Everything you wanted to know about CENTRAL SENSITISATION

BiM review of a J Pain paper by Alban Latremoliere and Clifford J. Woolf (AKA L&W)

By Kerwin Talbot & Lorimer Moseley

Another of our series on the Journal of Pain’s most downloaded articles – this one on central sensitisation. There is no doubt that central sensitisation has such a prominent role in our pain lexicon that it almost deserves upper case letters. This paper examines the role that CENTRAL SENSITISATION has in enhancing the function of the neurons and circuits in nociceptive pathways. CENTRAL SENSITISATION (OK – I will now leave the upper case thing alone) provides a physiological explanation for the many alterations in the temporal, spatial and threshold systems associated with persistent pain. This review is clearly a fan favourite and I can understand why – it is comprehensive in the extreme and to cover it here is a distant second to you getting a copy and reading it. There are heaps of pictures that are well captioned and the text is not intimidatingly jargonised.

I want to flag one important issue, but let’s first set the scene:

  • Central sensitisation, as it is discussed in this paper, concerns changes in the functional properties of spinal nociceptors in the dorsal horn.
  • Broadly speaking, there are two patterns of sensitisation – homosynaptic and heterosynaptic.
  • Homosynaptic refers to sensitisation of the spinal nociceptors that code for the tissue in which the primary nociceptor – the nociceptor that started it all – sits. Homosynaptic sensitisation leads to allodynia and hyperalgesia in the culprit area.
  • Heterosynaptic refers to sensitisation of nearby spinal nociceptors, which code for areas adjacent to those in which the primary nociceptor – the nociceptor that started it all – sits. Heterosynaptic sensitisation leads to secondary hyperalgesia and allodynia – when the pain and sensitivity to noxious stimuli spreads to adjacent body areas.

L&W take care to emphasise that central sensitization provides an explanation for the presence of ongoing pain in the absence of ongoing primary nociception, tissue damage or inflammation. They then hone in on the two ‘causes’ of central sensitisation – ongoing inflammation or peripheral nerve damage/dysfunction – and describe the differences in central sensitisation in these two situations. They stress that the multiple inputs to the spinal nociceptor is what determines central sensitisation although they do not seem to consider descending modulation as part of that mix. I am surprised at that, but it is very difficult to think of experiments that would successfully interrogate that in animals, or humans for that matter.

L&W instead attribute central sensitisation to these two processes – inflammation or nerve injury. In clinical terms, this is profound – central sensitisation applies to your patients who have an inflammatory disorder, for example rheumatoid arthritis and to those who have a peripheral nerve injury. What proportion of your patients is that?

Does this seem odd to you? I reckon it does and I think this is because the term central sensitisation is used to explain the pain of anyone with reduced pain thresholds away from the primary nociceptive site (if indeed a primary site can be identified). The review article itself even slips into this ambiguity by referring to central sensitisation in fibromyalgia, yet they cite papers that describe reduced pain thresholds and temporal wind-up of repeated stimuli at remote sites, and decreased conditioned pain modulation at remote sites, in people with fibromyalgia. As far as I can see from the L&W review, these phenomena are consistent with neither homosynaptic nor heterosynaptic mechanisms. I contend that they point to a different mechanism altogether. I concede that there are human studies, also cited by L&W, that show enhanced activation of cortical structures in states of central sensitisation, but that would make sense the spinal nociceptor is upregulated wouldn’t it?

Aside from offering a top shelf review of true central sensitisation, L&W present to us a challenging reality – that central sensitisation causes allodynia and hyperalgesia in the problem area (primary allodynia and hyperalgesia) and the surrounding tissue (secondary….), but it does not cause reduced pain thresholds, temporal wind-up or deficient conditioned pain modulation elsewhere; and central sensitisation is caused by ongoing inflammation or nerve damage, which means it does not explain the vast majority of the patients we see.

Clearly there is an alternate version of central sensitisation out there that is applied, more and more, to the people we do see. But where did this alternate central sensitisation come from? I wonder if it is another manifestation of the difficulty we have in separating pain from nociception. I think reduced pain thresholds at remote sites and dodgy conditioned pain modulation would be a very appropriate adaptation for an organism with good reason to be hyperprotective of their body, and I can see no other place this would happen than in the brain (not necessarily via neuronal mechanisms per se). However, to call it central sensitisation is a bit misleading. When I talk about this stuff to people in pain, or to clinicians who treat them, I refer to ‘facilitation of protective neurotags’ and it seems to work. I know that any self-respecting journal editor would feel nauseous at such a term, but it seems easy to grasp down here at the coalface.

