Smertelege dr med; Spesialist i allmennmedisin & psykiatri

Presentasjon om: "Smertelege dr med; Spesialist i allmennmedisin & psykiatri"— Utskrift av presentasjonen:

1 Smertelege dr med; Spesialist i allmennmedisin & psykiatri
Smerte og fibromyalgi Egil A. Fors, Smertelege dr med; Spesialist i allmennmedisin & psykiatri ,

2 What is this thing called (love) pain?
En subjektiv opplevelse Overtar hele oppmerksomheten Overskygger alt Det eneste som betyr noe Vanskelig “å gjøre noe med” Woolf CJ. What is this thing called pain? J Clin Invest Nov;120(11): doi: /JCI Epub 2010 Nov 1. Review.

3 Arthur Aron, professor of psychology at State University of New York
Dopaminprojeksjoner fra ”lystsenteret” (nucleus accumbens) til orbitofrontal cortex "the areas of the brain activated by intense love are the same areas that drugs use to reduce pain,“ Arthur Aron, professor of psychology at State University of New York Younger J, Aron A, Parke S, Chatterjee N, Mackey S. Viewing pictures of a romantic partner reduces experimental pain: involvement of neural reward systems. PLoS One Oct 13;5(10):e doi: /journal.pone

4 Fra Twitter Å være syk er ille. Å være syk uten diagnose er værre.
Å være syk uten å bli trodd, er et sant helvete. Egil Madsen

5 Smerte-fysiologiske prosesser:
Transduksjon = Omkoding av smertestimuluser med omforming til svakstrøm (i nosiceptoren). Transmisjon = Ledning av disse elektriske impulsene videre Modulasjon = Endring (+/-) av transmisjon Persepsjon = Den subjektive oppfatningen av smerten sentralt

6 Smerte og nocisepsjon er ikke nødvendigvis det samme
Aktivitet i nociseptorer genererer som oftest smerte, men dette er ikke bestandig! * Smerte kan oppstå uten aktivitet i nociseptorer! * Beecher, H. K. (1956). "Relationship of significance of wound to pain experienced." J Am Med Assoc 161(17):

7 Smerte: Supraspinal (“over ryggmargen”) påvirkning
Forsterkende (gass) Blokkerende (brems) Substans P Glutamat Nerve Vekst Faktor (NGF) CCK Nedadstigende anti-nosiceptive baner Norepinephrine – serotonin (5HT1a,b), dopamin Opioider GABA Cannabinoider +

8 Perifer eller sentralisert smerte?
Kronisk nosicepsjon (vevsskade) Kronisk smerte uten nosicepsjon –mulig økt følsomhet i nervesystemet (sensitivisering) og kan regnes som en sykdom i seg selv Blanding av 1 og 2. Bonezzi, C., L. Demartini, et al. (2012). "Chronic pain: not only a matter of time." Minerva Anestesiologica.

9 Hvilken person har smerte?

10 Hva er Fibromyalgi? Mekanismer Klinikk og diagnosis 10/19/2017 10 10

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12 Fibromyalgi (FM) regnes som prototypen på et sentralt smerte-syndrom
Langvarige smerter, som flytter på seg og varierer i intensitet Hyperalgesi + allodyni Endret funksjon i hjernenettverkene?

13 Smertepersepsjon SMERTE-PERSEPSJON
Figuren gir en meget forenklet fremstilling av hvordan smertenettverket – og derved subjektiv smerteopplevelse – antas å kunne «drives» på ulike måter SMERTE-PERSEPSJON Per Brodal: Tidsskr Nor Lægeforen nr. 17, 2005; 125: 2370–3

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16 Mest aktivt ved hvile og konsentrasjon
Introspeksjon,snettverket DMN(= Default Mode network) og kopling til insula Introspeksjons-hjerne-nettverket er en konstellasjon av flere områder i hjernen Mest aktivt ved hvile og konsentrasjon Anatomisk: Nedre parietal-lapp, bakre cingulate cortex, precuneus, hippocampus, og laterale temporal cortex. Napadow, V., L. LaCount, et al. (2010). "Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity." Arthritis and Rheumatism 62(8):

17 FM har endret aktivitet i hvilenettverket (= Default Mode Network, DMN)
Endringen varierer med spontan smerte FM: Hvilenettverket kopler seg tettere mot insula Executive Attention Network (EAN) kopler seg også tettere mot insula

18 Smerte ”overtar hele oppmerksomheten”: Redusert nevropsykologisk funksjon
Nils Inge Landrø, Egil A Fors et al. The extent of neurocognitive dysfunction in a multidisciplinary pain centre population. Is there a relation between reported and tested neuropsychological functioning? PAIN 2013 (in press)

