Effects of Chronic Pain, Morphine, and Placebo

多份报告表明，用于缓解慢性疼痛的阿片类药物的接受度和使用率正在大幅上升，阿片类药物(尤其是大剂量)和慢性疼痛都会扰乱神经内分泌功能，特别是下丘脑-垂体-肾上腺和下丘脑-垂体-性腺轴的功能。此外，大量控制良好的止痛试验证明了安慰剂效应在疼痛治疗中的高频率和重要性。一些研究表明，神经内分泌的改变低于安慰剂效应的生物学效应。最近的神经成像研究表明，安慰剂止痛与皮质类似解剖成分的激活有关，这与真正的止痛药摄入有关，这使得后一种观察更具挑衅性。然而，到目前为止，在明确定义的慢性肌肉骨骼疼痛人群中，很少有系统的研究比较慢性(与急性)疼痛、常规(与大剂量)阿片类药物使用和安慰剂给药对神经内分泌功能、疼痛症状或生活质量的影响。因此，本研究的目的是评估中年男性骨关节炎(OA)慢性肌肉骨骼疼痛本身与长期使用阿片类药物对神经内分泌功能(ACTH、皮质醇、黄体生成素和睾酮分泌)、疼痛症状、情绪和生活质量的影响，以及安慰剂止痛是否对神经内分泌功能、疼痛症状、情绪和生活质量产生与阿片类止痛剂相似但较轻的影响。 为了解决这些问题，我们启动了一项由四部分组成的研究。在第一部分中，12名患有慢性骨关节炎(OA)疼痛的麻醉性天真男性将与12名健康、年龄和体重指数匹配的男性进行比较，方法是连夜抽血12小时，20分钟，测量ACTH、皮质醇、黄体生成素和睾酮，以及疼痛症状、情绪和生活质量。 在第二部分中，36例麻醉性幼稚的慢性骨性关节炎疼痛患者(包括上述12名男性)将被随机分为三个治疗组：美施康定(15-90 mg)、安慰剂或标准治疗。安慰剂和美施康定的剂量将以类似的方式在4周内逐步增加，维持2周，减少2周。在6周维持结束时，所有患者将返回重复12小时的频繁采样和神经心理学检查，如第一部分所述。 在第二部分结束时，患者被邀请继续使用MS Contin(15-120毫克)进行开放标签治疗期(第三部分)，这将包括6周的剂量递增和8周的阿片类药物维持。在第三部分结束时，患者将在门诊就诊，并接受AM内分泌测试和重复神经心理评估。如果患者对这一选择感兴趣，他们将被转介回他们的医生那里，并建议继续使用MS Contin治疗。在研究的第四部分，患者将被电话跟踪6个月，之后他们将被要求返回进行门诊评估，就像第三部分结束时那样。 这项研究的主要终点将是ACTH、皮质醇、黄体生成素和睾酮分泌的测量，而次要终点将包括选定的疼痛和烦扰症状的神经行为指数，以及情绪和生活质量的测量。预计这项研究将提供有关慢性肌肉骨骼疼痛以及阿片类药物与安慰剂治疗对男性特定神经内分泌功能影响的新信息。 这项研究的招募工作于2004年11月1日开始，迄今取得了相当大的成功。截至2005年9月15日，114名阿片类药物幼稚骨性关节炎患者已接受电话筛查，22人已完成门诊筛查，15人已完成第一部分，13人已完成第二部分，12人已完成第三部分，4人已完成第四部分。39名健康男性接受了电话筛查，13人接受了筛查，12人完成了第一部分。

Multiple reports suggest that acceptance and use of opioid medicines for relief of chronic pain are increasing substantially, and that opioidergic medications (especially in high doses) and chronic pain each perturb neuroendocrine functions, particularly those of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes. In addition, numerous well-controlled analgesic trials attest to the high frequency and importance of the placebo effect in the treatment of pain. Several investigations suggest that neuroendocrine alterations underly the biology of the placebo effect. The latter observation is made more provocative by recent neuroimaging studies suggesting that placebo analgesia is associated with activation of similar anatomic components of the cortex as with bona fide analgesic intake. To date, however, there has been little systematic inquiry comparing the effects of chronic (versus acute) pain, conventional (versus high) dose opioid use and placebo administration on neureoendocrine function, pain symptomatology, or quality of life in a well-defined population of individuals with chronic musculoskeletal pain. Thus, the objectives of the current study are to evaluate, in middle-aged men with chronic musculoskeletal pain due to osetoarthritis (OA), the effects of chronic OA pain per se versus long-term opioid usage on neuroendocrine function (ACTH, cortisol, LH and testosterone secretion), pain symptomatology, mood and quality of life, and whether placebo analgesia results in similar, albeit soemwhat lesser, effects on on neuroendocrine function, pain symptomatology, mood and quality of life as those elicited by an opioid analgesic. To address these questions, we have initiated a 4-part study. In part I, 12 narcotic naive men with chronic osteoarthritis (OA) pain will be comapred with 12 healthy, age- and BMI-matched men by assessing 12 hour overnight q 20 min blood sampling for measurements of ACTH, cortisol, LH and testosterone, as well as measures of pain symptomatology, mood and QOL. In part II, 36 narcotic naive patients with chronic OA pain (including the 12 men above), all of whom will have undergone overnight hormone sampling and neuropsychological evaluations in Part I, will be randomized to one of three treatment groups: MS Contin (15-90 mg), placebo or ?standard treatment? with NSAID's. Doses of placebo and MS Contin will be escalated over 4 weeks in a similar fashion with two-week maintenance and 2 week taper. At the end of maintenance at 6 weeks, all patients will return for repeat 12 hour frequent sampling and neuropsychological studies as in Part I. At the end of part II, patients are invited to go on to an open label treatment period (Part III) with MS Contin (15-120 mg), which will consist of a 6-week dose escalation and 8 weeks of maintenance on opioid medication. At the conclusion of Part III, patients will be seen in outpatient clinic, and undergo AM endocrine testing and repeat neurpopsychologcal assessment. They will then be referred back to their physicians with recommendations for continued treatment with MS Contin, if patients are interested in this option. In Part IV of the study, patients will be followed by telephone for 6 months, after which they will be asked to return for an outpatient assessment like that at the end of Part III. The primary endpoints of this study will be measures of ACTH, cortisol, LH, and testosterone secretion, whereas the secondary endpoints will include selected neurobehavioral indices of pain and bothersomeness symptomatology, and measures of mood and quality of life. It is anticipated that this study will provide novel information regarding the effects of chronic musculoskeletal pain, and treatment with opioids versus placebo, on selected neuroendocrine functions in men. Recruitment for this study began on 11/1/04, with considerable success to date. As of 9/15/05, 114 opioid naive OA patients have been phone screened, 22 have completed out-patient screeening visits, 15 have completed Part I, 13 have completed Part II, 12 have completed Part III and 4 have finished Part IV. 39 healthy men were phone screened, 13 underwent screening visits, and 12 have completed Part I.