Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia

Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia Using Filaments, an Algometer, and Interleukins: a Double-blind, Randomized Study

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.

Remifentanil, Hyperalgesia, Ketamine, Von Frey's filament, Algometer, Interleukines, Opioid-induced hyperalgesia

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.

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.

The scale measure pain after 30 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 60 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 90 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 120 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 150 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 180 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 210 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 240 minutes (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 6 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 12 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 18 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

The scale measure pain after 24 hours (0 - without pain and 10 worst pain possible). The individual can choose any number between 0 - 10.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

The evaluations using the soft brush were performed in the thenar eminence of the nondominant hand before the procedure

The evaluations using the soft brush were performed in the thenar eminence of the non dominant hand 24 h after 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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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