LEADING ARTICLE

Drug Safety 10 (3): 183-195, 1994 0114-5916/94/0003-0183/$06.50/0 © Adis International Limited. All rights reserved.

Differences in NSAID Tolerability Profiles Fact or Fiction?

Kenneth J. Skeith, !,2 Matthew Wright2 and Paul Davis!

Rheumatic Disease Unit, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada 2 Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective and widely prescribed group of drugs. Within this class of agents the choice for physicians is extensive and ever-expanding. Based on the evidence to date, all NSAIDs, when given in equipotent doses, have comparable efficacy (Epstein et al. 1984; Willkens 1992). Given this equivalent efficacy, the safety or tolerability pro­file of the individual agent has become the princi­pal criterion for selection for many physicians. These adverse effects are related to either prosta­glandin (PG) synthesis inhibition or are idiosyn­cratic, and can affect nearly every organ system. Recognising that some reactions, such as upper gastrointestinal (GI) toxicity, are much more frequent than other adverse effects, the following discussion will attempt to outline the relative tolerabilities of different NSAIDs in relation to various organ systems.

1. Differences in Individual Tolerability Profiles

Listed below is an overview of adverse reac­tions affecting individual organ systems, and the demonstrated differences between individual NSAIDs for each system, if such information is available.

1.1 Upper Gastrointestinal

The association of NSAIDs with upper GI

toxicity has been confirmed and extensively re­viewed (Fries 1991 b; Hochberg 1992). Most of the available evidence is derived from epidemiological case-control and cohort studies. Randomised clin­ical trials and comparative endoscopic evaluations almost always lack sufficient power to reach any conclusions about rates of upper GI complications.

While many clinical trials have concluded that aspirin (acetylsalicylic acid) is less well tolerated than other NSAIDs, Chalmers et al. (1988) in a meta-analysis of these studies determined that as­pirin use was associated with a relative risk of 1.4 for GI haemorrhage, while non-aspirin NSAIDs had a relative risk of 3.0.

A number of studies have identified a dose-de­pendency for NSAID-induced upper GI toxicity. Griffin et al. (1991) showed that patients ingesting a greater daily dosage of NSAIDs had up to an 8-fold greater risk of hospitalisation for ulcer dis­ease or GI bleeding than patients receiving a lower daily dosage. Carson et al. (1987a) in a prospective study showed a linear relationship between dose and risk (fig. 1).

Many investigators have attempted to determine the relative risks for upper GI toxicity between dif­ferent NSAIDs. Essentially, all randomised clinical comparative studies of NSAIDs have concluded with comments on relative toxicity, but these stud­ies are too small to derive meaningful information.

A number of case-control and cohort studies have evaluated the relative risks of different

184

50 -

-

o ~--~~----~~--~--~-

Low Medium High

Dose

Fig. 1. Linear dose-response relationship between use of non­steroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding (from Carson et al. I 987a, with permission).

NSAIDs, but results have been inconsistent and at times contradictory. This is partly due to the meth­odologicallimitations, with limited numbers of pa­tients for individual drugs, as well as variations in local prescribing practices. Using this approach, Griffin and colleagues (1991) determined that naproxen 500 mg/day, piroxicam 20 mg/day, tolmetin 600 mg/day, and meclofenamic acid (meclofenamate) 200 mg/day were associated with a significantly greater relative risk than ibuprofen 1200 mg/day for hospitalisation due to ulcer dis­ease or upper GI bleeding.

This study is an example of another limitation in such comparative analysis; namely the accurate definition of dose-equivalency between NSAlDs. With the dose-dependency of GI toxicity already established, and precise pharmacodynamic NSAID data for either efficacy or toxicity lacking, the assumed dose-equivalency in these published reports may lack validity. In the above study, for example, comparing naproxen (at one-half of the recommended maximal dosage) with piroxicam (at the recommended maximum dosage for non-el­derly) with ibuprofen (at the minimal anti-inflam­matory dosage) limits the usefulness of any con­clusions.

Carson et al. (1987b) identified sulindac in 2 separate cohort studies as the NSAID with the highest relative risk, compared to the standard drug

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ibuprofen. Another report (Laporte et al. 1991) found piroxicam to have the highest relative risk of 19. It has been concluded from these data that al­though there is evidence that ibuprofen may be less inclined than other NSAIDs to cause serious upper GI complications, no other conclusions can be drawn (Henry et al. 1992) [table I].

