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Since 1965, when Swedish authors first suggested that analgesic abuse could cause uroepithelial tumors associated with or without analgesic nephropathy, an increasing number of cases have been reported from many parts of the world. In a retrospective analysis of all patients admitted to the medical department of the University Hospital in Basel from 1966 to 1976, records of 20 patients with analgesic nephropathy and tumors of the urinary tract (excluding hypernephroma) were found (17 uroepithelial tumors, 2 sarcomas, 1 chorionepithelioma). Typical symptoms, outcome and actuarial survival of the patients with uroepithelial tumors are summarized. Phenacetin as the common ingredient in analgesic mixtures has been regarded as carcinogenic, since some of its metabolites are similar in chemical structure to well-known industrial carcinogens. In animal experiments malignant tumors have in fact been induced with 2-hydroxylated metabolites and areneoxydes of phenacetin and paracetamol, and there is even more convincing evidence of the carcinogenic properties of N-oxydized metabolites such as N-hydroxy-phenetidine and N-hydroxy-phenacetin. Dimethylnitrosamine formed from aminophenazone appears to be improbable as a cause of uroepithelial tumors associated with analgesic abuse, since aminophenazone has not been a common ingredient of analgesic mixtures in Australia, where the incidence of uroepithelial tumors appears to be as high as in Sweden, where abuse of aminophenazone-containing analgesics has been massive.

From the 24 683 autopsies performed at the Institute of Pathology of Zurich University from 1963 to 1973, all cases with hypernephroid carcinoma or carcinoma of the urinary tract were listed. For each type of carcinoma the extent of phenacetin abuse, the sex and the mean age of the patients were established. The positive relationship between phenacetin abuse and carcinoma of the renal pelvis and the urinary bladder confirms the results of other investigators. In addition, a relationship between phenacetin abuse and hypernephroid carcinoma is discussed.

Between 1978-1890 the incidence of analgesic (phenacetin) abuse in autopsies of adult inhabitants of Basle was 3.87%. Only 2.3% of these were known abusers. The incidence of abuse varied considerably in different age groups, with a maximum of 16% in women in the age group 50-59 years. The sex distribution was male/female 1:1.93. It can therefore be assumed that 1500-3000 inhabitants of Basle actively abuse or abused phenacetin containing analgesics. Extension of the prescription requirement to all salicylate and paracetamol containing analgesics is accordingly recommended.

Current concepts of the mode of action of analgesics are presented, together with some pharmacokinetic characteristics. This information may serve as a basis for rational therapy, and may also help in understanding important side effects of these drugs.

971 samples of urine and washes of the urinary bladder in 643 patients were investigated cytologically. Urothelial carcinoma was present in 27 patients. In 11 cases the carcinoma was diagnosed by urinary cytology; 7 of the carcinomas were localized in the urinary bladder, 3 in the renal pelvis and 1 in the ureter. By contrast, all 19 tumors diagnosed in washes were localized in the urinary bladder. Diagnostic sensitivity was 100% in urine and about 75% in bladder washes. In 5 other patients cytologic diagnosis of carcinoma could not be confirmed by histology. In 4 of these, urothelial papillomas were present and in 1 patient a carcinoma of the bladder had been resected previously. Thus, the diagnostic accuracy of urinary cytology is good if essential methodological prerequisites are fulfilled. Therefore, urinary cytology appears to be an appropriate method for screening programmes in high risk patients such as phenacetin abusers. The estimated costs of a screening programme in Basel are 50 000-150 000 Swiss francs. However, a preliminary study to verify the value of such a screening programme is suggested.

