Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 1 Sleep disorders z Review An update on sleep disorders and their treatment Michele Sie GPhC, MCMHP In the third of this series of updated reviews on the major psychiatric drug groups, produced in association with the College of Mental Health Pharmacy (CMHP; www.cmhp.org.uk), Michele Sie describes the main types of sleep disorder and their features, and provides an overview of their treatment. S leep is a fundamental necessity that is required by all of us. Sleep requirements vary with age and between individuals but in general the average requirement for a healthy adult is between seven and eight hours of sleep per night.1 Sleep is divided into two types. Rapid eye movement (REM) sleep and non-rapid eye movement (non-REM) sleep. REM sleep, as the name suggests, is characterised by rapid movements of the eyes, while in non-REM sleep there is little or no movement of the eyes and any eye movement is slow.2 The five stages of sleep There are five stages of sleep.3 Stage 1 is superficial sleep and only lasts for about five to ten minutes. It is the transition from being awake to going to sleep. Body movement slows down, there is some loss of muscle tone and there may be twitching or sudden myoclonic jerks. During this time it is easy to be aroused. Stage 2 is light sleep and accounts for around 50 per cent of sleep in adults. Muscle movement decreases, eye movements stop, heart rate slows and the body temperature can drop. This stage lasts about 20 minutes. Stage 3 is the start of deep or slow wave sleep. Stage 4 is also deep or slow wave sleep, lasts for around 30 minutes and is the restorative period of sleep. During this stage it is hard to be aroused and if woken then a period of disorientation and sedation often occur. Stage 5 is REM sleep. It occurs rapidly after stage 4 and accounts for around 25 per cent of sleep in adults. During REM sleep, there is increased brain activity and dreaming occurs. It is believed that processing and consolidating of information and emotions occur while in REM sleep. During this time, heart rate and respiration increase and atonia occurs causing a temporary paralysis. These five stages of sleep make up the sleep cycle, which lasts for about 90 minutes. This cycle is generally repeated five to six times each night. www.progressnp.com • Have a good bedtime routine, go to bed and get up at the same time every day and avoid daytime naps • Avoid stimulants such as caffeine, nicotine, chocolate and alcohol six hours before bedtime • Take regular exercise during the day, but avoid strenuous exercise within four hours of bedtime • Avoid large meals close to bedtime • Associate your bed with sleep. Do not watch TV or listen to music when retiring to bed • The bedroom should be a quiet, relaxing place to sleep; make sure the room is not too hot or too cold • If after 30 minutes you cannot get off to sleep then get up. Leave the bedroom and try to do something else, return to bed when sleepy. This can be repeated as often as necessary until you are asleep Table 1. Sleep hygiene advice for patients Neurotransmitter involvement There are a number of neurotransmitters that have been implicated in the sleep-wake cycle. During wakefulness there is high activity of histaminergic, noradrenergic and serotonergic neurones. This activity slows down during non-REM sleep and nearly stops during REM sleep, suggesting that these neurotransmitters have a role to play in promoting an awake state. Cholinergic activity is also high in wakefulness, and although it slows during non-REM sleep, it increases in activity during REM sleep, suggesting a role in not only maintaining an awake state but also possibly in dreaming. Adenosine is considered to be a mediator of non-REM sleep, and dopamine may play a role in the transition from sleep to wakefulness. 4 Gamma-aminobutyric acid (GABA), the inhibitory neurotransmitter, helps induce relaxation and sleep.5 Melatonin is a naturally occurring hormone, produced by the pineal gland, which regulates the circadian rhythm of sleep. It starts being released once it becomes dark, and continues to be released until the first light of day. It has been shown that melatonin release decreases with age.6 Orexins, produced Progress in Neurology and Psychiatry September/October 2013 15 CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 2 Review z Sleep disorders in hypothalamic neurones, also have an important role in regulating the sleep-wake cycle and deficiencies have been identified in narcolepsy.7 Types of sleep disorder Sleep disorders are defined as conditions characterised by disturbances of usual sleep patterns or behaviours, that cause distress and impair daytime functioning. The International Classification of Diseases version 10 (ICD-10)8 has two main diagnostic categories – sleep disorders and non-organic sleep disorders. Further classification includes insomnias (disorders of initiatMedication ing and maintaining sleep), hyersomnias (disorders of excessive somnolence), sleep apnoea, narcolepsy and cataplexy, restless legs syndrome, sleep walking, sleep terrors and nightmare disorder.8 The prevalence of sleep disorders is hard to quantify, as problems with sleep may be a symptom of another condition. It has been estimated that