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A. Del Favero

10

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout found that erosive or ulcerative esophagitis was present in 20% of a consecutive series of 60 arthritic patients who were receiving chronic NSAID therapy; esophageal symptoms, including heartburn, regurgitation and/or dysphagia, were noted in 83% of those with esophagitis. Endoscopic findings, characterized by esophageal erosion (or, in 2 cases, ulceration) were similar in all patients. On the barium esophagogram, 9 patients displayed hiatal hernia; 2 of these had coexisting esophageal rings and another 2 strictures. Esophageal manometry performed in 8 patients revealed abnormal esophageal motility in only one. Ambulatory esophageal pH monitoring performed on 6 patients disclosed abnormal gastroesophageal reflux in all. The results of this study must, however, be interpreted with caution as it did not include a non-NSAID-treated control group of patients. Another 3 studies, 2 casecontrolled and 1 experimental, have reported similar findings. Heller et al (2c) obtained drug histories from 76 patients referred for dilatation of benign esophageal strictures. Six had consumed drugs known to cause esophageal ulceration (emepronium bromide or potassium preparations). Of the remaining 70 patients, 53 had a history of reflux symptoms and 22 had taken NSAID before the onset of dysphagia, as compared with l0 patients in the control group. Wilkins et al (3 c) assessed drug histories in patients with benign esophageal strictures seen in a dysphagia clinic and in a matched control group from the community: 49% of patients had received NSAID in the preceeding 12 months, compared with 12% of controls, a highly significant difference. In our own series of 79 young healthy volunteers enrolled in 3 double-blind randomiz-

GENERAL TOPICS NON-STEROIDAL ANTIINFLAMMATORY DRUGS (NSAID) (SED11, 170; SEDA-12, 79; SEDA-13, 71; SEDA14, 79) Esophageal damage by NSAID Esophageal injury is a rare adverse reaction to NSAID. The published evidence comprises only a few specific studies and a small number of single casereports. The clinical pattern of esophageal damage is characterized by inflammatory changes (erosive and/or ulcerative esophagitis), ulceration with or without bleeding and/or perforation and strictures. Patients with esophageal lesions usually have typical symptoms, distinguishing them from those with gastroduodenal injuries which may be asymptomatic. No relationship is generally found between esophageal and gastroduodenal lesions in NSAID-treated patients. The incidence of esophagitis in NSAID-treated patients has probably been underestimated, perhaps because esophageal symptoms (heartburn, regurgitation) can be misinterpreted due to the gastrotoxic effect of NSAID, or because the esophagus is not always carefully examined during upper gastrointestinal endoscopy screening. The few careful studies that have been carried out have found that the incidence of patients suffering from esophageal symptoms or esophagitis is relatively high. Semble et al (1CR)

9 1991 ElsevierSciencePublishersB.V. Side Effects of Drugs Annual 15 M.N.G. Dukesand J.K. Aronson,editors 92

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout ed endoscopic studies designed to c o m p a r e the gastrointestinal toxicity o f various piroxicam f o r m u l a t i o n s with that of placebo, we observed a similar percentage (16%) of esophageal lesions in subjects treated with N S A I D a n d one in those receiving placebo. Five subjects h a d slight to m o d e r a t e esophagitis, 2 ulcerative esophagitis a n d 2 a m e m b r a n o u s esophagitis. Since pret r e a t m e n t endoscopy findings were n o r m a l in all patients a n d n o n e had other predisposing conditions, the causal relationship between piroxicam a n d esophageal injury is certain (4c). While esophagitis has been occasionally reported with most N S A I D , only a few casereports have d o c u m e n t e d m o r e severe injuries. In some o f these there was esophageal ulceration with bleeding a n d / o r p e r f o r a t i o n [associated with i n d o m e t a c i n (5c), t o l m e t i n (6c), sulindac (lC), i b u p r o f e n a n d piroxicam (7c)] but in most o f these cases, an associated predisposing condition was suspected, n o t a b l y Barrett's esophagus, g a s t r o e s o p h a g e a l reflux or factors predisposing to a reduced esophageal clearance o f medication.

Barrett's esophagus is a condition characterized by the replacement of a portion of the normal stratified squamous esophageal epithelium by columnar glandular metaplastic epithelium, and in some patients with this condition NSAID have inevitably been used. Cooper et al (8c) found that 16/52 patients with Barrett's esophagus were taking NSAID and l 1 of them had esophageal ulceration. As ulceration and strictures are typical complications of Barrett's esophagus, patients who develop esophageal injury while receiving NSAID should undergo appropriate diagnostic studies to identify this predisposing condition. Gastroesophageal reflux can play an important role in the mechanism of NSAID-induced lesions, and there is some evidence that its prevalence is high in patients with esophageal damage attributable to NSAID therapy ( l C - 3 c, 9c). Since NSAID are weakly acidic molecules with pH values between 4 and 5, which are relatively lipid-soluble at low pH, in the presence ofgastroesopbageal reflux and pH < 4, t hey may enter the esophageal mucosal cells and cause tissue damage. NSAtD may therefore exacerbate the esophagitis found in patients with gastroesophageal reflux and may increase the risk of complications (i.e. hemorrhage, ulceration, esophageal strictures). There is no evidence that NSAID either affect lower esophageal sphincter pressure or function or disrupt the physiological components of the mucosal barrier of the esophagus, such as mucus, bicarbonate and prostaglandins.

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One important pathogenic factor in any drugrelated injury is theefficiencyofesophagealclearance of injested medications. Esophageal clearance may be reduced during recumbency, when the water bolus usually given with the drug is too small or there is an abnormality in esophageal motility due to functional dysmotility or organic obstruction. However, although esophageal dysmotility has been reported in patients with rheumatoid arthritis (10c), esophageal monitoring detected abnormalities in only a minorily of patients with esophagitis on NSAID therapy (l c). The role of coexisting esophageal anatomic abnormalities, such as hiatal hernia or esophageal ring, in determining NSAID-associated esophageal injury is not known. In conclusion, the a b o v e d a t a suggest that the frequency of erosive/ulcerative esophagitis in patients taking N S A I D is n o t so rare as previously t h o u g h t . N S A I D can cause direct esophageal d a m a g e or can exacerbate esophageal injury in patients with g a s t r o e s o p h a g e a l reflux, a n d increase the risk of complications of esophagitis, such as stricture or bleeding. However, more epidemiological a n d experimental prospective studies are needed to define better the role o f N S A I D in inducing esophageal injury. Once a patient who takes N S A I D has been diagnosed as having esophageal damage, the drug should be discontinued a n d the s y m p t o m s treated, even if the suitability of ' s t a n d a r d ' t h e r a p y to heal (or prevent) the N S A I D p r o v o k e d esophagitis has not been formally assessed in clinical trials. In the meantime, it would seem wise to suggest t h a t patients taking N S A I D swallow their pills with large a m o u n t s o f water, in the upright position at least 1 h o u r b e f o r e retiring.

