Sleep disorders: treatment

Selecting active treatments for sleep disorders mostly occurs in the absence of significant controlled data from trials or evidence-based protocols. Drug treatments used in clinical practice to improve sleep-wake disturbances are frequently recommended empirically, almost always in the absence of a formal licence from regulatory authorities. Nevertheless, given the numerous deleterious effects of a disordered sleep-wake cycle on a patient’s ability to function normally, even small improvements following therapeutic intervention are welcome.

This article will focus primarily on the treatment of insomnia, sleep-related breathing disorders and central disorders of hypersomnolence.

Insomnia

One third of patients visiting their GP will report that their sleep pattern is disturbed if directly asked, a figure that rises to two thirds if the primary complaint relates to mental health^[1]
. Insomnia is therefore an extremely common complaint. Persistent insomnia often appears as a predominant and potentially disabling factor that dominates any medical consultation and merits direct attention. Prior to diagnosing primary insomnia, other secondary causes of insomnia should be sought and treated where possible.

Non-pharmacological treatment for primary insomnia initially relies on fostering good ‘sleep hygiene’, although relatively few patients and doctors alike have a full understanding of this term and the factors involved^[2]
. Optimisation of the sleeping environment and improving routines, behaviours or attitudes conductive to good sleep are crucial (see ‘Maladaptive behaviours that can be adjusted to improve sleep quality or ‘sleep hygiene’’). No universal approach for optimising the sleeping environment exists and individual preferences should be explored. For example, the sensory deprivation associated with complete darkness or ear plugs may suit some, but others may find they then focus on internal noises such as breathing, which is counterproductive to sleep onset. Appropriate temperature and light levels in the bedroom should also be explored. Excluding televisions and computers from the sleeping environment is also advisable.

Mild insomnia may respond to the correction of maladaptive routines, such as the avoidance of large meals, stimulant drinks or exercise within two hours of intended sleep onset. Various techniques to actively encourage relaxation at least 30 minutes before bed may also help. Focused breathing exercises developed from yoga and centred on the diaphragm can be particularly beneficial^[3]
. A consistent sleep-wake schedule across the week is also recommended. Daytime naps should generally be avoided to optimise the drive to sleep before bed.

For patients with moderate or severe insomnia who are not responsive to simple sleep hygiene advice, current guidelines recommend more structured non-pharmacological approaches as first-line treatment^[4]
. Although cognitive behaviour therapy tailored to treat insomnia (CBT-I) is the best proven therapy, its availability varies greatly between health systems. In the UK, where the majority of health provision is funded from public finance, insomnia services have struggled to become established, partly as a result of competition for resources from more established areas of health where clear targets have become defined^[5]
. To improve the cost-effectiveness of CBT-I, a ‘stepped care’ approach has been proposed that comprises a hierarchy of five levels of CBT-I with options of referring subjects ‘upstream’ if there is an incomplete therapeutic response^[5]
.

Another approach is to provide detailed self-help guides or online packages that deliver a form of CBT-I as an alternative cost-effective treatment. Measures of efficacy have shown mild to moderate objective improvements, but adherence rates are good^[6]
. Computerised CBT-I has not yet been compared systematically with face-to-face consultations either individually or in groups.

A typical CBT-I programme of any kind will last six weeks and will cover at least four areas^[7]
(see ‘CBT-I programmes’). It is likely that some insomnia patients will respond to a combination of CBT-I and drug therapy, although there is no evidence to support or refute this. Some evidence suggests, however, that CBT-I during hypnotic drug discontinuation can be useful^[4]
.

Drug treatment for insomnia is controversial, especially when symptoms are chronic. Many patients harbour unrealistic expectations that simple drug therapy will solve the issue. In practice, short-term treatment with hypnotic agents for a week or two in the context of a life event, such as bereavement, can be helpful. If sleep remains abnormal for longer, chronic use of drugs is of questionable benefit and is accompanied by fears of developing tolerance, physical dependence and withdrawal reactions^[11]
. Long-term data proving harmful effects or poor outcomes are lacking^[12]
, although epidemiological evidence suggests that long-term benzodiazepine use may be a risk factor for developing dementia^[13]
. This conclusion has been challenged by case control analyses^[14]
and some argue that the underlying reasons for the sleep-related symptoms leading to hypnotic use are more pertinent.

