Journal of Medical Toxicology

, Volume 9, Issue 2, pp 155–162

The Clinical and Forensic Toxicology of Z-drugs

Review Article

Abstract

The Z-drugs zolpidem, zopiclone, and zaleplon were hailed as the innovative hypnotics of the new millennium, an improvement to traditional benzodiazepines in the management of insomnia. Increasing reports of adverse events including bizarre behavior and falls in the elderly have prompted calls for caution and regulation. Z-drugs have significant hypnotic effects by reducing sleep latency and improving sleep quality, though duration of sleep may not be significantly increased. Z-drugs exert their effects through increased γ-aminobutyric acid (GABA) transmission at the same GABA-type A receptor as benzodiazepines. Their pharmacokinetics approach those of the ideal hypnotic with rapid onset within 30 min and short half-life (1–7 h). Zopiclone with the longest duration of action has the greatest residual effect, similar to short-acting benzodiazepines. Neuropsychiatric adverse events have been reported with zolpidem including hallucinations, amnesia, and parasomnia. Poisoning with Z-drugs involves predominantly sedation and coma with supportive management being adequate in the majority. Flumazenil has been reported to reverse sedation from all three Z-drugs. Deaths from Z-drugs are rare and more likely to occur with polydrug overdose. Z-drugs can be detected in blood, urine, oral fluid, and postmortem specimens, predominantly with liquid chromatography–mass spectrometry techniques. Zolpidem and zaleplon exhibit significant postmortem redistribution. Zaleplon with its ultra-short half-life has been detected in few clinical or forensic cases possibly due to assay unavailability, low frequency of use, and short window of detection. Though Z-drugs have improved pharmacokinetic profiles, their adverse effects, neuropsychiatric sequelae, and incidence of poisoning and death may prove to be similar to older hypnotics.

