Kidney International, Vol. 13 (1978), pp. 58-63

Analgesic nephropathy in Canada: Clinical syndrome, management, and outcome

M. H. GAULT and DOUGLAS R. WILSON

The Faculty of Medicine, Memorial University, St. John's, Newfoundland, and the Division of Nephrology, Toronto General Hospital, Toronto, Ontario

The association between heavy consumption of sumption of APC analgesics are far more common analgesics and nephropathy was first described in than nephropathy [51; the first major study in man of Canada in 1961 [1]. Thirty-seven such patients were kidney tissue in early stages of this disorder by elec- reported in 1968 [2, 3], and an additional 314 were tron microscopy suggesting that an increase in med- reported in 1972 from a survey of Canadian nephrol- ullary collagen is a very early feature and providing ogists [41, which provides a baseline from which an further evidence that the primary lesion occurs in the evaluation of the effect of removal of phenacetin can medulla [6]; and the demonstration of a major papilla be made. to cortex gradient in rabbits and dogs for '4C-ASA The analgesic taken by the great majority of these and metabolites in hydropoenia [7]. Canadian patients was a 222® tablet, containing phenacetin, 160 mg; acetylsalicylic acid, 220 mg; Syndrome caffeine, 32 mg; and codeine, 8 mg. Phenacetin was The syndrome associated with abuse of APC anal- available in this and other analgesic combinations gesics containing ASA, phenacetin, and caffeine over the counter, but sales were largely limited to (APC) [31 is of considerable help in pointing to the pharmacies. In 1970, the phenacetin was voluntarily diagnosis of analgesic nephropathy which is often replaced by Frosst Company in this and their related missed [81. Analgesic consumption is frequently compound analgesics by an additional 220 mg of denied, and the syndrome can often be recognized acetylsalicylic acid. In 1973, federal legislation was without prior knowledge of analgesic consumption passed prohibiting the sale of phenacetin in combina- [91. tion with salicylic acid and its derivatives. As the sale Patients with this syndrome are usually females of phenacetin had been almost completely in combi- between the ages of 30 and 65 yr, with a history of nation with acetylsalicylic acid, this virtually elimi- heavy APC consumption for 5 to 20 yr before renal nated phenacetin both from prescription and over- disease is discovered. Clinical features of renal dis- the-counter markets. Estimated Canadian consump- ease are frequently preceded by long-standing evi- tion of phenacetin and acetylsalicylic acid (ASA) is dence of psychiatric disorder and headache, and the shown in Figure 1. Up to 8 mg of codeine can be sold more recent onset of upper gastrointestinal disease in combination with other analgesics without pre- and . Renal symptomatology may include scription in Canada and may commonly contribute to flank or abdominal pain, acute or chronic pyelone- habituation and occasionally to addiction [31. Anti- phritis, bacteriuria, pyuria (often without infection), pyrine (phenazone) has not recently been sold in hematuria, hypertension, acidosis, passage of papil- Canada. lae, and renal failure. Some points of interest in relation to analgesic The psychiatric component in most of the patients nephropathy contributed by Canadian authors must be considered primary in the genesis of analge- include: formulation of the concept of the syndrome sic abuse and also with respect to treatment. Patients of APC analgesic abuse [3]; the finding that the may present with psychiatric problems, including upper gastrointestinal complications of heavy con- anxiety and depression. Poor adjustment in marriage and work is common, as is abuse or overdose of other drugs and habituation to . Most give a 0085-2538/78/0013-0436-0058 $1.20 history of long-standing emotional instability and © 1978, by the International Society of Nephrology. personality disorder, chiefly of an immature and 58 Analgesic nephropathy in Canada 59

26. . .0 22 // / 0 18. 00 / S / 14.

0C E S10. C 0 o—o 6- 0. 0-0- 2.

