In April of this year, a “Sex/Gender-Specific Medicine” research center was established at a university hospital in South Korea. The medical interest in examining diseases based on sex differences has existed for a long time. Institutions like Stanford University and Mayo Clinic in the United States, as well as Charité Berlin Medical School in Germany, already have dedicated research groups in this area. The International Association for the Study of Pain has chosen “Sex and Gender Disparities in Pain and Pain Care” as this year’s focus, conducting reviews and discussions on the biological, psychological, and sociocultural reasons behind these disparities. Reflecting the growing interest in this area, this paper aims to investigate the specific characteristics of sex-based differences in pain, particularly in the context of chronic pain.

1. Epidemiology

The prevalence of chronic pain is estimated to range from 11% to 40%, with the U.S. Centers for Disease Control and Prevention reporting it at 20.4% [1]. Groups with higher prevalence include women, individuals with low socioeconomic status, those in rural areas, and veterans. Prevalence rates vary by race, with some studies showing the highest rates among non-Hispanic Whites, while others report a higher prevalence among minorities, including African Americans and Indigenous populations [2]. In South Korea, data from a sample of approximately 60,000 people collected between 2006 and 2013 indicated that 28.1% experienced mild chronic pain and 1.7% severe chronic pain. Orofacial pain affects between 17% and 26% of patients, with 7%-11% experiencing chronic symptoms [3]. While often associated with toothaches, chronic orofacial pain (lasting over six months) is distributed across various types, including joint pain (15.5%), face pain (9.3%), toothache (26.8%), oral sores (26.2%), and burning mouth syndrome (14.2%) in South Korea [4]. In the United States, approximately one in three individuals seeks medical care for chronic pain, costing an estimated USD $560-635 billion annually in medical expenses and lost productivity [5]. In South Korea, annual healthcare expenses also differ by sex: men rank self-harm, liver cirrhosis, and ischemic heart disease in their top five conditions, while women rank low back pain and osteoarthritis in the top four, highlighting the existence of sex-based differences [6]. Globally, chronic pain is a leading cause of disability, impairs quality of life, and imposes financial burdens on patients, leading to lost workdays and broader socioeconomic costs. Effective management, particularly in pediatric chronic pain, has been shown to reduce long-term healthcare expenses [7]. Additionally, studies indicate that economic instability and concerns over medical expenses increase the risk of chronic pain, underscoring the importance of addressing these financial stressors in effective pain management [8].

2. Characteristics

Chronic pain is recognized as a pathological condition when it persists beyond the typical healing period, often defined as three months per the International Classification of Diseases, 11th Edition (ICD-11) [9]. Unlike acute pain, which has evolutionary advantages by signaling harm, chronic pain lacks adaptive value and is therefore classified as a disease. It induces neuroplastic changes in the central and peripheral nervous systems, reinforcing its detrimental impact on quality of life. Management strategies focus on symptom control and restoring functionality and emotional well-being rather than complete pain elimination. Various predisposing factors, including physical and emotional stressors, can increase the risk of chronic pain development, while resilience factors like emotional support and good overall health promote recovery and prevent chronicity.

The biopsychosocial model of chronic pain, as illustrated by Meints and Edwards [10], provides a holistic framework for understanding pain as a complex interaction of biological, psychological, and sociocultural factors. Biological contributors, such as genetics, age, and the nervous system’s response to injury, significantly shape pain perception. Psychological factors—including depression, anxiety, and coping mechanisms—affect not only the pain experience but also the level of associated suffering. Sociocultural influences, such as social expectations, job satisfaction, and cultural barriers, further shape individual responses to chronic pain. This model emphasizes the importance of a multifaceted approach to pain management that goes beyond physical symptoms to address psychological and social dimensions as well.

Chronic pain can be categorized into three primary types: nociplastic, neuropathic, and nociceptive [11]. Nociceptive pain, associated with identifiable tissue damage, is further divided into somatic pain (e.g., joint and bone pain) and visceral pain (e.g., organ-related pain). Neuropathic pain results from direct damage to the somatosensory system and can be classified as central (e.g., spinal cord injury, stroke) or peripheral (e.g., diabetic neuropathy). Nociplastic pain, characterized by altered sensory processing in the absence of clear tissue damage, involves central and peripheral sensitization and is commonly observed in conditions like fibromyalgia and irritable bowel syndrome.

Nociplastic pain represents a distinct category recognized in the ICD-11 and challenges conventional pain classifications by emphasizing sensory dysfunction within pain-related pathways [12]. This type of pain may coexist with nociceptive or neuropathic pain, complicating diagnosis and management. Chronic primary pain, as outlined in ICD-11, includes five main categories: chronic widespread pain, complex regional pain syndrome, chronic primary headache and orofacial pain, chronic primary visceral pain, and chronic primary musculoskeletal pain. These diverse conditions underscore the need for biopsychosocial approaches in treatment, aiming to address the interplay of biological, psychological, and social factors and thereby mitigate the profound emotional and functional impacts of chronic pain.

