Non-Steroidal Anti-Inflammatory Drugs Side Effects & Toxicities

Based on "Essential Pain Pharmacology"
written by Howard S. Smith MD, Marco Pappagallo MD

NSAIDs can cause a number of adverse effects. The two main adverse reactions, associated with NSAIDs relate to gastrointestinal tract and renal function. The side effects are usually dose-dependent, and in some cases are severe enough to pose serious health risks.

Cardiovascular Side Effects

Both COX-2-selective and nonselective NSAIDs may cause adverse cardiovascular effects9, including:

Increased risk of myocardial infarction. Risk is greatest during the first month of NSAID use and with higher doses 1.
Increased risk of stroke2. NSAIDs affect vasoconstriction and sodium excretion, which can lead to elevated blood pressure, a risk factor for stroke.
Thrombosis.

Diclofenac has a cardiovascular risk very similar to rofecoxib, which was withdrawn from worldwide markets because of cardiovascular toxicity3.

Naproxen appears to have a better cardiovascular safety profile than other NSAIDs and does not appear to significantly increase the risk cardiovascular disease. Currently naproxen is considered to be the safest NSAID with respect to cardiovascular side effects.

NSAIDs rated by relative risk for cardiovascular events (in ascending order) 3:

Naproxen < Celecoxib < Piroxicam < Ibuprofen < Meloxicam < Indomethacin < Diclofenac < Rofecoxib (at doses more than 25 mg)

Gastrointestinal Side Effects

NSAIDs gastrointestinal toxicity from high to low

The main problem with of NSAIDs is gastrointestinal toxicity.

Common gastrointestinal side effects include:

Nausea
Vomiting
Dyspepsia
Peptic ulcers
Perforations of the upper gastrointestinal tract
Gastrointestinal bleeding.

Parts of the gastrointestinal tract that may be damaged by NSAIDs:

Esophagus
Stomach
Duodenum
Small intestine
Colon

Risk factors for NSAID related gastrointestinal damage:

Age (especially over 70)
History of ulceration
First three months of treatment with NSAID
Concomitant use with of corticosteroids and anticoagulants
High dose and multiple NSAIDs.

Relative risks of gastrointestinal complications 4:

Low Risk: ibuprofen, aceclofenac, nimesulide, fenoprofen, aspirin, diclofenac, sulindac, nabumetone, etodolac
Medium Risk: diflunisal, naproxen, indomethacin, tolmetin, meloxicam
High Risk: piroxicam, ketoprofen, azapropazone, flurbiprofen, ketorolac

NSAIDs can damage gastric and duodenal mucosavia several mechanisms5:

Topical irritation of epithelium.
Impairment of the barrier properties of the mucosa and increased intestinal permeability alterations in gastric mucosal barrier function.
Suppression of gastric prostaglandin synthesis.
Reduction of gastric mucosal blood flow and bicarbonate secretion.
Increase of acid secretion.
Interference with the repair of superficial injury.

Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimize gastrointestinal side effects, it is prudent to use the lowest effective dose for the shortest period of time. To help protect the stomach, NSAIDs should always be taken with food or directly after a meal.

Hypertension (High blood pressure)

NSAIDs may potentially increase blood pressure or aggravate existing hypertension. All NSAID users experience some degree of salt and water retention, and hypertension occurs in less than 10% of users.

NSAIDs-induced hypertension is due to the effects on renal function. Specifically, NSAIDs cause dose-related increases in sodium and water retention. In addition, NSAID use may reduce the effect of antihypertensive drugs except calcium channel blockers.

Kidney Damage (Nephrotoxicity)

NSAIDs reduce the blood flow to the kidneys, which makes them work more slowly. This is due to the inhibition of production of the vasodilatory renal prostaglandins. When the kidneys are not working well, fluid builds up in the body leading to edema. The more fluid in the bloodstream -- the higher blood pressure. The reduced blood flow can permanently damage the kidneys. It can eventually lead to kidney failure and require dialysis.

Renal impairment is especially a risk if a patient concomitantly takes an ACE inhibitor, a diuretic, or other nephrotoxic agent.

NSAIDs are cleared from the blood stream by the kidney, so it is very important that patients over 65 years of age or patients with kidney disease consult a physician prior to taking them. If patients take an NSAID for an extended period of time (six months or more), a blood test needs to be performed to check for early signs of kidney damage.

Long-term use of oxicams (piroxicam, meloxicam) and ketorolac is associated with an increased risk of chronic kidney disease 6.

Most people with chronic kidney disease are advised to avoid all types of NSAIDs. For healthy persons at therapeutic dosages NSAIDs pose a negligible threat of renal toxicity.

Composite cardiovascular /renal risk (in ascending order):
rofecoxib > indomethacin > diclofenac > celecoxib > naproxen > ibuprofen > meloxicam7.

Allergic Reactions

NSAIDs can also cause extreme allergy. People suffering from asthma are more likely to experience serious allergic reaction. Many specialists recommend that people who have asthma stay away from any NSAID, especially if they have sinus problems or nasal polyps. Individuals with a serious allergy to one NSAID are likely to experience a similar reaction to a different NSAID.

Use of aspirin in children and teenagers with chicken pox or influenza has been associated with the development of Reye's syndrome. Therefore, aspirin and nonaspirin salicylates (e.g. salsalate) should not be used in children and teenagers with suspected or confirmed chicken pox or influenza.

NSAIDs do not directly cause bleeding, but they make bleeding worse, for example, when there is a cut.

A meta-analysis of 11 case-control studies and one cohort study found that ibuprofen was significantly less toxic than other NSAID.

Serious side effects are especially likely with phenylbutazone. Patients of age 40 and over are especially at risk of side effects from phenylbutazone, and the likelihood of serious side effects increases with age. Because of these potential problems, it is especially important to check with a physician before taking this medicine.

References & Resources

1. Bally M, Dendukuri N, Rich B, Nadeau L, Helin-Salmivaara A, Garbe E, Brophy JM. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data.BMJ. 2017 May 9;357 PubMed
2. Park K, Bavry AA. Risk of stroke associated with nonsteroidal anti-inflammatory drugs. Vasc Health Risk Manag. 2014;10:25-32. PubMed
3. McGettigan P, Henry D. Use of non-steroidal anti-inflammatory drugs that elevate cardiovascular risk. PLoS Med. 2013;10(2):e1001388.
4. Castellsague J, Pisa F, Rosolen V, Drigo D, Riera-Guardia N, Giangreco M, Clagnan E, Tosolini F, Zanier L, Barbone F, Perez-Gutthann S. Risk of upper gastrointestinal complications in a cohort of users of nimesulide and other nonsteroidal anti-inflammatory drugs. Pharmacoepidemiol Drug Saf. 2013 Apr;22(4):365-75.
5. Wallace JL.How do NSAIDs cause ulcer disease? Baillieres Best Pract Res Clin Gastroenterol. 2000 Feb;14(1):147-59.
6. Ingrasciotta Y, Sultana J, Giorgianni F, et al. Association of individual non-steroidal anti-inflammatory drugs and chronic kidney disease: a population-based case control study. PLoS One. 2015 Apr 16;10(4):e0122899. PubMed
7. Asghar W, Jamali F. The effect of COX-2-selective meloxicam on the myocardial, vascular and renal risks: a systematic review. Inflammopharmacology. 2015 Feb;23(1):1-16. PubMed

Published: June 05, 2018
Last updated: June 05, 2018