the prevalence of sleep disorders in the general population could be as high as 37 per cent,9 with sleep disorders of clinical significance and public health importance occurring in 10 per cent of the population.10 Insomnia is the most commonly reported sleep Available as Form available Half-life, Licensed indication hrs (adults) Tolerance Dependence Diazepam Generic 21-50 Insomnia (short-term use) Yes Yes Loprazolam Lorazepam Lormetazepam Nitrazepam Generic Generic Generic Generic 10 12-16 10 18-36 Insomnia (short-term use) Insomnia (short-term use) Insomnia (short-term use) Insomnia (short-term use) Yes Yes Yes Yes Yes Yes Yes Yes Temazepam (Schedule 3 controlled drug) Generic Tablets, solution Tablets Tablets Tablets Tablets, suspension Tablets, oral solution 5-11 Insomnia (short-term use) Yes Yes Insomnia (short-term use up to 2 weeks) Insomnia (short-term use up to 4 weeks) Insomnia (short-term use up to 4 weeks) Yes Yes Yes Yes Yes Yes Benzodiazepines Z-hypnotics Zaleplon Sonata Capsules 2 Zolpidem Generic Tablets 2-3 Zopiclone Generic Tablets 3.5-6 Generic Welldorm Mixture Tablets, elixir 8-10 7-10 Insomnia (short-term use) Insomnia (short-term use) Yes Yes Yes Yes Circadin Modifiedrelease tablets Capsules, 3.5-4 Insomnia in adults over 55 years (short-term use) No No 4-5 Severe insomnia in elderly Yes (short-term use) Sedation and insomnia Yes (short-term use) Yes Chloral and derivatives Chloral hydrate Cloral betaine Others Melatonin Clomethiazole Promethazine (antihistamine) Phenergan Tablets, elixir 10-19 No *Refers to the active metabolite Table 2. Treatments for insomnia and their licensed indications25 16 Progress in Neurology and Psychiatry September/October 2013 www.progressnp.com CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 3 Sleep disorders disorder, followed by sleep apnoea and then restless legs syndrome.10 Sleep disorders have been associated with a number of adverse effects including increased risk of road traffic accidents,11 medical errors,12 industrial accidents,13 obesity, type 2 diabetes, 14 hypertension, 15 heart disease 16 and a decrease in performance and functioning.17 Insomnias Insomnias are disorders of initiating and maintaining sleep, leading to an inadequate quantity or quality of sleep or both. Problems can include difficulty falling asleep, difficulty staying asleep, or early morning wakening, which can lead to fatigue and impairment of cognitive function during waking hours.13 Insomnia is a common symptom of many mental disorders (nonorganic) including mania and depression18 and can also present in physical conditions (organic) such as pain and asthma.19,20 Insomnia affects around 20 per cent of the adult population and can be either transient, occurring in those who normally sleep well, as a result of exceptional circumstances such as shift work; short term, caused by emotional problems or a serious medical condition; or chronic, relating to an enduring physical or mental health condition.18 It can lead to a significant impairment in quality of life and affects the functioning and mental health of those affected. 21 Economic implications of insomnia include costs relating to absenteeism and decreased productivity, as well as increased use of the GP.22 Treatment of insomnias Non-pharmacological approaches are recommended as first-line treatment of insomnia23 including sleep hygiene18,24 (see Table 1), encouraging the use of techniques to promote and maintain sleep. For chronic insomnia, cognitive behavioural therapy (CBT), stimulus control therapy, sleep restriction and progressive muscle relaxation are recommended first line as they have been shown to be as effective as pharmacotherapy and, unlike medication, the beneficial effects of CBT may last beyond the active treatment phase.23 If insomnia is a symptom of a mental or physical condition then the precipitating cause should be treated effectively – this often leads to a resolution of the insomnia. If these techniques are ineffective then a hypnotic medication may be considered.18 A short course of a z-hypnotic (zaleplon, zolpidem, zopiclone) is recommended first line for the management of insomnia precipitated by a life stressor that is expected to resolve in the near future.23 A number of different classes of medication are licensed as hypnotics. These include benzodiazepines, www.progressnp.com z Review Mild • rebound anxiety and insomnia • sleep disturbance • irritability • panic attacks • tremor • sweating • poor concentration • dry retching and nausea • palpitations • headache • muscular pain and stiffness Moderate • perceptual changes, eg hypersensitivity to light or sound • generalised feelings of distress • flu-like symptoms • sore eyes • decreased appetite and weight loss • depression • depersonalisation • abnormal sensations of movements Severe (rare) • seizures • psychotic symptoms Table 3. Symptoms of benzodiazepine withdrawal syndrome36 z-hypnotics, chloral derivatives, clomethiazole, antihistamines and melatonin.25 Benzodiazepines, z-hypnotics, chloral derivatives and clomethiazole all act by binding to the GABAA receptor and enhancing the effect of GABA.26,27 Activation of this receptor leads to an influx of chloride ions into the neurone reducing its excitability, thereby reducing activity in the brain. This results in sedation, helping to induce sleep. Antihistamines that act as antagonists at the H1receptor and cross the blood-brain barrier cause sedation. 