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Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia

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ClinicalTrials.gov Identifier: NCT01301079
Recruitment Status : Completed
First Posted : February 23, 2011
Results First Posted : November 10, 2014
Last Update Posted : November 10, 2014
Sponsor:
Collaborator:
Fundação de Amparo à Pesquisa do Estado de São Paulo
Information provided by (Responsible Party):
Plínio da Cunha Leal, Federal University of São Paulo

Tracking Information
First Submitted Date  ICMJE February 22, 2011
First Posted Date  ICMJE February 23, 2011
Results First Submitted Date  ICMJE November 10, 2013
Results First Posted Date  ICMJE November 10, 2014
Last Update Posted Date November 10, 2014
Study Start Date  ICMJE September 2010
Actual Primary Completion Date September 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 6, 2014)
  • Pain 30 Minutes [ Time Frame: 30 minutes ]
    The scale measure pain after 30 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 60 Minutes [ Time Frame: 60 minutes ]
    The scale measure pain after 60 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 90 Minutes [ Time Frame: 90 minutes ]
    The scale measure pain after 90 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 120 Minutes [ Time Frame: 120 minutes ]
    The scale measure pain after 120 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 150 Minutes [ Time Frame: 150 minutes ]
    The scale measure pain after 150 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 180 Minutes [ Time Frame: 180 minutes ]
    The scale measure pain after 180 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 210 Minutes [ Time Frame: 210 minutes ]
    The scale measure pain after 210 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 240 Minutes [ Time Frame: 240 minutes ]
    The scale measure pain after 240 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 6 Hours [ Time Frame: 6 hours ]
    The scale measure pain after 6 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 12 Hours [ Time Frame: 12 hours ]
    The scale measure pain after 12 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 18 Hours [ Time Frame: 18 hours ]
    The scale measure pain after 18 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
  • Pain 24 Hours [ Time Frame: 24 hours ]
    The scale measure pain after 24 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.
Original Primary Outcome Measures  ICMJE
 (submitted: February 22, 2011)
  • Pain [ Time Frame: 24 hours ]
    Pain will be evaluated on postoperative through morphine consumption by patient controlled analgesia, by the pain threshold using monofilaments and pressure algometer around cicatrix surgery.
  • Inflammatory response [ Time Frame: 24 hours ]
    Inflammatory response will be observed through the measurement of interleukin - 6 and CRP in the postoperative.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 6, 2014)
  • Time to First Morphine Supplementation [ Time Frame: 24 hours ]
  • Morphine Consumption Within 24 h [ Time Frame: 24 hours ]
  • Hyperalgesia in the Preoperative Period as Measured With Monofilaments in Thenar Eminence [ Time Frame: Before the procedure (Baseline) ]
    The pain threshold was assessed using six von Frey monofilaments (0,05 g; 0,2 g; 2 g; 4 g; 10 g e 300 g) in thenar eminence in the preoperative period. The use of different von Frey monofilaments, starting with the lightest and ending with the heaviest, was separated by at least 30 seconds to reduce any anticipated responses due to a new stimulation that was performed too soon after the preceding stimulation. Three assessments were made for each monofilament, and this was considered positive when the patient responded to two of the determinations for each monofilament.
  • Hyperalgesia in the Postoperative Period as Measured With Monofilaments in Thenar Eminence [ Time Frame: 24 hours after procedure ]
    The pain threshold was assessed using six von Frey monofilaments (0,05 g; 0,2 g; 2 g; 4 g; 10 g e 300 g) in thenar eminence in the postoperative period (24 hours after procedure). The use of different von Frey monofilaments, starting with the lightest and ending with the heaviest, was separated by at least 30 seconds to reduce any anticipated responses due to a new stimulation that was performed too soon after the preceding stimulation. Three assessments were made for each monofilament, and this was considered positive when the patient responded to two of the determinations for each monofilament.
  • Hyperalgesia in the Preoperative Period as Measured With Monofilaments in the Periumbilical Region [ Time Frame: Before the procedure (Baseline) ]
    The pain threshold was assessed using six von Frey monofilaments (0,05 g; 0,2 g; 2 g; 4 g; 10 g e 300 g) in the periumbilical region in the preoperative period. The use of different von Frey monofilaments, starting with the lightest and ending with the heaviest, was separated by at least 30 seconds to reduce any anticipated responses due to a new stimulation that was performed too soon after the preceding stimulation. Three assessments were made for each monofilament, and this was considered positive when the patient responded to two of the determinations for each monofilament.
  • Hyperalgesia in the Postoperative Period as Measured With Monofilaments in the Periumbilical Region [ Time Frame: 24h after the procedure ]
    The pain threshold was assessed using six von Frey monofilaments (0,05 g; 0,2 g; 2 g; 4 g; 10 g e 300 g) in the periumbilical region in the postoperative period (24h after the procedure). The use of different von Frey monofilaments, starting with the lightest and ending with the heaviest, was separated by at least 30 seconds to reduce any anticipated responses due to a new stimulation that was performed too soon after the preceding stimulation. Three assessments were made for each monofilament, and this was considered positive when the patient responded to two of the determinations for each monofilament.
  • Hyperalgesia in the Preoperative Period as Measured With Algometer in Thenar Eminence [ Time Frame: Baseline (before the procedure) ]
