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== Central sensitization == === Chronic pain might be more disabling than chronic fatigue === Most of Jo Nijs’ research focuses on the treatment of [[chronic pain]]. He argues that fatigue has been arbitrarily put forward as the primary symptom of ME/CFS patients.<ref name="NijsPain2005" /> In his own research, he found that pain explained as much of the activity limitations and participation restrictions of ME/CFS patients as fatigue,<ref name="DutchAPQ">Nijs J, Vaes P, McGregor N, Van Hoof E, De Meirleir K. Psychometric properties of the Dutch chronic fatigue syndrome–activities and participation questionnaire (CFS–APQ). Phys Ther 2003;83:444–54</ref> concluding that chronic pain might thus be more disabling than chronic fatigue in this disease.<ref name="MSK2007" /> === An increased reactivity of the central nervous system === Nijs suspects pain in ME/CFS might be explained be the process of '[[central sensitization]]' (CS). This refers to a heightened responsiveness of the central nervous system (CNS) to nociceptive stimuli. Because no lesions or neural damage can be found to explain the pain of ME/CFS patients, it is assumed that the CNS overreacts to normal stimuli, seeing them as more threatening than they are. According to Nijs this might explain why ME/CFS patients often perceive painful stimuli as more intense ([[hyperalgesia]]) or experience pain after normally innocuous stimuli ([[allodynia]]). Nijs has argues that CS might also explain other symptoms besides pain, such as the sensitivity to light, sound and various chemicals that many ME/CFS patients display.<ref name="NijsMind2012" /> === Secondary hyperalgesia === Researchers use various methods to evaluate if the CNS overreacts to stimuli. The easiest way is to measure pain thresholds all over the body, using an algometer. The research team of Nijs tested this in 30 ME/CFS patients who were suffering from chronic pain. Pain pressure thresholds were significantly lower compared to those of the control group when pain-free areas of the body were tested (a phenomenon known as secondary [[hyperalgesia]]).<ref name="Meeus2010" /> In an additional study it was shown that ME/CFS patients experienced more pain following heat stimuli.<ref name="Noxious2008" /> === Wind-up and temporal summation === Another method to test CS is to look at ‘temporal summation’, also called wind up. This refers to the process where neurons of the CNS respond to a repeated stimuli with an increased reactivity. If one quickly repeats a fixed noxious stimulus 10 times, then the last one will be experienced as more painful that the first. Researchers can measure the amount of ‘wind up’ of the neurons by looking at the difference between the first and the last stimulus. In chronic pain conditions like fibromyalgia, that difference is greater than in normal controls, suggesting these patients experience a heightened form of temporal summation. Nijs’ research group tested this procedure in 48 ME/CFS patients, but the results were ambiguous. There was only a difference in windup compared to control subjects if the pain stimuli were administered to the finger and not to the shoulder.<ref name="Polli, 2017" /> === Conditioned pain modulation: pain inhibits pain === Central sensitization doesn’t necessary involve an increased susceptibility to stimuli. It can also be explained by a defect in the inhibitory pain pathways of the body. One highly researched mechanism in this respect is called 'conditioned pain modulation' or CPM (an older name is 'diffuse noxious inhibitory control'). This refers to the fact that pain in one area of the body can decrease pain in another area. Nijs’ research group tested this in 2009 using heat stimuli showing that conditioned pain modulation was normal but delayed in ME/CFS patients.<ref name="Noxious2008" /> In two other studies,<ref name="MeeusAce2013" /><ref name="Polli, 2017" /> Nijs' research group tested CPM using the pressure of an inflatable occlusion cuff as the conditioning stimulus. In both cases there were no differences between ME/CFS patients and healthy controls. === Endogenous pain inhibition after exercise === Another way to induce endogenous inhibition is to exercise. When healthy people exercise, their brain induces the production of endorphins that increase pain thresholds. In some chronic pain patients like fibromyalgia and whiplash associated disorders, this endogenous pain inhibition is defective and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004, Whiteside et al.<ref>Whiteside A, Hansen S, Chaudhuri A. Exercise lowers pain threshold in chronic fatigue syndrome. Pain. 2004 Jun;109(3):497-9.</ref> first showed this defect in ME/CFS patients, though their study only involved five patients. The Pain in Motion group of Nijs and colleagues confirmed these results in two of their studies.<ref name="Threshold2010" /><ref name="Oosterwijck2010" /> While pain thresholds increased in normal controls, they decreased in the ME/CFS patient group. These studies however, only included ME/CFS that were suffering from chronic pain.<ref name="NijsMind2012" /> It therefore remains uncertain whether similar results will also show up in ME/CFS patients that do not have comorbid FM.<ref>Yunus MB. Editorial review: an update on central sensitivity syndromes and the issues of nosology and psychobiology. Curr Rheumatol Rev. 2015;11(2):70-85.