We were very fortunate to have Prof Srinivasa Raja and A/Prof Matthias Ringkamp write a post for us on the high profile papers that just came out in PAIN, both relevant to the ongoing debate of peripheral vs central mechanisms of neuropathic pain. In case you are not in the know, these guys are big wigs in the neuropathic pain scene and it is great to see BiM attracting such highly expert and high profile writers – thanks very much to Raj and Matthias. I found the report pretty remarkable so I have taken the time to read the papers a bit more carefully and then reflect on them here. First, the Vaso et al paper. As you hopefully know by now, the big claim from that paper is that ‘phantom limb pain comes from the periphery’. Aside from the predictable sigh of discontent at what Patrick Wall would have called the trivialisation of pain (I still see no evidence that pain originates anywhere south of the foramen magnum), this study is, in my view, a very very important one. First the obvious caveats:
I think Marshal Devor et al have put the spin on it in the interests of media and scientific attention, which is what we all tend to do at times (see a post on this here) and here. That is, I don’t think they should be describing it like they have in the title and in media releases/interviews for the above reasons as well as the very same reasons the authors cite in the paper – this study falls short of the design and controls that are required to conclude efficacy – an RCT. I suspect this is why this paper was in PAIN and not Lancet or NEJM. but I can appreciate that they are excited by the finding. I would be.
I would be excited because I think it is a fabulous study. I think it offers compelling evidence that stopping ectopic input generated at the dorsal root ganglion (DRG) stops phantom limb pain. Sure, a double blind design, and checking out the importance of which DRG is hit, are important, but the authors actually did some innovative controls, misleading expectations and concealing delivery, adjusting the protocol and starting again once it became clear that the injection could be detected – these are excellent strategies that offer compelling support for the result. And just take a moment to reflect on the size of the effect – complete elimination of phantom limb pain in the vast majority of cases and return of pain coincident in time to the duration of action of the drug. This is an effect size that might only need 10 people in a double blind RCT to detect! On top of that, presuming the idea is supported in such a trial, there are already strategies for drip feeding analgesics via pumps – the drug companies will be falling over each other to fund an RCT on this one. And so they should – it is potentially huge.
Already however, as I write, comments have come in response to Raj and Matthias’ post that argue that if blocking the peripheral input stops the pain, then perhaps the peripheral input is ‘malprocessed’ (my term), thus triggering pain, a possibility not considered by the authors. It is a nice and important argument and one that struck me immediately. We have no problem with this possibility elsewhere – think of photosensitivity in migraine — we might be able to eliminate the pain by closing the eyes, but we don’t conclude that the eyes are the problem, we conclude instead that there is a malprocessing issue. So, I agree that we can’t, on the basis of this study, conclude that the problem is in the periphery, even though the backstory, that ectopic impulse generation in the DRG is the thing being stopped, and ectopic impulse generation in the DRG is not normal, is a very attractive backstory indeed. Nonetheless, at the moment, there is no reason to conclude against central mechanisms playing an important role and I am unconvinced of Vaso et al’s arguments otherwise. Not that that should stop Marshal marshalling his troops to go hard towards a clinically viable application of this work and testing it in a robust clinical trial. I suspect that this paper will generate a flurry of studies targeting the DRG, which makes me realise I don’t know much about it really. But I know someone who does…..
So, revolution or red herring? I reckon revolution is much more likely and time will tell.
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.
Vaso A, Adahan HM, Gjika A, Zahaj S, Zhurda T, Vyshka G, & Devor M (2014). Peripheral nervous system origin of phantom limb pain. Pain, 155 (7), 1384-91 PMID: 24769187