Sleep 2007; 30 Suppl.: A245

    Google Scholar 

  85. Fry J, Scharf M, Mangano R, et al. Zaleplon improves sleep without producing rebound effects in outpatients with insomnia. Zaleplon Clinical Study Group. Int Clin Psychopharmacol 2000 May; 15(3): 141–52

    Article  PubMed  CAS  Google Scholar 

  86. Moldofsky H, Lue FA, Mously C, et al. The effect of zolpidem in patients with fibromyalgia: a dose ranging, double blind, placebo controlled, modified crossover study. J Rheumatol 1996 Mar; 23(3): 529–33

    PubMed  CAS  Google Scholar 

  87. Monti JM, Attali P, Monti D, et al. Zolpidem and rebound insomnia: a double-blind, controlled polysomnographic study in chronic insomniac patients. Pharmacopsychiatry 1994 Jul; 27(4): 166–75

    Article  PubMed  CAS  Google Scholar 

  88. Perlis ML, McCall WV, Krystal AD, et al. Long-term, nonnightly administration of zolpidem in the treatment of patients with primary insomnia. J Clin Psychiatry 2004 Aug; 65(8): 1128–37

    Article  PubMed  CAS  Google Scholar 

  89. Scharf M, Mendels J, Thorpy M, et al. Safety of long-term zolpidem treatment in patients with insomnia. Curr Ther Res 1994; 55(9): 1100–11

    Article  Google Scholar 

  90. Schlich D, L’Heritier C, Coquelin JP, et al. Long-term treatment of insomnia with zolpidem: a multicentre general practitioner study of 107 patients. J Int Med Res 1991 May–Jun; 19(3): 271–9

    PubMed  CAS  Google Scholar 

  91. Allain H, Arbus L, Schuck S, et al. Efficacy and safety of zolpidem administered ‘as needed’ in primary insomnia: results of a double-blind, placebo-controlled study. Clin Drug Invest 2001; 21(6): 391–400

    Article  CAS  Google Scholar 

  92. Evans SM, Funderburk FR, Griffiths RR. Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability. J Pharmacol Exp Ther 1990 Dec; 255(3): 1246–55

    PubMed  CAS  Google Scholar 

  93. Mintzer MZ, Frey JM, Griffiths RR. Zolpidem is differentiated from triazolam in humans using a three-response drug discrimination procedure. Behav Pharmacol 1998 Nov; 9(7): 545–59

    Article  PubMed  CAS  Google Scholar 

  94. Hajak G, Muller WE, Wittchen HU, et al. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 2003 Oct; 98(10): 1371–8

    Article  PubMed  CAS  Google Scholar 

  95. Soyka M, Bottlender R, Moller HJ. Epidemiological evidence for a low abuse potential of zolpidem. Pharmacopsychiatry 2000 Jul; 33(4): 138–41

    Article  PubMed  CAS  Google Scholar 

  96. Erman M, Krystal A, Zammit G, et al. Long-term efficacy of zolpidem extended-release in the treatment of sleep maintenance and sleep onset insomnia with improvements in next-day functioning [abstract]. Sleep 2007; 30 Suppl.: A241

    Google Scholar 

  97. Erman M, Krystal A, Zammit G, et al. No evidence of rebound insomnia in patients with chronic insomnia treate with zolpidem extended-release 12.5 mg administered “as needed” 3–7 nights/week for 6 months [abstract]. Sleep 2007; 30 Suppl.: A241–2

    Google Scholar 

  98. Walsh JK, Fry J, Erwin CW, et al. Efficacy and tolerability of 14-day administration of zaleplon 5mg and 10mg for the treatment of primary insomnia. Clin Drug Invest 1998; 16(5): 347–54

    Article  CAS  Google Scholar 

  99. Ancoli-Israel S, Walsh JK, Mangano RM, et al. Zaleplon: a novel nonbenzodiazepine hypnotic, effectively treats insomnia in elderly patients without causing rebound effects. Prim Care Companion J Clin Psychiatry 1999 Aug; 1(4): 114–20

