Doubts about a particularly high nephrotoxicity of combination analgesics

Johannes M. Fox

University of Saar, Faculty of Theoretical, Medicine, Homburg/Saar and, Merz Research, Laboratories, Frankfurt

Sir,

In this journal [1], the Berlin nephrology group has again presented very valuable data on end-stage renal disease (ESRD) in general and on ESRD induced by analgesics in particular.

And again we find ourselves [2] incorrectly cited: `A lack of absence of proof does not imply the absence of analgesic nephropathy without phenacetin, a conclusion which is sometimes drawn'. In fact, we never have drawn such conclusion, but—as a result of an official reevaluation of combination analgesics by the Drug Evaluation Committee B3 (Neurology/Psychiatry) at the German Federal Health administration—we have demonstrated that there is no proof nor even a scientifically reasonable suspicion that combination analgesics without phenacetin cause a higher nephrotoxic risk than monoanalgesics do [2,3]. And this conclusion was drawn, mainly but not limited to, on the basis of the results of their fundamental case control study of 1989 [4]. Table 1Go represents their original data from Table 6 409, comparing all combinations with and without phenacetin and all analgesics containing paracetamol. It is obvious from these data that a statistically significant relative risk for phenacetin-containing analgesics was found already above 100 g cumulative phenacetin intake, indicated by (*) in Table 1Go, whereas this was true only for non-phenacetin combinations at cumulative doses above 2000 g, i.e. a dose factor of 20!


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Table 1. Dose dependent relative risk (RR) by analgesic substances used in combination drugs (matched analysis); cited from [4], p. 409, Table 6
 
A similar dose factor of approximately 20 was found between phenacetin and all analgesics containing paracetamol. On the other hand, there is no risk increase for all analgesics not containing phenacetin (**), however, there is a statistically significant increase in relative risk for all analgesics except paracetamol (***) (i.e. all other analgesic substances including phenacetin, combination or single analgesics), and important enough, there is a statistically significant increase in relative risk for all single analgesics (****) (without phenacetin, because there was no single phenacetin preparation available). Thus, the work of the Berlin nephrologists group contributed the essential data to our knowledge on the role of combination analgesics with and without phenacetin and demonstrated that phenacetin was the key agent being associated with analgesic nephropathy and confirming the longitudinal study of Dubach et al. [5]. In addition, the Berlin nephrologists group found that there might be a low nephrotoxic risk due to analgesics other than phenacetin, in line with other observations (see [6] for review), with no quantitative difference between single and combination analgesics (Table 1Go).

The essential role of phenacetin in analgesic nephropathy was confirmed by the EDTA data demonstrating a considerable and continuous decrease of incidence of ESRD due to analgesic intake in all countries after the ban of phenacetin with a lag-time of several years [7]. And exactly this was corroborated by the new study of Schwarz et al. [1]. Although they broadened their dialysis operation by 37% on the average from 57 new cases within 18 months 1982/3 to 81 or 76 new cases in 1991/2 or 1995/7, the absolute number of cases of analgesic nephropathy stayed constant before and 4 years after the ban of phenacetin and dropped to about one half 10 years after the ban ([1], Table 1Go), exactly as it was predicted. So, there is nothing to be debated about this fact, not even by employing post-hoc descriptive statistical analyses.

There was the famous senator Cato (234–149 B.C.) who stated after every of his speeches in the senate of Rome independent of the topic: `ceterum censeo, Carthaginem esse delendam'.

The difficulties to interpret the existing data on analgesic nephropathy (including the `Australian and Belgian perspectives') have rarely been that precisely described as by Schwarz et al. [1]. However, their conclusion again is not supported by their data: as demonstrated above it is possible `to determine whether compound analgesic with components other than phenacetin are less toxic'; they themselves have provided the evidence [4].

