Effect of intravenous low-dose S-ketamine on pain in patients with Complex Regional Pain Syndrome: A retrospective cohort study

Thomas J P Mangnus, Maaike Dirckx, Krishna D Bharwani, Cecile C de Vos, Sander P G Frankema, Dirk L Stronks, Frank J P M Huygen, Thomas J P Mangnus, Maaike Dirckx, Krishna D Bharwani, Cecile C de Vos, Sander P G Frankema, Dirk L Stronks, Frank J P M Huygen

Abstract

Objective: The objective of this study was to assess the effectiveness of a low-dose intravenous S-ketamine treatment on refractory pain in patients with Complex Regional Pain Syndrome (CRPS).

Methods: In this retrospective study, patients with CRPS who received intravenous S-ketamine from March 2010 to April 2019 were included. According to our inpatient protocol, S-ketamine dose was increased until pain reduction was achieved or side effects were observed. Maximum dose was 14 mg/h and treatment duration was 7 days. Primary outcome parameters were pain scores (Numeric Rating Scale) at baseline (T0), end of infusion (T1), and approximately 4 weeks postinfusion (T2). Patients were categorized as responder/nonresponder at T1 and T2. Patients were considered a responder in case there was pain score reduction of greater than or equal to 2 points or if treatment was reported as successful.

Results: Forty-eight patients were included. Mean disease duration was 5 years (interquartile range [IQR] = 6 years). Median pain score significantly decreased from 8 (IQR = 2) at T0 to 6 (IQR = 4) at T1 (p < 0.001). At T1, 62% of the patients were responders. At T2, 48% of the patients remained a responder. A significant proportion of the responders at T1 turned into nonresponders at T2 (p = 0.03).

Conclusion: In a group of patients with CRPS with refractory pain, low-dose intravenous S-ketamine treatment resulted in effective pain relief during infusion. Although a significant proportion of initial responders became nonresponders at follow-up, half of the patients were still a responder at ~ 4 weeks postinfusion. Further research is needed to investigate mechanisms responsible for pain relief by S-ketamine infusions and to ascertain possible predictors of response to the treatment.

Keywords: Complex Regional Pain Syndrome (CRPS); S-ketamine; dose; intravenous; pain.

Conflict of interest statement

None of the authors have any conflict of interest.

© 2021 The Authors. Pain Practice published by Wiley Periodicals LLC on behalf of World Institute of Pain.

Figures

FIGURE 1
FIGURE 1
Flowchart of patient selection. MC, Medical Center; CRPS, Complex Regional Pain Syndrome
FIGURE 2
FIGURE 2
Pain scores of patients with CRPS before start of the S‐ketamine infusion (T0, n = 42), at discharge of the treatment (T1, n = 36), and at first follow‐up visit to the clinic after treatment (T2, n = 18) NRS, Numeric Rating Scale. *p < 0.001, **p = 0.015

