Effects of Testosterone Replacement on Pain Sensitivity and Pain Perception (TAP)

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

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:

1. To evaluate the effects of testosterone replacement on pain sensitivity, pain tolerance, and pain modulation in men with opioid-induced hypogonadism.
2. To determine the effects of testosterone replacement on health-related quality of life.
3. 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.

Study Overview

• Status: Completed
• Conditions: Pain; Hypogonadism
• Intervention / Treatment: Drug: AndroGel; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Testosterone Values at Week 14	Total testosterone was measured in a CDC-certified laboratory using an LC-MS/MS method with a sensitivity of 2 ng/dL.	Week 14 after intervention
Free Testosterone Values at Week 14	Free testosterone was calculated using a law of mass action equation.	Week 14 after intervention
Sex Hormone Binding Globulin (SHBG) at Week 14	Sex hormone binding globulin was measured using immunofluorometric assays, with limits of quantification of 2.5 nmol/L.	Week 14 after intervention
Luteinizing Hormone Values at Week 14	Luteinizing hormone was measured using immunofluorometric assays, with limits of quantification of 0.05 U/L.	Week 14 after intervention
Inflammatory Cytokines at Week 14	The pathophysiology of pain is measured by the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-Alpha).	Week 14 after intervention
Body Composition at Week 14	Body composition was measured using dual-energy X-ray absorptiometry scan.	Week 14 after intervention
Lipid Profile at Week 14	Serum total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol levels were measured by enzymatic assays and standardized to the CDC using the Lipid Research Clinic protocol. Low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald equation.	Week 14 after intervention
HbA1c at Week 14		Week 14 after intervention
Glucose Level in Oral Glucose Tolerance Test (OGTT) at Week 14	All participants underwent 75-g oral glucose tolerance test (OGTT) after a 12-h fast, The plasma glucose level were analyzed at baseline and at 60 and 120 min after glucose loading.	Week 14 after intervention
Insulin Level in Oral Glucose Tolerance Test (OGTT) at Week 14	All participants underwent 75-g oral glucose tolerance test (OGTT) after a 12-h fast, The insulin level were analyzed at baseline and at 60 and 120 min after glucose loading.	Values at week 14 after intervention
HOMA IR Score at Week 14	Insulin resistance was calculated using the homeostatic model assessment (HOMA) index: glucose * insulin / 22.5.	Week 14 after intervention
Adiponectin at Week 14	Total adiponectin was measured using an RIA kit with an interassay CV of 6.9-9.3% and an intra-assay CV of 1.8-6.2% (Millipore).	Week 14 after intervention
Leptin at Week 14	Leptin levels were measured using ELISA with an interassay CV of 2.6% to 6.2% and in intra-assay CV of 2.6% to 4.6% (Millipore, Billerica, MA, USA).	Week 14 after intervention
C-reactive Protein (CRP) at Week 14	High-sensitivity C-reactive protein (Alpco Diagnostics) was measured using a high-sensitivity sandwich ELISA with an intra-assay CV of 5.6%	Week 14 after intervention
Insomnia Severity Index (ISI) at Week 14	ISI is comprised of 7 items assesses a participant's perception of insomnia. Each item is rated on a 5-point scale from 0 (none) to 4 (very severe). Scores from the questions are summed to assign a total score ranging from 0 to 28, where higher score represents worse insomnia problem.	Week 14 after intervention

Collaborators and Investigators

• Sponsor: Boston University

Publications and helpful links

General Publications

• Bhasin S, Travison TG, O'Brien L, MacKrell J, Krishnan V, Ouyang H, Pencina K, Basaria S. Contributors to the substantial variation in on-treatment testosterone levels in men receiving transdermal testosterone gels in randomized trials. Andrology. 2018 Jan;6(1):151-157. doi: 10.1111/andr.12428. Epub 2017 Oct 5.
• Gagliano-Juca T, Icli TB, Pencina KM, Li Z, Tapper J, Huang G, Travison TG, Tsitouras P, Harman SM, Storer TW, Bhasin S, Basaria S. Effects of Testosterone Replacement on Electrocardiographic Parameters in Men: Findings From Two Randomized Trials. J Clin Endocrinol Metab. 2017 May 1;102(5):1478-1485. doi: 10.1210/jc.2016-3669.
• Basaria S, Travison TG, Alford D, Knapp PE, Teeter K, Cahalan C, Eder R, Lakshman K, Bachman E, Mensing G, Martel MO, Le D, Stroh H, Bhasin S, Wasan AD, Edwards RR. Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial. Pain. 2015 Feb;156(2):280-288. doi: 10.1097/01.j.pain.0000460308.86819.aa.

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): November 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: July 12, 2006
• First Submitted That Met QC Criteria: July 12, 2006
• First Posted (Estimate): July 13, 2006

Study Record Updates

• Last Update Posted (Actual): June 28, 2017
• Last Update Submitted That Met QC Criteria: May 26, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Pain; Opioid; Hypogonadism; Testosterone
• Additional Relevant MeSH Terms: Endocrine System Diseases; Gonadal Disorders; Hypogonadism; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Androgens; Testosterone
• Other Study ID Numbers: H-27995

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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