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

A. del Favero

10

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

Renal side effects of non-steroidal anti-inflammatory drugs (SED-IO, 152; SEDA-5, 88; SEDA-8, 101; SEDA-9, 84; SEDA-IO, 76) In the past few years evidence has accumulated that non-steroidal anti-inflammatory drugs ( NSAID ) are able to produce a whole spectrum of renal diseases (1 oR, 2 R, 3 R, 4 oR, 5R). As our knowledge of renal prostaglandins and their role in modulating renal function in health and disease increased, it became clear that most NSAID-induced renal effects were related to the potential of these drugs to alter renal prostaglandin metabolism. This review is intended to summarize present knowledge on the renal effects of NSAID, the possible prostaglandin mechanism for these effects and the practical considerations for therapy. The spectrum of renal side effects caused by NSAID

An extensive review of the medical literature reveals a large variety of untoward renal effects associated with the use of NSAID (Table 1), but 3 main nephrologic syndromes can be identified as the most distinctive of NSAID nephrotoxicity: (a) functional renal insufficiency due to hemodynamic factors; (b) acute interstitial nephritis with nephrotic syndrome, and (c) disturbances of water and electrolyte homeostasis. Functional renal insufficiency (FRI) Due to hemodynamic factors FRI is probably the most common renal complication of NSAID. It is a functional variety of acute renal failure which Side Effects of Drugs Annual 11 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1987

results from hemodynamic changes secondary to inhibition of prostaglandin synthesis by NSAID. It occurs in a predictable fashion in some disease states in which prostaglandins have become significant determinants of renal function. These clinical disorders fall into 2 basic groups: the first group is characterized by an ineffective circulatory volume and renal hypoperfusion; the second consists o f primary renal diseases. However, other, less understood, pathophysiological conditions probably exist that also induce dependence on renal prostaglandin production for maintenance of normal renal function (Table 2). In all these conditions the use of NSAID, by inhibiting renal prostaglandin synthesis, may have a detrimental effect on renal function. NSAID-FRI is usually characterized by increasing BUN, creatinine, serum potassium, and, frequently, by decreasing urine output with weight gain. Urinalysis is negative or shows only mild degrees"of proteinuria ( < 100 mg/lO0 ml). Most often these signs and symptoms appear rapidly following introduction or increase in the dose of the offending agent or as a consequence of a change in the patient's renal or cardiovascular status. The degree of renal failure is usually moderate and complete recovery in most cases ensues within 24-72 hours after cessation of NSAID administration. However, continuation of therapy in some patients can precipitate more severe acute renal failure, and even irreversible renal failure. Life-threatening hyperkalemia, often disproportionate with respect to the severity of renal insufficiency, hepatorenal syndrome in cirrhotic patients, volume overload, acidosis, and adjunctive toxicity from drugs eliminated by the kidney have also been described. Early recognition of this syndrome is therefore crucial to reduce the risk of these complications. Although the incidence of acute renal failure attributable to NSAID is unknown,

Anti-inflammatory analgesics Table 1.

83

Chapter 10

Renal side effects o f N S A I D

Drug

FRI

NSIN

PN

TN

GLN

NS

VASC

ON

Phenylbutazone Sulfinpyrazone Azapropazone Feprazone Indometacin Clometacin Sulindac Alclofenac Benoxaprofen Bucloxic acid Dielofenac Fenclofenac Fenoprofen Flurbiprofen Ibuprofen Ketoprofen Naproxen Tolmetin Zomepirac Antrafenine Glafenine Mefenamic acid Piroxicam lsoxicam

+ + + + +

+ /| + | | +/|

+ +

+ -

. .

+

+ +

+

|

+ -

+ + | . + + + . + | +/| + /|

+ . . + . + +

-

+ + + + + + + -

.

. . + + .

.

+ / |

-

-

| + /| +/| + .

. + + .

-

. . .

.

. -

-

.

. + + -

. . +

.

.

-

. +

-

-

-

. + +

+

. . .

+ .

. .

. . + .

.

-

.

.

-

.

.

.

.

.

+ +

.

.

.

.

.

+

.

. + +

. + .

.

. . .

. + -

+

+ . + .

.

.

.

.

. . .

.

+ +

+

+ + + +

. .

.

.

( + ) = observed; ( - ) = not observed; F R I =functional renal insufficiency; NS1N = interstitial nephritis with ( + ) or without ( | nephrotic syndrome; P N = papillary necrosis; T N = tubular necrosis; G L N = glomerulonephritis; N S = nephrotic syndrome (without interstitial nephritis); VASC = vasculitis; O N = obstructive nephropathy. Table 2.

Patient groups most susceptible to functional renal insufficiency due to N S A I D

Proved

Possible

Congestive heart failure Liver failure with ascites* Nephrotic syndrome Other disorders of volume contraction (i.e. dehydration) Premature infants with P.D.A. Chronic glomerulonephritis Chronic renal insufficiency* SLE Myeloma

Elderly (especially with diabetes and hypertension) Atherosclerotic cardiovascular disease Acute gouty arthritis (precipitated by diuretics in the elderly) Patients undergoing general anesthesia Patients with sepsis, endotoxemia, serious infections Concurrent diuretic therapy Patients on low-sodium diets Chronic pyelonephritis (6c)

*Additionally, changed handling o f some N S A I D may result in patients being exposed to high concentrations of drug with possible additional injury (7 R). F R I is the m o s t c o m m o n and, in the presence o f predisposing f a c t o r s , it m a y f o l l o w the use o f any effective prostaglandin-synthetase-inhibiting drug.

Interstitial nephritis and nephrotic syndrome (NSIN) Evidence has accumulated that N S I N is the second m o s t f r e q u e n t variety o f N S A I D induced renal insufficiency. N S I N is clinically and possibly also pathologically distinct f r o m the

"classical" allergic meticillin-like interstitial nephritis seen with m a n y drugs, including s o m e N S A I D themselves. The hallmarks o f this renal s y n d r o m e which s e e m s to be characteristic o f N S A I D use (a similar occurrence has been described with only a f e w other classes o f drugs: 8 c - 1 0 c) usually include a full-blown nephrotic syndrome, often accompanied by renal failure, and the histologic demonstration o f a combination o f acute interstitial nephritis with a glomer-

Chapter 10 A. del Favero

84

ular lesion characterized by fusion o f the epithelial foot process. Factors that help to distinguish this entity from an acute hypersensitivity interstitial nephritis are the longer duration o f drug exposure (weeks or months), the higher age o f patients, the rarity o f appearance o f hypersensitivity features (such as fever, rash, eosinophilia and eosinophiluria) and the almost constant presence o f nephrotic range proteinuria. The pathophysiological mechanism o f N S I N may be one o f disordered T-cell-mediated immunity and has already been discussed (SEDA-IO, 76). Direct tubular toxicity combined with the ischemic effect o f prostaglandin inhibition could account for the renal failure seen in many patients. Clinical features that distinguish this type o f renal failure from the functional one ( FRI) are the lack o f evidence o f underlying hemodynamic or renal predisposing factors and the greater severity and duration o f renal insufficiency which, although reversible in most cases, often requires dialysis and/or steroid therapy. Although it is likely that all N S A I D can cause this syndrome, it is noteworthy that the greatest number o f cases have occurred in patients treated with fenoprofen (so-called fenoprofennephropathy ). As already mentioned, N S A I D can also produce acute interstitial nephritis with proteinuria that is not in the nephrotic range and, conversely, lipoid nephrosis unassociated with interstitial disease has occasionally been reported (see Table 1).

Interference with fluid and electrolyte homeostasis There is now substantial evidence that renal prostaglandins regulate in a complex way the maintenance o f water and electrolyte balance

and that prostaglandin inhibition induced by N S A I D administration can lead to water or salt retention, a hypo-osmolar state, or hyperkalemia. Possible pathogenic mechanisms o f these side effects are illustrated in Table 3. Although all o f these complications have been described, the vast majority o f patients tolerate N S A I D without observable symptoms. Thus, other factors must come into play to produce the abovementioned clinical syndromes. Edema A variable percentage, but still a minority o f patients receiving N S A I D (2-20% o f patients in most studies) develop some edema. The reason why most patients do not develop edema is that the control o f extracellular volume and sodium homeostasis is very closely regulated by other control systems and that edema can develop only when some avid stimulus to the kidney to reabsorb sodium is already present. This occurs most frequently in those patients who are at risk for developing FRL in particular those with borderline congestive heart failure, cirrhosis, nephrotic syndrome, and decreased renal function. All N S A I D can induce edema and their relative prostaglandin-inhibiting potency is probably less important than patient susceptibility. Hyponatremia is very rare (11 c, 12~) and has been described only in patients with renal insufficiency or receiving long-term thiazide therapy and in very low-birth-weight neonates (13c). Hyperkalemia should be considered a major side effect o f N S A I D and its incidence is probably underestimated (14 c, 15c, 16cR). Patients at risk for this complication are most often elderly "diabetics, with or without mild to moderate renal insufficiency, who may have covert hyporeninemic hypoaldosteronism. Other

Table 3. Effects of NSA1D on water, sodium and potassium metabolism Effect

Mechanisms

Clinical syndrome

Water retention

ADH effect T Medullary interstitial osmotic gradient T Renal blood flow J, Filtered load NaCl ~

Hyponatremia (Inappropriate secretion of ADH) Edema Blunting effects of diuretics and beta-blockers Hyperkalemia and related morbidity ( hyporeninemichypoaldosteronism )

Salt retention

Hyperkalemia

Tubular reabsorption NaCI T Renin, angiotensin H, Aldosterone Cellular uptake of K J, Tubular distal delivery of Na

T increased; ~ reduced.