    Article  PubMed  Google Scholar 

  100. Ator NA, Weerts EM, Kaminski BJ, et al. Zaleplon and triazolam physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons. Drug Alcohol Depend 2000 Dec 22; 61(1): 69–84

    Article  PubMed  CAS  Google Scholar 

  101. Ator NA. Zaleplon and triazolam: drug discrimination, plasma levels, and self-administration in baboons. Drug Alcohol Depend 2000 Dec 22; 61(1): 55–68

    Article  PubMed  CAS  Google Scholar 

  102. Jaffe JH, Bloor R, Crome I, et al. A postmarketing study of relative abuse liability of hypnotic sedative drugs. Addiction 2004 Feb; 99(2): 165–73

    Article  PubMed  Google Scholar 

  103. Bechelli LP, Navas F, Pierangelo SA. Comparison of the reinforcing properties of zopiclone and triazolam in former alcoholics. Pharmacology 1983; 27 Suppl. 2: 235–41 747

    Article  Google Scholar 

  104. Lovett B, Watts D, Grossman M. Prolonged coma after eszopiclone overdose. Am J Emerg Med 2007 Jul; 25(6): 735 e5-6

    Article  PubMed  Google Scholar 

  105. Krystal A, Walsh JK, Rubens R, et al. Efficacy and safety of six-months of nightly eszopiclone in patients with primary insomnia: a second long term placebo-controlled study [abstract]. Sleep 2006; 29 Suppl.: A249

    Google Scholar 

  106. Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003 Nov 1; 26(7): 793–9

    PubMed  Google Scholar 

  107. Roth T, Walsh JK, Krystal A, et al. An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Med 2005 Nov; 6(6): 487–95

    Article  PubMed  Google Scholar 

  108. France C, Weltman R, Cruz C, et al. Ramelteon does not have benzodiazepine agonist-like discriminative stimulus effects in normal or diazepam-dependent rhesus monkeys [abstract]. Sleep 2005; 28 Suppl.: A45

    Google Scholar 

  109. France C, Weltman R, Cruz C. Lack of primary physical dependence effects of ramelteon in rhesus monkeys [abstract]. Sleep 2005; 28 Suppl.: A45

    Google Scholar 

  110. Nishida N, Sasaki M, Wakasa Y, et al. Reinforcing effect of ramelteon assessed by intravenous self-administration experiments in rhesus monkeys [abstract]. Sleep 2005; 28 Suppl.: A45

    Google Scholar 

  111. Zammit G, Roth T, Erman M, et al. Double-blind, placebo-controlled polysomnography and outpatient trial to evaluate the efficacy and safety of ramelteon in adult patients with chronic insomnia [abstract]. Sleep 2005; 28 Suppl.: A228–9

    Google Scholar 

  112. Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry 2006 Oct; 63(10): 1149–57

    Article  PubMed  CAS  Google Scholar 

  113. Roehrs T, Rosenthal L, Koshorek G, et al. Effects of zaleplon or triazolam with or without ethanol on human performance. Sleep Med 2001 Jul; 2(4): 323–32

    Article  PubMed  Google Scholar 

  114. Karim A, Cao C, Zhao Z, et al. Pharmacokinetic interaction between ramelteon (tak-375) and ethanol in healthy adults [abstract]. AAPS J 2004; 6(4): R6196

    Google Scholar 

  115. Hesse LM, von Moltke LL, Greenblatt DJ. Clinically important drug interactions with zopiclone, zolpidem and zaleplon. CNS Drugs 2003; 17(7): 513–32

    Article  PubMed  CAS  Google Scholar 

  116. Wilkinson CJ. The abuse potential of zolpidem administered alone and with alcohol. Pharmacol Biochem Behav 1998 May; 60(1): 193–202

    Article  PubMed  CAS  Google Scholar 

  117. Tuk B, van Gool T, Danhof M. Mechanism-based pharmacodynamic modeling of the interaction of midazolam, bretazenil, and zolpidem with ethanol. J Pharmacokinet Pharmacodyn 2002 Jun; 29(3): 235–50