19 Denne økte kontakten er uavhengig av depresjon

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21 Oppsummert: Hjernenettverk og ”connectivity”
Forstyrrelse av “connectivity” (koplingsevneen) mellom spesielle hjernenettverk ved FM FM har økt koplingsevne mellom diverse hjernenettverk og insula (som er viktig for opplevd smerte) Koplingsevnen er assosiert med økende spontan smerte Nevronal link til spontan smerte Økt glutamat i insula Stemmer bra med andre undersøkelser

22 Forskjellige typer smerte
10/19/2017 Forskjellige typer smerte Ref 2.a Giordano & Schatman Pg 484 Col 1 Par 5 Lin 3 Ref 2.b Pg 487 Col 2 Par 4 Lin 1-2 Ref 2.c Pg 486 Par 1 Lin 8-10 Ref 2.d Pg 485 Par 2 Lin 9-10 Ref 1.a Woolf C Pg 441 Figure 1 Sentral smerte- forsterkning Avvikende smertebearbeiding i sentralnervesystemet (f.eks, Fibromyalgia) Nosiceptiv Smerte vevsødeleggelse (f.eks brannsår) Neuropatisk Smerte Nerveskade (f.eks helvetesild) Inflammatorisk Smerte Inflammasjon/betennelse (f.eks Rheumatoid artritt ) Pain is common and often chronic, under-diagnosed, and undertreated2 Pain carries a tremendous burden for patients and society2 Presence of pain complicates diagnosis and treatment of other medical and psychiatric conditions2 In the spectrum of clinical pain syndromes, fibromyalgia lies in the realm of dysfunctional pain or central pain amplification A broad spectrum of pain syndromes is seen in the clinic. Types of pain can be differentiated by the patients’ threshold to pain and by the initiating causes1 Nociceptive pain is a normal response to a noxious stimulus such as heat or pressure with a relatively high threshold1 In neuropathic pain and conditions of central pain amplification, there are chronic alterations or lesions in the peripheral nervous system and/or central nervous system. Neuronal damage can be due to injury, viral infection (post-herpetic neuropathy) or diabetes (diabetic peripheral neuropathy)1 In inflammatory pain, the pain threshold is somewhat lower. A variety of immunologic mediators can give rise to inflammatory pain1 The etiology of dysfunctional chronic pain conditions may be less clearly defined than that of neuropathic pain conditions. Often times no noxious stimuli or inflammation or neuronal damage can be identified, yet patients report extreme pain to non-noxious stimuli (allodynia) or an extreme pain to mild stimuli (hyperalgesia)1 Reference: 1. Woolf CJ. Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management. Ann Intern Med. 2004;140: 2. Giordano J and Schatman ME, Pain Physician;11: Ref 1.a Woolf C Pg 442 Figure 1 Kronisk Smerte Akutt Smerte Ref 1.a Woolf C Pg 441 Figure 1 Ref 1.b Pg 443 Col 1 Par 4 Lin 1-6 Fra: Woolf C. Ann Intern Med. 2004;140: Ref 1.a Woolf C Pg 441 Figure 1 Pg 443 Col 1 Par 4 Lin 6-17 22

23 Omstridt diagnose. Kontinuitetsteori
Omstridt diagnose? Kontinuitetsteori? ”Endestasjon” for kronisk aktivering? Sentral sensitivisering? Del av en ”spektrumlidelse” Nevroplastisistet? ”Allodyni-syndrom”

