DIAGNOSIS AND TREATMENT Drugs Five Years Later
Ibuprofen THOMAS G. KANTOR, M.D.; New York, New York
Ibuprofen was introduced in England in 1 9 6 7 and in the United States in 1974 as an anti-inflammatory drug in humans. It has weak but definite anit-inflammatory properties similar to those of aspirin, milligram for milligram, but with considerably less adverse effect on the stomach. Ibuprofen is chemically related to fenoprofen and naproxen, but lack of effect for any one in this chemical class of propionic-acid derivatives does not necessarily mean lack of effect for any other in an individual patient. The drug has analgesic properties, probably related to its anti-inflammatory effect. It inhibits prostaglandin synthesis and has no effect on the adrenopituitary axis, making it a nonsteroidal agent. Ibuprofen has been shown to be efffective in rheumatoid arthritis and osteoarthritis and is probably effective in ankylosing spondylitis, gout, and Bartter's syndrome.
IBUPROFEN (Motrin® [Upjohn Co., Kalamazoo, Michigan] in the United States; Brufen [Boots Pure Drug Co. Ltd., Nottingham, England] elsewhere) is a 2-phenylpropionic acid and the chemical relative of a group of substituted phenylalkanoic acids prepared during the early 1960s. The drug ibufenac, introduced in England and proven hepatotoxic, was shown before its removal from the market to have useful anti-inflammatory properties. This engendered a search for safer, equally potent drugs of the same general class, culminating in the introduction of ibuprofen or 2 (4-isobutylphenyl) propionic acid. Ibuprofen was the first of three propionic acid compounds introduced into the United States, the others being fenoprofen and naproxen. The proven anti-inflammatory effect of, and the relative gastrointestinal tolerance to, the drug have been discussed in several excellent reviews (1, 2), and there was a wide experience with ibuprofen in Europe before its introduction here. Ibuprofen was introduced in England in 1967 and in the United States in 1974. Pharmacology
Animal screens have shown a moderately potent antiinflammatory effect for ibuprofen clearly not due to either a direct or indirect effect on the adrenal production of corticosteroids. The drug, therefore, is a prominent class member of the so-called nonsteroidal anti-inflammatory drugs. EFFECT O N M E D I A T O R S OF I N F L A M M A T I O N
As with others in its class, ibuprofen interferes with the • From the N e w York University Study Group on Rheumatic Diseases, and Section of Clinical Pharmacology, Department of Medicine, N e w York University School of Medicine; N e w York, New York.
metabolism of arachidonic acid by inhibiting the enzyme cyclo-oxygenase. This inhibits the subsequent production of the short-lived endoperoxides and the stable inflammation-mediating prostaglandins PGE 2 and PGF 2a (3). Superoxide production is a consequence of endoperoxide metabolism and is also inhibited. These effects are time dependent and, in pharmacologically achievable doses, reversible, unlike the effect of aspirin. Aspirin donates its acetyl group to cyclo-oxygenase and in so doing irrevocably destroys the enzyme (4). The time-effect action of ibuprofen on prostaglandins is clearly related to its pharmacokinetics, whereas that of aspirin may depend on the rate of replacement of the enzyme. Through its effect on prostaglandins, ibuprofen also affects the kinin and histamine (5) systems of inflammation mediation. The production of slow-reacting substance-A may also be affected (6). Lysosomal enzymes are known to amplify the inflammatory state by production of mediators in situ. Ibuprofen has a slight effect as a lysosomal membrane stabilizer (7). OTHER EFFECTS R E L A T E D TO I N F L A M M A T I O N
Ibuprofen has been tested for its interference with mitochondrial oxidative phosphorylation, an effect widely held to relate to anti-inflammation by reduction of the energy required to mount the inflammatory state. Here ibuprofen was less potent than aspirin and far more potent than flufenamic acid. In the same system, phenylbutazone and indomethacin were also active but reduced the energy needed for inflammation by other, more potent means (8). Leukocyte motility and phagocytosis are partially suppressed by ibuprofen (9). Sulfate uptake in human cartilage tissue culture is inhibited (10), an effect that may modify the connective tissue milieu of inflammation. I M M U N O L O G I C EFFECTS
Immune mechanisms may be affected by ibuprofen. Although humoral mechanisms do not appear to be directly affected, high concentrations of ibuprofen do perturb cell membranes of peripheral lymphocytes and thymocytes, which may confound receptor-site recognition at lower concentrations (11). Phenylbutazone, indomethacin, and ibuprofen all inhibit phytohemagglutinin lymphocyte stimulation, ibuprofen at a concentration greater than 5 jug/dL. Two hundred milligrams of ibuprofen given orally three times
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daily will lead to a blood level of about 2 to 5 jag/dL; thus the inhibitory blood level is pharmacologically achievable (12). OTHER EFFECTS