28 Melatonin, as previously discussed, is a naturally occurring hormone, produced by the pineal gland, which regulates the circadian rhythm of sleep.6 Hypnotics decrease time to sleep onset and episodes of waking in sleep as well as increasing total sleep time.29 They can also affect the architecture (length of stages) of sleep. Benzodiazepines suppress stages 3 and 4 of sleep, but only cause a slight decrease in REM sleep. Z-hypnotics shorten stage 1 of sleep and prolong stage 2 of sleep but have little effect on stages 3, 4 and REM sleep. Chloral derivatives do not affect sleep architecture.26,27 Melatonin promotes sleep initiation and helps to reset the circadian clock, allowing uninterrupted sleep. It has also been shown to improve next day functioning.30 Progress in Neurology and Psychiatry September/October 2013 17 CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 4 Review z Sleep disorders Most medications used to treat insomnia can cause tolerance and dependence (see Table 2).25 Tolerance occurs following continued administration of a medication and is characterised by a decrease in susceptibility to the medicinal effects.31 Tolerance has been observed with all currently licensed hypnotics with the exception of melatonin. Dependence occurs when there is a need to take repeated doses of a medication to maintain wellbeing or to prevent withdrawal symptoms and can be psychological, physical or both.32 Psychological dependence is a craving or compulsion to continue using the medication to maintain a feeling of wellbeing. Physical dependence is the need to continue taking medication to prevent physical withdrawal effects. Withdrawal syndrome is most often associated with the benzodiazepines33 (see Table 3), but withdrawal symptoms have also been documented with chloral derivatives, clomethiazole and z-hypnotics.34,35 To reduce the risk of dependence and tolerance, it is recommended that hypnotics are only used in severe and disabling insomnia, which is causing extreme distress. For transient insomnia, only one or two doses should be given and for short-term insomnia, hypnotics should only be used for a limited course of up to three weeks, preferably intermittently. In chronic insomnia, hypnotics are rarely beneficial and the underlying illness needs to be managed.25 If hypnotics that cause a withdrawal syndrome are used for more than three weeks they should be withdrawn slowly. For those wishing to withdraw from long-term, short-acting benzodiazepines, switching to diazepam, a long-acting benzodiazepine, can be useful (see Table 4). Diazepam can then be reduced slowly, for example by one-eighth of the daily dose every fortnight.25,33,36 NICE carried out a Technology Appraisal on the newer hypnotics in 200424 and reported that there was a lack of compelling evidence to distinguish between the z-hypnotics and the shorter-acting benzodiazepine hypnotics and concluded that prescribing decisions should be made on a cost basis. They recommended that patients who had not responded to either a benzoBenzodiazepine Approximate equivalent dose to diazepam 5mg Chlordiazepoxide Loprazolam Lorazepam Lormetazepam Nitrazepam Oxazepam Temazepam 15mg 0.5-1mg 0.5-1mg 0.5-1mg 5mg 15mg 10mg Table 4. Diazepam equivalent doses25,36 18 diazepine or a z-hypnotic should not be prescribed the other. Switching between these two classes of hypnotics should only occur if the adverse effects experienced could be directly related to a specific agent.24 The therapeutic use of some older hypnotics has also been questioned. Chloral derivatives are now considered less suitable for prescribing due to their adverse effects and abuse potential and clomethiazole is only recommended for use in insomnia in those over 55 years of age.25 Clomethiazole only has evidence to support its use in this age group when other hypnotics have failed, although it is rarely used now due to the risk of accidental overdose and respiratory depression.25 Some hypnotics cause a hangover effect, i.e. sedation and impairment of psychomotor performance, including driving ability and memory on the following day. To avoid this, it is recommended that medications with a short half-life of between four and six hours should be used. Medications with shorter half-lives than this can give rise to early morning wakening.36 Excessive daytime sleepiness, hypersomnia and narcolepsy Excessive daytime sleepiness occurs in about 3-5 per cent of the population and can be caused by poor sleep quality and duration due to either a concurrent sleep, mental health or medical disorder. Hypersomnia is characterised by excessive daytime sleepiness or daytime sleep episodes that cause severe distress or impairment in functioning and occur almost daily but are not part of a concurrent sleep, mental health or medical disorder. It is hard to quantify the prevalence of hypersomnia as symptoms of excessive daytime sleepiness can occur with any sleep disorder that causes a loss of night-time sleep.18 Narcolepsy, a condition that normally presents with excessive daytime sleepiness, can be distinguished from other sleep disorders by the presence of cataplexy (a sudden and