Journal of Medical Toxicology

, Volume 9, Issue 2, pp 163–171

In the Zzz Zone: The Effects of Z-Drugs on Human Performance and Driving

Review Article

Abstract

Despite their improved pharmacokinetic profile, the Z-drugs, zolpidem, zopiclone, and zaleplon, have a spectrum of adverse effects comparable to benzodiazepines. This review focuses on the impairment from Z-drugs on cognition, behavior, psychomotor performance, and driving ability. Z-drugs are short-acting GABA agonists that reduce sleep latency without disturbing sleep architecture. Bizarre behavioral effects have prompted warnings on the prescription, dispensation, and use of Z-drugs. Psychomotor impairment, falls, and hip fractures are more likely to occur with Z-drugs that have longer half-lives, that are taken at higher-than-recommended doses and when mixed with other psychoactive substances including alcohol. Zopiclone and higher doses of zolpidem are more likely to cause anterograde amnesia than zaleplon. Z-drugs, especially zolpidem, are associated with complex behaviors such as sleepwalking, sleep-driving, and hallucinations. Patients taking zopiclone and zolpidem have an increased risk of motor vehicle collisions, over double that of unexposed drivers. Driving impairment occurs with zopiclone and higher doses of zolpidem but is unlikely to occur after 4 h post-zaleplon administration. The residual effect of Z-drugs on next-day cognitive and psychomotor performance has significant impact on lifestyle, safety, and occupational considerations, including motor vehicle and machine operation. The risk–benefit analysis of Z-drugs in the treatment of insomnia, particularly in the elderly, may not favor treatment due to the increased risks of falls and motor vehicle collisions. Prescribers should warn patients taking Z-drugs of minimum time thresholds before they operate machinery or drive motor vehicles.

