Correspondence
Analgesic Nephropathy
N Engl J Med 1998; 339:48-50July 2, 1998
- Article
To the Editor:
To substantiate their thesis on the nephrotoxicity of mixed analgesics, De Broe and Elseviers (Feb. 12 issue)1 claim that in Belgium the decrease in the frequency of analgesic nephropathy began only in 1992, five years after unspecified legislative measures led to a dramatic decrease in the sales of analgesic mixtures. The complete data (Figure 1Figure 1
Incidence of Analgesic Nephropathy among Patients Starting Dialysis in Belgium and in Australia.), drawn from the same European Dialysis and Transplantation Association registry as that in the reference quoted by De Broe and Elseviers,2 show a maximal incidence in 1976, so the decrease began much earlier than 1992 and could not be related to the dramatic decrease in the sales of combined analgesics said to have occurred in 1987. Sales of phenacetin in Belgium decreased progressively after the removal of the drug from the three most popular analgesics in 1967, 1972, and 1981. They fell to zero in 1994. This correlates well with the observed decrease in the incidence of analgesic nephropathy, starting in 1977.De Broe and Elseviers also claim that in Australia the decrease in the frequency of analgesic nephropathy began in 1985. But the study by Nanra3 they cite does not refer to a decrease beginning in 1985 but gives incidence data per million population and per year. However, there was also progressive loosening of the eligibility criteria for dialysis that led to an increased number of admissions for the procedure, especially of elderly patients. To eliminate this confounding factor, the percentage of patients with analgesic nephropathy admitted for dialysis, not the absolute number, must be used. When the correct parameter is used (Figure 1), it is clear that in Australia the decrease began earlier than 1985.
The similarity of the curves in Figure 1 indicates that the isolated ban on phenacetin in Belgium was as efficient as the prohibition of the free sale of all combined analgesics in Australia. These data contradict the thesis that all mixed analgesics are nephrotoxic, whether or not they contain phenacetin.
3 ReferencesPaul Michielsen, M.D.
Paul De Schepper, M.D., Ph.D.
Katholieke Universiteit Leuven, B 3000 Leuven, Belgium1
De Broe ME ,Elseviers MM . Analgesic nephropathy. N Engl J Med 1998;338:446-452
Full Text | Web of Science | Medline2
Brunner FP ,Selwood NH . End-stage renal failure due to analgesic nephropathy, its changing pattern and cardiovascular mortality. Nephrol Dial Transplant 1994;9:1371-1376
Web of Science | Medline3
Nanra RS . Analgesic nephropathy in the 1990s -- an Australian perspective. Kidney Int Suppl 1993;44:Suppl 42:S86-S92
To the Editor:
The conclusion by De Broe and Elseviers that habitual use of analgesic mixtures containing at least two antipyretics and caffeine or codeine causes analgesic nephropathy is not supported by the data, because most of the studies refer to combinations containing phenacetin. The data indicate only that abuse of mixed analgesics containing phenacetin causes end-stage renal disease. There is no convincing evidence that phenacetin-free mixtures contribute to the disease.1
The authors state that experimental (animal) data support the theory that acetaminophen has a predominant role in causing nephrotoxicity and that its actions are potentiated by one or more of the other agents, particularly aspirin. This hypothesis of a synergistic toxicity is, however, based primarily on theoretical considerations and not proved by the results of relevant long-term studies in animals.2 In contrast, experimental data show that coformulation with caffeine antagonizes the aspirin-induced inhibition of renal prostaglandin E2 biosynthesis, which is the main mechanism of nephrotoxicity caused by nonsteroidal antiinflammatory drugs.3 Furthermore, the combination of acetaminophen, aspirin, and caffeine was evaluated in a 26-week toxicity study in rats conducted under the guidelines for good laboratory practice.4 The combination of acetaminophen, aspirin, and caffeine, as well as the single compounds, showed no significant nephrotoxicity when given at doses far above the therapeutic levels. High doses of acetaminophen produced slight ultrastructural changes in proximal-tubule brush borders.
The risk of renal damage from the use of the analgesic combination as compared with the single compounds is not increased at pharmacologically equipotent doses and clinically relevant exposures. Accordingly, the toxic threshold for the combination analgesic is distinctly higher than for the single drugs. Since the combination of acetaminophen, aspirin, and caffeine also shows better clinical efficacy, it is appropriate for over-the-counter use.5
5 ReferencesManfred Baumeister, D.V.M.
Bernhard Aicher, Ph.D.
