Skip to main content

Efficacy and Safety of Ketamine in Patients with Complex Regional Pain Syndrome

A Systematic Review

CNS Drugs volume 26, pages 215–228 (2012)Cite this article

Abstract

Despite being a recognized clinical entity for over 140 years, complex regional pain syndrome (CRPS) remains a difficult-to-treat condition. While there have been multiple therapies explored in the treatment of CRPS, NMDA antagonists such as ketamine continue to hold significant interest because of their potential ability to alter the central sensitization noted in chronic pain states. The objective of this review is to identify published literature for evidence of the efficacy and safety of ketamine in the treatment of CRPS.

PubMed and the Cochrane Controlled Trials Register were searched (final search 26 May 2011) using the MeSH terms ‘ketamine’, ‘complex regional pain syndrome’, ‘analgesia’ and ‘pain’ in the English literature. The manuscriptbibliographies were then reviewed to identify additional relevant papers. Observational trials were evaluated using the Agency for Healthcare Research and Quality criteria; randomized trials were evaluated using themethodological assessment of randomized clinical trials.

The search methodology yielded three randomized, placebo-controlled trials, seven observational studies and nine case studies/reports. In aggregate, the data available reveal ketamine as a promising treatment for CRPS. The optimum dose, route and timing of administration remain to be determined. Randomized controlled trials are needed to establish the efficacy and safety of ketamine and to determine its long-term benefit in CRPS.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

49,54 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Table I
Table II
Table III
Table IV
Table V
Table VI
Table VII
Table VIII

References

  1. de Mos M, de Bruijn AG, Huygen FJ, et al. The incidence of complex regional pain syndrome: a population-based study. Pain 2007 May; 129(1–2): 12–20

    PubMed  Article  Google Scholar 

  2. Sandroni P, Benrud-Larson LM, McClelland RL, et al. Complex regional pain syndrome type I: incidence and prevalence in Olmsted county, a population-based study. Pain 2003 May; 103(1–2): 199–207

    PubMed  Article  Google Scholar 

  3. Tran de QH, Duong S, Bertini P, et al. Treatment of complex regional pain syndrome: a review of the evidence. Can J Anaesth 2010 Feb; 57(2): 149–66

    Article  Google Scholar 

  4. Stanton-Hicks M, Janig W, Hassenbusch S, et al. Reflex sympathetic dystrophy: changing concepts and taxonomy. Pain 1995 Oct; 63(1): 127–33

    PubMed  Article  CAS  Google Scholar 

  5. Raja SN, Grabow TS. Complex regional pain syndrome I (reflex sympathetic dystrophy). Anesthesiology 2002 May; 96(5): 1254–60

    PubMed  Article  Google Scholar 

  6. Dijkstra PU, Groothoff JW, ten Duis HJ, et al. Incidence of complex regional pain syndrome type I after fractures of the distal radius. Eur J Pain 2003; 7(5): 457–62

    PubMed  Article  Google Scholar 

  7. Janig W, Baron R. Complex regional pain syndrome: mystery explained? Lancet Neurol 2003 Nov; 2(11): 687–97

    PubMed  Article  Google Scholar 

  8. Merskey H, Bogduk N, editors. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms. 2nd ed. Seattle (WA): IASP Press, 1994: 40–2

    Google Scholar 

  9. Harden RN, Bruehl S, Stanton-Hicks M, et al. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med 2007 May–Jun; 8(4): 326–31

    PubMed  Article  Google Scholar 

  10. Harden RN, Bruehl S, Perez RS, et al. Validation of proposed diagnostic criteria (the “Budapest criteria”) for complex regional pain syndrome. Pain 2010 Aug; 150(2): 268–74

    PubMed  Article  Google Scholar 

  11. Oaklander AL, Rissmiller JG, Gelman LB, et al. Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy). Pain 2006 Feb; 120(3): 235–43

    PubMed  Article  Google Scholar 

  12. Devor M. Centralization, central sensitization and neuropathic pain: focus on “sciatic chronic constriction injury produces cell-type-specific changes in the electrophysiological properties of rat substantia gelatinosa neurons”. J Neurophysiol 2006 Aug; 96(2): 522–3

