The treatment - insomnia
Sleep specialists Professor Adrian J Williams and Dr Panagis Drakatos discuss the current treatment options for insomnia.
Insomnia is difficulty in getting to sleep, difficulty staying asleep, early wakening, or non-restorative sleep despite adequate time and opportunity, resulting in impaired daytime functioning, such as poor concentration, mood disturbance and daytime tiredness.
Insomnia is a symptom, much like fever or stomach ache. Although it may be secondary, or comorbid, it may also develop de novo. The pathogenesis of primary insomnia is felt to revolve around a state of hyperarousal.
Over the past years, insomnia has been moved from a mere nuisance to a potentially serious medical condition, with physical and mental consequences. Chronic insomnia is a persistent problem with both short-term consequences (fatigue, concentration problems, memory impairment) and long-term risks (impaired immune function, impaired memory and other cognitive functions).1
Treatment revolves around universal application of sleep hygiene, disease-specific interventions for psychiatric and medical conditions like restless legs, depression and circadian disturbances and, more importantly, modification in the form of cognitive behavioural therapy for insomnia (CBTi).
Finally, after consideration of the use of non-pharmacological measures, hypnotic drug therapy prescribed for a short period of time is considered appropriate for the management of severe insomnia that interferes with normal daily life.2
Standard current treatment
Once insomnia has been diagnosed, sleep hygiene advice should be offered to all patients, although our experience has shown that further management is often required. CBTi is a very effective way of controlling insomnia symptoms, especially in the long term, and also helps in avoiding the use of hypnotic drug therapy (over the counter or not), or decreasing the amount and duration. Pharmacotherapy may be required in the short term with the smallest possible dose.
Short-term insomnia (less than four weeks)
• Advise good sleep hygiene.
• If daytime impairment is severe, consider a short course (no more than two weeks) of a hypnotic drug. None of the medicines used to treat insomnia are licensed for children.
• The drugs that are licensed for short-term treatment of insomnia are the short-acting Z- drugs – zaleplon (5-10mg nocte), zolpidem (5-10mg nocte) and zopiclone (3.75-7.5mg nocte)2,3 – and the short-acting benzodiazepines temazepam (10-40mg nocte), loprazolam (0.5-2mg nocte) and lormetazepam (0.5-1.5mg nocte).3
• Zaleplon, which has a shorter half-life, is licensed for people who have difficulty falling asleep. Zopiclone has a longer half-life than the rest of the Z-drugs and is more effective in patients who also have nocturnal awakening and early awakening, and insomnia secondary to psychiatric disturbances.
• Diazepam (5-15mg nocte) and lorazepam (1-4mg daily in divided doses)3 are licensed both for insomnia and anxiety, and are listed in the anxiolytic section of BNF.
Long-term insomnia (more than four weeks)
• Manage any underlying cause or associated comorbidities.
• Advise good sleep hygiene.
• Modified-release melatonin (2mg, one to two hours before bed time)4 if the patient is older than 55 years of age with persistent insomnia. Maximum duration of 13 weeks, if there is a response to an initial three-week trial.
It is very important to realise that insomnia should be treated not only as a diagnosis (primary insomnia) but also as a symptom (comorbid insomnia).
Possible causes should be considered:
• Physical – primary sleep disorder, arthritis, back pain, asthma, menopausal symptoms.
• Environmental – noise, jet lag, shift work.
• Psychological – bereavement, work worries, relationship problems.
• Psychiatric – depression, anxiety, dementia, substance/alcohol misuse.
• Pharmacological – some antidepressants, anxiolytics, antipsychotics, ß-blockers, steroids.
Persistent poor sleep, apart from the daytime consequences, also elevates the risk of developing new illnesses. This has been shown for hypertension, and also very convincingly in depression.
