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.