Small and large bowel damage by NSAID N S A I D have long been k n o w n to d a m a g e the intestine. The evidence comes mainly f r o m the results o f a case-control study (1 lC), experience with i n d o m e t a c i n in i n f a n t s with patent ductus arteriosus (12c), as well as experience with Osm o s i n (13c). These two topics have been reviewed previously (SEDA-8, 102; SEDA-10, 76, 80) and a brief s u m m a r y o f their conclusions will be given here. L a n g m a n et al (11 c) studied 268 patients admitted to N o t t i n g h a m hospitals over 5 years for small- or large-bowel p e r f o r a t i o n or bleeding a n d c o m p a r e d the drug histories of these patients with those of a sex- a n d age-matched

94 group of patients affected by uncomplicated bowel diseases. They found that patients with intestinal complications were twice as likely to have taken NSAID as controls. According to this study, the expected incidence of lower bowel perforations and bleedings would be 10 and 7 per 100 000, respectively. Further data on NSAID-related gut damage come from studies on the efficacy of indometacin to induce closure of a patent ductus arteriosus in infants. When given orally, the drug caused serious intestinal complications, such as necrotizing enterocolitis and isolated intestinal perforations in these patients (SEDA10, 80; 12c). As the oral route of administration was accompanied by a substantially greater risk for these complications, a local toxic effect of indometacin has been advocated for the intestinal damage. Convincing evidence supporting this hypothesis comes from the Osmosin experience (13c). This slow-release formulation of indometacin was found to cause fatal gastrointestinal complications including intestinal perforations distal to the duodenum. On the basis of the above summarized published evidence, and despite the fact that the majority of NSAID have occasionally been blamed for provoking ulceration a n d / o r perforation of the intestine (14R), severe intestinal damage seems to be a very rare complication of NSAI D therapy. This also appears to agree with the experience of some drug reaction monitoring centers, such as the U.K. Committee on Safety of Medicines (CSM), which has recorded only 42 cases of intestinal perforations attributed to NSAID, including aspirin, during the last 25 years (13c). However, whether this reflects a genuinely low incidence or is due to a lack of recognition of the cases in question is unknown. Moreover, no data are available to indicate that the incidence of uncomplicated intestinal mucosal lesions is equally rare. On the contrary, it has recently been suggested that NSAID are responsible for small intestine enteropathy, particularly when given long-term, and reports on bowel damage related to NSAID use continue to be published (15 R - 17R). The clinical presentations of NSAID-associated lower gastrointestinal tract toxicity are illustrated in Table 1 and the topic deserves further attention. Small intestine enteropathy Evidence for the capacity of NSAID to induce small intestinal in-

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Table 1. NSA1D-associated lower gastrointestinal tract toxicity Small bowel*

Enteropathy Asymptomatic

Symptomatic Ulcerations Strictures

Experimental evidence of: inflammation blood and protein loss ileal dysfunction Diarrhea, loss of weight, abdominal symptoms With or without complications: bleeding, perforation, stricture Diaphragm-like, with intestinal obstruction

Large bowel*

Colitis

Ulcerations

De novo or exacerbation of

inflammatory bowel disease with: diarrhea, weight loss, abdominal symptoms With or without complications: bleeding, perforation, stricture

* Toxicity may affect both small and large bowel at the same time. flammation and malfunction derives from a number of experimental studies carried out on healthy volunteers and arthritic patients. Using 51Cr-EDTA and tllln_labelled leukocyte techniques, Bjar~aason et al (18 c, 19c, 20 cR) have shown that NSAID can increase intestinal permeability and cause intestinal inflammation. The altered permeability seems to occur throughout the intestine, but the exact pathogenic mechanism is unknown. The fact that when misoprostol (21 c) was given before NSAID it provided a degree of protection suggests that inhibition of mucosal prostaglandin production is important. The increased permeability of the small intestine brought about by NSAID administration would favor the development of inflammation by exposing the intestinal mucosa to luminal substances or, as has been shown in experimental animals, to bacterial invasion. A large proportion of patients on long-term NSAID treatment (exceeding 6 months) have indeed been shown to have indirect evidence of inflammation which, once developed, takes months to resolve despite the interruption of NSAID therapy (22R). However, the evidence for and the clinical relevance of NSAID-related intestinal inflammation in

A nti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout

arthritic patients has been questioned (23 c, 24c). Inflammation might represent a primary abnormality in these patients (25) and the importance of NSAID-related inflammatory damage of the small intestine should be measured in terms of associated clinical complications. It is worth noting that, despite the experimental evidence of intestinal inflammation, the majority of patients are asymptomatic. Only a few individuals on long-term treatment present with loss of appetite and weight, iron deficiency anemia or a diarrheal disorder mimicking the clinical features of Crohn's disease. Even the experimental evidence that intestinal inflammation may be associated with blood and protein loss and ileal dysfunction relies on radioisotopic studies carried out on a very small number of patients (20OR). Among NSAID, mefenamic acid appears unique in causing symptomatic inflammation of the intestine when used long term. Watery diarrhea with or without steatorrhea and weight loss are common and often due to combined enteritis and colitis. A very tiny percentage of patients have a history of acute or subacute small intestinal obstruction (26c-31r Often no obvious cause of obstruction can be found at laparotomy and barium studies are also likely to be normal. Appropriate investigation can, however, identify strictures of the small intestine, which Bjarnason describes as comprising multiple thin diaphragm-like septa narrowing the intestinal lumen to a pin-hole. The histological abnormality is a submucosal fibrosis with imprecisely understood pathogenesis that does not seem to be a direct consequence of the NSAIDprovoked inflammation. Bjarnason believes that these features define a new NSAID-related disease, which he has termed 'diaphragmic disease' (32R). Whether this is a new nosological entity or only a variant form of congenital intestinal diaphragms remains to be clarified. The close similarities between established NSAID enteropathy and small bowel Crohn's disease can make differential diagnosis difficult in symptomatic patients. The fact that NSAID can exacerbate Crohn's disease (SEDA-10, 76; 33CR) also renders diagnosis problematical and it is worth noting that the recently reported rise in the incidence of this condition has, in part, been linked to an increased consumption of NSAID (34c). Large bowel damage

