The analgesic effects of exogenous melatonin in humans

The hormone, melatonin is produced with circadian rhythm by the pineal gland in humans. The melatonin rhythm provides an endogenous synchronizer, modulating e.g. blood pressure, body temperature, cortisol rhythm, sleep-awake-cycle, immune function and anti-oxidative defence. Interestingly, a number of experimental animal studies demonstrate significant dose-dependent anti-nociceptive effects of exogenous melatonin. Similarly, recent experimental- and clinical studies in humans indicate significant analgesic effects. In study I, we systematically reviewed all randomized studies investigating clinical effects of perioperative melatonin. Meta-analyses demonstrated significant analgesic and anxiolytic effects of melatonin in surgical patients, equating reductions of 20 mm and 19 mm, respectively on a VAS, compared with placebo. Profound heterogeneity between the included studies was, however, present. In study II, we aimed to investigate the analgesic, anti-hyperalgesic and anti-inflammatory effects of exogenous melatonin in a validated human inflammatory pain model, the human burn model. The study was performed as a randomized, double blind placebo-controlled crossover study. Primary outcomes were pain during the burn injury and areas of secondary hyperalgesia. No significant effects of exogenous melatonin were observed with respect to primary or secondary outcomes, compared to placebo. Study III and IV estimated the pharmacokinetic variables of exogenous melatonin. Oral melatonin demonstrated a t_max value of 41 minutes. Bioavailability of oral melatonin was only 3%. Elimination t_1/2 were approximately 45 minutes following both oral and intravenous administration, respectively. High-dose intravenous melatonin was not associated with increased sedation, in terms of simple reaction times, compared to placebo. Similarly, no other adverse effects were reported. In Study V, we aimed to re-analyse data obtained from a randomized analgesic drug trial by a selection of standard statistical test. Furthermore, we presented an integrated assessment method of longitudinally measured pain intensity and opioid consumption. Our analyses documented that the employed statistical method impacted the statistical significance of post-operative analgesic outcomes. Furthermore, the novel integrated assessment method combines two interdependent outcomes, lowers the risk of type 2 errors, increases the statistical power, and provides a more accurate description of post-operative analgesic efficacy. Exogenous melatonin may offer an effective and safe analgesic drug. At this moment, however, the results of human studies have been contradictory. High-quality randomized experimental- and clinical studies are still needed to establish a "genuine" analgesic effect of the drug in humans. Other perioperative effects of exogenous melatonin should also be investigated, before melatonin can be introduced for clinical routine use in surgical patients. Despite promising experimental and clinical findings, several unanswered questions also relate to optimal dosage, timing of administration and administration route of exogenous melatonin.