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实验性疼痛和持续临床疼痛对静脉输注瑞芬太尼的反应，来验证潜在疼痛机制是阿片类药物敏感性决定因素的假设。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觉过敏区域。在健康志愿者中，该模型对阿片类药物有反应。研究1是对60例非阿片类慢性疼痛患者脑内输注高效、超短效阿片类药物瑞芬太尼对实验和临床疼痛的影响进行两期、安慰剂对照研究。(2)在研究2中，我们将确定长期静脉输注瑞芬太尼是否会对有害热刺激和实验诱导的皮肤继发性痛觉过敏产生急性镇痛耐受性。然后，我们将对持续慢性疼痛的患者进行测试，以表明在长期阿片类药物治疗期间镇痛耐受是可能的。如果出现急性耐受性，则输注瑞芬太尼后可能出现戒断症状、对有害刺激的痛觉过敏以及疼痛比预处理水平反弹增加等形式的身体依赖。(3)慢性非恶性疼痛的长期阿片类药物治疗未显示镇痛耐受性的发展。在研究3中，非阿片类药物使用的慢性疼痛患者将在9周的随机平行双盲试验之前和之后进行静脉注射瑞芬太尼对急性实验性和慢性疼痛的镇痛效果的安慰剂对照研究。40名受试者接受阿片类药物氢吗啡酮治疗，20名对照组接受三环阿米替林治疗。在初始3周剂量滴定期结束和固定给药6周后，再次静脉滴注瑞芬太尼，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.