transient loss of muscle tone, while awake, usually triggered by strong emotions such as laughing), sleep paralysis and sleep-related hallucinations. These symptoms are believed to be characteristics of REM sleep, which do not normally occur during the awake state. Narcolepsy is reported to affect around 0.05 per cent of the population and normally begins between the ages of 10 and 20 years.18,37 Recent evidence has suggested a strong correlation between decreased levels of orexins (also called hypocretins) and narcolepsy.38 Treatment of excessive daytime sleepiness, hypersomnia and narcolepsy Excessive daytime sleepiness should be managed by treating the underlying cause.37 Guidance from the Progress in Neurology and Psychiatry September/October 2013 www.progressnp.com CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 5 Sleep disorders Treatment Modafinil Sodium oxybate Methylphenidate Dexamfetamine Selegiline Tricyclic antidepressants† SSRIs Venlafaxine Reboxetine Licensed for narcolepsy z Review Shown to be effective in: * Daytime sleepiness Disrupted sleep Cataplexy Sleep-related hallucinations Sleep paralysis Yes Yes No Yes No No Yes Yes Yes Yes Maybe No No Yes No No No No No Yes No No Maybe Maybe No Maybe No No Maybe Maybe No Maybe No No Maybe Maybe No No No No No No No No No Maybe Maybe Maybe Maybe Maybe Maybe Maybe Maybe Maybe * Yes = there is evidence provided by randomised trials or meta-analysis of randomised controlled trials; maybe = there is evidence provided by poorly conducted case-control or cohort studies, case series or expert opinion † Clomipramine is licensed for the adjuctive treatment of cataplexy associated with narcolepsy Table 5. Treatment options for the symptoms of narcolepsy39 American Academy of Sleep Medicine39 recommends treatment options for hypersomnia and narcolepsy based on the current evidence available. For hypersomnia, modafinil may be effective for the treatment of daytime sleepiness due to idiopathic hypersomnia, Parkinson’s disease, multiple sclerosis or myotonic dystrophy. Methylphenidate may also be effective for the treatment of daytime sleepiness due to myotonic dystrophy. Lithium carbonate may be effective for treatment of recurrent hypersomnia. None of these treatments are licensed for hypersomnia and their use would be off-label. The American Academy of Sleep Medicine also recommends a number of treatment options for the different symptoms experienced in narcolepsy (see Table 5). The pharmacology of narcolepsy treatments4,39-42 The stimulants dexamfetamine and methylphenidate block the reuptake of, and enhance the release of, noradrenaIine, dopamine and serotonin, all of which could be responsible for their wake-promoting effects. These stimulants have been shown to increase arousal, decrease sleepiness, increase latency to sleep and produce a severe decrease in REM sleep. The mode of action of sodium oxybate (the sodium salt of gamma hydroxybutyrate) is unclear. It has been shown to reduce the number of episodes of cataplexy and daytime napping, to improve excessive daytime sedation, with restoration of fragmented sleep, as well as increase the duration of stage 3 and 4 non-REM sleep. Although the mode of action of modafinil is unclear, it may act by blocking dopamine and noradrenaline reuptake as well as increasing dopamine, serotonin, glutamate and www.progressnp.com histamine release. It may also activate orexin neurones and reduce GABA. Modafinil increases wakefulness and latency to sleep, as well as reducing non-REM and REM sleep. Dexamfetamine, methylphenidate and sodium oxybate all have abuse potential and this has led to modafinil (which has less abuse potential) being the first-line treatment for narcolepsy. Obstructive sleep apnoea The most common sleep-related breathing disorder is obstructive sleep apnoea, occurring in approximately 3-7 per cent of men and 2-5 per cent of women. It is more likely to occur in patients with cardiac or metabolic disorders. Risk factors include obesity, upper airway abnormalities, male gender, menopause and age. It is characterised by loud snoring, followed by apnoea (a period of silence, when breathing ceases due to complete airway obstruction), which can last up to 90 seconds. Following each apnoea there is a wakening episode and these episodes occur many times during the night, although those affected do not normally recall these arousals. This interrupted night-time sleep leads to excessive daytime sleepiness, which in turn affects quality of life and alters social, familial and professional performance.43 Treatment for this condition includes lifestyle changes such as weight loss, smoking cessation and avoidance of alcohol. Sedatives and sleeping tablets at night are not recommended as these can decrease dilation of the airways, thus worsening the condition. Obstructive sleep apnoea may also be treated with continuous positive airway pressure (CPAP), which forces air into the lungs via a face mask, keeping the airways open and preventing the apnoea.44 Progress in Neurology and Psychiatry September/October 2013 19 CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 6 Review z Sleep disorders Restless legs syndrome Restless legs syndrome is a neurological disorder associated with pain or paraesthesia in the legs that is temporarily relieved by movement; it is often accompanied by periodic limb movements during sleep. The prevalence of the disorder has been reported to be up to 10 per cent and it occurs more frequently in women and those over 65 years of age. Restless legs syndrome expresses a circadian rhythm, being worse in the evening and at night and easing in the morning. It is caused by a decrease in dopamine function in the CNS.13,45 As expected, dopaminergic agonists have been shown to alleviate the symptoms of restless legs syndrome in 70 to 100 per cent of patients and are the first-line treatment option. Ropinirole, pramipexole and rotigotine are all licensed for the treatment of moderate to severe restless legs syndrome. 