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

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

Canada in 1961 [1]. Thirty-seven such patients were reported in 1968 [2, 3], and an additional 314 were reported in 1972 from a survey of Canadian nephrologists [41, which provides a baseline from which an evaluation of the effect of removal of phenacetin can be made. The analgesic taken by the great majority of these

sumption of APC analgesics are far more common than nephropathy [51; the first major study in man of kidney tissue in early stages of this disorder by electron microscopy suggesting that an increase in medullary collagen is a very early feature and providing further evidence that the primary lesion occurs in the medulla [6]; and the demonstration of a major papilla to cortex gradient in rabbits and dogs for '4C-ASA and metabolites in hydropoenia [7].

Canadian patients was a 222® tablet, containing phenacetin, 160 mg; acetylsalicylic acid, 220 mg;

Syndrome

The association between heavy consumption of analgesics and nephropathy was first described in

The syndrome associated with abuse of APC anal-

caffeine, 32 mg; and codeine, 8 mg. Phenacetin was available in this and other analgesic combinations

gesics containing ASA, phenacetin, and caffeine (APC) [31 is of considerable help in pointing to the diagnosis of analgesic nephropathy which is often missed [81. Analgesic consumption is frequently denied, and the syndrome can often be recognized without prior knowledge of analgesic consumption

over the counter, but sales were largely limited to pharmacies. In 1970, the phenacetin was voluntarily replaced by Frosst Company in this and their related

compound analgesics by an additional 220 mg of acetylsalicylic acid. In 1973, federal legislation was passed prohibiting the sale of phenacetin in combination with salicylic acid and its derivatives. As the sale of phenacetin had been almost completely in combination with acetylsalicylic acid, this virtually eliminated phenacetin both from prescription and overthe-counter markets. Estimated Canadian consumption of phenacetin and acetylsalicylic acid (ASA) is shown in Figure 1. Up to 8 mg of codeine can be sold in combination with other analgesics without prescription in Canada and may commonly contribute to habituation and occasionally to addiction [31. Anti-

[91.

upper gastrointestinal complications of heavy con-

Patients with this syndrome are usually females between the ages of 30 and 65 yr, with a history of heavy APC consumption for 5 to 20 yr before renal disease is discovered. Clinical features of renal disease are frequently preceded by long-standing evidence of psychiatric disorder and headache, and the more recent onset of upper gastrointestinal disease and anemia. Renal symptomatology may include flank or abdominal pain, acute or chronic pyelonephritis, bacteriuria, pyuria (often without infection), hematuria, hypertension, acidosis, passage of papillae, and renal failure. The psychiatric component in most of the patients must be considered primary in the genesis of analgesic abuse and also with respect to treatment. Patients may present with psychiatric problems, including anxiety and depression. Poor adjustment in marriage

0085-2538/78/0013-0436-0058 $1.20

other drugs and habituation to alcohol. Most give a history of long-standing emotional instability and

pyrine (phenazone) has not recently been sold in Canada.

Some points of interest in relation to analgesic

nephropathy contributed by Canadian authors include: formulation of the concept of the syndrome

of APC analgesic abuse [3]; the finding that the

and work is common, as is abuse or overdose of personality disorder, chiefly of an immature and

© 1978, by the International Society of Nephrology.

58

59

Analgesic nephropathy in Canada 26.

.

.

22

/

0 0

18.

/

S 14.

0

//

0

/

C

0

E S 10. C

00

o—o 0. 0-0-

6-

2. • 1946

I

I 50

I

I

54

I

I 58

I

I 62

I--E 66

I

I

70

I

1

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 population increased from 12.3 million in 1946 to 22.4 million in 1974 [25, 261. The closed circles

and solid line (.s) represents phenacetin x 10; the open circles and broken line (00) represent acetytsalicylic

acid x l0.

dependent nature. In the Canadian series of 351 patients [4], 36% were considered to have major and 40% moderately severe psychiatric problems.

The majority of patients who abuse analgesics state the primary reason for consumption is headache. Migraine is often mentioned, but the symptoms are frequently not characteristic. More often, a feel-

ing of tension, heaviness, or fullness in the head is described. Some patients may later take increasing

quantities of analgesics for reasons unrelated to headaches—for relief of tension, to get a "lift" or other psychic benefit. Less frequently, back pain, arthritis, abdominal pain, inability to concentrate, fatigue, or desire to increase work output are reasons stated for consumption. Gastrointestinal symptoms often precede sympto-

matic evidence of renal disease by several years.

