Osteoporosis International

, Volume 27, Issue 8, pp 2423–2431 | Cite as

Management of patients with complex regional pain syndrome type I

  • D. GattiEmail author
  • M. Rossini
  • S. Adami


Complex regional pain syndrome type I (CRPS-I) includes different conditions characterized by regional pain and sensory, motor, sudomotor, vasomotor, and/or trophic findings, affecting a peripheral limb usually after a noxious event, such as a trauma or surgery. The pathophysiology is still poorly understood. Limited data are available on the incidence of CRPS-I, and the disease is underestimated and under-diagnosed. The disease shows a female preponderance approximately 3:1 with a peak age of incidence around the 5th and 6th decade. The available diagnostic criteria for CRPS-I rely on clinical criteria that are unfortunately focused on the signs and symptoms of the chronic and late disease, while little emphasis is given to the typical imaging (X-rays, bone scintigraphy, MRI) findings of the early phase. Over the last decades, several therapies have been proposed but the few studies available are often too small to be conclusive and rarely evolved to randomized controlled trials (RCTs). On the basis of the results of a few RCTs, only short courses of high bisphosphonate doses appear to provide substantial benefits. The best results are seen in patients in the early phase of the disease, often with the persistent remission or complete healing of the conditions. Since the only accredited mechanism of action of bisphosphonates is the suppression of osteoclastic bone resorption, it is likely the initial dramatic bone loss plays a role in the maintenance and evolution of CRPS-I. Short courses of high doses of bisphosphonates should be considered the treatment of choice for patients with CRPS-I.


