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

Disclosures

BMC Nephrology 

In This Article

Discussion

The objective of this study was the investigation of the effect of lifetime use of phenacetin-free analgesics on ESRD occurrence in a younger population. The restriction to a study group below the age of 50 was a prerequisite for the effective exclusion of phenacetin use, and we believe that this is the first study to completely avoid phenacetin contamination in the assessment of ESRD associated with analgesic uses. The results suggest that there is no association between ESRD and analgesic use in general, nor with the use of specific analgesics or combinations with or without additional caffeine in the age group below 50 years.

The direct comparison of baseline users of no or very low lifetime analgesic doses with the tertile distributions of lifetime doses in grams of the user group shows no increased ESRD risk associated with phenacetin-free analgesics in the highest tertile. Instead, there was a significantly reduced risk ESRD for the lower two tertiles for all analgesics, mono-preparations, and combination products. No clinically relevant increase of ESRD risk with increasing dose was found in an analysis of the effect of ASA, paracetamol, and other ingredients with full adjustment including other analgesic combinations. Users of lower doses of analgesics showed a decreased risk of ESRD independent of duration of use ( Table 3 ). The group of users of high lifetime doses showed a non-significant tendency for higher risks when these substances were taken within a shorter period. We cannot draw any strong conclusions from the findings related to the combined associations of dose and duration of analgesic use.

The detailed examination of dose-response distributions showed no association or significantly reduced risks of ESRD for almost all levels of analgesic use. However, a tiny group of cases and controls showed a significantly increased risk associated with a dose over 3.5 kg in the dose-stratified analyses. This was found to significantly increase around a dose of 4–5 kg lifetime use of analgesics in the continuous dose analyses. This level of use corresponds to a daily consumption of 200 to 400 grams of analgesic over a 30-year period. Because the numbers in this subgroup were too low for estimation, a detailed description was prepared for this upper-most dose group (22 cases and 19 controls). The main distinction between cases and controls were the much higher prevalence of factors closely associated with later development of ESRD among the cases, so that we interpret this group as being defined by their high-risk status rather than by their use of analgesics which is incidental to their prior health condition. The same conclusion was reached by an external expert in nephrology (Prof. Michielsen) who was asked by the Scientific Advisory Committee of the study and by the German Drug Authority to individually evaluate the likelihood that high analgesic use in these cases is is the cause of their ESRD. Prof. Michielsen expressed in his report that the individual assessment of lifetime users of 2.5 kg analgesic user indicated:1)There is no evidence of classical analgesic nephropathy, and 2) that there is no indication that analgesic use influenced the evolution to ESRD in this small group of extremely high users (cf. full assessment report at the SAN website[12]).

The two important advantages of this study are the use of a 5-year lag-time across all analyses on analgesic exposure and ESRD risk and the presumably complete exclusion of past use of phenacetin. The 5-year lag time has previously been used in only two[14,15] studies. It addresses the issue of temporality and reduces the risk of showing estimates based on analgesic use prompted by an incipient renal condition rather than on the occurrence of a renal condition following a period of analgesic use (reverse causality bias). To our knowledge, no previous study has eliminated phenacetin use from its population to the extent this study has, and we consider this a condition sine qua non for the estimation of ESRD risk associated with the currently available analgesics.

Every effort was made to minimize recall and information bias by using face-to-face interviews with a set of aids and procedures to jog memory, check the plausibility of recalled analgesic use, and to provide similar conditions for cases and controls. Selection bias is addressed in the community-based approach of this case-control study. Logbooks were maintained in dialysis centers to assure complete coverage. Nonetheless, and although comparable with other studies in this area, a non-response rate of around 30% leaves some possibility for bias. It is reassuring that the information available on non-responders did not differ from the information for those included in the study. Finally, the study suffers the limitations of all observational studies in that the participation of cases may be very much determined by intentions of the treating physician who invited patients, while the situation could differ for controls. Differences in reporting behavior between cases and controls can never be entirely excluded, and controls who consumed large amounts of analgesics may have a poor health-related quality of life which prevents them from volunteering for such a study.

The age limit of 50 years is strength of the study because it largely eliminates phenacetin users from this population, but it may also restrict the generalizability of the findings. However, this study feature was considered an essential safeguard against confounding by phenacetin use. Reliable results for the risk of ESRD and analgesic use in the population aged 50 to 70 years, for example, could be obtained only in the decades when phenacetin users had slowly depleted. Even then, the much higher potential of serious confounding and bias in the higher age group would make it difficult to interpret an association because, if any association is found, it is likely to be small. Although the possibility that some persons might not have sufficient time to accumulate a harmful lifetime dose up to the age of 50 years, we consider the evidence of no clinically important association between analgesic use and ESRD provided by this study to be the best currently available. Therefore, and in the absence of other reliable evidence, the results of this study most likely also apply to higher age groups.

The debate on analgesic use and nephropathy has gone on for decades and is not yet concluded.[16] Many earlier studies which did not exclude past phenacetin use found a significant association between analgesic use and chronic renal failure/ESRD with relative risk increases ranging from 2- to 8-fold.[17,18,19,20,21,22] Other studies observed no or no clearly increased risk or variations among formulations [14,15,23,24]or else were inconclusive.[25,26] Fored et al. (2003)[15] did not rule out that the associations found in their study might be due to bias, i.e. that the use of analgesics was triggered by conditions associated with the renal disease.

Recently, Mihatsch et al. (2006),[27] conducted an exact replication of the benchmark autopsy studies on analgesic nephropathy which he performed 1978–80 in Basel.[28] The author wrote: "The last and single autopsy case of proven classic analgesic nephropathy detected only with the present sophisticated histological study at the end of the year 2000 can thus be taken as further evidence that this type of chronic renal disease was due to nothing but phenacetin-containing mixed analgesics. Some 20 years after removal of phenacetin from the market classic analgesic nephropathy is all but disappearing and will no longer be a health hazard in the 21st century.".[27] The results of the present study on a population of individuals with no prior phenacetin use supports this finding.

The present study adds to the available data characterizing the association of ESRD risk and lifetime consumption of analgesics applying advanced methods. Our data show no significant association between ESRD and analgesic use in general or for the use of specific analgesics or combinations with or without additional caffeine. The descriptive analysis of a small highly exposed subgroup indicates that their very high cumulative lifetime use of analgesics is based on a pattern of chronic, painful ill health and does not constitute a causal association with ESRD. However, further research on extreme users of analgesics is recommended.

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