Definition

Insomnia, as clarified by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Edition (DSM-IV TR), is a sleep disorder where the predominant complaint is difficulty initiating or maintaining sleep, or non-restorative sleep, occurring at least 3 times a week for at least 1 month. This can be more formally defined as a delay of greater than 30 minutes in falling asleep and/or sleep efficacy (the percentage of time in bed and actually asleep) of less than 85%. DSM-IV TR further states that the sleep disturbance, or associated daytime fatigue, must cause clinically significant distress or impairment in social, occupational or other important areas of functioning. Somewhat confusingly, DSM-IV TR states that insomnia cannot occur exclusively during the course of another sleep disorder (e.g. narcolepsy), or during a mental disorder (e.g. generalized anxiety), or be due to the direct psychological effects of a substance (e.g. drug abuse) or other medical condition. In essence, the DSM-IV TR criteria separate primary insomnia from what others call secondary insomnia.

Other ways of dividing this sleep disturbance labelled insomnia include ‘acute’ (less than 1 month duration) and chronic insomnia, transient (2–3 days)/short term (less than 3 weeks) and long-term, early/middle/late insomnia (difficulty falling asleep, maintaining sleep or waking too early) and mild/moderate/severe insomnia. Each has clinical usefulness. For the purpose of this review, insomnia will be that defined by DSM-IV TR, except that in some situations it will not have persisted for a month (e.g. insomnia due to hospitalization/environmental changes).

Prevalence

Insomnia is a common condition. One-third of people have sleep disturbance fulfilling DSM-IV TR criteria for insomnia at some time, and 6% have such insomnia at any one time. Sleep dissatisfaction occurs in 8–18% of the population at any one time and daytime consequences of insomnia (fatigue, distress) are present in 9–15% of the population. Australian data show 32.6% of the population have symptoms of insomnia at any one time and 75% have had sleep difficulties over the previous year.Reference Bartlett, Marshall, Williams and Grunstein² Only 11% of people had sought help from a doctor specifically for insomnia – most had tried to self medicate (herbal or over-the-counter medicine) or had accepted prescription drugs from friends or family. Whilst these incidence and prevalence figures apply to the whole population, older people contribute significantly as sleep disorder symptoms are more common with increasing age.

A community study of 3000 people found 14% of those aged 18–34 years had insomnia compared with 25% of those aged 65–76 years.Reference Mellinger, Bolten and Uhlentruth³ A more recent German study found insomnia affected 4.1% of men and 3.1% of women aged 20–29 years, but 12% of men and 35% of women over age 70 years.Reference Weyerer and Dilling⁴ Dissatisfaction with sleep is also more common with older age,Reference Jacobs, Cohen, Hammerman-Rozenberg and Stessman⁵ and complaints of sleep disturbance and transient (<1 month) insomnia affect 40% of the general population but over 50% of older people.Reference Ancoli-Israel⁶ Sleep disturbances are particularly of concern in residential care and hospital settings.Reference Fetveit and Bjorvatn⁷

An Australian community survey of 3300 people found older age is a risk factor for chronic daytime sleepiness.Reference Bartlett, Marshall, Williams and Grunstein⁸ Daytime napping affects 25–46% of older people.Reference Foley, Monjan, Brown, Simonsick, Wallace and Blazer^{9, 10} Insomnia symptoms are more prevalent in older women than in older menReference Foley, Monjan, Brown, Simonsick, Wallace and Blazer^9–Reference Ohayon, Zulley, Guilleminault, Smirne and Priest¹¹ but gender differences with daytime napping are not as well demonstrated.Reference Ancoli-Israel and Martin¹²

Causes

Old age itself is a risk factor for insomnia, for all sleep disturbances and for dissatisfaction with sleep, although few studies have included all co-morbidities to establish the independent contribution of old age. Similarly, it can be difficult to separate potential causes from consequences of sleep disturbances, with many appearing to be causative.

It is helpful to conceptualize sleep complaints as a multifactional geriatric syndrome, akin to other syndromes such as falls, incontinence and mobility disorders. Fragoso and GillReference Fragoso and Gill¹³ propose that sleep complaints and subsequent adverse outcomes can be caused by predisposing factors (normal ageing), precipitating factors (usual ageing) and perpetuating factors (which are usually psycho-social). Their model is shown in Figure 2.

Figure 2.

Mechanisms underlying sleep complaints and associated adverse outcomes¹³

Age-related changes in physiological functions cause the changes in the stages of sleep described above. These changes reflect changes in homeostatic mechanisms and circadian rhythms. Usual ageing is characterized by increased prevalence of a range of diseases, loss of function and also an increased prevalence of primary sleep disorders, and these can all precipitate sleep complaints and insomnia. Psychological factors that can precipitate sleep complaints include isolation, poor sleep hygiene, bereavement and the stresses of care-giving.

More often, the precipitating and predisposing factors are combined as ‘causes’ of insomnia and sleep complaints. An extensive, but by no means exhaustive, list of common causes and associations with sleep disturbance is shown in Table 2. Some of these causes/associations warrant further discussion.

Table 2.

