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Central sensitization
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==Evidence for central sensitization in ME/CFS == === Pain thresholds and hyperalgesia === Various quantitative sensory tests (QST) can be used to evaluate if the CNS overreacts to stimuli and the presence of CS is to be suspected.<ref>{{Cite journal | last = Staud | first = Roland | date = May 2012 | title = Abnormal endogenous pain modulation is a shared characteristic of many chronic pain conditions |url =http://dx.doi.org/10.1586/ern.12.41 | journal = Expert Review of Neurotherapeutics | volume = 12 | issue = 5 | pages = 577–585|doi=10.1586/ern.12.41|issn=1473-7175|quote= | authorlink = Roland Staud|via=}}</ref> One method involves measuring pain thresholds all over the body with an algometer. The Belgian Pain in Motion research group tested this in 30 ME/CFS who suffered from chronic pain. Pain pressure thresholds were significantly lower compared to those of the control group, also when pain-free areas of the body were tested (secondary hyperalgesia).<ref>{{Cite journal | last = Meeus | first = Mira | last2 = Nijs | first2 = Jo | last3 = Huybrechts | first3 = Sven | last4 = Truijen | first4 = Steven | date = 2010-01-14 | title = Evidence for generalized hyperalgesia in chronic fatigue syndrome: a case control study | url = http://dx.doi.org/10.1007/s10067-009-1339-0 | journal = Clinical Rheumatology | volume = 29 | issue = 4 | pages = 393–398|doi=10.1007/s10067-009-1339-0|issn=0770-3198|quote= | authorlink = Mira Meeus | author-link2 = Jo Nijs|via=}}</ref> In an additional study it was shown that ME/CFS patients experienced more pain following heat stimuli.<ref name=":6">{{Cite journal | last = Meeus | first = Mira | last2 = Nijs | first2 = Jo | last3 = Van de Wauwer | first3 = Naomi | last4 = Toeback | first4 = Linda | last5 = Truijen | first5 = Steven | date = Oct 2008 | title = Diffuse noxious inhibitory control is delayed in chronic fatigue syndrome: An experimental study | url = http://dx.doi.org/10.1016/j.pain.2008.05.018 | journal = Pain | volume = 139 | issue = 2 | pages = 439–448|doi=10.1016/j.pain.2008.05.018|issn=0304-3959|quote= | authorlink = Mira Meeus | author-link2 = Jo Nijs|via=}}</ref> In a large Norwegian study involving 120 adolescent with ME/CFS, pain pressure thresholds were significantly lower in patients compared to healthy controls.<ref>{{Cite journal | last = Winger | first = Anette | last2 = Kvarstein | first2 = Gunnvald | last3 = Wyller | first3 = Vegard Bruun | author-link3 = Vegard Bruun Wyller | last4 = Sulheim | first4 = Dag | last5 = Fagermoen | first5 = Even | last6 = Småstuen | first6 = Milada Cvancarova | last7 = Helseth | first7 = Sølvi | date = Oct 2014 | title = Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study | url = http://dx.doi.org/10.1136/bmjopen-2014-005920 | journal = BMJ Open | volume = 4 | issue = 10| pages = e005920|doi=10.1136/bmjopen-2014-005920|issn=2044-6055}}</ref> Other studies yielded conflicting results. Using cold pressor tests, Schmaling et al. did not find any differences in pain thresholds between ME/CFS patients and healthy controls.<ref>{{Cite journal | last = Schmaling | first = Karen B. | last2 = Hamilos | first2 = Daniel L. | last3 = Diclementi | first3 = Jeannie D. | last4 = Jones | first4 = James F. | date = Jan 1998 | title = Pain Perception in Chronic Fatigue Syndrome | url =http://dx.doi.org/10.1300/j092v04n03_03 | journal = Journal of Chronic Fatigue Syndrome | volume = 4 | issue = 3 | pages = 13–22|doi=10.1300/j092v04n03_03|issn=1057-3321}}</ref> The same finding was reported by Buchwald and colleagues in a study involving 15 twin pairs discordant for [[Chronic fatigue syndrome|CFS]].<ref>{{Cite journal | last = Ullrich | first = Philip M. | last2 = Afari | first2 = Niloofar | last3 = Jacobsen | first3 = Clemma | last4 = Goldberg | first4 = Jack | last5 = Buchwald | first5 = Dedra | date = 2007-02-07 | title = Cold Pressor Pain Sensitivity in Monozygotic Twins Discordant for Chronic Fatigue Syndrome | url =http://dx.doi.org/10.1111/j.1526-4637.2007.00277.x | journal = Pain Medicine | volume = 0 | issue = 0 | pages = 070207140827002–???