Is it safe to take lithium and ibuprofen (Nonsteroidal Anti-Inflammatory Drug (NSAID)) at the same time?

Concurrent Use of Lithium and Ibuprofen: Not Recommended

NSAIDs, including ibuprofen, should not be used in patients taking lithium due to the significant risk of lithium toxicity from reduced renal clearance and elevated serum lithium levels. 1, 2

Mechanism and Clinical Significance

The interaction between lithium and ibuprofen is well-established and clinically significant:

• Ibuprofen reduces renal lithium clearance by approximately 19% and increases mean minimum lithium concentrations by 15%, leading to potential lithium toxicity even in patients with normal renal function 3, 4
• The FDA drug label for ibuprofen explicitly states that "ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance" and warns that "subjects should be observed carefully for signs of lithium toxicity" 3
• The FDA drug label for lithium specifically warns that "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" 2

Evidence Base

Multiple lines of evidence demonstrate this interaction:

• Clinical studies show marked interindividual variation in the magnitude of this interaction, with some patients experiencing significant increases in lithium levels while others show minimal changes 5, 6
• Research demonstrates that ibuprofen significantly increases lithium area under the curve, red blood cell concentrations, and decreases both total body and renal clearance 4
• A case-control study found that starting potentially interacting co-medication (including NSAIDs) was associated with elevated lithium levels requiring clinical intervention 7

Guideline Recommendations

The KDIGO/KDOQI guidelines explicitly state: "NSAIDs should not be used in people taking lithium" 1

Additional guideline recommendations include:

• Lithium is nephrotoxic and may cause renal tubular dysfunction with prolonged use, even at therapeutic levels 1
• The combination requires avoidance of concomitant NSAIDs and maintenance of hydration during intercurrent illness 1
• NSAIDs should be avoided in patients with GFR < 30 ml/min/1.73 m², and prolonged therapy is not recommended in those with GFR < 60 ml/min/1.73 m² 1

Alternative Pain Management Options

When patients on lithium require analgesia:

• Acetaminophen is the preferred first-line analgesic as it does not affect lithium levels or renal prostaglandin synthesis 8
• Maximum acetaminophen dosing is 650-1000 mg every 6 hours (maximum 4000 mg/day in patients with normal liver function) 9
• For more severe pain, tramadol or short-term opioid analgesics may be appropriate alternatives 8
• Topical analgesics or intra-articular corticosteroid injections can be considered for localized musculoskeletal pain 8

If Concurrent Use Cannot Be Avoided

In rare circumstances where ibuprofen must be used despite lithium therapy:

• Monitor serum lithium levels every 4-5 days until the extent of drug interaction is assessed 5
• Check baseline renal function (BUN, creatinine) and electrolytes before initiating ibuprofen 1
• Use the lowest effective dose of ibuprofen (≤400 mg per dose, maximum 1200 mg/day) for the shortest duration possible (ideally <5 days) 9
• Lithium dosage reduction of 15-20% may be needed based on the average increase in lithium levels observed in clinical studies 4
• Monitor for signs of lithium toxicity: diarrhea, vomiting, tremor, mild ataxia, drowsiness, or muscular weakness 2

Common Pitfalls to Avoid

• Do not assume all NSAIDs have equal interaction potential: Indomethacin and piroxicam have the most potent effects on lithium levels, while sulindac and aspirin appear to have minimal clinically significant effects 5, 10
• Do not overlook over-the-counter NSAID use: Patients must be educated that ibuprofen purchased without prescription carries the same interaction risk 3
• Do not forget that the interaction can occur even with short-term NSAID use: Significant increases in lithium levels can occur within days of starting ibuprofen 4, 6
• Recognize that patients with compromised renal function, dehydration, or concurrent use of diuretics or ACE inhibitors are at particularly high risk 1, 2