Is melatonin an effective treatment option for the prevention of hospital-induced delirium?

Background

Melatonin is a hormone generated endogenously in the pineal gland.1,2 The hormone is derived from the amino acid trypotophan, and is thought to impact regulation of the body’s sleep-wake cycle (ie, circadian rhythm), endocrine secretions, and other sleep patterns. Evidence suggests that in certain disease states, melatonin levels are decreased (eg, insomnia, depression).3 Due to the over-the-counter (OTC) availability of melatonin, oral supplementation for disorders such as jet lag, insomnia, and shift-work disorder is common.4 According to the National Center for Complementary and Integrative Health, 1.3% of US adults (3.1 million) report using melatonin, making it one of the most used natural products in the United States, fourth behind fish oils, glucosamine, and probiotics. 

Delirium is an acute confusional state and is among the most common mental disturbance noted in patients with medical illness admitted to the hospital.5,6 The most common risk factors associated with the development of in-hospital delirium include advanced age (age > 65 years) and baseline cognitive function (eg, low scores on standardized tests).6 The relationship between sleep disruption and in-hospital delirium is poorly defined; however, frequent disturbances in sleep, like those observed in an intensive care unit (ICU), such as abnormal light exposure, mechanical ventilation, pain, and anxiety are thought to contribute to ICU delirium.7 Significant mortality rates are associated with this disorder, ranging from 25 to 33%. Furthermore, a diagnosis of delirium has been associated with longer hospital stays and higher medical costs.

Guideline recommendations

The Society of Critical Care Medicine (SCCM) updated clinical practice guidelines on the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS) in adult patients in the ICU in 2018.8 Current guidelines do not recommend the use of haloperidol, atypical antipsychotics, dexmedetomidine, statins, or ketamine for the prevention of delirium and suggest not routinely using haloperidol and atypical antipsychotics for the treatment of delirium. When agitation is preventing ventilator extubation, SCCM recommends using dexmedetomidine to facilitate ventilator weaning and removal. Regarding sleep, the guidelines make no recommendation about the use of melatonin or dexmedetomidine to improve sleep in critically ill adults, but recommend against the use of propofol.

Literature review

A literature search was performed to identify systematic reviews and meta-analyses, as well as recent clinical trials not encompassed in the systematic reviews or meta-analyses regarding the use of melatonin for the prevention of delirium in hospitalized patients.

Overall, the evidence for the use of melatonin as a preventative strategy for delirium is conflicting (Table 1). Recently, 2 randomized controlled trials and 1 observational cohort have been published.9-11 The use of melatonin as a preventative strategy has also been explored in some recent meta-analyses.12-14 In general, most of the single studies researching the use of melatonin as delirium prophylaxis are small and likely underpowered to find a difference between the treatment groups; however a recent retrospective cohort found a significant difference in the incidence of delirium in patients that received melatonin (median dose 3.5 mg, range 1 to 10 mg) during their hospitalization.10 The meta-analyses offer conflicting conclusions as well. In a network meta-analysis, however, researchers concluded that melatonin was a protective agent against the incidence of delirium and via surface under the cumulative ranking curve (SUCRA), ranked a dose of 0.5 mg/day as most likely to be beneficial for delirium prophylaxis, followed by melatonin 5 mg/day.14  The mean age of participants were reported in all of the studies; however, baseline cognitive function was inconsistently reported. Only 1 single study reported the Modified Interview for Cognitive Status (TICS-M) despite cognitive status being a risk factor for development of delirium.6

Table 1. Literature evaluating melatonin for the prevention of delirium.9-14
Citation and study designSubjects

InterventionResultsConclusions
Single studies
Ford 20209

DB, PC, MC, RCT		N=210 patients aged ≥ 50 years undergoing cardiac surgery.

Excluded: Patients already using melatonin, diagnosis of dementia, score 15 on Alcohol Use Disorders Identification test		7 days of 3 mg melatonin (n=105) or placebo (n=105) starting 2 days prior to surgeryMean age = 68.3 years
Mean TICS-M = 34.8

Primary outcome:

The incidence of delirium between groups within 7 days of surgery was similar 21.4% melatonin vs 20.2% placebo (OR=1.08; 95% CI =0.55 to 2.13).

Secondary outcomes:

Duration of delirium

-          3 days (IQR=2 to 4)  melatonin vs 2 days  (IQR=1 to 3) placebo (p=0.304)

Median MDAS score

-          9 (range=3 to 26) with melatonin vs 8.5 (range=3 to 22) in placebo (p=0.221)

Length of stay

-          Median LOS in the placebo group was shorter than the melatonin group (7 days vs 8 days; p=0.013)

Mood, anxiety, cognitive dysfunction

-          Treatment groups did not differ at discharge or at 3 months

Safety:

Melatonin was not associated with a difference in developing a postoperative complication (OR=1.24; 95% CI=0.59 to 2.60).		Results did not support the prophylactic use of melatonin for the prevention of delirium after major cardiac surgery.
Baumgartner 201910 

R, OC, SC		N=232 patients aged ≥ 18 years admitted to the cardiac or medical-surgical ICU

Excluded: Positive CAM-ICU reading prior to melatonin initiation, prescription for antipsychotic or sleep aid prior to admission, primary admission for neurologic injury, history of hepatic encephalopathy or ESLD, active alcohol withdrawal, condition, 2 “unable to assess” CAM-ICU recordings		Patients treated with melatonin (prescriber discretion) ≥ 48 hours (n=117)  while admitted to the ICU versus no melatonin (n=115)Mean age = 60 years

Primary outcome:

The incidence of delirium in the melatonin group was lower (n=9, 7.7%) vs the control group (n=28, 24.3%) (p=0.001).

