Contents

Search

non-steroidal anti-inflammatory agent (NSAID)

An aspirin-like drug that reduces pain & inflammation arising from injured tissue through inhibition of prostaglandin synthesis. Indications: 1) temporary relief of minor aches & pains 2) reduction of inflammation 3) reduction of fever 4) may reduce risk of colon cancer [5]; (see Nurses Health Study) 5) may reduce risk of prostate cancer [5] 6) many reduce risk of skin cancer 7) investigational treatment of Alzheimer's disease Contraindications: Cautions: 1) NSAIDs may cause severe asthma 2) a triad of asthma, nasal polyposis & aspirin sensitivity shows cross-reactivity with other NSAIDs 3) avoid in patients with: a) heart failure [8] b) peptic ulcer disease c) renal insufficiency d) cardiovascular risk factors: - hypertension, hyperlipidemia ... [3,21] 4) NSAIDs considered safe before 20 weeks gestation [3,38] Dosage: (administration) - see specific NSAID - Guidelines for use [17] {based on expert opinion} a) patients with low GI & low cardiovascular risks should receive a non-specific NSAID b) patients with low GI & high cardiovascular risks should receive naproxen c) patients with high GI & low cardiovascular risks should receive a COX-2 inhibitor plus a proton-pump inhibitor - patients taking an NSAID + an antianticoagulant should be on a proton pump inhibitor (standard dose) [42 d) patients with high GI & high cardiovascular risks should receive a careful assessment to prioritize risks e) NSAIDs should be prescribed at the lowest effective dose & for the shortest possible duration. f) ibuprofen & naproxen drugs of choice in this class [32] Pharmacokinetics: - NSAIDs bind extensively to plasma proteins Monitor: - monitor blood pressure as hypertension can occur with NSAIDs Adverse effects: 1) gastrointestinal (GI) intolerance a) NSAID gastropathy 1] dyspepsia (may or may not be present) 2] upper GI bleed, occult blood loss & iron deficiency anemia 3] release of nitric oxide seems to protect against NSAID gastropathy [6] 4] proton pump inhibitor (PPI) provides symptomatic relief [13] - use of Cox-2 inhibitor in combination with PPI in high-risk patients if NSAID use unavoidable [3] b) peptic ulcer 1] 25% of NSAID users 2] may be asymptomatic [3] 3] risk factors a] age > 65 years b] high-dose NSAID c] concurrent use of low-dose aspirin, anticoagulants, or glucocorticoids d] history of peptic ulcer [3] 4] standard dose proton pump inhibitors are 1st line for prevention NSAID-related peptic ulcers [3] 5] combining COX-2 inhibitor with proton pump inhibitor is the most effective strategy to reduce the risk of peptic ulcer complications [27] c) NSAID enterocolopathy [12] - diarrhea [43] - chronic blood loss & iron-deficiency anemia [43] - worsening of inflammatory bowel disease [43] - small increase in risk of inflammatory bowel disease - 6-7 additional cases per 100,000 person-years - exception is aspirin d) nausea/vomiting e) constipation 2) renal (NSAID nephropathy) a) reduced renal blood flow secondary to intrarenal vasoconstriction b) reduced glomerular filtration rate c) NSAID use by older adults (mean age, 74 years) is not associated with a decline in glomerular filtration rate or an increase in albuminuria [39] d) pyuria e) interstitial nephritis* [37] f) papillary necrosis g) membranous nephropathy h) nephrotic syndrome - minimal change glomerulonephropathy [37] i) hyperkalemia & type IV renal tubular acidosis (RTA) o) hyponatremia k) fluid retention - Na+ retention - may exacerbate congestive heart failure (CHF) [8,28] l) excess cases of acute & chronic kidney disease in young adults, ~50 excess cases per 100,000 people annually [35] 3) hepatic a) mild elevation in serum transaminases b) rarely associated with severe liver damage 4) hematologic a) bone marrow suppression 1] agranulocytosis 2] aplastic anemia 3] thrombocytopenia [41] b) iron deficiency anemia c) platelet aggregating defect d) NSAIDs not associated with postoperative bleeding [40] 5) neurologic a) confusion & delirium b) headache c) dizziness d) blurred vision e) mood swings f) aseptic meningitis 6) dermatologic a) urticaria b) erythema multiforme c) toxic epidermal necrolysis d) oral ulcers e) dermatitis 7) pulmonary a) pulmonary infiltrates b) non-cardiac pulmonary edema c) bronchospasm, asthma exacerbation 8) anaphylaxis 9) nasal polyps 10) hyperkalemia via inhibition of renin synthesis & aldosterone secretion resulting in hyporeninemic hypoaldosteronism [3] 11) gestational [4, 7] a) increased risk of miscarriage b) prolonged gestation & labor, increased bleeding c) fetal renal toxicity d) premature closure of ductus arteriosus 12) cardiovascular risk a) increased risk of myocardial infaction [14]; RR: 1.2-1.5 for use within 3 months of MI b) increased mortality & cardiovascular morbidity in patients with heart failure [16] c) risk allegedly lowest for naproxen [18,19,23,33] d) increased risk of heart attack or stroke [26] e) increased risk for heart failure hospitalization [29] f) even 1 week use of NSAID associated with increased risk of myocardial infarction [31] - naproxen alone among NSAIDs not associated with increased risk of myocardial infarction [33] g) congestive heart failure* 14) hypertension a) antagonism of beta-blockers & Ca+2 channel blockers b) on average, NSAIDs increase blood pressure ~5 mmHg in patients with hypertension [19] 15) tinnitus [41] - increased risk of hearing loss in women (RR=1.1) [30] * NSAIDS may increase salt & water retention - in the setting of compensated heart failure, NSAIDs can lead to decompensated heart failure [28] * 10 days of NSAID therapy prior to interstitial nephritis [42] Overdose: 1) manifestations: a) lethargy b) nausea/vomiting c) epigastric pain d) gastrointestinal hemorrhage 2) management: supportive care Risk factors for adverse effects [3] 1) age > 60 years 2) history of gastritis or peptic ulcer 3) history of alcohol abuse 4) history of kidney disease 5) history of chronic systemic illness a) diabetes mellitus b) rheumatoid arthritis c) others 6) history of cardiovascular disease 7) history of hypertension 8) Helicobacter pylori infection 9) use of NSAID at maximal dose 10) concurrent use of multiple NSAIDs 11) coadministration of glucocorticoid 12) coadministration of anticoagulant Drug interactions: 1) NSAIDs enhance hemostatic effect of warfarin 2) NSAIDs may attenuate antihypertensive effects of: a) diuretics b) beta blockers c) ACE inhibitors 3) NSAIDs may enhance catabolism (elimination) of: a) methotrexate (high dose) b) lithium c) oral hypoglycemic agents 4) NSAIDs in combination with ACE inhibitors increase risk of hyperkalemia 5) NSAIDs may increase toxicity of diuretics [16] 6) NSAIDs may precipitate decompensated acute heart failure in elderly taking ACE inhibitor or ARB & a diuretic [44] 7) other drugs in combination increase risk of upper GI bleed (RR relative to non-selective NSAID alone) [25] - aldosterone antagonists (RR=11.0) - glucocorticoids (RR=12.8) - SSRI (data conflicting) - other antiplatelet agents in combination do not increase risk [25] Laboratory: - nonsteroidal antiinflammatory drug in body fluid - nonsteroidal antiinflammatory drug in blood - nonsteroidal antiinflammatory drug in serum/plasma - nonsteroidal antiinflammatory drug in urine Mechanism of action: 1) inhibition of cyclooxygenase, thus reducing formation of prostaglandins a) anti-inflammatory actions of NSAIDs are primarily due to cyclooxygenase-2 (COX-2) inhibition b) toxic reactions are primarily due to inhibition of COX-1 c) blocking of arachidonate to prostaglandins by NSAIDs increases substrate for conversion of arachidonate to lipoxygenase metabolites including leukotrienes 2) inhibition of renal afferent arteriolar dilatation, thus diminishing renal blood flow & GFR 3) inhibition of renin production

