Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) effectively control the symptoms of many of the rheumatic diseases although they have little effect on the underlying causes. Their effect is mainly on the mediators of the inflammatory process. Unfortunately, these mediators have important physiological roles in the maintenance of health, particularly in the gastrointestinal tract and the kidney, so that their inhibition results in many unwanted reactions of varying severity. The mechanisms underlying these reactions are described. Their occurrence varies, both qualitatively and quantitatively, and an attempt is made to assess these differences, although it may be that they are related directly to differences in dosage and therapeutic efficacy.
In addition, immunologically mediated adverse reactions occur. These mechanisms are outlined and related to the clinical picture. There are considerable differences in frequency of reactions between the compounds: in particular there is a wide variation in the rate of dermatological reactions of this type. Agranulocytosis has been particularly assodated with the pyrazolone compounds, although it has been reported with most others. Aplastic anaemia, which may not be an immune-mediated reaction, is also thought of as a pyrazolone reaction, but the incidence with indomethacin approaches a similar level. Although all drugs analysed may cause hepatic reactions, these are rare except with the now withdrawn benoxaprofen. Several types of immunologically mediated renal reactions occur and these rarities are also described.
Paracetamol does not have any effect on the inflammatory mediators. Anxieties about this substance relates to the parent compound phenacetin and its necrotic effect on the renal papillae. There is extensive literature on this subject concerning not only paracetamol, but also aspirin and other NSAIDs. This is also assessed and summarised. The danger of paracetamol as a direct hepatic toxin in self-poisoning is discussed.
Novel NSAIDs are introduced and others withdrawn with frequent and monotonous regularity. Sometimes the reasons have some medical or scientific plausibility, but often they are over-reactions by registration authorities or pharmaceutical companies in response to uninformed media publicity. The problems of the numerically and scientifically accurate collection and assessment of adverse reaction data are legion and as a result useful agents have been lost. Some of these difficulties are described, and some non-drug ‘adverse reactions’ are described.
New publications on this subject continue to appear so that ideas and concepts are continually changing. The perfect NSAID — a powerful anti-inflammatory analgesic without side effects — does not yet exist. A very low dose of a bland compound may be almost without side effects, but is of little comfort to the patient afflicted with severe rheumatoid arthritis. Comparative side effect rates are thus irrelevant unless related to therapeutic efficacy. This article describes side effects, mechanisms and some comparative frequency rates, but because of the efficacy constraint makes no attempt to discuss relative merits of the various compounds.
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References
Abrahams C, Levin NW. Analgesic nephropathy. Lancet 1: 645, 1968
Ackroyd JF. Allergic purpura including purpura due to foods, drugs and infections. American Journal of Medicine 14: 603, 1953
Adams SS, Warwick-Buckler J. Ibuprofen and flurbiprofen. In Huskisson EC (Ed.) Antirheumatic Drugs, pp. 243–264, Praeger Publishers, Eastbourne, 1983
Akyol SM, Thompson M, Kerr DNS. Renal function after prolonged consumption of aspirin. British Medical Journal 284: 631–632, 1982
Allen SG, Knox J, Kerr F. Interaction between diuretics and indomethacin. British Medical Journal 283: 1611, 1981
Ayres JG, Fleming DM, Whittington RM. Asthma death due to ibuprofen. Lancet 1: 1082, 1987
Bender WL, Whelton A, Beschorner WE, Darwish MO, Hall-Craggs M, et al. Interstitial nephritis, proteinuria and renal failure caused by NSAIDs. American Journal of Medicine 76: 1006–1012, 1984
Billings RA, Burry HC, Emslie FS, Kerr GD. Vasculitis with alclofenac therapy. British Medical Journal 4: 263–265, 1974.