Bisphosphonates Complex regional pain syndrome type I Neridronate 


Compliance with ethical standard

Conflict of interest



  1. 1.
    Casale R, Atzeni F, Masala IF, Sarzi-Puttini P (2015) The words of pain in complex regional pain syndrome. Best Pract Res Clin Rheumatol 29:71–76. doi: 10.1016/j.berh.2015.04.032 CrossRefPubMedGoogle Scholar
  2. 2.
    Borchers AT, Gershwin ME (2014) Complex regional pain syndrome: a comprehensive and critical review. Autoimmun Rev 13:242–265. doi: 10.1016/j.autrev.2013.10.006 CrossRefPubMedGoogle Scholar
  3. 3.
    Birklein F, O’Neill D, Schlereth T (2015) Complex regional pain syndrome: an optimistic perspective. Neurology 84:89–96. doi: 10.1212/WNL.0000000000001095 CrossRefPubMedGoogle Scholar
  4. 4.
    Bruehl S, Harden RN, Galer BS et al (2002) Complex regional pain syndrome: are there distinct subtypes and sequential stages of the syndrome? Pain 95:119–124CrossRefPubMedGoogle Scholar
  5. 5.
    Casale R, Atzeni F, Sarzi-Puttini P (2015) From Mitchell’s causalgia to complex regional pain syndromes: 150 years of definitions and theories. Clin Exp Rheumatol 33:S7–13PubMedGoogle Scholar
  6. 6.
    Varenna M, Zucchi F (2015) Algodystrophy: recent insight into the pathogenic framework. Clin Cases Miner Bone Metab Off J Ital Soc Osteoporos Miner Metab Skelet Dis 12:27–30Google Scholar
  7. 7.
    Birklein F, Schmelz M, Schifter S, Weber M (2001) The important role of neuropeptides in complex regional pain syndrome. Neurology 57:2179–2184CrossRefPubMedGoogle Scholar
  8. 8.
    Schinkel C, Gaertner A, Zaspel J et al (2006) Inflammatory mediators are altered in the acute phase of posttraumatic complex regional pain syndrome. Clin J Pain 22:235–239. doi: 10.1097/01.ajp.0000169669.70523.f0 CrossRefPubMedGoogle Scholar
  9. 9.
    Schinkel C, Scherens A, Köller M et al (2009) Systemic inflammatory mediators in post-traumatic complex regional pain syndrome (CRPS I)—longitudinal investigations and differences to control groups. Eur J Med Res 14:130–135CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Geertzen JHB, Bodde MI, van den Dungen JJA et al (2015) Peripheral nerve pathology in patients with severely affected complex regional pain syndrome type I. Int J Rehabil Res Int Z Für Rehabil Rev Int Rech Réadapt 38:121–130. doi: 10.1097/MRR.0000000000000096 Google Scholar
  11. 11.
    Tan ECTH, Ter Laak HJ, Hopman MTE et al (2012) Impaired oxygen utilization in skeletal muscle of CRPS I patients. J Surg Res 173:145–152. doi: 10.1016/j.jss.2010.08.043 CrossRefPubMedGoogle Scholar
  12. 12.
    Schürmann M, Zaspel J, Löhr P et al (2007) Imaging in early posttraumatic complex regional pain syndrome: a comparison of diagnostic methods. Clin J Pain 23:449–457. doi: 10.1097/AJP.0b013e31805c9e66 CrossRefPubMedGoogle Scholar
  13. 13.
    de Mos M, de Bruijn AGJ, Huygen FJPM et al (2007) The incidence of complex regional pain syndrome: a population-based study. Pain 129:12–20. doi: 10.1016/j.pain.2006.09.008 CrossRefPubMedGoogle Scholar
  14. 14.
    Marinus J, Moseley GL, Birklein F et al (2011) Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurol 10:637–648. doi: 10.1016/S1474-4422(11)70106-5 CrossRefPubMedGoogle Scholar
  15. 15.
    Sandroni P, Benrud-Larson LM, McClelland RL, Low PA (2003) Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 103:199–207CrossRefPubMedGoogle Scholar
  16. 16.
    Beerthuizen A, Stronks DL, Van’t Spijker A et al (2012) Demographic and medical parameters in the development of complex regional pain syndrome type 1 (CRPS1): prospective study on 596 patients with a fracture. Pain 153:1187–1192. doi: 10.1016/j.pain.2012.01.026 CrossRefPubMedGoogle Scholar
  17. 17.
    Harden RN, Bruehl S, Perez RSGM et al (2010) Validation of proposed diagnostic criteria (the “Budapest Criteria”) for Complex Regional Pain Syndrome. Pain 150:268–274. doi: 10.1016/j.pain.2010.04.030 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Stanton-Hicks M, Jänig W, Hassenbusch S et al (1995) Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain 63:127–133CrossRefPubMedGoogle Scholar