Keywords

Zolpidem Zopiclone Zaleplon Poisoning Analysis 

References

  1. 1.
    Montplaisir J, Hawa R, Moller H et al (2003) Zopiclone and zaleplon vs benzodiazepines in the treatment of insomnia: Canadian consensus statement. Hum Psychopharmacol 18(1):29–38PubMedCrossRefGoogle Scholar
  2. 2.
    Stewart R, Besset A, Bebbington P et al (2006) Insomnia comorbidity and impact and hypnotic use by age group in a national survey population aged 16 to 74 years. Sleep 29(11):1391–1397PubMedGoogle Scholar
  3. 3.
    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
  4. 4.
    Dolder C, Nelson M, McKinsey J (2007) Use of non-benzodiazepine hypnotics in the elderly: are all agents the same? CNS Drugs 21(5):389–405PubMedCrossRefGoogle Scholar
  5. 5.
    Dang A, Garg A, Rataboli PV (2011) Role of zolpidem in the management of insomnia. CNS Neurosci Ther 17(5):387–397PubMedCrossRefGoogle Scholar
  6. 6.
    Wagner J, Wagner ML (2000) Non-benzodiazepines for the treatment of insomnia. Sleep Med Rev 4(6):551–581PubMedCrossRefGoogle Scholar
  7. 7.
    Dolder CR, Nelson MH (2008) Hypnosedative-induced complex behaviours: incidence, mechanisms and management. CNS Drugs 22(12):1021–1036PubMedCrossRefGoogle Scholar
  8. 8.
    Barbera J, Shapiro C (2005) Benefit-risk assessment of zaleplon in the treatment of insomnia. Drug Saf 28(4):301–318PubMedCrossRefGoogle Scholar
  9. 9.
    Verster JC, Veldhuijzen DS, Volkerts ER (2004) Residual effects of sleep medication on driving ability. Sleep Med Rev 8(4):309–325PubMedCrossRefGoogle 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.
    Sanofi-Aventis (2012) Product Information: Stilnox ® CR Modified Release Tablets. http://products.sanofi.com.au/aus_pi_stilnoxCR.pdf Accessed on 1 Dec 2012
  12. 12.
    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
  13. 13.
    Holm KJ, Goa KL (2000) Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 59(4):865–889PubMedCrossRefGoogle Scholar
  14. 14.
    Nutt DJ, Feetam CL (2010) What one hand giveth the other taketh away: some unpredicted effects of enantiomers in psychopharmacology. J Psychopharmacol 24(8):1137–1141PubMedCrossRefGoogle Scholar
  15. 15.
    George CF (2001) Pyrazolopyrimidines. Lancet 358(9293):1623–1626PubMedCrossRefGoogle Scholar
  16. 16.
    Drover DR (2004) Comparative pharmacokinetics and pharmacodynamics of short-acting hypnosedatives: zaleplon, zolpidem and zopiclone. Clin Pharmacokinet 43(4):227–238PubMedCrossRefGoogle Scholar
  17. 17.
    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
  18. 18.
    Halas CJ (2006) Eszopiclone. Am J Health Syst Pharm 63(1):41–48PubMedCrossRefGoogle Scholar
  19. 19.
    Najib J (2006) Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia. Clin Ther 28(4):491–516PubMedCrossRefGoogle Scholar
  20. 20.
    Staner L, Eriksson M, Cornette F et al (2009) Sublingual zolpidem is more effective than oral zolpidem in initiating early onset of sleep in the post-nap model of transient insomnia: a polysomnographic study. Sleep Med 10(6):616–620PubMedCrossRefGoogle Scholar
  21. 21.
    US Food & Drug Administration (2013) FDA requires lower recommended doses for certain drugs containing zolpidem http://www.fda.gov/Drugs/DrugSafety/ucm334033.htm Accessed 20 Jan 2013
  22. 22.
    Brunello N, Bettica P, Amato D et al (2008) Pharmacokinetics of (S)-zopiclone and (S)-desmethylzopiclone following dosing with zopiclone and eszopiclone. Eur Neuropsychopharmacol 18(S4):S581–S582CrossRefGoogle Scholar
  23. 23.
    Fernandez C, Maradeix V, Gimenez F et al (1993) Pharmacokinetics of zopiclone and its enantiomers in Caucasian young healthy volunteers. Drug Metab Dispos 21(6):1125–1128PubMedGoogle Scholar
  24. 24.
    Cienki JJ, Burkhart KK, Donovan JW (2005) Zopiclone overdose responsive to flumazenil. Clin Toxicol (Phila) 43(5):385–386CrossRefGoogle Scholar
  25. 25.
    Yang C-C, Deng J-F (2008) Utility of flumazenil in zopiclone overdose. Clin Toxicol (Phila) 46(9):920–921CrossRefGoogle Scholar
  26. 26.
    Patat A, Naef MM, van Gessel E et al (1994) Flumazenil antagonizes the central effects of zolpidem, an imidazopyridine hypnotic. Clin Pharmacol Ther 56(4):430–436PubMedCrossRefGoogle Scholar
  27. 27.
    Hojer J, Salmonson H, Sundin P (2002) Zaleplon-induced coma and bluish-green urine: possible antidotal effect by flumazenil. J Toxicol Clin Toxicol 40(5):571–572PubMedGoogle Scholar
  28. 28.
    Olubodun JO, Ochs HR, Truten V et al (2002) Zolpidem pharmacokinetic properties in young females: influence of smoking and oral contraceptive use. J Clin Pharmacol 42(10):1142–1146PubMedCrossRefGoogle Scholar