24 Antall tenderpunker for cfs/me og fibromyalgi
(Buchwald, Rheum Dis Clin N Amer, 1996)

25 Diagram showing 18 tender points
10/19/2017 Fibromyalgi (FM): Kroniske, generelle smerter. Er det en nevrologisk tilstand? Ref 1.a Wolfe et al Pg 19 Col 1 Par 1 Lin 1-3 FM er generelle smerter + trykkømhet 1 American College of Rheumatology (ACR) kriterier for FM diagnosen:2 Kroniske, generelle smerter Smerter ≥ 3 måneder Alle “4 kvadranter” + skjelett/ midtlinjen Smerter i ≥11 of 18 tender punkter utløst ved et 4 kg trykk pr cm2 NYE KRITERIER?? (ref) Ref 2.a Wolfe et al Pg 160 Abst Par 2 Lin 1-6 Ref 2.b Pg 171 Table 8 Ref 2.d Wolfe et al Pg 169 Col 1 Par 1 Lin 1-4 Diagram showing 18 tender points Fibromyalgia (FM) is one of the most common chronic widespread pain Conditions1 with an incidence rate of 2-5% of the adult population FM, a chronic widespread neurologic pain condition is characterized by pain in all 4 quadrants and tenderness to stimuli The ACR criteria for the diagnosis of FM is used to differentiate FM from other rheumatologic conditions It is sensitive (88.4%) and specific (81.1%) tool that can be used to differentiate FM from other rheumatologic conditions.2 To diagnose FM, using the ACR Diagnostic criteria: The patient must have chronic, widespread pain for ≥3 months The pain had to include all 4 quadrants of the body – that is both above and below the waist and on left and right sides of the body The pain must include the axial skeleton The patient must have pain in at least 11 of the 18 tender points identified by the ACR2 TPs are at defined locations and using your thumb of your dominant hand, palpating with 4kg of pressure (blanching of the thumbnail) a patient with FM should feel pain at these locations at least 11/18 locations References: 1. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995;38:19-28. 2. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33: Ref 1.a Wolfe et al Pg 19 Col 1 Par 1 Lin 1-3 Ref 2.c Wolfe et al Pg 169 Col 1 Par 1 Lin 1-4 Ref 2.a Wolfe et al Pg 160 Abst Par 2 Lin 1-6 Ref 2.b Pg 171 Table 8 1. Wolfe F, et al. Arthritis Rheum. 1995;38(1):19-28. 2. Wolfe F, et al. Arthritis Rheum. 1990;33:

26 Abnormal Smerte Sensitivitet Smertebevisst og atferd
SANNSYNLIGE MEKANISMER FOR FIBROMYALGI Genetisk sårbarhet Emosjonelle Traumer/Stress Infeksjoner Fysiske Traumaer Søvnforstyrrelser Muskel Mikrotraumer Neurohormonelle forstyrrelser med immunforandringer Structurelle Defecter GH Axis HPA aksen* Hypotalamus, hypofyse, binyrebarken Dorsal Horn Excitabilitet Perifere Nociceptive Transmisjon  NGF ­ Neuro- transmittorer Det autonome nervesystemet  Excitatoriske Amino syrer Forandringer I rCBF Abnormal Smerte Sensitivitet Model of abnormal pain perception in FM (Weigent DA et al, Am J Med Sci 315:405, 98; modified) Smertebevisst og atferd

27 Patogenese (mekanisme) Klinikk og diagnose
10/19/2017 10/19/2017 Hva er fibromyalgi? Patogenese (mekanisme) Klinikk og diagnose 27 27

28 Smertens vei: ¨Smerte oppfattes
10/19/2017 10/19/2017 Smertens vei: 4. Nedadstignede baner har en modererende effekt på signalene som kommer til ryggmargen Et signal sendes via en oppadstigene bane til hjernen, og oppfattes da som smerte ¨Smerte oppfattes Ref 1.a Staud & Rodriguez Pg 92 Figure 2 Ref 2.a Gottschalk & Smith Pg 1981 Glutamat Substans P Ref 1.b Staud & Rodriguez Pg 93 Col 1 Par 2 Ref 3.a Henriksson Pg 91 Par 3 Ref 2.a Gottschalk & Smith Pg 1979 Col 2 Par 2 Lin 5-10 Inngående signaler depolariserer (”antenner”) nerveceller i ryggmargen som fører til at kalsium [Ca2 +] trekker inn i nervesellennevroner og forårsaker utslipp av smerte nevrotransmittere: Glutamat og Substans P <<Animated slide: Please advance to view entire sequence.>> Activation of peripheral pain receptors, or nociceptors, by noxious stimuli generates signals that travel to the dorsal horn of the spinal cord via the dorsal root ganglion2 Within the synapse of the dorsal horn, entry of calcium causes release of glutamate and Substance P into the synaptic cleft, to affect the next neuron1,3 From the dorsal horn, the signals are carried along the ascending pain pathway or the spinothalamic tract to the thalamus and the cortex2 Pain can be controlled by pain-inhibiting and pain-facilitating neurons Descending signals originating in supraspinal centers can modulate activity in the dorsal horn by controlling spinal pain transmission2 References: 1. Staud R, Rodriguez ME. Mechanisms of disease: pain in fibromyalgia syndrome. Nat Clin Pract Rheumatol. 2006;2:90-98. 2. Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001;63: 3. Henriksson KG. Fibromyalgia – from syndrome to disease. Overview of pathogenetic mechanisms. J Rehabil Med. 2003;(suppl 41):89-94. Stignal fanget opp av perfere smertereseptorer (dvs, I huden) Ref 2.b Gottschalk & Smith Pg 1979 Col 2 Par 3 Lin 1-3 Ref 2.c Pg 1980 Col 1 Par 1 1. Staud R and Rodriguez ME. Nat Clin Pract Rheumatol. 2006;2:90-98. 2. Gottschalk A and Smith DS. Am Fam Physician. 2001;63: 28

