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Z-drugs and sleep in older adults

Drug-class library

Zolpidem, zaleplon and eszopiclone were introduced as the safer alternative to benzodiazepines for sleep. They act at largely the same receptor complex, and on the outcome that matters most in an older adult they are not safer.

Before you read on

Never stop or change a prescribed medication without speaking to your own prescriber. Several of the classes described on this site rebound, or cause a withdrawal syndrome, when they are stopped abruptly, and some have to be reduced gradually over weeks or months under supervision. Nothing here is advice about your own medication, and nothing here is a reason to change anything on your own.

The comparison that undoes the premise

A systematic review and meta-analysis of hip fracture risk in older people found Z-drugs at relative risk 1.90 (95% CI 1.68 to 2.13) against benzodiazepines at 1.52 (95% CI 1.37 to 1.68). Risk was greatest in newly prescribed patients in both classes — short-term use relative risk 2.39 for Z-drugs and 2.40 for benzodiazepines.

Switching from a benzodiazepine to a Z-drug in the name of fracture safety is therefore not supported by the fracture data.

What the evidence does and does not show

Sedating medications impair gait, balance and reaction time, and their labels say so. That part is not in doubt. What has not been shown is that a deprescribing program reduces fall rates — the trials that tested it were small, short, and mostly measured a medication count rather than a fracture. Those are two different questions, and absence of evidence from underpowered trials is not evidence that the drugs do not cause falls. What the evidence actually shows about deprescribing and falls.

How much do they actually help?

A meta-analysis of the data submitted to the FDA for approval — 13 studies, 65 drug-placebo comparisons, 4,378 participants — found Z-drugs reduced polysomnographic sleep latency by 22 minutes versus placebo (95% CI −33 to −11 minutes; standardized mean difference −0.36). Subjective sleep latency showed a standardized mean difference of −0.33. There were no significant effects on wake after sleep onset, number of awakenings, total sleep time or sleep efficiency.

The authors characterized the drug effect as “rather small and of questionable clinical importance,” with much of the total response attributable to placebo.

For sedative-hypnotics as a class in adults over 60, the trade-off is documented: total sleep time increased by 25.2 minutes, against adverse cognitive events 4.78 times more common, adverse psychomotor events 2.61 times more common, and daytime fatigue 3.82 times more common than placebo.

The 2019 boxed warning

On April 30, 2019 the FDA added a boxed warning and a new contraindication to eszopiclone (Lunesta), zaleplon (Sonata) and zolpidem (Ambien, Ambien CR, Edluar, Intermezzo, Zolpimist) for complex sleep behaviors.

The agency’s finding: “rare but serious injuries have happened with certain common prescription insomnia medicines because of sleep behaviors, including sleepwalking, sleep driving, and engaging in other activities while not fully awake. These complex sleep behaviors have also resulted in deaths. These behaviors appear to be more common with [these three drugs] than other prescription medicines used for sleep.”

The contraindication: “Healthcare professionals should not prescribe eszopiclone, zaleplon, or zolpidem to patients who have previously experienced complex sleep behaviors after taking any of these medicines.”

The FDA notes these behaviors may occur after a first dose or after continued use, may occur at lower dosages and not only high ones, and that patients may not remember them.

What the guidelines say

The American Academy of Sleep Medicine’s 2017 pharmacologic guideline grades every one of its drug recommendations as weak under GRADE — zolpidem, eszopiclone, zaleplon, temazepam, triazolam, suvorexant, ramelteon and doxepin alike. The same organization’s 2021 behavioral guideline gives multicomponent cognitive behavioral therapy for insomnia a strong recommendation.

The American College of Physicians reaches the same asymmetry: cognitive behavioral therapy for insomnia is a strong recommendation as initial treatment for all adults with chronic insomnia; adding a drug is a weak, short-term, shared-decision-making recommendation for those in whom therapy alone was unsuccessful.