Common causes and associations with sleep disturbance

Medications

Medication use is greater in older than in younger people, with the mean number of different medications used by a community-dwelling older person being around 4.Reference Cohen, Rogers, Burke and Beilin¹⁴ Some 44% of community-dwelling older Americans reported taking more than 5 medications in a week.Reference Kaufman, Kelly, Rosenberg, Anderson and Mitchell¹⁵ On discharge from hospital, the mean number of medications taken by an older person rose from 6.8 in 1999 to 7.5 within 2 years.Reference Scott and Jayathissa¹⁶ In residential care, the mean number of medications is around 6.Reference Tjia, Rothman, Kiely, Shaffer, Holmes, Sachs and Mitchell¹⁷ Many medications can disturb sleep – for instance, selective serotonin reuptake inhibitors (SSRIs) have been associated with reduced sleep efficiency and suppression of REM sleep. Even after excluding subjects with depression, SSRIs were associated with a greater chance of having 5 hours or fewer sleep per night and sleep efficiency of less than 70%.Reference Ensrud, Blackwell, Ancoli-Israel, Redline, Yaffe, Diem, Claman and Stone¹⁸ Medications that more frequently affect sleep, including causing insomnia, are those that act on the central nervous system, but other medications have been associated with insomnia. Adverse effects from medications (e.g. rash, urinary frequency, dyspepsia) are more common in older people and can also impact on sleep. Under-use of medications (e.g. to adequately treat pain, or to reduce nocturnal breathlessness from heart failure) can also impair sleep. Medications are also used extensively to improve sleep, as will be described below, and thus contribute both to polypharmacy in older age and the association between high medication use and sleep disturbance.

Chronic medical conditions

A range of medical conditions has been associated with impaired sleep, as outlined in Table 2. The list is not comprehensive – virtually any condition that causes discomfort by day can also affect sleep at night. Chronic physical conditions are very common in older people, with a recent USA National Sleep Foundation (NSF) poll showing 43% had 2–3 chronic conditions, 24% had 4 or more and only 10% had none.¹⁰ Most of the more prevalent conditions can be directly linked to sleep problems. For instance cardiac failure is causally related to insomnia, Parkinson's disease is linked to REM behaviour disorder, and nocturia is reported by older people to be one of the symptoms most disruptive to sleep.

Psychiatric and cognitive disorders

Both cognitive impairment and dementia are associated with sleep disorders. In the NSF poll some 62% of the older respondents who felt they had memory problems also had insomnia.¹⁰ In a community-based study, self-reports of excessive daytime sleepiness were associated with cognitive impairment in several domains, including recall, orientation and attention.Reference Obayon and Vecchierinni¹⁹ Dementia is associated with non-restorative sleep that has more stage 1 non-REM and less REM sleep along with more frequent nocturnal awakenings.Reference Moran, Lynch, Walsh, Coen, Coakley and Lawlor²⁰ Several conditions that can disrupt sleep are associated with dementia, including REM sleep behaviour disorder, psychosis and late afternoon agitation (‘sundowning’).Reference Moran, Lynch, Walsh, Coen, Coakley and Lawlor²⁰

Depression is also strongly associated with sleep impairment. In the NSF poll, 70% of older people who self-reported depression had insomnia and 32% said they were drowsy by day.¹⁰ Numerous studies have shown an association between depression and insomnia, and it is likely that this link is causal. Resolution of depression, either spontaneously or by treatment, leads to improved sleeping, supporting the causal link.

Delirium is characterized by a disturbed sleep/wake cycle and poor night-time sleeping. Older people are more likely to develop a hypoactive form of delirium that can be difficult to distinguish from daytime sleepiness/drowsiness. They may also develop a mixed hypoactive/hyperactive delirium that can mimic a sleep disturbance. Delirium is very common in hospital settings, with up to 40% of older patients affected at some stage during their admission.Reference Levkoff, Evans, Liptzin, Cleary, Lipsitz, Wetle, Reilly, Pilgrim, Schor and Rowe²¹

Other more common psychiatric disorders that cause or are linked with sleep disorders are shown in Table 2, but this list is not comprehensive. For instance mania, paraphrenia and psychosis are all linked with impaired sleep.

Consequences

Insomnia and other sleep disturbances are far from benign. It can be difficult to distinguish between associations, causes and consequences of insomnia and the consequences of the treatments used for insomnia. Likely consequences of insomnia are shown in Table 3.

Table 3.

Consequences of insomnia

Some of these consequences have been subject to more rigorous evaluation. Poor reported sleep quality, prolonged sleep latency, daytime drowsiness, low sleep efficiency and sleep-disordered breathing have been associated with increased frailty, although causation has not been fully establishedReference Ensrud, Blackwell, Redline, Ancoli-Israel, Paudel, Cawthon, Dam, Barrett-Connor, Leung and Stone^22, Reference Fragoso, Gahbauer, Van Ness and Gill²³ and insomnia itself was not independently associated with frailty. Daytime sleepiness has also been associated with functional impairment.Reference Gooneratne, Weaver, Cater, Pack, Arner, Greenberg and Pack²⁴ In elderly nursing home residents, insomnia but not hypnotic use was found to be associated with a greater risk of falls,Reference Avidan, Fries, James, Szafara, Wright and Chervin²⁵ and an association between sleep problems and falls has also been found in community studies.Reference Brassington, King and Bliwise²⁶ Subjective sleep problems were found to predict cognitive decline over a period of 3 years in the Maastricht Ageing Study,Reference Jelicic, Bosma, Ponds, Boxtel, Houx and Jolles²⁷ and chronic insomnia, somewhat loosely defined, predicted incident cognitive decline over 3 years in a study of 6444 community-dwelling men and women from four sites in the US Established Populations for Epidemiological Studies of the Elderly Study.Reference Cricco, Simonsick and Foley²⁸

