Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia
Information source: Federal University of São Paulo
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pain; Hyperalgesia; Inflammatory Response
Intervention: Ketamine (Drug); Saline (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: Federal University of São Paulo Official(s) and/or principal investigator(s): PlÃnio da Cunha Leal, PhD, Principal Investigator, Affiliation: Federal University of São Paulo
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).
Clinical Details
Official title: Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia Using Filaments, an Algometer, and Interleukins: a Double-blind, Randomized Study
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
Primary outcome: Pain 30 MinutesPain 60 Minutes Pain 90 Minutes Pain 120 Minutes Pain 150 Minutes Pain 180 Minutes Pain 210 Minutes Pain 240 Minutes Pain 6 Hours Pain 12 Hours Pain 18 Hours Pain 24 Hours
Secondary outcome: Time to First Morphine SupplementationMorphine Consumption Within 24 h Hyperalgesia in the Preoperative Period as Measured With Monofilaments in Thenar Eminence Hyperalgesia in the Postoperative Period as Measured With Monofilaments in Thenar Eminence Hyperalgesia in the Preoperative Period as Measured With Monofilaments in the Periumbilical Region Hyperalgesia in the Postoperative Period as Measured With Monofilaments in the Periumbilical Region Hyperalgesia in the Preoperative Period as Measured With Algometer in Thenar Eminence Hyperalgesia in the Postoperative Period as Measured With Algometer in Thenar Eminence Hyperalgesia in the Preoperative Period as Measured With Algometer in the Periumbilical Region Hyperalgesia in the Postoperative Period as Measured With Algometer in the Periumbilical Region Extension of Hyperalgesia Allodynia as Detected With a Soft Brush in the Periumbilical Region Before the Procedure Allodynia as Detected With a Soft Brush in the Periumbilical Region 24 h After the Procedure Allodynia as Detected With a Soft Brush in the Thenar Eminence Before the Procedure Allodynia as Detected With a Soft Brush in the Thenar Eminence 24 h After the Procedure Serum Level of Interleukin (IL)-6 Before the Procedure Serum Level of Interleukin (IL)-6 5 h After the Procedure Serum Level of Interleukin (IL)-6 24 h After the Procedure Serum Level of Interleukin (IL)-8 Before the Procedure Serum Level of Interleukin (IL)-8 5 h After the Procedure Serum Level of Interleukin (IL)-8 24 h After the Procedure Serum Level of Interleukin (IL)-10 Before the Procedure Serum Level of Interleukin (IL)-10 5h After the Procedure Serum Level of Interleukin (IL)-10 24 h After the Procedure
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.
Eligibility
Minimum age: 18 Years.
Maximum age: 78 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- ≥ 18 years old
- both sexes
- ASA physical status I or II
- undergoing laparoscopic cholecystectomy
Exclusion Criteria:
- chronic users of analgesics or had used opioids within 12 h of surgery
- history of drug or alcohol abuse or psychiatric disorder
- contraindications to self-administration of opioids (ie, unable to understand the
patient-controlled analgesia [PCA] device)
- contraindication for the use of ketamine, such as a psychiatric disorder, acute
cardiovascular disorder, or unstable hypertension
Locations and Contacts
Federal University of São Paulo, São Paulo, Brazil
Additional Information
Related publications: Liang D, Shi X, Qiao Y, Angst MS, Yeomans DC, Clark JD. Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision. Mol Pain. 2008 Feb 22;4:7. doi: 10.1186/1744-8069-4-7. Zhang RX, Li A, Liu B, Wang L, Ren K, Zhang H, Berman BM, Lao L. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain. 2008 Apr;135(3):232-9. Epub 2007 Aug 6. Dale O, Somogyi AA, Li Y, Sullivan T, Shavit Y. Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesth Analg. 2012 Oct;115(4):934-43. Epub 2012 Jul 23. Review.
Starting date: September 2010
Last updated: November 6, 2014
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