Opioid-induced Hyperalgesia After Remifentanil Infusion

NCT ID: NCT01702389

Last Updated: 2014-10-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-10-31
• Study Completion Date: 2012-12-31

Brief 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. 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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Remifentanil

Intervention Type: DRUG

Interventions

Remifentanil

Intervention Type: DRUG

Other Intervention Names

Ultiva

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: Yes

Sponsors

Oslo University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Marlin Comelon

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Marlin Comelon, MD

Role: PRINCIPAL_INVESTIGATOR

Oslo UH

Locations

Oslo University Hospital

Oslo, , Norway

Countries

Norway

References

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Reference Type: BACKGROUND

PMID: 17021484 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14581110 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12933407 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 9620525 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10910490 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15983467 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12826855 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17065897 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21396775 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19590003 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26934941 (View on PubMed)

Other Identifiers

2011-002734-39

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

11/14666

Identifier Type: OTHER

Identifier Source: secondary_id

2011/1639

Identifier Type: -

Identifier Source: org_study_id