References

    1. Harden RN, Bruehl S, Stanton‐Hicks M, Wilson PR. Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med. 2007;8:326–31.
    1. Veldman PHJM, Reynen HM, Arntz IE, Goris RJA. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet. 1993;342:1012–6.
    1. 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.
    1. de Mos M, De Bruijn AGJ, Huygen F, Dieleman JP, Stricker BHC, Sturkenboom M. The incidence of complex regional pain syndrome: a population‐based study. Pain. 2007;129:12–20.
    1. Harden RN, Bruehl S, Perez RSGM, Birklein F, Marinus J, Maihofner C, et al. Development of a severity score for CRPS. Pain. 2010;151:870–6.
    1. de Boer RDH, Marinus J, van Hilten JJ, Huygen FJ, van Eijs F, van Kleef M, et al. Distribution of signs and symptoms of complex regional pain syndrome type I in patients meeting the diagnostic criteria of the International Association for the Study of Pain. Eur J Pain. 2011;15(830):830.e831–838.
    1. Perez RS, Zollinger PE, Dijkstra PU, Thomassen‐Hilgersom IL, Zuurmond WW, Rosenbrand KCJ, et al. Evidence based guidelines for complex regional pain syndrome type 1. BMC Neurol. 2010;10:1–14.
    1. Domino EF, Warner DS. Taming the ketamine tiger. Anesthesiology. 2010;113:678–84.
    1. Li L, Vlisides PE. Ketamine: 50 years of modulating the mind. Front Hum Neurosci. 2016;10:612.
    1. Visser E, Schug SA. The role of ketamine in pain management. Biomed Pharmacother. 2006;60:341–8.
    1. Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate. Br J Pharmacol. 1983;79:565–75.
    1. Thomson AM, West DC, Lodge D. An N‐methylaspartate receptor‐mediated synapse in rat cerebral cortex: a site of action of ketamine? Nature. 1985;313:479–81.
    1. Fisher K, Coderre TJ, Hagen NA. Targeting the N‐methyl‐D‐aspartate receptor for chronic pain management: preclinical animal studies, recent clinical experience and future research directions. J Pain Symptom Manage. 2000;20:358–73.
    1. Yang Y, Maher DP, Cohen SP. Emerging concepts on the use of ketamine for chronic pain. Expert Rev Clin Pharmacol. 2020;13:135–46.
    1. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N‐methyl‐D‐aspartic acid receptor activation; implications for the treatment of post‐injury pain hypersensitivity states. Pain. 1991;44:293–9.
    1. Davies SN, Lodge D. Evidence for involvement of N‐methylaspartate receptors in ‘wind‐up’ of class 2 neurones in the dorsal horn of the rat. Brain Res. 1987;424:402–6.
    1. Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology. 1987;26:1235–8.
    1. Sigtermans MJ, Van Hilten JJ, Bauer MCR, Arbous MS, Marinus J, Sarton EY, et al. Ketamine produces effective and long‐term pain relief in patients with Complex Regional Pain Syndrome Type 1. Pain. 2009;145:304–11.
    1. Zhao J, Wang Y, Wang D. The effect of ketamine infusion in the treatment of complex regional pain syndrome: a systemic review and meta‐analysis. Curr Pain Headache Rep. 2018;22:12.
    1. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11‐point numerical pain rating scale. Pain. 2001;94:149–58.
    1. Cohen SP, Bhatia A, Buvanendran A, Schwenk ES, Wasan AD, Hurley RW, et al. Consensus guidelines on the use of intravenous ketamine infusions for chronic pain from the American Society of Regional anesthesia and pain medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43:521–46.
    1. Schwartzman RJ, Alexander GM, Grothusen JR, Paylor T, Reichenberger E, Perreault M. Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double‐blind placebo controlled study. Pain. 2009;147:107–15.
    1. Maher DP, Chen L, Mao J. Intravenous ketamine infusions for neuropathic pain management: a promising therapy in need of optimization. Anest Analg. 2017;124:661–74.
    1. Grieve S, Perez RSGM, Birklein F, Brunner F, Bruehl S, Harden N, et al. Recommendations for a first Core Outcome Measurement set for complex regional PAin syndrome Clinical sTudies (COMPACT). Pain. 2017;158:1083–90.
    1. Xu J, Herndon C, Anderson S, Getson P, Foorsov V, Harbut RE, et al. Intravenous ketamine infusion for complex regional pain syndrome: survey, consensus, and a reference protocol. Pain Med. 2019;20:323–34.
