“Hey, doc, the patient wants to know if you could give him something for sleep. He has not slept well over the past three days.”
Sleep aids are requested by patients in the ICU due to sleep disturbances caused by environmental disruptions and underlying illness. Guidelines recommend nonpharmacologic strategies as first-line interventions to promote sleep and reduce delirium, including minimizing nighttime noise and light, promoting day-night orientation, and encouraging sleep hygiene practices. Pharmacologic agents are generally not recommended due to risks of adverse effects and lack of consistent evidence for benefit but can be considered on a case-by-case basis. Here, we review oral sleep medications used in the ICU, beginning with those that have the strongest evidence for safety and efficacy.
1. Melatonin and ramelteon (low risk)
Melatonin and its receptor agonist ramelteon help regulate circadian rhythms and improve sleep without significant cognitive side effects. Both have shown benefit in ICU settings, with ramelteon reducing the incidence of delirium in a randomized trial.1 A meta-analysis also supports melatonin’s safety and possible benefit in delirium prevention.2 These are first-line pharmacologic options.
2. Gabapentin (low to moderate risk)
Gabapentin, commonly used for neuropathic pain, has sedative properties that may improve sleep without major cognitive effects. While data in ICU patients are limited, it appears to have a low risk of delirium.3 However, high doses may cause confusion, especially in older adults.
3. Trazodone (moderate risk)
Trazodone is often used for insomnia due to its sedative properties. ICU studies show mixed results: Some suggest less delirium risk than benzodiazepines while others raise concerns about cognitive effects, particularly in those with baseline impairment.4
4. Clonidine (moderate risk)
An α2-agonist with sedative effects, clonidine may be helpful in ICU patients, especially during sedative withdrawal. However, it can cause hypotension and bradycardia.5
5. Zolpidem and other Z-drugs (high risk)
Zolpidem promotes sleep through gamma-aminobutyric acid activity but is linked to confusion and falls, particularly in older patients. It has been associated with a higher delirium risk than melatonin in hospitalized patients.6
6. Hydroxyzine and diphenhydramine (high risk)
These antihistamines have anticholinergic properties and are well known to increase delirium risk. Diphenhydramine, in particular, is strongly associated with delirium in older ICU patients and should generally be avoided.7
7. Antipsychotics, like quetiapine (high risk)
Used off-label for sleep or agitation, antipsychotics may reduce delirium duration but carry significant metabolic and cognitive risks. Their role in promoting sleep alone is controversial and not generally recommended.8
8. Benzodiazepines (highest risk)
Although effective for anxiety and alcohol withdrawal, benzodiazepines significantly increase delirium risk and should be avoided for sleep unless no safer options exist.8
Conclusion
In ICU patients who are not intubated, pharmacologic sleep aids should be used cautiously. Melatonin and gabapentin are preferred due to favorable safety profiles. Agents like trazodone, clonidine, and Z-drugs may be used selectively. And antihistamines, antipsychotics, and benzodiazepines should generally be avoided due to their high risk for delirium. Individualized treatment considering patient comorbidities and risk factors is crucial in optimizing sleep while minimizing adverse outcomes.
References
1. Hatta K, Kishi Y, Wada K, et al. Preventive effects of ramelteon on delirium: a randomized placebo-controlled trial. JAMA Psychiatry. 2014;71(4):397-403. doi:10.1001/jamapsychiatry.2013.3320
2. Khaing K, Nair BR. Melatonin for delirium prevention in hospitalized patients: a systematic review and meta-analysis. J Psychiatr Res. 2021;133:181-190. Preprint. Posted online December 13, 2020. PMID: 33348252. doi: 10.1016/j.jpsychires.2020.12.020
3. Liu GJ, Karim MR, Xu LL, et al. Efficacy and tolerability of gabapentin in adults with sleep disturbance in medical illness: a systematic review and meta-analysis. Front Neurol. 2017;8:316. PMID: 28769860; PMCID: PMC5510619. doi: 10.3389/fneur.2017.00316
4. Jaffer KY, Chang T, Vanle B, et al. Trazodone for insomnia: a systematic review. Innov Clin Neurosci. 2017;14(7-8):24-34. PMID: 29552421; PMCID: PMC5842888.
5. Liu D, Hallt E, Platz A, et al. Low-dose clonidine infusion to improve sleep in postoperative patients in the high-dependency unit. A randomised placebo-controlled single-centre trial. Intensive Care Med. 2024;50(11):1873-1883. Preprint. Posted online September 23, 2024. PMID: 39311905; PMCID: PMC11541301. doi: 10.1007/s00134-024-07619-w
6. Kolla BP, Lovely JK, Mansukhani MP, Morgenthaler TI. Zolpidem is independently associated with increased risk of inpatient falls. J Hosp Med. 2013;8(1):1-6. Preprint. Posted online November 19, 2012. PMID: 23165956. doi: 10.1002/jhm.1985
7. Agostini JV, Leo-Summers LS, Inouye SK. Cognitive and other adverse effects of diphenhydramine use in hospitalized older patients. Arch Intern Med. 2001;161(17):2091-2097. doi:10.1001/archinte.161.17.2091
8. Pandharipande P, Shintani A, Peterson J, et al. Lorazepam is an independent risk factor for transitioning to delirium in intensive care unit patients. Anesthesiology. 2006;104(1):21-26. doi:10.1097/00000542-200601000-00005