85

Anti-inflammatory analgesics Chapter 10 patients can develop hyperkalemia in association with FRL Coexisting therapy with potassiumsparing diuretics, fl-adrenoceptor blockers, ACE inhibitors or potassium-containing salt substitutes may aggravate NSAID-induced hyperkalemia. The serum potassium concentration should be carefully monitored in these high-risk conditions and therapy discontinued in any patient who demonstrates hyperkalemia. Although most frequently reported with indometacin, this side effect can probably occur with all NSAID. Blunting of natriuretic effects of diuretics (7 R, 17") is frequently found and therefore the development of a clinical condition requiring the use of diuretics in a patient receiving N S A I D demands a reassessment of the necessity o f these drugs, and should alert the clinician to the likely need for increased dosage of diuretics. If resistant edema is encountered, the NSAID should be discontinued if at all possible. The ability of NSAID to interfere with the antihypertensive effect of diuretics as well as with that of beta-blockers, prazosin and ACE inhibitors is also well documented (17 k, 18c). This effect may be partly due to retention of salt and water, since a positive correlation between changes in body weight and the pressor effect has been found in some patients (19c). However, the sustained and substantial pressor effect that occurs in treated hypertensir subjects who receive NSAID may also be due to the inhibition of PGEt synthesis. Hypertension is associated with raised blood viscosity and PGE1 appears to play an important part in improving the flow properties of blood through its effect on red cell deformability. Thus, NSAID-induced reduction in PGE1 synthesis could be associated with raised blood viscosity, increased peripheral resistance and further increment in blood pressure (20). Sulindac may be less likely to antagonize the action of antihypertensive drugs (21R). Other less frequently encountered NSAIDinduced renal side effects can be briefly mentioned. Renal papillary necrosis and chronic interstitial nephritis Analgesic nephropathy due to longterm ingestion of compound analgesics is the most common cause of drug-related chronic renal failure and is characterized by interstitial nephritis and papillary necrosis. Although most NSAID can cause papillary necrosis in experimental animals, the clinical occurrence of this complication has been documented infrequently probably because it requires the presence of predisposing factors such as advanced age, cardiovascular disease, or volume depletion, in

addition to NSAID-induced medullary ischemia. Recently a report has been published suggesting that irreversible chronic renal failure due to interstitial fibrosis can be caused by long-term treatment with NSAID (22c). This suggestion that long-term treatment with NSAID can lead to end-stage renal failure awaits confirmation by further reports. Chronic inhibition of renal prostaglandin synthesis and/or progression of unrecognized interstitial nephritis are possible pathogenic mechanisms. Acute tubular necrosis (ATN) Acute renal failure due to NSAID may be caused by ATN. The mechanism is unclear. Tubular damage may represent the most severe expression of ischemia due to renal prostaglandin inhibition which, fortunately, in the majority o f cases is not severe enough to cause ATN. Patients at risk for FRI are also at increased risk of developing A TN and A T N is also frequently found in patients with NSIN. In this case direct tubular toxicity of the offending drug combined with the isehemic effect of prostaglandin inhibition could account for renal insufficiency in these patients. Vasculitis or glomerulonephritis Only a few cases have been described, and the vasculitis was associated with clinical syndromes such as renal failure, nephrotic syndrome or multiple organ involvement. Histological changes have included membranous glomerulonephritis, crescentic glomerulonephritis, and vascuHtis. Obstructive nephropathy This is an exceptionally rare form o f NSAID-induced renal failure. Phenylbutazone, sulfinpyrazone and piroxicam have been blamed as the cause of this complication. The drug-mediated inhibition o f uric acid reabsorption leads to hyperuricosuria and hence to uric acid precipitation with anuria. The possible pathogenic mechanisms of NSAID-induced renal insufficiency There is good evidence that the renal prostaglandin-inhibiting ability of N S A I D is the most important factor in many of the above-mentioned renal syndromes (23R). It is now clear that although during basal conditions inhibition of prostaglandin synthesis by NSAID has no significant effect on renal blood flow or glomerular filtration rate, a number of conditions characterized by decreased intravascular or effective volume with reduced renal perfusion increase the dependence of renal hemodynamic function on renal prostaglandin synthesis. These

86 conditions (see Table 2) are accompanied by increased activity of various neurohumoral vasoactive systems which results in a compensatory increase in renal prostaglandin synthesis. Consequently in these conditions, inhibition of prostaglandin synthesis induced by NSAID administration produces deleterious effects on renal blood flow and glomerular filtration rate (24 ~, 25R). Although the above-described mechanism can account for most NSAID-induced renal effects, a number of other mechanisms are less frequently involved in the pathogenesis of NSAID-related renal insufficiency; of these, immunologicallymediated mechanisms, direct tubular toxicity and precipitation of uric acid crystals are noteworthy and have already been mentioned. In some cases a drug interaction could be responsible for acute renal failure in some patients. A noteworthy example of this possibility is the concomitant administration of methotrexate ( M T X ) with various NSAID. A number of reports (7", 26c-28 c, 29~, 30~) show that this drug interaction can cause severe toxicity, including acute renal failure in most cases. Due to intrinsic nephrotoxicity o f MTX, it is difficult to say whether NSAID or M T X is responsible for the renal dysfunction, but a possible mechanism could be that inhibition of renal prostaglandin synthesis by NSAID which decreases renal perfusion and thus inhibits M T X clearance causing excessive blood M T X levels and renal and/or systemic toxicity. Since NSAID are being used with increasing frequency us pain-relieving agents in cancer patients and that M T X can be used in the treatment of rheumatoid arthritis, this interaction is of special importance. Practical considerations of therapy Are there any NSAID less likely to affect renal function? It has been suggested that sufindac differs from other NSAID by sparing renal prostaglandin synthesis (21 R, 23 R, 31c). This lack o f inhibitory action on the kidney is probably based on the pro-drug nature of sulindac. Sulindac is administered as the sulfoxide form, and is reduced to the active form in the liver. Mixed-function oxidases in the kidney can oxidize the reduced form back to the inactive pro-drug, thereby preventing cyclo-oxygenase inhibition in the kidney. However, what is emerging from the most recent literature is that sufindac's sparing of renal function is only a matter of degree and that there is clearly a susceptibility to sulindac in susceptible patients and/or at appropriate doses

Chapter 10 A. del Favero (SEDA-IO, 82; 7", 16R, 32c). Whether sulindac is substantially safer than other NSAID in the majority of conditions listed in Table 2 remains to be proved. Therefore, as far as nephrotoxicity is concerned, there is no safe NSAID. Caution concerning their use should be observed in all of them and renal function should be monitored in all patients at risk, including those treated with sufindac. What recommendations should be provided to physicians and patients for preventing NSAID renal unwanted effects? (33R) The first golden rule is to prescribe these drugs with extreme caution, at least to those high-risk subjects that have already been identified (see Table 2). If a NSAID is clearly needed in these patients, probably sufindac, due to its relative kidneysparing properties, at doses below 400 mg/d (or aspirin), could be the first choice. In patients of advanced age or with impaired renal or fiver function the selection of NSAID and of its most appropriate dosage should also take into consideration the changed handling o f some compounds in these clinical conditions (7 R, 34 R, 35R). Adequately tested guidelines for monitoring renal function in patients receiving NSAID are not yet available, but it would seem wise to suggest that, at least in the high-risk group of patients, serum creatinine and electrolytes should be measured before starting treatment, again after a week, and thereafter every 3-4 months or earlier if changes in renal or cardiovascular status occur. Patients should weigh themselves regularly, as reduction in renal function is usually associated with weight gain. With the availability, in some countries, of non-prescription preparations of some NSAID (ibuprofen, diclofenac) there is the potential for development of nephrotoxic effects in persons who are not monitored by physicians. In the United States, a Committee of the National Kidney Foundation (36) recently addressed the issue o f including warning labels with these overthe-counter preparations. The Committee recommended that the labeling include a warning in bold print: 'Do not take this product without physician supervision if." (1) you are allergic to aspirin; (2) you are under a physician's care for asthma or stomach problems (such as heartburn); (3) you take a diuretic medicine; (4) you have heart disease, high blood pressure, kidney disease or liver disease; (5) you are over 65 years of age.' Wisdom would suggest that all national drug regulatory authorities should adopt these recommendations.