• I I I I I I I I I--E I I I 1 1946 50 54 58 62 66 70 74 Year Fig. 1. Estimated Canadian consumption as indicated by two-year means for acetylsalicylic acid [21, 221 and phenacetin used by the pharmaceutical industry [23, 241. Canadian popula- tion increased from 12.3 million in 1946 to 22.4 million in 1974 [25, 261. The closed circles and solid line (.s)representsphenacetin x 10; the open circles and broken line (00) representacetytsalicylic acid x l0. dependent nature. In the Canadian series of 351 Anemia, out of proportion to the degree of renal patients [4], 36% were considered to have major failure, is a common feature, and values and 40% moderately severe psychiatric problems. of <10 gIdl were present at the time of diagnosis of The majority of patients who abuse analgesics nephropathy in 42% of the Canadian patients [4]. state the primary reason for consumption is head- Blood loss from chronic ASA consumption and from ache. Migraine is often mentioned, but the symptoms peptic ulceration, with iron deficiency, is an impor- are frequently not characteristic. More often, a feel- tant component, and ASA may also cause anemia ing of tension, heaviness, or fullness in the head is unrelated to bleeding. Absorptive defects may be described. Some patients may later take increasing present in those who have had a gastrectomy and in quantities of analgesics for reasons unrelated to whom macrocytic anemia has been observed. Phena- headaches—for relief of tension, to get a "lift" or cetin may result in , usually of the other psychic benefit. Less frequently, back pain, oxidative type, with a hyperplastic marrow, reticulo- arthritis, abdominal pain, inability to concentrate, cytosis, Heinz bodies, distorted mor- fatigue, or desire to increase work output are reasons phology, and met- and with stated for consumption. cyanosis; these features are no longer seen in Canada Gastrointestinal symptoms often precede sympto- since the removal of phenacetin from the market. matic evidence of renal disease by several years. Minor features also reported with heavy APC con- Peptic ulceration, with a higher than usual frequency sumption include dementia [10] and darkening of the of gastric involvement is common and is probably urine on standing related to phenacetin [11]. due to salicylate. Ulcers in these patients are fre- quently resistant to treatment and have a high inci- dence of bleeding, often leading to surgery such as Management gastrectomy. Of the 351 Canadian patients [4], 50% A good long term outlook is more likely when the had had radiologic evidence of peptic ulcer and 36% patient admits the true quantity of compound analge- had undergone an upper gastrointestinal tract sics taken, accepts that habituation is a factor, and operation. that the habit has been injurious. ASA blood levels 60 Gault and Wilson and information from family or pharmacist may be Outcome helpful. The assistance of a psychiatrist may be invaluable, particularly when depression is promi- At the end of 1971, a survey of Canadian nephrolo- nent. Establishment of the reason why the patient gists was undertaken by one of the authors for the started taking analgesics and the factors that led to Canadian Society of Nephrology, and data concern- abuse permits the most appropriate treatment. ing 351 cases of analgesic nephropathy were A trial in hospital off the offending analgesics, obtained. About 60 new cases were reported annual- particularly those containing caffeine, is important ly for the three years 1969—1971. The prevalence was for those with headaches, as these sometimes are 50 per million in Toronto, where reporting was prob- predominantly of the caffeine withdrawal type and ably most complete. Renal function declined in 42% may then largely disappear. Only occasionally have of the 222 patients with follow-up values for serum our patients discarded all analgesics permanently. creatinine, particularly in those who continued use of When this is not possible, we introduce a trial with analgesics, or had