Postoperative Pain After Orthopedic Surgery: Does it Help to Give Fentanyl Before Start of Remifentanil Based Anesthesia?
Condition: Pain, Postoperative
MeSH terms: Pain, Postoperative
Study type: Interventional
Phase: Phase 3

Summary: 
      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).
    

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).

      Literature:

        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.
    

Intervention name(s): fentanyl
Intervention type(s): Drug
Intervention MeSH terms: Fentanyl
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double
Primary purpose: Treatment
Keywords: pain; hyperalgesia; drug tolerance; remifentanil; fentanyl; Anterior Cruciate Ligament; Posterior Cruciate Ligament; Medial Collateral Ligament, Knee