Biological effects of technique-specific manual therapy in healthy individuals and people with musculoskeletal disorders: a systematic review with meta-analysis.

Abstract

Introduction Manual therapy (MT) is widely recommended for musculoskeletal disorders, yet its biological mechanisms remain poorly synthesized, with existing evidence often aggregating distinct techniques and outcome domains. This systematic review and meta-analysis evaluates the neurophysiological and metabolic effects of MT, exploring differences between technique characteristics (high-velocity low-amplitude [HVLA] vs. non-HVLA) and anatomical regions. Methods Registered prospectively (PROSPERO CRD42024497251), five databases (MEDLINE, CINAHL, Web of Science, Scopus and CENTRAL) were searched through 14 July 2025. Randomized controlled trials and controlled clinical trials evaluating neurophysiological or metabolic outcomes following MT in adults, with or without musculoskeletal pain, were included. Risk of bias was assessed using Cochrane RoB 2.0. Meta-analyses used random-effects models; certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Fifty studies (2,147 participants) were included. Meta-analyses showed that joint mobilization significantly increased skin conductance (sympathetic marker) versus sham in healthy cohorts. Conversely, non-HVLA MT, particularly soft tissue techniques, was associated with reduced heart rate and increased RMSSD (parasympathetic marker). No consistent effects were observed for blood pressure, skin temperature, or frequency-domain HRV. Narrative synthesis indicated that HVLA manipulation may attenuate somatosensory evoked potentials and increase muscle conduction velocity, while soft tissue approaches were linked to increased oxytocin and reduced adrenocorticotropic hormone levels. Overall, certainty of evidence ranged from low to moderate due to methodological heterogeneity and imprecision. Conclusion Manual therapy is associated with short-term modulation of neurophysiological regulation, characterized by technique-specific response profiles. Joint mobilization primarily induces sympathetic-driven responses, whereas soft tissue techniques are more frequently associated with parasympathetic-driven markers. The overall pattern of findings suggests that MT interacts with regulatory systems in a technique-dependent manner rather than producing uniform systemic physiological effects.