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).

Study Overview

• Status: Completed
• Conditions: Pain; Inflammatory Response; Hyperalgesia
• Intervention / Treatment: Drug: Ketamine; Drug: Saline

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: Interventional
• Enrollment (Actual): 60
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil
    • Federal University of São Paulo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Drug: Ketamine; Patients in group ketamine was administrated ketamine (5mcg/kg/min) during the surgery.
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.	Drug: Saline; Patients in group N (placebo) was administrated saline during surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First Morphine Supplementation		24 hours
Morphine Consumption Within 24 h		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.	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.	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.	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.	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.	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.	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.	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.	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.	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	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	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	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	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.	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.	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.	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.	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.	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.	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.	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.	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.	24 h after the procedure

Collaborators and Investigators

• Sponsor: Federal University of São Paulo
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo
• Investigators: Principal Investigator: Plínio da Cunha Leal, PhD, Federal University of São Paulo

Publications and helpful links

General 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):232-239. doi: 10.1016/j.pain.2007.05.023. 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. doi: 10.1213/ANE.0b013e3182662e30. Epub 2012 Jul 23.
• Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006 Mar;104(3):570-87. doi: 10.1097/00000542-200603000-00025.
• Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schuttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology. 2003 Jul;99(1):152-9. doi: 10.1097/00000542-200307000-00025.
• Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000 Aug;93(2):409-17. doi: 10.1097/00000542-200008000-00019.
• Celerier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, Simonnet G. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology. 2000 Feb;92(2):465-72. doi: 10.1097/00000542-200002000-00029.
• Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, Chauvin M. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005 Jul;103(1):147-55. doi: 10.1097/00000542-200507000-00022.
• Engelhardt T, Zaarour C, Naser B, Pehora C, de Ruiter J, Howard A, Crawford MW. Intraoperative low-dose ketamine does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery. Anesth Analg. 2008 Oct;107(4):1170-5. doi: 10.1213/ane.0b013e318183919e.
• Johnston IN, Milligan ED, Wieseler-Frank J, Frank MG, Zapata V, Campisi J, Langer S, Martin D, Green P, Fleshner M, Leinwand L, Maier SF, Watkins LR. A role for proinflammatory cytokines and fractalkine in analgesia, tolerance, and subsequent pain facilitation induced by chronic intrathecal morphine. J Neurosci. 2004 Aug 18;24(33):7353-65. doi: 10.1523/JNEUROSCI.1850-04.2004.

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: February 22, 2011
• First Submitted That Met QC Criteria: February 22, 2011
• First Posted (Estimate): February 23, 2011

Study Record Updates

• Last Update Posted (Estimate): November 10, 2014
• Last Update Submitted That Met QC Criteria: November 6, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Keywords: Remifentanil; Ketamine; Hyperalgesia; Von Frey's filament; Algometer; Interleukines; Opioid-induced hyperalgesia
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Sensation Disorders; Somatosensory Disorders; Hyperalgesia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Ketamine
• Other Study ID Numbers: anaana

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No