|doi=10.1111/j.1526-4637.2007.00277.x|issn=1526-2375|quote= | author-link3 = | author-link4 = | author-link5 = Dedra Buchwald|via=}}</ref> An Italian group of the D’Annuzio University of Chieti found pain thresholds in the skin and subcutis to be normal in ME/CFS.<ref>{{Cite journal | last = Vecchiet | first = Leonardo | last2 = Montanari | first2 = Giuseppe | last3 = Pizzigallo | first3 = Eligio | last4 = Iezzi | first4 = Sabina | last5 = de Bigontina | first5 = Paolo | last6 = Dragani | first6 = Luca | last7 = Vecchiet | first7 = Jacopo | last8 = Giamberardino | first8 = Maria Adele | date = Apr 1996 | title = Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome | url =http://dx.doi.org/10.1016/0304-3940(96)12559-3 | journal = Neuroscience Letters | volume = 208 | issue = 2 | pages = 117–120|doi=10.1016/0304-3940(96)12559-3|issn=0304-3940}}</ref> They did however find hyperalgesia in the muscles of these patients. Because a number of “anatomical muscle alterations” were discovered, the authors speculated the hyperalgesia to be caused by peripheral instead of central mechanisms. === Wind-up and temporal summation === To assess pain facilitation, researchers can test temporal summation of second pain. This refers to the process where neurons of the CNS react to repeated stimuli with an increased response. If one quickly repeats a fixed noxious stimulus 10 times, the last one will be experienced as more painful than 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 (TS). Collin et al. tested this procedure in 48 ME/CFS patients, but the results were ambiguous. There was only a difference in wind-up compared to control subjects if the pain stimuli were administered to the finger and not to the shoulder.<ref name=":7">{{Cite journal | last = Collin | first = Simon M. | last2 = Nijs | first2 = Jo | last3 = Meeus | first3 = Mira | last4 = Polli | first4 = Andrea | last5 = Willekens | first5 = Barbara | last6 = Ickmans | first6 = Kelly | date = May 2017 | title = Endogenous Pain Facilitation Rather Than Inhibition Differs Between People with Chronic Fatigue Syndrome, Multiple Sclerosis, and Controls: An Observational Study | url = https://www.ncbi.nlm.nih.gov/pubmed/28535557 | journal = Pain Physician | volume = 20 | issue = 4| pages = E489–E497|issn=2150-1149|pmid=28535557|quote= | authorlink = Simon Collin | author-link2 = Jo Nijs | author-link3 = Mira Meeus | author-link4 = Andrea Polli | author-link5 = Barbara Willekens|via= | author-link6 = Kelly Ickmans}}</ref> Testing of temporal summation was part of the procedure in three other studies without it being the primary outcome measure. One study<ref name=":12">{{Cite journal | last = Hermans | first = Linda | last2 = Nijs | first2 = Jo | last3 = Calders | first3 = Patrick | last4 = De Clerck | first4 = Luc | last5 = Moorkens | first5 = Greta | last6 = Hans | first6 = Guy | last7 = Grosemans | first7 = Sofie | last8 = Roman De Mettelinge | first8 = Tine | last9 = Tuynman | first9 = Joanna | date = Nov 15, 2017 | title = Influence of Morphine and Naloxone on Pain Modulation in Rheumatoid Arthritis, Chronic Fatigue Syndrome/Fibromyalgia, and Controls: A Double-Blind, Randomized, Placebo-Controlled, Cross-Over Study | url = http://dx.doi.org/10.1111/papr.12613 | journal = Pain Practice | volume = 18 | issue = 4 | pages = 418–430|doi=10.1111/papr.12613|issn=1530-7085|quote= | authorlink = Linda Hermans | author-link2 = Jo Nijs | author-link3 = Patrick Calders | author-link4 = Luc De Clerck | author-link5 = Greta Moorkens|via=}}</ref> found TS to be higher in ME/CFS patients than controls, while two others did not find significant differences.