Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
Condition: Hypogonadism; Opioid-Related Disorders; Male Infertility
MeSH terms: Infertility; Infertility, Male; Hypogonadism; Opioid-Related Disorders
Intervention: Clomiphene citrate; Placebo
Intervention description: Placebo pill that will have appearance identical to the treatment pill but will not contain active medication.
Intervention MeSH terms: Clomiphene; Enclomiphene; Zuclomiphene
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 13.0
Sex: Male
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Chronic pain; Low testosterone; Hypogonadism; Opioid analgesics; Narcotics; Opioid-induced androgen deficiency; OPIAD; Male infertility; Clomiphene citrate; Selective Estrogen Receptor Modulators; Testosterone replacement therapy

Summary:

      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.
    

Eligibility criteria:

        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).