Keywords

Zolpidem Zopiclone Zaleplon Automobile driving Psychomotor performance 

References

  1. 1.
    Gunja N (2013) The clinical & forensic toxicology of Z-drugs. J Med Toxicol. doi:10.1007/s13181-013-0292-0
  2. 2.
    Dang A, Garg A, Rataboli PV (2011) Role of zolpidem in the management of insomnia. CNS Neurosci Ther 17(5):387–397PubMedCrossRefGoogle Scholar
  3. 3.
    Wagner J, Wagner ML (2000) Non-benzodiazepines for the treatment of insomnia. Sleep Med Rev 4(6):551–581PubMedCrossRefGoogle Scholar
  4. 4.
    Barkin RL (2007) Zolpidem extended-release: a single insomnia treatment option for sleep induction and sleep maintenance symptoms. Am J Ther 14(3):299–305PubMedCrossRefGoogle Scholar
  5. 5.
    Drover DR (2004) Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet 43(4):227–238PubMedCrossRefGoogle Scholar
  6. 6.
    George CF (2001) Pyrazolopyrimidines. Lancet 358(9293):1623–1626PubMedCrossRefGoogle Scholar
  7. 7.
    Greenblatt DJ, Legangneux E, Harmatz JS et al (2006) Dynamics and kinetics of a modified-release formulation of zolpidem: comparison with immediate-release standard zolpidem and placebo. J Clin Pharmacol 46(12):1469–1480PubMedCrossRefGoogle Scholar
  8. 8.
    Halas CJ (2006) Eszopiclone. Am J Health Syst Pharm 63(1):41–48PubMedCrossRefGoogle Scholar
  9. 9.
    Najib J (2006) Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia. Clin Ther 28(4):491–516PubMedCrossRefGoogle Scholar
  10. 10.
    Nutt DJ, Stahl SM (2010) Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics. J Psychopharmacol 24(11):1601–1612PubMedCrossRefGoogle Scholar
  11. 11.
    Paul MA, Gray G, MacLellan M et al (2004) Sleep-inducing pharmaceuticals: a comparison of melatonin, zaleplon, zopiclone, and temazepam. Aviat Space Environ Med 75(6):512–519PubMedGoogle Scholar
  12. 12.
    US Food and Drug Administration (2007) FDA requests label change for all sleep disorder drug products. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108868.htm. Accessed 1 Dec 2012
  13. 13.
    Therapeutic Goods Administration (2007) Zolpidem and bizarre sleep related effects. Aust Adverse Drug React Bull 26(1):2–3, http://www.tga.gov.au/pdf/aadrb-0702.pdf Google Scholar
  14. 14.
    Ben-Hamou M, Marshall NS, Grunstein RR et al (2011) Spontaneous adverse event reports associated with zolpidem in Australia 2001–2008. J Sleep Res 20(4):559–568PubMedCrossRefGoogle Scholar
  15. 15.
    Dolder CR, Nelson MH (2008) Hypnosedative-induced complex behaviours: incidence, mechanisms and management. CNS Drugs 22(12):1021–1036PubMedCrossRefGoogle Scholar
  16. 16.
    Forrester MB (2006) Comparison of zolpidem and zaleplon exposures in Texas, 1998–2004. J Toxicol Environ Health A 69(20):1883–1892PubMedCrossRefGoogle Scholar
  17. 17.
    Verster JC, Volkerts ER, Schreuder AH et al (2002) Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. J Clin Psychopharmacol 22(6):576–583PubMedCrossRefGoogle Scholar
  18. 18.
    Vermeeren A, Danjou PE, O’Hanlon JF (1998) Residual effects of evening and middle-of-the-night administration of zaleplon 10 and 20 mg on memory and actual driving performance. Hum Psychopharmacol 13(S2):S98–S107CrossRefGoogle Scholar
  19. 19.
    Hindmarch I, Patat A, Stanley N et al (2001) Residual effects of zaleplon and zolpidem following middle of the night administration five hours to one hour before awakening. Hum Psychopharmacol 16(2):159–167PubMedCrossRefGoogle Scholar
  20. 20.
    Stone BM, Turner C, Mills SL et al (2002) Noise-induced sleep maintenance insomnia: hypnotic and residual effects of zaleplon. Br J Clin Pharmacol 53(2):196–202PubMedCrossRefGoogle Scholar