There is no doubt that this is a fantastically comprehensive coverage of central sensitisation and I highly recommend it to anyone who really wants to understand AND who has the temperament to take on the gaggle of acronyms. I think you should read it and then decide if central sensitisation as L&W know it, is an explanation for widespread pain, for chronic non-specific low back pain that moves or swaps sides or just covers your whole back and legs, or spreads up to your neck, or for fibromyalgia or for CRPS or for whiplash associated disorder or for myofascial pain syndrome (whatever that is).

About Lorimer Moseley

grey Everything you wanted to know about CENTRAL SENSITISATIONLorimer is NHMRC Senior Research Fellow with twenty years clinical experience working with people in pain. After spending some time as a Nuffield Medical Research Fellow at Oxford University he returned to Australia in 2009 to take up an NHMRC Senior Research Fellowship at Neuroscience Research Australia (NeuRA). In 2011, he was appointed Professor of Clinical Neurosciences & the Inaugural Chair in Physiotherapy at the University of South Australia, Adelaide. He runs the Body in Mind research groups. He is the only Clinical Scientist to have knocked over a water tank tower in Outback Australia.

Link to Lorimer’s published research hereDownloadable PDFs here.

Reference

Latremoliere A, & Woolf CJ (2009). Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain, 10 (9), 895-926 PMID: 19712899

  1. If they do not understand Myofascial Pain syndrome how can they profess to understand anything in regards to pain and the Central nervous system? Read all about Myofascial pain syndrome and more here>>> http://homepages.sover.net/~devstar/myopain.htm
    More Studies needed Uni-SA..
    By the way, I suffer Chronic Myofascial Pain and Fibromyalgia and I can only say what rings TRUE for me when I read material like this.

  2. Very good point Lorimer! I’ve always been wondering about these same questions. Central Sensitization is often talked about as if it was one single entity whereas I’ve always found it seemed to be more a phenomenon of increased sensitivity caracterized with very different mechanisms depending on the clinical presentation. Woolf also wrote a more «accessible» and general review article (http://www.ncbi.nlm.nih.gov/pubmed/20961685) about central sensitization that was, I found, more encompassing than the more in depth mechanistically he did with Latremolliere.

  3. Hi Lorimer. Thanks for the reference to this article and for this site. Several things occur to me: it is possible that local inflammatory changes in the spinal chord can be present without this manifesting systemically – (why else use steroid injection?). I do not see why changes in pain phenomena at sites distant to the original site cannot be explained (at least in part) by heterosynaptic phenomena, although I agree there is almost certainly more to it (e.g. brain involvement). I also wonder about the use of the seemingly ill defined term “central sensitisation”; l and W seem to apply this only to spinal phenomena whilst I gather you and others might intend it to cover the whole of the central nervous system? Semantics are important here.

  4. Sorry to disappoint you Judith, but about 20 years ago, the MPS/trigger point theory was exposed as conjecture, with high face validity but no basis in science. Nothing has changed since then, with all subsequent research perpetuating the fundamental epistemological errors made by Travell and Simons (and their followers). We have just completed a comprehensive review of the subject and will soon be submitting our article to a respected pain journal.

    References:

    Quintner JL, Cohen ML. Referred pain of peripheral nerve origin: an alternative to the “Myofascial Pain” construct. Clin J Pain 1994:10; 243-251.

    Quintner JL, Cohen ML. Are peripheral pain generators important in Fibromyalgia and chronic widespread pain? Pain Medicine 2014 (in press).

  5. Lorimer, your post (with Kerwin) provides us with much food for thought. Recently, a clinician/researcher proposed that “central sensitisation” constituted the pathology of the newly proposed disease entity called “chronic pain”! If one were to follow this line of thinking, we would have to call the disease “central sensitisation”? Ambiguity or circular argument? Take your pick.

    About 6 or so years ago, it became obvious to me that I needed to look at the bigger picture and try to understand how organisms have evolved to survive, and even flourish, in hostile environments. Of course, all too often they succumb. The neurophysiological phenomenon we call “central sensitisation” appears to be but one of the many important mechanisms in the repertoire of animals, such as human beings.

