Can nonsteroidal anti-inflammatory drugs (NSAIDs) be taken concurrently with lithium?

NSAIDs and Lithium: Use with Extreme Caution and Close Monitoring

NSAIDs can be taken with lithium, but this combination requires close monitoring of lithium levels due to significant risk of lithium toxicity. The FDA drug label explicitly warns that lithium toxicity has resulted from NSAID-lithium interactions, with some NSAIDs increasing steady-state lithium concentrations by 17% or more 1.

Mechanism of Interaction

NSAIDs reduce renal clearance of lithium by decreasing glomerular filtration and altering renal tubular function, leading to elevated serum lithium levels and potential toxicity 1. This pharmacokinetic interaction is well-established across multiple drug classes, including both traditional NSAIDs and COX-2 selective inhibitors 2.

Clinical Evidence of Risk

The interaction is clinically significant:

• Indomethacin and piroxicam have been reported to significantly increase steady-state plasma lithium concentrations 1
• Celecoxib increased lithium levels by approximately 17% in controlled studies 1
• Rofecoxib caused lithium increases up to 448% in adverse event reports 2
• Case reports document toxicity with naproxen, diclofenac, ibuprofen, and indometacin 3

Management Algorithm

If concurrent use is necessary:

1. Monitor lithium levels closely when initiating or discontinuing any NSAID 1, 4
2. Check baseline lithium level before starting NSAID
3. Recheck lithium level within 4-7 days after NSAID initiation
4. Reduce lithium dose preemptively if NSAID use is planned, particularly in high-risk patients 1
5. Ensure adequate hydration as NSAIDs can cause acute kidney injury, especially in elderly or dehydrated patients 5
6. Monitor renal function (creatinine, BUN) alongside lithium levels 5

High-Risk Populations Requiring Extra Vigilance

• Elderly patients (reduced renal function baseline) 5
• Patients with existing renal impairment 5
• Dehydrated patients 5
• Patients on diuretics or ACE inhibitors (additive effects on lithium clearance) 1

Preferred NSAID Choices

While all NSAIDs can interact with lithium, aspirin and sulindac have been suggested as potentially safer alternatives in some older literature 6, 7, though this remains controversial and monitoring is still mandatory. The evidence is mixed, with some reports showing decreased lithium levels with these agents, but increased levels have also been documented 2.

Signs of Lithium Toxicity to Monitor

Patients should discontinue lithium and contact their physician immediately if experiencing 1:

• Diarrhea or vomiting
• Tremor
• Mild ataxia
• Drowsiness
• Muscular weakness
• Confusion

Important Caveat

One recent study found no effect of NSAIDs or paracetamol on mood-stabilizing treatment outcomes in 482 bipolar patients over 6 months 8. However, this study measured clinical outcomes rather than lithium levels directly, and the lack of mood destabilization does not negate the pharmacokinetic interaction and toxicity risk.

Bottom Line

The combination is not absolutely contraindicated but requires proactive management. The safest approach is to avoid NSAIDs when possible and use alternative analgesics like acetaminophen (paracetamol), which does not affect lithium levels 8. When NSAIDs are medically necessary, implement intensive monitoring protocols to prevent potentially life-threatening lithium toxicity.