29 Sentral sensitisering forårsaker unormale smertesignaler
10/19/2017 Sentral sensitisering forårsaker unormale smertesignaler Ref 1.a Gottschalk & Smith Pg 1981 Figure 2 Ref 2.a Woolf CJ Pg 442 Figure 1 Etter en nerveskade kan økt mengde smertesignaler til ryggmargen forårsake sentral sensitivisering Opplevd smerte Nerve som ikke fungerer Oppadstigende signaler Nedadstigende modulering Nosiceptiv inngående fiber igangstetting av sentral sensitisering Oppevd smerte (hyperalgesi/allodyni) <<Animated slide: Please advance to view entire sequence.>> Note to speaker: This slide contains an animated build to show that central sensitization involves changes at the level of the dorsal horn neurons. Clicking on this slide will cause subsequent components of the build to appear automatically. On this slide, pain processing is demonstrated. The peripheral nerve/nociceptive afferent fiber is stimulated and sends pain signals to the spinal cord. At the dorsal horn of the spinal cord, pain neurotransmitters are released (substance P and Glutamate), stimulating the ascending tract (spinothalamic tract). The ascending tract sends signals to the brain, where pain is perceived. The body can modulate pain signals that are sent to the brain. This is done with the descending fiber (green), which sends signals to the dorsal horn of the spinal cord, modulating the signals going to the brain. FM, a neurologic pain condition, occurs when there is an abnormality in the pain processing. The bottom illustration shows when minimal stimuli sends pain signals to the spinal cord. In FM, elevated NTs are released in response to the minimal stimuli at the dorsal horn of the spinal cord. The exaggerated release of NTs results in elevated pain signals sent to the brain – where the brain perceives elevated pain, although the stimuli is minimal. The descending fiber sends a decreased amount of signals to modulate the signals going to the brain. Overall, this demonstrates the hyperalgesia and allodynia in FM. Under pathological conditions:1,2 Abnormal ectopic discharges from damaged/diseased nociceptors can induce central sensitization of spinal dorsal horn neurons Initially, it is activity dependent (triggered by repetitive peripheral input or ectopic discharge beyond the initial stimuli or in the absence of a known stimuli) and later it becomes sustained beyond the initial stimulus, maintained by transcriptional changes Central sensitization is thought to involve changes: In the postsynaptic dorsal horn neurons that may be triggered by increased release of transmitters from presynaptic central nociceptor terminals This leads to alterations in synaptic receptor density and lowering of activation threshold This results in amplification of the pain signal in the dorsal horn For a patient with FM, a normally minimally painful stimuli may cause an amplified response to normal stimuli (hyperalgesia), or normal stimuli may result in pain (allodynia) Note that the theory of central sensitization may be applicable to many other pain conditions References: 1. Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001;63: 2. Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140: Økt frigjøring av Glutamat og Substans P Minimale stimuli Ref 1.a Gottschalk & Smith Pg 1981 Figure 2 Ref 2.a Woolf CJ Pg 442 Figure 1 Smerte forsterkning Økt smertesansing 1. Adapted from Gottschalk A and Smith DS. Am Fam Physician. 2001;63: 2. Woolf CJ. Ann Intern Med. 2004;140:

30 FM: forsterket smerte-respons
10/19/2017 FM: forsterket smerte-respons Ref 1.a Gottschalk & Smith Pg 1980 Figure 1 10 Fibromyalgi-smerte Normal smerte respons 8 Forsterket smerte- respons Hyperalgesi 6 Subjektiv smerte- intensitet 4 <<Animated slide: Please advance to view entire sequence.>> In the normal pain response, pain intensity increases as the stimulus intensity increases1 Due to central sensitization, FM patients have an amplification of pain response, which presents an increased response at lower stimuli, causing the curve to shift to the left In FM patients, lower stimulus produces an elevated subjective pain intensity demonstrated by: Hyperalgesia, in which noxious stimuli cause greater and more prolonged pain Allodynia, in which pain results from normally painless stimuli References: Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001;63: Allodyni Ref 1.a Gottschalk & Smith Pg 1980 Figure 1 2 Stimulus intensitet Adapted from Gottschalk A and Smith DS. Am Fam Physician. 2001;63:

