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HyperalgesiaPhase 4NCT01702389

Opioid-induced Hyperalgesia After Remifentanil Infusion

A Phase 4 study testing Remifentanil in people with Hyperalgesia, run by Oslo University Hospital at 1 site in Norway.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 to 60 years, men onlyHealthy volunteers can take part
Conditions the study is for
Hyperalgesia
What is being tested?
Remifentanil
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
16 participants
Where
1 siteNorway
Study dates
Oct 2012to Dec 2012
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 60 years
  • Men only
  • Healthy volunteers accepted
  • Adult

Who may be able to join

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

Who cannot join

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

Trial locations and contacts

1 site in 1 country.

Norway1 site

  • Oslo University Hospital

    Oslo, 0424

Other trials in Norway

About this study

Official title: 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.

Conditions
Hyperalgesia
Being tested
Remifentanil
Keywords
opioid induced hyperalgesia, Pain, Postoperative pain, Hyperalgesia
Medical subject headings
Hyperalgesia, Pain, Pain, Postoperative

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT01702389
Study groupRoleWhat they receive
RemifentanilExperimentalThe 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.
Receives: Drug: Remifentanil

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Hyperalgesia measured by numeric rating scale for pain

    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).

    Measured: 3 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Oct 2012 (estimated)
  2. Study startOct 2012
  3. Primary completionDec 2012
  4. Study completionDec 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Prevention
Allocation
Not applicable
Intervention model
Single group
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
16 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01702389
Sponsor's protocol ID
2011/1639
Other IDs
2011-002734-39, 11/14666
Status last verified
Oct 2014
First submitted
4 Oct 2012
Last updated
29 Oct 2014
Results posted
No
Data monitoring committee
No

Publications

  • Servin FS. Remifentanil: an update. Curr Opin Anaesthesiol. 2003 Aug;16(4):367-72. doi: 10.1097/01.aco.0000084479.59960.3f.

    PubMed 17021484

  • Angst MS, Koppert W, Pahl I, Clark DJ, Schmelz M. Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain. 2003 Nov;106(1-2):49-57. doi: 10.1016/s0304-3959(03)00276-8.

    PubMed 14581110

  • Hood DD, Curry R, Eisenach JC. Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg. 2003 Sep;97(3):810-815. doi: 10.1213/01.ANE.0000078811.80093.88.

    PubMed 12933407

  • Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg. 1998 Jun;86(6):1307-11. doi: 10.1097/00000539-199806000-00033.

    PubMed 9620525

  • 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.

    PubMed 10910490

  • 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.

    PubMed 15983467

  • 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.

    PubMed 12826855

  • Troster A, Sittl R, Singler B, Schmelz M, Schuttler J, Koppert W. Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecoxib in humans. Anesthesiology. 2006 Nov;105(5):1016-23. doi: 10.1097/00000542-200611000-00024.

    PubMed 17065897

  • Lenz H, Raeder J, Draegni T, Heyerdahl F, Schmelz M, Stubhaug A. Effects of COX inhibition on experimental pain and hyperalgesia during and after remifentanil infusion in humans. Pain. 2011 Jun;152(6):1289-1297. doi: 10.1016/j.pain.2011.02.007. Epub 2011 Mar 10.

    PubMed 21396775

  • Drdla R, Gassner M, Gingl E, Sandkuhler J. Induction of synaptic long-term potentiation after opioid withdrawal. Science. 2009 Jul 10;325(5937):207-10. doi: 10.1126/science.1171759.

    PubMed 19590003

  • Comelon M, Raeder J, Stubhaug A, Nielsen CS, Draegni T, Lenz H. Gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia. Br J Anaesth. 2016 Apr;116(4):524-30. doi: 10.1093/bja/aev547. Epub 2016 Mar 1.

    PubMed 26934941

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Remifentanil in people with Hyperalgesia, run by Oslo University Hospital at 1 site in Norway.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 29 Oct 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Norway. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Hyperalgesia measured by numeric rating scale for pain (time frame: 3 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01702389, which also lists 11 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Oct 2014.

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