Anti-inflammatory analgesics Chapter 10 In conclusion, NSAID, on the basis of their wide use and of the relatively few published reports of nephrotoxicity appear to be relatively safe drugs for the kidney, at least in nonpredisposed individuals. However, published cases and reports to national monitoring systems probably underestimate the true incidence, especially outside the hospital, of acute effects on renal function and electrolyte balance characteristics of these drugs. An improved awareness of the potential renal toxicity of NSAID, a more precise identification of patients who are most vulnerable to these unwanted effects, and serial monitoring of patients" body weight, serum creatinine and electrolyte levels may substantially decrease the risk of NSAID-induced renal side effects.

Dangers of long-term use of NSAID in osteoarthritis The use of NSAID in the routine management of osteoarthritis has been questioned on the basis of a suspected deleterious effect o f these drugs in the evolution of the disease (37 R, 38"). Disruption of joint articular cartilage and bone destruction have been described as consequences of long-term use of NSAID (39c-45c). The possible mechanisms of such deleterious effects on joints of patients with osteoarthritis are said to be of 3 types: (a) The inhibition of glycosaminoglycan synthesis in joint articular cartilage Experimentally, NSAID have been shown to suppress proteoglycan synthesis of articular cartilage and the loss of proteoglycans from cartilage is an early event in osteoarthritis, preceding mechanically-induced disruption of the collagenous network. (b) The inhibition of necrotic bone repair - In animal models NSAID have been shown to impair the ability of bone to adapt itself to increasedfunctional demands. ( c ) The deprivation of osteoarthritic joints of protective painful stimuli - The proved efficacy of NSAID in reducing pain and swelling can lead patients, whose symptoms are relieved by these drugs, to increase their activities sufficiently to cause relative joint abuse with acceleration of articular damage. If, however, one looks at the body of evidence that supports the hypothesis of such deleterious effects of NSAID on joints in human subjects, few and unconvincing data are found. Articular cartilage is composed of cells set in a matrix which comprises a collagenous framework (the fibrillary matrix) within which is entrapped the ground substance (the interfibril-

87

lary matrix) rich in water and proteoglycans. Collagen fibers (an aggregate o f collagen fibrils) have great tensile strength but cannot support a compressive load. It is the hydrostatic pressure of the water inbibed by proteoglycan aggregates retained and restrained by the collagen meshwork which gives cartilage its resilience and its load-bearing properties. Agents that suppress proteoglycan metabolism or interfere with proteoglycan aggregation in articular cartilage in vivo might therefore have a deleterious influence on the ability of the joint to resist mechanical stress and accelerate the cartilage degeneration in osteoarthritis. There is experimental evidence that inhibition o f proteoglycan synthesis in vitro and loss of these structural components is associated with cartilage softening and fibrillation. Inhibition of proteoglycan metabolism by some, but not all, NSAID has been demonstrated in vitro in animals as well as in human joint cartilage, but the degree of inhibition varied from substantial to none not only among various NSAID, animal species or individuals, but also between loaded and unloaded areas of the same cartilage. This effect appears to be independent of prostaglandin synthesis and is greater in osteoarthritic cartilage than in normal cartilage (38, 46-48). In vivo, in some animal models NSAID have been shown to accelerate spontaneous cartilage destruction, but that is not the case with all drugs or in all experimental models. The adverse effects of NSAID on cartilage appear to be inversely related to the proteoglycan content of the cartilage matrix and to the integrity of the articular surface and to be directly related to the molar concentration of the drug within the cartilage (47-52). Inhibition o f bone remodelling and delayed fracture-healing by NSAID have also been shown in some experimental models. Treatment decreases the rate of bone formation during the recovery of weakened bones. The possible mechanism of this action has not been clarified but NSAID-related prostaglandin-inhibitory activity may be important in this case. Prostaglandins may be responsible for new bone formation, since their level has been noted to increase during fracture healing and in osteomyelitis (53-55). It should be emphasized that these data are derived only from experimental studies. The effects of NSAID on the pathophysiological characteristics of the human osteoarthritic joint cannot be extrapolated from these animal data. Furthermore, our understanding of the biochemistry of the osteoarthritic process is largely incomplete. For example, we have yet to identify the role played by prostaglandins in the disorder,

Chapter 10 A. del Favero

88

and therefore the possible deleterious effect of NSAID cannot be firmly supported even on theoretical grounds. The clinical evidence supporting possible harmful effects of NSAID on cartilage and bone in human subjects is meager. Acceleration of osteoarthritis, femoral head collapse and acetabular bone destruction have been described in association with regular NSAID intake in patients with osteoarthritis of the hip. Reports of single cases or small series of clinical observations (39c-43 c) and 2 retrospective studies provide support for the hypothesis of a causal relationship between NSAID use and hip-joint damage. The first retrospective study (44 c) evaluated the radiographic deterioration of osteoarthritic hip joints in 186 patients admitted to 1 institution. The study revealed that deterioration of osteoarthritic hip joints occurred more frequently among indometacin-treated patients than in the control group. Furthermore, in the indometacin-treated hips that progressed a more serious destruction was found. However, the results of this study are difficult to interpret because the treated patients had, compared to the controls, a slightly greater (although statistically not significant) severity index at first examination and reliable information about duration and dosage of indometacin administered to the patients was not available in all cases. More detailed data come from a more recent study (45c), carried out on 64 patients who underwent primary hip replacements. In these patients acetabular destruction (measured as cranial acetabular migration on successive radiographs) was significantly correlated with regular intake of various NSAID over the period of migration. All but 6 of the 37 hips showing migration were in patients regularly taking NSAID. O f the 32 patients with non-migrating hips, only 12 had taken NSAID and of these only 7 had taken them regularly. Characteristically, NSAID use was associated with progressive formation of multiple small acetabular cysts and femoral subchondral bone thinning. Impairment of repair of necrotic bone in femoral head necrosis and of trabecular microfractures implicated in the formation of femoral and acetabular cysts is suggested as the most probable mechanism of NSAID-induced joint damage. The deprivation of osteoarthritic joints of protective painful stimuli, with consequent joint abuse, as the cause of articular damage by NSAID seems a less likely hypothesis. In fact, drugs seldom abolish pain completely and there is no evidence

that pain has a protective effect in chronic arthritis or that patients with more severe pain fare better for this reason. Furthermore, although it is widely accepted that mechanical factors are among the prime factors in the etiology of osteoarthritis, their exact role in the development of the disease is not as yet clear (56). Despite the results o f the above-mentioned studies that suggest a possible association of NSAID use with more severe joint damage, a causal relationship is by no means proven. In fact, not only have other studies (57c, 58c'), although small and uncontrolled, found no correlation between rapidly destructive arthropathy and NSAID intake, but it is also impossible to answer the important question of whether the pain is caused by destructive changes in cartilage and/or bone that lead the patients to take NSAID, or whether it is the NSAID intake that precedes or causes joint damage. Patients with a more aggressive disease might use NSAID more often and more regularly because their pain responds better to NSAID than to simple analgesics, as happens in patients with osteolytic bone metastases (59). Doubts about the suitability of NSAID for the long-term management of osteoarthritis cannot be easily dismissed in view of the wide-spread use of N S A I D and the possible negative consequences on osteoarthritic joint integrity and the results of arthroplasties. However, it seems unwise to restrain patients from using such effective painrelieving drugs when they are really needed. A clear-cut answer is therefore needed and this should be provided by a large controlled prospectire study of simple analgesics versus NSAID in the therapy of patients with osteoarthritis.

NSAID MEDICATION IN PREGNANCY AND LACTATION Musculoskeletal disorders and pain may complicate pregnancy and require drug treatment. The effects on fetal physiology as well as possible dysmorphogenic effects of NSAID need to be considered before prescribing. Moreover, when treating rheumatic disorders in women of child-bearing age, or when prescribing N S A I D for dysmenorrhea, it seems wise to select drugs that will pose the least risk to the developing fetus, thereby minimizing anxiety for the patient, should pregnancy occur. This topic has recently been reviewed

(60 R, 61R).

