In the evolving landscape of biomedical research, a crucial yet often overlooked dimension is the consistent and rigorous inclusion of sex and gender as fundamental biological variables. Addressing this gap head-on, the international PAINDIFF Network has emerged with a landmark set of recommendations designed to transform how sex and gender are integrated into pain research studies. Although these recommendations originate within the specialized field of pain research, their implications and applications resonate broadly across the diverse terrain of biopsychosocial science, signaling a paradigm shift in experimental design, analysis, and reporting.
At the core of the PAINDIFF Network’s initiative lies the recognition that sex and gender profoundly influence physiological, psychological, and behavioral responses to pain. Despite this, historical and contemporary research has often either neglected these variables or treated them superficially, leading to data variability, poor reproducibility, and ultimately limited translatability from bench to bedside. To counteract these issues, the network advocates for five universal strategies that should be considered foundational in nearly every research undertaking involving biological subjects or human participants.
Foremost among these is the unequivocal recommendation to include both males and females as a standard practice in research protocols. This inclusivity is not merely about representation but about capturing the full spectrum of biological and experiential variance that sex and gender confer. The network highlights that excluding one sex invariably biases results and undercuts the generalizability of findings. A balanced inclusion ensures that discoveries are more reflective of the population’s true heterogeneity.
Complementing this, robust experimental designs must account for sex in procedures like randomization, counterbalancing, and testing order. These design elements are critical to mitigating confounding variables that might otherwise obscure sex-related effects. Randomly or alternately assigning participants or animals of different sexes to various conditions helps avoid systematic biases that could influence outcomes. The inclusion of sex as a variable in these foundational steps marks a substantial refinement in methodological rigor.
Moreover, when the central aim of a study involves discerning sex differences, the PAINDIFF Network underscores the importance of statistically powering these analyses appropriately. Underpowered studies risk missing or overstating differences, contributing further to the reproducibility crisis. This entails calculating sample sizes that are sufficiently large to detect meaningful interactions or contrasts between sexes, ensuring that the conclusions drawn hold firm under scrutiny.
Accurate and detailed reporting forms the backbone of scientific transparency and rigor. To this end, the network counsels researchers to provide explicit descriptions of experimental designs, especially outlining how sex and gender variables were incorporated. This includes detailing the methods used to classify subjects, controlling for sex-related confounds, and any sex-specific nuances in methodology. Such thoroughness not only aids replication but enables meta-analyses that can synthesize data across studies with confidence in variable comparability.
Finalizing these universal guidelines is the call for sex-disaggregated analysis and reporting—a practice that remains insufficiently adopted but is vital for uncovering nuanced biological insights. By separating data by sex, researchers can identify differential mechanisms, risks, or therapeutic responses that would be masked in aggregated datasets. This stratification empowers personalized approaches and more effective medical interventions.
Beyond these five cornerstone recommendations, the PAINDIFF Network addresses the distinct challenges and requirements in preclinical versus clinical research domains. For preclinical investigations, which commonly utilize animal models, three additional targeted strategies are outlined. These include considerations such as hormonal status control, appropriate model selection reflective of both sexes, and the incorporation of sex-specific endpoints to capture relevant biological phenomena accurately.
On the human clinical side, the network elaborates five further recommendations. These underscore the necessity to rigorously define and operationalize gender as a complex socio-cultural construct, distinct from biological sex, which modulates pain experiences and healthcare outcomes. Human studies are encouraged to embrace gender diversity, consider gender-related psychosocial factors, employ validated instruments to assess gender identity and roles, and ensure inclusive recruitment strategies that do not unintentionally marginalize underrepresented or non-binary groups.
Recognizing that systemic change demands coordinated action, the PAINDIFF Network also extends its recommendations to key stakeholders beyond the laboratory bench or clinic. Editors and reviewers of scientific journals are urged to demand rigorous sex- and gender-inclusive methodologies and transparent reporting as publication prerequisites, thereby influencing the cultural standards of scientific excellence and accountability. Funding bodies are called upon to prioritize and incentivize research that conscientiously integrates sex and gender variables, potentially tying grant approvals or renewals to adherence with these best practices.
Policymakers, too, have a pivotal role in shaping the broader biomedical research ecosystem. By embedding these recommended standards into regulatory frameworks and research oversight mechanisms, policymakers can ensure that scientific inquiry progresses equitably and with heightened relevance to all segments of the population. Such top-down reinforcement complements grassroots efforts within research communities, fostering a holistic environment conducive to systemic adoption.
The tangible benefits of embracing these comprehensive recommendations are manifold. Researchers can expect reductions in data variability that may otherwise stem from unaccounted sex and gender differences. Enhanced reproducibility will emerge from methodological transparency and appropriately powered analyses. Crucially, the translatability of findings will improve, bridging the critical gap between experimental discoveries and their application in diverse clinical populations with varied sex and gender profiles.
This concerted movement toward inclusivity and rigor aligns with broader scientific imperatives advocating personalized medicine and precision health. Understanding how sex and gender intersect with genetic, environmental, and psychosocial factors to influence pain and other health outcomes is indispensable for developing tailored interventions. The PAINDIFF Network’s recommendations offer a pragmatic blueprint to integrate these dimensions, propelling research toward greater depth, accuracy, and social relevance.
Moreover, the network’s initiatives echo a growing recognition that sex and gender are inseparable from the biological and lived realities influencing health and disease. By transcending tokenistic or superficial treatment of these variables, biomedical research stands to uncover previously hidden mechanisms, identify novel therapeutic targets, and dismantle health disparities rooted in historical neglect.
Implementing these recommendations presents challenges, not least the need for increased resources, training, and cultural shifts within scientific communities. However, the potential rewards—in terms of scientific robustness, ethical integrity, and clinical impact—justify the investment. The PAINDIFF Network’s guidelines serve as both a call to action and a roadmap for transforming pain research and beyond, ensuring that future investigations are built upon foundations of equity, rigor, and inclusivity.
In sum, the incorporation of sex and gender as central, meticulously studied variables is not merely a nicety but a scientific necessity. The PAINDIFF Network’s comprehensive recommendations mark a pivotal moment, pioneering a framework that promises to elevate the quality and applicability of biomedical research globally. By embracing these guidelines, the scientific community will be better equipped to unravel the complex tapestry of factors shaping human health, ultimately leading to more effective and equitable therapies for all.
Subject of Research: Inclusion and study of sex and gender variables in pain research and biopsychosocial science.
Article Title: Recommendations for the inclusion and study of sex and gender in research.
Article References:
Finn, D.P., McGuire, B.E., Beggs, S. et al. Recommendations for the inclusion and study of sex and gender in research. Nat Neurosci (2025). https://doi.org/10.1038/s41593-025-02164-1
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41593-025-02164-1
Tags: addressing data variability in biomedical researchbiopsychosocial factors in pain researchexperimental design in pain studiesgender as a biological variablehistorical neglect of gender in researchimpact of sex on physiological responsesimproving reproducibility in researchinclusion of females in research studiesPAINDIFF Network recommendationssex and gender analysis in biomedical researchsex differences in pain responsetranslatability of research findings
