Trial document





This trial has been registered retrospectively.
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  DRKS00009002

Trial Description

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Title

Influence of intraoperative opioids on quantitative sensory testing.

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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

Morphine – like analgesics are still a cornerstone for intra- and postoperative pain therapy. Besides their analgesics effects opioids can also increase pain perception. This phenomenon is called opioid induced hyperalgesia (OIH). Due to at least in part contradicting results of studies the clinical relevance of OIH is still a matter of debate. One reason for the inconsistent results of these studies may be the use of the postoperative pain intensity or the need for postoperative analgesia as indirect parameters for OIH. Goal of this study is to investigate the influence of intraoperative administered opioids on sensory thresholds measured by Quantitive Sensory Testing (QST), still subjective but reproducible parameters for the perception of pain and therefor a more valid parameter for OIH. Changes in QST as a sign for OIH where already detected in chronic pain patients. In the perioperative setting especially remifentanil, as an ultra-short acting opioid, is suspected to induce OIH. Thus the goal of this study is to investigate the influence of intraoperative Remifentanil on postoperative QST. Sufentanil – as prototype for an intermediate acting opioid with a lower risk for a development of OIH is used as comparator.

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Brief Summary in Scientific Language

Opioids are still a cornerstone for intra- and postoperative pain therapy. On one hand intraoperative opioids are indispensably to warrant cardiovascular stability, on the other hand the intraoperative use of high dose opioids especially remifentanil is associated with increased postoperative opioid-consumption and pain intensity [1]. This may be due to an acute opioid withdrawal or a paradoxical increased pain sensitivity called opioid-induced hyperalgesia (OIH) [2]. In several different animal models opioids induce a long lasting hyperalgesic effect that outlasts the analgesic effect of the drugs [3-5]. In humans, especially remifentanil is associated with OIH. In a human pain model remifentanil leads to an increased pain perception and punctate hyperalgesia after termination of the opioid-infusion [6]. In clinical settings OIH is often defined by a higher postoperative opioid-consumption [1, 7]. This postoperative pain therapy may itself interfere with and induce OIH itself making the interpretation of the results difficult. Interestingly, some studies were not able to detect any influence of intraoperative high dose remifentanil compared to other analgesic concepts on postoperative pain intensity or treatment [8-10]. A recent meta-analysis suggests that intraoperative high doses of remifentanil are associated with a small but significant increased acute pain after surgery [11]. Thus a more sensitive outcome parameter for the detection of OIH than the postoperative pain intensity or opioid-consumption is desirable. Since chronic opioid therapy alters the outcome of quantitative sensory testing (QST) in humans [12], QST may be a tool to detect OIH also in the postoperative phase.
Thus, the aim of the study was to investigate the influence of intraoperative remifentanil compared to sufentanil on somatosensory thresholds investigated with QST in a prospective study in patients undergoing surgery in general anaesthesia. The comparison of the two opioids is based on the hypothesis that the probability or extent of OIH is increased after relative high doses of remifentanil compared to low dose sufentanil.
1. Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology. 2000;93(2):409-17.
2. Angst MS, Clark JD. Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology. 2006;104(3):570-87
3. Ohnesorge H, Feng Z, Zitta K, Steinfath M, Albrecht M, Bein B. Influence of clonidine and ketamine on m-RNA expression in a model of opioid-induced hyperalgesia in mice. PLoS One. 2013;8(11):e79567
4. Celerier E, Rivat C, Jun Y, Laulin JP, Larcher A, Reynier P, et al. Long-lasting hyperalgesia induced by fentanyl in rats: preventive effect of ketamine. Anesthesiology. 2000;92(2):465-72
5. Li X, Angst MS, Clark JD. A murine model of opioid-induced hyperalgesia. Molecular Brain Research. 2001;86(1-2):56-62
6. 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;99(1):152-9.
7. Joly V, Richebe P, Guignard B, Fletcher D, Maurette P, Sessler DI, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology. 2005;103(1):147-55
8. Lee LH, Irwin MG, Lui SK. Intraoperative remifentanil infusion does not increase postoperative opioid consumption compared with 70% nitrous oxide. Anesthesiology. 2005;102(2):398-402
9. Cortinez LI, Brandes V, Munoz HR, Guerrero ME, Mur M. No clinical evidence of acute opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth. 2001;87(6):866-9
10. Treskatsch S, Klambeck M, Mousa SA, Kopf A, Schäfer M. Influence of high-dose intraoperative remifentanil with or without amantadine on postoperative pain intensity and morphine consumption in major abdominal surgery patients. European Journal of Anaesthesiology. 2014;31(1):41-9
11. Fletcher D, Martinez V. Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis. Br J Anaesth. 2014;112(6):991-1004
12. Chen L, Malarick C, Seefeld L, Wang S, Houghton M, Mao J. Altered quantitative sensory testing outcome in subjects with opioid therapy. Pain. 2009;143(1-2):65-70

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Organizational Data

  •   DRKS00009002
  •   2015/08/28
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  •   yes
  •   Approved
  •   A 188/09, Ethikkommission der Christian-Albrechts-Universität zu Kiel
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Secondary IDs

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Health Condition or Problem studied

  •   R20.8 -  Other and unspecified disturbances of skin sensation
  •   opioid induced hyperalgesia (OIH)
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Interventions/Observational Groups

  •   Remifentanil (0.4 µg/kg/min) based total intravenous anesthesia
  •   Sufentanil (0,25 µg/kg) based total intravenous anesthesia
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist, assessor
  •   Active control (effective treament of control group)
  •   Basic research/physiological study
  •   Parallel
  •   N/A
  •   No
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Primary Outcome

sensory thresholds (quantitative sensory testing) 22h postoperative

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Secondary Outcome

/

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2010/05/04
  •   30
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Female
  •   18   Years
  •   99   Years
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Additional Inclusion Criteria

Age >18 years
ASA physical status I-III
elective surgery of the female breast, including segmental resections or mastectomy with or without sentinel lymph node biopsy
written informed consent

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Exclusion Criteria

allergies to remifentanil, sufentanil or paracetamol, preoperative acute or chronic pain states, preoperative intake of any analgesic drugs, history of drug or alcohol abuse, renal insufficiency (serum creatinin >1,5 mg/dl), impaired liver function (GTT >100U/l), neurologic diseases that might have an impact on QST (PNP, ED), gravidity, diabetes mellitus

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Addresses

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    • Universitätsklinikum Schleswig-Holstein,Campus Kiel,Klinik für Anästhesiologie und Operative Intensivmedizin
    • Arnold-Heller Str. 3
    • 24105  Kiel
    • Germany
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    • UKSH, Campus Kile, Klinik für Anästhesiologie und Operative Intensivmedizin
    • Mr.  Dr.  Henning  Ohnesorge 
    • Arnold-Heller Str. 3
    • 24105  Kiel
    • Germany
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    • UKSH, Campus Kile, Klinik für Anästhesiologie und Operative Intensivmedizin
    • Mr.  Dr.  Henning  Ohnesorge 
    • Arnold-Heller Str. 3
    • 24105  Kiel
    • Germany
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Sources of Monetary or Material Support

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    • Universitätsklinikum Schleswig-Holstein,Campus Kiel,Klinik für Anästhesiologie und Operative Intensivmedizin
    • Arnold-Heller Str. 3
    • 24105  Kiel
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2011/03/31
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Trial Publications, Results and other Documents

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