Zespół bólowy kompleksowy – Patofizjologia i mechanizm

Zespół bólowy kompleksowy
Patofizjologia i mechanizm

Zespół bólowy kompleksowy (CRPS) to złożone zaburzenie neuropatyczne charakteryzujące się przewlekłym bólem kończyny po urazie, wynikające z interakcji procesów zapalnych, immunologicznych, sensytyzacji obwodowej i centralnej oraz dysfunkcji autonomicznego układu nerwowego. W patogenezie kluczową rolę odgrywa neurozapalenie z udziałem cytokin prozapalnych (IL-1, IL-2, IL-6, TNF-α) i neuropeptydów (CGRP, substancja P), które nasilają odpowiedź zapalną i prowadzą do nadwrażliwości nocyceptorów. U około 70% pacjentów wykrywa się przeciwciała IgG przeciwko antygenom neuronów autonomicznych, co wskazuje na komponent autoimmunologiczny. Genetyczne predyspozycje, w tym allel HLA-DQ1, HLA-B62 i HLA-DQ8, oraz polimorfizmy SNP w genach ANO10, P2RX7, PRKAG1 i SLC12A9, zwiększają ryzyko rozwoju CRPS. Sensytyzacja obwodowa i centralna prowadzi do hiperalgezji i allodynii, a dysfunkcja układu współczulnego powoduje zaburzenia naczynioruchowe, manifestujące się zmianami temperatury i koloru skóry kończyny. Stres oksydacyjny i dysfunkcja mitochondrialna również przyczyniają się do patogenezy, co potwierdza skuteczność witaminy C w profilaktyce CRPS po złamaniach nadgarstka.

Patogeneza zespołu bólowego kompleksowego

Procesy zapalne w zespole bólowym kompleksowym
Komponenta autoimmunologiczna
Sensytyzacja obwodowa i centralny układ nerwowy
Dysfunkcja autonomicznego układu nerwowego
Stres oksydacyjny i dysfunkcja mitochondrialna
Zmiany neuroplastyczne i reorganizacja kory mózgowej

Mechanizmy patofizjologiczne w różnych typach zespołu bólowego kompleksowego

CRPS typ I (bez uszkodzenia nerwu)
CRPS typ II (z uszkodzeniem nerwu)
Wspólne mechanizmy w obu typach CRPS

Neuroinflammacja w zespole bólowym kompleksowym

Rola neuropeptydów w procesie neuroinflammacji
Interakcja między komórkami immunologicznymi a neuronami
Rola komórek glejowych w centralnej sensytyzacji

Wpływ czynników genetycznych na rozwój zespołu bólowego kompleksowego

Markery genetyczne związane z CRPS
Znaczenie czynników genetycznych w diagnostyce i leczeniu

Mechanizmy bólu w zespole bólowym kompleksowym

Ból nocyceptywny w CRPS
Ból neuropatyczny w CRPS
Ból nocyplastyczny w CRPS

Podsumowanie patofizjologii zespołu bólowego kompleksowego

Kolejne rozdziały

Patogeneza zespołu bólowego kompleksowego

Zespół bólowy kompleksowy, znany również jako Complex Regional Pain Syndrome (CRPS), jest wieloczynnikowym zaburzeniem neuropatycznym charakteryzującym się nadmiernym i przedłużonym odczuwaniem bólu w kończynie po urazie. Pomimo intensywnych badań klinicznych w ostatnich dziesięcioleciach, dokładna patogeneza tego schorzenia pozostaje nie w pełni wyjaśniona¹². W mechanizmie rozwoju CRPS uczestniczy złożona interakcja systemów immunologicznych, neurologicznych i autonomicznych³.

Procesy zapalne w zespole bólowym kompleksowym

Wyniki badań wskazują, że zapalenie odgrywa kluczową rolę w patogenezie CRPS. Charakterystyczną cechą fazy początkowej jest nasilona odpowiedź zapalna na uraz początkowy⁴. W CRPS dochodzi do wyzwolenia klasycznych oznak zapalenia, w tym bólu, obrzęku, zaczerwienienia, zwiększonej temperatury i upośledzenia funkcji⁵. Markery zapalenia, takie jak cytokiny prozapalne (IL-1, IL-2, IL-6, TNF-α) oraz neuropeptydy (peptyd związany z genem kalcytoniny (CGRP), bradykinina i substancja P), przyczyniają się do intensywnej odpowiedzi zapalnej po urazie, co ostatecznie inicjuje rozwój CRPS⁶⁷.

Warto zauważyć, że u pacjentów z CRPS stwierdzono podwyższone poziomy markerów zapalnych nie tylko miejscowo w zajętej kończynie, ale również w krwiobiegu i płynie mózgowo-rdzeniowym⁸. Zaburzenia odpowiedzi immunologicznej mogą prowadzić do utrzymywania się stanu zapalnego, zamiast jego normalnego wygaszania, co obserwuje się u pacjentów z CRPS⁹.

Komponenta autoimmunologiczna

Istotnym odkryciem w patogenezie CRPS jest udział mechanizmów autoimmunologicznych. Badania wykazały obecność przeciwciał klasy IgG skierowanych przeciwko antygenom powierzchniowym neuronów autonomicznych we krwi około 70% pacjentów z CRPS¹⁰. CRPS może być uznawany za zespół autoimmunologiczny mediowany przez przeciwciała, o zlokalizowanym przebiegu¹¹.

Dodatkowo, badania genetyczne wykazały związek pomiędzy CRPS a określonymi allelami HLA (Human Leukocyte Antigen), w tym HLA-DQ1, HLA-B62 i HLA-DQ8, szczególnie u pacjentów z dystonią¹²¹³. Odkrycia te sugerują, że predyspozycje genetyczne mogą odgrywać rolę w podatności na rozwój CRPS po urazie¹⁴.

Wykazano również zwiększoną ekspresję genów związanych z procesami zapalnymi i immunologicznymi u pacjentów z CRPS, w tym HLA-DRB1, MMP9, PTGS2, IL-8 i STAT3¹⁵. Szczególnie interesujące jest, że ekspresja MMP9, która odgrywa istotną rolę w bólu neuropatycznym, jest charakterystycznie podwyższona zarówno w CRPS typu I, jak i II¹⁶.

Sensytyzacja obwodowa i centralny układ nerwowy

W patogenezie CRPS istotną rolę odgrywa sensytyzacja obwodowego układu nerwowego, która jest wywołana przez uwalnianie markerów prozapalnych po początkowym urazie¹⁷. Dochodzi do uwrażliwienia obwodowych nocyceptorów, co powoduje ich nadmierną reaktywność na bodźce, które normalnie nie wywołują bólu¹⁸.

Bodźce mechaniczne, termiczne i chemiczne aktywują obwodowe nocyceptory, które przewodzą sygnały bólowe przez lekko zmielinizowane włókna A-delta i niezmielinizowane włókna C do warstw I, II i V według Rexeda w rdzeniu kręgowym¹⁹. Proces ten prowadzi do uwolnienia pobudzających aminokwasów, takich jak glutamina i asparagina, które działają na receptory NMDA, powodując uwolnienie substancji P²⁰.

W CRPS obserwuje się również zwiększoną pobudliwość drugorzędowych neuronów rogów grzbietowych²¹. Ciągła stymulacja nocyceptywna prowadzi do centralnej sensytyzacji, co objawia się nadwrażliwością na bodźce (hiperalgezja) i odczuwaniem bólu w odpowiedzi na bodźce, które normalnie nie wywołują bólu (allodynia)²²²³.

Hiperalgezja i allodynia początkowo rozwijają się w miejscu urazu, jednak po wystąpieniu centralnej sensytyzacji poprzez aktywność neuronów o szerokim zakresie dynamicznym (WDR), obszar bólu rozszerza się poza początkowy region patologii tkankowej²⁴.

Dysfunkcja autonomicznego układu nerwowego

Dysfunkcja autonomicznego układu nerwowego jest kolejnym istotnym mechanizmem w patogenezie CRPS²⁵. Układ współczulny odgrywa kluczową rolę w utrzymywaniu bólu i dysfunkcji autonomicznej w zajętej kończynie²⁶.

W CRPS dochodzi do sprzężenia współczulno-aferentnego w wyniku nadekspresji receptorów współczulnych na włóknach nocyceptywnych²⁷. Sprzężenie to jest mediowane przez noradrenalinę, która jest uwalniana z nowo wytworzonych zakończeń współczulnych i adrenoreceptorów na aferentnych neuronach nocyceptywnych²⁸. Rzeczywiście, zwiększone mRNA dla receptorów alfa-2-adrenergicznych wykazano w neuronach zwojów korzeni grzbietowych po urazie nerwu²⁹.

Zaburzenia naczynioruchowe obserwowane w CRPS mogą wynikać z dysfunkcji układu współczulnego. Badania przepływu krwi w skórze i temperatury u pacjentów z CRPS wykazały, że ocieplenie zajętej kończyny w ostrej fazie choroby wynika z funkcjonalnego zahamowania skórnej współczulnej aktywności naczynioskurczowej, prowadząc do rozszerzenia naczyń skórnych³⁰.

Stres oksydacyjny i dysfunkcja mitochondrialna

Stres oksydacyjny odgrywa kluczową rolę w patogenezie CRPS³¹. Istnieją spekulacje, że generowanie wolnych rodników przez mitochondrialny łańcuch oddechowy przyczynia się do patofizjologii CRPS typu I³². Badania wykazały, że witamina C jako przeciwutleniacz zmniejsza częstość występowania CRPS u ludzi po złamaniach nadgarstka, co potwierdza hipotezę stresu oksydacyjnego³³.

Ponieważ mitochondria są głównym źródłem reaktywnych form tlenu (ROS), uzasadnione jest przypuszczenie, że dysfunkcja mitochondrialna związana ze stresem oksydacyjnym może odgrywać rolę w patogenezie CRPS³⁴.

Zmiany neuroplastyczne i reorganizacja kory mózgowej

W CRPS dochodzi do zmian neuroplastycznych, które obejmują reorganizację korową³⁵. Badania neuroobrazowe u pacjentów z CRPS wykazały zmiany strukturalne w obszarach kory ruchowej i homunkulus sensoryczny³⁶. W wyniku tych zmian dochodzi do mniejszej reprezentacji zajętej kończyny w porównaniu z kończyną niezajętą, co prowadzi do zaburzonego postrzegania i ruchu zajętej kończyny³⁷.

Funkcjonalne badania obrazowe wykazały, że zmiany adaptacyjne w obrębie ośrodkowego układu nerwowego mogą przyczyniać się do objawów ruchowych w CRPS³⁸. Stopień reorganizacji somatotopowej koreluje istotnie z intensywnością bólu i stopniem hiperalgezji³⁹.

Mechanizmy patofizjologiczne w różnych typach zespołu bólowego kompleksowego

Zespół bólowy kompleksowy dzieli się na dwa typy. CRPS typ I stanowi większość przypadków i jest definiowany jako CRPS bez znanego uszkodzenia nerwu. CRPS typ II jest podobny do typu I, ale obejmuje jawne uszkodzenie nerwu obwodowego⁴⁰.

CRPS typ I (bez uszkodzenia nerwu)

W CRPS typu I, mimo braku jawnego uszkodzenia nerwu, dochodzi do podobnych mechanizmów patofizjologicznych jak w typie II. Występuje obwodowa i centralna sensytyzacja, które wyjaśniają patofizjologię bólu spontanicznego i hiperalgezji⁴¹. U pacjentów konsekwentnie obserwuje się zaburzenia czuciowe, które rozprzestrzeniają się poza uszkodzony obszar, a ból spontaniczny często obejmuje kwadrant lub region półsensoryczny⁴².