Peptic ulceration, with a higher than usual frequency of gastric involvement is common and is probably due to salicylate. Ulcers in these patients are frequently resistant to treatment and have a high incidence of bleeding, often leading to surgery such as gastrectomy. Of the 351 Canadian patients [4], 50% had had radiologic evidence of peptic ulcer and 36%

had undergone an upper gastrointestinal tract operation.

Anemia, out of proportion to the degree of renal failure, is a common feature, and hemoglobin values of <10 gIdl were present at the time of diagnosis of

nephropathy in 42% of the Canadian patients [4]. Blood loss from chronic ASA consumption and from peptic ulceration, with iron deficiency, is an important component, and ASA may also cause anemia

unrelated to bleeding. Absorptive defects may be present in those who have had a gastrectomy and in whom macrocytic anemia has been observed. Phenacetin may result in hemolytic anemia, usually of the oxidative type, with a hyperplastic marrow, reticulocytosis, Heinz bodies, distorted red blood cell mor-

phology, and met- and sulfhemoglobinemia with cyanosis; these features are no longer seen in Canada since the removal of phenacetin from the market. Minor features also reported with heavy APC consumption include dementia [10] and darkening of the urine on standing related to phenacetin [11]. Management

A good long term outlook is more likely when the patient admits the true quantity of compound analge-

sics taken, accepts that habituation is a factor, and 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 prominent. Establishment of the reason why the patient started taking analgesics and the factors that led to abuse permits the most appropriate treatment. A trial in hospital off the offending analgesics, particularly those containing caffeine, is important for those with headaches, as these sometimes are predominantly of the caffeine withdrawal type and may then largely disappear. Only occasionally have our patients discarded all analgesics permanently. When this is not possible, we introduce a trial with propoxyphene, adding oral codeine when necessary under strict control. If abuse is related to relief of

anxiety, diazepam or a comparable drug may be given. Effective treatment of hypertension and urinary tract infection can be critical in arresting the decline in renal function, and long-term therapy with

At the end of 1971, a survey of Canadian nephrolo-

gists was undertaken by one of the authors for the Canadian Society of Nephrology, and data concern-

ing 351 cases of analgesic nephropathy were obtained. About 60 new cases were reported annually for the three years 1969—1971. The prevalence was 50 per million in Toronto, where reporting was probably most complete. Renal function declined in 42% of the 222 patients with follow-up values for serum creatinine, particularly in those who continued use of analgesics, or had severe impairment at the time of diagnosis. Twenty-five percent showed improvement

in function, particularly those who stopped taking analgesics. Followup was mainly for one to three years. Two other studies [10, 11] illustrate that when nephropathy is established, continued consumption

an antibacteriaI agent may be required. Some

of APC analgesics usually leads to a continuing decline in renal function, and that abstinence fre-

patients require therapy for acidosis, electrolyte disturbances, and other manifestations of renal failure. A normal salt and fluid intake is ordinarily advised. Patients are followed initially at monthly intervals when blood samples are drawn for ASA levels, serum creatinine, and hemoglobin; and urine is obtained for routine analysis and culture when indicated. Salicylate consumption can immediately be checked by

quently leads to stabilization or improvement. ASA, caffeine, and codeine may be less likely to cause a progressive decline in renal function than APC and codeine (Fig. 2). Results of a new survey (1972—1976) represent, to date, about one half the population covered by the first [41. The new data are all from specific nephrologists and hospitals who contributed to the first sur-

testing urine with Phenistix® or ferric chloride. If abuse of any other drug is suspected, this is estab-

vey and come mainly from London, Hamilton,

lished by assay. Blood pressure is measured, special

events and consumption of analgesics and other drugs since the last visit are reviewed, and the previous month's ASA level is discussed. The approach is primarily supportive. Early relief of ureteral obstruction due to sloughed papillae is critical, especially if infection is present; and occasionally, multiple pieces of necrotic papillae lodge in the pelvis leading to repeated episodes of obstruction and may require removal surgically. Special care must be taken to avoid volume or sodium depletion, as acute renal failure can supervene, espe-

