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Over-The-Counter Analgesic Use CLINICAL COMMENTARY www.jasn.org Over-the-Counter Analgesic Use Marc E. De Broe and Monique M. Elseviers Laboratory of Pathophysiology and Department of Nursing Sciences, University of Antwerp, Antwerp, Belgium ABSTRACT Chronic analgesic nephropathy, particularly chronic interstitial nephritis and renal or chronic interstitial nephritis. Still, papillary necrosis, results from daily use for many years of mixtures containing at other investigators have used this vali- least two analgesics and caffeine or dependence-inducing drugs. Computed to- dated diagnostic test in an epidemiologic mography scan can accurately diagnose this disease even in the absence of reliable study related to late referral of patients information on previous analgesic use. The occasion to moderate regular use of with severe renal failure toward renal aspirin and nonsteroidal anti-inflammatory drugs is without renal risk when renal units. function is normal. Paracetamol use is less clear although the risk is not great. The A study of patients with ESRD (Na- continued use of non–phenacetin-combined analgesics with or without nonsteroi- tional Analgesic Nephropathy Study dal anti-inflammatory drugs is associated with faster progression toward renal [NANS]) in the United States evaluated impairment. As long as high-risk analgesic mixtures are available over the counter, the value of the non–contrast-enhanced analgesic nephropathy will continue to be a problem. CT as diagnostic test for AN.4 It turns out that in comparison with previous stud- J Am Soc Nephrol 20: 2098–2103, 2009. doi: 10.1681/ASN.2008101097 ies, the sensitivity of the noncontrast CT scan for the detection of analgesic-asso- ciated kidney injury was too low to be Chronic analgesic nephropathy (AN) is a test to diagnose or rule out AN as a pos- used as a routine test; that is, a specificity slowly progressive renal disease resulting sible cause of renal disease in patients of Ͼ95%, comparable with the earlier from daily use for many years of mix- with ESRD as well as in patients with reports, was found. The low prevalence tures containing at least two analgesics stages 3 to 4 chronic kidney disease of AN (clearly Ͻ5%) found in the United (e.g., aspirin, paracetamol, pyrozolones, (CKD), even in the absence of reliable States, however, precluded calculating phenacetin) and caffeine, codeine, information on the use of combined an- the clinically relevant sensitivity of the and/or barbiturates, which may lead to algesics (Figure 1).3 test. psychological dependence and overuse. Known causes of renal papillary ne- The disease is characterized by capillary crosis/calcifications other than com- sclerosis, renal cortical atrophy, chronic bined analgesic use are diabetes, sickle WHAT KIND OF ANALGESICS ARE interstitial nephritis, and papillary scle- cell disease, and pyelonephritis, the INVOLVED IN THE GENERATION rosis/necrosis/calcifications. In a num- differential diagnosis of the two first OF AN? ber of cases, not related to the progres- conditions being straightforward. sion or stage of renal failure, the Chronic pyelonephritis is associated Phenacetin was present in all products uroepithelia can develop transitional cell with progressive renal scarring, in the used by patients described in the early carcinoma.1,2 context of intrarenal reflux of infected reports of AN. This finding is the sole The lack of reliable validated criteria, urine. Calcified papillary necrosis ob- argument to support the generally ac- the high prevalence of AN in 1980 served in the majority of the papilla in cepted “phenacetin kidney’ concept. Ex- through 1990 in Belgium (Ͼ15% of the both kidneys of patients with AN is not dialysis population), and the underesti- seen in chronic pyelonephritis. Published online ahead of print. Publication date mation of the disease in Europe led us to Several studies using this validated di- available at www.jasn.org. perform studies defining and validating agnostic test showed either the absence Correspondence: Dr. Marc E. De Broe, University of the criteria for AN. On the basis of the or low prevalence of AN, whereas others Antwerp, Laboratory of Pathophysiology, Univer- siteitsplein 1, B-2610, Wilrijk/Antwerpen, Belgium. results of three multicenter multina- confirmed the underestimation of AN in Phone: ϩ32-3-820-2599; Fax: ϩ32-3-820-2592; tional studies, computed tomography their country and showed a substantial E-mail: [email protected] (CT) scanning without contrast medium number of patients with AN exist in the Copyright ᮊ 2009 by the American Society of turned out to be a valuable and validated cohort of patients with unknown cause Nephrology 2098 ISSN : 1046-6673/2010-2098 J Am Soc Nephrol 20: 2098–2103, 2009 www.jasn.org CLINICAL COMMENTARY Figure 1. Diagnostic criteria of analgesic nephropathy. (A) Macroscopic aspect of an AN kidney from a patient with ESRD. (B) Diagnostic criteria used. (C) CT scans without contrast material of an individual with