Interesujące jest, że pomimo klasyfikacji CRPS typu I jako niezwiązanego z uszkodzeniem nerwu, w niektórych przypadkach wykryto drobne uszkodzenia nerwowe. Neuropatia małych włókien może mieć znaczenie kliniczne, ponieważ zmniejszenie liczby małych włókien po urazie może zmienić sąsiednie włókna w stan o obniżonych progach depolaryzacji i ektopowym wyładowywaniu⁴³.

CRPS typ II (z uszkodzeniem nerwu)

CRPS typu II charakteryzuje się jawnym uszkodzeniem nerwu obwodowego⁴⁴. W tym typie CRPS mechanizmy patofizjologiczne obejmują zarówno komponenty obwodowe, jak i centralne układu nerwowego⁴⁵.

Obecność demonstrowalnego uszkodzenia nerwu w CRPS typu II podkreśla zaangażowanie zarówno mechanizmów obwodowego, jak i ośrodkowego układu nerwowego w patofizjologii tego stanu⁴⁶.

Wspólne mechanizmy w obu typach CRPS

Zarówno w CRPS typu I, jak i II, występują podobne mechanizmy patofizjologiczne, w tym zapalenie neurogenne, sensytyzacja obwodowa i centralna oraz dysfunkcja autonomiczna⁴⁷. Obserwowane objawy kliniczne, takie jak zaburzenia czuciowe, które wykraczają poza uszkodzony obszar, wskazują na podobne podstawowe mechanizmy w obu typach⁴⁸.

W CRPS mogą występować kombinacje bólu nocyceptywnego, neuropatycznego i nocyplastycznego, ponieważ jest to zespół wielomechanizmowy⁴⁹. Ta złożoność mechanizmów podkreśla potrzebę indywidualnego podejścia do leczenia, ukierunkowanego na dominujące mechanizmy patofizjologiczne u danego pacjenta⁵⁰.

Neuroinflammacja w zespole bólowym kompleksowym

Neuroinflammacja, czyli odpowiedź zapalna w obwodowym i ośrodkowym układzie nerwowym, odgrywa kluczową rolę w inicjacji i podtrzymywaniu bólu oraz sensytyzacji neuronów nocyceptywnych w CRPS⁵¹.

Rola neuropeptydów w procesie neuroinflammacji

Zapalenie neurogenne jest uważane za główny mechanizm wyzwalający w patogenezie CRPS⁵². Neuropeptydy, szczególnie substancja P (SP) i peptyd związany z genem kalcytoniny (CGRP), pośredniczą w nasilonym zapaleniu neurogennym i bólu w CRPS⁵³.

W miejscu urazu obwodowe nocyceptory włókien C przekazują sygnały bólu, które powodują orto- i wsteczne uwalnianie SP i CGRP do uszkodzonych tkanek, powodując rozszerzenie naczyń, wynaczynienie mediatorów pronociceptywnych, reaktywację i dalszą sensytyzację aferentów włókien C oraz zwiększoną chorobowość tkanek w uszkodzonym obszarze⁵⁴.

Interakcja między komórkami immunologicznymi a neuronami

Interakcja między komórkami immunologicznymi a neuronami odgrywa kluczową rolę w rozwoju zapalenia neurogennego w CRPS⁵⁵. Główne komórki zaangażowane w ten proces obejmują nocyceptory, neurony, komórki glejowe (takie jak komórki Schwanna, astrocyty, mikroglej i oligodendrocyty), komórki immunologiczne (w tym komórki T, makrofagi i komórki tuczne) oraz keratynocyty⁵⁶.

Liczne badania wykazały zwiększoną populację limfocytów CD4 i CD8 u pacjentów z CRPS, co sugeruje odpowiedź komórek T mediowaną antygenowo⁵⁷. Te odkrycia potwierdzają udział komponentu autoimmunologicznego w patogenezie CRPS.

Rola komórek glejowych w centralnej sensytyzacji

Komórki glejowe zostały zidentyfikowane jako główny czynnik przyczyniający się do centralnej sensytyzacji nocyceptywnej i uważa się, że są zaangażowane w patogenezę CRPS w fazie przewlekłej⁵⁸. Podczas procesu neuroinflammacji w CRPS, neuropeptydy i neurotransmitery generowane przez zapalenie neurogenne mogą aktywować mikroglej i astrocyty, prowadząc do kaskady mediatorów glejowych, które uwrażliwiają neurony i wpływają na plastyczność synaptyczną⁵⁹.

Długotrwałe uwalnianie cytokin prozapalnych podczas przewlekłej „zimnej fazy” CRPS powoduje nadaktywność współczulnego układu nerwowego, co zwiększa poziom noradrenaliny, zmniejsza ekspresję receptorów alfa-1 adrenergicznych i prowadzi do skurczu naczyń oraz rozwoju zimnej, niebieskiej i wilgotnej kończyny⁶⁰.

Wpływ czynników genetycznych na rozwój zespołu bólowego kompleksowego

Istnieją dowody na to, że czynniki dziedziczne przyczyniają się do skłonności do rozwoju CRPS⁶¹. Genetyczne predyspozycje mogą wyjaśniać, dlaczego niektóre osoby rozwijają CRPS po urazie, a inne nie⁶².

Markery genetyczne związane z CRPS

Badania wykazały związek między CRPS a określonymi markerami genetycznymi. Polimorfizmy w genach TNF-alfa i ACE zostały powiązane z CRPS⁶³. Dodatkowo, badania genetyczne wykazały związek między CRPS a określonymi allelami HLA, w tym HLA-DQ1, HLA-DR13, HLA-B62 i HLA-DQ8⁶⁴.

Odkryto, że rzadkie allele czterech polimorfizmów pojedynczego nukleotydu (SNP) w czterech genach (ANO10, P2RX7, PRKAG1 i SLC12A9) występują częściej niż oczekiwano u osób, które cierpiały na CRPS przez ponad rok⁶⁵. Wyniki te sugerują, że te cztery specyficzne SNP zwiększają ryzyko rozwoju CRPS po urazie⁶⁶.

Znaczenie czynników genetycznych w diagnostyce i leczeniu

Identyfikacja markerów genetycznych związanych z CRPS może mieć istotne implikacje dla diagnostyki i leczenia tego schorzenia. Zrozumienie podłoża genetycznego CRPS może pomóc w opracowaniu bardziej ukierunkowanych i spersonalizowanych strategii terapeutycznych⁶⁷.

Badania sugerują, że CRPS jest wynikiem permisywnego tła genetycznego w około jednej trzeciej przypadków, przy czym efekt ten jest najbardziej widoczny u mężczyzn⁶⁸. Odkrycie to może mieć implikacje dla identyfikacji osób o zwiększonym ryzyku rozwoju CRPS po urazie.

Mechanizmy bólu w zespole bólowym kompleksowym

CRPS jest uznawany za zespół wielomechanizmowy, a doświadczany przez pacjentów ból można powiązać z różnymi mechanizmami, w tym zapaleniem, zaburzeniami naczynioruchowymi oraz sensytyzacją obwodową i centralną⁶⁹.

Ból nocyceptywny w CRPS

Ból nocyceptywny w CRPS może być wynikiem utrzymującego się zapalenia⁷⁰. W dysregulacji immunologicznej CRPS rolę odgrywają zarówno zaburzenia w układzie odpornościowym wrodzonym, jak i adaptacyjnym⁷¹.

Ból nocyceptywny może być również wynikiem zaburzeń motorycznych spowodowanych pobudzeniem nocyceptorów mięśniowych, na przykład w przykurczach i dystonii⁷². Ten rodzaj bólu jest typowo miejscowy i może być wywołany przez określone ruchy, może mu również towarzyszyć miejscowe objawy zapalne⁷³.

Ból neuropatyczny w CRPS

Ból neuropatyczny to kliniczny opis, który wymaga demonstrowalnej zmiany lub choroby spełniającej ustalone kryteria diagnostyczne neurologiczne⁷⁴. W CRPS typu 1 nie ma zweryfikowanej zmiany nerwowej, co wyklucza CRPS typu 1 z bólu neuropatycznego⁷⁵.

Interesujące jest, że drobne uszkodzenia nerwów wykryto również u niektórych pacjentów z CRPS typu 1 bez ciężkiego urazu⁷⁶. Neuropatia małych włókien ma znaczenie kliniczne, ponieważ zmniejszenie ilości małych włókien po urazie może zmienić sąsiednie włókna w stan o obniżonych progach depolaryzacji i ektopowym wyładowaniu⁷⁷.

Ból nocyplastyczny w CRPS

Wskazaniem na ból nocyplastyczny w CRPS jest to, że allodynia i hiperalgezja nie są koniecznie ograniczone do zajętej kończyny z CRPS⁷⁸. Dowody na to, że centralna sensytyzacja przyczynia się do patofizjologii CRPS, polegają na tym, że sumowanie czasowe jest zwiększone w zajętej kończynie z CRPS⁷⁹.

W CRPS możliwe są kombinacje bólu nocyceptywnego, neuropatycznego i nocyplastycznego, ponieważ CRPS jest zespołem wielomechanizmowym⁸⁰. Kluczowe jest rozpoznanie mieszanego bólu w CRPS i rozważenie wczesnego leczenia wielomodalnym planem terapeutycznym ukierunkowanym na ból nocyceptywny, neuropatyczny i nocyplastyczny⁸¹.

Podsumowanie patofizjologii zespołu bólowego kompleksowego

Zespół bólowy kompleksowy (CRPS) jest wieloczynnikowym zaburzeniem z udziałem procesów zapalnych, immunologicznych, centralnej i obwodowej sensytyzacji oraz dysregulacji autonomicznej⁸². Różnorodność objawów klinicznych odzwierciedla różne mechanizmy patofizjologiczne leżące u podstaw tego schorzenia⁸³.

Procesy zapalne, autoimmunologiczne, dysregulacja układu współczulnego, sensytyzacja obwodowa i centralna, zaburzenia naczynioruchowe oraz zmiany neuroplastyczne w korze mózgowej przyczyniają się wspólnie do złożonej patogenezy CRPS⁸⁴. Stopień, w jakim poszczególne mechanizmy przyczyniają się do CRPS, może różnić się między pacjentami, a nawet u jednego pacjenta może się zmieniać w czasie⁸⁵.

Lepsze zrozumienie mechanizmów leżących u podstaw CRPS ma kluczowe znaczenie dla opracowania skutecznych interwencji terapeutycznych⁸⁶. Strategie leczenia oparte na mechanizmach, które celują w dominujące ścieżki patofizjologiczne u poszczególnych pacjentów, mogą przynieść lepsze wyniki kliniczne⁸⁷⁸⁸.

