Skip to main navigation menu Skip to main content Skip to site footer

Original article

Vol. 141 No. 1920 (2011)

The ED50and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil-based anaesthesia in patients undergoing laparoscopic cholecystectomy

  • L Hang
  • D Shao
  • W Sun
Cite this as:
Swiss Med Wkly. 2011;141:w13195


OBJECTIVE: Various research programmes have shown that intraoperative infusion of remifentanil has been associated with postoperative hyperalgesia. Previous studies have demonstrated that low-dose ketamine can inhibit central sensitisation and prevent opioid-induced hyperalgesia (OIH). However, the optimal ketamine dose to prevent OIH has not been determined. In the present study we aimed to determine the ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil-based anaesthesia in patients undergoing laparoscopic cholecystectomy.

METHODS: Fifty-four patients undergoing laparoscopic cholecystectomy were randomised into two groups: group C and group K. Group K was given ketamine before skin incision. An equal volume of normal saline was given to the patients in group C. Pain was assessed using visual analog scale (VAS) at 10 min after tracheal extubation. The ED50and ED95 were determined by modified up-and-down method and the incidences of adverse effects were recorded.

RESULTS: The incidences of adverse effects were similar in the two groups and the VAS score was significantly lower in group K than in group C. The ED50 and ED95of ketamine for prevention of postoperative hyperalgesia were 0.24 mg/kg (95%CI, 0.20~0.30 mg/kg) and 0.33 mg/kg (95%CI, 0.28~0.62 mg/kg) respectively.

CONCLUSIONS: The ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil-based anaesthesia in patients undergoing laparoscopic cholecystectomy were 0.24 mg/kg and 0.33 mg/kg respectively.


  1. Colvin LA, Fallon MT. Opioid-induced hyperalgesia: a clinical challenge. Br J Anaesth. 2010;104(2):125–7.
  2. Minville V, Fourcade O, Girolami JP, Tack I. Opioid-induced hyperalgesia in a mice model of orthopaedic pain: preventive effect of ketamine. Br J Anaesth. 2010;104(2):231–8.
  3. Zissen MH, Zhang G, McKelvy A, Propst JT, Kendig JJ, Sweitzer SM. Tolerance, opioid-induced allodynia and withdrawal associated allodynia in infant and young rats. Neuroscience. 2007;144(1):247–62.
  4. Chu LF, Angst MS, Clark D. Opioid-induced hyperalgesia in humans – Molecular mechanisms and clinical considerations. Clin J Pain. 2008;24(6):479–96.
  5. Silverman SM. Opioid induced hyperalgesia: clinical implications for the pain practitioner. Pain Physician. 2009;12(3):679–84.
  6. De Baerdemaeker LE, Jacobs S, Pattyn P, Mortier EP, Struys MM. Influence of intraoperative opioid on postoperative pain and pulmonary function after laparoscopic gastric banding: remifentanil TCI vs sufentanil TCI in morbid obesity. Br J Anaesth. 2007;99(3):404–11.
  7. Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003;106(1–2):49–57.
  8. Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005;103(1):147–55.
  9. Gu X, Wu X, Liu Y, Cui S, Ma Z. Tyrosine phosphorylation of the N-Methyl-D-Aspartate receptor 2B subunit in spinal cord contributes to remifentanil-induced postoperative hyperalgesia: the preventive effect of ketamine. Mol Pain. 2009;5:76.
  10. Delage N, Maaliki H, Beloeil H, Benhamou D, Mazoit JX. Median effective dose (ED50) of nefopam and ketoprofen in postoperative patients: a study of interaction using sequential analysis and isobolographic analysis. Anesthesiology. 2005;102(6):1211–6.
  11. Launo C, Bassi C, Spagnolo L, Badano S, Ricci C, Lizzi A, et al. Preemptive ketamine during general anesthesia for postoperative analgesia in patients undergoing laparoscopic cholecystectomy. Minerva Anestesiol. 2004;70(10):727–34.
  12. Jung H, Choi SC. Sequential method of estimating the LD50 using a modified up-and-down rule. J Biopharm Stat. 1994;4(1):19–30.
  13. Albertin A, Casati A, Bergonzi P, Fano G, Torri G. Effects of two target-controlled concentrations (1 and 3 ng/ml) of remifentanil on MAC(BAR) of sevoflurane. Anesthesiology. 2004;100(2):255–9.
  14. Butwick AJ, Coleman L, Cohen SE, Riley ET, Carvalho B. Minimum effective bolus dose of oxytocin during elective Caesarean delivery. Br J Anaesth. 2010;104 (3):338–43.
  15. Carvalho B, Durbin M, Drover DR, Cohen SE, Ginosar Y, Riley ET. The ED50 and ED95 of intrathecal isobaric bupivacaine with opioids for cesarean delivery. Anesthesiology. 2005;103(3):606–12.
  16. Gemma M, Tommasino C, Cozzi S, Narcisi S, Mortini P, Losa M et al. Remifentanil provides hemodynamic stability and faster awakening time in transsphenoidal surgery. Anesth Analg. 2002;94(1):163–8.
  17. Koppert W, Schmelz M. The impact of opioid-induced hyperalgesia for postoperative pain. Best Pract Res Clin Anaesthesiol. 2007;21(1):65–83.
  18. Bannister K, Dickenson AH. Opioid hyperalgesia. Curr Opin Support Palliat Care. 2010;4(1):1–5.
  19. Chen Y, Yang C, Wang ZJ. Ca2+/calmodulin-dependent protein kinase II alpha is required for the initiation and maintenance of opioid-induced hyperalgesia. J Neurosci. 2010;30(1):38–46.
  20. Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999;82(2):111–25.
  21. Zakine J, Samarcq D, Lorne E, Moubarak M, Montravers P, Beloucif S, et al. Postoperative ketamine administration decreases morphine consumption in major abdominal surgery: a prospective, randomized, double-blind, controlled study. Anesth Analg. 2008;106(6):1856–61.
  22. Engelhardt T, Zaarour C, Naser B, Pehora C, de Ruiter J, Howard A, et al. Intraoperative low-dose ketamine does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery. Anesth Analg. 2008;107(4):1170–5.
  23. Luginbuhl M, Gerber A, Schnider TW, Petersen-Felix S, Arendt-Nielsen L, Curatolo M. Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg. 2003;96(3):726–32.