31 fMRI studie støtter økt smertefølsomhet ved FM
10/19/2017 fMRI studie støtter økt smertefølsomhet ved FM Ref 1.a Gracely et al Pg 1338 Figure 2 14 12 10 8 6 4 2 Ref 1.g Gracely et al Pg 1340 Col 1,2 Par 1 Smerte intensitet Ref 1.b Gracely et al Pg 1333 Col 1,2 Par 3 Ref 1.g Gracely et al Pg 1340 Col 1,2 Par 1 1.5 Pain processing is augmented in FM patients. The pain they experience is real.1 This slide shows the results of an fMRI study measuring the subjective pain with increasing stimulus in fibromyalgia patients against controls by measuring areas of activation in the brain In FM patients, some pain processing areas of the brain are activated at a much lower level of stimulus than in controls. There is overlap (as indicated by the yellow area on the fMRI) between the areas activated at low intensity stimulus in FM patients (red area) and high intensity stimulus in control subjects (green area) indicating that the pain FM patients experience is real The graph on the left depicts pain intensity against stimulus intensity. In FM patients, a low stimulus pressure produced a high pain level (hyperalgesia); however, in stimulus pressure controls, a similar pressure resulted in low levels of pain and a much higher stimulus pressure was required to elicit similar levels of pain Background Information fMRI was used to evaluate cerebral activation patterns during the application of painful and non-painful pressure in FM patients (n=16) and controls (n=16) No subjects were clinically depressed, and FM patients met the American College of Rheumatology criteria for FM. Mean age of patients was 52.6 years; range Mean age of controls was 45.8 years; range Patients taking opioid analgesics were excluded; other analgesics were discontinued 12 hours prior to procedures Each patient underwent fMRI while pressure was applied to the thumbnail bed for 5 seconds using a hard rubber probe attached to a hydraulic piston. Subjects rated the intensity and unpleasantness of sensations evoked by pressure from 0.45 kg/cm2 to the maximum tolerated, with a limit of 9 kg/cm2. Every 10 seconds, FMRI brain scans recorded areas of increased cerebral blood flow produced when pressure was applied 13 regions of increased brain activation were revealed in the FM group, compared with 1 in the control group Enhanced responses were noted in multiple areas of the brain, including somatosensory primary and secondary cortex, insula, putamen, and cerebellum; this provides supporting evidence that CNS alterations may underlie FM pathophysiology Reference: 1. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46: 2.5 3.5 4.5 Rød: Hjerneområder aktivert ved svake trykk hos FM Stimulus intensitet (kg/cm2) Ref 1.a Gracely et al Pg 1338 Figure 2 Patsienter med FM opplevde mye smerte ved svake stimuli Grønn: Områder aktivert ved hardt trykk hos friske Ref 1.c Gracely et al Pg 1333 Col 1 Par 2 Gul: Overlappende områder FM (n=16) Subjektiv smerte-kontroll Trykk-kontroll (n=16) fMRI = functional magnetic resonance imaging Ref 1.e Gracely et al Pg 1334 Col 2 Par 4 Lin 5-14 Gracely RH, et al. Arthritis Rheum. 2002;46: Ref 1.d Gracely et al Pg 1334 Col 2 Par 3 Lin 9-10 Ref 1.f Gracely et al Pg 1339 Col 1 Par 2 Lin 2-4, 9-10 Ref 1.h Col 2 Par 1

32 FM har økt Substans P i CSF (spinalvæsken)
10/19/2017 FM har økt Substans P i CSF (spinalvæsken) Ref 1.a Russell et al Pg 1595 Table 2 Ref 2.a Abst Ref 3.a Bradley et al Pg 1 Par 3 Lin 1-3 Flere studier 1-3 P<0.001 P<0.001 42.8 43 Ref 4.a Burke et al Pg 681 Col 1 Par 4 Lin 5-6 Substance P concentration (fmoles/mL)† P<0.03 19.26 16.3 17 12.83 In multiple studies, levels of substance P (SP) have been shown to be significantly higher in the cerebrospinal fluid (CSF) of FM patients than in normal controls.1-3 The pain neurotransmitter substance P may play a key role in the transmission of pain to the central nervous system4 Input from nociceptive afferent nerves cause a release of SP in the dorsal horn of the spinal cord5 The objective of 3 separate studies was to measure levels of SP in patients with FM compared with controls1-3 CSF samples were collected by lumbar puncture from patients diagnosed with FM and healthy control subjects. The CSF level of SP were measured by radioimmunoassay1-3 All 3 studies showed that SP levels were significantly elevated in FM patients compared to normal values in healthy control subjects1-3 References: Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, Lopez Y, MacKillip F. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum. 1994;37: Russell IJ, Orr MD, Michalek JE. Substance P [SP], SP endopeptidase activity [SPE] and SP N-terminal peptide [SP1-7] in fibromyalgia syndrome [FS] cerebrospinal fluid [CSF]. Myopain 1995: Abstracts from the 3rd World Congress on Myofascial Pain and Fibromyalgia; July 30-August 3, 1995; San Antonio, TX. Bradley LA, Alberts KR, Alarcon GS, et al. Abnormal brain regional cerebral blood flow (rCBF) and cerebrospinal fluid (CSF) levels of substance P (SP) in patients and non-patients with fibromyalgia (FM). Arthritis Rheum. 1996;suppl 9:212. Abstract 1109. Burke A, Smyth EM, FitzGerald GA. Analgesic-antipyretic agents. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006: 681. Staud R, Rodriguez ME. Mechanisms of disease: pain in fibromyalgia syndrome. Nat Clin Pract Rheumatol. 2006;2:90-98. Ref 5.a Staud & Rodriguez Pg 92 Figure 2 * 1 * 2 * 3 n= n= n=14 n= n= n=10 CSF = spinalvæske Ref 1.a Russell et al Pg 1595 Table 2 Ref 2.a Abst Ref 3.a Bradley et al abst 1. Russell IJ, et al. Arthritis Rheum. 1994;37: 2. Russell IJ, et al. Myopain 1995: Abstracts from the 3rd World Congress on Myofascial Pain and Fibromyalgia; July 30 - August 3, 1995; San Antonio, TX. 3. Bradley LA, et al. Arthritis Rheum. 1996;suppl 9:212. Abstract 1109. Ref 1.b Russell et al Pg 1594 Col 1 Par 6 Lin 1-4

