Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia
Condition: Pain; Hyperalgesia; Inflammatory Response
MeSH terms: Hyperalgesia
Study type: Interventional
Phase: Phase 3

Summary: 
      The aim of this study was to determine if the addition of ketamine reduces
      remifentanil-induced hyperalgesia, improves its analgesic effect, inhibits IL(interleukin)-6
      and IL-8 (inflammatory cytokines), and stimulates IL-10 (an anti-inflammatory cytokine).
    

Detailed description: 
      Opioids are very effective in pain relief, but they might lower pain threshold, making the
      patient more sensitive to a pain stimulus, a condition known as hyperalgesia [Angst; Clarck,
      2006]. Opioid-induced hyperalgesia (OIH) is usually defined as a reduction in nociceptive
      thresholds in the peripheral field of the sensitized fibers [Koppert et al., 2003], and it is
      associated with increased pain and higher demand for postoperative analgesia [Guignard et
      al., 2000]. This phenomenon adversely impacts pain control, and has been suggested to occur
      in the peri-operative context, especially associated with the use of remifentanil, a
      short-acting opioid [Guignard et al., 2000].

      Several mechanisms have been proposed to explain the hyperalgesia phenomenon, but the most
      important seems to be the activation of N-methyl-D-aspartate (NMDA) receptors [Célèrier et
      al., 2000]. Ketamine is a NMDA receptor antagonist that has been shown to reduce
      postoperative pain and the need for postoperative anesthetics and analgesics. Therefore, it
      is proposed that ketamine could prevent hyperalgesia, resulting in more effective and
      long-lasting postsurgical analgesia [Célèrier et al. 2000].

      The results of studies of low dose of ketamine in the prevention of remifentanil-induced
      hyperalgesia are controversial. Joly et al. [2005] demonstrated a reduction in the
      consumption of opioids and in hyperalgesia assessed with monofilaments. However, Engelhardt
      et al [2008] showed no differences in pain scores or in postoperative opioid consumption.

      In addition, some authors observed higher levels of proinflammatory cytokines, associated
      with increased pain in mice receiving chronic opioid (morphine) infusion [Johnston et al.,
      2004; Liang et al., 2008]. Also, administration of proinflammatory cytokine inhibitors
      reduced phosphorylation of NMDA receptors [Zhang et al., 2008]. However, no study has
      examined the relationship between the use of remifentanil, the most frequently implicated
      opioid in OIH [Guignard et al., 2000], ketamine (drug capable of inhibiting NMDA-receptors
      and cytokines) [Dale et al., 2012], and the inflammatory response.

      The aim of this study was to determine if the addition of ketamine reduces
      remifentanil-induced hyperalgesia, improves its analgesic effect, inhibits IL-6 and IL-8
      (inflammatory cytokines), and stimulates IL-10 (an anti-inflammatory cytokine) in patients
      submitted to laparoscopic cholecystectomy, a procedure with an usually neglected potential
      for postoperative pain and that has been poorly investigated in association with OIH.
    

Intervention name(s): Ketamine; Saline
Intervention type(s): Drug; Drug
Intervention description(s): Patients in group ketamine was administrated ketamine (5mcg/kg/min) during the surgery.; Patients in group N (placebo) was administrated saline during surgery.
Intervention MeSH terms: Ketamine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Remifentanil; Hyperalgesia; Ketamine; Von Frey's filament; Algometer; Interleukines; Opioid-induced hyperalgesia