COX-2 Inhibition to Reduce Persistent Pain After Breast Cancer Surgery?

A randomized, double-blind, placebo-controlled trial reported in PLoS One found that inhibiting cyclooxygenase-2 (COX-2) in the perioperative period, in addition to standard antinociceptive treatment did not prevent central sensitization or persistent pain following breast cancer surgery.¹

Though regional anesthesia is associated with fewer cases of persistent pain after breast cancer surgery compared with general anesthesia alone, a significant number of patients are still affected. Previous findings, for example, show that approximately 22% of those who received paravertebral blockade experienced ongoing pain 6 months post-surgery.^2,3   

Surgical nociception leads to changes in CNS pain processing via inflammation and nerve damage–a mechanism known as central sensitization  that has been implicated in chronic pain.^4-6 The authors of the current study aimed to inhibit the inflammatory component of the process by adding COX-2 inhibitors to standard treatment. These agents “interfere with prostaglandin production and may counteract central sensitization development by inhibiting peripheral sensitization and reducing nociceptive input,” wrote the authors. “Additionally, COX-2 inhibitors may prevent central sensitization by a central mechanism.”

They used quantitative sensory testing to test their primary hypothesis that the addition of COX-2 inhibitors would reduce postoperative hyperalgesia and persistent pain. The secondary hypothesis was that patients who developed persistent pain would also show more hyperalgesia after surgery. The final sample consisted of 94 women undergoing lumpectomy, total simple mastectomy, or modified radical mastectomy under general anesthesia with a paravertebral block. They were randomly assigned to receive a placebo or 2×40 mg of parecoxib on the day of surgery, followed by 2×200 mg of celecoxib daily until day 5.

Outcome measures were assessed preoperatively and at multiple points after surgery. The primary outcome measure was the change in electric and pain pressure tolerance thresholds after surgery compared to baseline. The secondary outcome measures were scores on the Visual Analog Scale for Pain (VAS Pain) and the sum of scores from the functional, symptom, and quality of life (QOL) scales of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30).

In contrast to the primary hypothesis, no difference in the change of pain tolerance thresholds was found between the placebo group and the COX-2 inhibition group. However, COX-2 inhibition led to lower VAS score on movement on postoperative day 5 (P < .01). At 12 months after surgery, 13% of patients reported persistent pain with VAS >30 mm. Patients with persistent pain also demonstrated significantly higher postoperative VAS Pain scores at rest and on movement at nearly all time points vs patients without persistent pain. In line with the secondary hypothesis, these patents exhibited significantly more postoperative hyperalgesia to pressure stimulation (P < .01) compared with patients without pain from day 5 to 1 year after surgery.

These findings indicate that perioperative COX-2 inhibition does not prevent hyperalgesia and persistent pain following breast cancer surgery, though they do offer clues for future research avenues. “Central sensitization seems to play a role in the genesis of persistent post-surgical pain, and early postoperative quantitative sensory testing may be able to predict long-term persistent pain development,” and future prospective studies should investigate this possibility, said study author Noud van Helmond, MD, of Radboud University Nijmegen Medical Center in the Netherlands. “Based on results of perioperative quantitative sensory testing, it may be possible to develop individualized perioperative treatment strategies to prevent persistent postoperative pain,” he told Clinical Pain Advisor.   

Summary and Clinical Applicability

Contrary to the researchers’ hypothesis, the addition of COX-2 inhibitors to standard treatment did not prevent central sensitization or persistent pain in patients who had undergone breast cancer surgery. 

Limitations and Disclosures

Limitations: Some of the initial 138 patients had to be excluded because of treatment failure or an inaccurate diagnosis, and the number of patients who developed pain in the year following surgery was relatively small.

Conflicts: This research was supported by a grant from Pfizer to Dr van Helmond, though the article states that the company “had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

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References

1. van Helmond N, Steegers MA, Filippini-de Moor GP, Vissers KC, and Wilder-Smith OH. Hyperalgesia and persistent pain after breast cancer surgery: a prospective randomized controlled trial with perioperative COX-2 inhibition. PLoS One. 2016; 11(12): e0166601.
2. Kairaluoma PM, Bachmann MS, Rosenberg PH, Pere PJ. Preincisional paravertebral block reduces the prevalence of chronic pain after breast surgery. Anesth Analg. 2006; 103(3):703–708.
3. Ibarra MM, GC SC, Vicente GU, Cuartero del Pozo A, Lopez Rincon R, Fajardo del Castillo MJ. [Chronic postoperative pain after general anesthesia with or without a single-dose preincisional paravertebral nerve block in radical breast cancer surgery]. Rev Esp Anestesiol Reanim. 2011; 58(5):290–294. 
4. Hickey OT, Burke SM, Hafeez P, Mudrakouski AL, Hayes ID, Shorten GD. Severity of acute pain after breast surgery is associated with the likelihood of subsequently developing persistent pain. Clin J Pain. 2010; 26(7):556–560.
5. Katz J, Jackson M, Kavanagh BP, Sandler AN. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain. 1996; 12(1):50–55.
6. Tasmuth T, Kataja M, Blomqvist C, von Smitten K, Kalso E. Treatment-related factors predisposing to chronic pain in patients with breast cancer—a multivariate approach. Acta oncol. 1997; 36(6):625–630.