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Abstract

Endogenous pain modulation is a valuable non-pharmacological way to alter pain, yet responses to both clinical and experimental interventions vary widely. This variability often limits mechanistic understanding and clinical translation, and is frequently dismissed as methodological noise rather than examined as a potential source of insight. This dissertation investigates pain modulation across four common and clinically relevant paradigms, focusing on biological, psychological, and social influences on variability in pain responses. Study one was a systematic review and meta-analysis comparing conditioned pain modulation (CPM) in athletes and non-athletes. No overall group differences were found, but greater weekly training volume was associated with larger CPM responses in athletes, suggesting inhibitory capacity may be trainable rather than innate. Study two was a cross-sectional study examining participant sex and muscle dynamic stiffness in exercise-induced hypoalgesia (EIH). Male participants demonstrated hypoalgesia following exercise, whereas females did not. In females, EIH magnitude was associated with exercise-related changes in muscle dynamic stiffness, suggesting peripheral contributors to EIH responses. Study three was a single-blinded crossover study evaluating examiner-participant gender dynamics and pain reporting type. Examiner gender influenced verbal pain ratings, but not temperature-based pain report, indicating that social context can shape some forms of pain reporting more than others. Study four was a double-blinded randomized controlled trial examining acute social stress as a pain modulator. Acute stress selectively altered temporal summation, a dynamic pain measure, but did not affect pain thresholds or capsaicin flare size, suggesting stress may preferentially influence central facilitatory processes rather than static pain outcomes. Collectively, these studies demonstrate that no single paradigm elicits pain modulation uniformly across individuals. Instead, pain modulation reflects interactions among biopsychosocial factors, including sex and gender, exercise exposure, stress state, and social context. Sources of variation in pain modulation should therefore be viewed not as noise, but as meaningful indicators of underlying mechanisms. Future research should move beyond asking whether a paradigm “works” and instead determine which mechanisms are engaged, in whom, and under which conditions, to improve precision in pain assessment and treatment.