Hyperalgesia in Methadone Patients: Can it be Treated?

描述（由申请人提供）：解决临床疼痛治疗不足已成为国家优先考虑的问题，其中心目标是为那些最有可能遭受未缓解疼痛的亚组患者确定有效的干预措施（NIH项目公告PA-01 -115）。事实上，对疼痛治疗不足最近被裁定为虐待病人的一种形式，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。我们的调查小组积累的新数据表明，与正常对照相比，持续使用阿片类药物激动剂美沙酮治疗成瘾的患者对冷压实验性疼痛明显过敏。这种疼痛耐受性的降低，加上向已知的阿片类药物成瘾者提供阿片类镇痛药的上下文禁令，使他们成为一个特别容易受到疼痛治疗的人群。不幸的是，对于如何最好地控制这个国家超过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。

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.