Boston Collaborative Drug Surveillance Program. Drug induced deafness: a cooperative study. Journal of the American Medical Association 224: 515–516, 1973
Brater DC, Fox WR Chennavasin P. Interaction studies with bumetanide and furosemide: effects of probenecid and indomethacin on response to bumetanide in man. Journal of Clinical Pharmacology 21: 647–653, 1981
Brock PG, Jackson D. UK general practitioners experience of fenbufen in elderly patients. European Journal of Inflammation 5: 326–331, 1982
Buchanan WW, Rooney PJ, Rennie JAN. Aspirin and the salicylates. In Huskisson EC (Ed.) Antirheumatic drugs, pp. 55–95, Praeger Press, Eastbourne, 1983
Burns JJ, Rose RK, Chenkin T, Goldman A, Schulert A, et al. Physiology disposition of phenylbutazone (butazolidin) in man and method for its estimation in biological material. Journal of Pharmacology and Experimental Therapeutics 109: 346–357, 1953
Burry AF. The pathology and pathogenesis of renal papillary necrosis. In Kincaid-Smith & Fairley (Eds) Renal infection and renal scarring, p. 135, Mercedes, Melbourne, 1971
Burry HC. Reduced glomerular function in rheumatoid arthritis. Annals of the Rheumatic Diseases 31: 65–68, 1972
Burt RAP, Gruber CM, Irons MR. Fenoprofen calcium: a review. In Huskisson EC (Ed.) Antirheumatic drugs, pp. 233–242, Praeger Press, Eastbourne, 1983
Buxton R, Grennan DM, Palmer DG. Fenbufen compared with indomethacin in osteoarthritis. Current Medical Research and Opinion 5: 682–687, 1978
Cardoe N. A review of long-term experience with ibuprofen, with special reference to gastric tolerance. Rheumatology and Physical Medicine (Suppl.): 28–31, 1970
Cardoe N, Fowler PD. Diclofenac sodium (Voltarol R): a double-blind comparative study with ibuprofen in patients with rheumatoid arthritis. Rheumatology and Rehabilitation (Suppl. 2): 89–99, 1979
Carmichael J, Skankel SW. Effects of non-steroidal anti-inflammatory drugs on prostaglandins and renal function. American Journal of Medicine 79: 992–1000, 1985
Chapman P. Naproxen and sudden hearing loss. Journal of Laryngology and Otology 96: 163–166, 1982
Ciabatoni G, Cinotti G, Pierucci A, et al. Effects of sulindac and ibuprofen in patients with chronic glomerular disease. New England Journal of Medicine 310: 279–283, 1984
Ciccolunghi SN, Schubiger BI, Reddrop R. Comparison of tolerability in international clinical trials. Rheumatology and Rehabilitation (Suppl. 2): 122-134, 1979
Ciucci A. A review of spontaneously reported adverse drug reactions. Rheumatology and Rehabilitation (Suppl. 2): 116-121, 1979
Clive DM, Stoff JS. Renal syndromes associated with non-steroidal anti-inflammatory drugs. New England Journal of Medicine 310: 163–572, 1984
Cohen PM. A report on the incidences of rash in an open study investigating safety and efficacy of fenbufen in the treatment of 8,640 patients. Data on file, Lederle, 1986
Currey HLF. Side effects. In Practical problems in rheumatology. International Congress Symposium Series No. 32, p. 31, Royal Society of Medicine, London, 1980
Davis M, Simmons CJ, Harrison NG, Williams R. Paracetamol overdose in man: relationship between pattern of urinary metabolites and severity of liver damage. Quarterly Journal of Medicine 45: 181–191, 1976
De Bono GG, Pearlgood M. General practice trials: a reappraisal in the light of the findings of a general practice study of Oruvail. British Journal of Clinical Practice 40: 421–428, 1986
Doherty M, Holt M, Macmillan P, Watt I, Dieppe P. A reappraisal of ‘analgesic’ hip. Annals of the Rheumatic Diseases 45: 272–279, 1986
Duggin GG, Mudge GH. Analgesic nephropathy: renal distribution of acetaminophen and its conjugates. Journal of Pharmacology and Experimental Therapeutics 199: 1–9, 1976
Dunn AM, Buckley BM. Non-steroidal anti-inflammatory drugs and the kidney. British Medical Journal 293: 202–203, 1986
