Alleviating Opioid-Induced Hyperalgesia with Novel Pharmacotherapy

用新型药物疗法减轻阿片类药物引起的痛觉过敏

• 批准号: 9220818
• 负责人: JIANREN MAO
• 金额: $ 43.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220818
• 关键词: Adverse effects; Affect; Agonist; Analgesics; Attention deficit hyperactivity disorder; Biological Availability; Cardiovascular system; Clinical; Clinical Data; Clinical Research; Clonidine; Data; Development; Dexmedetomidine; Dose; Double-Blind Method; Effectiveness; FDA approved; Formulation; Guanfacine; Half-Life; Hour; Human; Hyperalgesia; Hypertension; Label; Methodology; Morphine; Muscle relaxants; Needlestick Injuries; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Rotation; Oral; Outcome; Outcome Study; Pain; Pain intensity; Pain management; Patients; Pharmacotherapy; Placebo Control; Placebos; Plasma; Pre-Clinical Model; Prevention; Randomized; Recruitment Activity; Regimen; Sensory; Supervision; Testing; Time; Visual Analogue Pain Scale; capsule; chronic pain; compliance behavior; diffuse noxious inhibitory control; experience; improved; novel; novel therapeutic intervention; opiate tolerance; opioid abuse; prescription opioid; prevent; prospective; public health relevance; response; subcutaneous; tizanidine

DESCRIPTION (provided by applicant): Opioids are strong analgesics for the treatment of moderate to severe pain. However, paradoxical opioid-induced hyperalgesia (OIH) has become a significant clinical issue that reduces the effectiveness of opioid therapy and contributes to prescription opioid addiction and abuse. Despite significant progress in defining clinical features (markers) of OIH, no effective pharmacotherapies are currently available to prevent and reverse OIH. For years, supervised opioid dose reduction or opioid rotation has been proposed to manage suspected OIH. However, a major clinical challenge in implementing this strategy is the need to maintain adequate pain relief while opioid dose is reduced. Centrally acting alpha2-adrenoreceptor (alpha2-AR) agonists have long been known to improve opioid tolerance and dependence. Recently, alpha2-AR agonists also have been suggested to be useful to improve OIH. Among FDA-approved alpha2-AR agonists (e.g., clonidine, dexmedetomidine, tizanidine), guanfacine possesses a stable cardiovascular side effect profile, is used in a single daily dose regimen, and has been used (off-label) for the treatment of attention deficit hyperactivity disorder. Our preliminary data has shown that alpha-2AR agonist effectively reduces OIH in a preclinical model and maintains the opioid analgesic effect in chronic pain patients. In this application, we propose to conduct two double-blind, randomized, and placebo-controlled clinical studies in order to examine the effectiveness of guanfacine in the prevention and reversal of OIH. In the first study (Aim 1), we will recruit chronic pain subjects who currently ar experiencing unsatisfactory pain relief with non-opioid treatment to assess whether guanfacine can prevent the development of OIH as they commence opioid therapy. In the second study (Aim 2), we will recruit chronic pain subjects who experience moderate to severe pain despite having taken opioid for at least three months and demonstrate signs of OIH to assess whether guanfacine can reverse OIH. Methodologically, we will use both quantitative sensory testing (QST including assessment of temporal summation and diffuse noxious inhibitory control) and clinical (visual analog scale of pain intensity and affect; subcutaneous needle stick test) markers of OIH to assess the effectiveness of guanfacine. We expect that the proposed prospective human studies will yield important and timely clinical data regarding a novel and practical approach to managing OIH. Since OIH decreases the overall effectiveness of opioid therapy, developing this novel pharmacotherapy for OIH treatment will help reduce unnecessary opioid dose escalation, improve clinical outcome of opioid therapy, and diminish the liability of prescription opioid addiction and abuse related to chronic pain management.

描述（由申请人提供）：阿片类药物是治疗中度至重度疼痛的强效镇痛药。然而，矛盾阿片类药物诱导的痛觉过敏（OIH）已经成为一个重要的临床问题，降低了阿片类药物治疗的有效性，并导致处方阿片类药物成瘾和滥用。尽管在定义临床特征方面取得了重大进展