Pain Alleviation With Testosterone in Opioid-Induced Hypogonadism (PATH)

Androgen Replacement to Improve Patient-Important Outcomes in Men With Opioid-Induced Hypogonadism

The aim of this trial is to evaluate whether testosterone replacement results in greater improvement in pain perception, pain tolerance, sexual function, fatigue, and quality of life when compared with placebo in men with chronic back pain treated with opioids who have opioid-induced hypogonadism (low testosterone).

Study Overview

• Status: Recruiting
• Conditions: Pain; Opioid Use; Hypogonadism, Male
• Intervention / Treatment: Drug: Testosterone Undecanoate 250 MG/ML; Drug: Placebo

Detailed Description

This single-center, randomized, double-blind, placebo-controlled, parallel-group trial will evaluate pain and quality of life outcomes associated with 6 months of treatment with testosterone or placebo in men aged 18 years or older with chronic non-cancer back pain who are taking opioid analgesics for at least 6 months and have opioid-induced hypogonadism.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Leila Chammas; Phone Number: 617-278-0722; Email: lchammas@bwh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Brigham and Women's Hospital
      • Principal Investigator: Robert R Edwards, PhD
      • Sub-Investigator: Vitaly Napadow, PhD
      • Sub-Investigator: Thomas G Travison, PhD
      • Sub-Investigator: Grace Huang, MD
      • Contact: Leila Chammas; Phone Number: 617-278-0722; Email: lchammas@bwh.harvard.edu
      • Principal Investigator: Shehzad Basaria, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men, age 18 years and older.
• Chronic non-cancer back pain.
• Use of opioid analgesics for at least 6 months.
• Serum total testosterone (measured by mass spectrometry) <348 ng/dL and/or free testosterone <70 pg/mL.
• Ability and willingness to provide informed consent.

Exclusion Criteria:

• History of prostate cancer or breast cancer.
• Known history of organic hypogonadism (e.g., due to hypothalamic, pituitary or testicular disease).
• Use of testosterone within the past 6 months.
• Baseline hematocrit >48%.
• Prostate-specific antigen (PSA) level >4 ng/mL in Caucasians or >3 ng/mL in African-Americans.
• Presence of prostate nodule or induration on digital rectal examination.
• Uncontrolled congestive heart failure.
• Myocardial infarction, acute coronary syndrome, revascularization surgery or stroke within 3 months.
• Serum creatinine >2.5 mg/dL.
• Alanine aminotransferase (ALT) level 3 times above the upper limit of normal.
• Diagnosis of bipolar disorder or schizophrenia.
• Presence of metallic implants (pacemakers, aneurysm clips, etc.) that preclude the patient from undergoing functional magnetic resonance imaging (MRI). In subjects who are otherwise eligible and either do not qualify for MRI or are reluctant to undergo imaging, the investigators may consider enrolling such participants on a case-by-case basis.

