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Scandinavian Journal of Pain

Official Journal of the Scandinavian Association for the Study of Pain

Editor-in-Chief: Breivik, Harald

CiteScore 2017: 0.84

SCImago Journal Rank (SJR) 2017: 0.401
Source Normalized Impact per Paper (SNIP) 2017: 0.452

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Volume 7, Issue 1


Intra- and postoperative intravenous ketamine does not prevent chronic pain: A systematic review and meta-analysis

Elena Klatt
  • Department for Anaesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University of Basel Hospital, CH-4031 Basel Switzerland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Thomas Zumbrunn / Oliver Bandschapp
  • Department for Anaesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University of Basel Hospital, CH-4031 Basel Switzerland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Thierry Girard
  • Department for Anaesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University of Basel Hospital, CH-4031 Basel Switzerland
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Wilhelm Ruppen
  • Corresponding author
  • Department for Anaesthesia, Surgical Intensive Care, Prehospital Emergency Medicine and Pain Therapy, University of Basel Hospital, CH-4031 Basel Switzerland
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-04-01 | DOI: https://doi.org/10.1016/j.sjpain.2014.12.005


Background and aims

The development of postoperative chronic pain (POCP) after surgery is a major problem with a considerable socioeconomic impact. It is defined as pain lasting more than the usual healing, often more than 2–6 months. Recent systematic reviews and meta-analyses demonstrate that the N-methyl-D-aspartate-receptor antagonist ketamine given peri- and intraoperatively can reduce immediate postoperative pain, especially if severe postoperative pain is expected and regional anaesthesia techniques are impossible. However, the results concerning the role of ketamine in preventing chronic postoperative pain are conflicting. The aim of this study was to perform a systematic review and a pooled analysis to determine if peri- and intraoperative ketamine can reduce the incidence of chronic postoperative pain.


Electronic searches of PubMed, EMBASE and Cochrane including data until September 2013 were conducted. Subsequently, the titles and abstracts were read, and reference lists of reviews and retrieved studies were reviewed for additional studies. Where necessary, authors were contacted to obtain raw data for statistical analysis. Papers reporting on ketamine used in the intra- and postoperative setting with pain measured at least 4 weeks after surgery were identified. For meta-analysis of pain after 1, 3, 6 and 12 months, the results were summarised in a forest plot, indicating the number of patients with and without pain in the ketamine and the control groups. The cut-off value used for the VAS/NRS scales was 3 (range 0–10), which is a generally well-accepted value with clinical impact in view of quality of life.


Our analysis identified ten papers for the comprehensive meta-analysis, including a total of 784 patients. Three papers, which included a total of 303 patients, reported a positive outcome concerning persistent postsurgical pain. In the analysis, only one of nine pooled estimates of postoperative pain at rest or in motion after 1, 3, 6 or 12 months, defined as a value ≥3 on a visual analogue scale of 0–10, indicated a marginally significant pain reduction.


Based on the currently available data, there is currently not sufficient evidence to support a reduction in chronic pain due to perioperative administration of ketamine. Only the analysis of postoperative pain at rest after 1 month resulted in a marginally significant reduction of chronic postoperative pain using ketamine in the perioperative setting.


It can be hypothesised, that regional anaesthesia in addition to the administration of perioperative ketamine might have a preventive effect on the development of persistent postsurgical pain. An additional high-quality pain relief intra- and postoperatively as well after discharge could be more effective than any particular analgesic method per se. It is an assumption that a low dose infusion ketamine has to be administered for more than 72 h to reduce the risk of chronic postoperative pain.

Keywords: Intra- and postoperative ketamine; Chronic pain; Prevention of chronic pain; Meta-analysis


  • [1]

    Dahl JB, Kehlet H. Preventive analgesia. Curr Opin Anaes the siol 2011;24:331–8.CrossrefGoogle Scholar

  • [2]

    Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006;367:1618–25.CrossrefPubMedGoogle Scholar

  • [3]

    Chauvin M. [Chronic pain after surgery]. Presse Med 2009;38:1613–20.Web of SciencePubMedGoogle Scholar

  • [4]

    Merskey H, Bogduk N. Classification of chronic pain: descriptions of chronic pain syndromes and definitions of painterms. 2nd ed. Seattle: IASP Press; 1994.Google Scholar

  • [5]

    Macrae WA, Davies HTO. Chronic postsurgical pain. In: Crombie IK, Linton S, Croft P, Von Korff M, LeResche L, editors. Epidemiology of pain. Seattle: IASP Press; 1999. p. 125–42.Google Scholar

  • [6]

    Romundstad L, Breivik H, Roald H, Skolleborg K, Romundstad PR, Stubhaug A. Chronic pain and sensory changes after augmentation mammoplasty: long term effects of preincisional administration of methylprednisolone. Pain 2006;124:92–9.PubMedCrossrefGoogle Scholar