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Materiały źródłowe

#1 Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis – UpToDate
https://www.uptodate.com/contents/complex-regional-pain-syndrome-in-adults-pathogenesis-clinical-manifestations-and-diagnosis
Complex regional pain syndrome (CRPS) is a disorder of a body region, usually of the distal limbs, which is characterized by pain, swelling, limited range of motion, vasomotor instability, skin changes, and patchy bone demineralization. It frequently begins following a fracture, soft tissue injury, or surgery. […] The etiology, pathophysiology, clinical manifestations, and diagnosis of CRPS in adults are reviewed here. […] The consensus definition of CRPS is as follows: „CRPS describes an array of painful conditions that are characterized by a continuing (spontaneous and/or evoked) regional pain that is seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is regional (not in a specific nerve territory or dermatome) and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time.”
#2 Algodystrophy (Complex Regional Pain Syndrome) – Rheumatology – Diseases – McMaster Textbook of Internal Medicine
https://empendium.com/mcmtextbook/chapter/B31.II.16.22.
Complex regional pain syndrome (CRPS) type 1 is also termed algodystrophy, Sudeck atrophy, reflex sympathetic dystrophy, shoulder-hand syndrome, posttraumatic dystrophy, or posttraumatic osteoporosis. […] The pathogenesis of CRPS remains unclear.
#3 Mechanisms of complex regional pain syndrome
https://pmc.ncbi.nlm.nih.gov/articles/PMC11140106/
Complex Regional Pain Syndrome (CRPS) is a chronic pain disorder characterized by a diverse array of symptoms, including pain that is disproportionate to the initial triggering event, accompanied by autonomic, sensory, motor, and sudomotor disturbances. […] Recent studies started to unravel the complex pathogenic mechanisms of CRPS, particularly from an autoimmune and neuroimmune interaction perspective. CRPS is now recognized as a systemic disease that stems from a complex interplay of inflammatory, immunologic, neurogenic, genetic, and psychologic factors. […] Key mechanisms underlying clinical manifestations include peripheral and central sensitization, sympathetic dysregulation, and alterations in somatosensory processing. Enhanced understanding of the mechanisms of CRPS is crucial for the development of effective therapeutic interventions.
#4 Mechanisms of complex regional pain syndrome
https://pmc.ncbi.nlm.nih.gov/articles/PMC11140106/
The etiology and pathogenesis of CRPS may exhibit inter-individual heterogeneity and even intra-individual variability over time. The most common inciting events are surgery, nerve compression, fractures, tissue trauma, ischemia, and sprains. Inflammation, oxidative stress, and neuronal mechanisms have been postulated as pivotal factors in the pathogenesis of CRPS. Current evidence suggests that the development of CRPS involves multiple mechanisms originating from a complex interplay between the immune system, the neural systems (including the peripheral nervous system (PNS), central nervous system (CNS), and autonomic nervous system), and genetic predisposition. […] The hallmark of the initial phase of CRPS is an exaggerated inflammatory response to the initial trauma. CRPS manifests with all the cardinal signs of inflammation, including pain, edema, erythema, increased temperature, and impaired function. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-2, IL-6, and tumor necrosis factor- (TNF-), as well as neuropeptides like calcitonin gene-related peptide (CGRP), bradykinin, and substance P, contribute to the intense inflammatory response following trauma or injury, ultimately instigating the development of CRPS.
#5 Mechanisms of complex regional pain syndrome
https://pmc.ncbi.nlm.nih.gov/articles/PMC11140106/
The etiology and pathogenesis of CRPS may exhibit inter-individual heterogeneity and even intra-individual variability over time. The most common inciting events are surgery, nerve compression, fractures, tissue trauma, ischemia, and sprains. Inflammation, oxidative stress, and neuronal mechanisms have been postulated as pivotal factors in the pathogenesis of CRPS. Current evidence suggests that the development of CRPS involves multiple mechanisms originating from a complex interplay between the immune system, the neural systems (including the peripheral nervous system (PNS), central nervous system (CNS), and autonomic nervous system), and genetic predisposition. […] The hallmark of the initial phase of CRPS is an exaggerated inflammatory response to the initial trauma. CRPS manifests with all the cardinal signs of inflammation, including pain, edema, erythema, increased temperature, and impaired function. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-2, IL-6, and tumor necrosis factor- (TNF-), as well as neuropeptides like calcitonin gene-related peptide (CGRP), bradykinin, and substance P, contribute to the intense inflammatory response following trauma or injury, ultimately instigating the development of CRPS.
#6 Mechanisms of complex regional pain syndrome
https://pmc.ncbi.nlm.nih.gov/articles/PMC11140106/
The etiology and pathogenesis of CRPS may exhibit inter-individual heterogeneity and even intra-individual variability over time. The most common inciting events are surgery, nerve compression, fractures, tissue trauma, ischemia, and sprains. Inflammation, oxidative stress, and neuronal mechanisms have been postulated as pivotal factors in the pathogenesis of CRPS. Current evidence suggests that the development of CRPS involves multiple mechanisms originating from a complex interplay between the immune system, the neural systems (including the peripheral nervous system (PNS), central nervous system (CNS), and autonomic nervous system), and genetic predisposition. […] The hallmark of the initial phase of CRPS is an exaggerated inflammatory response to the initial trauma. CRPS manifests with all the cardinal signs of inflammation, including pain, edema, erythema, increased temperature, and impaired function. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-2, IL-6, and tumor necrosis factor- (TNF-), as well as neuropeptides like calcitonin gene-related peptide (CGRP), bradykinin, and substance P, contribute to the intense inflammatory response following trauma or injury, ultimately instigating the development of CRPS.
#7 Complex Regional Pain Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK430719/
Both the clinical presentation and elevated inflammatory laboratory markers suggest that inflammation is a key mechanism underlying the development of CRPS. […] Autoimmune factors appear to play a role in the pathogenesis of CRPS. […] Sensitization of the peripheral nervous system is triggered by the release of pro-inflammatory markers after the initial injury. […] Increased excitability of secondary dorsal horn neurons occurs in CRPS. […] Sympathetic-afferent coupling occurs in CRPS due to the upregulation of sympathetic receptors on nociceptive nerve fibers.
#8 Complex Regional Pain Syndrome Part 1: Essentials of Assessment and Diagnosis | PM&R KnowledgeNow
https://now.aapmr.org/complex-regional-pain-syndrome-part-1-essentials-of-assessment-and-diagnosis/
A new overarching hypothesis that may explain the condition invokes four dynamically changing and interacting components of tissue trauma, pathological pain processing, autonomic dysfunction (both peripheral and central) and immune dysfunction, primarily involving excessive and pathological activation of dendritic cells following trauma or atrophy. […] Other proposed mechanisms include classic and neurogenic inflammation. It has been found that patients with CRPS present with increased pro-inflammatory cytokines locally, in the bloodstream and in CSF. […] Neuroimaging studies suggest a reorganization of somatotopic maps in the cortex of patients with CRPS. The degree of somatotopic reorganization correlates significantly with pain intensity and degree of hyperalgesia. […] The degree to which individual mechanisms contribute to CRPS may differ between patients and even within one patient over time.
#9 Mechanisms of complex regional pain syndrome
https://pmc.ncbi.nlm.nih.gov/articles/PMC11140106/
An important recent finding is that autoimmunity has a significant role in the development of CRPS. This is supported by compelling evidence such as the detection of immunoglobulin G (IgG) autoantibodies targeting surface antigens on autonomic neurons in the bloodstream of 70% of CRPS patients. […] Overactive immune reaction in response to inflammation leads to tissue damage in the acute phase of CRPS. Though the immune response is a normal physiological reaction to tissue damage, neuroimmune interactions and subsequent neuroinflammation tend to persist instead of diminishing in patients with CRPS. […] CRPS could be regarded as an autoantibody-mediated autoimmune syndrome with a localized course. In autoimmune diseases, the innate immune system triggers an immune response by the adaptive immune system against its tissues. […] The sustained or dysregulated signaling of complement factors observed in chronic pain suggests a plausible involvement of complement in the maladaptive mechanisms underlying CRPS.
#10 Mechanisms of complex regional pain syndrome
https://pmc.ncbi.nlm.nih.gov/articles/PMC11140106/
An important recent finding is that autoimmunity has a significant role in the development of CRPS. This is supported by compelling evidence such as the detection of immunoglobulin G (IgG) autoantibodies targeting surface antigens on autonomic neurons in the bloodstream of 70% of CRPS patients. […] Overactive immune reaction in response to inflammation leads to tissue damage in the acute phase of CRPS. Though the immune response is a normal physiological reaction to tissue damage, neuroimmune interactions and subsequent neuroinflammation tend to persist instead of diminishing in patients with CRPS. […] CRPS could be regarded as an autoantibody-mediated autoimmune syndrome with a localized course. In autoimmune diseases, the innate immune system triggers an immune response by the adaptive immune system against its tissues. […] The sustained or dysregulated signaling of complement factors observed in chronic pain suggests a plausible involvement of complement in the maladaptive mechanisms underlying CRPS.
#11 Mechanisms of complex regional pain syndrome
https://pmc.ncbi.nlm.nih.gov/articles/PMC11140106/
An important recent finding is that autoimmunity has a significant role in the development of CRPS. This is supported by compelling evidence such as the detection of immunoglobulin G (IgG) autoantibodies targeting surface antigens on autonomic neurons in the bloodstream of 70% of CRPS patients. […] Overactive immune reaction in response to inflammation leads to tissue damage in the acute phase of CRPS. Though the immune response is a normal physiological reaction to tissue damage, neuroimmune interactions and subsequent neuroinflammation tend to persist instead of diminishing in patients with CRPS. […] CRPS could be regarded as an autoantibody-mediated autoimmune syndrome with a localized course. In autoimmune diseases, the innate immune system triggers an immune response by the adaptive immune system against its tissues. […] The sustained or dysregulated signaling of complement factors observed in chronic pain suggests a plausible involvement of complement in the maladaptive mechanisms underlying CRPS.
#12 Journal of Biomedical and Translational Research
https://www.jbtr.or.kr/archive/view_article?pid=jbtr-23-4-109
Notably, MMP9 expression was characteristically up-regulated in CRPS I and CRPS II patients; MMP9, which plays an important role in neuropathic pain, is closely associated with CRPS I. […] Many researchers studied the role of genes in CRPS; a few studies published significant findings. […] Recent studies reported an association between HLA-B62 and HLA-DQ8. In a study on patients with fixed dystonia, a significant association between the specific phenotype of CRPS with HLA-B62 and HLA-DQ8 was found. […] Determining whether CD4 T-cell clones with specific receptors penetrate and destroy certain nerve cells using a mechanism similar to that of T1D is necessary. […] Further studies are required to study the association between neuro-inflammation and MMP-9 gene expression.
#13 Complex Regional Pain Syndrome : Virtual Library
https://resources.wfsahq.org/atotw/complex-regional-pain-syndrome/
Evidence suggests a link between psychological stress and CRPS disease development and progress. […] A Dutch study showed HLA (Human Leucocyte Antigen) DQ1, HLA B62, and HLA DQ8 to be associated with CRPS with fixed dystonia. […] These findings have postulated that CRPS can be autoimmune in origin.
#14 Evidence of a genetic background predisposing to complex regional pain syndrome type 1 | Journal of Medical Genetics
https://jmg.bmj.com/content/61/2/163
Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. […] A heritable component to CRPS has been suggested and leads to the hypothesis that there is a genetic predisposition to developing CRPS-1 following trauma. […] Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1. […] The discovery of a genetic background composed of four SNPs permissive for the development of CRPS-1, in about a third of the cases. […] This study provides evidence that some people develop CRPS-1 due to genetically altered disease susceptibility. […] We found that the rare allele of four SNPs in four genes were more common than expected in individuals who had suffered CRPS-1 for more than a year; rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9.
#15 Journal of Biomedical and Translational Research
https://www.jbtr.or.kr/archive/view_article?pid=jbtr-23-4-109