Secondary outcomes:

No significant differences were observed between groups for LOS (hospital and ICU), duration of mechanical ventilation, mortality, or antipsychotic use.

Multivariate regression

A multivariate model found that patients who received melatonin ≥ 48 hours had reduced odds of ICU delirium (OR=0.28; 95% CI 0.11 to 0.70).		The incidence of ICU delirium was significantly lower in the melatonin treated group compared with the control group.
Abassi 201811 

DB, PC, SC, RCT		N=172 patients aged ≥ 18 years admitted to the ICU

Excluded: ICU stay < 5 days, sensitivity to melatonin, pregnancy, history of seizure, heart failure class III/IV		Melatonin 3 mg daily for 5 consecutive days (n=87) or placebo (n=85) administered within 24 hours after admisisonMean age = 51.2 years

Primary outcome:

The incidence of delirium was similar between melatonin (n=3, 4.5%) and placebo (n=1, 1.4%) (p=0.36).

Secondary outcomes:

Duration of delirium, cumulative dose haloperidol, ICU LOS, hospital LOS, and mortality rate were not significantly different between groups.		Administration of melatonin did not reduce the risk of delirium development in the ICU population.

 
Meta-analysis
Ng 202012Included 16 RCTs (N=1634) evaluating melatonin use for the prevention of delirium in hospitalized patientsMelatonin/melatonin agonist (range 0.5 mg to 50 mg/kg) vs placeboMean age = > 50 years

Primary outcome:

The incidence of delirium was similar between melatonin (19.8%) and placebo (26%) (OR=0.55; 95% CI 0.24 to 1.26) (n = 1047, 9 RCTs)

Secondary outcomes:

ICU LOS (n = 411, 5 RCTs)

-          Melatonin treated patients had significantly shorter ICU associated stay (MD -1.84 days; 95% CI -2.46 to -1.21)

Need for physical restraints, sedative agents, duration of mechanical ventilation, hospital stay were not significantly different between groups.

Safety:

Melatonin administration was not associated with a difference in adverse events compared with placebo		Administration of melatonin or melatonin agonists did not result in a lower incidence of delirium; however, melatonin administration was associated with a shorter ICU LOS.
Zhang 201913Included 8 RCTs (N=409) evaluating melatonin use for the prevention of delirium in ICU patientsMelatonin/melatonin agonist (range 1 mg to 30 mg) vs placeboMean age = 58.8 years

Primary outcome

The prevalence of delirium was decreased in the melatonin treated group vs placebo (RR=0.49; 95% CI 0.28 to 0.88, p=0.017).

Secondary outcomes:

Number of awakenings per night

-          Melatonin treated patients had significantly fewer awakenings per night (WMD -2.03; 95% CI -3.83 to -0.22, p=0.028)

ICU LOS

-          Melatonin was associated with a shorter ICU LOS vs placebo (SMD=-0.32; 95% CI -0.56 to -0.07, p=0.002)

Sleep time, duration of mechanical ventilation, and mortality were not significantly different between groups.		Administration of melatonin resulted in a reduction in the risk of delirium and duration of ICU stay and number of nighttime awakenings.
Yang 201914 

NMA		Included 6 RCTs (N=913) evaluating the preventative effects of melatonin agents in hospitalized patients with a high risk of developing deliriumMelatonin/melatonin agonists (range 0.5 mg to 8 mg per day) vs placeboMean age = 78.8 years

Primary outcome:

Melatonin 5 mg/d (OR=0.21; 95% CI 0.07 to 0.64) melatonin 0.5 mg/d (OR=0.16; 95% CI 0.03 to 0.75), were associated with significant decreases in the incidence of delirium vs placebo

Secondary outcomes:

Melatonin (5 and 0.5 mg/d) administration was associated with lower incidence of delirium compared with clonidine or midazolam

Treatment rankings (estimated using SUCRA)

Found melatonin 0.5 mg/d (88.3) as most likely to be effective in the prevention of delirium, followed by melatonin 5 mg/d (84.2), ramelteon (76.7), placebo (40.4), clonidine (28.1), melatonin 3 mg (20.5), and midazolam (11.8)		Prophylactic melatonin reduced the incidence of delirium. A dose of 0.5 mg/d was most likely to be associated with a preventative effect.
Abbreviations: CAM-ICU = Confusion Assessment Method for the Intensive Care Unit; CI = confidence interval; DB = double blind; ESLD = end stage liver disease; ICU = intensive care unit; IQR = interquartile range; LOS = length of stay; MC = multicenter; MD = mean difference; MDAS = memorial delirium assessment scale; NMA = network meta-analysis; OC = observational cohort; OR = odds ratio; PC = placebo-controlled; R = retrospective; RCT = randomized controlled trial; RR = relative risk; SC = single-center; SMD = standardized mean difference; SUCRA = surface under the cumulative ranking curve; TICS-M = Modified Telephone Interview for Cognitive Status; WMD = weighted mean difference

Safety

In general, the majority of the clinical trials and meta-analyses that reported on adverse events and safety concluded there were no significant differences in adverse events when melatonin was compared with placebo.9,12 Other than hypersensitivity to melatonin or any components of the product, there are no contraindications to therapy.15 Headache, sedation, somnolence are reported with melatonin use, but the incidence of these side effects is low (ie, < 1%).

