Analgesic Nephropathy: Removal of Phenacetin from Proprietary Analgesics

Since phenacetin was withdrawn from Askit Powders and Beecham''s Powders in 1966 these preparations have declined in importance as a cause of analgesic nephropathy in Western Scotland. In most patients with analgesic nephropathy who persist in abuse of compound analgesics renal function continues to decline. The deterioration, however, is less rapid among those taking aspirin and caffeine mixtures than in those taking preparations which also contain phenacetin.     

Letter: The clinical course of patients with analgesic nephropathy.

Thirty-four patients with analgesic nephropathy were followed at intervals of 1 to 3 months with measurements of creatinine clearance and serum concentration of acetylsalicylic acid (ASA) for a total of 105 patient-years. Diagnostic criteria included total consumption of at least 2 kg of phenacetin and 3 kg of ASA, compatible tissue abnormality on biopsy and evidence of papillary necrosis on an intravenous pyelogram. Nephropathy was induced by the same compound analgesic containing ASA, pehnacetin, caffeine and codeine (APC&C) in 30. Phenacetin was removed from this preparation in 1970 and replaced by an approximately equal amount of ASA (ACC). Creatinine clearance remained unchanged or improved in 11 of 15 patients who stopped taking analgesics containing phenacetin or ASA and in 10 of 11 of those who continued to take the ACC preparation. In contrast, renal function deteriorated in seven of eight patients who continued to abuse APC&C analgesics. The results suggest that phenacetin is necessary for the major nephrotoxic effect of this APC&C combination, but that ASA is not absolved of some nephrotoxicity.     

III. Evidence for the nephrotoxicity of analgesics

Analgesic nephropathy in man is a definite but complex and probably multifactorial disorder, which largely follows long-term abuse of mixed analgesics. In North America the disorder has been almost entirely associated with heavy ingestion of the combination acetylsalicylic acid (ASA), phenacetin and caffeine. There is less clinical and experimental evidence for the nephrotoxicity of single analgesics; however, evidence for the nephrotoxicity of ASA alone is greater than that for phenacetin. In view of the evidence for nephrotoxicity of most mild analgesics, removal of phenacetin from the market would be unlikely to eliminate the problem of analgesic nephropathy.     

Papillary Necrosis in Rats Caused by Aspirin and Aspirin-containing Mixtures

Nearly half the rats gavage-fed with aspirin and aspirin-containing mixtures developed papillary necrosis in 20 weeks. This incidence is similar to that found in rats on A.P.C. mixtures with high and low concentrations of p-chloracetanilide, an impurity of phenacetin. Aspirin alone produced necrosis in 7 out of 19 rats (36·8%) whereas phenacetin in the same dose had failed to cause any renal damage over six to nine months. If these results also apply to man they suggest that aspirin and not phenacetin may be the major factor in analgesic nephropathy in patients taking A.P.C. mixtures. An augmented clearance of aspirin appeared to afford some protection to the medulla, and it is suggested that this observation may have important clinical and epidemiological applications.     

Declining incidence of analgesic nephropathy in Canada.

Surveys of nephrologists in Canada indicate that the incidence of analgesic nephropathy has decreased by about 50% in less than a decade in association with the removal of phenacetin from the market and restrictions on the availability analgesic mixtures containing acetaminophen and acetylsalicylic acid. The number of patients presenting with end-stage renal disease attributed to analgesics has shown a similar drop. These decreases have occurred in spite of increased consumption of acetaminophen as a single analgesic. Analgesic nephropathy should not be expected to disappear, however, since there is evidence that the drugs still in use have the potential to cause renal damage.     

Nephrotoxic Lesions from 5-Aminosalicylic Acid

5-Aminosalicylic acid given to rats as a single intravenous injection led to necrosis of the proximal convoluted tubules and of the renal papilla. These two lesions developed at the same time and the cortical lesions did not appear to be a consequence of the renal papillary necrosis. Since the compound possesses the molecular structure both of a phenacetin derivative and of a salicylate these observations may be relevant to the problem of renal damage incident to abuse of analgesic compounds and suggest the possibility that in this syndrome cortical lesions may develop independently of renal papillary necrosis.     

Papillary Necrosis in Experimental Analgesic Nephropathy

A proprietary aspirin, phenacetin, and caffeine preparation given to rats in a dose equivalent to that taken by patients with analgesic nephropathy produced papillary necrosis in 55%. There was a higher incidence in rats deprived of fluids overnight.Papillary necrosis was not noted in rats receiving twice as much phenacetin.These findings support the argument that phenacetin should not be singled out as the substance responsible for analgesic nephropathy in man.     