The effects of NSAID

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on the large bowel have hardly been examined in appropriate epidemiological studies, the only exception being the study by Langman already referred to above (11 r Individual case-reports have described large bowel lesions characterized by colonic or rectal ulcerations, with or without perforation or bleeding, inflammation and strictures. Ulcerations, simple or multiple, with or without complications, have been reported following oral ingestion of various NSAID (SEDA-7, 105; SEDA-10, 77; 3 5 c - 4 0 c ) . However, the etiology of these lesions may be multifactorial and the causal responsibility of the drugs is difficult to evaluate. Of possible contributory factors, constipation and diverticular disease may be important. Diverticula are implicated in several reports of perforation (41 r 1 6 2 while in recent retrospective studies NSAID have also been shown to increase both the risk of laparatomy for diverticulitis (44c) and septic complications (45c). Constipation, excessive doses of NSAID and concurrent therapy with other gastrointestinal irritants have also been considered predisposing factors in single case-reports (46c, 39c). More convincing is the direct causal relationship between rectally administered NSAID and rectal ulceration, with or without perforation or bleeding, and this complication seems to occur more frequently when doses are high or treatment prolonged (47c - 49c). Many publications have documented the association between NSAID and colonic and/or rectal inflammation (SEDA-10, 77; 33 CR) and new reports continue to appear in the literature (50r 1 6 2 NSAID have been reported to promote de n o v o colonic inflammation or cause exacerbation of underlying inflammatory bowel disease, but the differential diagnosis between these two conditions, which are probably different in terms of pathogenesis and clinical relevance, can be difficult. Inflammation of large bowel caused by NSAID de n o v o has been described as nonspecific colitis or proctitis, ulcerative colitis, Crohn's disease, collagenous colitis and necrotizing enterocolitis. It is however unclear whether this reflects a real pattern of clinical presentations of NSAID-associated inflammatory damage of the lower gastrointestinal tract or (at least in part) merely the conclusions drawn by the individual authors who described single cases with no reference to standardized

96 uniform diagnostic endoscopic and/or histological criteria. Although many NSAID (phenylbutazone, indometacin, ibuprofen, fenbufen, naproxen, pirprofen, diclofenac, piroxicam) have been claimed to cause large bowel inflammation de novo, the fenamates (mefenamic acid and possibly meclofenamate) are clearly the most likely to do so, colitis usually being associated with small bowel inflammation (56c-63c). They also cause diarrhea in a greater proportion of patients than other NSAID and, when administered long-term, steatorrhea (64 c, 65c). Inflammation caused be fenamates is usually characterized by watery diarrhea, without associated mucus or blood, abdominal pain and weight loss which appear after a few months of treatment and rapidly recur on rechallenge. Although the colonic mucosa often appears macroscopically normal, histology reveals severe inflammation (50c). A similar clinical presentation has been described only occasionally with other NSAID, i.e. piroxicam (50c) naproxen (66c). The causal connection between NSAID administration and de novo large bowel inflammation is substantiated only by reports that describe a suggestive temporal relationship, with improvement after withdrawal of the offending agent and, in some instances, recurrence of colitis on rechallenge with the same or an unrelated NSAID. Appropriate epidemiological studies would be welcome. Even more controversial is the role of NSAID in aggravating ulcerative colitis or Crohn's disease (SEDA-10, 76) or other inflammatory bowel disease (53c, 67c). The few studies which have investigated drugs as a cause of relapse of chronic inflammatory bowel disease have failed to demonstrate that NSAID are a major contributing factor (68 c, 69c). However, welldocumented published series of patients with quiescent inflammatory bowel disease, whose colitis became active shortly after they were given NSAID (33 cR, 70r make the causal relationship probable, at least in some patients. In these cases, symptoms usually occur soon after starting NSAID therapy, respond to the usual treatment if the offending agent is withdrawn, and recur if the patient is re-exposed to the causative or other NSAID. Because the pathogenesis of inflammatory bowel disease is unknown, it is impossible to say whether the episodes of colitis are exacerba-

Chapter 10 A. Del Favero

tions of the underlying disease or are unrelated events caused by NSAID in predisposed patients. Practical implications It has been argued that if NSAID cause major damage to the intestine, adverse effects would be encountered more frequently. Unfortunately, the topic has not received the attention it deserves and any evaluation of the prevalence of NSAIDinduced disease in the small and large bowel is hypothetical. However, there is little doubt that assessment of adverse effects in the distal gut should be added to the routine gastroduodenal endoscopy investigation. At present, no single appropriate investigative technique is available and the clinical relevance of the results provided by the various radioisotope techniques already mentioned, except for the fecal blood loss determination, is not clear. However, recognition of the clinical picture putatively associated with NSAID toxicity in the lower gastrointestinal tract (Table l) and the inclusion of a thorough drug history that explicitly questions all these patients on the use of NSAID should prove of major therapeutic benefit. If the association between NSAID medications and intestinal problems is appreciated, it should be possible to avoid unnecessary and protracted investigations and start appropriate therapy early in some patients. Patients who present with major complications (perforations, b~eeding, obstructions) obviously require immediate surgery. In the case of symptomatic inflammation, stopping the NSAID treatment usually leads to rapid recovery without subsequent relapse, but sometimes, especially in patients with relapsing inflammatory bowel disease, the use of steroids and/or sulfasalazine may be necessary. Despite the meagre evidence that activation of a quiescent inflammatory bowel disease is frequently causally related to NSAID therapy, these medications are best avoided in patients with Crohn's disease or ulcerative colitis. Moreover, it seems prudent that patients who develop severe diarrhea during treatment with NSAID should be evaluated for occult inflammatory bowel disease. Despite the encouraging results of some experimental studies (21 c, 71 c) the clinical relevance of prostaglandin analogs and glucose-citrate formulations in preventing lower gastrointestinal tract damage remains