  21. 21.
    Mets MA, de Vries JM, de Senerpont Domis LM et al (2011) Next-day effects of ramelteon (8 mg), zopiclone (7.5 mg), and placebo on highway driving performance, memory functioning, psychomotor performance, and mood in healthy adult subjects. Sleep 34(10):1327–1334PubMedGoogle Scholar
  22. 22.
    Rosenberg R, Caron J, Roth T et al (2005) An assessment of the efficacy and safety of eszopiclone in the treatment of transient insomnia in healthy adults. Sleep Med 6(1):15–22PubMedCrossRefGoogle Scholar
  23. 23.
    Zammit GK, McNabb LJ, Caron J et al (2004) Efficacy and safety of eszopiclone across 6-weeks of treatment for primary insomnia. Curr Med Res Opin 20(12):1979–1991PubMedCrossRefGoogle Scholar
  24. 24.
    Boyle J, Trick L, Johnsen S et al (2008) Next-day cognition, psychomotor function, and driving-related skills following nighttime administration of eszopiclone. Hum Psychopharmacol 23(5):385–397PubMedCrossRefGoogle Scholar
  25. 25.
    Boyle J, Groeger JA, Paska W et al (2012) A method to assess the dissipation of residual hypnotics: eszopiclone versus zopiclone. J Clin Psychopharmacol 32(5):704–709PubMedCrossRefGoogle Scholar
  26. 26.
    Stoops WW, Rush CR (2003) Differential effects in humans after repeated administrations of zolpidem and triazolam. Am J Drug Alcohol Abuse 29(2):281–299PubMedCrossRefGoogle Scholar
  27. 27.
    Kleykamp BA, Griffiths RR, McCann UD et al (2012) Acute effects of zolpidem extended-release on cognitive performance and sleep in healthy males after repeated nightly use. Exp Clin Psychopharmacol 20(1):28–39PubMedCrossRefGoogle Scholar
  28. 28.
    Frey DJ, Ortega JD, Wiseman C et al (2011) Influence of zolpidem and sleep inertia on balance and cognition during nighttime awakening: a randomized placebo-controlled trial. J Am Geriatr Soc 59(1):73–81PubMedCrossRefGoogle Scholar
  29. 29.
    Morgan PT, Kehne JH, Sprenger KJ et al (2010) Retrograde effects of triazolam and zolpidem on sleep-dependent motor learning in humans. J Sleep Res 19(1 Pt 2):157–164PubMedCrossRefGoogle Scholar
  30. 30.
    Zanin KA, Patti CL, Sanday L et al (2012) Effects of zolpidem on sedation, anxiety, and memory in the plus-maze discriminative avoidance task. Psychopharmacology (Berl). doi:10.1007/s00213-012-2756-3
  31. 31.
    Olson LG (2008) Hypnotic hazards: adverse effects of zolpidem and other z-drugs. Aust Prescr 31(6):146–149Google Scholar
  32. 32.
    Tsai MJ, Tsai YH, Huang YB (2007) Compulsive activity and anterograde amnesia after zolpidem use. Clin Toxicol (Phila) 45(2):179–181CrossRefGoogle Scholar
  33. 33.
    Tsai JH, Yang P, Chen CC et al (2009) Zolpidem-induced amnesia and somnambulism: rare occurrences? Eur Neuropsychopharmacol 19(1):74–76PubMedCrossRefGoogle Scholar
  34. 34.
    Pressman MR (2011) Sleep driving: sleepwalking variant or misuse of z-drugs? Sleep Med Rev 15(5):285–292PubMedCrossRefGoogle Scholar
  35. 35.
    Southworth MR, Kortepeter C, Hughes A (2008) Nonbenzodiazepine hypnotic use and cases of “sleep driving”. Ann Intern Med 148(6):486–487PubMedCrossRefGoogle Scholar
  36. 36.
    Doane JA, Dalpiaz AS (2008) Zolpidem-induced sleep-driving. Am J Med 121(11):e5PubMedCrossRefGoogle Scholar
  37. 37.
    Hoque R, Chesson AL Jr (2009) Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: fluorine-18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other unexpected clinical effects of zolpidem. J Clin Sleep Med 5(5):471–476PubMedGoogle Scholar
  38. 38.
    Pressman MR (2011) Sleep and drug-impaired driving overlap syndrome. Sleep Medicine Clin 6(4):441–445CrossRefGoogle Scholar
