drug adverse effects of NSAIDs
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Etiology
Risk factors for adverse effects[3]
- age > 60 years
- history of gastritis or peptic ulcer
- history of alcohol abuse
- history of kidney disease
- history of chronic systemic illness
- history of cardiovascular disease
- history of hypertension
- Helicobacter pylori infection
- use of NSAID at maximal dose
- concurrent use of multiple NSAIDs
- coadministration of glucocorticoid
- coadministration of anticoagulant
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]
- peptic ulcer
- 25% of NSAID users
- may be asymptomatic[3]
- risk factors
- age > 65 years
- high-dose NSAID
- concurrent use of low-dose aspirin, anticoagulants, or glucocorticoids
- history of peptic ulcer[3]
- standard dose proton pump inhibitors are 1st line for prevention of NSAID-related peptic ulcers[3]
- combining COX-2 inhibitor with proton pump inhibitor is the most effective strategy to reduce the risk of peptic ulcer complications[33]
- gastroesophageal reflux[3]
- NSAID enterocolopathy
- diarrhea[47]
- chronic blood loss & iron-deficiency anemia[47]
- worsening of inflammatory bowel disease[47]
- small increase in risk of inflammatory bowel disease
- nausea/vomiting
- constipation
- NSAID gastropathy
- renal (NSAID nephropathy)
- reduced renal blood flow secondary to intrarenal vasoconstriction
- most frequently occurs in patients with volume depletion, heart failure, cirrhosis
- reduced glomerular filtration rate
- NSAID use by older adults (mean age, 74 years) is not associated with a decline in glomerular filtration rate or an increase in albuminuria[43]
- pyuria
- allergic interstitial nephritis*
- papillary necrosis, acute tubular necrosis
- membranous nephropathy
- nephrotic syndrome
- hyperkalemia & type IV renal tubular acidosis (RTA)
- hyperkalemia via inhibition of renin synthesis & aldosterone secretion resulting in hyporeninemic hypoaldosteronism[3]
- hyponatremia
- fluid retention
- Na+ retention
- may exacerbate congestive heart failure (CHF)[4][34]
- hypertension
- excess cases of acute & chronic kidney disease in young adults, ~50 excess cases per 100,000 people annually[39]
- reduced renal blood flow secondary to intrarenal vasoconstriction
- hepatic
- mild elevation in serum transaminases
- rarely associated with severe liver damage
- hematologic
- bone marrow suppression
- hemorrhage
- NSAIDs are associated with increased risks for bleeding & thromboembolism in patients with atrial fibrillation[30]
- increased risk with or without anticoagulation[30]
- NSAIDs not associated with postoperative bleeding[44]
- NSAIDs are associated with increased risks for bleeding & thromboembolism in patients with atrial fibrillation[30]
- iron deficiency anemia
- a decrease in blood hemoglobin of > 2 g/dL
- 1.9-2.0% of patients treated with celecoxib
- 3.3-5.7% of patients treated with diclofenac[23]
- a decrease in blood hemoglobin of > 2 g/dL
- platelet aggregating defect
- neurologic
- dermatologic
- pulmonary
- pulmonary infiltrates
- non-cardiac pulmonary edema
- bronchospasm, exacerbation of asthma
- cardiovascular
- peripheral edema
- increased risk of heart failure
- increased mortality & cardiovascular morbidity in patients with heart failure[8]
- NSAIDS may increase salt & water retention & in the setting of compensated heart failure, can lead to decompensated heart failure[34]
- increased risk for heart failure hospitalization[35]
- NSAID use increases risk of first hospitalization for heart failure in patients with diabetes mellitus type 2[46] - older age, higher hemoglobin A1c & new NSAID used increases susceptibility[46]
- hypertension
- antagonism of beta-blockers & Ca+2 channel blockers
- on average, NSAIDs increase blood pressure ~5 mmHg in patients with hypertension[28]
- RR= 1.38 with frequent use[4][12]; RR=1.26 with aspirin)
- increased risk of heart attack or stroke[32]
- increased risk of myocardial infarction[7]
- increased mortality after myocardial infarction
- may be due to inhibition of COX-2 mediated prostacylin formation
- relative risk, see below
- high-dose NSAIDs including COX-2 inhibitors is associated with increased cardiovascular risk
- 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[9][26]
- nonselective agents with COX-1 > COX-2 inhibition not associated with increased cardiovascular risk in women[31]
- risk allegedly lowest for naproxen[20]