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout

speculative. Prevention still lies in reducing the number of prescriptions for NSAID by critically evaluating their indications and use and, since less toxic alternatives exist, avoiding fenamates. NSAID and dyspepsia Gastroduodenal intolerance, a dyspeptic syndrome characterized by upper abdominal pain, heartburn and/or indigestion, is one of the major factors limiting the use of NSAID in patients with rheumatic diseases. Although epidemiological studies of NSAID-associated dyspepsia do not provide consistent data on the incidence of this syndrome in treated patients as compared with findings in an appropriate control population, there is considerable evidence from controlled clinical trials that NSA1D significantly increase the frequency of dyspeptic symptoms over that of placebo and that dyspepsia is the most common reason for discontinuing NSAID therapy. The clinical importance of these symptoms remains uncertain. In fact, although it is well known that symptoms do not necessarily predict the presence of mucosal damage, it is still unclear whether patients who suffer dyspepsia associated with NSAID therapy are at greater or lesser risk for NSAID-induced serious gastroduodenal complications (i.e. bleeding or perforation). The value of dyspeptic symptoms as a warning signal of gastrointestinal damage may be altered in patients taking NSAID, which could lead to a delay in the diagnosis of peptic ulceration and in consequence to a higher risk for gastrointestinal complications. On the other hand, patients who experience NSAID-associated dyspepsia may lower their drug intake because of the drug-related symptoms and so may have proportionally less serious dose-related gastrointestinal complications. Three recent studies (72C, 73 CR, 74C) which addressed the issue of the effect of NSAID therapy on dyspeptic symptoms provided further evidence that NSAID not only contribute to the complications of peptic ulcerations, but also alter the profile of symptoms that would otherwise alert clinicians to the need for further investigation (i.e. endoscopy or barium meal examination). The fact that dyspeptic symptoms are an unreliable indicator of peptic ulceration in patients taking NSAID is a troublesome problem

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in everyday practice, since physicians have no scientifically based criteria derived from appropriate studies for identifying the patients at risk who should undergo endoscopy (75r). However, on the basis of current (albeit scanty) knowledge of the problem, some tentative practical guidelines can be proposed. Before performing endoscopy in a symptomatic patient who has recently started a NSAID and has no history of ulcer or evidence of bleeding, the dosage of the NSAID should if feasible be reduced to the lowest possible level or another NSA1D substituted, and other simple measures instituted such as taking the drug with meals or with antacids. It should he remembered that spontaneous pain refief can occur over the first few weeks of treatment in patients on NSAID (and that there will thus be an apparent response even to placebo) probably because of an adaptation in pain threshold that develops over time (SEDA-14, 79; 76c). The usefulness of an antiulcer drug is controversial, as symptomatic improvement is not often achieved with either H 2receptor blocking agents (77c, 78c) or prostaglandin-analogs (75 c, 79c, 80c). If these changes, made on a trial-and-error basis, do not lead to the desired beneficial effect or the patient suffers from long-lasting persisting symptoms, has a history of prior peptic ulcer or develops occult bleeding, further appropriate investigations should be undertaken. Even though painless lesions might progress and severe complications might develop in a small percentage of asymptomatic patients before a proper diagnosis is made, no specific diagnostic evaluations are required in these patients. Death from peptic ulcer complications and NSAID The true incidence of death related to peptic ulcer complications is unknown. A recent study provides further evidence for the potential hazards of NSAID use. A 10-year study of nearly 10 000 autopsies performed in an English health district revealed 154 patients who died from undiagnosed peptic ulcer complications. In all, 118 of these patients died suddenly at home and 36 died in hospital. NSAID were being used by 81 of these patients, an incidence of 60% where full drug histories were available (81c). NSAID and renal side effects

Two recent

98 studies suggest that the clinically recognized incidence of N S A I D nephrotoxicity is small overall (82 c, 83c), but certain groups of patients are at increased risk (SEDA- 11, 82). Patients with sickle-cell anemia can probably be added to the list (84c).

INDIVIDUAL DRUGS AND CLASSES PHENYLBUTAZONE AND RELATED C O M P O U N D S (SED-11, 173; SEDA-12, 83;

SEDA-14, 92) Pyraziuobutazone (SEDA-12, 83) Hematological Agranulocytosis and liver injury have been described in a patient with Reiter's syndrome who received the drug for 6 weeks. It has been suggested that a hypersensitivity reaction is responsible for this adverse effect o f pyrazinobutazone (85c).

INDOMETACIN AND RELATED C O M P O U N D S (SED-11, 178; SEDA-12, 84;

SEDA-13, 79; SEDA-14, 92) Clometacin (SEDA-12, 83) Liver The hepatotoxic potential of clometacin was first reported in France in 1988 only 7 years after its commercialization. Since then several cases o f hepatic toxic effects have been described (SEDA-7, 109) and recently 2 retrospective studies describing the clinical, biochemical, histopathological and immunological features of 60 cases of clometacin-induced hepatitis have been published (86 or, 87Cr). More than 90% of patients were females and the most frequent presenting clinical features which usually became apparent after a few months of continuous use or shortly after a rechallenge with the drug were jaundice a n d / o r hepatomegalia (90% of patients), weakness (60%), fever (30%) and abdominal pain (20o/0) with or without diarrhea, nausea and vomiting. Cutaneous eruptions, generalized pruritus and weight loss were also reported. Hypergammagtobulinemia and high titers of anti-tissue antibodies were present in the great majority o f patients. Anti-smooth-muscle and, less frequently, anti-nucleus and anti-actin-

Chapter 10 A. Del Favero cable antibodies were found. Histological findings which were available for the great majority of patients were characteristic of acute hepatitis or chronic active hepatitis, in some cases with accentuated sclerosis and evolution towards cirrhosis. In a small percentage of patients with chronic active hepatitis, H L A antigens were determined and a high prevalence of antigen B8 was found. These immunological features, which suggest an autoimmune pathogenesis of chronic active hepatitis, have been reported in hepatitis induced by other drugs (88). The morbidity and mortality of clometacininduced hepatitis in these studies were significant and only a minority of the cases documented had been reported to regulatory authorities. Clometacin is still used as an analgesic drug despite the risks involved in its long-term or repeated use. A l t h o u g h the French authorities have already restricted clometacin use to prescriptions for no more than 8 days, it seems wise to recommend that the drug be no longer used.

