What Are the Most Common Side Effects of Diclofenac?

Gastrointestinal problems are the most common side effects of diclofenac by a wide margin. In one study of over-the-counter dosing, GI adverse events occurred in roughly 37% of diclofenac users, and those gut-related issues accounted for about three quarters of all adverse events recorded. But the stomach is only the beginning of the story. Diclofenac carries a distinct and sometimes underappreciated set of risks involving the heart, liver, kidneys, and skin that set it apart from other common pain relievers.

Stomach and Gut Problems

The most frequent complaints from people taking oral diclofenac are stomach pain, nausea, diarrhea, and indigestion. These show up more often with diclofenac than with comparable doses of ibuprofen or acetaminophen. One study comparing over-the-counter analgesics found a GI adverse event rate of 37% for diclofenac versus about 7% for ibuprofen and under 8% for acetaminophen, with GI effects making up 75% of all adverse events in the diclofenac group.¹ Most of these complaints are the everyday nuisance variety: an upset stomach, bloating, or loose stools that go away when you stop the drug or take it with food.

The more serious GI concern is peptic ulcers and upper gastrointestinal bleeding. At low doses, the bleeding rate is relatively small in absolute terms. A cohort study comparing low-dose diclofenac, naproxen, and ibuprofen found upper GI bleeding rates of about 1.8 per 10,000 users for diclofenac, 2.3 for naproxen, and 0.4 for ibuprofen.² The risk climbs with higher doses, longer treatment duration, older age, and use of alcohol or blood thinners.

If you need to take oral diclofenac for more than a few days, a proton pump inhibitor can substantially cut your risk of developing an ulcer. In one clinical trial of people infected with H. pylori who were starting diclofenac, peptic ulcers developed in about 6% of those receiving a placebo but in only around 1% of those given omeprazole or triple therapy beforehand.³ A separate study estimated that adding a proton pump inhibitor to diclofenac reduced the risk of hospitalization for ulcer disease by roughly 60%.⁴ Despite this, many people who are prescribed diclofenac long-term never receive a protective acid-suppressing drug alongside it.

Cardiovascular Risks

Diclofenac’s effect on the heart is the side effect that has attracted the most regulatory attention in the past decade. A large Danish study following the entire national population found that starting diclofenac increased the rate of major cardiovascular events by about 50% compared with not starting any painkiller, and by about 20% compared with starting ibuprofen or acetaminophen. The increase showed up across individual outcomes: a roughly 90% higher rate of heart attack, 70% higher rate of heart failure, 60% higher rate of ischemic stroke, and 70% higher rate of cardiac death, all compared to non-users. These elevations persisted even at low doses.⁵

Some researchers initially thought diclofenac’s cardiovascular risk could be explained by how selectively it blocks a particular enzyme pathway. Diclofenac behaves a lot like the prescription-only COX-2 inhibitors that generated headlines in the early 2000s when rofecoxib (Vioxx) was pulled from the market. A review found that diclofenac’s heart attack risk was similar to rofecoxib’s, though the proposed mechanisms involving enzyme selectivity and potency did not fully hold up on closer analysis.⁶ A more recent emulated-trial study confirmed that diclofenac raised the rate of major cardiovascular events by about 20% compared with other older COX-2 inhibitors like meloxicam and etodolac, driven especially by cardiac death. The risk was strongest for women, people with high baseline cardiovascular risk, and those on higher doses.⁷

The practical takeaway is that if you already have heart disease, uncontrolled high blood pressure, or heart failure, diclofenac is one of the worst NSAID choices you can make. Several European countries have moved it behind the pharmacy counter or restricted package sizes specifically because of these cardiovascular findings.

Liver Effects

Diclofenac is one of the more liver-unfriendly NSAIDs, though outright liver failure from it is vanishingly rare. In a large clinical trial following over 17,000 arthritis patients who took diclofenac for an average of 18 months, about 3% developed meaningfully elevated liver enzymes. A smaller fraction, around 0.5%, had very high elevations. Four patients were hospitalized for liver-related events, and no one in the trial experienced liver failure, needed a transplant, or died from liver injury.⁸ The enzyme elevations tended to appear within the first four to six months of therapy, which is why doctors often check liver function tests early in a course of treatment.