89

Anti-inflammatory analgesics Chapter 10 The potential of N S A I D for altering fetal physiology in the last trimester of pregnancy is well known. The evidence comes from the studies on indometacin treatment of premature labor (SEDA-5, 101; SEDA-7, 106). The drug readily crosses the placenta, reaching concentrations similar to maternal values and can have serious effects on the fetus. Renal insufficiency, oligohydramnios, water and electrolyte disturbances, intracranial or gastrointestinal bleeding, necrotizing enterocolitis and disturbed cardiopulmonary adaptation at birth have been observed. But primary pulmonary hypertension, causing respiratory distress and death, is the most severe (62c-64c). It should be mentioned, however, that such complications have, so far, not been reported in infants of patients with rheumatoid arthritis or ankylosing spondylitis who have used NSAID during pregnancy. In animal studies many N S A I D have teratogenic effects, but the only evidence in humans comes from a few reports of dubious significance (65 c, 66c). There is no evidence at present from epidemiological studies to suggest that N S A I D have an embryotoxic effect. Furthermore, when the sensitive method of determination of sister chromatid exchange frequencies was used to find possible damage by N S A I D in the hereditary material in vivo in human lymphocytes, no genetic toxic effects during a 2-week study were found (67). The clinical relevance of these studies is unknown. There is now no doubt that N S A I D can alter fetal physiology and prolong gestation and labor, and the use of these drugs in the last trimester should therefore be avoided. Unfortunately, the lack o f clinical and epidemiological studies does not allow us to make any firm suggestions about the correct use of N S A I D during the first 6 months of pregnancy. The decision must be made individually after having considered whether the potential benefits justify the possible risks. As the drug action may be a function of concentration and time, to minimize the pharmacological effects of N S A I D on the fetus, it would seem wise to use compounds with short elimination halflives at the maximally-tolerated dosage intervals. Some authorities suggest the need for contraception before prostaglandin-inhibitor drugs can be used in the premenstrual phase (68). On the evidence available this seems unnecessary. However, the risk can be avoided altogether as N S A I D for dysmenorrhea can be safely started at the onset of menstruation

without losing the therapeutic effect. The use of NSAID during breast feeding presents fewer problems (69R). Serious side effects in breastfed children have been described only with pyrazolones and indometacin (SED-10, 147; SEDA-10, 78). The newer N S A I D are all secreted into milk in amounts that are probably too small to affect the breast-fed infant. It has been suggested (69), however, that for minimal infant exposure the choice of N S A I D should be directed to compounds which have a short half-life, are found in minimal quantities in human milk, and have inactive metabolites, which also are present only in small amounts. NSAID that possess the above-mentioned characteristics are ibuprofen, flurbiprofen and diclofenac, and therefore they seem the most suitable compounds to be used during lactation. Moreover, in order to reduce the quantity of drug presented to the child, the drug should be taken by the mother at the time of breast feeding or immediately after, with the next feed occurring after a time period equivalent to the half-life of the drug. MISCELLANEOUS REPORTS Bee and wasp sting allergy alTected by NSAID? The U.K. Committee on Safety o f Medicine has received 2 reports of exaggerated responses (angioedema/malaise) to bee stings in patients taking NSAID. Both patients had been stung many times before without undue trouble. Although the evidence suggesting a causal relationship is meagre, and these reports require confirmation, it would seem wise to suggest that bee keepers should avoid the use of NSAID if at risk of being stung (70c).

Analgesic use and risks of agranulocytosis and aplastic anemia Blood dyscrasias can be caused by a variety of drugs, including many of the NSAID; among these, pyrazolone derivatives and butazones are most frequently blamed for causing agranulocytosis and aplastic anemia (SEDA-4, 63; SEDA-9, 85). Unfortunately a reasonably accurate estimate of the overall incidence of either disease and of the risk associated with the use of any particular NSAID is not available. The data published in the literature concern only the

90

effects o f some pyrazolone and butazone derivatives and risk estimates vary greatly between studies (71-75) and appear to be biased (76). The recently published International Agranulocytosis and Aplastic Anemia Study is therefore most welcome and merits a comment (77). It is a population-based case-control study conducted in 7 countries in Europe and Israel over a 4-year period: 590 defined cases and nearly 2000 controls were interviewed to determine drug exposures and other risk and disease factors; that means all detected cases in a total defined population o f 22.3 million. Efforts were made to avoid bias in case and control selection and in data selection. The final analysis involved only 221 community cases o f agranulocytosis (approximately one-third o f community cases were excluded from analysis for varhgus methodological problems) and 1425 controls, and 113 cases o f aplustic anemia and 1724 controls. Controls for community cases o f both agranulocytosis and aplastic anemia were selected from among other patients admitted to the same hospitals at about the same time, who were o f the same sex and approximately the same ages as the cases (78). The overall annual community incidence o f agranulocytosis was 4.4 per million (or 6.2 per million including hospital cases) with a fatality rate o f lO% and an annual mortality rate o f O.4 per million. Analgesics found to be significantly associated with agranulocytosis were dipyrone, indometacin and butazones (phenylbutazone and oxyphenbutazone). Individual drugs in the categories o f other pyrazolones (such as amidopyrine which is an acknowledged cause o f agranulocytosisJ or o f other N S A I D (which are not) could not be evaluated because o f the small number o f cases. The association o f dipyrone and butazones was not unexpected (79-81), but this is the first epidemiological study that suggests an increase in the risk o f agranulocytosis also with the use o f indometacin. A very disturbing finding emerges, however, in examining the excess risk f o r individual analgesic drug use. The use o f dipyrone was associated with agranulocytosis in some o f the regions under study but not in others. The estimate o f risk associated with different drugs was made by calculating the rate ratio for each drug obtained from the number o f community cases and o f controls who had taken it in the 7 days before admission to hospital. For dipyrone, but not for any other drug or group o f drugs, the rate ratio varied greatly between regions. In fact, whereas the rate-ratio estimate for all regions was 5.2, the region-specific estimate ranged from 0.9 in Budapest to 30.5 in Barcelona. Unfortunately, in

Chapter 10 A. del Favero individual regions the numbers were too small to control confounding from factors other than age and sex; hence, to provide stable multivariate estimates, the data were grouped in categories o f high rate-ratio ( Ulm, Berlin and Barcelona) and low rate-ratio (Israel and Budapest) and the results presented separately. Data from Milan and Sofia were excluded from analysis because they presented an intermediate crude rate-ratio estimate o f dipyrone use. In Ulm, Berlin and Barcelona, the multivariate rate-ratio estimate for any dipyrone use was 23.7 while in Israel and Budapest it was 0.8. This discrepancy between regions was not due to differing incidence o f agranulocytosis (17% o f the cases o f Israel and Budapest were apparently due to dipyrone, hardly less than the 23% in the study as a whole), but to the apparently high use o f dipyrone by the controls in the two above-mentioned regions. These huge disparities raise some doubts about the results, therefore, and one should be concerned about hidden bias or some methodological problems that might have affected the reliability o f the conclusions o f the study, as f a r as the estimated excess risk for dipyrone is concerned. Regional heterogeneity in the rate-ratio estimate was not evident for any other NSAID. In all regions combined, other analgesics significantly associated with agranulocytosis were indometacin (rate ratio o f 8.9) and butazones (3.8). Much lower, but not statistically significant, estimates were found for salicylates (1.6), pyrazolones other than dipyrone (1.2), and paracetamol (1.0). From these data the estimate o f the excess risk o f agranulocytosis from dipyrone use is much lower than that found in previous studies (71, 72, 74, 75). Although expressed in a somewhat confusing way, the excess risk attendant on at least 14 consecutive days o f use o f dipyrone is 3.3 per million takers for the regions where the association was strongest. Also very interesting are the data on aplastic anemia, since this study is the first to provide excess risk estimates o f this side effect in users o f NSAID. The overall annual incidence has been found to be 2.2 per million, with a 2-year fatality rate o f 49%. An estimate o f the risk associated with different analgesics was made by calculating the rate ratio f o r each drug obtained from the number o f cases and o f controls who had taken it in the period between 29 and 180 days before hospital admission. Approximately 33% o f cases were excluded from final analysis due to various methodological problems. Any exposure to 3 different drugs was found to be significantly