  19. 19.
    Allen G, Galer BS, Schwartz L (1999) Epidemiology of complex regional pain syndrome: a retrospective chart review of 134 patients. Pain 80:539–544CrossRefPubMedGoogle Scholar
  20. 20.
    van Rooijen DE, Roelen DL, Verduijn W et al (2012) Genetic HLA associations in complex regional pain syndrome with and without dystonia. J Pain Off J Am Pain Soc 13:784–789. doi: 10.1016/j.jpain.2012.05.003 CrossRefGoogle Scholar
  21. 21.
    Vaneker M, van der Laan L, Allebes WA, Goris JA (2002) Genetic factors associated with complex regional pain syndrome 1: HLA DRB and TNF alpha promotor gene polymorphism. Disabil Med 2:69–74Google Scholar
  22. 22.
    Beerthuizen A, Stronks DL, Huygen FJPM et al (2011) The association between psychological factors and the development of complex regional pain syndrome type 1 (CRPS1)—a prospective multicenter study. Eur J Pain Lond Engl 15:971–975. doi: 10.1016/j.ejpain.2011.02.008 CrossRefGoogle Scholar
  23. 23.
    Wüppenhorst N, Maier C, Frettlöh J et al (2010) Sensitivity and specificity of 3-phase bone scintigraphy in the diagnosis of complex regional pain syndrome of the upper extremity. Clin J Pain 26:182–189. doi: 10.1097/AJP.0b013e3181c20207 CrossRefPubMedGoogle Scholar
  24. 24.
    Varenna M, Adami S, Rossini M et al (2013) Treatment of complex regional pain syndrome type I with neridronate: a randomized, double-blind, placebo-controlled study. Rheumatol Oxf Engl 52:534–542. doi: 10.1093/rheumatology/kes312 CrossRefGoogle Scholar
  25. 25.
    Eriksen EF, Ringe JD (2012) Bone marrow lesions: a universal bone response to injury? Rheumatol Int 32:575–584. doi: 10.1007/s00296-011-2141-2 CrossRefPubMedGoogle Scholar
  26. 26.
    Cacchio A, De Blasis E, Necozione S et al (2009) Mirror therapy for chronic complex regional pain syndrome type 1 and stroke. N Engl J Med 361:634–636. doi: 10.1056/NEJMc0902799 CrossRefPubMedGoogle Scholar
  27. 27.
    Ezendam D, Bongers RM, Jannink MJA (2009) Systematic review of the effectiveness of mirror therapy in upper extremity function. Disabil Rehabil 31:2135–2149. doi: 10.3109/09638280902887768 CrossRefPubMedGoogle Scholar
  28. 28.
    Munts AG, van der Plas AA, Ferrari MD et al (2010) Efficacy and safety of a single intrathecal methylprednisolone bolus in chronic complex regional pain syndrome. Eur J Pain Lond Engl 14:523–528. doi: 10.1016/j.ejpain.2009.11.004 CrossRefGoogle Scholar
  29. 29.
    Kalita J, Vajpayee A, Misra UK (2006) Comparison of prednisolone with piroxicam in complex regional pain syndrome following stroke: a randomized controlled trial. QJM Mon J Assoc Physicians 99:89–95. doi: 10.1093/qjmed/hcl004 CrossRefGoogle Scholar
  30. 30.
    Christensen K, Jensen EM, Noer I (1982) The reflex dystrophy syndrome response to treatment with systemic corticosteroids. Acta Chir Scand 148:653–655PubMedGoogle Scholar
  31. 31.
    Goebel A, Baranowski A, Maurer K et al (2010) Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med 152:152–158. doi: 10.7326/0003-4819-152-3-201002020-00006 CrossRefPubMedGoogle Scholar
  32. 32.
    Zuurmond WW, Langendijk PN, Bezemer PD et al (1996) Treatment of acute reflex sympathetic dystrophy with DMSO 50% in a fatty cream. Acta Anaesthesiol Scand 40:364–367CrossRefPubMedGoogle Scholar
  33. 33.
    Gaspar M, Bovaira M, Carrera-Hueso FJ et al (2012) Efficacy of a topical treatment protocol with dimethyl sulfoxide 50% in type 1 complex regional pain syndrome. Farm Hosp Órgano Of Expr Científica Soc Esp Farm Hosp 36:385–391. doi: 10.1016/j.farma.2011.10.009 Google Scholar
  34. 34.
    Perez RSGM, Zuurmond WWA, Bezemer PD et al (2003) The treatment of complex regional pain syndrome type I with free radical scavengers: a randomized controlled study. Pain 102:297–307CrossRefPubMedGoogle Scholar
  35. 35.
    Sigtermans MJ, van Hilten JJ, Bauer MCR et al (2009) Ketamine produces effective and long-term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain 145:304–311. doi: 10.1016/j.pain.2009.06.023 CrossRefPubMedGoogle Scholar
