4.1. Implications for Opioid Analgesia
Converging evidence from preclinical, clinical, and epidemiological studies strongly indicate that women are more sensitive to pain and are more likely to suffer from pain disorders (Section 2.2.1). Some additional evidence also indicates that men are more sensitive to opioid analgesics and typically need lower doses (at least as a function of body weight) to obtain comparable levels of analgesia. A sizeable but underappreciated body of evidence suggests that these sex differences are due, in part, to greater androgenic activity in males. Indeed, preclinical and clinical data suggest that sex differences can be minimized by androgenic blockade in males or androgenic stimulation in females.
One obvious implication of androgen-induced enhancement opioid analgesia is that the effectiveness of opioid analgesics could be increased by direct or indirect activation of androgen receptors. Although clinically intriguing, this practice would have clinically limiting drawbacks for both men and women. In women, for instance, androgens produce masculinizing and anti-feminizing effects, whereas in men, exogenous androgens suppress endogenous androgenic activity, leading to problems with fertility and hypogonadism (Christou et al., 2017; de Souza & Hallak, 2011; Vorona & Nieschlag, 2018). Regardless, low levels of endogenous androgenic activity may be an unrecognized contributor to both chronic pain disorders and diminished sensitivity to opioid analgesics. Hypogonadism can quickly be diagnosed by simple blood tests measuring free and total testosterone. Testosterone levels could guide initial dose determinations and subsequent dose adjustments. Moreover, in cases where hypogonadism is detected, opioid treatment could be augmented by androgen treatment to simultaneously decrease pain sensitivity and enhance opioid analgesia.