Anti-inflammatory analgesics Chapter 10 associated with an increased risk of aplastic anemia: indometacin (multivariate rate-ratio of 12.7), butazones (8.7) and, unexpectedly, diclofenac (8.8). Although based on small numbers, there is some evidence that the risk is 4 times higher if indometacin or butazones, but not diclofenac, were taken regularly and for a sustained period. There was no evidence of an association with the use of dipyrone or other pyrazolones. Somewhat elevated rate-ratio (approx. 2.1) estimates were also found for other NSAID, but these results could have been due to chance. However, due to the fact that individual drugs in this category have been implicated in case-reports as possible cases of aplastic anemia (SEDA-5, 96), these agents will require further study. Also for aplastic anemia the absolute risk associated with all of these drugs appears to be very low: for exposures occurring in a 5-month interval, the estimated excess risk of aplastic anemia ranges from 6.6 to 10.1 per million, but the fatality rate is very high. A final comment on the possible public health implications of the results of this study would seem in order, particularly in view of the recent claims made by Hoechst, the main dipyrone manufacturer, that the study provides evidence that dipyrone is clearly safer than had been thought, and that in view of the improved risk~benefit status of the drug, ~ has to consider submitting an application for marketing approval in countries where dipyrone has never been launched or is no longer available due to regulatory actions (82). The company's main message that agranulocytosis had been 'the problem' with dipyrone and that this problem is now "solved" is, in fact, misleading. The study confirmed that dipyrone can induce agranulocytosis. It has been found responsible for about a quarter of the drug-induced cases in the participating countries; in some regions patients who had taken dipyrone in the previous week were 20-30 times more likely to develop agranulocytosis than non-takers. Although the absolute risk is much lower than was previously thought, it is, however, by no means slight if one takes into account the size of the drug-exposed population. It has been calculated from the excess risk of 1.1~million~week which arises from the study and from Hoechst's estimates of 20 million doses dispensed daily, that 22 cases of dipyroneinduced agranulocytosis would be seen daily, or over 7000 cases annually worldwide (82). Since safer and equally effective drugs, for the main indications of dipyrone, exist (i.e. paracetamol and salicylates) , dipyrone use should be at

91

least restricted to patients who cannot use the above-mentioned drugs. Unfortunately the drug is still freely available over-the-counter in many developing countries and even in some countries in Europe (83, 84). This study is very impressive and the results, despite some setbacks (or drawbacks), very important for the prescribers, drug regulators and pharmaceutical companies. It indicates the way in which the risks of marketed drugs should be examined, provided that such studies are carefully designed and conducted to deal with confounding factors and other complexities characteristic of observational studies of this type. What is clear is that such studies are in the interest of the consumer, the medical community, the government and the pharmaceutical industry itself. Who will fund and conduct them remains, however, an unanswered question (85).

PYRAZOLONE DERIVATIVES (SED-IO, 153; SEDA-9, 84; SEDA-IO, 78)

Dipyrone (SED-IO, 158) (see Special Review above) Hematemesis and melena occurred in a child treated with dipyrone and betamethasone. A 4-year-old child received combined treatment with dipyrone (750 mg/d for 3 days) and betamethasone (2 0.2 mg doses) for an acute febrile pharyngitis. Twenty-four hours after the last dose the child was admitted to hospital with severe abdominal pain, hematemesis, melena and anemia requiring blood transfusion. After supportive treatment, including cimetidine, rapid recovery ensued and a gastroscopy performed 1 month later disclosed a healed prepyloric ulcer (86c).

Pirazolac This is a pyrazoleacetic acid derivative under early clinical evaluation. Side effects observed during clinical trials include: heartburn and upper abdominal pain occasionally severe enough to require interruption of treatment; lip ulcers; cutaneous manifestations (scaly rash, papular skin eruptions, exacerbations of preexisting eczema) and eosinophilia (87c).

4-(lsopropylamino)phenazone(Tomanoi) Embolia cutis medicamentosa is a wellknown side effect of parenterally administered pyrazolone derivatives (SEDA-8, 102). This

92 inappropriate route of administration may have even more severe consequences as were seen, for example, in a young man treated parenterally with Tomanol for 'flu'. The inadvertent intra-arterial injection caused brachial artery occlusion and gangrene of the hand and distal forearm which necessitated amputation

(88% Azapropazone ( SED- I O, 156; SED A-8, 102; SEDA-9, 87) Risk situations Azapropazone protein binding is considerably reduced both in cirrhotic and in renal insufficiency patients. Furthermore, clearance of the unbound drug is reduced by cirrhosis and, probably, also by renal insufficiency. To reduce the risk of dose-related side effects it would seem wise to carefully adjust the dose in these patients (89, 90). I N D O M E T A C I N AND RELATED COMPOUNDS (SED-IO, 158; SEDA-8, 102;

SEDA-9, 88; SEDA-IO, 79) Acemetacin (SED-IO, 161) As experience accumulates, it is becoming apparent that the side effect profile of this drug is similar to that found with the parent compound, with gastrointestinal adverse symptoms being the most commonly encountered (91c), despite the fact that in a 10-day endoscopic study on volunteers treated with acemetacin fewer mucosal lesions were seen than with indometacin itself (92).

lndometacin (SED-IO, 158; SEDA-8, 102; SEDA-9, 88; SEDA-IO, 79) Renal potassium wasting and hypokalemia are constant features of Bartter's syndrome, and NSAID administration usually improves but does not completely correct the hypokalemia. Severe hyperkalemia has been observed in a 48-year-old patient with Bartter's syndrome receiving concomitant treatment with indometacin and oral potassium chloride (93c).

Sulindac (SED-IO, 160; SEDA-8, 105; SEDA-9, 89; SEDA-IO, 82) Nervous system Acute encephalopathy has been reported after sulindac (SEDA-5, 101), but a recent case is characterized by the fact that CNS symptoms were accompanied by

Chapter 10 A. del Favero other clinical and laboratory findings. A 38year-old patient with ankylosing spondylitis developed a diffuse maculopapular rash and fever and he became confused and agitated within l0 days after initiating therapy. Elevation of liver enzymes, bilirubin and creatine phosphokinase was also present. The patient made a rapid and complete recovery (94c).

Liver New cases of sulindac hepatitis have been described (95 c, 96c). Liver biopsy in these cases disclosed similar histological features: a striking variability in hepatocyte nuclear morphology, marked anisonucleosis with cytoplasmic invagination into the nucleus, prominent nuclear vacuolation and binuclear hepatocytes. Whether the liver damage in these patients was due to a toxic effect of the drug rather than being immune-mediated is not clear. Gastrointestinal Both the pro-drug sulindac sulfoxide and the active sulfide metabolite failed to produce any significant gastric mucosal lesions when administered orally to normal volunteers for 7 days in a double-blind, crossover endoscopic study (97). Skin Multiple erythematous nodules, an expression of subcutaneous fat necrosis, confined to the lower part of the legs appeared 289 months after treatment with sulindac. The nodules resolved over a 2-week period after stopping treatment, but recurred on readministration of the drug. Subcutaneous fat necrosis is a rare manifestation of underlying pancreatic disease. Sulindac can cause pancreatitis (SEDA-7, 105) and this patient presented the cutaneous ma~aifestations with a simultaneous rise in serum amylase, but never developed other signs of pancreatitis (98c).

Risk situations Sulindac seems well tolerated by geriatric patients, as it was not associated with any increased side effects when 2 age groups of patients were compared in a large open multicenter study (990. A R Y L A L K A N O I C A C I D DERIVATIVES A N D RELATED COMPOUNDS

(SED-IO, 161; SEDA-8, 105; SEDA-9, 89; SEDA-IO, 82) Carprofen (SED-IO, 166; SEDA-8, 105; SEDA-IO, 82) Respiratory system Asthma may be precipitated by carprofen in aspirin-sensitive patients (1000.

93

Anti-inflammatory analgesics Chapter10 Gastrointestinal

Carprofen seems to be well tolerated in patients with peptic ulcer treated with ranitidine, but in interpreting the results of such a trial it must not be presumed that carprofen can be used without risk in patients with ulcer disease (lOP).

Dexindoprofen ( SED A- I O, 82) Very preliminary experience with this indoprofen derivative shows that the drug can cause gastrointestinal symptoms (nausea, epigastric pain), skin reactions and stomatitis. Interruption of treatment due to drug-related side effects was necessary in 5% of patients in a short-term study (102c).

Diclofenac (SED-IO, 164; SEDA-8, 105; SEDA-9, 90; SEDA-IO, 82) Nervous system

Intravenous injection of diclofenac was well tolerated except for a stimulating effect characterized by euphoria and sleep disturbances (103c). Hematological Reversible hemolytic anemia or thrombocytopenia have been described in association with diclofenac treatment but Evan's syndrome (coexistence of immune thrombocytopenia and hemol)gtic anemia) has not been previously reported (104c). This patient exhibited an ~-methyldopa-type of autoantibody reaction.

