Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration

Chronic nonmalignant pain is a widespread issue affecting 15-30% of the population. Many
patients with chronic pain are responsive to first-line combination of physical modalities
and non-opioid analgesics. Up to 20% of these patients, however, require opioid therapy for
adequate pain relief. The use of long-acting opioids, including morphine sulfate, oxycodone,
fentanyl, and methadone, although effective for pain control, carries risks of addiction,
tolerance, and systemic side effects including nausea, itching, constipation, and
hypogonadotropic hypogonadism with consequent testosterone depletion (in up to 86% of
patients taking chronic pain medication) leading to the multiple adverse effects.
Opioid-induced androgen deficiency (OPIAD), occurs with high frequency and persistence, and
commonly remains undiagnosed in the pain clinic. Low testosterone may be treated using
exogenous testosterone (topical or gel) or other medications such as selective estrogen
receptor modulators (i.e. clomiphene citrate). While both medication types increase serum
testosterone levels, clomiphene citrate is known to benefit sperm parameters in hypogonadal
men while exogenous testosterone is known to inhibit sperm production. Few studies have
examined the hormonal changes caused by long-term opioid usage in men, and no studies have
formally studied clomiphene citrate for this patient population.

Inclusion Criteria:

- Male

- 18 years to 65 years

- Low testosterone as defined by criteria (serum total testosterone <350 ng/dl in men
<55 years, <300 ng/dl in men 55-65 years)

- EITHER taking opioid pain medication (see A below) OR planning to start new pain
medication regimen (see B below)

- A) EITHER continuous opioid treatment for chronic nonmalignant pain for >=6 months
receiving one of several specified opioid regimens for the past 1 month (including
>=20 mg/day of oral methadone, >=30 mg/day of oral sustained release oxycodone, >=30
mg/day of oral morphine sulfate, >=6 mg/day of oral dilaudid or >= 8 mg/day of
dilaudid ER, or >=25 mcg/hr of transdermal fentanyl or buprenorphine, or intrathecal
morphine pump)

- B) OR the pain management physician is planning to start pain medication (opioid or
non-opioid pain therapy) but you have not received it yet. If this is the case, your
testosterone will be checked before starting and during 1 month of pain therapy to
determine if you have low testosterone to qualify to begin medication (clomiphene or
placebo) treatment in this study.

- BMI (20-35 kg/m2)

- Presence of clear secondary hypogonadism with hypogonadal symptoms and low total
testosterone level (confirmed with morning testosterone level <= 350 ng/dL for men age
>= 55 and <= 300ng/dl for men age 55-65) or total testosterone <=200 ng/dl (regardless
of symptoms). Additionally luteinizing hormone (LH) should be <15 mIU
(milli-International unit )/mL (at baseline only). Symptoms of hypogonadism include
fatigue, decreased energy level/endurance, depressed mood, decreased libido, erectile
dysfunction.

- Chronic nonmalignant pain etiology includes rheumatoid arthritis, osteoarthritis,
spinal stenosis, polymyalgia, complex region pain syndrome I and II, neurinoma,
phantom limb pain, neuropathic pain of other origin, scoliosis, neck pain, failed back
surgery, or chronic pancreatitis.

- All patients must have ability to complete the study in compliance with the protocol,
and the ability to understand and provide written informed consent.

Exclusion Criteria:

- Chronic pain of malignant etiology (cancer-related)

- Preexisting testosterone deficiency

- Concomitant use of medication that could interfere with testosterone levels including
antidepressant medication, spironolactone, cimetidine, clomiphene (use in the past 1
year), human chorionic gonadotropin (hCG), androgen, estrogen, anabolic steroid,
5-alpha-reductase inhibitors such as finasteride, dehydroepiandrosterone (DHEA),
testosterone therapy (topical testosterone within 7 days of study, injectable
testosterone within 6 months of study),

- Uncontrolled hypertension

- Clinically significant abnormal findings on screening examination based on the
Investigator's assessment

- Known hypersensitivity to clomiphene

- Symptomatic cataracts

- Presence or history of known hyperprolactinemia with or without a tumor

- End-stage renal disease

- Any contraindication to testosterone supplementation therapy

- Absolute contraindications to hormone supplementation therapy which include active
prostate cancer (or suspicion of prostate disease unless ruled out by biopsy),
prostatic specific antigen (PSA)>=3.6, breast cancer, hematocrit>=51% (hemoglobin>=17
g/dL), uncontrolled congestive heart failure (CHF), myocardial infarction, acute
coronary event, unstable angina, coronary revascularization procedure in the preceding
6 months, untreated obstructive sleep apnea, high risk of prostate cancer (ethnicity
or family history), or severe lower urinary tract symptoms (AUA symptom score>19).