Effects of melatonin on physical fatigue and other symptoms in patients with advanced cancer receiving palliative care: A double‐blind placebo‐controlled crossover trial

This was a double-blind, placebo-controlled crossover trial conducted in adults with histologically confirmed stage IV cancer receiving palliative care and reporting significant fatigue. Patients were randomized 1:1 to melatonin followed by placebo or placebo followed by melatonin at Bispebjerg Hospital in Copenhagen, Denmark.

Melatonin (N-acetyl-5-methoxytryptamine; MLT) was given orally at 20 mg nightly, taken about 1 hour before sleep for 1 week, in a double-blind crossover design versus identical placebo capsules. A 2-day washout separated the two treatment periods.

Melatonin 20 mg nightly did not improve physical fatigue or any other measured symptom or quality-of-life outcome compared with placebo. In the pooled analysis, the difference in change in physical fatigue favored placebo by 2.8 points on a 0 to 100 scale, and the ITT estimate for physical fatigue was not significant (mean difference in change 22.1, 95% CI 29.1 to 4.9; P=.56). No significant differences were seen for fatigue, insomnia, loss of appetite, pain, emotional function, overall quality of life, or the other exploratory endpoints. The authors concluded that melatonin did not relieve cancer-related fatigue or improve overall symptom burden in this palliative care population.

The trial was small and had substantial attrition: 72 patients were randomized, 50 completed the intervention, and 44 were complete compliers. Treatment periods were short, outcomes were pooled across crossover sequences after testing showed no significant period or carryover effect, and several arm-specific details were not reported separately, limiting precision and generalizability.