Boehringer Ingelheim Pharma, 88397 Biberach, Germany1
Delzell E ,Shapiro S . Commentary on the National Kidney Foundation position paper on analgesics and the kidney. Am J Kidney Dis 1996;28:783-785
CrossRef | Web of Science | Medline2
Prescott LF. Paracetamol (acetaminophen): a critical bibliographic review. London: Taylor and Francis, 1996.
3
Engelhardt G . Effect of acetylsalicylic acid, paracetamol, caffeine and a combination of these substances on the renal prostaglandin E2, 6-keto-prostaglandin F1α, water, creatinine and electrolyte excretion of the rat. Arzneimittelforschung 1996;46:509-512
Web of Science | Medline4
Lehmann H ,Hirsch U ,Bauer E , et al. Studies on the chronic oral toxicity of an analgesic drug combination consisting of acetylsalicylic acid, paracetamol and caffeine in rats including an electron microscopical evaluation of kidneys. Arzneimittelforschung 1996;46:895-905
Web of Science | Medline5
Aicher B ,Kraupp O . Zweckmäβigkeit fixer Analgetikakombinationen am Beispiel von Thomapyrin. Wien Klin Wochenschr 1996;108:219-233
Web of Science | Medline
To the Editor:
De Broe and Elseviers state: “In summary, the withdrawal of phenacetin from the market did not completely eradicate analgesic nephropathy. There is experimental, pharmacologic, and epidemiologic evidence that other analgesic mixtures that do not contain phenacetin are also nephrotoxic and produce the classic renal lesions of the disease.”1 In their review, they restrict the cause of analgesic nephropathy to “mixtures”; they rule out the possibilities that single analgesics can cause analgesic nephropathy and that combinations cause nephropathy only to the same extent as single analgesics; only phenacetin is more nephrotoxic. The incidence of analgesic nephropathy decreased substantially in all countries after the banning of phenacetin,2 with the decrease in the countries that banned the drug later following exactly the time course observed earlier in Australia.
An evaluation of all the epidemiologic studies of nonnarcotic analgesics3 revealed no evidence that combination drugs are more nephrotoxic than single analgesics at equipotent doses provided they do not contain phenacetin. The case–control studies show a very uniform picture: odds ratios for analgesics containing phenacetin are extremely high (up to 19), whereas the odds ratios for single analgesics and for combination drugs (without phenacetin) are in the same range (i.e., 2 to 3) (Table 2 of the article).
Pommer et al.4 provide detailed data showing that phenacetin induces analgesic nephropathy at total doses below 500 g, but combinations containing no phenacetin have statistically different relative risks only at very high doses (>2000 g).
The evidence shows that any analgesic may induce nephropathy, but there is no evidence that combinations that do not contain phenacetin are more nephrotoxic than single analgesics.
4 ReferencesJohannes M. Fox, Ph.D., M.D.
Merz Research Laboratories, D-60318 Frankfurt am Main, Germany1
De Broe ME ,Elseviers MM . Analgesic nephropathy. N Engl J Med 1998;338:446-452
Full Text | Web of Science | Medline2
Brunner FP ,Selwood NH . Endstage renal failure due to analgesic nephropathy in Switzerland and Europe. Tijdschr Geneesk 1994;50:740-7433
Delzell E ,Shapiro S . A review of epidemiologic studies of nonnarcotic analgesics and chronic renal disease. Medicine (Baltimore) 1998;77:102-121
CrossRef | Web of Science | Medline4
Pommer W ,Bronder E ,Greiser E , et al. Regular analgesic intake and the risk of end-stage renal failure. Am J Nephrol 1989;9:403-412
CrossRef | Web of Science | Medline
To the Editor:
De Broe and Elseviers give the numbers of patients in various studies in whom renal papillary necrosis and chronic interstitial nephritis developed after long-term use of nonsteroidal antiinflammatory drugs. Between 1000 and 26,000 pills were listed per patient within the context of long-term analgesic use, which, for aspirin, might mean 650 mg taken four times daily. What was not mentioned was the possible incidence of this nephropathy in the many people who have been advised to take one tablet of aspirin (325 mg) daily. A thousand pills would be taken within 3 years, and 10,000 pills within less than 28 years. What are the implications for all those who are taking one tablet of aspirin a day?
William Thurlow, M.D.
