September 23, 2018
NSAIDS and gastrointestinal toxicity

NSAIDS and Gastrointestinal Complications

In part 2 of this Non-Steroidal Antiinflammatory Drugs (NSAIDS) review, we’ll review the risk of gastrointestinal complications. In our previous article, we discussed cardiovascular disease and NSAID use. Here we will review gastrointestinal complications. As discussed previously, NSAIDS are one of the most commonly used drugs in the world and their use is increasing in the US and globally. In 2013, NSAIDs had accounted for more than 70 million prescriptions and 30 billion over-the-counter purchases [1]. Sports medicine physicians should be cognizant of potential complications, especially gastrointestinal toxicity. Awareness can lead to better prescribing practices and increased safety for at-risk patients.
NSAIDS cause gastrointestinal injury by reducing availability of the prostaglandin substrates leading to mucosal injury. Inhibiting COX-1 blocks “production of prostaglandins that play an important protective role in the stomach by increasing mucosal blood flow and stimulating the synthesis and secretion of mucus and bicarbonate, as well as promoting epithelial proliferation” [2]. This leaves the gastrointestinal mucosa vulnerable to acid secretion, digestive enzymes and acidic diet which all contribute the development of gastrointestinal complications from NSAID use. COX-2 mediated prostaglandin inhibition primarily targets the anti-inflammatory cascade of the prostaglandin cycle, sparing COX-1 inhibition and reducing the risk of GI toxicity. This lead to the development of selective COX-2 inhibitors such as celecoxib.
Although many athletes may not be at high risk of GI complications, many patients with orthopedic injuries or illness are. In one study of patients with osteoarthritis, 86.6% were at increased risk of GI toxicity and 22.3% were at high risk. Evaluation of GI risk includes determination of the presence of well-known risk factors such as age greater than 60, severe illness, H. pylori infection, previous history of GI bleeding, complicated or uncomplicated peptic ulcer and/or GI symptoms (dyspepsia), high risk surgical history including bariatric procedures, the use of high-dose NSAIDs, the combination of two NSAIDs including low-dose aspirin, or the concomitant use of NSAIDs and anticoagulants or corticosteroids [3, 4].
Use of NSAIDS increases the risk of gastrointestinal complications by 3-5 fold compared to non-users [5]. The first two months of use may be the period of greatest risk [6], however risk remains elevated afterwards if treatment is continued. Patients experience upper GI complications at a rate of approximately 6 times more frequently than lower GI tract. The rate of lower gastrointestinal complications are less well characterized but thought to be increasingly common [7].
The first category of adverse events are symptom related. Patients may report multiple symptoms related to NSAID use including heartburn, dyspepsia, reflux, abdominal pain, nausea and vomiting. Between 40 and 60% of NSAID users will report at least one of these symptoms and they do not reliably predict future complications [8]. The poor tolerability often results in self discontinuation of therapy.
The second category of adverse events can be termed NSAID-related gastroduodenal injury of unclear clinical significance. Patients may be asymptomatic but have erosion or ulceration on EGD and somewhere between 15-30% of patients have endoscopically confirmed GI ulcers [9]. Lastly, patients may develop symptomatic ulcers, bleeding ulcers, obstruction or gastrointestinal bleeding. Complications occur at approximately 1-2% during the first year, increasing to 4-5% of patients with symptomatic ulcers [10]. Although data is scarce, one study in Spain estimated the mortality rate to be 15.3 deaths/100,000 NSAID/aspirin users [11]. In 2006 in the US, this rate was greater than the rate of death from a car accident or firearm injury, which are approximately 15 and 10 per 100,000 people respectively [12].
relative risk of gastrointestinal bleeding for individual NSAIDS

Image 1. Relative risk of upper GI bleeding for individual NSAIDS (courtesy of slideshare.net)

Clinicians should be familiar with which NSAIDs have the lowest risk of gastrointestinal toxicity. In one systematic review from 2012, the risk ratio of upper GI complications, which varied between studies but included upper GI bleeding, bleeding and/or perforation, and uncomplicated peptic ulcer disease,  ranged from 1.43 to 18.45 [13]. Stratified by specific drug, the follow risk ratios were found:
  • RR <2: aceclofenac, celecoxib and ibuprofens

  • RR 2-4: rofecoxib , sulindac, diclofenac , meloxicam, nimesulide and ketoprofen

  • RR 4-5: tenoxicam , naproxen , indomethacin and diflunisal

  • RR >5: piroxicam, ketorolac and azapropazone

In general, selective COX-2 inhibitors have been found to have fewer gastrointestinal symptoms and a lower risk of gastrointestinal complications than non-selective NSAIDS [14]. Diclofenac, nimesulide and sulindac have also been shown to be hepatotoxic [15].
algorithm for NSAID use based on patients gastrointestinal risk

Image 2. Algorithm for long-term NSAID therapy according to a patient’s GI and CV risk factors (courtesy of sciencedirect.com)

