Adverse reactions to nonsteroidal anti-inflammatory drugs diclofenac compared with other nonsteroidal anti-inflammatory drugs

Adverse Reactions to Nonsteroidal Anti-Inflammatory Drugs Diclofenac Compared with Other Nonsteroidal Anti-Inflammatory Drugs

WILLIAM M. O’BRIEN, M.D. Charlottesville,

The most common adverse effects of nonsteroidal anti-inflammatory drugs are gastritis, peptic ulceration, and depression of renal function, all of which result primarily from prostaglandfn inhibition. The types of side effects observed with diclofenac are similar to those of other nonsteroidal anti-inflammatory drugs and are unavoidable given that the drugs are prostaglandin inhibitors. However, the incidences of such side effects may be lower with diclofenac than with some of the other nonsteroidal anti-inflammatory drugs. Worldwide experience with diclofenac exceeds 7.6 million patientyears, which should provide estimates of the frequency of very rare adverse reactions. The latter include blood dyscrasias, erythema multiforme, hepatitis, and others, such as aseptic meningitis, anaphylaxis, and urticaria. Moreover, some nonsteroidal anti-inflammatory drugs appear to have unique side-effect profiles. Examples include a higher incidence of ulceration and erythema multlforme with piroxicam, and acute pancreatitis, in rare instances, with sulindac. From a careful survey of the world’s accumulated literature and reports to CIBA-GEIGY, diclofenac does not appear to have any unusual adverse reactions.

Virginia

From the Division of Rheumatology, Department of Internal Medicine, University of Virginia Hospital, Charlottesville, Virginia. Requests for reprints should be addressed to Dr. William M. O’Brien, University of Virginia School of Medicine, Box 213, Charlottesville, Virginia 22908.

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This article surveys rare adverse reactions caused by nonsteroidal antiinflammatory drugs, thereby emphasizing those which might suggest that a new drug is unsafe. All of the reported reactions to nonsteroidal antiinflammatory drugs are summarized, but a more detailed review with 491 references is published elsewhere [l]. In addition, the safety profile of diclofenac sodium is compared with the profiles accumulated during the past 20 years of other nonsteroidal anti-inflammatory drugs. Indeed, following the withdrawal of both benoxaprofen and zomepirac, along with the recent disquieting reports of serious skin reactions [2] and gastrointestinal bleeding [3-51 with piroxicam, this review is timely. Furthermore, several nonsteroidal anti-inflammatory drugs do cause minor but common side effects, such as diarrhea with meclofenamate and headache with indomethacin. Rare side effects that occur primarily with certain of these agents include granulomatous fiepatitis and acute pancreatitis with sulindac, hemolytic anemia with meclofenamate, and acute meningitis and febrile reactions with ibuprofen. Do these or other peculiar reactions also occur with diclofenac? The safety of diclofenac has been supported by extensive trials in the United States as well as widespread use of the drug throughout the world. In preparing this review, data of the worldwide experience submitted by CIBA-GEIGY to the United States Food and Drug Administration were utilized. This article summarizes the use of diclofenac in clinical trials with

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more than 40,000 subjects and in clinical reports of more than 85,000 patients. There have been 63 deaths in patients taking diclofenac in 7.6 million patient-years, which is probably less than would be expected by chance. Is there anything unusual, however, in the pattern of those deaths? From a review of all published case reports, three general types of adverse reactions appear to occur. First, the elderly are particularly susceptible to toxicity from nonsteroidal anti-inflammatory drugs with long half-lives. In fact, age has always been the major risk factor identified in studies of adverse reactions. Diclofenac should be relatively safe in this respect, however, since it has a short plasma half-life of about two hours in humans. The second type of reaction is due to direct effects on prostaglandin synthesis. Prostaglandins stimulate the production of mucus, which protects the stomach [6,7]. Therefore, any drug that inhibits mucus production is likely to be ulcerogenic, at least to some degree. Diclofenac should produce no more or fewer gastric problems than do other nonsteroidal anti-inflammatory drugs. When moderate renal failure is present, prostaglandin secretion produces renal vasodilation. Consequently, prostaglandin inhibitors may precipitate renal failure in a patient. Diclofenac probably does this, but, because of its short half-life, the effect might be less enduring than that induced by nonsteroidal anti-inflammatory drugs that are more slowly metabolized and excreted. The third mechanism is purely idiosyncratic. This is a rare but sometimes fatal reaction that would be difficult to detect in clinical trials involving only one or two thousand subjects. The most feared of these reactions are hepatocellular necrosis, aplastic anemia, and anaphylaxis. Because of the extensive use of diclofenac overseasinstead of the usual one thousand subjects included in United States trials-we can survey the drug from a vast clinical experience. Thus, the chance of detecting these rare reactions is better with diclofenac than with previous nonsteroidal anti-inflammatory drugs submitted for approval in the United States. COMMON SIDE EFFECTS Gastrointestinal Effects. The gastrointestinal side effects of nonsteroidal anti-inflammatory drugs are well known. They include two major problems: diffuse gastritis and discrete ulcers, both gastric and duodenal. Diffuse gastritis, which occurs with several of the nonsteroidal anti-inflammatory drugs introduced in the last 20 years, is not a major problem with any of them. It is, however, a major problem with aspirin. In fact, the study by Silvoso and associates [8] demonstrates the magnitude of this problem. In patients receiving long-term aspirin therapy, gastric ulcers developed in 17 percent, gastric erosions in 40 percent, and gastric erythema in 76 percent. Ulcers developed even with the administration of buffered and enteric-coated preparations of aspirin. The real quesApril

