Potential Risks and Complications of NSAIDs

The potential side effects and risks associated with non-steroidal anti-inflammatory drugs (NSAIDs) are linked to the treatment's dosage and duration. To mitigate these risks, it is advisable to use NSAIDs at the lowest effective dose for the shortest possible period of time.¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147

In most cases, the risks of NSAIDs are related to the suppression of specialized enzymes called cyclooxygenase enzymes (COX-1 and COX-2), which perform multiple functions throughout the body in addition to regulating inflammation and pain.¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147

Common Side Effects of NSAIDs

The most common side effects associated with almost all types of NSAIDs involve gastrointestinal upset, including²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021:

• Abdominal pain
• Nausea
• Diarrhea
• Indigestion

Other frequently reported side effects include headache and dizziness.²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021

Less Common Side Effects of Commonly Prescribed NSAIDs

The following table lists the additional side effects of commonly prescribed NSAIDs.

NSAIDs impact everyone differently, and while some people may experience more side effects, others may have fewer or no side effects.¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147

Potential Side Effects of Topical NSAIDs

The side effect profile of topical NSAIDs differs from other modes of delivery because only a small amount of the drug is absorbed into the bloodstream. The most common side effects occur on the skin at the site of application of the medication and include⁹Voltaren gel. Package insert. Keltman Pharmaceuticals Inc.; 2011^,10Voltaren Arthritis Pain. Package Insert. GlaxoSmithKline Consumer Healthcare Holdings (US) LLC; 2023:

• Dermatitis (irritation)
• Itching 
• Redness
• Dryness
• Small bumps or nodules

Gastrointestinal side effects generally do not occur with short-term use of topical NSAIDs. However, the risk is increased if more than the recommended amount of medication is used and/or when NSAIDs are used long-term (longer than 3 to 6 months).¹¹Diclofenac sodium 1.5%. Package Insert. SOLA Pharmaceuticals; 2022

Potential Serious Risks of NSAIDs

In rare cases, serious risks, such as organ damage, can arise from the prolonged and high-dose utilization of NSAIDs.¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147

Allergic reactions to NSAIDs

In some cases, NSAIDs may cause severe allergic reactions, especially in individuals who are allergic to aspirin, including¹²Blanca-López N, Soriano V, Garcia Martin E, Canto G, Blanca M. NSAID-induced reactions: classification, prevalence, impact, and management strategies. Journal of Asthma and Allergy. 2019;Volume 12:217-233. doi:https://doi.org/10.2147/jaa.s164806^,13Minaldi E, Cahill K. Recent Updates in Understanding NSAID Hypersensitivity. Curr Allergy Asthma Rep. 2023;23(3):181-188. doi:10.1007/s11882-023-01064-3:

• Hives
• Swelling of the face
• Asthma 
• Skin reddening
• Skin rash
• Blisters

Symptoms of an allergic reaction usually occur immediately after taking an NSAID, but delayed reactions are possible.¹²Blanca-López N, Soriano V, Garcia Martin E, Canto G, Blanca M. NSAID-induced reactions: classification, prevalence, impact, and management strategies. Journal of Asthma and Allergy. 2019;Volume 12:217-233. doi:https://doi.org/10.2147/jaa.s164806^,13Minaldi E, Cahill K. Recent Updates in Understanding NSAID Hypersensitivity. Curr Allergy Asthma Rep. 2023;23(3):181-188. doi:10.1007/s11882-023-01064-3

Gastrointestinal risks of NSAIDs

NSAIDs cause damage to the lining of the stomach and intestines, and this is more likely to occur with non-selective NSAIDs (eg, Advil and Aleve) compared to COX-2 selective NSAIDs (eg, Celebrex).¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147

COX-1 and COX-2 enzymes play a protective role in the gastrointestinal system, and inhibiting their protective mechanisms may cause the following injuries and complications¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147:

• Ulcers (painful wounds in the stomach or intestines)
• Bleeding in the gastrointestinal tract
• Anemia (low red blood cell count)
• Perforation (hole or tear) in the gastrointestinal tract
• Intestinal stricture (narrowing of the intestines) 
• Obstruction (partial or complete blockage of the intestines)

Individuals with ulcerative conditions (eg, ulcerative colitis or peptic ulcer disease) have an elevated risk for gastrointestinal damage.²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021

Cardiovascular risks of NSAIDs

Most NSAIDs, excluding low-dose aspirin, may increase the risk of these events. NSAIDs have also been associated with increased blood pressure.¹⁴US FDA Drug Safety Communication. FDA strengthens warning that non-aspirin nonsteroidal antiinflammatory drugs (NSAIDs) can cause heart attacks or strokes. https://www.fda.gov/media/92768/download (Accessed on July 27, 2023)

The exact cause of cardiovascular injury is unknown, but NSAIDs have been associated with causing¹⁵Ghlichloo I, Gerriets V. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547742/:

• Heart attack
• Stroke
• Atrial fibrillation

The likelihood of experiencing significant cardiovascular events is elevated in the initial week of NSAID usage, and this risk intensifies with prolonged periods of use.¹²Blanca-López N, Soriano V, Garcia Martin E, Canto G, Blanca M. NSAID-induced reactions: classification, prevalence, impact, and management strategies. Journal of Asthma and Allergy. 2019;Volume 12:217-233. doi:https://doi.org/10.2147/jaa.s164806

