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Complex Regional Pain Syndrome: State of the Art Update

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Although the pathophysiology of complex regional pain syndrome (CRPS) is not fully understood, it appears to reflect multiple interacting mechanisms. In addition to altered autonomic function, a role for inflammatory mechanisms and altered somatosensory and motor function in the brain is increasingly suggested. Several possible risk factors for development of CRPS, including genetic factors, have been identified. Few treatments have been proven effective for CRPS in well-designed clinical trials. However, recent work suggests that bisphosphonates may be useful in CRPS management and that the N-methyl-d-aspartate receptor antagonist ketamine significantly reduces CRPS pain when administered topically or intravenously at subanesthetic dosages. Extended use of ketamine at anesthetic dosages (“ketamine coma”) remains a controversial and unproven treatment for CRPS. Spinal cord stimulation may be effective for reducing pain in approximately two thirds of CRPS patients not responding to other treatments, but its efficacy appears to diminish over time.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Merskey H, Bogduk N: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, edn 2. Seattle: IASP Press; 1994.

    Google Scholar 

  2. Cheng JK, Ji RR: Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res 2008, 33:1970–1978.

    Article  PubMed  CAS  Google Scholar 

  3. Birklein F: Complex regional pain syndrome. J Neurol 2005, 252:131–138.

    Article  PubMed  Google Scholar 

  4. Vaneker M, van der Laan L, Allebes WA, Goris J: Genetic factors associated with Complex Regional Pain Syndrome I: HLA DRB and TNF alpha promoter gene polymorphism. Disabil Med 2002, 2:69–74.

    Google Scholar 

  5. Kemler MA, van de Vusse AC, van den Berg-Loonen EM, et al.: HLA-DQ1 associated with reflex sympathetic dystrophy. Neurology 1999, 53:1350–1351.

    PubMed  CAS  Google Scholar 

  6. van Hilten JJ, van de Beek WJ, Roep BO: Multifocal or generalized tonic dystonia of complex regional pain syndrome: a distinct clinical entity associated with HLA-DR13. Ann Neurol 2000, 48:113–116.

    Article  PubMed  Google Scholar 

  7. de Rooij AM, FlorenciaGosso M, Haasnoot GW, et al.: HLA-B62 and HLA-DQ8 are associated with Complex Regional Pain Syndrome with fixed dystonia. Pain 2009, 145:82–85.

    Article  PubMed  CAS  Google Scholar 

  8. Devor M: Nerve pathophysiology and mechanisms of pain in causalgia. J Auton Nerv Syst 1983, 7:371–384.

    Article  PubMed  CAS  Google Scholar 

  9. Jänig W, Baron R: The role of the sympathetic nervous system in neuropathic pain: clinical observations and animal models. In Neuropathic Pain: Pathophysiology and Treatment. Edited by Hansson PT, Fields HL, Hill RG, Marchettini P. Seattle: IASP Press; 2001.

    Google Scholar 

  10. Schürmann M, Gradl G, Zaspel J, et al.: Peripheral sympathetic function as a predictor of complex regional pain syndrome type I (CRPS I) in patients with radial fracture. Auton Neurosci 2000, 86:127–134.

    Article  PubMed  Google Scholar 

  11. Harden RN, Rudin NJ, Bruehl S, et al.: Increased systemic catecholamines in complex regional pain syndrome and relationship to psychological factors: a pilot study. Anesth Analg 2004, 99:1478–1485.

    Article  PubMed  CAS  Google Scholar 

  12. Koban M, Leis S, Schultze-Mosgau S, Birklein F: Tissue hypoxia in complex regional pain syndrome. Pain 2003, 104:149–157.

    Article  PubMed  CAS  Google Scholar 

  13. Ji RR, Woolf CJ: Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiol Dis 2001, 8:1–10.

    Article  PubMed  CAS  Google Scholar 

  14. Juottonen K, Gockel M, Silén T, et al.: Altered central sensorimotor processing in patients with complex regional pain syndrome. Pain 2002, 98:315–323.

    Article  PubMed  Google Scholar 

  15. Maihöfner C, Handwerker HO, Neundörfer B, Birklein F: Patterns of cortical reorganization in complex regional pain syndrome. Neurology 2003, 61: 1707–1715.

    PubMed  Google Scholar 

  16. Maihöfner C, Handwerker HO, Neundörfer B, Birklein F: Cortical reorganization during recovery from complex regional pain syndrome. Neurology 2004, 63:693–701.

    PubMed  Google Scholar 

  17. Pleger B, Ragert P, Schwenkreis P, et al.: Patterns of cortical reorganization parallel impaired tactile discrimination and pain intensity in complex regional pain syndrome. Neuroimage 2006, 32:503–510.

