Original Article
An Epidemiologic Study of Abuse of Analgesic Drugs — Effects of Phenacetin and Salicylate on Mortality and Cardiovascular Morbidity (1968 to 1987)
N Engl J Med 1991; 324:155-160January 17, 1991
- Abstract
- Abstract
Background.
Phenacetin abuse is known to produce kidney disease; salicylate use is supposed to prevent cardiovascular disease. We conducted a prospective, longitudinal epidemiologic study to examine the effects of these drugs on cause-specific mortality and on cardiovascular morbidity.
Methods.
In 1968 we evaluated a study group of 623 healthy women 30 to 49 years old who had evidence of a regular intake of phenacetin, as measured by urinary excretion of its metabolites, and a matched control group of 621 women. Salicylate excretion was also measured. All subjects were examined over a period of 20 years.
Results.
Life-table analyses of mortality during the 20 years, with adjustment for the year of birth, cigarette smoking, and length of follow-up, revealed significant differences between the groups in overall mortality (study group vs. control group, 74 vs. 27 deaths; relative risk, 2.2; 95 percent confidence interval, 1.5 to 3.3), deaths due to urologic or renal disease (relative risk, 16.1; 95 percent confidence interval, 3.9 to 66.1), deaths due to cancer (relative risk, 1.9; 95 percent confidence interval, 1.1 to 3.3), and deaths due to cardiovascular disease (relative risk, 2.9; 95 percent confidence interval, 1.5 to 5.5). The relative risk of cardiovascular disease (fatal or nonfatal myocardial infarction, heart failure, or stroke) was 1.8, and the 95 percent confidence interval 1.3 to 2.6. The odds ratio for the incidence of hypertension was 1.6, and the 95 percent confidence interval 1.2 to 2.1. The effects of phenacetin on morbidity and mortality, with adjustment for base-line salicylate excretion, were similar. In contrast, salicylate use had no effect on either mortality or morbidity.
Conclusions.
Regular use of analgesic drugs containing phenacetin is associated with an increased risk of hypertension and mortality and morbidity due to cardiovascular disease, as well as an increased risk of mortality due to cancer and urologic or renal disease. The use of salicylates carries no such risk. (N Engl J Med 1991; 324:155–60.)
Media in This Article
Table 1
Effect of NAPAP Level at Base Line on Total Mortality.*Table 2
Effect of NAPAP Level at Base Line on Cause-Specific Mortality.*Article Activity
- Article
SINCE it was suggested in 1953 that analgesic drugs could cause chronic renal disease,1 the relation between prolonged ingestion of such drugs and the development of renal disease has been well studied.2 3 4 However, none of the investigations were longitudinal, most were case–control studies, and few used objective measures of drug use. As a result, none clearly demonstrated whether excessive or prolonged use of analgesic agents by healthy persons causes renal disorders.5
In 1967 we designed the present study to determine the incidence of renal disease among 623 apparently healthy women 30 to 49 years old who regularly took analgesic drugs containing phenacetin, in relation to the incidence among 621 similar women who took such drugs less regularly or not at all. A previous epidemiologic survey in Switzerland had indicated that heavy use of analgesics containing phenacetin was more prevalent among women than men and most prevalent among women in the age group that we studied.6
This report describes the total and cause-specific mortality and cardiovascular morbidity over a 20-year follow-up period (1968 through 1987) and addresses the question of whether the use of analgesic drugs containing phenacetin or salicylate is a risk factor for disease.