We agree with them that it is not justified that `analgesics without phenacetin are now safe with regard to nephrotoxicity' (except that they are safer by a dose factor of approximately 20 [4]), however, it is not yet possible to discern between single or combination analgesics in that respect. So the ceterum censeo of the Berlin nephrologists group `remedia contra dolorem composita esse delenda' being independent of the results they presented may nevertheless in a long run be successful (as with Cato).

In collaboration with K. Menges, Berlin and the following members of the Drug Evaluation Committee B3 (Neurology & Psychiatry) at the German Federal Health Administration (Bundesgesundheitsamt), Berlin

H. Coper Berlin

A. Doenicke, München

U. J. Ferner, Basel

H. J. Gaertner, Tübingen

F. Hoffmeister, Wupertal

W. Janke, Würzburg

R. W. C. Janzen, Frankfurt/M.

S. Kanowski, Berlin

H. Kreiskott, Ludwigshafen

B. Müller-Oelinghausen, Berlin (chairman)

P. Netter, Gießen

H. Oerschläger, Jena

W. Poser, Göttingen

J. Radke, Halle

E. Rüther, Göttingen

M. Schultz, Eschborn

Note added in proof

The conclusion of the reply (below) is again not supported by the data; it should read `. . .cannot be used as an argument for the low toxicity of any non-phenacetin analgesics'. (JMF)

References

  1. Schwarz A, Preuschof L, Zellner D. Incidence of analgesic nephropathy in Berlin since 1983. Nephrol Dial Transplant 1999; 14: 109–112[Abstract]
  2. Fox JM and members of the German Federal Evaluation Committee. No proof of a particular role of combination analgesics causing end stage renal failure. Nephrol Dial Transplant 1996; 11: 2519–2525[ISI][Medline]
  3. Fox JM. Analgesic nephropathy. N Engl J Med 1998; 339: 49
  4. 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[ISI][Medline]
  5. Dubach UC, Rosner B, Pfister E. Epidemiologic study of abuse of analgesics containing phenacetin. Renal morbidity and mortality (1968–1979). N Engl J Med 1983; 308: 357–362[Abstract]
  6. Delzell E, Shapiro S. A review of epidemiologic studies of nonnarcotic analgesics and chronic renal disease. Medicine 1998; 77: 102–121[ISI][Medline]
  7. 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[Abstract]

 

Reply

A. Schwarz

Department of Nephrology, University Hospital, Benjamin, Franklin, Berlin, Germany

Sir,

Papers on the current state of analgesic nephropathy [1] continue to produce heated discussions [2], and this is as it should be.

However, two studies are compared in the above letter that have nothing to do with each other. The study by Pommer et al. [3] is one of several case-control studies examining the correlation between cumulative analgesic intake and end-stage renal disease from 1984 to 1986. The other one is our recently published study on the `Incidence of analgesic nephropathy in Berlin since 1983' [1]. The author of the above letter should have noticed that neither the authors or co-authors nor the study hospitals of the two studies are identical, but that merely the two study groups come from Berlin. I therefore will not comment in detail on the first part of the letter but would rather leave this to the authors of the cited study [3].

The results of the case-control studies demonstrate that the risk of renal disease associated with analgesic abuse is increased by a factor of 1.08–2.89 (odds ratio or relative risk) [39]. The relative risk is highest at 4.8–19.0 for phenacetin-containing mixed analgesics but is also markedly increased at 2.1–6.9 for paracetamol-containing mixed analgesics.

The criticism of case-control studies is well known [10]. Beside statistical objections, it must be considered that all of these studies rely on questioning patients known to deny analgesic intake, feeling that they may have caused the disease themselves [11]. However, the toxicity of phenacetin-containing analgesics has also not been scientifically confirmed in in-vitro or animal experiments [12], and there is no longer any doubt about the clinical evidence for this disease. Thus, the demand for scientific evidence regarding paracetamol-containing analgesics is difficult to fulfill.

