Efficacy and safety of Z-substances in the management of insomnia in older adults: a systematic review for the development of recommendations to reduce potentially inappropriate prescribing

Abstract

Background Z-drugs are usually prescribed as first line pharmacological therapy for insomnia. However, the benefits and risks of Z-drugs may differ for older adults. This systematic review investigated the available evidence on the efficacy and safety of Z-drugs in the management of insomnia in older adults. Methods The Cochrane database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed/MEDLINE and EMBASE were searched for systematic reviews, meta-analyses, controlled interventional and observational studies using a pre-formulated search term. The target population was older adults (≥65 years old) with insomnia. Studies were included if they reported efficacy and/or safety outcomes of the use of Z-drugs for the management of insomnia compared to placebo, usual or no treatment, or other pharmacological agents. Results Eighteen studies were included (8 interventional and 10 observational studies). In short-term interventional studies, Z-drugs were similarly or better efficacious in improving both sleep and daytime parameters than placebo or other pharmacological treatments, while showing good results on measures of safety. However, in longer-term observational studies, Z-drugs significantly increased the risk for falls and fractures in comparison to no treatment or melatonin agonists. Conclusions Analyzing the evidence from short-term interventional studies, Z-drugs appear effective and safe for treatment of insomnia in older adults, but they may have unfavorable side effects when used for longer periods of time. We, therefore, recommend discontinuing Z-drugs, principally because of the high risk for falls and fractures. Nonetheless, quality and quantity of evidence are low. Due to the scarcity of data, especially concerning drug dependence after longer periods of treatment and due to the significantly increased risk for falls and fractures, further studies are needed to evaluate the benefit-risk profile of Z-drugs use in older patients, particularly for long-term use.

Potentially inappropriate medications and potential prescribing omissions in hospitalised older adults in New Zealand: A retrospective study

“…Zopiclone was another commonly used medicine in patients with a history of recent falls or prior history of use for over 4 weeks. Central nervous system (CNS) depressants, particularly those associated with a high risk of falls, are common PIMs in older adults, particularly in the oldest old group, 4,6 and can increase the risk of falls in this vulnerable population 14 …”

Use of low‐dose quetiapine increases the risk of major adverse cardiovascular events: results from a nationwide active comparator‐controlled cohort study

“…First, no ideal comparator to off-label, low-dose quetiapine exists, as other antipsychotics have at least some risk of cardiometa-bolic adverse events and are not used for the same indication as quetiapine, especially outside psychiatry. Z-drugs were chosen as the primary comparator, as they are a common alternative to low-dose quetiapine use as hypnotics 20 . However, Z-drug users are not an ideal comparator, likely having more comorbidities (especially in long-term users) than the average low-dose quetiapine user.…”

“…We conducted a new‐user, active‐comparator cohort study based on data from Danish nationwide health care registers. We included initiators of benzodiazepine‐related drugs (Z‐drugs) as an active comparator, because this drug class is widely used for the treatment of insomnia 20 . In sensitivity analyses, we also used SSRIs as an active comparator, which are used to treat anxiety, the second off‐label indication for low‐dose quetiapine.…”

Unveiling the sleep‐cardiovascular connection: Novel perspectives and interventions—A narrative review

“…59 On the other hand, a systematic review advises against using Z-drugs, for treating insomnia, despite its benefit in lengthening sleep, primarily due to the significant risk of fractures. 60 Melatonin used exogenously has positive impacts on cardiovascular health and improves the quality of sleep in patients with insomnia. 61 Another study demonstrated that 8 weeks, oral, 3 g…”

“…By speeding the beginning of sleep, increasing its efficiency, and lengthening the total time, dual and selective orexin‐2 receptor antagonists have demonstrated effectiveness in causing sleep in patients with insomnia disorders 59 . On the other hand, a systematic review advises against using Z‐drugs, for treating insomnia, despite its benefit in lengthening sleep, primarily due to the significant risk of fractures 60 …”