Edwards OM, Edwards P, Huskisson EC, Taylor RT. Paracetamol and renal damage. British Medical Journal 2: 87–89, 1971
Elliot HC. Reduced adrenocortical steroid excretion rates in man following aspirin administration. Metabolism 11: 615–618, 1962
Farid NR, Johnson RL, Low WT. Haemolytic reaction to mefenamic acid. Lancet 2: 382, 1971
Favre L, Glasson Ph, Riondel A, Valloton MD. Interaction of diuretics and NSAIDs in man. Clinical Sciences 64: 407–415, 1983
Findling JW, Beckstrom D, Rawsthorne L, Kozin F, Itskovitz H. Indomethacin-induced hyperkalaemia in three patients with gouty arthritis. Journal of the American Medical Association 244: 1127–1128, 1980
Flanagan RJ. The role of acetylcysteine in clinical toxicology. Medical Toxicology 2: 93–104, 1987
Fowler PD. Phenylbutazone. In Huskinsson EC (Ed.) Antirheumatic drugs, pp. 353–370, Praeger Press, Eastbourne 1983
Fowler PD. Marrow toxicity of the pyrazoles. Annals of the Rheumatic Diseases 26: 344–345, 1967
Fowler PD. Major toxic reactions. In Hart & Klinenberg (Eds) Choosing NSAID therapy, pp. 41–57, ADIS Press, Auckland, 1985
Fowler PD, Crook PR, Hothersall TE. Diclofenac sodium and thyroid function tests. Rheumatology and Rehabilitation 21: 42–47, 1982
Fowler PD, Faragher EB. Drug and non-drug factors affecting adverse reactions to pyrazoles. International Journal of Medical Research 5 (Suppl. 2): 108–120, 1977
Fowler PD, Woolfe D, Alexander S. Phenylbutazone and hepatitis. Rheumatology and Rehabilitation 14: 71–75, 1975
Fowler RW, Arnold KG. Non-steroidal analgesic and anti-inflammatory agents. British Medical Journal 287: 8835, 1983
Gazzard BG, Hughes RD, Widdop B, Goulding R, Davis M, et al. Early prediction of the outcome of paracetamol overdose. Postgraduate Medical Journal 53: 243, 1977
Girdwood RH. Death after taking medicaments. British Medical Journal 1: 501–504, 1974
Goldberg AAJ, Godfrey KE. Fenclofenac. In Huskinsson EC (Ed.) Antirheumatic drugs, pp. 201–232, Praeger Press, Eastbourne, 1983
Goldszer RC, Coodley EL, Rosner MJ, Simons WM, Schwartz AB. Hyperkalaemia associated with indomethacin. Archives of Internal Medicine 141: 802–804, 1981
Hanzlik PJ. A study of the toxicity of salicylates based on clinical statistics. Journal of the American Medical Association 60: 957–962, 1913
Harvald B, Pedersen J. Shock som patogenetisk faklar ved papillitis necrotican i renova. Ugeskrift For Laeger 122: 499, 1960
Husby G, Holme I, Rugstead HE, Herland OB, Gierksky KE. A double-blind multicentre trial of piroxicam and naproxen in osteoarthritis. Clinical Rheumatology 5: 84–91, 1986
Inman WHW. Study of fatal bone marrow depression with special reference to phenylbutazone and oxyphenbutazone. British Medical Journal 1: 1500–1505, 1977
International Agranulocytosis and Aplastic Anemia Study. Risk of agranulocytosis and aplastic anemia. Journal of the American Medical Association 256: 1749–1757, 1986
Jensen MK. Phenylbutazone, chloramphenicol and mammalian chromosomes. Humangenetik 17: 61 1972
Kincaid-Smith P. Effects of non-narcotic analgesics on the kidney. Drugs 32 (Suppl. 4): 109–128, 1986
Kornberg A, Polliak A. Paracetamol-induced thrombocytopenia and haemolytic anaemia. Lancet 2: 1159, 1978
Laakso M, Mutro O, Isomaki H, Koota K. Mortality from amyloidosis and renal diseases in patients with rheumatoid arthritis. Annals of Rheumatic Diseases 45: 663–667, 1986
Lopez-Ovejero JA, Weber MA, Drayer JIM, Sealy JE, Laragh JH. Effects of indomethacin alone and during diuretic and -adrenoreceptor-blockage therapy on blood pressure and the renin system in essential hypertension. Clinical Science and Molecular Medicine 55 (Suppl.): 203S–205S, 1978
McDonald JR, Mathison DA, Stevenson DD. Aspirin intolerance in asthma: detection by oral challenge. Journal of Allergy and Clinical Immunology 50: 198–207, 1972