33 Forhøyet glutamat i spinalvæsken ved FM
10/19/2017 Ref 1.c Sarchielli et al Pg 738 Col 2 Par 5 Lin 1-2 Ref 1.d Pg 739 Col 1 Par 8 Lin 3-5 Ref 1.a Sarchielli et al Pg 740 Table 2 Glutamat-nivåer i spinalvæske P<0.003 Ref 1.a Sarchielli et al Pg 740 Table 2 Ref 1.b Col 1 Par 2 Lin 5-7 Glutamat-nivå i spinalvæsken (µg/mL) CSF levels of glutamate were higher in FM patients compared with controls. Sarchielli et al measured CSF levels of glutamate in 20 FM patients and 20 age-matched control subjects undergoing lumbar puncture for diagnostic purposes Controls were drug free for at least 2 months and blood and CSF testing ruled out CNS or systemic disease FM patients had not taken amitriptyline, SSRIs, gabapentin, benzodiazepines or muscle relaxants in the 2 months prior to sampling Levels of glutamate were significantly higher in the CSF of FM patients compared with controls (P<0.003) References: Sarchielli P, Mancini ML, Floridi A, et al. Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome. J Pain. 2007;8: Ref 1.c Sarchielli et al Pg 738 Col 2 Par 5 Lin 1-2 Ref 1.d Pg 739 Col 1 Par 8 Lin 3-5 Ref 1.a Sarchielli et al Pg 740 Table 2 Ref 1.b Col 1 Par 2 Lin 5-7 CSF = cerebrospinal fluid = spinalvæske Sarchielli P, et al. J Pain. 2007;8:

34 Hva er fibromyalgia? Patogenese Klinikk og diagnosis 10/19/2017 34 34

35 Kroniske generelle smerter
10/19/2017 10/19/2017 Ref 2.a Wolfe F et al Pg 19 Col 1 Par 1 Ln 1-3 Ref 1.a Leavitt F et al Pg 779 Table 6 Kliniske trekk ved FM Ref 2.b Wolfe F et al Pg 19 Col 2 Par 2 Ln 1-3 Ref 4.a Wolfe F et al Pg 160 Col 1,2 Par 1 Lin 11-13 Staud R Pg 210 Col 1 Par 3 Lin 1-3 Ref 4.b Par 2 Lin 10-12 Ref 4.a Wolfe F et al Pg 160 Col 1,2 Par 1 Lin 11-13 Staud R Pg 210 Col 1 Par 3 Lin 1-3 Ref 4.b Par 2 Lin 10-12 FIBROMYALGI Kroniske genrelle smerter 1,2 Kriterier for FM Smerte er tilstede i alle kroppens 4 kvadranter ≥3 måneder Patsientens smertebeskrivelse:4 Verkende, energi-tappende, irriterende Kroniske generelle smerter Trykkømhet Trykkømhet 2 Økt følsomhet for trykk Klemmer, ta folk i hånde kan kjennes vondt Tender punkt undersøkelse Viktigste srtrekk ved FM4 Hyperalgesi AllodynI Ref 5.a Harding Pg 369 Col 1 Par 1 Ln 1-10 Ref 3.a Roizenblatt et al Pg 222 Col 2 Ln 1-2 Ref 2.c Wolfe F et al Pg 24 Lin 9-14 Ref 2.a Wolfe F et al Pg 19 Col 1 Par 1 Ln 1-3 <<Animated slide: Please advance to view entire sequence.>> Although chronic widespread pain and tenderness are the defining features of FM, sleep disturbances, morning stiffness, and other pain-related conditions may also be present.2 Patients often describe the pain of FM as aching, exhausting, nagging, and hurting1 Wolfe et al demonstrated that fatigue and morning stiffness were present in >75% of FM patients6 FM is commonly associated with non-restorative sleep which is characterized by prominent alpha wave intrusion3,5 References: 1. Leavitt F, Katz RS, Golden HE, Glickman PB, Layfer LF. Comparison of pain properties in fibromyalgia patients and rheumatoid arthritis patients. Arthritis Rheum. 1986;29: 2. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995;38:19-28. 3. Roizenblatt S, Moldofsky H, Benedito-Silva AA, Tufik S. Alpha sleep characteristics in fibromyalgia. Arthritis Rheum. 2001;44: 4. Staud R. Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome. Arthritis Res Ther. 2006;8(3): 5. Harding SM. Sleep in fibromyalgia patients: subjective and objective findings. Am J Med Sci. 1998;315: 6. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990;33: Andre symptomer2,3,5 Fatigue Andre smerte-syndromer Kronisk hodepine migrene, IBS, IC, TMJ, PMS Morgen stivhet Nevrologiske symptomer Nondermatomal paresthesier Nummenhet, stikking I armer/ben Søvproblemer Ikke uthvilt om natten Andre symptomer Ref 3.a Roizenblatt et al Pg 222 Col 2 Par 1 Ln 1-2 Ref 5.a Harding Pg 369 Col 1 Ln 1-10 Ref 6.a Wolfe F et al Pg 165 Table 3 1. Leavitt F, et al. Arthritis Rheum. 1986;29: 2. Wolfe F, et al. Arthritis Rheum. 1995;38:19-28. 3. Roizenblatt S, et al. Arthritis Rheum. 2001;44: Ref 1.a Leavitt F et al Pg 779 Table 6 4. Staud R. Arthritis Res Ther. 2006;8(3): 5. Harding SM. Am J Med Sci. 1998;315: 35 35

36 FM pasienter har gjerne andre kroniske smertelidelser i tillegg
10/19/2017 FM pasienter har gjerne andre kroniske smertelidelser i tillegg Ref 1.a Weir et al Pg 126 Table 3 FM Pasienter Kvinner = 906 Menn, n=1689 Baseline† ‡ Ref 1.a Weir et al Pg 126 Table 3 Ref 1.b Pg 124 Col 2 Par 3 Lin 1-3 Ref 1.c Pg 125 Col 1 Lin 1-4 Ref 1.a Weir et al Pg 126 Table 3 Patients with FM are more likely to be diagnosed with other pain-related conditions than those who do not suffer from FM.1 As illustrated in this graph, FM patients were 2 to 7 times more likely than baseline patients without FM to have been diagnosed with these comorbid conditions This study was conducted using the Deseret Mutual Benefits Administration (DMBA) database Claims from 1997 to 2002 were examined using ICD-9-CM (International Classification of Diseases, 9th Revision, Clinical Modification) codes to identify FM cases and other pain-related conditions 2595 cases pf FM were compared with non-FM controls (52,698 females and 53,323 males) Among the other pain-related conditions were: SLE (systemic lupus erythematosus) RA (rheumatoid arthritis), IBS (irritable bowel syndrome), and headache. Headache was identified using codes for headache, tension headache, classical migraine, common migraine, variants of migraine, other forms of migraine, migraine unspecified Because patients with FM are often diagnosed with other pain-related conditions, FM may go undetected Reference: 1. Weir PT, Harlan GA, Nkoy FL, Jones SS, Hegmann KT, Gren LH, Lyon JL. The incidence of fibromyalgia and its associated comorbidities. J Clin Rheumatol. 2006;12: 2. Wolfe F and Rasker JJ. Fibromyalgia. In: Firestein, ed. Kelly’s Textbook of Rheumatology, 8th Edition. St. Louis, MO: WB Saunders Co; 2008. 20% av pasienter med SLE, RA and OA har FM I tillegg 2 Derfor er ofte FM oversett hos mange pasinter Ref 1.a Weir et al Pg 126 Table 3 Ref 1.c Pg 125 Col 1 Par 3 Lin 1-4 SLE = Systemic lupus erythematosus; RA = Rheumatoid Arthritis; IBS = Irritable Bowel Syndrome *†Baseline fra 52,698 kvinner og 52,232 menn uten FM ‡Risk ratio = Sannsynligheten for hver tilstand sammenliknet med nen frisk kontroll-gruppe (baseline=1) 1. Weir PT, et al. J Clin Rheumatology. 2006;12(3): 2. Wolfe F and Rasker JJ. Fibromyalgia. In: Firestein, ed. Kelly’s Textbook of Rheumatology, 8th Edition. St. Louis, MO: WB Saunders Co; 2008.