<ref name=":13">{{Cite journal | last = Meeus | first = Mira | last2 = Ickmans | first2 = Kelly | last3 = Struyf | first3 = Filip | last4 = Hermans | first4 = Linda | last5 = Van Noesel | first5 = Kevin | last6 = Oderkerk | first6 = Jorinde | last7 = Declerck | first7 = Luc S. | last8 = Moorkens | first8 = Greta | last9 = Hans | first9 = Guy | date = Mar 2013 | title = Does acetaminophen activate endogenous pain inhibition in chronic fatigue syndrome/fibromyalgia and rheumatoid arthritis? A double-blind randomized controlled cross-over trial | url = https://www.ncbi.nlm.nih.gov/pubmed/23511692 | journal = Pain Physician | volume = 16 | issue = 2| pages = E61–70|issn=2150-1149|pmid=23511692|quote= | authorlink = Mira Meeus | author-link2 = Kelly Ickmans | author-link3 = Filip Struyf | author-link4 = Linda Hermans | author-link5 = Kevin Van Noesel|via= | author-link6 = Jorinde Oderkerk | author-link8 = Luc Declerck | author-link8 = Greta Moorkens | author-link9 = Guy Hans}}</ref><ref name=":15" /> === Conditioned pain modulation: pain inhibits pain === Central sensitization doesn’t necessarily involve an increased susceptibility to stimuli; it can also be caused by a defect in the inhibitory pain pathways of the body. One highly researched mechanism in this respect is called 'conditioned pain modulation'<ref>{{Cite journal | last = Kennedy | first = Donna L. | authorlink = Donna Kennedy | last2 = Kemp | first2 = Harriet I. | last3 = Ridout | first3 = Deborah | last4 = Yarnitsky | first4 = David | last5 = Rice | first5 = Andrew S.C. | date = Nov 2016 | title = Reliability of conditioned pain modulation | url =http://dx.doi.org/10.1097/j.pain.0000000000000689 | journal = PAIN | volume = 157 | issue = 11 | pages = 2410–2419|doi=10.1097/j.pain.0000000000000689|issn=0304-3959}}</ref> (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. The chronic pain in your back for example might lessen if you sprain your ankle because your brain will focus more on the new information and dampen the other pain stimuli it receives. Meeus & Nijs of the Pain in Motion group tested this using heat stimuli and reported that conditioned pain modulation was normal but delayed in ME/CFS patients.<ref name=":6" /> In four other studies, <ref name=":7" /><ref name="MeeusIck2013">{{Cite journal | last = Meeus | first = Mira | last2 = Ickmans | first2 = Kelly | last3 = Struyf | first3 = Filip | last4 = Hermans | first4 = Linda | last5 = Van Noesel | first5 = Kevin | last6 = Oderkerk | first6 = Jorinde | author-link6 = Jorinde Oderkerk | last7 = Declerck | first7 = Luc S. | last8 = Moorkens | first8 = Greta | last9 = Hans | first9 = Guy | date = Mar 2013 | title = Does acetaminophen activate endogenous pain inhibition in chronic fatigue syndrome/fibromyalgia and rheumatoid arthritis? A double-blind randomized controlled cross-over trial | url = https://www.ncbi.nlm.nih.gov/pubmed/23511692 | journal = Pain Physician | volume = 16 | issue = 2| pages = E61–70|issn=2150-1149|pmid=23511692|quote= | authorlink = Mira Meeus | author-link2 = Kelly Ickmans | author-link3 = Filip Struyf | author-link4 = Linda Hermans | author-link5 = Kevin Van Noesel|via=}}</ref><ref name=":12" /><ref name=":15">{{Cite journal | last = Ickmans | first = Kelly | last2 = Meeus | first2 = Mira | last3 = De Kooning | first3 = Margot | last4 = Lambrecht | first4 = Luc | last5 = Pattyn | first5 = Nathalie | last6 = Nijs | first6 = Jo | date = Sep 2015 | title = Associations Between Cognitive Performance and Pain in Chronic Fatigue Syndrome: Comorbidity with Fibromyalgia Does Matter |url =http://dx.doi.org/10.1016/j.physio.2015.03.3465 | journal = Pain Physician | volume = 18 | issue = 5| pages = E841–852|issn=2150-1149|pmid=26431138|quote= | authorlink = Kelly Ickmans | author-link2 = Mira Meeus | author-link3 = Margot De Kooning | author-link4 = Luc Lambrecht | author-link5 = Nathalie Pattyn|via= | author-link6 = Jo Nijs}}</ref> the same research group tested CPM using the pressure of an inflatable occlusion cuff as the conditioning stimulus. In all cases there were no significant 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 produces endorphins that increase pain thresholds. In some chronic pain patients like fibromyalgia and whiplash associated disorders, this endogenous pain inhibition response is defect and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004 Whiteside et al. first showed this defect in ME/CFS patients, though their study only involved 5 patients.