Effects of Testosterone Replacement on Pain Sensitivity and Pain Perception

Study Overview
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Brief Summary
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Naturally occurring opiates (endorphins) decrease testosterone levels by inhibiting the synthesis of gonadotropin releasing hormone (GnRH) and also inhibiting testosterone synthesis by the testes. Similarly, men with addiction to narcotics and those on exogenous opioids for pain control have decreased serum testosterone levels. Indeed, these men complain of decreased libido, erectile dysfunction and impaired quality of life. Animal studies have shown that gonadectomy results in a decrease in pain threshold in rats and repletion of testosterone elevates that threshold. These observations suggest that testosterone may possess analgesic properties. Hence, the investigators hypothesize that hypogonadism developing in men on opioids results in an increased sensitivity to pain and requirement of higher doses of opioids. In this study, the investigators plan to administer testosterone to men with opioid-induced hypogonadism and evaluate their pain perception, pain sensitivity in response to noxious stimuli and changes in the requirement of opioids in response to testosterone administration. Hypothesis: Testosterone replacement in men with opioid-induced hypogonadism will improve pain tolerance, pain perception and quality of life. Specific aims: To evaluate the effects of testosterone replacement on pain sensitivity, pain tolerance, and pain modulation in men with opioid-induced hypogonadism. To determine the effects of testosterone replacement on health-related quality of life. To determine whether testosterone replacement in hypogonadal men induces changes in the dosage requirements of opioid medications for pain control. To accomplish our specific aims, the investigators propose a randomized, double blind, placebo-controlled, parallel arm study in which hypogonadal men with non-cancer chronic back pain syndrome on chronic opioids and low testosterone levels (<300 ng/dl) will be randomized to exogenous testosterone replacement therapy vs placebo. Our primary outcome is change in pain tolerance using various external painful stimuli. Secondary outcomes are change in pain sensitivity and modulation, quality of life and opioid requirements.

Official Title
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Effects of Testosterone Replacement on Pain Sensitivity and Pain Perception in Men With Chronic Pain Syndrome

Conditions
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Pain, Hypogonadism

Intervention / Treatment
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* Drug: AndroGel
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men Age 18 years and older Non-cancer chronic pain Serum total testosterone level <350 ng/dl Consumption of at least 20 mg of hydrocodone (or analgesic equivalent of another opioid) for at least 4 weeks Absence of hospitalization in the past 2 months No acute illness in the past 2 months No current anabolic therapy (growth hormone, DHEA, etc) No current use or consumption in the past 2 months of melatonin Normal prostate exam Normal PSA level Exclusion Criteria: Cancer-related chronic pain Liver enzymes > 3 times upper limit of normal Serum creatinine > 2 times upper limit of normal Neurological disease Active psychiatric illness Any addictive drug use Alcoholism (>3 drinks/day) Patients currently receiving melatonin or anabolic agents Hospitalization in the past 2 months Acute illness in the past 2 months Consumption of < 20 mg of hydrocodone (or analgesic equivalent of another opioid) Severe BPH PSA > 4.0 ng/ml Prostate cancer Breast cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Androgel (testosterone gel)<br>Testosterone replacement therapy | Drug: AndroGel<br>* 5g gel, applied once daily to the upper arms, upper back or shoulders.<br>* Other names: testosterone gel;|
| Placebo Comparator: Placebo<br>Placebo gel | Other: Placebo<br>* 5g gel, applied once daily to the upper arms, upper back or shoulders.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brief Pain Inventory (BPI) at Week 14 | BPI is a self-administered questionnaire that measuring chronic pain. BPI gives two main scores: a pain severity score and a pain interference score. The pain severity score assesses the severity of pain on a continuous scale from 0 (no pain) to 10 (severe pain). The pain interference score corresponds to the item on pain interference, ranging from 0 (does not interfere) to 10(completely interferes). The total score is the sum of the pain severity score and pain interference score, ranging from 0(no pain) to 20 (severe and completely interfered pain). | Week14 after intervention | 
| Algometer-induced Pressure Pain at Week 14 | A digital pressure algometer at the trapezius muscle and the metacarpophalangeal joint of the thumb was used to measure pressure pain thresholds. Higher values represent a better tolerance of pressure pain. | Week 14 after intervention | 
| Weighted Pinprick Stimulator-induced Mechanical Pain at Week 14 | Weighted pinprick stimulators are used to assess mechanical pain. Lower values represent better tolerance of pain. | Week 14 after intervention | 
| Ice Water-induced Cold Pain and Its After-sensation at Week 14 | Cold-pressor tests measure cold-induced pain and its sensation. Time was measured when a participant reached pain tolerance in cold water and after sensation. Higher values of time in Cold pain tolerance and lower values of time in Cold pain after-sensation (30 seconds) represent better tolerance of pain. | Week 14 after intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sexual Functioning as Assessed by International Index of Erectile Function (IIEF) at Week 14 | IIEF is a validated, 15-item questionnaire that assesses 5 domains of sexual function: erectile function (range 1-30), orgasmic function (range 0-10), sexual desire (range 2-10), intercourse satisfaction (range 0-15), and overall sexual satisfaction (range 2-10). Each question was answered on a 6-point or 5-point scale from 0/1 to 5 (best) with a total possible score (sum of 5 domains) range of 5 to 75 with higher scores representing better function. | Week14 after intervention | 
| Health Quality of Life (QoL) as Assessed by Short Form 36 (SF-36) at Week 14 | The SF-36 measures 8 domains of the QoL: physical function, bodily pain, vitality, role limitations due to physical problems, general health perceptions, emotional well-being, social function, and role limitations due to emotional problems. Each domain is scored separately from 0 to 100 with higher scores representing better health-related QoL. | Week 14 after intervention | 
| Pain Catastrophizing Scale (PCS) at Week 14 | PCS questionnaire measures self-assessment of pain catastrophizing. This questionnaire consists of 13 items on past painful experiences and rate on 5-point scales ranging from 0 (not at all) to 4 (all the time). The PCS yields three subscale scores assessing rumination (range 0-16), magnification (range 0-12), helplessness (range 0-24), and a composite score (sum of three domains, ranging 0-52). Higher score represents worse painful experiences. | Values at week 14 after intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Testosterone, Pain, Opioid, Hypogonadism