normal kidneys and patients with AN and with stage 3 CKD and ESRD. Adapted from De Broe and Elseviers.2 perimental studies revealed, however, any analgesic mixtures containing two and Morlans et al.16 resulted in comparable that aspirin and phenazone derivatives— analgesic components combined with odds ratios (ORs) between 2 and 3, despite the drugs invariably taken with phenace- caffeine and/or codeine.9 differences in study design. McCredie’s11 tin—all produce experimental nephro- Clinical observations performed study showed a considerably higher OR by toxicity more readily than phenacetin.5 within the framework of the diagnostic using the more specific lesion of renal pap- Whether phenacetin is the sole re- criteria of AN document the nephrotox- illary necrosis as the primary identifier of sponsible ingredient causing AN still is a icity of the combinations of salicylic acid disease. matter of intense debate. Phenacetin be- with paracetamol, pyrazolones, paracet- A solid demonstration of the associa- lievers argue it was the ban of phenacetin amol-pyrazolones, or two pyrazolones tion between analgesic use and renal failure that caused the decline in AN incidence associated with dependence-producing is also provided by two prospective, con- observed in Switzerland6 and in other drugs.10 Additional data from Australia trolled, cohort studies performed of pa- countries.7 In contrast, researchers in the and Belgium support the suggestion that tients with excessive use of analgesic mix- field of AN have joined forces to identify withdrawal of phenacetin is not solely re- tures in Switzerland and Belgium with a the nephrotoxic potential of all analgesic sponsible for the decline in AN.2 Only follow-up of 10 and 6 yr, respectively.21,22 mixtures with or without phenacetin. In after the drastic decrease in the sales of all Although both studies differed substan- 1995, the ad hoc committee of the Na- analgesic mixtures was a substantial de- tially with respect to study populations, an- tional Kidney Foundation in the United cline in the incidence of AN observed. algesics consumed, and length of follow- States examined the available informa- Many epidemiologic studies have in- up, the increased ORs were remarkably tion from hundreds of peer-reviewed ar- vestigated the risk for renal failure related similar. In contrast, the observational studies ticles and stated that habitual consump- to the prolonged excessive consumption of of Kurth et al.23 and Curhan et al.24 could tion of both phenacetin-containing analgesics (Figure 2). In case-control stud- not demonstrate an increased risk after the mixtures and non–phenacetin-contain- ies, the overall risk after any analgesic con- (nonexcessive) consumption of any anal- ing mixtures is associated with AN.8 One sumption ranged from 1.02 (95% confi- gesic in a population of healthy US male year later, European nephrologists prof- dence interval 0.80 to 1.30) to 17.20 (95% physicians or female nurses, respectively. fered a similar viewpoint, asking for the confidence interval 8.50 to 34.70). The It is inherent to the case-control design prohibition of over-the-counter sales of studies of Sandler et al.13, Pommer et al.15, that the observed association between J Am Soc Nephrol 20: 2098–2103, 2009 Over-the-Counter Analgesic Use 2099 CLINICAL COMMENTARY www.jasn.org tain, necessitating the use of special inter- view techniques. Interviews by tele- phone13,14,17 or written self-reports of analgesic consumption in the past23,24 were not the methods of choice to detect hidden consumption of analgesics (infor- mation bias). Half of the case-control stud- ies as well as all of the cohort studies also suffer from indication (protopathic) bias; that is, not being able to distinguish be- tween analgesic consumption preceding de novo development of renal disease and the analgesic consumption because of symp- toms of other diseases (e.g., diabetes) that predispose patients to renal failure. Finally, it is well established that patients with AN used analgesics on a daily basis and at least for a period of 5 yr, resulting in a total an- algesic consumption of at least 1500 U.4,8 As shown in Figure 2, several studies suf- fered from dosage bias because they used a total amount that was far below the mini- mum consumption described in patients with AN.13,19,20 The epidemiologic literature concern- ing the role of different substances that cause AN is limited and controversial. Sub- stances combined in analgesic mixtures are invariably taken together. Most case-con- trol studies suffer from ingredient bias be- cause they present risk ratios based on analyses without making a distinction be- tween analgesics used as single ingredient or in combination. Mainly because of in- gredient bias, the potential nephrotoxicity of paracetamol remains a matter of debate, with six studies showing an increased risk and three studies not (Figure 3). The safety of aspirin used as a single ingredient is eas- ier to evaluate.
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