Dr. Damon Bescia DPT

How Does Orthopedic Manual Physical Therapy Work?

Dr. Damon Bescia DPT, orthopedic manual physical therapist of Naperville Manual Physical Therapy

The short answer: “Orthopedic manual physical therapy decreases pain and improves mobility by acting as a mechanical stimulus to the tissue that causes transient biomechanical effects and a cascade of neurophysiological responses in the peripheral nervous system, the spinal cord, and the brain.”

For the long answer, please consider the comprehensive summary below of the scientific evidence on the mechanisms of orthopedic manual physical therapy along with brief plain-language summaries interjected throughout. (For a step back to the basics of orthopedic manual physical therapy, please see my blog “What is Orthopedic Manual Physical Therapy?”)

Manual Therapy Causes Transient Biomechanical Effects

Orthopedic manual physical therapy acts as a mechanical stimulus to the tissue that causes transient biomechanical effects. In other words, we have evidence that motion occurs at the targeted structures inside a patient’s body while orthopedic manual physical therapy is being performed: segments of the spine, joints, nerves, etc. have been observed to move along with the application of manual therapy techniques. However, this motion – or change in position – appears to be temporary. There is no evidence that there is a lasting change in position or that anything is being permanently pushed or popped back into place – even in the presence of tribonucleation (pops, clicks, or other noise from the joint). Granted, a dislocated shoulder, finger, kneecap, or other joint that presents with a gross visible deformity, oftentimes following trauma, may be reduced or “put back in place” manually; but, this would be the exception, not the rule. Here are a few examples of transient biomechanical effects in the research literature:

Gal et al observed significant relative movements at the targeted and immediately adjacent vertebrae of cadavers during posterior-to-anterior thrusts to the transverse process of T10, T11, or T12 and noted that “these vertebral pairs remained slightly hyper-extended” after the manipulation ceased.[1] This means that when manual therapy was applied to a segment of the thoracic spine, it moved as intended. Note: Before concluding that an application of orthopedic manual physical therapy may lead to permanent changes in the position of vertebrae, this study must be viewed in light of the fact that the subjects were deceased – and we cannot assume that living structures move in the same manner, to the same extent, or maintain a new position as these cadaveric structures did.
Colloca et al noted that the displacement of L3 was linearly correlated to the posterior-to-anterior force applied to the spinous process by a “computer-controlled mechanical testing apparatus”.[2] So, when this machine pushed down on a segment of the lumbar spine (of sheep in this case), the segment did indeed move along with it as anticipated.
Kulig observed via dynamic MRI that a manual posterior-to-anterior mobilization to a single lumbar spinous process caused motion of the entire lumbar region, and motion at the target segment was always into extension.[3]
Coppieters and Alshami evaluated various nerve sliding and gliding techniques that targeted the median nerve in cadaveric subjects, and in fact measured significant excursion of the median nerve during the application of these orthopedic manual physical therapy techniques.[4] This study observed that the targeted nerve did indeed move as intended by the technique. While this study was not performed on living subjects, it may be reasonable to hypothesize that living nervous tissue may glide even better through the surrounding living tissue than what this study had observed in cadaveric tissue.
Coppieters and Butler measured excursion of the median and ulnar nerve during sliding and tensioning nerve mobilization techniques, and confirmed that sliding techniques result in a substantially larger excursion of the nerve than tensioning techniques and that this larger excursion is associated with a much smaller change in strain.[5] Again, the nerves did indeed move as intended with the orthopedic manual physical therapy applied.
Hsieh et al considered the case of a 79-year-old female with right thumb pain of seven months duration.[6] There was a complete resolution of pain and improvement in function after 3 weeks of orthopedic manual physical therapy, but there was no lasting change in the observed “positional fault” as determined by comparing MRIs before and after treatment.
Tullberg et al used Roentgen stereophotogrammetry (RSA) to assess the effect thrust manipulation had on the position of the sacroiliac joint.[7] RSA is a highly accurate assessment three-dimensional migration and micromotion of a joint by placing small markers percutaneously into relevant structures within the body and then taking a stereo image with two synchronized x-ray foci. In this study of 10 patients with symptoms or “dysfunction” of the sacroiliac joint, markers were implanted into the sacrum and the ilium, and x-rays were taken before and after thrust manipulation. Though this orthopedic manual physical therapy technique led to significant improvement in symptoms, it did not cause a lasting change in the position of the sacroiliac joint.
Kardouni et al observed no significant changes in thoracic spine extension and excursion following thoracic spine thrust manipulation administered to 52 participants with shoulder impingement symptoms, though patient-reported pain improved.[8]
Carpine et al set out to determine whether manual therapy (MT) affects functional performance and biomechanical performance during a sit-to-stand (STS) task in a population with low back pain (LBP). Kinematic data were recorded from the pelvis and thorax of participants with LBP, using an optoelectronic motion capture system as they performed a STS task before and after MT. MT for each participant consisted of two high-velocity low-amplitude spinal manipulations, as well as two grade IV mobilizations of the lumbar spine and pelvis targeted toward the third lumbar vertebra and sacroiliac joint in a side-lying position; the order of these treatments was randomized. Pelvis and thorax kinematic data were used to derive the time-varying lumbar angle in the sagittal plane for each STS trial. The difference between the maximum and minimum lumbar angles during the STS trial determined the sagittal range of motion (ROM) that was used as the biomechanical outcome. Time to complete each STS trial was used as a functional measure of performance. After MT, lumbar sagittal ROM increased by 2.7 ± 5.5 degrees. Time to complete the STS test decreased by 0.4 ± 0.4 s. These findings provide preliminary evidence that MT might influence the biomechanical and functional performance of an STS task in populations with LBP. Future work will expand upon these data as a basis for targeted investigations on the effects of either spinal manipulation and mobilization on neuromuscular control and movement in populations with LBP. [41]

