April 23, 2019

Melatonin Prophylaxis for Delirium

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by Sathyanand Kumaran, MFSc, MS, PharmD and Lisa Hutchison, PharmD, FCCP, MPH, BCPS, BCGP
University of Arkansas for Medical Sciences (UAMS) College of Pharmacy

 

Delirium is a common clinical syndrome characterized by inattention and acute cognitive dysfunction and manifests clinically with a wide range of neuropsychiatric abnormalities. 1 It can occur at any age, but it occurs more commonly in patients who are elderly and have a previously compromised mental status. One of the common features associated with delirium is disturbances of sleep. 2 Disturbances in the sleep-wake cycle observed in delirium include daytime sleepiness, nighttime agitation, and disturbances in sleep continuity. In some cases, complete reversal of the night-day sleep-wake cycle or fragmentation of the circadian sleep-wake pattern can occur. Pharmacological treatment for delirium after non-pharmacologic measures have failed includes antipsychotics such as haloperidol, risperidone, olanzapine and quetiapine. 1 However, the antipsychotic medications have several side effects including prolonged QT intervals, extrapyramidal symptoms, and increased risk of fatal cardiovascular incidents. 3

The pathophysiology of delirium is still unclear. 4 Multiple inflammatory and cholinergic pathways are likely involved and melatonin might play an important role. Melatonin is an important modulator of circadian rhythm, especially sleep-wake cycle. The results from observational studies suggest people with delirium have lower plasma and salivary melatonin than those without delirium. 5,6  Several studies in older adults provide support for use of melatonin in delirium, particularly as prophylaxis to prevent its occurrence.

In a study assessing the role of perioperative melatonin in the prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly, 300 patients over 65 years of age were randomly distributed to one of the four groups. 7 Group 1 was the control and received nothing for sedation. Group 2 received 5 mg melatonin. Group 3 received 7.5 mg midazolam and Group 4 received 100 µg clonidine. These medications were given orally the night before the operation and another dose 90 min before the scheduled time for hip arthroplasty. Patients who developed postoperative delirium received melatonin for three successive days.   The percentage of postoperative delirium in the control group was 32.65% compared to the melatonin group which was 9.43% (p < 0.05). Melatonin was successful in treating 58.06% of patients who demonstrated postoperative delirium (36/62 patients). Overall this study supports melatonin as useful in decreasing postoperative delirium when used preoperatively and in treating postoperative delirium. Some of the weaknesses in this study were exclusion of patients with underlying dementia, severe infections, and acute cardiac events. As a result, the study population is not a true representation of patients who would develop delirium.

Al-Aama et al evaluated low dose melatonin in decreasing delirium. 8 A randomized, double-blinded, placebo-controlled study was conducted at an internal medicine service. One hundred and forty patients were randomized to receive either 0.5 mg of melatonin or placebo every night for 14 days or until discharge. The primary outcome was the occurrence of delirium. Melatonin was associated with a lower risk of delirium (12% vs 31%, p = 0.014), with an odds ratio adjusted for dementia and comorbidities of 0.19 (95% CI 0.06 – 0.32).

In a study conducted by de Jonghe et al, 378 patients who were scheduled for acute hip surgery received 3 mg melatonin or placebo for 5 consecutive days. 9 The primary outcome was incidence of delirium within 8 days of admission. No effect of melatonin on the incidence of delirium was observed in the study: 55/186 (29.6%) in the melatonin group versus 49/192 (25.5%) in the placebo group. However, the duration of delirium was lower with melatonin compared to placebo.

In another randomized placebo-controlled trial, ramelteon was associated with lower risk of delirium (3% vs 32%; p = 0.03). 10 Sixty-seven patients were randomly assigned to either ramelteon or placebo every night for 7 days. The primary outcome measure was incidence of delirium.  Although the study showed a lower risk of delirium with ramelteon, the sleep metrics between the two treatments were not different. The investigators mention that melatonin may be preventing delirium by a different pathway other than via sleep. In addition, the study excluded very seriously ill patients and patients with certain types of dementia such as Lewy body dementia.

In a retrospective, observational cohort study evaluating the effectiveness of melatonin for the prevention of intensive care unit delirium, 117 adults who received melatonin for at least 48 hours were compared to a control group of 115 adults. 11 The primary outcome was development of delirium. The development of delirium was significantly lower in the melatonin group: 9 (7.7%) versus 28 (24.3%) patients (p = 0.001).

Although not conclusive, the above studies support use of melatonin prophylaxis in elderly hospitalized patients. However, all the studies had a small population size, the scales for measuring delirium were not uniform, doses of melatonin were different, and exclusion criteria varied from one study to another. It is not clear whether the patients in these randomized controlled studies were treated in the ICU or other units with less aggressive care. Given the fact that the incidence of delirium is as high as 82% in patients in the intensive care, it would be worthwhile to include these patients in the clinical trials. It is not clear whether there is a true benefit with the use of melatonin in all elderly patients admitted to hospitals. Some subgroups of elderly patients might benefit with the use of prophylactic melatonin such as critically ill patients. Interestingly, the studies did not show a difference in sleep parameters between placebo and melatonin which is thought to be the primary effect of melatonin. Larger randomized controlled trials with standard melatonin doses are needed to establish efficacy. However, since the side effects are few and some studies indicate a possible benefit, administering prophylactic melatonin to hospitalized critically ill elderly patients at high risk for development of delirium may be considered.

 

References

  1. Fong TG, Tulebaev SR, Inouye SK. Delirium in elderly adults: diagnosis, prevention and treatment. Nat Rev Neurol. 2009;5(4):210–220. doi:10.1038/nrneurol.2009.24.
  2. APA. Diagnostic and Statistical Manual of Mental Disorders. Text Revision (DSM-IV-TR). 4th ed Arlington, VA: American Psychiatric Press; (2000). p. 553–7
  3. Blaszczyk AT, Hutchison LC. Central nervous system disorders. In: Hutichison LC, Sleeper RB, EDS. Geriatric Pharmacotherapy 2nd ed. American Society of Health System Pharmacists, Bethesda, MD.
  4. Choy SW, Yeoh AC, Lee ZZ, Srikanth V, Moran C. Melatonin and the Prevention and Management of Delirium: A Scoping Study. Front Med (Lausanne). 2018;4:242. Published 2018 Jan 8. doi:10.3389/fmed.2017.00242
  5. Yoshitaka S, Egi M, Morimatsu H, Kanazawa T, Toda Y, Morita K. Perioperative plasma melatonin concentration in postoperative critically ill patients: its association with delirium. J Crit Care. 2013. 28(3):236–42.10.1016/j.jcrc.2012.11.004
  6. Angeles-Castellanos M, Ramirez-Gonzalez F, Ubaldo-Reyes L, Rodriguez-Mayoral O, Escobar C. Loss of melatonin daily rhythmicity is associated with delirium development in hospitalized older adults. Sleep Sci. 2016: 9(4):285–8.10.1016/j.slsci.2016.08.001
  7. Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth. 2010;4(3):169–173. doi:10.4103/1658-354X.71132
  8. Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM,Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry. 2011: 26(7):687–694. doi:10.1002/gps.2582
  9. De Jonghe A, van Munster BC, Goslings JC, et al. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial. CMAJ. 2014;186(14):E547–E556. doi:10.1503/cmaj.140495
  10. 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
  11. Baumgartner L, Lam K, Lai J, Barnett M, Thompson A, Gross K, Morris A. Effectiveness of melatonin for the prevention of intensive care unit delirium. Pharmacotherapy. 2019:39(3) 280-287