Conclusion

Overall, data on the prophylactic use of melatonin for delirium are conflicting. Other pharmacologic agents approved by the Food and Drug Administration (FDA) for the treatment of insomnia, like ramelteon, are being applied with some promise for the prevention of delirium as well. The OTC nature of melatonin and labeling as a natural product may result in manufacturer and inter-lot variability in quality and potency. This limitation may prohibit the broad applicability of results seen in individual clinical trials. Given the extreme morbidity and mortality associated with hospital-associated delirium, a strategy for prevention is highly desirable.  Further studies examining this clinical question are ongoing aiming to clarify the utility of melatonin for the prevention of delirium.16,17

References

  1. Therapeutic Research Center. Melatonin. Natural Medicines. https://naturalmedicines.therapeuticresearch.com/. November 25, 2019. Accessed January 14, 2020.
  2. Dietary Supplements & Herbal Medications. In: Katzung BG, Kruidering-Hall M, Trevor AJ. eds. Katzung & Trevor’s Pharmacology: Examination & Board Review, 12e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com. Accessed January 14, 2020.
  3. Brzezinski A. Melatonin in humans. New Engl J Med. 1997;336(3):186-195.
  4. National Institutes of Health. Most used natural products. National Center for Complementary and Integrative Health website. https://nccih.nih.gov/research/statistics/NHIS/2012/natural-products/melatonin. September 24, 2017. Accessed January 14, 2020.
  5. Schrijver EJM, de Graaf K, de Vries OJ, Maier AB, Nanayakkara PWB. Efficacy and safety of haloperidol for in-hospital delirium prevention and treatment: A systematic review of current evidence. European Journal of Internal Medicine. 2016;27:14-23.
  6. Josephson S, Miller BL. Confusion and Delirium. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 20e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com/content.aspx?bookid=2129§ionid=192011608. Accessed January 15, 2020.
  7. Pisani MA, D’Ambrosio C. Sleep and delirium in critically ill adults: a contemporary review chest. December 2019. doi:10.1016/j.chest.2019.12.003
  8. Devlin JW, Skrobik Y, Gélinas C, et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Critical Care Medicine. 2018;46(9):e825.
  9. Ford AH, Flicker L, Kelly R, et al. The healthy heart-mind trial: randomized controlled trial of melatonin for prevention of delirium. J Am Geriatr Soc. 2020;68(1):112-119.
  10. Baumgartner L, Lam K, Lai J, et al. Effectiveness of melatonin for the prevention of intensive care unit delirium. Pharmacotherapy. 2019;39(3):280-287.
  11. Abbasi S, Farsaei S, Ghasemi D, Mansourian M. Potential role of exogenous melatonin supplement in delirium prevention in critically ill patients: a double-blind randomized pilot study. Iran J Pharm Res. 2018;17(4):1571-1580.
  12. Ng KT, Teoh WY, Khor AJ. The effect of melatonin on delirium in hospitalised patients: A systematic review and meta-analyses with trial sequential analysis. J Clin Anesth. 2020;59:74-81.
  13. Zhang Q, Gao F, Zhang S, Sun W, Li Z. Prophylactic use of exogenous melatonin and melatonin receptor agonists to improve sleep and delirium in the intensive care units: a systematic review and meta-analysis of randomized controlled trials. Sleep Breath. 2019;23(4):1059-1070.
  14. Yang C-P, Tseng P-T, Pei-Chen Chang J, Su H, Satyanarayanan SK, Su K-P. Melatonergic agents in the prevention of delirium: A network meta-analysis of randomized controlled trials. Sleep Med Rev. 2019;50:101235.
  15. Micromedex Solutions [database online]. Greenwood Village, CO: Truven Health Analytics, Inc; 2019. http://www.micromedexsolutions.com/. Accessed January 16, 2019.
  16. US National Library of Medicine. Prevention of delirium in intensive care by melatonin. NCT03524937. Clinicaltrials.gov website. https://clinicaltrials.gov. May 15, 2018. Accessed January 17, 2020.
  17. US National Library of Medicine. Efficacy of the administration of melatonin 5 mg in the prevention of delirium in older adults hospitalized in the emergency department. NCT04187807. Clinicaltrials.gov website. https://clinicaltrials.gov. December 5, 2019. Accessed January 17, 2020.

Prepared by:
Lauren Endriukaitis, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

February 2020

The information presented is current as January 13, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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