Guidance from the National Institute for Care and Health Excellence (NICE) suggests that the use of hypnotic agents for more than four weeks is inadvisable^[15]
. Recent guidelines from the British Association of Psychopharmacology (BAP) propose a less strict approach when using short-acting hypnotics to treat insomnia and advise that there is an ‘exit strategy’ for discontinuation of drug therapy^[12]
. In particular, given uncertainties regarding optimum or safe length of any drug treatment, a strategy of periodically trying to taper medication has been advocated with a view to restarting if unsuccessful^[16]
. The BAP also advocates that the properties of an individual hypnotic agent should be tailored to the patient’s particular pattern of insomnia^[12]
. 

The majority of hypnotic agents, including benzodiazepines and the so-called “Z drugs”, enhance the inhibitory effects of gamma-aminobutyric acid (GABA) at the GABA_A receptor to induce sleepiness^[12]
. Extremely short-acting agents to aid significant sleep-onset insomnia include zaleplon and zolpidem. Zaleplon is licensed for short-term use (up to two weeks) and has few residual morning side effects given its short half-life (less than one hour). As with all hypnotics, the potential adverse effects on driving or other potentially dangerous pursuits should be emphasised. However, regarding zaleplon, it is worth noting that the US aviation authorities allow pilots to fly six hours after taking the agent^[17]
. Zolpidem is a similar agent but it is formally licensed for use for up to four weeks. Both drugs are typically used in doses of 10mg before bed and are not safe to take with alcohol, largely because of risks of respiratory depression. The elderly population may not tolerate these drugs well and care should be taken. Pregnancy data is lacking but regular use is not advised. 

Zopliclone, another Z-drug more commonly used in the UK at a dose of 7.5mg, has a slightly longer half-life (four to six hours) and may be the drug of choice if sleep maintenance is also a symptomatic issue. It is licensed for use for up to four weeks and has few significant side effects other than a metallic taste, which can be unpleasant. As with the majority of hypnotic agents, it is relatively contraindicated in those with generalised muscle weakness or significant sleep apnoea.

Relatively short-acting benzodiazepines, such as temazepam, are being used less, largely because of concerns about misuse or dependence^[12]
. 

Melatonin, usually in a prolonged release formulation, is widely used in practice to aid sleep onset and continuity, but it is only licenced for fairly short-term use in those aged over 55 years^[7]
. This restricted licence reflects the available drug trial evidence^[18]
and most authorities consider it to be an extremely safe agent free of side effects, albeit with limited efficacy. Caution is recommended when used in subjects with an autoimmune disease, although this concern is debated, especially as the drug has reported antioxidant effects and might actually be helpful in reducing inflammation^[19],[20]
. The long-acting preparation currently available in the UK is Circadin (Neurim Pharmaceuticals), most often used at a dose of 2mg once daily, one to two hours before bedtime, for up to 13 weeks.

Although formal data are lacking, in practice it is common in both primary and secondary care settings to prescribe sedating antidepressants or other psychoactive drugs as surrogate hypnotic agents in the absence of any clear mood disorder or psychosis^[12]
. Amitriptyline is most commonly used in this setting at a dose of 10–50mg, although trazodone (100–150mg) and mirtazapine (15–30mg) are also prescribed, usually at doses lower than those that produce an antidepressant effect. In cases of primary insomnia, however, it is not advisable to prescribe antidepressants or antipsychotic agents, such as quetiapine, unless there is clear evidence for associated mental health problems^[12]
. The risks of harm after overdose are considerably higher than with hypnotic drugs of the “Z class”, for example^[12]
. 