- naproxen is associated with increased cardiovascular risk in women (RR=1.22)[31]
- naproxen alone among NSAIDs not associated with increased risk of myocardial infarction[38]
- anaphylaxis[29]
- nasal polyps
- gestational [4, 7]
- increased risk of miscarriage[22]
- no increase in risk[27]
- indomethacin may be exception[27]
- prolonged gestation, delayed labor, increased bleeding
- fetal renal toxicity leading to low levels of amniotic fluid[42]
- premature closure of ductus arteriosus after 30 weeks[3]
- increased risk of miscarriage[22]
- tinnitus[45]
- increased risk of hearing loss in women (RR=1.1)[36]
* 10 days of NSAID therapy prior to interstitial nephritis[15]
- manifestations:
- management: supportive care
| NSAID | Dose | Relative risk of death |
|---|---|---|
| Rofecoxib | high-dose* | 5.0 |
| Rofecoxib | low-dose | 2.2 |
| Celecoxib | high-dose# | 4.2 |
| Celecoxib | low-dose | 1.7 |
| Diclofenac | high-dose | 3.8 |
| Diclofenac | low-dose | 0.7 |
| Ibuprofen | high-dose | 2.0 |
| Ibuprofen | low-dose | 0.7 |
| Naproxen | high-dose | 1.0 |
| Naproxen | low-dose | 1.0 $ |
* Rofecoxib (high-dose) 25 mg/day
# Celecoxib high-dose 200 mg/day
$ No increased risk for naproxen[11]
gastrointestinal effects (cont)[10]
1) Ulcerations of the
- 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
- diclofenac: 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
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 792
- ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 14, 598, 853
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018.
- ↑ 4.0 4.1 4.2 Prescriber's Letter 8(3):14 2001
- ↑ Prescriber's Letter 9(5):29 2002
- ↑ 6.0 6.1 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: https://www.ncbi.nlm.nih.gov/pubmed/12612897
Peura DA Mandate to modify a medicinal mantra: maybe not yet? Gastroenterology 124:842, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/12612918 - ↑ 7.0 7.1 Prescriber's Letter 10(10):58 2003
- ↑ 8.0 8.1 Prescriber's Letter 11(11): 63 2004
- ↑ 9.0 9.1 Internal Medicine News, Jan 1, 2006 http://www.internalmedicinenews.com
- ↑ 10.0 10.1 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: https://www.ncbi.nlm.nih.gov/pubmed/15887101
- ↑ 11.0 11.1 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: https://www.ncbi.nlm.nih.gov/pubmed/16740558
- ↑ 12.0 12.1 Forman JP et al, Frequency of analgesic use and risk of hypertension among men. Arch Intern Med 2007, 167:394 PMID: https://www.ncbi.nlm.nih.gov/pubmed/17325302
- ↑ 13.0 13.1 Abraham NS et al, Effectiveness of national provider prescription of PPI gastroprotection among elderly NSAID users. Am J Gastroenterol 2008, 103:323 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18289200
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/15172772
- ↑ 15.0 15.1 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: https://www.ncbi.nlm.nih.gov/pubmed/12612897
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/15842575
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/15947398 <Internet> http://bmj.bmjjournals.com/cgi/content/full/330/7504/1366 - ↑ Gislason GH et al Increased mortality and cardiovascular morbidity associated with the use of nonsteroidal anti-inflammatory drugs in chronic heart failure. PMID: https://www.ncbi.nlm.nih.gov/pubmed/19171810
- ↑ 19.0 19.1 Gonzalez ELM et al Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding. Arthritis Rheum 2010 Jun; 62:1592 http://dx.doi.org/10.1002/art.27412
- ↑ 20.0 20.1 Prescriber's Letter 17(8): 2010 Managing NSAID Risks Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=260810&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 21.0 21.1 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: https://www.ncbi.nlm.nih.gov/pubmed/21555710
- ↑ 22.0 22.1 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: https://www.ncbi.nlm.nih.gov/pubmed/21896698 <Internet> http://www.cmaj.ca/content/early/2011/09/06/cmaj.110454.full.pdf+html
- ↑ 23.0 23.1 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: https://www.ncbi.nlm.nih.gov/pubmed/21810115
- ↑ 24.0 24.1 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: https://www.ncbi.nlm.nih.gov/pubmed/22393130
- ↑ Cryer B et al. GI-REASONS: A novel 6-month, prospective, randomized, open-label, blinded endpoint (PROBE) trial. Am J Gastroenterol 2013 Mar; 108:392. PMID: https://www.ncbi.nlm.nih.gov/pubmed/23399552