Analgesic Nephropathy. Clinical Course after Withdrawal of Phenacetin

Of 14 patients with analgesic nephropathy 11 were followed up for 9 to 88 (mean 36) months after withdrawal of analgesics containing phenacetin. Ten of these 11 are still alive and have improving, static, or very slowly declining renal function. Analgesic withdrawal is therefore worth achieving even in the presence of advanced renal failure. Careful prolonged follow-up is required to prevent or detect relapse and to deal with the complications of prolonged renal failure, particularly bone disease and acidosis.Early diagnosis is life-saving in this condition. Attention is drawn to the diagnostic value of sterile pyuria, but the best screening test for the condition is careful interrogation of all patients with chronic renal disease of unknown aetiology; analgesic intake is rarely denied if asked for specifically.     

Possible Role of Laxatives in Analgesic Nephropathy

Eight out of ten of patients with analgesic nephropathy were regular and usually heavy laxative takers compared with 12 out of 200 controls from the general population and four out of 70 patients attending a renal clinic. The finding that regular laxative taking was greatly increased in patients with analgesic nephropathy suggests that this condition may often be due to the combined abuse of both laxatives and analgesics. In a series of 40 patients with rheumatoid arthritis all were found to have normal renal function and no patient took laxatives regularly. This finding would explain why analgesic nephropathy is so uncommon in patients with rheumatoid arthritis despite the fact that they are regular and heavy analgesic takers.     

Genotoxicity of analgesic compounds assessed by an in vitro micronucleus assay

Several analgesic compounds and mixtures of analgesics were examined for both cytotoxicity and ability to induce chromosomal damage in the normal rat-kidney cell line NRK-49F. Chromosomal damage was assessed using an in vitro micronucleus assay. Of all the compounds tested, only N-hydroxyparacetamol caused a high degree of cell death at the concentrations used. 4 analgesic compounds were found to be inducers of micronuclei in NRK cells; in order of decreasing potency these were: N-hydroxyparacetamol, N-hydroxyphenacetin, caffeine and paracetamol. An aspirin, phenacetin, caffeine mixture (APC) failed to induce micronuclei above the background level, and a paracetamol-codeine combination did not increase the level of micronuclei induction above that induced by paracetamol alone. This report suggests paracetamol and some related compounds are capable of inducing chromosomal damage in mammalian cells in vitro, which is consistent with recent reports of a possible paracetamol-DNA interaction.     

A rapid method for evaluation of analgesic and anti-inflammatory activity in rats

Carrageenin (2%) was used to produce edema and hyperalgesia; indomethacin, phenylbutazone, aspirin, ibuprofen, analgin, paracetamol and phenacetin were tested at different doses for anti-inflammatory and analgesic activity in the same rats as the peak for the edema reached at the end of 3rd hr and for the hyperalgesia at the end of 4th hr. Indomethacin, phenylbutazone and ibuprofen reduced edema and increased the pain threshold. Analgin and aspirin increased the pain threshold relatively at a low dose. Paracetamol and phenacetin were inactive in the doses tested. Carrageenin (2%) was observed to possess both phlogistic and allogenic properties.     

Comparative Nephrotoxicity of Aspirin and Phenacetin Derivatives

Both aspirin and phenacetin derivatives were shown to be nephrotoxic when administered to rats as a single intravenous injection. Phenacetin derivatives tended to produce more severe renal damage and to be nephrotoxic in smaller doses than aspirin derivatives. With the exception of a single derivative, the renal lesions were confined to the proximal convoluted tubule, even after administration of compounds which under other conditions have induced renal papillary necrosis.     

Anti-inflammatory and analgesic activity of Indian Hypericum perforatum L

A standardised 50% aqueous ethanolic extract of the Indian variety of Hypericum perforatum (IHp) was examined for its putative anti-inflammatory and analgesic activity at the doses of 100 and 200 mg/kg, po. The experimental paradigms used were carrageenan induced pedal edema and cotton pellet induced granuloma for anti-inflammatory activity, whereas the tail flick, hot plate and acetic acid induced writhing methods were used to asses analgesic activity. Indomethacin (20 mg/kg, ip) was used as the standard anti-inflammatory drug. Pentazocine (10 mg/kg, ip) and aspirin (25 mg/kg, ip), both clinically used analgesics, were used as standard analgesics for comparison. IHp extract showed significant anti-inflammatory and analgesic activity at both dose levels, in all the paradigms used. Additionally, IHp potentiated the anti-inflammatory activity of indomethacin and analgesic activities of pentazocine and aspirin.     

