Analgesic Nephropathy: A Reassessment of the Role of Phenacetin and Other Analgesics

Summary

The weight of clinical evidence linking analgesic abuse with chronic renal disease is overwhelming and analgesic nephropathy continues to be an important problem. The characteristic lesion is renal papillary necrosis with secondary cortical damage leading to progressive renal failure. The development of uroepithelial tumours represents a further serious long term complication.

The large majority of reports of analgesic nephropathy have involved analgesic mixtures containing phenacetin with aspirin or pyrazolones such as antipyrine and amidopyrine together with caffeine and sometimes codeine and barbiturates. This is because analgesic abusers prefer combination to single drug products, and until phenacetin was restricted it was present in most popular analgesic combinations. Abuse of aspirin and paracetamol alone is uncommon.

From the outset, phenacetin was singled out as the common denominator, but it has been implicated solely on the basis of association and circumstantial evidence. Insufficient attention has been given to the more obvious nephrotoxicity of the other analgesics invariably taken with it.

Analgesic nephropathy is more likely to be caused by aspirin, pyrazolones and other acidic anti-inflammatory analgesics, rather than by phenacetin itself, and the common belief that phenacetin is the primary cause of analgesic nephropathy can be challenged on many counts

a) Numerous chronic toxicity studies in animals with phenacetin have failed to produce renal papillary necrosis. The few positive results have usually been obtained only with enormous doses in the range of the LD₅₀ and in the highly susceptible Gunn rat.

b) The removal of phenacetin from non-prescription analgesics in some countries has not been followed by the expected fall in mortality from analgesic nephropathy. Such decreases as have been observed have also been seen with other renal diseases and could be explained by better treatment of terminal renal failure (e.g. by dialysis and transplantation). In Australia analgesic nephropathy is, if anything, increasing despite the restriction of phenacetin.

c) Analgesic nephropathy has a poor prognosis if phenacetin is discontinued but other analgesics are allowed. In contrast, the prognosis is good if all analgesics and anti-inflammatory drugs are discontinued.

d) Salicylates, antipyrine and amidopyrine —the analgesics usually taken in combination with phenacetin —are clearly nephrotoxic and produce renal papillary necrosis in animals much more readily than does phenacetin. They may also cause renal failure and papillary necrosis in man.

e) More than 150 cases of analgesic nephropathy have been reported involving consumption of aspirin without phenacetin. In addition, chronic renal disease and papillary necrosis are common in patients with rheumatoid arthritis where aspirin has been the mainstay of drug treatment.

f) Asa group, aspirin and the anti-inflammatory analgesics share many properties, including nephrotoxicity. Unlike phenacetin, these drugs have demonstrable acute adverse effects on renal function in man. They cause sodium and fluid retention and reduce renal blood flow, probably through the common mechanism of inhibition of renal synthesis of vasodilator prostaglandins. Most, if not all, cause renal tubular damage and renal papillary necrosis in animals, again more readily than phenacetin.

g) There have been numerous reports of renal impairment in patients given anti-inflammatory analgesics and papillary necrosis has been reported with phenylbutazone, indomethacin, ibuprofen, alclofenac, mefenamic acid and fenoprofen.

Phenacetin is thus not the only drug which can cause renal papillary necrosis, and in comparison with these other drugs it appears to be relatively safe as far as the kidney is concerned. Paracetamol, as the major metabolite of phenacetin, has long been under suspicion. However, it has the same relatively low potential for nephrotoxicity in animals as phenacetin, and despite wide usage there have been no properly documented reports of analgesic nephropathy associated with paracetamol alone. Paracetamol is unlikely to be an important cause of analgesic nephropathy.

The mechanisms of analgesic nephropathy are unknown. Inhibition of synthesis of the vasodilator prostaglandin E may result in medullary ischaemia and hence papillary necrosis. Analgesics or their metabolites may also have a cytotoxic action on medullary structures —an effect which would be most marked at the sites of maximal urinary concentration. The prostaglandin hypothesis is attractive in that it accounts for the nephrotoxicity of the anti-inflammatory analgesics as a group, while phenacetin and paracetamol are much less active in this respect. On the other hand, cytotoxicity is much more in keeping with the appearance and distribution of the early lesions at the sites of urinary concentration. Both mechanisms could account for the potentiation of nephrotoxicity by dehydration. Aspirin, phenacetin and paracetamol are all converted in the kidney to potentially cytotoxic intermediate metabolites, but their relevance to the genesis of analgesic nephropathy is unknown. Renal tubular injury and papillary necrosis may represent different forms of expression of a common mechanism of analgesic nephrotoxicity, medullary ischaemia playing a dominant role with aspirin and anti-inflammatory analgesics.

Phenacetin has also been considered the cause of urinary tract tumours in patients with analgesic nephropathy. However, it is not known whether phenacetin or other analgesics are specific urinary tract carcinogens. Uroepithelial tumours seem to develop following chronic renal injury from many causes, of which analgesic nephropathy is only one. They have been reported in patients abusing analgesics without phenacetin and at present there is no justification for the specific implication of phenacetin.

Serious doubt must be cast on the supposed role of phenacetin as the major aetiological agent in analgesic nephropathy. The only conclusion which can be drawn from this review is that phenacetin and its metabolite paracetamol are probably the least nephrotoxic of the currently available antipyretic and anti-inflammatory analgesics.