<ref>{{Cite journal | last = Whiteside | first = Alan | last2 = Hansen | first2 = Stig | last3 = Chaudhuri | first3 = Abhijit | date = Jun 2004 | title = Exercise lowers pain threshold in chronic fatigue syndrome | url =http://dx.doi.org/10.1016/j.pain.2004.02.029 | journal = Pain | volume = 109 | issue = 3 | pages = 497–499|doi=10.1016/j.pain.2004.02.029|issn=0304-3959}}</ref> The Pain in Motion group confirmed these results in two of their studies.<ref>{{Cite journal | last = Meeus | first = M | last2 = Roussel | first2 = NA | last3 = Truijen | first3 = S | date = 2010 | title=Reduced pressure pain thresholds in response to exercise in chronic fatigue syndrome but not in chronic low back pain: An experimental study | url = http://dx.doi.org/10.2340/16501977-0595 | journal = Journal of Rehabilitation Medicine | volume = 42 | issue = 9 | pages = 884–890|doi=10.2340/16501977-0595|issn=1650-1977|quote= | authorlink = Mira Meeus|via=}}</ref><ref>{{Cite journal | last = Van Oosterwijck | first = J. | last2 = Nijs | first2 = J. | last3 = Meeus | first3 = M. | last4 = Lefever | first4 = I. | last5 = Huybrechts | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Paul | first7 = L. | date = 2010-03-03 | title = Pain inhibition and postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: An experimental study | url = http://dx.doi.org/10.1111/j.1365-2796.2010.02228.x | journal = Journal of Internal Medicine | volume = 268 | issue = 3 | pages = 265–278|doi=10.1111/j.1365-2796.2010.02228.x|issn=0954-6820|quote= | authorlink = Jessica Van Oosterwijck | author-link2 = Jo Nijs | author-link3 = Mira Meeus | author-link4 = | author-link5 = |via=}}</ref> While pain thresholds increased in normal controls they decreased in the ME/CFS patient group. As a caveat, one must note that these studies only included ME/CFS patients that were suffering from chronic pain while comorbid fibromyalgia (FM) was not assessed. It remains unclear if these results will also hold true in ME/CFS patients that do not have comorbid FM.<ref name=":14">{{Cite journal | last = Yunus | first = Muhammad | date = Jul 2, 2015 | title = Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology) | url = http://dx.doi.org/10.2174/157339711102150702112236 | journal = Current Rheumatology Reviews | volume = 11 | issue = 2 | pages = 70–85|doi=10.2174/157339711102150702112236|issn=1573-3971|quote= | authorlink = Muhammad Yunus|via=}}</ref> === Other findings === In 2015 Staud et al. found indirect evidence for sensitized fatigue pathways in ME/CFS. Patients underwent exhausting handgrip-exercises and showed higher increased fatigue ratings than healthy controls after muscle metabolites were trapped in forearm tissues. The fact that fatigue ratings returned to baseline rapidly after removing the forearm occlusion suggests that ME/CFS patients display an increased sensitivity to exercise metabolites.<ref>{{Cite journal | last = Staud | first = Roland | last2 = Mokthech | first2 = Meriem | last3 = Price | first3 = Donald D. | last4 = Robinson | first4 = Michael E. | date = Apr 2015 | title = Evidence for sensitized fatigue pathways in patients with chronic fatigue syndrome | url =http://dx.doi.org/10.1097/j.pain.0000000000000110 | journal = PAIN | volume = 156 | issue = 4 | pages = 750–759|doi=10.1097/j.pain.0000000000000110|issn=0304-3959}}</ref> In 2009 Light et al. found an increase in metabolite detecting receptors in the white blood cells of ME/CFS patients after an exercise test - an increase that was not seen in controls.