And it works at this age

A meta-analysis of 23 randomized trials found adults over 55 showed improvements in sleep quality, sleep latency and wake-after-sleep-onset similar in magnitude to those in middle-aged adults. A randomized, double-blind, placebo-controlled trial of 46 older adults with chronic primary insomnia, using clinical polysomnography, found cognitive behavioral therapy beat zopiclone on three of four outcomes at six months — sleep efficiency improved from 81.4% to 90.1% with therapy against 82.3% to 81.9% with the drug — and that for most outcomes zopiclone did not differ from placebo. That trial is small; the sample size belongs with the finding.

Discontinuation

Z-drugs are covered by the same 2018 deprescribing guideline as benzodiazepines, which treats them together as benzodiazepine receptor agonists and recommends that slow tapering be offered to adults aged 65 and over regardless of duration of use — with the same exclusion for untreated anxiety, depression or other sleep disorders. Benzodiazepines.

Common questions

Are Z-drugs safer than benzodiazepines?

Not for hip fracture in older people, where the pooled relative risk was higher for Z-drugs (1.90) than for benzodiazepines (1.52). They were introduced as a safer alternative and that framing has not survived the fracture data. Deprescribing and falls.

How much extra sleep does a Z-drug actually give?

In the data submitted to the FDA for approval, about 22 minutes off the time to fall asleep, with no significant effect on total sleep time, awakenings or sleep efficiency. The authors called the effect “of questionable clinical importance.” What replaces the medication.

Back to the drug-class library.

References

  1. Donnelly K, Bracchi R, Hewitt J, Routledge PA, Carter B. Benzodiazepines, Z-drugs and the risk of hip fracture: A systematic review and meta-analysis. PLoS One. 2017;12(4):e0174730. PMID 28448593 · DOI 10.1371/journal.pone.0174730.
  2. Huedo-Medina TB, Kirsch I, Middlemass J, Klonizakis M, Siriwardena AN. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ. 2012;345:e8343. PMID 23248080 · DOI 10.1136/bmj.e8343.
  3. Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331(7526):1169. PMID 16284208 · DOI 10.1136/bmj.38623.768588.47.
  4. U.S. Food and Drug Administration. Certain Prescription Insomnia Medicines: New Boxed Warning — Due to Risk of Serious Injuries Caused by Sleepwalking, Sleep Driving and Engaging in Other Activities While Not Fully Awake. Drug Safety Communication, April 30, 2019. fda.gov. 2019. https://www.fda.gov/safety/medical-product-safety-information/certain-prescription-insomnia-medicines-new-boxed-warning-due-risk-serious-injuries-caused.
  5. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. Journal of Clinical Sleep Medicine. 2017;13(2):307–349. PMID 27998379 · DOI 10.5664/jcsm.6470.
  6. Edinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline. Journal of Clinical Sleep Medicine. 2021;17(2):255–262. PMID 33164742 · DOI 10.5664/jcsm.8986.
  7. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians. Annals of Internal Medicine. 2016;165(2):125–133. PMID 27136449 · DOI 10.7326/M15-2175.
  8. Irwin MR, Cole JC, Nicassio PM. Comparative meta-analysis of behavioral interventions for insomnia and their efficacy in middle-aged adults and in older adults 55+ years of age. Health Psychology. 2006;25(1):3–14. PMID 16448292 · DOI 10.1037/0278-6133.25.1.3.
  9. Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA. 2006;295(24):2851–2858. PMID 16804151 · DOI 10.1001/jama.295.24.2851.
  10. Pottie K, Thompson W, Davies S, et al. Deprescribing benzodiazepine receptor agonists: Evidence-based clinical practice guideline. Canadian Family Physician. 2018;64(5):339–351. PMID 29760253.
  11. Lee J, Negm A, Peters R, Wong EKC, Holbrook A. Deprescribing fall-risk increasing drugs (FRIDs) for the prevention of falls and fall-related complications: a systematic review and meta-analysis. BMJ Open. 2021;11(2):e035978. PMID 33568364 · DOI 10.1136/bmjopen-2019-035978.

Bibliographic records on this page were retrieved from PubMed. Every reference links to its DOI or PubMed record.

Written and medically reviewed by Dr. Gurpreet Singh Padda, MD, MBA, MHP, founder and medical director of DWARAA. Last reviewed . This page is educational. DWARAA does not prescribe, deprescribe, diagnose or treat.