Manual Therapy Causes Neurophysiological Responses in the Peripheral Nervous System and Spinal Cord

Orthopedic Manual Physical Therapy acts as a mechanical stimulus to the tissue that causes neurophysiological responses in the peripheral nervous system and spinal cord. However, it does not appear to influence the autonomic nervous system. Here are a few references:

Herzog et al studied ten young and asymptomatic males who received spinal manipulation targeted to the cervical, thoracic, lumbar, and sacroiliac joint. 16 pairs of bipolar surface electrodes measured consistent reflex responses in back and proximal limb muscular within 50-200 msec of the thrust manipulation, and these responses lasted for 100-400 msec. The authors thus hypothesized, “Because reflex pathways are evoked systematically during spinal manipulative treatment, there is a distinct possibility that these responses may cause some of the clinically observed beneficial effects, such as a reduction in pain and a decrease in hypertonicity of muscles.”[9]
Suter et al measured the maximal active isometric knee extensor strength of individuals with anterior knee pain using electromyographic (EMG) surface electrodes before and after a sidelying thrust manipulation technique targeting the sacroiliac joints.[10] Muscle inhibition (MI) – the inability to fully contract a muscle actively – was assessed by the interpolated twitch technique in the form of two electrical twitches applied by a muscle stimulator to the femoral nerve during the active maximal isometric contraction; if an increase in torque is produced, muscle activation was considered incomplete due to muscle inhibition – which is often clinically associated with knee pain or injury. After the thrust manipulation, a decrease of 7.5% in muscle inhibition was observed in the involved legs but not in the contralateral legs. As these individuals had received prior rehabilitation targeted the local structures around the joint without success, the study remarks, “This finding may indicate a possible connection between SI-joint or lower back problems and the functional deficiencies of the knee extensors found in patients with AKP [anterior knee pain]… and the possible usefulness of spinal manipulation for the treatment of lower limb MI.”
Suter et al two years later likewise observed a decrease in muscle inhibition of the elbow flexors immediately after lower cervical spine manipulation was performed on patients with chronic neck pain, noting an increase in elbow flexion force afterward.[11]
DeVocht et al studied the effect of spinal manipulation on the electromyographic (EMG) activity of the lumbar paraspinals muscles of 16 patients with low back pain (8 participants receiving activator (a handheld spring-loaded instrument that produces a small impulse to the spine or other target as an alternative to manual therapy) treatment, the other 8 manual manipulation).[12] EMG activity decreased by at least 25% after treatment in 24 of the 31 sites monitored.
Raney et al published a case series of 9 patients that received supine lumbopelvic manipulation and immediately afterward presented with 1) decreased muscle thickness of their transversus abdominus at rest and 2) demonstrated an improved ability to increase the thickness during active contractions as measured with real-time ultrasound imaging.[13]
Colloca et al observed the response of an activator (a handheld spring-loaded instrument that produces a small impulse to the spine or other target as an alternative to manual therapy) when applied to the spine of patients with lumbar radiculopathy who were prepped for surgical decompression and under general anesthesia.[14] Electrodes were cradled around the spinal nerve roots at the level of the dorsal root ganglia to record neurophysiological responses in the form of compound action potentials (CAPs). The study concluded: “It is likely that the SMT-induced CAPs were afferent traffic resulting from the stimulation of mechanosensitive afferent fibers.” This spinal manipulative technique was indeed found to produce significant spinal nerve root responses in the form of greater CAPs, which suggests that vertebral motions produced by spinal manipulation may play a prominent role in eliciting neurophysiologic responses in patients.