Liver Two new cases of hepatitis with jaundice, probably due to diclofenac, have been described. In both cases the clinical, biochemical, and histopathological findings suggested an allergic drug reaction (105c). Urinary system Renal papillary necrosis occurred in a 59-year-old man treated for 5 years with diclofenac and previously with naproxen and ibuprofen for long periods (106c). Diclofenac should be added to the list of NSAID that cause interstitial nephritis with nephrotic syndrome (107c). Renal biopsy disclosed interstitial edema and inflammatory infiltration together with a diffuse fusion of the foot processes of the glomerular visceral epithelial cells.

Intramuscular administration Creatine-phosphokinase serum levels can be increased severalfold above normal limits by intramuscular injection of diclofenac. It seems that neither the mechanical trauma of the injection nor the

'volume effect' of injected fluid can be blamed for this increase (108c), and factors other than direct toxic effect of the drug on muscle tissue may contribute to this altered creatine-phosphokinase activity (109). This fact may be of clinical importance since intramuscular NSAID are often used inappropriately in the treatment of various acute pain syndromes and the rise in creatine-phosphokinase values can persist for several days after the last injection, thereby subjecting the patient to avoidable investigations.

Diphenpyramide ( S E D- I O, 167) A review of the side effects reported in clinical trials with diphenpyramide shows that the most frequent are gastrointestinal (heartburn, nausea, vomiting, epigastric and abdominal pain, diarrhea) followed by CNS (headache, vertigo, dizziness) and skin reactions (110R).

Etodolac (SEDA-8, 110; SEDA-9, 89; SEDA-IO, 83) Modest reductions in renal function, as measured by clearances of inulin and sodium p-aminohippurate have occurred in patients with moderate renal impairment, but not in normal subjects. Chronic therapy, however, has not led to any decreases in daily creatinine clearance (11 It). These findings should not be extrapolated to other etodolac regimens or other susceptible patient groups.

Fenclofenac ( SED-IO, 165; SEDA-9, 90; SEDA-IO, 83) Selective IgA deficiency has been reported with this drug in 1 patient with associated improvement of his rheumatoid arthritis (112~).

Flurbiprofen (SED-IO, 163; SEDA-8, 106; SEDA-9, 91; SEDA-IO, 83) Long-term studies aimed at evaluating both the efficacy and safety of flurbiprofen in the treatment of patients with various rheumatological disorders disclosed that side effects leading to interruption of treatment occurred in 19% of patients. These unwanted effects were similar to those of other NSAID, the most frequent being gastrointestinal, dermatological and neurological. There was no correlation between the frequency or severity of the side

94 effects and the dose of flurbiprofen administered (113 c- 115r Flurbiprofen suppositories may cause local discomfort and proctitis (116c).

lbuprofen (SED-IO, 162; SEDA-8, 106; SEDA-9, 91; SEDA-IO, 83)

Hematological A patient treated with ibuprofen presented with reversible pure white-cell aplasia and bone marrow plasmocytosis. The occurrence of a complement dependent IgG antibody was demonstrated in the patient's serum. In the presence of ibuprofen this antibody significantly inhibited the in-vitro growth of myeloid precursors in bone marrow from both the patient and a normal volunteer

(117c).

Skin Contact dermatitis caused by an ointment containing ibuprofen has been reported (ll8r

Chapter 10 A. del Favero

Oxaprozin (SED-IO, 168; SEDA-8, 107; SEDA-9, 92) More experience has accumulated with this propionic acid derivative (123r162 131R). The adverse reaction profile of oxaprozin, as far as is known from the published literature, seems to be comparable to that found with other compounds of the same class. In longterm clinical trials, oxaprozin was better tolerated than aspirin and had an overall incidence of side effects similar t o that of comparable drugs (ibuprofen, piroxicam). The incidence of side effects during treatment varied from 26% to 53 %, but the percentage of adverse reactions judged to be definitely drug-related by the investigators was much lower. Treatment had to be interrupted due to side effects in 8-31% of patients.

Nervous system Although headache, dizziness, vertigo and tinnitus were observed, they were less frequent than with indometacin or aspirin (126 r 130~).

lndoprofen (SED-IO, 166; SEDA-8, 106; SEDA-9, 91) Aplastic anemia, possibly related to indoprofen treatment, has been observed in a patient with systemic lupus erythematosus (119c).

Ketoprofen (SED-IO, 163; SEDA-8, 106; SEDA-9, 92) A cholinergic crisis was precipitated by a single dose of ketoprofen in a myasthenic patient well controlled by neostigmine bromide. Ingestion of aspirin provoked a milder reaction but paracetamol was reaction-free (120c). Risk situations The clearance of total drug in elderly patients is approximately half that in young age groups. No data are available on free-drug concentrations, but it would appear wise to decrease the dose of ketoprofen in the elderly in order to avoid dose-related side effects (12V).

Naproxen (SED-IO, 166; SEDA-8, 107; SEDA-9, 92; SEDA-IO, 84) A case of Coombs' positive autoimmune hemolytic anemia was reported after a 2-week course of naproxen. This is the second case to be reported (122c),

Hematological Despite frequent decreases in hemoglobin levels (0.5-3.7 g/100 ml) they were not generally considered serious or related to gastrointestinal bleeding (125 c, 127c, 130~). A decreased leukocyte count was also found in 1 patient (126c). Liver An analysis of data collected in Phase I and III studies in 1338 patients reveals that oxaprozin treatment can lead to minor ( < 3 times the upper limits of normal) rises in transaminase in 10-20~ of patients with various rheumatic diseases, but a much lower percentage had elevations of greater clinical significance (1.1%). Anicteric drug hepatitis developed in 1 patient (132cR). Sometimes the elevated values returned to normal despite continuation of therapy. The mechanism and the clinical significance of these modifications are not clear, but it would seem appropriate to monitor liver function, especially during the first 6 months of treatment, and to withdraw the drug if significant laboratory abnormalities persist. Gastrointestinal As usual, gastrointestinal disturbances were the most frequently reported side effects and the most often cited reason for discontinuation of treatment. Abdominal pain or discomfort, diarrhea, nausea, vomiting and dyspepsia were observed. Gastric or duodenal ulcer or overt gastrointestinal bleeding were

95

Anti-inflammatory analgesics Chapter 10 rarely reported. Occult bleeding also occurred (123 ~, 125~, 12&).

Urinary system Oxaprozin probably does not differ significantly from other NSAID in its capacity to adversely affect renal hemodynamics and salt and water homeostasis. In studies performed in normal, sodium-depleted, volunteers, chronic oxaprozin administration has been shown to produce a slight but persistent decrease in the glomerular filtration rate, which was not seen with indometacin. Oxaprozin also reduced potassium clearance, without altering serum potassium. It also reduces urine flow rate and free water excretion (133c). In 3-12month clinical trials oxaprozin was responsible for the same low incidence (4-6%) of potentially important increases in BUN or creatinine, as were both aspirin and ibuprofen (131r). Skin Macular, unspecified rashes occurred in less than 5% of patients and were sometimes the reason for interrupting treatment (124 r 125~, 130r Risk situations Analysis of adverse reactions encountered in controlled clinical trials with oxaprozin, stratified by age, revealed that older patients may be more likely to suffer gastrointestinal reactions, hematological toxicity and nephrotoxicity than younger patients (134c). These observations were not uniformly seen in all studies and factors other than age may have contributed to the overall toxicity of oxaprozin in older patients. However, the observed agerelated increase in adverse reactions could be related to the kinetic characteristics of the drug. A recent report that assessed the handling of oxaprozin in elderly patients (135) showed that both renal clearance and volume of distribution decreased with age. The elderly patients' clearance of the total drug was approximately half that of the young patients. If the decreased total drug clearance is indicative of decreased clearance of unbound drug, then the dose of oxaprozin should be reduced in elderly patients. This may also be true in patients with renal insufficiency (131 ~, 13&, 137~).

Pirprofen (SED-IO, 164; SEDA-8, 107; SEDA-9, 92; SEDA-IO, 84) Liver Three more cases of pirprofen-induced icteric hepatitis have been reported (138r All exhibited the pattern usually described in these cases: relatively long incubation period (from 1 to several months of treatment); mixed cytolytic-

cholestatic hepatitis; a prodromic phase characterized by general malaise, vomiting and fever; and progression of the disease, sometimes to death. The mechanism of this drug-induced hepatitis is unknown. A tardive cutaneous reaction has been described in 2 of these patients. Close monitoring of liver enzymes and the clinical condition is obligatory in all patients taking pirprofen for more than 2 weeks until the safety of this drug has been better established.

