The Therapeutics Initiative is at arms length from government and other vested interest groups. Our function is unbiased review and dissemination of therapeutic evidence. Assessments apply to most patients; exceptional patients require exceptional approaches. We are committed to evaluate the effectiveness of our educational activities using the Pharmacare database without identifying individual physicians, pharmacies or patients.

Therapeutics Letter, issue 11, November/December 1995

To Sleep or Not to Sleep: Here Are Your Questions


Many psychiatric and medical disorders present with symptoms of insomnia and associated daytime impairment. It is essential to first identify such disorders if present (e.g. depression, chronic anxiety or obstructive sleep apnea) so that they can be treated specifically. The remaining cases represent primary transient or chronic insomnia. An approach to management of this common condition in the primary care setting follows.

What are the goals of therapy in managing a patient with transient or chronic insomnia?

What approaches are essential in managing all patients?

An improvement in sleep habits is the initial and continuing goal in all patients. This includes appropriate caffeine, alcohol and nicotine restriction, daily physical aerobic exercise, regular sleep and awakening times (including weekends), avoidance of large meals late in the evening, and maintaining a good sleep environment. Counseling, encouragement and reinforcement are essential to achieve compliance with this program.(1)

What non-prescription drugs are useful in treating insomnia?

Most over-the-counter hypnotics are antihistamines in which sedation is a significant dose related side effect. Anticholinergic side effects also occur with these drugs, including confusion, especially in the elderly. The principles for their appropriate use are similar to prescription hypnotics; never combine hypnotic drugs.

Alcohol does not improve sleep; despite initial sedation, alcohol is associated with an increased number of awakenings. (1)

Are there clinically significant differences between available prescription hypnotics?

The recommended drugs, benzodiazepines and zopiclone, have a similar mechanism of action on the benzodiazepine receptor complex in the brain. They differ in potency, duration of effect (half-life), side effects and cost (see Table). The difference in duration of effect is the most clinically relevant. The drugs with the shortest half-lives (2-3 hours) are more appropriate when the main difficulty is falling asleep. Drugs with intermediate half-lives (4-10 hours) are more appropriate when the goal is to reduce nocturnal awakenings. Drugs with half-lives >10 hours are likely to have residual effects after awakening and to be associated with accumulation if taken on a daily basis. They should be limited to patients with chronic anxiety (a secondary cause of insomnia) when one wants an anxiolytic effect the next day.

The fact that a benzodiazepine, (eg. oxazepam) is marketed as an anxiolytic, does not diminish its usefulness as a hypnotic.

What pharmacological actions of these drugs are important to appreciate before prescribing?

Objective evidence of effectiveness of hypnotics in double-blind placebo controlled sleep laboratory trials is small; total sleep duration is only 15 minutes longer with active drug than placebo.(2)

Because of the development of tolerance, most hypnotic drugs rapidly lose effectiveness with continuous nightly use. It makes sense, therefore, to prescribe hypnotics to be taken intermittently for short periods (e.g. once every second or third night for 1-3 weeks). This approach is widely recommended(3), however, randomized controlled trials of the effectiveness of this approach are needed.

The major adverse effect of hypnotics, residual or carry-over effects upon awakening, should be avoided as much as possible. The potential risks of residual effects are manifest in the Saskatchewan study(4), which showed that current users of long half-life benzodiazepines have a 1.7 relative risk of hip fracture as compared to current users of short half-life drugs. To minimize such risks use short half-life drugs in the lowest effective dose; start at ˝ of the usual recommended dose (see Table). Remember that the response rate to placebo in chronic insomnia is high (~33%) so you can anticipate a good rate of response to low doses.

How should I manage a new patient with insomnia?

Work on long term improvements in sleep habits. If adjunctive medication is needed in the short term use low doses and explain why it should be taken intermittently to maintain effectiveness. Don't prescribe enough for continuous nightly use. A major goal in new patients is to avoid regular nightly use.

How should I manage the patient who is taking a hypnotic every night?

The patient who is already a nightly user is a more difficult problem. Some of these patients can be motivated to stop (as mentioned above the medication is unlikely to be improving the duration of sleep). Before stopping, the dose must be reduced by ˝ every 1-2 weeks until the lowest dose in the dose range (see Table) is achieved. Even after tapering, the patient should be warned that they might experience mild rebound insomnia for the first 2-3 nights after stopping.(3)

What about older sedative-hypnotics?

The following drugs are still prescribed in British Columbia in order of decreasing use: chloral hydrate (Noctec), secobarbital (Seconal), meprobamate (Equanil), ethchlorvynol (Placidyl), butabarbital (Butisol), pentobarbital (Nembutal), and amobarbital (Amytal). These drugs are dangerous in overdose, have no advantages over benzodiazepines and are not recommended.

Conclusions:

Manage insomnia in your practice by education and encouragement of appropriate sleep habits. If indicated prescribe hypnotics with short half-lifes, in low doses, for short duration, and not for regular nightly use.


TABLE: SEDATIVES-HYPNOTICS IN BRITISH COLUMBIA

Generic Name Trade Name Dose Range Mean Elim* t˝(hr) (5) Cost** for Single Lowest Dose ($)
Triazolam Halcion/Novotriolam 0.0625-0.5 mg 3 0.03
Zopiclone Imovane 3.75-7.5 mg 5 0.34
Oxazepam Serax 7.5-30 mg 7 <0.01
Alprazolam Xanax 0.125-1.0 mg 12 0.05
Bromazepam Lectopam 0.75-6.0 mg 12 0.06
Temazepam Restoril 7.5***-30 mg 13 0.20
Lorazepam Ativan 0.25-2.0 mg 14 0.03
Estazolam Prosam 0.5-2 mg 15 0.22
Clonazepam Rivotril 0.25 mg 23 0.08
Nitrazepam Mogadon 2.5-10 mg 26 0.08
Diazepam Valium 2.0-10 mg 43 <0.01
Ketazolam Loftran 7.5***-30 mg 43 0.62
Chlordiazepoxide Librium/Corax/Solium 2.5-25 mg 64 <0.01
Clorazepate Tranxene/Novoclopate 1.9-15 mg 64 0.04
Flurazepam Somnol/Dalmane 7.5***-30 mg 74 0.02

* Ranked according to half-life of most slowly eliminated active metabolite.

** 1994 Pharmacare Data.

*** Appropriate low starting dose for this drug is not possible, as it is only available as a capsule.


REFERENCES

  1. Maczaj M. Pharmacological Treatment of Insomnia. Drugs. 45(1):44-55; 1993.
  2. Nicholson AN, Stone BM. Zopiclone: Sleep and performance studies in healthy man. Pharmacology. 27: suppl. 2, 92-97; 1982.
  3. Kryger MH, Roth T, Dement WC. Principles and Practice of Sleep Medicine. Second edition, 1994. Chapter 30: Hypnotics: Clinical pharmacology and therapeutics. 355-363.
  4. Ray WA, Griffin MR, Downey W. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. JAMA. 262(23):3303-3307; 1989.
  5. Goodman Gilman A, Rall TW, Nies AS, Taylor P. The pharmacological basis of therapeutics. Eighth edition, 1990. Appendix II. Design and optimization of dosage regimens; pharmacokinetic data. 1655-1715.

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