Abstract
This year marks the 60th anniversary of the first observation of lithium's anti-manic effects by John Cade [1]. Lithium remains the first-line therapeutic choice for preventing bipolar mania. Being a salt, lithium is excreted by the kidney; and concomitant agents that alter renal function, such as non-steroidal anti-inflammatory drugs (NSAIDs), can precipitate toxicity. NSAIDs inhibit the cyclooxygenase enzyme, thereby reducing the production of renal prostaglandins, which regulate the glomerular hydrostatic pressure. NSAIDs thus decrease renal blood flow and the glomerular filtration rate, which in turn stimulates sodium and lithium [2] reabsorption within the proximal tubules and leads to an increase in serum lithium concentration.
We report the case of a 49-year-old woman with well-controlled bipolar disorder who presented with lethargy, diarrhoea, nausea, vomiting, hypersalivation, tremors, muscle weakness and confusion. These side-effects reportedly developed 3 days after being started on meloxicam 15 mg day−1. There was no past history of renal disease and laboratory records back to 2002 were all normal. The patient had no allergies and was not known to use illicit substances.
On assessment the patient was awake, verbally confused, febrile and hypertensive. Neurological examination indicated gross facial fasciculations, irregular coarse tremors of all four extremities, generalized ataxia, hyper-tonia and hyperreflexia. Investigations showed a serum lithium level of >5 mmol L−1 (the therapeutic range being 0.6-1.0 mmol L−1), as well as an acutely deteriorated estimated glomerular filtration rate of 49 mL min−1 (normal: >60 mL min−1).
The patient was promptly admitted to the intensive care unit where she underwent veno-venous haemodialysis. Serial lithium levels fell to 0.1 mmol L−1 at 26 h after the initial measurement.
Despite rapid and effective management, the patient experienced continuing coarse tremors, impaired balance, ataxia and muscle weakness, requiring a 3 week admission to the rehabilitation ward. At the time of discharge the patient continued to show impaired cognition. The event was reported to the Adverse Drug Reactions Advisory Committee (ADRAC).
This is the first clinical report of a potentially life-threatening interaction between meloxicam and lithium. A previous pharmacokinetic study concluded that concomitant administration of meloxicam 15 mg day−1 with lithium caused only a modest increase in serum lithium levels, the largest being 21% [2]. Other NSAIDs, namely ibuprofen and celecoxib, have also been reported to induce elevated lithium levels that were below 2 mmol L−1 [3,4]. The magnitude of lithium toxicity caused by meloxicam in this case, however, appears to be far more severe and potentially fatal and has also left the patient with long-term neurological and cognitive impairments.
The long term sequelae of lithium toxicity are not well researched. Despite rapid correction of lithium levels, however, persistent neurological sequelae can develop [5]. There have also been reports of lithium-induced encephalitis that may lead to permanent cerebellar lesions and atrophy [6].
In light of the fact that this patient had normal renal function prior to the commencement of meloxicam, the speed and severity of the lithium toxicity is particularly noteworthy. This case highlights the significant risks associated with lithium therapy and its interaction with meloxicam, a commonly prescribed NSAID among primary healthcare physicians in Australia.