褪黑素作为多模式镇痛中的整合性辅助手段：连接昼夜节律调节、抗炎调节与阿片类药物节约机制

摘要(中文译文)

综述目的——睡眠障碍是急性术后疼痛患者的主要主诉。睡眠障碍还可能增加疼痛敏感性，并促进慢性疼痛的发生和维持。疼痛的病理生理机制复杂；围术期疼痛管理和预防慢性疼痛是临床面临的挑战。使用阿片类药物进行疼痛管理仍是治疗的主要手段，在短期内用于缓解严重术后疼痛时通常是安全的。长期使用可能产生耐受性，而由于其欣快作用，成瘾、过量事件甚至死亡可能成为社会问题。因此，在当前术后疼痛管理中，推荐使用节省阿片类药物的多模式镇痛（MMA）进行疼痛管理。成功的MMA疼痛管理将促进患者术后恢复，减少慢性CPSP和长期阿片使用障碍（OUD）。本综述讨论了当前使用的所有镇痛药物的作用及相互作用，以及围术期疼痛管理中的节省阿片类药物或无阿片类药物镇痛。重大创伤或手术后的急性疼痛可能起源于伤害性和神经病理性机制。约10-50%的手术患者会发展为慢性术后疼痛，这不仅导致持续性不适，还导致功能受限和心理困扰。越来越多的证据强调睡眠与疼痛之间密切的双向关系：疼痛破坏睡眠结构，而睡眠剥夺加剧疼痛敏感性并损害恢复。这种相互作用形成恶性循环，给有效疼痛管理带来挑战。褪黑素——一种由松果体分泌的神经激素——在调节昼夜节律和睡眠-觉醒周期中发挥关键作用。除其生物钟调节作用外，褪黑素还具有抗伤害感受、抗炎和节省阿片类药物的特性。近期临床前研究表明，外源性褪黑素可减弱对有害刺激的伤害性反应，并增强吗啡镇痛，同时减轻吗啡耐受。此外，保留昼夜节律的环境光照操纵已被证明可协同维持褪黑素分泌、改善睡眠质量，并调节参与疼痛调控的神经免疫反应。总之，这些发现表明，昼夜节律对齐和褪黑素补充可能代表一种有前景的整合方法，用于改善围术期和慢性疼痛状况下的疼痛控制和睡眠健康。慢性疼痛患者在长期治疗中经常出现阿片耐受，导致镇痛疗效下降和需要增加剂量。我们最近的研究揭示，在神经病理性疼痛模型中，持续光照会抑制内源性褪黑素，升高促炎细胞因子（TNF-α、IL-1β），降低IL-10，并加速吗啡耐受。相反，维持昼夜光暗周期或补充褪黑素可保留褪黑素节律，减少胶质细胞激活，并维持吗啡抗伤害感受作用。褪黑素联合给药不仅减轻吗啡耐受，还通过调节炎症和胶质通路增强吗啡疗效。这些发现强调了褪黑素作为时间治疗剂和神经保护剂的多方面作用，将昼夜节律调节与疼痛调节相结合。在临床上，应用褪黑素或昼夜节律对齐策略可以指导个性化疼痛和睡眠管理，提供更安全、更有效的多模式镇痛方案，减少阿片依赖并改善生活质量。

Abstract

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.

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