clinical topic updates

Differential Adverse-Effect Profiles Among Sleep Medication Classes

by John W. Winkelman, MD, PhD


There are a number of pharmacologic options that can be utilized to assist with sleep, which may be a reflection of the fact that sleep is regulated by several brain systems. In addition to half-life and timing of administration, the class of insomnia medication can have an important influence on the types of side effects that patients may experience.

Expert Commentary

John W. Winkelman, MD, PhD

Professor of Psychiatry
Chief, Sleep Disorders Clinical Research Program
Department of Psychiatry
Massachusetts General Hospital
Harvard Medical School
Boston, MA

“We try to approximate the ‘ideal’ insomnia therapy by selecting the particular medication and, in some cases, adjusting the timing or strength of the dose, in view of the particular agent’s half-life.”

John W. Winkelman, MD, PhD

The good news about patients with insomnia and hypnotic medications is that we have several options. The wide variety of pharmacologic alternatives that are available reflects the fact that sleep is regulated by various brain systems: inhibitory systems that can be promoted and excitatory systems whose effects can be reduced, both to assist with sleep. Some medications are specifically indicated for insomnia, while others, such as antidepressants, may be used off-label to address sleeplessness. Unfortunately, details on the adverse effects of such off-label uses for insomnia are less precisely known because these agents have not been studied in those with insomnia, and the data on both efficacy and side effects are more anecdotal.

One of the most important common side effects of any sleep medication is sedation. The ideal medication would work the minute you take it while lying in bed and would stop working 1 minute before you want to wake up, but this is not how medications, or our bodies, work. So, we try to approximate the “ideal” insomnia therapy by selecting the particular medication and, in some cases, adjusting the timing or strength of the dose, in view of the particular agent’s half-life. All medications used for insomnia have benefits and shortcomings, and all are accompanied by a range of adverse effects.

Benzodiazepines and benzodiazepine receptor agonists together comprise the largest group of US Food and Drug Administration–approved medications for insomnia. Along with daytime sedation, they are also associated with nighttime sedation, which can be problematic among patients with nocturia, restless legs syndrome, or pain, who may experience gait instability when getting up in the middle of the night. Falls, driving, overnight cognitive impairment, and complex sleep-related behaviors are a concern with benzodiazepine receptor agonist use, so these agents should be prescribed with caution.

Antidepressants comprise a second class of drugs that are often prescribed for insomnia. Trazodone is commonly prescribed for patients with insomnia. The main side effect of trazodone is morning sedation, although orthostatic hypotension can also be an issue.

Orexin antagonists are yet another therapeutic class, and these agents have a unique mechanism of action. Suvorexant and lemborexant are both approved by the US Food and Drug Administration for insomnia, and daridorexant is also being evaluated for this indication. Dose-related daytime sedition has been observed with orexin inhibition, but these agents appear to have a relatively low incidence of other side effects associated with hypnotics. I am not aware of any reports of complex sleep behaviors with orexin inhibitors, for instance.


Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry. 2016;79(2):136-148. doi:10.1016/j.biopsych.2014.10.003

Moore TJ, Mattison DR. Assessment of patterns of potentially unsafe use of zolpidem. JAMA Intern Med. 2018;178(9):1275-1277. doi:10.1001/jamainternmed.2018.3031

Rosenberg R, Murphy P, Zammit G, et al. Comparison of lemborexant with placebo and zolpidem tartrate extended release for the treatment of older adults with insomnia disorder: a phase 3 randomized clinical trial. JAMA Netw Open. 2019;2(12):e1918254. doi:10.1001/jamanetworkopen.2019.18254

Vgontzas AN, Puzino K, Fernandez-Mendoza J, Krishnamurthy VB, Basta M, Bixler EO. Effects of trazodone versus cognitive behavioral therapy in the insomnia with short sleep duration phenotype: a preliminary study. J Clin Sleep Med. 2020 Aug 11. doi:10.5664/jcsm.8740

Winkelman JW. Clinical practice: insomnia disorder. N Engl J Med. 2015;373(15):1437-1444. doi:10.1056/NEJMcp1412740

Zammit G, Dauvilliers Y, Pain S, Sebök Kinter D, Mansour Y, Kunz D. Daridorexant, a new dual orexin receptor antagonist, in elderly subjects with insomnia disorder. Neurology. 2020;94(21):e2222-e2232. doi:10.1212/WNL.0000000000009475

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