Attempts have been made made to mitigate the gastrointestinal risk by altering the preparation of the NSAID with an enteric coating or adding a second medication, namely a proton pump inhibitor, H2 blocker or misoprostol. Enteric coating of aspirin does not appear to reduce the gastrointestinal risk [16]. In patients with a history of bleeding ulcer, comparing the use of celecoxib to diclofenac plus omeprazole did not result in a significant difference in the recurrence of bleeding [17]. In a subsequent study, combining celecoxib with esomeprazole also significantly reduced the incidence of recurrent bleeding [18]. The addition of misoprostol reduced gastrointestinal complications by 40% [19]. PPIs appear to be superior to H2 blockers  but clinically equivalent to misoprostol in the treatment and prevention of peptic ulcers [20, 21]. The use of either NSAIDs plus PPI co-therapy or COX-2-selective agents compared with NSAIDs alone reduced hospitalizations by 54% [22].
In summary, there are no clear guidelines about the use of NSAIDS and screening for gastrointestinal complications. It is recommended that patients at risk of GI complications either receive a non-selective NSAID with a gastroprotective agent or a selective cox-2 inhibitor.  Clinicians should use the “safest” NSAIDS, at the lowest dose, for the shortest period of time. They should avoid NSAIDS with higher gastrointestinal risk. Patients on anticoagulation, oral corticosteroids, low dose ASA or antiplatelet medications should not take NSAIDS. Note that when combined with low-dose aspirin, the benefit of the low risk NSAIDS and coxibs tend to disappear [23]. This pharmacist letter from the therapeutic research center may help guide your decision making.

References

1. Wehling M. Non-steroidal anti-inflammatory drug use in chronic pain conditions with special emphasis on the elderly and patients with relevant comorbidities: management and mitigation of risks and adverse effects. Eur J Clin Pharmacol 2014;70(10):1159–72
2. Bhatt DL, Scheiman J, et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008 Oct 28;118(18):1894-909.
3. Lanas A, Tornero J, et al. Assessment of gastrointestinal and cardiovascular risk in patients with osteoarthritis who require NSAIDs: the LOGICA study. Ann Rheum Dis. 2010 Aug;69(8):1453-8.
4. Sostres C, Gargallo CJ, Arroyo MT, Lanas A. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2010 Apr;24(2):121-32.
5. Gabriel SE, Jaakkimainen L, Bombardier C. Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med. 1991 Nov 15;115(10):787-96.
6. de Abajo FJ, García Rodríguez LA. Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as plain and enteric-coated formulations. BMC Clin Pharmacol. 2001;1:1. Epub 2001 Feb 13.
7. Lanas A, García-Rodríguez LA, et al. (2009) Time trends and impact of upper and lower gastrointestinal bleeding and perforation in clinical practice. Am J Gastroenterol 104:1633–1641.
8. Armstrong CP, Blower AL. Non-steroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut. 1987 May;28(5):527-32.
9. PLanas A, Hunt R. Prevention of anti-inflammatory drug-induced gastrointestinal damage: benefits and risks of therapeutic strategies. Ann Med. 2006;38(6):415-28.
10. Tannenbaum H, Bombardier C, et al; Third Canadian Consensus Conference Group. An evidence-based approach to prescribing nonsteroidal antiinflammatory drugs. Third Canadian Consensus Conference. J Rheumatol. 2006 Jan;33(1):140-57.
11. Lanas A, Perez-Aisa MA, Feu F, et al; Investigators of the Asociación Española de Gastroenterología (AEG). A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol. 2005 Aug;100(8):1685-93.
12. Lanas A. A review of the gastrointestinal safety data–a gastroenterologist’s perspective. Rheumatology (Oxford). 2010 May;49
13. Castellsague J, Riera-Guardia N,et al; Safety of Non-Steroidal Anti-Inflammatory Drugs (SOS) Project. Individual NSAIDs and upper gastrointestinal complications: a systematic review and meta-analysis of observational studies (the SOS project). Drug Saf. 2012 Dec 1;35(12):1127-46.
14. Silverstein FE, Faich G, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000 Sep 13;284(10):1247-55.
15. Aithal GP, Day CP. Nonsteroidal anti-inflammatory drug-induced hepatotoxicity. Clin Liver Dis. 2007 Aug;11(3):563-75, vi-vii. Review.
16. De Abajo FJ, García Rodríguez LA. Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as plain and enteric-coated formulations. BMC Clinical Pharmacology. 2001;1:1. doi:10.1186/1472-6904-1-1.
17. Chan FK, Hung LC, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002 Dec 26;347(26):2104-10.
18. Chan FK, Wong VW, et al. Combination of a cyclo-oxygenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial. Lancet. 2007 May 12;369(9573):1621-6.
19. Silverstein FE, Graham DY, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1995 Aug 15;123(4):241-9.
20. Yeomans ND, Tulassay Z, Juhász L, Rácz I, Howard JM, van Rensburg CJ, Swannell AJ, Hawkey CJ. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med. 1998 Mar 12;338(11):719-26.
21. Graham DY, Agrawal NM, et al; NSAID-Associated Gastric Ulcer Prevention Study Group. Ulcer prevention in long-term users of nonsteroidal anti-inflammatory drugs: results of a double-blind, randomized, multicenter, active- and placebo-controlled study of misoprostol vs lansoprazole. Arch Intern Med. 2002 Jan 28;162(2):169-75.
22. Ray WA, Chung CP, et al. Risk of peptic ulcer hospitalizations in users of NSAIDs with gastroprotective cotherapy versus coxibs. Gastroenterology. 2007 Sep;133(3):790-8. Epub 2007 Jul 3.
23. Lanas A, García-Rodríguez LA, et al. Asociación Española de Gastroenterología. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut. 2006 Dec;55(12):1731-8.
24. Conaghan PG. A turbulent decade for NSAIDs: update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol Int. 2012 Jun;32(6):1491-502. doi: 10.1007/s00296-011-2263-6. Epub 2011 Dec 23. Review.

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