Hypnotics and the Treatment of Insomnia

Insomnia or poor sleep is very common. At least 15% adults report persistent and/or severe symptoms with higher rates in women, older people and those with medical or psychiatric disorders.¹
Such symptoms should not be underestimated since they are associated with fatigue, mood disturbances, problems with interpersonal relationships, occupational difficulties and a reduced quality of life.²

Primary insomnia is a diagnosis of exclusion and accounts for only 12-30% chronic insomnia. The majority of insomnia is due to external stimuli or somatic stimuli, physiological disturbance (eg due to shift work), psychological disorders, pharmacological effects of caffeine, alcohol and medication (eg beta-blockers, diuretics, SSRIs) and combinations of these factors.^1,3

Those affected commonly consult doctors, often with the expectation of a "sleeping tablet". 10 million scripts every year are dispensed for hypnotics.¹ Prescribing behaviour runs contrary to guidelines (Committee for Safety in Medicine,⁴ Royal College of Psychiatrists⁵) which have long advised that hypnotic drugs should be limited to short courses for acutely distressed patients and avoided in the elderly.⁶

Currently marketed hypnotic drugs are effective in promoting sleep in the short-term but there is little good evidence for their long term efficacy and there are serious concerns regarding the risk of dependence when these drugs are used in this way.^1,7

Benzodiazepines (nitrazepam, flurazepam, loprazolam, lormetazepam, temazepam)

• Act on the GABA-A receptor in the CNS, enhancing GABA-ergic neurotransmission.¹ Benzodiazepines are selected for use as anxiolytics, hypnotics or sedatives depending on their duration of action and when they are taken.⁶
• Nitrazepam and flurazepam are longer-acting compared to loprazolam, lormetazepam and temazepam and so are more likely to give rise to "hang-over" effects the next day and repeated doses may become cumulative. However, they are less likely to cause withdrawal phenomena than the short-acting benzodiazepines.⁶
• Diazepam (long-acting) is sometimes used as a single nocturnal dose to treat daytime anxiety associated with insomnia.⁶
• Benzodiazepines are effective in increasing sleep duration and decreased night-time awakenings but do not significantly decrease the time-taken to fall asleep.²

Z-drugs (zoplicone, zaleplon, zolpidem)

• Newer hypnotics acting at the GABA-A receptor but with different affinities and pharmacokinetics compared to the classical benzodiazepines. However, the hypnotic effect and related adverse effects of the Z-drugs are broadly similar to the short acting benzodiazepines.^1,8
• Tolerance and rebound insomnia can develop after repeated use for a few weeks and none are licensed for treatment of longer than 4 weeks.^1,9
• Dependence on Z-drugs is a recognised risk (most commonly in those with a history of drug or alcohol misuse or other psychiatric disorder but may occur outside of this group) and is characterised by dose escalation and withdrawal symptoms.¹
• Despite being shorter acting than the benzodiazepines, they have not shown consistent differences in safety or tolerability.^1,9 Zoplicone in normal dose can impair memory and driving ability for up to 11 hours in healthy adults and increases the likelihood of being involved in an RTA.¹
• NICE⁹ recommends that there is little compelling evidence to distinguish between the z-drugs and shorter acting benzodiazepines clinically, so that 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.

Comparison of benzodiazepine and z-drug hypnotics^1,2

Chloral hydrate and Chlormethiazole⁶

• Older hypnotics, now best avoided due to risk of adverse effects (eg dependence, dangerous respiratory depression in overdose, common gastric irritation)
• Chlormethiazole is sometimes still used as an adjunct to alcohol withdrawal in an in-patient setting.

• Transient insomnia in those who normally sleep well (<2-3 days, often caused by factors such as noise, shift work or jet lag) - hypnotic treatment should consist of one or two single doses at minimal effective dose.
• Short-term insomnia (lasts more than a few days but less than 3 weeks, usually due to emotional problems or physical illness) - short course of hypnotics, used at minimal effective dose, usually for less than 1 week. Intermittent doses may reduce the potential for tolerance and dependence.

Chronic insomnia is not an indication for hypnotics - tolerance can develop within 3-14 days of continuous use and so long-term efficacy is not maintained. They should be reserved only for short courses in the acutely distressed in this circumstance and avoided wherever possible.

• Respiratory depression
• Severe hepatic impairment
• Myasthenia gravis
• Sleep apnoea syndrome
• Pregnancy and breastfeeding

The elderly

The elderly are most at risk of becoming ataxic, confused and/or falling due to hypnotic treatment as they eliminate the drugs more slowly, are more susceptible to CNS depression and are more likely to be using potentially interacting drugs. The use of long-acting benzodiazepines and some z-drugs seems to be associated with an increased risk of falls and hip fractures in elderly patients.¹⁰

A recent meta-analysis looking at the risks and benefits of sedative use in the over-60s found a marginal improvement in sleep quality outweighed by risk of adverse event (number-needed-to-treat of 13 versus number-needed-to-harm of 6). This is particularly marked where patients have additional risk factors for cognitive or psychomotor adverse events.¹¹

Despite the wide-spread acceptance that hypnotics should be avoided amongst the elderly, approximately 80% of all hypnotics are prescribed to those aged over 65 years.