Neuropathic pain agents, such as pregabalin, may also be prescribed off licence in practice to help sleep continuity, especially if pain or anxiety are factors in fuelling insomnia. A dose of 75–150mg before bed can be helpful given the lack of contraindications and good side effect profile. Pregabalin has the advantage that it enhances the deeper non-rapid eye movement (NREM) stages of sleep, unlike many other psychoactive sedatives, and potentially could produce more refreshing sleep^[21]
.

The evidence that over-the-counter preparations, such as antihistamines, help those with significant chronic insomnia is limited^[22]
.

Sleep apnoea

When obstructive sleep apnoea (OSA) has been diagnosed and is severe enough to impact on daytime alertness, the first-line therapy is continuous positive airway pressure (CPAP), in which air is delivered to the upper airways at 10cmH₂ 0, via a mask^[30]
and acts to splint the airways and abolish snoring. CPAP masks can be poorly tolerated and a variety of shapes and types are now available, often with humidifiers. Encouragement from a multidisciplinary team with frequent follow-up assessments greatly helps compliance.

Surgical removal of pharyngeal tissue is now rarely considered a useful strategy, although a limited palatoplasty using laser treatment can be helpful in socially disruptive snoring. Similarly, if snoring and subsequent apnoeas are thought to be secondary to nasal pathology, surgery is often curative as is tonsillectomy in severely affected children^[31]
. Mandibular advancement devices are increasingly used in mild OSA, although their use requires good dentition^[32]
.

Hypersomnolence

The most disabling symptom of narcolepsy is the inability to stay appropriately alert for more than a few hours and a significant majority of patients benefit from wake-promoting drug therapy^[33]
. Lifestyle adjustments are often helpful; many patients are encouraged to plan a fairly short nap, usually in the afternoon. Most patients with narcolepsy are often refreshed by short sleep episodes, unlike most other sleep disorders causing hypersomnolence. Anecdotal evidence exists that narcolepsy sufferers are more prone to post-prandial sleepiness, especially after meals rich in carbohydrate^[34]
. Some patients report that dietary manipulation, such as consuming small meals high in protein several times a day, helps their hypersomnolence.

The number of stimulant drugs available for treating excessive sleepiness in narcolepsy is relatively small (see ‘Compounds used to treat excessive daytime sleepiness in narcolepsy’). Caffeine, whether taken as a food supplement or in drink form, can be useful, usually as an add-on therapy, and should not be overlooked. However, modafinil has emerged over the past 15 years as a first-line treatment and is typically started at a dose of 100mg morning and lunchtime, with a view to doubling the dose after a few weeks if necessary^[35]
. Modafinil’s mode of action is still debated but a dopaminergic mechanism is likely in the absence of direct synaptic effects on dopamine receptors. It is generally well tolerated with minor gastrointestinal side effects or headache as the only common problems. Mood disorder or personality change is occasionally encountered and can limit usefulness. Sympathomimetic side effects are usually trivial, but blood pressure monitoring is advisable and care is needed in the elderly with cardiac pathology or hypertension. It is usually contraindicated in severe uncontrolled hypertension or if there are significant cardiac arrhythmias.

A considerable proportion of narcoleptic patients will not achieve adequate control of excessive daytime sleepiness with modafinil alone and it is often useful to add an alternative psychostimulant, such as dexamphetamine or methylphenidate. These drugs have very similar modes of action (see ‘Compounds used to treat excessive daytime sleepiness in narcolepsy’) and can usually be used flexibly. At low doses, tolerability is not usually a problem, although weight loss caused by appetite suppression needs to be monitored. As with modafinil, these drugs are contraindicated in significant cardiovascular disease including arrhythmia. Of interest, the potential for abuse appears low in narcoleptic patient populations^[35]
.