Several studies have found a decrease in motor neuron pool excitability in response to orthopedic manual physical therapy.[15],[16],[17],[18],[19],[20],[21] On the other hand, some studies found an increase in excitability.[22],[23] (Note: one study by Suter et al found no effect when controlling for change in the subjects’ position, proposing that the change in position may have been responsible for the decrease in motor neuron pool excitability in prior studies – not the manual therapy technique itself.[24]) A motor neuron pool is a group of all individual motor neurons – or nerve cells – that innervate one muscle and signal it to contract. Motor neuron pool excitability is loosely the “eagerness” of a motoneuron pool to signal the muscle to contract. This excitability is measured with an H-reflex (Hoffmann’s reflex) test which is performed using an electric stimulator to sensory fibers (1a afferents) in their innervating nerves and an EMG to record the results. The H-reflex is similar to the muscle spindle reflex (MSR), such as the knee jerk reflex, but the H-reflex bypasses the muscle spindle to assess the modulation of monosynaptic reflex activity in the spinal cord. Therefore, it appears that orthopedic manual physical therapy has an effect on spinal cord activity.
A few studies have observed a decrease in temporal summation of thermal pain sensitivity following spinal manipulative therapy.[25],[26],[27] Temporal summations are the integration of repetitive sensory, or nociceptive, stimuli (think about moving your hand quickly back and forth under a faucet that is running very hot water – each time feels hotter even though the water temperature doesn’t change) and are important in chronic pain conditions since long lasting pain is one of the characteristics.
Coronado et al published a systematic review with meta-analysis on the changes in pain sensitivity following spinal manipulation, concluding that it has a favorable effect on mechanical pain pressure thresholds and appears to act through both central and peripheral pathways as well as a potential influence on the supraspinal levels.[28] A second systematic review in the same year (Millan et al) in the same year also confirmed that spinal manipulative therapy has a hypoalgesic (decreased sensitivity) effect more so on pressure pain thresholds than temperature pain thresholds.[29] This leads us nicely into our final subtopic.
Maxwell et all published a systematic review on the effects of spinal manipulative therapy on lower limb neurodynamics. They write: "Although the evaluation of changes in clinical presentation is complex, objective neurophysiological measures of sensitivity to movement (e.g. neurodynamic tests) can be a valuable clinical indicator in evaluating the effects of SMT (spinal manipulative therapy). SMT produced a clinically meaningful (≥6⁰) difference in five of these studies compared with inert control, hamstring stretching, and as an adjunct to conventional physiotherapy, but not compared with standard care, as an adjunct to home exercise and advice, or when comparing different SMT techniques. Findings compared to sham were mixed. When reported, effects tentatively lasted up to 6 weeks post-intervention. Limited evidence suggests SMT-improved range of motion and was more effective than some other interventions. Future research, using standardized Neurodynamic tests, should explore technique types and evaluate longer-term effects."[40]
Sampath et al in 2024 perform a systematic review and meta-analysis on whether or not high-velocity low-amplitude thrust manipulation affects the autonomic nervous system. It concluded: "Overall, there was low quality evidence that SM did not influence any measure of ANS including heart rate variability (HRV), oxy-hemoglobin, blood pressure, epinephrine and nor-epinephrine. However, there was low quality evidence that cervical spine manipulation may influence high frequency parameter of HRV, indicating its influence on the parasympathetic nervous system." [42]
Sampath et al also published a systematic review update in 2024 that looked for changes in biochemical markers after high-velocity low-amplitude thrust manipulation: "There was low-quality evidence that spinal manipulation influenced various biochemical markers (not pooled). There was low-quality evidence of significant difference that spinal manipulation is better than control in eliciting changes in cortisol levels immediately after intervention. Low-quality evidence further indicated that spinal manipulation can influence inflammatory markers such as interleukins levels post-intervention. There was also very low-quality evidence that spinal manipulation does not influence substance-P, neurotensin, oxytocin, orexin-A, testosterone and epinephrine/nor-epinephrine." [43]

