Why Sulindac is Safe with Lithium
Sulindac does not significantly increase serum lithium levels or decrease lithium clearance, making it one of the few NSAIDs that can be safely used in patients taking lithium without requiring dose adjustments or intensive monitoring. 1, 2, 3
Mechanism of Safety
Sulindac's unique pharmacokinetic profile explains its safety with lithium. Unlike other NSAIDs that directly inhibit renal prostaglandin synthesis and increase tubular reabsorption of lithium, sulindac appears to have minimal effect on renal lithium handling 2, 3
The FDA label for sulindac explicitly states that "NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance" as a general class effect, but clinical studies have demonstrated that sulindac is an exception to this rule 1
Sulindac is a prodrug that undergoes reversible metabolism to its active sulfide metabolite, which may explain why it behaves differently from other NSAIDs in terms of renal prostaglandin effects 4
Clinical Evidence Supporting Safety
Multiple controlled studies demonstrate no clinically significant interaction. In a study of four geriatric patients on stable lithium therapy, sulindac 300 mg/day failed to affect serum lithium levels or renal lithium clearance over 6 days of concurrent administration 3
A larger study of six patients confirmed these findings, showing that sulindac (300 mg/day) did not alter serum lithium levels when added to stable lithium therapy, in stark contrast to other NSAIDs 5
A comprehensive review concluded that "there is no convincing evidence that sulindac and aspirin affect serum lithium levels to a clinically significant degree," distinguishing these agents from indomethacin, ibuprofen, and naproxen 2
Comparison with Other NSAIDs
Indomethacin is the most potent lithium-interacting NSAID, causing substantial increases in serum lithium levels and frequently precipitating toxicity 2, 6
Ibuprofen and naproxen show marked interindividual variation, with naproxen causing lithium level increases ranging from 0% to 41.9% in different patients, requiring dose reductions and frequent monitoring 2, 5
Other NSAIDs documented to increase lithium levels include diclofenac, ketoprofen, mefenamic acid, niflumic acid, and piroxicam 6
Only sulindac and aspirin have been shown to lack clinically significant effects on lithium levels, making them the preferred NSAIDs when anti-inflammatory therapy is needed in lithium-treated patients 2, 6
Clinical Implications and Monitoring
Despite sulindac's safety profile, baseline monitoring remains prudent. The FDA label recommends that "subjects should be observed carefully for signs of lithium toxicity" when any NSAID is used concurrently with lithium 1
For patients requiring NSAID therapy while on lithium, sulindac represents the safest choice and does not require the intensive monitoring (lithium levels every 4-5 days) that is mandatory with other NSAIDs 2
Special attention should be paid to patients with renal impairment or metabolic defects that might increase sulindac blood levels, as these conditions could theoretically unmask an interaction 1
Common Pitfalls to Avoid
Do not assume all NSAIDs are equivalent in their lithium interaction. The magnitude of effect varies dramatically, with indomethacin being most dangerous and sulindac being safest 2
Avoid extrapolating sulindac's safety to other NSAIDs in the same chemical class. The lack of interaction appears specific to sulindac's unique metabolism and renal effects 4, 3
Do not use DMSO concomitantly with sulindac, as this combination reduces plasma levels of the active sulfide metabolite and has been reported to cause peripheral neuropathy 1
Remember that sulindac still carries standard NSAID risks including gastrointestinal toxicity, renal dysfunction in volume-depleted patients, and cardiovascular effects—the lithium interaction is simply not among these concerns 7, 1