Sex differences in the transition to chronic pain
Angela F. Smith, … , Giovanni Berardi, Kathleen A. Sluka
Angela F. Smith, … , Giovanni Berardi, Kathleen A. Sluka
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e191931. https://doi.org/10.1172/JCI191931.
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Sex differences in the transition to chronic pain

Abstract

Chronic pain affects more than 50 million Americans, with women disproportionately affected by severe pain, pain interference, and overall disability. The development of chronic pain is multifactorial and often begins with an incident of acute pain associated with an injury or a surgical procedure that transitions to persistent pain lasting for months or years. Despite this, there are limited clinical studies investigating sex differences in predictors and biomarkers for the transition to chronic pain. Several preclinical animal models have been developed to gain a better understanding of the mechanisms for the transition to chronic pain, and several sex-specific mechanisms have been identified across multiple systems. These preclinical models generally involve a multiple-insult approach, in which a priming insult enhances sensitivity to a subsequent induction stimulus. There is emerging evidence from preclinical research for several male-specific and female-specific mechanisms, as well as several studies showing shared mechanisms. Here, we review the clinical and preclinical literature covering sex differences in the periphery and immune system, the central nervous system, and the endocrine system related to the transition to chronic pain. We further highlight gaps in the literature and provide recommendations for future research to understand sex-specific differences in the transition to chronic pain.

Authors

Angela F. Smith, Ashley N. Plumb, Giovanni Berardi, Kathleen A. Sluka

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Figure 3

Summary of identified mechanisms involved in promoting and protecting from the transition to chronic pain.

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Summary of identified mechanisms involved in promoting and protecting fr...
Mechanisms identified in animals in the transition to chronic pain from the peripheral and central nervous systems, immune system, and endocrine system. Animal studies have provided evidence of a variety of underlying mechanisms involved in the transition to chronic pain (transition factors) or prevention of chronic pain (resilience factors). Importantly, a number of studies have examined both males and females and identified some sex-specific pathways across all systems. Those with known sex-specific mechanisms are labeled with an “(m)” to show this only occurs in males or an “(f)” to show this mechanism occurs in females. <m and <f indicate that the associated factor contributes to a greater degree in males or females, respectively. It should be noted however, that there are a number of mechanisms that are found in both sexes, and that the sex-specific differences noted may be dependent on the animal model or species used. An overview of the animal literature including mechanism and model details can be seen in Supplemental Table 2. Mechanisms involved in the transition to chronic pain involve peripheral, central, immune and endocrine factors.