    Article  PubMed  CAS  Google Scholar 

  118. Sanchez Garcia P, Paty I, Leister CA, et al. Effect of zaleplon on digoxin pharmacokinetics and pharmacodynamics. Am J Health Syst Pharm 2000 Dec 15; 57(24): 2267–70

    PubMed  CAS  Google Scholar 

  119. Tolbert D, Karim A, Cao C, et al. Multiple-dose study to assess the effect of ramelteon (tak-375) on the pharmacokinetics of digoxin in healthy subjects [abstract]. AAPS J 2004; 6(4): R6195

    Google Scholar 

  120. Caron J, Wessel T, Maier G. Evaluation of a pharmacokinetic interaction between eszopiclone and diogxin [abstract]. Sleep 2004; 27 Suppl.: A55

    Google Scholar 

  121. Karim A, Tolbert D, Cao C, et al. Open-label assessment of the pharmacokinetics and pharmacodynamics of warfarin in the presence of multiple doses of ramelteon in healthy adults [abstract]. Sleep 2005; 28 Suppl.: A45–6

    Google Scholar 

  122. Maier G, Roach J, Rubens R. Evaluation of a pharmacokinetic and pharmacodynamic interaction between eszopiclone and warfarin [abstract]. Sleep 2004; 27 Suppl.: A56

    Google Scholar 

  123. Karim A, Tolbert D, Cao C, et al. Effects of fluconazole and ketoconazole on the pharmacokinetics of ramelteon (TAK-375) in normal healthy male and female subjects [abstract]. Sleep 2004; 27 Suppl.: A53–4

    Google Scholar 

  124. Greenblatt DJ, von Moltke LL, Harmatz JS, et al. Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole. Clin Pharmacol Ther 1998 Dec; 64(6): 661–71

    Article  PubMed  CAS  Google Scholar 

  125. Renwick AB, Ball SE, Tredger JM, et al. Inhibition of zaleplon metabolism by cimetidine in the human liver: in vitro studies with subcellular fractions and precision-cut liver slices. Xenobiotica 2002 Oct; 32(10): 849–62

    Article  PubMed  CAS  Google Scholar 

  126. Karim A, Tolbert D, Cao C, et al. A multiple-dose openlabel study to evaluate the effect of rifampin on the pharmacokinetics of ramelteon (tak-375) in healthy men and women [abstract]. AAPS J 2004; 6(4): R6197

    Google Scholar 

  127. Villikka K, Kivisto KT, Luurila H, et al. Rifampin reduces plasma concentrations and effects of zolpidem. Clin Pharmacol Ther 1997 Dec; 62(6): 629–34

    Article  PubMed  CAS  Google Scholar 

  128. Desager JP, Hulhoven R, Harvengt C, et al. Possible interactions between zolpidem, a new sleep inducer and chlorpromazine, a phenothiazine neuroleptic. Psychopharmacology (Berl) 1988; 96(1): 63–6

    Article  CAS  Google Scholar 

  129. Allard S, Sainati SM, Roth-Schechter BF. Coadministration of short-term zolpidem with sertraline in healthy women. J Clin Pharmacol 1999 Feb; 39(2): 184–91

    Article  PubMed  CAS  Google Scholar 

  130. Hetta J, Broman JE, Darwish M, et al. Psychomotor effects of zaleplon and thioridazine coadministration. Eur J Clin Pharmacol 2000 Jun; 56(3): 211–7

    Article  PubMed  CAS  Google Scholar 

  131. Saul S. Some sleeping pill users range far beyond bed. The New York Times 2006 Mar 8 [online]. Available from URL: http://www.nytimes.com/2006/03/08/business/08ambien.html [Accessed 2009 Jun 16]

  132. Saul S. Study links Ambien use to unconscious food forays. The New York Times 2006 Mar 14 [online]. Available from URL: http://www.nytimes.com/2006/03/14/health/14sleep.html [Accessed 2009 Jun 16]