    The mechanical pain threshold was evaluated using an algometer. The pressure was increased by 0.1 kgf/second until the patient complained of pain. The mean of three determinations was calculated.
  • Hyperalgesia in the Postoperative Period as Measured With Algometer in Thenar Eminence [ Time Frame: 24 h after the procedure ]
    The mechanical pain threshold was evaluated using an algometer. The pressure was increased by 0.1 kgf/second until the patient complained of pain. The mean of three determinations was calculated.
  • Hyperalgesia in the Preoperative Period as Measured With Algometer in the Periumbilical Region [ Time Frame: Baseline (before the surgery) ]
    The mechanical pain threshold was evaluated using an algometer. The pressure was increased by 0.1 kgf/second until the patient complained of pain. The mean of three determinations was calculated.
  • Hyperalgesia in the Postoperative Period as Measured With Algometer in the Periumbilical Region [ Time Frame: 24 h after the procedure ]
    The mechanical pain threshold was evaluated using an algometer. The pressure was increased by 0.1 kgf/second until the patient complained of pain. The mean of three determinations was calculated.
  • Extension of Hyperalgesia [ Time Frame: 24 hours after the procedure ]
    The 300-g filament was used 24 hours after the operation to induce a stimulus and delineate the extent of hyperalgesia from the periumbilical region. The stimulus was started outside the periumbilical region, where no pain sensation was reported, and continued every 0.5 cm until the 4 points of the periumbilical scar were reached (top, right side, left side, and bottom). The first point where the patient complained of pain was marked. If no pain sensation was reported, the stimulus was terminated 0.5 cm from the incision. The distance of each point from the surgical incision was measured, and the sum of the distances of the points was determined.
  • Allodynia as Detected With a Soft Brush in the Periumbilical Region Before the Procedure [ Time Frame: Before the procedure (Baseline) ]
    The evaluations using the soft brush were performed 2-3 cm from the incision in the periumbilical region (where the large trocar was placed) before the procedure
  • Allodynia as Detected With a Soft Brush in the Periumbilical Region 24 h After the Procedure [ Time Frame: 24 h after the procedure ]
    The evaluations using the soft brush were performed 2-3 cm from the incision in the periumbilical region (where the large trocar was placed) 24 h after the procedure
  • Allodynia as Detected With a Soft Brush in the Thenar Eminence Before the Procedure [ Time Frame: Before the procedure (Baseline) ]
    The evaluations using the soft brush were performed in the thenar eminence of the nondominant hand before the procedure
  • Allodynia as Detected With a Soft Brush in the Thenar Eminence 24 h After the Procedure [ Time Frame: 24 h after the procedure ]
    The evaluations using the soft brush were performed in the thenar eminence of the non dominant hand 24 h after the procedure
  • Serum Level of Interleukin (IL)-6 Before the Procedure [ Time Frame: Baseline (Before the procedure) ]
    Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes before the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-6 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
  • Serum Level of Interleukin (IL)-6 5 h After the Procedure [ Time Frame: 5 h after the procedure ]
    Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 5 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-6 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
  • Serum Level of Interleukin (IL)-6 24 h After the Procedure [ Time Frame: 24 h after the procedure ]
    Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 24 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-6 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
  • Serum Level of Interleukin (IL)-8 Before the Procedure [ Time Frame: Baseline (Before the procedure) ]
    Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes before the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-8 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
  • Serum Level of Interleukin (IL)-8 5 h After the Procedure [ Time Frame: 5 h after the procedure ]
    Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 5 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-8 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
  • Serum Level of Interleukin (IL)-8 24 h After the Procedure [ Time Frame: 24 h after the procedure ]
    Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 24 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-8 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
  • Serum Level of Interleukin (IL)-10 Before the Procedure [ Time Frame: Baseline (Before the procedure) ]
    Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes before the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-6 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
  • Serum Level of Interleukin (IL)-10 5h After the Procedure [ Time Frame: 5h after the procedure ]
    Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 5 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-10 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
  • Serum Level of Interleukin (IL)-10 24 h After the Procedure [ Time Frame: 24 h after the procedure ]
    Blood samples were drawn in ethylenediaminetetraacetic acid (EDTA) tubes 24 h after the surgery. The blood was centrifuged to separate the plasma and was stored at -70°C. IL-6 was analyzed using the enzyme-linked immunosorbent assay (ELISA) methodology.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia
Official Title  ICMJE Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia Using Filaments, an Algometer, and Interleukins: a Double-blind, Randomized Study
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Pain
  • Hyperalgesia
  • Inflammatory Response
Intervention  ICMJE
  • Drug: Ketamine
    Patients in group ketamine was administrated ketamine (5mcg/kg/min) during the surgery.
  • Drug: Saline
    Patients in group N (placebo) was administrated saline during surgery.
Study Arms  ICMJE
  • Active Comparator: Ketamine

