Abstract
BackgroundPrevious studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation.ObjectiveThe objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects.MethodsSixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis.ResultsSerum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R2 = 0.492 for HPT, R2 = 0.538 for PPT, R2 = 0.558 for HPTo and R2 = 0.584 for PPTo).ConclusionsThe present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent. Brazilian Clinical Trials Registry (ReBec): (U1111-1123-5109). IRB: Research Ethics Committee at the Hospital de Clínicas de Porto Alegre.
Highlights
Melatonin is the major hormone synthesized by the pineal gland and is mainly involved in the control of circadian rhythm [1]
The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity
There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold
Summary
Melatonin is the major hormone synthesized by the pineal gland and is mainly involved in the control of circadian rhythm [1]. The antinociceptive effect of melatonin has been demonstrated in animal models of acute pain [2,3], inflammatory pain [4] and neuropathic pain [5] Preliminary studies in humans have shown melatonin effects on some pain syndromes, especially fibromyalgia [6] and acute postoperative pain [7,8,9] Despite these initial positive results, the dose-response effect of melatonin on pain has not been explored. For a given noxious stimulus, the intensity with which pain is felt varies from person to person, and a distinction has to be made between an individual’s pain threshold and pain tolerance [16] This was defined in experimental pain models in healthy human volunteers by measuring analgesic drug effects using a noninvasive, non-noxious, standardized and repeatedly applicable stimulus[17]. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation
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