  39. 39.
    Glass J, Lanctot KL, Herrmann N et al (2005) Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 331(7526):1169PubMedCrossRefGoogle Scholar
  40. 40.
    Woolcott JC, Richardson KJ, Wiens MO et al (2009) Meta-analysis of the impact of 9 medication classes on falls in elderly persons. Arch Intern Med 169(21):1952–1960PubMedCrossRefGoogle Scholar
  41. 41.
    Vermeeren A (2004) Residual effects of hypnotics: epidemiology and clinical implications. CNS Drugs 18(5):297–328PubMedCrossRefGoogle Scholar
  42. 42.
    Panneman MJ, Goettsch WG, Kramarz P et al (2003) The costs of benzodiazepine-associated hospital-treated fall injuries in the EU: a Pharmo study. Drugs Aging 20(11):833–839PubMedCrossRefGoogle Scholar
  43. 43.
    Kang DY, Park S, Rhee CW et al (2012) Zolpidem use and risk of fracture in elderly insomnia patients. J Prev Med Public Health 45(4):219–226PubMedCrossRefGoogle Scholar
  44. 44.
    Wang PS, Bohn RL, Glynn RJ et al (2001) Zolpidem use and hip fractures in older people. J Am Geriatr Soc 49(12):1685–1690PubMedCrossRefGoogle Scholar
  45. 45.
    Mets MA, Volkerts ER, Olivier B et al (2010) Effect of hypnotic drugs on body balance and standing steadiness. Sleep Med Rev 14(4):259–267PubMedCrossRefGoogle Scholar
  46. 46.
    Verster JC, Volkerts ER, Spence DW et al (2007) Effects of sleep medications on cognition, psychomotor skills, memory and driving performance in the elderly. Curr Psychiatry Rev 3(4):281–292CrossRefGoogle Scholar
  47. 47.
    Patat A, Paty I, Hindmarch I (2001) Pharmacodynamic profile of zaleplon, a new non-benzodiazepine hypnotic agent. Hum Psychopharmacol 16(5):369–392PubMedCrossRefGoogle Scholar
  48. 48.
    Troy SM, Lucki I, Unruh MA et al (2000) Comparison of the effects of zaleplon, zolpidem, and triazolam on memory, learning, and psychomotor performance. J Clin Psychopharmacol 20(3):328–337PubMedCrossRefGoogle Scholar
  49. 49.
    Paul MA, Gray G, Kenny G et al (2003) Impact of melatonin, zaleplon, zopiclone, and temazepam on psychomotor performance. Aviat Space Environ Med 74(12):1263–1270PubMedGoogle Scholar
  50. 50.
    Storm WF, Eddy DR, Welch CB et al (2007) Cognitive performance following premature awakening from zolpidem or melatonin induced daytime sleep. Aviat Space Environ Med 78(1):10–20PubMedGoogle Scholar
  51. 51.
    Ojaniemi KK, Lintonen TP, Impinen AO et al (2009) Trends in driving under the influence of drugs: a register-based study of DUID suspects during 1977–2007. Accid Anal Prev 41(1):191–196PubMedCrossRefGoogle Scholar
  52. 52.
    Ch’ng CW, Fitzgerald M, Gerostamoulos J et al (2007) Drug use in motor vehicle drivers presenting to an Australian, adult major trauma centre. Emerg Med Australas 19(4):359–365PubMedCrossRefGoogle Scholar
  53. 53.
    Hemmelgarn B, Suissa S, Huang A et al (1997) Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA 278(1):27–31PubMedCrossRefGoogle Scholar
  54. 54.
    Vingilis E, Wilk P (2012) Medical conditions, medication use, and their relationship with subsequent motor vehicle injuries: examination of the Canadian National Population Health Survey. Traffic Inj Prev 13(3):327–336PubMedCrossRefGoogle Scholar
  55. 55.
    Barbone F, McMahon AD, Davey PG et al (1998) Association of road-traffic accidents with benzodiazepine use. Lancet 352(9137):1331–1336PubMedCrossRefGoogle Scholar
  56. 56.
    Gustavsen I, Bramness JG, Skurtveit S et al (2008) Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam. Sleep Med 9(8):818–822PubMedCrossRefGoogle Scholar
  57. 57.