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tion, then, is whether aspirin is well tolerated as a longterm agent. The answer is clearly no. The second major gastrointestinal side effect of nonsteroidal anti-inflammatory drugs is discrete ulceration. Even in the absence of medication, it would appear that the incidence of peptic ulceration is higher (perhaps by a factor of three or four) in patients with rheumatoid arthritis than in other patient populations [9]. Rheumatoid arthritis seems to be a disease in which there is already a propensity for the development of ulcers. In early studies of indomethatin in patients with rheumatoid arthritis, gastric ulceration occurred, particularly at higher doses. This dose-related side effect occurs with all of the other nonsteroidal antiinflammatory drugs but is relatively rare in actual clinical practice. To view the problem in perspective: when prednisone is given at dosages of 20 mg per day for two years, the incidence of gastric ulceration in patients with rheumatoid arthritis is about 25 percent [l O-l 21; when indomethacin is given at dosages of more than 150 mg per day for two years, the rate of ulceration is less than 2 percent [I 31. However, since the spontaneous rate of ulcer formation in the general population is about 1 percent yearly, the rate observed with indomethacin is no greater than that which occurs spontaneously. On the other hand, spontaneous ulcers are primarily duodenal, whereas approximately two thirds of those induced by indomethacin or other nonsteroidal anti-inflammatory drugs are gastric [13]. Gastrointestinal side effects of nonsteroidal anti-inflammatory drugs may have a greater impact in the elderly. Of 531 admissions to a geriatric unit, 33 were due to gastrointestinal bleeding, 17 of which were related to the use of nonsteroidal anti-inflammatory drugs [14]. Assays in animals receiving diclofenac indicate that the drug is relatively nonulcerogenic, while trials with diclofenac in normal volunteers show that it causes little blood loss, as measured by 5gchromium-tagging of red blood cells. This suggests that the drug does not cause acute, diffuse gastritis. Nevertheless, as with all nonsteroidal anti-inflammatory drugs, long-term use of diclofenac does induce ulcers in humans, although the incidence appears to be slightly lower than with other agents. Compared with indomethatin, diclofenac produces slightly fewer gastrointestinal side effects and, because of its short half-life, causes fewer problems in the elderly. Renal Effects. All nonsteroidal anti-inflammatory drugs, but especially fenoprofen, can cause acute interstitial nephritis. Reports of nephritis from nonsteroidal antiinflammatory drugs are few, so the reaction is obviously a rare one. Interstitial nephritis induced by nonsteroidal antiinflammatory drugs is idiosyncratic and thus occurs suddenly. It is frequently characterized by eosinophils in the renal parenchyma and is usually reversible when the drug responsible for the reaction is promptly discontinued. Eosinophiluria is an important diagnostic clue to the presence of interstitial nephritis. The setting is quite different, however, in patients with The American

