Melatonin Falls Short In Neuropathic Pain Crossover Trial

Key Takeaways

• Melatonin did not show a primary pain advantage over placebo in the crossover comparison.
• No secondary outcomes differed significantly, including measures of sleep, mood, and quality of life.
• Treatment-emergent adverse events were infrequent and not statistically different from placebo, and the authors concluded the trial did not suggest promise for melatonin in neuropathic pain.

Melatonin did not outperform placebo on the primary pain endpoint in a randomized, double-blind, placebo-controlled crossover trial in adults with neuropathic pain. At maximally tolerated dose, mean daily pain was 4.1 with melatonin and 4.2 with placebo (P = 0.8). The primary analysis compared daily pain ratings during each treatment period at maximally tolerated dose, with no statistical separation between treatment conditions. The trial did not show an analgesic benefit for melatonin on the primary endpoint.

Neuropathic pain was described as a common and difficult condition, with sleep disturbance frequently accompanying it because pain can worsen at night. In the randomized crossover trial in adults with neuropathic pain, 31 participants were randomly allocated to one of two treatment sequences in a double-blind, placebo-controlled design. Each participant received two 4-week treatment periods separated by a 7-day washout, and 30 participants completed both periods. The primary endpoint was mean daily pain intensity on a 0-10 scale at the maximally tolerated dose during each period. The mean maximally tolerated dose of melatonin was 11.9 mg/day.

Results beyond the primary endpoint were also negative across the reported outcomes. Investigators found no statistically significant differences between melatonin and placebo for any secondary outcomes, including adverse events and measures of sleep, mood, and quality of life, all assessed at maximally tolerated dose. This allowed comparison across domains at the same tolerated dosing point used for the main analysis. The lack of separation extended beyond pain intensity to the other outcomes evaluated in the trial.

Safety findings likewise did not differ significantly from placebo in the crossover comparison. Treatment-emergent adverse events during melatonin exposure were infrequent and were not statistically different from placebo. The authors characterized the overall result as a negative efficacy signal rather than a mixed or exploratory finding based on isolated outcome changes. They concluded that the trial did not provide evidence to suggest promise for melatonin as an effective treatment for neuropathic pain.