    Gjerde H, Normann PT, Pettersen BS et al (2008) Prevalence of alcohol and drugs among Norwegian motor vehicle drivers: a roadside survey. Accid Anal Prev 40(5):1765–1772PubMedCrossRefGoogle Scholar
  58. 58.
    Gjerde H, Christophersen AS, Normann PT et al (2011) Toxicological investigations of drivers killed in road traffic accidents in Norway during 2006–2008. Forensic Sci Int 212(1–3):102–109PubMedCrossRefGoogle Scholar
  59. 59.
    Orriols L, Philip P, Moore N et al (2011) Benzodiazepine-like hypnotics and the associated risk of road traffic accidents. Clin Pharmacol Ther 89(4):595–601PubMedCrossRefGoogle Scholar
  60. 60.
    Elvik R (2012) Risk of road accident associated with the use of drugs: a systematic review and meta-analysis of evidence from epidemiological studies. Accid Anal Prev. doi:10.1016/j.aap.2012.06.017
  61. 61.
    Verster JC, Roth T (2012) Gender differences in highway driving performance after administration of sleep medication: a review of the literature. Traffic Inj Prev 13(3):286–292PubMedCrossRefGoogle Scholar
  62. 62.
    Riedel WJ, Vermeeren A, Van Boxtel MPJ et al (1998) Mechanisms of drug-induced driving impairment: a dimensional approach. Hum Psychopharmacol Clin Exp 13(S2):S49–S63CrossRefGoogle Scholar
  63. 63.
    Verster JC, Veldhuijzen DS, Volkerts ER (2004) Residual effects of sleep medication on driving ability. Sleep Med Rev 8(4):309–325PubMedCrossRefGoogle Scholar
  64. 64.
    Verster JC, Veldhuijzen DS, Patat A et al (2006) Hypnotics and driving safety: meta-analyses of randomized controlled trials applying the on-the-road driving test. Curr Drug Saf 1(1):63–71PubMedCrossRefGoogle Scholar
  65. 65.
    Leufkens TR, Lund JS, Vermeeren A (2009) Highway driving performance and cognitive functioning the morning after bedtime and middle-of-the-night use of gaboxadol, zopiclone and zolpidem. J Sleep Res 18(4):387–396PubMedCrossRefGoogle Scholar
  66. 66.
    Verster JC, Spence DW, Shahid A et al (2011) Zopiclone as positive control in studies examining the residual effects of hypnotic drugs on driving ability. Curr Drug Saf 6(4):209–218PubMedCrossRefGoogle Scholar
  67. 67.
    Vermeeren A, Riedel WJ, van Boxtel MP et al (2002) Differential residual effects of zaleplon and zopiclone on actual driving: a comparison with a low dose of alcohol. Sleep 25(2):224–231PubMedGoogle Scholar
  68. 68.
    Partinen M, Hirvonen K, Hublin C et al (2003) Effects of after-midnight intake of zolpidem and temazepam on driving ability in women with non-organic insomnia. Sleep Med 4(6):553–561PubMedCrossRefGoogle Scholar
  69. 69.
    Bocca ML, Marie S, Lelong-Boulouard V et al (2011) Zolpidem and zopiclone impair similarly monotonous driving performance after a single nighttime intake in aged subjects. Psychopharmacology (Berl) 214(3):699–706CrossRefGoogle Scholar
  70. 70.
    Meskali M, Berthelon C, Marie S et al (2009) Residual effects of hypnotic drugs in aging drivers submitted to simulated accident scenarios: an exploratory study. Psychopharmacology 207(3):461–467PubMedCrossRefGoogle Scholar
  71. 71.
    Gjerde H, Normann PT, Christophersen AS et al (2011) Prevalence of driving with blood drug concentrations above proposed new legal limits in Norway: estimations based on drug concentrations in oral fluid. Forensic Sci Int 210(1–3):221–227PubMedCrossRefGoogle Scholar
  72. 72.
    Chu M, Gerostamoulos D, Beyer J et al (2012) The incidence of drugs of impairment in oral fluid from random roadside testing. Forensic Sci Int 215(1–3):28–31PubMedCrossRefGoogle Scholar
  73. 73.
    Vindenes V, Lund HME, Andresen W et al (2012) Detection of drugs of abuse in simultaneously collected oral fluid, urine and blood from Norwegian drug drivers. Forensic Sci Int 219(1–3):165–171PubMedCrossRefGoogle Scholar