Related to the effect on prostaglandin synthesis by ibuprofen is an inhibition of secondary platelet aggregation, which in turn prolongs bleeding time. Prothrombin production, and therefore clotting time, is not interfered with. Interference with platelet aggregation triggered by contact with bare collagen fibers is more potent with aspirin and naproxen than with ibuprofen (13). Also apparently related to the effect on prostaglandin synthesis is the retention of salt and water by the kidney and an enhanced effect of antidiuretic hormone ( A D H ) . Although this effect is weaker than that of other nonsteroidal anti-inflammatory drugs, it has clinical applicability (see below). In animal screening procedures, ibuprofen has had no analgesic effects despite its moderately potent pain-reducing effects in humans. Antipyretic effects have also been noted. Clinical Pharmacology
Clinical testing for anti-inflammatory effect in humans is extraordinarily difficult, and despite a plethora of clinical trial methods, dosage estimates are often widely off the mark when such a drug is first introduced. Phenylbutazone, for example, was introduced into this country with a 300-mg tablet and suggested daily dose of 1200 mg. Indomethacin was introduced as a 25-mg capsule and a year later, as a 25- and 50- mg tablet. Ibuprofen was first used in England as a 200-mg tablet with a suggested total daily dose of 600 mg. When introduced into the United States 7 years later, both a 300-and 400-mg tablet were marketed with a suggested daily dose of 1200 to 1600 mg. Some of the early controversy in England on the efficacy of ibuprofen as an anti-inflammatory drug can be laid to confusion as to its optimal dose. Until clinical trial methods become more precise, using bioassay comparison with known standards, confusion in dosage at the initial stages of new nonsteroidal anti-inflammatory drug introduction will probably continue. Several English (1, 14) and one American (15) review considered ibuprofen to be mainly analgesic, not anti-inflammatory, before dose levels were raised. I believe that these two effects are merely two parts of a continuum and that much confusion in the categorization of nonsteroidal anti-inflammatory drugs, especially by regulatory agencies, might be resolved if this philosophy were more widespread. In fact, all nonsteroidal anti-innflammatory drugs tested in pain models such as postoperative, postpartum, and postdental extraction pain and headache pain are clearly analgesic. "Dolor" is, after all, one of the cardinal signs of inflammation. The definitive studies of Lim (16) showed that those nonsteroidal anti-inflammatory drugs tested worked as analgesics peripherally, presumably at the point of inflammation, as contrasted with narcotics, whose analge373
sic effects are in the central nervous system. In these experiments, acetaminophen was also shown to work peripherally. This was considered to be paradoxical at the time, since acetaminophen was not believed to have antiinflammatory properties. Recent evidence suggests, however, that it does act as an anti-inflammatory in high dosage (17). Therefore, the spectrum of these two effects suggests that all anti-inflammatory drugs, including ibuprofen, are analgesic in low dose, with the anti-inflammatory effect becoming clinically apparent at higher, more prolonged dosage. Possibly one or more chemical mediators of pain are also mediators of inflammation, the latter being a more complex process requiring more prolonged effect by the drug. Bradykinin fulfills some of the requirements for such a mediator. Pharmacokinetics
Ibuprofen is readily absorbed by mouth and does not seem to accumulate in tissues that are not in equilibrium with the plasma. It has two metabolites, both pharmacologically inactive, and urinary excretion of a single dose of the drug and its metabolites is complete in 24 h (18). In healthy female volunteers, 600 mg of ibuprofen every 6 h produced a steady state with a blood level of 20 to 30 jitg/dL (19). Plasma half-life of the drug is between 1 and 3 h in humans, and in a comparison of normal and adjuvant arthritic rats the half-life was the same for the two groups. Drug Interaction
There is some interaction of ibuprofen with aspirin, and the package insert supplied with the drug suggests that the two not be given together (both drugs are bound to serum albumin, aspirin with the higher affinity). There is a slight reduction of ibuprofen peak blood levels when given with aspirin (20). The clinical effect of this is as uncertain as the mechanism. With naproxen, another propionic acid, this effect has also been observed, but a clinical study suggests that the two drugs are additive (21). In an in-vitro study of human serum, added ibuprofen increased the amount of free salicylate when salicylate had been previously added. Empirically, many rheumatologists believe that adding ibuprofen to a tolerated dose of aspirin gives an increased clincial effect without added penalty of adverse reaction (22). Protein-binding considerations are complex, and clinical inferences cannot be made with certainty. In one study, ibuprofen displaced indomethacin from its albumin binding site even though indomethacin's binding affinity is much stronger. As an explanation, two binding sites were postulated and the hypothesis presented that ibuprofen, binding at a secondary binding site, perturbed the primary site for indomethacin in such a way that the latter drug was displaced (23). Much work on drug interaction in this field remains to be done. In terms of metabolic interaction, there is some evidence that phenobarbital induces the metabolism of ibuprofen and that ibuprofen itself inhibits those enzyme systems responsible for JV-demethylation (24). In the for-
