NSAID Gastropathy

Contents

Definition/Description


What is an NSAID? Nonsteroidal Anti-inflammatory drug.

  • “Despite well known complications, oral nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most commonly prescribed medications in the US for musculoskeletal disorders such as osteoarthritis”  [1]
  • NSAIDs are prescribed to decrease pain and inflammation.


What medications are NSAIDs? [2]

  • Ketorolac
  • Piroxicam
  • Naproxen
  • Indomethacin
  • Ketoprofen
  • Diclofenac
  • Ibuprofen
  • Nabumetone
  • Etodolac
  • Oxaprozin
  • Aspirin


NSAID induced gastropathy can result from too high of dosage or too frequent intake of NSAID drugs as well as long-term use. These drugs are used to decrease pain and inflammation and are often taken by those diagnosed with osteoarthritis and rheumatoid arthritis or other musculoskeletal conditions. Doctors often prescribe this drug to these individuals as well as suggest over the counter (OTC) types of NSAIDs. Because of the easy accessibility of these drugs, the incidence rate of NSAID induced gastropathy is high, especially among individuals who are >60 years. [2]

NSAID induced gastropathy can result in stomach or duodenal ulcers which may even lead to death. There are thousands of hospitalizations over each year just from symptoms resulting from NSAID use. Though these rates are high, most individuals do not know the risk of these medications and continue to take them. Also, this induced gastropathy goes on asymptomatically until it is too late and has caused further damage of the gastrointestinal tract. [2][1]

“NSAIDs are COX-1 inhibitors which suppress the mucous barrier in the gastrointestinal system which can lead to break down of the GI tract as well as increase in the acidity of the gastric contents.” [3]

Prevalence

  • “Patients with rheumatoid arthritis (RA) and osteoarthritis (OA) taking NSAIDs have an ulcer incidence of approximately 15-20%” [2]
  • “Although a 15-25% incidence of gastric and/or duodenal ulcer has been demonstrated in all patients taking NSAIDs, the bleeding rate is estimated by most experts at only 2-4%”. [2]
  • 1 in 10 NSAID induced ulcer bleeds. [2]
  • “In elderly patients taking NSAIDs, the relative risk of GI surgery is 10 times, and for GI cause of death, about 4.5 times greater than in control groups” [2]
  • “Approximately 20 million patients in the US take NSAIDs on a regular basis; the risk for hospitalization for serious GI adverse effects is 1-2%, resulting in approximately 200,000 to 400,000 hospitalizations per year at an average cost of $4,000 per patient, or 0.8-1.6 billion dollars annually” [2]
  • “An increased risk of GI bleeding has even been noted in patients taking low dose aspirin therapy for cardiovascular prophylaxis” [2]
  • “Gastric and duodenal lesions were more common in patients who took NSAIDs for <3 months, whereas patients with a longer duration of therapy tended to have more lesions in the small bowel and colon” [2]
  • “Some recent studies have shown that the incidence of duodenal ulcer is increased in Helicobacter pylori-positive patients taking NSAIDs…It has been recently reported that eradication of H.pylori before NSAID therapy strikingly reduces the incidence of ulcer disease in patients being treated with naproxen.” [2]
  • “Among individuals with arthritis, almost 30% report daily use of OTC NSAIDs…Safety often is not considered or well understood among consumers of OTC NSAIDS until after the occurrence of adverse events such as gastropathy” [1]
Figure 1: Comparison of mortality statistics on seven disorders

[4]

Characteristics/Clinical Presentation

Up to 50% of NSAID induced gastropathy is asymptomatic. [1]

  1. Mild dyspepsia
  2. Heartburn
  3. Nausea
  4. Abdominal discomfort
  5. Erosion
  6. Ulcers
  7. Hemorrhage
  8. Perforation
  9. Obstruction
  10. Occult and frank bleeding
  11. Acute colitis
  12. Exacerbation of existing colon disease

[3][1][2]

Associated Co-morbidities

Osteoarthritis

Rheumatoid Arthritis

Ankylosing Spondylitis

Other musculoskeletal conditions

Cardiovascular Complications

Medications

Prostaglandin E1 analog misoprostol can prevent gastric ulcer and duodenal ulcer [2]

