Tools for Practice


#126 Z-drugs for sleep: Should we “Catch Some Z’s”?


CLINICAL QUESTION
Are Z-drugs (zopiclone, zolpidem, and eszopiclone) safe and effective in insomnia?


BOTTOM LINE
Z-drugs help people fall asleep faster (~13-22 minutes) and perhaps get ~5% more time sleeping while in bed. Z-drugs may increase the risk of mild infections (one in 43 patients) and have some inconsistent cognitive effects like reduced verbal memory or attention. 



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EVIDENCE
Seven systematic reviews1-7 (with duplicate publications4-7), including 3-48 randomized controlled trials (RCTs) (96-10,926 patients). Some focused primarily on benzodiazepines (with Z-drugs secondarily considered).1,2 Compared to placebo,  Z-drugs significantly affected:  Falling asleep faster: ~13-22 minutes.3-5  
  • Total sleep time: Not statistically different3-5 except by patient diary, 32 minutes more.4,5  
  • Perceived sleep quality: No difference in two meta-analyses.1,3 Another showed “moderate” improvement (standard mean difference 0.48).4  
  • Time asleep while in bed: no difference3 or improved ~5%.4,5  
  • Limitations: Not all outcomes evaluated in all reviewsshort duration (example mean 34 days3), used multiple comparisons, funded by manufacturers or funding source not reported,5,7 and possible publication bias.1  
Adverse effects: 
  • Meta-analysis of 20 RCTs (367 patients, mean age 37) found no significant effects on speed of processing, working/verbal memory or attention nine hours after drug administration compared to “control” except for: 
    • Moderate” negative effects (effect sizes 0.42-0.56) on verbal memory (zopiclone and zolpidem) and attention (zolpidem).8 
  • Meta-analysis of 36 placebo-controlled RCTs (13,211 patients) found significantly increased infections (6.9% vs. 4.6%, number needed to harm 43 over 36 days). Most infections likely mild (example pharyngitis).9 
  • Z-drugs (and other sedative-hypnotics) have been associated with increased mortality in some,10,11 but not all,12,13 cohort studies. 
    • Numerous potential confounders (like Z-drug patients sicker) and causation unproven
Context: 
  • Compared to benzodiazepines, there is no difference in time to fall asleep,2,6 sleep quality1,6 or adverse events.1 Total sleep time may be better with benzodiazepines (23 minutes).2 
  • Guidelines recommend zopiclone for short-term (<7 consecutive nights) or long-term (<3 nights/week) as an adjunct to cognitive and behavioural therapies.14 


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Author(s):

  • Adrienne J Lindblad BSP ACPR PharmD
  • G. Michael Allan MD CCFP

1. Glass J, Lanctôt KL, Herrmann N, et al. BMJ. 2005 Nov 19; 331(7526):1169.

2. Holbrook AM, Crowther R, Lotter A, et al. CMAJ. 2000 Jan 25; 162(2):225-33.

3. Huedo-Medina TB, Kirsch I, Middlemass J, et al. BMJ. 2012 Dec 17; 345:e8343.

4. Buscemi N, Vandermeer B, Friesen C, et al. Evid Rep Technol Assess (Summ). 2005 Jun; (125):1-10.

5. Buscemi N, Vandermeer B, Friesen C, et al. J Gen Intern Med. 2007 Sep; 22(9):1335-50.

6. Dündar Y, Boland A, Strobl J, et al. Health Technol Assess. 2004 Jun; 8(24):iii-x, 1-125.

7. Dündar Y, Dodd S, Strobl J, et al. Hum Psychopharmacol. 2004 Jul; 19(5):305-22.

8. Stranks EK, Crowe SF. J Clin Exp Neuropsych. 2014 Sep; 36(7): 691-700.

9. Joya FL, Kripke DF, Loving RT, et al. J Clin Sleep Med. 2009; 5(4):377-83.

10. Weich S, Pearce HL, Croft P, et al. BMJ. 2014 Mar 19; 348:g1996.

11. Kripke DF, Langer RD, Kline LE. BMJ Open. 2012 Feb 27; 2(1):e000850.

12. Gisev N, Hartikainen S, Chen TF, et al. Can J Psychiatry. 2011 Jun; 56(6):377-81.

13. Jaussent I, Ancelin ML, Berr C, et al. BMC Med. 2013 Sep 26; 11:212.

14. Towards Optimized Practice. Adult Insomnia: Diagnosis to management. Available for download at: http://www.topalbertadoctors.org/download/439/insomnia_management_guideline.pdf. Accessed July 3, 2014.

Authors do not have any conflicts to disclose.