Much has been published on elimination half­lives (tyJ of NSAIDS and their relation to toxicity (Adams 1988; Furst 1992). This hypothesis, that the longer the tY2 the greater the toxicity, was de­rived from analysis of voluntary postmarketing surveillance data (Adams 1992; Collier & Pain 1985), epidemiological case-control studies, and the benoxaprofen-toxicity relationship (Borda 1992). Besides the limitations in some of the orig­inal data collection, this conclusion appears to be excessively simplistic. The elimination tl/2 is a composite pharmacokinetic parameter, which is a function of the apparent volume of distribution (Vd) and the clearance (CL) of a drug. Although the V d of all NSAlDs is similar because of their extensive protein binding in plasma, there is a wide range of clearance mechanisms for individual NSAlDs, with oxidation, conjugation, biliary ex­cretion, enterohepatic recirculation, renal elimina­tion and metabolism all of variable relevance. This argument also ignores the different physicochemi­cal properties of different agents and the different potencies of PG synthesis inhibition, the postu­lated central toxicity mechanism. In the absence of better comparative studies, the clinical selection of NSAlDs based simply on the pharmacokinetic pa­rameter of tY2 does not appear warranted.

Given the limitations of clinical trial-derived data, there are a number of newer NSAIDs that may demonstrate a more favourable GI toxicity profile. Nabumetone is a non-acidic prodrug that is rapidly converted to its active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA), in the liver. Because of its lack of 'ion-trapping' and accumulation in gastric mucosal cells, as well as its minimal entero­hepatic circulation, nabumetone has been postu­lated to pose less risk for gastric damage than other NSAlDs (Blower 1992). The ulcer occurrence fol-

Differences in NSAID Tolerability Profiles 185

Table I. Estimated risks of upper gastrointestinal haemorrhage with individual nonsteroidal anti-inflammatory drugs (from Henry 1992, with

permission)

Drug Griffin et al. (1991)

Odds ratio (95% GI)

Ibuprofen 2.3 (1.8-3.0)

Diclofenac

Fenoprofen 4.3 (2.8-6.6)

Indomethacin 3.8 (2.4-6.0)

Naproxen 4.3 (3.4-5.4)

Piroxicam 6.4 (4.8-8.4)

Sulindac 4.2 (2.8-6.3)

Tolmetin 8.5 (4.5-16.1)

lowing nabumetone therapy in the short (0.1 %) and long term (0.95%) in patients with osteoarthritis or rheumatoid arthritis has been found to be far below the 2 to 4% annual figure reported by the US Food and Drug Administration (Roth 1992).

Etodolac is the first of a new chemical class of NSAID, the pyranocarboxylic acids. This drug has been shown to be well tolerated in both the regular and sustained release formulations (Bacon 1993; Schattenkirchner 1993). Serious GI reactions were rare, with a reported rate of 0.3% (Schattenkirch­ner 1990). Various studies have documented less GI blood loss, fewer endoscopically identified complications and less gastric PG suppression than with a variety of other NSAIDs (Lanza et al. 1987; Russell 1990; Salom et al. 1984). This apparent superior tolerance must be confirmed by longer term evaluations in greater numbers of patients.

It can be concluded that although upper GI tox­icity is the principal adverse reaction related to NSAID use, there are still insufficient data to rank individual NSAID GI tolerability accurately. Ibuprofen appears to be better tolerated, but studies have not considered full anti-inflammatory dos­ages of 2400 to 3200 mg/day. NSAIDs with a longer tYz have not been shown to be necessarily more toxic than those with a short tY2' and further clinical experience is needed to substantiate the superior tolerability of nabumetone and etodolac.

Laporte et al. (1991)

Odds ratio (95% GI)

4.9 (2.0-12.2)

6.5 (2.2-19.6)

19.1 (8.2-44.3)

Henry et al. (1991)

Odds ratio (95% GI)

7.9 (4.3-14.6)

2.4 (1.2-4.9)

5.3 (2.7-10.2)

3.7 (2.0-6.9)

1.2 Lower Gastrointestinal

The clinical use of NSAIDs has commonly been associated with upper GI adverse effects such as gastric pain, heartburn, nausea, vomiting and diar­rhoea (Brogden 1986). In addition, it is well recognised that NSAIDs also induce a high inci­dence of gastric and duodenal ulceration and mu­cosal damage in the upper GI tract (Committee on Safety of Medicines 1986; Fries et al. 1991; Giercksky et al. 1989; Hayllar et al. 1992; Zeidler 1991; Wilkins 1992). Although upper gastrointes­tinal toxicity has been extensively examined, the effects of NSAIDs on the more distal portiol) of the small intestine have only recently received scru­tiny (Allison et al. 1992; Bjarnason et al. 1987a).