Proton pump inhibitor (PPI) omeprazole reduces gastric ulcer and prevents duodenal ulcer [2]. Though PPIs can help with gastric irritation, it is also found that they can induce risk of osteoporosis which often cause hip fractures in elderly patients as well as increase cardiovascular risk due to low serum magnesium levels in the blood. [1]

H2 receptor antagonists are effective in preventing duodenal ulcer but not gastric ulcer. [2]

“Studies have shown that antacids and buffered tablets do not protect against NSAID injury” [2]

Diagnostic Tests/Lab Tests/Lab Values

An early finding of anemia may warrant more extensive diagnostic testing such as an endoscopy or radiography in determination of NSAID gastropathy. Hematocrit and hemoglobin levels may also provide information about the extent of bleeding from perforation or hemorrhage. As NSAID induced ulcers are often asymptomatic, patient history and diagnostic tests/lab values are important in diagnosis[5]. Endoscopy has a success rate of 90% for diagnosis of a peptic ulcer, however, it is expensive and the rate of correct diagnosis of NSAID gastropathy is high among physicians. (See Tamblyn et al 1997 study on high gastropathy diagnostic rates by physicians[6].) Radiography with barium can also detect and diagnose peptic ulcers but is less common than endoscopy.


Stomach hematin-covered erosions typical of NSAID use
Stomach hematin-covered erosions typical of NSAID use
NSAID gastropathy with upper GI hemorrhage
NSAID gastropathy with upper GI hemorrhage
NSAID induced stomach ulcer (same pt as image to left)
NSAID induced stomach ulcer (same pt as image to left)

[7]

Etiology/Causes

NSAIDs inhibit the enzyme cyclooxygenase which is a necessary enzyme for the synthesis of prostaglandins from arachidonic acid. While inhibition of COX allows NSAIDs to have their anti-inflammatory and analgesic properties by blocking proinflammatory prostaglandins, it also blocks prostaglandins that protect the gastrointestinal system. Prostaglandins in the gastric system help maintain gastric blood flow, increase bicarbonate production, and increase mucus that serves as a protective barrier against bacteria colonization and mechanical injury. Decreased blood flow and decreased mucosa decrease the healing ability and leave the stomach more exposed to injury from pepsin and gastric acid. Furthermore, these decreases lead to “increased back-diffusion of hydrogen ions into epithelial cells with resultant impaired mucosal resistance to injury”.

The function of cyclooxygenase in this process led to the establishment of two COX isoforms: COX-1 and COX-2. COX-1 is found throughout all tissues of the body whereas COX-2 is in the area of inflammation such as in an area of osteoarthritis contributing to the inflammation. Previous NSAIDs included both COX-1 and COX-2 inhibitors, however, in the 1990s COX-2 medications were developed to act on the areas of inflammation without causing the mucosal effects to the GI tract from inhibitng COX-1. COX-2 inhibitors are associated with fewer upper GI side effects, however, they are not as symptom free as hoped and still place people at risk of gastroduodenal mucosa injury. The opinion that only COX-1 affects GI issues is simplistic and not the full story. Medications that suppress acid have shown to be effective in combination with NSAIDs to a greater extent than COX-2 medications alone[2]. These medications are discussed below in the medical management section.

Pathogenesis of NSAID-induced gastric injury via 3 pathways
Pathogenesis of NSAID-induced gastric injury via 3 pathways







[8]

Systemic Involvement

The effects of NSAIDs can occur throughout the GI tract from the esophagus to the colon. A potential complication of ulcers left untreated is that the ulcer can perforate through the stomach mucosa and cause infection to spread or the ulcer can erode stomach arteries creating a life-threatening bleed. In addition to effects on the GI system, NSAIDs also affect the renal and cardiovascular systems[9].  For more information on systemic involvement from NSAIDS, please see en.wikipedia.org/wiki/Non-steroidal_anti-inflammatory_drug.

