Tramadol- and codeine-induced severe hyponatremia: A Swedish population-based case-control study

Although tramadol and codeine occasionally have been reported to cause hyponatremia the evidence is scarce. The objective of this investigation was to study the association between weak opioids (tramadol and codeine) and hospitalization due to hyponatremia.

This was a register-based case-control study of the general Swedish population. Those hospitalized with a principal diagnosis of hyponatremia (n = 14,359) were compared with matched controls (n = 57,383). Multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations and socioeconomic factors was used to explore the association between severe hyponatremia and the use of tramadol or codeine. Furthermore, newly initiated (≤90 days) and ongoing use was investigated separately.

Compared to controls, the unadjusted OR (95%CI) for hospitalization due to hyponatremia was 2.45 (2.26-2.66) for tramadol and 3.19 (2.92-3.47) for codeine. However, after adjustment for confounding factors the risk decreased (adjusted OR: 1.17 [1.08-1.26] and 1.14 [1.03-1.26], respectively). Newly initiated treatment with tramadol or codeine showed a significant association (adjusted OR 2.34 [95%CI 2.01-2.72] and 2.20 [95%CI 1.87-2.60], respectively). In contrast, for ongoing therapy the corresponding adjusted ORs were not elevated (adjusted OR: 0.70 [95%CI 0.61-0.80] and 1.14 [95%CI 0.99-1.30, respectively).

Associations were found between tramadol or codeine usage and hospitalization due to hyponatremia which were markedly increased in those newly initiated. The risk associated with long-term use was not increased. The association may be causally related to the drugs, although an effect due to pain, nausea or the underlying disease cannot be excluded.