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The Role of Melatonin in Palliative Care

  • Georgina Waldman PharmD Candidate
  • Jennifer Pruskowski PharmD
  • Robert Arnold MD

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Background    Melatonin is a naturally occurring hormone classified as a dietary supplement in the United States (US) (1). It can be purchased over the counter (OTC) without a prescription and therefore is unregulated by the FDA. Many clinicians who care for seriously ill patients are asked about the use of melatonin to regulate the circadian rhythm and treat insomnia. This Fast Fact will focus on melatonin’s pharmacology and its potential uses in the adult palliative care population, while acknowledging the emerging evidence for the pediatric population (2).

Pharmacology    Melatonin is an endogenous metabolite of tryptophan and serotonin, released cyclically from the pineal gland according to the body’s circadian rhythm.  Plasma levels increase during the evening hours to encourage sleep onset and maintenance (3).  Research suggests oral doses of 5 mg produce blood levels 25 times higher than normal but do not appear to alter endogenous production (4).  When taken orally melatonin is rapidly absorbed; bioavailability ranges from 10-56% (5). This range may be due to extensive first pass metabolism, or variations between manufactured formulations. Due to its high lipophilicity, melatonin crosses the blood brain barrier quickly; onset and peak concentration are within 50 minutes and 2 ½ hours respectively (6). It is excreted quickly with a terminal half-life of only ~45 minutes; however, its duration of action is felt to be equal to four elimination half-lives (or about 3-5 hours) by most experts (7).   

Dosing    Melatonin is available in 1 mg, 3 mg, 5 mg and 10 mg immediate-release, and 3 mg and 5 mg controlled-release oral tablets. A prolonged-released 2 mg formulation is commercially available outside of the US.  A typical starting dose is 1 mg once daily, with a more conservative dose of 0.5 mg in geriatric patients.  Melatonin should be administered within 1 hour of bedtime to supplement the body’s endogenous nocturnal surge.  Due to its extensive hepatic metabolism, lower doses should be used in liver failure, although specific recommendations have not been published (5).

Research Data    There is insufficient evidence to support the use of melatonin for primary insomnia disorders in adults or in insomnia related to moderate to severe dementia.  However, data in the adult population suggests that short term use of melatonin (less than three months) may be effective in delayed sleep phase syndrome, where a person’s sleep is delayed by 2 or more hours beyond the conventional bedtime (8-10). Similar results have been replicated in children and infants via exposure to melatonin in breast milk (2).  Melatonin has been examined as an adjuvant to chemotherapy due to its antioxidant and immunomodulatory effects, but its role as an oncologic adjuvant needs further research and is not standard of care (11-12). An emerging role of great interest is in the prevention and management of delirium for adults.  Case reports have shown success in treating severe post-operative delirium refractory to antipsychotics or benzodiazepines (13).  One randomized, double-blinded, placebo-controlled study concluded that melatonin 0.5 mg/day was associated with a lower risk of delirium in hospitalized elderly patients (14).  Additionally ramelteon, a melatonin receptor agonist, demonstrated similar benefit in a small randomized, placebo-controlled study preventing delirium among hospitalized elderly patients (15). Although evidence is promising, more research is needed to establish the role of both melatonin and ramelteon for the prevention and management of delirium.

Adverse Drug Reactions and Cautions   Melatonin is relatively nontoxic in appropriate doses when used short term (4). The most common side effects are excess sedation and somnolence (4). Caution should be exhibited in the post organ transplant population as melatonin’s immune-boosting effects could increase the risk of graft rejection though more research is needed (16).

Cost    Due to its OTC status in the US, melatonin is rather inexpensive but is usually not covered by most private insurances or Medicare. Prices for over the counter melatonin range approximately from $5-15 for a ninety count bottle.

Summary   Melatonin is a naturally occurring hormone that has limited benefit in treatment of primary sleep disorders, but may have a potential benefit for the prevention and management of delirium.  Given its low cost and lack of side effects, while it cannot be recommended, it should not be discouraged.

References

  1. National Institute of Health. Dietary Supplements: What You Need To Know. Accessed 10 June 2015. Available at: http://ods.od.nih.gov/HealthInformation/DS_WhatYouNeedToKnow.aspx; 2011.
  2. Sánchez-Barceló EJ, Mediavilla MD, Reiter RJ. Clinical uses of melatonin in pediatrics. Int J Pediatr. 2011;2011:892624.
  3. Axelrod J, Shein HM, Wurtman RJ. Stimulation of C14-melatonin synthesis from C14-tryptophan by noradrenaline in rat pineal in organ culture. Proc Natl Acad Sci U S A. 1969 Feb;62(2):544-9.
  4. Mahmoud F, Sarhill N, Mazurczak MA. The therapeutic application of melatonin in supportive care and palliative medicine. Am J Hosp Palliat Care. 2005 Jul-Aug;22(4):295-309.
  5. Di WL, Kadva A, Johnston A, Silman R. Variable bioavailability of oral melatonin. N Engl J Med. 1997 Apr 3;336(14):1028-9.
  6. Harpsøe NG, Andersen LP, Gögenur I, Rosenberg J. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015 May 27. [Epub ahead of print]
  7. Harpsøe NG, Andersen LP, Gögenur I, Rosenberg J. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015 May 27. [Epub ahead of print]
  8. Buscemi N1, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Baker G, Klassen TP, Vohra S. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med. 2005 Dec;20(12):1151-8.
  9. McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in Alzheimer’s disease. Cochrane Database Syst Rev. 2014 Mar 21;3:CD009178.
  10. Xu J, Wang LL, Dammer EB, Li CB, Xu G, Chen SD, Wang G. Melatonin for Sleep Disorders and Cognition in Dementia: A Meta-Analysis of Randomized Controlled Trials. Am J Alzheimers Dis Other Demen. 2015 Jan 22. pii: 1533317514568005. [Epub ahead of print]
  11. Wang YM, Jin BZ, Ai F, Duan CH, Lu YZ, Dong TF, Fu QL. The efficacy and safety of melatonin in concurrent chemotherapy or radiotherapy for solid tumors: a meta-analysis of randomized controlled trials. Cancer Chemother Pharmacol. 2012 May;69(5):1213-20
  12. Sookprasert A, Johns NP, Phunmanee A, Pongthai P, Cheawchanwattana A, Johns J, Konsil J, Plaimee P, Porasuphatana S, Jitpimolmard S. Melatonin in patients with cancer receiving chemotherapy: a randomized, double-blind, placebo-controlled trial. Anticancer Res. 2014 Dec;34(12):7327-37.
  13. Hanania M, Kitain E. Melatonin for treatment and prevention of postoperative delirium. Anesth Analg. 2002;94:338-9.
  14. Al-Aama R, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. In J Geriatr Psychiatry. 2011;26:687-694.
  15. Hatta K, Kishi Y, et al. Preventive effects of ramelteon on delirium: a randomized placebo controlled trial.  JAMA Psychiatry 2014; 71:397-403.
  16. Fildes JE, Yonan N, Keevil BG. Melatonin–a pleiotropic molecule involved in pathophysiological processes following organ transplantation. Immunology. 2009 Aug;127(4):443-9.

Authors Affiliations: University of Pittsburgh Medical Center; UPMC Health System.

Conflict of Interest: The authors have disclosed no relevant conflicts of interest.

Version History: Copy edited by Sean Marks MD. First electronically published October 2015.