Adverse Effects
Diclofenac has many similar adverse effects shared with the NSAID family of drugs due to the inhibition of COX enzymes. Because diclofenac appears to act more selectively on COX-2 inhibition, it has an increased associated risk of cardiovascular events and less risk for gastrointestinal events, but this article will also examine the gastrointestinal risk for completeness. The following side effects involve systemic effects that arise from systemic exposure to diclofenac. These are less likely to be involved in the topical application of the medication, as there is less risk of systemic exposure to the drug.
Cardiovascular: all NSAIDs, especially more selective COX-2 inhibitors, carry an increased risk of myocardial infarction (MI), heart failure, stroke, and death. The risk of these events is worse for patients with pre-existing susceptibility for cardiovascular disease and with increasing doses. Therefore, it is crucial to use the lowest effective dose for the treatment of the patient’s condition. COX-2 inhibition decreases the synthesis of prostaglandin-I2 (PGI2), which has cardioprotective effects in the form of preventing thrombogenesis, increased blood pressure, and generation of atherosclerotic plaques. The risk of these events is worse for patients with pre-existing susceptibility for cardiovascular disease and with increasing doses. COX-2 inhibition decreases the synthesis of prostaglandin-I2 (PGI2), which has cardioprotective effects in the form of preventing thrombogenesis, increased blood pressure, and generation of atherosclerotic plaques.7 COX-1 is responsible for synthesizing thromboxane A2 (TXA2), a prothrombotic species, and the imbalance between TXA2 and PGI2 may contribute to these increased cardiovascular events.
Gastrointestinal (GI): NSAIDs that block COX-1 activity have correlations with GI complications due to the inhibition of the synthesis of gastroprotective agents such as PGE2 and other prostaglandins. This inhibition leads to decreased mucin production by gastric epithelial cells, less bicarbonate secretion, and less epithelial cell turnover, among other actions. This characteristic of the drug leads to an overall increased risk of acid-mediated damage to gastric epithelial cells and decreased ability to reproliferate the damaged areas and lead to GI injury ranging from mild erosion to frank ulceration visible through endoscopy. It is important to consider that studies have shown that GI damage occurs over extended periods of exposure to the adverse GI effects of NSAIDs. Therefore, clinicians frequently prescribe a gastroprotective agent such as a PPI or PGE2 analog to decrease acid production or increase gastroprotective activity, respectively. However, more selective COX-2 inhibitors such as diclofenac have decreased risk of GI adverse effects such as bleeding, perforation, and ulceration.
Renal: Extended NSAID use also correlates with the development of renal complications. Similar mechanisms of protective prostaglandin synthesis are involved in this and center on decreased PGE2 and PGI2 activity—these act to dilate the blood vessels in the kidney to allow for proper perfusion for the tissue. Decreased prostaglandin synthesis has links with decreased renal perfusion and the development of acute kidney injury (AKI). This risk increases in patients with prior history of kidney damage and reduced perfusion pressure.
Hepatic: NSAIDs, including diclofenac, can cause drug-induced hepatic damage and increases in liver transaminase levels. These events are usually transient and reversible.12 Although rare, patients exposed to long-term NSAID treatment can develop hepatitis and face a life-threatening adverse effect. These are more prevalent in patients taking long-term diclofenac for rheumatoid arthritis.13
Anaphylaxis: Anaphylaxis to NSAID medications is an uncommon reaction but is still worth noting. Patients with a history of anaphylactic reactions to this drug class are at a higher risk of developing a similar reaction to diclofenac. Symptoms of these types of reactions can include urticaria, flushing, changes in heart rate, bronchospasm, angioedema, hypotension, and others.
Hematologic: increased risk of bleeding has correlations with NSAID use due to the effects of inhibiting platelet aggregation and adhesion via COX-1 inhibition. Also, in rare instances, patients can experience neutropenia and aplastic anemia.
Dermatologic: the topical application of diclofenac may cause mild to moderate skin irritation at the application site.
