Opioid Responsivity/ Analgesic Tolerance in Chronic Pain

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(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.