  29. 29.
    Hines LE, Murphy JE (2011) Potentially harmful drug–drug interactions in the elderly: a review. Am J Geriatr Pharmacother 9(6):364–377PubMedCrossRefGoogle Scholar
  30. 30.
    Hesse LM, von Moltke LL, Greenblatt DJ (2003) Clinically important drug interactions with zopiclone, zolpidem and zaleplon. CNS Drugs 17(7):513–532PubMedCrossRefGoogle Scholar
  31. 31.
    Hojo Y, Echizenya M, Ohkubo T et al (2011) Drug interaction between St John’s wort and zolpidem in healthy subjects. J Clin Pharm Ther 36(6):711–715PubMedCrossRefGoogle Scholar
  32. 32.
    Swainston Harrison T, Keating GM (2005) Zolpidem: a review of its use in the management of insomnia. CNS Drugs 19(1):65–89PubMedCrossRefGoogle Scholar
  33. 33.
    Vlase L, Popa A, Neag M et al (2011) Pharmacokinetic interaction between zolpidem and carbamazepine in healthy volunteers. J Clin Pharmacol 51(8):1233–1236PubMedCrossRefGoogle Scholar
  34. 34.
    Vlase L, Popa A, Neag M et al (2011) Pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers. Eur J Drug Metab Pharmacokinet 35(3–4):83–87PubMedCrossRefGoogle Scholar
  35. 35.
    US Food & 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
  36. 36.
    Duggal HS (2007) New-onset transient hallucinations possibly due to eszopiclone: a case study. Prim Care Companion J Clin Psychiatry 9(6):468–469PubMedCrossRefGoogle Scholar
  37. 37.
    Stone JR, Zorick TS, Tsuang J (2008) Dose-related illusions and hallucinations with zaleplon. Clin Toxicol (Phila) 46(4):344–345CrossRefGoogle Scholar
  38. 38.
    Tsai MJ, Huang YB, Wu PC (2003) A novel clinical pattern of visual hallucination after zolpidem use. J Toxicol Clin Toxicol 41(6):869–872PubMedCrossRefGoogle Scholar
  39. 39.
    Elko CJ, Burgess JL, Robertson WO (1998) Zolpidem-associated hallucinations and serotonin reuptake inhibition: a possible interaction. J Toxicol Clin Toxicol 36(3):195–203PubMedCrossRefGoogle Scholar
  40. 40.
    Sanger DJ (2004) The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS Drugs 18(S1):9–15PubMedCrossRefGoogle Scholar
  41. 41.
    Hajak G, Muller WE, Wittchen HU et al (2003) Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 98(10):1371–1378PubMedCrossRefGoogle Scholar
  42. 42.
    Chien C-C, Huanga H-T, Lung F-W et al (2011) Zolpidem withdrawal delirium, seizure, and acute psychosis: case reports and literature review. J Subs Use 16(4):330–338CrossRefGoogle Scholar
  43. 43.
    Greenblatt DJ, Roth T (2012) Zolpidem for insomnia. Expert Opin Pharmacother 13(6):879–893PubMedCrossRefGoogle Scholar
  44. 44.
    Victorri-Vigneau C, Dailly E, Veyrac G et al (2007) Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. Br J Clin Pharmacol 64(2):198–209PubMedCrossRefGoogle Scholar
  45. 45.
    Cimolai N (2007) Zopiclone: is it a pharmacologic agent for abuse? Can Fam Physician 53(12):2124–2129PubMedGoogle Scholar
  46. 46.
    Tonon MA, Bonato PS (2012) Methods for the analysis of nonbenzodiazepine hypnotic drugs in biological matrices. Bioanalysis 4(3):291–304PubMedCrossRefGoogle Scholar
  47. 47.
    Boniface PJ, Russell SG (1996) Two cases of fatal zopiclone overdose. J Anal Toxicol 20(2):131–133PubMedCrossRefGoogle Scholar
  48. 48.
    Han E, Kim E, Hong H et al (2012) Evaluation of postmortem redistribution phenomena for commonly encountered drugs. Forensic Sci Int 219(1–3):265–271PubMedCrossRefGoogle Scholar
  49. 49.
    Kintz P, Villain M, Concheiro M et al (2005) Screening and confirmatory method for benzodiazepines and hypnotics in oral fluid by LC-MS/MS. Forensic Sci Int 150(2–3):213–220PubMedCrossRefGoogle Scholar
  50. 50.
    Leikin JB, Watson WA (2003) Post-mortem toxicology: what the dead can and cannot tell us. J Toxicol Clin Toxicol 41(1):47–56PubMedCrossRefGoogle Scholar
  51. 51.
    Levine B (2010) Principles of forensic toxicology. AACC, Washington, DCGoogle Scholar
  52. 52.
    Rust KY, Baumgartner MR, Meggiolaro N et al (2012) Detection and validated quantification of 21 benzodiazepines and 3 “z-drugs” in human hair by LC-MS/MS. Forensic Sci Int 215(1–3):64–72PubMedCrossRefGoogle Scholar
  53. 53.
    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
  54. 54.
    Scott-Ham M, Burton FC (2005) Toxicological findings in cases of alleged drug-facilitated sexual assault in the United Kingdom over a 3-year period. J Clin Forensic Med 12(4):175–186PubMedCrossRefGoogle Scholar
  55. 55.
    Bramness JG, Arnestad M, Karinen R et al (2001) Fatal overdose of zopiclone in an elderly woman with bronchogenic carcinoma. J Forensic Sci 46(5):1247–1249PubMedGoogle Scholar