46 Bromocriptine, cabergoline and pergolide are not recommended due to the risk of heart valve damage.45 Levodopa has also been shown to be effective but around 80 per cent of patients develop rebound, in which symptoms return within a few hours following administration, or augmentation, in which symptoms occur earlier in the evening, prior to treatment. The dopaminergic agonists may also cause rebound and augmentation but to a lesser extent than levodopa.47 There is limited evidence for the use of opioids, gabapentin, pregabalin, carbamazepine and clonidine, but it is unclear if the benefit/harm balance is advantageous. 45 Medicines associated with causing or exacerbating restless legs syndrome include some antidepressants, antipsychotics and sedating antihistamines. If these medicines are prescribed in those presenting with symptoms of restless legs syndrome, consideration should be made to reducing and stopping where possible or switching to an alternative agent.45,48 Sleep walking, sleep terrors and nightmare disorder Sleep walking, sleep terrors and nightmare disorder are all types of parasomnias. Parasomnias are described as abnormal behavioural or physiological events occurring in association with sleep, specific sleep stages or sleep-wake transitions.18 They are classified into two groups: disorders of REM sleep or disorders of non-REM sleep, as outlined below. Disorders of REM sleep Nightmare disorder is characterised by repetitive, frightening dreams, occurring during REM sleep, which lead to the patient waking and becoming fully alert. Those affected often have a lingering sense of fear or 20 anxiety that can cause difficulty in returning to sleep, leading to significant distress that may or may not affect daytime functioning.18 Between 2 and 5 per cent of the adult population suffer from frequent nightmares and these may be idiopathic or part of posttraumatic stress disorder (PTSD).49 Some medications may be associated with nightmares including baclofen, clarithromycin, beta-blockers and corticosteroids, and these should be avoided.25,36 For nightmares related to PTSD, prazosin, an alpha-adrenoceptor blocker, has been shown to be effective in reducing nightmare frequency, although it must be taken long-term as on cessation nightmares commonly recur. Clonidine, an alpha2-adrenergic receptor agonist, has a small evidence base for reducing nightmares in refugees at a dose of 0.2-0.6mg daily in divided doses and may be an option if prazosin is not effective.50 For idiopathic nightmares, CBT, including systematic desensitisation, lucid dreaming techniques and image rehearsal therapy have been shown to be effective in reducing nightmare frequency.49,50 There is no effective pharmacological treatment for idiopathic nightmares. REM sleep behaviour disorder occurs when there is a loss of the muscle atonia that normally occurs in REM sleep. This leads to motor activity, generally in response to a nightmare of being attacked or chased, which can often be of an unexpected and violent nature. If awoken, there is vivid recall of the dream.18 It can lead to accidental injury to oneself or one’s partner. The prevalence is estimated to be around 0.5 per cent of the population. It is more common in older males and may be a prodromal symptom of a neurological disease such as Parkinson’s disease or Lewy body dementia. It has been reported as an adverse effect of paroxetine, fluoxetine and impipramine in combination, venlafaxine, mirtazapine and beta-blockers.51 Clonazepam, 0.52.0mg at bedtime, has been shown to resolve or substantially reduce symptoms in up to 90 per cent of those treated, but long-term treatment is required as symptoms often return on cessation of clonazepam.52 It should be used with caution in patients with dementia, gait disorders or concomitant obstructive sleep apnoea. Melatonin, at a dose of 3-12mg at bedtime, has also been shown to be effective in treating this disorder.51 Disorders of non-REM sleep Sleep terror disorder (night terrors) is characterised by episodes of disruption of sleep that usually begin with a fearful scream or cry. There may be signs of arousal such as sitting up in bed with the eyes open, increased heart rate, rapid breathing and sweating, but the individual remains in a deep sleep and is hard to awaken Progress in Neurology and Psychiatry September/October 2013 www.progressnp.com CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 7 Sleep disorders Medication Common side-effects Treatments for insomnia Benzodiazepines Drowsiness, sedation, blurred vision, unsteadiness and ataxia all