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compromised renal function. Prostaglandins may now be produced at an unusually high rate in order to achieve renal vasodilation and thus increase renal blood flow so as to prevent renal failure. When these patients take nonsteroidal anti-inflammatory drugs, inhibition of the prostaglandins-which provide the only mechanism available to perfuse the kidneys-may precipitate sudden renal failure. Because this reaction is caused by the inhibition of renal prostaglandin production, it is a physiologic effect rather than an adverse one. With a decrease in renalfunction, hyperkalemia may also occur. Finally, inhibition of renal prostaglandins may cause a rare hyporeninemic hypoaldosteronism. Four major reviews of the effects of nonsteroidal anti-inflammatory drugs on renal function have appeared recently [15-l 81. An encouraging development was the report by Bunning and Barth [19] of three patients in whom azotemia developed after treatment with naproxen or ibuprofen but not after brief exposure to sulindac. In Rome, Ciabattoni et al [20] reported that sulindac had less effect than ibuprofen on renal blood flow and prostaglandins during oneweek trials with each drug. In a subsequent report, Mitnick [21] questioned Bunning and Barth’s conclusions, whereas Whelton and associates [22] reported a case of severe renal failure due to sulindac. Finally, a Danish group has failed to confirm that sulindac differed from naproxen in its effects on prostaglandins or renin during a two-week trial in patients with thiazide-treated heart failure [23]. Thus, it seems unlikely that renal effects are less with sulindac than with other nonsteroidal anti-inflammatory drugs. Enterohepatic Recirculation and Diarrhea. The enterohepatic recirculation of certain nonsteroidal anti-inflammatory drugs, particularly indomethacin, sulindac, and mefenamic acid, may also have adverse consequences. lndomethacin has produced diarrhea in about 5 percent of patients [24-261 and may also cause ileal [27] and jejunal ulceration [28,29]. The worst problems with mefenamic acid are severe diarrhea and even steatorrhea [30,31]. These can occur in up,to 30 percent of patients, but they promptly subside with discontinuation of mefenamic acid. Headaches. Many indoles, including serotonin, have central nervous system activity. Perhaps it is not surprising that high doses of indomethacin, which is chemically similar to serotonin, can induce severe, even disabling, headaches [13,32]. Such headaches are not usually observed with other nonsteroidal anti-inflammatory drugs, although occasionally all of them may cause drowsiness or dizziness. RARE ADVERSE REACTIONS Dermatologic Reactions. Etythema multiforme and its variants: Most dermal side effects caused by nonsteroidal anti-inflammatory drugs are fairly mild, but an extremely serious one, erythema multiforme, has been reported on a number of occasions. The outcome of this 72

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reaction can be fatal. A particularly severe variant of erythema multiforme, the Stevens-Johnson syndrome, also includes stomatitis and conjunctivitis. The fatality rate in this syndrome ranges from 6 to 25 percent [33]. Almost all nonsteroidal anti-inflammatory drugs have been reported to cause erythema multiforme [2,34,35]. The two once-a-day nonsteroidal anti-inflammatory drugs, piroxicam and benoxaprofen, introduced in 1982, carry a higher risk of serious dermal reactions. In its brief time on the market, benoxaprofen was implicated in at least 11 cases of erythema multiforme. In addition, a recent report from the spontaneous adverse reaction repotting system of the American Academy of Dermatology [2] noted that of 33 cases of nonphotosensitive vesiculobullous reactions reported with various nonsteroidal antiinflammatory drugs, 29 were associated with piroxicam. Overall, that report estimated that serious dermal reactions occur more frequently with benoxaprofen and piroxicam than with any other nonsteroidal anti-inflammatory drugs recently or currently marketed in the United States. Photosensitivity reactions: A significant number of nonsteroidal anti-inflammatory drugs, especially some of the phenylpropionic acids, cause a variety of photosensitivity reactions. Laboratory studies [36,37] indicate that minor phototoxic reactions, including immediate erythema and, in most cases, urticarial wheals, may occur on the sun-exposed areas of patients taking piroxicam, naproxen, and tiaprofenic acid. A similar reaction, manifest as a bullous erythematopapular eruption on sun-exposed areas of the skin, has been noted in eight Swiss patients taking carprofen [38], two of whom required hospitalization and treatment with systemic steroids. Again, as in the case of more serious dermatologic reactions, the once-aday nonsteroidal anti-inflammatory drugs may cause a disproportionate number of photosensitivity reactions. Benoxaprofen caused an unusual phototoxicity that may have occurred in all patients receiving the drug [39], as well as a bullous dermatitis on sun-exposed areas of the skin [40]. There have been more than 65 reported cases of similar reactions to piroxicam [2,41]-“photosensitivity eruptions” [41]-which in most cases involved vesicles or bullae. Such reactions have been rare with diclofenac. Miscellaneous dermatologic reactions: The most common cutaneous reaction to aspirin is urticaria, which may be seen in aspirin-sensitive patients or which may be exacerbated (apparently on a dose-related nonallergenic basis) in about 25 percent of patients with chronic urticaria [42-441. Unlike asthmatic episodes that occur in aspirinsensitive patients, this reaction does not appear to be due to prostaglandin inhibition [44]. Other nonsteroidal anti-inflammatory drugs may also cause urticaria, especially in patients who are sensitive to aspirin. Benign morbilliform eruptions (not erythema multiforme) may occur at high doses with most, if not all, of the phenylalkanoic acids. Musculoskeletal Reactions. Aseptic necrosis: Sev66 (suppl

