5. Future Directions
The role of androgens on opioid-mediated behavior is an area that is ripe for further research. There is ample evidence that androgens modulate central concentrations of both endogenous opioid peptides and opioid receptors, and that androgens contribute to reported sex differences in these proteins (Sections 2.4 and 3.4). It is unclear whether the effects of androgens are predominately developmental or activational in nature, whether the effects of androgens differ across age or developmental stage, and the degree to which the central effects of androgens are region specific. All the available data strongly suggest that the effects of androgens are age and region specific, but there are not enough data to create a working model to explain the limited number of empirical observations. The contribution of androgens to sex differences in opioid peptides and receptors is further complicated by the complex role of ovarian hormones on these same proteins in females. Future studies that explicitly explore sex differences must include the estrous cycle as a biological variable.
There is a sizable body of literature suggesting that androgens decrease pain sensitivity and increase opioid analgesia (Section 3.2). Clinical evaluation of testosterone levels, pain tolerance, and optimal dosing parameters are needed to maximize pain management in men with undiagnosed or borderline hypogonadism. In these populations, there are now sufficient data to begin clinical trials with androgen-augmented pain therapies. Such trials need not be limited to androgenic augmentation of opioid analgesics; indeed, androgenic augmentation of nonopioid analgesics may negate the need for opioid analgesia. Even if opioids are necessary, the available data suggest that the dose of opioid could be reduced, thus minimizing problematic side effects such as tolerance and abuse liability.
There is a dearth of information regarding the effects of androgens on opioid reward and reinforcement, particularly in the clinical and human laboratory literature. The available preclinical data are equivocal, and at this time it is difficult to draw conclusions regarding the effects of androgens on the risk for developing a substance use disorder. Although the epidemiological data indicate a clear link between AAS and opioid abuse, evidence of a causal relationship is absent. Preclinical research is perfectly positioned to start systematically examining the role of androgens in opioid reinforcement, including both physiological and supraphysiological concentrations characteristic of AAS abuse. Preclinical studies will need to be conducted in both males and females to determine the contribution of androgens to sex differences in opioids reward and reinforcement, taking into consideration the potential influence of ovarian hormones and the estrous cycle. These types of studies will ultimately be needed to determine whether androgenic activity serves as a risk factor (or protective influence) in the likelihood of developing an opioid use disorder.