Drug therapy is only one of the many stepping stones to the successful management of rheumatic diseases in children. Recently, however, it has gained an increasingly important role in the overall management program for this group of conditions. Aspirin is the original nonsteroidal anti-inflammatory drug (NSAID) and is effective in 40% to 70% of patients with juvenile rheumatoid arthritis (JRA) and related diseases.
The introduction of the newer NSAlDs has reduced morbidity greatly by adding signficantly to our ability to reduce pain, fever, and inflammation. Beginning in the late 1960s and extending until the present time, a group of compounds has been developed that are rapidly acting and capable of reducing fever along with gratifying analgesic qualities. The agents are also antiinflammatory in that they reduce swelling, pain, tenderness, pain on motion, and warmth of inflamed joints. The mechanism of action is not clear, but prostaglandin synthesis is inhibited by all of these compounds, including aspirin.
The proliferation of chemotherapeutic agents has created perplexing problems for the physician treating these patients. A rational approach to therapy is necessary, and the purpose of this discussion is to provide some order to seeming chaos.
The NSAIDs are usually classified by chemical groups: the salicylate group, of which aspirin is the prototype drug; the indole derivative group, which includes indomethacin (Indocin™), tolmetin sodium (Tolectin™), and sulindac (Clinoril™); the propionic acid group, which includes fenoprofen (Nalfon™), naproxen (Naprosyn™) and Ibuprofen (Advil™, Motrin™, Nupren™, and Rufen™); the fenamates, including meclofenamate sodium (Meclomen™); and the oxicams, which includes piroxicam (Feldene™) (Table 1).
Many of these drugs have been studied systematically in children. Unfortunately, however, at the present time the only NSAIDs approved by the FDA for use in children are aspirin and Tolectin™. The pediatrician needs a detailed knowledge of these drugs, since several have (and more will) become widely used to control fever, pain, and inflammation in children and teenagers.
Although not all of these drugs are closely related chemically, they possess in common the pharmacologic quality of being rapidly acting anti-inflammatory agents. The three main useful effects are analgesic, antipyretic, and anti-inflammatory. The relief of pain is perhaps the most striking attribute of the NSAIDs. This can occur in a matter of hours or days but is more often measured in weeks. Elimination or marked reduction of fever has been an important factor in reducing the need for steroids in patients with systemic JRA. This effect usually occurs in hours. The anti-inflammatory effect, recognized by reduction in swelling, pain on motion, tenderness and limitation of motion of involved joints, does not occur as quickly as the analgesic and antipyretic actions. Pediatric Rheumatology Collaborative Study Group (PRCSG) NSAID data reveal that favorable anti- inflammatory effects (defined as ≥25% improvement1) occur in about 57% of patients; the average time to achieve response is 30 to 37 days. Among those patients who ultimately respond favorably to NSAID therapy, only half improve within 2 weeks; 30% of the total group responded between 2 and 10 weeks. At 12 weeks, 20% of tiie responder patients had just responded. 2 Twelvemonth studies reveal that about 70% of patients receiving only an NSAID improve 25% or more, compared with only 50% at 12 weeks of therapy.3 Thus, these medications should not be discontinued too quickly in favor of some other agent, even if they seem ineffective after several weeks of therapy. At least 1 month's trial is reasonable.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
PRCSG data reveal that 50% of patients who experience no relief with the first NSAID will improve when another is tried. A trial of three or four NSAlDs may be necessary before a drug is found that is both effective and safe for a given patient. At times it is necessary to add a second NSAlD to enhance the partial effect produced by the first drug. In some situations an NSAID will be effective for a number of months and then cease to help (tachyphylaxis), requiring substitution of another NSAID.
The NSAIDs are not considered disease-modifying agents and are said to be less effective than slower acting antirheumatic drugs (SAARDs) in their ability to restore lost motion and truly alter the course of disease. However, placebo-controlled studies in children using SAARDs have not been convincing in showing superiority over NSAIDs. The erythrocyte sedimentation rate may be decreased during NSAID therapy, but NSAIDs usually do not decrease antiimmunoglobulin (rheumatoid factor) or antinuclear antibody (ANA) titers. They do not impede erosive arthritis. Thus, while not offering a cure for the underlying disease, these agents can enable a better lifestyle, more effective participation in physical therapy programs, and reduction of morbidity. We are convinced that the long-term disease severity of JRA has been reduced significantly in the past 10 years since more NSAIDs have been introduced.
