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Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia

Information source: Federal University of So 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 So Paulo

Official(s) and/or principal investigator(s):
Plínio 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 Minutes

Pain 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 Supplementation

Morphine 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

Page last updated: August 23, 2015

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