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Melatonin for Pain

March 9, 2020
Increasing evidence shows that the hormone may play a role in the modulation of neuropathic and inflammatory pain.

A PPM Brief

Melatonin is most widely known for its role in regulating circadian rhythms, particularly the sleep-wake cycle.1 However, this hormone also has been shown to have antioxidant, anti-inflammatory, anti-neoplastic, and immuno-modulary properties,2 and increasing evidence has shown that melatonin may play a role in the modulation of pain.

The connection between sleep and pain may be a significant part of the puzzle. “The structures in the brain that are associated with sleep are also associated with pain,” Gabriella Gobbi, MD, a neuroscientist at McGill University in Montreal, told PPM. “If you don’t sleep, the threshold of pain decreases.”

However, at this point, there is still little clarity on what mechanisms might account for any anti-nociceptive effect of melatonin. A review published in the Journal of Pain Research earlier this year2 explored the recent evidence for the use of melatonin for pain and looked at several potential underlying cellular mechanisms.

There is evidence that melatonin alleviates thermal hyperalgesia, cold allodynia, and oxidative stress caused by constriction of the sciatic nerve. (Image: iStock)


The study’s authors analyzed a body of recent research on melatonin and melatonin analogs in both human and animal models, including trials of UCM924, a drug being developed in Dr. Gobbi’s lab. They found that administration of melatonin or its analogs through peripheral or central pathways has been shown to reduce pain in a dose-dependent fashion in acute, neuropathic, and inflammatory pain. Effects included reduced flinching responses, reversed hyperalgesia, alleviation of pain behavior, and anti-nociceptive activity, among others.

In the case of chronic inflammatory pain, the reviewers found that melatonin’s effect may be due to the hormone’s ability to lessen inflammation and oxidative stress. Some trials, for instance, have found that a reduction in the synthesis of melatonin and an increase in 6-sulfatoxymelatonin secretion is positively correlated with clinical symptoms of fibromyalgia indicating that melatonin may, they wrote, be useful in patients with fibromyalgia syndrome. In addition, they found that melatonin supplementation may also relieve abdominal pain caused by irritable bowel syndrome.

When examining the hormone’s role in attenuating neuropathic pain, the reviewers found evidence that melatonin alleviated thermal hyperalgesia, cold allodynia, and oxidative stress caused by constriction of the sciatic nerve. However, pre-treatment with L-arginine reversed the protective effect of melatonin, suggesting to the researchers that the nitric acid pathway may be involved. In cases where melatonin increased the mechanical pain threshold and the thermal hyperalgesia threshold, they found that naloxone pre-treatment eliminated the mechanical anti-nociceptive effect but did not interfere with the thermal effect. The review also shared a growing body of evidence that melatonin may reverse the nociceptive threshold in spinal nerve ligation animal models.

The reviewers concluded that there is animal model evidence and some human trial evidence that melatonin may attenuate acute, neuropathic, and inflammatory pain. However, the mechanisms for this effect are not well understood.


More Work to Do

To better understand potential clinical applications of melatonin for the treatment of pain, Dr. Gobbi’s lab is working to uncover the mechanism by which melatonin helps with pain. She’s found that the melatonin receptors in the brain, MT1 and MT2, are highly specialized and that MT2 is involved in pain as well as sleep.

Until more melatonin analogs—like the one Gobbi is working on—become available, many patients may be able to trial over-the-counter melatonin. But Dr. Gobbi cautions to limit this use.  “Only a minimal part [of the melatonin] goes into the brain. You need a very high dose to have an effect,” she explained. “Clinicians can use it, but the effect will be limited by the absorption.” Nonetheless, Dr. Gobbi believes melatonin may be a new frontier in the treatment of pain; there’s just more work to do to get there.

Last updated on: March 12, 2020
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Nonpharmacologic Treatments for Patients With Sleep Disorders and Pain
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