Is central sensitisation really a thing?


It seems odd to me that there’s much argument about central sensitisation in pain circles. I thought the idea of central sensitisation was well-established based on research from some years ago – but apparently there are still arguments about its relevance, and lots of debate about how to identify it clinically. This post is based mainly on a presentation by Jo Nijs from Pain in Motion, at the recent NZ Pain Society meeting in Nelson. In this post I want to briefly review the material presented by Jo suggesting that central sensitisation is a thing. I’ll write more about assessment in a future blog, or this post will be the longest ever!

Firstly, what is it and why should it matter? Researchers have long been aware that when a nerve is repeatedly stimulated, in future stimulation it will respond for longer and with more intensity – this is called long-term potentiation. Recently, the contribution of glial cells to this situation has been identified (remember glia? Those little cells whose purpose no-one really knew? Turns out they release gliotransmitters that circulate throughout the spinal cord and allow information to be transmitted widely, far from the original source of stimulation – see Kronschlager, Drdla-Schutting, Gassner, Honsek et al, (2016). Glial cells occur widely throughout the central nervous system, and while LTP is a process we’ve known about in the CNS for some time – we’ve known because this is how “memories” are formed (remember “nerves that fire together wire together”? Pathways that frequently activate develop the tendency to continue to activate together) – we’ve perhaps not been aware that this occurs in the spinal cord as well. So, LTP occurs in both the spinal cord and the brain, and there is more than one way this process is facilitated. Glial cells are one. Central sensitisation involves this process of long-term potentiation across and amongst pathways within our nervous system – it means information from peripheral regions like your big toe are more likely to be transmitted to areas in the brain responsible for attending and responding to threatening information.

Why does this matter? Well, if we think of ourselves as a finely tuned homeostatic machine, one that wants to remain in a stable state, we can think of two systems balanced with one another. One system works to facilitate information transmission (nociceptive facilitation), while the other works to reduce or modulate this transmission (endogenous hypoalgesia). If we continue with the machine analogy, we want to know about “trouble” as soon as possible – so our nociceptive facilitatory system is like an accelerator, working promptly to make sure we know about the state of play very quickly. If you’ve ever driven a race car, you’ll know how twitchy the accelerators are! The brakes on this system is our endogenous opioid system which reduces the influence of the nociceptive system so we can keep moving forward. If the brakes fail, for whatever reason, in a race car we’ll burst forward! Similarly, if the endogenous modulatory system fails, for whatever reason, far more information ascends to relevant regions in the brain for interpretation – and ouch.

What sorts of things enhance connectivity between areas of the brain that deal with nociceptive information? Well, this is where things get all woolly and psychosocial for a while (sorry guys!). From many fMRI studies, it’s possible to establish that “pain catastrophising” or the tendency to brood on pain, feel helpless about it, and regard the pain as seriously intense activates brain areas like the dorsolateral prefrontal cortex, the anterior cingulate cortex, and the insula, which in term reduces the efficiency of the opioid analgesic system (that endogenous opioid system), makes it harder to distract attention from the pain, and increases facilitation (ie the transmission of nociceptive information from lower CNS to higher). In other words, this very psychological construct has a biological component to it.

Central sensitisation has been identified in many different pain problems, ranging from osteoarthritis in the knee (Akinci, Al Shaker, Chang, et al, 2016), post-cancer pain (Lam, 2016), shoulder pain (Sanchis, lluch, Nijs, Struyf & Kangasperko, 2015), and yes, those messy complicated ones like whiplash (Coppieters, Ickmans, Cagnie, Nijs, et al, 2015), low back pain (Sanzarello, Merlini, Rosa, Perrone et al, 2016) and fibromyalgia (Walitt, Ceko, Gracely & Gracely, 2016). Rates of central sensitisation vary from 10% in shoulder pain to 100% in fibromyalgia. For some good reading on central sensitisation in these disorders, take a look at the references I’ve cited.

So yes, central sensitisation is a thing, and it results in increased pain experiences that last longer and spread. Why do some people experience while others don’t? Now we’re venturing into rather more speculative areas, but some findings seem clinically useful. People who have, in their early years, experienced physical and/or psychological trauma, those who tend to catastrophise or have unhelpful beliefs (often inaccurate beliefs) about their pain,  those who have poor sleep, and those who have an elevated stress response seem more likely to have pain that fits with what we’d expect with central sensitisation (See Nijs & Ickmans, 2014).

