Effects of Osteoarthritis Pain, Morphine, and Placebo on Neuroendocrine Function in Men
Condition: Osteoarthritis
MeSH terms: Osteoarthritis
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will examine the effects of morphine on leuteinizing hormone, testosterone,
      adrenocorticotropic hormone and cortisol in men. The use of long-term opioids, such as
      morphine, to treat patients with pain is increasing, despite a dearth of information about
      their effects on hormones. The study will also look at the effect of chronic pain on these
      hormone levels and the effect of placebo on pain.

      Men between 30 and 65 years of age who have had moderate to severe chronic pain due to
      osteoarthritis for at least 3 months and healthy, pain-free men in the same age range may be
      eligible for this study. Patients taking an opioid-based medication such as percocet,
      vicodin, or morphine for pain relief, as well as patients who are not taking opioids, may
      participate. Candidates are screened with a medical history, physical examination, blood
      tests, including a blood test to look for possible "pain genes," electrocardiogram, x-ray,
      and questionnaires that assess the impact of pain on functional level and psychological well
      being.

      This is a four-part study. Healthy volunteers and patients who are taking opioids for their
      arthritis pain end their participation after Part I; those who are not taking opioids
      continue with Parts II, III, and IV, as follows:

      Part I: Participants are admitted to the NIH Clinical Center at 4 p.m. for an overnight stay.
      At 6 p.m. a catheter (plastic tube) is placed in a vein in the forearm and remains in place
      throughout the night. Blood samples of 3 cc's each (less than a teaspoon) are collected
      through the catheter every 20 minutes for 12 hours, from 8 p.m. until 8 a.m. Participants
      also collect their urine starting from 8 a.m. on the morning of hospital admission and
      continue the collection throughout their 24-hour hospital stay. Patients are discharged at
      the completion of the blood sampling.

      Part II: Patients are randomly assigned to take morphine (MS Contin), placebo, or standard
      treatment, which consists of anti-inflammatory medications and acetaminophen as needed, but
      no opioids. (Patients in groups I and II are also permitted to take anti-inflammatory drugs
      and acetominophen, in addition to their study medication.) Patients are monitored for drug
      side effects by phone twice a week, and medication doses are adjusted as needed. The morphine
      dose is gradually increased over a 4-week period if no side effects develop. After 2 weeks on
      the highest dose of morphine, hormone blood levels are measured and patients complete
      questionnaires. Patients are readmitted to the hospital for a repeat blood sampling and blood
      collection as in Part I. Patients on morphine and placebo are then gradually tapered off drug
      over 12 days and remain drug-free for 2 days before starting Part III.

      Part III: All patients are given morphine in this part of the study and are monitored for
      drug side effects by phone twice a week, with doses adjusted as needed. The morphine is
      gradually increased over a 6-week period if no side effects develop and is maintained at the
      highest dose for another 8 weeks. Hormone levels are measured and the blood and urine studies
      and questionnaires are repeated. Patients interested in continuing long-term treatment with
      MC Contin are referred back to their physicians with recommendations to that effect.

      Part IV: Patients are followed by phone for 6 months, at which time they return to the
      Clinical Center for hormone level measurements, repeat blood and urine tests, and
      questionnaires.
    

Detailed description: 
      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.
    

Intervention name(s): Blood Draw
Intervention type(s): Procedure
Primary purpose: Treatment
Keywords: Osteoarthritis; MS Contin; Placebo; Cortisol; Testosterone; Degenerative Joint Disease; OA; Arthritis; Joint Pain; Arthritic Pain; Opioid