Hormone Function in Men Treated for Pain With Opioids or Placebo

Use of opioid medicines for relief of chronic pain is increasing substantially but
opioidergic medications and chronic pain have been both shown to perturb neuroendocrine
function. The objective of this protocol is:

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.

This protocol is a revised continuation of a two phase protocol with the same name which was
initiated at NCCAM in 2004. In the first phase of this study 12 opioid na ve men with
chronic OA pain were compared to12 healthy men by means of 12 hour overnight frequent blood
sampling for measurement of baseline ACTH, cortisol, LH and testosterone. The results of
phase 1 suggest that chronic osteoarthritis pain does not affect ACTH, cortisol, LH and
testosterone secretion in middle aged men as compared to matched controls. In the second
phase the NCCAM protocol intended to evaluate the effect of long term opioid usage AND the
placebo effect -if any- on the same hormones in men with chronic OA pain. Therefore the
NCCAM study had a three arm design comparing MS Contin to placebo and standard treatment.
When the protocol was being revised under NINR, review of the placebo literature suggested
that placebo effect becomes negligible with time and therefore a two arm design was chosen
comparing morphine to placebo. Baseline overnight blood hormone sampling, doses of
medication, escalation and tapering schedules will be the same as in phase II of the NCCAM
protocol.

Because of design changes the sample size was however recalculated to be a total of 30
opioid na ve patients with chronic OA pain. Fourteen patients, previously recruited under
NCCAM, had been randomized to either morphine or placebo and finished the study. Therefore
16 additional patients need to complete the study. Taking into consideration a 25% drop out
rate therefore a total of 20 patients need to be recruited. After undergoing overnight
baseline hormone sampling all patients will be randomized to one of two treatment groups: MS
Contin (15-90 mg), or placebo Doses of placebo and MS Contin will be escalated over 4-8
weeks in a similar fashion followed by a two-week maintenance period. At that point patients
will return for repeat 12 hour frequent sampling of the same hormones as at baseline. They
will then be tapered off of study medications over a period of 2-4 weeks as outpatients.
Subjects will then return to clinic for a final visit and, AM blood will be obtained for
ACTH, cortisol, LH, and testosterone.

The primary endpoints of this study are measures of ACTH, cortisol, LH, and testosterone
secretion, whereas secondary endpoints are neurobehavioral indices such as pain
symptomatology on a 0-10 (Likert) scale, the Oswestry Disability Index, Multidimensional
Pain Inventory, and the Beck Depression Inventory. It is anticipated that the results of the
second phase of this study will provide novel information regarding the effects of treatment
with opioids on selected neuroendocrine functions in men.

-INCLUSION CRITERIA:

1. Clinical evidence of chronic OA by history, examination and radiological examination

- a. Pain level of 4/10 or greater on a scale of 0 to 10 over a 2 week screening
period

- b. Pain for a duration of 3 months or longer present at least 5 out of 7 days a
week by history

- c. Radiographic evidence of moderate to severe OA in at least one joint
selected for study based on the Kellgren and Lawrence scoring scale (Appendix
I:Table 2)

2. Age between 30-65 at study entry. This age range was chosen as osteoarthritis is rare
in people younger than 30 and to minimize the effect of the neuroendocrine changes
associated with aging on study outcome measures.

3. Men of all ethnicities

4. Ability to provide his own consent and to cooperate with study procedures

5. Willingness to refrain from drinking alcohol during the study because alcohol may
exacerbate the sedative effects of morphine

6. Willingness to refrain from using muscle relaxers, antiepileptic medications and
antidepressants within 6 weeks of starting study procedures

7. Willingness not to be on opioids other than prescribed by the study for the duration
of the study and willingness to come off of opioids six weeks prior to starting study
procedures

EXCLUSION CRITERIA:

1. Impaired pulmonary, renal, hepatic, cardiovascular or endocrine-metabolic function or
major coexisting medical condition such as cancer, Cushing's disease, and diabetes
which may make participation unsafe or interfere with hormone measurements

2. Prostatic disease or hypertrophy which would make subjects prone to urinary retention
or require medication that would interfere with study hormone measurements

3. Sexual dysfunction including lack of libido, impotence or erectile abnormalities for
safety reasons as these symptoms may be worsened by morphine

4. Rheumatoid arthritis other types of inflammatory arthritis

5. Use of systemic corticosteroids in the two months before study entry which might
interfere with study hormone measurements

6. Present or past history of alcohol dependence which might predispose subjects to
problems with opioid dependence based on 2 or more positive responses to the CAGE
questionnaire (the latter group will be referred to psychiatry for further evaluation
and excluded from study if found to fulfill psychiatric criteria for alcohol
dependence or abuse)

7. Current usage of any recreational or unauthorized prescription drugs because this may
indicate abuse potential based on positive urine drug test at study screening visit

8. History of opioid abuse at any time in the past based on patient report or a urine
drug screen positive for opioids

9. Major depression based on a score of greater than or equal to 20 on the Beck
Depression Inventory at screening, present history of major depression or treatment
for major depression because these may effect endocrine function

10. Hct < 35; anemia or bleeding disorder because subjects will undergo serial blood
sampling to assess hormone function

11. Allergy or inability to tolerate to morphine

12. Current or past fibromyalgia according to Wolfe criteria (1990)

13. Present or past history of sleep apnea because of increased risk of respiratory
depression with morphine

14. Body mass index (BMI) > 30kg/m(2) and BMI < 20kg/m(2)

15. Local steroid injections during the study because weight has significant effects on
hormone levels

16. Addition of or changes to complementary or alternative treatments during the study