Methods
Study Design
In 1967, employers at 88 companies agreed to allow their employees to participate in our study on a voluntary basis. These companies, described elsewhere,7 8 9 employed about 13,000 women 30 to 49 years old. Initially, all women in this category were sent letters signed by the employers offering a health evaluation for the detection of kidney disease. This offer was accepted by 7300 women. At the first evaluation we collected demographic data and a urine sample from each woman and asked her to mail us two additional urine specimens collected at home on two different days within a week after the first contact. All specimens were analyzed for the presence of A-acetyl=p-aminophenol (NAPAP), the principal metabolite of phenacetin10; those in which the NAPAP concentration was greater than 0.18 mmol per liter were considered positive.11 If none of the three specimens were positive, the subject was considered not to be taking phenacetin; otherwise, she was tested again. The three screening urine samples were also analyzed for salicylate by means of a colorimetric method; any specimen containing 1.46 mmol per liter (20 mg per deciliter) or more was regarded as positive. The status of a subject was classified as positive for salicylate use if at least one of the three urine samples was positive, as negative if all three specimens were negative, or as unknown if any of the specimens were missing.9 Six to eight weeks later, all women who had at least one positive urine sample among the first three were asked to submit another specimen immediately and to mail two more from home. All women with a second positive test for NAPAP were then eligible for inclusion in the study group. Matched controls (see below) were selected from among the women who were negative for NAPAP according to either the first or the second series of tests.
By means of this procedure a study group of 623 working women 30 to 49 years old with objective evidence of intake of analgesic drugs containing phenacetin and a control group of 621 women without such intake in 1968 were formed. Matching was based on age (within a five-year range), parity (0 vs. ≥1), nationality (Swiss vs. non-Swiss), marital status, and type of work. The mean NAPAP concentration was derived from the values recorded on the six tests. The women in the study group who had a mean concentration of ≥0.77 mmol per liter were placed in the high-NAPAP subgroup, and the others were placed in the low-NAPAP subgroup. All the women were then screened six times between 1969 and 1978 for laboratory evidence of urinary tract disorders (serum creatinine concentration, specific gravity of urine after water deprivation, two bacterial counts in urine, and dipstick examination for hematuria and proteinuria) and for excretion of NAPAP and salicylate.9 At each periodic examination three urine specimens were obtained.
Mortality was surveyed from 1968 until December 1987. Vital status could be ascertained for 1109 of the 1244 women. In the 101 women who died, the cause of death was documented by autopsy reports (n = 50), clinical reports from hospitals (n = 83), and reports from attending physicians or death certificates (n = 100). The diagnoses were tabulated by a physician who was not aware of assignment to the study or control group, with use of the International Classification of Diseases (1969).
A questionnaire concerning the use of antihypertensive medications was administered to the women still living in Switzerland in 1984. In 1988, we obtained objective information on cardiovascular morbidity during the period 1968 through 1987 from the attending physicians of each woman who was living or who had died in Switzerland, by sending a questionnaire to one or more of the physicians mentioned by the subject during the periodic assessments performed between 1968 and 1987. These physicians were asked for information concerning blood-pressure levels, medication history, and cardiovascular morbidity (heart attack, heart failure, arrhythmia requiring therapy, and stroke). We received responses from 1028 physicians to questionnaires about 844 women.
Statistical Analysis
A life-table analysis12 that included adjustment for the year of birth and for cigarette smoking was performed to compare the total study group, the high-NAPAP subgroup, and the low-NAPAP subgroup with the control group for overall and cause-specific mortality as well as for total cardiovascular morbidity and specific types of cardiovascular morbidity. Women with any previous specific cardiac condition (present in 1967 or before) were excluded from the analysis of that condition as well as the analysis of total cardiovascular morbidity. The test-based method was used to obtain 95 percent confidence limits for the estimates of relative risk.13 We also performed stratified analyses to determine the joint effects of NAPAP and salicylate on the mortality and morbidity end points in the context of the life-table analyses. Information about smoking was collected in 1968 and 1972. For these analyses, women were categorized during each survey as nonsmokers, former smokers, or current smokers (1 to 9, 10 to 19, or ≥20 cigarettes per day). The smoking status reported in 1968 was assumed to be the status from 1968 to 1971, and the status reported in 1972 was assumed to be that from 1972 to 1987.
Since the precise time when hypertension developed during the period 1968 through 1987 was often unknown, life-table methods could not be used, and instead cumulative incidence rates were compared. The MantelHaenszel test14 was used to assess the specific effect of the NAPAP level after control for the salicylate level, and of the salicylate level after control for the NAPAP level.
