Journal of Anesthesia

, Volume 25, Issue 4, pp 516–522

The effect of target-controlled infusion of low-dose ketamine on heat pain and temporal summation threshold

  • Joon-Ho Lee
  • Sung-Hwan Cho
  • Sang-Hyun Kim
  • Won-Soek Chae
  • Hee-Cheol Jin
  • Jeong-Seok Lee
  • Yong-Ik Kim
Original Article



We investigated the heat pain threshold (HPT) and temporal summation threshold (TST) before and after target-controlled infusion (TCI) of ketamine with an effect-site concentration (Ce) of 30 and 60 ng/ml.


Healthy young volunteers (n = 20) were enrolled. A thermode was applied to the volar side of each volunteer’s right forearm, and HPT and TST were measured before and after TCI of ketamine. Vital signs and psychedelic effects according to ketamine infusion were also observed before and after TCI of ketamine.


Mean HPT after TCI of ketamine with a Ce of 30 and 60 ng/ml did not increase significantly. However, mean TST after TCI of ketamine with a Ce of 30 and 60 ng/ml increased significantly, in a dose-dependent fashion, compared with the value before ketamine TCI. Vital signs showed no significant difference before and after ketamine TCI. The visual analog scale score of psychedelic symptoms was higher with a Ce of 60 ng/ml than with 30 ng/ml.


TCI of ketamine with a Ce of 30 and 60 ng/ml increased TST but not HPT.


Heat pain threshold Low-dose ketamine Quantitative sensory testing Temporal summation 