The mechanism behind diclofenac’s liver toxicity is complex and considered partly idiosyncratic, meaning it depends on individual vulnerability rather than dose alone. The drug’s breakdown products can stress liver cells through oxidative damage and disruption of mitochondrial function, and in some people the injury involves an immune-mediated reaction.⁹ Because the liver damage can be silent at first, the advice to watch for symptoms like unusual fatigue, dark urine, or yellowing of the skin is genuinely worth heeding if you are on diclofenac for weeks or months.

Kidney Concerns

All NSAIDs can harm the kidneys by reducing blood flow to them, and diclofenac is no exception. NSAIDs as a class account for a substantial share of drug-induced kidney failure cases, estimated around 15–16% in one review.¹⁰ The risk is highest in people who are dehydrated, elderly, or already have reduced kidney function, and it gets compounded by conditions like high blood pressure or concurrent use of other drugs that affect the kidneys. In most cases, NSAID-induced kidney problems resolve once the drug is stopped, but occasionally the damage can be severe and require hospitalization. If you take diclofenac regularly and have any of these risk factors, periodic kidney function monitoring is a sensible precaution.

How the Topical Form Changes the Picture

Diclofenac gel and patches are increasingly popular precisely because they sidestep many of the systemic side effects. The reason is straightforward: topical diclofenac delivers far less drug into your bloodstream. In a pharmacokinetic study comparing the 1% gel to an oral tablet, systemic exposure with the gel was five to seventeen times lower than with oral diclofenac. The oral form inhibited platelet function and both COX enzymes noticeably; the gel did not inhibit platelet aggregation at all and had much weaker effects on the enzymes. Adverse events from the gel were limited to mild skin reactions at the application site, while the oral group experienced gastrointestinal complaints.¹¹

The trade-off is that topical diclofenac concentrates in the tissue directly beneath the skin rather than flooding the whole body, which is the point for localized joint pain. Data confirm that it penetrates through to deeper tissues while maintaining a lower ratio of drug in the blood versus the tissue compared with oral dosing.¹² For people with knee osteoarthritis or similar localized pain who want to avoid gut and cardiovascular exposure, the gel or patch formulation is a genuinely safer route.

Skin Reactions from Topical Diclofenac

The most common side effect of topical diclofenac is, unsurprisingly, irritation right where you apply it. In pooled data from three randomized trials of the gel for knee osteoarthritis, application site dermatitis was the main treatment-related adverse event, occurring in about 4–6% of users versus under 1% with the vehicle control. GI side effects, by contrast, were uncommon and no different from placebo.¹³ The dermatitis rates were slightly higher in patients aged 65 and older compared to younger adults.

A rarer but more dramatic skin reaction is photosensitivity. Diclofenac, both oral and topical, can make the skin unusually sensitive to sunlight, and in some people this escalates into a genuine photoallergic contact dermatitis where sun-exposed areas treated with the gel develop blistering or severe redness.¹⁴ Case reports have also documented cross-reactivity, meaning someone who develops photoallergic dermatitis from diclofenac may react to chemically related NSAIDs like aceclofenac as well.¹⁵ If you are using the gel on areas that get sun exposure, covering the treated skin or applying it at night reduces the chance of a reaction.

Eye Drop Formulations and Corneal Safety

Diclofenac is also available as an ophthalmic solution, commonly used to control inflammation and pain after eye surgery. For most patients this works well, but a small number of serious corneal complications have been documented, particularly corneal melting, where the surface of the eye thins and breaks down. In a case series, 11 patients experienced severe corneal toxicity following use of 0.5% diclofenac eye drops, with the time between starting the drops and corneal melting ranging from 6 days to 17 months.¹⁶

The patients at highest risk appear to be those with pre-existing conditions that compromise the corneal surface. A case report described corneal melting within two weeks of starting diclofenac 0.1% eye drops after eye surgery in a patient with rheumatoid arthritis.¹⁷ Another case involved bilateral corneal melting in a patient with Sjögren’s syndrome, a condition that causes severe dry eyes, just 10 days after cataract surgery with diclofenac drops.¹⁸ These are rare events, but ophthalmologists are generally cautious about prescribing NSAID eye drops to anyone with autoimmune disease affecting the eyes or chronic dry eye.

