Diclofenac stands out as a frequently prescribed nonsteroidal anti-inflammatory drug (NSAID). It plays a crucial role in managing long-term arthritis and alleviating mild to moderate acute pain. While diclofenac is effective, it’s important to recognize that its use, particularly at higher doses, can sometimes lead to elevated liver enzymes. In rare situations, this medication has been linked to significant liver issues, ranging from acute to chronic conditions.
Diclofenac: An Overview
Diclofenac is classified as a phenylacetic acid derivative, placing it within the acetic acid group of NSAIDs. This category also includes other well-known drugs like indomethacin, etodolac, and ketorolac. Like its NSAID counterparts, diclofenac works by inhibiting cyclooxygenases, specifically both Cox-1 and Cox-2 enzymes. This action reduces the body’s production of prostaglandins, prostacyclin, and thromboxanes – key substances that fuel inflammation and pain. Diclofenac provides relief from pain and also has antipyretic and anti-inflammatory properties.
First approved for use in the United States in 1988, diclofenac has become a widely used medication with millions of prescriptions filled annually. It is indicated for various conditions including osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, targeting the pain and inflammation associated with these joint disorders. It is also prescribed to alleviate dysmenorrhea symptoms and manage mild to moderate pain from various other causes.
Diclofenac is available under numerous brand names and in generic forms, often combined with other medications like analgesics or gastroprotective agents such as misoprostol. While it is not available over-the-counter in the U.S., many countries do offer it without prescription for conditions like muscle pain from injuries, bursitis, tendonitis, headaches, and menstrual cramps. This broad availability contributes to diclofenac being one of the most commonly used NSAIDs globally. Popular brand names include Arthrotec, Cataflam, Voltaren, and Zorvolex. It comes in various oral dosages, typically tablets or capsules of 25, 50, and 75 mg. For chronic arthritis, a common adult dose is 50 mg taken three times daily, with lower or less frequent doses used for general pain management. While generally well-tolerated, diclofenac can cause side effects like headaches, dizziness, nausea, and gastrointestinal issues, similar to other NSAIDs.
Diclofenac also comes in topical formulations, such as ophthalmic solutions (0.1%) used post-surgery to manage pain and inflammation after cataract or corneal procedures. Dermatological gels are available for treating actinic keratoses. Patches are also available for acute pain from minor injuries. Topical diclofenac gels and creams are used for osteoarthritis, particularly in joints that are easily treated topically. These topical forms are sold under brand names like Flector Patch, Pennsaid, Solaraze, and Voltaren Gel.
Diclofenac and Liver Toxicity: A Closer Look
While effective for pain relief and inflammation, diclofenac, like many NSAIDs, carries a risk of liver-related side effects.
Elevations in serum aminotransferase levels are not uncommon in patients taking oral diclofenac long-term, occurring in up to 15% of users. However, significant elevations, more than three times the upper limit of normal, are less frequent, observed in 2% to 4% of patients. Clinically evident liver disease with jaundice due to diclofenac is rare, estimated at 1 to 5 cases per 100,000 prescriptions. Despite being infrequent, numerous cases of diclofenac-induced liver injury have been documented, placing diclofenac among the top drug causes of liver injury in many studies.
Liver injury from diclofenac can appear at varying times after starting the medication, from within a week to over a year. Most cases manifest within 2 to 6 months, with more severe cases often appearing earlier. The primary pattern of liver injury is hepatocellular, although mixed patterns have been reported. Patients typically present with jaundice, preceded by symptoms like anorexia, nausea, vomiting, and general malaise. Fever and rash are reported in about 25% of cases. Some cases show features of an allergic reaction, while others resemble chronic hepatitis, including autoimmune characteristics. Liver biopsies often reveal acute lobular hepatitis. In cases with a longer onset, chronic hepatitis features can be observed. Women appear to be more susceptible to diclofenac-related liver injury than men. Severe liver damage, including acute liver failure, has been attributed to diclofenac use in some instances.
Topical diclofenac formulations are associated with a much lower risk of liver enzyme elevations, generally less than 1%, which may be similar to placebo rates. However, product labels for topical diclofenac still mention the potential for liver injury, and rare cases have been reported. Clinically significant liver injury from topical diclofenac is considered extremely rare.