    Article  PubMed  Google Scholar 

  18. Pleger B, Tegenthoff M, Ragert P, et al.: Sensorimotor retuning in complex regional pain syndrome parallels pain reduction. Ann Neurol 2005, 57:425–429.

    Article  PubMed  Google Scholar 

  19. Florence SL, Taub HB, Kaas JH: Large-scale sprouting of cortical connections after peripheral injury in adult macaque monkeys. Science 1998, 282:1117–1121.

    Article  PubMed  CAS  Google Scholar 

  20. de Mos M, Huygen FJ, Dieleman JP, et al.: Medical history and the onset of complex regional pain syndrome (CRPS). Pain 2008, 139(2):458–466.

    Article  PubMed  Google Scholar 

  21. de Mos M, Huygen FJ, Stricker BH, et al.: Estrogens and the risk of complex regional pain syndrome (CRPS). Pharmacoepidemiol Drug Saf 2009, 18(1):44–52.

    Article  PubMed  Google Scholar 

  22. Peterlin BL, Rosso AL, Nair S, et al.: Migraine may be a risk factor for the development of complex regional pain syndrome. Cephalalgia 2009 Jul 9 (Epub ahead of print).

  23. de Mos M, de Bruijn AGJ, Huygen FJPM, et al.: The incidence of complex regional pain syndrome: a population-based study. Pain 2007, 129:12–20.

    Article  PubMed  Google Scholar 

  24. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA: Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 2003, 103:199–207.

    Article  PubMed  Google Scholar 

  25. de Mos M, Huygen FJ, Stricker BH, et al.: The association between ACE inhibitors and the complex regional pain syndrome: suggestions for a neuro-inflammatory pathogenesis of CRPS. Pain 2009, 142(3):218–224.

    Article  PubMed  CAS  Google Scholar 

  26. Higashimoto T, Baldwin EE, Gold JI, Boles RG: Reflex sympathetic dystrophy: complex regional pain syndrome type I in children with mitochondrial disease and maternal inheritance. Arch Dis Child 2008, 93(5):390–397.

    Article  PubMed  CAS  Google Scholar 

  27. de Rooij AM, de Mos M, Sturkenboom MC, et al.: Familial occurrence of complex regional pain syndrome. Eur J Pain 2009, 13(2):171–177.

    Article  PubMed  Google Scholar 

  28. Kemler MA, van de Vusse AC, van den Berg-Loonen EM, et al.: HLA-DQ1 associated with reflex sympathetic dystrophy. Neurology 1999, 53(6):1350–1351.

    PubMed  CAS  Google Scholar 

  29. Vaneker M, van der Laan L, Allebes WA, Goris RJA: Genetic factors associated with complex regional pain syndrome 1: HLA DRB and TNF alpha promotor gene polymorphism. Disabil Med 2002, 2(3):69–74.

    Google Scholar 

  30. van Hilten JJ, van de Beek WJ, Roep BO: Multifocal or generalized tonic dystonia of complex regional pain syndrome: a distinct clinical entity associated with HLA-DR13. Ann Neurol 2000, 48(1):113–116.

    Article  PubMed  Google Scholar 

  31. de Rooij AM, Florencia Gosso M, Haasnoot GW, et al.: HLA-B62 and HLA-DQ8 are associated with Complex Regional Pain Syndrome with fixed dystonia. Pain 2009, 145(1–2):82–85.

    Article  PubMed  CAS  Google Scholar 

  32. Tan EC, van de Sandt-Renkema N, et al.: Quality of life in adults with childhood-onset of Complex Regional Pain Syndrome type I. Injury 2009, 40(8):901–904.

    Article  PubMed  Google Scholar 

  33. Sherry DD, Wallace CA, Kelley C, et al.: Short- and long-term outcomes of children with complex regional pain syndrome type I treated with exercise therapy. Clin J Pain 1999, 15:218–223.

    Article  PubMed  CAS  Google Scholar 

  34. Schinkel C, Scherens A, Köller M, et al.: Systemic inflammatory mediators in post-traumatic complex regional pain syndrome (CRPS I)—longitudinal investigations and differences to control groups. Eur J Med Res 2009, 14(3):130–135.

    PubMed  Google Scholar 

  35. Del Valle L, Schwartzman RJ, Alexander G: Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome. Brain Behav Immun 2009, 23(1):85–91.

    Article  PubMed  Google Scholar 

  36. Kohr D, Tschernatsch M, Schmitz K, et al.: Autoantibodies in complex regional pain syndrome bind to a differentiation-dependent neuronal surface autoantigen. Pain 2009, 143(3):246–251.