Allergic and Hypersensitivity Reactions

Like other NSAIDs, diclofenac can trigger allergic reactions ranging from mild hives to life-threatening anaphylaxis. One case report documented severe bronchospasm immediately after intravenous diclofenac was administered during surgery, with the patient’s oxygen levels dropping to 82% and airway pressures spiking before the reaction was brought under control with intubation and treatment.¹⁹ Severe reactions like this are uncommon but not negligible, especially in people with a history of asthma or known NSAID sensitivity. The so-called “aspirin triad” of asthma, nasal polyps, and NSAID intolerance is a classic risk pattern. If you have had a reaction to aspirin or any other NSAID in the past, diclofenac deserves extra caution.

How Diclofenac Compares to Other Common NSAIDs

One of the most useful things to understand about diclofenac’s side effects is how they stack up against the alternatives, because the choice of NSAID is often a trade-off between different risks.

A network meta-analysis comparing diclofenac to other NSAIDs and COX-2 inhibitors in arthritis patients found that diclofenac actually had lower rates of major upper GI events than naproxen or ibuprofen, comparable rates to celecoxib, and higher rates than etoricoxib. For cardiovascular events, all the drugs were broadly similar, though diclofenac’s cardiovascular signal in observational data is consistently among the worst in the class.²⁰ This creates a paradox: diclofenac may be somewhat gentler on the stomach than naproxen in terms of serious ulcer complications, but harder on the heart. Naproxen is generally considered the most cardiovascular-friendly NSAID, though it is rougher on the GI tract.

The Danish population study mentioned earlier quantified this cardiovascular gap: starting diclofenac raised major cardiovascular event rates by about 30% compared with starting naproxen.²¹ That difference may sound modest, but across millions of users it translates to a meaningful number of additional heart attacks and strokes. For someone with significant cardiovascular risk factors, naproxen or topical diclofenac are both better choices than oral diclofenac.

Why Side Effects Hit Some People Harder

Not everyone metabolizes diclofenac at the same speed. The drug is primarily broken down in the liver by specific enzymes, and genetic variations in these enzymes can make a real difference in how much active drug accumulates in your body. People carrying certain gene variants that slow down diclofenac’s metabolism end up with higher blood levels of the drug and its reactive breakdown products, raising their risk of liver toxicity and GI bleeding.²² Laboratory studies have confirmed that some of these genetic variants substantially reduce the body’s ability to clear diclofenac.²³

In theory, genetic testing could identify people who should use a lower dose or a different drug entirely. In practice, this kind of pharmacogenomic screening before prescribing an over-the-counter painkiller is not standard care anywhere yet. What it does explain, though, is why two people can take the same dose of diclofenac and have completely different experiences: one tolerates it without issue, while the other develops stomach problems or abnormal liver tests within weeks. Age, hydration status, alcohol intake, and other medications all layer on top of the genetic baseline to shape your individual risk.

Diclofenac’s Unexpected Ecological Footprint

One of the most striking chapters in diclofenac’s history has nothing to do with human patients. In the 1990s, vulture populations across the Indian subcontinent collapsed by over 95%, and researchers eventually traced the cause to diclofenac residues in livestock carcasses. Vultures that fed on the remains of cattle treated with veterinary diclofenac developed fatal kidney failure.²⁴ A normal veterinary dose given to a cow shortly before death was enough to kill the birds that scavenged its body.

India, Pakistan, and Nepal eventually banned veterinary diclofenac, and populations of several vulture species have begun a slow recovery. The episode remains one of the most dramatic examples of a pharmaceutical’s environmental side effects, and it prompted broader scrutiny of how excreted drug residues enter waterways and affect aquatic organisms. Diclofenac is now on the European Union’s watch list of environmental pollutants in surface water, a distinction shared by very few individual drugs.