There is a growing body of evidence that more distal damage may be more widespread and of more serious consequence than previously thought (Rampton 1987). Allison and colleagues (1992) have recently reported the increased incidence of small intestinal ulceration in patients prescribed NSAIDs, although these ulcers are less common than those in the stomach or duodenum. In addi­tion, Bjarnason and co-workers (1986a,b) have demonstrated that NSAIDs cause increased small intestinal permeability at the level of the mucosal tight junction. This may lead to intestinal mucosal inflammation associated with both blood and pro­tein loss in nearly 75% of patients on long term

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NSAID therapy (Bjamason et al. 1987b). In tum, this intestinal inflammation may precede more serious sequelae including intestinal stricture and ulceration (Bjamason et al. 1986b). Thus, the overt evidence of small intestinal inflammation and its more serious sequelae may be preceded by increased intestinal permeability (Bjamason et al. 1987c; Jenkins et al. 1987).

Since it has previously been demonstrated that the permeability of tight junctions may be, at least in part, regulated by PGs (Powell 1981; Stevenson et al. 1988) it is not unexpected that use of NSAIDs could result in changes in intestinal permeability and hence the unexpected incidence of more distal GI damage. There are numerous reports in humans of changes in intestinal permeability induced by NSAIDs (Bjamason & Peters 1989; Bjamason et al. 1984, 1986a, 1987d, 1991, 1992; Jenkins et al. 1987, 1991). Uniformly, these studies demonstrate increased intestinal permeability in both healthy volunteers and patients exposed to NSAIDs.

In spite of the relatively large number of studies reporting adverse effects of NSAIDs in the lower GI tract, few allow for true comparison of the rel­ative abilities of NSAIDs to cause this damage. However, a few generalisations are possible. Al­though definitive data are not available, it does ap­pear that the risk oflower GI tract damage is lower with nonacetylated salicylates (Fries et al. 1991). A disproportionate number of cases of NSAID-in­duced colitis occurs with the use of the fenamate derivatives mefenamic and flufenamic acid (Bjarnason et al. 1993).

At present, although there is good evidence that NSAIDs may induce damage in the lower GI tract, more controlled studies are needed to assess the relative risks between the various compounds.

1.3 Renal

Renal adverse effects of NSAIDs consist of ei­ther functional and haemodynamic alterations or direct nephrotoxicity resulting from drug-induced interstitial nephritis, with or without an associated nephrotic syndrome (Murray & Brater 1993). De­creases in renal or tubular function due to NSAID-

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induced reductions in PG production are most of­ten encountered in states of reduced renal perfu­sion, and as such can be caused by any NSAID now in clinical use, including sodium salicylate and aspirin (Hamzlik et al. 1917; Kimberley & Plotz 1977). Interstitial nephritis is a rare and idiosyn­cratic event, and has been described with many of the current available NSAIDs, most often with fenoprofen (Finklestein et al. 1982; Garella & Matarese 1984).

It is not possible to definitively rank the individ­ual NSAIDs in relation to their potential for renal function impairment, as such comparative studies in large numbers of patients at risk for renal dys­function have not been carried out. However, several NSAIDs have been identified as potentially renal sparing. Sulindac, because of its unique metabolic pathway that limits renal exposure to the active sulphide metabolite, was initially postulated to cause less alteration in renal function than other NSAIDs excreted by the kidney (Bunning & Barth 1982; Duggan et al. 1977). Further investigation showed, however, that this drug is also capable of inducing the same renal toxicity as other NSAIDs. Quintero and colleagues (1986) noted in 5 patients with cirrhosis and ascites that sulindac 400 mg/day caused significant decreases in glomerular filtra­tion rate (GFR), free water clearance and urinary excretion ofPGE2 and 6-keto-PGFla . Roberts et al. (1985) concluded that sulindac has renal effects comparable to those of indomethacin. Apparent differences between sulindac and other NSAIDs have been attributed by some authors to weaker PG inhibitory effects rather than any intrinsic renal­sparing mechanism.