  • [7]

    Eisenach JC. Preventing chronic pain after surgery: who, how, and when. Reg Anesth Pain Med 2006;31:1–3.PubMedGoogle Scholar

  • [8]

    Dahl JB, Erichsen CJ, Fuglsang-Frederiksen A, Kehlet H. Pain sensation and nociceptive reflex excitability in surgical patients and huma volunteers. Br J Anaesth 1992;69:117–21.CrossrefGoogle Scholar

  • [9]

    Gottschalk A, Cohen SP, Yang S, Ochroch EA. Preventing and treating pain after thoracic surgery. Anesthesiology 2006;104:594–600.CrossrefPubMedGoogle Scholar

  • [10]

    Brennan TJ, Kehlet H. Preventive analgesia to reduce wound hyperalgesia and persistent post surgical pain:notaneasy path. Anesthesiology2005;103:681–3.CrossrefGoogle Scholar

  • [11]

    Dualé C, Sibaud F, Guastella V, Vallet L, Gimbert YA, Taheri H, Filaire M, Schoef- fler P, Dubray C. Perioperative ketamine does not prevent chronic pain after thoracotomy. EurJ Pain 2009;13:497–505.Web of SciencePubMedCrossrefGoogle Scholar

  • [12]

    Dullenkopf A, Muller R, Dillmann F, Wiedemeier P, Hegi TR, Gautsch S. An intraoperative pre-incision single dose of intravenous ketamine does not have an effect on postoperative analgesic requirements under clinical conditions. Anaesth Intensive Care 2009;37:753–7.PubMedGoogle Scholar

  • [13]

    Burton AW, Lee DH, Saab C, Chung JM. Preemptive intrathecal ketamine injection produces a long-lasting decrease in neuropathic pain behaviors in a rat model. Reg Anesth Pain Med 1999;24:208–13.Google Scholar

  • [14]

    Laskowski K, Stirling A, McKayWP, Lim HJ.A systematic review of intravenous ketamine forpostoperative analgesia. Can J Anaesth2011; 58: 911–23.CrossrefPubMedGoogle Scholar

  • [15]

    Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev 2006,http://dx.doi.org/10.1002/14651858.CD004603.pub2. Issue 1. Art. No.: CD004603.Web of SciencePubMed

  • [16]

    Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss A. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997;41:1124–32.CrossrefPubMedGoogle Scholar

  • [17]

    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary. Control Clin Trials 1996;17:1–12.PubMedCrossrefGoogle Scholar

  • [18]

    Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009: 339.Web of ScienceGoogle Scholar

  • [19]

    De Kock M, Lavand’homme P, Waterloos H. ‘Balanced analgesia’ in the perioperative period: is there a place for ketamine. Pain 2001;92:373–80.CrossrefGoogle Scholar

  • [20]

    Kwok RF, Lim J, Chan MT, Gin T, Chiu WK. Preoperative ketamine improves postoperative analgesia after gynecologic laparoscopic surgery. Anesth Analg 2004;98:1044–9 (table of contents).PubMedGoogle Scholar

  • [21]

    Sen H, Sizlan A, Yanarates O, Emirkadi H, Ozkan S, Dagli G, Turan A. A comparison of gabapentin and ketamine in acute and chronic pain after hysterectomy. Anesth Analg 2009;109:1645–50.CrossrefWeb of SciencePubMedGoogle Scholar

  • [22]

    Bilgen S, Köner O, Türe H, Menda F, Fiçicioğlu C, Aykaç B. Effect of three different doses of ketamine prior to general anaesthesia on postoperative pain following Caesarean delivery: a prospective randomized study. Minerva Anestesiol 2012;78:442–9.PubMedGoogle Scholar

  • [23]

    Sveticic G, Farzanegan F, Zmoos P, Zmoos S, Eichenberger U, Curatolo M. Is the combination of morphine with ketamine better than morphine alone for postoperative intravenous patient-controlled analgesia. Anesth Analg 2008;106:287–93.Web of SciencePubMedCrossrefGoogle Scholar

  • [24]

    Crousier M, Cognet V, Khaled M, Gueugniaud PY, Piriou V. Effect of ketamine on prevention of postmastectomy chronic pain. A pilot study. Ann Fr Anesth Reanim 2008;27:987–93.PubMedWeb of ScienceGoogle Scholar

  • [25]

    Joseph C, Gaillat F, Duponq R, Lieven R, Baumstarck K, Thomas P, Penot-Ragon C, Kerbaul F. Is there any benefit to adding intravenous ketamine to patient- controlled epidural analgesia after thoracic surgery? A randomized doubleblind study. Eur J Cardiothorac Surg 2012;42:58–65.CrossrefGoogle Scholar