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nonsteroidal anti-inflammatory drugs, although it has not been described with diclofenac. Anaphylaxis. Anaphylaxis has been reported with all nonsteroidal anti-inflammatory drugs. The largest number of published cases involved zomepirac, which was withdrawn from the market by the manufacturer in 1983, after two reactions proved fatal. The true nature of this “anaphylactoid” reaction is not known. It differs in one crucial respect from true anaphylaxis: it is distinctly less severe and, as far as is known, has proved fatal only in two zomepirac-treated patients, which subsequently led to that drug’s withdrawal from the market. In patients in whom anaphylaxis has occurred, several have had low serum complement levels and extractable nuclear antigens. Since the syndrome resembles hereditary angioneurotic edema, it is possible that these drugs induce similar symptoms in persons who are inherently susceptible. A single unpublished case of anaphylaxis has occurred with diclofenac, but the patient was taking several Dther drugs at the time of the reaction. Febrile Reactions. Six patients treated with ibuprofen, five for lupus erythematosus [64,65] or mixed connective tissue disease [60] and the other for dental pain [66], have experienced a generalized reaction characterized by fever, abdominal pain, nausea, vomiting, and elevated levels of hepatic enzymes. In two cases, biopsy revealed fatty tissue changes in the liver. Some patients had additional symptoms, including headache, rash, or joint and muscle pain. With a single exception (a patient with bilateral pleural effusion and serious hepatic changes who died from shock and respiratory failure [SO]), all patients recovered after treatment with steroids, including one patient [66] who also required intensive care for hypoxemic respiratory failure. This reaction may be unique to ibuprofen. Drug-Induced Lupus-Like Syndrome. Both phenylbutazone [67] and ibuprofen [68] have been reported to induce a lupus-like syndrome. This is evidently a hypersensitivity reaction that produces fever, a diffuse erythematous rash, generalized myalgia, and arthralgia. The results of the immunofluorescent test for antinuclear antibodies were positive in both cases, and the direct Coombs’ test results were positive in one [68]. One case [671 also had renal complications (proteinuria and hematuria). In a related phenomenon, oxyphenbutazone has been reported to cause the L.E. cell phenomenon and thrombocytopenia [69]. Vasculitis. The induction of cutaneous vasculitis is another peculiar allergic reaction that seems to be extremely rare. It has been observed in nine cases following the use of nonsteroidal anti-inflammatory drugs. Cutaneous vasculitis has been observed with almost every drug but only rarely with nonsteroidal anti-inflammatory drugs. It has yet to be described with diclofenac. Other Generalized Reactions. A single case of peripheral and mediastinal lymphadenopathy associated with

era1 investigators have reported that long-term indomethacin therapy might cause aseptic necrosis of the hip [45], but this association has not been substantiated. It is possible, if not likely, that the osteonecrosis had been present before drug treatment was started. To the extent that the condition did worsen during indomethacin therapy, it is possible that by relieving pain, the drug enabled patients to be more active so that the additional movement was responsible for the joint damage [46]. This would appear, therefore, to have been a “pseudo” adverse reaction. Pulmonary Reactions. Asthma in aspirin-sensitive patients: In 2 to 20 percent of adult patients with asthma [47], as well as in a smaller number of asthmatic children, an unusual syndrome develops that is marked by nasal polyps and a hypersensitivity to aspirin, which apparently involves a general lack of prostaglandins [48,49]. Even without exposure to aspirin, this syndrome may become progressively worse. If such asthmatic patients do take aspirin, however, they may experience rhinitis, wheezing, or bronchospasm [50], which can be fatal. In the last two decades, there has been mounting evidence that hypersensitivity reactions to aspirin are dependent not on immunologic mechanisms but on inhibition of prostaglandins. Consequently, laboratory tests [51-541 have shown that if affected persons (especially those who are also intolerant of iodides [55]) are exposed to any of the nonsteroidal agents, they may experience immediate bronchial constriction. Acute pulmonary edema: Cases of pulmonary edema from salicylate intoxication, usually in heavy smokers [56], have been described in the last 30 years. The reaction has not been observed with other nonsteroidal anti-inflammatory drugs. Diffuse pulmonary infiltrates: Several nonsteroidal anti-inflammatory drugs cause hypersensitivity pneumonitis. Signs and symptoms usually include fever, a nonproductive cough, wheezing, and rales. Chest radiography usually discloses diffuse bilateral infiltrates. Almost all patients with the reaction have eosinophilia in the blood and/ or sputum. In three cases in which lung biopsy was performed, there was thickening of the alveolar walls and an inflammatory infiltrate, either of monocytes and polycytes [571, of lymphocytes, histiocytes, and eosinophils [58], or of epithelioid granulomas [59]. Of 11 patients with this reaction, the only death [60] appeared to result primarily from hepatic involvement. All other patients recovered either after simple withdrawal of nonsteroidal anti-inflammatory drug therapy or after treatment with corticosteroids. Hypersensitivity pneumonitis has not yet been reported with diclofenac. Possible reactivation of latent tuberculosis: At least one case [61] has been described in which latent pulmonary tuberculosis may have been reactivated in a patient treated with ibuprofen plus indomethacin suppositories. Subsequent reports from that same clinic [62,63] suggested that the problem may also occur with other April