Like sulindac, nabumetone is a prodrug, and is rapidly metabolised in the liver to 6MNA. Nabumetone has been reported to cause little renal toxicity, with an effect on renal function in less than 1 % of patients, even with advanced age (Aronoff 1992). Urinary concentrations of 6MNA are low (approximately 1 % of plasma concentra­tion), and the glucurono and demethyl derivatives of 6MNA found in urine are weak cyclo-oxygenase inhibitors. Because of this, it has been postulated

Differences in NSAID Tolerability Profiles

that nabumetone has some renal-sparing properties in comparison to other NSAIDs (De Caterina et al. 1992). However, renal failure has been reported as a consequence of nabumetone use (Bernhard 1992) in small numbers of patients, and further evalua­tions are necessary to confirm the potentially greater tolerability of this drug.

Uncontrolled hypertension has a deleterious effect on renal function, and NSAID use, by ele­vating blood pressure in treated or untreated hyper­tensive patients, can contribute to renal dysfunc­tion. Sulindac has been reported to have the least effect on blood pressure control of all NSAIDs. Indomethacin 75 mg/day increased blood pressure by an average of 11/4mm Hg in treated hyperten­sive patients, but sulindac decreased the mean blood pressure, similar to placebo (Puddey et al. 1985). Rodack and Deck (1987) reviewed 31 of these comparative studies and concluded that sul­indac is less likely than piroxicam, naproxen or indomethacin to cause an attenuation of antihy­pertensive efficacy.

In summary, adequate comparative evaluations of NSAID-induced renal dysfunction have not been performed. Fenoprofen may be more likely to cause an interstitial nephritis and nephrotic syn­drome, but this is a rare occurrence with any NSAID. Possibly sulindac and nabumetone may produce less renal haemodynamic and functional impairment, but they are still capable of inducing these adverse events, including renal failure. Sul­indac appears to be better tolerated than other NSAIDs when blood pressure control is critical.

1.4 Hepatic

Salicylates have been associated with hepato­toxicity more than any other NSAID. It was recognised as early as 1955 (Manso et al. 1956; Nydick et al. 1955) that children treated for rheu­matic fever with salicylates may develop elevated transaminases. A considerable volume of literature was subsequently generated on the effect of salicy­lates on the liver in patients with juvenile chronic polyarthritis. Russell and colleagues (1971) reported eight of 32 such patients who developed

187

markedly raised transaminases. Numerous other reports made similar observations. The elevation of the transaminases in these patients appeared to be an isolated phenomenon in that other abnormal­ities of hepatic function such as hyperbiliru­binaemia and changes in prothrombin time were relatively uncommon. The effect of salicylates on hepatic function appeared to be dose-dependent, and in most cases the abnormality was reversible on reducing salicylate dosage.

The mechanism of salicylate-induced hepato­toxicity is not known and it is not clear whether this is a specific phenomenon or one that is poten­tially a risk of high therapeutic dosages with other NSAIDs. The issue and potential clinical signifi­cance was thoroughly reviewed by Schaller (1978). Very few studies are available which com­pare salicylates with other NSAIDs in terms of potential to induce transaminasaemia. Nonethe­less, the report of the JRA collaborative study group (Levinson et al. 1977) compared salicylates with tolmetin sodium and demonstrated that trans­aminasaemia occurred in 13 of the 54 patients receiving salicylates but in only 1 of 53 receiving tolmetin sodium.

Adverse events affecting the liver have been re­ported with other NSAIDs. In particular, mild transaminasaemia is occasionally seen, although rarely are these events considered to be clinically significant. Indeed, the more significant and occa­sionally fatal adverse events appear to be extremely rare and only appear in the literature as isolated case reports. Under these circumstances the direct cause and effect relationship between NSAIDs and hepatotoxicity often remains in doubt.

In 1 study, naproxen was thoroughly investi­gated for long term hepatotoxicity (Turner 1988). In this study 586 patients taking naproxen 750 to 1500 mg/day were followed over a period of 6 months. An elevation of liver enzymes was only observed in 3 patients and was not considered to be clinically significant in any of them.