Mason RM. The treatment of gout. Prescribers Journal 7: 125–131, 1968
Mauer I, Weinstein D, Solomon MH. Acetylsalicylic acid: no chromosome damage in human leukocytes. Science 169: 198–201, 1970
Meisner LF, Inhorn SL. Chemically induced chromosome changes in human cells in vitro. Acta Cytologica 16: 41–47, 1972
Meredith TJ, Prescott LF, Vale JA. Why do patients still die from paracetamol poisoning? Lancet 293: 345–346, 1986
Mikulaschek W. Long term safety of benoxaprofen. Journal of Rheumatology 7 (Suppl. 6): 100–107, 1980
Miller JJ, Weissman DB. Correlations between transaminase concentrations and serum salicylate concentration in juvenile rheumatoid arthritis. Arthritis and Rheumatism 19: 115–118, 1976
Moeschlin S, Wagner K. Agranuloctosis due to occurrence of leucocyte agglutinins. Acta Haematologica 8: 29–41, 1952
Nanra RS, Chirawong P, Kincaid-Smith P. Medullary ischacmia in experimental analgesic nephropathy: the pathogenesis of renal papillary necrosis. Australian and New Zealand Medical Journal 3: 580, 1973
Nanra RS, Stuart-Taylor J, deLeon AH, White KH. Analgesic nephropathy: etiology, clinical syndrome and clinicopathologic correlations in Australia. Kidney International 13: 79–92, 1978
Office of Population Censuses and Surveys. Mortality statistics: accidents and violence. Series BH4 (table 10). Her Majesty’s Stationary Office, London, 1984
O’Gorman T, Koff RS. Salicylate hepatitis. Gastroenterology 72: 726–728, 1977. O’Laughlin JC, Hoftiezer JW, Mahoney J, Ivey KJ. Effect of aspirin on the human stomach in normals: endoscopic comparison of damage produced one hour, 24 hours and 2 weeks after administration. Scandinavian Journal of Gastroenterology 16 (Suppl. 67): 211-214, 1981
Oliw E, Ängaard E, Fredholm BB. Effect of indomethacin on the renal effects of theophylline. European Journal of Pharmacology 43: 9–16, 1987
Pitts N. Efficacy and safety of piroxicam. American Journal of Medicine 72 (Suppl. 2A): 77–87, 1982
Prescott LF. Analgesic nephropathy. Drugs 23: 75–159, 1982
Prescott LF. Paracetamol overdose: pharmacological considerations and clinical management. Drugs 25: 290–314, 1983
Ratcliffe WA, Hazleton RA, Thompson JA. Effect of fenclofenac on thyroid function tests. Lancet 1: 432, 1980
Rawlins MD, Thompson JW. Pathogenesis of adverse reactions. In Davies DM(Ed.) Textbook of adverse drug reactions, p. 44, Oxford University Press, Oxford, 1977
Rhymer AR. Sulindac. In Huskisson EC (Ed.) Antirheumatic drugs, pp. 421–438, Praeger Press, Eastbourne, 1983
Rhymer AR, Gingos DC. Indomethacin. In Huskisson EC (Ed.) Antirheumatic drugs, pp. 265–278, Praeger Press, Eastbourne, 1983
Robertson JH, Kennedy CC, Hill CM. Haemolytic anaemia associated with mefenamic acid. Irish Journal of Medical Science 140: 226, 1971
Rossi AC, Hsu JP, Faich GA. Ulcerogenicity of piroxicam: an analysis of spontaneously reported data. British Medical Journal 294: 147–150, 1987
Rushford WH, Fowler PD. Butacote: the first assessment in general practice. Journal of International Medical Research 5 (Suppl. 2): 67–669, 1977
Russell AS, Sturge RA, Smith MA. Serum transaminases during salicylate therapy. British Medical Journal 2: 428–429, 1971
Sams Jr WM, Thorne EG, Small P, Moss MF, Mclntosh RM, et al. Leukocytoclastic vasculitis. Archives of Dermatology 112: 219–226, 1976
Sasisekhar PR, Penn RG, Haslock I, Wright V. A comparison of aspirin and benorylate in the treatment of rheumatoid arthritis. Rheumatology and Rehabilitation (Suppl.): 31-38, 1973
Schwertschlag V, Gerber JG, Barnes JS, Nies AS. A dual effect of non-steroidal anti-inflammatory drugs on renal water handling in humans. Journal of Pharmacology and Experimental Therapeutics 228: 653–658, 1986
Scott GL, Myles AB, Bacon PA. Autoimmune haemolytic anaemia and mefenamic acid. British Medical Journal 3: 534–535, 1968