    We need to heed the warning contained in your post. Our attempts to “neuralize” the experience we call pain have not met with great success, at least in terms of improving the lot of so many of our patients.

    As always, I may be wrong or off message!

  6. Thanks again for another very interesting post Lorimer. I have not read the paper in detail yet, but based on your own summary I think that variations in what we mean when we say “central sensitisation” are important in this regard. We must be careful that we don’t add to the confusion, by focussing on the small areas of controversy between research groups, at the expense of ignoring the vast swathe of literature which is in agreement on the vital role of the CNS in persistent pain. I accept that in terms of fully understanding the phenomenon of pain, differentiating the precise mechanisms involved (homo- v hetero-synaptic, role of descending modulation etc..) is clearly important work. But none of the current controversies or points of confusion on “central sensitisation” weaken the evidence that pain involves a hell of a lot more than a local tissue (joint, disc, muscle, “trigger point” or whatever). It might seem simplistic, but my impression is that wider society (and sadly a majority of healthcare professionals) are still wedded to the predominant role of peripheral tissue “damage” as a cause of pain. Therefore, the message that CNS changes are pivotal in pain needs to be heard loud and clear by the public. In the meantime, we can try to figure out exactly how these CNS changes work (facilitation, inhibition, etc…) and what we can do to address them.
    Kieran

  7. Thank you for your insightful comments Lorimer, your idea of hyperprotection being the facilitator to protective neurotags is definately what we see clinically. The more protective we become the less harmonious are our responses. I would agree that this happens in the brain but I believe in many is first instigated through the heart. As we know there are more connections up from the heart (80%) to the brain than descending. Research from may areas is pointing to this.

  8. Thanks very much Lorimer for the critical review. I havent got through their review yet, but if they wish to limit the term of central sensitization to dorsal horn, then perhaps they should offer a term for covering the other circumstances that you point clearly to. John – a point well made, we have gone through the hardware for pain, the software for pain, with often only lip service to the other systemic features.

  9. Thanks Kerwin and Lorimer for the stimulating commentary. In our ‘Pain and Movement Reasoning’ Model, Des O’Shaughnessy and I recently renamed the category ‘Central Sensitisation’ to ‘Central Modulation’ (article under review). In part, this was because we felt the term ‘Central Sensitisation’ was increasingly being hijacked to mean reorganisation of neural structures and even directly, chronic pain. I interpret Lorimer’s comments about facilitation of protective neurotags as a similar concern. Two things that I base my conceptual understanding of pain on and may be valuable here are that (1) it is part of the body protection system and the interrelationships of components of this system are complex and difficult to isolate (i.e. influences on protective neurotags) and (2) the underpinning process of sensitisation is neuroplasticity which classically can be defined as functional or structural. I have hung on to Trojan and Pokorny’s late 1990′s review (rightly or wrongly) to anchor my definitions and concepts of neuroplasticity. Available at http://www.biomed.cas.cz/physiolres/pdf/48/48_87.pdf

    I would of course be interested in what others think, but wonder that if we consider the processes and influences of neural adaptation more explicitly – with attention to functional and structural levels of change – then our understanding of central nervous system influence on the human pain experience might be enhanced.

  10. I am hoping that Lorimer may do an article comparing and contrasting the views and terminology that occur in Explain Pain and noigroup framework to Woolf , Kathleen Sluka, Graven-Nielsen and Flora and Turk as per the IASP site. I read a few Woolf articles and I’ve been perusing the IASP open access part of the site and there is much in common re nervous system areas involved but it would be nice ti have a translation key on the terminology that differs in meaning like central sensitisation and the potential reason for the differences. Do the semantics affect treatment approach?

  11. I would appreciate some clarification on this excerpt:

    The review article itself even slips into this ambiguity by referring to central sensitisation in fibromyalgia, yet they cite papers that describe reduced pain thresholds and temporal wind-up of repeated stimuli at remote sites, and decreased conditioned pain modulation at remote sites, in people with fibromyalgia.

    As I understand it, you think that the cited papers on fibromyalgia are in conflict with the thesis that central sensitisation is caused by two processes – inflammation or nerve injury. Would you please explain this conflict to a nonprofessional (sufferer).