Diclofenac is another widely used NSAID which has come under some attention for its poten-

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tial hepatotoxicity. Here again, transient elevation of transaminases and occasionally hyperbili­rubinaemia have been noted but are usually not clinically significant. Clinically significant hepatitis has, however, been reported in a few case studies although such cases appear to be relatively rare but occasionally fatal (Helftott et al. 1990). As with other types of NSAID-associated trans­aminasaemia and hepatotoxicity the mechanism remains unclear although idiosyncratic hyper­sensitivity reactions may well playa key role.

Fortunately, other forms of hepatotoxicity are rare with NSAIDs. In the majority of cases this is due to the careful premarketing screening of patients. One exception to this was the drug ben­oxaprofen, which showed considerable clinical po­tential and was released on the market in the UK. This drug was subsequently withdrawn because of a high incidence of cholestatic jaundice and mor­tality (Taggart & Alderdice 1982). Hepatotoxicity associated with phenylbutazone has become a rel­ative non-issue clinically, now that the drug is not very widely prescribed.

In summary, it would appear that with salicy­lates marked transaminasaemia is relatively com­mon, particularly in juveniles. Most other NSAIDs are associated with mildly elevated liver enzymes less frequently. Clinically relevant and significant hepatitis is rare with all NSAIDs but is occasion­ally fatal. The mechanism of action is not clear and the problem appears to be an unpredictable risk. Few worthwhile comparative studies have been performed to determine whether anyone drug is a more potential hepatotoxic agent than others.

1.5 Central Nervous System

Although relatively uncommon, many NSAIDs have been implicated in adverse effects in the cen­tral nervous system (CNS). Although it is likely that minor adverse reactions, including headaches, drowsiness, tinnitus and dizziness may occur with all NSAIDs, they have most commonly been asso­ciated with the use of indomethacin (O'Brien & Bagby 1985a). The apparently high incidence of indomethacin-associated CNS toxicity may be the

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result of its indole structure which has chemical similarity to the endogenous indole, serotonin (5-hydroxytryptamine; 5-HT).

The occurrence of tinnitus with salicylates has long been recognised as a prewarning of toxicity, although it is not a reliable indicator of salicylate blood concentrations (Mongan et al. 1973). How­ever, permanent hearing impairment and deafness may be caused by long term salicylate use (Miller 1978; Myers et al. 1965). Rarely, transient hearing loss has been reported with indomethacin (Robin­son 1965; Taylor & Rothermich 1973), phenyl­butazone and ibuprofen (Ajodhia & Dix 1976).

In rare cases, aseptic meningitis has occurred in individuals treated (14 cases) with NSAIDs (O'Brien & Bagby 1985a). The majority of these cases (8 of 14) occurred in patients with systemic lupus erythematosus (SLE). Of the NSAIDs impli­cated, the majority of cases involved ibuprofen, with sulindac and tolmetin mentioned less fre­quently. These effects are reproducible on challenge with single doses of ibuprofen and all of the reported cases were reversible on discontinua­tion of NSAID therapy. It should be noted that the interpretation of these data must be qualified by the high frequency of clinical use of ibuprofen and the abundance of occurrences in patients with SLE.

Even more rarely, extrapyramidal reactions have been reported with mefenamic acid (Cremona­Barbaro 1983; Redmond 1981), ibuprofen (Sandyk et al. 1987), sulindac (Sandyk & Gillman 1987) and azapropazone (Wood et al. 1988).

In terms of psychological effects, NSAIDs may have subtle effects on mentation and cognition (O'Brien & Bagby 1985a). Indomethacin (Carney 1977; Gotz 1977), ibuprofen (Griffith et al. 1982) and sulindac (Kruis & Barger 1980) have been implicated in acute depressive and psychotic episodes which resolved on discontinuation of the drug.

In general, differential patterns of CNS toxicity between the various NSAIDs are not marked, but indomethacin use has the greatest risk, particularly in elderly patients (Hoppmann et al. 1991; Sager & Bennett 1992).

Differences in NSAID Tolerability Profiles

1.6 Ocular

Adverse ocular reactions to NSAIDs are gener­ally both rare and reversible, with most accounts involving the two most widely used NSAIDs, ibuprofen and indomethacin (O'Brien & Bagby 1985a).