lndometaciu (SED-11, 178; SEDA-12, 84; SEDA-13, 79; SEDA-14, 92) Nervous system Modest but clinically significant impairment of psychomotor function has been induced by a single dose o f 50 mg of indometacin in healthy volunteers (age 2 0 - 5 4 years), but tolerance occurs over the course o f a week (89c). Indometacin is widely used for non-invasive closure o f symptomatic ductus arteriosus in the preterm infant. Two studies have recently been published which stress possible risks of such a treatment. A first study showed that administration of an intravenous dose of 0.1 mg/kg of indometacin causes an instantaneous increase in cerebral vascular resistance and a consequent decrease in cerebral blood flow, which lasted for about 2 hours after administration (90c). This effect of indometacin seems to be largely independent of ductus closure and is accompanied by a degree of vasoconstrictive action of the drug on the systemic circulation. The clinical significance of these hemodynamic changes is unknown. The second study (91 c) revealed that all preterm infants affected by patent ductus arteriosus treated by either rapidly of slowly infused indometacin (0.1 0.2 mg/kg) suffered a sharp fall in cerebral blood

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout Chapter 10 flow, oxygen delivery, blood volume and reactivity of blood volumes to changes in arterial carbon dioxide tension. Such falls and disruption of cerebrovascular control might compromise the availability of cellular oxygen in the brain and so harm brain tissue and function. Although none of the infants studied manifested clinical signs of impaired cerebral function, the risk cannot be excluded when dealing with preterm infants with unstable hemodynamics and pulmonary function, and care should be taken to ensure that oxygen delivery is optimal before administering indometacin to preterm infants. On the other hand, the reduction in cerebral blood flow brought about by intravenous indometacin may allow it to be used for reducing intracranial hypertension in patients with severe head injury (92c).

Urinary system

lndometacin, occasionally, can induce severe reversible loss of renal function in patients with systemic lupus erythematosus (SLE) without evidence of active renal disease (93c). A recent study in these SLE patients with a normal or only slightly impaired glomerular filtration rate (GFR) showed that indometacin can significantly reduce GFR without affecting the effective renal plasma flow. The fall in G F R might be due to a direct effect of the drug on the glomerulus, causing mesangial contraction and consequently a reduction of capillary surface area available for filtration (94c). One should be aware that N S A I D can also decrease renal function in SLE patients with no active renal disease and normal or only slightly impaired GFR.

Risk situations

Several neonatal complications have been associated with the use of indometacin to inhibit preterm uterine contractions (SEDA-11, 88). Three preterm infants exposed antenatally to the drug developed a syndrome characterized by edema and bleeding disorder at birth, renal dysfunction (oliguria, hyponatremia, elevation of serum creatinine levels) during the first 3 postnatal days, and acute pneumoperitoneum resulting from localized ilealperforations at the end of the first week of life. Oligohydramnios was also present. Two out of 3 mothers received no more than 500 - 600 mg of indometacin over a period of 2 - 3 days, and all 3 were also administered ritodrine close to the time of delivery. A synergistic adverse effect cannot be excluded (95c). Indometacin can arrest premature labor for a

99

short time, but there is no evidence that it can reduce the incidence of premature delivery. On the other hand, the risks of using indometacin during pregnancy are well documented and the evidence which they provide supports the contention that the hazards outweigh any theoretical advantage (SEDA-5, 101).

Interactions

Life-threatening acute water intoxication and severe hyponatremia have been observed in a patient with multiple myeloma and normal renal function, following treatment with oral indometacin and low-dose intravenous cyclophosphamide (96c). High-dose cyclophosphamide can cause water intoxication and indometacin water retention and hyponatremia. Synergy between these two drugs cannot be excluded and they should be used in combination only with extreme caution.

Lonazolac Clinical experience with this drug is still very limited. Some patients on short-term treatment have complained of side effects similar to those encountered with the related drug indometacin, mainly transient drowsiness and headache (97c).

Sulindac (SED-11, 180; SEDA-12, 84; SEDA-13, 79; SEDA-14, 93) Urinary system

Contrasting results have been reported on renal-function-sparing effects of sulindac (98 R, 99 R, 100c). Reversible hyponatremia without edema or renal function impairment has been described following a short course of therapy with sulindac in an elderly patient on a hyponatremic diet (101c). Analysis of small renal and biliary stones obtained from a few patients who were taking sulindac revealed that the drug or its metabolite were present in the material (102c). The clinical significance of these findings in unknown. ARYLALKANOIC ACID DERIVATIVES A N D R E L A T E D C O M P O U N D S (SED-I1,

184; SEDA-12, 85; SEDA-13, 79; SEDA-14,

93) Aceelofenac (SED-11, 186) Gastric intolerance leading to interruption of

100 treatment was observed in 3 out of 29 osteoarthritic patients included in a 4-week study (103c).

Diclofenac (SED-11, 184; SEDA-12, 85; SEDA-13, 80; SEDA-14, 93) Hematological Spontaneous non-gastrointestinal bleeding has been associated with diclofenac use. Extensive subcutaneous bruises (104c), spontaneous hematoma (105c) and significantly greater wound drainage with a postoperative fall in hemoglobin (106c) have been reported in patients taking diclofenac. Diclofenac, as other NSAID, can cause reversible inhibition of platelet aggregation with or without prolonging bleeding time. Liver and kidney Hepatotoxicity associated with diclofenac has been documented in isolated case-reports. The clinical presentation is that of an acute hepatit&. Although recovery is usually rapid after withdrawal of the drug, fatal cases have occurred (SEDA-11, 93; SEDA-12, 85; SEDA-13, 80). Two patients who developed steroid-responsive chronic active hepatitis have recently been reported (107 C, 108c). Two cases of combined reversible hepato-renal damage attributed to diclofenac therapy have also been described (109 c, 110c). Liver and kidney biopsy documented acute hepatitis consistent with a drug reaction and tubulointerstithT1 nephrit& in the first (109 c) and the hepatorenal damage was accompanied by fever, cutaneous rash and increase in IgE in the second (110c), suggesting an immunological mechanism in both cases. Urinary system Nephrotic syndrome with acute renal failure appeared after 2 months on diclofenac treatment in an elderly patient. Interruption of drug and steroid therapy led to a progressive improvement of renal function and reduction in the proteinuria. Histological examination revealed a membranous nephropathy associated with an interstitial nephritis (lllC). Nephrotic syndrome during NSAID therapy is more often dependent on minimalchange nephropathy. Interactions Case-reports documenting enhancement of ciclosporin nephrotoxicity by diclo fenac suggest that caution is required when

Chapter 10 A. Del Favero this or other NSAID are used in patients taking ciclosporin (112 c, 113c).

