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

Clomiphene Citrate for the Treatment of Opioid-Induced Androgen Deficiency: Randomized Controlled Clinical Trial

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.

Study Overview

• Status: Completed
• Conditions: Hypogonadism; Opioid-Related Disorders; Male Infertility
• Intervention / Treatment: Drug: Clomiphene citrate; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical College, Department of Urology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clomiphene citrate; The initial dose of clomiphene citrate will be 25 mg (po, pill by mouth) every other day. This will be started at visit 2, week 0 of the study following diagnosis of low baseline testosterone (serum total testosterone <350 ng/dl in men <55 years, <300 ng/dl in men 55-65 years). Clomiphene citrate dose will be titrated up to a maximum of 50 mg daily according to serum total testosterone levels measured at follow-up visits during the 3 month duration of the study.	Drug: Clomiphene citrate; Other Names: Clomid; Serophene; Milophene
Placebo Comparator: Placebo; Placebo pill will be administered (po, pill by mouth) every other day starting at week 0 of the study in men diagnosed with low testosterone. Treatment will be delayed in these men until the 3 month completion of the study, at which time this group may also receive testosterone replacement therapy.	Drug: Placebo; Placebo pill that will have appearance identical to the treatment pill but will not contain active medication.; Other Names: Sugar pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Total Testosterone (Change From Baseline)	Morning venipuncture of serum total testosterone.	3 months post initial visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other Hormonal Profile (Change From Baseline)	Luteinizing hormone (LH)	3 months post initial visit
Androgen Deficiency in the Aging Male (ADAM) Questionnaire	Overall, study subjects will be assessed for possible change in hypogonadal, sexual function, and pain symptoms. Minimum score is 0 and maximum score is 10. 0 is most symptomatic, and 10 is least symptomatic.	3 months post initial visit
Hematocrit (%)	Measure hematocrit from baseline.	3 months post initial visit
Estradiol		3 months post initial visit
Sexual Health Inventory for Men (SHIM) Questionnaire	Overall, study subjects will be assessed for possible change in hypogonadal, sexual function, and pain symptoms. Minimum score is 1, maximum score is 25. The minimum value is most symptomatic and maximum value is least symptomatic.	3 months post initial visit
Men's Sexual Health Questionnaire (MSHQ) Questionnaire	Overall, study subjects will be assessed for possible change in hypogonadal, sexual function, and pain symptoms. Minimum score is 1, maximum score is 20. Minimum score is considered most symptomatic, maximum score is considered least symptomatic.	3 months post initial visit

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Investigators: Principal Investigator: Peter N Schlegel, MD, Weill Medical College of Cornell University

Publications and helpful links

Helpful Links

• Weill Cornell Medical College, Department of Urology

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): November 1, 2017

Study Registration Dates

• First Submitted: June 7, 2013
• First Submitted That Met QC Criteria: June 13, 2013
• First Posted (Estimate): June 18, 2013

Study Record Updates

• Last Update Posted (Actual): July 17, 2018
• Last Update Submitted That Met QC Criteria: June 18, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Chronic pain; Narcotics; Hypogonadism; Clomiphene citrate; Male infertility; Opioid analgesics; Low testosterone; Opioid-induced androgen deficiency; OPIAD; Selective Estrogen Receptor Modulators; Testosterone replacement therapy
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Endocrine System Diseases; Gonadal Disorders; Narcotic-Related Disorders; Infertility; Hypogonadism; Opioid-Related Disorders; Infertility, Male; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Estrogen Antagonists; Reproductive Control Agents; Fertility Agents, Female; Fertility Agents; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Clomiphene; Enclomiphene; Zuclomiphene
• Other Study ID Numbers: Cornell-1301013472

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No