Manual Therapy Causes Neurophysiological Responses in the Supraspinal Pathways

Orthopedic Manual Physical Therapy acts as a mechanical stimulus to the tissue that causes neurophysiological responses in the brain. In other words, orthopedic manual physical therapy appears to have an effect on the brain’s activity as well:

McGuiness et al observed a significant increase in respiratory rate, heart rate, systolic and diastolic blood pressure during the application of grade III posterior-to-anterior mobilization of C5/6, when compared to the control and placebo conditions, indicating changes in sympathetic nervous system activity.[30]
McPartland et al investigated whether osteopathic manipulative treatment (OMT – a branch of manual therapy) generated cannabimimetic (euphoriant, sedating, “feel-good”) effects and found a significant increase in subjective scores of descriptors such as “good, high, hungry, light-headed, and stoned” and significant decreases in subjective scores of descriptors such as “inhibited, sober, uncomfortable” after treatment.[31] Additionally, serum levels of anandamide (AEA) increased 168%, and oleylethanolamide (OEA) decreased 27% over pretreatment levels. The authors proposed, “Healing modalities popularly associated with changes in the endorphin system, such as OMT, may actually be mediated by the endocannabinoid system [located in the brain and throughout the central and peripheral nervous system].”
Teodorczyk-Injeyan et al examined the effect of spinal manipulation on the production of inflammatory cytokines, tumor necrosis factor alpha and interleukin 1 beta, in relation to the systemic levels of neurotransmitter substance P. They found that subjects receiving spinal manipulation show a time-dependent attenuation of LPS-induced production of the inflammatory cytokines unrelated to systemic levels of substance P, suggesting a manipulation-related down-regulation of inflammatory-type responses via a central mechanism.[32]
Degenhardt et al set out to determine if manual therapy influences levels of circulatory pain biomarkers (Beta-Endorphin, Serotonin 5-HT, Serotonin Metabolite 5-HIAA, 5-HIAA/5-HT Turnover, Anandamide, N-Palmitoylethanolamide) by collecting and analyzing blood samples of the participants.[33] While high-velocity low-amplitude (HVLA) manipulation was excluded in this study, various other manual techniques were utilized. The study concluded that concentrations of several of these circulatory pain biomarkers were altered after OMT.
Bialosky et al published a perspective article on the how patient expectation (including via clinician-induced bias) influences the outcome of treatment with improvement reported in those who expect it and a worsening of pain being reported by individuals who expected more pain (nocebo effect).[34]
Cook and Sheets proposed that clinician biases (or lack of personal equipoise) are likely to influence the findings of randomized clinical trials when assessing the outcomes of certain manual therapy interventions.[35]
Gay et al somehow convinced 24 healthy participants to complete an “exercise-injury protocol to induce low back pain” (ouch?) that was followed by one of three types of manual therapy: spinal thrust manipulation, spinal mobilization, and therapeutic touch.[36] Functional MRIs were then used to investigate the immediate changes in functional connectivity between brain regions that process and modulate the pain experience. Changes were found between several brain regions after all interventions, and significant improvement was reported in pain intensity across all groups receiving manual therapy.
Sparks et al also used Functional MRIs (fMRI) to assess supraspinal activation, but they set out to determine if cerebral hemodynamic responses to pain change after manual therapy (thoracic spine thrust manipulation).[37] The ten subjects underwent fMRI scanning while receiving noxious stimuli applied to the cuticle of the index finger at a rate of 1 Hz for periods of 15 seconds, alternating with periods of 15 seconds without stimuli, for a total duration of 5 minutes. Thoracic thrust manipulation was then performed followed immediately by reimaging with a second delivery of noxious stimuli. The data indicated a significant reduction in reported pain, as well as a reduction in cerebral blood flow as measured by the blood oxygenation level-dependent response to areas associated with the pain matrix. There was a significant relationship between reduced activation in the insular cortex and decreased subjective pain ratings.
Sparks et al later randomized 24 volunteers with acute or subacute mechanical (nontraumatic) neck pain to receive either thoracic spine thrust manipulation or a sham and then undergo functional magnetic resonance scanning (fMRI) while receiving noxious stimuli before and after.[38] Blood oxygenation level–dependent functional magnetic resonance imaging recorded the cerebral hemodynamic response to the mechanical stimuli. The imaging revealed significant group differences, with those individuals in the manipulation group exhibiting increased areas of activation (postmanipulation) in the insular and somatosensory cortices and individuals in the sham group exhibiting greater areas of activation in the precentral gyrus, supplementary motor area, and cingulate cortices. This study provides preliminary evidence suggesting cortical responses in patients with nontraumatic neck pain may vary between thoracic spine thrust manipulation and a sham.
Weber et al in 2019 performed a secondary analysis of the two aforementioned studies by Sparks et al and concluded that the findings provide preliminary evidence that spinal manipulation may alter the processing of pain-related brain activity within specific pain-related brain regions and support the use of brain-based models as clinical biomarkers of pain.[39]