Two groups of investigators (Burns 1968; Palimeris et al. 1972) have reported that indometh­acin may alter retinal sensitivity and cause corneal deposits. However, a third group found no retinal differences between patients receiving indometh­acin and a control group not taking the drug (Carr & Siegel 1973). With ibuprofen there are individ­ual case reports of toxic amblyopia (Palmer 1972; Thompson 1972), central field defects (Collum & Bowen 1971), colour blindness (Palmer 1972), transient diplopia (Asherov et al. 1982) and hallu­cinations (Collum & Bowen 1971; Tullio 1981). However, studies involving more than 900 patients treated with ibuprofen found no occurrence of ocular adverse effects, which may emphasise the rarity of these effects (O'Brien & Bagby 1985a). In addition, there are individual case reports of aspirin-induced myopia (Sandford-Smith 1974) and ketoprofen-induced conjunctivitis (Umez­Eronini 1978).

1. 7 Cutaneous

NSAID-induced adverse reactions of the skin occur relatively frequently in comparison to those occurring in the CNS (Brooks & Day 1991). There is little doubt that the most toxic NSAIDs in this regard are phenylbutazone and its active metabo­lite, oxyphenbutazone (O'Brien & Bagby 1985b). Although most dermal reactions are mild, a serious adverse effect, erythema multiforme, has been de­scribed frequently (O'Brien & Bagby 1985b). A particularly severe variant of erythema multi­forme, Stevens-Johnson syndrome, with a fatality rate of 6 to 25% (Chanda & Callan 1978) has also been described. Another closely related variant, toxic epidermal necrolysis or Lyell's syndrome, has also been reported with NSAID administration.

189

There are reports, with varying incidences, of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis with almost all NSAIDs including aspirin, indomethacin, sul­indac, diclofenac, ibuprofen, fenbufen, diflunisal, naproxen, tolmetin sodium, zomepirac and meclofenamic acid (O'Brien & Bagby 1985b). Much higher incidences of these serious reactions were encountered with piroxicam and, during its brief marketing period, benoxaprofen.

The highest incidence of erythema multi­forme and its associated syndromes occurs with phenylbutazone and oxyphenbutazone. These agents have been responsible for at least 15 cases of erythema multiforme (at least four fatal) [Blue­farb & HIot 1955; Cone et al. 1954; Kuokkanen 1972; Maberly & Greenhalgh 1970; Mauer 1955; van Joost et al. 1974], at least 3 cases of Stevens­Johnson syndrome (Kuokkanen 1972; Ritland 1968; Steel & Moffatt 1954), and more than 150 cases of toxic epidermal necrolysis (Bailin & Matkaluk 1982; Montgomery 1970).

A number of NSAIDs, particularly the phenylpropionic acids, have been implicated in photosensitivity reactions. These reactions gener­ally occur on exposed skin areas of patients taking ketoprofen, naproxen, tiaprofenic acid and pirox­icam (Diffey et al. 1983). Carprofen has also been implicated in a more serious photodermatitis (Merot et al. 1983). A significant number of cases of benoxaprofen-induced photosensitivity had been reported prior to the withdrawal of this drug from the market (Stern 1983; Stern & Bigby 1984).

1.8 Haematological

A variety of haematological adverse reactions have been reported in association with different NSAIDs. These include aplastic anaemia, pure red cell aplasia, thrombocytopenia and haemolytic anaemia. Fortunately, as with many of the other adverse effects attributed to NSAIDs, the preva­lence of these is relatively low, although in many instances the mortality rate, particularly with aplastic anaemia, is high.

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Many of the commonly prescribed NSAIDs have been reported to produce aplastic anaemia, usually ranging from an isolated case to a maxi­mum of four or five. The exceptions to this have been oxyphenbutazone and phenylbutazone. It has been known for some time that there may be an increased risk of aplastic anaemia with these two drugs compared to other anti-inflammatory medi­cations (Inman 1977). As a result of this, the pre­viously widespread use of these medications has been considerably curtailed, in light of their ad­verse effects and the ability to achieve adequate therapeutic benefit with alternate medications.