  • [26]

    Mendola C, Cammarota G, Netto R, Cecci G, Pisterna A, Ferrante D, Casadio C, Corte FD. S (+)-ketamine for control of perioperative pain and prevention of post thoracotomy pain syndrome: a randomized, double-blind study. Minerva Anestesiol 2012;78:757–66.PubMedGoogle Scholar

  • [27]

    Spreng UJ, Dahl V, Raeder J. Effects of perioperative S (+) ketamine infusion added to multimodal analgesia in patients undergoing ambulatory haemor- rhoidectomy. Scand J Pain 2010;1:100–5.CrossrefPubMedGoogle Scholar

  • [28]

    Suzuki M, Haraguti S, Sugimoto K, Kikutani T, Shimada Y, Sakamoto A. Low- dose intravenous ketamine potentiates epidural analgesia after thoracotomy. Anesthesiology 2006; 105: 111–9.PubMedCrossrefGoogle Scholar

  • [29]

    Remérand F, Le Tendre C, Baud A, Couvret C, Pourrat X, Favard L, Laffon M, Fusciardi J. The early and delayed analgesic effects of ketamine after total hip arthroplasty: a prospective, randomized, controlled, double-blind study. Anaesth Intensive Care 2009;109:1963–71.Google Scholar

  • [30]

    Hayes C, Armstrong-Brown A, Burstal R. Perioperative intravenous ketamine infusion for the prevention of persistent post-amputation pain: a randomized, controlled trial. Anaesth Intensive Care 2004;32:330–8.Google Scholar

  • [31]

    Lavand’homme P, De Kock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing majordigestive surgery. Anesthesiology 2005;103:813–20.CrossrefPubMedGoogle Scholar

  • [32]

    Tiippana E, Nelskylä K, Nilsson E, Sihvo E, Kataja M, Kalso E. Managing post-thoracotomy pain: epidural or systemic analgesia and extended care – a randomized study with an as usual control group. Scand J Pain 2014;5: 240–7.CrossrefPubMedGoogle Scholar

  • [33]

    Breivik H. Persistent post-surgical pain (PPP) reduced by high-quality management of acute pain extended to sub-acute pain at home. Scand J Pain 2014;5:237–9.CrossrefPubMedGoogle Scholar

  • [34]

    Andreae MH, Andreae DA. Local anaesthetics and regional anaesthesia for preventing chronic pain after surgery. Cochrane Database Syst Rev 2012:10.Web of ScienceGoogle Scholar

  • [35]

    Moore RA, Gavaghan D, Tramer MR, Collins SL, McQuay HJ. Size is everything - large amounts of information are needed to overcome random effects in estimating direction and magnitude of treatment effects. Pain 1998;78: 209–16.CrossrefPubMedGoogle Scholar

  • [36]

    Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 2001;135:982–9.CrossrefPubMedGoogle Scholar

  • [37]

    Nuesch E, Trelle S, Reichenbach S, Rutjes AW, Tschannen B, Altman DG, Egger M, Juni P. Small study effects in meta-analyses of osteoarthritis trials: meta- epidemiological study. BMJ 2010:341.Google Scholar

  • [38]

    Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis. Anesth Analg 2012;115:428–42.Web of ScienceCrossrefPubMedGoogle Scholar

  • [39]

    Solak O, Metin M, Esme H, Yaman M, Pekcolaklar A, Gurses A, Kavuncu V. Effectiveness of gabapentin in the treatment of chronic post-thoracotomy pain. Eur J Cardiothorac Surg 2007;32:9–12.CrossrefPubMedGoogle Scholar

  • [40]

    Weber T, Mätzl J, Rokitansky A, Klimscha W, Neumann K, Deusch E. Superior postoperative pain relief with thoracic epidural analgesia versus intravenous patient-controlled analgesi a afterminimally invasive pectus excavatum repair. J Thorac Cardiovasc Surg 2007;134:865–70.CrossrefGoogle Scholar

About the article

Tel.: +41 61 328 6496; fax: +41 61 265 7320

Received: 2014-09-21

Revised: 2014-12-19

Accepted: 2014-12-22

Published Online: 2015-04-01

Published in Print: 2015-04-01

Summary statement A systematic review with a comprehensive meta-analysis demonstrated that intra- and postoperatively administered ketamine is not effective to prevent chronic postoperative pain.

Funding Support was provided solely from departmental sources.

Conflict of interest There are no conflicts of interest to declare.

Citation Information: Scandinavian Journal of Pain, Volume 7, Issue 1, Pages 42–54, ISSN (Online) 1877-8879, ISSN (Print) 1877-8860, DOI: https://doi.org/10.1016/j.sjpain.2014.12.005.

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