Complex Regional Pain Syndrome Type 1

1. Complex Regional Pain Syndrome Type 1 Anke GJ De Bruijn

2. Perception Pain Cerebral cortex Limbic system Emotion Higher centers Modulation Spinal cord Transduction Transmission Stimulus Mediators Receptor

3. Complex Regional Pain Syndrome • Definition • 72 different names: • Sudeck’s atrophy • Posttraumatic dystrophy • Sympathetic reflex dystrophy • Shoulder-hand syndrome • Veldman criteria, IASP criteria, Bruehl criteria Veldman et al. 1993; Beek et al. 2002; Reinders et al. 2002

4. IASP Conference Orlando 1993 • Complex Regional Pain Syndrome • Spontaneous, continuing pain or allodynia/hyperalgesia, disproportionate to inciting event • Evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity • Exclusion of medical conditions that would otherwise account for the degree of pain and dysfunction • Type 1 without, type 2 with nerve injury Stanton Hicks et al. 1995

5. Bruehl criteria • Complex Regional Pain Syndrome • Continuing pain disproportionate to inciting event • Sensory (allodynia, hypesthesia) • Vasomotor (skin color changes, temperature) • Sudomotor (edema/swelling, sweating) • Motor/trophic signs and symptoms (weakness, dystonia, nail/hair growth) • At least one symptom in each category • At least one sign in two or more categories Bruehl et al. 1999

6. Complex Regional Pain Syndrome • Epidemiology • 1-2% following fracture • 7-35% following Colles’ fracture • 10-26% spontaneous • Other causes: MI, CVA, reperfusion syndrome • 8000 estimated new patients per year in NL • Female : Male ≈ 3:1 Veldman et al. 1993

8. Pathophysiology CRPS Higher centers Neuropeptides CNS Dorsal horn Neurogenic inflammation Substance P CGRP Blood vessel Nerve injury to C and Aδ fibres

9. Neuropeptides • Animal model • Loose ligation of sciatic nerve in the rat • Changing expression neuropeptides • CRPS symptoms appear • Increase skin blood flow is blocked by Capsaicin • NK1 receptor antagonist decreases CRPS symptoms Verge et al. 2002; Daemen et al. 1998; Kingerly et al. 2003

10. Neuropeptides • Patient model • Infusion of Substance P • aggravates CRPS • Depletion of Substance P with • Capsaicin decreases CRPS • Symptoms • Bradykinin, Neuropeptide Y, • CGRP and VIP increased • Transcutaneous electric stimulation • increases neuropeptides release Blair et al. 1998; Weber et al. 2001; Cheslie et al. 1990; Rumsfield et al. 1991

11. Pathophysiology CRPS Higher centers Pro-inflammatory agents CNS Mastcells IL6 TNFalfa Dorsal horn Pro-inflammatory agents Neurogenic inflammation Blood vessel

12. Inflammatory response • Animal Model • Loose ligation of sciatic nerve in the rat • Increase in cytokines: especially IL-6 and TNFalfa Wagner et al. 1996; Sommer et al. 1997; Shubayev et al. 2001; Cui et al. 2000

13. Inflammatory response • Patient model • IL-6 and TNFalfa are significantly higher in a CRPS extremity • Tryptase is significantly higher in CRPS • Succesful treatment with anti-TNF Huygen et al. 2002; Huygen et al. submitted 2003; Huygen et al. 2003

14. Free radicals • Animal model • Infusion of tert-butylhydroperoxide in rat paws induces: • Increased skin temperature • Increased volume • Skin redness • Impaired function • Pain Van der Laan et al. 1998

15. Free radicals • Patient model • CRPS resembles “local” sepsis, free radicals are possibly involved in sepsis • DMSO 50% relieves clinical symptoms in the warm phase • N-acetylcysteine relieves clinical symptoms in the cold phase Goris et al. 1987; Zuurmond et al. 1996; Perez et al. 2003

16. Pathophysiology CRPS Higher centers Sensitization 1 Sensory dysfunction CNS Sensitization GABA 2 Sympathetic disorder 3 Motor dysfunction Dorsal horn Neuropeptides Cytokines Blood vessel

17. Sensory dysfunction • Animal model • Loose ligation of sciatic nerve in the rat • Changes in the dorsal horn under influence of neuropeptides and cytokines Verge et al. 2002; Sorkin et al. 2002