While the statement “more research is needed” certainly applies here, we are at least beginning to understand the biomechanical and complex neurophysiological effects that orthopedic manual physical therapy may have on its recipients and why it produces the apparent clinical benefits it does – decreasing pain, improving both the quantity and quality of motion, and yielding the potentially addictive, “feel-good” effects for which it has been sought out. This ever-progressing understanding may help clinicians in guiding individualized treatment, patients in understanding the general mechanisms and potential effects of orthopedic manual physical therapy, referral sources and third-party payers in appreciating the scientific evidence and effectiveness of skilled orthopedic manual physical therapy for the patients who may benefit from it, and all of us in understanding how orthopedic manual physical therapy works.

Further Information on Orthopedic Manual Physical Therapy

Click on any of the following links for more information:

Would you like a brief overview of the basics of orthopedic manual physical therapy?
Have you ever wondered how pain works?
Do patients need an MRI or X-ray before beginning physical therapy?
What should you consider when choosing a physical therapist for an orthopedic condition?
What's an evidence-informed approach to the examination and treatment of sacroiliac joint pain?
How should one perform manual therapy for spondylolisthesis?

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Dr. Damon Bescia is a fellowship-trained Doctor of Physical Therapy, board certified in orthopedics and sports physical therapy, who specializes in Orthopedic Manual Physical Therapy and serves Naperville and its surrounding communities by way of his Concierge Practice, providing private one-to-one orthopedic manual physical therapy for his clients. For more information, please visit https://www.napervillemanualphysicaltherapy.com.

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[2] Colloca CJ, Keller TS, Harrison DE, Moore RJ, Gunzburg R, Harrison DD. Spinal manipulation force and duration affect vertebral movement and neuromuscular responses. Clinical Biomechanics. 2006 Mar 31;21(3):254-62.