Summerside Medical Center, Summerside, PE C1N 3N9, CanadaAuthor/Editor Response
The authors reply:
To the Editor: Classic analgesic nephropathy is the result of daily consumption for many years of mixtures containing at least two antipyretic analgesics combined with caffeine or codeine (or both). Individually, aspirin, phenacetin, and paracetamol, when given to animals in very large doses, induce only minor renal papillary necrosis. Epidemiologically, very few cases of classic analgesic nephropathy (renal papillary necrosis and chronic interstitial nephritis) have been reported with single analgesics taken alone. It can be concluded that the risk of renal impairment in the many people who have been advised to take one tablet of aspirin daily is negligible.
Several experimental studies1-3 have shown the difficulty of inducing renal papillary necrosis with single analgesics such as phenacetin, paracetamol, and aspirin, in contrast to the ease of doing so with such analgesic mixtures as aspirin, phenacetin, and caffeine; aspirin, acetaminophen, and caffeine; and aspirin, salicylamide, and caffeine. Furthermore, Duggin4 and others have demonstrated the synergistic nephrotoxic effect of the prostaglandin H synthase–dependent co-oxidation of acetaminophen to a cytotoxic metabolite with the capacity of aspirin to deplete renal glutathione in animals.
Published case–control studies failed to give a conclusive answer to the problem of the nephrotoxicity of analgesic mixtures that do not contain phenacetin. First, these studies did not focus on the nephrotoxicity of the currently available combinations on the market. Apart from the distinction between single analgesics and mixtures, only the different ingredients used in analgesic mixtures were analyzed separately. Second, the number of cases in which only mixtures that did not contain phenacetin were used was limited in the late 1980s, since phenacetin was present in most analgesic mixtures in the past. In contrast, in our cohort of 226 patients with documented abuse and a clear diagnosis based on validated criteria, we were able to identify 46 patients who consumed only mixtures not containing phenacetin.5
There are reasons to disagree with the interpretation that the declining incidence in Australia is due to the withdrawal of phenacetin from the market. A definite and gradual decline in the incidence of analgesic nephropathy (measured as the proportion of the total number of patients commencing dialysis or as the number per capita population per year) was clearly related to the lack of availability of analgesic mixtures over the counter since 1980 (Nanra RS: personal communication).
5 ReferencesMarc E. De Broe, M.D., Ph.D.
Monique M. Elseviers, Ph.D.
University Hospital Antwerp, B-2650 Antwerp (Edegem), Belgium1
Prescott LF . Analgesic nephropathy: a reassessment of the role of phenacetin and other analgesics. Drugs 1982;23:75-149
CrossRef | Web of Science | Medline2
Prescott LF. Paracetamol (acetaminophen): a critical bibliographic review. London: Taylor and Francis, 1996.
3
Walker RJ ,Duggin GG . Drug nephrotoxicity. Annu Rev Pharmacol Toxicol 1988;28:331-345
CrossRef | Web of Science | Medline4
Duggin GG . Combination analgesic-induced kidney disease: the Australian experience. Am J Kidney Dis 1996;28:Suppl 1:S39-S47
CrossRef | Web of Science | Medline5
Elseviers MM ,De Broe ME . Combination analgesic involvement in the pathogenesis of analgesic nephropathy: the European perspective. Am J Kidney Dis 1996;28:Suppl 1:S48-S55
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
Johannes M. Fox, Ute Siebers. (2003) Caffeine as a promoter of analgesic-associated nephropathy - where is the evidence?. Fundamental & Clinical Pharmacology 17:3, 377-392
CrossRef2
Alvan R. Feinstein, for the members of the Ad Hoc. (2001) Reply from Alvan R. Feinstein. Kidney International 59:6, 2372-2373
CrossRef3
Wei-Ya Zhang. (2001) A Benefit-Risk Assessment of Caffeine as an Analgesic Adjuvant. Drug Safety 24:15, 1127-1142
CrossRef4
Alvan R Feinstein, Lothar A J Heinemann, Gary C Curhan, Elizabeth Delzell, Paul J DeSchepper, Johannes M Fox, Helmut Graf, Friedrich C Luft, Paul Michielsen, Michael J Mihatsch, Samy Suissa, Fokko van der Woude, Stefan Willich. (2000) Relationship between nonphenacetin combined analgesics and nephropathy: A review. Kidney International 58:6, 2259-2264
CrossRef
