Summary
Phenacetin-based analgesics have been linked to the development of renal pelvis cancer and renal cell carcinoma (RCC). The relationship between non-phenacetin types of analgesics and kidney cancer is less clear, although laboratory evidence suggests that these drugs possess carcinogenic potential. A population-based case–control study involving 1204 non-Asian RCC patients aged 25–74 and an equal number of sex-, age- and race-matched neighbourhood controls was conducted in Los Angeles, California, to investigate the relationship between sustained use of analgesics and risk of RCC according to major formulation categories. Detailed information on medical and medication histories, and other lifestyle factors was collected through in-person interviews. Regular use of analgesics was a significant risk factor for RCC in both men and women (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.4–1.9 for both sexes combined). Risks were elevated across all four major classes of analgesics (aspirin, non-steroidal anti-inflammatory agents other than aspirin, acetaminophen and phenacetin). Within each class of analgesics, there was statistically significant increasing risk with increasing level of exposure. Although there was some minor variability by major class of formulation, in general individuals in the highest exposure categories exhibited approximately 2.5-fold increase in risk relative to non- or irregular users of analgesics. Subjects who took one regular-strength (i.e. 325 mg) aspirin a day or less for cardiovascular disease prevention were not at an increased risk of RCC (OR = 0.9, 95% CI = 0.6–1.4).
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References
Adams, DH, Howie, AJ, Michael, J, McConkey, B, Bacon, PA & Adu, D (1986). Non-steroidal anti-inflammatory drugs and renal failure. Lancet 1: 57–60.
Antiplatelet Trialists’ Collaboration (1994). Collaborative overview of randomised trials of antiplatelet therapy. I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 308: 81–106.
Armstrong, B, Garrod, A & Doll, R (1976). A retrospective study of renal cancer with special reference to coffee and animal protein consumption. Br J Cancer 33: 127–136.
Asal, NR, Geyer, JR, Risser, DR, Lee, ET, Kadamani, S & Cherng, N (1988). Risk factors in renal cell carcinoma. II. Medical history, occupation, multivariate analysis, and conclusions. Cancer Detect Prev 13: 263–279.
Bengtsson, U, Angervall, L, Ekman, H & Lehmann, L (1968). Transitional cell tumors of the renal pelvis in analgesic abusers. Scand J Urol Nephrol 2: 145–150.
Breslow, NE & Day, NE (1980). Statistical Methods in Cancer Research, Volume I: The Analysis of Case–Control Studies. IARC Scientific publications 32, IARC: Lyon, France.
Brodie, BB & Axelrod, J (1949). The fate of acetophenetidin (phenacetin) in man and methods for the estimation of acetophenetidin and its metabolites in biological material. J Pharmacol Exp Ther 97: 58–67.
Burrell, JH, Yong, JL & Macdonald, GJ (1991). Analgesic nephropathy in Fischer 344 rats: comparative effects of chronic treatment with either aspirin or paracetamol. Pathology 23: 107–114.
Consumer Expenditure Study (1985). Product Marketing for Beauty Industry Retailers and Manufacturers 14: 19–20.
Derby, LE & Jick, H (1996). Acetaminophen and renal and bladder cancer. Epidemiology 7: 358–362.
Devesa, SS, Silverman, DT, McLaughlin, JK, Brown, CC, Connelly, RR & Fraumeni, JF Jr (1990). Comparison of the descriptive epidemiology of urinary tract cancers. Cancer Causes Control 1: 133–141.
Eberhart, CE, Coffey, RJ, Radhika, A, Giardiello, FM, Ferrenbach, S & Dubois, RN (1994). Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107: 1183–1188.
Emeigh Hart, SG, Beierschmitt, WP, Bartolone, JB, Wyand, DS, Khairallah, EA & Cohen, SD (1991). Evidence against deacetylation and for cytochrome P450-mediated activation in acetaminophen-induced nephrotoxicity in the CD-1 mouse. Toxicol Appl Pharmacol 107: 1–15.
Flaks, A & Flaks, B (1983). Induction of liver cell tumours in IF mice by paracetamol. Carcinogenesis 4: 363–368.
Giovannucci, E, Egan, KM, Hunter, DJ, Stampfer, MJ, Colditz, GA, Willett, WC & Speizer, FE (1995). Aspirin and the risk of colorectal cancer in women. N Engl J Med 333: 609–614.
Gobé, GC & Axelsen, RA (1991). The role of apoptosis in the development of renal cortical tubular atrophy associated with healed experimental renal papillary necrosis. Pathology 23: 213–223.