Bleeding risks of NSAIDs

NSAIDs can increase the time that it takes for blood to clot through their inhibition of COX enzymes, which increases the risk of serious bleeding events, bruising, and related complications such as anemia.²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021

The risk of bleeding is also increased when NSAIDs are used concomitantly with certain classes of medications, such as selective serotonin reuptake inhibitors (SSRIs) and blood thinners.²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021

Consuming alcohol while taking NSAIDs also increases the risk of bleeding events due to the anticoagulant effects of alcohol.²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021

Renal risks of NSAIDs

NSAIDs cause direct damage to the cells of the kidneys and changes in vessels that supply blood to the kidneys (which reduces blood flow), and these injuries can result in the following complications¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147:

• Acute kidney injury
• Chronic kidney disease
• Severe electrolyte imbalance
• Inflammation of the kidneys
• Fluid retention

High doses of NSAIDs – even for short periods of time – may cause acute kidney injury, while long-term use at any dose may cause chronic kidney disease.¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147

Hepatic risks of NSAIDs

While rare, NSAIDs have the potential to cause liver injury, which is characterized by increased liver enzyme levels on blood tests. Liver injury may range from mild to severe toxicity.²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021 

Symptoms of liver damage may appear quickly in cases of acute hepatitis, or they may be delayed due to slower changes in the liver in cases of chronic hepatitis.¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147

The exact cause of NSAID-induced liver injury is unknown.  

Respiratory risks of NSAIDs

In some cases, NSAIDs cause severe respiratory reactions in individuals with underlying conditions such as asthma.¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147

NSAIDs also trigger respiratory inflammation in some individuals with a sensitivity to aspirin, and this inflammation can cause bronchospasm (wheezing), which could be fatal if not treated quickly.¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147

When NSAIDs Should be Avoided in People with Underlying Medical Conditions

Use of NSAIDs in the following cases is associated with serious, potentially life-threatening adverse events²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021:

• Known hypersensitivity or serious allergic reaction to NSAIDs
• History of asthma attacks or difficulty breathing after taking NSAIDs 
• Coronary artery bypass graft (CABG) surgery

It is strongly advisable to avoid NSAIDs for the conditions listed above.²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021 

Concomitant medications to avoid with NSAIDs

Several types of medications have significant interactions with NSAIDs that can impact their effectiveness and/or safety, including²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021 :

• Anticoagulants (Coumadin, Xarelto, and Eliquis)) 
• High-dose aspirin (more than 81 mg per day)
• Phenytoin (anti-seizure medication)
• Corticosteroids (prednisone and methylprednisolone) 
• Diuretics (Lasix, Aldactone, and Hydrochlorothiazide)

It is advised to avoid concomitant use of these medications and NSAIDs.²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021 

When to Report NSAID- Related Side Effects to a Doctor

When taking NSAIDs (over the counter and prescription), it is advisable to promptly report any of the following side effects to a doctor because they could be signs of a serious adverse event²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021 :

• Lightheadedness or fainting
• Blood in vomit or stool
• Black tarry stool
• Stomach pain that does not get better 
• Bleeding or bruising that does not go away
• Swelling in any part of the body
• Chest pain
• Shortness of breath or trouble breathing
• Weakness on one side of the body
• Extreme fatigue
• Yellowing of the skin or eyes

If any of these side effects occur, it is strongly advised to seek medical care and stop taking the medication.

How to Manage a Potential Overdose of NSAIDs

Taking more than the recommended dose of an NSAID does not usually cause serious complications, but the common signs and symptoms of a potential overdose include²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021 :

• Lethargy
• Drowsiness
• Nausea
• Vomiting
• Stomach pain

These symptoms are usually reversible and may be treated with supportive care measures.²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021 

In some cases, NSAID overdose can cause acute kidney failure and severe gastrointestinal bleeding.²Caldolor. Package Insert. Cumberland Pharmaceuticals Inc; 2023^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021 

Suspected overdose of any medication that causes troubling symptoms must be immediately reported to a doctor.

Long-Term Use of NSAIDs

Long-term use of NSAIDs – defined as using an NSAID 3 or more times per week for more than 3 months – is generally not recommended due to the significantly increased risk for serious side effects and complications.¹Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol. 2020;180:114147. doi:10.1016/j.bcp.2020.114147^,3Celebrex. Package Insert. Pfizer Laboratories Div Pfizer Inc; 2021^,7Meloxicam. Package Insert. Lupin Pharmaceuticals, Inc; 2022^,16Zhou Y, Boudreau DM, Freedman Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general U.S. population. Pharmacoepidemiol Drug Saf. 2013;23(1):43-50. doi:10.1002/pds.3463

When used as directed, NSAIDs provide much-needed relief from pain and inflammation. With short-term use and careful monitoring for serious side effects, the benefits of NSAIDs are maximized while minimizing potential harm.

See Potential Safety Risks of Pain Medication for Back and Neck Pain