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