Multiple reports suggest that acceptance and use of opioid medicines for relief of chronic pain are increasing substantially, and that opioidergic medications (especially in high doses) and chronic pain each perturb neuroendocrine functions, particularly those of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes. In addition, numerous well-controlled analgesic trials attest to the high frequency and importance of the placebo effect in the treatment of pain. Several investigations suggest that neuroendocrine alterations underly the biology of the placebo effect. The latter observation is made more provocative by recent neuroimaging studies suggesting that placebo analgesia is associated with activation of similar anatomic components of the cortex as with bona fide analgesic intake. To date, however, there has been little systematic inquiry comparing the effects of chronic (versus acute) pain, conventional (versus high) dose opioid use and placebo administration on neureoendocrine function, pain symptomatology, or quality of life in a well-defined population of individuals with chronic musculoskeletal pain. Thus, the objectives of the current study are to evaluate, in middle-aged men with chronic musculoskeletal pain due to osetoarthritis (OA), the effects of chronic OA pain per se versus long-term opioid usage on neuroendocrine function (ACTH, cortisol, LH and testosterone secretion), pain symptomatology, mood and quality of life, and whether placebo analgesia results in similar, albeit soemwhat lesser, effects on on neuroendocrine function, pain symptomatology, mood and quality of life as those elicited by an opioid analgesic. ? ? To address these questions, we initiated a 2-part study. In part I, 16 opioid naove, non-obese men with chronic, moderate-severe osteoarthritis (OA) pain were comapred with 12 healthy men of similar ages and BMIs by assessing 12 hour overnight q 20 min blood sampling for measurements of ACTH, cortisol, LH and testosterone, as well as measures of pain symptomatology, mood and QOL.? ? In part II, 36 opioid naove men with chronic OA pain (including the 16 OA patients noted above), all of whom will have undergone overnight hormone sampling and neuropsychological evaluations in Part I, will be randomized to one of three treatment groups: MS Contin (15-90 mg), placebo or standard treatment with NSAID's. 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 overnight frequent blood sampling and neuropsychological studies as in Part I. Two weeks later, patients will be asked to return for an outpatient assessment, after which they will be discharged to the care of their personal physicians. ? ? The primary endpoints of this study are measures of nocturnal ACTH, cortisol, LH, and testosterone secretion, whereas the secondary endpoints include AM SHBG, CBG, DHEAS, and CRP; 2h hour urine cortisol and catecholamines; and selected neurobehavioral indices of pain, mood and quality of life. Parts I and II of 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.? ? This protocol was initially approved by the NIDCR IRB in May, 2004, and at the Annual Renewals in May, 2005, and May, 2006. This is a 2-part study evaluating the effects of chronic OA pain, morphine and placebo on nocturnal release of ACTH, cortisol, LH and testosterone. The last amendments for this study were submitted in November, 2005, and approved by the IRB in January, 2006. ? ? The study was revised from a 4-part study to a 2-part, 8-week study in 2006. This revision allowed for elimination of the recruitment of men with chronic OA pain on long term opioids from part I of the study. The amendment also eliminated original parts III and IV of the study. ? ? Obtaining two week pain diaries from prospective study participants after successful telephone screening, to determine their eligibility for an out-patient screening visit, rather than after the outpatient screening visit. The pain VAS and bothersomeness scales obtained at each visit were also eliminated.? ? Study recruitment was initiated in November, 2004. Since the last IRB renewal in May of 2006, an additional 123 participants, all Opioid naive men, have been telephone screened, for a total of 328 men screened since study inception. Of these 123, 11 men underwent out-patient screening assessments for this study, for a total of 59 participants. Of the 11 Opioid nave men screened, 7 participated in the first in-patient visit for a total of 39 men. Of these 7 men, all participated in the second in-patient and 3rd out-patient visits for totals of 24 and 22 men, respectively. Four additional opioid nave patients completed successful telephone screening and satisfactory pain diaries, but will not undergo out-patient screening histories and physical examinations because of study termination, and all will be contacted and so informed.? ? No SAEs have occurred since initiation of the study. In regard to routine AEs, 1 additional Opioid nave patient withdrew from the study since May, 2006, because of lack of interest, for a total of 6. We are unaware of new information in the literature that would affect the IRBs evaluation of the risk/benefit analysis of human subjects involved in this protocol. ? ? Judith Starling, NIH Clinical Center Pharmacy, contributed to the design and implementation of this study, and provided storage, randomization and dispensing of active and placebo study medications. ? ? Part II of the protocol requires completion of the first and second in-patient visits by a total of 36 Opioid nave men, randomized into 3 groups (n= 12) receiving either MS Contin, placebo for MS Contin, or control for Placebo (i.e. standard treatment with NSAIDs). As of this time, evaluable data from the 2 in-patient study visits exist for 23 patients. ? ? An abstract describing the results of part I of the study was presented at the 88th Annual Meeting of the Endocrine Society, held in Boston, MA, June 24-27, 2006. The final results of Part I of this study were published in the Journal of Clinical Endocrinology and Metabolism (91: 4313-4318, 2006). ? ? It is estimated that completion of Part II of this protocol would take about 12-18 months.
| Lao, Lixing; Huang, Yi; Feng, Chiguang et al. (2012) Evaluating traditional Chinese medicine using modern clinical trial design and statistical methodology: application to a randomized controlled acupuncture trial. Stat Med 31:619-27 |
| Muniyappa, Ranganath; Veldhuis, Johannes D; Harman, S Mitchell et al. (2010) Effects of testosterone administration on nocturnal cortisol secretion in healthy older men. J Gerontol A Biol Sci Med Sci 65:1185-92 |
| Khoromi, Suzan; Muniyappa, Ranganath; Nackers, Lisa et al. (2006) Effects of chronic osteoarthritis pain on neuroendocrine function in men. J Clin Endocrinol Metab 91:4313-8 |