Medical Management (current best evidence)

One of the difficulties of NSAID gastropathy is that its course is asymptomatic 50% of the time[1].  Therefore, it is essential that health care professionals assess each patient's risk factors and recommend either discontinued use of an NSAID or inclusion an accompanying cytoprotectant agent in those patients considered high risk.  A preventative approach of discontinued NSAID use is recommended over treating the gastropathy[1].

However, if it is not possible to discontinue use of the NSAID, PPIs or H2-receptor antagonists may be prescribed to reduce the gastric effects.  The use of a PPI along with NSAIDs has shown decreased risk of NSAID-related ulcers and adverse drug events compared with H2-receptor antagonists. A COX-2 selective NSAID along with a PPI has shown the best results for reducing gastropathy risk in those who must continue to take NSAIDs[10]. Other treatment options include misoprostol which is a synthetic prostaglandin designed to replace those loss by NSAIDs. However, misoprotol has a lot of side effects that have proved difficult such as abdominal pain, nausea, and diarrhea[11].

[12]

Physical Therapy Management (current best evidence)

Many of the patients seen in physical therapy will be taking NSAIDs for their disorder.  PTs must be aware of risk factors, clinical signs and systems (and be aware the patient may be asymptomatic but still have NSAID induced gastropathy), and they must take a detailed patient history including medication questions concerning multiple NSAIDs, prescription drugs combined with NSAIDs, and changes to medications. Any patient who presents with new onset of back or shoulder pain, who takes NSAIDs, and who presents with signs and symptoms of a peptic ulcer must be referred to the MD.  Goodman and Snyder list clinical signs and symptoms of NSAID induced impairment, risk factors for NSAID-induced gastropathy, and a formula for calculating a patient's risk of NSAID-induced gastropathy in their book Differential Diagnosis for Physical Therapists: Screening for Referral.[9]

          Below are clinical signs and systems associated with NSAID-induced impairment.

  • Asymptomatic
  • Stomach upset (nausea) and stomach pain
  • Indigestion, heartburn
  • Skin reactions (itching, rash, acne)
  • Tinnitus
  • CNS changes (headache, depression, confusion (older adult), memory loss (older adult), mood changes)
  • Renal involvement (muscle weakness, unusual fatigue, restless legs, polyuria, nocturia, pruritus, increased blood pressure)
  • New onset of back (thoracic) or shoulder pain 
  • Pain relief after eating
  • Melena                                                                                                                                                                                                                                                  Risk factors for NSAID induced gastropathy are listed below.  Any risk factor recognized should serve as a red flag.  The incidence of mortality and morbidity from NSAID use is high among the aging population and taking a detailed patient history is essential.
  • Age > 65 years
  • History of peptic ulcer or GI disease
  • Smoking, alcohol use
  • Oral corticosteroid use
  • Anticoagulation of use of other anticoagulants (even when used for heart patients at a lower dose
  • Renal complications in clients with hypertension or congestive heart failure or who use diuretics or ACE inhibitors
  • Use of acid suppressants (H2-receptor antagonists, antacids); these agents can mask the warning symptoms of more serious GI complications, leaving the client unaware of ongoing damage
  • NSAIDs combined with SSRIs          

          Calculating Your Client's Risk of NSAID-Induced Gastropathy:

     Risk is equal to the sum of                                            Calculation

  • Age in years                                                                Multiply x 2=
  • History of NSAID symptoms                                      If yes, add 50 points
  • ARA Class                                                                    Add 0, 10, 20, or 30 based on class 1-4
  • NSAID Dose (fraction of max recommended)         NSAID dose x 15
  • If currently using prednisone                                   Add 40 points

TOTAL SCORE
*Risk/year=[Total score-100]/40

Alternative/Holistic Management (current best evidence)

Up and coming nontoxic NSAIDs but little evidence [2]

COX-2 selective inhibitors

  • COX-1 enzyme is blocked, inflammation is reduced, but protection of stomach lining is lost with normal NSAID
  • COX-2 inhibitors block COX-2 enzyme and does not play a role in the gastroprotection, therefore decrease the incidence of gastrointestinal adverse effects and still reduce inflammation and pain. But it may cause cardiovascular complications because it can cause thrombosis due to suppression of inflammatory mediators in atherogenesis. It can also cause renal toxicity and peripheral edema. [1]
  • Two COX-2 inhibitors have been removed from the market recently (fecoxib in 2004 and valdecoxib in 2005)