In conclusion, CRPS is a complicated syndrome requiring further studies to determine its etiology, pathophysiology, and risk factors. Notably, identifying genetic risk factors and causes will provide more opportunities for better prevention, diagnosis, and treatment of CRPS. […] In this review, we summarized the studies that investigated the genetic factors of CRPS and genes that were closely associated with the occurrence and progression of CRPS. […] We provided an account of the genes associated with CRPS through a literature review. Of those genes, we described the key genes that indicated a significant association with CRPS, such those of human leukocyte antigen (HLA)-DQ1, HLA-DR13, HLA-B62, and HLA-DQ8. […] The study confirmed that 11 selected genes (HLA-DRB1, HLA-A29.1, HLA-DRB6, matrix metalloproteinase (MMP)9, PTGS2, IL-8, MMP26, ANPEP, HDC, G-CSF3R, and STAT3) were up-regulated and one selected gene (ARHGEF10) was down-regulated using gene expression profiling.
#16 Journal of Biomedical and Translational Research
https://www.jbtr.or.kr/archive/view_article?pid=jbtr-23-4-109
Notably, MMP9 expression was characteristically up-regulated in CRPS I and CRPS II patients; MMP9, which plays an important role in neuropathic pain, is closely associated with CRPS I. […] Many researchers studied the role of genes in CRPS; a few studies published significant findings. […] Recent studies reported an association between HLA-B62 and HLA-DQ8. In a study on patients with fixed dystonia, a significant association between the specific phenotype of CRPS with HLA-B62 and HLA-DQ8 was found. […] Determining whether CD4 T-cell clones with specific receptors penetrate and destroy certain nerve cells using a mechanism similar to that of T1D is necessary. […] Further studies are required to study the association between neuro-inflammation and MMP-9 gene expression.
#17 Complex Regional Pain Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK430719/
Both the clinical presentation and elevated inflammatory laboratory markers suggest that inflammation is a key mechanism underlying the development of CRPS. […] Autoimmune factors appear to play a role in the pathogenesis of CRPS. […] Sensitization of the peripheral nervous system is triggered by the release of pro-inflammatory markers after the initial injury. […] Increased excitability of secondary dorsal horn neurons occurs in CRPS. […] Sympathetic-afferent coupling occurs in CRPS due to the upregulation of sympathetic receptors on nociceptive nerve fibers.
#18 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
Mechanical, thermal, and chemical stimuli activate peripheral nociceptors that transmit pain messages through lightly myelinated A-delta fibers and unmyelinated C fibers projecting to Rexed layers I, II, and V in the spinal cord. This process leads to the release of excitatory amino acids, such as glutamine and asparagine, which then act upon N -methyl-D -aspartic acid (NMDA) receptors, causing the release of substance P (SP). SP then lowers the threshold for synaptic excitability in normally silent second-order interspinal synapses. […] Peripheral sensitization occurs when persistent or repetitive noxious stimulation of high-threshold, polymodal C fibers results in enhanced sensitivity, lower stimulus thresholds, and the prolonged, enhanced activation of dorsal horn cells, especially those with glutamate receptors. In addition to SP, algogenic substances that are typically involved in tissue damage and capable of inducing transduction centripetally include potassium, serotonin, bradykinin, histamine, prostaglandins, and leukotrienes. Neuropeptides, such as SP and calcitonin gene-related peptide (CGRP), are also transported to the endings of nociceptive afferents, where they can instigate orthograde and retrograde actions including, but not limited to, neurogenic inflammation, which can incite a host of additional hostile algogenic mechanisms.
#19 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
Mechanical, thermal, and chemical stimuli activate peripheral nociceptors that transmit pain messages through lightly myelinated A-delta fibers and unmyelinated C fibers projecting to Rexed layers I, II, and V in the spinal cord. This process leads to the release of excitatory amino acids, such as glutamine and asparagine, which then act upon N -methyl-D -aspartic acid (NMDA) receptors, causing the release of substance P (SP). SP then lowers the threshold for synaptic excitability in normally silent second-order interspinal synapses. […] Peripheral sensitization occurs when persistent or repetitive noxious stimulation of high-threshold, polymodal C fibers results in enhanced sensitivity, lower stimulus thresholds, and the prolonged, enhanced activation of dorsal horn cells, especially those with glutamate receptors. In addition to SP, algogenic substances that are typically involved in tissue damage and capable of inducing transduction centripetally include potassium, serotonin, bradykinin, histamine, prostaglandins, and leukotrienes. Neuropeptides, such as SP and calcitonin gene-related peptide (CGRP), are also transported to the endings of nociceptive afferents, where they can instigate orthograde and retrograde actions including, but not limited to, neurogenic inflammation, which can incite a host of additional hostile algogenic mechanisms.
#20 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
Mechanical, thermal, and chemical stimuli activate peripheral nociceptors that transmit pain messages through lightly myelinated A-delta fibers and unmyelinated C fibers projecting to Rexed layers I, II, and V in the spinal cord. This process leads to the release of excitatory amino acids, such as glutamine and asparagine, which then act upon N -methyl-D -aspartic acid (NMDA) receptors, causing the release of substance P (SP). SP then lowers the threshold for synaptic excitability in normally silent second-order interspinal synapses. […] Peripheral sensitization occurs when persistent or repetitive noxious stimulation of high-threshold, polymodal C fibers results in enhanced sensitivity, lower stimulus thresholds, and the prolonged, enhanced activation of dorsal horn cells, especially those with glutamate receptors. In addition to SP, algogenic substances that are typically involved in tissue damage and capable of inducing transduction centripetally include potassium, serotonin, bradykinin, histamine, prostaglandins, and leukotrienes. Neuropeptides, such as SP and calcitonin gene-related peptide (CGRP), are also transported to the endings of nociceptive afferents, where they can instigate orthograde and retrograde actions including, but not limited to, neurogenic inflammation, which can incite a host of additional hostile algogenic mechanisms.
#21 Complex Regional Pain Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK430719/
Both the clinical presentation and elevated inflammatory laboratory markers suggest that inflammation is a key mechanism underlying the development of CRPS. […] Autoimmune factors appear to play a role in the pathogenesis of CRPS. […] Sensitization of the peripheral nervous system is triggered by the release of pro-inflammatory markers after the initial injury. […] Increased excitability of secondary dorsal horn neurons occurs in CRPS. […] Sympathetic-afferent coupling occurs in CRPS due to the upregulation of sympathetic receptors on nociceptive nerve fibers.
#22 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
In most cases, experts believe that CRPS develops when persistent noxious stimuli from an injured body region leads to peripheral and central sensitization, whereby primary afferent nociceptive mechanisms demonstrate abnormally heightened sensation, including spontaneous pain and hyperalgesia. Allodynia and hyperalgesia occur when central nervous system (CNS) somatosensory processing misinterprets normal, nonpainful mechanical stimuli, such as light touching of the skin, as painful. Therefore, skin in the injured area becomes more sensitive to all stimuli, even nonpainful stimuli. In addition, the sensitization can extend beyond the originally injured area, thus enlarging the region of aberrant pain perception. […] The peripheral and central sensitization associated with impaired CNS processing is linked to proposed disturbances within the sympathetic nervous system (SNS) that lead to sympathetic hyperactivity adversely affecting the injured area. Studies suggest that an augmented inflammatory response coupled with impaired healing further contribute to the refractory nature of malevolent CRPS.
#23 Pain mechanisms in complex regional pain syndrome: a systematic review and meta-analysis of quantitative sensory testing outcomes | Journal of Orthopaedic Surgery and Research | Full Text
https://josr-online.biomedcentral.com/articles/10.1186/s13018-022-03461-2
Complex regional pain syndrome (CRPS) is a chronic condition following inciting events such as fractures or surgeries with sensorimotor and autonomic manifestations and poor prognosis. This review aimed to provide conclusive evidence about the sensory phenotype of CRPS based on quantitative sensory testing (QST) to understand the underlying pain mechanisms and guide treatment strategies. […] However, the pain mechanisms involved in CRPS are not fully understood. Neurogenic inflammation, peripheral sensitization (PS), central sensitization (CS), small nerve fiber pathology, autonomic dysregulation, and psychological states represent the shared model of the underlying pathophysiology of CRPS. Neurogenic inflammation is caused by neuropeptides released from the primary afferents resulting in axon reflex vasodilatation and protein extravasation. PS is defined as enhanced responsiveness and decreased threshold of nociceptive neurons within the afflicted receptive field, and it was demonstrated in CRPS by the presence of primary hyperalgesia in the affected regions.
#24 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
Chronic CNS sensitization is engendered through afferent processing by second-order nociceptor-specific neurons and wide-dynamic-range (WDR) neurons in the spinal cord. WDR neurons contribute more to sensitivity than nociceptor-specific neurons because both nociceptive and non-nociceptive afferents converge to synapse on a single WDR neuron, and WDR neurons respond with equal intensity regardless of whether the neural signal is noxious (hyperalgesia) or not. […] Hyperalgesia and allodynia initially develop at the injury site. However, after CNS sensitization occurs through WDR neural activity, the area of pain expands beyond the initial region of tissue pathology. The peripheral changes described eventually cause an injury environment, where primary afferents, including nociceptors, demonstrate an increased sensitivity to circulating or experimentally injected subcutaneous norepinephrine.
#25 The complex regional pain syndrome: Diagnosis and management strategies | Neurosciences Journal
https://nsj.org.sa/content/28/4/211
On the other hand, autonomic dysregulation is another major cause of CRPS, which can result from nerve damage or inflammation. There are several physiological processes controlled by the autonomic nervous system, such as blood pressure, heart rate and hidrosis. Thus, in CRPS patients, autonomic dysregulation leads to changes in blood flow and skin temperature and symptoms such as swelling and hypersensitivity to touch. […] Moreover, other causes of CRPS can include brain and spinal cord changes, such as altered neural activity between different nervous system regions. Patients with CRPS have functional connectivity changes between their primary somatosensory cortex and other brain regions. All these pathophysiological findings could have implications for developing potential new treatment strategies that target each mechanism of CRPS.
#26 Complex regional pain syndrome â diagnostic, mechanisms, CNS involvement and therapy | Spinal Cord
https://www.nature.com/articles/3101404
Complex regional pain syndromes (CRPS, formerly reflex sympathetic dystrophy and causalgia) are neuropathic pain conditions of one extremity developing inadequately after a trauma. […] Pathophysiologically there is evidence for functional changes within the central nervous system and for involvement of peripheral inflammatory processes. The sympathetic nervous system plays a key role in maintaining pain and autonomic dysfunction in the affected extremity. […] Recent investigations of autonomic, motor and somatosensory abnormalities indicate that the whole picture of CRPS is considered to be a neurological disorder involving the central nervous system as well as a peripheral neurogenic inflammatory process. […] The clinical picture of autonomic dysfunction with changes in skin blood flow, temperature and sweating, as well as the symptom of sympathetically maintained pain, suggests that the sympathetic nervous system is involved in the pathophysiology of CRPS.
#27 Complex Regional Pain Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK430719/
Both the clinical presentation and elevated inflammatory laboratory markers suggest that inflammation is a key mechanism underlying the development of CRPS. […] Autoimmune factors appear to play a role in the pathogenesis of CRPS. […] Sensitization of the peripheral nervous system is triggered by the release of pro-inflammatory markers after the initial injury. […] Increased excitability of secondary dorsal horn neurons occurs in CRPS. […] Sympathetic-afferent coupling occurs in CRPS due to the upregulation of sympathetic receptors on nociceptive nerve fibers.
#28 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
This coupling is mediated by norepinephrine, which is released from newly expressed sympathetic terminals and adrenoreceptors onto afferent nociceptive neurons. Indeed, increased mRNA for alpha-2-adrenoreceptors has been demonstrated in DRG neurons following a nerve injury. […] In both types of CRPS, peripheral and central sensitization explain the pathophysiology of spontaneous pain and hyperalgesia. Clinical findings in patients consistently show sensory impairments that spread beyond the injured territory, and spontaneous pain that often engulfs a quadrant or hemisensory region. […] After tissue injury, the body’s response is programmed to promote healing, with the goal of regaining full use of the injured body part. Some experts have hypothesized that CRPS is caused by an aberrant healing response that includes exaggerated and persistent inflammation and guarding.