Mode of Pharmacologic Action
A major mechanism of NSAID action is the inhibition of the synthesis of prostaglandins and related compounds.4 Many other mechanisms of action by which NSAIDs are thought to prevent inflammation have been postulated. The hypotheses with the most supporting experimental evidence include: blocking effect on the generation of toxic oxygen radicals; enhancement of the intracellular concentration of cyclic AMP; inhibition of neutrophil aggregation and lysosomal enzyme release; and inhibition of leukocytic Chemotaxis.5,7
The principal eliminati ve pathway of NSAIDs is hepatic metabolism. There is little renal clearance of unchanged drug. However, most of the altered or conjugated metabolites are excreted by the kidney. The therapeutic range of plasma concentrations has not been clearly established for any NSAID, including aspirin. 5,8
All NSAlDs are extensively bound to plasma protein, primarily albumin. This high degree of binding to plasma proteins gives these drugs the potential to displace other drugs from plasma proteins, but it is unlikely that significant potentiation of other drug results.9 Concomitant administration of aspirin with other NSAIDs results in competition for protein binding sites, resulting in displacement and decreased plasma levels of the NSAID with increased clearance.4,7 Some drug interactions involving NSAIDs have been studied. Of these, interactions between NSAIDs and anticoagulants are of major therapeutic significance. The potential for bleeding is enhanced owing to NSAID-induced platelet dysfunction and the propensity of these drugs to induce gastric bleeding. 10
Toxicity and Side Effects
Toxicity of a drug must always be balanced against its effectiveness. Drug toxicity is a problem when laboratory abnormalities occur that require discontinuation of the NSAID or when clinically significant signs and/or symptoms develop which necessitate discontinuation of the drug. The usual reactions are gastrointestinal (nausea, abdominal pain, diarrhea or even constipation), renal (hematuria or proteinuria), and hematologic (anemia, leukopenia, or thrombocytopenia). Other adversities which are observed occasionally are tinnitus, blurred vision, changes in personality including drowsiness, and mouth ulcers. The most common adverse effect, abdominal pain, can occur in 10% of patients and can be produced by most of the NSAIDs; however, it is especially proml· nent with aspirin therapy. Elevated serum transaminases account for the majority of abnormal laboratory results in patients receiving aspirin. Aspirin differs from the other NSAIDs in that up to 10% of patients must be removed when serum liver enzyme tests show levels several times greater than normal. In most of the patients the liver function tests promptly return to normal after discontinuation of the medication. Some pediatric rheumatologists feel that "enzymemia" does not represent true liver toxicity, but we do not share this opinion.
Anemia is the second most common laboratory abnormality and also usually resolves promptly following discontinuation of the drug. Anemia, proteinuria, and hematuria rarely occur due to aspirin, but these are the most common causes of significant adverse reactions with the other NSAIDs. Occult blood in stools and abnormal PTT can also occur. Careful monitoring of hemogram, urinalysis, and liver function tests (SGOT and/or SGPT) is important. One must remember that on rare occasions the NSAIDs can cause peptic ulcer, severe renal toxicity such as interstitial nephritis, severe liver toxicity, and severe allergic reactions.11-13
The rate of removal from aspirin therapy due to adverse reactions has been shown to be 11% to 15% in two blinded, controlled PRCSG studies.14,17 The adverse reaction removal rate for the other NSAIDs studied was less than 5%. Thus, in several objective studies, aspirin is two to three times more likely to cause clinically important adverse reactions.
Cross toxicity (adverse reactions occurring subsequently with a similar drug) is a continuing worry to the physician. Patients with JRA who develop a toxicity to one NSAID have a 50% chance of developing a significant toxicity to a second NSAID. 11 Even more important is that one patient in four develops a similar toxicity (ie, 25% of patients who experienced nausea with the first drug will have the same reaction to the second drug).
Except for aspirin, the incidence of serious toxicity due to acute poisoning with NSAIDs is low. It is also worth noting that serious toxicity in patients receiving large overdosages of NSAIDs other than aspirin, particularly ibuprofen, is very rare. In contrast, serious acute toxicity is well known in individuals who sustain serious overdosage with salicylates.15
DISCUSSION OF INDIVIDUAL DRUGS
The most common form of salicylate administered is aspirin. Until recently, aspirin has been the standard therapy for adult and pediatric arthritic patients. A dosage of 80 mg/kg/day in divided doses provides effective control of fever, joint swelling, pain, limitation of motion, myalgia, and morning stiffness in 40% to 50% of children and teenagers. Adverse reactions, however, are more frequent with aspirin than with other NSAIDs. A problem observed with aspirin tablets is the formation of caries in the chewing areas of the teeth, where material from chewed baby aspirin tablets tends to pack. There is also the issue of Reye's syndrome and its possible relationship to aspirin administration and an accompanying respiratory infection. In many parts of the US, aspirin can no longer be given to the majority of children because of the adverse publicity regarding aspirin and Reye's syndrome.
