Opioid-induced Hyperalgesia After Remifentanil Infusion

October 28, 2014 updated by: Marlin Comelon, Oslo University Hospital

Can Opioid-induced Hyperalgesia be Prevented by Gradual Dose Reduction vs. Abrupt Withdrawal of Remifentanil?

Remifentanil is a rapid-acting opioid which has been widely used in pain treatment during surgery for the last 15 years 1. Remifentanil is rapidly eliminated (minutes) from the body after end of infusion, and this makes it easily manageable compared to other opioids. However, there are both experimental and clinical studies indicating that remifentanil, after end of infusion, triggers increased pain sensation and increased opioid consumption post-operatively. Increased post-operative opioid consumption should be avoided due to the adverse effects of these drugs (nausea/vomiting, pruritus, dizziness, fatigue and reduced respiratory rate). Thus, it's important to investigate relevant strategies to avoid the increased pain sensation (opioid-induced hyperalgesia = hypersensitivity to pain stimuli) after end of infusion of remifentanil after surgery. Several experimental and clinical trials have been conducted in this field. Ketamine has been shown to block this effect, but its adverse effect profile (i.a. hallucinations) makes it not suitable in normal clinical use. In a study of healthy volunteers, it has been demonstrated that parecoxib (a COX-2 selective NSAID) can prevent remifentanil-induced hyperalgesia. Our group has previously shown that a relatively COX-1 selective NSAID (ketorolac) can prevent hyperalgesia in an experimental pain model.

This is of interest since NSAIDs are frequently administered as premedication before surgery. There are several disadvantages associated with the use of COX-2 inhibitors, e.g. the risk of myocardial infarction after long-term use (> 1 year), and potentially reduced bone healing after orthopedic surgery. However, this has not been shown with short-term use (days/week). The disadvantages associated with the use of e.g. ketorolac (a COX-1 inhibitor) are i.a. increased bleeding tendency, which is unfavourable for the surgeon, and increased risk of gastric ulcer. Therefore, it is of interest to investigate other ways of preventing opioid-induced hyperalgesia. In a recent animal study it has been shown that gradual dose reduction of remifentanil (vs. abrupt withdrawal of a relatively high remifentanil dose) can prevent the development of hyperalgesia after end of infusion. In this study we will i.a. investigate whether this is also the case in humans. In this new model, the study participants will get remifentanil infusion with two different dose reduction regimes: gradual reduction or abrupt withdrawal.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

16

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Norway
      • Oslo, Norway, 0424
        • Oslo University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 58 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Male
  • Age 18-60
  • Body mass index 17-30
  • Healthy volunteers

Exclusion Criteria:

  • Use of medication; alternative medicine
  • Substance abuse
  • Allergies towards medication used in the study
  • Participation in other clinical studies the previous 6 months

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Remifentanil
The study has only one arm. Same group of volunteers will receive remifentanil infusion with abrupt withdrawal, remifentanil infusion with gradual dose reduction and saline infusion at three separate trials.
Drug: Remifentanil
Other Names:
  • Ultiva

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hyperalgesia measured by numeric rating scale for pain
Time Frame: 3 weeks

Two pain models will be used - a heat-pain and a cold-pain model. Testing will be done before, during and after remifentanil infusion. NRS (Numeric rating Scale) will be used for pain scoring.

Heat model:

A computer-controlled Medoc ATS Thermal stimulator (3 x 3 cm) is applied to the left volar forearm at pre-defined areas.

Cold model:

In the cold test the study participant should keep his right hand in circulating cold water (3 ̊C) in up to 90 seconds.

The pain models will be applied during three separate trials using remifentanil infusion with abrupt withdrawal, remifentanil infusion with gradual withdrawal and saline infusion(placebo).
3 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Oslo University Hospital

Investigators

  • Principal Investigator: Marlin Comelon, MD, Oslo UH

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2012

Primary Completion (Actual)

December 1, 2012

Study Completion (Actual)

December 1, 2012

Study Registration Dates

First Submitted

October 4, 2012

First Submitted That Met QC Criteria

October 5, 2012

First Posted (Estimate)

October 8, 2012

Study Record Updates

Last Update Posted (Estimate)

October 29, 2014

Last Update Submitted That Met QC Criteria

October 28, 2014

Last Verified

October 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2011/1639
  • 2011-002734-39 (EudraCT Number)
  • 11/14666 (Other Identifier: Norwegian Medicines Agency)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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