What Really Happens When We Use Manual Therapy? A Fresh Look at the Mechanisms Behind Hands-On Approaches

Authors: Damian Keter DPT, PhD, Chad Cook PT, PhD, FAPTA

Manual therapy (MT) has been part of musculoskeletal care for centuries, yet one question continues to challenge clinicians and researchers alike: How does it actually work? A new living review by Keter et al. [1], sponsored by ForceNET [2], offers the most comprehensive attempt yet to answer that question. By synthesizing 62 systematic, narrative, and scoping reviews, the authors map out the complex, multisystem responses triggered by MT, and highlight just how much we still have to learn. This blog breaks down their findings in a clinically digestible, research‑informed way.

A Shift From “Bones Out of Place” to Multisystem Responses: Historically, MT was explained through biomechanical models—the idea that joints were “misaligned” or tissues needed to be “released.” Over the past several years, this model has been challenged, and the term ‘neurophysiological’ has become widely used to acknowledge that more is involved than biomechanical changes in isolation. While the term ‘neurophysiological’ may be correct, its vagueness does not clarify the actual responses observed in the body when MT techniques are applied. Keter and colleagues emphasize, modern evidence paints a far more nuanced picture. Across dozens of reviews, MT appears to influence multiple physiological systems simultaneously, including:

Table 1. Mechanistic Areas represented in the Manuscript.

Mechanism	One‑Sentence Definition
Neurological	How manual therapy influences the brain, spinal cord, and nerves to change how the body processes pain and movement.
Neurovascular	How manual therapy affects blood vessels and the autonomic nervous system, influencing circulation and physiological arousal.
Neuroimmune	How manual therapy interacts with the immune system, potentially altering inflammation‑related chemicals in the body.
Neuroendocrine	How manual therapy influences hormone‑related systems that help regulate stress, healing, and overall body balance.
Neuromuscular	How manual therapy affects the coordination, tension, and activation patterns of muscles and the nerves that control them.
Neurotransmitter / Neuropeptide Pathways	How manual therapy influences chemical messengers (such as oxytocin and endorphins) that affect pain, mood, and relaxation.
Biomechanical Responses	How manual therapy produces physical changes in joint motion, soft tissue behavior, or fluid mechanics in the body.

The findings aligned with the contemporary understanding that MT is not a single‑mechanism intervention but a multifactorial stimulus interacting with the patient’s biology, expectations, and context.

What the Evidence Shows—And How Strong It Is: One of the most important contributions of this review is its appraisal of evidence quality. Most included reviews were rated critically low to low quality, with only four reaching moderate quality. That means we must interpret mechanistic findings cautiously. Still, several patterns emerged.

1. Neurological Mechanisms: The Strongest Signal. The most consistent evidence supports neurological responses, including:

• Increased pressure pain thresholds after manipulation or mobilization
• Changes in cortical and subcortical activity (EEG, fMRI proxies)
• Improved conditioned pain modulation
• Reduced temporal summation

These findings reinforce the idea that MT may work primarily through descending inhibitory pathways, modulating nociceptive processing rather than “fixing” structural issues.

2. Neurovascular Responses: Sympathetic System on the Move. Thirty‑two reviews reported neurovascular effects, including:

• Sympathoexcitation following many MT techniques
• Decreased alpha‑amylase, suggesting sympathoinhibition in some contexts
• Increased skin conductance
• Variable heart rate and blood pressure responses

These findings suggest MT interacts with the autonomic nervous system, though the direction of change may depend on a number of patient and technique factors.

3. Neuroimmune and Neuroendocrine Responses: Promising but Preliminary. The review found trends toward:

• Decreased pro‑inflammatory cytokines (e.g., IL‑1β, TNF‑α)
• Increased anti‑inflammatory cytokines (e.g., IL‑10)
• Modulation of cortisol levels

However, these findings were based on low‑quality evidence, and the clinical relevance remains unclear. As the authors note, these immune and endocrine shifts are not unique to MT and may reflect general responses to touch, movement, or contextual factors.

4. Neurotransmitter & Neuropeptide Changes: Small but Notable. Some reviews reported:

• Increased oxytocin
• Changes in β‑endorphin
• Mixed findings for Substance P
• Little change in norepinephrine or epinephrine

These biochemical shifts may contribute to analgesia, relaxation, or affective responses, but again, evidence quality is limited.

5. Neuromuscular Responses: Altered Muscle Activity. Findings included:

• Reduced EMG activity in compensatory musculature post‑treatment
• Improved muscle recruitment (e.g., multifidi)
• Changes in muscle spindle discharge

These responses support the idea that MT may help “reset” or modulate neuromuscular tone and coordination.

