Research Review By Dr. Brynne Stainsby©


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Date Posted:

May 2018

Study Title:

Changes in biochemical markers following spinal manipulation – a systematic review and meta-analysis


Kovanur-Sampath K, Mani R, Cotter J et al.

Author's Affiliations:

Centre for Health, Activity and Rehabilitation Research, School of Physiotherapy, University of Otago, New Zealand; School of Physical Education, Sport and Exercise Sciences, University of Otago, New Zealand.

Publication Information:

Musculoskeletal Science and Practice 2017; 29: 120-131.

Background Information:

There is a growing body of evidence demonstrating the efficacy of spinal manipulation (SM) for the treatment of low back and neck pain (1-4). While it has been demonstrated to be clinically effective, the exact mechanism through which SM exerts if effect remains uncertain. Generally, SM is believed to create a number of neurophysiological changes in the body by affecting the peripheral and autonomic nervous systems, as well as the endocrine system (5).

With respect to the sensation of pain, nociception at the site of injury is mediated by biochemical markers that are produced both locally and remotely, such as neurotensin, oxytocin and substance-P (SP), which transmit the signal from the area of injury to the nervous system (6). These biochemical markers are also related to the initiation of the inflammatory response at the site of injury, which leads to the production of proinflammatory and immunoregulatory cytokines and neurotransmitters such as tumour necrosis factor-alpha (TNF-α), interleukins (IL), endogenous opioids, hormones and catecholamines (7).

While it has been hypothesized that SM activates the release of biochemical markers from neural tissue, no systematic review has evaluated the strength of this evidence. The objective of the current systematic review was to determine the effects of SM on biochemical markers in humans and establish the level of evidence for changes in biochemical biomarkers following SM.

Pertinent Results:

  • A total of 1217 citations were screened, with 45 potentially relevant articles fully assessed for eligibility.
  • Eight trials were included in the final review (12-19). All studies were RCTs and a total of 325 subjects were included in these eight studies. The average age of study participants was 26. Only one study (13) included participants with acute neck or thoracic pain.
  • Four studies (12, 16-18) used thoracic manipulation (due to the proposed relationship to the autonomic nervous system). Two studies used cervical manipulation (13, 19). Two studies used both cervical and thoracic SM (14, 15). Typically, low velocity, low amplitude mobilizations were used as the sham procedure, or touch with no pressure was used as control.
  • From the data extracted from the eight included studies, there was moderate quality evidence that SM was better than control in eliciting changes in biochemical markers. Specifically:
    1. There was low quality evidence from three studies (12, 14, 17) that SM is better at increasing SP levels immediately after intervention, but there was very low quality evidence at the short-term time point.
    2. There was low quality evidence from one study that SM was better than control at increasing neurotensin and oxytocin levels post-intervention (15).
    3. There was moderate quality evidence from three studies of a significant difference that SM is better than control in eliciting changes in cortisol levels immediately (13, 15, 19), however, there was low quality evidence of no significant difference at short-term.
    4. There was low quality evidence from one study of no difference immediately between SM and control on epinephrine and norepinephrine levels.

Clinical Application & Conclusions:

This review identified moderate level evidence supporting the use of SM in influencing biochemical markers immediately following the intervention. While the populations studied were mainly healthy subjects, these markers have important roles in the perception of pain and the inflammatory, healing and immune responses to injury (10, 20). Given the current challenges of managing pain using opioid medications, it is possible that non-drug interventions such as SM could have a valuable role to play in pain management (21, 22).

It is noteworthy that only one study included subjects with pain. Further, no patient-related or pain-related outcomes were assessed in the included studies. As such, it is not possible to comment on the clinical application of SM (as it pertains to biochemical markers), however, the authors noted its efficacy and effectiveness have been well documented previously.

Importantly, the reviewers noted implications for future research, including managing for covarying factors and examining the effects of SM on symptomatic subjects. Including patient-related outcomes may also allow for correlation between biochemical changes and clinical outcomes. Further, a broader age range of participants would also increase the generalizability of the findings, along with a longer assessment period. Lastly, the reviewers suggested it may be relevant to compare SM in different spinal regions (including the lumbar spine).

EDITOR’S NOTE: this line of work is essentially in its infancy, with very little data to go on, as has been discussed here. What we see in practice is patients who just feel better, both immediately after SM and over time as well. It will be interesting to see if research like this, as it progresses, can identify potential underlying mechanisms for these observed responses. It is worth noting that in many of the studies included in this review, the measurement of biochemical markers was recorded after only ONE treatment. It would be interesting to see what happens to these biomarkers over time when patients are under care – we just don’t have this data at this point! Remember, sometimes research has not fully caught up to what we see in practice – this is a challenging area to study properly, without many chiropractic or manual medicine-based experts to conduct the work!

Study Methods:

  • A bibliographic search was performed on ten databases from inception to September 2016. Additionally, grey literature and trial registries were searched.
  • Randomized controlled trials (RCT) or controlled clinical trials that involved humans (no conditions on age, gender, pain) published in the English language were eligible for this review. Included studies must have investigated SM, and the intervention must have been provided by a physiotherapist, osteopath or chiropractor. The comparator could have been control, usual care, GP care, placebo, sham or other therapy. Outcome measures were biochemical markers (in any bodily fluid).
  • Two authors independently screened titles and abstracts for inclusion.
  • Two authors then independently assessed risk of bias using the Cochrane Collaboration tool (23). Studies were considered to have low risk of bias if the random sequence generation, allocation concealment and incomplete outcome data domains were adequately met.
  • Two reviewers extracted data from included studies and built evidence tables.
  • Meta-analyses were performed when possible at immediate (up to 30 minutes) and short-term (hours) time points. All outcomes were examined as a standardized mean difference (SMD) and effect size and 95% confidence intervals were calculated for each treatment comparison.
  • Overall quality of the evidence was evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system (24).