[3] Kulig K, Landel RF, Powers CM. Assessment of lumbar spine kinematics using dynamic MRI: a proposed mechanism of sagittal plane motion induced by manual posterior-to-anterior mobilization. Journal of Orthopaedic & Sports Physical Therapy. 2004 Feb;34(2):57-64.

[4] Coppieters MW, Alshami AM. Longitudinal excursion and strain in the median nerve during novel nerve gliding exercises for carpal tunnel syndrome. Journal of Orthopaedic Research. 2007 Jul 1;25(7):972-80.

[5] Coppieters MW, Butler DS. Do ‘sliders’ slide and ‘tensioners’ tension? An analysis of neurodynamic techniques and considerations regarding their application. Manual therapy. 2008 Jun 30;13(3):213-21.

[6] Hsieh CY, Vicenzino B, Yang CH, Hu MH, Yang C. Mulligan's mobilization with movement for the thumb: a single case report using magnetic resonance imaging to evaluate the positional fault hypothesis. Manual therapy. 2002 Feb 28;7(1):44-9.

[7] Tullberg T, Blomberg S, Branth B, Johnsson R. Manipulation does not alter the position of the sacroiliac joint: a roentgen stereophotogrammetric analysis. Spine. 1998 May 15;23(10):1124-8.

[8] Kardouni JR, Pidcoe PE, Shaffer SW, Finucane SD, Cheatham SA, Sousa CO, Michener LA. Thoracic spine manipulation in individuals with subacromial impingement syndrome does Not immediately alter thoracic spine kinematics, thoracic excursion, or scapular kinematics: a randomized controlled trial. journal of orthopaedic & sports physical therapy. 2015 Jul;45(7):527-38.

[9] Herzog W, Scheele D, Conway PJ. Electromyographic responses of back and limb muscles associated with spinal manipulative therapy. Spine. 1999 Jan 15;24(2):146-52.

[10] Suter E, McMorland G, Herzog W, Bray R. Conservative lower back treatment reduces inhibition in knee-extensor muscles: a randomized controlled trial. Journal of manipulative and physiological therapeutics. 2000 Feb 29;23(2):76-80.

[11] Suter E, McMorland G. Decrease in elbow flexor inhibition after cervical spine manipulation in patients with chronic neck pain. Clinical Biomechanics. 2002 Aug 31;17(7):541-4.

[12] DeVocht JW, Pickar JG, Wilder DG. Spinal manipulation alters electromyographic activity of paraspinal muscles: a descriptive study. Journal of manipulative and physiological therapeutics. 2005 Sep 30;28(7):465-71.

[13] Raney NH, Teyhen DS, Childs JD. Observed changes in lateral abdominal muscle thickness after spinal manipulation: a case series using rehabilitative ultrasound imaging. journal of orthopaedic & sports physical therapy. 2007 Aug;37(8):472-9.

[14] Colloca CJ, Keller TS, Gunzburg R. Biomechanical and neurophysiological responses to spinal manipulation in patients with lumbar radiculopathy. Journal of manipulative and physiological therapeutics. 2004 Jan 31;27(1):1-5.

[15] Dishman JD, Bulbulian R. Spinal reflex attenuation associated with spinal manipulation. Spine. 2000 Oct 1;25(19):2519-25.

[16] Dishman JD, Burke J. Spinal reflex excitability changes after cervical and lumbar spinal manipulation: a comparative study. The spine journal. 2003 Jun 30;3(3):204-12.

[17] Bulbulian R, Burke J, Dishman JD. Spinal reflex excitability changes after lumbar spine passive flexion mobilization. Journal of manipulative and physiological therapeutics. 2002 Oct 31;25(8):526-32.

[18] Fryer G, Pearce AJ. The effect of lumbosacral manipulation on corticospinal and spinal reflex excitability on asymptomatic participants. Journal of manipulative and Physiological Therapeutics. 2012 Feb 29;35(2):86-93.

[19] Dishman JD, Dougherty PE, Burke JR. Evaluation of the effect of postural perturbation on motoneuronal activity following various methods of lumbar spinal manipulation. The Spine Journal. 2005 Dec 31;5(6):650-9.