Histopathological Findings in Diclofenac Hepatotoxicity
Diclofenac-induced liver injury typically presents with a hepatitis-like histological pattern, characterized by necrosis, often most pronounced in zone 3 of the liver lobule (the centrilobular region). While focal necrosis and inflammation are common, severe cases can show widespread or submassive necrosis. In cases with longer latency and a more prolonged course, chronic hepatitis-like injury may be observed, featuring portal inflammation, interface hepatitis, and fibrosis. A smaller proportion of cases exhibit a mixed hepatocellular-cholestatic injury, known as cholestatic hepatitis, with varying degrees of inflammation.
Mechanism of Liver Injury
The exact mechanism behind diclofenac-induced liver injury is complex and likely involves multiple factors. The causes of mild liver enzyme elevations may differ from those leading to severe liver injury. An immuno-allergic component is suspected, suggested by rapid recurrence of injury even after years of stopping and restarting the drug. Genetic studies have pointed to associations with variations in genes like UGT 2B7, CYP 2C8, and ABC C2, which are involved in diclofenac metabolism, conjugation, and excretion.
Outcome and Management of Diclofenac Hepatotoxicity
The severity of liver injury from diclofenac varies widely. It can range from asymptomatic elevations in liver enzymes to overt jaundice, acute liver failure, and in the most severe cases, death. Generally, recovery is expected upon discontinuation of the drug, typically taking 1 to 3 months for liver function to normalize. In rare instances, signs of chronic liver injury may persist, some of which have been treated with corticosteroids with apparent benefit, allowing for their later discontinuation without recurrence of liver issues. Re-exposure to diclofenac after a clinically significant liver injury should be avoided due to the risk of acute liver failure upon rechallenge.
Cross-sensitivity to liver injury between diclofenac and NSAIDs from other classes, such as propionic acids (ibuprofen, naproxen), appears to be low. However, safety data is limited, and careful monitoring is advised when switching to another NSAID.
Case Reports of Diclofenac-Induced Liver Injury
Case 1: A woman in her 30s with ankylosing spondylitis showed elevated liver enzymes one week after starting diclofenac. The drug was stopped, and her liver function normalized within a month. She had previously tolerated other NSAIDs like ibuprofen without issues. This case illustrates that even short-term diclofenac use can lead to liver enzyme elevations, although often transient and reversible upon stopping the medication.
Case 2: A woman in her early 40s, on long-term diclofenac for knee pain, developed elevated liver enzymes after five months, along with right upper quadrant pain and itching. Liver biopsy showed chronic hepatitis. Discontinuing diclofenac led to resolution of symptoms and liver enzyme abnormalities. This case highlights that liver injury can develop even with long-term use and may present with chronic hepatitis features.
Case 3: A woman in her 60s developed severe acute hepatitis and liver failure after three months of diclofenac use. She presented with jaundice and signs of liver failure but ultimately recovered after diclofenac was stopped. This case demonstrates the potential for diclofenac to cause severe, acute liver injury, even leading to liver failure, although recovery is possible with prompt discontinuation.
Case 4: A 65-year-old woman experienced acute liver failure and death following diclofenac use. She developed symptoms six weeks after starting diclofenac, and despite stopping the drug and receiving treatment, her condition rapidly deteriorated, leading to death from liver failure. This tragic case underscores the rare but serious potential for diclofenac to cause fatal liver injury.
Diclofenac Product Information
Diclofenac is available under various trade names, including Cataflam® and Voltaren®. It belongs to the drug class of Nonsteroidal Antiinflammatory Drugs (NSAIDs). For complete prescribing information, refer to the product labeling available at DailyMed, National Library of Medicine, NIH.
Chemical Formula and Structure of Diclofenac
Diclofenac’s chemical formula is C14-H11-Cl2-N-O2, and its CAS registry number is 15307-86-5.
In conclusion, diclofenac is a valuable medication for managing pain and inflammation, but it is essential to be aware of its potential side effects, particularly the risk of liver injury. Patients should discuss their medical history and any concerns with their healthcare provider before starting diclofenac treatment. Regular monitoring and prompt reporting of any unusual symptoms are crucial for safe and effective use.
