Analgesics Use And ESRD In Younger Age: A Case-control Study

Fokke J van der Woude; Lothar AJ Heinemann; Helmut Graf; Michael Lewis; Sabine Moehner; Anita Assmann; Doerthe Kühl-Habich

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BMC Nephrology 

In This Article

Abstract and Background

Background: An ad hoc peer-review committee was jointly appointed by Drug Authorities and Industry in Germany, Austria and Switzerland in 1999/2000 to review the evidence for a causal relation between phenacetin-free analgesics and nephropathy. The committee found the evidence as inconclusive and requested a new case-control study of adequate design.
Methods: We performed a population-based case-control study with incident cases of end-stage renal disease (ESRD) under the age of 50 years and four age and sex-matched neighborhood controls in 170 dialysis centers (153 in Germany, and 17 in Austria) from January 1, 2001 to December 31, 2004. Data on lifetime medical history, risk factors, treatment, job exposure and intake of analgesics were obtained in a standardized face-to-face interview using memory aids to enhance accuracy. Study design, study performance, analysis plan, and study report were approved by an independent international advisory committee and by the Drug Authorities involved. Unconditional logistic regression analyses were performed.
Results: The analysis included 907 cases and 3,622 controls who had never used phenacetin-containing analgesics in their lifetime. The use of high cumulative lifetime dose (3rd tertile) of analgesics in the period up to five years before dialysis was not associated with later ESRD. Adjusted odds ratios with 95% confidence intervals were 0.8 (0.7 – 1.0) and 1.0 (0.8 – 1.3) for ever- compared with no or low use and high use compared with low use, respectively. The same results were found for all analgesics and for mono-, and combination preparations with and without caffeine. No increased risk was shown in analyses stratifying for dose and duration. Dose-response analyses showed that analgesic use was not associated with an increased risk for ESRD up to 3.5 kg cumulative lifetime dose (98 % of the cases with ESRD). While the large subgroup of users with a lifetime dose up to 0.5 kg (278 cases and 1365 controls) showed a significantly decreased risk, a tiny subgroup of extreme users with over 3.5 kg lifetime use (19 cases and 11 controls) showed a significant risk increase. The detailed evaluation of 22 cases and 19 controls with over 2.5 kg lifetime use recommended by the regulatory advisors showed an impressive excess of other conditions than analgesics triggering the evolution of ESRD in cases compared with controls.
Conclusion: We found no clinically meaningful evidence for an increased risk of ESRD associated with use of phenacetin-free analgesics in single or combined formulation. The apparent risk increase shown in a small subgroup with extreme lifetime dose of analgesics is most likely an indirect, non-causal association. This hypothesis, however, cannot be confirmed or refuted within our case-control study. Overall, our results lend support to the mounting evidence that phenacetin-free analgesics do not induce ESRD and that the notion of "analgesic nephropathy" needs to be re-evaluated.

The publications by Spühler et al.,[1] Dubach et al.[2] and Zollinger[3] five decades ago on the relationship between kidney damage and phenacetin ultimately led to the recognition of a causal relation between the two. This was supported by the experience in the Swedish factory Husqvarna.[4] Many epidemiological studies and review papers contributed to this view. In the 1990ies, many nephrologists by extension suspected that non-phenacetin analgesic combinations, especially those containing paracetamol and aspirin (plus caffeine) might also cause end-stage renal disease (ESRD; cf. reviews[5,6,7]), and introduced the term "analgesic nephropathy." Since data were scarce, this hypothesis engendered some controversy,[8,9] and ultimately led the regulatory authorities of Germany, Austria and Switzerland to initiate a scientific re-evaluation. A peer review committee of scientists, jointly selected by the regulatory authorities and the pharmaceutical industry, was asked to critically review the data on the relationship between non-phenacetin combined analgesics and nephropathy on the basis of a systematic literature review. The committee's three main conclusions were that (1) existing studies show no justified suspicion of any increased risk of ESRD for phenacetin-free analgesic combinations, (2) there is insufficient evidence to associate non-phenacetin combined analgesics with nephropathy and (3) new studies should be done to provide appropriate data to resolve the issue.[10]

In their initial deliberations on such a study, the Scientific Board recommended that the outcome of interest be ESRD (defined as incident dialysis), and that the exposure of interest be all phenacetin-free analgesics, including NSAIDs), regardless of the formulation. The board was aware that the analysis would address several subgroups, including analgesics co-formulated with caffeine. The design efforts resulted in a detailed, published study protocol, confirmed and approved by the regulatory authorities.[11]

The primary objective of this study was to determine the association between the lifetime use of all phenacetin-free analgesics and the occurrence of ESRD. ESRD risk was to be evaluated for several mono substances ("Monos"), fixed combination analgesics ("Combis"), by cumulative lifetime dose, duration, and dose by duration of use of phenacetin-free analgesics. This paper presents the main results of the international case-control study on the association of phenacetin-free analgesics and ESRD.

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