Drug Adverse Effects Non Steroidal Anti Inflammatory Agent

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Adverse-effects

  • gastrointestinal (GI) intolerance
  • NSAID gastropathy
  • dyspepsia (may or may not be present)
  • occult blood loss & iron deficiency anemia
  • release of nitric oxide seems to protect against NSAID gastropathy [6]
  • concurrent proton-pump inhibitor diminishes risk [13]
  • NSAID enterocolopathy
  • 6-7 additional cases per 100,000 person-years
  • exception is aspirin [24]
  • see below
  • renal
  • reduced renal blood flow secondary to intrarenal vasoconstriction
  • most frequently occurs in patients with volume depletion, heart failure, cirrhosis
  • hepatic
  • mild elevation in serum transaminases
  • rarely associated with severe liver damage
  • hematologic
  • agranulocytosis
  • aplastic anemia
  • 1.9-2.0% of patients treated with celecoxib
  • 3.3-5.7% of patients treated with diclofenac [23]
  • platelet aggregating defect
  • neurologic
  • confusion & delirium
  • headache
  • dizziness
  • blurred vision
  • mood swings
  • aseptic meningitis
  • dermatologic
  • pulmonary
  • pulmonary infiltrates
  • non-cardiac pulmonary edema
  • bronchospasm
  • cardiovascular
  • peripheral edema
  • heart failure
  • hypertension
  • increased mortality after myocardial infarction
  • may be due to inhibition of COX-2 mediated prostacylin formation
  • relative risk, see below
  • hypertension, RR= 1.38 with frequent use [4,12] (RR=1.26 with aspirin)
  • anaphylaxis
  • nasal polyps
  • hyperkalemia via inhibition of aldosterone secretion
  • gestational [4, 7]
  • increased risk of miscarriage [22]
  • prolonged gestation & labor, increased bleeding
  • fetal renal toxicity
  • premature closure of ductus arteriosus
  • cardiovascular risk
  • increased risk of myocardial infaction [7]
  • RR: 1.2-1.5 for use within 3 months of MI
  • risk begins to appear within 1st week of use [21]
  • increased mortality & cardiovascular morbidity in patients with heart failure [8]
  • risk allegedly lowest for naproxen [20]
  • hypertension
  • Overdose:
  • manifestations:
  • lethargy
  • nausea/vomiting
  • epigastric pain
  • gastrointestinal hemorrhage
  • management: supportive care
  • 8d (cont) [9]
  • use of high-dose* NSAID after acute myocardial infarction is associated with increased risk of mortality (during time patient is taking NSAID). Risk greater for COX2 inhibitors 

* NSAID           Dose         Relative risk of death 
* Rofecoxib      high-dose*       5.0 
*                low-dose         2.2 
* Celecoxib      high-dose#       4.2 
*                low-dose         1.7 
* Diclofenac     high-dose        3.8 
*                low-dose         0.7 
* Ibuprofen      high-dose        2.0 
*                low-dose         0.7 
* Naproxen         no increase in risk [11]


  • * Rofecoxib (high-dose) 25 mg/day
  • # Celecoxib high-dose 200 mg/day
  • 1a&b (cont) [10]
  • 1) Ulcerations of the
  • stomach
  • duodenum
  • jejunum
  • ileum
  • colon
  • inflammation, strictures & perforation of the small bowel
  • a 2 week course of slow-release diclofenac 75 mg PO BID results in small bowel lesion in 68% of subjects
  • mucosal breaks (40%)
  • petechiae (33%)
  • blood in small bowel lumen (8%)
  • relative risks of upper GI bleed (vs no NSAID)
  • NSAID in general: 4.5
  • celecoxib: 1.4
  • rofecoxib: 2.1
  • ibuprofen: 2.7
  • diclofenace: 4/0
  • meloxicam: 2.7
  • indomethacin: 5.3
  • naproxen: 5.6
  • ketoprofen: 5.6
  • piroxicam: 9.9
  • ketorolac 14.5 [19]

More General Terms

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 792
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 14, 598, 853
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, American College of Physicians, Philadelphia 1998
  4. Prescriber's Letter 8(3):14 2001
  5. Prescriber's Letter 9(5):29 2002
  6. Journal Watch 23(8):63, 2003
    - Fiorucci S et al Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study. Gastroenterology 124:600, 2003 PMID: [1]
    - Peura DA Mandate to modify a medicinal mantra: maybe not yet? Gastroenterology 124:842, 2003 PMID: [2]
  7. Prescriber's Letter 10(10):58 2003
  8. Prescriber's Letter 11(11): 63 2004
  9. Internal Medicine News, Jan 1, 2006 [3]
  10. Journal Watch 25(13):102, 2005 Maiden L, Thjodleifsson B, Theodors A, Gonzalez J, Bjarnason I. A quantitative analysis of NSAID-induced small bowel pathology by capsule enteroscopy. Gastroenterology. 2005 May;128(5):1172-8. PMID: [4]
  11. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006 Jun 3;332(7553):1302-8. PMID: [5]
  12. Forman JP et al, Frequency of analgesic use and risk of hypertension among men. Arch Intern Med 2007, 167:394 PMID: [6]
  13. Abraham NS et al, Effectiveness of national provider prescription of PPI gastroprotection among elderly NSAID users. Am J Gastroenterol 2008, 103:323 PMIDL 18289200
  14. Journal Watch 24(14):109, 2004 Mamdani M, Juurlink DN, Lee DS, Rochon PA, Kopp A, Naglie G, Austin PC, Laupacis A, Stukel TA. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet. 2004 May 29;363(9423):1751-6. PMID: [7]
  15. Journal Watch 23(8):63, 2003 Fiorucci S et al Gastrointestinal safety of NO-aspirin (NCX-4016) in healthy human volunteers: a proof of concept endoscopic study. Gastroenterology 124:600, 2003 PMID: [8]
  16. Journal Watch 25(13):102, 2005 Hawkey C, Talley NJ, Yeomans ND, Jones R, Sung JJ, Langstrom G, Naesdal J, Scheiman JM; NASA1 SPACE1 Study Group. Improvements with esomeprazole in patients with upper gastrointestinal symptoms taking non-steroidal antiinflammatory drugs, including selective COX-2 inhibitors. Am J Gastroenterol. 2005 May;100(5):1028-36. PMID: [9]
  17. Journal Watch 25(16):126, 2005
    - Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo- oxygenase-2 inhibitors or conventional non-steroidal anti- inflammatory drugs: population based nested case-control analysis. BMJ. 2005 Jun 11;330(7504):1366. <PubMed> PMID: [10] <Internet> [11]
  18. Gislason GH et al Increased mortality and cardiovascular morbidity associated with the use of nonsteroidal anti-inflammatory drugs in chronic heart failure. PMID: [12]
  19. Gonzalez ELM et al Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding. Arthritis Rheum 2010 Jun; 62:1592 [13]
  20. Prescriber's Letter 17(8): 2010 Managing NSAID Risks Detail-Document#: [14] (subscription needed) [15]
  21. Schjerning Olsen A-M et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: A nationwide cohort study. Circulation 2011 May 24; 123:2226. PMID: [16]
  22. Nakhai-Pour HR et al Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion CMAJ September 6, 2011 <PubMed> PMID: [17] <Internet> [18]
  23. Goldstein JL et al. Haemoglobin decreases in NSAID users over time: An analysis of two large outcome trials. Aliment Pharmacol Ther 2011 Oct; 34:808 PMID: [19]
  24. Ananthakrishnan AN et al. Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn disease and ulcerative colitis: A cohort study. Ann Intern Med 2012 Mar 6; 156:350 PMID: [20]

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