Results
Validity of Group Assignment
We used the same laboratory methods to screen for the intake of preparations containing phenacetin or salicylate during the entire study period. During the 10-year period in which the six follow-up examinations were performed, testing was positive for NAPAP in 79 percent of the determinations in the high-NAPAP subgroup (1380 of 1741), 48 percent of those in the low-NAPAP subgroup (702 of 1469), and 15 percent of those in the control group (497 of 3408) (i.e., at least one of three samples was positive at a particular examination). Similarly, among the women who were positive for salicylate at base line, 43 percent of the follow-up determinations were positive (515 of 1207), as compared with 10 percent among women who were negative at base line (507 of 5154). Thus, there was continued, objective evidence that indicated differential intake of phenacetin and salicylate during the follow-up period.
Mortality
Of the 1244 women who entered the study in 1968, 8 percent died (n = 101) and 11 percent were lost to follow-up (n = 135). The life-table analyses of the effect of the level of NAPAP on overall mortality are shown in Table 1Table 1
Effect of NAPAP Level at Base Line on Total Mortality.*. The 20-year death rates were 14.8, 10.7, and 5.1 percent in the high-NAPAP, low-NAPAP, and control groups, respectively. The relative risk of death in the total study group as compared with the control group was 2.2 (P<0.001); there was little difference in mortality between the high-NAPAP and low-NAPAP subgroups.Table 2Table 2
Effect of NAPAP Level at Base Line on Cause-Specific Mortality.* shows the analysis of cause-specific mortality. The incidence rates of mortality due to urologic or renal disease (pyelonephritis, chronic nephritis, uremia, and cystitis) were 4.3, 1.1, and 0.2 percent in the high-NAPAP, low-NAPAP, and control groups, respectively. The relative risk in the total study group was 16.1 (P<0.001) as compared with the risk in the control group, and a clear gradient of risk was found between the high-NAPAP subgroup (relative risk, 22.9; P<0.001) and the low-NAPAP subgroup (relative risk, 5.9; P not significant). There was a small but significant difference in mortality due to cancer between the total study group and the control group (relative risk, 1.9; P = 0.027). Similarly, there was a significant excess risk of cardiovascular mortality in the total study group as compared with the control group (relative risk, 2.9; P = 0.002). There was no gradient in risk between the high-NAPAP and low-NAPAP subgroups (as compared with the control group) in either mortality due to cancer or mortality due to cardiovascular disease.The results of the analyses of the joint effects of NAPAP and salicylate on mortality are shown in Table 3Table 3
Effect of Presence of NAPAP and Salicylates at Base Line on Total and Cause-Specific Mortality.*. After adjustment for the salicylate level at base line, the relative risk in the study group as compared with the control group was 2.1 for total mortality (P<0.001), 12.5 for mortality due to urologic or renal disease (P<0.001), 1.8 for mortality due to cancer (P = 0.031), and 2.5 for mortality due to cardiovascular disease (P = 0.002). In contrast, salicylate use had no effect on mortality after control for the initial NAPAP concentration.Cardiovascular Morbidity
Physician's reports were received for 844 women (68 percent), and the rate of response for the study group (70 percent) was similar to that for the control group (65 percent). The life-table analyses of the effect of NAPAP on total and cause-specific cardiovascular disease are shown in Table 4Table 4
Effect of NAPAP Level at Base Line on Total and Cause-Specific Cardiovascular Morbidity.*. Over a period of 20 years, the incidence rates of total cardiovascular disease were 20.9, 16.5, and 10.3 percent in the high-NAPAP, low-NAPAP, and control groups, respectively. The relative risk of cardiovascular disease in the total study group as compared with the control group was 1.8 (P<0.001). When specific types of cardiovascular morbidity were examined, the relative risk in the total study group as compared with the control group was elevated for myocardial infarction (relative risk, 2.0; P = 0.045), heart failure (relative risk, 1.9; P = 0.014), and stroke (relative risk, 2.9; P = 0.017). No significant association was found for arrhythmia (relative risk, 1.4; P = 0.35). The values for both overall and cause-specific cardiovascular morbidity in the high-NAPAP and low-NAPAP subgroups were similar and remained so after adjustment for the salicylate level at base line (relative risk of overall cardiovascular morbidity, 1.7; P<0.001) (Table 5Table 5