Perhaps the most concerning consequence of insomnia and sleep disturbance is mortality. Numerous community studies have shown increased mortality in those with daytime sleepiness, daytime napping and fatigue,Reference Newman, Spiekerman, Enright, Lefkowitz, Manolio, Reynolds and Robbins^29–Reference Hardy and Studenski³² but others have not found such an association.Reference Althuis, Fredman, Langenberg and Magaziner^33, Reference Rockwood, Davis, Merry, MacKnight and McDowell³⁴ Interestingly, increased hours of evening sleep, rather than insomnia, have also been associated with increased mortality,Reference Stone, Ewing, Ancoli-Israel, Ensrud, Redline, Bauer, Cauley, Hillier and Cummings^31, Reference Mesas, Lopez-Garcia, Leon-Munoz, Guallar-Castillon and Rodriguez-Artalejo³⁵ suggesting that insomnia itself may not be causing increased mortality. Co-morbidity such as chronic physical illness and depression may be mediating the apparent association between sleep disturbances and increased mortalityReference Gureje, Kola, Ademola and Olley³⁶ – this association needs further evaluation.

Diagnosis

The presence of insomnia should be established using recognized criteria such as DSM-IV TR. Other sleep disorders are diagnosed by their characteristic features and are described below. It is not enough to simply diagnose the presence of insomnia; a cause or contributing factors should also be sought (Figure 3).

Figure 3.

An approach to the evaluation and treatment of insomnia

There is a range of sleep assessment tools. A 2-week sleep diary designed by the American Academy of Sleep Medicine can be useful.³⁷ The individual records use of stimulants such as coffee, taking medications, alcohol use and exercise. They record the time they go to bed and when they believe they fell asleep, and record whether they were asleep or awake throughout the 24-hour day. It is important to emphasize that they do not fill it in throughout the night. This diary, most importantly, can combat the mistaken perception that they are having very little sleep – for instance it may reveal that they are having 14 hours in bed overnight and whilst awake for 7 hours they are still having 7 hours sleep. It can also reveal excessive use of stimulants late in the day and insufficient exercise, amongst other useful information.

Other assessment approaches include a collaborative history from their bed partner or others who may be aware of them being awake or asleep overnight. Formal assessment tools include the 19-item self-rated Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI), the Sleep Problems Scale (SPS) and the Epworth Sleepiness Scale.

Tests that can be used in sleep disorder clinics and sleep laboratories include the multiple sleep latency tool (measuring speed to fall asleep), the maintenance of wakefulness test (the person is told to stay awake in a chair in a darkened room), polysomnography and actigraphy (the latter is especially useful in confirming the accuracy of a sleep diary).

A range of specialists may have interests and training in sleep disorders, including respiratory physicians, psychiatrists, geriatricians and neurologists – these are all a useful resource for more difficult cases. Sleep disorder clinics are found in larger cities and provide comprehensive assessment and management services.

Restless legs syndrome and periodic limb movements in sleep

These are the most common of the sleep-related movement disorders – approximately 10% of people over age 65 have restless legs syndrome, and this increases to 19% of those over the age of 80 years. This sleep disorder is characterized by an urge to move, particularly the legs, that worsens with inactivity and later in the day. About 80% of people with restless legs syndrome also have the other common sleep movement disorder, periodic limb movements in sleep, characterized by repetitive leg kicking (every 20–40 seconds) whilst asleep and often leading to awakenings. Restless legs syndrome may respond to dopaminergic therapy such as pramipexole, whilst the treatment of periodic limb movements in sleep usually requires specialist input.

Sleep disordered breathing (including sleep apnoea)

Sleep disordered breathing is common in older adults but frequently either not recognized or not diagnosed. Whilst prevalence studies based on sleep laboratory studies suggest a declining prevalence and severity with older age, community-based studies show high morbidity attributable to sleep disordered breathing. Clinical manifestations in older people include cognitive impairment, loss of function, and increased risk of accidents such as falls and motor vehicle crashes. Cardiovascular consequences include stroke, ischaemic heart disease and hypertension. Diagnosis is based on symptoms, observations including of periods of apnoea overnight, loud snoring and daytime drowsiness. The definitive diagnostic test is a sleep study – an apnoea-hypopnoea index of 5 or greater diagnoses sleep disordered breathing but treatment may not be needed unless there are accompanying symptoms. For obstructive sleep apnoea, at least 70% of older people can tolerate the preferred treatment, continuous positive airways pressure (CPAP) overnight and it is worth persisting if initially CPAP is not tolerated. Central sleep apnoea may be secondary to insomnia, hypoxaemia, respiratory depressant medications and neurological disorders, and usually requires detailed input from sleep and other specialists.

