Modulation of Remifentanil-induced Postinfusion Hyperalgesia

Modulation of Remifentanil-induced Analgesia and Postinfusion Hyperalgesia by Parecoxib or Ketorolac in Humans

In addition to alleviate pain there is growing evidence that µ-opioids enhance pain. This problem is known as opioid induced hyperalgesia(OIH).The NMDA receptor is involved in opioid induced hyperalgesia it may be possible to block OIH by cyclooxygenase inhibitors. This has been demonstrated with parecoxib, a COX-II inhibitor, in a experimental pain model.Both COX-1 and COX-2 are expressed in the spinal cord. It would be of interest to investigate whether a COX-1 preferring inhibitor like ketorolac also can reduce opioid induced hyperalgesic in this experimental pain model.

Study Overview

• Status: Completed
• Conditions: Hyperalgesia, Secondary
• Intervention / Treatment: Other: Placebo; Drug: Remifentanil; Drug: Ketorolac and remifentanil; Drug: Parecoxib and remifentanil

Detailed Description

Remifentanil is an fast acting opioid which has become very popular to use during surgery.

There are studies, both experimental 1-3 and clinical 4;5, which indicate that remifentanil after end of infusion trigger enhanced pain experience and enhanced opioid consumption postoperatively.

Therefore it is important to look at possibilities to block this enhanced pain experience (opioid induced hyperalgesia - OIH). Ketamin has demonstrated to block this effect 5;6 through the NMDA receptor. Unfortunately ketamin has some seriously side-effects like hallucinations, and is therefore not suitable in ordenary clinical use.

Recently, it has been demonstrated that parecoxib (a COX-2 inhibitor) can prevent remifentanil-induced postinfusion hyperalgesia in a study on healthy volunteers.7 COX-2 inhibitors have some disadvantages because of the longterm adverse effects like cardiac arrest. Therefore it would be of interest to look at a COX-1 preferring NSAID, like ketorolac, to see if also non-selective NSAIDs can partly block remifentanil-induced postinfusion hyperalgesia.

To investigate this and to provoke pain and secondary hyperalgesia we use an intradermal electrical pain model which is well established.1;7-9 Detailed description of this model look at reference 7. H0 : Parecoxib prevents remifentanil postinfusion secondary hyperalgesi. Ketorolac does not prevent remifentanil postinfusion secondary hyperalgesi HA : Parecoxib and ketorolac prevent remifentanil postinfusion secondary hyperalgesi.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 4

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0407
    • Ullevaal University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy volunteers

Exclusion Criteria:

• Allergy to the drugs used in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Placebo IV before placebo infusion
Active Comparator: Remifentanil	Drug: Remifentanil; placebo IV and remifentanil infusion; Other Names: Ultiva
Active Comparator: Ketorolac and remifentanil	Drug: Ketorolac and remifentanil; Ketorolac IV and remifentanil infusion; Other Names: Toradol
Active Comparator: Parecoxib and remifentanil	Drug: Parecoxib and remifentanil; Parecoxib IV and remifentanil infusion; Other Names: Dynastat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
H0 : Parecoxib prevents remifentanil postinfusion secondary hyperalgesi. Ketorolac does not prevent remifentanil postinfusion secondary hyperalgesi.	during the study

Secondary Outcome Measures

Outcome Measure	Time Frame
HA : Parecoxib and ketorolac prevent remifentanil postinfusion secondary hyperalgesi.	During the study

Collaborators and Investigators

• Sponsor: Ullevaal University Hospital
• Collaborators: University of Oslo; Rikshospitalet University Hospital
• Investigators: Principal Investigator: Harald Lenz, MD, Ullevaal University Hospital; Study Director: Johan Raeder, Prof.,MD,PhD, Ullevaal University Hospital; Study Director: Audun Stubhaug, Prof.,MD,PhD, Rikshospitalet University Hospital

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): April 1, 2009
• Study Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: November 4, 2008
• First Submitted That Met QC Criteria: November 4, 2008
• First Posted (Estimate): November 5, 2008

Study Record Updates

• Last Update Posted (Estimate): July 1, 2011
• Last Update Submitted That Met QC Criteria: June 30, 2011
• Last Verified: November 1, 2008

More Information

Terms related to this study

• Keywords: COX-2 inhibitor; ketorolac; remifentanil; hyperalgesia; parecoxib; COX-1 inhibitor
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Sensation Disorders; Somatosensory Disorders; Hyperalgesia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Analgesics, Opioid; Narcotics; Cyclooxygenase 2 Inhibitors; Remifentanil; Ketorolac; Parecoxib
• Other Study ID Numbers: 2008-000904-10