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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01880086

Enrollment

Registered

2013-06-18

Start date

2013-08-31

Completion date

2017-11-30

Last updated

2018-07-17

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypogonadism, Male Infertility, Opioid-Related Disorders

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

Brief 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.

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.

Interventions

DRUGClomiphene citrate

DRUGPlacebo

Placebo pill that will have appearance identical to the treatment pill but will not contain active medication.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

MALE

Age

18 Years to 65 Years

Healthy volunteers

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).

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Androgen Deficiency in the Aging Male (ADAM) Questionnaire	3 months post initial visit	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.
Hematocrit (%)	3 months post initial visit	Measure hematocrit from baseline.
Other Hormonal Profile (Change From Baseline)	3 months post initial visit	Luteinizing hormone (LH)
Sexual Health Inventory for Men (SHIM) Questionnaire	3 months post initial visit	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.
Men's Sexual Health Questionnaire (MSHQ) Questionnaire	3 months post initial visit	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.
Estradiol	3 months post initial visit	—

Countries

United States

Participant flow

Participants by arm

Arm	Count
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. Clomiphene citrate	5
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. Placebo: Placebo pill that will have appearance identical to the treatment pill but will not contain active medication.	6
Total	11

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	1

Baseline characteristics

Characteristic	Clomiphene Citrate	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	5 Participants	6 Participants	11 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	2 Participants	1 Participants	3 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	2 Participants	5 Participants	7 Participants
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants
Sex: Female, Male Male	5 Participants	6 Participants	11 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 5	0 / 6
other Total, other adverse events	0 / 5	0 / 6
serious Total, serious adverse events	0 / 5	0 / 6