Kingston, Toronto, Ontario; St. John, New Brunswick; Victoria, British Columbia; and two hospitals in Montreal, Quebec. The number of new cases presenting each year has

fallen an average by about 40% for the last three years (1974—1976), compared with 1970—1973. The number reaching end-stage, as reflected by the num-

circumstances. Most of these patients are acceptable for management by dialysis or transplantation when necessary. Rarely, renal function improves enough that dialysis can later be withdrawn [121. Urothelial neoplasms, particularly of the renal pelvis, may complicate analgesic nephropathy, at times several years after consumption of phenacetin has

bers commencing dialysis, however, has not greatly changed (Table 1). This may be interpreted as evidence that ASA can contribute to deterioration of function in established analgesic nephropathy. It is important, however, to appreciate that 87% of the 114 new cases had a history of heavy phenacetin ingestion for three years or more and 50% for ten years or more; only 5% claimed they had taken no phenacetin. A comparison of changes in renal function for the two surveys is shown in Table 2. The first survey represents a period when analgesic consumption was primarily the combination of ASA, phenacetin, caffeine, and codeine; and the second survey, consumption 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 cytology at regular intervals may be of value.

survey. In 1976, 2.5% of patients on dialysis in Canada had

cially if major surgery is undertaken under these

Analgesic nephropathy in Canada

61

Analgesic consumption continued

Analgesic consumption ceased

— APC&C ACC

0 C.) C 'a C0

0 0 0 C C 'a

0

0

20 10

0

1

2

3

4

56 7 8Jo

0

1

2

3

4

5

6

7

8

Time after 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. (Reproduced with permission from Can Med Assoc J [11].) Table 1. Incidence of new cases of analgesic nephropathy and patients starting dialysis in hospitals reporting continuously 1970— 1976a

New patients 1970 1971

1972 1973

1974 1975

1976

Patients starting dialysis

23 35 31

6 5 10

31 17 14 21

5 6 8 5

a Data was selected from individual nephrologists and hospitals from 1971 and 1976 surveys to include only those with continuous reporting from 1970 to 1976. Legislation virtually removed phenacetin from Canadian markets in 1973.

analgesic nephropathy (SHIMIzu A: Canadian dialysis and transplant registry statistics, 1976, personal communication). This compares with 5% for Ontario in 1972 [14]. Discussion

Removal of phenacetin voluntarily by pharma-

to a decline in mortality due to this disorder [16], and to a decrease in the frequency of papillary necrosis

found at autopsy [17]. The effects of reduced consumption appear particularly after four to six years [15, 16]. Our recent survey was made six years after a major decrease in availability and three years after

virtual elimination of phenacetin. Prospective recording of the incidence of analgesic nephropathy for several more years will be required to determine the long term effects of the removal of phenacetin in Canada.

There is relatively little information about the course of patients with analgesic nephropathy who continue to use or abuse analgesics containing ASA. Reports from Australia [18, 191 have suggested that ASA, even in small doses, and other analgesics or antiinflammatory agents may lead to progression of

the renal disease with further papillary necrosis. Nanra [20] has reported 47 patients who presented

with analgesic nephropathy within the previous 2/2 years, and had been taking acetylsalicylic acid, salicylamide and caffeine as Vincent's® powders, from which phenacetin had been removed in 1968. Renal

function may continue to deteriorate in many

ceutical companies or decreased consumption relat-

patients with established analgesic nephropathy who 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.

Gault and Wilson

62

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

No. of cases

Followup renal functiona % cases

Worse'

Improved"

Initial renal function

1971

Normal Mild to moderate impairment Severe impairmente All cases

30

19

124

75 28

57

39

122

42"

31d

68 222

1976

1971

Unchangedb

1976

1971

1976

1971

1976

33

5 35

0 24 37 25

5 25 54 29

67

35

90 40 7

41

6 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 to present, and our index of suspicion must remain high. The importance of this disorder rests on the fact that it is a potentially preventable cause of renal disease and renal failure. Acknowledgments

6. GAULT MH, BLENNERI-IASSETT J, MUEHRCKE RC: Analgesic

nephropathy: A clinicopathologic study using electron microscopy. Am J Med 51:740—756, 1971 7. GAULT MH: Intrarenal gradients of radioactive acetylsalicylic acid and inulin (abstr.). C/in Res 18:808, 1971 8. MURRAY T, GOLDBERG M: Chronic interstitial nephritis: Etiologic 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 of Nephrology. The authors acknowledge the following members of the Canadian Society of Nephrology who contributed to the recent followup study: Dr. P.