Nitric oxide- releasing NSAIDs

Topical NSAIDs          

  • Deliver the drug directly to the tissue but avoids absorption through the gastrointestinal tract. [1]

Differential Diagnosis

Peptic ulcers are typically caused by H. pylori infection or acid related consumption and are commonly in young males [1]

Crohn's Disease is a type of inflammatory bowel disease which causes the gastrointestinal tract to be chronically inflammed.  Common symptoms of this disease include abdominal pain, diarrhea, blood in the stool and vomiting and can even cause rectal or gastrointestinal bleeding, loss of appetite and liver inflammation. [13]

Gastroesophageal Reflux Disease (GERD) is caused by stomach acid back flowing into the esophagus.  The most common symptom is heartburn but those with GERD can also have a dry cough, asthma-like symptoms, and trouble swallowing. [14]

Case Reports/ Case Studies

Case Study #1: The relationship between upper gastrointestinal hemorrhage and drug use: a case control study.

Tamblyn, R, Berkson, L, Dauphinee, WD, Gayton, D, Grad, R, Huang, A, Issac, L, McLeod, P, Snell, L[15]

Abstract:
• This prospective cohort study examined the way in which NSAIDs are necessarily or unnecessarily prescribed, if MDs are effective at diagnosing NSAID related problems, and if NSAID side effects are treated effectively. The authors searched for common factors present in suboptimal prescription and use of NSAIDs.


Patient Characteristics:
• 112 physicians (general practitioners and residents in family medicine and internal medicine
• Each MD saw 2-4 elderly patients over a 6-8 month period and were


Examination:
• Patients presented to the MD’s office with one of two cases: either a recent exacerbation of chronic hip pain (with treatment options either lifestyle modification, physical therapy or medication), or the patient presented with epigastric pain secondary to NSAID use, and the MDs must recognize, diagnose, and determine the best course of action.


Findings:
• Unnecessary NSAID prescriptions were written during 41.7% of the visits and often to patients who were elderly and had relative contraindications to NSAID use
• NSAID gastropathy was correctly diagnosed 93.4% of the time and was acceptably managed 77.4% of the visits.


Case study #2: Risk of upper gastrointestinal events with the use of various NSAIDs: A case-control study in a general population
Helin-Salmivaara, A, Saarelainen, S, Grönroos, JM, Vesaleinen, R, Klaukka, T, Huupponen, R[16]

Abstract:
 • The authors performed a case-control study of a national database to examine the risk of non-selective NSAIDs verse COX-2 selective NSAIDs in the general population


Patient Characteristics:

• 9191 patients with upper GI events requiring hospitalization and matched controls from a hospital database


Findings:
• When comparing COX-2 selective NSAIDs with non-selective NSAIDs, the authors did not find a substantial enough difference in outcomes to warrant the higher cost of COX-2 specific drugs. Additionally, semi-selective drugs did not show any advantage over       other NSAIDs in protection of the GI system.
• Avoid multiple NSAIDs. Multiple NSAIDs increase the risk of a GI event by 5x someone who does not use NSAIDs
• NSAID and misoprostol may be a good alternative for patients at risk of GI injury.


Case Study #3: A healthy 59 year old woman with osteoarthritis

Lee, L[17]

Abstract:
This case study examines a 59-year old female with osteoarthritis who is in the no risk/low risk category for GI events for what medications would be best.


Patient Characteristics:
• 59 yo female, previously worked as a secretary
• Takes 4g acetaminophen daily, but that only provides some relief of pain and stiffness


Examination:
• VS and auscultation normal, blood chemistry and lipids WNR, osteoarthritis of knees, hips and lower back evident on radiography


Findings:
• For someone with little to no risk for GI complications, no known cardiovascular requirements, and who does not use aspirin chronically, a traditional nonselective NSAID would be fine. COX-2 inhibitors are an option but they are more expensive.
• If GI symptoms (dyspepsia) develop while taking the NSAIDs for osteoarthritis, an antacid, PPI or H2-receptor antagonist should be added
• Misoprostol and PPIs have been shown most effective at healing and preventing NSAID related ulcers.