REM sleep behaviour disorder

REM sleep behaviour disorder (RBD) is a sleep disorder in which patients appear to be enacting their dreams whilst in the REM stage of sleep.Reference Trotti³⁸ The behaviours can be quite violent, and are associated with violent dream content. Injury to self or bed partner can ensue. The disorder mainly affects older adults, with onset in the sixth and seventh decades, with a prevalence of around 0.5%. The frequency is much higher, however, in certain neurodegenerative diseases such as dementia with Lewy bodies, Parkinson's disease and multi-system atrophy (Shy Drager syndrome). An idiopathic form can occur, but individuals with this may subsequently develop one of these neurodegenerative diseases. The underlying mechanism appears to be lack of normal REM muscle atonia and a lack of the normal suppression of locomotor generators during REM sleep. Alpha-synuclein deposition in brainstem areas may be the main underlying pathology. It can occur when treatment with an antidepressant is commenced, or upon withdrawal of a hypnotic or of alcohol.

Whilst clonazepam is an effective therapy, a high risk of adverse effects in older people make it less useful in this age group. Slow-release melatonin has demonstrated effectiveness in uncontrolled case studies, and there are also reports of responses to acetylcholinesterase inhibitors such as rivastigmine. Interventions to improve the safety of the sleep environment, and particularly to prevent injuries, are important.

General advice

After adequate assessment, initial management of insomnia should be treatment of identified causes. For example, excess caffeine should be reduced, late night meals avoided, pain treated and environmental noise reduced. These approaches should be combined with providing information about normal sleep patterns, and general sleep hygiene measures, as outlined in Table 4.

Table 4.

Sleep hygiene

Usually these general, non-pharmacological approaches are sufficient, especially for acute insomnia. Before resorting to pharmacological approaches, other management options should be explored. These include cognitive behavioural therapy, and light therapy.

Psychological treatment

A range of psychological therapies has proved useful for the management of insomnia. There is a perception that older people respond less well to psychotherapy, but this is not supported by evidence. Useful approaches include:

• • stimulus control: this associates the bedroom with sleep alone – prohibiting most other activities such as lying in bed watching TV.

• • temporal control: this sets up a consistent time of waking and prohibits daytime napping.

• • sleep restriction: time in bed is limited to short periods that are gradually increased.

• • relaxation therapy: biofeedback and progressive muscle relaxation can be utilized. Listening to soothing music is also useful.

• • paradoxical therapy: the fear of insomnia is reduced by encouraging the individual to remain awake for as long as possible.

• • cognitive behavioural therapies (CBT): there is a wide range of CBT approaches that can be administered by trained health professionals who may not necessarily be psychologists.

Professionals who regularly manage individuals with insomnia and other sleep disorders are best suited to administer most of these approaches, but a family (general) physician trained in them can also utilize them with success. Even one or two 60–90 minute sessions can be efficacious.

The benefits of psychological approaches have been established in two meta-analyses, a systematic review and a review of 23 randomized controlled trials. Individual studies used a mixture of single behaviour therapy techniques and more formal CBT.Reference Riemann and Perlis³⁹ Outcomes included improved sleep latency (by about 3 min), reduced wake time after sleep onset (by about 22 min), increased total sleep time (by 15 min) and improved sleep quality. Effect sizes were generally around 0.6, but ranged from 0.17 to 0.94, with 0.2–0.3 considered clinically meaningful.

In 2006 a task force commissioned by the American Academy of Sleep Medicine (AASM) published a revised report in order to update its practice parameters on psychological and behaviour therapies for insomnia.Reference Morin, Bootzin, Buysse, Edinger, Espie and Lichstein⁴⁰ This systematic review was conducted on 37 studies comprising 2346 patients and provided findings consistent with the meta-analyses described above. The authors concluded that five treatments (stimulus control, relaxation, paradoxical therapy, sleep restriction and multimodal CBT) met criteria for empirically supported psychological therapies for insomnia. In addition, the changes in sleep parameters were well maintained at short (1–3 months), intermediate (6 months) and long term (>12 months) follow-ups, although there were few long-term studies, so the long-term data need to be interpreted with caution.

Education

Education programmes with literature and tape-recorded instructions on progressive relaxation training have proved effective for up to 1 year. At that time, 90% of the individuals had been successfully trained, and 82% of them had experienced greater ease in falling asleep, staying asleep and reduced use of hypnosedatives.Reference Gustafson⁴¹ All non-pharmacological approaches should be accompanied by educational material.

Light therapy

Early studies suggested a benefit of bright light exposure, presumably via effects on the circadian rhythms. In a community study of older people with over 1 year of insomnia, daily exposure to bright light reduced the time awake at night by 1 hour and improved sleep efficiency from 78 to 90%.Reference Campbell⁴² Similar results have been demonstrated in a nursing home settingReference Ancoli-Israel, Martin, Kripke, Marler and Klauber⁴³ and in those with dementia.Reference Sloane, Williams, Mitchell, Preisser, Wood, Barrick, Hickman, Gill, Connell, Edinger and Zimmerman⁴⁴ More recent studies show less convincing results.Reference Friedman, Zeitzer, Kushida, Zhdanova, Noda, Lee, Schneider, Guilleminault, Sheikh and Yesavage⁴⁵ It may be that the timing of the light exposure and the intensity of the light moderate the effectiveness of this approach. Bright light (74,000 lux) has also been shown to improve performance in older people with sleep maintenance insomnia.Reference Murphy and Campbell⁴⁶

Other non-pharmacological approaches

Low energy emission therapy utilizing an electrically conducing mouthpiece used for about 20 minutes in the late afternoon has been shown to increase sleep time, and acupuncture has also been utilized frequently for insomnia (both have been reviewedReference Asplund⁴⁷). Daytime napping has been used successfully to increase the 24-hour sleeping time,Reference Campbell, Murphy and Stauble⁴⁸ and Tai Chi has been shown to improve self-rated sleep quality, reduce sleep onset latency (by 18 min), and increase sleep duration (by 48 min).Reference Li, Fisher, Harmer, Irbe, Tearse and Weimer⁴⁹