In spite of these criticisms of aspirin, none of the other NSAIDs has shown greater effectiveness, and the cost is a fraction of the newer agents. In our center, aspirin is tried first for at least a month. When control of fever is the primary goal, a trial lasting 1 week is sufficient.
Preparations of choline salicylate (Arthropan™) or choline magnesium trisalicylate (Trilisate™) have been found to be just as effective as aspirin in comparable dosages and offer the advantage of a liquid preparation.
When salicylate is given three or four times daily at meals and at bedtime, the serum salicylate level is adequately maintained overnight after 3 days of therapy. 16 Therefore, the administration of salicylate every 6 hours or during the night is unnecessary.
Diflunisal is a salicylate derivative that has a longer pharmacologic half-life, which permits twice daily dosage. This accounts for its trade name in the US, Dolobid™. The dosage is 10 to 20 mg/kg/day. Diflunisal is thought to cause less upper gastrointestinal toxicity than aspirin. In our center we find that many children who are unable to take aspirin can successfully tolerate Dolobid™; however, pediatric studies have not been reported.
Tolmetin sodium is the only agent in this group approved by the FDA for use in children with rheumatic disease and was the first medication to be systematically studied by the PRCSG. Forty percent to 50% of children with JRA can be expected to respond clinically with regard to joint swelling, pain on motion, tenderness, and duration of morning stiffness. About 25% of patients may have an increase in the range of motion in affected joints. It was found to be as effective as aspirin. The dosage used today is 20 to 50 mg/kg/day.
Indomethacin is an effective antipyretic agent in children whose fever is not adequately controlled by salicylates or other NSAIDs. In a blinded study it was shown to be superior to acetaminophen and placebo as an antipyretic agent. 18 It is thought to be more effective for certain kinds of arthritis, such as juvenile ankylosing spondylitis and other spondyloarthropathies. In children the dosage should be 1 to 2.5 mg/kg/ day, not to exceed 150 mg/day. In patients with severe intermittent fever the medication must be given every 4 hours. It is also available as rectal suppositories. The principal side effect of indomethacin in children is headache, which may be relieved by a temporary decrease in dose. After a period of time the dose may again be increased and headache usually does not recur. In some children, the headache may spontaneously abate after continued usage of the drug for several days. Serious adverse reactions in children possibly attributable to the drug were reported in the late 1960s. This resulted in a ban on its use for many years in children. Currently its usage is still restricted to seriously ill patients. Indomethacin is superior to aspirin or acetaminophen in controlling fever.
Sulindac (Clinoril™) is the newest member of the indomethacin group to receive FDA approval for use in adult arthritic patients. Adequate studies for dosage, efficacy and toxicity of sulindac have not been completed in children. The maximum adult dose is 400 mg per day, and the theoretical dose would be 6 to 8 mg/ kg/day divided into two doses.
RELATIVE COST OF NSAIDS
Propionic Acid Group
In this group fenoprofen and ibuprofen have been studied by the PRCSG and have been found useful, but unfortunately have not been approved by the FDA yet. Ibuprofen has been demonstrated to have a definite antipyretic steroid sparing effect in JRA patients. Ibuprofen's ability to reduce fever may exceed that of aspirin or steroids in some patients. The dosage is 30 to 40 mg/kg/day divided in 3 to 4 doses. 19
Fenoprofen (Nalfon™ ) does seem to be a useful drug in children with JRA and, like other NSAIDs, is better tolerated than aspirin. The dosage is 1,200 to 1,800 mg/mp 2/day in 3 or 4 divided doses.
Most of the preliminary evaluation for the safety and efficacy of naproxen (Naprosyn™) usage in JRA has been done in Europe.20,21 The clinical impression is that naproxen is roughly equivalent in terms of efficacy to the other NSAIDs of this group. The dose is 10 to 20 mg/kg/day in two doses because the half-life of the compound is 12 to 14 hours. The two times per day dosage requirement increases therapeutic adherence and patient acceptance. A liquid preparation is available in Canada and in much of the world except the US.
