In search of sleep

“Insomnia is often multifactorial and, unless validated by sleep laboratory results, a subjective condition based on reports by the patient.”

Insomnia, or concerns about the quantity, quality or timing of sleep, is a common complaint.

In the UAE, most pharmacists identify sleep the sleeping pill Sominex is identical: 25 mg of diphenhydramine hydrochloride). While there’s no doubt that antihistamines are sedating, they can further impair quality of sleep and adversely affect the next day’s performance. Antihistamines also have anticholinergic effects, which can cause blurry vision, dry mouth, and confusion.

When assessing a patient with sleep concerns, physicians should consider the root cause. Is the insomnia a symptom (secondary insomnia) or a syndrome (primary insomnia)? Insomnia is often multifactorial and it is also important to note that, unless validated by sleep laboratory results, insomnia is a subjective condition based on reports by the patient.

Possible root causes include concurrent medical conditions and their treatment, psychiatric disorders, use of substances such as caffeine or alcohol, stress or an irregular schedule.

It may be helpful to ask your patient to complete a two-week sleep log detailing their sleep/wake schedule, use of any substances or medication (prescribed and over-the-counter), their quality and quantity of sleep and a rating of subjective sleep quality and daytime symptoms. By providing a detailed day-to-day picture of the patient’s experience, such information may provide clues that lead to a different diagnosis.

A general physical exam to rule out any underlying medical disorder or condition associated with insomnia is appropriate. This may include sources of chronic pain, signs of respiratory compromise, signs of hyper- or hypothyroidism and neurological disorders.

If you suspect the patient of having sleep-disordered breathing, if chronic insomnia persists after pharmacological or behavioural intervention (see below), or if the extent of the sleep disorder is not adequately explained by identification of root causes, consider referring the patient to a sleep specialist.

"In the 1990s, reports of confusion, hallucinations and amnesia led to triazolam being pulled from the market in several European countries."

In recent decades, the most common approach to treating insomnia has been with pharmacological intervention. Several basic principles underscore this therapy, namely:

- use the lowest effective dose for the shortest period of time,
- aim for intermittent dosing,
- if use is prolonged or if the dose is high, discontinue medication gradually and be alert for rebound insomnia.

The primary medications indicated for insomnia treatment are benzodiazepines, although their use has declined this decade. Five are currently FDA-approved for the treatment of insomnia; flurazepam, quazepam, triazolam, estazolam and temazepam, and the major difference between them is how long they last. Some, like triazolam (Halcion), stay in the blood for just a few hours; others, like flurazepam (Dalmane), linger for days.

Sleep induced by benzodiazepines is not as refreshing as natural sleep, so patients may not feel as well-rested. But less-than-ideal sleep is still a blessing for those struggling with insomnia.

Although useful for the short-term treatment of insomnia, there are potential drawbacks to benzodiazepine use. Various studies have reported a decline in functional status, cognitive impairment and a higher risk for falls and fractures, among elderly users.

In the 1990s, reports of confusion, hallucinations and amnesia were associated with the use of triazolam, which eventually led to it being pulled from the market in countries such as Norway, Denmark, Brazil and the United Kingdom. However, in the United States, a 1997 Institute of Medicine report concluded that it posed no greater risk than other benzodiazepines, and it’s still being sold there.

Questions remain over the long-term use of benzodiazepines, particularly the risk of physical dependence, the potential for tolerance and the risk of rebound insomnia when the drugs are stopped. Such concerns led the FDA to establish guidelines that discourage the use of benzodiazepine agents for more than four weeks.

"Whether Ambien and Sonata are that much of an improvement over the short-acting benzodiazepines is debatable."

Benzodiazepine worries have fuelled a move in the treatment of sleep disorders towards alternative medications. Enter zolpidem (Ambien), approved by the FDA in 1992, and zaleplon (Sonata), approved in 1999, nonbenzodiazepine sedative hypnotics. A third, zopiclone, is not available in the US but is one of the most commonly prescribed agents outside it.

The term nonbenzodiazepines is slightly misleading because these drugs work in a similar but more specific fashion to benzodiazepines, targeting GABA-A receptors containing alpha1 subunits. However, they also demonstrate pharmokinetic differences from some benzodiazepines, which may produce fewer treatment-emergent side-effects.

