Role of Lormetazepam in the Treatment of Insomnia in the Elderly

Maurizio De Vanna; Marta Rubiera; Maria Luisa Onor; Eugenio Aguglia


Clin Drug Invest. 2007;27(5):325-332. 

In This Article

Abstract and Introduction

Background and Objective: Sleep architecture changes with age, both in terms of efficiency and total duration of sleep. Hypnotic benzodiazepines promote rapid onset of sleep, uninterrupted sleep and longer duration of sleep in the absence of carryover sedation the following morning; therefore, these may be appropriate for use in older patients. This study was performed to evaluate the efficacy and safety of lormetazepam in elderly patients with primary insomnia when used in association with sleep hygiene training (SHT). The impact of restored sleep on daily sleepiness was also investigated.
Patients and Methods: In this open-label study, 30 elderly outpatients with insomnia were randomised to receive 2 weeks of treatment with lormetazepam 0.5mg + SHT or SHT alone, followed by a 1-week observation period. Details on sleep latency, number of awakenings and freshness on awakening were recorded by patients in a daily sleep diary. The Epworth Sleepiness Scale (ESS) and Stanford Sleepiness Scale (SSS) were used to measure daily sleepiness.
Results: Addition of lormetazepam to SHT improved all sleep parameters measured compared with SHT alone. Mean duration of sleep improved significantly from baseline (mean rank = 1.00) in the lormetazepam + SHT group after 2 weeks of treatment (mean rank 2.87; Friedmann test = 27.448; p < 0.001), but declined significantly in the group receiving SHT alone (from mean rank 2.33 to 1.57; Friedmann test = 6.465; p < 0.05). Mean duration of sleep increased by approximately 150 minutes each night in the lormetazepam + SHT group but decreased by more than 30 minutes in the SHT-only group. Improvement in sleep quality from baseline was statistically significant only in the lormetazepam + SHT group: for both deepness of sleep and the perception of awakening refreshed, mean scores increased from approximately 3 at baseline to approximately 8 (on a scale of 1–10) after 2 weeks in this group. Sleep latency also decreased significantly in the lormetazepam + SHT group: after 2 weeks, on average patients were awakening less than once per night. SSS and ESS scores also improved significantly in the lormetazepam + SHT group; in contrast, in the SHT-only group, the mean ESS score worsened significantly from baseline and the mean SSS score remained relatively constant. No rebound insomnia was reported during follow-up in patients in the lormetazepam group. Vital signs did not change from baseline and no adverse events were reported for either group.
Conclusion: Management of insomnia in the elderly appears to have a better outcome when pharmacotherapy is combined with SHT rather than SHT alone. The earlier improvement in sleep quality with lormetazepam when used in combination with a sleep training programme may help to maintain adherence to treatment.

With senescence comes a decline in sleep efficiency and total sleep time.[1,2] In a National Institute on Ageing (NIA) survey of 9000 American seniors aged >65 years, 28% reported difficulty falling asleep and/or maintaining sleep, and 18% reported early awakening and the inability to fall asleep again.[3] Although the actual time spent asleep decreases with age, total time spent in bed increases. Polysomnography studies have demonstrated that the amount of deep stage 3–4 sleep decreases relative to stage 1–2 sleep with increasing age. Rapid eye movement (REM) sleep also declines.[4] As many as 50% of elderly people report increases in time to initiate sleep, disruption of sleep maintenance and an overall dissatisfaction with the quality of sleep.[5,6] These sleep disturbances are associated with daytime napping and drowsiness, poor daytime functioning, reduced quality of life and the burden of increased healthcare costs.

Insomnia in the elderly may be classified as primary (that is, not caused by any known physical or mental condition) or secondary (that is, as a consequence of a number of factors, such as a personality trait[7] or physical, psychiatric or social changes).[8] Both neuroendocrine changes and changes in social rhythms of sleep hygiene may contribute to insomnia in later life. However, rather than aging per se, circadian rhythm shifts, primary sleep disorders, co-morbid medical and psychiatric illnesses, and medication use cause sleep difficulties in older people.[9]

Among non-pharmacological interventions, the most effective are sleep hygiene training (SHT), relaxation training, sleep restriction and biofeedback training.[10] Use of cognitive behavioural therapy (CBT) has been shown to be beneficial in treating between 70% and 80% of middle-aged adults with insomnia, according to the results of three meta-analyses.[11,12,13] Furthermore, a Cochrane systematic review of randomised controlled trials conducted in adults aged ≥60 years found that CBT had a mild benefit on insomnia, particularly in terms of sleep maintenance.[14]

Once underlying physical or psychiatric causes of insomnia have been addressed and attention has been paid to improving sleep hygiene, treatment with hypnotic agents can be effective in promoting sleep and improving sleep quality. Pharmacological management of insomnia in the general practice setting usually involves the use of benzodiazepines with short half-lives, even though controversy still exists because of alterations in pharmacodynamic/pharmacokinetic parameters with age. Furthermore, there is a risk of tolerance or dependence that has been described with this class of agents. These concerns, however, do not preclude the judicious use of benzodiazepines in selected cases where the potential benefits outweigh the risks. In particular, the risk of cognitive and psychomotor impairment associated with benzodiazepines needs to be weighed against the risk of cognitive and psychomotor impairments associated with sleep deprivation. In addition, the tendency to self-increase the dose of drug can be avoided by explaining that the purpose of pharmacological treatment is to restore good sleeping patterns rather than to eliminate the cause of insomnia. Hypnotic benzodiazepines approach the ideal when they promote rapid onset of sleep, uninterrupted sleep and longer duration of sleep in the absence of carryover sedation the following morning. However, there are relatively few robust studies that have compared the effects of benzodiazepines with non-pharmacological methods for improving sleep in older patients. One randomised, controlled trial that compared the effect of temazepam and CBT in older patients with primary insomnia demonstrated similar efficacy between treatments in terms of short-term effects, but a superior benefit with CBT over the long term.[15] In addition, Sivertsen and colleagues recently demonstrated that CBT has greater short- and long-term efficacy than zopiclone in older adults.[16]

Lormetazepam, a short-acting benzodiazepine widely used for the treatment of insomnia, is used in the elderly[17] and has demonstrated less dependence potential than some other benzodiazepines.[18] After oral administration, lormetazepam reaches maximum plasma levels in 2–3 hours, has a bioavailability of 70–80%, and has a plasma elimination half-life of 10–13 hours.[19] Unlike many other hypnotics, lormetazepam does not alter sleep patterns.[20]

The aim of the present open-label, randomised study was to investigate the short-term efficacy of lormetazepam in combination with SHT versus SHT alone in older adults.


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