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. 2021 Jan;25(1):1–202. doi: 10.3310/hta25010

Non-benzodiazepine hypnotic use for sleep disturbance in people aged over 55 years living with dementia: a series of cohort studies.

Kathryn Richardson, George M Savva, Penelope J Boyd, Clare Aldus, Ian Maidment, Eduwin Pakpahan, Yoon K Loke, Antony Arthur, Nicholas Steel, Clive Ballard, Robert Howard, Chris Fox
PMCID: PMC7812417  PMID: 33410736

Abstract

BACKGROUND

Sleep disturbance affects around 60% of people living with dementia and can negatively affect their quality of life and that of their carers. Hypnotic Z-drugs (zolpidem, zopiclone and zaleplon) are commonly used to treat insomnia, but their safety and efficacy have not been evaluated for people living with dementia.

OBJECTIVES

To estimate the benefits and harms of Z-drugs in people living with dementia with sleep disturbance.

DESIGN

A series of observational cohort studies using existing data from (1) primary care linked to hospital admission data and (2) clinical cohort studies of people living with dementia.

DATA SOURCES

Primary care study - Clinical Practice Research Datalink linked to Hospital Episode Statistics and Office for National Statistics mortality data. Clinical cohort studies - the Resource Use and Disease Course in Dementia - Nursing Homes (REDIC) study, National Alzheimer's Coordinating Centre (NACC) clinical data set and the Improving Well-being and Health for People with Dementia (WHELD) in nursing homes randomised controlled trial.

SETTING

Primary care study - 371 primary care practices in England. Clinical cohort studies - 47 nursing homes in Norway, 34 Alzheimer's disease centres in the USA and 69 care homes in England.

PARTICIPANTS

Primary care study - NHS England primary care patients diagnosed with dementia and aged > 55 years, with sleep disturbance or prescribed Z-drugs or low-dose tricyclic antidepressants, followed over 2 years. Clinical cohort studies - people living with dementia consenting to participate, followed over 3 years, 12 years and 9 months, for REDIC, NACC and WHELD, respectively.

INTERVENTIONS

The primary exposure was prescription or use of Z-drugs. Secondary exposures included prescription or use of benzodiazepines, low-dose tricyclic antidepressants and antipsychotics.

MAIN OUTCOME MEASURES

Falls, fractures, infection, stroke, venous thromboembolism, mortality, cognitive function and quality of life. There were insufficient data to investigate sleep disturbance.

RESULTS

The primary care study and combined clinical cohort studies included 6809 and 18,659 people living with dementia, with 3089 and 914 taking Z-drugs, respectively. New Z-drug use was associated with a greater risk of fractures (hazard ratio 1.40, 95% confidence interval 1.01 to 1.94), with risk increasing with greater cumulative dose (p = 0.002). The hazard ratio for Z-drug use and hip fracture was 1.59 (95% confidence interval 1.00 to 2.53) and for mortality was 1.34 (95% confidence interval 1.10 to 1.64). No excess risks of falls, infections, stroke or venous thromboembolism were detected. Z-drug use also did not have an impact on cognition, neuropsychiatric symptoms, disability or quality of life.

LIMITATIONS

Primary care study - possible residual confounding because of difficulties in identifying patients with sleep disturbance and by dementia severity. Clinical cohort studies - the small numbers of people living with dementia taking Z-drugs and outcomes not necessarily being measured before Z-drug initiation restricted analyses.

CONCLUSIONS

We observed a dose-dependent increase in fracture risk, but no other harms, with Z-drug use in dementia. However, multiple outcomes were examined, increasing the risk of false-positive findings. The mortality association was unlikely to be causal. Further research is needed to confirm the increased fracture risk. Decisions to prescribe Z-drugs may need to consider the risk of fractures, balanced against the impact of improved sleep for people living with dementia and that of their carers. Our findings suggest that when Z-drugs are prescribed, falls prevention strategies may be needed, and that the prescription should be regularly reviewed.

FUTURE WORK

More research is needed on safe and effective management strategies for sleep disturbance in people living with dementia.

STUDY REGISTRATION

This study is registered as European Union electronic Register of Post-Authorisation Studies (EU PAS) 18006.

FUNDING

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 1. See the NIHR Journals Library website for further project information.

Plain language summary

WHAT WAS THE PROBLEM?

Poor sleep is common in people living with dementia. It can worsen their own and their carer’s quality of life. Sleeping tablets called Z-drugs (zolpidem, zopiclone and zaleplon) are often given to people with dementia. Some studies suggest that Z-drugs may be harmful, but no studies have looked into the effects of Z-drugs for people with dementia. Good sleep is important, but we need to understand if Z-drugs cause harm.

WHAT DID WE DO?

Using existing medical records, we compared the quality of life, memory and number of falls, infections, strokes, broken bones and deaths for a group of people living with dementia taking a Z-drug, with those for a group not taking any sleep drug.

WHAT DID WE FIND?

Z-drug users were no more likely to suffer falls, infection or stroke, but they were more likely to break a bone. We also found that Z-drug users died earlier, but we could not be sure that this was as a result of taking the Z-drug. Using Z-drugs did not appear to affect quality of life or memory. We talked to carers and health-care practitioners, who told us that decisions about Z-drugs need to balance a range of complicated health and social factors.

WHAT DOES THIS MEAN?

We found that people living with dementia who take Z-drugs are more likely to break a bone or to die sooner than similar people with dementia who are not taking Z-drugs. However, we cannot be certain that these problems are caused by Z-drugs, as many other factors can also lead to broken bones and death. Further work is needed to clarify the risk of broken bones, but if sleep problems can be managed in other ways then this may be preferable. Patients and family carers should be involved in decisions about Z-drugs, so that they can balance the possible harms against the benefits.

Full text of this article can be found in Bookshelf.

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