<ref name="Light2009">{{Cite journal | last = Light | first = Alan R. | last2 = White | first2 = Andrea T. | last3 = Hughen | first3 = Ronald W. | last4 = Light | first4 = Kathleen C. | date = Oct 2009 | title = Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects |url =https://www.ncbi.nlm.nih.gov/pubmed/19647494 | journal = The Journal of Pain: Official Journal of the American Pain Society | volume = 10 | issue = 10 | pages = 1099–1112|doi=10.1016/j.jpain.2009.06.003|issn=1528-8447|pmc=2757484|pmid=19647494|quote= | authorlink = Alan Light | author-link2 = | author-link3 = | author-link4 = Kathleen Light | author-link5 = |via=}}</ref> Results were confirmed by three other studies.<ref>{{Cite journal | last = Light | first = A.R. | last2 = Bateman | first2 = L. | last3 = Jo | first3 = D. | last4 = Hughen | first4 = R.W. | last5 = Vanhaitsma | first5 = T.A. |last6 = White | first6 = A.T. | last7 = Light | first7 = K.C. | date = Jan 2012 | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/21615807 | journal = Journal of Internal Medicine | volume = 271 | issue = 1 | pages = 64–81|doi=10.1111/j.1365-2796.2011.02405.x|issn=1365-2796|pmc=3175315|pmid=21615807|quote= | authorlink = Alan Light | author-link2 = Lucinda Bateman|via= | author-link8 = Kathleen Light}}</ref><ref>{{Cite journal | last = Meyer | first = Jacob D. | last2 = Light | first2 = Alan R. | last3 = Shukla | first3 = Sanjay K. | last4 = Clevidence | first4 = Derek | last5 = Yale | first5 = Steven | last6 = Stegner | first6 = Aaron J. | last7 = Cook | first7 = Dane B. | date = Oct 2013 | title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression | url =https://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444|journal = Fatigue: Biomedicine, Health & Behavior |language=en | volume = 1 | issue = 4 | pages = 190–209|doi=10.1080/21641846.2013.838444|issn=2164-1846|quote= | authorlink = | author-link2 = Alan Light|via= | author-link8 = Dane Cook}}</ref><ref>{{Cite journal | last = White | first = Andrea T. | last2 = Light | first2 = Alan R. | last3 = Hughen | first3 = Ronald W. | last4 = Vanhaitsma | first4 = Timothy A. | last5 = Light | first5 = Kathleen C. | date = Jan 2012 | title = Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls |url =https://www.ncbi.nlm.nih.gov/pubmed/22210239 | journal = Psychosomatic Medicine | volume = 74 | issue = 1 | pages = 46–54|doi=10.1097/PSY.0b013e31824152ed|issn=1534-7796|pmc=3256093|pmid=22210239|quote= | authorlink = | author-link2 = Alan Light | author-link3 = | author-link4 = | author-link5 = Kathleen Light|via=}}</ref> The authors speculate this might reflect an increased sensitivity to fatigue pathways in ME/CFS: <blockquote>“If these receptors are increased in CFS patients, it is possible that low levels of metabolites can activate leukocytes, and moderate exercise could increase the signal, thereby increasing cytokine levels that sensitize muscle sensory fatigue signaling afferents.”<ref name="Light2009" /></blockquote>In 2002 Nijs et al. reported bronchial hyperesponsiveness (BHR) after a histamine provocation test in 77 ME/CFS patients out of a sample of 137. Further research into immune factors failed to show a link with IGE-mediated activation of mast cells and eosinophils as is seen in asthma patients, but there was a connection with increased [[cytotoxic T-cell]] count and BHR.<ref>{{Cite journal | last = Nijs | first = Jo | last2 = De Becker | first2 = Pascale | last3 = De Meirleir | first3 = Kenny | last4 = Demanet | first4 = Christian | last5 = Vincken | first5 = Walter | last6 = Schuermans | first6 = Daniel | last7 = McGregor | first7 = Neil | date = Apr 2003 | title = Associations Between Bronchial Hyperresponsiveness and Immune Cell Parameters in Patients With Chronic Fatigue Syndrome | url =http://dx.doi.org/10.1378/chest.123.4.998 | journal = Chest | volume = 123 | issue = 4 | pages = 998–1007|doi=10.1378/chest.123.4.998|issn=0012-3692|quote= | authorlink = Jo Nijs | author-link2 = Pascale De Becker | author-link3 = Kenny De Meirleir | author-link4 = | author-link5 = |via=}}</ref> According to Nijs “the high prevalence of bronchial hyperresponsiveness can be viewed as another piece of evidence in support of central sensitisation in at least a large subset of the CFS population.”