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38 Økende smertestimulering hos FM pasienter
Transverse Transverse Thalamus SPM analysis of change in brain blood flow within the FM subject group also produced results in accord with our hypotheses. Compared to rest, stimulation of right-side sites produced significant increases in blood flow in both the left and right thalamus L R L R Regions with higher blood flow during pain, p=.01

39 VAS (Smerte) likt ved ulikt trykk (svakt trykk for FM)
VAS Intensity

40 10/19/2017 Oppsummering: Sentral Sensitivisering, en nevrologisk teori for smerterøkning over tid ved fibromyalgi? Ref 2.a Williams & Clauw Pg 779 Col 2 Par 2 Lin 1-2 Par 3 Lin 2-4 Ref 1.a Staud & Rodriguez Pg 90 Col 2 Par 1 Lin 5-8 Sentral sensitivisering regnes som en undeliggende årsak til forsterket smertefølelse pga endringer i CNS funksjonen1 Kan forklare økt smertefølsomhet ved FM 2 Hyperalgesi – Forsterket respons på smertefulle stimuli Allodynia – Smerterespons etter normale stimuli Teorien om sentral sensitivisering støttes av: Økte nivåer av smerterelaterte nevrotransmittorer 3,4 Glutamat Substans P fMRI data har vist at fibromyalgi-pasienter opplever like mye smerte som friske kontroller selv om de har lettere smertestimulering (trykk) 5 Økt kopling ((connectivity) til insula fra hvile- (DMN) og oppmerksomhetsnettverkene (EAN) 6 Ref 5.a Gracely et al Pg 1338 Figure 2 Ref 3.a Sarchielli et al Pg 742 Col 1 Par 1 Lin 1-5 Ref 4.a Vaeroy et al Pg 23 Col 2 Ref 2.a Williams & Clauw Pg 779 Col 1 Par 3 Lin 11-15 While the pathogenesis of FM is not completely understood, alterations of the CNS may contribute to the chronic pain of FM2 FM is characterized by a heightened sensitivity to pain2 Central sensitization is a theory of the development of fibromyalgia as a consequence of functional changes in the CNS that result in hyperexcitability of the spinal cord neurons which then release excess substance P and glutamate1,4 This may explain why in patients with FM, sensory input that would normally invoke an innocuous response, may result in pain6 fMRI data demonstrate that response to low intensity stimuli in patients with FM is comparable to the response to high intensity stimuli in controls5 References: Staud R, Rodriguez ME. Mechanisms of disease: pain in fibromyalgia syndrome. Nat Clin Pract Rheumatol. 2006;2:90-98. Williams DA, Clauw DJ. Understanding Fibromyalgia: Lessons from the Broader Pain Research Community. J Pain. 2009;10(8): Sarchielli P, Mancini ML, Floridi A, et al. Increased levels of neurotrophins are not specific for chronic migraine: evidence from primary fibromyalgia syndrome. J Pain. 2007;8: Vaerøy H, Helle R, Forre O, Kåas E, Terenius L. Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis. Pain. 1988;32:21-26. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional Magnetic Resonance Imaging Evidence of Augmented Pain Processing in Fibromyalgia. Arthritis Rheum. 2002;46(5): Henriksson KG. Fibromyalgia – from syndrome to disease. Overview of pathogenetic mechanisms. J Rehabil Med. 2003;41(suppl 41):89-94. Ref 6.a Henriksson KG Pg 89 Col 2 Par 3 Lin 1-5 Ref 6.b Pg 91 Col 1 Lin 1-7 Ref 1.b Staud & Rodriguez Pg 92 Figure 2 Ref 4.a Vaeroy et al Pg 24 Col 2 Par 3 Lin 5-8 1. Staud R and Rodriguez ME. Nat Clin Pract Rheumatol. 2006;2: Williams DA and Clauw DJ. J Pain. 2009;10(8): 3. Sarchielli P, et al. J Pain. 2007;8: Vaerøy H, et al. Pain. 1988;32: Gracely RH, et al. Arthritis Rheum. 2002;46: Napadow 2010 "Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity." Arthritis and Rheumatism 62(8): Ref 5.b Gracely et al Pg 1340 Col 1,2 Par 1