CBTi could be provided by an insomnia specialist or an appropriately trained primary care professional. Although the latter is not yet widely available, the internet has allowed the introduction of scientifically based online CBTi courses, widening the management options for insomnia.5 In addition, the Improving Access to Psychological Therapies (IAPT) services initiative, in conjunction with the NHS, has initiated certified training programmes for CBT for GPs.6
In 2009, modified-release melatonin became licensed for the management of patients aged 55 years with primary insomnia (usually defined as more than four weeks’ duration). Melatonin is a hormone naturally produced nocturnally by the pineal gland, serving as a circadian time cue and sleep-anticipating signal. Data indicate shortened sleep latency, improved sleep quality and improved morning alertness, along with no tendency to induce falls, especially for patients aged over 55 years.7 Current literature supports that insomnia and ageing are associated with decreased melatonin production and so melatonin supplementation would be of benefit. For the younger ages it has been hypothesised that the large inter-individual variations in ‘normal’ physiological levels of melatonin across (as well as within) age groups have prevented beneficial effects from melatonin being demonstrated. Promising research data also support safe extended use of modified-release melatonin for all adults (up to 12 months) and also in children with attention deficit hyperactivity disorder.8,9,10
In 2004, and in a subsequent review in 2010, the Z-drugs were included as eligible short-term treatment for insomnia. The rationale behind their development was to create a drug with the effectiveness of benzodiazepines in inducing sleep without anxiolytic, myorelaxant or anticonvulsant effects, and relief from daytime sedation, drug tolerance and withdrawal problems. Current data are still lacking to support this, but Z-drugs are currently a licensed and effective short-term treatment for insomnia, and are not yet misused as benzodiazepines are. Caution should be used when prescribing them in the elderly, as Z-drugs have been related to an increased risk of road traffic accidents and hip fracture.11,12,13 Hypnotics have been linked to an increased mortality and incidence of cancer.14
NICE advises that there is little compelling evidence to distinguish clinically between the Z-drugs and shorter-acting benzodiazepines, and so recommends the cheapest drug should be used – usually temazepam. Only if side-effects specific to that drug develop does NICE suggest switching to a different hypnotic. There is no evidence of benefit of switching between Z-class drugs.
What has fallen out of fashion and why
Antihistamines – while several studies investigating their efficacy for insomnia are inconclusive, they remain the major ingredient in over-the-counter sleep aids. Adverse effects can be troublesome and include dizziness, fatigue and morning hangover, and there are limited data on their efficacy and safety. A sedative antihistamine may be appropriate for when insomnia is secondary to an allergy.
Barbiturates – they are effective in short-term insomnia, but gradually lose the ability to induce and maintain sleep, and if used for longer periods are associated with tolerance, confusion, hallucinations, and lethargy. As such, they should rarely be used as sleep aids.
Depression and insomnia seem to be interdependent. Around 50% of patients with depression have comorbid insomnia, and isolated sleep disturbance can predict the development of a new depressive episode one to three years later.
The likelihood of the co-occurrence of these two comorbidities should be examined regularly and proper psychiatric assessment provided if needed, along with a sedating antidepressant such as doxepin, trimipramine, amitriptyline, mirtazapine or trazodone.
Evidence for their efficacy as a standalone treatment is relatively weak, even though amitriptyline is widely prescribed in primary care as a long-term treatment for insomnia without co-occurrence of depression.
Even though no specific agent is recommended in this group, trazodone seems to have fewer or no anticholinergic activity compared with doxepin and amitriptyline, while mirtazapine has been associated with weight gain.15,16
Sleep breathing disorders and restless legs syndrome could contribute to the development of symptoms likely to be expressed initially as insomnia. A referral to a sleep clinic or a specialist with expertise in sleep medicine may be required.
Drugs like ß-blockers, SSRIs and sympathomimetics usually used for asthma or COPD treatment should not be overlooked as possible causes for insomnia.
Z-drugs have been included in trials as a long-term treatment for insomnia with promising results, but because of remaining concerns they are recommended only as a short-term treatment.
Their usage could be extended to up to a month if they are taken on a scheduled basis, for example only on alternating nights, or three times a week, and at the lowest effective dose.
Zolpidem has been associated with parasomnias like sleep eating and sleep talking, and therefore clinicians should warn patients about possible abnormal sleep behaviours.
Non-drug options and their evidence base
CBTi has been proved efficacious in controlling insomnia in both primary and comorbid form. It is the gold standard treatment for long-term insomnia, focusing on correcting maladaptive thought patterns and behaviours that can cause or worsen insomnia, regardless of the underlying cause. The goal of the technique is to empower the patient by providing a sense of control over sleep.