[20] Dishman JD, Weber KA, Corbin RL, Burke JR. Understanding inhibitory mechanisms of lumbar spinal manipulation using H-reflex and F-wave responses: A methodological approach. Journal of neuroscience methods. 2012 Sep 30;210(2):169-77.

[21] Orakifar N, Kamali F, Pirouzi S, Jamshidi F. Sacroiliac joint manipulation attenuates alpha-motoneuron activity in healthy women: a quasi-experimental study. Archives of physical medicine and rehabilitation. 2012 Jan 31;93(1):56-61.

[22] Herzog W, Scheele D, Conway PJ. Electromyographic responses of back and limb muscles associated with spinal manipulative therapy. Spine. 1999 Jan 15;24(2):146-52.

[23] Suter E, Herzog W, Conway PJ, Zhang YT. Reflex response associated with manipulative treatment of the thoracic spine. Manuelle Medizin. 2005;43(5):305-10.

[24] Suter E, McMorland G, Herzog W. Short-term effects of spinal manipulation on H-reflex amplitude in healthy and symptomatic subjects. Journal of manipulative and physiological therapeutics. 2005 Dec 31;28(9):667-72.

[25] George SZ, Bishop MD, Bialosky JE, Zeppieri G, Robinson ME. Immediate effects of spinal manipulation on thermal pain sensitivity: an experimental study. BMC Musculoskeletal disorders. 2006 Aug 15;7(1):1.

[26] Bialosky JE, Bishop MD, Robinson ME, Zeppieri G, George SZ. Spinal manipulative therapy has an immediate effect on thermal pain sensitivity in people with low back pain: a randomized controlled trial. Physical therapy. 2009 Dec 1;89(12):1292-303.

[27] Bishop MD, Beneciuk JM, George SZ. Immediate reduction in temporal sensory summation after thoracic spinal manipulation. The Spine Journal. 2011 May 31;11(5):440-6.

[28] Coronado RA, Gay CW, Bialosky JE, Carnaby GD, Bishop MD, George SZ. Changes in pain sensitivity following spinal manipulation: a systematic review and meta-analysis. Journal of Electromyography and Kinesiology. 2012 Oct 31;22(5):752-67.

[29] Millan M, Leboeuf-Yde C, Budgell B, Amorim MA. The effect of spinal manipulative therapy on experimentally induced pain: a systematic literature review. Chiropractic & manual therapies. 2012 Aug 10;20(1):1.

[30] McGuiness J, Vicenzino B, Wright A. Influence of a cervical mobilization technique on respiratory and cardiovascular function. Manual Therapy. 1997 Nov 1;2(4):216-20.

[31] McPartland JM, Giuffrida A, King J, Skinner E, Scotter J, Musty RE. Cannabimimetic effects of osteopathic manipulative treatment. JOURNAL-AMERICAN OSTEOPATHIC ASSOCIATION. 2005 Jun 1;105(6):283.

[32] Teodorczyk-Injeyan JA, Injeyan HS, Ruegg R. Spinal manipulative therapy reduces inflammatory cytokines but not substance P production in normal subjects. Journal of manipulative and physiological therapeutics. 2006 Jan 31;29(1):14-21.

[33] Degenhardt BF, Darmani NA, Johnson JC, Towns LC, Rhodes DC, Trinh C, McClanahan B, DiMarzo V. Role of osteopathic manipulative treatment in altering pain biomarkers: a pilot study. The Journal of the American Osteopathic Association. 2007 Sep 1;107(9):387-400.

[34] Bialosky JE, Bishop MD, Robinson ME, Barabas JA, George SZ. The influence of expectation on spinal manipulation induced hypoalgesia: an experimental study in normal subjects. BMC Musculoskeletal Disorders. 2008 Feb 11;9(1):1.

[35] Cook C, Sheets C. Clinical equipoise and personal equipoise: two necessary ingredients for reducing bias in manual therapy trials. Journal of Manual & Manipulative Therapy. 2014 Feb 24.