Similar comments relate to the induction of isolated neutropenia by NSAIDs. Once again, it appears that phenylbutazone and oxyphen­butazone above all others may be associated with this adverse reaction, although other NSAIDs have occasionally been incriminated (Morris et al. 1981; Sakai & Joseph 1978). Although very little is known about the relative risk of these drugs in in­ducing these rare and potentially serious effects, one report from the International Agranulocytosis and Aplastic Anemia study (1986) did compare risk rate in a multicentre study. Apart from the not sur­prising finding that the risk of aplastic anaemia and agranulocytosis was elevated with the butazones, the drugs dipyrone, indomethacin, and to a lesser extent diclofenac, were also reported to be associ­ated with an increased risk of these effects.

The effect of NSAIDs on platelet numbers and functions is also well-recognised, and once again a variety of NSAIDs have been incriminated in the induction of thrombocytopenia. These all appear to be relatively isolated cases with the exception of the butazones. Salicylates are somewhat different in that not only have they been associated with the induction of thrombocytopenia, but also are known to affect platelet function more than any other NSAID. It has been known for some time that sa­licylates inhibit platelet aggregation and may pro­long the bleeding time and that this effect may last for many days, whereas the effect of other NSAIDs is relatively short-lived. Hence, salicylates appear to be in a separate class to the other NSAIDs in

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their effects on platelet function. Their ability to inhibit hepatic synthesis of vitamin K is also an effect which sets them in a class separate from the other NSAIDs.

Haemolytic anaemia has also been reported with a number of the NSAIDs. Once again these appear to be isolated cases, and unlike aplastic anaemia and agranulocytosis, there is very little comparative evidence to determine the relative risk of this complication in patients receiving NSAIDs compared with a non treated background popula­tion. It is also not possible to compare and contrast the relative risk between NSAID subclasses.

1.9 Hypersensitivity Reactions

Anaphylactic and hypersensitivity reactions to medications are well known and NSAIDs are no exception to this. Fortunately, as with other medi­cations, the prevalence of hypersensitivity reac­tions is exceptionally small, but unfortunately al­most invariably unpredictable. At the present time, there is no evidence to suggest that anyone drug is more prone to result in hypersensitivity or anaphy­lactic reactions than any other within this group.

There is ample literature relating to this type of reaction with a variety of NSAIDs and there appears to be few exceptions. Even the develop­ment of the newer NSAIDs such as sulindac (Smith & Linberg 1980), tolmetin sodium (Restevo & Paulus 1978) and diclofenac (Dux et al. 1983) has not resulted in a reduction in this potential risk. No studies are available which compare this potential risk between different classes of NSAIDs.

Aspirin sensitivity seems to be the major excep­tion and it is well recognised that there may be intolerance to aspirin in patients with urticaria, asthma, nasal polyps and sinusitis. Cross-reaction between aspirin and other NSAIDs has been pos­tulated and previously reported (Merritt & Selle 1978). Nonetheless, in clinical practice it does not appear to be a major clinical issue and once again few studies have been undertaken to help clearly delineate the potential size of this problem.

Differences in NSAID Tolerability Profiles

1.10 Pregnancy

Numerous biochemical processes of pregnancy are influenced by PGs and their metabolites (Chal­lis & Patrick 1980). By virtue of their known phar­macological activities, NSAIDs can cause subtle but potentially pervasive effects in both the mother and fetus (Heymann 1986). Given current esti­mates of the extent of drug use by pregnant women (Rurak et al. 1991), it is not unexpected that NSAIDs may be ingested in a significant number of such women. In common with most other drugs, the technical and ethical restraints placed 011 inves­tigations during the course of pregnancy has re­sulted in only very limited information regarding the effects of NSAIDs during pregnancy.

Despite the relatively widespread clinical use of NSAIDs in the general population, reports of their use and association with adverse maternal and/or fetal effects have largely been confined to aspirin, indomethacin and sulindac. Early studies with as­pirin (Turner & Collins 1975; Lewis & Schulman 1973) demonstrated a correlation between inges­tion of aspirin and delay in the onset of normal term parturition. These observations have led to the in­creased study of NSAIDs, particularly indometha­cin, as possible tocolytics (Johnson 1993). Given the significant involvement of PGs in labour and parturition and the common pharmacological mechanism of NSAIDs, it is reasonable to assume that all maternally administered NSAIDs could de­lay these processes.