Non-pharmacological approaches in varied settings

Most of the interventions described above were used in community settings. A sleep protocol for hospitalized elderly requesting a hypnotic has been shown to improve sleep quality as well as reduce use of hypnotics from 54 to 31% (P < 0.002).Reference McDowell, Mion, Lydon and Inouye⁵⁰ The regime included a back/shoulder rub, a warm non-stimulant bedtime drink, relaxation tapes and reduced environmental noise and light. In residential care (nursing homes) a multi-component programme that included reduced time in bed, 30 minutes exposure to sunlight, increased physical activity, a structured bed-time routine and reduced night-time noise and light, resulted in improvements in night-time wakenings and day-time sleeping.Reference Alessi, Schnelle, MacRae, Ouslander, al-Samarrai, Simmons and Traub⁵¹ In a separate study, however, a similar programme was not successful.Reference Ouslander, Connell, Bliwise, Endeshaw, Griffiths and Schnelle⁵²

Utilizing non-pharmacological approaches

Older people are usually open to a ‘wait and see’ approach to insomnia – this includes avoiding hypnosedatives and utilizing basic non-pharmacological approaches. Similarly, health professionals can be trained to avoid the ‘prescription reflex’ even though this may be different from current practice. One USA study of family physicians found 53% failed to ask about sleep, and 46% identified a prescription as best therapy.Reference Everitt, Avorn and Baker⁵³ Non-pharmacological approaches should always be utilized, although the risks of not immediately reducing sleep deprivation (e.g. daytime drowsiness associated with some behavioural therapies) should be explained. In practice, both non-pharmacological and pharmacological approaches are often commenced together – indeed, there is some evidence that combined hypnotic and CBT is more effective than CBT alone acutely, but long-term outcome is optimized when the hypnotic is discontinued and CBT continued.Reference Morin, Vallières, Guay, Ivers, Savard, Mérette, Bastien and Baillargeon⁵⁴

Pharmacological management

Whilst there is justified concern about the overuse of BZDs and other modern hypnosedatives in older people, they represent a major advance over older agents and have a definite place in the management of insomnia and sleep disorders. The history of pharmacological management of sleep disorders shows how far we have come. Alcohol has been used for millennia, and still is, but the first drugs used specifically for hypnotic effects were the bromides in the 19th century. In 1903, barbiturates were first used, with a great deal of associated toxicity and morbidity. They were replaced by the much safer BZDs in the 1950s, with chlordiazepoxide (Librium) first used in 1959, then diazepam, from the same Roche Laboratory in 1963. The ‘Z’ drugs (e.g. zolpidem and zopiclone) were developed in the late 1980s. New hypnotics continue to be developed, with the melatonin receptor agonist ramelteon one of the most recent. The quest is for safer rather than necessarily more effective drugs, but this enthusiasm is sometimes over-embraced by prescribers as a guarantee of safety. Correctly used, hypnotic agents are useful but there is still far too much, and inappropriate, use.

Benzodiazepines (BZDs)

Commonly used BZD hypnotics

The BZDs most commonly used for hypnotic effects are shown in Table 5. The most favourable pharmacokinetic profile in older people is exhibited by temazepam with metabolism by liver conjugation rather than CYP450 oxidation of the drug, a reasonably rapid onset of action and an acceptable elimination half-life. In many countries, including Australia, it is the most widely prescribed hypnotic BZD.

Table 5.

Commonly used BZD hypnotics

Adverse effects of BZDs

Whilst BZDs are much safer than earlier hypnotics, they still have a wide range of adverse effects, as shown in Table 6. Particular concerns in older people include sedation, cognitive impairment, psychomotor impairment and discontinuation syndrome. The consequences of longer-term use in older people include falls, fractures, motor vehicle accidents and indeed increased mortality.Reference Woodward⁵⁶ The major drug interactions of concern are outlined in Table 7.

Table 6.

Adverse events associated with BZD use

Table 7.

Major drug interactions with hypnotic BZDs

‘Z’ drugs

Mechanism of action

These also interact with the GABA_A–BZD receptor complex to potentiate the inhibiting actions of GABA at the receptor. At least three types of BZD receptors have been described. The Z-drugs bind preferentially to the BZD₁ receptor, in contrast to the BZDs, which non-selectively bind to, and activate, all BZD receptor subtypes. This selective binding of the Z-drugs to the BZD₁ receptor may explain their predominantly selective hypnotic properties and their minimal anxiolytic, muscle relaxant and anti-epileptic properties.

Like the BZDs, the most important differences between the Z-drugs are their pharmacokinetics, particularly their duration of action, as outlined in Table 8.

Table 8.

Commonly used Z-drugs

Adverse effects of Z-drugs

Zolpidem has been associated with unusual reactions including bizarre behaviours such as sleepwalking, sleep eating and sleep driving, sometimes with fatal consequences. Other adverse effects include diarrhoea, dizziness, visual disturbances and changes in colour perception. The most common adverse effects reported with zopiclone use are a metallic taste and dry mouth.