Seaman WE, Plotz PH. Effect of aspirin on liver tests in patients with RA or SLE and in normal volunteers. Arthritis and Rheumatism 19: 155–160, 1976
Sheldrake FE, Webber JM, Marsh BD. A long term assessment of flurbiprofen. Current Medical Research and Opinion 5: 106–116, 1977
Silanpaa M, Kasanen A, Elonen A. Changes of panorama in renal disease mortality in Finland after phenacetin restriction. Acta Medica Scandinavica 212: 313–317, 1982
Smith AP. Response of aspirin-allergic patients to challenge by some analgesics in common use. British Medical Journal 2: 494–496, 1971
Stern RS, Bigby M. Cutaneous reactions to non-steroidal anti-inflammatory drugs. Journal of the American Medical Association 252: 1433–1437, 1984
Stevenson AC, Patel AR, Bedford J, Hill AGS, Hill HFH. Chromosomal studies-in patients taking phenylbutazone. Annals of the Rheumatic Diseases 30: 487–500, 1971
Swain MC, Smith DW, Goldberg AAJ. Fenclofenac: a five year review of patient tolerance. In Fenclofenac in Arthritis, Royal Society of Medicine, International Congress Series No 28, p. 73, Academic Press, 1980
Symmons DPM, Kendall MJ, Rees JA, Hind ID. The effect of flurbiprofen on the response to frusemide in healthy volunteers. International Journal of Clinical Pharmacology, Therapeutics and Toxicology 21: 350–354, 1983
Szczeklik A. Analgesics allergy and asthma. Drugs 32 (Suppl. 4): 148–163, 1986
Szczeklik A, Gryglewski RJ, Czerniawaska-Mysik G. Participation of prostaglandins in pathogenesis of aspirin-sensitive asthma. Naunyn Schmiedeberg’s Archives of Pharmacology 297 (Suppl.): 99, 1977a
Szczeklik A, Gryglewski RJ, Czerniawaska-Mysik G. Clinical patterns of hypersensitivity of non-steroidal anti-inflammatory drugs and their pathogenesis. Journal of Allergy and Clinical Immunology 60: 276–284, 1977b
Tamiser JN. Ketoprofen. In Huskisson EC (Ed.) Antirheumatic drugs, 307–318, Praeger Press, Eastbourne, 1983
Tan SY, Shapiro, Kish MA. Reversible acute renal failure induced by indomethacin. Journal of the American Medical Association 241: 2732–2733, 1979
Templeton JS. Azapropazone. In Huskisson EC (Ed.) Antirheumatic Drugs, pp. 97–116, Praeger Publishers, Eastbourne, 1983
van Winzun C, Verhaest L, von Poelnitz M. Diflunis. In Huskisson EC (Ed.) Antirheumatic drugs, pp. 157–182, Praeger Press, Eastbourne, 1983
von Rechenberg HK. Phenylbutazone, pp. 57–61, Edward Arnold, London, 1962a
von Rechenberg HK. Phenylbutazone, p. 106, Edward Arnold, London, 1962b
Walshe JJ, Venuto RC. Acute oliguric renal failure induced by indomethacin. Annals of Internal Medicine 91: 47–49, 1979
Weber JCP. Epidemiology of adverse reactions to non-steroidal anti-inflammatory drugs. In Rainsford & Velo (Eds) Advances in inflammatory research, Vol. 6, pp. 1–7, Raven Press, New York, 1984
Weissman JI, Bloom B. Anuria following phenylbutazone therapy. New England Journal of Medicine 252: 1086–1087, 1955
Williams RL, Davies R, Berman RS, Holmes GI, Huber P, et al. Hydrochlorothiazide pharmacokinetics and pharmacologic effect and influence of indomethacin. Journal of Clinical Pharmacology 22: 32–41, 1982
Wong DG, Spence JD, Lamki L, Freeman D, McDonald JWD. Effect of non-steroidal anti-inflammatory drugs on control of hypertension by β-blockers and diuretics. Lancet 1: 997–1000, 1986
Yeung Laiwah AC, Mactier RA. Antagonistic effects of non-steroidal anti-inflammatory drugs on frusemide-induced cardiac failure. British Medical Journal 283: 714, 1981
Zimmerman HJ, Lewis JH. Drug-induced cholestasis. Medical Toxicology 2: 112–160, 1987
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Fowler, P.D. Aspirin, Paracetamol and Non-Steroidal Anti-Inflammatory Drugs. Med Toxicol Adverse Drug Exp 2, 338–366 (1987). https://doi.org/10.1007/BF03259953
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DOI: https://doi.org/10.1007/BF03259953