Impact of sex on pain and opioid analgesia: a review

Abstract

Chronic pain is a debilitating condition that impacts tens of millions each year, resulting in lost wages for workers and exacting considerable costs in health care and rehabilitation. A thorough understanding of the neural mechanisms underlying pain and analgesia is critical to facilitate the development of therapeutic strategies and personalized medicine. Clinical and epidemiological studies report that women experience greater levels of pain than men and have higher rates of pain-related disorders. Studies in both rodents and humans report sex differences in the anatomical and physiologic properties of the descending antinociceptive circuit, mu opioid receptor (MOR) expression and binding, morphine metabolism, and immune system activation, all of which likely contribute to the observed sex differences in pain and opioid analgesia. Although more research is needed to elucidate the underlying mechanisms, these sex differences present potential therapeutic targets to optimize pain management strategies for both sexes.

Figure 1.

Noxious stimuli activate nociceptors located on primary afferents, which then relay nocispecific information to the dorsal horn of the spinal cord via the dorsal root ganglia (DRG). From here, nociceptive-specific information is relayed supraspinally to the PAG, thalamus and higher cortical regions. Both endogenous and exogenous opioids activate the PAG and its descending projections to the RVM and spinal cord to ultimately inhibit incoming pain signals (adapted from Guo et al., 2006).

Figure 2.

TLR4 binding leads to the transcription and release of pro-inflammatory products.

Figure 3.

Morphine is metabolized via glucuronidation to produce M3G and M6G which bind to TLR4 and MOR, respectively (adapted from Doyle and Murphy 2018).

Figure 4.

Summary of sex differences in pain and opioid analgesia.