Common drug interactions with the Z-drugs include increased central nervous system (CNS) depression with CNS depressants such as alcohol and opioids, increased plasma levels when administered with CYP34A inhibitors such as ketoconazole, erythromycin and ritonavir, and decreased plasma levels when given with hepatic enzyme inducers such as rifampicin, phenytoin and St John's Wort.

Effectiveness of Z-drugs

The short-term effectiveness (up to 6 weeks) of the Z-drugs was analysed in a meta-analysis that compared these drugs with a range of BZDs.Reference Dündar, Boland, Strobl, Dodd, Haycox, Bagust, Bogg, Dickson and Walley⁵⁸ The evaluations include 24 randomized controlled trials that compared either the Z-drugs with several BZDs (17 trials) or any two of three Z-drugs (zopiclone, zolpidem, zaleplon (7 trials)). There were no significant variations in safety or efficacy between the Z-drugs and the BZDs. Minor differences were noted within the Z-drug class but the clinical significance was unknown.

In another meta-analysis confined to older people (>60 years of age) with insomnia and otherwise free of psychiatric or psychological disorders, 24 randomized controlled short-term trials used either Z-drugs, several BZDs or an antihistamine (diphenhydramine) for at least 5 nights.Reference Glass, Lanctôt, Herrman, Sproule and Busto⁵⁹ The hypnotic group combined, compared with placebo, modestly improved sleep quality (effect size 0.14, P < 0.05), total sleep time (mean 25.2 min, P < 0.001), and the number of sleep awakenings decreased (by 0.63, P < 0.001). Adverse effects were, however, more common with hypnotic versus placebo – these included adverse cognitive effects, psychomotor effects and day-time fatigue. No differences were reported between the various drug groups; certainly the Z-drugs were at least as effective as the BZDs.

Longer-term effectiveness of the Z-drugs has been evaluated (unlike the BZDs). One study of 250 patients aged 59–95 years with chronic insomnia showed zaleplon used continuously for 1 year significantly improved sleep latency, number of awakenings and total sleep time (P < 0.001 for each variable) for up to the full year.Reference Ancoli-Israel, Richardson, Mangano, Jenkins, Hall and Jones⁵⁵ Sleep latency improved from a baseline mean of 79.6 ± 47.0 min to 44.4 ± 33.6 min at 1 year, and total sleep time improved from 300.2 ± 67.8 to 356.7 ± 71.0 min. It was, however, an open-label single-blind extension study.

In another randomized, double-blind placebo-controlled trial to determine the long-term effectiveness of eszopiclone, nearly 800 patients aged 21–69 years with primary insomnia were treated nightly for 6 months.Reference Krystal, Walsh, Laska, Caron, Amato, Wessel and Roth⁶⁰ Eszopiclone produced significant improvements in sleep latency, number of awakenings and total sleep time compared with placebo (P = 0.003) and these improvements were sustained over the 6-month period. The most common adverse events were unpleasant taste and headaches. To date, eszopiclone is the only hypnotic approved by the USA FDA for use longer than 35 days. It is to be noted, however, that this trial did not include people over 70 years of age.

Efficacy of BZD and Z-drugs compared with behavioural therapies

A number of clinical trials have assessed the efficacy of the BZD and Z-drugs combined with, or compared with, behavioural therapy in the treatment of insomnia. These generally show short-term benefits of the hypnotic but longer term benefits only from behavioural therapy. A meta-analysis comparing pharmacological and non-pharmacological treatments included 21 studies (7 only had pharmacological treatment, 13 only behavioural and one compared both) and showed comparable short-term effectiveness (2–4 weeks) for both psychological/behavioural treatments and pharmacotherapy in patients (of all ages) with primary insomnia.Reference Smith, Perlis, Park, Smith, Pennington, Giles and Buysse⁶¹ The 2009 study by Morin et al.,Reference Morin, Vallières, Guay, Ivers, Savard, Mérette, Bastien and Baillargeon⁵⁴ referred to above, examined long-term intermittent zolpidem therapy (6 months) in conjunction with CBT in 160 patients with persistent insomnia. There were added benefits of the combined therapies compared with either alone in the acute phase, but long-term outcome was optimized when medication was discontinued, rather than continued, during long-term maintenance CBT. This is an extremely important finding as it demonstrates not only the benefits of long-term behavioural therapy but also the importance of NOT continuing hypnotic therapy long term.

Melatonin and related therapies

Melatonin may be useful in those who have insomnia related to circadian rhythm disturbances, especially where they have difficulty falling asleep. Initial short studies (up to 7 weeks) with standard melatonin failed to show benefits, but more recent studies with a controlled (slow) release formulation have demonstrated effectiveness. In a large, randomized double-blind, placebo-controlled study (354 individuals), which included patients aged 55–80 years, 3 weeks treatment with controlled release melatonin was associated with significant improvements in sleep scales, daytime alertness, quality of life and sleep latency (13 min, compared with 25 with placebo).Reference Wade, Ford, Crawford, McMahon, Nir, Laudon and Zisapel⁶² Other studies have shown similar benefits,Reference Lemoine, Nir, Laudon and Zisapel⁶³ with newer research suggesting that benefits persist beyond 3 weeks.

The melatonin receptor agonist ramelteon has also been shown to be effective in older people. A trial in 829 individuals over 65 showed an improvement in sleep latency with up to 5 weeks of therapy (17 versus 37 min at 5 weeks).Reference Mini, Wang-Weigand and Zhang⁶⁴ This drug has now been approved in several countries.