Of the remaining compounds marketed in the US, only meclofenamate sodium (Meclomen™) has been studied by the PRCSG for dosage and safety.22 The dosage is 4 to 7.5 mg/kg/day in 3 or 4 divided doses. The safety data were similar to other NSAIDs except that anemia was more frequent, along with a nonspecific skin rash of no consequence. The most interesting facet of this drug is the observation that patients who have psoriasis, with or without arthritis, seemed to improve remarkably well with regard to their psoriasis.23
Piroxicam (Feldene™) is a separate class of NSAID with the excellent quality of requiring only one dose daily due to a 40-hour half-life. The dosage is 10 to 20 mg/day in the adult. Pediatric studies have not been done, but proportionate doses seem to be tolerated in the few patients treated in our center. Efficacy and safety seem to be about the same as the other NSAIDs.
COST OF NSAIDS
Many of the NSAIDs are very expensive (Table 2). These costs are based on relative wholesale prices and are not actual retail costs. Table 2 is intended only to give a relative comparison of costs. The benefit to the patient must be weighed against the cost. Aspirin is more toxic to children in blinded, controlled studies, but the adverse effects are almost always reversible, and the lower cost of aspirin sometimes means the difference between receiving or not receiving therapy.
GUIDELINES FOR NSAID USAGE
The intermittent fever of JRA should respond to the proper dosage of NSAID within hours or at least in 1 or 2 days. In the past some authors, including ourselves, have advocated increasing the dosage of aspirin to over 100 mg/kg/day to control fever.24,25 Several European authors have pointed out that hepatic toxicity is almost a certainty with dosages over 80 mg/kg/ day.26 In Europe the dose of salicylate is always less than 80 mg/kg/day because of increased toxic risks and the availability of other NSAIDs that are many times less toxic.
Naproxen has the advantage of a 14-hour pharmacologic half-life, and overnight fever control can sometimes be achieved using this medication. At times, however, the antipyretic effect only lasts 4 or 5 hours. Ibuprofen, tolmetin or the other NSAIDs offer adequate antipyretic effect. In a double-blinded controlled study indomethacin was shown to be superior to acetaminophen for control of fever over 1020F.18
Pain and Inflammation
As discussed earlier, at least a 4- to 8-week therapeutic trial needs to be given to a JRA patient before prescribing another NSAID. Usually a patient requires a trial of three NSAIDs before settling on an effective drug that is satisfactorily tolerated. A few patients have responded to the addition of a second NSAID. In general, if a patient has not responded to three or four NSAIDs or has unpleasant adverse reactions to several drugs, the probability is that the pattern will continue. Usually, however, the patient has a 50% chance of achieving clinical improvement with each new drug tried. The results of the recently completed USA-USSR study of NSAID + hydroxychloroquine vs. NSAID + d-penicillamine vs. NSAID + placebo showed that NSAID alone after 1 year of therapy is just as effective as either of the SAARDs.3 Thus, the NSAIDs probably should be given a longer chance to succeed if they are the least bit beneficial in the first 2 months of therapy.
Usual Order of NSAID Therapy
The usual order of therapy for NSAID in our center is: aspirin, tolmetin sodium (Tolectin™), naproxen (Naprosyn™ ), ibuprofen (Rufen™, Advil™, Nuprin™, or Motrin™), fenoprofen (Nalfon™), diflunisal (Dolobid™), piroxicam (Feldene™), and meclofenamate sodium (Meclomen™ ). Occasionally a patient improves satisfactorily on acetaminophen.
Frequency of Clinical and Laboratory Safety Checks
In our center, the patient returns 2 weeks afer beginning a new drug to see the physician and obtain a hemogram, urinalysis, and liver function test (SGOT). The same procedure is followed 1 month later and every 2 or 3 months thereafter for as long as the patient takes the drug. We have seen toxicity after many months of safe and effective treatment.
1. Giannini EH, Brewer EJ: Standard methodology for segments I, II and III Pediatric Rheumatology Collaborative Study Group Studies - II. Analysis and Presentation of Data. ; Rheumatol 1982; 9:114-122.
2. Lovell DJ, Giannini EH, Brewer E): Time course of response to nonsteroidal antiinflammatory drugs in patients with juvenile rheumatoid arthritis. Arthritis Rheum 1984; 27:1433-1437.
