(von Rechenberg 1962; Fowler 1967; Bottiger and Westerholm 1973; Ramsey and Golde 1976; Smith et al. 1977; Chaplin 1986; Faich 1987)
Restrictions on the use of phenylbutazone in man in the 1980s resulted from the recognition that it can induce blood dyscrasias, including aplastic anaemia, leukopenia, agranulocytosis and thrombocytopenia, in some cases leading to death. Fatalities were associated with use at the manufacturer's recommended dose rate, generally after therapy over several weeks or months. Nevertheless, therapeutic use was still allowed in individual patients, under specialist control and with regular blood profile monitoring. In some countries, phenylbutazone licensed by generic companies has continued to be used to this day in human medicine.
Von Rechenberg (1962) reported 51 deaths and 38 nonfatal cases of agranulocytosis linked to phenylbutazone usage from an estimated population of 50 million treated human patients. In the early period of phenylbutazone usage (commonly with the high dosage of 1 g [or higher]/subject/day), fatal blood dyscrasias were reported in 133 human patients, comprising an incidence of 1 in 20,000 treated patients/annum. Subsequent surveys indicated that deaths from aplastic anaemia occurred in the UK with an incidence of ∼1 in 40,000–50,000 phenylbutazone treated patients.
In a 1984 FDA analysis of NSAID-associated fatalities attributable to haematological conditions, the highest percentage was for phenylbutazone (54%), followed by ibuprofen (24%), fenoprofen (23%) and naproxen (0%). Therefore, haematopathology-based fatalities are not unique to phenylbutazone and other pyrazolones. Similar estimated fatality rates of 15–20 per million exposures for: 1) phenylbutazone and aplastic anaemia; 2) aspirin and gastrointestinal bleeding; and 3) penicillin-induced anaphylaxis have been made.
Based on in vitro studies designed to elucidate the mechanism(s) of phenylbutazone-induced blood dyscrasias, several groups have demonstrated concentration dependency of myelotoxicity. It has also been reported, from clinical use of phenylbutazone, that ‘although the mechanism of its haematologic toxicity is not known, there is some evidence that it is dose related. The incidence of leucopenia, thrombocytopenia, anaemia and aplastic anaemia, in the earliest clinical trials using doses up to 1.6 g per subject daily, was considerably higher than later trials using lower dosages.’ (Ramsey and Golde 1976).
The possibility of rare individual sensitivity, even to very low phenylbutazone/oxyphenbutazone concentrations, cannot be excluded: it is not possible to prove a negative. However, the available human data relate to rare sensitivity to full therapeutic doses. Even if the sensitivity, as well as being very rare, were to occur at low concentrations, there must be a limiting lower concentration and period of exposure, below which this type of toxicity will not occur. The epidemiological finding of medium (several weeks) to long (several months) median daily exposures, prior to the occurrence of agranulocytosis and aplastic anaemia, respectively, points towards a likely dependence on daily dose and duration of dosing.