#29 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
This coupling is mediated by norepinephrine, which is released from newly expressed sympathetic terminals and adrenoreceptors onto afferent nociceptive neurons. Indeed, increased mRNA for alpha-2-adrenoreceptors has been demonstrated in DRG neurons following a nerve injury. […] In both types of CRPS, peripheral and central sensitization explain the pathophysiology of spontaneous pain and hyperalgesia. Clinical findings in patients consistently show sensory impairments that spread beyond the injured territory, and spontaneous pain that often engulfs a quadrant or hemisensory region. […] After tissue injury, the body’s response is programmed to promote healing, with the goal of regaining full use of the injured body part. Some experts have hypothesized that CRPS is caused by an aberrant healing response that includes exaggerated and persistent inflammation and guarding.
#30 Complex regional pain syndrome â diagnostic, mechanisms, CNS involvement and therapy | Spinal Cord
https://www.nature.com/articles/3101404
Studies on skin blood flow and temperature in CRPS I demonstrated that the warmer affected extremity in the acute stage of the disease is due to a functional inhibition of cutaneous sympathetic vasoconstrictor activity, leading to cutaneous vasodilatation. […] The locus of pathophysiological changes underlying such disturbed reflex activity must be in the central nervous system. […] Autonomic disturbances indicate a centrally located thermoregulatory dysfunction in CRPS. […] All these data indicate that alterations of the central nervous system play an important role in CRPS. However, it is not clear, whether these are primary abnormalities in the disease or whether they are changes secondary to the pain.
#31
https://link.springer.com/article/10.1007/s12630-012-9748-y
This review summarises the effect of oxidative stress and mitochondrial dysfunction in the pathogenesis of CRPS. It also addresses the question of whether there is a potential role for Nrf2 (activated by pharmacological or nutritional activators) in alleviating the clinical features of CRPS or preventing its progression. […] The stress oxydatif joue un rle essentiel dans la pathogense du SDRC. […] Oxidative stress has been involved in a number of diseases, including cardiac, respiratory, neurodegenerative, and gastrointestinal diseases and cancer; and it has been associated with aging and pain. […] It has been speculated that free radical generation by the mitochondrial respiratory chain contributes to the pathophysiology of CRPS I. […] Supporting the oxidative stress hypothesis, it has been observed that vitamin C as an antioxidant reduces the prevalence of CRPS in humans after wrist fractures.
#32
https://link.springer.com/article/10.1007/s12630-012-9748-y
This review summarises the effect of oxidative stress and mitochondrial dysfunction in the pathogenesis of CRPS. It also addresses the question of whether there is a potential role for Nrf2 (activated by pharmacological or nutritional activators) in alleviating the clinical features of CRPS or preventing its progression. […] The stress oxydatif joue un rle essentiel dans la pathogense du SDRC. […] Oxidative stress has been involved in a number of diseases, including cardiac, respiratory, neurodegenerative, and gastrointestinal diseases and cancer; and it has been associated with aging and pain. […] It has been speculated that free radical generation by the mitochondrial respiratory chain contributes to the pathophysiology of CRPS I. […] Supporting the oxidative stress hypothesis, it has been observed that vitamin C as an antioxidant reduces the prevalence of CRPS in humans after wrist fractures.
#33
https://link.springer.com/article/10.1007/s12630-012-9748-y
This review summarises the effect of oxidative stress and mitochondrial dysfunction in the pathogenesis of CRPS. It also addresses the question of whether there is a potential role for Nrf2 (activated by pharmacological or nutritional activators) in alleviating the clinical features of CRPS or preventing its progression. […] The stress oxydatif joue un rle essentiel dans la pathogense du SDRC. […] Oxidative stress has been involved in a number of diseases, including cardiac, respiratory, neurodegenerative, and gastrointestinal diseases and cancer; and it has been associated with aging and pain. […] It has been speculated that free radical generation by the mitochondrial respiratory chain contributes to the pathophysiology of CRPS I. […] Supporting the oxidative stress hypothesis, it has been observed that vitamin C as an antioxidant reduces the prevalence of CRPS in humans after wrist fractures.
#34
https://link.springer.com/article/10.1007/s12630-012-9748-y
As the mitochondrion is the major source of ROS, it is reasonable to speculate that mitochondrial dysfunction related to oxidative stress might play a role in the pathogenesis of CRPS. […] Nuclear factor erythroid 2-related factor is a basic leucine-zipper motif transcription factor that heterodimerically binds the antioxidant-responsive element (ARE) in the promoter regions of many cytoprotective genes. […] At the present time, there is no proof directly linking Nrf2 to the CRPS mechanism. However, taking the Nrf2 multifunction protection phenomenon into consideration with Nrf2 coordinately up-regulating antioxidant and antiinflammatory genes and cell type-specific genes that are required for the defense system, we suggest that suboptimal Nrf2 activity may be involved in a subgroup of CRPS patients. […] Understanding the pathways by which oxidative stress influences CRPS can help us better understand the biological mechanisms of its pathogenesis, eventually leading to the discovery of better therapies.
#35 Mechanism-based treatment in complex regional pain syndromes | Nature Reviews Neurology
https://www.nature.com/articles/nrneurol.2014.140
Complex regional pain syndromes (CRPS) are multifactorial disorders; the heterogeneity of clinical signs and symptoms reflects different underlying pathophysiological mechanisms. […] Peripheral mechanisms of CRPS include inflammation, peripheral sensitization and sympatho-afferent coupling. […] Central mechanisms include neuroplastic changes, such as cortical reorganization, afferent-efferent feedback conflicts and central autonomic dysregulation. […] The interactions between the multiple pathophysiological mechanisms that contribute to the development, progression and maintenance of CRPS remain poorly understood. […] Increased understanding of the pathogenesis of CRPS has provided the opportunity to develop mechanism-based treatments. […] An update on the pathophysiology of complex regional pain syndrome.
#36 Complex Regional Pain Syndrome : Virtual Library
https://resources.wfsahq.org/atotw/complex-regional-pain-syndrome/
It has been suggested that deep tissue hypoxia and reperfusion injury resulting in release of free radicals and cytokines result in endothelial damage and nociceptor excitation. […] Continuous peripheral activation increases firing frequency in synapses in the dorsal horn resulting in decreasing threshold of responses to mechanical and thermal stimuli, causing symptoms of allodynia and hyperpathia. […] Functional magnetic resonance imaging studies have shown structural changes in motor cortex areas and the sensory homunculus resulting in smaller representation of an affected limb than an unaffected limb, resulting in patients having altered perception and movement of the affected limb. […] There is thought to be a small-fibre neuropathy aspect, which could explain the trophic changes (decreased number of sweat glands and epidural nerve fibres).
#37 Complex Regional Pain Syndrome : Virtual Library
https://resources.wfsahq.org/atotw/complex-regional-pain-syndrome/
It has been suggested that deep tissue hypoxia and reperfusion injury resulting in release of free radicals and cytokines result in endothelial damage and nociceptor excitation. […] Continuous peripheral activation increases firing frequency in synapses in the dorsal horn resulting in decreasing threshold of responses to mechanical and thermal stimuli, causing symptoms of allodynia and hyperpathia. […] Functional magnetic resonance imaging studies have shown structural changes in motor cortex areas and the sensory homunculus resulting in smaller representation of an affected limb than an unaffected limb, resulting in patients having altered perception and movement of the affected limb. […] There is thought to be a small-fibre neuropathy aspect, which could explain the trophic changes (decreased number of sweat glands and epidural nerve fibres).
#38 Functional Imaging of Central Nervous System Involvement in Complex Regional Pain Syndrome | American Journal of Neuroradiology
https://www.ajnr.org/content/30/7/1279
These motor changes are unlikely to be related to a peripheral process but are supposed to be the result of specific alterations of the central motor system induced by the disease. […] During the past few years, increasing evidence for the hypothesis of CRPS as a CNS disease has come from a number of studies involving functional imaging methods. […] This was the first functional imaging study providing evidence for an important role of the CNS in the pathogenesis of CRPS. […] The results by Juottonen et al were reproduced in another MEG study conducted by Maihfner et al, who also observed an increased strength of magnetic fields and a reduced distance between thumb and little finger representation after tactile stimulation in S1 contralateral to the affected hand. […] The authors concluded that substantial adaptive changes within the CNS might contribute to motor symptoms in CRPS.
#39 Complex Regional Pain Syndrome Part 1: Essentials of Assessment and Diagnosis | PM&R KnowledgeNow
https://now.aapmr.org/complex-regional-pain-syndrome-part-1-essentials-of-assessment-and-diagnosis/
A new overarching hypothesis that may explain the condition invokes four dynamically changing and interacting components of tissue trauma, pathological pain processing, autonomic dysfunction (both peripheral and central) and immune dysfunction, primarily involving excessive and pathological activation of dendritic cells following trauma or atrophy. […] Other proposed mechanisms include classic and neurogenic inflammation. It has been found that patients with CRPS present with increased pro-inflammatory cytokines locally, in the bloodstream and in CSF. […] Neuroimaging studies suggest a reorganization of somatotopic maps in the cortex of patients with CRPS. The degree of somatotopic reorganization correlates significantly with pain intensity and degree of hyperalgesia. […] The degree to which individual mechanisms contribute to CRPS may differ between patients and even within one patient over time.
#40 Complex Regional Pain Syndrome (CRPS) – Neurologic Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/neurologic-disorders/pain/complex-regional-pain-syndrome-crps
CRPS is divided into 2 types. CRPS type I accounts for a majority of cases and is defined as CRPS without known nerve injury. […] CRPS type II is similar to type I but involves overt damage to a peripheral nerve. […] Pathophysiology is unclear, but peripheral nociceptor and central sensitization and release of neuropeptides (substance P, calcitonin gene-related peptide) help maintain pain and inflammation. The sympathetic nervous system is more involved in CRPS than in other neuropathic pain syndromes. Central sympathetic activity is increased, and peripheral nociceptors are sensitized to norepinephrine (a sympathetic neurotransmitter); these changes may lead to sweating abnormalities and poor blood flow due to vasoconstriction. […] The goals of physical therapy include desensitization, strengthening, increased range of motion, and vocational rehabilitation. In some patients with sympathetically maintained pain, regional sympathetic blockade relieves pain, making physical therapy possible. […] Other interventions for CRPS include sympathetic blockade, neuromodulation, and trigger point injections, though evidence in their favor is limited and of lower quality.
#41 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
This coupling is mediated by norepinephrine, which is released from newly expressed sympathetic terminals and adrenoreceptors onto afferent nociceptive neurons. Indeed, increased mRNA for alpha-2-adrenoreceptors has been demonstrated in DRG neurons following a nerve injury. […] In both types of CRPS, peripheral and central sensitization explain the pathophysiology of spontaneous pain and hyperalgesia. Clinical findings in patients consistently show sensory impairments that spread beyond the injured territory, and spontaneous pain that often engulfs a quadrant or hemisensory region. […] After tissue injury, the body’s response is programmed to promote healing, with the goal of regaining full use of the injured body part. Some experts have hypothesized that CRPS is caused by an aberrant healing response that includes exaggerated and persistent inflammation and guarding.
#42 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
This coupling is mediated by norepinephrine, which is released from newly expressed sympathetic terminals and adrenoreceptors onto afferent nociceptive neurons. Indeed, increased mRNA for alpha-2-adrenoreceptors has been demonstrated in DRG neurons following a nerve injury. […] In both types of CRPS, peripheral and central sensitization explain the pathophysiology of spontaneous pain and hyperalgesia. Clinical findings in patients consistently show sensory impairments that spread beyond the injured territory, and spontaneous pain that often engulfs a quadrant or hemisensory region. […] After tissue injury, the body’s response is programmed to promote healing, with the goal of regaining full use of the injured body part. Some experts have hypothesized that CRPS is caused by an aberrant healing response that includes exaggerated and persistent inflammation and guarding.
#43 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