Interactions

drug interactions drug adverse effects of NSAIDs monitor with non steroidal anti-inflammatory agents (NSIADs)

Related

cyclooxygenase (prostaglandin endoperoxide synthase, COX) investigational therapies for treatment of Alzheimer's disease NSAID enterocolopathy NSAID gastropathy NSAID nephropathy

Specific

amfenac azapropazone; apazone; cinnopropazone; Prolixan; Tolyprin bromfenac (Duract, Xibrom) cyclooxygenase-2 (COX-2) specific inhibitor diclofenac (Voltaren, Cataflam, Flector patch, Cambia, Pennsaid, Zipsor, Zorvolex) diflunisal (Dolobid) etodolac (Lodine) exisulind; sulindac sulfone (Aptosyn) fenoprofen (Nalfon) flunixin (FluMeglumine) flurbiprofen (Ansaid, Ocufen, Ropion, Flurofen) grapiprant (Galliprant) ibuprofen (Motrin, Advil, Nuprin, Rufen, NeoProfen, Caldolor) indomethacin (Indocin) ketoprofen (Orudis Oruvail) ketorolac (Toradol, Acular, Acuvail) meclofenamate (Meclomen) mefenamic acid (Ponstel) meloxicam (Mobic) metamizole; dipyrone (Busprina, Conmel, Dalmasin, Neo-Melubrina, Prolidina, Mexican aspirin) nabumetone (Relafen) naproxen (Naprosyn, Aleve Anaprox) nepafenac (Nevanac) NO aspirin (NCX-4016, nitric oxide releasing) oleocanthal (Hyeda) oxaprozin (Daypro) oxyphenbutazone phenylbutazone (Butazolidin) piroxicam (Feldene) salicylamide (Flarpirina) salicylate salsalate (Salflex, Disalcid, sasapyrine) sulfinpyrazone (Anturane) sulindac (Clinoril) suprofen (Profenal) tolmetin (Tolectin)

