Opioid Responsivity/ Analgesic Tolerance in Chronic Pain

(1)我们将通过同时测量神经性和非神经性慢性疼痛患者的实验诱导疼痛和持续临床疼痛对静脉注射的反应，来检验潜在的疼痛机制是阿片类药物敏感性的决定因素的假设。瑞芬太尼输液。对于实验性疼痛，我们将使用一种结合非损伤性加热和局部辣椒素的模型来产生稳定的皮肤继发性痛敏区域。在健康的志愿者中，这种模式是阿片类药物反应的。研究1是一项为期两个疗程的安慰剂对照研究，研究高效、超短效阿片类药物瑞芬太尼对60名使用非阿片类药物的慢性疼痛患者脑部输注对实验性和临床疼痛的影响。(2)在研究2中，我们将确定静脉注射时间是否延长。在阿片类药物未成熟的志愿者中输注瑞芬太尼将产生对伤害性热刺激和实验诱导的皮肤继发性痛敏的急性止痛耐受性。然后，我们将测试持续慢性疼痛的患者，这将表明在长期阿片类药物治疗期间，止痛耐受是可能的。如果出现急性耐受，在注射瑞芬太尼后，可能会出现戒断症状、对伤害性刺激的痛觉过敏和疼痛反弹增加等形式的身体依赖。(3)在慢性非恶性疼痛的长期阿片类药物治疗过程中，未显示出镇痛耐受的形成。在研究3中，使用非阿片类药物的慢性疼痛患者将接受一项关于静脉注射止痛效果的安慰剂对照研究。瑞芬太尼治疗急性实验性疼痛和慢性疼痛9周、随机平行设计、双盲试验。40名受试者将接受阿片类氢吗啡治疗，20名对照组将接受三环阿米替林治疗。在最初的3周剂量滴定周期结束时，以及在6周固定剂量后再次静脉注射。瑞芬太尼将重复输注以重建实验性和慢性疼痛的剂量-反应曲线。

(1) We will test the hypothesis that underlying pain mechanism is a determinant of opioid sensitivity by simultaneously measuring in both neuropathic and non-neuropathic chronic pain patients the response of experimentally induced pain and ongoing clinical pain to i.v. remifentanil infusion. For experimental pain we will use a model which combines non-injurious heating and topical capsaicin to produce stable areas of cutaneous secondary hyperalgesia. In healthy volunteers, this model is opioid responsive. Study 1 is a two session, placebo-controlled study of the effect on experimental and clinical pain of brain infusions of the high efficacy, ultra-short acting opioid remifentanil in 60 non-opioid using chronic pain patients. (2) In study 2 we will determine whether a prolonged i.v. remifentanil infusion in opioid-naive volunteers will produce acute analgesic tolerance to both noxious thermal stimulation and experimentally induced cutaneous secondary hyperalgesia. We will then test patients with ongoing chronic pain would indicate that analgesic tolerance is possible during long term opioid therapy. If acute tolerance develops, physical dependence in the form of withdrawal symptoms, hyperalgesia to noxious stimuli, and a rebound increase in pain over pretreatment levels may follow the remifentanil infusion. (3) Analgesic tolerance has not been shown to develop during long term opioid therapy of chronic non-malignant pain. In Study 3, non-opioid using chronic pain patients will undergo a placebo-controlled study of the analgesic effect of i.v. remifentanil on acute experimental and chronic pain before and following a 9 week, randomized parallel design, double- blind trial. Forty subjects will receive the opioid hydromorphone and a control group of 20 will receive the tricyclic amitriptyline. At the end of the initial 3 week dose titration period and again after 6 weeks of fixed dosing, the i.v. remifentanil infusion will be repeated to reconstruct the dose-response curves for experimental and chronic pain.