    PubMed  Article  Google Scholar 

  13. Alexander GM, van Rijn MA, van Hilten JJ, et al. Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS. Pain 2005 Aug; 116(3): 213–9

    PubMed  Article  CAS  Google Scholar 

  14. Blair SJ, Chinthagada M, Hoppenstehdt D, et al. Role of neuropeptides in pathogenesis of reflex sympathetic dystrophy. Acta Orthop Belg 1998 Dec; 64(4): 448–51

    PubMed  CAS  Google Scholar 

  15. Wesseldijk F, Fekkes D, Huygen FJ, et al. Increased plasma glutamate, glycine, and arginine levels in complex regional pain syndrome type 1. Acta Anaesthesiol Scand 2008 May; 52(5): 688–94

    PubMed  Article  CAS  Google Scholar 

  16. Groeneweg JG, Huygen FJ, Heijmans-Antonissen C, et al. Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1. BMC Musculoskelet Disord 2006; 7: 91

    PubMed  Article  Google Scholar 

  17. Dayan L, Salman S, Norman D, et al. Exaggerated vasoconstriction in complex regional pain syndrome-1 is associated with impaired resistance artery endothelial function and local vascular reflexes. J Rheumatol 2008 Jul; 35(7): 1339–45

    PubMed  Google Scholar 

  18. Ferreira SH, Lorenzetti BB, Poole S. Bradykinin initiates cytokine-mediated inflammatory hyperalgesia. Br J Pharmacol 1993 Nov; 110(3): 1227–31

    PubMed  Article  CAS  Google Scholar 

  19. Schlereth T, Dittmar JO, Seewald B, et al. Peripheral amplification of sweating: a role for calcitonin gene-related peptide. J Physiol 2006 Nov 1; 576 (Pt 3): 823–32

    PubMed  Article  CAS  Google Scholar 

  20. Maihofner C, Handwerker HO, Neundorfer B, et al. Mechanical hyperalgesia in complex regional pain syndrome: a role for TNF-alpha? Neurology 2005 Jul 26; 65(2): 311–3

    PubMed  Article  Google Scholar 

  21. Uceyler N, Eberle T, Rolke R, et al. Differential expression patterns of cytokines in complex regional pain syndrome. Pain 2007 Nov; 132(1–2): 195–205

    PubMed  Article  Google Scholar 

  22. Wesseldijk F, Huygen FJ, Heijmans-Antonissen C, et al. Six years follow-up of the levels of TNF-alpha and IL-6 in patients with complex regional pain syndrome type 1. Mediators Inflamm 2008; 2008: 469439

    PubMed  Article  Google Scholar 

  23. Ludwig J, Binder A, Steinmann J, et al. Cytokine expression in serum and cerebrospinal fluid in non-inflammatory polyneuropathies. J Neurol Neurosurg Psychiatry 2008 Nov; 79(11): 1268–73

    PubMed  Article  CAS  Google Scholar 

  24. Wasner G, Schattschneider J, Heckmann K, et al. Vascular abnormalities in reflex sympathetic dystrophy (CRPS I): mechanisms and diagnostic value. Brain 2001 Mar; 124 (Pt 3): 587–99

    PubMed  Article  CAS  Google Scholar 

  25. Wasner G, Heckmann K, Maier C, et al. Vascular abnormalities in acute reflex sympathetic dystrophy (CRPS I): complete inhibition of sympathetic nerve activity with recovery. Arch Neurol 1999 May; 56(5): 613–20

    PubMed  Article  CAS  Google Scholar 

  26. Cheng JK, Ji RR. Intracellular signaling in primary sensory neurons and persistent pain. Neurochem Res 2008 Oct; 33(10): 1970–8

    PubMed  Article  CAS  Google Scholar 

  27. Groeneweg JG, Antonissen CH, Huygen FJ, et al. Expression of endothelial nitric oxide synthase and endothelin-1 in skin tissue from amputated limbs of patients with complex regional pain syndrome. Mediators Inflamm 2008; 2008: 680981