Henderson, BE, Ross, RK & Pike, MC (1991). Toward the primary prevention of cancer. Science 254: 1131–1138.
International Agency for Research on Cancer (1987). Analgesic mixtures containing phenacetin. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Updating of IARC Monographs, IARC: Lyon, France Vol 1–42: 310–312.
Jensen, OM, Knudsen, JB, Tomasson, H & Sorensen, BL (1989). The Copenhagen case-control study of renal pelvis and ureter cancer: role of analgesics. Int J Cancer 44: 965–968.
Johansson, SL (1981). Carcinogenicity of analgesics: long-term treatment of Sprague-Dawley rats with phenacetin, phenazone, caffeine and paracetamol (acetamidophen). Int J Cancer 27: 521–529.
Kari, F, Bucher, J, Haseman, J, Eustis, S & Huff, J (1995). Long-term exposure to the anti-inflammatory agent phenylbutazone induces kidney tumors in rats and liver tumors in mice. Jpn J Cancer Res 86: 252–263.
Kokmen, E, Beard, CM, O’Brien, PC, Offord, KP & Kurland, LT (1993). Is the incidence of dementing illness changing? A 25-year time trend study in Rochester, Minnesota (1960–1984). Neurology 43: 1887–1892.
Kreiger, N, Marrett, LD, Dodds, L, Hilditch, S & Darlington, GA (1993). Risk factors for renal cell carcinoma: results of a population-based case-control study. Cancer Caus Contr 4: 101–110.
Kyle, ME & Kocsis, JJ (1985). The effect of age on salicylate-induced nephrotoxicity in male rats. Toxicol Appl Pharmacol 81: 337–347.
Liu, L, Deapen, D, Bernstein, L & Ross, R (1998). Cancer in Los Angeles County: Incidence and Mortality by Race/Ethnicity 1988–1995. Los Angeles County Cancer Surveillance Program, University of Southern California: Los Angeles, CA.
McCredie, M, Ford, JM, Taylor, JS & Stewart, JH (1982). Analgesics and cancer of the renal pelvis in New South Wales. Cancer 49: 2617–2625.
McCredie, M, Ford, JM & Stewart, JH (1988). Risk factors for cancer of the renal parenchyma. Int J Cancer 42: 13–16.
McCredie, M, Stewart, JH & Day, NE (1993). Different roles for phenacetin and paracetamol in cancer of the kidney and renal pelvis. Int J Cancer 53: 245–249.
McCredie, M, Pommer, W, McLaughlin, JK, Stewart, JH, Lindblad, P, Mandel, JS, Mellemgaard, A, Schlehofer, B & Niwa, S (1995). International renal-cell cancer study. II. Analgesics. Int J Cancer 60: 345–349.
McGeer, PL, Schulzer, M & McGeer, EG (1996). Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology 47: 425–432.
McLaughlin, JK, Blot, WJ, Mehl, ES & Fraumeni, JF Jr (1985). Relation of analgesic use to renal cancer: population-based findings. Natl Cancer Inst Monogr 69: 217–222.
Maclure, M & MacMahon, B (1985). Phenacetin and cancers of the urinary tract. N Engl J Med 313: 1479–1480.
McMurtry, RJ, Snodgrass, WR & Mitchell, JR (1978). Renal necrosis, glutathione depletion, and covalent binding after acetaminophen. Toxicol Appl Pharmacol 46: 87–100.
Mahony, JF, Storey, BG, Ibanez, RC & Stewart, JH (1977). Analgesic abuse, renal parenchymal disease and carcinoma of the kidney or ureter. Aust N Z J Med 7: 463–469.
Mellemgaard, A, Niwa, S, Mehl, ES, Engholm, G, McLaughlin, JK & Olsen, JH (1994). Risk factors for renal cell carcinoma in Denmark: role of medication and medical history. Int J Epidemiol 23: 923–930.
Meyer, JS, Rogers, RL, McClintic, K, Mortel, KF & Lotfi, J (1989). Randomized clinical trial of daily aspirin therapy in multi-infarct dementia. A pilot study. J Am Geriatr Soc 37: 549–555.
Mitchell, JR, McMurtry, RJ, Statham, CN & Nelson, SD (1977). Molecular basis for several drug-induced nephropathies. Am J Med 62: 518–526.
