Effects of Nefopam on Hyperalgesia After Cardiac Surgery

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%.

Inclusion criteria

• 55-75 years old
• ASA score: 1-3
• Patients scheduled for Cardiac surgery with median sternotomy for : single valve replacement or Bentall or Benson or Tyron David surgery, single or multiple Cardiac Artery Bypass Grafting (CABG) , combined surgery (valve replacement + CABG) without preoperative risk of postoperative complications
• Informed consent obtained from the patient

Exclusion criteria

• Drug or alcohol abuse history
• Analgesic or opioid consumption within the 12hs preceding the surgery
• Chronic use of analgesic drugs or history of chronic pain
• Convulsion or epilepsy history
• Glaucoma history
• Disability to understand morphine PCA use
• Allergy to nefopam