Etodolac (SED-11, 188; SEDA-12, 85; SEDA-13, 80) Gastrointestinal The results of an endoscopic study that compared the effects of 1-month treatment with etodolac or naproxen in rheumatoid arthritis patients showed that etodolac had a less damaging effect on the stomach. However, long-term data are required before any claim can be made that this drug is le~ gastrotoxic (114c). Skin A cutaneous leukocytoclastic vasculitis involving the lower limbs with features of inflammatory edema, erythematous plaques and purpuric spots, was observed in a patient after 1 week of treatment with etodolac. Recovery was complete and rapid after interruption of therapy (115c). Fenbufen (SED-11, 186; SEDA-12, 85; SEDA-13, 80," SEDA-14, 93) Respiratory F e n b u f e n c a n c a u s e a p u l m o n a r y alveolitis accompanied by rash, fever and hypoxia (SEDA-12, 85; SEDA-13, 80). A recent report described the clinical features of 4 cases recently traced from the files of Britain's Commission on Safety of Medicines (CSM) (116c). Clinical findings were characterized by rash, dry cough, breathlessness, eosinophilia and bilateral alveolar shadowing or infiltrates. Complete clinical and radiological recovery was obtained in all patients after they stopped taking fenbufen. The CSM has issued a warning that rashes have frequently been reported in patients receiving fenbufen and that, in a small proportion of cases, the reaction is followed by a severe illness characterized by an allergic alveolitis or pulmonary eosinophilia (117r Interactions A warning to avoid prescribing a combination of enoxacin and fenbufen was issued to physicians in 1986 by the Japanese Ministry of Health after several patients experienced seizures while receiving this combination. The first case-report has now been published (118c).

Anti-inflammatory analgesics and drugs used in rheumatoid arthritis and gout Chapter tO A 64-year-old woman experienced a generalized seizure and loss of consciousness, 4 days after starting enoxacin (300 me/d) and fenbufen (200 me/d). After admission to hospital the patient experienced a further 3 seizures. The patient regained consciousness after 4 hours without further seizures.

Flurbiprofen (SED-11, 183; SEDA-12, 85) Nervous system A 52-year-old man developed a severe symmetricalparkinsonian syndrome responsive to levodopa. The striking feature was its sudden onset after 1 week of flurbiprofen treatment for a painful knee. A positron emission tomography scan indicated nigrostriatal cell loss, suggesting that the patient had a predisposing subclinical idiopathic Parkinson's disease (119c). Flurbiprofen can be added to the list of N S A I D able to precipitate, albeit rarely, extrapyramidal reactions (120R). Skin A leukocytoclastic vasculitis with features o f dermatitis-herpetiformis-like drug eruption has been caused by flurbiprofen started 7 days earlier for rheumatoid arthritis (121c). Ibuprofen (SED-11, 182; SEDA-12, 86; SEDA-13, 81; SEDA-14, 94) Interactions

Ibuprofen can be added to the list of N S A I D that can increase methotrexateinduced renal toxicity (122c).

Indobufen

101

Respiratory A case o f acute onset of severe bronchospasm after the ingestion of ketoprofen that rapidly led to respiratory and cardiac arrest has been reported in a young man with a history of mild asthma that only required the occasional use of a 32-adrenoceptor agonist inhaler (124c). Asthma attacks can also be provoked by topical application of the drug in predisposed subjects (125c). These cases support again the need for great caution in prescribing N S A I D to asthmatic patients.

Loxoprofen Two cases of a type I hypersensitivity to this drug, characterized by generalized urticarial rash and dyspnea, have been reported (126 c, 127c). Skin

reaction

Nabumetone (SED-I1, 188; SEDA-12, 87; SEDA-13, 81) Gastrointestinal

The preliminary results of an ongoing long-term study of patients with osteoor rheumatoid arthritis show that nabumetone is relatively gastric-sparing compared with naproxen. At the end of 4 years of treatment, 8 out of 20 patients treated with naproxen developed ulcers and 16 dropped out due to gastrointestinal intolerance. In contrast, only one in the nabumetone group (20 patients) developed ulcer and 9 dropped out (128c).

Naproxen (SED-11, 184; SEDA-12, 87; SEDA-13, 82; SEDA-14, 94)

This N S A I D is marketed as an inhibitor of platelet aggregation and used an an antithrombotic drug. A general practice survey conducted by 300 GPs throughout Italy allowed more than 5000 patients with a mean age of 63 years to be studied. Indobufen administered at a dosage of 1 0 0 - 400 m g / d for a duration of no less than 2 consecutive months was well tolerated. Side effects prompted interruption of indobufen in 1.9~ of patients. Adverse events, most frequently gastrointestinal disturbances, were experienced by 3.9070 of patients. One case of melena was recorded. Other side effects were minor bleeding disorders and skin problems (urticaria and rashes) (123c).

New formulations Safety of new formulations (suspension and controlled-release tablets) has been evaluated and found to have the usual pattern of side effects (129 c, 130c). The gastrointestinal side effects of 2 types of enteric-coated formulations were also studied in young volunteers by endoscopy and the 5 t C r - E D T A absorption test. Enteric-coated tablets induced fewer endoscopic lesions than enteric-coated granules and plain tablets in the stomach and duodenal bulb, but there were no differences in the middle and distal duodenum lesions. All drugs induced a similar significant increase in intestinal permeability (131c).

Ketoprofen (SED-11, 183; SEDA-12, 86; SEDA-13, 81; SEDA-14, 94)

Nervous system Abnormalities in cognitive capacity have been described in elderly patients

Chapter 10 A. Del Favero

102 taking naproxen (SEDA-8, 107). A recent study conducted in a small number of elderly taking a 3-week course of naproxen (750 mg/d) confirmed a tendency for cognitive function to decline in these patients (132c), but the clinical significance of such mild impairment is questionable.

Overdosage

Intentional ingestion of more than 10 g of naproxen caused severe metabolic acidosis. Clinical features were loss of consciousness, focal and generalized seizures and apnea that required mechanical ventilation. Recovery was uneventful (139c).

