The emergence of sex differences in primary pain during adolescence: a conceptual developmentally-oriented biopsychosocial model and opportunities for further investigation

Adolescence begins with puberty and is characterized by striking hormonal, physical, psychosocial and neurobiological changes. In childhood, male and female youth have a similar prevalence of chronic pain conditions and similar pain processing. However, this changes dramatically during puberty when females become more pain sensitive and develop significantly more chronic pain compared to males. This pattern persists throughout the lifespan, with female adults twice as likely to report chronic widespread pain as males. The type of pain that seems to increase in prevalence during adolescence (especially in females) is now termed primary pain, meaning that the pain is the primary problem (not secondary to tissue damage or inflammation), and is likely due to nociplastic pain mechanisms. This review takes a developmentally-oriented biopsychosocial perspective on the emergence of sex and gender differences in primary pain by highlighting adolescence as a pivotal period marked by pubertal maturation. Drawing from larger literatures on pediatric pain, neuroimaging, and adolescent development, we identify key biological, behavioral, cognitive-affective, and sociocultural factors that may influence the emergence of sex or gender differences in pain, focusing on primary pain. We then make recommendations for future studies, highlighting the unique insights that can be garnered by considering sex and gender differences and puberty in pain research to inform precision treatments at the most critical developmental periods.