In our article on Drugs for Chronic Insomnia, we said there is little evidence that antidepressants such as trazodone, mirtazapine, or amitriptyline are effective in treating insomnia not associated with depression. We received a comment from a reader who has prescribed the tricyclic antidepressant amitriptyline for insomnia, particularly for patients with headache disorders, and finds that most patients are satisfied with the treatment.

View the Expanded Table: Some Oral Drugs for Chronic Insomnia

Cognitive behavioral therapy for insomnia (CBT-I) is recommended for initial treatment of chronic insomnia. CBT-I includes stimulus control, sleep education and hygiene, sleep restriction, relaxation training, and cognitive therapy. When CBT-I alone is not effective, pharmacologic treatment should be added.

The FDA has approved daridorexant (Quviviq – Idorsia), an orexin receptor antagonist, for treatment of sleep-onset and/or sleep-maintenance insomnia in adults. Daridorexant is the third orexin receptor antagonist to be approved for this indication; suvorexant (Belsomra) and lemborexant (Dayvigo) were approved earlier.

The FDA has approved lemborexant (Dayvigo – Eisai), an orexin receptor antagonist, for treatment of sleep-onset and/or sleep-maintenance insomnia in adults. It is the second orexin receptor antagonist to be approved for this indication; suvorexant (Belsomra) was the first.

Over-the-counter products containing melatonin are widely used as sleep aids in children and adults.

Cannabis (marijuana) contains more than 60 pharmacologically active cannabinoids; delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best known. THC is the main psychoactive constituent of cannabis. CBD, unlike THC, does not produce intoxication or euphoria.

Patients who receive pretravel advice can reduce their risk for many travel-related conditions. Vaccines recommended for travelers are reviewed in a separate issue.

View the Expanded Table: Some Drugs for Altitude Illness, Jet Lag, and Motion Sickness

Cognitive behavioral therapy for insomnia (CBT-I) is recommended for initial treatment of chronic insomnia. Pharmacologic treatment should be used in addition to CBT-I when CBT-I alone is not effective.

View the Expanded Table: Some Oral Hypnotics for Insomnia

Pharmacological treatment of insomnia includes prescription drugs, non-prescription medications, and "natural" remedies. Behavioral approaches such as cognitive behavioral therapy, which are not discussed here, are also used. Pharmacologic treatment and behavioral therapy are often combined.

The FDA has approved suvorexant (Belsomra – Merck), the first orexin receptor antagonist to become available in the US, for treatment of sleep-onset and/or sleep-maintenance insomnia.

The FDA has required the manufacturer of eszopiclone (Lunesta – Sunovion), a benzodiazepine receptor agonist approved for the treatment of insomnia, to lower the current recommended starting dose to 1 mg for both men and women because a new study found that an evening dose of 3 mg can impair driving skills, memory, and coordination for more than 11 hours.1 Eszopiclone’s half-life is longer than that of any other drug in its class, which includes zolpidem (Ambien, and generics) and zaleplon (Sonata, and generics).

All benzodiazepine receptor agonists may impair performance the next morning, including driving.2 Anterograde amnesia and complex sleep-related behaviors without conscious awareness may also occur. Hallucinations have been reported. Like the benzodiazepines, benzodiazepine receptor agonists are schedule IV controlled substances; withdrawal, dependence, and abuse can occur.

1. FDA Drug Safety Communication. FDA warns of next-day impairment with sleep aid Lunesta (eszopiclone) and lowers recommended dose. Available at www.fda.gov. Accessed May 29, 2014.

2. Drugs for insomnia. Treat Guidel Med Lett 2012; 10:57.

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The FDA has approved the melatonin receptor agonist tasimelteon (Hetlioz – Vanda) for treatment of non-24-hour sleep-wake disorder (non-24), which is common in totally blind persons. Tasimelteon is the first drug approved for this indication and the second melatonin receptor agonist approved for use in the US; ramelteon (Rozerem) was approved earlier for treatment of insomnia. Melatonin itself has not been approved by the FDA for any indication; it is available in the US as a dietary supplement and is promoted as a sleep aid.

On January 10, 2013, the FDA issued a news release to announce that it was requiring the manufacturers of the zolpidem-containing products Ambien, Ambien CR, Edluar and Zolpimist, which are all approved for treatment of insomnia, to lower the doses for women and to recommend in their labeling consideration of a lower dose for men. No change will be required in the dose of Intermezzo, a low-dose sublingual formulation of zolpidem for middle-of-the-night awakening, which is already recommended in a lower dose for women.

Pharmacological treatment of insomnia includes prescription drugs, non-prescription medications and "natural" remedies. Behavioral changes are often needed as well.

The FDA has approved a new low-dose sublingual tablet formulation of the benzodiazepine receptor agonist zolpidem tartrate (Intermezzo – Transcept/Purdue) for treatment of insomnia due to middle-of-the-night awakening. Ambien and other zolpidem formulations available in the US are labeled for use only at bedtime.