General

analgesic (antalgic) antipyretic agent anti-inflammatory agent enzyme inhibitor

Properties

INHIBITS: cyclooxygenase

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, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018, 2021.
  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: 12612897 - Peura DA Mandate to modify a medicinal mantra: maybe not yet? Gastroenterology 124:842, 2003 PMID: 12612918
  7. Prescriber's Letter 10(10):58 2003
  8. 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: 15172772
  9. Prescriber's Letter 12(2): 2005 Update on the Safety and Use of COX-2 Inhibitors and Traditional NSAIDs Detail-Document#: 210202 (subscription needed) http://www.prescribersletter.com
  10. Prescriber's Letter 12(5): 2005 FDA Announces Important Changes and Additional Warnings for COX-2s and NSAIDs Detail-Document#: 210505 (subscription needed) http://www.prescribersletter.com
  11. FDA MedWatch COX-2 Selective (includes Bextra, Celebrex, and Vioxx) and Non-Selective Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#NSAID
  12. 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: 15887101
  13. 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: 15842575
  14. 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. PMID: 15947398 http://bmj.bmjjournals.com/cgi/content/full/330/7504/1366
  15. Prescriber's Letter 12(9): 2005 Non-narcotic Analgesics and the Risk of Hypertension in Women Detail-Document#: 210915 (subscription needed) http://www.prescribersletter.com
  16. Gislason GH et al Increased mortality and cardiovascular morbidity associated with the use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med 2009 Jan 26; 169:141. PMID: 19171810
  17. Rostom A et al. Canadian consensus guidelines on long-term nonsteroidal anti-inflammatory drug therapy and the need for gastroprotection: Benefits versus risks. Aliment Pharmacol Ther 2009 Mar 1; 29:481. PMID: 19053986
  18. Prescriber's Letter 17(8): 2010 Managing NSAID Risks Detail-Document#: 260810 (subscription needed) http://www.prescribersletter.com
  19. Prescriber's Letter 18(12): 2011 NSAIDs and Hypertension Detail-Document#: 271224 (subscription needed) http://www.prescribersletter.com
  20. Johannesdottir SA et al Nonsteroidal anti-inflammatory drugs and the risk of skin cancer Cancer, May 29, 2012 PMID: 22644960 http://onlinelibrary.wiley.com/doi/10.1002/cncr.27406/abstract
  21. Burmester G, Lanas A, Biasucci L et al The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opinions of a multidisciplinary European expert panel. Ann Rheum Dis. 2011 May;70(5):818-22 PMID: 20833736
  22. Farkouh ME, Greenberg BP. An evidence-based review of the cardiovascular risks of nonsteroidal anti-inflammatory drugs. Am J Cardiol. 2009 May 1;103(9):1227-37. PMID: 19406264
  23. Prescriber's Letter 21(3): 2014 NSAID Safety in Patients with Heart Disease Detail-Document#: 300322 (subscription needed) http://www.prescribersletter.com
  24. Antman EM, Bennett JS, Daugherty A et al Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation. 2007 Mar 27;115(12):1634-42. Epub 2007 Feb 26. PMID: 17325246
  25. Masclee GMC et al. Risk of upper gastrointestinal bleeding from different drug combinations. Gastroenterology 2014 Oct; 147:784 PMID: 24937265 - Laine L. NSAID-associated gastrointestinal bleeding: Assessing the role of concomitant medications. Gastroenterology 2014 Oct; 147:730. PMID: 25167988
  26. FDA Drug Safety Alert. July 9, 2014 Non-aspirin Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Drug Safety Communication - FDA Strengthens Warning of Increased Chance of Heart Attack or Stroke http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm454141.htm
  27. Yuan JQ et al. Systematic review with network meta-analysis: Comparative effectiveness and safety of strategies for preventing NSAID- associated gastrointestinal toxicity. Aliment Pharmacol Ther 2016 Jun; 43:1262 PMID: 27121479
  28. Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016 - Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019 - Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022