Nakanishi, K, Kurata, Y, Oshima, M, Fukushima, S & Ito, N (1982). Carcinogenicity of phenacetin: long-term feeding study in B6c3fl mice. Int J Cancer 29: 439–444.
Nanra, RS (1983). Renal effects of antipyretic analgesics. Am J Med 75: 70–81.
National Center for Health, Statistics (1996). Vital Statistics of the United States, 1992: Vol 2, Mortality, Part A. Hyattsville MD: US Dept of Health and Human Services, Public Health Service, CDC: 1996. United States Department of Health and Human Services publication PHS 96-1101.
Paganini-Hill, A, Chao, A, Ross, RK & Henderson, BE (1989). Aspirin use and chronic diseases: a cohort study of the elderly. Br Med J 299: 1247–1250.
Parker, SL, Tong, T, Bolden, S & Wingo, PA (1996). Cancer statistics, 1996. CA Cancer J Clin 46: 5–27.
Perneger, TV, Whelton, PK & Klag, MJ (1994). Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs. N Engl J Med 331: 1675–1679.
Plummer, DT, Leathwood, PD & Blake, ME (1975). Urinary enzymes and kidney damage by aspirin and phenacetin. Chem Biol Interact 10: 277–284.
Pommer, W, Bronder, E, Greiser, E, Helmert, U, Jesdinsky, HJ, Klimpel, A, Borner, K & Molzahn, M (1989). Regular analgesic intake and the risk of end-stage renal failure. Am J Nephrol 9: 403–412.
Prescott, LF (1982). Analgesic nephropathy: a reassessment of the role of phenacetin and other analgesics. Drugs 23: 75–149.
Rosenberg, L, Rao, RS, Palmer, JR, Strom, BL, Zauber, A, Warshauer, ME, Stolley, PD & Shapiro, S (1998). Transitional cell cancer of the urinary tract and renal cell cancer in relation to acetaminophen use (United States). Cancer Caus Contr 9: 83–88.
Ruffin, MT, Krishnan, K, Rock, CL, Normolle, D, Vaerten, MA, Peters-Golden, M, Crowell, J, Kelloff, G, Boland, CR & Brenner, DE (1997). Suppression of human colorectal mucosal prostaglandins: determining the lowest effective aspirin dose. J Natl Cancer Inst 89: 1152–1160.
Sabatini, S (1996). Pathophysiologic mechanisms in analgesic-induced papillary necrosis. Am J Kidney Dis 28: S34–S38.
Sandler, DP, Smith, JC, Weinberg, CR, Buckalew, VM Jr, Dennis, VW, Blythe, WB & Burgess, WP (1989). Analgesic use and chronic renal disease. N Engl J Med 320: 1238–1243.
Sandler, DP, Burr, FR & Weinberg, CR (1991). Nonsteroidal anti-inflammatory drugs and the risk for chronic renal disease. Ann Intern Med 115: 165–172.
Segasothy, M, Samad, SA, Zulfigar, A & Bennett, WM (1994). Chronic renal disease and papillary necrosis associated with the long-term use of nonsteroidal anti-inflammatory drugs as the sole or predominant analgesic. Am J Kidney Dis 24: 17–24.
Steering Committee of the Physicians’ Health Study Research Group (1989). Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 321: 129–135.
Tsuda, H, Sakata, T, Masui, T, Imaida, K & Ito, N (1984). Modifying effects of butylated hydroxyanisole, ethoxyquin and acetaminophen on induction of neoplastic lesions in rat liver and kidney initiated by N-ethyl-N-hydroxyethylnitrosamine. Carcinogenesis 5: 525–531.
Yu, MC, Yuan, J-M & Ross, RK (1999). Epidemiology of renal cell carcinoma. 3–13.
Yuan, J-M, Castelao, JE, Gago-Dominguez, M, Ross, RK & Yu, MC (1998a). Hypertension, obesity and their medications in relation to renal cell carcinoma. Br J Cancer 77: 1508–1513.
Yuan, J-M, Castelao, JE, Gago-Dominguez, M, Yu, MC & Ross, RK (1998b). Tobacco use in relation to renal cell carcinoma. Cancer Epidemiol Biomarkers Prev 7: 429–433.
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Gago-Dominguez, M., Yuan, JM., Castelao, J. et al. Regular use of analgesics is a risk factor for renal cell carcinoma. Br J Cancer 81, 542–548 (1999). https://doi.org/10.1038/sj.bjc.6690728
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DOI: https://doi.org/10.1038/sj.bjc.6690728
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