Snprofen (SEDA-8, 107; SEDA-9, 93; SEDA-IO, 84; 122R) Suprofen given in single or multiple intramuscular or intravenous doses in patients and healthy volunteers is well tolerated (139r Side effects observed were burning pain, urticarial reactions and pruritus. Intramuscular injection caused significant elevations of serum creatine-phosphokinase levels that returned to normal within a few days after stopping treatment (108c). Whether this good tolerability also applies to patients, especially with respect to the possible impairment of renal function, requires more studies (141c).

Urinary system In the United States, 16 cases of abrupt onset of loin pain accompanied by evidence of decreased renal function occurring shortly after an initial dose of suprofen have been reported by the manufacturer to the FDA. Very few similar reports have come from Europe, despite the longer and more extensive use of the drug. In all cases renal function returned to normal within 5-10 days after discontinuation of suprofen. The United Kingdom drug data sheet has been amended accordingly and, in the United States and the United Kingdom, the manufacturer has issued a 'dear doctor' letter asking physicians to prescribe suprofen only with caution, and to consider alternative analgesics while the case frequency and severity of this reaction are being assessed (143 c, 144c).

Tiaprofenic acid (SED-IO, 166; SEDA-8, 107; SEDA-9, 84; SEDA-IO, 84) Liver Anorexia, extreme lethargy and increases in serum transaminase and alkalinephosphatase levels but not in total bilirubin, occurred in 1 patient on 2 occasions following therapy with this drug (145c). Skin A case of polymorphous allergic vasculitis has been reported (146c).

Chapter 10 A. del Favero

96 Tolmetin (SED-IO, 165; SEDA-9, 93;

SEDA-IO, 84) Tolmetin precipitated a Coombs' positive immune-hemolytic anemia in 1 patient. The mechanisms of the immune hemolysis are unclear (147c).

Zomepirac (SED-IO, 167; SEDA-8, 108; SEDA-9, 93; SEDA-IO, 84) Zomepirac has been reported to cause a wide range of renal side effects. A recent report describes reversible renal failure and nephrotic syndrome with a biopsy showing fusion of foot processes consistent with minimal change disease but without evidence of an interstitial nephritis. This has never been described before (148c). A N T H R A N Y L I C ACID DERIVATIVES

(SED-IO, 168; SEDA-8, 109; SEDA-9, 93; SEDA-IO, 84) A review of side effects related to glafenine, antrafenine and floctafenine therapy reported to the 'Centres des Pharmacovigilance Hospitali~re' and to 'Laboratoires Pharmaceutiques' (France) has been published (149a). During the 31 months of surveillance, 734 reports were

judged to be possibly or probably drug-related (therapeutic doses only) for glafenine, 33 for antrafenine and 38 for floctafenine (Table 4). The side effect profile is very similar for these 3 chemically-related compounds. The most frequent and serious side effect - shock occurred almost always after injection of only 1 dose. Shock was accompanied in many cases by Quincke's edema, dyspnea or urticaria. In almost 50% of cases the drug history revealed previous exposure to glafenine or other anthranylic acid derivatives, suggesting a sensitization mechanism. A very rough estimate of the relative incidence of side effects gives 3.4 side effects per 105 treatment courses for glafenine, 1.3 for antrafenine and 0.5 for floctafenine.

Glafenine Occurrence of Coombs' positive hemolytic anemia with or without renal failure is not infrequent in patients taking glafenine (SED-10, 169). Two patients who developed acute hemolytic anemia with renal failure after administration of glafenine were found to have anti-glafenine antibodies with an associated red blood cell autoantibody. Both antibodies were shown to have the same membrane receptor (150c).

Table 4. Results in a 31-month-longprospective study on side effects of glafenine ( G), antrafenine (A ) and floctafenine (F) (149) Side effects

Systemic effects (cardiovascular)

Skin

Kidney

Number of reports G

A

F

Total

155 107 71 333 (45%)

5 5 6 16 (48%)

2 3 5' I0 (26%)

Total

78 144 222 (30%)

1 6 7 (22%)

6 6 12 (32%)

Acute renal insufficiency Loin pain Total

56 22 78 (I1%)

2 3 5 (15%)

4 4 (10%)

69 (9%)

2 (6%)

3 (8%)

5 1 2 8 (1%)

1 I (3%)

3 3 (8%)

4 (0.5%)

0

1 (3%)

2 (6%)

5 (13%)

Shock Hypotension Faintness Urticaria Other

Quincke's edema (isolated) Hematological

Hemolytic anemia Thrombocytopenia Leukopenia Total

Liver Others

Hepatitis

20 (3%)

Anti-inflammatory analgesics Chapter 10

Etofenamate

97

Piroxicam (SED-IO, 170; SEDA-8, 110; SEDA-9, 94; SEDA-IO, 85)

This topical anthranylic acid derivative can cause local irritation or contact dermatitis in less than 0.8-2% of patients; therapy had to be interrupted due to side effects in 0.1% of cases (151 r 152c).

Mefenamic acid Kidney Despite the well-known risk of renal failure during therapy with mefenamic acid in the elderly, when dehydration secondary to drug-related diarrhea or to the concomitant use of diuretics occurs, this drug continues to be prescribed for this group (153 c, 154c).

Skin An unusual association of Coombs' positive hemolytic anemia, diarrhea and bullous pemphigoid developed in a 52-year-old man treated with mefenamic acid for 9 months. Complete recovery ensued when therapy was stopped (155c). Pancreas Acute pancreatitis has been described in a 20-year-old woman taking mefenamic acid for dysmenorrhea. Pancreatitis recurred on rechallenge with the drug (156c).

Meclofenamate sodium This drug, like other NSAID, may reduce proteinuria in some patients with nephrotic syndrome, but can cause deterioration in renal function in some cases (157c).

OXICAM DERIVATIVES

lsoxicam (SED-IO, 170; SEDA-9, 95; SEDA-IO, 88) Data collected from more than 1800 patients with rheumatoid arthritis or degenerative joint disease in Phase III clinical studies indicated that isoxicam is well tolerated on both a short- and a long-term basis. Noteworthy is the fact that although adverse reactions affecting the skin ranked as the second most frequent group of side effects after those affecting the gastrointestinal system, no severe mucocutaneous reactions similar to those that prompted withdrawal of the drug were reported. The unwanted effects on the gastrointestinal system appear to be doserelated (158r).

Intramuscular administration The side effect profile with intramuscular administration o f piroxicam is similar to that found with oral medication (159 c, 160~ gastrointestinal side effects being the most frequent. Local tolerability seems good. Gastrointestinal toxicity o f piroxicam in the elderly The suspicion that piroxicam may cause peptic ulceration and severe gastrointestinal bleeding, especially in the elderly, continues to be discussed. The topic has recently been reviewed (SEDA-IO, 85) and new data were presented early in 1986, at the FDA hearing on piroxicam (161c). The controversial questions o f this problem are: (a) Is there any convincing evidence that piroxicam causes more damage in the stomach than other NSAID? (b) Is its gastrointestinal toxicity more serious in the elderly or does it simply appear in that age group because these drugs are more commonly used in older patients? (c) Is there any pharmacological basis for increased toxicity in the elderly? The evidence The new data presented at the FDA hearing included the results of 4 studies and 2 reports to regulatory national agencies (see Table 5) that blamed piroxicam for greater gastrotoxicity. Other studies have found that the gastrointestinal intolerance o f piroxicam is similar to that of other NSAID (161 c, 162~, 163"). The conflicting results in these studies are difficult to interpret, not only because the available data make calculating the absolute risk o f gastrointestinal piroxicam toxicity impossible, but also because the relative-risk evaluation with respect to other NSAID is open to a number of criticisms (161, 164-167). It cannot, therefore, be concluded with any confidence that piroxicam is more toxic than other NSAID (SEDA-IO, 85; 168~-170~).