  36. 36.
    Schwartzman RJ, Alexander GM, Grothusen JR et al (2009) Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain 147:107–115. doi: 10.1016/j.pain.2009.08.015 CrossRefPubMedGoogle Scholar
  37. 37.
    Bussa M, Guttilla D, Lucia M et al (2015) Complex regional pain syndrome type I: a comprehensive review. Acta Anaesthesiol Scand 59:685–697. doi: 10.1111/aas.12489 CrossRefPubMedGoogle Scholar
  38. 38.
    Zollinger PE, Tuinebreijer WE, Kreis RW, Breederveld RS (1999) Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet Lond Engl 354:2025–2028. doi: 10.1016/S0140-6736(99)03059-7 CrossRefGoogle Scholar
  39. 39.
    Stanton TR, Wand BM, Carr DB et al (2013) Local anaesthetic sympathetic blockade for complex regional pain syndrome. Cochrane Database Syst Rev 8:CD004598. doi: 10.1002/14651858.CD004598.pub3 PubMedGoogle Scholar
  40. 40.
    Adami S, Fossaluzza V, Gatti D et al (1997) Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis 56:201–204CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Robinson JN, Sandom J, Chapman PT (2004) Efficacy of pamidronate in complex regional pain syndrome type I. Pain Med Malden Mass 5:276–280. doi: 10.1111/j.1526-4637.2004.04038.x CrossRefGoogle Scholar
  42. 42.
    Adami S, Bevilacqua M, Broggini M et al (2002) Short-term intravenous therapy with Neridronate in Paget’s disease. Clin Exp Rheumatol 20:55–58PubMedGoogle Scholar
  43. 43.
    Merlotti D, Gennari L, Martini G et al (2007) Comparison of different intravenous bisphosphonate regimens for Paget’s disease of bone. J Bone Miner Res Off J Am Soc Bone Miner Res 22:1510–1517. doi: 10.1359/jbmr.070704 CrossRefGoogle Scholar
  44. 44.
    Manicourt D-H, Brasseur J-P, Boutsen Y et al (2004) Role of alendronate in therapy for posttraumatic complex regional pain syndrome type I of the lower extremity. Arthritis Rheum 50:3690–3697. doi: 10.1002/art.20591 CrossRefPubMedGoogle Scholar
  45. 45.
    Varenna M, Zucchi F, Ghiringhelli D et al (2000) Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized, double blind, placebo controlled study. J Rheumatol 27:1477–1483PubMedGoogle Scholar
  46. 46.
    Adami S, Gatti D, Colapietro F et al (2003) Intravenous neridronate in adults with osteogenesis imperfecta. J Bone Miner Res Off J Am Soc Bone Miner Res 18:126–130. doi: 10.1359/jbmr.2003.18.1.126 CrossRefGoogle Scholar
  47. 47.
    Braga V, Gatti D, Colapietro F et al (2003) Intravenous intermittent neridronate in the treatment of postmenopausal osteoporosis. Bone 33:342–345CrossRefPubMedGoogle Scholar
  48. 48.
    Gatti D, Antoniazzi F, Prizzi R et al (2005) Intravenous neridronate in children with osteogenesis imperfecta: a randomized controlled study. J Bone Miner Res Off J Am Soc Bone Miner Res 20:758–763. doi: 10.1359/JBMR.041232 CrossRefGoogle Scholar
  49. 49.
    Rossini M, Viapiana O, Kalpakcioglu B et al (2011) Long-term effects of neridronate and its discontinuation in patients with primary hyperparathyroidism. Calcif Tissue Int 89:21–28. doi: 10.1007/s00223-011-9489-x CrossRefPubMedGoogle Scholar
  50. 50.
    Gatti D, Rossini M, Viapiana O et al (2013) Clinical development of neridronate: potential for new applications. Ther Clin Risk Manag 9:139–147. doi: 10.2147/TCRM.S35788 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Rossini M, Adami S, Viapiana O et al (2012) Long-term effects of amino-bisphosphonates on circulating γδ T cells. Calcif Tissue Int 91:395–399. doi: 10.1007/s00223-012-9647-9 CrossRefPubMedGoogle Scholar
  52. 52.
    Rossini M, Adami S, Viapiana O et al (2013) Acute phase response after zoledronic acid is associated with long-term effects on white blood cells. Calcif Tissue Int 93:249–252. doi: 10.1007/s00223-013-9750-6 CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2016

Authors and Affiliations

  1. 1.Rheumatology UnitUniversity of Verona, Policlinico Borgo RomaVeronaItaly

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