Is Melatonin the Next “New” Therapy to Improve Sleep and Reduce Pain?

Sleep has long been considered important for recovery from surgery. Surgical trauma initiates tissue inflammatory responses and activates both mechanisms of peripheral and central nervous system sensitization that sustain pain.¹ Polysomnographic evidence of disturbed sleep during the first few postoperative days after a variety of surgical procedures shows reduced total sleep time, highly fragmented sleep, with significant reductions in slow wave and REM sleep.² Importantly, disturbed sleep increases the risk of developing chronic pain following acute injury.³ Sleep deprivation is associated with reduced pain thresholds,⁴ and hyperalgesia (an exaggerated response to noxious stimuli) is common following experimental total or partial sleep deprivation in healthy subjects and in animals.^2,5 However, little is known about the underlying neurobiological mechanisms. Important questions remain unanswered: What mechanisms of peripheral or central sensitization are impacted by disrupted or lost sleep? How and where in the nervous system do these mechanisms operate? Are effects of sleep loss on pain sensitivity generalized or are there specific changes in mechanisms of pain processing or modulation? Activation of inflammatory processes in the central nervous system might be one mechanism underlying increased pain during and after sleep deprivation.

In the current issue of SLEEP, Huang and colleagues⁶ provide evidence for a novel neuroimmune mechanism of enhanced pain (nociceptive) processing after total sleep deprivation in a pre-clinical rat model of neuropathic pain. Neuropathic pain is associated with lesions of the peripheral or central nervous system and is common in many types of peripheral neuropathies, central pain syndromes, low back pain, and cancer.⁷ Much of the knowledge about the pathophysiology of neuropathic pain has been derived from preclinical studies of chronic constriction injury (CCI) in the sciatic nerve.⁸ Huang and colleagues applied loose ligatures around the median nerve in the forelimb rather than the sciatic nerve in the hind limb.⁶ Total sleep deprivation (TSD) applied for 72 hours by a modification of the disk-over-water method immediately after, but not before, surgery to induce nerve injury was associated with augmentation of nociceptive behavioral responses and enhanced expression of a biomarker of microglial activation in the cuneate nucleus of TSD rats compared to controls. Throughout the sleep deprivation period, serum levels of melatonin were reduced and supplemental melatonin (given during the dark period of the diurnal cycle) dose dependently reduced allodynia and hyperalgesia and reduced microglial activation and proinflammatory cytokines in the cuneate nucleus both in TSD CCI and CCI control rats. One limitation, acknowledged by the investigators, is the lack of sleep physiological recordings to quantify the changes in sleep that occurred during the study period.

Increased systemic levels of proinflammatory cytokines and prostaglandins have been observed after experimental chronic sleep restriction⁹ and TSD¹⁰ along with spontaneous reports of increased pain symptoms. Proinflammatory cytokines released from circulating lymphocytes lead to release of cytokines by glia and an increase in chemical mediators (e.g., excitatory amino acids, prostaglandins, nerve growth factors, and nitric oxide) in the spinal cord that facilitate development of central sensitization and pain hypersensitivity.¹¹ Prostaglandin E2 is an important mediator of inflammation in peripheral tissues, capable of increasing peripheral nerve sensitivity and cellular excitability in the spinal cord.^12,13 Glial cell activation in the central nervous system has been hypothesized as a key mechanism contributing to the development of chronic pathological pain.¹⁴

Of considerable interest in the Huang study is the finding of reduced melatonin (MT) throughout the sleep deprivation period, and the observation that supplemental melatonin dose-dependently produced analgesia and reduced inflammatory processes.

The main function of melatonin is a physiological signal of environmental darkness and as such melatonin levels are higher during the sleep period in humans and the active period in rodents. In sleep medicine, melatonin and melatonin receptor agonists have been used to treat insomnia, but are considered most effective in the management of circadian rhythm sleep disorders.¹⁵ However, melatonin has diverse physiological actions, including anti-inflammatory and analgesic effects. Melatonin has been used to treat pain associated with endometriosis, temporomandibular joint disorders, irritable bowel syndrome, fibromyalgia, migraine, neonatal pain, and when administered before or during surgery has been shown to reduce postoperative pain.^16–22 In two recent small randomized clinical trials, in addition to reducing pain, melatonin improved self-reported sleep quality that was interpreted as independent from its analgesic effects.^16,17 Melatonin is thought to induce analgesia, in part, through activation of MT1 and MT2 receptors, but it also acts through opioid receptors. A novel MT1/MT2 agonist, piromelatine, has been shown to reduce allodynia and hyperalgesia and increase NREM sleep in the mouse model of CCI.²³ How melatonin induces analgesia is still under investigation,²⁴ but reducing glial cell activation and inflammatory mediators, as shown by Huang,⁶ is one plausible mechanism. Future studies testing the analgesic effects of melatonin on pain in humans would be improved with the addition of polysomnographic or actigraphic measures of sleep.

The findings of enhanced behavioral nociceptive responses after, but not before, nerve injury in the Huang study are interesting in light of recent findings from a study of sleep fragmentation in a mouse model of muscle sensitization.²⁵ The induction of muscle sensitization requires two injections of acidified saline into the muscle spaced 5 days apart. Sleep fragmentation by forced locomotion applied for 5 days after, but not before, the first injection lead to an exacerbation of muscle hypersensitivity and to increased sleep fragmentation both during the light and dark periods. In both of these studies,^6,25 there was no control for the increased walking sleep deprived animals had to experience. Thus, the extent to which prolonged weight bearing or frequent and increased limb movements contributed to the exacerbation of nociception, glial cell activity, or muscle hypersensitivity is not known.

There is a substantial and growing clinical and experimental literature on the interaction of pain and sleep.^2,26 Recent longitudinal and prospective studies of pain and sleep in humans have revealed that sleep duration and disturbed sleep more reliably predict future pain than pain predicts disturbed sleep.²⁷ Most studies of sleep in preclinical pain models show sleep fragmentation and reduced slow wave and REM sleep, but not total sleep deprivation.^28,29 Sleep fragmentation or sleep restriction paradigms may better model disrupted sleep effects on nociception and inflammation,^25,30 and use of the TSD paradigm ought to be reconsidered. In future studies, to enhance the relevance of findings from preclinical studies to chronic pain in humans, investigators ought to (a) conduct nociceptive testing in animals during the dark period of the diurnal cycle when rodents are awake, (b) include the study of females, and (c) monitor stress reactivity. Behavioral studies of nociceptive responses in rats show lower pain thresholds during NREM sleep compared to waking during the light period.³¹ Female sex and stress reactivity confer heightened susceptibility to develop persistent pain.^29,30 Although there are challenges to the use of preclinical models, these models provide unique knowledge about neurobiological mechanisms that underlie sleep and pain interactions, and importantly, the identification of new therapies.

CITATION

Landis CA. Is melatonin the next “new” therapy to improve sleep and reduce pain? SLEEP 2014;37(9):1405-1406.

DISCLOSURE STATEMENT

Dr. Landis has received support through grants from the National Institute of Nursing Research, T32NR007106, NR012734, and Center for Research on Management of Sleep Disturbances, NR011400.