10. LINTON AL: Renal disease due to analgesics: I. Recognition of the problem of analgesic nephropathy. Can Med Assoc J

Handa, St. John, N.B.; Drs. D. McGoldrick and J. Seely, Montreal, Quebec; Drs. P. Morrin and E. Yendt, Kingston; Drs. G. deVeber, G. Smith, M.

nephropathy. Can Med Assoc J 113:204—207, 1975 12. GAULT MH, MUEHRCKE RC: Some clinical-pathological cor-

Goldstein, M. Johnson, R. Charron, S. Fenton, Toronto, Ontario; Drs. A. Linton, P. Cordy, London, Ontario; Drs. A. Shimizu and E. K. M. Smith, Hamilton, Ontario; Dr. M. Baltzon, Saskatoon, Saskatche-

wan; Dr. A. Siddiqui, Victoria, British Columbia. This work was supported in part by grants MA5322 of the Medical Research Council of Canada and M15-74 of the Department of Veterans Affairs, Canada. Miss

M. Everard prepared the manuscript. Reprint requests to Dr. M. H. Gault, The General Hospital, St. John's, Newfoundland, AlA 1E5 Canada.

References 1. LAKEY WH: Interstitial nephritis due to chronic phenacetin poisoning. Can Med Assoc J 85:477—479, 1961 2. KOCH B, IRVINE AH, MCIVER JR, LIEPA E: Renal papillary necrosis and abuse of analgesics. Can Med Assoc J 98:8—15, 1968

68 (4): 949—952, 1968

107:749—751, 1972

I!. GAULT MH: The clinical course of patients with analgesic relations in patients with analgesic nephropathy, in Proceedings of International Symposium on Problems of Phenacetin Abuse, edited by HASCHEK H, Vienna, Facta Pub!., 1973, pp. 11—23

13. JOHANSSON S, ANGERVALL L, BENGTSSON U, WAHLQVIST

L: Uroepithelial tumors of the renal pelvis associated with abuse of phenacetin-containing analgesics. Cancer 33:743— 753, 1974 14. SHIMIZU A: Incidence of terminal renal failure and facilities for its management. Ont Med Rev: May, 1972 MURRAY RM: Analgesic nephropathy: Removal of phenaceiin from proprietary analgesics. Br MedJ 4:131—132, 1972

16. NORDENFELT 0: Deaths from renal failure in abusers of phenacetin-containing drugs. Ada Med Scand 191:11—16, 1972

17. KJAERULFF J, HARVALD B: Incidence of papillitis necroticane. Nord Med 80:1588—1590, 1968 18. NANRA RS, KINCAID-SMITI-I P: Experimental and clinical analgesic nepropathy with aspirin, in Proceedings of International Symposium on Problems of Phenacetin Abuse, edited by HASCHEK H, Vienna, Facta Pub!., 1973, p. 114 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 analgesics. Ann Intern Med 68:906—925, 1968 4. WILSON DR: Renal disease due to analgesics: II. Analgesic nephropathy in Canada: Retrospecitive study of 351 cases.

Proceedings of International Symposium on Problems of Phenacetin Abuse, edited by HASCHEK H, Vienna, Facta

Can Med Assoc J 107:752—755, 1972 5. GAULT MH, RUDWAL TC, REDMOND NI: Analgesic habits of

500 veterans: Incidence and complications of abuse. Can Med Assoc J 98:619—626, 1968

Publ., 1973, pp. 157—184 20. NANRA RS: Pathology, aetiology and pathogenesis of analgesic nephropathy. Aust NZ J Med 6 (Suppl. 1):33—37, 1976 21. Canada Bureau of Statistics, External Trade Division: Trade of Canada: Imports by Commodities. Monthly publ. Vols. 322: 1946, 1963 (including Queen's Printer, Ottawa)

Analgesic nephropathy in Canada 22. Statistics Canada (Cat. 65-203): Imports Merchandise Trade. 1964—1974

23. Canada Bureau of Statistics, Industry and Merchandising Division: Medicinal and pharmaceutical preparations industry. Queen's Printer, Ottawa, 1950—1961 24. Idem: Manufacturers of Pharmaceuticals and Medicines (formerly the medical and pharmaceutical preparations industry):

Annual census of manufacturers, Queen's Printer, Ottawa, 1962—74

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25. Canada Bureau of Statistics, Census Division: Population estimates (age and sex), 192 1—1952. DBS Reference Paper No. 40,

Queen's Printer, Ottawa, 1953 26. Canada Bureau of Statistics, Census Division: Vital Statistics, 1974: Preliminary Annual Report, Queen's Printer, Ottawa, 1974