Effect of Presence of NAPAP and Salicylates at Base Line on Total Cardiovascular Morbidity.*); similar results were found for cause-specific cardiovascular morbidity (data not shown). In contrast, the salicylate level had no effect on either total cardiovascular morbidity (relative risk, 1.2; P = 0.279) (Table 5) or cause-specific cardiovascular morbidity (data not shown).Incidence of Hypertension
During the 20 years of follow-up, hypertension developed in 338 (29 percent) of the women (Table 6Table 6
Effect of NAPAP Level at Base Line on the Incidence of Hypertension.*). The odds ratio in favor of incident hypertension in the study group as compared with the control group was 1.6 (P<0.001). Interestingly, a significant association was found in the high-NAPAP subgroup (odds ratio, 2.5; P<0.001), but not in the low-NAPAP subgroup (odds ratio, 0.9; P = 0.76). This association persisted after control for the salicylate level (data not shown: odds ratio for high-NAPAP subgroup vs. control group, 2.3; P<0.001; odds ratio for low-NAPAP subgroup vs. control group, 0.9; P = 0.73). In contrast, no significant effect of the salicylate level on incident hypertension was evident after control for the NAPAP level at base line (odds ratio, 1.3; P = 0.11).Discussion
This epidemiologic study in Switzerland was a prospective, longitudinal investigation of a healthy, young and middle-aged population of 1244 working women that started in 1968.8 , 9 Until 1978, phenacetin was present in most leading brands of analgesic drugs marketed in Switzerland, whereas salicylate was used to a lesser extent; however, 5 of the 10 most commonly used brands of analgesics contained salicylate.7
Sixty-four to 89 percent of an oral dose of phenacetin is excreted in the urine as NAPAP, which is thus its most important metabolite.10 About half of subjects tested at random within 12 hours after they have taken one pill containing 250 mg of phenacetin are likely to have a positive test for NAPAP as defined in the present study (>0.18 mmol per liter). Urinary levels of NAPAP ≥0.77 mmol per fiter may be found in random samples from persons who have taken at least five tablets, each containing 250 mg of phenacetin, up to 12 hours before urine collection.11 Thus, although our criteria for selecting women for the study and control groups and the high-NAPAP and low-NAPAP subgroups were subject to problems involving sensitivity and specificity, we believe that these standards were justified by previous studies and that the screening procedure produced a control group consisting of nonusers of NAPAP, a low-intake subgroup of light-to-moderate users, and a high-intake subgroup of heavy users.
Most analgesic drugs that are abused are compounds containing agents such as phenacetin, acetaminophen, and salicylate. They have been reported to influence renal function,15 16 17 blood pressure, platelets, and vessel walls18 19 20 to various degrees. It is accepted that analgesic drugs containing phenacetin cause capillary sclerosis and damage the walls of vessels in the kidney.21 Salicylate use is known to inhibit platelet aggregation and to influence cardiovascular morbidity and mortality. We found no effect of salicylate use on mortality and cardiovascular morbidity — a finding consistent with those of Sandier et al.4
We found a strong dose–response effect for the relation between NAPAP use and death due to urologic or renal disease. In addition to the 17 women who we found had died of such disorders, we identified 4 women surviving with end-stage renal disease (all of whom were in the high-NAPAP subgroup) by a systematic review of the registry of the European Dialysis and Transplant Association in London. This result is important evidence that long-term abuse of analgesic drugs can lead to severe if not fatal urologic or renal injury; the results in those who ingested smaller quantities of analgesic drugs containing phenacetin are less certain. These results may explain why investigators in the United States, where the incidence of such abuse is lower, have found no significant correlation between the intake of analgesic drugs (assessed by history taking) and the presence of end-stage renal failure.22