of which may persist the following day Clomethiazole Sedation, nasal congestion and irritation, gastrointestinal disturbances Cloral and derivatives Gastric irritation, nausea and vomiting, abdominal distention, flatulence, headache, tolerance, dependence, excitement, delirium, ketonuria, rash Melatonin Headache, pharyngitis, back pain, asthenia Promethazine Drowsiness, dizziness, restlessness, headaches, nightmares, tiredness, disorientation, blurred vision, dry mouth, urinary retention Z-hypnotics Drowsiness, mild bitter or metallic after-taste (with zopiclone only), gastrointestinal disturbances, nausea and vomiting, dizziness, headache, dry mouth Treatments for hypersomnia and narcolepsy Dexamfetamine Palpitations, tachycardia, increased blood pressure, overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, tremor, headache, dry mouth, unpleasant taste, diarrhoea, constipation, anorexia and weight loss, growth retardation in children Methylphenidate Abdominal pain, nausea, vomiting, dyspepsia, dry mouth, anorexia, reduced weight gain, tachycardia, palpitation, arrhythmias, changes in blood pressure, cough, tics, insomnia, nervousness, weakness, depression, irritability, aggression, headache, drowsiness, dizziness, fever, arthralgia, rash, pruritus, alopecia Modafinil Headache, dizziness, somnolence, paraesthesia, blurred vision, constipation, dry mouth, decreased appetite, abdominal pain, nausea, diarrhoea, dyspepsia, nervousness, insomnia, anxiety, depression, abnormal thinking, confusion, weakness, tachycardia, palpitations, chest pain, vasodilatation, abnormal liver function tests Reboxetine Constipation, dizziness, dry mouth, insomnia, sweating SSRIs Anxiety or restlessness, insomnia, diarrhoea, nausea and vomiting, loss of appetite Selegiline Nausea, constipation, diarrhoea, dry mouth, postural hypotension, dyskinesia, vertigo, sleeping disorders, confusion, hallucinations, arthralgia, myalgia, mouth ulcers Sodium oxybate Nausea, vomiting, diarrhoea, abdominal pain, anorexia, hypertension, peripheral oedema, fainting, sleep disorders, confusion, disorientation, paraesthesia, hypoesthesia, impaired attention, depression, drowsiness, anxiety, dizziness, headache, tremor, asthenia, fatigue, urinary incontinence, nocturnal enuresis, arthralgia, muscle cramps, blurred vision and sweating. Requires re-titration if a treatment interval of 14 days or more Tricyclic antidepressants Drowsiness, blurred vision, dry mouth, constipation, urinary retention, weight gain Venlafaxine Gastrointestinal disturbances, constipation, diarrhoea, nausea, headache, dizziness, insomnia, sweating, anxiety Treatment for restless leg syndrome Dopamine agonists Abnormal dreams, insomnia, dizziness, headache, somnolence, constipation, nausea and vomiting Treatment for PTSD-related nightmares Prazosin Dizziness, drowsiness, headache, fainting, depression, nervousness, vertigo, palpitations, oedema, nasal congestion, blurred vision, constipation, diarrhoea, dry mouth, urinary frequency, nausea, vomiting, rash, lack of energy, weakness Table 6. Common side-effects of medications used to treat sleep disorders25 www.progressnp.com Progress in Neurology and Psychiatry September/October 2013 21 z Review CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 8 Review z Sleep disorders or comfort. The episodes occur during stage 3 and 4 of non-REM sleep and can last up to 10 minutes, before the individual calms down and returns to sleep. Unlike nightmares, there is no recall of the episode the following morning. In childhood, the prevalence of sleep terrors is between 1 and 6 per cent, and it is more common in boys. In children, the disorder usually resolves spontaneously by adolescence. In adults, the prevalence is less than 1 per cent, with episodes generally beginning between the ages of 20 and 30 years, and the disorder being of a chronic nature. There is often a family history of sleep terrors or sleep walking. Fever and lack of sleep have been shown to increase the frequency of sleep terror episodes.53 Sleep walking disorder is characterised by episodes of complex motor behaviour initiated during sleep, including rising from bed, walking about, eating and talking. An episode is accompanied by reduced alertness and responsiveness and the individual can be hard to awaken. An episode can either spontaneously end in arousal with brief confusion, or the individual returns to bed and sleeps until morning with no recall of the episode on awakening. Episodes also occur during stage 3 and 4 of non-REM sleep and can last from a few minutes to half an hour. The prevalence in children is between 1 and 5 per cent and, like sleep terrors, the disorder normally resolves during adolescence. It is rare for episodes to occur for the first time in adults, and if they do this may be associated with a sleeprelated breathing disorder, hyperthyroidism, personality disorder, mood disorder or anxiety disorder.53 Sleep terrors and sleep walking are more likely to occur near the beginning of sleep whereas nightmares are more likely to occur later in the night.53 Treatment of sleep terror and sleep walking disorders Non-pharmacological treatments are the first-line option for these conditions, including reduction of trigger factors such as stress, fever and sleep deprivation.53 