Hyperalgesia in Methadone Patients: Can it be Treated?

描述（由申请人提供）： 解决临床疼痛的治疗不足问题已成为国家的优先事项，其中心目标是为那些最有可能遭受未缓解疼痛的患者亚组确定有效的干预措施（NIH计划公告PA-01 - 115）。事实上，对疼痛治疗不足最近被裁定为一种虐待病人的形式，加州一家法院判给这样一名病人的家属100万美元的赔偿金。我们的研究小组积累的新数据表明，与正常对照组相比，维持μ阿片激动剂美沙酮治疗成瘾的患者对冷加压实验性疼痛显着痛觉过敏。这种疼痛耐受性的降低，加上与向已知的阿片类成瘾者提供阿片类镇痛剂相关的背景禁令，使他们成为唯一容易受到疼痛治疗不足影响的人群。不幸的是，关于如何最好地管理这个国家超过120，000名美沙酮维持（MM）患者所遭受的疼痛，人们知之甚少，部分原因是他们所遭受的痛觉过敏似乎类似于神经性疼痛和阿片类药物引起的疼痛。 在拟议的一系列研究中，主要研究者（首次申请RO 1）将在她先前验证和表征MM样本中痛觉过敏的研究的基础上，从药理学角度探索其潜在机制。利用略有不同的双盲、安慰剂对照设计，拟定的工作将评价三类药物（N-甲基-D-天冬氨酸（NMDA）拮抗剂、辅助抗惊厥镇痛剂和新型阿片类镇痛剂）减少或逆转阿片类诱导的痛觉过敏并发MM患者疼痛状态的能力。具体地，在MM患者的样品中，（1）干扰阿片样物质诱导的痛觉过敏的发展的美沙芬，（2）已被证明在治疗神经性疼痛中有效的加巴喷丁，和（3）具有新的阿片样物质活性的羟考酮，将评估每种药物改善或减少阿片类药物的能力，在这些患者中诱导痛觉过敏，如通过疼痛阈值和对冷加压和电疼痛的耐受性的变化所反映的，在峰值和通过美沙酮血液水平。这项工作的结果不仅将提供药理学的洞察力，在这个高危人群的疼痛耐受性差的机制，但也为阿片类药物诱导的痛觉过敏的疼痛复杂的医疗管理的方向。

DESCRIPTION (provided by applicant): Addressing the under-treatment of clinical pain has become a national priority, with a central goal being to identify effective interventions for those subgroups of patients most at risk for suffering unrelieved pain (NIH Program Announcement PA-01 -115). In fact, the under-treatment of pain was recently ruled a form of patient abuse with a California court awarding one million dollars in damages to the family of such a patient. Novel data accumulated by our investigative group has shown that patients maintained on the mu-opioid agonist, methadone, for the treatment of addiction, are significantly hyperalgesic to cold-pressor experimental pain as compared to normal controls. This diminished pain tolerance, in addition to the contextual prohibitions associated with providing known opioid addicts with opioid analgesics, makes them a population uniquely vulnerable to the under treatment of pain. Unfortunately, little is known about how to best manage the pain suffered by the over 120,000 methadone-maintained (MM) patients in this country, in part because the hyperalgesia they suffer appears to be akin to neuropathic pain and opioid-induced. In the proposed series of studies, the Principal Investigator (a first-time RO1 applicant) will build upon her previous studies validating and characterizing hyperalgesia in MM samples to explore it's underlying mechanism from a pharmacological perspective. Utilizing slightly different double-blind, placebo-controlled designs, the proposed work will evaluate the ability of three classes of medication (N-methyl-D-aspartate (NMDA)-antagonists, adjuvant anticonvulsant analgesics, and novel opioid analgesics) to diminish or reverse the opioid-induced hyperalgesia complicating the pain states suffered by MM patients. Specifically, in a sample of MM patients, (1) dextromethorphan, which interferes with the development of opioid-induced hyperalgesia, (2) gabapentin, which has proven efficacy in treating neuropathic pain, and (3) oxycodone, which has novel opioid activity, will each be evaluated for its ability to ameliorate or diminish the opioid-induced hyperalgesia in these patients as reflected by changes on pain threshold and tolerance to both cold-pressor and electrical pain, at peak and through methadone blood levels. The results of this work will not only provide pharmacologic insight into the mechanisms underlying poor pain tolerance in this at-risk population, but also direction for the medical management of pain complicated by opioid-induced hyperalgesia.