What is the probability of an interaction between Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Lithium?

From the Guidelines

The interaction between NSAIDs and lithium is a significant concern, and concomitant use should be avoided due to the increased risk of lithium toxicity, as highlighted in the 2014 commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD 1. The mechanism of this interaction involves NSAIDs reducing prostaglandin synthesis in the kidneys, which decreases lithium clearance and raises serum concentrations.

• Key points to consider:
  • NSAIDs can increase lithium levels by approximately 15-60%, potentially leading to lithium toxicity
  • Most NSAIDs, including ibuprofen, naproxen, diclofenac, and COX-2 inhibitors like celecoxib, are implicated in this interaction
  • Acetaminophen (paracetamol) is generally a safer alternative for pain management in patients on lithium, as it doesn't significantly affect lithium levels
  • When NSAID use cannot be avoided, lithium dosage may need to be reduced by 15-20%, and more frequent monitoring of lithium levels is essential
  • Symptoms of lithium toxicity to watch for include tremor, confusion, nausea, diarrhea, and ataxia As noted in the 2014 commentary, it is essential to monitor GFR, electrolytes, and lithium levels 6 monthly or more frequently if the dose changes or the patient is acutely unwell, and to maintain hydration during intercurrent illness 1.
• The risk-benefit of concomitant NSAID and lithium use must be carefully weighed, and alternative pain management strategies should be considered to minimize the risk of lithium toxicity.

From the FDA Drug Label

Non-steroidal anti-inflammatory drugs (NSAIDS): Lithium levels should be closely monitored when patients initiate or discontinue NSAID use. In some cases, lithium toxicity has resulted from interactions between an NSAID and lithium. Indomethacin and piroxicam have been reported to increase significantly steady-state plasma lithium concentrations There is also evidence that other nonsteroidal anti-inflammatory agents, including the selective cyclooxygenase-2 (COX-2) inhibitors, have the same effect. In a study conducted in healthy subjects, mean steady-state lithium plasma levels increased approximately 17% in subjects receiving lithium 450 mg BID with celecoxib 200 mg BID as compared to subjects receiving lithium alone NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20% These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

The probability of an interaction between NSAIDs and Lithium is high, as both drug labels warn about the potential for increased lithium toxicity due to elevated plasma lithium levels and reduced renal clearance when these medications are used concomitantly 2 3. Key points to consider:

• Lithium levels should be closely monitored when patients initiate or discontinue NSAID use.
• NSAIDs can increase lithium plasma levels by approximately 15-17%.
• Renal lithium clearance can be decreased by approximately 20% when using NSAIDs. It is essential to exercise caution and monitor patients carefully for signs of lithium toxicity when administering NSAIDs and Lithium concurrently.

From the Research

Interaction between NSAIDs and Lithium

The probability of an interaction between NSAIDs and Lithium is supported by several studies.

• The interaction between NSAIDs and lithium can lead to an increase in plasma lithium levels, resulting in potential intoxication 4, 5, 6.
• This interaction occurs because NSAIDs can reduce urinary clearance of lithium, leading to increased tubular reabsorption 4.
• Not all NSAIDs interact with lithium to the same extent; for example, aspirin does not appear to interact with lithium, while indomethacin, ibuprofen, and naproxen can significantly increase serum lithium levels 4, 6.
• Patients taking lithium and NSAIDs should have their serum lithium levels monitored closely to avoid potential toxicity 6.
• The interaction between NSAIDs and lithium is a significant concern, and patients should be informed of the risks associated with taking these medications together 4, 5, 6.

Specific NSAIDs and Their Interaction with Lithium

• Indomethacin, diclofenac, ketoprofen, mefenamic acid, niflumic acid, and piroxicam have been reported to interact with lithium 4.
• Ibuprofen and naproxen can also increase serum lithium levels, but the extent of the interaction can vary between individuals 6.
• Aspirin does not appear to interact with lithium, suggesting that the inhibition of prostaglandin synthesis is not the mechanism responsible for the decrease in urinary elimination of lithium 4.

Clinical Significance of the Interaction

• The interaction between NSAIDs and lithium can lead to lithium toxicity, which can affect multiple organ systems, including the central nervous system 5.
• Patients taking lithium and NSAIDs should be closely monitored for signs of lithium toxicity, and their serum lithium levels should be checked regularly 6.
• In some cases, a reduction in lithium dosage may be necessary to avoid potential toxicity 6.