Some medications may cause sleep disorders as an adverse effect. An association between z-hypnotics and sleep walking has been documented and dexamfetamine, oxybutynin and ethosuximide may cause night terrors.25 It is also important to ensure a safe environment to reduce the risk of causing injury during an episode, including secure locks on doors and windows, and heavy curtains to protect windows. A consistent bedtime routine should be maintained to reduce the risk of sleep deprivation, which may further worsen episodes.53 Medication is rarely indicated, particularly in children, unless the disorder is of a severe nature causing distress and loss of daytime functioning. There are reports of imipramine, nortriptyline, sertraline, 22 paroxetine, carbamazapine, diazepam and valproate semisodium, all at low doses, being successful at managing both sleep terror and sleep walking disorders, but there is a lack of controlled studies to confirm their effectiveness.53 Other sleep disorders Sleep disorders may also relate to either another mental health disorder or general medical condition, or may be substance-induced. These sleep disorders are mainly managed by optimising the treatment of the underlying mental health or physical health condition, or withdrawing the substance causing the sleep disorder.18 Future developments There are a number of treatments currently being investigated in phase 2 and 3 clinical trials including: pitolisant, a histamine H3- receptor inverse agonist, for the treatment of narcolepsy, cataplexy and excessive daytime sleepiness, and ‘ADX-N05’ also for the treatment of narcolepsy and excessive daytime sleepiness. Tasimelteon, a melatonin MT1 and MT2receptor agonist, is currently waiting approval of FDA for the treatment of non-24-hour sleep-wake disorder, a circadian rhythm disorder that affects the majority of totally blind individuals who lack light perception and who therefore cannot entrain their master body clock to the 24-hour day. Armodafinil, the r-enantiomer of modafinil, a stimulant for the management of narcolepsy and shift work sleep disorder, has been approved in the USA. Development of almorexant, an orexin OX1 and OX2-receptor antagonist, for the treatment of primary insomnia has ceased as a result of its side-effect profile.54 Conclusion There are a large number of different sleep disorders, ranging from disorders affecting the induction of sleep to disorders that cause disturbance during sleep. Insomnia is the most prevalent disorder and should initially be managed with sleep hygiene techniques. If hypnotics are necessary, they should only be used short term to avoid dependence and tolerance. Sleep disorders that occur in childhood generally resolve spontaneously around adolescence and often do not require psychological or pharmacological treatment. Most medications for sleep disorders other than insomnia are not licensed and their use would be ‘offlabel’, so consent issues need to be considered and clearly documented. Declaration of interests None declared. Progress in Neurology and Psychiatry September/October 2013 www.progressnp.com CMHP Review Sleep_Layout 1 26/09/2013 11:19 Page 9 Sleep disorders Michele Sie is Chief Pharmacist, West London Mental Health Trust, St. Bernards Hospital, West London Mental Health NHS Trust, Southall References 1. Klerman E, Dijk D. Age-related reduction in the maximal capacity for sleep - Implications for insomnia. Current Biology 2008;18:1118-23. 2. Carskadon M, Dement, W. Normal human sleep: An overview. In: M Kryger, T Roth, W Dement (eds). Principles and Practice of Sleep Medicine, 3rd edn. Philadelphia: WB Saunders 2000;15-25. 3. Besset A. Guidelines for visual sleep analysis. In: M Billiard, ed. Sleep: Physiology, Investigations and Medicine. New York: Kluwer Academic/Plenum Publishers, 2003;151-8. 4. Boutrel B, Koob G. What keeps us awake: the neuropharmacology of stimulants and wakefulness-promoting medications. Sleep 2004;27(6):1181-94. 5. Gottesmann, C. GABA mechanisms and sleep. Neuroscience 2002;111(2):231-9. 6. Zhdanova I, Wurtman R, Regan M, et al. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab 2001;86(10):4727-30. 7. Sakurai T, Mieda M, Tsujino N. The orexin system: roles in sleep/wake regulation. Ann N Y Acad Sci 2010;1200:149-61. 8. World Health Organization. International Classification of Disease Version 10 (ICD-10). WHO, 2010. http://apps.who.int/classifications/ icd10/browse/2010/en 9. Ohayon MM, Partinen M. Insomnia and global sleep dissatisfaction in Finland. J Sleep Res 2002;11: 339-46. 10. Ram S, Seirawan H, Kumar SK, et al. Prevalence and impact of sleep disorders and sleep habits in the United States. Sleep Breath 2010;14: 63-70. 11. Connor J, Whitlock G, Norton R, et al. The role of driver sleepiness in car crashes: a systematic review of epidemiological studies. Accid Anal Prev 2001;33(1):31-41. 12. Mountain SA, Quon BS, Dodek P, et al. The impact of housestaff fatigue on occupational and patient safety. Lung 2007;185(4):203-9. 13. Wells ME, Vaughn BV. Poor sleep challenging the health of a nation. Neurodiagnostic J 2012;52:233-49. 14. Spiegel K, Tasali E, Leproult R, et al. Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol 2009;5:253-61. 15. Gangwisch J, Heymsfield S, Boden-Albala B, et al. Short sleep duration as a risk factor for hypertension. Hypertension 2006;47:833. 