A number of unlicensed medications are used in practice to improve wakefulness. Selegiline was originally developed for Parkinson’s disease and has a complex metabolic pathway that results in several amphetamine derivatives^[36]
. Daily doses of 20–40mg can be a useful strategy in improving daytime alertness, particularly in the elderly or if conventional medication is not tolerated. Pitolisant, a new drug developed for narcolepsy, is an inverse histamine (H3) receptor agonist, which is likely to gain a formal licence for treating sleepiness in narcolepsy in 2016^[37]
. Trial data are limited to date^[38]
but the drug is likely to be a useful addition, especially given its novel mode of action.

In theory, improving the characteristically fragmented nocturnal sleep in narcolepsy might be expected to improve daytime wakefulness. However, the only drug with evidence-based data to support this approach is sodium oxybate, which was originally licenced for treating cataplexy (see ‘Cataplexy’)^[39]
.

Other central hypersomnias

Although not formally licenced for conditions other than narcolepsy, modafinil, with or without additional amphetamine-like agents, is used in practice for conditions such as idiopathic hypersomnolence (IH). Experimental evidence suggests that flumazenil given via the oral route may benefit some patients with IH, a finding of interest given the demonstration of an endogenous benzodiazepine-like substance in the cerebrospinal fluid of some patients^[43]
.

Rarely, narcolepsy-like levels of sleepiness may occur after brain surgery involving regions near the hypothalamus and drug treatment to improve wakefulness is appropriate. More commonly, after head trauma or other global insults such as meningitis, severe daytime sleepiness may persist as a significant isolated symptom^[44]
. On the grounds that these subjects have a secondary form of narcolepsy, often with presumed damage to the hypothalamus or its output pathways, treatment protocols for narcolepsy are used with modafinil as a first-line agent.

In a number of neurological conditions, severe daytime sleepiness may occur as a relatively isolated and largely unexplained phenomenon. These include Parkinson’s disease, myotonic dystrophy and inflammatory diseases such as multiple sclerosis^[35]
. Modafinil is often used empirically to promote wakefulness, given its relatively benign safety profile. The drug is much less efficacious if the symptom is predominantly fatigue as opposed to frank hypersomnolence^[45]
.

Parasomnias

Most children with frequent parasomnias arising from non-rapid eye movement (NREM) sleep find that the problem improves with age, however, it is not uncommon for adults exhibiting frequent or particularly disturbing nocturnal disturbances to be referred to sleep clinics for advice on management. Unfortunately, there is little evidence-based data to guide treatment options^[12]
.

In general, sleep deprivation acts to provoke NREM parasomnia activity and advice on obtaining sufficient sleep may be helpful. Overnight testing with polysomnography is sometimes useful to identify potentially reversible factors such as severe snoring or excessive limb movements that might potentially be fuelling a parasomnia. If drug treatment is thought appropriate, short courses for a few weeks are usual. If sleepwalking or similar phenomena are particularly more likely when sleeping in hotels, for example, intermittent therapy during risky periods is sometimes advocated. Little evidence is available to help guide drug choice, but most sleep physicians would use clonazepam as a first-line agent (dose 0.25–2mg before bed). Anecdotal evidence suggests that selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, can be helpful. If the parasomnia is particularly agitated, clomipramine (dose around 25mg) is sometimes beneficial. Long-acting melatonin is also occasionally recommended as an agent to improve general sleep continuity.

Rapid eye movement (REM) sleep behaviour disorder (RBD), which most often affects middle-aged or elderly men, is the most common REM sleep parasomnia observed in sleep clinics. In RBD, aggressive dream enactment with vocalisation on a nightly basis happens regularly, with risk of injury to the subjects themselves and their bed partners. Clonazepam has become established as the first-line treatment, again in the absence of detailed or controlled trial data^[46]
. Prolonged release melatonin, often at doses higher than used for simple insomnia (2–8mg), is also increasingly used to apparent good effect^[47]
. Perhaps paradoxically, drugs that tend to suppress REM sleep, such as venlafaxine or mirtazepine, often worsen RBD, particularly if there is an underlying condition such as Parkinson’s disease^[48]
. Such agents should be discontinued if possible.