Treatment of Rheumatoid Arthritis with Fenoprofen: Comparison with Aspirin

Fenoprofen, a compound with analgesic, anti-inflammatory, and antipyretic properties in animals, has been compared with placebo in a double-blind cross-over trial in 60 patients with rheumatoid arthritis. There was a statistically highly significant reduction in pain, duration of morning stiffness, analgesic requirements, and articular index, with increase in grip strength. There was no significant reduction in joint size or temperature. In a subsequent double-blind group-comparative study fenoprofen proved to be as effective as aspirin in relieving the symptoms of rheumatoid arthritis, with strikingly fewer side effects. Almost half of the patients taking aspirin were unable to tolerate the drug in adequate dosage for six months. The remainder were able to take on average only 4 g daily, and at this dose almost half still complained of tinnitus and deafness.Fenoprofen is likely to be useful for patients who cannot tolerate aspirin and other more toxic anti-inflammatory drugs or whose disease is not of sufficient severity to justify their use.     

I. Recognition of the problem of analgesic nephropathy

The incidence of renal impairment secondary to the abuse of analgesic compounds now accounts for a significant proportion of patients requiring renal replacement therapy. The clinical features of 100 cases of analgesic nephropathy are described; essentially these consist of otherwise unexplained renal impairment, urinary tract symptoms, radiological changes and sterile pyuria, often associated with dyspepsia, anemia and psychiatric disturbances. The classical pathological changes consist of interstitial nephritis and progressive reduction in renal size, secondary to repeated episodes of papillary necrosis. Cessation of analgesic abuse usually arrests the deterioration in renal function, and indeed some recovery of function may occur.     

Aspirin and bleeding peptic ulcers in the elderly.

A case-control study was performed to determine whether aspirin confers a similar risk of bleeding from gastric or duodenal ulcers in the elderly as non-aspirin, non-steroidal anti-inflammatory drugs. The intake of analgesics in 230 patients with bleeding ulcers aged 60 and over and in hospital and community controls matched for age and sex was examined. Those who had taken aspirin were between two and three times more likely to be admitted to hospital with bleeding ulcers. This increased risk was not accounted for by aspirin taken for indigestion or by concurrent use of non-aspirin, non-steroidal anti-inflammatory drugs. A similar effect was not seen for paracetamol. When aspirin and other non-steroidal anti-inflammatory drugs were considered together the overall risk attributed to the drugs suggested that these drugs may be responsible for over a third of admissions for bleeding peptic ulcers in the elderly.     

Phenacetin and the liver. The influence of phenacetin in acute and chronic doses on membrane-bound mitochondrial enzymes in the rat.

Following the administration of phenacetin in single and in multiple high doses, enzymes bound to the inner mitochondrial membrane of the liver were determined. Acute doses of phenacetin (75% of oral LD50) failed to produce any effect. The chronic administration of phenacetin provoked a small but statistically significant decrease in the TD-trnashydrogenase activity. This observation indicates that liver damage may occur in patients with phenacetin abuse.     

Renal Function in Analgesic Nephropathy

Comprehensive one-day renal function tests in 20 patients with a history of analgesic abuse showed varying degrees of chronic renal failure in all. There was no evidence of a selective defect in proximal tubular function, while a defective concentrating mechanism, usually considered necessary for the diagnosis of analgesic-induced renal damage, could be demonstrated in only 16 patients. A urinary acidification defect associated with a concentrating defect was found in nine cases and was thought to reflect specific collecting duct dysfunction. Urinary ammonium excretion was reduced in 13 subjects, owing to a reduced number of functioning nephrons or inadequate acidification, or both. Low citrate excretion was frequently encountered, and this, as well as defective urinary acidification, may play some part in predisposing patients with analgesic nephropathy to intrarenal calcification and progressive renal failure.     

II. Analgesic nephropathy in Canada: a retrospective study of 351 cases

Data concerning 351 patients with analgesic nephropathy was obtained by a survey of Canadian nephrologists and suggested an incidence of at least 20, and of perhaps 50 cases per million population. Renal function at the time of diagnosis (as judged by serum creatinine level) was normal in 15%, mildly to moderately impaired in 59%, and severely impaired in 26% of cases. Follow-up serum creatinine level in 222 cases showed that renal function became worse in 42% of cases, with terminal renal failure developing in one-half of these patients. However, significant improvement in kidney function was observed in 25% of patients. Cessation of analgesic abuse considerably increased the likelihood of improvement in renal function.