Neuropathic pain is a clinical description which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. […] In CRPS type 1, there is no verified nerve lesion, excluding CRPS type 1 from neuropathic pain. […] Interestingly, small nerve lesions were also detected in some CRPS type 1 patients without severe trauma. […] Small fiber neuropathy is of clinical importance because a decrease in small fibers after trauma can change neighboring fibers to a state with reduced depolarization thresholds and ectopic firing. […] An indication for nociplastic pain in CRPS is that allodynia and hyperalgesia are not necessarily restricted to the affected CRPS extremity. […] Evidence that central sensitization contributes to the pathophysiology of CRPS, is that temporal summation is increased in the affected CRPS extremity.
#44 Complex Regional Pain Syndrome (CRPS) – Neurologic Disorders – Merck Manual Professional Edition
https://www.merckmanuals.com/professional/neurologic-disorders/pain/complex-regional-pain-syndrome-crps
CRPS is divided into 2 types. CRPS type I accounts for a majority of cases and is defined as CRPS without known nerve injury. […] CRPS type II is similar to type I but involves overt damage to a peripheral nerve. […] Pathophysiology is unclear, but peripheral nociceptor and central sensitization and release of neuropeptides (substance P, calcitonin gene-related peptide) help maintain pain and inflammation. The sympathetic nervous system is more involved in CRPS than in other neuropathic pain syndromes. Central sympathetic activity is increased, and peripheral nociceptors are sensitized to norepinephrine (a sympathetic neurotransmitter); these changes may lead to sweating abnormalities and poor blood flow due to vasoconstriction. […] The goals of physical therapy include desensitization, strengthening, increased range of motion, and vocational rehabilitation. In some patients with sympathetically maintained pain, regional sympathetic blockade relieves pain, making physical therapy possible. […] Other interventions for CRPS include sympathetic blockade, neuromodulation, and trigger point injections, though evidence in their favor is limited and of lower quality.
#45 Understanding The Complex Regional Pain Syndrome (CRPS) – Atlas Pain Specialists
https://atlaspainspecialists.com/complex-regional-pain-syndrome-crps/
Complex Regional Pain Syndrome (CRPS) is a multifaceted chronic pain condition that presents with a wide array of symptoms, often affecting one or more extremities. This condition is characterized by disproportionate and continuous pain that is typically more severe than expected based on the initial injury or inciting event. […] Despite the lack of identifiable nerve damage, CRPS Type I is associated with dysregulation of the ANS (autonomic nervous system), leading to symptoms such as changes in skin color, temperature, texture, and abnormal sweating and swelling. […] The presence of demonstrable nerve damage in CRPS Type II underscores the involvement of both peripheral and central nervous system mechanisms in the pathophysiology of the condition. […] Although the exact etiology of CRPS is still unknown, several risk factors have been found to raise the chance of developing the condition. Trauma or injury, such as fractures, sprains, or surgical procedures, is a well-established trigger for CRPS, particularly in cases of CRPS Type I.
#46 Understanding The Complex Regional Pain Syndrome (CRPS) – Atlas Pain Specialists
https://atlaspainspecialists.com/complex-regional-pain-syndrome-crps/
Complex Regional Pain Syndrome (CRPS) is a multifaceted chronic pain condition that presents with a wide array of symptoms, often affecting one or more extremities. This condition is characterized by disproportionate and continuous pain that is typically more severe than expected based on the initial injury or inciting event. […] Despite the lack of identifiable nerve damage, CRPS Type I is associated with dysregulation of the ANS (autonomic nervous system), leading to symptoms such as changes in skin color, temperature, texture, and abnormal sweating and swelling. […] The presence of demonstrable nerve damage in CRPS Type II underscores the involvement of both peripheral and central nervous system mechanisms in the pathophysiology of the condition. […] Although the exact etiology of CRPS is still unknown, several risk factors have been found to raise the chance of developing the condition. Trauma or injury, such as fractures, sprains, or surgical procedures, is a well-established trigger for CRPS, particularly in cases of CRPS Type I.
#47 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
This coupling is mediated by norepinephrine, which is released from newly expressed sympathetic terminals and adrenoreceptors onto afferent nociceptive neurons. Indeed, increased mRNA for alpha-2-adrenoreceptors has been demonstrated in DRG neurons following a nerve injury. […] In both types of CRPS, peripheral and central sensitization explain the pathophysiology of spontaneous pain and hyperalgesia. Clinical findings in patients consistently show sensory impairments that spread beyond the injured territory, and spontaneous pain that often engulfs a quadrant or hemisensory region. […] After tissue injury, the body’s response is programmed to promote healing, with the goal of regaining full use of the injured body part. Some experts have hypothesized that CRPS is caused by an aberrant healing response that includes exaggerated and persistent inflammation and guarding.
#48 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
This coupling is mediated by norepinephrine, which is released from newly expressed sympathetic terminals and adrenoreceptors onto afferent nociceptive neurons. Indeed, increased mRNA for alpha-2-adrenoreceptors has been demonstrated in DRG neurons following a nerve injury. […] In both types of CRPS, peripheral and central sensitization explain the pathophysiology of spontaneous pain and hyperalgesia. Clinical findings in patients consistently show sensory impairments that spread beyond the injured territory, and spontaneous pain that often engulfs a quadrant or hemisensory region. […] After tissue injury, the body’s response is programmed to promote healing, with the goal of regaining full use of the injured body part. Some experts have hypothesized that CRPS is caused by an aberrant healing response that includes exaggerated and persistent inflammation and guarding.
#49 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
In CRPS, combinations of nociceptive, neuropathic, and nociplastic are possible because CRPS is a multi-mechanism syndrome. […] Altogether, it is crucial to detect mixed pain in CRPS and to consider early treatment, with a multimodal treatment plan targeting nociceptive, neuropathic, and nociplastic pain. […] Pain experienced by CRPS patients should be differentiated between nociceptive, neuropathic, and nociplastic pain to optimize the management of CRPS.
#50 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
In CRPS, combinations of nociceptive, neuropathic, and nociplastic are possible because CRPS is a multi-mechanism syndrome. […] Altogether, it is crucial to detect mixed pain in CRPS and to consider early treatment, with a multimodal treatment plan targeting nociceptive, neuropathic, and nociplastic pain. […] Pain experienced by CRPS patients should be differentiated between nociceptive, neuropathic, and nociplastic pain to optimize the management of CRPS.
#51 The Role of Neuroinflammation in CRPS | JPR
https://www.dovepress.com/the-role-of-neuroinflammation-in-complex-regional-pain-syndrome-a-comp-peer-reviewed-fulltext-article-JPR
Complex Regional Pain Syndrome (CRPS) is an excess and/or prolonged pain and inflammation condition that follows an injury to a limb. The pathogenesis of CRPS is multifaceted that remains incompletely understood. Neuroinflammation is an inflammatory response in the peripheral and central nervous systems. Dysregulated neuroinflammation plays a crucial role in the initiation and maintenance of pain and nociceptive neuronal sensitization, which may contribute to the transition from acute to chronic pain and the perpetuation of chronic pain in CRPS. […] Neuroinflammation is typically a tightly regulated physiological process that facilitates the regeneration and healing of damaged tissue. However, if the regression of neuroinflammation is impeded, sustained neuroinflammation will decrease the threshold of nociceptors, leading to their activation by subthreshold stimuli.
#52 The Role of Neuroinflammation in CRPS | JPR
https://www.dovepress.com/the-role-of-neuroinflammation-in-complex-regional-pain-syndrome-a-comp-peer-reviewed-fulltext-article-JPR
Recent studies have provided supportive evidence for the role of neuroinflammation in CRPS, which may contribute to both the transition from acute to chronic pain and the persistence of chronic pain. […] Neuroinflammation is a form of localized inflammation that surpasses systemic inflammation in its ability to initiate and sustain CRPS pain. […] Neurogenic inflammation serves as the primary trigger mechanism in the pathogenesis of CRPS and has been considered central in the development of CRPS. […] The primary cells involved in this process include nociceptors, neurons, glial cells (such as Schwann cells, astrocytes, microglia, and oligodendrocytes), immune cells (including T cells, macrophages, and mast cells), keratinocytes and others. […] In summary, neuropeptides, particularly SP and CGRP, mediate the enhanced neurogenic inflammation and pain in CRPS.
#53 The Role of Neuroinflammation in CRPS | JPR
https://www.dovepress.com/the-role-of-neuroinflammation-in-complex-regional-pain-syndrome-a-comp-peer-reviewed-fulltext-article-JPR
Recent studies have provided supportive evidence for the role of neuroinflammation in CRPS, which may contribute to both the transition from acute to chronic pain and the persistence of chronic pain. […] Neuroinflammation is a form of localized inflammation that surpasses systemic inflammation in its ability to initiate and sustain CRPS pain. […] Neurogenic inflammation serves as the primary trigger mechanism in the pathogenesis of CRPS and has been considered central in the development of CRPS. […] The primary cells involved in this process include nociceptors, neurons, glial cells (such as Schwann cells, astrocytes, microglia, and oligodendrocytes), immune cells (including T cells, macrophages, and mast cells), keratinocytes and others. […] In summary, neuropeptides, particularly SP and CGRP, mediate the enhanced neurogenic inflammation and pain in CRPS.
#54 Complex Regional Pain Syndromes: Background, Pathophysiology, Epidemiology
https://emedicine.medscape.com/article/1145318-overview
At the site of injury, peripheral C-fiber nociceptors transmit pain messages that cause orthograde and retrograde release of SP and CGRP into the damaged tissues, resulting in vasodilation, extravasation of pronociceptive mediators, reactivation and further sensitization of C-fiber afferents, and increased tissue comorbidity in the injured area. […] Decreased use of an injured body part would appear to be a normal postinjury reaction. After injury, the organism protects and guards the injured body part to optimize healing and prevent reinjury. A normally healing organism gradually increases its use of the injured region, which aids in recovery and reintegration of the body part into the organisms normal sense of self. However, excessive protection and guarding, such as via casting or splinting, is commonly promoted by care providers, increasing the patients disuse of the extremity and promoting fear-avoidance, which may progress into a neurologic neglect-like syndrome.
#55 The Role of Neuroinflammation in CRPS | JPR
https://www.dovepress.com/the-role-of-neuroinflammation-in-complex-regional-pain-syndrome-a-comp-peer-reviewed-fulltext-article-JPR
The development of pharmaceuticals targeting the inhibition of SP or CGRP signaling pathways may represent a promising approach for alleviating CRPS-associated pain. […] Multiple pro-inflammatory cytokines play important roles in neuroinflammation and pain in CRPS. […] The interaction between immune cells and neurons plays a crucial role in the development of neurogenic inflammation in CRPS. […] Glial cells have been identified as a major contributor to central nociceptive sensitization and are believed to be involved in the pathogenesis of CRPS in the chronic phase. […] During the neuroinflammatory process in CRPS, neuropeptides and neurotransmitters generated by neurogenic inflammation can activate microglia and astrocytes, leading to a cascade of glial mediators that sensitize neurons and impact synaptic plasticity.
#56 The Role of Neuroinflammation in CRPS | JPR
https://www.dovepress.com/the-role-of-neuroinflammation-in-complex-regional-pain-syndrome-a-comp-peer-reviewed-fulltext-article-JPR
Recent studies have provided supportive evidence for the role of neuroinflammation in CRPS, which may contribute to both the transition from acute to chronic pain and the persistence of chronic pain. […] Neuroinflammation is a form of localized inflammation that surpasses systemic inflammation in its ability to initiate and sustain CRPS pain. […] Neurogenic inflammation serves as the primary trigger mechanism in the pathogenesis of CRPS and has been considered central in the development of CRPS. […] The primary cells involved in this process include nociceptors, neurons, glial cells (such as Schwann cells, astrocytes, microglia, and oligodendrocytes), immune cells (including T cells, macrophages, and mast cells), keratinocytes and others. […] In summary, neuropeptides, particularly SP and CGRP, mediate the enhanced neurogenic inflammation and pain in CRPS.
#57 Diagnosis of complex regional pain syndrome
https://www.e-acn.org/journal/view.php?number=618