CBTi consists of four parts:
• Stimulus control therapy provides methods to remove factors that condition the mind to resist sleep, by keeping, for example, a regular sleep-wake pattern and leaving the bedroom if you can’t sleep within 20 minutes.
• Sleep restriction aims to increase sleep by initially sleep depriving patients so that they feel more tired and susceptible to sleep.
• Paradoxical intention sees patients advised to avoid any effort to fall asleep, as worrying about not being able to sleep could actually be keeping them awake.
• Relaxation training, including meditation, muscle relaxation and others methods, focuses on calming the patient’s mind and body.
The importance of these non-pharmacological approaches lies in both sustained benefits for over six to 24 months and minimal risk of adverse effects. The only disadvantages include high initial cost and lack of availability in primary care.17,18
Sleep hygiene is a part of CBTi, but could easily be provided at no cost in primary care. As a standalone treatment it has not been shown to be successful, but it does have an add-on effect in the insomnia treatment algorithm.
Dr Panagis Drakatos is an honorary clinical and research fellow at the Sleep Disorders Centre at Guy’s and St Thomas’ NHS Foundation Trust
Professor Adrian J Williams is a professor of sleep medicine at King’s College London and consultant physician at the Sleep Disorders Centre at Guy’s and St Thomas’ NHS Foundation Trust
1 Ohayon MM. Prevalence and correlates of nonrestorative sleep complaints. Arch Intern Med, 2005;165(1):35-41
2 NICE. Clinical knowledge summaries – insomnia. NICE; London;2009
3 Medicines Complete. Hypnotics and anxiolytics. Royal Pharmaceutical Society, 2014. Available at: http://www.medicinescomplete.com/mc/bnf/current/PHP2093-hypnotics-and-anxiolytics.htm
4 Medicines Complete. Circadin. Royal Pharmaceutical Society, 2014. Available at: http://www.medicinescomplete.com/mc/bnf/current/PHP2150-circadin.htm#PHP2150-circadin
5 Sleepio, 2014. Available at: http://www.sleepio.com/
6 National Health Service. IAPT – cognitive behavioural therapy competences framework. NHS. Available at: http://www.iapt.nhs.uk/about-iapt/website-archive/competencies-and-national-occupational-standards/cognitive-behavioural-therapy-competences-framework/
7 Zammit G, Erman M, Wang-Weigand S et al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med, 2007;3(5):495–504
8 Wade A, Ford I, Crawford G et al. Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Med, 2010;8:51
9 Lemoine P, Garfinkel D, Laudon M et al. Prolonged-release melatonin for insomnia - an open-label long-term study of efficacy, safety, and withdrawal. Ther Clin Risk Manag, 2011;7:301-11
10 Hoebert M, van der Heijden KB, van Geijlswijk IM et al. Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia. J Pineal Res, 2009;47(1):1-7
11 Gustaven I, Bramness JG, Skurtveit S et al. Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam. Sleep Med, 2008;9(8):818-22
12 Wagner AK, Zhang F, Soumerai SB et al. Benzodiazepine use and hip fractures in the elderly. Who is at greatest risk? Arch Intern Med, 2004;164(14):1557-72
13 Weich S, Pearce HL, Croft P et al. Effect of anxiolytic and hypnotic drug prescriptions on mortality hazards: retrospective cohort study. BMJ, 2014;348:g1996
14 Kripke D, Langer R, Kline L. Hypnotics’ association with mortality or cancer: a matched cohort study. BMJ Open, 2012;2:e000850
15 Schutte-Rodin S, Broch L, Buysse D et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med, 2008;4(5):487-504
16 Everitt H, McDermott L, Leydon G et al. GPs’ management strategies for patients with insomnia: a survey and qualitative interview study. Br J Gen Pract, 2014;64(619):e112-9
17 Morgenthaler T, Kramer M, Alessi C et al. Practice parameters for the psychological and behavioural treatment of insomnia: an update. An American academy of sleep medicine report. Sleep, 2006;29(11):1415-1419
18 Morin CM, Bootzin RR, Buysse DJ et al. Psychological and behavioral treatment of insomnia: update of the recent evidence (1998-2004). Sleep, 2006;29(11):1398-1414