Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia

Pain Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01301079
• Other study ID #: anaana
• Status: Completed
• Phase: Phase 3
• First received: February 22, 2011
• Last updated: November 6, 2014
• Start date: September 2010
• Est. completion date: September 2012

Study information

• Verified date: October 2014
• Source: Federal University of São Paulo
• Contact: n/a
• Is FDA regulated: No
• Health authority: Brazil: National Committee of Ethics in Research
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: September 2012
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 78 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Hyperalgesia
• Inflammatory Response
• Pain

Intervention

Drug:
• Ketamine
Patients in group ketamine was administrated ketamine (5mcg/kg/min) during the surgery.
• Saline
Patients in group N (placebo) was administrated saline during surgery.

Locations

Country	Name	City	State
Brazil	Federal University of São Paulo	São Paulo

Sponsors (2)

Lead Sponsor	Collaborator
Federal University of São Paulo	Fundação de Amparo à Pesquisa do Estado de São Paulo

Country where clinical trial is conducted

Brazil, 

References & Publications (10)

Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006 Mar;104(3):570-87. Review. — View Citation

Célèrier 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. — View Citation

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. — View Citation

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 — View Citation

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. — View Citation

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 facilit — View Citation

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. — View Citation

Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schüttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology. 2003 Jul;99(1):152-9. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Primary	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	No
Secondary	Time to First Morphine Supplementation		24 hours	No
Secondary	Morphine Consumption Within 24 h		24 hours	No
Secondary	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)	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No