Study Review: Elevated production of nociceptive CC-chemokines and sE-selectin in patients with low back pain and the effects of spinal manipulation

Study Title: Elevated production of nociceptive CC-chemokines and sE-selectin in patients with low back pain and the effects of spinal manipulation: A non-randomized clinical trial

Authors: Teodorczyk-Injeyan J, McGregor M, Triano J, Injeyan HS

Publication Information: The Clinical Journal of Pain; 2018; 34(1): 68-75. doi: 10.1097/AJP.0000000000000507

Comment from Dr. Shawn Thistle:

One of the most complex and misinterpreted lines of research in chiropractic and manual medicine is the immuno-physiological-endocrine (I made up that term, but you know what I mean!) effects of spinal manipulation and other manual interventions. The research group out of the Canadian Memorial Chiropractic College (CMCC) in Toronto, Canada, has done the bulk of the work in this area. This Research Review discusses their latest publication, which had some very interesting results…enjoy!


Spinal manipulative therapy (SMT) has been shown to be effective for both chronic and acute low back pain (LBP), even though the associated biological mechanisms remain unclear (1). It has been suggested that SMT may exert anti-inflammatory effects that influence the inflammatory and immunoregulatory mediators that are inherent in spinal pain.

Tissue injury gives rise to an inflammatory response that increases neuronal excitability and an influx of leukocytes to the affected sites, which contribute to pain transmission. Several types of chemotactic cytokines (chemokines) facilitate this process, including:

  • macrophage chemotactic protein (CCL2),
  • macrophage inflammatory protein 1α (CCL3) and
  • macrophage inflammatory protein 1β (CCL4).

A potent mediator of leukocyte movement into tissues during an inflammatory response is sE-selectin, which is a vascular adhesion protein.

A study by Teodorczyk-Injeyan et al. (2) showed that the production of inducible CCL2 and CCL3, as well as inflammatory cytokines, were significantly increased in patients with chronic and recurrent neck pain. However, chemokines have not been examined in patients with non-specific low back pain.

Therefore, the purpose of this study was to assess the production of migratory/nociceptive chemokines CCL2, CCL3 and CCL4, and that of sE-selectin in patients with acute and chronic LBP before and after a course of SMT.

Pertinent Results:

Subjects, Baseline Measures & Visual Analogue Scale (VAS)/Oswestry Disability Index (ODI) Changes:

  • Nineteen acute and 23 chronic LBP patients were included in the study, along with a control group of 21 asymptomatic volunteers. The demographic profiles (age and gender) of patients and control subjects were similar.
  • At admission, VAS scores were not significantly different between acute and chronic patient groups (6.3 and 5.1 respectively). Following SMT, VAS scores decreased significantly to 2.9 and 2.9, respectively.
  • At admission, ODI scores for the acute and chronic LBP groups were 38.6 and 27.5, respectively. Following SMT, ODI scores declined significantly in both groups to 14.1 and 16.5, respectively.
  • At baseline, there were significant differences in chemokine levels between LBP patients and asymptomatic controls. When compared to controls, the production of CCL2, CCL3 and CCL4 was significantly augmented in acute LBP patients. Chronic LBP patients’ production of CCL2 and CCL4 was also significantly elevated, while CCL3 production trended higher, but was not significant.
  • Plasma sE-selectin levels in patients with acute LBP were not significantly different from controls, whereas they were significantly elevated in the chronic LBP group.

Chemokine and sE-selectin Levels After SMT:

  • Average chemokine production declined in both acute and chronic LBP patients following SMT, while it remained virtually unchanged in asymptomatic controls.
  • There was a significantly greater change in CCL3 production for both acute and chronic LBP patients as compared to the asymptomatic controls. There was a statistically significant difference in CCL4 production between the acute pain and the control groups, but not for the chronic pain group.
  • CCL2 production was markedly reduced following SMT in both patient groups, but the change was not statistically significant.
  • SMT had no significant effect on the levels of sE-selectin production in either acute or chronic LBP patients.

Clinical Application & Conclusions:

This study demonstrated that the synthesis of the CC-subfamily chemokines was significantly enhanced in patients presenting with non-specific acute and chronic LBP, as compared with asymptomatic controls. In addition, the production of CCL4 was significantly higher at baseline in the acute versus chronic pain group.

The production of the investigated chemokines declined in both groups following two weeks of SMT treatment, which was statistically significant for both CCL3 and CCL4 in acute pain patients, but only for CCL3 in chronic LBP patients.

The results of this study represent nascent evidence of the relationship between LBP and the production of chemokines, which may be ameliorated by SMT. Further research is needed to confirm these findings and clarify their clinical relevance.

Study Methods:

This was a non-randomized clinical trial that involved adults between the ages of 22 and 60 with acute (less than 4 weeks in duration) or chronic (12 weeks or longer in duration) non-specific low back pain.

Patients were excluded from the study if they:

  • were outside the inclusionary age limits;
  • had a pain level below 3/10 on the Visual Analogue Scale (VAS);
  • had received any form of manual treatment in the preceding 15 days;
  • had taken anti-inflammatory medications in the preceding 48 hours;
  • had any type of unresolved, known inflammatory condition, autoimmune condition, coagulopathy, infection, or neoplastic disease;
  • were pregnant;
  • were unwilling to sign the study consent form; or
  • were unwilling or unable to adhere to the study schedule.

Participants completed the Oswestry Disability Index (ODI) questionnaire and a 10-point visual analogue scale (VAS) for pain at baseline and following a 2-week treatment period.

A group of age- and sex-matched, healthy, asymptomatic subjects recruited from the general population was included to serve as a control group. Control subjects did not receive treatment, but were included to control for any changes in outcomes that might occur naturally during the two-week observation period.

SMT consisted of a single, high-velocity low-amplitude thrust (HVLT) to the involved segment (i.e. segmental restriction) in the lumbosacral region. Patients received six SMT treatments provided on alternate days over a 2-week period.

Peripheral blood was drawn from patients and controls prior to any manipulative intervention and at their 7th visit, which took place within 48 hours of the last treatment. The VAS and ODI questionnaires were also administered a second time at the 7th visit.

Study Strengths / Weaknesses

The treatment phase of this study only spanned 2 weeks and patients only received six SMT interventions. Furthermore, it was not a randomized clinical trial, which remains the gold standard of clinical research. Therefore, the suggestion that there is an association between SMT and the observed reduction in the production of inflammatory chemokines needs to be confirmed. The authors recommend that further studies that involve long-term follow up and include a parallel LBP control group that receives another type of treatment (other than SMT) are needed.

Finally, it is possible that the observed changes in clinical outcomes following SMT in this study might have been due to the placebo effect. It is also possible that improvements, especially observed in the acute patients, could have been due to natural progression of the condition.

Additional References:

  1. Teodorczyk-Injeyan J, Injeyan H, Ruegg R. Spinal manipulative therapy reduces inflammatory cytokines but not substance P production in normal subjects. J Manipulative Physiol Ther 2006; 29: 14-21.
  2. Teodorczyk-Injeyan J, Triano J, McGregor M et al. Elevated production of inflammatory mediators including nociceptive chemokines in patients with neck pain: a cross sectional evaluation. J Manipulative Physiol Ther 2011; 34: 498-505.

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