6. Biomechanical Mechanisms: The Weakest Evidence. Despite their historical prominence, biomechanical explanations had the lowest quality evidence. While some reviews reported:

• Changes in joint position
• Altered soft tissue properties
• Increased disc diffusion

These findings were inconsistent and often unrelated to clinical outcomes. This reinforces a key message: MT is not primarily a biomechanical intervention.

So… Why Does Manual Therapy Work? Keter et al. conclude that MT likely works through peripheral, spinal, and supraspinal mechanisms that interact dynamically. These findings complement several recent reviews comparing specific and non-specific spinal manipulations[3-5], as they help us better understand ‘why’ a positive response can occur when not targeting a specific biomechanical limitation.

While findings from this review are promising, two major limitations remain:

1. Mechanisms are not unique to MT. Many responses also occur with touch and  movement
2. Contextual factors directly affect the treatment mechanisms of MT. [6]
3. Mechanisms vary across individuals. This may explain why MT has small‑to‑moderate effect sizes and why some patients respond dramatically while others do not.

Potential implications:

Better understanding mechanisms opens the door for mechanism‑based treatment stratification, matching patients to interventions based on their underlying neurophysiological profiles; however, we are not yet at this point, as several things need to be done to tighten up our understanding:

1. High-quality studies and reviews are needed to establish a more concrete understanding of what is occurring.
2. Translational studies to establish which treatment mechanisms are relevant to clinical outcomes (just because it happens, doesn’t mean it matters).
3. Developing phenotypes based on responder status to determine who does (and who does not) benefit from these treatment mechanisms.

What This Means for Clinicians: This review supports a modern, evidence‑aligned approach to MT. We have several recommendations for practicing clinicians on how to adapt their practices based on these findings, if they are not already practicing in this way (Figure 1).

Conclusion: While recent findings are promising for a future in which we understand ‘Why’ MT works, there are still many unknowns and areas for change and improvement in both research and clinical practice. (Figure 2)

Layperson’s Summary (for patients): There are a lot of things that happen in the body when we lay our hands on an individual (called manual therapy). This includes things like massage, manipulation, or any other hands-on treatment. While this area is still under investigation, the ‘why’ manual therapy works when you are dealing with pain or a stiff joint is starting to become clearer. While previously we promised ‘structural corrections’ and ‘realigning the body’ as if it were a car, we now know that structural changes are likely not the cause of why manual therapy works. Our current understanding is that many complex processes occur among the brain, muscles, joints, and the many chemicals in your body, which work together to cause this response. The good news is that we know it still works and is a recommended treatment for many conditions!

References

1. Keter DL, Bialosky JE, Brochetti K, Courtney CA, Funabashi M, Karas S, Learman K, Cook CE. The mechanisms of manual therapy: A living review of systematic, narrative, and scoping reviews. PLoS One. 2025 Mar 18;20(3):e0319586.
2. Bridging the knowledge gap between research in mechanisms and clinical outcomes. Duke University. https://sites.duke.edu/forcenet/. . Accessed February 24, 2025.
3. Nim C, Aspinall SL, Cook CE, et al. The Effectiveness of Spinal Manipulative Therapy in Treating Spinal Pain Does Not Depend on the Application Procedures: A Systematic Review and Network Meta-analysis. Journal of Orthopaedic & Sports Physical Therapy. 2025;55(2):109-122. doi:2519/jospt.2025.12707
4. Nim CG, Downie A, O’Neill S, Kawchuk GN, Perle SM, Leboeuf-Yde C. The importance of selecting the correct site to apply spinal manipulation when treating spinal pain: Myth or reality? A systematic review. Sci Rep. 2021;11(1):23415. doi:1038/s41598-021-02882-z
5. Sørensen PW, Nim CG, Poulsen E, Juhl CB. Spinal Manipulative Therapy for Nonspecific Low Back Pain: Does Targeting a Specific Vertebral Level Make a Difference?: A Systematic Review With Meta-analysis. Journal of Orthopaedic & Sports Physical Therapy. 2023;53(9):529-539. doi:2519/jospt.2023.11962
6. Keter D, Loghmani MT, Rossettini G, Esteves JE, Cook CE. Context is Complex: Challenges and opportunities in manual therapy mechanisms research involving contextual factors. International Journal of Osteopathic Medicine. 2025;55. doi: 10.1016/j.ijosm.2025.100750