Unfortunately, the two prospective follow-up studies from Switzerland and Belgium do not differentiate between phenacetin- and paracetamol-containing mixed analgesics [13,14]. They report a relative risk of 6.7 (measured as increased serum creatinin) and 6.1 (measured as calculated creatinin clearance) for the development of renal insufficiency associated with analgesic abuse. A 10-year prospective study in patients with abuse of paracetamol-containing mixed analgesics confirmed by metabolite detection in blood and urine would clarify the question of the toxicity of this drug. This type of a study has not yet been initiated.

The study on the `Incidence of analgesic nephropathy in Berlin since 1983' [1] does not deal with the difficult problem of confirming the toxicity of paracetamol-containing mixed analgesics. It is a differential study of potential factors influencing the incidence of analgesic nephropathy. It examines the question whether the general decrease of analgesic nephropathy [15] can be considered as proof that only phenacetin, used until 1986, and not the currently used paracetamol, is nephrotoxic in mixed analgesics. It was found that other factors such as advanced age and an increasing prevalence of type II diabetes influence the relative frequencies of primary renal disease in patients with end-stage renal diseases to such a degree that the relative decrease of analgesic nephropathy in Berlin can not be related to a change from phenacetin to paracetamol. This has been confirmed by appropriate statistical analysis. Thus, the relative decrease of analgesic nephropathy cannot be used as an argument for the non-toxicity of paracetamol-containing mixed analgesics.

References

  1. Schwarz A, Preuschof L, Zellner D. Incidence of analgesic nephropathy in Berlin since 1983. Nephrol Dial Transplant 1999; 14: 109–112[Abstract]
  2. Fox JM. Doubts about a particularly high nephrotoxicity of combination analgesics. Nephrol Dial Transplant 1999; 14: 2966–2968[Free Full Text]
  3. Pommer W, Bronder E, Greiser E et al. Regular analgesic intake and the risk of end-stage renal disease. Am J Nephrol 1989; 9: 403–412[ISI][Medline]
  4. McCredie M, Stewart JH, Mahony JF. Is phenacetin responsible for analgesic nephropathy in New South Wales? Clin Nephrol 1982; 17: 134–140[ISI][Medline]
  5. Murray TG, Stolley PD, Anthony JC, Schinnar R, Hepler-Smith E, Jeffreys JL. Epidemiologic study of regular analgesic use and end-stage renal disease. Arch Intern Med 1983; 143: 1687–1693[Abstract]
  6. Sandler DP, Smith JC, Weinberg CR et al. Analgesic use and chronic renal disease. N Engl J Med 1989; 320: 1238–1243[Abstract]
  7. Morlans M, Laporte J-R, Vidal X, Cabeza D, Stolley PD. End-stage renal disease and non-narcotic analgesics: a case-control study. Br J Clin Pharmac 1990; 30: 717–723[ISI][Medline]
  8. Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal drugs. N Engl J Med 1994; 331: 1675–1679[Abstract/Free Full Text]
  9. De Broe M, Elseviers MM. Analgesic nephropathy. N Engl J Med 1998; 338: 446–452[Free Full Text]
  10. Delzell E, Shapiro S. Commentary on the National Kidney Foundation Position Paper on analgesics and the kidney. Am J Kidn Dis 1996; 28: 783–785[ISI][Medline]
  11. Schwarz A, Faber U, Borner K, Keller F, Offermann G, Molzahn M. Reliability of drug history in analgesic users. Lancet 1984; ii: 1163–1164 (letter)
  12. Schwarz A. Analgesic-associated nephropathy. Klin Wochenschr 1987; 65: 11–16
  13. Dubach UC, Rosner B, Stürmer T. Epidemiologic study of abuse of analgesic drugs containing phenacetin. Renal morbidity and mortality (1968–1987). N Engl J Med 1983; 308: 357–361[Abstract]
  14. Elseviers MM, De Broe M. A long-term prospective controlled study of analgesic abuse in Belgium. Kidney Int 1995; 48: 1912–1919[ISI][Medline]
  15. 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[Abstract]