Clinical trial NCT01301079: Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia
Official title: Evaluation of the Effect of Ketamine on Remifentanil-induced Hyperalgesia Using Filaments, an Algometer, and Interleukins: a Double-blind, Randomized Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pain
Hyperalgesia
Inflammatory Response
Keywords: Remifentanil
Hyperalgesia
Ketamine
Von Frey's filament
Algometer
Interleukines
Opioid-induced hyperalgesia
Lead sponsor: Federal University of São Paulo
Sponsor class: OTHER
Collaborators: name: Fundação de Amparo à Pesquisa do Estado de São Paulo
First posted: 2011-02-23
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 78
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Pain 30 Minutes
timeFrame: 30 minutes
measure: Pain 60 Minutes
timeFrame: 60 minutes
measure: Pain 90 Minutes
timeFrame: 90 minutes
measure: Pain 120 Minutes
timeFrame: 120 minutes
measure: Pain 150 Minutes
timeFrame: 150 minutes
measure: Pain 180 Minutes
timeFrame: 180 minutes
measure: Pain 210 Minutes
timeFrame: 210 minutes
measure: Pain 240 Minutes
timeFrame: 240 minutes
measure: Pain 6 Hours
timeFrame: 6 hours
measure: Pain 12 Hours
timeFrame: 12 hours
measure: Pain 18 Hours
timeFrame: 18 hours
measure: Pain 24 Hours
timeFrame: 24 hours
Secondary outcomes:
measure: Time to First Morphine Supplementation
timeFrame: 24 hours
measure: Morphine Consumption Within 24 h
timeFrame: 24 hours
measure: Hyperalgesia in the Preoperative Period as Measured With Monofilaments in Thenar Eminence
timeFrame: Before the procedure (Baseline)
measure: Hyperalgesia in the Postoperative Period as Measured With Monofilaments in Thenar Eminence
timeFrame: 24 hours after procedure
measure: Hyperalgesia in the Preoperative Period as Measured With Monofilaments in the Periumbilical Region
timeFrame: Before the procedure (Baseline)
measure: Hyperalgesia in the Postoperative Period as Measured With Monofilaments in the Periumbilical Region
timeFrame: 24h after the procedure
measure: Hyperalgesia in the Preoperative Period as Measured With Algometer in Thenar Eminence
timeFrame: Baseline (before the procedure)
measure: Hyperalgesia in the Postoperative Period as Measured With Algometer in Thenar Eminence
timeFrame: 24 h after the procedure
measure: Hyperalgesia in the Preoperative Period as Measured With Algometer in the Periumbilical Region
timeFrame: Baseline (before the surgery)
measure: Hyperalgesia in the Postoperative Period as Measured With Algometer in the Periumbilical Region
timeFrame: 24 h after the procedure
measure: Extension of Hyperalgesia
timeFrame: 24 hours after the procedure
measure: Allodynia as Detected With a Soft Brush in the Periumbilical Region Before the Procedure
timeFrame: Before the procedure (Baseline)
measure: Allodynia as Detected With a Soft Brush in the Periumbilical Region 24 h After the Procedure
timeFrame: 24 h after the procedure
measure: Allodynia as Detected With a Soft Brush in the Thenar Eminence Before the Procedure
timeFrame: Before the procedure (Baseline)
measure: Allodynia as Detected With a Soft Brush in the Thenar Eminence 24 h After the Procedure
timeFrame: 24 h after the procedure
measure: Serum Level of Interleukin (IL)-6 Before the Procedure
timeFrame: Baseline (Before the procedure)
measure: Serum Level of Interleukin (IL)-6 5 h After the Procedure
timeFrame: 5 h after the procedure
measure: Serum Level of Interleukin (IL)-6 24 h After the Procedure
timeFrame: 24 h after the procedure
measure: Serum Level of Interleukin (IL)-8 Before the Procedure
timeFrame: Baseline (Before the procedure)
measure: Serum Level of Interleukin (IL)-8 5 h After the Procedure
timeFrame: 5 h after the procedure
measure: Serum Level of Interleukin (IL)-8 24 h After the Procedure
timeFrame: 24 h after the procedure
measure: Serum Level of Interleukin (IL)-10 Before the Procedure
timeFrame: Baseline (Before the procedure)
measure: Serum Level of Interleukin (IL)-10 5h After the Procedure
timeFrame: 5h after the procedure
measure: Serum Level of Interleukin (IL)-10 24 h After the Procedure
timeFrame: 24 h after the procedure
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: Federal University of São Paulo
Study officials:
affiliation: Federal University of São Paulo
name: Plínio da Cunha Leal, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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):232-239. doi: 10.1016/j.pain.2007.05.023. Epub 2007 Aug 6.
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. doi: 10.1213/ANE.0b013e3182662e30. Epub 2012 Jul 23.
citation: Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006 Mar;104(3):570-87. doi: 10.1097/00000542-200603000-00025.
citation: 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.
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. doi: 10.1097/00000542-200008000-00019.
citation: 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.
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. doi: 10.1097/00000542-200507000-00022.
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):1170-5. doi: 10.1213/ane.0b013e318183919e.
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 facilitation induced by chronic intrathecal morphine. J Neurosci. 2004 Aug 18;24(33):7353-65. doi: 10.1523/JNEUROSCI.1850-04.2004.