    PubMed  Article  Google Scholar 

  28. England S, Bevan S, Docherty RJ. PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade. J Physiol 1996 Sep 1; 495 (Pt 2): 429–40

    PubMed  CAS  Google Scholar 

  29. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000 Jun 9; 288(5472): 1765–9

    PubMed  Article  CAS  Google Scholar 

  30. Hewitt DJ. The use of NMDA-receptor antagonists in the treatment of chronic pain. Clin J Pain 2000 Jun; 16 (2 Suppl. ): S73–9

    PubMed  Article  CAS  Google Scholar 

  31. Price DD, Mayer DJ, Mao J, et al. NMDA-receptor antagonists and opioid receptor interactions as related to analgesia and tolerance. J Pain Symptom Manage 2000 Jan; 19 (1 Suppl. ): S7–11

    PubMed  Article  CAS  Google Scholar 

  32. Hocking G, Cousins MJ. Ketamine in chronic pain management: an evidence-based review. Anesth Analg 2003 Dec; 97(6): 1730–9

    PubMed  Article  CAS  Google Scholar 

  33. Nourozi A, Talebi H, Fateh S, et al. Effect of adding ketamine to pethidine on postoperative pain in patients undergoing major abdominal operations: a double blind randomized controlled trial. Pak J Biol Sci 2010 Dec 15; 13(24): 1214–8

    PubMed  Article  CAS  Google Scholar 

  34. 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 Nov; 146(1–2): 18–25

    PubMed  Article  CAS  Google Scholar 

  35. Collins S, Sigtermans MJ, Dahan A, et al. NMDA receptor antagonists for the treatment of neuropathic pain. Pain Med 2010 Nov; 11(11): 1726–42

    PubMed  Article  Google Scholar 

  36. West S, King V, Carey TS, et al. Systems to rate the strength of scientific evidence. Evid Rep Technol Assess (Summ) 2002 Mar; (47): 1-11

  37. Koes BW, Scholten RJ, Mens JM, et al. Efficacy of epidural steroid injections for low-back pain and sciatica: a systematic review of randomized clinical trials. Pain 1995 Dec; 63(3): 279–88

    PubMed  Article  CAS  Google Scholar 

  38. 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 Oct; 145(3): 304–11

    PubMed  Article  CAS  Google Scholar 

  39. Schwartzman RJ, Alexander GM, Grothusen JR, et al. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. Pain 2009 Dec 15; 147(1–3): 107–15

    PubMed  Article  CAS  Google Scholar 

  40. Sunder RA, Toshniwal G, Dureja GP. Ketamine as an adjuvant in sympathetic blocks for management of central sensitization following peripheral nerve injury. J Brachial Plex Peripher Nerve Inj 2008; 3: 22

    PubMed  Article  Google Scholar 

  41. Kiefer RT, Rohr P, Ploppa A, et al. A pilot open-label study of the efficacy of subanesthetic isomeric S(+)-ketamine in refractory CRPS patients. Pain Med 2008 Jan–Feb; 9(1): 44–54

    PubMed  Article  Google Scholar 

  42. 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 2010 Mar; 14(3): 302–7

    PubMed  Article  CAS  Google Scholar 

  43. Goldberg ME, Domsky R, Scaringe D, et al. Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician 2005 Apr; 8(2): 175–9

    PubMed  Google Scholar 

  44. Correll GE, Maleki J, Gracely EJ, et al. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med 2004 Sep; 5(3): 263–75

    PubMed  Article  Google Scholar 

  45. 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 Nov; 9(8): 1173–201

    PubMed  Article  Google Scholar 

  46. Goldberg ME, Torjman MC, Schwartzman RJ, et al. Pharmacodynamic profiles of ketamine (R)- and (S)- with 5-day inpatient infusion for the treatment of complex regional pain syndrome. Pain Physician 2010 Jul–Aug; 13(4): 379–87

