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的问题已成为国家的优先事项，中心目标是为那些最有可能遭受未缓解疼痛的风险最高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，疼痛治疗不足最近被裁定为虐待患者的一种形式，加州一家法院判给这样一名患者的家人100万美元的损害赔偿金。我们研究小组积累的新数据表明，与正常对照组相比，服用Mu阿片激动剂美沙酮治疗成瘾的患者对冷加压实验性疼痛有显著的痛敏反应。这种疼痛耐受性的降低，再加上向已知的阿片成瘾者提供阿片类止痛剂的相关背景禁令，使他们成为一个特别容易受到疼痛治疗不足的人群。不幸的是，关于如何最好地管理这个国家超过12万名美沙酮(MM)患者遭受的疼痛，人们知之甚少，部分原因是他们遭受的疼痛过敏似乎类似于神经性疼痛和阿片类药物诱导的疼痛。 在拟议的一系列研究中，首席研究员(第一次申请RO1)将在她之前对MM样本中痛觉过敏的验证和特征的研究基础上，从药理学的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，拟议的工作将评估三类药物(N-甲基-D-天冬氨酸(NMDA)拮抗剂、辅助抗惊厥止痛剂和新型阿片类止痛药)减轻或逆转阿片类药物诱导的痛觉过敏的能力，这些药物使MM患者的疼痛状态复杂化。具体地说，在MM患者的样本中，(1)干扰阿片类药物诱导的痛敏发展的右美沙芬，(2)已被证明治疗神经性疼痛有效的加巴喷丁，以及(3)具有新的阿片类药物活性的羟考酮，将分别评估其缓解或减轻阿片类药物诱导的痛敏的能力，这反映在痛阈值和对冷加压和电刺激疼痛的耐受性的峰值和美沙酮的血液水平。这项工作的结果不仅将为这一高危人群疼痛耐受性差的机制提供药理学方面的见解，也将为阿片类药物诱导的痛敏并发的疼痛的医学治疗提供指导。

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.