  133. Dowd M. Valley of the rolls. The New York Times 2006 Mar 18 [online]. Available from URL: http://select.nytimes.com/2006/03/18/opinion/18dowd.html?_r=1 [Accessed 2009 Jun 16]

  134. Morgenthaler TI, Silber MH. Amnestic sleep-related eating disorder associated with zolpidem. Sleep Med 2002 Jul; 3(4): 323–7

    Article  PubMed  Google Scholar 

  135. Doane JA, Dalpiaz AS. Zolpidem-induced sleep-driving. Am J Med 2008 Nov; 121(11): e5

    Article  PubMed  Google Scholar 

  136. Dolder CR, Nelson MH. Hypnosedative-induced complex behaviours: incidence, mechanisms and management. CNS Drugs 2008; 22(12): 1021–36 748

    Article  PubMed  CAS  Google Scholar 

  137. Southworth MR, Kortepeter C, Hughes A. Nonbenzodiazepine hypnotic use and cases of “sleep driving”. Ann Intern Med 2008 Mar 18; 148(6): 486–7

    PubMed  Google Scholar 

  138. Najjar M. Zolpidem and amnestic sleep related eating disorder. J Clin Sleep Med 2007 Oct 15; 3(6): 637–8

    PubMed  Google Scholar 

  139. Tsai MJ, Tsai YH, Huang YB. Compulsive activity and anterograde amnesia after zolpidem use. Clin Toxicol (Phila) 2007; 45(2): 179–81

    Article  CAS  Google Scholar 

  140. Chiang A, Krystal A. Report of two cases where sleep related eating behavior occurred with the extended-release formulation but not the immediate-release formulation of a sedative-hypnotic agent. J Clin Sleep Med 2008 Apr 15; 4(2): 155–6

    PubMed  Google Scholar 

  141. Najjar M. Zolpidem and amnestic sleep related eating disorder. J Clin Sleep Med 2007 Oct 15; 3(6): 637–8

    PubMed  Google Scholar 

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Acknowledgements

The author would like to thank Ms Bridget Banas for her assistance in preparation of the manuscript. ## The author declares the following potential conflicts of interest: ## Grants/research support: Ancile Pharmaceuticals, Arena, Aventis, Cephalon Inc., Elan, Epix, Evotec, Forest, Glaxo-SmithKline, H. Lundbeck A/S, King Pharmaceuticals, Merck and Co., National Institute of Health (NIH), Neurim, Neurocrine Biosciences, Neurogen, Organon, Orphan Medical, Pfizer, Respironics, sanofi-aventis, Sanofi-Synthelabo, Schering-Plough, Sepracor, Somaxon, Takeda Pharmaceuticals North America, Transcept, UCB Pharma, Predix, Vanda, Wyeth-Ayerst Research. ## Consultancies: Aventis, Biovail, Boehringer-Ingelheim, Cephalon, Elan, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Jazz, King Pharmaceuticals, Ligand, McNeil, Merck, Neurocrine Biosciences, Organon, Pfizer, Renovis, sanofi-aventis, Select Comfort, Sepracor, Shire, Somnus, Takeda Pharmaceuticals, Vela, Wyeth. ## Honoraria: Neurocrine Biosciences, King Pharmaceuticals, McNeil, sanofi-aventis, Sanofi-Synthelabo, Sepracor, Takeda Pharmaceuticals, Vela Pharmaceuticals, Wyeth-Ayerst Research. ## Ownership/directorship: Clinilabs, Inc., Clinilabs IPA, Inc., Clinilabs Physician Services, PC. ## No industry stocks were held outside of mutual funds. ## No sources of funding were received for the preparation of this review.

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  1. Clinilabs, 423 W. 55th Street/4th Floor, New York, New York, 10019, USA

    Gary Zammit

  2. Columbia University College of Physicians and Surgeons, New York, New York, USA

    Gary Zammit

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Zammit, G. Comparative Tolerability of Newer Agents for Insomnia. Drug-Safety 32, 735–748 (2009). https://doi.org/10.2165/11312920-000000000-00000

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