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Postoperative Pain After Orthopedic Surgery: Does it Help to Give Fentanyl Before Start of Remifentanil Based Anesthesia?

This study has been completed.
University of Oslo
Information provided by:
Oslo University Hospital Identifier:
First received: October 17, 2005
Last updated: July 3, 2011
Last verified: September 2005
The aim of this trial is to examine the possibility that fentanyl 1,5 µgr/kg given intravenously (i.v.) before the start of remifentanil infusion for anesthesia gives less development of tolerance/hyperalgesia postoperative than fentanyl given at the end of surgery (the traditional method).

Condition Intervention Phase
Pain, Postoperative
Drug: fentanyl
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: Prophylaxis Against Postoperative Pain After Orthopedic Surgery: Does it Help to Give Fentanyl Before Start of Remifentanil/Propofol Based Anesthesia?

Resource links provided by NLM:

Further study details as provided by Oslo University Hospital:

Primary Outcome Measures:
  • Less use of postoperative opioids
  • Less visual analog scale (VAS) and verbal rating scale (VRS) in the treatment group

Estimated Enrollment: 100
Study Start Date: October 2005
Study Completion Date: July 2006
Detailed Description:

Postoperative pain can contribute to reduction in the patient's well-being and, if it is pronounced, delayed rehabilitation and an increase in the total cost for nursing and treatment.

Experimental studies has shown that infusion of remifentanil over some period of time, can result in acute opioid tolerance and hyperalgesia (1-2).

One clinical trial has shown that intraoperative infusion of remifentanil gives acute opioid tolerance with subsequent increased postoperative pain and increased opioid consume postoperative (3).

The development of opioid tolerance probably has several mechanisms. One topical mechanism is opioid induced influence of N-methyl-d-aspartate (NMDA)-receptor and its intracellular second-messenger-systems. This results in central sensitization to pain stimulus in the dorsal horn and the brain (4-5), with following development of hyperalgesia.

Several strategies can be successful to reduce or prevent opioid induced hyperalgesia, for example NMDA-receptor antagonists, alfa-2 agonists, opioid rotation or combination of opioids with different receptor selectivity (6-8).

The theoretical background for pre-treating the opioid receptor with an other opioid (fentanyl) that gives less tendency to hyperalgesia than remifentanil, is that it can reduce the development of tolerance and hyperalgesia of remifentanil.

The aim of this trial is to examine the possibility that i.v. administration of fentanyl 1,5 µgr/kg before start of remifentanil infusion for anesthesia gives less development of tolerance/hyperalgesia postoperative than fentanyl given in the end of surgery (the traditional method).

This is to be measured by less pain postoperative (VAS, visual analog scale, and a five point verbal rating scale) and less fentanyl consumed (measured by using PCA).


  1. Vinik HR, Kissin I (1998) Rapid development of tolerance to analgesia during remifentanil infusion in human. Anesth Analg 86:1307-1311.
  2. Angst MS, Koppert W, Pahl I, Clark JD, Schmelz M (2003) Short-term infusion of the µ-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 106:49-57.
  3. Guignard et al. (2000) Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 93:409-417.
  4. Larcher A, Laulin JP, Celerier E, Le Moal M, Simonnet G (1998) Acute tolerance associated with a single opioid administration: involvement of N-methyl-D-aspartate-dependent pain facilitatory systems. Neuroscience Vol 84:583-589.
  5. Celerier E, Laulin J, Larcher A, Le Moal M, Simonnet G (1999) Evidence for opiate-activated NMDA processes masking opiate analgesia in rats. Brain Research 849:18-25.
  6. Celerier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, Simonnet G(2000) Long-lasting hyperalgesia induced by fentanyl in rats: preventive Effect of ketamin. Anesthesiology 92:465-472.
  7. Bie B, Fields HL, Williams JT, Pan ZZ (2003) Roles of a alfa-1 and alfa-2-adrenoreceptors in the nucleus raphe magnus in opioid analgesia and opioid abstinence-induced hyperalgesia. Journal of Neuroscience 23:7950-7957.
  8. Mao J, Prince DD, Caruso F, Mayer DJ (1996) Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats. Pain 67:361-368.

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Women and men > 18 years.
  • Informed consent.
  • Elective day-orthopedic surgery: damage to anterior cruciate ligament and/or posterior cruciate ligament with or without medial collateral ligament.

Exclusion Criteria:

  • Patients who use nonsteroidal anti-inflammatory drugs (NSAID's) or are allergic to NSAID's.
  • Patients using steroids, anti-emetics, drugs or opioids.
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Please refer to this study by its identifier: NCT00241332

Ullevaal University Hospital
Oslo, Norway, 0407
Sponsors and Collaborators
Ullevaal University Hospital
University of Oslo
Study Director: Johan Ræder, Prof.MD,Phd Ullevaal University Hospital
  More Information Identifier: NCT00241332     History of Changes
Other Study ID Numbers: 510-05165
Study First Received: October 17, 2005
Last Updated: July 3, 2011

Keywords provided by Oslo University Hospital:
drug tolerance
Anterior Cruciate Ligament
Posterior Cruciate Ligament
Medial Collateral Ligament, Knee

Additional relevant MeSH terms:
Pain, Postoperative
Neurologic Manifestations
Nervous System Diseases
Postoperative Complications
Pathologic Processes
Signs and Symptoms
Analgesics, Opioid
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Adjuvants, Anesthesia
Anesthetics, Intravenous
Anesthetics, General
Hypnotics and Sedatives processed this record on April 28, 2017