<ref name="Nijs2011a" /> The research group of Jo Nijs was initially drawn to exploring central sensitization in ME/CFS because of increased nitric oxide (NO) levels in these patients, as reported by Kurup & Kurup in 2003.<ref>{{Cite journal | last = Nijs | first = Jo | last2 = Van de Velde | first2 = Bart | last3 = De Meirleir | first3 = Kenny | date = Jan 2005 | title = Pain in patients with chronic fatigue syndrome: Does nitric oxide trigger central sensitisation? | url = http://dx.doi.org/10.1016/j.mehy.2004.07.037 | journal = Medical Hypotheses | volume = 64 | issue = 3 | pages = 558–562|doi=10.1016/j.mehy.2004.07.037|issn=0306-9877|quote= | authorlink = Jo Nijs | author-link2 = | author-link3 = Kenny De Meirleir | author-link4 = | author-link5 = |via=}}</ref> Subsequent research however showed that NO concentrations were normal and unrelated to activity levels in 30 ME/CFS patients.<ref>{{Cite journal | last = Meeus | first = Mira | last2 = Van Eupen | first2 = Inge | last3 = Hondequin | first3 = Jasmien | last4 = DE Hauwere | first4 = Lieve | last5 = Kos | first5 = Daphne | last6 = Nijs | first6 = Jo | date = Nov 2010 | title = Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: a case-control study | url = https://www.ncbi.nlm.nih.gov/pubmed/21164046 | journal = In Vivo (Athens, Greece) | volume = 24 | issue = 6 | pages = 865–869|issn=1791-7549|pmid=21164046|quote= | authorlink = Mira Meeus|via= | author-link6 = Jo Nijs}}</ref> Substance P is another element believed to be involved in central sensitization. Increased levels of [[Substance P]] in [[cerebrospinal fluid]] have been reported in patients with [[fibromyalgia]]<ref>{{Cite journal | last = Russell | first = I. Jon | last2 = Orr | first2 = Malcolm D. | last3 = Littman | first3 = Bruce | last4 = Vipraio | first4 = Gilbert A. | last5 = Alboukrek | first5 = David | last6 = Michalek | first6 = Joel E. | last7 = Lopez | first7 = Yolanda | last8 = Mackillip | first8 = Fane | date = Nov 1994 | title = Elevated cerebrospinal fluid levels of substance p in patients with the fibromyalgia syndrome | url =http://dx.doi.org/10.1002/art.1780371106 | journal = Arthritis & Rheumatism | volume = 37 | issue = 11 | pages = 1593–1601|doi=10.1002/art.1780371106|issn=0004-3591}}</ref><ref>{{Cite journal | last = Vaerøy | first = Henning | last2 = Helle | first2 = Robert | last3 = Førre | first3 = Øystein | last4 = Kåss | first4 = Erik | last5 = Terenius | first5 = Lars | date = Jan 1988 | title = Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis |url =http://dx.doi.org/10.1016/0304-3959(88)90019-x | journal = Pain | volume = 32 | issue = 1 | pages = 21–26|doi=10.1016/0304-3959(88)90019-x|issn=0304-3959}}</ref> – the prototype of central sensitivity syndromes. A small Swedish study involving 15 patients found values of Substance P to be in the normal range in ME/CFS.<ref>{{Cite journal | last = Evengard | first = B. | last2 = Nilsson | first2 = C.G. | last3 = Lindh | first3 = G. | last4 = Lindquist | first4 = L. | last5 = Eneroth | first5 = P. | last6 = Fredrikson | first6 = S. | last7 = Terenius | first7 = L. | last8 = Henriksson | first8 = K.G. | date = Nov 1998 | title = Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/9839828 | journal = Pain | volume = 78 | issue = 2 | pages = 153–155|issn=0304-3959|pmid=9839828|quote=|via=}}</ref> === Conclusion === Interpretations of these preliminary findings on central sensitization in ME/CFS have been discordant. In a 2012 review, Nijs & Meeus concluded that “mounting evidence supporting a role for central sensitisation in at least a large subset of the CFS population is currently available.”<ref name="Nijs2011a" /> Mohammed Yunus however omitted ME/CFS on his list of central sensitivity disorders in 2015, due to a lack of evidence: <blockquote>“Despite the fact that chronic fatigue syndrome (CFS) (systemic exertion intolerance disease) clinically overlaps with other members of the CSS family, definitive evidence of CS in this disease (excluding those having pain) is lacking, and was, therefore, not included.”<ref name=":14" /></blockquote>
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