Despite a clear relationship in rodents and bea­gles between aspirin and both embryotoxicity and teratogenesis (Robertson et al. 1979; Wilson et al. 1977) there does not appear to be a definite parallel in early human gestation (first 16 weeks of preg­nancy) [McNeil 1973; Turner & Collins 1975]. Un­fortunately, the teratogenic effects of other NSAIDs do not appear to have been evaluated in humans but there does not seem to be a higher in­cidence of congenital malformations in the off­spring of mothers who have ingested these agents (Heymann 1986).

Although there have been a significant number of studies examining the fetal effects of NSAIDs

191

in the late gestation mammalian fetus (Heymann 1986), which have demonstrated widespread changes in fetal physiological functions, there ap­pears to be only a few parallel observations in hu­mans. Given the similarity in biochemical and car­diovascular responses between mammalian fetuses (Comline & Silver 1974; Szeto et al. 1978; van Petten et al. 1978), it is likely that similar effects are present in the human fetus but may have gone unnoticed and unstudied.

In human pregnancy, indomethacin has been re­ported to cause reduction in fetal urine output (Kirshon et al. 1988), oligohydramnios (Gold­enberg et al. 1989; Hickok et al. 1989) and after long term administration, neonatal pulmonary hy­pertension (Besinger et al. 1991). Indomethacin has also been demonstrated to be as effective as the ~2-adrenergic agonist, ritodrine, in delaying partu­rition. In contrast, sulindac, although as effective as indomethacin in delaying delivery, appears to maintain fetal urine output, amniotic fluid volume, and ductus arteriosus flow (Carlan et al. 1992). These apparent differences may, however, be rea­sonably explained by different pharmacokinetic behaviour and differing extents of placental trans­fer rather than by differences in pharmacology be­tween the two drugs.

Given that the changes in fetal physiological behaviour may be explained by PG synthetase in­hibition it must be considered that all PG syn­thetase inhibitors may exhibit similar effects.

2. Conclusion

All NSAIDs currently on the market have been exhaustively studied in clinical trials and there is little evidence to suggest that one is significantly more effective than another for the variety of rheu­matic disorders for which they are generally pre­scribed.

Therefore, in the choice of a particular NSAID for an individual patient, tolerability profiles re­main a potential way in which it may be possible to discriminate between different drugs. Clearly, all NSAIDs are associated with adverse effects, the most notable of which is NSAID gastropathy.

192

Despite the extensive studies that have been per­formed to determine the differences between NSAIDs and the induction of this effect, there is still no evidence to suggest that one NSAID is a 'better buy' than any other. Studies are currently underway, however, to try and clarify this issue.

It is not surprising that no clear-cut statement on different tolerability profiles can be made for the less common and rare adverse effects that have at times been associated with NSAIDs. Clearly, as a result of pre marketing and postmarketing studies, drugs that demonstrate any unexpected increased risk are rapidly withdrawn from the market, as was seen with benoxaprofen. Other drugs which have been in use for somewhat longer periods of time, such as the butazones, have subsequently either been withdrawn or prescribed under restricted cir­cumstances as a result of an increased risk of ad­verse effects (eg. aplastic anaemia).

There appears to be little evidence with the newer NSAIDs that one drug can be considered significantly preferable to another in terms of its tolerability profile. However, under some clinical situations one drug, because of a greater risk of a particular adverse effect, might be considered less appropriate than others. For example, most physi­cians would avoid the use of indomethacin in the elderly patient because of its greater risk of induc­ing CNS effects. Others would avoid the use of salicylates in patients on anticoagulants because of the potential for a drug interaction, but situations of this kind suggest relative contraindications to use rather than absolute contraindications.

Apart from upper GI complications, most potentially serious adverse effects with NSAIDs and those associated with significant mortality are uncommon or rare and unpredictable. Conse­quently, it seems likely that physicians and their patients are prepared to accept the continued use of these medications as their benefit-to-risk ratio is high. Whether physicians will eventually be able to choose one NSAID over another on the basis of tolerability profiles has yet to be demonstrated.

With the common adverse effects such as NSAID gastropathy it is possible that studies of

Drug Safety 10 (3) 1994

adequate power will be able to produce data that will indicate a clinical advantage of one NSAID over another. Exceptionally large studies compar­ing drugs of different NSAID classes would be required to determine definitively whether there are major differences in the tolerability of different NSAIDs with respect to the less common and rare adverse effects. It seems unlikely that studies of this particular type will be feasible in the near future.

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