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: Testosterone; Intramuscular injections of testosterone undecanoate 750 mg.	Drug: Testosterone Undecanoate 250 MG/ML; Intramuscular administration at a dose of 750 mg at baseline, weeks 4, and week 14.; Other Names: Testosterone
Placebo Comparator: Placebo; Intramuscular injections of placebo.	Drug: Placebo; Intramuscular administration of placebo at baseline, weeks 4, and week 14.; Other Names: Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in scores in the Pain Interference Subscale of the Brief Pain Inventory (BPI) questionnaire	The Pain Interference Subscale of the BPI is specifically relevant to patients with chronic back pain who are using opioids and correlates strongly with the patient's quality of life.	Baseline, 3 months, and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in response to quantitative sensory testing of pain under pressure stimulus	Responses to pressure stimulation (pressure pain threshold) will be evaluated using a digital pressure algometer.	Baseline, 3 months, and 6 months
Changes in response to quantitative sensory testing of pain under deep pressure stimulus	Response to deep pressure pain will be ascertained using cuff pressure algometry.	Baseline, 3 months, and 6 months
Changes in response to quantitative sensory testing of pain under a mechanical stimulus	Responses to mechanical pain will be assessed using repetitive stimuli (temporal summation or "windup") with a set of punctate mechanical probes.	Baseline, 3 months, and 6 months
Changes in response to quantitative sensory testing of pain under heat stimulus	Responses to heat pain will be assessed using a contact thermode that will deliver thermal stimulation to the skin.	Baseline, 3 months, and 6 months
Changes in response to quantitative sensory testing of pain under cold stimulus	Responses to cold pain will be assessed using a cold pressor task, which involves immersion of the dominant hand in a circulating water bath at a temperature of 4°C.	Baseline, 3 months, and 6 months
Changes in default mode network connectivity	Patients with chronic pain show increased default mode network (DMN) connectivity to the anterior/mid-insula, a brain region that integrates multiple dimensions of pain, while reduced DMN connectivity to the insula has been significantly associated with pain reduction. In this trial, we plan to determine the influence of testosterone replacement on DMN connectivity by performing functional magnetic resonance imaging (MRI) before and after testosterone/placebo administration and correlate changes in pain with changes in DMN connectivity.	Baseline and 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in quality of life assessed using the 36-Item Short-Form Survey (SF-36)	The SF-36 measures eight QOL domains: 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. The questionnaire also includes a single item that provides an indication of perceived change in health.	Baseline, 3 months, and 6 months
Changes in depressive symptoms assessed with the Patient Health Questionnaire-9 (PHQ-9)	The PHQ-9 is a validated health questionnaire that will be administered in this trial to evaluate depression among the participants.	Baseline, 3 months, and 6 months
Changes in mood and well-being, assessed using the by Positive and Negative Affect Scale (PANAS) affectivity balance scale	The PANAS affectivity balance scale includes 10 questions evaluating positive and negative affect.	Baseline, 3 months, and 6 months
Changes in energy, assessed with the Hypogonadism Energy Diary (HED)	The HED questionnaire is a self-administered instrument that evaluates energy levels in men with hypogonadism.	Baseline, 3 months, and 6 months
Changes in sexual function, assessed with the Sexual Arousal, Interest, and Drive (SAID) questionnaire	The SAID questionnaire is a five-item self-administered instrument that evaluates the level of thinking about sex, arousal, and rating the level of interest in sex and sex drive in men with hypogonadism.	Baseline, 3 months, and 6 months
Changes in fatigue assessed with the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) questionnaire	The FACIT-F questionnaire is a self-reported instrument that evaluates fatigue and its impact on daily activities and function.	Baseline, 3 months, and 6 months
Changes in catastrophizing assessed with the Pain Catastrophizing Scale (PCS) questionnaire	The PCS is a measure of cognitive and affective responses to pain that consists of 13 items assessing the pain catastrophizing domains of rumination, magnification, and helplessness.	Baseline, 3 months, and 6 months
Changes in Patient's Global Impression of Change (PGIC) scores	The PGIC is a questionnaire that asks how subjects feel their health status has changed at the end of the study compared with baseline.	Baseline and 6 months

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Shehzad Basaria, MD, Brigham and Women's Hospital; Principal Investigator: Robert R Edwards, PhD, Brigham and Women's Hospital