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sulindac has been described [70]. Erythema multiforme also developed in this patient. The lymphadenopathy reversed when sulindac was withdrawn but recurred on rechallenge with the drug. It has been suggested that at least one nonsteroidal anti-inflammatory drug, indomethatin, might decrease the ability of a patient to respond to infection [71]. Severe hemorrhagic chicken pox developed in one child treated with indomethacin for juvenile rheumatoid arthritis, despite the fact that she received no steroids [72]. However, that indomethacin increases susceptibility to infection is unconvincing from animal studies. Occasionally reported cases, such as the one with hemorrhagic variceila from indomethacin, may well be coincidental to nonsteroidal anti-inflammatory drug therapy. Cardiovascular Reactions. Nonsteroidal anti-inflammatory drugs probably have little direct effect on those prostagfandins that are involved in the functioning of the heart or coronary circulation. In animals, aspirin, indomethacin, and ibuprofen, given intravenously in doses resulting in blood levels 300 times those achieved with the usual oral doses, have been shown to render the myocardium more sensitive to ouabain [73]. Likewise, in humans with arteriosclerosis, indomethacin, given intravenously in doses resulting in blood levels 56 times those achieved with usual oral doses, resulted in weak catheter evidence of vasoconstriction, but in no clinical evidence of angina or ST-segment changes [74]. On the other hand, there is preliminary evidence that indomethacin may aggravate myocardial ischemia [75], and thus perhaps angina1 pain, in some patients. For most patients, however, it seems unlikely that the usual oral doses of indomethacin or other nonsteroidal anti-inflammatory drugs produce such side effects. The most significant cardiovascular effects of the nonsteroidal anti-inflammatory drugs are not likely to result directly from inhibition of prostaglandins in the heart itself, but evolve indirectly, from the inhibition of circulating prostaglandins. Researchers at Harvard University have recently shown that in patients with severe congestive heart failure, especially those with hyponatremia, indomethacin decreases cardiac output, presumably by reducing the levels of circulating prostaglandins [76]. In such patients, any nonsteroidal anti-inflammatory drug might exacerbate congestive heart failure. Hematologic ReaMions. The majority of serious adverse reactions to nonsteroidal anti-inflammatory drugs are idiosyncratic, especially blood dyscrasias. Fortunately, these reactions are extremely rare, considering the widespread and long-term use of these drugs. Aplastic anemia: The most feared blood dyscrasia is aplastic anemia. The mortality rate in drug-induced cases is approximately 67 percent [77]. Although it is often difficult to be certain of a direct causal link between a particular drug and aplastic anemia (especially in patients who are taking several drugs, each of which may depress the

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marrow), there is good evidence for individual cases of aplastic anemia with all nonsteroidal anti-inflammatory drugs. There were 13 case reports describing 21 patients, including 14 deaths: two case reports (both fatalities) involved diclofenac [78,79]. In registries of drug reactions, however, neither aspirin nor any of the newer nonsteroidal anti-inflammatory drugs appear as leading causes of aplastic anemia. These data support my contention that these are extremely rare reactions with nonsteroidal antiinflammatory drugs. Pure red cell aplasia: An extremely rare pure red cell aplasia has been described on five occasions with nonsteroidal anti-inflammatory drugs, but has never been reported with diclofenac. Inhibition of platelet function: Of the nonsteroidal anti-inflammatory drugs, aspirin has the most striking and long-lasting effects in inhibiting platelet aggregation. In some patients, aspirin also prolongs bleeding time. Although the newer nonsteroidal anti-inflammatory drugs inhibit platelet aggregation for only a few hours (during which time they remain in the bloodstream), the effects of aspirin may last 12 to 15 days. Moreover, because aspirin affects the hepatic synthesis of vitamin K, its effects on bleeding time are considerably more complex than those of other nonsteroidal anti-inflammatory drugs. Not surprisingly, then, virtually any of the newer agents, especially those with short half-lives, appear to be safer than aspirin for patients with hemophilia. Nevertheless, they should be administered to these patients only with careful monitoring [80]. As a result of their effects on platelet function, virtually all nonsteroidal anti-inflammatory drugs may cause, rarely, serious bleeding. Thrombocytopenia: Rare cases of thrombocytopenia, some severe, have been described with many nonsteroidal anti-inflammatory drugs. Thirty-five cases with indomethacin, which included five deaths [81], as well as isolated cases with other agents, have been reported. Neutropenia: Isolated cases of neutropenia or agranulocytosis, which are rarely fatal, have also been obsewed with several nonsteroidal anti-inflammatory drugs. Indeed, recent evidence suggests that neutropenia induced by nonsteroidal anti-inflammatory drugs is rare. A Swedish survey (821 disclosed only 0.07 cases per million tablets of indomethacin sold, a rate approximately SO that found with d-penicillamine. Neutropenia seems to be notably more rare with newer nonsteroidal anti-inflammatory drugs, although it has been noted in about a dozen cases. Hemolytic anemia: At least seven cases of autoimmune hemolytic anemia have been reported with mefenamic acid, three with ibuprofen, three with naproxen [83851, and two with diclofenac [78]. To my knowledge, the reaction has not been observed with other nonsteroidal anti-inflammatory drugs. Although it appears to be rare [86], the reaction can be severe. Rare Gastrointestinal Reactions. Stomatitis and