    PubMed  Google Scholar 

  47. Koffler SP, Hampstead BM, Irani F, et al. The neurocognitive effects of 5 day anesthetic ketamine for the treatment of refractory complex regional pain syndrome. Arch Clin Neuropsychol 2007 Aug; 22(6): 719–29

    PubMed  Article  Google Scholar 

  48. Berg AO, Allan JD. Introducing the third US Preventive Services Task Force. Am J Prev Med 2001 Apr; 20 (3 Suppl. ): 3–4

    PubMed  Article  CAS  Google Scholar 

  49. Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest 2006 Jan; 129(1): 174–81

    PubMed  Article  Google Scholar 

  50. Villanueva-Perez VL, Cerda-Olmedo G, Samper JM, et al. Oral ketamine for the treatment of type I complex regional pain syndrome. Pain Pract 2007 Mar; 7(1): 39–43

    PubMed  Article  Google Scholar 

  51. Kiefer RT, Rohr P, Ploppa A, et al. Complete recovery from intractable complex regional pain syndrome, CRPS-type I, following anesthetic ketamine and midazolam. Pain Pract 2007 Jun; 7(2): 147–50

    PubMed  Article  Google Scholar 

  52. Becerra L, Schwartzman RJ, Kiefer RT, et al. CNS measures of pain responses pre- and post-anesthetic ketamine in a patient with complex regional pain syndrome. Pain Med. Epub 2009 Feb 25

  53. Shirani P, Salamone AR, Schulz PE, et al. Ketamine treatment for intractable pain in a patient with severe refractory complex regional pain syndrome: a case report. Pain Physician 2008 May–Jun; 11(3): 339–42

    PubMed  Google Scholar 

  54. Everett A, McLean B, Plunkett A, et al. A unique presentation of complex regional pain syndrome type I treated with a continuous sciatic peripheral nerve block and parenteral ketamine infusion: a case report. Pain Med 2009 Sep; 10(6): 1136–9

    PubMed  Article  Google Scholar 

  55. Nama S, Meenan DR, Fritz WT. The use of sub-anesthetic intravenous ketamine and adjuvant dexmedetomidine when treating acute pain from CRPS. Pain Physician 2010 Jul–Aug; 13(4): 365–8

    PubMed  Google Scholar 

  56. Harbut RE, Correll GE. Successful treatment of a nine-year case of complex regional pain syndrome type-I (reflex sympathetic dystrophy) with intravenous ketamine-infusion therapy in a warfarin-anticoagulated adult female patient. Pain Med 2002 Jun; 3(2): 147–55

    PubMed  Article  Google Scholar 

  57. Ushida T, Tani T, Kanbara T, et al. Analgesic effects of ketamine ointment in patients with complex regional pain syndrome type 1. Reg Anesth Pain Med 2002 Sep–Oct; 27(5): 524–8

    PubMed  Google Scholar 

  58. Sigtermans M, Dahan A, Mooren R, et al. S(+)-ketamine effect on experimental pain and cardiac output: a population pharmacokinetic-pharmacodynamic modeling study in healthy volunteers. Anesthesiology 2009 Oct; 111(4): 892–903

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

There was no funding provided and there were no funding organizations providing for preparation of this review. The authors have no relevant conflicts of interest. All persons who made substantial contributions to the work are listed as authors.

Author information

Affiliations

  1. Department of Anesthesiology, Division of Pain Management, Duke University School of Medicine, Durham, NC, USA

    Pari Azari, David R. Lindsay, Dean Briones, Collin Clarke, Thomas Buchheit &  Srinivas Pyati

Authors
  1. Pari Azari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David R. Lindsay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dean Briones
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Collin Clarke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas Buchheit
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Srinivas Pyati
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Srinivas Pyati.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Azari, P., Lindsay, D.R., Briones, D. et al. Efficacy and Safety of Ketamine in Patients with Complex Regional Pain Syndrome. CNS Drugs 26, 215–228 (2012). https://doi.org/10.2165/11595200-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11595200-000000000-00000

Keywords

  • Ketamine
  • Central Sensitization
  • Complex Regional Pain Syndrome
  • Reflex Sympathetic Dystrophy
  • Ketamine Infusion