Numerous investigations have found increased CD4 and CD8 lymphocyte populations in CRPS patients, suggesting an antigen-mediated T-cell response. […] Neuropathic inflammation is also considered a major factor in the progression of CRPS. […] Previous research has found that autoantibody levels in the serum, skin, and tissues are higher in CRPS patients and animal models, which supports CRPS being an autoimmune disorder. […] Additionally, CRPS induced elevations of IgM antibody levels in the skin and spinal tissue of rats, which were assumed to cause increased nociceptive sensitization. […] Prolonged proinflammatory cytokine release during the chronic cold phase of CRPS causes hyperactivity of the sympathetic nervous system, which increases norepinephrine levels, decreases -1 adrenergic receptor expression, and culminates in vasoconstriction and the development of a cold, blue, and clammy limb.
#58 The Role of Neuroinflammation in CRPS | JPR
https://www.dovepress.com/the-role-of-neuroinflammation-in-complex-regional-pain-syndrome-a-comp-peer-reviewed-fulltext-article-JPR
The development of pharmaceuticals targeting the inhibition of SP or CGRP signaling pathways may represent a promising approach for alleviating CRPS-associated pain. […] Multiple pro-inflammatory cytokines play important roles in neuroinflammation and pain in CRPS. […] The interaction between immune cells and neurons plays a crucial role in the development of neurogenic inflammation in CRPS. […] Glial cells have been identified as a major contributor to central nociceptive sensitization and are believed to be involved in the pathogenesis of CRPS in the chronic phase. […] During the neuroinflammatory process in CRPS, neuropeptides and neurotransmitters generated by neurogenic inflammation can activate microglia and astrocytes, leading to a cascade of glial mediators that sensitize neurons and impact synaptic plasticity.
#59 The Role of Neuroinflammation in CRPS | JPR
https://www.dovepress.com/the-role-of-neuroinflammation-in-complex-regional-pain-syndrome-a-comp-peer-reviewed-fulltext-article-JPR
The development of pharmaceuticals targeting the inhibition of SP or CGRP signaling pathways may represent a promising approach for alleviating CRPS-associated pain. […] Multiple pro-inflammatory cytokines play important roles in neuroinflammation and pain in CRPS. […] The interaction between immune cells and neurons plays a crucial role in the development of neurogenic inflammation in CRPS. […] Glial cells have been identified as a major contributor to central nociceptive sensitization and are believed to be involved in the pathogenesis of CRPS in the chronic phase. […] During the neuroinflammatory process in CRPS, neuropeptides and neurotransmitters generated by neurogenic inflammation can activate microglia and astrocytes, leading to a cascade of glial mediators that sensitize neurons and impact synaptic plasticity.
#60 Diagnosis of complex regional pain syndrome
https://www.e-acn.org/journal/view.php?number=618
Numerous investigations have found increased CD4 and CD8 lymphocyte populations in CRPS patients, suggesting an antigen-mediated T-cell response. […] Neuropathic inflammation is also considered a major factor in the progression of CRPS. […] Previous research has found that autoantibody levels in the serum, skin, and tissues are higher in CRPS patients and animal models, which supports CRPS being an autoimmune disorder. […] Additionally, CRPS induced elevations of IgM antibody levels in the skin and spinal tissue of rats, which were assumed to cause increased nociceptive sensitization. […] Prolonged proinflammatory cytokine release during the chronic cold phase of CRPS causes hyperactivity of the sympathetic nervous system, which increases norepinephrine levels, decreases -1 adrenergic receptor expression, and culminates in vasoconstriction and the development of a cold, blue, and clammy limb.
#61 Diagnosis of complex regional pain syndrome
https://www.e-acn.org/journal/view.php?number=618
Another suggested underlying mechanism is abnormal cortical reorganization, which has also been described as a form of maladaptive plasticity. […] There is abundant evidence that hereditary factors contribute to the propensity to develop CRPS. […] Psychosocial factors and pain outcomes are correlated in CRPS patients. […] It has been proposed that psychological conditions including depression play a role in the emergence of CRPS.
#62
https://www.orthobullets.com/basic-science/6095/complex-regional-pain-syndrome-crps
Complex Regional Pain Syndrome, also known as reflex sympathetic dystrophy, is an idiopathic condition caused by an aberrant inflammatory response that leads to sustained sympathetic activity in a perpetuated reflex arc. […] Aberrant inflammatory response […] vasomotor dysfunction […] maladaptive neuroplasticity […] thought to have a genetic predisposition […] associated with polymorphisms in TNF-alpha and ACE genes.
#63
https://www.orthobullets.com/basic-science/6095/complex-regional-pain-syndrome-crps
Complex Regional Pain Syndrome, also known as reflex sympathetic dystrophy, is an idiopathic condition caused by an aberrant inflammatory response that leads to sustained sympathetic activity in a perpetuated reflex arc. […] Aberrant inflammatory response […] vasomotor dysfunction […] maladaptive neuroplasticity […] thought to have a genetic predisposition […] associated with polymorphisms in TNF-alpha and ACE genes.
#64 Journal of Biomedical and Translational Research
https://www.jbtr.or.kr/archive/view_article?pid=jbtr-23-4-109
In conclusion, CRPS is a complicated syndrome requiring further studies to determine its etiology, pathophysiology, and risk factors. Notably, identifying genetic risk factors and causes will provide more opportunities for better prevention, diagnosis, and treatment of CRPS. […] In this review, we summarized the studies that investigated the genetic factors of CRPS and genes that were closely associated with the occurrence and progression of CRPS. […] We provided an account of the genes associated with CRPS through a literature review. Of those genes, we described the key genes that indicated a significant association with CRPS, such those of human leukocyte antigen (HLA)-DQ1, HLA-DR13, HLA-B62, and HLA-DQ8. […] The study confirmed that 11 selected genes (HLA-DRB1, HLA-A29.1, HLA-DRB6, matrix metalloproteinase (MMP)9, PTGS2, IL-8, MMP26, ANPEP, HDC, G-CSF3R, and STAT3) were up-regulated and one selected gene (ARHGEF10) was down-regulated using gene expression profiling.
#65 Evidence of a genetic background predisposing to complex regional pain syndrome type 1 | Journal of Medical Genetics
https://jmg.bmj.com/content/61/2/163
Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. […] A heritable component to CRPS has been suggested and leads to the hypothesis that there is a genetic predisposition to developing CRPS-1 following trauma. […] Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1. […] The discovery of a genetic background composed of four SNPs permissive for the development of CRPS-1, in about a third of the cases. […] This study provides evidence that some people develop CRPS-1 due to genetically altered disease susceptibility. […] We found that the rare allele of four SNPs in four genes were more common than expected in individuals who had suffered CRPS-1 for more than a year; rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9.
#66 Evidence of a genetic background predisposing to complex regional pain syndrome type 1 | Journal of Medical Genetics
https://jmg.bmj.com/content/61/2/163
If our findings are correct, then this suggests that these four specific SNPs are each able to increase the risk of a person developing CRPS-1 after injury. […] For these SNPs to predispose a person to develop CRPS-1, they must cause alterations in the function of the proteins ANO10, P2RX7, PRKAG1 and SLC12A9. […] The role of inflammation in the development and propagation of CRPS is not a novel concept and has been well documented. […] The unpicking of the pathophysiology of CRPS will not simplistically align to a single cell lineage, but the alleles identified are plausible clustered to have a biological response that would align with the clinical presentation of sensory, motor and autonomic changes. […] Our data support an underlying genetic predisposition to CRPS-1 in up to a third of cases, with this effect being most prominent in males.
#67 Journal of Biomedical and Translational Research
https://www.jbtr.or.kr/archive/view_article?pid=jbtr-23-4-109
In conclusion, CRPS is a complicated syndrome requiring further studies to determine its etiology, pathophysiology, and risk factors. Notably, identifying genetic risk factors and causes will provide more opportunities for better prevention, diagnosis, and treatment of CRPS. […] In this review, we summarized the studies that investigated the genetic factors of CRPS and genes that were closely associated with the occurrence and progression of CRPS. […] We provided an account of the genes associated with CRPS through a literature review. Of those genes, we described the key genes that indicated a significant association with CRPS, such those of human leukocyte antigen (HLA)-DQ1, HLA-DR13, HLA-B62, and HLA-DQ8. […] The study confirmed that 11 selected genes (HLA-DRB1, HLA-A29.1, HLA-DRB6, matrix metalloproteinase (MMP)9, PTGS2, IL-8, MMP26, ANPEP, HDC, G-CSF3R, and STAT3) were up-regulated and one selected gene (ARHGEF10) was down-regulated using gene expression profiling.
#68 Evidence of a genetic background predisposing to complex regional pain syndrome type 1 | Journal of Medical Genetics
https://jmg.bmj.com/content/61/2/163
If our findings are correct, then this suggests that these four specific SNPs are each able to increase the risk of a person developing CRPS-1 after injury. […] For these SNPs to predispose a person to develop CRPS-1, they must cause alterations in the function of the proteins ANO10, P2RX7, PRKAG1 and SLC12A9. […] The role of inflammation in the development and propagation of CRPS is not a novel concept and has been well documented. […] The unpicking of the pathophysiology of CRPS will not simplistically align to a single cell lineage, but the alleles identified are plausible clustered to have a biological response that would align with the clinical presentation of sensory, motor and autonomic changes. […] Our data support an underlying genetic predisposition to CRPS-1 in up to a third of cases, with this effect being most prominent in males.
#69 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
Complex regional pain syndrome (CRPS) is a debilitating painful state of an extremity that can develop after trauma. CRPS is diagnosed by the new International Association for the Study of Pain (IASP) diagnostic criteria for CRPS. The syndrome is characterized by continuing regional pain with abnormal sensory, motor, sudomotor, vasomotor, edema, and/or trophic signs. […] CRPS is considered a multi-mechanism syndrome, and the experienced continuous pain can be linked to mechanisms such as inflammation, vasomotor disturbances, and peripheral and central sensitization. […] To personalize the management of CRPS, several subgroups have been suggested. […] The IASP recognizes nociceptive (tissue damage), neuropathic (nerve injury), and nociplastic pain (sensitized nervous system) as distinct pain types driven by different mechanisms.
#70 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
The aim of this narrative review is threefold: 1) to describe the types of pain in CRPS and link these pain types to pathophysiological underlying mechanisms in CRPS; 2) to explain how these pain types can be differentiated by history taking, physical examination, and diagnostic tests; 3) to illustrate how these pain types can be specifically targeted to optimize treatment effectiveness. […] Nociceptive pain in CRPS can be the result of persistent inflammation. […] In the immune dysregulation of CRPS, both disturbances in the innate and adaptive immune system play a role. […] Nociceptive pain can also be the result of motor disturbances caused by excitation of muscle nociceptors in, for instance, contractures and dystonia. […] Nociceptive pain is typically local and can for instance be triggered by specific movements and may be accompanied by local inflammatory signs.
#71 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
The aim of this narrative review is threefold: 1) to describe the types of pain in CRPS and link these pain types to pathophysiological underlying mechanisms in CRPS; 2) to explain how these pain types can be differentiated by history taking, physical examination, and diagnostic tests; 3) to illustrate how these pain types can be specifically targeted to optimize treatment effectiveness. […] Nociceptive pain in CRPS can be the result of persistent inflammation. […] In the immune dysregulation of CRPS, both disturbances in the innate and adaptive immune system play a role. […] Nociceptive pain can also be the result of motor disturbances caused by excitation of muscle nociceptors in, for instance, contractures and dystonia. […] Nociceptive pain is typically local and can for instance be triggered by specific movements and may be accompanied by local inflammatory signs.
#72 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
The aim of this narrative review is threefold: 1) to describe the types of pain in CRPS and link these pain types to pathophysiological underlying mechanisms in CRPS; 2) to explain how these pain types can be differentiated by history taking, physical examination, and diagnostic tests; 3) to illustrate how these pain types can be specifically targeted to optimize treatment effectiveness. […] Nociceptive pain in CRPS can be the result of persistent inflammation. […] In the immune dysregulation of CRPS, both disturbances in the innate and adaptive immune system play a role. […] Nociceptive pain can also be the result of motor disturbances caused by excitation of muscle nociceptors in, for instance, contractures and dystonia. […] Nociceptive pain is typically local and can for instance be triggered by specific movements and may be accompanied by local inflammatory signs.
#73 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