3. Sex Bias in Preclinical and Clinical Studies

Sex bias in preclinical research, especially in pain studies, remains a persistent concern in the scientific community. Between 1996 and 2005, 79% of rodent studies published in Pain used only male rats or mice, reflecting a strong male predominance in animal research across neuroscience, physiology, pharmacology, and endocrinology [13]. Pain was selected as a sample for analysis due to its broad representation of basic and clinical research across diverse fields. Despite growing awareness of sex differences in research outcomes, female animals continue to be underrepresented in preclinical studies. In contrast, immunology research more frequently uses female animals, likely due to recognized immune system differences between sexes.

A commonly cited reason for preferring male animals is the perceived variability in female responses due to hormonal cycles, which some researchers believe complicates data interpretation. However, studies suggest that this variability is often overstated and may not exceed male-specific sources of variability, such as dominance and aggression behaviors within cages. This male-centric focus persists even when data are collected from both sexes, as sex-based analyses are rarely conducted or reported—a pattern that extends to human clinical studies as well.

In response to this longstanding bias, the United States implemented “Sex as a Biological Variable” (SABV) policies in 2016. Around the same period, several European countries, including Austria, France, Germany, Ireland, and the United Kingdom, recognized similar issues and have progressively incorporated sex-based considerations into their policies. These policies emphasize the importance of investigating sex differences to enhance the generalizability and relevance of research findings. By mandating the inclusion of sex-based analyses, SABV policies promote a more balanced approach in both preclinical and clinical research.

Recent analyses reveal gradual but positive changes in the inclusion of sex as a variable in pain research. Between 2015 and 2019, the journal Pain reported an increase in studies that addressed sex differences. However, a significant portion of studies still featured male-only subjects or lacked sex-based analyses. A 2019 PubMed review on pain sensitivity, analgesic sensitivity, and manipulation effects showed substantial disparities: only 22.6% of studies where sex was specified examined female responses, compared to 77.4% focusing on males. Additionally, 72.4% of studies assessing qualitative outcomes centered solely on male subjects, underscoring the ongoing sex bias in pain research.

This continued sex bias limits our understanding of sex-specific responses to pain and analgesics, potentially hindering the development of effective treatments for both sexes. With the implementation of SABV policies, a paradigm shift is expected, advocating a more rigorous and balanced approach to studying sex differences in pain research. Moving forward, incorporating sex-based analyses in study designs is essential for developing comprehensive, effective, and personalized treatments for chronic pain conditions across sexes.

Chronic pain exhibits distinct sex-based differences influenced by biological, genetic, neurological, neuroimmune, and brain-related factors. These differences contribute to the variability in pain perception and response to treatments between males and females. Understanding these factors can lead to more tailored and effective approaches in pain management.

1. Hormonal Influence on Pain Perception

Sex steroid hormones, including estrogens, progesterone, and testosterone, play a significant role in modulating pain sensitivity. Estrogen can have both pain-suppressing and pain-amplifying effects, mediated by the hormonal fluctuations within the menstrual cycle. Elevated estrogen levels have been associated with reduced musculoskeletal pain [14] and a protective effect against chronic post-traumatic pain in women. Conversely, progesterone is generally associated with pain amplification, though high levels during pregnancy may reduce pain sensitivity. Testosterone is linked to pain reduction in both sexes, particularly through descending inhibitory pathways, and testosterone treatment has shown promise in reducing chronic pain in men [15].

Prolactin, traditionally known for its role in lactation, also contributes to nociceptor sensitization in a female-selective manner [16]. Specific isoforms of prolactin receptors are implicated in protecting against pain under normal conditions, but dysregulation can lead to pathological pain, especially in females [17]. Targeting prolactin and its receptors presents a promising avenue for novel pain treatments tailored to women.

2. Genetic Mediation of Pain

Genetic differences between sexes contribute to pain modulation and perception. Studies have identified sex-specific associations with certain genes involved in pain pathways.

Genome-wide association studies have identified loci on chromosomes 1 and 8 associated with painful diabetic neuropathy in women and men, respectively [18]. Furthermore, single-nucleotide polymorphisms linked to temporomandibular disorder also show female-specific associations [19]. Table 1 [20-31] provides a comprehensive summary of genes associated with sex differences in pain sensitivity, detailing their functions and sex-specific effects. For instance, variations in the OPRM1 gene, which encodes the μ-opioid receptor, can result in reduced opioid efficacy in females compared to males, underscoring the importance of genetic contributions to individualized pain management.

3. Neuroimmune Contributions to Pain

Sex differences in neuroimmune function, particularly in macrophage-related gene expression, impact chronic pain. Transcriptome analysis of human tibial nerves has revealed that pain-related conditions regulate macrophage-related genes differently in men compared to women, consistent with known neuroimmune sex differences observed in rodents [32]. Additionally, studies of human dorsal root ganglia indicate that macrophage-related genes are primarily regulated in men, further suggesting a role of immune modulation in sex-specific pain responses [33].