16. Roux F. Sleep-related breathing disorders and cardiovascular disease. Am J Med 2000;108(5):396-402. 17. Groegerf JA, Zijlstra FR, Dijk D. Sleep quantity, sleep difficulties and their perceived consequences in a representative sample of some 2000 British adults. J Sleep Res 2004;13:359-71. 18. Cowen P, Harrison P, Burns T. Shorter Oxford Textbook of Psychiatry, 6th Edn. Oxford University Press, 2012. 19. Bender B, Leung, D. Sleep disorders in patients with asthma, atopic dermatitis, and allergic rhinitis. J Allergy Clin Immunol 2005; 116(6):1200-1. 20. Moldofsky H. Sleep and pain. Sleep Medicine Reviews 2001;5(5): 385-96. 21. Roth T, Franklin M, Bramley T. The state of insomnia and emerging trends. Am J Manag Care 2007;13:S117-S120. 22. Daley M, Morin C, LeBlanc M, et al. The economic burden of insomnia: Direct direct and indirect costs for individuals with insomnia syndrome, insomnia symptoms, and good sleepers. Sleep 2009;32(1):55-64. 23. Wilson SJ, Nutt DJ, Alford C, et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol 2010;24(11):1577-1600. 24. National Institute for Health and Clinical Excellence Technology Appraisal (TA) 77. Insomnia - newer hypnotic drugs: guidance. NICE, 2004. http://guidance.nice.org.uk/TA77/Guidance/pdf/English 25. British National Formulary (BNF) 65. March-September 2013. London: BMJ Group and RPS Publishing, 2013. 26. Brunton L, Goodman L, Blumenthal D, et al. Goodman and Gilman’s Manual of Pharmacology and Therapeutics. USA: Mcgraw Hill www.progressnp.com z Review Companies, 2008:262-79. 27. Hartmann E, Cravens J. The effects of long-term administration of psychotropic drugs on human sleep: V. The effects of chloral hydrate. Psychopharmacologia 1973;33(3):219-32. 28. Nolen TM. Sedative effects of antihistamines: safety, performance, learning and quality of life. Clin Therapeutics 1997;19:39-55. 29. Sateia M, Nowell P. Insomnia. Lancet 2004;364:1959-73. 30. Hardeland R. New approaches in the management of insomnia: weighing the advantages of prolonged-release melatonin and synthetic melatoninergic agonists. Neuropsychiatr Dis Treat 2009:5;341-54. 31. Dorland’s Medical Dictionary for Health Consumers. Saunders, an imprint of Elsevier, Inc, 2010. http://medical-dictionary. thefreedictionary.com 32. Lexicon of Alcohol and Drug Terms. World Health Organization, 2010. http://www.who.int/substance_abuse/terminology/who_lexicon/ en/print.html 33. Tyrer P, Silk KR, eds. Treatment of sedative-hypnotic dependence. Cambridge Textbook of Effective Treatments in Psychiatry, 1st edn. Cambridge University Press, 2008. 34. Waller D, Renwick A, Hillier K. Anxiolytics, Sedatives and Hypnotics in Medical Pharmacology and Therapeutics, 3rd edn. Edinburgh: Harcourt Publishers Ltd, 2009. 35. Hajak G, Müller W, Wittchen H, et al. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 2003:98;1371-8. 36. Bazire S. Psychotropic Drug Directory. Lloyd-Reinhold Communications LLP, 2012. 37. Pagel J. Excessive daytime sleepiness. Am Family Physician 2009;79(5):391-6. 38. Mieda MM, Sakurai, T. Orexin (hypocretin) receptor agonists and antagonists for treatment of sleep disorders. CNS Drugs 2013;27(2): 83-90. 39. Morgenthaler T, Kapur V, Brown T, et al. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin: An American Academy of Sleep Medicine report. Sleep 2007;30(12):1705-11. 40. Young J. Dopamine D1 and D2 receptor family contributions to modafinil-induced wakefulness. J Neurosci 2009;29(9):2663-5. 41. Black J, Houghton W. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep 2006;29(7):939-46. 42. Minzenberg MS, Carter CS. Modafinil neurochemistry and cognition. Neuropsychopharmacology 2008;33:1477-1502. 43. Lurie A. Obstructive sleep apnea in adults: epidemiology, clinical presentation, and treatment options. Adv Cardiol 2011;46:1-42. 44. http://guidance.nice.org.uk/TA139/QuickRefGuide/pdf/English 45. Aurora RN, Kristo DA, Bista SR, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults - an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses. Sleep 2012;35(8):1039-62. 46. Karatas M. Restless legs syndrome and periodic limb movements during sleep: diagnosis and treatment. The Neurologist 2007;13(5):294-301. 47. Comella C. Restless legs syndrome treatment with dopaminergic agents. Neurology 2002;58:87-92. 48. Cohrs S. Sleep disturbances in patients with schizophrenia: impact and effect of antipsychotics. CNS Drugs 2008;22(11):939-62. 49. Lancee J, Spoormaker V, Krakow B, et al. A systematic review of cognitive-behavioral treatment for nightmares: toward a well-established treatment. J Clin Sleep Med 2008;4(5):475-80. 50. Aurora RN, Zak RS, Auerbach SH, et al. Best practice guide for the treatment of nightmare disorder in adults. J Clin Sleep Med 2010; 6(4):389-401. 51. Aurora RN, Zak RS, Maganti RK, et al. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med 2010;6(1):85-95. 52. Paparrigopoulos T. REM sleep behaviour disorder: Clinical profiles and pathophysiology. Int Review of Psychiatry 2005;17(4):293-300. 53. Thorpy M, Plazzi G. The parasomnias and other sleep-related movement disorders. Cambridge University Press, 2010. 54. US National Institutes of Health. http://clinicaltrials.gov/ct2/home Progress in Neurology and Psychiatry September/October 2013 23