severe impairment at the time of propoxyphene, adding oral codeine when necessary diagnosis. Twenty-five percent showed improvement under strict control. If abuse is related to relief of in function, particularly those who stopped taking anxiety, diazepam or a comparable drug may be analgesics. Followup was mainly for one to three given. Effective treatment of hypertension and uri- years. Two other studies [10, 11] illustrate that when nary tract infection can be critical in arresting the nephropathy is established, continued consumption decline in renal function, and long-term therapy with of APC analgesics usually leads to a continuing an antibacteriaI agent may be required. Some decline in renal function, and that abstinence fre- patients require therapy for acidosis, electrolyte dis- quently leads to stabilization or improvement. ASA, turbances, and other manifestations of renal failure. caffeine, and codeine may be less likely to cause a A normal salt and fluid intake is ordinarily advised. progressive decline in renal function than APC and Patients are followed initially at monthly intervals codeine (Fig. 2). when blood samples are drawn for ASA levels, ser- Results of a new survey (1972—1976) represent, to um creatinine, and hemoglobin; and urine is obtained date, about one half the population covered by the for routine analysis and culture when indicated. Sali- first [41. The new data are all from specific nephrolo- cylate consumption can immediately be checked by gists and hospitals who contributed to the first sur- testing urine with Phenistix® or ferric chloride. If vey and come mainly from London, Hamilton, abuse of any other drug is suspected, this is estab- Kingston, Toronto, Ontario; St. John, New Bruns- lished by assay. Blood pressure is measured, special wick; Victoria, British Columbia; and two hospitals events and consumption of analgesics and other in Montreal, Quebec. drugs since the last visit are reviewed, and the pre- The number of new cases presenting each year has vious month's ASA level is discussed. The approach fallen an average by about 40% for the last three is primarily supportive. years (1974—1976), compared with 1970—1973. The Early relief of ureteral obstruction due to sloughed number reaching end-stage, as reflected by the num- papillae is critical, especially if infection is present; bers commencing dialysis, however, has not greatly and occasionally, multiple pieces of necrotic papillae changed (Table 1). This may be interpreted as evi- lodge in the pelvis leading to repeated episodes of dence that ASA can contribute to deterioration of obstruction and may require removal surgically. Spe- function in established analgesic nephropathy. It is cial care must be taken to avoid volume or sodium important, however, to appreciate that 87% of the depletion, as acute renal failure can supervene, espe- 114 new cases had a history of heavy phenacetin cially if major surgery is undertaken under these ingestion for three years or more and 50% for ten circumstances. years or more; only 5% claimed they had taken no Most of these patients are acceptable for manage- phenacetin. ment by dialysis or transplantation when necessary. A comparison of changes in renal function for the Rarely, renal function improves enough that dialysis two surveys is shown in Table 2. The first survey can later be withdrawn [121. represents a period when analgesic consumption was Urothelial neoplasms, particularly of the renal pel- primarily the combination of ASA, phenacetin, caf- vis, may complicate analgesic nephropathy, at times feine, and codeine; and the second survey, consump- several years after consumption of phenacetin has tion of combined ASA, caffeine, and codeine. The ceased [13]. The appearance of hematuria should results show a slight improvement for the second particularly make one suspect this possibility. Urine survey. cytology at regular intervals may be of value. In 1976, 2.5% of patients on dialysis in Canada had Analgesic nephropathy in Canada 61

