title: Hyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 Inhibition.
abstract: BACKGROUND
  Persistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia.
  
  
  METHODS
  138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition (2x40mg parecoxib on day of surgery, thereafter 2x200mg celecoxib/day until day five) or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months.
  
  
  RESULTS
  48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively.
  
  
  CONCLUSIONS
  Perioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of persistent postsurgical pain.
authors.affiliation: Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Noud
authors.initials: N
authors.lastname: van Helmond
authors.affiliation: Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Monique A
authors.initials: MA
authors.lastname: Steegers
authors.affiliation: Department of Anesthesiology, Bernhoven Hospital, Uden, The Netherlands.
authors.forename: Gertie P
authors.initials: GP
authors.lastname: Filippini-de Moor
authors.affiliation: Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Kris C
authors.initials: KC
authors.lastname: Vissers
authors.affiliation: Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.|Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
authors.forename: Oliver H
authors.initials: OH
authors.lastname: Wilder-Smith
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D000068579:Celecoxib / Q000627:therapeutic use; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D007555:Isoxazoles / Q000627:therapeutic use; D008408:Mastectomy / Q000009:adverse effects / Q000379:methods; D015412:Mastectomy, Segmental / Q000009:adverse effects / Q000379:methods; D008875:Middle Aged; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010149:Postoperative Pain / Q000188:drug therapy* / Q000209:etiology; D059035:Perioperative Period; D011446:Prospective Studies; D011788:Quality of Life; D011795:Surveys and Questionnaires; D016896:Treatment Outcome
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; C409945:parecoxib; D000068579:Celecoxib