    Article  PubMed  CAS  Google Scholar 

  37. Li WW, Sabsovich I, Guo TZ, et al.: The role of enhanced cutaneous IL-1beta signaling in a rat tibia fracture model of complex regional pain syndrome. Pain 2009, 144(3):303–313.

    Article  PubMed  CAS  Google Scholar 

  38. Sabsovich I, Guo TZ, Wei T, et al.: TNF signaling contributes to the development of nociceptive sensitization in a tibia fracture model of complex regional pain syndrome type I. Pain 2008, 137(3):507–519.

    Article  PubMed  CAS  Google Scholar 

  39. Wei T, Sabsovich I, Guo TZ, et al.: Pentoxifylline attenuates nociceptive sensitization and cytokine expression in a tibia fracture rat model of complex regional pain syndrome. Eur J Pain 2009, 13(3):253–262.

    Article  PubMed  CAS  Google Scholar 

  40. Sabsovich I, Wei T, Guo TZ, et al.: Effect of anti-NGF antibodies in a rat tibia fracture model of complex regional pain syndrome type I. Pain 2008, 138(1):47–60.

    Article  PubMed  CAS  Google Scholar 

  41. Wei T, Li WW, Guo TZ, et al.: Post-junctional facilitation of Substance P signaling in a tibia fracture rat model of complex regional pain syndrome type I. Pain 2009, 144(3):278–286.

    Article  PubMed  CAS  Google Scholar 

  42. Chung OY, Bruehl SP: Complex regional pain syndrome. Curr Treat Options Neurol 2003, 5(6):499–511.

    Article  Google Scholar 

  43. Muizelaar JP, Kleyer M, Hertogs IAM, Delange DC: Complex regional syndrome (reflex sympathetic dystrophy and causalgia): management with the calcium channel blocker nifedipine and/or the alpha sympathetic blocker phenoxybenzamine in 59 patients. Clin Neurol Neurosurg 1997, 99:26–30.

    Article  PubMed  CAS  Google Scholar 

  44. Ghostine SY, Comair YG, Turner DM, et al.: Phenoxybenzamine in the treatment of causalgia. Report of 40 cases. J Neurosurg 1984, 60:1263–1268.

    Article  PubMed  CAS  Google Scholar 

  45. Davis KD, Treede RD, Raja SN, et al.: Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain 1991, 47:309–317.

    Article  PubMed  CAS  Google Scholar 

  46. Stanton-Hicks MD, Burton AW, Bruehl SP, et al.: Complex Regional Pain Syndromes: updated interdisciplinary clinical pathway: report of an expert panel. Pain Pract 2002, 2:1–16.

    Article  PubMed  Google Scholar 

  47. Oerlemans HM, Oostendorp RAB, de Boo T, Goris RJA: Pain and reduced mobility in complex regional pain syndrome I: outcome of a prospective randomized controlled clinical trial of adjuvant physical therapy versus occupational therapy. Pain 1999, 83:77–83.

    Article  PubMed  CAS  Google Scholar 

  48. Moseley GL, Wiech K: The effect of tactile discrimination training is enhanced when patients watch the reflected image of their unaffected limb during training. Pain 2009, 144(3):314–319.

    Article  PubMed  Google Scholar 

  49. Christensen K, Jensen EM, Noer I: The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chir Scand 1982, 148:653–655.

    PubMed  CAS  Google Scholar 

  50. Braus DF, Krauss JK, Strobel J: The shoulder-hand syndrome after stroke: a prospective clinical trial. Ann Neurol 1994, 36:728–733.

    Article  PubMed  CAS  Google Scholar 

  51. Sindrup SH, Jensen ST. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999, 83:389–400.

    Article  PubMed  CAS  Google Scholar 

  52. Collins SL, Moore RA, McQuay HJ, Wiffen P: Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage 2000, 20:449–458.

    Article  PubMed  CAS  Google Scholar 

  53. Wiffen P, Collins S, McQuay H, et al.: Anticonvulsant drugs for acute and chronic pain. Cochrane Database Sys Rev 2000, 3:CD001133.

    Google Scholar 

  54. van de Vusse AC, Stomp-van den Berg SG, Kessels AH, Weber WE: Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type 1 [ISRCTN84121379]. BMC Neurol 2004, 4:13.

    Article  PubMed  CAS  Google Scholar 

  55. McQuay HJ, Tramer M, Nye BA, et al.: A systematic review of antidepressants in neuropathic pain. Pain 1996, 68:217–227.

    Article  PubMed  CAS  Google Scholar 

  56. Watson CP, Babul N: Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology 1998, 50:1837–1841.

    PubMed  CAS  Google Scholar 

  57. Dellemijn PL, Van Duijn H, Vanneste JA: Prolonged treatment with transdermal fentanyl in neuropathic pain. J Pain Symptom Manage 1998, 16:220–229.