  1. 1.
    Meller ST. Ketamine: relief from chronic pain through actions at the NMDA receptor? Pain. 1996;68:435–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Kohrs R, Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg. 1998;87:1186–93.PubMedGoogle Scholar
  3. 3.
    Pekoe GM, Smith DJ. The involvement of opiate and monoaminergic neuronal systems in the analgesic effects of ketamine. Pain. 1982;12:57–73.PubMedCrossRefGoogle Scholar
  4. 4.
    Hustveit O, Maurset A, Oye I. Interaction of the chiral forms of ketamine with opioid, phencyclidine, sigma and muscarinic receptors. Pharmacol Toxicol. 1995;77:355–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Eide PK, Stubhaug A, Breivik H, Oye I. Ketamine: relief from chronic pain through actions at the NMDA receptor? Reply. Pain. 1997;72:289–91.PubMedCrossRefGoogle Scholar
  6. 6.
    Arendt-Nielsen L, Petersen-Felix S, Fischer M, Bak P, Bjerring P, Zbinden AM. The effect of N-methyl-d-aspartate antagonist (ketamine) on single and repeated nociceptive stimuli: a placebo-controlled experimental human study. Anesth Analg. 1995;81:63–8.PubMedGoogle Scholar
  7. 7.
    Eide PK. Wind-up and the NMDA receptor complex from a clinical perspective. Eur J Pain. 2000;4:5–15.PubMedCrossRefGoogle Scholar
  8. 8.
    Ren K. Wind-up and the NMDA receptor: from animal studies to humans. Pain. 1994;59:157–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Gracely R. Studies of pain in human subjects. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack’s textbook of pain. 5th edn. Edinburgh: Churchill Livingstone; 2006. p. 267–84.Google Scholar
  10. 10.
    Granot M, Granovsky Y, Sprecher E, Nir RR, Yarnitsky D. Contact heat-evoked temporal summation: tonic versus repetitive-phasic stimulation. Pain. 2006;122:295–305.PubMedCrossRefGoogle Scholar
  11. 11.
    Staud R, Price DD, Fillingim RB. Advanced continuous-contact heat pulse design for efficient temporal summation of second pain (windup). J Pain. 2006;7:575–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Ilkjaer S, Petersen KL, Brennum J, Wernberg M, Dahl JB. Effect of systemic N-methyl-d-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans. Br J Anaesth. 1996;76:829–34.PubMedGoogle Scholar
  13. 13.
    Guirimand F, Dupont X, Brasseur L, Chauvin M, Bouhassira D. The effects of ketamine on the temporal summation (wind-up) of the R(III) nociceptive flexion reflex and pain in humans. Anesth Analg. 2000;90:408–14.PubMedGoogle Scholar
  14. 14.
    Arendt-Nielsen L, Nielsen J, Petersen-Felix S, Schnider TW, Zbinden AM. Effect of racemic mixture and the (S+)-isomer of ketamine on temporal and spatial summation of pain. Br J Anaesth. 1996;77:625–31.PubMedGoogle Scholar
  15. 15.
    Granovsky Y, Granot M, Nir RR, Yarnitsky D. Objective correlate of subjective pain perception by contact heat-evoked potentials. J Pain. 2008;9:53–63.PubMedCrossRefGoogle Scholar
  16. 16.
    Arendt-Nielsen L, Chen AC. Lasers and other thermal stimulators for activation of skin nociceptors in humans. Neurophysiol Clin. 2003;33:259–68.PubMedCrossRefGoogle Scholar
  17. 17.
    Willer JC. Comparative study of perceived pain and nociceptive flexion reflex in man. Pain. 1977;3:69–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Lautenbacher S, Kunz M, Strate P, Nielsen J, Arendt-Nielsen L. Age effects on pain thresholds, temporal summation and spatial summation of heat and pressure pain. Pain. 2005;115:410–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Slugg RM, Meyer RA, Campbell JN. Response of cutaneous A- and C-fiber nociceptors in the monkey to controlled-force stimuli. J Neurophysiol. 2000;83:2179–91.PubMedGoogle Scholar
  20. 20.
    Domino EF, Domino SE, Smith RE, Domino LE, Goulet JR, Domino KE, Zsigmond EK. Ketamine kinetics in unmedicated and diazepam-premedicated subjects. Clin Pharmacol Ther. 1984;36:645–53.PubMedCrossRefGoogle Scholar
  21. 21.
    Bowdle TA, Radant AD, Cowley DS, Kharasch ED, Strassman RJ, Roy-Byrne PP. Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology. 1998;88:82–8.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Price DD, Hu JW, Dubner R, Gracely RH. Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses. Pain. 1977;3:57–68.PubMedCrossRefGoogle Scholar
  24. 24.
    Woolf CJ, Thompson SW. 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.PubMedCrossRefGoogle Scholar
  25. 25.
    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.PubMedCrossRefGoogle Scholar
  26. 26.
    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;82:111–25.PubMedCrossRefGoogle Scholar
  27. 27.
    Graven-Nielsen T, Aspegren Kendall S, Henriksson KG, Bengtsson M, Sorensen J, Johnson A, Gerdle B, Arendt-Nielsen L. Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain. 2000;85:483–91.PubMedCrossRefGoogle Scholar
  28. 28.
    Correll GE, Maleki J, Gracely EJ, Muir JJ, Harbut RE. Subanesthetic ketamine infusion therapy: a retrospective analysis of a novel therapeutic approach to complex regional pain syndrome. Pain Med. 2004;5:263–75.PubMedCrossRefGoogle Scholar
  29. 29.
    Goldberg ME, Domsky R, Scaringe D, Hirsh R, Dotson J, Sharaf I, Torjman MC, Schwartzman RJ. Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician. 2005;8:175–9.PubMedGoogle Scholar
  30. 30.
    Webster LR, Walker MJ. Safety and efficacy of prolonged outpatient ketamine infusions for neuropathic pain. Am J Ther. 2006;13:300–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Gilron I, Quirion R, Coderre TJ. Pre- versus postformalin effects of ketamine or large-dose alfentanil in the rat: discordance between pain behavior and spinal Fos-like immunoreactivity. Anesth Analg. 1999;89:128–35.PubMedGoogle Scholar
  32. 32.
    Maurset A, Skoglund LA, Hustveit O, Oye I. Comparison of ketamine and pethidine in experimental and postoperative pain. Pain. 1989;36:37–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Parsons CG, Gibbens H, Magnago TS, Headley PM. At which ‘sigma’ site are the spinal actions of ketamine mediated? Neurosci Lett. 1988;85:322–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Tucker AP, Kim YI, Nadeson R, Goodchild CS. Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: a double-blinded, randomised, placebo controlled, crossover study of experimental pain. BMC Anesthesiol. 2005;5:2–13.PubMedCrossRefGoogle Scholar
  35. 35.
    Cvrcek P. Side effects of ketamine in the long-term treatment of neuropathic pain. Pain Med. 2008;9:253–7.PubMedCrossRefGoogle Scholar
  36. 36.
    McAllister RM, Urban LA, Dray A, Smith PJ. Comparison of the sensory threshold in healthy human volunteers with the sensory nerve response of the rat in vitro hindlimb skin and saphenous nerve preparation on cutaneous electrical stimulation. J Hand Surg Br. 1995;20:437–43.PubMedCrossRefGoogle Scholar
  37. 37.
    Mauderli AP, Vierck CJ Jr, Cannon RL, Rodrigues A, Shen C. Relationships between skin temperature and temporal summation of heat and cold pain. J Neurophysiol. 2003;90:100–9.PubMedCrossRefGoogle Scholar

Copyright information

© Japanese Society of Anesthesiologists 2011

Authors and Affiliations

  • Joon-Ho Lee
    • 1
  • Sung-Hwan Cho
    • 1
  • Sang-Hyun Kim
    • 1
  • Won-Soek Chae
    • 1
  • Hee-Cheol Jin
    • 1
  • Jeong-Seok Lee
    • 1
  • Yong-Ik Kim
    • 1
  1. 1.Department of Anesthesiology and Pain MedicineUniversity of Soonchunhyang, Bucheon HospitalBucheon-SiKorea

Personalised recommendations