Why does this occur? Well, stress increases release of glutamate and this in turn increases CNS excitability (makes sense – let’s react faster to everything, at least for a short time). At the same time, stress reduces GABA and serotonin, and as a result inhibition is reduced (the brakes come off). If we add microglial activity to the mix (remember that’s going to increase the connectivity between neurones), and if we add ongoing release of adrenaline in because the stress has been continuing for a while, we’re going to end up with activated glial activity in the prefrontal cortex, amygdala and hippocampus, all important areas for detecting salience and making decisions to act. These glial cells release chemicals known to increase neuroinflammation, reducing hippocampal activity (ultimately reducing volume of neurones in this area), increasing the size of the amygdala (which means it’s more capable of responding to threat), and reducing the prefrontal cortex size, reducing the capacity to make considered decisions (Kregel, Meeus, Malfliet et al, 2015). Ew… nasty! In longterm stressful situations, it seems our brains adapt – and not in a helpful way when it comes to experiencing pain. Whatever you do DON’T say to your patients  “Oh and by the way, your back pain means your brain is inflamed and parts of your brain are shrinking” – this is NOT helpful!

Next post I’ll discuss assessing for central sensitisation – but before I do, remember that central sensitisation is not the only factor at play in ongoing pain. In fact, some people don’t seem to develop central sensitisation even with ongoing nociception from either disease processes, or inflammation. We don’t really know why. What we do know is that simply treating peripheral nociceptive input when central sensitisation is present may fail to help the person – so keeping an eye out for it is important.

 

Akinci, A., Al Shaker, M., Chang, M. H., Cheung, C. W., Danilov, A., Jose Duenas, H., . . . Wang, Y. (2016). Predictive factors and clinical biomarkers for treatment in patients with chronic pain caused by osteoarthritis with a central sensitisation component. International Journal of Clinical Practice, 70(1), 31-44.

Coppieters, I., Ickmans, K., Cagnie, B., Nijs, J., De Pauw, R., Noten, S., & Meeus, M. (2015). Cognitive performance is related to central sensitization and health-related quality of life in patients with chronic whiplash-associated disorders and fibromyalgia. Pain Physician, 18(3), E389-401.

Kregel, J., Meeus, M., Malfliet, A., Dolphens, M., Danneels, L., Nijs, J., & Cagnie, B. (2015). Structural and functional brain abnormalities in chronic low back pain: A systematic review☆. Paper presented at the Seminars in arthritis and rheumatism.

Kronschläger, M. T., Drdla-Schutting, R., Gassner, M., Honsek, S. D., Teuchmann, H. L., & Sandkühler, J. (2016). Gliogenic ltp spreads widely in nociceptive pathways. Science, 354(6316), 1144-1148. doi:10.1126/science.aah5715

Lam, D. K. (2016). Emerging factors in the progression of cancer-related pain. Pain Management, 6(5), 487-496.

Nijs, J., & Ickmans, K. (2014). Chronic whiplash-associated disorders: To exercise or not? The Lancet, 384(9938), 109-111.

Sanchis, M. N., Lluch, E., Nijs, J., Struyf, F., & Kangasperko, M. (2015). The role of central sensitization in shoulder pain: A systematic literature review. Seminars in Arthritis & Rheumatism, 44(6), 710-716.

Sanzarello, I., Merlini, L., Rosa, M. A., Perrone, M., Frugiuele, J., Borghi, R., & Faldini, C. (2016). Central sensitization in chronic low back pain: A narrative review. Journal of Back & Musculoskeletal Rehabilitation, 29(4), 625-633.
Walitt, B., Ceko, M., Gracely, J. L., & Gracely, R. H. (2016). Neuroimaging of central sensitivity syndromes: Key insights from the scientific literature. Current Rheumatology Reviews, 12(1), 55-87.
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4 comments

  1. If I’m not mistaking the references you quote that supposedly find the same kind of Central Sensitization in humans as Kronschlager et al. found in rodents, are either systematic reviews (keyword based) or in direct opposition to your statement? This is what Walitt et al. (whom you reference) conclude:

    “…A coherent picture of a “central sensitization” mechanism that bridges across all of these syndromes does not emerge from the existing scientific evidence.”

    Your references would seem to point to a much more clinical phenomena: Central Sensitization Syndrome. Thus, I urge serious, academic clinicians, such as your self, to understand and respect basic science for it’s possibilities and limitations before suggesting that Central Sensitization (of which LTP is a hallmark phenomena), should be the same as or the only underlying mechanism behind any clinical syndrome or diagnose.

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