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consumption of nonSteroidal anti-inflammatory drugs among patients as among matched cohtrol subjects; 64 patients had taken these drugs, suggesting that the problem might be more common than previously believed [106]. Hepatic Reactions. Transaminitis; Of idiosyncratic reactions involving the liver, the problem of transamihitis has been well described. In patients receiving aspirin therapy, elevations in serum transaminase frequently develop [107,108], and the same phenomenon may occur with other nonSteroidal anti-inflamm&ory drugs. The misnomer “transaminitis” indicates a mild form of hepatitis. Biopsy reveals anatomic lesions in the liver, often minor, but with infiltrates of monocytes [109,1 lo]. Electron microscopy has also shown uitrastructural changes In the hepatocytes [ill]. Clinically, transaminitis is a nuisance in most cases, perhaps because it necessitates wlthdrawal of nonsteroidal anti-inflammatory drug therapy rather than because it is a serious adverse effect. Hepatitis: Aspirin is unique among the honsteroidal anti-inflammaJory drugs in its effects on the liver, particularly in its alteration of hepatic synthesis of vitamin K, which, in turn, may prolong the prothrombin time. A significant number 9f cases of salicylate-induced hepatitis have been reporied (at IeaSt 11 since 1977). Two patients receiving diclofenac died from hepatitis, although both events were only possibly related to use of the drug., Only one case has ever been published implicating diclofenac [112], and, considering th8 widespread use of the drug, this may be no more than the background “noise” of unrelated non-A, non-B hepatitis. In considering hepatitis caused by most nonsteroidal anti-inflammatory drugs, several chatacieristics stand but. First, the reaction appears to be extremely rare: only 35 case reports have been documented, and only a handful involve even such widely used agents as indomethacin tind ibuprofen. Second, hepatitis induced by most nonsteroidal anti-inflammatory drugs seems clearly to be a,hypersensitivity reaction. This is suggested by the fact that mariy cases occur within two to 12 weeks after the initiation of drug therapy. It is also supported by the finding that at least one third of the affected patients also had other organ involvement, including dermal [97,113-l 161, pulmonary [60,114], hematologic [85,115,117,118], and renal [85]. About one half of the patients had fever. Finally, the mortality rate among patients with hepatitis induced by nonsteroidal anti-inflammatory drugs has been comparatively moderate: six deaths in 35 cases (17.1 percent). The low mortality rate differs drastically from other instances of drug-induced hepatitis, again suggesting that these cases may be examples of incidental viral infections rather than true drug reactions. Finally, it seems likely that the hepatitis that occurred with benoxaprofen was not an idiosyncratic allergic reaction but a direct toxic effect from drug accumulation. Sev-

sialadenitis: Stomatitis may occur with any nonsteroidal anti-inflammatory drug. If oral ulcers persist, then therapy should be switched to another nonsteroidal anti-inflammatory drug. A number of patients have also experienced an acute, mumps-like swelling of the salivary (usually parotid) glands. Phenylbutazone [87,88] and oxyphenbutazone [89] also cause enlargement of the thyroid gland, which is occasionally striking, and hypothyroidism. Although diclofenac and fenclofenac are two other honsteroidal antiinflammatory drugs that are strut&rally similar to tetraiodothyronine, they appear to liave no effect on thyroid function [go]. Esophageal injury: Two recent studies [91,92] suggest that nonsteroidal anti-inflammatory drugs may cause benign esophageal stricture, especially in patients with gastroesophageal reflux, perhaps by inhibiting the production of mucosal prostaglandins. In on8 survey [92], 49 percent of patients hospitalized for benign esophageal stricture had received nonsteroidal anti-inflammatory drugs in the preceding year, versus only 12 percent of control subjects. In another study [91], 22 of 70 patients hospitalized for benign esophageal stricture had “regularly consumed” nonsteroidal anti-inflammatory drugs, versus only 10 of 70 matched control Subjects (p ~0.02). In the latter study, eight different agents were recorded as having been taken regularly. The three most frequently named-aspirin, indomethacin, and ibuprofen-are also the three most widely prescribed. There have also been three case reports of frank esophageal ulceration associated with indomethacin therapy [93-951. All three patients had received low dosages of indomethacin (mean: 83.3 mg per day) for a short period of time (mean:‘25 weeks). One patient, nonetheless, bled to death [93]. This problem is more apt to occur in elderly bedridden patients, in whom there is more prolonged contact of the drug with the esophageal mucosa. Pancreatitis has been repotted with slilindac in several instances [96-1001 and with indomethaein at least once [loll. This may result from intensive enterohepatic recirculation, which causes the pancreas to be continuously exposed to the drug. Although episodes of pancreatitis may be quite severe, they can be relieved by discontlnuing drug therapy. Lower gastrointestinal tract complications:, Any nonsteroidal anti-inflammatory drug may reactivate lower bowel disease in patients with a history of such disease. Ibuprofen has caused flares in quiescent ulcerative colitis in at least three cases [102-l 041; indomethacin has led to acute perforations of sigmoid divetticula in two patients with no recent history of gastrointestinal symptoms [105]; and in two patients with diverticulitis, naproxen has caused bleeding in one and perforation in the other [103]. One recent survey that compared 268 patients with coIonic or small bowel perforations found twice as much

