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THE LANCET Neurology Vol 2 September 2003 http://neurology.thelancet.com524

For years osteoarthritis was the preserveof rheumatologists, with joint erosionassumed as the be-all and end-all of thedisease. However, important findings inpain research are forcing a shake up inthinking, and osteoarthritis is nowincreasingly seen as a neurologicaldisease with a powerful central input. Ata Novartis Foundation meeting inLondon, UK (July 1, 2003) rheumat-ologists and neuroscientists came head-to-head to discuss the clinicalimplications of these emerging ideas.

The prevalence of osteoarthritis ison the rise. 13% of people aged over55 years have the disorder, and thenumbers are set to double in the next17 years. This situation prompts fears ofan “epidemic” driven by the two mainrisk factors: ageing and obesity.

“People come to us because they arein pain”, says rheumatologist DavidFelson (Boston University School ofMedicine, MA, USA). “Unfortunatelytreatments are limited, and preventingcartilage loss is not necessarily thesolution.” To develop better paincontrol it is crucial to understand whatis generating osteoarthritic joint pain.

“The nervous system isn’t a passivebystander; it is an important player inthe persistence of joint pain”, assertsBruce Kidd (Bart’s & The LondonSchool of Medicine, London, UK).Kidd, a rheumatologist, has pinneddown one important difference betweenhow people with arthritis and howhealthy individuals process pain. Heused a capsaicin-based test that elicits anintense, short-lived pain. Whereascontrols soon recover, patients witharthritis develop a neurogenic flare with heightened sensitivity in areassurrounding the affected joints.

Kidd proposes that this hyper-sensitivity results from a complexinteraction between the immune andnervous systems. Sensory fibres at thesite of injury release neuropeptides, suchas substance P and calcitonin-gene-related peptide (CGRP). These changesin sensory fibres not only trigger paindirectly but also sensitise the peripheraland central nociceptive systems, whichleads to a hypersensitive state. As aresult, the person’s pain threshold islowered to the extent that even

movements within the normal rangebecome painful. “We should considerusing neuropeptide antagonists to act asmodulators in the long term”, says Kidd.

For Gunnar Ordeberg (KarolinskaInstitute, Stockholm, Sweden), anorthopaedic surgeon, sensitisationexplains the baffling symptoms of thisjoint disease. “Osteoarthritis symptomsusually start with localised pain thatresponds to analgesics”, he explains.“Eventually the response to pain killersis lost and the area with pain spreads, tothe thigh and knee, then the leg, andoften there is pain all over the body.”

To test whether sensitisation isdriving patients’ spontaneous painand hyperalgesia, Ordeberg applieda tourniquet in 15 patients withosteoarthritis and in 13 healthy controlswhile testing for pain. He found thatalthough the tourniquet increases thepain threshold for healthy people—asign of pain inhibition—there is no sucheffect in patients. This finding suggeststhat the chronic pain in inflamed jointsdisrupts central inhibitory controls,resulting in central hyperexcitability.“When patients complain of widespreadpain it is often regarded as a sign ofpsychological distress”, says Ordeberg,“but it appears that central sensitisationis driving these abnormal pain states.”

This state of hyperexcitability is notconfined to human beings. Hans-GeorgSchaible (University of Jena, Germany)has used neuronal recordings from catand rat spinal cords to show that a

painful message from the periphery maycreate a state of central sensitisation. “Ifyou trigger inflammation in the joint,not only does the pain increase in theinflamed joint but there is an expansionof the neuronal receptive field leading tosymptoms in healthy adjacent and evenremote tissues”, says Schaible.

How much noxious stimulus ittakes for central sensitisation to kick in is not known. Schaible hasfound that, in addition to substance P,several mediators contribute to thisinflammation-induced spinal hyper-excitability: glutamate, neurokinin A,CGRP, prostaglandins, and others mayall serve as potential drug targets. “TheCNS is not just a cable from a diseasedjoint to the brain. It is also modifyingthe whole pain story for the humanbeing”, explains Schaible.

David Blake (University of Bath,UK) pushes the case for CNSinvolvement even further. “Probablyevery pain becomes central if you knowhow to find it”, he says. His assertionstems from clinical experience of thetreatment of “inappropriate” pain.Puzzled as to why many people with arheumatological disorders have painthat cannot be matched to physicalfindings, he thought that it may be asituation similar to phantom limb painin amputees. Blake set out to test thehypothesis that a mismatch betweenmotor intentions and sensory feedbackunderlies this type of pain.

With Candy McCabe, Blake hasadapted Ramachandran’s mirror experi-ments and tested them on people withcomplex regional pain syndrome. Bypracticing movements in the mirrors tocorrect the incongruent perception,pain and stiffness subsided. “In somepeople we can induce this in seconds”,says Blake, who believes these findingsmay have important implications for thetreatment of rheumatological pain.

As James Henry (University ofWestern Ontario, Canada) puts it:“arthritis should be seen as a disordernot only of the periphery but also of theCNS”. The hope is that, by examiningosteoarthritis in this new light,researchers will come up with a host ofnew, more effective therapies.Lisa Melton

Osteoarthritis pain goes central

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Osteoarthritis pain with central involvement