Attractions of melatonin-based therapies include safety and the low risk of dependency/abuse, although long-term data are still lacking. Melatonin can potentially cause coronary vasoconstriction, but this has not been found in the trials. The study of ramelteon showed a slightly higher rate of dysgeusia (altered taste) and dizziness in the ramelteon-treated group compared with the placebo-treated group.

Valerian

This herb has long been regarded as a safe, effective sleep-promoting agent. A systematic review, however, produced inconsistent resultsReference Stevinson and Ernst⁶⁵ and a recent small study showed no benefit.Reference Taibi, Vitiello, Barsness, Elmer, Anderson and Landis⁶⁶ Another recent trial showed benefits on sleep latency if used with hops, but not if used alone.Reference Koetter, Schrader, Kaufeler and Brattstrum⁶⁷ Daytime sleepiness from valerian has been reported, and there have been rare cases of hepatotoxicity.

Other drugs

Antidepressants may be beneficial when depression or anxiety is associated with insomnia, but their side-effect profile in older people makes them inappropriate as first-line therapy for insomnia not associated with these disorders. There are no studies of antipsychotic agents, including the newer ‘atypical’ agents, for insomnia and again the risk of adverse effects precludes their use for insomnia alone. Sedating antihistamines have been shown to have some beneficial effects on insomnia but they also can reduce sleep quality, increase daytime drowsiness and rapidly induce tolerance. Their side-effects profile also makes them inappropriate as treatment of insomnia in older individuals.

Recommended use of pharmacological management of insomnia

Pharmacological therapy should only be utilized when non-pharmacological approaches have failed after an appropriate period (3–6 weeks ideally). In some settings, however, where adequate sleep is needed immediately (e.g. in rehabilitation units), it may be appropriate to initiate pharmacotherapy after a shorter period. Non-pharmacological approaches should be continued along with pharmacotherapy. As there is little evidence to support long-term use of hypnotic agents, and as all are associated with adverse effects, therapy should not be continued beyond 6 weeks – a possible exception is slow release melatonin, which is relatively safe and has been shown to be effective for up to 13 weeks. Cessation of the hypnotic after 6 weeks may enhance the longer-term benefits of ongoing behavioural therapy.

Preferred BZD receptor acting agents in older people are temazepam (initially 5–10 mg), zolpidem (5–10 mg) and zopiclone (3.75–7.5 mg). Slow-release melatonin is an alternative choice.

Recently the American Academy of Sleep medicine produced a recommended hierarchy of pharmacological approaches to the management of chronic insomnia in adults.Reference Schutte-Rodin, Broch, Buysse, Dorsey and Sateia⁶⁸ They recommended only short-term use of a hypnotic and supplementing this with behavioural and cognitive therapies when possible. When pharmacological therapy is utilized, the choice of a specific pharmacological agent should be directed by factors including patient preferences, the symptom pattern, past treatment responses, co-morbid conditions and adverse effects of the agent. They recommended one of temazepam, zolpidem, zaleplon, eszopiclone or ramelteon as the first choice and trialling another drug from this group of five if the first choice fails. They somewhat surprisingly then recommend a sedating antidepressant, but couch this by saying this is especially when there is co-morbid depression/anxiety. Most specialists in the treatment of older adults would be far more cautious in the use of these agents if there were no depression or anxiety. The guidelines also state that, if there is epilepsy or psychosis, sedating agents used for these conditions may also assist sleep but they should not be utilized in the absence of the primary indication. They state that antihistamines, analgesics and herbal or nutritional substances (including valerian and immediate-release melatonin) are not recommended for chronic insomnia, nor are all other agents (e.g. barbiturates and chloral hydrate). They recommend an initial 2–4 week trial, and utilization of the lowest effective dose. The guidelines were produced before controlled-release melatonin had been sufficiently evaluated.

Deprescribing hypnotic agents

BZD and Z-drug overuse and abuse are major concerns. Long-term use of these medications is associated with tolerance and dependence. Risk factors for these include psychiatric co-morbidity, older age, an avoidance style of coping, lower education and longer-term use. Tolerance to the hypnotic effects of these agents can develop within days to a few weeks, and is to be distinguished from the much longer time to develop tolerance to anxiolytic effects (4–6 months). This tolerance may lead to dose escalations and a higher risk of adverse effects. Dependence may be physiological, leading to withdrawal symptoms when ceased, and psychological – including fear/anxiety (especially at the thought of discontinuation), loss of confidence and drug-seeking behaviour.

It is thus essential to avoid unnecessary longer term use of these agents, and to cease/reduce (‘deprescribe’) them whenever possible. Discontinuation syndromes include confusion, anxiety, temporarily increased insomnia and autonomic features. These can be overcome by patient education, treatment of withdrawal symptoms and ongoing support. There is a lack of clear guidelines but several articles have specifically addressed deprescribing hypnotics in older individuals.Reference Woodward^69–Reference Woodward⁷¹ There is support for substituting an equivalent dose of a longer-acting drug such as diazepam, then slowly tapering (e.g. from 15 mg diazepam to cessation over 26 weeks). Other approaches, including non-substitution with sudden cessation or cessation through utilization of alternative, then every third and so on, night use of the initial shorter-acting agent, also have support.