  29. Arfe A et al Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ 2016;354:i4857 PMID: 27682515 http://www.bmj.com/content/354/bmj.i4857 - Gislason GH, Torp-Pedersen C NSAIDs and the failing heart BMJ 2016;354:i5163 PMID: 27681451 http://www.bmj.com/content/354/bmj.i5163
  30. Lin B, Curhan SG, Wang M et al Duration of Analgesic Use and Risk of Hearing Loss in Women. Am J Epidemiol (2016) 1-8. Published 14 December 2016 PMID: 27974293 https://academic.oup.com/aje/article/doi/10.1093/aje/kww154/2661733/Duration-of-Analgesic-Use-and-Risk-of-Hearing-Loss
  31. Bally M, Dendukuri N, Rich B et al Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ 2017;357:j1909 PMID: 28487435 http://www.bmj.com/content/357/bmj.j1909
  32. Therapeutics Letter #108. Therapeutics Initiative Drugs to Avoid. http://www.ti.ubc.ca/2018/01/04/108-drugs-avoid/
  33. Dubreuil M, Louie-Gao Q, Peloquin CE, Choi HK, Zhang Y, Neogi T. Risk of myocardial infarction with use of selected non-steroidal anti-inflammatory drugs in patients with spondyloarthritis and osteoarthritis. Ann Rheum Dis 2018 Aug; 77:1137 PMID: 29674321 https://ard.bmj.com/content/77/8/1137
  34. Bouck Z, Mecredy GC, Ivers NM et al. Frequency and associations of prescription nonsteroidal anti- inflammatory drug use among patients with a musculoskeletal disorder and hypertension, heart failure, or chronic kidney disease. JAMA Intern Med 2018 Oct 8; PMID: 30304456 https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2705693
  35. Nelson DA et al. Association of nonsteroidal anti-inflammatory drug prescriptions with kidney disease among active young and middle-aged adults. JAMA Netw Open 2019 Feb 15; 2:e187896 Not indexed in PubMed https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2724772
  36. Zhang X, Donnan PT, Bell S, Guthrie B. Non-steroidal anti-inflammatory drug induced acute kidney injury in the community dwelling general population and people with chronic kidney disease: systematic review and meta-analysis. BMC Nephrol. 2017 Aug 1;18(1):256. Review. PMID: 28764659 Free PMC Article
  37. Baccouche K, Alaya Z, Azzabi A et al Minimal-change disease and interstitial nephritis secondary to non-steroidal anti-inflammatory drugs (naproxen). Therapie. 2016 Oct;71(5):515-517. PMID: 27203163
  38. FDA MedWatch. Oct 15, 2020 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Drug Safety Communication - Avoid Use of NSAIDs in Pregnancy at 20 Weeks or Later. https://www.fda.gov/safety/medical-product-safety-information/nonsteroidal-anti-inflammatory-drugs-nsaids-drug-safety-communication-avoid-use-nsaids-pregnancy-20
  39. Amatruda JG et al. Association of non-steroidal anti-inflammatory drugs with kidney health in ambulatory older adults. J Am Geriatr Soc 2021 Mar; 69:726 PMID: 33305369 https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.16961
  40. Bongiovanni T et al. Systematic review and meta-analysis of the association between non-steroidal anti-inflammatory drugs and operative bleeding in the perioperative period. J Am Coll Surg 2021 May; 232:765. PMID: 33515678 https://www.journalacs.org/article/S1072-7515(21)00048-X/fulltext
  41. Windle ML Rapid Rx Quiz: Headache Medications Medscape. Sept 12, 2022 https://reference.medscape.com/viewarticle/980181
  42. NEJM Knowledge+ Complex Medical Care
  43. Davies NM. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Dis Colon Rectum. 1995 Dec;38(12):1311-21. PMID: 7497845 Review.
  44. Sunaga T, Yokoyama A, Nakamura S et al. Association of potentially inappropriate medications with all-cause mortality in the elderly acute decompensated heart failure patients: importance of nonsteroidal anti-inflammatory drug prescription. Cardiol Res. 2020;11(4):239-246 PMID: 32595809 PMCID: PMC7295559 Free PMC article
  45. Symptoms & Causes of Peptic Ulcers (Stomach Ulcers) https://www.niddk.nih.gov/health-information/digestive-diseases/peptic-ulcers-stomach-ulcers/symptoms-causes