The aim of this narrative review is threefold: 1) to describe the types of pain in CRPS and link these pain types to pathophysiological underlying mechanisms in CRPS; 2) to explain how these pain types can be differentiated by history taking, physical examination, and diagnostic tests; 3) to illustrate how these pain types can be specifically targeted to optimize treatment effectiveness. […] Nociceptive pain in CRPS can be the result of persistent inflammation. […] In the immune dysregulation of CRPS, both disturbances in the innate and adaptive immune system play a role. […] Nociceptive pain can also be the result of motor disturbances caused by excitation of muscle nociceptors in, for instance, contractures and dystonia. […] Nociceptive pain is typically local and can for instance be triggered by specific movements and may be accompanied by local inflammatory signs.
#74 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
Neuropathic pain is a clinical description which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. […] In CRPS type 1, there is no verified nerve lesion, excluding CRPS type 1 from neuropathic pain. […] Interestingly, small nerve lesions were also detected in some CRPS type 1 patients without severe trauma. […] Small fiber neuropathy is of clinical importance because a decrease in small fibers after trauma can change neighboring fibers to a state with reduced depolarization thresholds and ectopic firing. […] An indication for nociplastic pain in CRPS is that allodynia and hyperalgesia are not necessarily restricted to the affected CRPS extremity. […] Evidence that central sensitization contributes to the pathophysiology of CRPS, is that temporal summation is increased in the affected CRPS extremity.
#75 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
Neuropathic pain is a clinical description which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. […] In CRPS type 1, there is no verified nerve lesion, excluding CRPS type 1 from neuropathic pain. […] Interestingly, small nerve lesions were also detected in some CRPS type 1 patients without severe trauma. […] Small fiber neuropathy is of clinical importance because a decrease in small fibers after trauma can change neighboring fibers to a state with reduced depolarization thresholds and ectopic firing. […] An indication for nociplastic pain in CRPS is that allodynia and hyperalgesia are not necessarily restricted to the affected CRPS extremity. […] Evidence that central sensitization contributes to the pathophysiology of CRPS, is that temporal summation is increased in the affected CRPS extremity.
#76 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
Neuropathic pain is a clinical description which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. […] In CRPS type 1, there is no verified nerve lesion, excluding CRPS type 1 from neuropathic pain. […] Interestingly, small nerve lesions were also detected in some CRPS type 1 patients without severe trauma. […] Small fiber neuropathy is of clinical importance because a decrease in small fibers after trauma can change neighboring fibers to a state with reduced depolarization thresholds and ectopic firing. […] An indication for nociplastic pain in CRPS is that allodynia and hyperalgesia are not necessarily restricted to the affected CRPS extremity. […] Evidence that central sensitization contributes to the pathophysiology of CRPS, is that temporal summation is increased in the affected CRPS extremity.
#77 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
Neuropathic pain is a clinical description which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. […] In CRPS type 1, there is no verified nerve lesion, excluding CRPS type 1 from neuropathic pain. […] Interestingly, small nerve lesions were also detected in some CRPS type 1 patients without severe trauma. […] Small fiber neuropathy is of clinical importance because a decrease in small fibers after trauma can change neighboring fibers to a state with reduced depolarization thresholds and ectopic firing. […] An indication for nociplastic pain in CRPS is that allodynia and hyperalgesia are not necessarily restricted to the affected CRPS extremity. […] Evidence that central sensitization contributes to the pathophysiology of CRPS, is that temporal summation is increased in the affected CRPS extremity.
#78 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
Neuropathic pain is a clinical description which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. […] In CRPS type 1, there is no verified nerve lesion, excluding CRPS type 1 from neuropathic pain. […] Interestingly, small nerve lesions were also detected in some CRPS type 1 patients without severe trauma. […] Small fiber neuropathy is of clinical importance because a decrease in small fibers after trauma can change neighboring fibers to a state with reduced depolarization thresholds and ectopic firing. […] An indication for nociplastic pain in CRPS is that allodynia and hyperalgesia are not necessarily restricted to the affected CRPS extremity. […] Evidence that central sensitization contributes to the pathophysiology of CRPS, is that temporal summation is increased in the affected CRPS extremity.
#79 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
Neuropathic pain is a clinical description which requires a demonstrable lesion or a disease that satisfies established neurological diagnostic criteria. […] In CRPS type 1, there is no verified nerve lesion, excluding CRPS type 1 from neuropathic pain. […] Interestingly, small nerve lesions were also detected in some CRPS type 1 patients without severe trauma. […] Small fiber neuropathy is of clinical importance because a decrease in small fibers after trauma can change neighboring fibers to a state with reduced depolarization thresholds and ectopic firing. […] An indication for nociplastic pain in CRPS is that allodynia and hyperalgesia are not necessarily restricted to the affected CRPS extremity. […] Evidence that central sensitization contributes to the pathophysiology of CRPS, is that temporal summation is increased in the affected CRPS extremity.
#80 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
In CRPS, combinations of nociceptive, neuropathic, and nociplastic are possible because CRPS is a multi-mechanism syndrome. […] Altogether, it is crucial to detect mixed pain in CRPS and to consider early treatment, with a multimodal treatment plan targeting nociceptive, neuropathic, and nociplastic pain. […] Pain experienced by CRPS patients should be differentiated between nociceptive, neuropathic, and nociplastic pain to optimize the management of CRPS.
#81 Different Types of Pain in Complex Regional Pain Syndrome | JPR
https://www.dovepress.com/different-types-of-pain-in-complex-regional-pain-syndrome-require-a-pe-peer-reviewed-fulltext-article-JPR
In CRPS, combinations of nociceptive, neuropathic, and nociplastic are possible because CRPS is a multi-mechanism syndrome. […] Altogether, it is crucial to detect mixed pain in CRPS and to consider early treatment, with a multimodal treatment plan targeting nociceptive, neuropathic, and nociplastic pain. […] Pain experienced by CRPS patients should be differentiated between nociceptive, neuropathic, and nociplastic pain to optimize the management of CRPS.
#82 Complex Regional Pain Syndrome – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK430719/
Complex regional pain syndrome represents a neuropathic pain disorder defined by allodynia, hyperalgesia, vasomotor and sudomotor abnormalities, and trophic changes. […] The etiology remains unclear but likely involves genetic, inflammatory, and psychological factors. Pathophysiology includes dysregulation of pain processing in both the sympathetic and central nervous systems. Altered neuroplasticity, peripheral sensitization, and central amplification contribute to persistent pain and autonomic dysfunction. […] Multiple pathophysiologic mechanisms have been described in the literature to explain CRPS. Scientific evidence does not point to a single principal mechanism. The condition is therefore considered multifactorial, involving inflammatory, immunologic, central, and peripheral sensitization, and autonomic dysregulation.
#83 Mechanism-based treatment in complex regional pain syndromes | Nature Reviews Neurology
https://www.nature.com/articles/nrneurol.2014.140
Complex regional pain syndromes (CRPS) are multifactorial disorders; the heterogeneity of clinical signs and symptoms reflects different underlying pathophysiological mechanisms. […] Peripheral mechanisms of CRPS include inflammation, peripheral sensitization and sympatho-afferent coupling. […] Central mechanisms include neuroplastic changes, such as cortical reorganization, afferent-efferent feedback conflicts and central autonomic dysregulation. […] The interactions between the multiple pathophysiological mechanisms that contribute to the development, progression and maintenance of CRPS remain poorly understood. […] Increased understanding of the pathogenesis of CRPS has provided the opportunity to develop mechanism-based treatments. […] An update on the pathophysiology of complex regional pain syndrome.
#84 Diagnosis of complex regional pain syndrome
https://www.e-acn.org/journal/view.php?number=618
Complex regional pain syndrome (CRPS) is a chronic regional pain disorder that most frequently affects the limbs. […] The multifactorial pathophysiological etiology of CRPS includes inflammation, autoimmune responses, abnormal cytokine production, autonomic dysfunction, altered blood flow, psychological factors, and central cortical reorganization. […] While the pathophysiology of CRPS is still unknown, it is considered to involve dysfunction of both the central and peripheral nerve systems. […] CRPS is characterized by an inappropriate tissue response to injury as well as increased sensitization of the peripheral and central nervous systems along with accompanying inflammatory alterations and autonomic dysfunction. […] Both a proinflammatory immune response and impaired neuropeptide signaling are characteristics of CRPS.
#85 Complex Regional Pain Syndrome Part 1: Essentials of Assessment and Diagnosis | PM&R KnowledgeNow
https://now.aapmr.org/complex-regional-pain-syndrome-part-1-essentials-of-assessment-and-diagnosis/
A new overarching hypothesis that may explain the condition invokes four dynamically changing and interacting components of tissue trauma, pathological pain processing, autonomic dysfunction (both peripheral and central) and immune dysfunction, primarily involving excessive and pathological activation of dendritic cells following trauma or atrophy. […] Other proposed mechanisms include classic and neurogenic inflammation. It has been found that patients with CRPS present with increased pro-inflammatory cytokines locally, in the bloodstream and in CSF. […] Neuroimaging studies suggest a reorganization of somatotopic maps in the cortex of patients with CRPS. The degree of somatotopic reorganization correlates significantly with pain intensity and degree of hyperalgesia. […] The degree to which individual mechanisms contribute to CRPS may differ between patients and even within one patient over time.
#86 Mechanisms of complex regional pain syndrome
https://pmc.ncbi.nlm.nih.gov/articles/PMC11140106/
Complex Regional Pain Syndrome (CRPS) is a chronic pain disorder characterized by a diverse array of symptoms, including pain that is disproportionate to the initial triggering event, accompanied by autonomic, sensory, motor, and sudomotor disturbances. […] Recent studies started to unravel the complex pathogenic mechanisms of CRPS, particularly from an autoimmune and neuroimmune interaction perspective. CRPS is now recognized as a systemic disease that stems from a complex interplay of inflammatory, immunologic, neurogenic, genetic, and psychologic factors. […] Key mechanisms underlying clinical manifestations include peripheral and central sensitization, sympathetic dysregulation, and alterations in somatosensory processing. Enhanced understanding of the mechanisms of CRPS is crucial for the development of effective therapeutic interventions.
#87 Current and Evolving Concepts in the Management of Complex Regional Pain Syndrome: A Narrative Review
https://www.mdpi.com/2075-4418/15/3/353
Complex regional pain syndrome (CRPS) is characterized by severe pain and reduced functionality, which can significantly affect an individualâs quality of life. […] Research has identified three primary pathophysiological pathways that may explain the clinical variability observed in CRPS: inflammatory mechanisms, vasomotor dysfunction, and maladaptive neuroplasticity. […] Marinus et al. proposed three main pathophysiological pathways to explain this clinical variability: inflammatory mechanisms, vasomotor dysfunction, and maladaptive neuroplasticity. […] Inflammation is well documented in CRPS, with elevated levels of biomarkers such as substance P (SP), calcitonin gene-related peptide (CGRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF-Î±), though their reliability remains uncertain.
#88 Current and Evolving Concepts in the Management of Complex Regional Pain Syndrome: A Narrative Review
https://www.mdpi.com/2075-4418/15/3/353
Mechanism-based treatment has been a longstanding objective in the management of CRPS. […] Researchers are investigating new methods to better understand the pathophysiology of CRPS and to develop more effective therapies. […] Some emerging areas of interest include the following: N-Methyl-D-aspartate (NMDA) Receptor Antagonists: Agents such as ketamine target central sensitization mechanisms by blocking NMDA receptors. […] Low-Dose Naltrexone (LDN): Toll-like receptor 4 (TLR4) receptors present in glial cells enhance the release of pro-inflammatory cytokines in the central nervous system. […] Immune and Glial-Modulating Agents: These approaches aim to regulate glial cell activity, addressing their role in central sensitization and inflammation. […] Alpha-Adrenergic Modulators: Evidence suggests an upregulation of Î±-adrenergic receptors in the skin of CRPS patients, and activation of these receptors leads to increased noradrenaline release, which hyperstimulates nociceptive fibers, resulting in pain and hyperalgesia.