Modulation of Remifentanil-induced Postinfusion Hyperalgesia

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Hyperalgesia, Secondary

Intervention / Treatment
-----------------
* Other: Placebo
* Drug: Remifentanil
* Drug: Ketorolac and remifentanil
* Drug: Parecoxib and remifentanil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy volunteers Exclusion Criteria: Allergy to the drugs used in the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* Placebo IV before placebo infusion<br>|
| Active Comparator: Remifentanil<br> | Drug: Remifentanil<br>* placebo IV and remifentanil infusion<br>* Other names: Ultiva;|
| Active Comparator: Ketorolac and remifentanil<br> | Drug: Ketorolac and remifentanil<br>* Ketorolac IV and remifentanil infusion<br>* Other names: Toradol;|
| Active Comparator: Parecoxib and remifentanil<br> | Drug: Parecoxib and remifentanil<br>* Parecoxib IV and remifentanil infusion<br>* Other names: Dynastat;|

What is the study measuring?
-----------------
Primary Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hyperalgesia, remifentanil, ketorolac, parecoxib, COX-1 inhibitor, COX-2 inhibitor