  74. 74.
    Jones AW, Holmgren A (2012) Concentrations of zolpidem and zopiclone in venous blood samples from impaired drivers compared with femoral blood from forensic autopsies. Forensic Sci Int 222(1–3):118–123PubMedCrossRefGoogle Scholar
  75. 75.
    Gustavsen I, Al-Sammurraie M, Morland J et al (2009) Impairment related to blood drug concentrations of zopiclone and zolpidem compared to alcohol in apprehended drivers. Accid Anal Prev 41(3):462–466PubMedCrossRefGoogle Scholar
  76. 76.
    Fell JC, Voas RB (2006) The effectiveness of reducing illegal blood alcohol concentration (BAC) limits for driving: evidence for lowering the limit to.05 BAC. J Safety Res 37(3):233–243PubMedCrossRefGoogle Scholar
  77. 77.
    Verster JC, Roth T (2012) Blood drug concentrations of benzodiazepines correlate poorly with actual driving impairment. Sleep Med Rev. doi:10.1016/j.smrv.2012.05.004
  78. 78.
    Norwegian Institute of Public Health (2012) New legal limits in traffic for drugs other than alcohol. http://www.fhi.no/eway/default.aspx?pid=238&trg=MainLeft_5895&MainArea_5811=5895:0:15,5123:1:0:0:::0:0&MainLeft_5895=5825:95784::1:5896:1:::0:0. Accessed 30 Jan 2013
  79. 79.
    Vindenes V, Jordbru D, Knapskog AB et al (2012) Impairment based legislative limits for driving under the influence of non-alcohol drugs in Norway. Forensic Sci Int 219(1–3):1–11PubMedCrossRefGoogle Scholar
  80. 80.
    Drover D, Lemmens H, Naidu S et al (2000) Pharmacokinetics, pharmacodynamics, and relative pharmacokinetic/pharmacodynamic profiles of zaleplon and zolpidem. Clin Ther 22(12):1443–1461PubMedCrossRefGoogle Scholar
  81. 81.
    Reisfield GM, Goldberger BA, Gold MS et al (2012) The mirage of impairing drug concentration thresholds: a rationale for zero tolerance per se driving under the influence of drugs laws. J Anal Toxicol 36(5):353–356PubMedCrossRefGoogle Scholar
  82. 82.
    The International Council on Alcohol, Drugs and Traffic Safety (ICADTS) (2007) Categorization system for medicinal drugs affecting driving performance. http://www.icadts.org/reports/medicinaldrugs1.pdf. Accessed 2 Dec 2012
  83. 83.
    The International Council on Alcohol, Drugs and Traffic Safety (2007) ICADTS drugs list. http://www.icadts.org/reports/medicinaldrugs2.pdf. Accessed on 2 Dec 2012
  84. 84.
    Verster JC, Mets MAJ (2009) Psychoactive medication and traffic safety. Int J Environ Res Public Health 6(3):1041–1054PubMedCrossRefGoogle Scholar
  85. 85.
    Poceta JS (2011) Zolpidem ingestion, automatisms, and sleep driving: a clinical and legal case series. J Clin Sleep Med 7(6):632–638PubMedGoogle Scholar
  86. 86.
    Daley C, McNiel DE, Binder RL (2011) “I did what?” Zolpidem and the courts. J Am Acad Psychiatry Law 39(4):535–542PubMedGoogle Scholar
  87. 87.
    Weiss KJ, Del Busto E (2010) Sleep-driving and pathological intoxication: saved by the FDA? Am J Forensic Psychiatry 31(1):5–15Google Scholar
  88. 88.
    Weiss KJ, Watson C, Markov D et al (2011) Parasomnias, violence and the law. J Psychiatry Law 39(2):249–286Google Scholar
  89. 89.
    Horn M (2004) A rude awakening: what to do with the sleepwalking defense? BCL Rev 46(1):149–182Google Scholar

Copyright information

© American College of Medical Toxicology 2013

Authors and Affiliations

  1. 1.NSW Poisons Information CentreThe Children’s Hospital at WestmeadSydneyAustralia
  2. 2.Discipline of Emergency Medicine, Sydney Medical SchoolUniversity of SydneySydneyAustralia

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