Cancer was the most common specific cause of mortality among the women we studied (47 deaths) (Table 2). Breast cancer was the most frequent type of cancer, with 13 cases in the study group and 5 in the control group. Except for transitional-cell carcinoma, of which only two cases were found (both in the high-NAPAP subgroup), no other type of cancer has been reported to be linked to abuse of analgesic agents.23 Cardiovascular disease constituted the second most important cause of mortality (40 deaths) (Table 2). The relative risks of both cardiovascular death (2.9) and total cardiovascular disease (1.8) were increased in the study group as compared with the control group. Is abuse of analgesics containing phenacetin a risk factor for cardiovascular disease? In 1968 relatively few risk factors for cardiovascular events were known5 , 6; the results that we have reported were adjusted for age and smoking, but not for blood pressure and blood lipid levels. Analgesic drugs may influence the cardiovascular system in two ways: by inducing changes in the kidneys and by acting on vessel walls and on hemostasis. Several groups of investigators have described a high prevalence of cardiovascular disease among patients with analgesic nephropathy.24 25 26 27
Although the incidence of hypertension was increased in the high-NAPAP subgroup (Table 6), no such effect was found for salicylate. These results suggest that the use of analgesic drugs containing phenacetin leads to hypertension, but only in persons who take large amounts for many years. The development of hypertension may partially explain the excess cardiovascular mortality and morbidity in persons who abuse analgesics containing phenacetin. Additional life-table analyses that controlled for hypertension revealed that this factor had little effect on mortality; however, approximately half the excess risk of myocardial infarction, heart failure, and stroke in relation to phenacetin use was attributable to the excess risk of hypertension (data not shown). Although the cause of hypertension in patients with analgesic nephropathy is not known, such hypertension may be the result of a suppression of the production of vasodilative prostaglandins.
In summary, we found a strong dose–response relation between death due to urologic or renal disease and the NAPAP level at base line, making a causal role of phenacetin likely. The incidence of overall cardiovascular disease was almost twice as high in the study group as in the control group, which may be explained in part by the strong dose–response relation between the NAPAP level and the incidence of hypertension. We cannot rule out the possibility that the women who chose to take analgesic drugs regularly differed in some other relevant way from those who did not, so that phenacetin was only indirectly related to mortality and cardiovascular disease. If that had been the case, however, we would have expected to observe an effect of salicylates on mortality and cardiovascular disease, and we did not.
We are indebted to Professor Peter Miescher (University of Geneva) and Professor Edward H. Kass (Harvard Medical School) for their valuable help as consultants; to Professor Paul S. Levy (University of Chicago) for helping with the statistical work at the beginning of the study; to medical research fellows Drs. G. Diener, H.R. Baumeler, A. Müller, A. Peier, Th. Ehrensperger, Ch. Ettling, E. Pfister, M. Dreher, and M. Tschudi for their collaboration; to P.D. Dr.med. U. Ackermann (University of Basel) for advice on epidemiologic matters; to Mrs. S. Boetsch-Burri, Mrs. E. Fischer, and Mrs. S. Jaquemet for assistance in the preparation of the manuscript; to Dr. Th. Spühler (Schweizerisches Bundesamt für Statistik) for providing the death certificates; and to Mr. Chr. Tschudin (Universitäts-Rechenzentrum Basel), Mrs. Marion McPhee, and Mr. Martin Vandenburgh (Boston) for programming assistance.
Cosponsored by the Toxicological Branch of the World Health Organization (Geneva) and supported by grants (3.840–0.77, 3.902–0.80, and 3.857–0.86) from the Swiss National Science Foundation; by Hoffmann—LaRoche, Basel, Switzerland; by Bayer, Leverkusen, Germany; and by Burroughs Wellcome, Research Triangle Park, N.C.
Source Information
From the Medizinische Universitäts-Poliklinik, Department of Internal Medicine, Kantonsspital, Basel, Switzerland (U.C.D., T.S.), and the Channing Laboratory, Harvard Medical School, Boston (B.R.). Address reprint requests to Dr. Dubach at Medizinische Universitäts-Polikünik, Petersgraben 4, CH-4031 Basel, Switzerland.
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