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).
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
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
60
Federal University of São Paulo
São Paulo, São Paulo, Brazil
Pain 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.
Time frame: 30 minutes
Pain 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.
Time frame: 60 minutes
Pain 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.
Time frame: 90 minutes
Pain 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.
Time frame: 120 minutes
Pain 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.
Time frame: 150 minutes
Pain 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.
Time frame: 180 minutes
Pain 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.
Time frame: 210 minutes
Pain 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.
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Time frame: 240 minutes
Pain 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.
Time frame: 6 hours
Pain 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.
Time frame: 12 hours
Pain 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.
Time frame: 18 hours
Pain 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.
Time frame: 24 hours
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
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.
Time frame: Before the procedure (Baseline)
Hyperalgesia in the Postoperative Period as Measured With Monofilaments in Thenar Eminence
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.
Time frame: 24 hours after procedure
Hyperalgesia in the Preoperative Period as Measured With Monofilaments in the Periumbilical Region
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.
Time frame: Before the procedure (Baseline)
Hyperalgesia in the Postoperative Period as Measured With Monofilaments in the Periumbilical Region
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.
Time frame: 24h after the procedure
Hyperalgesia in the Preoperative Period as Measured With Algometer in Thenar Eminence
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.
Time frame: Baseline (before the procedure)
Hyperalgesia in the Postoperative Period as Measured With Algometer in Thenar Eminence
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.
Time frame: 24 h after the procedure
Hyperalgesia in the Preoperative Period as Measured With Algometer in the Periumbilical Region
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.
Time frame: Baseline (before the surgery)
Hyperalgesia in the Postoperative Period as Measured With Algometer in the Periumbilical Region
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.
Time frame: 24 h after the procedure
Extension of Hyperalgesia
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.
Time frame: 24 hours after the procedure
Allodynia as Detected With a Soft Brush in the Periumbilical Region Before 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) before the procedure
Time frame: Before the procedure (Baseline)
Allodynia as Detected With a Soft Brush in the Periumbilical Region 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
Time frame: 24 h after the procedure
Allodynia as Detected With a Soft Brush in the Thenar Eminence Before the Procedure
The evaluations using the soft brush were performed in the thenar eminence of the nondominant hand before the procedure
Time frame: Before the procedure (Baseline)
Allodynia as Detected With a Soft Brush in the Thenar Eminence 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
Time frame: 24 h after the procedure
Serum Level of Interleukin (IL)-6 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.
Time frame: Baseline (Before the procedure)
Serum Level of Interleukin (IL)-6 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.
Time frame: 5 h after the procedure
Serum Level of Interleukin (IL)-6 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.
Time frame: 24 h after the procedure
Serum Level of Interleukin (IL)-8 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.
Time frame: Baseline (Before the procedure)
Serum Level of Interleukin (IL)-8 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.
Time frame: 5 h after the procedure
Serum Level of Interleukin (IL)-8 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.
Time frame: 24 h after the procedure
Serum Level of Interleukin (IL)-10 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.
Time frame: Baseline (Before the procedure)
Serum Level of Interleukin (IL)-10 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.
Time frame: 5h after the procedure
Serum Level of Interleukin (IL)-10 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.
Time frame: 24 h after the procedure