Analgesic consumption ceased Analgesic consumption continued — APC&C ACC

0 C.) C 'a 0C0 0 0 C C 0'a 0 20

10 Jo 0 1 2 3 4 567 8 0 1 2 3 4 5 6 7 8 Timeafter diagnosis of renal disease, yr

Fig. 2. Changes in creatinine clearance over one to eight years after analgesic nephropathy was diagnosed in patients who stopped taking analgesics containing phenacetin or ace jylsalicylic acid (ASA) (left), compared with those who continued to take either ASA-caffeine-codeine (ACC) or ASA-phenacetin-caffeine-codeine (APC & C) analgesics (right). Renal function deteriorated in only one of the patients who continued to ingest the ACC preparation, but it deteriorated in most of the patients who continued to ingest the APC & C preparation. (Re- produced with permission from Can Med Assoc J [11].)

Table 1. Incidence of new cases of analgesic nephropathy and to a decline in mortality due to this disorder [16], and patients starting dialysis in hospitals reporting continuously 1970— to a decrease in the frequency of papillary necrosis 1976a found at autopsy [17]. The effects of reduced con- Patients sumption appear particularly after four to six years New starting [15, 16]. Our recent survey was made six years after patients dialysis a major decrease in availability and three years after 1970 23 6 virtual elimination of phenacetin. Prospective 1971 35 5 recording of the incidence of analgesic nephropathy 1972 31 10 1973 31 5 for several more years will be required to determine 1974 17 6 the long term effects of the removal of phenacetin in 1975 14 8 Canada. 1976 21 5 There is relatively little information about the a Data was selected from individual nephrologists and hospitals course of patients with analgesic nephropathy who from 1971 and 1976 surveys to include only those with continuous reporting from 1970 to 1976. Legislation virtually removed phena- continue to use or abuse analgesics containing ASA. cetin from Canadian markets in 1973. Reports from Australia [18, 191 have suggested that ASA, even in small doses, and other analgesics or antiinflammatory agents may lead to progression of analgesic nephropathy (SHIMIzu A: Canadian the renal disease with further papillary necrosis. dialysis and transplant registry statistics, 1976, per- Nanra [20] has reported 47 patients who presented sonal communication). This compares with 5% for with analgesic nephropathy within the previous 2/2 Ontario in 1972 [14]. years, and had been taking acetylsalicylic acid, sali- cylamide and caffeine as Vincent's® powders, from which phenacetin had been removed in 1968. Renal Discussion function may continue to deteriorate in many Removal of phenacetin voluntarily by pharma- patients with established analgesic nephropathy who ceutical companies or decreased consumption relat- continue to take analgesics containing ASA, although ed to legislation has been reported to lead to a perhaps less rapidly than in those who continue to decrease in new cases of analgesic nephropathy [15], take analgesics containing phenacetin. 62 Gault and Wilson

Table 2. Comparison of initial and follow-up renal function: 1971 and 1976 surveys

No. ofcases Followup renal functiona % cases Worse' Improved" Unchangedb Initial renal function 1971 1976 1971 1976 1971 1976 1971 1976

Normal 30 19 33 5 0 5 67 90 Mild to moderate impairment 124 75 35 35 24 25 41 40 Severe impairmente 68 28 57 39 37 54 6 7 All cases 222 122 42" 31d 25 29 34 40 a 64%of patients had renal function followed by serum creatinine determination for three or more years and 88% for one or more years in the 1976 survey, compared with 45% and 82% for the 1971 survey. All patients had followup data for at least three months. For serum creatinine values <4 mg/dl, renal function was considered unchanged unless the serum creatinine had changed by 0.5 mg/dl. When the value was >4 mg/dl the change required was 20%. Serum creatinine >5 mgldl. d 50% of these patients in the 1971 survey developed terminal renal failure requiring dialysis, compared with 60% in the 1976 survey.

