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. Women not only have 20-fold lower serum testosterone concentrations compared to men but also experience a reduction in testosterone levels with age. Taken together, these data suggest that testosterone has anti-nociceptive properties which may explain why women have a higher incidence and severity of chronic pain compared to men. Additionally, patients who are prescribed opioid-analgesics for chronic pain experience further reduction in testosterone levels as opioids potently suppress the gonadal axis. Both pre- and postmenopausal women on chronic opioids demonstrate >50% reduction in testosterone levels compared to women not using opioids. In recent years, the use of sustained-action opioids in the management of chronic non-cancer pain has grown with many women taking multiple opioid analgesics. The development of opioid-induced hypogonadism deprives these women 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. Previous trials of testosterone replacement in men with opioid-induced hypogonadism have shown improvement in both clinical and experimental pain, and improvement in quality of life (QOL). However, despite having significantly higher burden of chronic pain, the efficacy of testosterone replacement on pain perception and tolerance has not been studied in women. The overall goal of this proposal is to evaluate the efficacy of physiologic testosterone replacement in improving clinical and experimental pain in a double-blind, randomized-controlled trial in postmenopausal women with chronic back pain who are being treated with opioid-analgesics for at least 6 months and have low testosterone. We will also assess the efficacy of testosterone replacement on QOL, mood and physical function. We propose a 12-week double-blind, randomized-controlled, proof-of-concept trial to determine the efficacy of physiologic testosterone replacement with weekly intramuscular injections versus placebo injections in women age 60 years and older with chronic back pain and testosterone deficiency. The following outcomes will be measured: 1) clinical pain, 2) experimental pain with quantitative sensory testing, and 3) QOL, mood and physical function. 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 pot...