Calcium (Ca) metabolism was compared in 2 groups of patients with chronic interstitial nephritis: in 21 patients (AAN-group) nephropathy was due to exposure for 5 to 50 years (mean 21.1) to phenacetin containing analgesics, whereas in 21 other patients (controls) it was due to exposure for 1 to 80 years (mean 21.4) (NS) to other causes. Patients were followed for 2.5 +/- 0.6 and 1.6 +/- 0.6 years respectively (mean +/- SEM) (NS). Blood Ca, P, protein, creatinine, alkaline phosphatase, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH-D), together with arterial acid-base status and urinary excretion rate of Ca, P and creatinine were measured serially. For each patient the results were averaged for 2 degrees of renal failure, i.e. for creatinine levels below and above 400 mumol/l (logarithmic mean). Results were included only when P was maintained between 0.7 and 1.9 mmol/l. The range of creatinine levels studied was 95 to 1600 mumol/l. No differences were found between the 2 groups with respect to creatinine clearance, blood, P, protein, arterial pH and urinary excretion rates of Ca and P. There was a trend for blood HCO3 to be lower in the AAN group. Mean plasma Ca was significantly lower, and PTH was significantly higher, in the AAN than in the control group at both degrees of renal failure; mean plasma alkaline phosphatase activity was also significantly higher in the AAN group, but at severe degrees of renal failure only. Significant correlations were observed between individual values of both Ca and PTH (r = -0.747) and PTH and alkaline phosphatase (r = 0.603). The degree of hypocalcemia and of hyperparathyroidism was not related to the plasma level of 25-OH-D. It is concluded that at comparable degrees and duration of renal failure patients with AAN, when compared with patients with interstitial nephritis of other origins, have lower blood Ca and consequently higher PTH levels and alkaline phosphatase activities, suggesting more severe osteodystrophy.

The frequency of chronic terminal renal failure (CTRF) (serum creatinine greater than or equal to 4,5 mg/dl) in an unselected autopsy material was about 1.7% from 1968 to 1976. Based on this figure, the estimated yearly incidence is 160 to 200/10(6) inhabitants of the Basel area. In inhabitants of Basel, analgesic nephropathy (42.2%) was the most important cause of CTRF (excluding obstructive nephropathy). Pyelonephritis (without evidence of analgesic abuse) represented only 25.7%. All other nephropathies were less common: glomerulonephritis 14.6%, diabetic nodular glomerulosclerosis 11.6%, cystic kidney disease and vascular nephropathies (each 4.5%). By contrast, in patients treated by hemodialysis and renal transplantation glomerulonephritis (28.7%) is the most important cause of CTRF, followed by analgesic nephropathy (20%), pyelonephritis (15%) and cystic disease of the kidney (12.5%). The difference between the two groups can be explained by the lower mean age of patients treated by hemodialysis and transplantation. Incidence and disease course can be affected significantly only in analgesic nephropathy. It is therefore very important to prohibit legally the use of phenacetin or paracetamol containing analgesics without medical prescription. In addition, these drugs should be replaced by other analgesic compounds.

From 1965 to 1981, 9 out of 346 patients treated by chronic hemodialysis or kidney transplants had tumours of the lower urinary tract. All the tumour patients belonged to the analgesic abusers group (n = 87). The frequency of urinary tract tumours in this analgesic abusers group does not differ from the frequency in analgesic abusers in general (about 10%). In the 9 analgesic abusers a total of 18 urothelial tumours were recorded: 4 tumours of the renal pelvis, 3 of the ureter and 8 tumours of the urinary bladder. One female patient had a tumour of the urethra. Diagnostic and therapeutic problems are discussed on the basis of two case histories. Our experience in recent years is summarized in a program for tumour-screening, diagnosis and therapy for analgesic abusers treated by dialysis and kidney transplantation.

A simple thinlayer chromatographic method for the detection of pyrithyldion in 5 ml of urine per analysis is described. Sensitivity (0.01 mug of pyrithyldion) and specificity (reaction still positive 5-6 days after injection of 50 mg of pyrithyldion) of the method are considered acceptable. The duration of elimination for pyrithyldion is relatively long (5-6 days). Epidemiological investigations were conducted in two different patient groups to analyze spontaneously voided urine samples. The incidence of positive urine samples in 204 ambulatory internal medicine patients was only 0.5% for pyrithyldion and N-acetyl-p-amino-phenol (the main metabolite of phenacetin). In contrast, the incidence in a specially selected group of 600 working women with regular intake of analgesics was much higher (between 17.7% and 28%) in the period 1969 to 1972.

