Intravenous Flurbiprofen Axetil Enhances Analgesic Effect of Opioids in Patients with Refractory Cancer Pain by Increasing Plasma β-Endorphin

  • Wu, Ting-Ting (1Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army) ;
  • Wang, Zhi-Gang (1Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army) ;
  • Ou, Wu-Ling (Department of Oncology, Hubei Cancer Hospital) ;
  • Wang, Jun (Department of Oncology, General Hospital of Jinan Command, People's Liberation Army) ;
  • Yao, Guo-Qing (1Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army) ;
  • Yang, Bo (1Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army) ;
  • Rao, Zhi-Guo (1Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army) ;
  • Gao, Jian-Fei (1Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army) ;
  • Zhang, Bi-Cheng (1Department of Oncology, Wuhan General Hospital of Guangzhou Command, People's Liberation Army)
  • Published : 2015.01.22


Background: The study aimed to investigate the analgesic effect of a combination of intravenous flurbiprofen axetil and opioids, and evaluate the relationship between refractory pain relief and plasma ${\beta}$-endorphin levels in cancer patients. Materials and Methods: A total of 120 cancer patients was randomly divided into two groups, 60 patients took orally morphine sulfate sustained-release tablets in group A, and another 60 patients receiving the combination treatment of intravenous flurbiprofen axetil and opioid drugs in group B. After 7 days, pain relief, quality of life improvement and side effects were evaluated. Furthermore, plasma ${\beta}$-endorphin levels were measured by radioimmunoassay. Results: With the combination treatment of intravenous intravenous flurbiprofen axetil and opioids, the total effective rate of pain relief rose to 91.4%, as compared to 82.1% when morphine sulfate sustained-release tablet was used alone. Compared with that of group A, the analgesic effect increased in group B (p=0.031). Moreover, satisfactory pain relief was associated with a significant increase in plasma ${\beta}$-endorphin levels. After the treatment, plasma ${\beta}$-endorphin level in group B was $62.4{\pm}13.5pg/ml$, which was higher than that in group A ($45.8{\pm}11.2pg/ml$) (p<0.05). Conclusions: Our results suggest the combination of intravenous flurbiprofen axetil and opioids can enhance the analgesic effect of opioid drugs by increasing plasma ${\beta}$-endorphin levels, which would offer a selected and reliable strategy for refractory cancer pain treatment.