Suprofen (SED-11, 188; SEDA-12, 88) Hematological Acute severe thrombocytopenia occurred after 3-weeks of treatment in a patients who had previously received naproxen without problems. The clinical features and the demonstration of anti-platelet and plateletassociated antibody suggest an immunologically mediated reaction (133c). Urinary system Systemic lupus erythematosus (SLE) is a recognized risk factor for hemodynamically mediated NSAID-induced acute renal failure (SEDA-11, 85), but additional NSAID-induced renal syndromes can occur in patients with SLE. A young female with a history of SLE had intermittent long-term therapy with naproxen presented acute oliguric renal failure with nephrotic syndrome. Kidney biopsy disclosed chronic, active interstitial nephritis with no evidence of immune deposits at immunofluorescence. Non-sclerotic glomeruli revealed diffuse foot process fusion without cellular proliferation (minimal-change glomerulopathy). Therapy was discontinued, peritoneal dialysis instituted and corticosteroid treatment started. Improvement of renal function was slow and incomplete (134C). The slow and incomplete recovery in this case contrasts with the usual complete recovery of renal function found in patients with NSAIDrelated minimal change glomerulopathy (135c).

Skin and appendages A case of generalized pustular dermatosis, starting on the hands and feet, with associated fever and cholestaticjaundice has been described (136c). Hair loss can be induced by NSAID (SEDA-13, 71) and naproxen can now be added to the list of the drugs involved (137c). Genital system Two young women experienced interruption o f menstrual blood flow soon after taking naproxen (138c). NSAID are known to reduce the amount of blood loss in menorrhagia and may occasionally also interfere with the normal course of menstruation.

Urinary system In May, 1987, sales of the drug were suspended worldwide in the face of an unusual clinical syndrome of acute flank pain and nephrotoxicity (SEDA-12, 89). A case-control study was performed to elucidate the epidemiology of the syndrome (140c). Although the ability to control for confounding factors was limited, the study identified for this syndrome the following as risk factors: male sex, hay fever and asthma, participation in exercise, and alcohol consumption. Another study aimed at clarifying the pathogenesis of suprofen nephrotoxicity was carried out in young healthy volunteers. Ingestion of suprofen was followed by a transient decrease in renal plasma flow and glomerular filtration rate possibly due to intratubular precipitation of uric acid, as the urine was supersaturated with undissociated uric acid. However, decrease in renal function was observed even when, under conditions of forced water diuresis, supersaturation for undissociated uric acid did not occur, suggesting that another nephrotoxicity mechanism may have been responsible (141c).

A N T H R A N I L I C ACID DERIVATIVES

(SED-11, 190; SEDA-12, 90; SEDA-13, 82; SEDA-14, 95)

Glafenine (SED-11, 190; SEDA-12, 90; SEDA-13, 82; SEDA-14, 95) On 1st January 1991 the manufacturer withdrew glafenine, which is available in about 70 countries, from the Belgian market at the request of the Belgian Secretary of State for Health. The authority said that all the products containing glafenine should be withdrawn because of its side effects. At the December 1989 meeting of the European Community Committee on Proprietary Medicinal Products (CPMP), it had recommended that glafenine be

Anti-inflammatory analgesics and drugs used in rheumatoidarthritis and gout Chapter 10 kept on the market but with stricter control on its distribution and closer side effects monitoring (142c). In France, the indications for glafenine were restricted and stern warnings were added to the data sheet (143c). The CPMP invited the manufacturer (Roussell) to prepare a safety update for review in June, 1991, after which the Commission will declare whether in its opinion the drug should be withdrawn or not (144c).

103

12 weeks' duration compared the efficacy and tolerability of tenoxicam and piroxicam. The 2 drugs had a similar tolerance rating: 13 % of patients suffered severe side effects, most often gastrointestinal (i.e. melena, hematemesis, rectal bleeding, exacerbation of ulcerative colitis) and serious rashes (148c).

MISCELLANEOUS DRUGS Diacerein (SEDA-14, 96)

OXICAM DERIVATIVES (SED-11, 191;

SEDA-12, 91; SEDA-13, 83; SEDA-14, 95) Piroxicam (SED-11, 191; SEDA-12, 91;

SEDA-13, 83; SEDA-14, 95) Parenteral formulation The local and systemic toterability of 2 parenteral formulations of piroxicam were compared with that of diclofenac in a double-blind trial. Systemic adverse complaints included more frequent somnolence with piroxicam and gastric discomfort with nausea when taking diclofenac. Local adverse effects for all drugs were pain, burning and induration at the site of injection. The rise in creatine phosphokinase was consistently greater in the diclofenac-treated patients (145c). Skin Light-induced skin eruptions have been reported with piroxicam (SEDA-13, 72). Photoreactions are generally reported to occur only 1 - 6 days after the start of piroxicam therapy and are generally characterized by pruritic, papulovesicular, and sometimes bullous, eruptions usually restricted to lightexposed areas of the skin. Photosensitivity is probably not caused by piroxicam itself but by piroxicam photoproducts or metabolites. It has been suggested that both phototoxic and photoallergic mechanisms underlie piroxicam photosensitivity (146R). A phototoxic mechanism fits poorly with the clinical pattern, histopathology and negative photopatch tests, but could explain the preponderance of early reactions. A photoallergic mechanism seems more likely (147c). Tenoxicam (SED-11, 192; SEDA-12, 93;

Very few clinical data are available on rhein, the active metabolite of diacetylrhein, a recently developed drug said to be effective in osteoarthritis treatment. The drug does not affect arachidonic acid metabolism and, therefore, seems to be better tolerated than other NSAID as far as renal and gastric toxicity are concerned (149 c, 150c). However, epigastric or abdominal pain and diarrhea, the latter sometimes requiring interruption of treatment, remain the most frequent side effects in some studies. Skin reactions such as itchy macupapular rashes have also been reported (151c). Hyaluronate sodium Intra-articular sodium hyaluronate injection for the treatment of osteoarthritis of the knee has been reported to cause hemarthrosis, an increase in joint effusion volume and, possibly, phlebitis (152c). More experience is needed to establish whether this form of treatment is an efficacious and well-tolerated alternative therapy. Monokin-release inhibitor (MW-2884) MW-2884, i.e. 10-methoxy-4H-benzo(4-5)cyclo-hepto-thiophene-4-glindene-acetic acid, is a monokin-release inhibitor. In 1 out of 12 rheumatoid arthritis patients the drug had to be discontinued because of severe urticaria. Other side effects were gastrointestinal disturbances (4/12), temporary impairment o f liver function (4/12) and allergic skin reactions (3/12) (153c). Nefopam (SED-11, 193)

SEDA-13, 83; SEDA-14, 95) A large multicenter hospital-based study of

The unsatisfactory side effects profile of this drug has been confirmed in 2 recent studies car-

Chapter 10 A. Del Favero

104 ried out on cancer and rheumatoid arthritis patients. Most o f the adverse reactions responsible for the interruption o f treatment were related to the anticholinergic properties of the compound (154 c, 155c).