- ↑ 26.0 26.1 26.2 Coxib and traditional NSAID Trialists' (CNT) Collaboration Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. The Lancet, Early Online Publication, 30 May 2013 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23726390 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60900-9/abstract
Griffin MR High-dose non-steroidal anti-inflammatories: painful choices. The Lancet, Early Online Publication, 30 May 2013 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23726391 <Internet> http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)61128-9/fulltext - ↑ 27.0 27.1 27.2 Daniel S et al Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. CMAJ. Feb 3, 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24491470 <Internet> http://www.cmaj.ca/content/early/2014/02/03/cmaj.130605.full.pdf+html
- ↑ 28.0 28.1 Prescriber's Letter 18(12): 2011 NSAIDs and Hypertension Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=271224&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 29.0 29.1 Aun MV, Blanca M, Garro LS eta al Nonsteroidal anti-inflammatory drugs are major causes of drug- induced anaphylaxis. J Allergy Clin Immunol Pract. 2014 Jul-Aug;2(4):414-20 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25017529
- ↑ 30.0 30.1 30.2 Lamberts M et al Relation of Nonsteroidal Anti-inflammatory Drugs to Serious Bleeding and Thromboembolism Risk in Patients With Atrial Fibrillation Receiving Antithrombotic Therapy: A Nationwide Cohort Study Ann Intern Med. 2014;161(10):690-698. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25402512 <Internet> http://annals.org/article.aspx?articleid=1935053
- ↑ 31.0 31.1 31.2 Bavry AA, Thomas F, Allison M, et al. Nonsteroidal anti-inflammatory drugs and cardiovascular outcomes in women: results from the Women's Health Initiative. Circ Cardiovasc Qual Outcomes. 2014;7:603-610 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25006185
- ↑ 32.0 32.1 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
- ↑ 33.0 33.1 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: https://www.ncbi.nlm.nih.gov/pubmed/27121479
- ↑ 34.0 34.1 34.2 Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022 - ↑ 35.0 35.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27682515 <Internet> http://www.bmj.com/content/354/bmj.i4857
Gislason GH, Torp-Pedersen C NSAIDs and the failing heart BMJ 2016;354:i5163 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/27681451 <Internet> http://www.bmj.com/content/354/bmj.i5163 - ↑ 36.0 36.1 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: https://www.ncbi.nlm.nih.gov/pubmed/27974293 https://academic.oup.com/aje/article/doi/10.1093/aje/kww154/2661733/Duration-of-Analgesic-Use-and-Risk-of-Hearing-Loss
- ↑ 37.0 37.1 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 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28487435 <Internet> http://www.bmj.com/content/357/bmj.j1909
- ↑ 38.0 38.1 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: https://www.ncbi.nlm.nih.gov/pubmed/29674321 https://ard.bmj.com/content/77/8/1137
- ↑ 39.0 39.1 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
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/28764659 Free PMC Article
- ↑ 41.0 41.1 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: https://www.ncbi.nlm.nih.gov/pubmed/27203163
- ↑ 42.0 42.1 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 - ↑ 43.0 43.1 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: https://www.ncbi.nlm.nih.gov/pubmed/33305369 https://agsjournals.onlinelibrary.wiley.com/doi/10.1111/jgs.16961
- ↑ 44.0 44.1 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: https://www.ncbi.nlm.nih.gov/pubmed/33515678 https://www.journalacs.org/article/S1072-7515(21)00048-X/fulltext
- ↑ 45.0 45.1 45.2 Windle ML Rapid Rx Quiz: Headache Medications Medscape. Sept 12, 2022 https://reference.medscape.com/viewarticle/980181
- ↑ 46.0 46.1 46.2 Holt A, Strange JE, Nouhravesh N et al Heart Failure Following Anti-Inflammatory Medications in Patients With Type 2 Diabetes Mellitus. J Am Coll Cardiol. 2023 81(15):1459-1470. April PMID: https://www.ncbi.nlm.nih.gov/pubmed/37045515 https://www.sciencedirect.com/science/article/abs/pii/S0735109723004217
NEJM Knowledge+ - ↑ 47.0 47.1 47.2 47.3 Davies NM. Toxicity of nonsteroidal anti-inflammatory drugs in the large intestine. Dis Colon Rectum. 1995 Dec;38(12):1311-21. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7497845 Review.