They’re also shorter-acting than many of the benzodiazepines, Halcion being an exception, which may explain the lower incidence of daytime fatigue in users.

Sonata may be a little too short-acting. Its half-life is very short, approximately one hour, and it is usually used only for sleep induction, either in the beginning or middle of the night. Aggressive marketing and Sonata’s shortcomings have made Ambien the top-selling sleeping pill in the United States and the 10th-best-selling prescription drug over all.

But whether Ambien and Sonata are that much of an improvement over the short-acting benzodiazepines is debatable. All three “Z” agents are still only recommended for a limited period of use, even with chronic, relapsing insomnia, and there are few side-by-side comparisons.

In 2004, the UK’s National Health Service watchdog, NICE, concluded that the “Z” compounds are no better than short-acting benzodiazepines and that price should dictate which drug is used. British sleep experts strongly objected to the decision, citing the increased risk of daytime sleepiness associated with benzodiazepine use.

Serotonin-specific antidepressants, such as paroxetine, nefazodone and particularly trazodone (Desyrel), are often prescribed for insomnia. They alleviate the sleep disturbance that can accompany depressions and have fewer side effects than tertiary amine antidepressants. While many doctors and patients say trazodone works well, it is a prime example of off-label prescribing.

Trazodone was approved by the FDA as an antidepressant, not as a sleeping pill. Despite all the anecdotal evidence, there has been little systematic study of its safety or effectiveness as a sleeping pill and possible side effects include orthostatic hypotension.

Patients who take trazodone for insomnia and another antidepressant, such as Prozac, for depression have also been known to develop serotonin syndrome. The combined effect of the drugs raises levels of the neurological protein so they are too high.

Nonprescription remedies include melatonin, but it’s questionable how effective synthetic melatonin is as a sleeping pill. Some research suggests that it may be helpful with circadian disturbances, but evidence is still weak.

“I don’t like the term addiction when it comes to sleeping pills. If you have diabetes and you need insulin, do we say you’re addicted to it?"

Whatever their virtues, Ambien and Sonata are only FDA-approved for short-term use. In actual practice, though, many patients take them and benzodiazepines for months or even years.

By some estimates, 14% of Americans treated for insomnia have taken some kind of sleeping pill for more than a year. Meanwhile, as studies reveal the negative health consequences of insomnia and not getting enough sleep, the risk-benefit calculus of sleeping pills is changing. Their drawbacks have to be weighed against the consequences of not treating chronic sleeping problems.

Moreover, some sleep experts are putting a different spin on sleeping pill dependence.

“I don’t like the term addiction when it comes to sleeping pills,” says Dr David P. White, director of the sleep disorders program at Harvard-affiliated Brigham and Women’s Hospital. “If you have diabetes and you need insulin, do we say you’re addicted to it?”

Such debate has sparked a great deal of interest in identifying drugs that could win FDA approval as long-term sleeping pills. Currently, there are two leading candidates, eszopiclone (Estorra) and indiplon.

Eszopiclone won FDA approval in February 2004, and is indicated for treatment of insomnia characterised by difficulty falling asleep and/or maintaining sleep during the night and early morning. This dual indication is particularly important, in view of the changing nature of chronic insomnia.

To date, the majority of sleeping pill trials are short-term. However, Sepracor, the US-based company behind Estorra, has plowed millions of dollars into studies that have lasted six months and sometimes longer.

A company-sponsored, six-month-long study published in patients with chronic insomnia, published in 2003, reported that the drug helped with a variety of sleep problems and, the authors said, with no evidence of tolerance.

A 12-month open-label extension of the study showed continued efficacy. Eszopiclone is the first approved hypnotic not to carry a short-term recommendation as to duration of treatment and may very well be the product that pioneers the market for long-term sleeping pills.

Indiplon however, another nonbenzodiazapine agent, is still awaiting FDA approval. Two formulations of indiplon, immediate release (IR) capsules and modified release (MR) tablets, have been evaluated in clinical trials to date and have shown good results.

Indiplon has a short half-life so should produce little daytime drowsiness and it is hoped the MR version of the compound will overcome the traditional disadvantages of short-acting sleeping pills. Indiplon is scheduled for release, FDA permitting, sometime in 2007.