Nimesulide (SED-11, 193; SEDA-14, 96) This c o m p o u n d was shown to cause less gastric damage than indometacin in an endoscopic short-term study (156c). Gastric pain and skin rashes were the most frequently reported side effects in a small study on elderly osteoarthritic patients. Fever and facial edema have also been attributed to the drug (157c). Both the efficacy and tolerability of this compound need further evaluation.

Podophyllum derivatives Proresid (mitopodozide) is a mixture of more than 20 Podophyllum emodi derivatives used for many years in the treatment of rheumatoid arthritis as a disease-modulating agent. It is a microtubulin antagonist that is comparable to colchicine and griseofulvin (158). Its use, however, has been limited because the treatment is often complicated by severe diarrhea,

Steopronine The side effects profile o f this sulfhydryl c o m p o u n d which is used in rheumatoid arthritis seems to be similar to that o f penicillamine. In a long-term open study, treatment had to be interrupted in 30% of 36 patients due to severe side effects. Seven patients presented mucocutaneous reactions (dermatitis, pruritus, stomatitis, glossitis and ageusia), 3 proteinuria and 1 thrombocytopenia and leukopenia (162c).

Timegadine (SED-11, 193) Severe stomatitis, accompanied by cutaneous rashes and complicated by severe edema of the lips and ulcerations of the mucous membranes, prompted interruption of treatment in 3 out of 20 rheumatoid arthritis patients enrolled in a 24-week study. Slight elevations in liver enzymes have also been recorded, confirming data f r o m previous studies (SEDA-14, 96; 163c).

D R U G S U S E D IN T H E T R E A T M E N T O F G O U T (SED-11, 194; SEDA-12, 94; SEDA-

abdominal pain, nausea and vomiting. Leukopenia and thrombocytopenia have also

13, 84; SEDA-14, 96)

been reported (159CR). C P H - 8 is composed of two semisynthetic lignam glycosides and, when used in the treatment of rheumatoid arthritis, causes the same gastrointestinal problems as Proresid (160c).

AIIopurinol (SED-11, 194; SEDA-12, 94; SEDA-13, 84; SEDA-14, 96)

Pyritinol (SED-11, 192) An a u t o i m m u n e hypoglycemic syndrome recurred twice in an elderly w o m a n following treatment with pyritinol (161c). This side effect has been described with other drugs containing a sulfhydryl group, but the pathogenic mechanism in unknown.

Skin Strong H L A associations were found in Southern Chinese patients with severe skin reactions due to allopurinol. The positive associations were with AW33 and B17, suggesting a genetic predisposition to these reactions (164c).

Special senses

There is controversial evidence that allopurinol has a cataractogenic effect. A recent study found no evidence to confirm this risk (165c).

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of its effect. Pediatrics, 84, 802. 91. Edwards AD, Wyatt JS, Richardson C et al (1990) Effects of indomethacin on cerebral haemodynamics in very preterm infants9 Lancet, 335, 1491. 92. Jensen K, Cold GE, Astrup J et al (1990) Indomethacin in severe head injury. Lancet, 336, 246. 93. ter Borg E J, de Jong PE, Meijer Set al (1987) lndomethacin and ibuprofen induced reversible renal failure in a patient with systemic lupus erythematosus. Neth. J. Med., 30, 181. 94. ter Borg E J, de Jong PE, Meijer S, Kallenberg CGM (1989) Renal effects of indomethacin in patients with systemic lupus erythematosus. Nephron, 53, 238. 95. Vanhaesebrouck P, Thiery M, Leroy JG et al (1988) Oligohydramnios, renal insufficiency, and ileal perforation in preterm infants after intrauterine exposure to indomethacin. J. Pediatr., 113, 738. 96. Webberley M J, Murray JA (1989) Lifethreatening acute hyponatraemia induced by low dose cyclophosphamide and indomethacin. Postgrad. Med. J., 65, 950. 97. Janssen M, Van Leeuwen MH, Albrecht H, Dijkmans BAC (1988) A double-blind parallel group comparative study of lonazolac-calcium and diclofenac in patients with rheumatoid arthritis9 Clin. Rheumatol., 7, 545. 98. Dunn M J, Simonson M, Davidson EW et al (1988) Nonsteroidal anti-inflammatory drugs and renal function. J. Clin. Pharmacol., 28, 524. 99. Stillman MT, Schlesinger PA (1990) Nonsteroidal antiinflammatory drug nephrotoxicity. Should we be concerned? Arch. Intern9 Med., 150, 268. 100. Whelton A, Stout RL, Spilman PS et al (1990) Renal effects of ibuprofen, piroxicam and sulindac in patients with asymptomatic renal failure. Ann. Intern9 Med., 112, 568. 101. Chamontin B, Fille A, Salva P, Salvador M (1988) L'inhibition s61ective des prostaglandines exist6t-elle? Presse Mdd., 17, 2140. 102. Paulus HE (1988) FDA arthritis advisory committee meeting: drug-containing renal and biliary stones. Arthritis Rheum., 31, 1450. 103. Diaz C, Rodriguez A, Geli C et al (1988) Comparison of aceclofenac and diclofenac in osteoarthritis pain. Curr. Ther. Res., 44, 252. 104. Khazan U, Toth M, Mutgi A (1990) Diclofenac sodium and bruising. Ann. Intern. Med., 112, 472. 105. Price A J, Obeid D (1989) Spontaneous nongastrointestinal bleeding associated with diclofenac 9 Lancet, 2, 1520. 106. Francis JL, Dawes RFH, Roath OS (1988) The effect of diclofenac on platelet aggregation and post-operative bleeding. Haematol. Rev., 2, 283. 107. Mazeika PK, Ford MJ (1989) Chronic active hepatitis associated with diclofenac sodium therapy. Br. J. Clin. Pract., 43, 125.

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