    1. Miller ET, Abu‐Alhaija DM. Cultural influences on pain perception and management. Pain Manag Nursing. 2019;20:183–4.
    1. Kirkpatrick AF, Saghafi A, Yang K, Qiu P, Alexander J, Bavry E, et al. Optimizing the treatment of CRPS with ketamine. Clin J Pain. 2020;36:516–23.
    1. Bosma RL, Cheng JC, Rogachov A, Kim JA, Hemington KS, Osborne NR, et al. Brain dynamics and temporal summation of pain predicts neuropathic pain relief from ketamine infusion. Anesthesiology. 2018;129:1015–24.
    1. Birklein F, Ajit SK, Goebel A, Perez RSGM, Sommer C. Complex regional pain syndrome—phenotypic characteristics and potential biomarkers. Nat Rev Neurol. 2018;14:272–84.
    1. Hudak PL, Wright JG. The characteristics of patient satisfaction measures. Spine. 2000;25:3167–77.
    1. Group TE . EuroQol‐a new facility for the measurement of health‐related quality of life. Health Policy. 1990;16:199–208.
    1. Woolf CJ, Decosterd I. Implications of recent advances in the understanding of pain pathophysiology for the assessment of pain in patients. Pain. 1999;82:S141–7.
    1. Gierthmühlen J, Binder A, Baron R. Mechanism‐based treatment in complex regional pain syndromes. Nat Rev Neurol. 2014;10:518–28.
    1. Bharwani KD, Dirckx M, Huygen FJPM. Complex regional pain syndrome: diagnosis and treatment. BJA Educ. 2017;17(8):262–68.
    1. Schwartzman RJ, Alexander GM, Grothusen JR. The use of ketamine in complex regional pain syndrome: possible mechanisms. Expert Rev Neurother. 2011;11:719–34.
    1. Sorel M, Zrek N, Locko B, Armessen C, Ayache SS, Lefaucheur J‐P. A reappraisal of the mechanisms of action of ketamine to treat complex regional pain syndrome in the light of cortical excitability changes. Clin Neurophysiol. 2018;129:990–1000.
    1. De Kock M, Loix S, Lavand'homme P. Ketamine and peripheral inflammation. CNS Neurosci Ther. 2013;19:403–10.
    1. Loix S, De Kock M, Henin P. The anti‐inflammatory effects of ketamine: state of the art. Acta Anaesthesiol Belg. 2011;62:47–58.
    1. Strasburger SE, Bhimani PM, Kaabe JH, Krysiak JT, Nanchanatt DL, Nguyen TN, et al. What is the mechanism of Ketamine's rapid‐onset antidepressant effect? A concise overview of the surprisingly large number of possibilities. J Clin Pharm Ther. 2017;42:147–54.
    1. Pochwat B, Nowak G, Szewczyk B. An update on NMDA antagonists in depression. Expert Rev Neurother. 2019;19:1055–67.
    1. Bharwani KD, Dik WA, Dirckx M, Huygen FJPM. Highlighting the role of biomarkers of inflammation in the diagnosis and management of complex regional pain syndrome. Mol Diagn Ther. 2019;23:615–26.
    1. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.
    1. Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell. 2012;148:1172–87.
    1. Douglas SR, Shenoda BB, Qureshi RA, Sacan A, Alexander GM, Perreault M, et al. Analgesic response to intravenous ketamine is linked to a circulating microRNA signature in female patients with complex regional pain syndrome. J Pain. 2015;16:814–24.
    1. Vranken JH, Dijkgraaf MGW, Kruis MR, Van Dasselaar NT, Van der Vegt MH. Iontophoretic administration of S (+)‐ketamine in patients with intractable central pain: a placebo‐controlled trial. Pain. 2005;118:224–31.
    1. Casale R, Symeonidou Z, Bartolo M. Topical treatments for localized neuropathic pain. Curr Pain Headache Rep. 2017;21:15.
    1. 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;146:18–25.
    1. Lara DR, Bisol LW, Munari LR. Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J Neuropsychopharmacol. 2013;16:2111–7.
    1. Nguyen L, Marshalek PJ, Weaver CB, Cramer KJ, Pollard SE, Matsumoto RR. Off‐label use of transmucosal ketamine as a rapid‐acting antidepressant: a retrospective chart review. Neuropsychiatr Dis Treat. 2015;11:2667.
    1. Swainson J, Khullar A. Sublingual ketamine: an option for increasing accessibility of ketamine treatments for depression? J Clin Psychiatry. 2020;81(1):19.

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