Physicians have noted since antiquity that their patients complained of less pain and required fewer analgesics at night times. In most species, including the humans, the circulating levels of melatonin, a substance with analgesic and hypnotic properties, exhibit a pronounced circadian rhythm with serum levels being high at night and very low during day times. Moreover, melatonin exhibits maximal analgesic effects at night, pinealectomy abolishes the analgesic effects of melatonin, and mu opioid receptor antagonists disrupt the day-night rhythm of nociception. It is believed that melatonin, with its sedative and analgesic effects, is capable of providing a pain free sleep so that the body may recuperate and restore itself to function again at its peak capacity. Moreover, in conditions when pain is associated with extensive tissue injury, melatonin's ability to scavenge free radicals and abort oxidative stress is yet another beneficial effect to be realized. Since melatonin may behave as a mixed opioid receptor agonist-antagonist, it is doubtful that a physician simply could potentiate the analgesic efficacy of narcotics such as morphine by coadministering melatonin. Therefore, future research may synthesize highly efficacious melatonin analogues capable of providing maximum analgesia and hopefully being devoid of addiction liability now associated with currently available narcotics.
Evidence for a relationship between melatonin, nociception, and analgesia in humans is based on data that are only linked by association and simultaneous occurrence. Studies have reported inverse correlation of the circadian melatonin rhythm with nociception latency and enhancement of opioid analgesia by simultaneous administration of melatonin in animals. This study examines the response of salivary melatonin to acute pain stimuli in 18 healthy subjects ranging in age from 19 to 50 years. A biphasic melatonin response following an acute pain stimulus of 36 V was observed, F(8, 8) = 17.839, P < 0.001. Within 5 min of the stimulus, melatonin decreased and reached a plateau of 36 pg/mL below baseline by 20 min. This decrease was followed by an increase of 5 pg/mL. Melatonin levels subsequently decreased until they had reached levels similar to those anticipated for the time of day and did not vary thereafter. The magnitude of the melatonin response was not related to age or gender. There was no association between voltage and magnitude of the melatonin responses observed at 15 min (r =0.185, P=0.51) or at 30 min (r = 0.468, P = 0.09). This study provides the first evidence of melatonin utilization and subsequent pineal gland synthesis following acute pain episodes in humans.
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