Zolpidem oral spray (Zolpimist – NovaDel/ECR), a new formulation of the oral hypnotic zolpidem tartrate (Ambien, and others), has been approved by the FDA for short-term treatment of insomnia characterized by difficulty falling asleep.

The FDA has approved a new low-dose formulation of the tricyclic antidepressant doxepin (Silenor – Somaxon) for treatment of insomnia associated with sleep maintenance. The manufacturer claims that this dose retains the hypnotic effect of doxepin, without typical tricyclic adverse effects. Doxepin is available generically in higher-strength capsules and in a liquid formulation.

Edluar (Meda), a new sublingual tablet formulation of the benzodiazepine receptor agonist zolpidem (Ambien, and others), has been approved by the FDA for treatment of insomnia.

The majority of patients with insomnia do not have a predisposing psychiatric disease. Rather, untreated insomnia may be a risk factor for development of psychiatric problems such as depression or anxiety.

Many drugs are used to treat insomnia, but for some patients nonpharmacological treatments such as changing sleep habits, relaxation training and cognitive therapy may be more effective and durable than treatment with drugs. Hypnotic drugs are generally FDA-approved only for short-term use, but in practice they often are taken much longer.

Zolpidem (Ambien - Sanofi-Aventis), a nonbenzodiazepine benzodiazepine receptor agonist, is the most frequently prescribed hypnotic in the US. As its patent approaches expiration, its manufacturer has received FDA approval to market an extended-release formulation of the drug, Ambien CR. The pharmacological rationale for doing so is that short-acting hypnotics like zolpidem are more effective at inducing sleep than they are at maintaining it.

Ramelteon (Rozerem - Takeda), a melatonin receptor agonist, has been approved by the FDA for treatment of insomnia characterized by difficulty falling asleep. Unlike all other prescription hypnotics, which are classified as schedule IV drugs, ramelteon is not a controlled substance.

Ropinirole (Requip - GlaxoSmithKline), a dopamine agonist already available for treatment of Parkinson's disease, is now the first drug approved by the FDA for treatment of moderate to severe restless legs syndrome (RLS).

Eszopiclone (Lunesta - Sepracor), a benzodiazepine-like drug, has been approved by the FDA for oral treatment of insomnia. It is the S-isomer of zopiclone (Imovane, and others in Canada), which has been available in other countries for almost 20 years. Unlike similar drugs such as zolpidem (Ambien) or zaleplon (Sonata), Lunesta is not being restricted in its labeling to short-term use. Like other hypnotics, eszopiclone is a schedule IV drug.

Superseded by Drugs of Choice Handbook
Many drugs are used to treat insomnia, but for some patients nonpharmacological treatments such as changing sleep habits, relaxation training and cognitive therapy may be more effective than drugs.

Superseded by Drugs of Choice Handbook
Insomnia is a commom complaint, particularly among the elderly. Many drugs are approved by the US Food and Drug Administration (FDA) for treatment of insomnia, including five benzodiazepines and zolpidem (Ambien), a non-benzodiazepine that binds to benzodiazepine receptors in the brain. Some drugs marketed for other indications, such as antihistamines, antidepressants and antipsychotics, are also used as hypnotics. For many patients, nonpharmacological treatment of insomnia may be more effective than drugs, especially in the long term (CM Morin et al, Am J Psychiatry, 151:1172, 1994).

Several readers have asked the Medical Letter to evaluate the effectiveness and safety of exogenous melatonin for treatment of insomnia and jet lag. Melatonin has not been approved by the US Food and Drug Administration (FDA), but is available in health food stores and apparently is being used as self-medication to treat a wide variety of disorders.

Zolpidem (Ambien - Searle), an imidazopyridine hypnotic available in Europe for several years, was recently approved by the US Food and Drug Administration for short-term treatment of insomnia.

Estazolam (ProSom - Abbott), a triazolobenzodiazepine derivative similar in structure to alprazolam (Xanax) and triazolam (Halcion), was recently marketed in the USA for treatment of insomnia.

Quazepam (Doral - Baker Cummins, Wallace) is a trifluoroethyl benzodiazepine made by Schering and approved in 1985 by the US Food and Drug Administration for treatment of insomnia. Like other benzodiazepines, it is a Schedule IV controlled substance.Quazepam (Doral - Baker Cummins, Wallace) is a trifluoroethyl benzodiazepine made by Schering and approved in 1985 by the US Food and Drug Administration for treatment of insomnia. Like other benzodiazepines, it is a Schedule IV controlled substance.

Three benzodiazepines and 16 other compounds are marketed in the USA for treatment of insomnia. Many authorities believe that insomnia is overdiagnosed and overtreated (MK Erman, ed, Sleep Disorders, Psychiatr Clin North Am, Volume 10, Dec 1987).

Since The Medical Letter last reviewed the choice of benzodiazepines (Volume 23, page 41, 1981), several new drugs have been marketed and some old ones are now available generically. Most of the benzodiazepines available for oral use in the USA are listed in the table on page 28.