According to press reports, we may see an advertising blitz of Viagra-like proportions, which will also coincide with current market-leader Ambien losing its patent rights. This prospect has some doctors worried about overuse of sleeping pills. Insomnia can be its own condition, but is often a symptom of others. Rather than paper over such problems with a sleeping pill, skeptics ask, wouldn’t it be better to treat the root causes?

“Many physicians are wary of using behavioural techniques within a primary care setting, for fear the methods will be too time-consuming or complex.”

Much primary care treatment of insomnia focuses on symptom management.

Although in the short-term medication produces more immediate results, intermediate and long-term management of insomnia may benefit from the use of behavioural interventions.

These might include education on sleep hygiene, stimulus control, sleep restriction or cognitive therapies. Many physicians are wary of using these techniques within a primary care setting, for fear the methods will be too time-consuming or complex.

However, studies suggest that patients receiving nonpharmacological therapies benefit from long-lasting relief from insomnia, whereas many of those treated with medication suffer from recurring bouts of insomnia. Essentially, behavioural treatments can have long-term benefits for both you and your patient.

According to the American Academy of Sleep Medicine’s evidence-based review of nonpharmacological treatments, stimulus control is the most effective approach.

This is followed by progressive muscle relaxation and paradoxical intention, while sleep restriction and cognitive behavioural therapy are also recommended as options. All are generally combined with sleep hygiene education which, while not an effective treatment alone, does educate the patient on positive health practices for good sleep.

These practices include diet, exercise and substance use, and environmental factors that may hamper sleep including light, noise and temperature.

Stimulus control

The concept behind stimulus control is that insomnia is a conditioned response to bedtime and cues related to sleep. The idea is to retrain the patient to associate the bed and bedroom with the rapid onset of sleep, by employing a consistent sleep/wake schedule and limiting activities not compatible with sleep.

Patients are instructed to: go to bed only when sleepy; avoid naps and use the bed only for sleep and sex; if unable to sleep within 20 minutes, get up and go into another room, returning only when sleepy; have a regular rise time, even after a bad night’s sleep.

Progressive muscle relaxation

Relaxation techniques are intended to inhibit anxiety-related arousal that may be linked to insomnia. Progressive muscle relaxation, or systematically tensing and releasing all the muscle groups of the body to reduce somatic arousal, has been shown in studies to be more effective than placebo.

Paradoxical intention

As the name suggests, paradoxical intention involves the patient deliberately trying to remain awake. It is thought that, for insomniacs, performance anxiety may prevent proper sleep. As the patient stops trying to sleep, the anxiety disappears aiding the onset of sleep.

Sleep restriction

Sleep restriction encourages the patient to spend less time in bed, in the hope of creating slight sleep deprivation that will eventually cause a more rapid onset, and more consistent duration, of sleep. If a patient reports spending eight hours in bed, but only sleeping for five of them, the patient should only be in bed for five hours. After that time period, the patient must get out of bed.
The time spent in bed in reviewed weekly, and either increased by 15-20 minutes (if sleep efficiency increases) or decreased by 15-20 minutes (where sleep efficiency decreases). The time in bed is unchanged if sleep efficiency is roughly between 80-90%.

To calculate sleep efficiency, divide the reported time spend asleep, by the hours spent lying in bed and then multiply by 100. For example, if the patient went to bed at 11pm and rose at 7am, but reported her actual sleep time as five hours, her sleep efficiency score would be 62.5%. (5/8 * 100 = 62.5%.)

Many clinicians have reported sleep restriction to be a very useful aid in treating insomnia, a statement supported by numerous studies.

Cognitive behavioural therapy

This approach utilises CBT to change distorted beliefs and attitudes about sleep, replacing them with more positive substitutes. When combined with other techniques, such as stimulus control and relaxation therapies, CBT has showed a positive outcome in studies.

Primary care physicians are often called upon to deal with patients with insomnia. The use of behavioural therapies in association with pharmacological interventions may point the way to safer and more effective therapies, allowing the clinician to take the initiative with treatment rather than needing to refer to a specialist.

While the success of such combination therapies requires consideration discipline on the part of the patient, studies have shown they can have a significant impact on the morbidity of insomnia with resulting patient satisfaction.