Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
The purpose of this randomized controlled clinical trial is to evaluate the effects of
 clomiphene citrate compared to placebo (substance without active medication) in men who are
 taking pain medication (opioids) for chronic pain conditions and who have low blood
 testosterone levels.

 The condition of men having low testosterone with long-term pain medication (opioid) usage is
 called opioid-induced androgen deficiency (OPIAD). Low testosterone can be caused by pain
 medication effects on part of the brain (hypothalamic-pituitary axis) which ultimately result
 in decreased testosterone production by the testes. Typical symptoms of low testosterone
 (hypogonadism) may include decreased muscle mass, increased fat, osteoporosis, anemia,
 erectile dysfunction, delayed ejaculation. In addition, men with low testosterone may
 experience decreased attention, and decreased libido, fatigue, and depressed mood. Few
 studies have looked at hormonal changes caused by long-term opioid usage in men.

 Clomiphene citrate, a selective estrogen receptor modulator (SERM) oral medication which
 inhibits estrogen effects (feedback) on the brain, has been identified by prior studies to
 raise testosterone in men with low testosterone (due to reasons other than chronic pain
 medication). Clomiphene citrate is also known to lead to increased sperm production in men
 with low testosterone unlike testosterone topical or injection medications. Although
 clomiphene citrate has been studied in hypogonadal men with beneficial outcomes and minimal
 side effects, no group has previously studied clomiphene citrate as treatment in patients
 with OPIAD.
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).