Immune cells are critical mediators in pain transmission and chronic pain development, with emerging evidence indicating sex-specific roles. In male rats, spinal microglia and purinergic receptors are primary players in neuropathic and inflammatory pain, while in females, T cells of the adaptive immune system are more influential. Testosterone further modulates these pathways by influencing the balance between microglial and T-cell activation, potentially explaining some of the observed sex differences in pain processing and immune response [34].

4. Neural Mediation of Sex Differences in Pain

Research demonstrates distinct neural pathways and mechanisms underlying sex differences in pain perception and modulation. Calcitonin gene-related peptide (CGRP) plays a significant role in these differences, particularly in migraine pain [35]. When CGRP is applied to the dura mater in rodent models, it causes pain hypersensitivity in females but not in males [36]. This finding aligns with clinical observations where CGRP inhibitors are effective for both sexes in preventing migraines [37]. However, the effectiveness of these inhibitors in acute migraine treatment appears to be less consistent for men compared to women [38].

5. Brain Modular Organization and Chronic Pain

Sex differences also extend to the modular organization of brain networks involved in chronic pain. Resting-state functional MRI studies indicate that individuals with chronic pain exhibit altered connectivity in brain networks associated with sensory and emotional regulation. Both males and females with chronic low back pain show increased connectivity in the sensorimotor (SM), salience, and midcingulate cortex networks. However, men tend to exhibit more cross-network connectivity in the SM module, enhancing sensory and motor integration, whereas women display atypical segregation in networks like the default mode and frontoparietal, suggesting a shift towards cognitive-emotional regulation in pain modulation [39].

The findings and recommendations outlined in this study underscore the necessity of adopting a sex-specific approach to chronic pain management. Biological, hormonal, and psychosocial factors significantly contribute to differences in pain perception and treatment responses between men and women. Integrating these considerations into clinical practice can lead to more personalized and effective management strategies.

1. Pharmacological Management

Opioids and Analgesics: Sex-specific differences in opioid metabolism, dependency risks, and side effect profiles necessitate individualized pharmacological strategies. Women’s faster opioid metabolism and heightened dependency risks demand cautious titration and alternatives to mitigate adverse outcomes such as opioid-induced nausea and dependency [40]. Conversely, the testosterone-suppressing effects of chronic opioid use in men highlight the need for monitoring hormonal profiles and considering testosterone replacement therapy (TRT) [15].

1) Hormonal therapies

Hormonal fluctuations are critical in modulating pain perception. For women, hormone replacement therapy has shown potential in managing pain linked to menopause and menstrual cycles, though evidence remains limited [14]. During pregnancy, elevated progesterone levels have demonstrated pain-relieving properties, suggesting therapeutic possibilities. In men, TRT can effectively reduce pain sensitivity, particularly in those with hypogonadism and chronic pain [15].

2) Neuropathic pain treatments

Medications such as pregabalin and duloxetine, widely used for neuropathic pain, present distinct side effect profiles across sexes. Women’s higher susceptibility to adverse effects like dizziness and nausea underscores the importance of dose adjustments. In men, faster drug clearance rates may allow for higher therapeutic doses, optimizing efficacy [9,41].

2. Non-Pharmacological Management

1) Physical therapy

Sex differences in physical responses to rehabilitation should inform therapy design. Women benefit more from low-impact exercises, such as yoga and Pilates, which improve flexibility and alleviate musculoskeletal pain [42]. Men, on the other hand, achieve better outcomes with strength training and high-intensity exercises that enhance muscular endurance and pain relief [43].

2) Cognitive-behavioral therapy

Adapting cognitive-behavioral therapy approaches to align with sex-specific coping styles enhances therapeutic outcomes. For women, emotionally focused therapies emphasizing social support demonstrate higher efficacy [44]. In men, goal-oriented and problem-solving strategies are better suited to their typical coping mechanisms [45].

3) Mind-body interventions

Mindfulness and meditation can be highly effective for managing chronic pain but require tailoring to individual needs. For women, standalone mind-body interventions show promise, particularly for conditions like fibromyalgia [12]. In men, combining mindfulness with structured physical activities yields enhanced results [42].

4) Lifestyle adjustments

Incorporating hormonal cycles into treatment plans for women allows for the optimization of intervention timing, particularly in exercise and dietary programs. For men, structured lifestyle interventions that account for individual preferences can significantly improve outcomes [40].

Chronic pain management must recognize and integrate sex-specific factors, as evidence increasingly shows that pain perception, response to treatment, and side effects differ significantly between men and women. These differences are driven by a complex interplay of hormonal, genetic, neurobiological, and psychosocial factors. Understanding these distinctions can support the development of personalized therapeutic strategies, incorporating tailored pharmacological and non-pharmacological interventions that address the unique pain mechanisms present in each sex. By accounting for these variations, clinicians can improve treatment efficacy, reduce adverse effects, and ultimately enhance quality of life for individuals with chronic pain. Further research is essential to advance these personalized approaches and ensure equitable, effective pain management across sexes.

No potential conflict of interest relevant to this article was reported.

This is a narrative review; therefore, no datasets were generated or analyzed in this study.

None.