Publications and helpful links

General Publications

• Chou R, Turner JA, Devine EB, Hansen RN, Sullivan SD, Blazina I, Dana T, Bougatsos C, Deyo RA. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015 Feb 17;162(4):276-86. doi: 10.7326/M14-2559.
• Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain. 2002 Oct;3(5):377-84. doi: 10.1054/jpai.2002.126790.
• Von Korff M, Kolodny A, Deyo RA, Chou R. Long-term opioid therapy reconsidered. Ann Intern Med. 2011 Sep 6;155(5):325-8. doi: 10.7326/0003-4819-155-5-201109060-00011.
• Forman LJ, Tingle V, Estilow S, Cater J. The response to analgesia testing is affected by gonadal steroids in the rat. Life Sci. 1989;45(5):447-54. doi: 10.1016/0024-3205(89)90631-0.
• Frye CA, Seliga AM. Testosterone increases analgesia, anxiolysis, and cognitive performance of male rats. Cogn Affect Behav Neurosci. 2001 Dec;1(4):371-81. doi: 10.3758/cabn.1.4.371.
• Kregel J, Meeus M, Malfliet A, Dolphens M, Danneels L, Nijs J, Cagnie B. Structural and functional brain abnormalities in chronic low back pain: A systematic review. Semin Arthritis Rheum. 2015 Oct;45(2):229-37. doi: 10.1016/j.semarthrit.2015.05.002. Epub 2015 May 16.
• Aloisi AM, Ceccarelli I, Fiorenzani P. Gonadectomy affects hormonal and behavioral responses to repetitive nociceptive stimulation in male rats. Ann N Y Acad Sci. 2003 Dec;1007:232-7. doi: 10.1196/annals.1286.022.
• Fillingim RB, Edwards RR, Powell T. The relationship of sex and clinical pain to experimental pain responses. Pain. 1999 Dec;83(3):419-425. doi: 10.1016/S0304-3959(99)00128-1.
• Basaria S. Male hypogonadism. Lancet. 2014 Apr 5;383(9924):1250-63. doi: 10.1016/S0140-6736(13)61126-5. Epub 2013 Oct 10.
• Fillingim RB, Edwards RR. The association of hormone replacement therapy with experimental pain responses in postmenopausal women. Pain. 2001 May;92(1-2):229-34. doi: 10.1016/s0304-3959(01)00256-1.
• Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, Kaur G, Bruera E. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004 Feb 15;100(4):851-8. doi: 10.1002/cncr.20028.
• 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.
• Huang G, Travison TG, Edwards RR, Basaria S. Effects of Testosterone Replacement on Pain Catastrophizing and Sleep Quality in Men with Opioid-Induced Androgen Deficiency. Pain Med. 2017 Jun 1;18(6):1070-1076. doi: 10.1093/pm/pnw159.
• Meints SM, Mawla I, Napadow V, Kong J, Gerber J, Chan ST, Wasan AD, Kaptchuk TJ, McDonnell C, Carriere J, Rosen B, Gollub RL, Edwards RR. The relationship between catastrophizing and altered pain sensitivity in patients with chronic low-back pain. Pain. 2019 Apr;160(4):833-843. doi: 10.1097/j.pain.0000000000001461.
• Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain. 2009 Feb;25(2):170-5. doi: 10.1097/AJP.0b013e3181850df6.
• Edwards RR, Dolman AJ, Michna E, Katz JN, Nedeljkovic SS, Janfaza D, Isaac Z, Martel MO, Jamison RN, Wasan AD. Changes in Pain Sensitivity and Pain Modulation During Oral Opioid Treatment: The Impact of Negative Affect. Pain Med. 2016 Oct;17(10):1882-1891. doi: 10.1093/pm/pnw010. Epub 2016 Mar 1.
• Daniell HW, Lentz R, Mazer NA. Open-label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency. J Pain. 2006 Mar;7(3):200-10. doi: 10.1016/j.jpain.2005.10.009.
• Aloisi AM, Ceccarelli I, Carlucci M, Suman A, Sindaco G, Mameli S, Paci V, Ravaioli L, Passavanti G, Bachiocco V, Pari G. Hormone replacement therapy in morphine-induced hypogonadic male chronic pain patients. Reprod Biol Endocrinol. 2011 Feb 18;9:26. doi: 10.1186/1477-7827-9-26.

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2022
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): April 30, 2025

Study Registration Dates

• First Submitted: March 10, 2021
• First Submitted That Met QC Criteria: March 12, 2021
• First Posted (Actual): March 15, 2021

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: August 2, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Pain; Testosterone; Opioid Analgesics
• Additional Relevant MeSH Terms: Endocrine System Diseases; Gonadal Disorders; Hypogonadism; Eunuchism; Physiological Effects of Drugs; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Androgens; Anabolic Agents; Testosterone; Methyltestosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
• Other Study ID Numbers: 2021P000331

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