    A cardioscope, a capnograph, a pulse oximeter, and a noninvasive blood pressure meter were used to monitor the patients. Propofol (2-4 mg/kg), remifentanil (1 μg/kg), and atracurium (0.5 mg/kg) were administered for intubation. Atracurium was titrated to maintain muscle relaxation. Anesthesia was maintained with remifentanil, 0.8% isoflurane, and 50% oxygen without nitrous oxide. Infusion of the solutions was continued until skin closure.

    The patients in group ketamine received remifentanil (0.4 μg/kg/min) and ketamine (5 μg/kg/min).

    Remifentanil was administered as necessary until skin closure. Neostigmine was used for antagonizing the neuromuscular block.

    Intervention: Drug: Ketamine
  • Placebo Comparator: Saline

    A cardioscope, a capnograph, a pulse oximeter, and a noninvasive blood pressure meter were used to monitor the patients. Propofol (2-4 mg/kg), 1 μg/kg remifentanil, and atracurium (0.5 mg/kg) were administered for intubation. Atracurium was titrated to maintain muscle relaxation. Anesthesia was maintained with remifentanil, 0.8% isoflurane, and 50% oxygen without nitrous oxide. Infusion of the solutions was continued until skin closure.

    The patients in group saline received remifentanil (0.4 μg/kg/min) and saline solution.

    Remifentanil was administered as necessary until skin closure. Neostigmine was used for antagonizing the neuromuscular block.

    Intervention: Drug: Saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 6, 2014)
60
Original Estimated Enrollment  ICMJE
 (submitted: February 22, 2011)
40
Actual Study Completion Date  ICMJE September 2012
Actual Primary Completion Date September 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 78 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01301079
Other Study ID Numbers  ICMJE anaana
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Plínio da Cunha Leal, Federal University of São Paulo
Original Responsible Party Plínio da Cunha Leal, Federal University of São Paulo
Current Study Sponsor  ICMJE Federal University of São Paulo
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Fundação de Amparo à Pesquisa do Estado de São Paulo
Investigators  ICMJE
Principal Investigator: Plínio da Cunha Leal, PhD Federal University of São Paulo
PRS Account Federal University of São Paulo
Verification Date October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP