What is safer for the gastrointestinal-tract: Coxibs or meloxicam?

Are high cyclooxygenase-2 (COX-2) selectivity and the absence of its impact on COX-1 the most important benefit of coxibs? Based on the classical concepts that nonsteroidal anti-inflammatory drugs (NSAIDs) are implicated in the pathogenesis of the most well-known complication – NSAID gastropathy, this must be so. Indeed, the development of gastrointestinal tract (GIT) diseases associated with NSAID use is mainly related to the blockade of COX-1 and to the decreased synthesis of cytoprotective prostaglandins. However, the clinical experience with etoricoxib, one of the most selective coxibs, casts doubt on this fact. There are well-known data of the MEDAL study, which show the equal rate of gastrointestinal bleeding in patients receiving etoricoxib and diclofenac. At the same time, moderately selective NSAIDs that include very popular meloxicam demonstrate a good tolerability and a low risk for GIT complications. A network meta-analysis of 36 studies covering a total of 112,351 patients indicates that there are no significant differences in the incidence of complicated and uncomplicated ulcers in patients receiving coxibs (a group analysis) and moderately selective NSAIDs (meloxicam, nabumetone, and etodolac). It is important that meloxicam demonstrates not only the low total frequency of GIT complications, but a quite moderate (as compared with diclofenac and etoricoxib) risk for cardiovascular and renal complications, which determines its benefit when used in real clinical practice.

1. Harirforoosh S, Asghar W, Jamali F. Adverse Effects of Nonsteroidal Antiinflammatory Drugs: An Update of Gastrointestinal, Cardiovascular and Renal Complications. J Pharm Pharm Sci. 2013;16(5):821-47.

2. Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti- inflammatory drugs. J Pain Res. 2015 Feb 20;8:105-18. doi: 10.2147/JPR.S75160. eCollection 2015.

3. Danelich IM, Wright SS, Lose JM, et al. Safety of nonsteroidal antiinflammatory drugs in patients with cardiovascular disease. Pharmacotherapy. 2015 May;35(5):520-35. doi: 10.1002/phar.1584. Epub 2015 May 4.

4. Scarpignato C, Lanas A, Blandizzi C, et al. Safe prescribing of non-steroidal anti- inflammatory drugs in patients with osteoarthritis – an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks. BMC Med. 2015 Mar 19;13:55. doi: 10.1186/s12916-015-0285-8.

5. Каратеев АЕ, Насонов ЕЛ, Яхно НН и др. Клинические рекомендации «Рациональное применение нестероидных противовоспалительных препаратов (НПВП) в клинической практике». Современная ревматология. 2015;9(1):4-24. [Karateev AE, Nasonov EL, Yakhno NN, et al. Clinical guidelines «Rational use of nonsteroidal antiinflammatory drugs (NSAIDs) in clinical practice». Sovremennaya revmatologiya = Modern Rheumatology Journal. 2015;9(1):4-24. (In Russ.)]. doi: 10.14412/1996-7012-2015-1-4-23.

6. Rainsford K. Anti-inflammatory drugs in the 21st century. Subcell Biochem. 2007;42:3-27.

7. Gargiulo G, Capodanno D, Longo G, et al. Updates on NSAIDs in patients with and without coronary artery disease: pitfalls, interactions and cardiovascular outcomes. Expert Rev Cardiovasc Ther. 2014 Oct;12(10):1185-203. doi: 10.1586/14779072. 2014.964687. Epub 2014 Sep 15.

8. Martina S, Vesta K, Ripley T. Etoricoxib: a highly selective COX-2 inhibitor. Ann Pharmacother. 2005 May;39(5):854-62. Epub 2005 Apr 12.

9. Schwartz J, Dallob A, Larson P, et al. Comparative inhibitory activity of etoricoxib, celecoxib, and diclofenac on COX-2 versus COX-1 in healthy subjects. J Clin Pharmacol. 2008 Jun;48(6):745-54. doi: 10.1177/0091270008317590. Epub 2008 Apr 23.

10. Brooks P, Kubler P. Etoricoxib for arthritis and pain management. Ther Clin Risk Manag. 2006 Mar;2(1):45-57.

11. Ramey D, Watson D, Yu C, et al. The incidence of upper gastrointestinal adverse events in clinical trials of etoricoxib vs. non-selective NSAIDs: an updated combined analysis. Curr Med Res Opin. 2005 May;21(5):715-22.

12. Hunt R, Harper S, Watson D, et al. The gastrointestinal safety of the COX-2 selective in- hibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events. Am J Gastroenterol. 2003 Aug;98(8):1725-33.