    Article  PubMed  CAS  Google Scholar 

  58. Cherny NI, Thaler HT, Klar HF, et al.: Opioid responsiveness of cancer pain syndromes caused by neuropathic or nociceptive mechanisms: a combined analysis of controlled, single dose studies. Neurology 1994, 44:857–861.

    PubMed  CAS  Google Scholar 

  59. Harke H, Gretenkort P, Ladleif HU, et al.: The response of neuropathic pain and pain in complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients pretreated with spinal cord stimulation: a double-blinded randomized study. Anesth Anal 2001, 92:488–495.

    Article  CAS  Google Scholar 

  60. Gilron I, Bailey JM, Tu D, et al.: Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005, 352:1324–1334.

    Article  PubMed  CAS  Google Scholar 

  61. Price DD, Long S, Wilsey B, Rafii A: Analysis of peak magnitude and duration of analgesia produced by local anesthetics injected into sympathetic ganglia of complex regional pain syndrome patients. Clin J Pain 1998, 14:216–226.

    Article  PubMed  CAS  Google Scholar 

  62. Perez RSGM, Kwakkel G, Zuurmond WWA, de Lange JJ: Treatment of reflex sympathetic dystrophy (CRPS Type I): a research synthesis of 21 randomized clinical trials. J Pain Symptom Manage 2001, 21:511–526.

    Article  PubMed  CAS  Google Scholar 

  63. Hanna MH, Peat SJ: Ketanserin in reflex sympathetic dystrophy: a double-blind placebo-controlled crossover trial. Pain 1989, 38:145–150.

    Article  PubMed  CAS  Google Scholar 

  64. Hord AH, Rooks MD, Stephens BO, et al.: Intravenous regional bretylium and lidocaine for treatment of reflex sympathetic dystrophy: a randomized, double-blind study. Anesth Analg 1992, 74:818–821.

    Article  PubMed  CAS  Google Scholar 

  65. Morley S, Eccleston C, Williams A: Systematic review and meta-analysis of randomized controlled trials of cognitive behavior therapy and behavior therapy for chronic pain in adults, excluding headache. Pain 1999, 80:1–13.

    Article  PubMed  CAS  Google Scholar 

  66. Kemler MA, de Vet HC, Barendse GA, et al.: Effect of spinal cord stimulation for chronic complex regional pain syndrome Type I: five-year final follow-up of patients in a randomized controlled trial. J Neurosurg 2008, 108(2):292–298.

    Article  PubMed  Google Scholar 

  67. Sigtermans MJ, van Hilten JJ, Bauer MC, et al.: Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain 2009, 145(3):304–311.

    Article  PubMed  CAS  Google Scholar 

  68. Sigtermans M, Noppers I, Sarton E, et al.: An observational study on the effect of S(+)-ketamine on chronic pain versus experimental acute pain in Complex Regional Pain Syndrome type 1 patients. Eur J Pain 2009 Jun 17 (Epub ahead of print).

  69. Kiefer RT, Rohr P, Ploppa A, et al.: Efficacy of ketamine in anesthetic dosage for the treatment of refractory complex regional pain syndrome: an open-label phase II study. Pain Med 2008, 9(8):1173–1201.

    Article  PubMed  Google Scholar 

  70. Finch PM, Knudsen L, Drummond PD: Reduction of allodynia in patients with complex regional pain syndrome: a double-blind placebo-controlled trial of topical ketamine. Pain 2009, 146(1–2):18–25.

    Article  PubMed  CAS  Google Scholar 

  71. Brunner F, Schmid A, Kissling R, et al.: Bisphosphonate for the therapy of complex regional pain syndrome I—systematic review. Eur J Pain 2009, 13(1):17–21.

    Article  PubMed  CAS  Google Scholar 

  72. Breuer B, Pappagallo M, Ongseng F, et al.: An open-label pilot trial of ibandronate for complex regional pain syndrome. Clin J Pain 2008, 24(8):685–689.

    Article  PubMed  Google Scholar 

  73. Munts AG, van der Plas AA, Voormolen JH, et al.: Intrathecal glycine for pain and dystonia in complex regional pain syndrome. Pain 2009, 146(1–2):199–204.

    Article  PubMed  CAS  Google Scholar 

  74. van Rijn MA, Munts AG, Marinus J, et al.: Intrathecal baclofen for dystonia of complex regional pain syndrome. Pain 2009, 143(1–2):41–47.

    Article  PubMed  Google Scholar 

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Henson, P., Bruehl, S. Complex Regional Pain Syndrome: State of the Art Update. Curr Treat Options Cardio Med 12, 156–167 (2010). https://doi.org/10.1007/s11936-010-0063-z

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