18. Sensory dysfunction • Patient model • > 70% glove or stocking like pattern • Allodynia and/or hyperalgesia • Central mechanisms Veldman et al. 1993; Boas et al. 1996; Thimineur et al. 1998; Rommel et al. 1999,2001

19. Sympathetic dysfunction • Animal model • Loose ligation of sciatic nerve in the rat • CRPS symptoms • Sympathetic dysfunction is caused by denervation induced hypersensitivity of catecholamines Kurvers et al. 1998

20. Sympathetic dysfunction • Patient model • Density of alpha receptors in the skin of CRPS patients is greater than in control subjects • Decreased sympathetic activity in acute phase induces hypersensitivity to catecholamines Drummond et al. 1996; Birklein et al. 2001

21. Motor dysfunction • Patient model • Dystonia, weakness, myoclonus and tremor • Changes in CNS by abnormal input can result in a neglect like syndrome • Clinical picture of disuse is diffucult to discern from CRPS 1 • Changes in sensory and motor integration in spinal cord, involvement of GABA system Swartzman et al. 1990; Galer et al. 1995; Butler et al. 1996; Hilten et al. 2000

22. Immunologic considerations • Patient model • Genetic abnormality (HLA-DR2) on chromosome 6 is more often found in chronic CRPS • HLA-DQ1 is significantly increased in CRPS • Association HLA-DR13 in CRPS • Significant association TNF2 allele in warm CRPS and even homozygote in CRPS patients with  2 extremities affected • Seropositivity Parvovirus B12 is associated with CRPS Mailis et al. 1994; Kemler et al. 2000; Hilten et al. 2000; Vaneker et al. 2002; van de Vusse et al. 2001

23. Drug-induced CRPS • Case reports • Phenobarbital • Improvement on withdrawal or treatment with Gabapentin • Described since 1966 • Isoniazide • Cyclosporin A in renal transplant patients • Heroin induced rhabdomyolysis • Cocain injected intra-arterially Van der Korst et al. 1966; Rovetta et al. 2001; Lee et al. 2001; Gay et al. 2000; Marshall et al. 2000

24. Psychological factors • Patient model • No evidence that these factors play an aetiological role • Psychological and/or emotional factors are able to intensify pain in CRPS • Prospective studies for psychological and psychiatric factors in CRPS Bruehl et al. 2002; Bruehl et al. 1992; Beerthuizen et al. 2003

25. Pathophysiology CRPS Higher centers Sensory dysfunction Mastcells CNS Sympathetic disorder GABA Motor dysfunction IL6 TNFalfa Dorsal horn Pro-inflammatory agents Neurogenic inflammation Substance P CGRP Blood vessel Nerve injury

26. Therapy CRPS • Limited effect sympathetic blocks, radical scavengers (mannitol, DMSO, acetylcysteine), vasodilators, prednisone, acupuncture and lymphe drainage • Analgetics: antidepressants, carbamazepine • Limited effect vitamin C in prevention • Proven effect calcium regulators (Bisphosphonates) • Calcitonine relieves pain effectively • Capsaicin Forouzanfar et al. 2002; Perez et al. 2001

27. Complex Regional Pain Syndrome type 1 • Future • Diagnosis, gold standard, epidemiology • Pathophysiology: • Pathway analysis, genetics, adverse drug reactions • Interventions, antagonists, synthesis inhibitors

28. Trend Project(Trauma Related Neuronal Dysfunction) • Knowledge consortium with multi-disciplinary approach: • Epidemiology • Assessment technologies • Pharmacotherapeutics • Proteomics • Genetics

29. PhD project Epidemiology • Incidence and prevalence • Disease course • Applied treatments and effectiveness • Intrinsic and extrinsic factors that precipitate and sustain CRPS • Phenotype spectrum

30. IPCI Database • Integrated Primary Care Information Database • Longitudinal observational database • Electronic patient records of 150 GP’s: 500.000 patients in the Netherlands • Coded and anonymous data on demographics, symptoms, diagnosis (from GP and specialist), physical examination, discharge letters, referrals and prescriptions

31. Complex Regional Pain Syndrome type 1 • Future • Diagnosis, gold standard, epidemiology • Pathophysiology: • Pathway analysis, genetics, adverse drug reactions • Interventions, antagonists, synthesis inhibitors • Trend and Infobiomed join forces? • Integration patient data and molecular data?

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