Children

The use of hypnotics in children is not normally justified - the exceptions being occasional use for night terrors and sleep-walking.⁶

Potential for abuse

All hypnotics have the potential for abuse. Be vigilant prescribing particularly when a patient is temporarily registered or unknown. Temazepam is the most commonly abused of these drugs, but other benzodiazepines and more recently zoplicone have all been implicated in illicit drug use.⁸

Driving

Hypnotics impair judgement and increase reaction times so affect the ability to drive or operate machinery, increasing risk of RTAs.¹⁰ Patients must be aware of this and the fact that hangover effects of a night dose may still manifest themselves the following day. DVLA advice that any patient suffering from excessive awake-time sleepiness, regardless of cause (including due to the insomnia itself) should cease to drive until there is satisfactory control of symptoms.⁸

Persistent use or dependency on benzodiazepines will lead to licence refusal or revocation for a minimum of 1 year.¹²

• CNS adverse effects common : ataxia, confusion, drowsiness
• Paradoxical aggression (rare)
• Benzodiazepine dependence - common with prolonged use. Dependency is also a risk with z-drugs.
• Respiratory depression

• Alcohol and other CNS depressants potentiate benzodiazepine effects.
• Macrolides and antifungals inhibit the metabolism of benzodiazepines and potentiate their action.

• Before prescribing any hypnotic, underlying causes of insomnia should be actively sought and treated. Treat any underlying physical or psychiatric condition (eg restless legs syndrome, nocturia, pain, depression).
• Non-drug treatment should always be used wherever possible (although this has resource implications).
• Address patient ideas, concerns and expectations regarding "sleeping tablets".
• Hypnotics should only be offered as an adjunct to non-drug treatment of chronic insomnia and reserved for those with the most severe symptoms.
• To minimise next-day sedative effects, prescribe a shorter-acting drug in the lowest effective dose.
• Where a decision is made to prescribe hypnotics, prescribe short courses (<2-3 weeks), encourage intermittent use and review the patient frequently.
• Do not use repeat prescribing for hypnotics and maintain very frequent reviews.
• Be alert for signs of dependency and tolerance - complaints of return of insomnia symptoms, withdrawal symptoms, early requests for next script, active request for help etc.
• Abrupt withdrawal of benzodiazepines can cause confusion, convulsions and psychosis in a few, but more commonly insomnia, anxiety, sweating, appetite loss, disturbed sleep and vivid dreams. Since these symptoms are often similar to those which led to the original prescribing of benzodiazepines, they are often wrongly diagnosed as a recurrence of symptoms leading to repeat prescribing.
• Withdrawal symptoms can occur within a few hours of short-acting drugs but up to 3 weeks following the cessation of longer acting ones.

• The NSF for Mental Health stated that chronic users of hypnotic drugs should be encouraged to stop their medication with the help of withdrawal programmes.¹³
• Gradual withdrawal of benzodiazepines is desirable and achievable in many patients who have been using them long-term as hypnotics. Cognitive function improved without detrimental effect on sleep or anxiety in a study group (mean age 77 years) who withdrew over 8-9 weeks with blind tapering of their dose and psychological support when compared to a control group who opted to stay on hypnotics. Approximately 80% of the study group (self-selected and excluding those with psychiatric illness) successfully stopped their hypnotic.¹⁴
• There is limited evidence as to the best way to withdraw from benzodiazepines: expert opinion suggests switching to a nocturnal dose of diazepam and once stabilized reducing the dose sequentially in small steps (usually 2-2.5mg reductions in diazepam every fortnight). Divide the daily dose if necessary to prevent intoxication or daytime drowsiness. If withdrawal symptoms develop, the dose of diazepam should be maintained or temporarily increased until they abate. Often the final reduction is the hardest to achieve - smaller doses of diazepam are possible by cutting scored tablets in half.
• Experience of managing z-drug withdrawal is even more limited. Withdrawal by switching to diazepam is advised.

Other drugs

• Antihistamines - promethazine (Phenergan nightime™, Sominex™), diphenhydramine (Dreemon™, Medinex™, Nightcalm™ and Nytol™) - these are widely purchased OTC but good evidence of their efficacy is lacking, hangover effects are common and rebound insomnia can occur after prolonged use.^1,2
• Herbal remedies eg valerian - rarely associated with cardiotoxicity or hepatotoxicity.¹
• Melatonin - is not licensed in the UK. There is only weak evidence for its efficacy and no large-scale studies published.¹
• Antidepressants - where sleep disturbance is thought to be a manifestation of underlying depression, it seems sensible to select treatment with a sedating anti-depressant (eg. amitriptyline, mirtazapine, trazodone) in full therapeutic dose. However, there is limited evidence only that such treatment is helpful to treat insomnia in patients without depression and these drugs have potentially serious side-effects (antimuscarinic side-effects, cardiotoxicity etc).^1,2

Non-pharmacological treatment³

• Stimulus control therapy (go to bed only when sleepy, maintain a regular schedule, avoid naps, use the bed only for sleep, remove yourself from bed if unable to fall asleep <20min, engage in relaxing activity and try again)
• Sleep restriction (maintain a sleep log, determine mean total sleep time for baseline period, where sleep efficiency is less than 80%, decrease time in bed by 15minutes and repeat adjustment every 5-7days)
• Sleep hygiene (maintain a regular sleep-wake schedule, do not nap, avoid sleeping-in, do not lie in bed for prolonged periods awake, avoid excessive fluid or food intake in evenings, exercise regularly but not within 3 hours of bedtime, no caffeine after noon, minimise alcohol, tobacco and other stimulants)
• Paradoxical intention (advise patient to deliberately remain awake, reducing performance anxiety that can interfere with ability to initiate sleep)
• Progressive muscle relaxation (alternate tensing and relaxing of muscles, facilitates relaxation, inhibits anxiety-associated arousal that can block sleep)
• Biofeedback
• Cognitive therapy (identify problem cognitions eg "I will never sleep without medications" and replace with more adaptive beliefs and attitudes)
• Multi-component strategies

There is evidence that psychological treatments' efficacy is comparable with hypnotics in the short-term (although slower in onset), gain is maintained for 6 months following therapy and is cost-effective. However, a lack of trained staff limits the scope for delivering many of these treatments in primary care.¹