Effects of Osteoarthritis Pain, Morphine, and Placebo on Neuroendocrine Function in Men

Several studies suggest that acceptance and use of opioid medicines for relief of chronic pain are increasing substantially, and that opiodergic medications and chronic pain each perturb neuroendocrine functions, especially those of the hypothalamic pituitary, adrenal, and gonadal axes. The objectives of the proposed protocol, entitled "Effects of Chronic Musculoskeletal Pain and Opioidergic versus Placebo Interventions on Neuro-endocrine Function in Men," are three fold: 1. To determine whether long term opioid usage in men with chronic pain due to osteoarthritis results in abnormalities of ACTH, cortisol, LH and testosterone secretion. 2. To evaluate whether placebo analgesia results in a similar hormonal response as elicited by an opioid analgesic. Prior imaging studies have shown that placebo analgesia is associated with activation of similar parts of the cortex as with analgesic intake. 3. To evaluate the effects of chronic pain per se on ACTH, cortisol, LH and testosterone secretion. To address these questions, we propose a 4-part study. In part I, 12 healthy men will be compared with 12 men with chronic osteoarthritis (OA) pain on long term opioids and 12 narcotic naive men with chronic OA pain by means of 12 hour overnight frequent blood sampling for measurement of cortisol, ACTH, LH and testosterone. In part II, 36 narcotic naive patients with chronic OA, pain, all of whom will have undergone overnight hormone sampling in Part I, will be randomized to one of three treatment groups: MS Contin (15-90 mg), placebo and "standard treatment." 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 of the same hormones as in Part I. At the end of part II, patients will be invited to go on to an open label treatment period with MS Contin (15-120 mg) in part III of the study, which will consist of 6-week dose escalation and 8 weeks maintenance. At that point patients will be referred back to their physicians with recommendations for continued treatment with MS Contin, if patients are interested in this option. Patients will be followed by phone for 6 months. At that point they will be asked to return to clinic for part IV, an outpatient AM sample of testosterone, LH, ACTH and cortisol. The primary endpoints of this study will be measures of LH, testosterone, ACTH, and cortisol secretion, whereas the secondary endpoints will be neurobehavioral indices such as pain and bothersomeness on visual analog scales, the Oswestry Disability Index, Multidimensional Pain Inventory, and the Beck Depression Inventory. 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.