Melatonin as an Integrative Adjunct in Multimodal Analgesia: Linking Circadian Regulation, Anti-Inflammatory Modulation, and Opioid-Sparing Mechanisms

Purpose of Review-sleep disturbance is the main complaint associated with patients who suffer acute postoperative pain. Sleep disturbance may also increase the pain sensitivity and contribute to the development and maintenance of chronic pain. The pathophysiology of pain is complex; management of perioperative pain and preventing chronic pain are challenges in clinical. Use of opioids for pain management are still a therapeutic mainstay and generally safe when taken, in a short time, for severe postoperative pain relief. For long-term use tolerance may be developed, and for their euphoric property, addiction, overdose incidents, and even death may be the social problems. Therefore, the opioid-sparing multimodal analgesia (MMA) for pain management is recommended in current postoperative pain management. The successful MMA for pain management will enhance patient recovery after surgery with less chronic CPSP and long-term opioid use disorder (OUD). The present review discusses all currently used analgesics actions and interactions, and opioid-sparing or opioid-free analgesia in perioperative pain management. Acute pain following major trauma or surgery may originate from both nociceptive and neuropathic mechanisms. Approximately 10-50% of surgical patients develop chronic postoperative pain, which not only causes persistent discomfort but also leads to functional limitations and psychological distress. Growing evidence highlights a close and bidirectional relationship between sleep and pain: pain disrupts sleep architecture, while sleep deprivation intensifies pain sensitivity and impairs recovery. This reciprocal interaction forms a vicious cycle that poses challenges for effective pain management. Melatonin-a neurohormone secreted by the pineal gland-plays a crucial role in regulating circadian rhythm and sleep-wake cycles. Beyond its chronobiotic action, melatonin exhibits anti-nociceptive, anti-inflammatory, and opioid-sparing properties. Recent preclinical studies have demonstrated that exogenous melatonin can attenuate nociceptive responses to noxious stimuli and enhance morphine analgesia while attenuating morphine tolerance. Moreover, environmental light manipulation preserving the circadian rhythm has been shown to synergistically maintain melatonin secretion, improve sleep quality, and modulate neuroimmune responses involved in pain regulation. Together, these findings suggest that circadian alignment and melatonin supplementation may represent a promising integrative approach for improving both pain control and sleep health in perioperative and chronic pain conditions. Chronic pain patients frequently experience opioid tolerance during long-term therapy, resulting in diminished analgesic efficacy and a need for escalating doses. Our recent work revealed that constant light exposure suppresses endogenous melatonin, heightens pro-inflammatory cytokines (TNF-α, IL-1β), reduces IL-10, and accelerates morphine tolerance in a neuropathic pain model. In contrast, maintaining circadian light-dark cycles or supplementing melatonin preserves melatonin rhythm, reduces glial activation, and sustains morphine antinociception. Melatonin's co-administration not only attenuates morphine tolerance but also enhances morphine efficacy through the modulation of inflammatory and glial pathways. These findings underscore melatonin's multifaceted role as both a chronotherapeutic and neuroprotective agent, integrating circadian regulation with pain modulation. Clinically, the application of melatonin or circadian-aligned strategies could guide personalized pain and sleep management, offering safer and more effective multimodal analgesic protocols with reduced opioid dependence and improved quality of life.