Regardless of your preferences in health care, pain management is a complicated topic that researchers remain invested in. Issues like sensitivity to pain, learned responses to pain and of course misuse of pain medication in many cases make it an important and complicated topic. That’s what makes the following study a particularly poignant one: it looked at the impact of spinal manipulation on two biomarkers associated with pain perception and sensitivity.

The study of pain sensitivity and perception is an ongoing area and will likely remain so. Previous studies focussing on the effects spinal manipulation can have on pain sensitivity used a variety of sensory measures. This current study wanted to investigate the effects spinal manipulation has on pain sensitivity on two particular markers: Nitric Oxide and Substance P. Both biomarkers sound like something you would hear on a spy-fi show, but in fact they are naturally occurring in the body:

  • Nitric oxide is considered as the major local vasodilator. It’s involved with cell survival and nociception (Nociception is the neural process of encoding responses to noxious stimuli, such as physical or chemical stressors, in the sensory parts of the nervous system). Evidence exists that demonstrates the potential benefits of Nitric Oxide in small amounts, as it can inhibit nociceptive pathways. Other research suggests Nitric Oxide could contribute to hyperalgesia, which is an increase in sensitivity to pain.
  • Substance P is thought to have an analgesic or pain-relieving effect on the processing of sensory stimuli relating to pain. It is related to vasodilation induced by the release of Nitric Oxide, contributes to vasodilation and is thought to have sensitising effect on peripheral nociceptors. Some studies suggest that Substance P can lower an individual’s pain threshold by causing generalised spinal cord hyperexcitability, although this was specific to individuals with chronic conditions such as fibromyalgia.

In order to examine the impact of spinal manipulation on pain via these two biomarkers, researchers created a single-blind, randomised controlled trial involving forty healthy, asymptomatic participants. Thirty were included in the trial after screening was conducted in order to make sure there was no musculoskeletal pain at the time of the study, and that no other drugs or manipulation was being used by the participants. In the end, 16 men and 14 women took part and they were divided into three groups of ten participants. Blood samples were taken and pressure pain threshold measures were recorded pre-intervention, immediately after the intervention and two hours after the intervention. In terms of the groups:

  • The first group, the control group, received no intervention
  • The second group received Cervical manipulation (which is the upper neck area)
  • The third group received thoracic manipulation (which is the upper back/chest area)

It was a simple study design, and while further research would be helpful in order to see the longer-term effects or the results of a longer course of care, the results were positive:

  • Cervical manipulation increased Substance P in asymptomatic participants along with an increase in upper-limb pressure pain threshold. The increase in this threshold was determined to be related to the increase in Substance P as Nitric Oxide showed no change.
  • The thoracic experimental group did not show any significant change in the measures.
  • The study is novel in a way, as it records no change in Nitric Oxide blood plasma concentrations, which have been recorded in a variety of other manual interventions such as massage and acupuncture.
  • This study supports the inverse relationship between Nitric Oxide and pain.

The nature of research is that one study always seems to lead to another area of potential increased understanding. The limitations of one study lead to potential further studies aiding in the human understanding of what goes on inside our bode and brain. In this case, as in all studies, there are limitations. The difference in Nitric Oxide levels for the experimental groups could be due to the healthy population the results were obtained from, as many things can influence basal Nitric Oxide levels. Additionally, the study had a very small sample size which means it is unlikely the sample is representative of the wider population of healthy individuals and makes the findings harder to generalise.

The sample was taken from asymptomatic individuals; thus, the findings cannot be generalised to people with chronic illnesses. In fact, the Nitric Oxide levels may be different or more extreme and respond differently in patients with chronic pain. Although the results from this study did not add depth to the role Nitric Oxide plays in pain sensitivity, there is a large body of work that supports an existing correlation between Nitric Oxide and Pressure Pain Thresholds as well as musculoskeletal pain perception and thus the study is a valuable addition to the knowledge bank. Increasing the sample size and diversity may generate more results that support this.

If you are interested, you can check out the full study at the reference below.



  1. Molina-Ortega F, Lomas-Vega R, Hita-Contreras F, et al. Immediate effects of spinal manipulation on nitric oxide, substance P and pain perception. Manual Therapy. 2014;19(5):411-417. doi:10.1016/j.math.2014.02.007


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