Aim of the study is to evaluate whether gastric ulcer, hypertension, myocardial infarction etc. form part of the analgesic syndrome in Switzerland. About 160 autopsies of phenacetin abusers and an appropriate number of non-abusers were systematically evaluated. 18% of phenacetin abusers have gastric ulcers. Thus, gastric ulcers are more frequent in phenacetin abusers than in non-abusers and are probably the consequence of the admixture of salicylates in several compound analgesics. A low body weight (body index 1), which--together with the brownish pigmentation of the skin--contributes to premature aging, is also part of the analgesic syndrome. 50-70% (clinical/pathological findings) of phenacetin abusers are hypertensive. Hypertension is more frequent in phenacetin abusers than in controls but is less likely to be due to the analgesic abuse itself than to analgesic nephropathy. Myocardial infarctions are found in 32% of phenacetin abusers (males 50%, females 20%). Myocardial infarction is not markedly more frequent in phenacetin abusers than in non-abusers. Thromboembolic diseases are clearly increased in controls. Splenomegaly does not, on the basis of autopsy findings, form part of the analgesic syndrome.

The diagnosis of analgesic-associated nephropathy (AAN) may be missed because of the patients denial or regular analgesic intake. We therefore performed a cross-sectional study of the 144 patients of our hemodialysis center to investigate differences between the 48 patients with AAN (33%) and patients with other kidney diseases who served as controls. The aim was to find other attributes of analgesic users relating to social history, habits and morbidity. Dialysis patients with AAN were significantly older (60 +/- 10 versus 52 +/- 15 years) and more frequently women (65% versus 37%) compared with controls; they often had a family history of analgesic abuse. Comparison with an age-matched control group of hemodialysis patients with other kidney diseases showed that AAN patients smoked, used hypnotics and laxatives, and required prescriptions significantly more frequently; they were less frequently willing to undergo renal transplantation. With regard to accompanying diseases, they suffered significantly more often than the age-matched controls from anemia, renal osteodystrophy, peptic ulcer disease, diverticulosis, hemorrhoids, atrial fibrillation, coronary heart disease, hyperlipidemia, carpal tunnel syndrome, and urinary tract infections. The characteristic pattern of habits, social history and accompanying diseases may facilitate the diagnosis of AAN even in cases where analgesic consumption is denied.

Side effects due to ingestion of nalidixic acid in a 46 year old patient with phenacetine-induced interstitial nephritis and severe renal failure are reported. This observation underlines the point that, besides the direct neurotoxic effect of nalidixic acid, disturbance of the acid-basic equilibrium could be seen in patients with renal failure in particular. A hypothetical pharmacokinetic model suggests that two metabolites of nalidixic acid could provide enough hydrogen ion to induce acidosis in cases of renal failure.

In 442 inhabitants of Basel 451 malignant tumors of the lower urinary tract were found at autopsy or biopsy from 1963 to 1977. 69/442 patients were abusers of phenacetin containing analgesics. Carcinomas and sarcomas of the lower urinary tract were nearly 13 times as frequent in abusers as in non-abusers. Carcinomas of the renal pelvis were 77 times, carcinomas of the ureter 89 times and those of the urinary bladder 7 times as frequent among abusers. The differences in incidence of malignant tumors are statistically highly significant for all localizations and for multiple carcinomas as well, even if smokers are excluded. "Phenacetin tumors" occurred in younger patients and were more common in women than in non-abusers. They were ofen, though not always, accompanied by analgesic nephropathy. Comparison with other etiological factors such as aromatic amines or thorotrast demonstrated that phenacetin abuse is of greatest importance. The significance of smoking cannot be established unequivocally. Because of the occurrence of a large number of malignant tumors in phenacetin abusers it is very important to prohibit by legislation the use of phenacetin or paracetamol containing analgesics without medical prescription. In addition, these drugs should be replaced by other analgesic compounds.