Study Strengths / Weaknesses:

  • The authors used a clearly defined research question with a thorough and systematic search.
  • Independent screening of titles, abstracts and full texts.
  • Only those trials assessed as being of high quality were included.
  • Assessment of risk of biased was performed with a validated set of criteria.
  • Two authors independently extracted the data from the included articles.
  • The reviewers provided a thoughtful reflection regarding the strengths and weaknesses of the review.
  • The primary limitation of this study relates more to the quality of the body of evidence than the methodology of the review itself.
  • Although the authors used a validated tool to assess risk of bias, only three criteria were required for inclusion in the review.
  • The sample sizes of the included studies were small.
  • The included participants were young and healthy and thus limit the generalizability of the review.
  • Only one included study provided data regarding harm/adverse events (16).
  • Given the lack of symptomatic patients in all but one study, clinical correlations cannot be made.

Additional References:

  1. Huisman PA, Speksnijder CM, De-Wijer A. The effect of thoracic spine manipulation on pain and disability in patients with non-specific neck pain: A systematic review. Disabil Rehabil 2013; 35(20): 1677-1685.
  2. Hurwitz EL. Epidemiology: Spinal manipulation utilization. J Electromyogr Kinesiol 2012; 22(5): 648-654.
  3. Coronado RA, Gay CW, Bialosky JE, et al. Changes in pain sensitivity following spinal manipulation: A systematic review and meta-analysis. J Electromyogr Kinesiol 2012; 22(5): 752-767.
  4. Gross A, Miller J, D'Sylva J, et al. Manipulation or mobilisation for neck pain: A Cochrane review. Man Ther 2010; 15(4): 315-333.
  5. Bialosky JE, Bishop MD, Price DD, et al. The mechanisms of manual therapy in the treatment of musculoskeletal pain: A comprehensive model. Man Ther 2009; 14: 531-538.
  6. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001; 413(6852): 203-210.
  7. Goebel MU, Mills PJ, Irwin MR et al. Interleukin-6 and tumor necrosis factor-A production after acute psychological stress, exercise, and infused isoproterenol: differential effects and pathways. Psychosom Med 2000; 62(4): 591-598.
  8. Lotz M, Vaughan JH, Carson DSA. Effect of neuropeptides on production of inflammatory cytokines by human monocytes. Science 1998; 241, 1218-1221.
  9. Suffredini AF, Fantuzzi G, Badolato R et al. New insights into the biology of the acute phase response. J Clin Immunol 1999; 19(4): 203-214.
  10. Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol 2009; 5(7): 374-381.
  11. Elenkov IJ, Wilder RL, Chrousos GP, et al. The sympathetic nerve and integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev 2000; 52(4): 595-638.
  12. Brennan PC, Kokjohn K, Kaltinger CJ, et al. Enhanced phagocytic cell respiratory burst induced by spinal manipulation: potential role of substance P. J. Manip Physiol Ther 1991; 14(7): 399-408.
  13. Christian GF, Stanton GJ, Sissons D, et al. Immunoreactive ACTH, [beta]-endorphin, and cortisol levels in plasma following spinal manipulative therapy. Spine 1988; 13(12): 1411-1417.
  14. Molina-Ortega F, Lomas-Vega R, Hita-Contreras F, et al. Immediate effects of spinal manipulation on nitric oxide, substance P and pain perception. Man Ther 2014; 19(5): 411-417.
  15. Plaza-Manzano G, Molina F, Lomas-Vega R, et al. Changes in biochemical markers of pain perception and stress response after spinal manipulation. J Orthop Sports Phys Ther 2014; 44(4): 231-239.
  16. Puhl AA, Injeyan HS. Short-term effects of manipulation to the upper thoracic spine of asymptomatic subjects on plasma concentrations of epinephrine and norepinephrineda randomized and controlled observational study. J Manip Physiol Ther 2012; 35(3): 209-215.
  17. Teodorczyk-Injeyan JA, Injeya HS, Ruegg R. Spinal manipulative therapy reduces inflammatory cytokines but not substance P production in normal subjects. J Manip Physiol Ther 2006; 29(1): 14-21.
  18. Teodorczyk-Injeyan JA, McGregor M, Ruegg R et al. Interleukin 2-regulated in vitro antibody production following a single spinal manipulative treatment in normal subjects. Chiropr Osteopat 2010; 18(1): 1.
  19. Whelan TL, Dishman JD, Burke J, et al. The effect of chiropractic manipulation on salivary cortisol levels. J Manip Physiol Ther 2002; 25(3): 149-153.
  20. Huada A, Stanley WJ, Elisabeth Y, et al. Endogenous opioids: biology and function. Annu Rev.Neurosci 1984; 7(1): 223-255.
  21. Ballantyn JC, Shin NS. Efficacy of opioids for chronic pain: a review of the evidence. Clin J Pain 2008; 24(6): 469-478.
  22. Cepeda MS, Farrar JT, Baumgarten M, et al. Side effects of opioids during short-term administration: effect of age, gender, and race. Clin Pharmacol Ther 2003; 74(2): 102-112.
  23. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions the Cochrane Collaboration. 2011.
  24. Schünemann HJ, Oxman AD, Higgins JP et al. Presenting results and ‘Summary of findings’ tables. In: Cochrane Handbook for Systematic Reviews of Interventions. In Version, 2008; Vol. 5(02).