3. Brewer E], Giannini EH, for the USA Pediatric Rheumatology Collaborative Study Group. Kuzrnina N, Alekseev L, D-Penicillamine and Hydroxychloroquine in Juvenile Rheumatoid Arthritis - Results of the USA-USSR double-blind, placebo controlled trial. N Engl ) Med 1986; 314:1269-1276.
4. Vane JR: Inhibition of prostaglandin synthesis as a mechanism for aspirin-like drugs. Nature 1971; 231:232-234.
5. Bollet AJ: Nonsteroidal Anti-Inflammatory Drugs: Textbook of Rheumatology (2nd Ed). Philadelphia, WB Saunders Company. 198S. pp 752-773.
6. Abramson S, Edelson H, Kaplan H, et al: Inhibition of neutrophil activation by nonsteroidal anti-inflammatory drugs- AmJ Med 1984; 77:3-6.
7. Goodwin JS: Immunologic effects of nonsteroidal anti- inflammatory drugs. Am J Med 1984; 77:7-15.
8. Graham G, Day R, Champion D, et al: Aspects of the clinical pharmacology of nonsteroidal anti-inflammatory drugs. CIm Rheum Du 1984; 10:229-249.
9. Sellers EM: Plasma protein displacement interactions are rarely of clinical significance. Pharmacology 1979; 18:225-227.
10. Day R, Graham G, Champion D, et ai: Anti-rheumatic drug interactions. CIm Rheum Dis 1984; VO-.2S1-I75.
11 . Barron K, Person D, Brewer EJ: The toxicity of nonsteroidal anti-inflammatory drugs in juvenile rheumatoid arthritis. J Rheum 1982; 9:149-155.
12. Brewer EJ: Pharmacologic management of JRA and related rheumatic diseases. Proceedings of the Model Community Program for Arthritic Children. October, 1980, pp 26.
13. Allen RC, Rttty RE, et al: Renal papillary necrosis in chronic arthritis. AmJ Du Child 1986; 140:20-22.
14. Brewer EJ, Giannini EH, BaumJ, etat: Aspirin (ASA) and fenoprofen (Nalfon) in the treatment of juvenile rheumatoid arthritis: Results of the double blind trial. A segment 11 study. ) Rheum 1982; 9:123-128.
15. Court H, Volani G: Poisoning after overdose with nonsteroidal anti-inflammatory drugs. Adv Drug React Ac Pou Rev 1984; 3:1-21.
16. Brewer EJ: Proceedings of the Conference on the Effects of Chronic Salicylate Administration. Lamont-Havers RW, Wagner BM (eds) US Department of Health, Education and Welfare, US Government Printing Office, Washington, DC, 1966, pp 26-37.
17. Levinson JE. Baum J. Brewer EJ, Jr, et al: Comparison of tolmetin sodium and aspirin in the treatment of juvenile rheumatoid arthritis. J Pcdiatr 1977; 91:799-804.
18. Brewer EJ: A comparative evaluation of indomethacin, acetaminophen and placebo as antipyretic agents in children. Arthritis Rheum 1968; 11:645.
19. Brewer EJ: Nonsteroidal anti-inflammatory agents. Arthritis Rheum 1977; 20(suppl):513-524.
20. Makela AL: Naproxen in the treatment of juvenile rheumatoid arthritis. Scand J Rheumatol 1977; 6:193-205.
21 . Ansell BM, Hanna B, Moran H, et al: Naproxen in juvenile chronic polyarthritis. Eur J Rheumatol 1979; 2:79-83.
22. Brewer EJ, Giannini EH, Baum J, et al: Sodium meclofenamate (meclomen) Vn the treatment of juvenile rheumatoid arthritis. ) Rheumatol 1982; 9:129-134.
23. Wintrop GJ: Does meclofenamate help psoriasis and arthritis? (Letter to the editor) N Eng J Med 1982; 307:1528.
24. Calabro JJ: Management of juvenile rheumatoid arthritis. J Pedían 1970; 77:355-365.
25. Schaller J1 Wedgwood RJ: Diseases of connective tissue. Juvenile rheumatoid arthritis, in Gellis SS, Kagan BM (eds): Current Pedíame Therapy. Vol 4, WB Saunders, Philadelphia, 1970. p 536.
26. Makeila A, Yrjana T, Haapasaari J: Dosage of salicylates for children with juvenile rheumatoid arthritis. Scand J Rheumatol 1975; 4:250-252.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
RELATIVE COST OF NSAIDS