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era1 facts point to this conclusion: (1) the greater frequency of hepatitis with benoxaprofen (at least 14 published cases in less than two years of marketing); (2) the reaction usually did not occur early in drug therapy but after several months of treatment; and (3) the reaction affected a high proportion of elderly patients (mean age of the 14 patients in the published cases was 75.9 years). Benoxaprofen had an unusually long half-life-more than 100 hours in older people. In elderly patients, especially those given the full therapeutic dosage, the drug almost surely accumulated, leading to direct cytotoxic effects on the liver and renal tubules (of what was in effect a drug overdose). Histologic evidence of extensive bile plugging of the cholangioles and subsequent hepatocellular necrosis suggests that the insoluble glucurdnide of benoxaprofen directly injured the liver. The mortality rate in the 14 published cases was 78:6 percent, so the drug was understandably withdrawn from the market. Miscellaneous Genitourinary Reactions. At high doses, some of the nonsteroidal anti-inflammatory drugs can produce a cfiemical cystitis. This has occurred, for instance, with zomepirac, but it can easily be prevented by forcing fluids. Central Nervous System tieactions. Aseptic meningitis: Sonic persons may be inherently susceptible to tfie side effects of nonsteroidal anti-inflammatory drugs. There have been 14 case reports of aseptic meningitis induced by nonsteroidal anti-inflammatory drugs; the majority of cases involved ibuprofen. The reaction, Which has been reproduced by challenges with a single tablet of ibuprofen, is manifest primarily by headache, fever, chills, mental confusion, nuchal rigidity, and, occasionally, generalized arthralgia, conjunctivitis, and lymphadenopathy. Typically, samples of cerebrospinal fluid show elevated leukocyte counts (almost entirely neutrophils in some cases) and protein levels, but there is no evidence of infection. In all published cases to date, the meningitis was reversed with discontinuation of nonsteroidal anti-inflammatory drug therapy, despite the fact that in one case [119] there was also evidence of acute pancreatitis, pneu: monitis, and parotitis, and evidence of acute renal failure with tubular,necrosis in another case [120]. Ocular Reactions. Ocular reactions to nonsteroidal antiinflammatory drugs have likewise been both rare and generally reversible. Most accounts of these reactions involve indomethacin and ibuprofen, perhaps not surprisingly, since these are two of the most widely used nonsteroidal anti-inflammatory drugs. Surveys involving a total of nearly 906 patients have found no ocular side effects, a fact that suggests that they must be quite rare. Moreover, patients treated with ibuprofen do not show macular degeneration as is observed in patients treated with antimalarials. Miscellaneous Reactions. It has long been known that hearing impairment and even permanent deafness may

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be caused by long-term use of aspirin or other salicylates [121,122]. Rare cases of transient loss of hearing have been noted with indomethacin [123,124], phenylbutazone, and ibuprofen [125]. In the area of psychologic effects, clinicians should be alerted to the fact that nonsteroidal anti-inflammatory drugs may have subtle effects on mentation. Especially at high doses, the drugs can depress mental function in older patients [126]. lndomethacin may cause severe, even suicidal, depression in some patients [123]. There have also been several reports of acute psychosis following the administration of Indomethacin. Finally, two cliriicians have noted cognitive dysfunction (forgetfulness, inability to concentrate, or depression; or a combination of these) in eight elderly patients, four taking naproxen and four taking ibuprofen [127]. Overdo&a. Accidental overdose with nonsteroidal antiinflammatory drugs has been reported very rarely, perhaps because of the presence of a kind of built-in safety mechanism. Moreover, the drugs are gastric irritants, so that large doses might be expected to induce vomiting. Even if large amounts of these drugs were kept down, one would expect adverse reactions to be rel,atively mild; most of the drugs have relatively simple excretion mechanisms and are likely to be quickly cleared by the kidney. For most drugs, it appears that, once the albumin binding sites are saturated, the free drug is rapidly excreted. Since diclofenac has a short half-life and nonfinear kinetics, a comparatively greater margin of safety can be expected. Drtig Interactions. Drug interactions involving nonsteroidal anti-inflammatory drugs appear to be relatively rare. The most likely interactions are probably those with diuretics and antihypettensives. In patients receiving beta blockers, such as propranolol, the concomitant use of indomethacin (perhaps of any prostaglandin inhibitor) may cause an increase in blood pressure [128]. In patients receiving thiazide diuretics, especially furosemide, indomethacin may blunt the diuretic effect of the thiazides [128], thus exacerbating congestive heart failure and hypertension. In some patients, the combined use of indomethacin and triamterene (a weak potassium-sparing diuretic) may lead to reversible acute rehal failure [129]. in addition, all of the nonsteroidal anti-inflammatory drugs, because of their effects on prostaglandins, can cause an acute decrease in renal blood flow and a sudden, even lethal, increase in potassium levels. Physicians should exercise caution in prescribing a nonsteroidal anti-inflammatory drug along with a beta blocker qr diuretic, and should keep patients taking these CQf’tIbinatiOnS under close supervision. Although the short half-life of.diclofenac makes it less likely to cause renal side effects, the best course is to proceed cautidusly with any elderly patient who has impaired renal function and is receiving antihypertensive drugs.’ Most of the nonsteroidal anti-inflammatory drugs are

