Please select the eligibility criteria that correspond to the clinical trial below.
Title: Effects of Testosterone Replacement on Pain Sensitivity and Pain Perception in Men With Chronic Pain Syndrome
Brief Summary: 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.


Options:
A: Inclusion Criteria:

* Subjects were at least 50 years of age
* A body mass index (BMI) between 18 and 34 kg/m\^2
* Symptoms of androgen deficiency (as indicated by a positive Androgen Deficiency in Aging Males (ADAM) questionnaire)
* Calculated free testosterone measurement of \<0.26 nmol/L in the morning

Exclusion Criteria:

* History or current diagnosis of breast or prostate cancer
* any clinically significant abnormal finding on physical examination including the prostate
* Clinical symptoms of obstructive benign prostate hyperplasia (International Prostate Symptom Score (IPSS) \>14)
* Prostate specific antigen (PSA) level \> 4 ng/mL at screening
* Cause of androgen deficiency other than aging, e.g. 'classical' diagnosis of primary or secondary hypogonadism
* Hyperprolactinaemia or treatment with prolactin-lowering drugs
* History of known chronic polycythemia and/or hematocrit \>50% at screening
* History or presence of severe sleep apnea
* Unstable or untreated endocrine disorders
* History or presence of clinically significant depression or other psychiatric disorder or any clinically relevant cardiovascular, cerebrovascular, endocrine, hepatic, renal or hematological disease, thromboembolism/thrombosis etc. which, in the opinion of the investigator, might compromise the subject's participation in the trial
* Use of medication that would interfere with the efficacy and safety objectives of the trial
B: Inclusion Criteria:

* Male gender age 50-70
* Bioavailable testosterone \< 7,3 nmol/L
* Metformin treatment of T2DM for 3 months or more

Exclusion Criteria:

* HbA1c \> 9,0 %, BMI \> 40 kg/m2, Haematocrit \> 50%,
* Known malignant disease, PSA \> 3 ug/L, Nycturia \> 3 times,
* Abnormal routine blood samples,
* Severe hypertension,
* Significant EKG-changes,
* Wish of parenthood,
* Active mental illness,
* former or present abuse,
* Severe illness of heart-, lung- or kidney,
* Primary or secondary hypogonadism.
C: 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
D: Inclusion Criteria:

Subjects will be

* older (65-85 yr)
* obese (BMI 30 kg/m2 or greater) Veteran men with low testosterone (less than 300 mg/dL) as defined by the Endocrine Society
* mild to moderately frail
* must have stable weight (\~not less than or more than 2 kg) during the last 6 months
* sedentary (regular exercise less than 1 h/week or less than 2x/week for the last 6 months)

Exclusion Criteria:

* Any major chronic diseases, or any condition that would interfere with exercise or dietary restriction, in which exercise or dietary restriction are contraindicated, or that would interfere with interpretation of results.
* Examples include, but are not limited to:

  * cardiopulmonary disease (e.g. recent myocardial infarction (MI), unstable angina, stroke etc) or unstable disease (e.g. CHF)
  * severe orthopedic/musculoskeletal or neuromuscular impairments
  * visual or hearing impairments
  * cognitive impairment (Mini Mental State Exam Score less than 24)
  * current use of bone active drugs
  * uncontrolled diabetes (i.e. fasting blood glucose more than 140 mg/dl and/or HbA1c greater than 9.5%).
* Any contraindications to testosterone supplementation

  * history of prostate or breast cancer
  * history of testicular disease
  * untreated sleep apnea
  * hematocrit more than 50%
  * prostate-related findings of palpable nodule on exam, a serum PSA of 4.0 ng/ml or greater
  * International Prostate Symptom Sore more than 19
  * history of venous thromboembolism
* Osteoporosis or a BMD T-score of -2.5 in the lumbar spine or total hip as well as those patients with a history of osteoporosis-related fracture (spine, hip, or wrist)

Answer: C