  56. 56.
    Garnier R, Guerault E, Muzard D et al (1994) Acute zolpidem poisoning—analysis of 344 cases. J Toxicol Clin Toxicol 32(4):391–404PubMedCrossRefGoogle Scholar
  57. 57.
    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
  58. 58.
    Gock SB, Wong SH, Nuwayhid N et al (1999) Acute zolpidem overdose—report of two cases. J Anal Toxicol 23(6):559–562PubMedCrossRefGoogle Scholar
  59. 59.
    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
  60. 60.
    Sanofi-Aventis (2011) Product monograph: Imovane (zopiclone). http://products.sanofi.ca/en/imovane.pdf Accessed 1 Dec 2012
  61. 61.
    Takayasu T, Ishida Y, Kimura A et al (2008) Distribution of zolpidem in body fluids and organ tissues in five autopsy cases. Forensic Toxicol 26(2):80–84CrossRefGoogle Scholar
  62. 62.
    Baselt RC (2004) Disposition of toxic drugs and chemicals in man. Biomedical, FosterGoogle Scholar
  63. 63.
    Bosker WM, Huestis MA (2009) Oral fluid testing for drugs of abuse. Clin Chem 55(11):1910–1931PubMedCrossRefGoogle Scholar
  64. 64.
    Laloup M, Ramirez Fernandez Mdel M, De Boeck G et al (2005) Validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of 26 benzodiazepines and metabolites, zolpidem and zopiclone, in blood, urine, and hair. J Anal Toxicol 29(7):616–626PubMedCrossRefGoogle Scholar
  65. 65.
    Kintz P (2012) Value of the concept of minimal detectable dosage in human hair. Forensic Sci Int 218(1–3):28–30PubMedCrossRefGoogle Scholar
  66. 66.
    Anderson DT, Budd RD (2009) Zaleplon (Sonata) analysis in postmortem specimens by gas chromatography-electron capture detection. J Anal Toxicol 33(8):481–485PubMedCrossRefGoogle Scholar
  67. 67.
    Levine B, Wu SC, Smialek JE (1999) Zolpidem distribution in postmortem cases. J Forensic Sci 44(2):369–371PubMedGoogle Scholar
  68. 68.
    Pounder DJ, Davies JI (1994) Zopiclone poisoning: tissue distribution and potential for postmortem diffusion. Forensic Sci Int 65(3):177–183PubMedCrossRefGoogle Scholar
  69. 69.
    Zosel A, Osterberg EC, Mycyk MB (2011) Zolpidem misuse with other medications or alcohol frequently results in intensive care unit admission. Am J Ther 18(4):305–308PubMedCrossRefGoogle Scholar
  70. 70.
    Louis CJ, Fernandez B, Beaumont C et al (2008) A case of zaleplon overdose. Clin Toxicol (Phila) 46(8):782CrossRefGoogle Scholar
  71. 71.
    Kuzniar TJ, Balagani R, Radigan KA et al (2010) Coma with absent brainstem reflexes resulting from zolpidem overdose. Am J Ther 17(5):e172–e174PubMedCrossRefGoogle Scholar
  72. 72.
    Hamad A, Sharma N (2001) Acute zolpidem overdose leading to coma and respiratory failure. Intensive Care Med 27(7):1239PubMedCrossRefGoogle Scholar
  73. 73.
    Lovett B, Watts D, Grossman M (2007) Prolonged coma after eszopiclone overdose. Am J Emerg Med 25(6):735, e735-736PubMedCrossRefGoogle Scholar
  74. 74.
    Fung HT, Lai CH, Wong OF et al (2008) Two cases of methemoglobinemia following zopiclone ingestion. Clin Toxicol (Phila) 46(2):167–170CrossRefGoogle Scholar
  75. 75.
    Fung HT, Lai CH, Wong OF et al (2009) Hemolytic anemia after zopiclone overdose. Clin Toxicol (Phila) 47(9):902–903CrossRefGoogle Scholar
  76. 76.
    Kung SW, Tse ML, Chan YC et al (2008) Zopiclone-associated methemoglobinemia and renal impairment. Clin Toxicol (Phila) 46(10):1099–1100CrossRefGoogle Scholar
  77. 77.
    Kurta DL, Myers LB, Krenzelok EP (1997) Zolpidem (Ambien): a pediatric case series. J Toxicol Clin Toxicol 35(5):453–457PubMedCrossRefGoogle Scholar
  78. 78.
    Carbajal R, Blanc P, Paupe A et al (1996) Flumazenil dans les intoxications au Zolpidem chez l'enfant. Arch Ped 3(2):191–192CrossRefGoogle Scholar
  79. 79.
    Darke S, Deady M, Duflou J (2012) Toxicology and characteristics of deaths involving zolpidem in New South Wales, Australia 2001–2010. J Forensic Sci 57(5):1259–1262PubMedCrossRefGoogle Scholar
  80. 80.
    Buckley NA, McManus PR (2004) Changes in fatalities due to overdose of anxiolytic and sedative drugs in the UK (1983–1999). Drug Saf 27(2):135–141PubMedCrossRefGoogle Scholar
  81. 81.
    Reith DM, Fountain J, McDowell R et al (2003) Comparison of the fatal toxicity index of zopiclone with benzodiazepines. J Toxicol Clin Toxicol 41(7):975–980PubMedCrossRefGoogle Scholar
  82. 82.
    Moore KA, Zemrus TL, Ramcharitar V et al (2003) Mixed drug intoxication involving zaleplon (“Sonata”). Forensic Sci Int 134(2–3):120–122PubMedCrossRefGoogle 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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