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Opioid-induced Hyperalgesia After Remifentanil Infusion

Information source: Oslo University Hospital
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Hyperalgesia

Intervention: Remifentanil (Drug)

Phase: Phase 4

Status: Completed

Sponsored by: Oslo University Hospital

Official(s) and/or principal investigator(s):
Marlin Comelon, MD, Principal Investigator, Affiliation: Oslo UH


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.

Clinical Details

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

Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Primary outcome: Hyperalgesia measured by numeric rating scale for pain


Minimum age: 18 Years. Maximum age: 60 Years. Gender(s): Male.


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

Locations and Contacts

Oslo University Hospital, Oslo 0424, Norway
Additional Information

Related publications:

Servin FS. Remifentanil: an update. Curr Opin Anaesthesiol. 2003 Aug;16(4):367-72.

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.

Hood DD, Curry R, Eisenach JC. Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg. 2003 Sep;97(3):810-5.

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

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.

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.

Koppert W, Sittl R, Scheuber K, Alsheimer M, Schmelz M, Schüttler J. Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology. 2003 Jul;99(1):152-9.

Tröster A, Sittl R, Singler B, Schmelz M, Schüttler J, Koppert W. Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecoxib in humans. Anesthesiology. 2006 Nov;105(5):1016-23.

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):1289-97. doi: 10.1016/j.pain.2011.02.007. Epub 2011 Mar 10.

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

Starting date: October 2012
Last updated: October 28, 2014

Page last updated: August 23, 2015

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