13. Cannon C, Curtis S, FitzGerald G, et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Longterm (MEDAL) programme: a randomised comparison. Lancet. 2006 Nov 18;368(9549): 1771-81.

14. Laine L, Curtis SP, Cryer B, et al. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 2007 Feb 10; 369(9560):465-73.

15. Laine L, Curtis S, Langman M, et al. Lower gastrointestinal events in a doubleblind trial of the cyclo-oxygenase-2 selective inhibitor etoricoxib and the traditional nonsteroidal anti- inflammatory drug diclofenac. Gastroenterology. 2008 Nov; 135(5):1517-25. doi: 10.1053/j.gastro.2008.07.067. Epub 2008 Aug 3.

16. Bhala N, Emberson J, Merhi A, et al. Vascular and upper gastrointestinal effects of non- steroidal anti-inflammatory drugs: metaanalyses of individual participant data from randomised trials. Coxib and traditional NSAID Trialists' (CNT) Collaboration. Lancet. 2013 Aug 31;382(9894):769-79.

17. Krum H, Swergold G, Curtis SP, et al. Factors associated with blood pressure changes in patients receiving diclofenac or etoricoxib: results from the MEDAL study. J Hypertens. 2009 Apr;27(4):886-93. doi: 10.1097/HJH.0b013e328325d831.

18. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011 Sep;8(9):e1001098. doi: 10.1371/journal.pmed.1001098. Epub 2011 Sep 27.

19. Varas-Lorenzo C, Riera-Guardia N, Calingaert B, et al. Myocardial infarction and individual nonsteroidal anti-inflammatory drugs meta-analysis of observational studies. Pharmacoepidemiol Drug Saf. 2013 Jun;22(6): 559-70.

20. Gates BJ, Nguyen TT, Setter SM, Davies NM. Meloxicam: a reappraisal of pharmacokinetics, efficacy and safety. Expert Opin Pharmacother. 2005 Oct;6(12):2117-40.

21. Xu S, Rouzer CA, Marnett LJ. Oxicams, a class of nonsteroidal anti-inflammatory drugs and beyond. IUBMB Life. 2014 Dec;66(12):803-11. doi: 10.1002/iub.1334. Epub 2014 Dec 23.

22. Schoenfeld P. Gastrointestinal safety profile of meloxicam: a meta-analysis and systematic review of randomized controlled trials. Am J Med. 1999 Dec 13;107(6A): 48S-54S.

23. Singh G, Lanes S, Triadafilopoulos G. Risk of serious upper gastrointestinal and cardiovascular thromboembolic cpmplications with meloxicam. Am J Med. 2004 Jul 15;117(2):100-6.

24. Kivitz AJ, Greenwald MW, Cohen SB, et al. Efficacy and safety of rofecoxib 12.5 mg versus nabumetone 1,000 mg in patients with osteoarthritis of the knee: a randomized controlled trial. J Am Geriatr Soc. 2004 May;52(5):666-74.

25. Weaver AL, Messner RP, Storms WW, et al. Treatment of patients with osteoarthritis with rofecoxib compared with nabumetone. J Clin Rheumatol. 2006 Feb;12(1):17-25.

26. Yang M, Wang HT, Zhao M, et al. Network Meta-Analysis Comparing Relatively Selective COX-2 Inhibitors Versus Coxibs for the Prevention of NSAID-Induced Gastrointestinal Injury. Medicine (Baltimore). 2015 Oct;94(40):e1592. doi: 10.1097/MD.0000000000001592.

27. Layton D, Heeley E, Hughes K, Shakir SA. Comparison of the incidence rates of selected gastrointestinal events reported for patients prescribed rofecoxib and meloxicam in general practice in England using prescription- event monitoring data. Rheumatology (Oxford). 2003 May;42(5):622-31.

28. Layton D, Hughes K, Harris S, Shakir SA. Comparison of the incidence rates of selected gastrointestinal events reported for patients prescribed celecoxib and meloxicam in general practice in England using prescription-event monitoring (PEM) data. Rheumatology (Oxford). 2003 Nov;42(11): 1332-41. Epub 2003 Jun 16.

29. Asghar W, Jamali F. The effect of COX-2-selective meloxicam on the myocardial, vascular and renal risks: a systematic review. Inflammopharmacology. 2015 Feb;23(1):1-16. doi: 10.1007/s10787-014-0225-9. Epub 2014 Dec 17.

30. Каратеев АЕ, Насонов ЕЛ. Мелоксикам в России: 20 лет вместе. Терапевтический архив. 2016;88(12):149-58. [Karateev AE, Nasonov EL. Meloxicam in Russia: 20 years together. Terapevticheskii arkhiv. 2016;88(12):149-58. (In Russ.)].