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both the patient and the physician to tolerate the side effect. For example, if a nonsteroidal anti-inflammatory drug causes edema, the edema can be treated with a thiazide. If, however, the side effect is serious, the drug should be discontinued and another nonsteroidal anti-inflammatory drug tried. Gastric irritation, I believe, is the central clinical point concerning the most frequent adverse reaction of all nonsteroidal anti-inflammatory drugs. In practical terms, we are not seeking a drug that is totally free of this effect. If patients are carefully monitored once the drug is prescribed, symptoms of gastric distress are readily apparent so that the drug may be promptly discontinued. In uncontrolled trials of indomethacin in which patients were not systematically monitored, the incidence of ulcers was much higher than in controlled trials in which patients were seen frequently. Under controlled circumstances, ulcers developed in less than 0.5 percent of the patients [13]. Thus, the problem of ulceration can be minimized with careful supervision by physicians. Although gastrointestinal side effects sometimes occur, they are usually not serious. Epigastric distress is readily apparent, and physicians must listen to the patient. In turning to the rare, idiosyncratic side effects, these occur with such statistical infrequency that there is no reasonable way to avoid them. Some reactions, however, can be fatal-obviously a very serious medicolegal problem. The best and most practical recommendation is that the caring physician be knowledgeable about the potential reactions, alert to detect them should they occur, and quick to discontinue the drug responsible for the reaction. In conclusion, although I have tried to play the devil’s advocate, I have failed to find documentation of any unusual toxicity with diclofenac. It is less ulcerogenic than piroxicam but not strikingly different from other nonsteroidal anti-inflammatory drugs. It may be somewhat safer in patients with poor renal function who are taking diuretics, but it should still be used with caution in this complex therapeutic setting. Diclofenac appears to be a safe, effective, and well-tolerated nonsteroidal anti-inflammatory drug, particularly in the elderly, who inherently have the highest risk for adverse effects.

highly bound to albumin and might theoretically produce problems when given with anticoagulants or oral antidiabetics. It appears, however, that most nonsteroidal anti-inflammatory drugs are bound at different sites on albumin and are much less likely than other types of drugs to cause such interactions [130,131]. In particular, several studies have indicated that at least some of these drugsibuprofen [132], naproxen, and tolmetin [130], all with relatively short half-lives and presumably weaker albumin binding-can safely be given to patients receiving some anticoagulants. Nevertheless, physicians should exercise caution in prescribing a nonsteroidal anti-inflammatory drug for a patient who is also taking an anticoagulant, oral antidiabetic, or any drug that is highly bound to albumin. Lithium has been widely used to treat depression, and there is evidence that its effects may be accentuated by nonsteroidal anti-inflammatory drugs, perhaps especially with indomethacin [133,134] and diclofenac [135]. Patients given both lithium and other nonsteroidal antiinflammatory drugs (e.g., ibuprofen) have experienced symptoms of nausea and drowsiness [134]. Since lithium may also be used to treat the neutropenia of Felty’s syndrome, there could be potential interactions with nonsteroidal anti-inflammatory drugs also being administered to these patients. Probenecid decreases the excretion of indomethacin [136] and naproxen [137] and has been used therapeutically to increase blood levels of some nonsteroidal antiinflammatory drugs in hopes of preventing the severe morning stiffness of rheumatoid arthritis. Probenecid should be used with caution with any nonsteroidal antiinflammatory drug. COMMENTS

The major question of safety in treating rheumatic diseases is this: Are we trying to avoid the minor adverse reaction, such as gastritis, or the rare idiosyncrasy? We presumably do not want a drug that is totally without side effects if the price of such safety is a loss of therapeutic potency. If the drug is effective therapeutically and the side effect is easily detected, it may well be acceptable to

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