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

PROJECT SUMMARY
There is abundant evidence that women and men do not experience pain equally. Compared to men, women
are overrepresented in the majority of clinical pain conditions and also exhibit greater sensitivity to
experimental pain. Similarly, use of analgesics is twice as common in women, compared to men, for conditions
of comparable severities. These data suggest that testosterone has anti-nociceptive properties. However; this
analgesic cushion provided by testosterone is lost when men are prescribed opioid-analgesics as opioids
potently suppress testosterone production. Indeed, ~70-100% of men on chronic opioids are hypogonadal. In
recent years, the use of sustained-action opioids in the management of chronic non-cancer pain has grown
with many men taking multiple opioid analgesics. The development of opioid-induced hypogonadism deprives
these men of the anti-nociceptive properties of testosterone and leads to a vicious cycle resulting in
perpetuation of chronic pain despite being on opioids, subjecting patients to long-term requirement of even
higher doses of opiates. Preliminary trials of testosterone replacement in men with opioid-induced
hypogonadism have shown improvement in both clinical and experimental pain, and also improvement in
certain aspects of QOL. However, the efficacy of testosterone replacement on pain perception has not been
studied in adequately-powered trials. The overall goal of this proposal is to evaluate the efficacy of
physiologic testosterone replacement therapy in improving clinical and experimental pain in a double-blind,
randomized, placebo-controlled trial in men with chronic back pain who are being treated with opioid-
analgesics for at least 6 months and have opioid-induced hypogonadism. We also plan to perform fMRI during
quantitative sensory testing to characterize the central mechanisms underpinning the changes in pain
processing that occur over the course of testosterone replacement in these hypogonadal men. We will also
assess the efficacy of testosterone replacement on QOL, mood and depression. We propose a large, double-
blind, randomized, placebo-controlled, 6-month trial in which we will compare the efficacy of physiologic
testosterone replacement with weekly intramuscular injections (the most reliable form of testosterone
replacement) versus placebo injections in men age 18 and older with chronic back pain and opioid-induced
hypogonadism. The following outcomes will be measured: 1) clinical pain, 2) quantitative sensory testing along
with fMRI, and 3) QOL, mood and depression. Because chronic pain is a major public health problem for which
existing therapies are suboptimal and only provide partial relief, if this trial confirms benefits of testosterone
therapy, patients will have an inexpensive, relatively safe and easy to administer medication available that has
the potential to transform the care of these patients.

Grant Number: 5R01AG066921-04
NIH Institute/Center: NIH
Principal Investigator: Shehzad Basaria