More serious toxicity in the elderly? There is no doubt that serious gastrointestinal reactions with NSAID occur more commonly in the elderly, especially in elderly women, than in younger patients. The Committee on Safety of Medicine (U.K.) received about 3500 reports of upper gastrointestinal bleeding or perforation suspected of being caused by N S A I D between

98

Chapter 10 .4. del Favero

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r~

~^

Anti-inflammatory analgesics Chapter 10 1964 and 1985. Nearly 75% o f these reports concerned patients aged 60 or older. Over 600 o f these 3500 reports involved deaths and roughly 90% o f them were in people aged 60 or over (168 c, 169c). Other studies support this pattern o f spontaneous reports (163 c, 171c-175 c) and the 2 most recently published are worth noting (176 c, 177c). Sommerville's study is a case-control study that provides evidence that the risk o f admission to hospital with bleeding peptic ulcer f o r patients o f both sexes aged 60 or over is substantially increased in takers o f NSAID, irrespective o f whether the ulcers are gastric or duodenal. However, the study did not provide sufficient data to say with any confidence that piroxicam (or other N S A I D ) is likely to be especially harmful. Walt's study adds further evidence on the contribution o f N S A I D to peptic ulceration in the elderly. It shows that the annual number o f NSAID prescribed between 1967 and 1982 to women over 65 years increased 3-fold and that admissions for perforated ulcer doubled during that period. In men, there has been a similar increase in prescriptions associated with a fall in duodenal ulcer admissions in those aged between 64 and 74 years, and a sharp increase in those aged over 74 years during the same period. Admission rates for ulcer perforation have fallen in all other age groups despite annual increases in the number o f N S A I D prescri~tions. However, that the excess o f side effects in the elderly is, at least in part, due to the fact that the elderly are more likely to be exposed to NSAID, rather than to their potential danger in these patients, cannot be completely refuted, even in the face o f the growing evidence that the elderly, part&ularly women, may be unduly susceptible to serious gastrointestinal adverse reactions o f NSAID. This is the case not only f o r the whole category o f NSAID, but also f o r piroxicam itself. Two large studies, I double-blind comparative in 2035 patients, and the other open-label in 2845 patients (162 r 163 c) found hardly any variation in the incidence rate o f gastrointestinal side effects between the individual age group, or between piroxicam and the comparative drug, naproxen, thereby confirming previous similar experience (SEDA-IO, 85). Unfortunately, the number o f patients included in these studies was not large enough for the conclusions to be entirely reliable. On the whole, we can conclude that the elderly, especially women over 60, are certainly contributing to the occurrence o f severe gastrointestinal side effects more than other groups. The factors responsible for their undue susceptibility

99

to NSAID bleeding and/or perforated peptic ulceration are at present ill-defined.

Pharmacological basis Critical points are our knowledge o f the pharmacokinetic characteristics o f piroxicam in the elderly and the evidence that gastrointestinal side effects are dose related. Multiple-dose studies carried out in the elderly (178, 179) have disclosed that they have a higher mean steady-state plasma concentration and a greater variation in blood levels than younger age groups, though conflicting data have been published (161), Although the clinical significance o f these age-related pharmacokinetic modifications are not completely clear, they are probably important. In fact, at the Feldene hearing at the FDA, an internal manufacturer's document was cited which showed that the ulceration rate increases with the dose:from 0.4% (2/526 patients) f o r a 10 mg daily dose to 5.9% (22/372) for a 40mg daily dose (SEDA-6, 99; 161). Other studies have failed to correlate piroxicam blood concentrations with gastrointestinal side effects (178), but the fact that gastrointestinal toxicity is at least partly a systemic effect (180, 181) and the fact that intramuscular piroxicam is characterized by the same gastrointestinal side effect profile as that experienced with the oral dosage form, suggest that more serious gastrotoxic effects may be related to higher blood levels o f the drug. In conclusion, we can say that clear-cut data showing a greater gastrointestinal toxicity o f piroxicam than o f other NSAID are simply not available but that clinical and pharmacokinetic data tend to support the fact that piroxicam increases the risk o f dose-related gastrointestinal side effects, especially in elderly women. Whether this is a common property o f most N S A I D or only a few requires clarification. At the same time, some suggestions can be made regarding the use o f piroxicam in the elderly. Its long half-life should not be considered a totally beneficial characteristic and the drug should be given to the elderly only after other forms o f treatment have been carefully considered. Moreover, it would seem wise to start treatment at the lowest end o f the dose range, and avoid increasing the daily dose above 20 mg.

Skin The simultaneous occurrence of a photosensitivity eruption and palmar dyshidrotic eczema in 2 patients has been described. Whether these manifestations are a variant of drug-

Chapter 10 A. del Favero

100 induced photosensitivity or simply a coincidence is not clear (182c). Special senses Tinnitus has been observed in a small percentage of patients (0.2%) taking part in clinical trials. A case of permanent sensorineural hearing loss secondary to piroxicam usage has been described. Two cases have also been reported to the manufacturer in the United States, but they reversed with cessation of the drug. Coincidental onset of sudden hearing loss when the drug was started cannot be excluded, however (183c).

relatively frequent with nausea, drowsiness and sweating being the most frequently reported. Insomnia, pruritus, malaise, dizziness, urine retention, respiratory depression and convulsions are also described (see Chapter 8).

Orgotein (SED-IO, 172; SEDA-9, 85) Intradermal injection of orgotein caused long-lasting skin atrophy (192~). Pyritinol (SED-IO, 1721" SEDA-8, 111; SEDA-9, 96; SEDA-IO, 89)

Tenoxicam (SEDA-8, 111) A relatively high percentage of patients (15-20%) was withdrawn from treatment due to the occurrence of drug-related side effects. Most of these patients suffered from gastrointestinal adverse reactions (abdominal pain, indigestion, vomiting, dry mouth). Other side effects encountered were headaches, skin rashes and polyuria (184 r 185r

Aggressive behavior has been described in 2 elderly patients treated with pyritinol (193c).

DRUGS USED IN THE TREATMENT OF GOUT (SED-IO, 172; SEDA-8, 111; SEDA-9, 96; SEDA-IO, 89)

Allopurinol MISCELLANEOUS DRUGS Benzydamine Skin reactions, including cases of photosensitivity, have been reported (186). When used topically it can cause contact dermatitis (187c).

Emorfazone This anti-inflammatory and analgesic compound is in its initial clinical investigation. Side effects reported in the very few clinical studies are sleepiness, dry mouth, rash, anorexia, nausea, vomiting, diarrhea and constipation (188r).

Flupirtine In a comparative study of treatment of postoperative pain, flupirtine was found to cause minor side effects in 26% of patients. CNS symptoms were the most common (visual disturbances, disorientation, hallucinations, confusion and tremors) (189c).

In normal subjects a low-protein diet greatly reduces the total body clearance of the allopurinol metabolite, oxypurinol, because of a large increase in its net renal tubular reabsorption. This finding may have important clinical implications since malnourished patients, patients on low-Protein diets, and those receiving prolonged intravenous dextrose infusions without protein or amino acid supplementation may develop increased plasma concentrations of oxypurinol during long-term therapy with allopurinol, thus increasing the risk of side effects (194c).

Interactions The increased incidence of exanthemas previously observed in patients concomitantly treated with aminopenicillins and allopurinol has not been confirmed by a recent study (195c). The uricosuric agent benzbromarone can increase oxipurinol renal clearance when given concomitantly with allopurinol (196c).

Sulfinpyrazone

Nefopam This derivative of orphenadrine has analgesic properties (190 c, 191r Side effects are

Sulfinpyrazone, like other NSAID, interferes with the antihypertensive activity of betablockers (197c).

Anti-inflammatory analgesics

Chapter 10

101

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Anti-inflammatory analgesics

Chapter 10

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Anti-inflammatory analgesics

Chapter 10

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106 192. Goerz G, Kurz E (1985) Passagere Hautatrophie nach lokaler superoxid-dismutase Injektion. Aktuel. DermatoL, 1l, 88. 193. Kanowski S (1985) Zunehmende Aggressivit/it durch Pyritinol? Dtsch. Med. Wochenschr., 110, 1142. 194. Berlinger WG, Park GD, Spector R (1985) The effect of dietary protein on the clearance of allopurinol and oxypurinol. N. Engl. J. Med., 313, 771. 195. Sonntag MR, Zoppi M, Fritschy D et al (1986) Exantheme unter h/iufig angewandten Antibiotika und antibakteriellen Chemotherapeutika 0Penicilline, speziell Amino-penicilline, Cephalo-

Chapter 10 A. del Favero sporine und Cotrimoxazol) sowie Allopurinol. Schweiz. Med. Wochenschr., 116, 142. 196. Farinotti R, Fredj G, Clavel JP et al (1986) Interaction pharmacocin~tique entre le m6tabolite actif de l'allopurinol et la benzbromarone. Presse M~d., 15, 579. 197. Ferrara LA, Mancini M, Marotta T et al (1986) Interference by sulphinpyrazone with the antihypertensive effects of oxprenolol. Eur. J. Clin. Pharmacol., 29, 717. 198. St. John Collier D, Pain JA (1986) Ulcer perforation in the elderly and non-steroidal antiinflammatory drugs. Lancet, 1, 971.