Patients with analgesic nephropathy will continue 6. GAULT MH, BLENNERI-IASSETT J, MUEHRCKE RC: Analgesic to present, and our index of suspicion must remain nephropathy: A clinicopathologic study using electron micros- copy. Am J Med 51:740—756, 1971 high. The importance of this disorder rests on the 7. GAULT MH: Intrarenal gradients of radioactive acetylsalicylic fact that it is a potentially preventable cause of renal acid and inulin (abstr.). C/in Res 18:808, 1971 disease and renal failure. 8. MURRAY T, GOLDBERG M: Chronic interstitial nephritis: Etio- Acknowledgments logic factors. Ann Intern Med 82:453—459, 1975 9. KINCAID-SMITII P: Analgesic nephropathy. Ann Intern Med This study was conducted for the Canadian Society 68 (4): 949—952, 1968 of Nephrology. The authors acknowledge the follow- 10. LINTON AL: Renal disease due to analgesics: I. Recognition ing members of the Canadian Society of Nephrology of the problem of analgesic nephropathy. Can Med Assoc J who contributed to the recent followup study: Dr. P. 107:749—751, 1972 I!. GAULT MH: The clinical course of patients with analgesic Handa, St. John, N.B.; Drs. D. McGoldrick and J. nephropathy. Can Med Assoc J 113:204—207, 1975 Seely, Montreal, Quebec; Drs. P. Morrin and E. 12. GAULT MH, MUEHRCKE RC: Some clinical-pathological cor- Yendt, Kingston; Drs. G. deVeber, G. Smith, M. relations in patients with analgesic nephropathy, in Proceed- Goldstein, M. Johnson, R. Charron, S. Fenton, ings of International Symposium on Problems of Phenacetin Toronto, Ontario; Drs. A. Linton, P. Cordy, London, Abuse, edited by HASCHEK H, Vienna, Facta Pub!., 1973, pp. Ontario; Drs. A. Shimizu and E. K. M. Smith, Hamil- 11—23 13. JOHANSSON S, ANGERVALL L, BENGTSSON U, WAHLQVIST ton, Ontario; Dr. M. Baltzon, Saskatoon, Saskatche- L: Uroepithelial tumors of the renal pelvis associated with wan; Dr. A. Siddiqui, Victoria, British Columbia. abuse of phenacetin-containing analgesics. Cancer 33:743— This work was supported in part by grants MA5322 of 753, 1974 the Medical Research Council of Canada and M15-74 14. SHIMIZU A: Incidence of terminal renal failure and facilities for its management. Ont Med Rev: May, 1972 of the Department of Veterans Affairs, Canada. Miss MURRAY RM: Analgesic nephropathy: Removal of phenaceiin M. Everard prepared the manuscript. from proprietary analgesics. Br MedJ 4:131—132, 1972 16. NORDENFELT 0: Deaths from renal failure in abusers of Reprint requests to Dr. M. H. Gault,The General Hospital,St. John's, Newfoundland, AlA 1E5 Canada. phenacetin-containing drugs. Ada Med Scand 191:11—16, 1972 References 17. KJAERULFF J, HARVALD B: Incidence of papillitis necroti- cane. Nord Med 80:1588—1590, 1968 1. LAKEY WH: Interstitial nephritis due to chronic phenacetin 18. NANRA RS, KINCAID-SMITI-I P: Experimental and clinical poisoning. Can Med Assoc J 85:477—479, 1961 analgesic nepropathy with aspirin, in Proceedings of Interna- 2. KOCH B, IRVINE AH, MCIVER JR, LIEPA E: Renal papillary tional Symposium on Problems of Phenacetin Abuse, edited necrosis and abuse of analgesics. Can Med Assoc J 98:8—15, by HASCHEK H, Vienna, Facta Pub!., 1973, p. 114 1968 19. KINCAID-SMITH P. WHITWORTH J, FAIRLEY KF, NANRA RS: 3. GAULT MH, RUDWAL TC, ENGLES WD, DossEToR JB: Syn- Clinical course of analgesic nephropathy with renal failure, in drome of analgesic nephropathy associated with the abuse of Proceedings of International Symposium on Problems of analgesics. Ann Intern Med 68:906—925, 1968 Phenacetin Abuse, edited by HASCHEK H, Vienna, Facta 4. WILSON DR: Renal disease due to analgesics: II. Analgesic Publ., 1973, pp. 157—184 nephropathy in Canada: Retrospecitive study of 351 cases. 20. NANRA RS: Pathology, aetiology and pathogenesis of analge- Can Med Assoc J 107:752—755, 1972 sic nephropathy. Aust NZ J Med 6 (Suppl. 1):33—37, 1976 5. GAULT MH, RUDWAL TC, REDMOND NI: Analgesic habits of 21. Canada Bureau of Statistics, External Trade Division: Trade 500 veterans: Incidence and complications of abuse. Can Med of Canada: Imports by Commodities. Monthly publ. Vols. 3- Assoc J 98:619—626, 1968 22: 1946, 1963 (including Queen's Printer, Ottawa) Analgesic nephropathy in Canada 63

22. StatisticsCanada (Cat. 65-203): Imports Merchandise Trade. 25. Canada Bureau of Statistics, Census Division: Population esti- 1964—1974 mates (age and sex), 192 1—1952. DBS Reference Paper No. 40, 23. Canada Bureau of Statistics, Industry and Merchandising Queen's Printer, Ottawa, 1953 Division: Medicinal and pharmaceutical preparations indus- 26. Canada Bureau of Statistics, Census Division: Vital Statistics, try. Queen's Printer, Ottawa, 1950—1961 1974: Preliminary Annual Report, Queen's Printer, Ottawa, 24. Idem: Manufacturers of Pharmaceuticals and Medicines (for- 1974 merly the medical and pharmaceutical preparations industry): Annual census of manufacturers, Queen's Printer, Ottawa, 1962—74