A Drug-by-Drug Guide to Treating Insomnia

Question

Which drugs and supplements commonly used for the treatment of insomnia are supported by clinical evidence and practice guidelines?

Response from Expert Alyson P. Lozicki, PharmD
Postgraduate Fellow, Clinical Pharmacology Services, Inc., Tampa, Florida

Unmanaged sleep disorders are creating a public health epidemic. So says the Centers for Disease Control and Prevention and the American Academy of Sleep Medicine (AASM).^[1] An estimated 30%-50% of people suffer acute or transient symptoms at some point in their lifetime, and in 5%-10% of cases, these symptoms persist and develop into a chronic condition.^[2,3] Poor sleep is increasingly recognized to have broadly negative effects on a range of health outcomes, including mortality, accidents, injury, and disability.

Insomnia is broadly defined as subjective difficulty with initiating or maintaining sleep that results in some form of daytime impairment. However, several types and subtypes of insomnia exist and are differentiated by etiology and pathophysiology. Primary insomnia may be idiopathic in nature or the result of conditioned sleep difficulty/heightened arousal (psychophysiologic insomnia).^[3] More commonly, insomnia presents secondary to an acute or chronic medical condition (eg, obstructive sleep apnea, chronic obstructive pulmonary disease, allergies), medications (eg, decongestants, opioids, stimulants), substances (eg, caffeine, alcohol, nicotine), or other environmental factors and life changes.^[4] The goals of treatment are to improve both sleep quality and insomnia-related daytime impairment. Patients should be re-evaluated periodically until symptoms have stabilized or resolved.

For all patients suffering from symptoms of insomnia, the initial management should include counseling and assessment of any precipitating or perpetuating factors, education about proper sleep hygiene and techniques, and management of contributing comorbidities.

When behavioral therapy and nonpharmacologic interventions are insufficient, or when the duration of treatment is expected to be short (eg, in acute settings of stress), pharmacologic management should be considered.^[3] Several classes of medications and natural supplements are used in the treatment of insomnia, and selection of drug therapy will vary depending on etiology, symptoms, treatment goals, past treatment responses, patient preference, cost and availability, comorbid conditions, contraindications, drug interactions, and adverse-effect profiles.

The agents and recommendations for use, according to the AASM clinical practice guidelines (most recently updated in 2017), are summarized in the Table. It is important to note that these recommendations are based on moderate- to low-quality evidence, with the caveat that most patients would use a particular treatment over no treatment.^[5]

Table. Summary of AASM Recommendations for the Pharmacologic Treatment of Insomnia^[5]

Drug	Sleep-Onset Insomnia	Sleep Maintenance Insomnia	NOT Recommended*
Diphenhydramine (Benadryl)			X
Doxepin (Silenor)		X
Eszopiclone (Lunesta)	X	X
L-tryptophan			X
Melatonin			X
Ramelteon (Rozerem)	X
Suvorexant (Belsomra)		X
Temazepam (Restoril)	X	X
Tiagabine (Gabitril)			X
Trazodone (Desyrel)			X
Triazolam (Halcion)	X
Valerian			X
Zaleplon (Sonata)	X
Zolpidem (Ambien)	X	X
*Little to no improvement in quality of sleep compared with placebo

Pharmacologic Treatment of Insomnia

While pharmacologic management has many advantages, a thorough understanding of the unique pharmacokinetic and pharmacodynamic properties of sleep aids is critical for the development of individual treatment plans to optimize therapeutic benefit and to ensure the safe use of these medications. The guidelines from the AASM also emphasize the importance of patient education and close monitoring to assess efficacy of treatment, risk factors for and emergence of adverse drug reactions, and the need for ongoing medication.^[3]

The sleep aids recommended for treatment of insomnia include benzodiazepines, benzodiazepine receptor agonists ("Z-drugs"), orexin receptor antagonists, tricyclic antidepressants, and melatonin receptor agonists. These agents have demonstrated short-term efficacy (ie, 4-6 weeks) compared with placebo in clinical trials, and there is no specific agent that is preferred. Timing of administration and duration of use can have a significant impact on the therapeutic effect of sleep aids, and some agents have the potential to cause rebound insomnia or rebound anxiety if not managed appropriately. Patients should be maintained on the lowest effective dose, and the medication should be tapered/discontinued when conditions allow.

Long-term (eg, nightly, intermittently, or as needed) use of these medications may be indicated for those with severe or refractory insomnia or chronic comorbidities, and chronic use of pharmacologic treatment should be supplemented by cognitive-behavioral therapy when possible.^[3,5] The safety and efficacy of long-term use of these agents also have not been established.

In general, over-the-counter agents (eg, diphenhydramine) and herbal/dietary supplements (eg, melatonin, valerian) are not recommended, owing to the relative lack of evidence supporting efficacy and safety.^[5]

Clinical Pearls in Insomnia

Clinical pearls regarding dosing and potentially serious adverse side effects in the pharmacologic treatment of insomnia include^[6,7]:

Administer on an empty stomach at least 30 minutes before bedtime; administration with food can delay onset.
Patients should not take a dose if they plan to get less than 7-8 hours of sleep, and middle-of-the-night dosing is not recommended.
Use of benzodiazepines and "Z-drugs," short- or long-term, has the potential to cause physical dependence. Rapid dose decreases or abrupt discontinuation can produce withdrawal symptoms, including rebound insomnia and anxiety.
Agents with long half-lives (eg, eszopiclone, temazepam) are associated with a greater risk for next-day impairment.
High doses of hypnotics with both short and long half-lives are more likely to cause symptoms of sedation and next-day impairment.
All agents have the potential to cause significant cognitive impairment, including abnormal thinking and behavior changes, memory impairment, and central nervous system (CNS) depression.
There is an additive effect on psychomotor performance with concomitant CNS depressants or alcohol use.
Sleepwalking, sleep-driving, sleep-eating, sleep-sex, night terrors, and other abnormal sleep-related behaviors are most frequently associated with the use of zolpidem. However, these concerning side effects have also been reported with the other "Z-drugs" and, more rarely, benzodiazepines.

Special Populations

Pharmacologic treatment for chronic insomnia in the elderly should be initiated with caution. Evidence demonstrates a minimally improved quality of sleep with pharmacologic agents and a significantly increased risk for adverse events.^[8,9] The American Geriatrics Society 2019 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults recommends avoiding benzodiazepines due to a significant risk for adverse effects (eg, cognitive impairment, delirium, falls, fractures). Avoidance of benzodiazepine receptor agonists ("Z-drugs") in older adults is also recommended due to their minimal efficacy in treating insomnia and an adverse-effect profile similar to that of benzodiazepines.^[10]

Benzodiazepines and "Z-drugs" are generally not recommended for the management of insomnia during pregnancy or in women who are breastfeeding.^[3]

Efficacy and safety of the medications and supplements discussed above for the treatment of insomnia in pediatric patients have not been established, and use is not recommended.^[5]

Additionally, for patients receiving pharmacologic therapy for the management of comorbid psychiatric conditions (eg, depression, anxiety, mood disorder), medication regimens may be optimized on the basis of the clinical effects of an agent. For example, antidepressant or antipsychotic agents with sedating properties may be administered at night or before bedtime to facilitate sleep, and it may be recommended to administer agents with greater activating properties in the morning to avoid interference with sleep.^[5]

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