The recreational use of agents such as BZDs is beyond the scope of this review but is not confined to younger people. Easy availability of large quantities of these agents may promote this, and monitoring use as well as ongoing attempts to deprescribe are essential.

Dementia

All forms of cognitive impairment, including mild cognitive impairment, are associated with an increased risk of sleep disorders including insomnia, which affects up to 70% of people with cognitive impairment. Dementia with Lewy bodies seems to carry the highest risk of sleep disturbance. Pharmacological treatment of insomnia can lead to cognitive decline. The long-acting BZDs are most commonly associated with cognitive impairment in this population, and longer terms of use of these agents pose a greater risk than short-term use. The cognitive impairment is manifested by anterograde amnesia, reduced short-term recall and increased forgetfulness. BZD use and withdrawal is a risk factor for delirium, commonly in the in-patient setting.

It is thus important to give preference to non-pharmacological over pharmacological management of sleep disorders in those with cognitive impairment, and to deprescribe hypnotic agents in these individuals wherever possible. If a hypnotic must be used, short courses of shorter acting BZD receptor agents such as temazepam or possibly the use of slow-release melatonin, are preferable. The aim should always be to cease pharmacological management as soon as possible.

Caregivers can also suffer insomnia, especially if depressed, and this also needs to be recognized and managed. Indeed, caregiving is associated with poorer health, poorer quality of life and even increased mortality, and this may be partly mediated by sleep disturbances in the caregivers.

Depression

Depression is a very common disorder in older age but is often mis-diagnosed and incorrectly treated. If insomnia or anxiety are presenting features, a BZD may be inappropriately used as first-line therapy. Many studies have found a strong association between BZD use and depression, suggesting that BZD use may actually lead to or prolong depression. In a study of 599 subjects aged 85 years at baseline and followed for 5 years, BZD users were 1.6 times more likely (95% CI = 1.05–2.55, P = 0.028) to develop new depressive symptoms.Reference van Vlier, Van der Mast, van den Bruek, Westendorp and de Craen⁷² Thus it is important to diagnose depression in those with sleep disorders such as insomnia, and to treat this with an appropriate antidepressant rather than a hypnotic agent. More sedating antidepressants may be preferable when insomnia is a prominent feature, but need to be used with caution in those prone to falls and confusion. Again, if a hypnotic is needed, a short-acting agent is preferable. Newer antidepressants acting on the melatonin pathway may also be agents of choice in this situation but more evidence is needed to support this.

Hip fractures and falls

A range of sedatives have been associated with a greater risk of hip fractures and falls in older adults, especially the longer acting BZDs. Thus where an individual prone to falls is suffering from insomnia, non-pharmacological approaches are vital, and hypnotics such as a BZD should not be initiated, especially in the in-patient setting, where falls risk is often even higher. Deprescribing these agents is vital. It is encouraging that there is evidence that clinicians are less likely to prescribe a BZD for people with established risk factors for falls, but overuse of these agents in this high-risk group is still a major concern.

Motor vehicle accidents

BZDs, presumably by their effects on psychomotor and cognitive functions, have been associated with increased risk of motor vehicle accidents in older individuals. Thus use of these agents in older drivers with insomnia should be avoided wherever possible. The risk of crashes is greater in the first week of usage, so avoiding initiation is probably more important than deprescribing these agents. Deprescribing, however, remains a high priority if these agents are being used in those who are driving. Parasomnias such as sleep-driving, associated with zolpidem and possibly other hypnotics, also contribute to the link between crashes and hypnotic use.

In-patient settings

There is a high prevalence of BZD prescribing to elderly in-patients, predominantly to promote sleep. It is ideal to keep such medications use to a minimum and discontinuation of these drugs is often appropriate. An algorithm has been developed to assess the appropriateness of BZD prescribing amongst in-patients (Figure 4) and this can be used both to guide deprescribing and to audit appropriateness of BZD use in this setting.Reference Elliott, Woodward and Oborne⁷³ Audit results fed-back to the prescribing team, along with educational material about the dangers of BZD use in the older in-patient, has been shown to both reduce overall BZD prescribing and also to increase the appropriateness of remaining prescribing. A sleep protocol for in-patients, described above, provides an alternative to the use of BZDs and other hypnotics in this setting.

Figure 4.

Algorithm to assess appropriateness of prescribing BZDs in hospital in-patients over age 64 yearsReference Elliott, Woodward and Oborne⁷³

Residential care

As in hospitals, there is often excessive use of hypnotics in residential care facilities, especially when the frailty, prevalence of co-morbidity and extreme age of many of the residents is considered. Deprescribing, and limiting new prescribing, should be the aim. Non-pharmacological approaches, described above, should be utilized well before medications are considered. It is vital, however, to try to improve sleep – poor sleep in residential care has been associated with declining function, declining quality of life and greater risk of depression.Reference Martin, Fiorentino, Jouldjian, Josephson and Alessi⁷⁴

Palliative/end of life care

Hypnotic and sedative therapy is often appropriate in the palliative care setting. Agitation and insomnia are common as people approach the end of life and even deep sedation (palliative or terminal sedation) may be clinically and ethically appropriate. This deep sedation is administered to up to 50% of terminally ill patients with refractory symptoms. The agents used differ from those used primarily as hypnotics, but they do have sleep-promoting activity. Commonly used agents include midazolam, clonazepam and diazepam.