  1. Alicino I, Giglio M, Manca F, Bruno F, Puntillo F (2012). Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice. Pain, 153, 245-9.
  2. Arslan D, Koca T, Akar E, Tural D, Ozdogan M (2014). Cancer pain prevalence and its management. Asian Pac J Cancer Prev, 15, 8557-62.
  3. Atkin N, Jackson KA, Danks RA (2010). Bilateral open thoracic cordotomy for refractory cancer pain: a neglected technique? J Pain Symptom Manage, 39, 924-9.
  4. Befon S, Mystakidou K, Lyra M, Tubanakis N, Vlahos L (2000). Continuous subcutaneous octreotide in gastrointestinal cancer patients: pain control and beta-endorphin levels. Anticancer Res, 20, 4039-46
  5. Davies NM (1995). Clinical pharmacokinetics of flurbiprofen and its enantiomers. Clin Pharmacokinet, 28, 100-14.
  6. El-Sheikh N, Boswell MV (2004). Plasma Beta-endorphin levels before and after relief of cancer pain. Pain Physician, 7, 67-70.
  7. Facchinetti F, Nappi G, Savoldi F, Genazzani AR (1981). Primary headaches: reduced circulating beta-lipotropin and beta-endorphin levels with impaired reactivity toacupuncture. Cephalalgia, 1, 195-201.
  8. Fujii Y, Itakura M (2009). Pretreatment with flurbiprofen axetil, flurbiprofen axetil preceded by venous occlusion, and a mixture of flurbiprofen axetil and propofol in reducing pain on injection of propofol in adult Japanese surgical patients: a prospective, randomized, double-blind, placebo-controlled study. Clin Ther, 31, 721-7.
  9. Fujii Y, Itakura M (2011). Efficacy of the lidocaine/flurbiprofen axetil combination for reducing pain during the injection of propofol. Minerva Anestesiol, 77, 693-7.
  10. Fujimoto Y, Nomura Y, Hirakawa K, et al (2012). Flurbiprofen axetil provides a prophylactic benefit against mesenteric traction syndrome associated with remifentanil infusion during laparotomy. J Anesth, 26, 490-5.
  11. Hao J, Wang K, Shao Y, Cheng X, Yan Z (2013). Intravenous flurbiprofen axetil to relieve cancer-related multiple breakthrough pain: a clinical study. J Palliat Med, 16, 190-202.
  12. Hargreaves KM, Flores CM, Dionne RA, Mueller GP (1990). The role of pituitary beta-endorphin in mediating corticotropin-releasing factor-induced antinociception. Am J Physiol, 258, 235-42.
  13. Indelicato RA, Portenoy RK (2002). Opioid rotation in the management of refractory cancer pain. J Clin Oncol, 20, 348-52.
  14. Lin CP, Lin WY, Lin FS, et al (2012). Efficacy of intrathecal drug delivery system for refractory cancer pain patients: a single tertiary medical center experience. J Formos Med Assoc, 111, 253-7.
  15. Liu ZF, Chai XQ, Chen KZ (2011). Flurbiprofen axetil enhances analgesic effect of fentanyl associated with increase in $\beta$-endorphin levels. J Anesth, 25, 679-84.
  16. ona V (1985). Plasmatic beta-endorphin levels and thalamic surgery for pain. Neurol Res, 7, 35-8.
  17. Meuser T, Pietruck C, Radbruch L, et al (2001). Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain, 93, 247-57.
  18. Mizushima Y, Shoji Y, Kato T, Fukushima M, Kurozumi S (1986). Use of lipid microspheres as a drug carrier for antitumour drugs. J Pharm Pharmacol, 38, 132-44.
  19. Mystakidou K, Befon S, Hondros K, Kouskouni E, Vlahos L (1999). Continuous subcutaneous administration of high-dose salmon calcitonin in bone metastasis: pain control and beta-endorphin plasma levels. J Pain Symptom Manage, 18, 323-30.
  20. Park KM, Lee MK, Hwang KJ, Kim CK (1999). Phospholipid-based microemulsions of flurbiprofen by the spontaneous emulsification process. Int J Pharm, 183, 145-54.
  21. Portenoy RK, Ganae-Motan ED, Allende S, et al (2012). Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain, 13, 438-49.
  22. Robinson RL, Kroenke K, Mease P, et al (2012). Salas Burden of illness and treatment patterns for patients with fibromyalgia. Pain Med, 13, 1366-76.
  23. Roszkowski MT, Swift JQ, Hargreaves KM (1997). Effect of NSAID administration on tissue levels of immunoreactive prostaglandin E2, leukotriene B4, and (S)-flurbiprofen following extraction of impacted third molars. Pain, 73, 339-45.
  24. Sanchez R, Alexander-Sierra F, Oliveros R (2012). Relationship between quality of life and clinical status in patients with gastrointestinal cancer. Rev Esp Enferm Dig, 104, 584-91.
  25. Shaiova L, Sperber KT, Hord ED (2002). Methadone for refractory cancer pain. J Pain Symptom Manage, 23, 178-80.
  26. Smith TJ, Coyne PJ (2005). Implantable drug delivery systems (IDDS) after failure of comprehensive medical management (CMM) can palliate symptoms in the most refractory cancer pain patients. J Palliat Med, 8, 736-42.
  27. Su C, Su Y, Chou CW, et al (2012). Intravenous flurbiprofen for post-thymectomy pain relief in patients with myasthenia gravis. J Cardiothorac Surg, 7, 98
  28. Takada M, Taruishi C, Sudani T, Suzuki A, Iida H (2013). Intravenous flurbiprofen axetil can stabilize the hemodynamic instability due to mesenteric traction syndrome--evaluation with continuous measurement of the systemic vascular resistance index using a $FloTrac^{(R)}$ sensor. J Cardiothorac Vasc Anesth, 27, 696-702.
  29. Tseng LF (2001). Evidence for epsilon-opioid receptor-mediated beta-endorphin-induced analgesia. Trends Pharmacol Sci, 22, 623-30.
  30. Vendramini-Costa DB, Carvalho JE (2012). Molecular link mechanisms between inflammation and cancer. Curr Pharm Des, 18, 3831-52.
  31. Wu H, Chen Z, Sun G, et al (2009). Intravenous flurbiprofen axetil can increase analgesic effect in refractory cancer pain. J Exp Clin Cancer Res, 28, 33-43.
  32. Xu Y, Tan Z, Chen J, Lou F, Chen W (2008). Intravenous flurbiprofen axetil accelerates restoration of bowel function after colorectal surgery. Can J Anaesth, 55, 414-22.
  33. Yamashita K, Fukusaki M, Ando Y, et al (2006). Preoperative administration of intravenous flurbiprofen axetil reduces postoperative pain for spinal fusion surgery. J Anesth, 20, 92-5.
  34. Zhang WZ, Yu WJ, Zhao XL, He BX (2014). Pharmacoeconomics evaluation of morphine, ms contin and oxycodone in the treatment of cancer pain. Asian Pac J Cancer Prev, 15, 8797-800.
  35. Zhang Z, Zhao H, Wang C, Han F, Wang G (2011). Lack of preemptive analgesia by intravenous flurbiprofen in thyroid gland surgery: a randomized, double-blind and placebo-controlled clinical trial. Int J Med Sci, 8, 433-8.

Cited by

  1. Do Resting Plasma β-Endorphin Levels Predict Responses to Opioid Analgesics? vol.33, pp.1, 2017,