Resources

American College of Gastroenterology website

gi.org/guideline/prevention-of-nsaid-related-ulcer-complications/


American College of Gastroenterology's informational brochure Understanding Ulcers, NSAIDs and GI bleeding
s3.gi.org/patients/pdfs/UnderstandGIBleednew.pdf

Recent Related Research (from Pubmed)

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References

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  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Roth S. Coming to terms with nonsteroidal anti-inflammatory drug gastropathy. Drugs(2012, May 7), 72(7): 873-879.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 Lanza F. A guideline for the treatment and prevention of NSAID-induced ulcers. Members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. The American Journal Of Gastroenterology. (1998, Nov), 93(11): 2037-2046.
  3. 3.0 3.1 Gigante A, Tagarro I. Non-steroidal anti-inflammatory drugs and gastroprotection with proton pump inhibitors: a focus on ketoprofen/omeprazole. Clinical Drug Investigation. (2012, Apr 1),32(4): 221-233.
  4. Gastrosource. Non-steroidal anti-inflammatory drug (NSAID)-associated upper gastrointestinal side-effects. http://www.gastrosource.com/disease-area-information/11674565?itemId=11674565 (accessed 9 March 2013).
  5. Taylor, RB. Manual of Family Practice, 2e. Lippincott Williams &amp;amp;amp;amp;amp; Wilkins, 2002.
  6. Tamblyn, R, Berkson, L, Dauphinee, WD, Gayton, D, Grad, R, Huang, A, Isaac, L, McLeod, P, Snell, L. Unnecessary prescribing of NSAIDs and the management of NSAID-related gastropathy in medical practice. Ann Intern Med 1997;127:429-438
  7. Atlas of Gastroenterological Endoscopy. Stomach: NSAID Gastropathy. http://www.endoskopischer-atlas.de/m15e.htm (accessed 9 March 2013).
  8. Wallace, JL. Prostaglandins, NSAIDs, and Gastric Mucosal Protection: Why Doesn't the Stomach Digest Itself? Physio Rev 2008;88(4):1547-65.
  9. 9.0 9.1 Goodman, CC, Snyder, TEK. Differential Diagnosis for Physical Therapists: Screening for Referral. St. Louis: Saunders Elsevier, 2007.
  10. Becker, JC, Domschke W, Pohle T. Current Approaches to prevent NSAID-induced gastropathy—COX selectivity and beyond. Br J Clin Pharmacol.2004;58:6:587-600.
  11. Lanza, F, Chan, FKL, Eamonn, MMQ, and the Practice Parameters Committee of the American College of Gastroenterology. Guidelines for Prevention of NSAID-related ulcer complications. Am J Gastroenterol.2009;104:728-738.
  12. Schellack, N. Overview of gastropathy induced by nonsteroidal anti-inflammatory drugs. S Afr Pharm J 2012;79(4):12-18.
  13. IU health. Riley Hospital for Children: 2013. Available from: http://iuhealth.org/riley/gastroenterology/diseases-conditions/crohns-disease/
  14. Berry, J., PhD, APRN. IU Health. Health Encyclopedia. April 2012. Available from: http://iuhealth.staywellsolutionsonline.com/Library/Encyclopedia/85,P00381
  15. Tamblyn, R, Berkson, L, Dauphinee, WD, Gayton, D, Grad, R, Huang, A, Issac, L, McLeod, P, Snell, L. Unnecessary prescribing of NSAIDs and the management of NSAID-related gastropathy in medical practice. Ann Int Med. 1997;127:429-438.
  16. Helin-Salmivaara, A, Saarelainen, S, Grönroos, JM, Vesaleinen, R, Klaukka, T, Huupponen, R. Risk of upper gastrointestinal events with the use of various NSAIDs: a case control study in a general population. Scandinavian Journal of Gastroenterology 2007; 42:923-32.
  17. Lee, L. A healthy 59-year-old woman with osteoarthritis. Adv Studies in Medicine 2003;3(6B):S519-20.