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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shehzad Basaria, Brigham and Women's Hospital
ClinicalTrials.gov Identifier:
NCT00351819
First received: July 12, 2006
Last updated: May 26, 2017
Last verified: May 2017
  Purpose

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.


Condition Intervention Phase
Pain Hypogonadism Drug: AndroGel Other: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Investigator
Primary Purpose: Treatment
Official Title: Effects of Testosterone Replacement on Pain Sensitivity and Pain Perception in Men With Chronic Pain Syndrome

Resource links provided by NLM:


Further study details as provided by Shehzad Basaria, Brigham and Women's Hospital:

Primary Outcome Measures:
  • Brief Pain Inventory (BPI) at Week 14 [ Time Frame: Week14 after intervention ]
    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).

  • Algometer-induced Pressure Pain at Week 14 [ Time Frame: Week 14 after intervention ]
    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.

  • Weighted Pinprick Stimulator-induced Mechanical Pain at Week 14 [ Time Frame: Week 14 after intervention ]
    Weighted pinprick stimulators are used to assess mechanical pain. Lower values represent better tolerance of pain.

  • Ice Water-induced Cold Pain and Its After-sensation at Week 14 [ Time Frame: Week 14 after intervention ]
    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.


Secondary Outcome Measures:
  • Sexual Functioning as Assessed by International Index of Erectile Function (IIEF) at Week 14 [ Time Frame: Week14 after intervention ]
    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.

  • Health Quality of Life (QoL) as Assessed by Short Form 36 (SF-36) at Week 14 [ Time Frame: Week 14 after intervention ]
    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.

  • Pain Catastrophizing Scale (PCS) at Week 14 [ Time Frame: Values at week 14 after intervention ]
    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.


Other Outcome Measures:
  • Total Testosterone Values at Week 14 [ Time Frame: Week 14 after intervention ]
    Total testosterone was measured in a CDC-certified laboratory using an LC-MS/MS method with a sensitivity of 2 ng/dL.

  • Free Testosterone Values at Week 14 [ Time Frame: Week 14 after intervention ]
    Free testosterone was calculated using a law of mass action equation.

  • Sex Hormone Binding Globulin (SHBG) at Week 14 [ Time Frame: Week 14 after intervention ]
    Sex hormone binding globulin was measured using immunofluorometric assays, with limits of quantification of 2.5 nmol/L.

  • Luteinizing Hormone Values at Week 14 [ Time Frame: Week 14 after intervention ]
    Luteinizing hormone was measured using immunofluorometric assays, with limits of quantification of 0.05 U/L.

  • Inflammatory Cytokines at Week 14 [ Time Frame: Week 14 after intervention ]
    The pathophysiology of pain is measured by the proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-Alpha).

  • Body Composition at Week 14 [ Time Frame: Week 14 after intervention ]
    Body composition was measured using dual-energy X-ray absorptiometry scan.

  • Lipid Profile at Week 14 [ Time Frame: Week 14 after intervention ]
    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.

  • HbA1c at Week 14 [ Time Frame: Week 14 after intervention ]
  • Glucose Level in Oral Glucose Tolerance Test (OGTT) at Week 14 [ Time Frame: Week 14 after intervention ]
    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.

  • Insulin Level in Oral Glucose Tolerance Test (OGTT) at Week 14 [ Time Frame: Values at week 14 after intervention ]
    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.

  • HOMA IR Score at Week 14 [ Time Frame: Week 14 after intervention ]
    Insulin resistance was calculated using the homeostatic model assessment (HOMA) index: glucose * insulin / 22.5.

  • Adiponectin at Week 14 [ Time Frame: Week 14 after intervention ]
    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).

  • Leptin at Week 14 [ Time Frame: Week 14 after intervention ]
    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).

  • C-reactive Protein (CRP) at Week 14 [ Time Frame: Week 14 after intervention ]
    High-sensitivity C-reactive protein (Alpco Diagnostics) was measured using a high-sensitivity sandwich ELISA with an intra-assay CV of 5.6%

  • Insomnia Severity Index (ISI) at Week 14 [ Time Frame: Week 14 after intervention ]
    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.


Enrollment: 84
Study Start Date: April 2006
Study Completion Date: November 2012
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Androgel (testosterone gel)
Testosterone replacement therapy
Drug: AndroGel
5g gel, applied once daily to the upper arms, upper back or shoulders.
Other Name: testosterone gel
Placebo Comparator: Placebo
Placebo gel
Other: Placebo
5g gel, applied once daily to the upper arms, upper back or shoulders.

  Eligibility

Ages Eligible for Study:   18 Years to 100 Years   (Adult, Senior)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00351819

Locations
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
Boston University
Investigators
Principal Investigator: Shehzad Basaria, MD Brigham and Women's Hospital
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Shehzad Basaria, ASSOCIATE PROFESSOR, Brigham and Women's Hospital
ClinicalTrials.gov Identifier: NCT00351819     History of Changes
Other Study ID Numbers: H-27995
Study First Received: July 12, 2006
Results First Received: March 24, 2017
Last Updated: May 26, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Shehzad Basaria, Brigham and Women's Hospital:
Testosterone
Pain
Opioid
Hypogonadism

Additional relevant MeSH terms:
Hypogonadism
Gonadal Disorders
Endocrine System Diseases
Testosterone
Testosterone enanthate
Testosterone undecanoate
Testosterone 17 beta-cypionate
Methyltestosterone
Androgens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Anabolic Agents

ClinicalTrials.gov processed this record on July 19, 2017