Table 3 Results of causality assessment on hydrochlorothiazide and hearing disorder using Austin Bradford-Hill criteria

1.

Strength of association

IC value is negative (no statistical signal).

2.

Consistency of the cases

In many of the cases, reaction manifested within a few days (between 1 and 7 days) following the commencement of HCTZ. The cases have wide geographical distribution with similar clinical features that ranges from tinnitus to deafness shortly following administration of HCTZ.

3.

Specificity of the association

In 26 of the cases, HCTZ was the only suspected drug with no other concomitants and patients experienced reactions with similar clinical features like tinnitus, ototoxicity, hearing loss, and/or deafness. Nevertheless, the availability of multiple co-reported drugs and reactions in many of the other cases make the association nonspecific.

4.

Temporal relationship

All reactions manifested after HCTZ was administered with median time to reaction onset of 3 days. In six cases, hearing loss manifested on the second day following administration of only HCTZ.

5.

Dose–response relationship

In the case reported from Eritrea, a patient experienced irreversible deafness within 3 days after taking an overdose of HCTZ (25 mg five times a day for 3 days).

6.

Biological mechanism or plausibility

There is no clear biological mechanism by which HCTZ causes hearing loss. However, medications affecting sodium and potassium transport in kidney tissues alter ionic homeostasis of the inner ear causing functional problems like hearing loss, tinnitus and vertigo. This is evidenced by inner ear tissues being immunologically, biochemically, and functionally related to kidney tissues [19].

7.

Experimental evidence

No evidence found in animal studies. However, the positive dechallenge and rechallenge supports the association.

8.

Analogy

There are also reports of tinnitus in the combination product, amiloride and HCTZ, though tinnitus is not yet associated with HCTZ. Loop diuretics are also known to cause hearing disorder through different mechanism of action.

9.

Coherence

Not applicable