</ref> === Criteria for the classification of central sensitization pain === Jo Nijs is regarded as an international expert in central sensitization. He has researched CS in patients with chronic spinal pain, chronic low back pain,<ref>Nijs J, Apeldoorn A, Hallegraeff H, Clark J, Smeets R, Malfliet A, et al. Low back pain: guidelines for the clinical classification of predominant neuropathic, nociceptive, or central sensitization pain. Pain Physician. 2015 May-Jun;18(3):E333-46.</ref> shoulder pain,<ref>Sanchis MN, Lluch E, Nijs J, Struyf F, Kangasperko M. The role of central sensitization in shoulder pain: A systematic literature review. Semin Arthritis Rheum. 2015 Jun;44(6):710-6.</ref> knee osteoarthritis,<ref name="Lluch2017">Lluch E, Nijs J, Courtney CA, Rebbeck T, Wylde V, Baert I, et al. Clinical descriptors for the recognition of central sensitization pain in patients with knee osteoarthritis. Disabil Rehabil. 2017 Aug 2:1-10.</ref> cancer-related pain<ref name="Cancer2016">Nijs J, Leysen L, Adriaenssens N, Aguilar Ferrándiz ME, Devoogdt N, et al. Pain following cancer treatment: Guidelines for the clinical classification of predominant neuropathic, nociceptive and central sensitization pain. Acta Oncol. 2016 Jun;55(6):659-63.</ref> and chronic whiplash.<ref name="Oosterwijck2013">Van Oosterwijck J, Nijs J, Meeus M, Paul L. Evidence for central sensitization in chronic whiplash: a systematic literature review. Eur J Pain. 2013 Mar;17(3):299-312.</ref> In 2014, he was first author of a consensus paper in which 18 experts set out criteria for the diagnosis of central sensitivity.<ref name="Neuroscience2014">Nijs J, Torres-Cueco R, van Wilgen CP, Girbes EL, Struyf F, Roussel N, et al. Applying modern pain neuroscience in clinical practice: criteria for the classification of central sensitization pain. Pain Physician. 2014 Sep-Oct;17(5):447-57.</ref> After neuropathic pain has been ruled out, the criteria propose to assess if the severity of pain is “disproportionate to the nature and extent of injury and pathology”. This is an obligatory criterion; if pain is not disproportionate, then it doesn’t involve CS. Secondly it is proposed to look at the pain distribution; if pain is widespread and diffuse then the clinician can diagnose CS in his patient. If this is not the case, then the clinician can use the central sensitization inventory (CSI), a questionnaire that has been developed to assess CS and mostly looks at secondary symptoms like sensitivity to light, bad sleep and concentration problems. If the patient scores 40 or more on the CSI, than the clinician can make the diagnosis of CS. === Treating central sensitization === Together with long-time collaborator [[Mira Meeus]], Nijs wrote two reviews<ref name="Options2011" /><ref name="NijsCS2014" /> on the treatment of CS. Special attention goes to medications that target central pathways of the pain response. One example is acetaminophen (paracetamol) that reinforces the inhibitory serotonergic pathway. Meeus & Nijs tested this in ME/CFS patients with comorbid fibromyalgia. Though pain thresholds rose, there was no influence on temporal summation or conditioned pain modulation.<ref name="MeeusAce2013" /> [[Selective serotonin reuptake inhibitor]]s (SSRIs) also activate the serotonergic descending pathways. In a 2011 study, Meeus & Nijs gave their test subjects intravenous SSRI ([[citalopram]]) but the trial had to be stopped prematurely, since the medication caused too many side-effects.<ref name="MeeusSero2011" /> [[Opioid]]s form another option, although these drugs are now restricted and rather controversial because they can lead to [[substance use disorder|addiction]]<ref name="OpioidRisk">{{Cite web | url = http://www.medscape.com/viewarticle/547066 | title = Prescribing Opioids for Chronic Pain| website = Medscape |language=en|access-date=2022-04-03}}</ref> and cause selective pain sensitization. In 2017 Meeus & Nijs tested [[morphine]] and [[naloxone]] (an opioid antagonist) against a placebo, but the results were rather bleak: <blockquote>"[...] neither morphine nor naloxone influenced deep tissue pain, temporal summation or CPM. Therefore, these results suggest that the opioid system is not dominant in (enhanced) bottom-up sensitization (temporal summation) or (impaired) endogenous pain inhibition (CPM) in patients with CFS/FM or RA."<ref name="Hermans, 2017" /></blockquote>There are other therapeutic options to treat central sensitization like N-methyl-D-aspartate –receptor antagonists (e.g. ketamine), GABA-antagonists (e.g. pregabalin) or a ketogenic diet. Nijs & Meeus also propose exercise therapy and emphasize that a time-contingent approach is preferable in treating CS:<blockquote>"A symptom-contingent approach may facilitate the brain in its production of nonspecific warning signs like pain, whereas a time-contingent approach may deactivate brain-orchestrated top-down pain facilitatory pathways."<ref name="NijsCS2014" /></blockquote>The authors do however caution that this approach might not work in every CS-patient group: <blockquote>"[...] some patients with CS pain, including those with chronic whiplash associated disorders , chronic fatigue syndrome and fibromyalgia, are unable to activate endogenous analgesia following exercise. It remains to be established whether long-term exercise therapy accounting for the dysfunctional endogenous analgesia is able to 'treat' CS in these patients."<ref name="NijsCS2014" /></blockquote>
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