Effects of Nefopam on Hyperalgesia After Cardiac Surgery
Condition: Hyperalgesia; Pain, Postoperative; Pain, Chronic Disease
MeSH terms: Hyperalgesia; Pain, Postoperative; Chronic Disease; Chronic Pain
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Postoperative pain after major surgery is consecutive not only to the nociceptive inputs
      coming from the surgical lesion, but also to peripheral and central neuronal sensitization.
      This lead to postoperative hyperalgesia and allodynia that are enhanced by the per operative
      use of high opioid doses. Anti-NMDA drugs have been reported as able to reduce this
      sensitization process and then to decrease acute morphine tolerance during the postoperative
      period. Nefopam has been lately shown to combine in experimental trials analgesic and anti
      hyperalgesic effects. The aim of this study is to compare anti-hyperalgesic effects of
      nefopam given either before incision and continuously for the following 48hours or starting
      from the end of the surgery and given for 48hours to a control group that would receive
      placebo for 48hours. Postoperative analgesia will be based on morphine PCA. Pain scores,
      hyperalgesia, allodynia, postoperative morphine consumption, and development of chronic pain
      will be the main criteria that will be evaluated during this study
    

Detailed description: 
      Introduction :

      Postoperative pain is not only a consequence of the surgical lesion, but is also related to
      sensitization processes that appear in peripheral and central nerves. This sensitization
      induce clinically hyperalgesia and allodynia. From an experimental viewpoint it comes mainly
      from a central activation of NMDA receptors in neurons that conduct the nociceptive message.

      Recent studies have shown that high-dose opioids were able, via NMDA receptors, to enhance
      postoperative hyperalgesia and to increase pain scores and morphine consumption after
      surgery. Nevertheless per operative use of opioid is still necessary to avoid per operative
      stress and systemic consequence of the surgical stimulation.

      Some drugs (ketamine, nitrous oxide…) succeeded in reducing postoperative hyperalgesia and
      pains scores and acute morphine tolerance. They also were able to decrease pain
      chronicization.

      Nefopam, well known as an analgesic since the 80's, presents both analgesic and anti
      hyperalgesic properties as lately demonstrated in experimental trials. Nevertheless these
      anti hyperalgesic properties have never been evaluated in humans scheduled for cardiac
      surgery. Nefopam administration could reduce acute morphine tolerance and could enhance
      postoperative pain management by reducing sensitization processes and hyperalgesia.

      Objective :

      The main purpose of this clinical trial will be to evaluate in patients scheduled for cardiac
      surgery with sternotomy the nefopam effects on the nociceptive threshold evaluated with
      dynamic Von Frey mechanical stimulation.

      The secondary objectives will evaluate static hyperalgesia, postoperative pain scores,
      morphine consumption, cognitive functions, and development of chronic pain and dysesthesia.

      Methods :

      Prospective, randomized, double-blind study that will compare three parallel groups that will
      receive the same per operative anesthesia except for the nefopam doses.

      Group 1: nefopam infusion will start before the surgical incision, at the induction time of
      anesthesia and will be continued until postoperative H48. Group 2: nefopam administration
      will start at the end of the surgery and will be continued until postoperative H48. Group 3:
      control group that will receive a placebo from the induction time of anesthesia until H48.
      All patients will receive postoperatively morphine infusion following the Patient Controlled
      Analgesia concept.

      Number of patients to be included : 90 Duration of the study : 2 years Start : second
      semester of 2006

      Expected result :

      Reduction of the extend of hyperalgesia around the wound evaluated with dynamic Von Frey
      mechanical stimulation more than 20%.
    

Intervention name(s): Nefopam; néfopam; Placebo comparator
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 0,3mg/kg IV bolus preoperative and 65 µg/kg/h during H48 postoperative; bolus Néfopam (0,3mg/kg) during 10 min at the end of surgery and 65 µg/kg/h during postoperative H48; bolus NaCl during 10 min at the end of surgery and during postoperative H48
Intervention MeSH terms: Nefopam
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Postoperative Hyperalgesia; cardiac Surgical Procedures; Nefopam; Randomized Controlled Trials; Pain and chronic disease