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mer circumstance, barbiturates might reduce the effectiveness of ibuprofen and in the latter, the effect of aminopyrine and narcotics might be increased. There have been no clinical studies to prove or disprove either possiblity. Ibuprofen enhances the toxicity of oubain in dogs, an effect partially reversed by guanethidine (25). The authors of this study doubted any clinical consequence. Interaction with coumarin derivatives has been examined. In 36 normal male volunteers receiving 1200 to 1600 mg of ibuprofen daily and 7.5 mg of coumarin for 14 d, no effect was noted on Coumadin binding to albumin, on prothrombin and partial thromboplastin times, or on levels of coagulation factors II, V, VII, and IX (26). In rats given enormous doses of ibuprofen, however, slight displacement of warfarin from the albumin binding site was observed. Neither prothrombin production nor its effect was reduced. Clinical Effects R H E U M A T O I D ARTHRITIS
A considerable number of clinical trials of ibuprofen have been done, the earliest by J. J. R. Duthie in Scotland in 1967 (27). Those that I consider adequate are reviewed here. Among those trials comparing ibuprofen to placebo or other marketed nonsteroidal anti-inflammatory drugs, and using less than 1000 mg daily, there is general agreement that some analgesia has been conferred but some doubt that a true anti-inflammatory effect, in the sense of reduction in joint swelling and tenderness, has been produced. In general, there are statistically significant differences between ibuprofen and placebo in analgesic variables but little or none between the two in a distressingly large number of studies for anti-inflammatory variables (28-30). In most instances where ibuprofen was compared to standard nonsteroidal anti-inflammatory drugs in relatively short-term ( < 6 weeks) clinical studies, there were no significant differences between ibuprofen and aspirin (31) or phenylbutazone (32). In some cases, other nonsteroidal anti-inflammatory drugs fared better, though rarely by statistically significant margins (P < 0.05) (33). As more propionic-acid derivatives were introduced into the British market, comparative evaluations between them often put ibuprofen behind, especially in regard to patient and observer total assessment (28). With the added experience of the late 1960s and early 1970s, the relative safety of ibuprofen seemed well established and higher doses began to be used. Even here, ibuprofen in doses higher than 1000 mg seemed to have similar characteristics to studies using lower doses (34, 35). A study purporting to show a dose-response relation in rheumatoid arthritis between 1200 mg and 2400 mg (36) has been severely criticized as inadequate. With its introduction into the United States in a suggested dose of 1600 mg daily, a similar situation has developed. While the larger doses seem safe, little if any advantage over other drugs in anti-inflammatory effect has been noted. In a recent well-performed study using
parallel, double-blind conditions in 83 patients treated with either 4 g of aspirin or 3200 mg of ibuprofen daily for 6 weeks, ibuprofen again showed similar analgesic effects, but aspirin was clearly superior in measurements of swollen joints. Although the adverse effects of ibuprofen, especially with respect to the gastrointestinal tract, were less than those of aspirin in this study, ibuprofen's advantage was by no means as great as in studies using the lower doses (37). One wonders if a milligram-for-milligram comparison between aspirin and ibuprofen would show differences between them in any respect. OSTEOARTHRITIS
The clinical efficacy of ibuprofen in osteoarthritis is somewhat similar to the experience in rheumatoid arthritis, although the overall advantage of ibuprofen in the therapeutic ratio of effectiveness to toxicity seems slightly better (38). On theoretical grounds, an analgesic effect in osteoarthritis might seem more advantageous than an anti-inflammatory one, although cautions against a tendency to joint overuse have already been voiced (39). Again, there is little to choose in effectiveness between ibuprofen in doses greater than 1000 mg daily and other nonsteroidal anti-inflammatory drugs in conventional doses. Differences in side effects, however, clearly favor ibuprofen. A N K Y L O S I N G SPONDYLITIS
A sparse literature suggests that ibuprofen has no clinical advantage over other nonsteroidal anti-inflammatory drugs except with respect to gastrointestinal adverse effects. Here the therapeutic ratio of ibuprofen is less than with the previously discussed diseases, primarily because of the effectiveness of indomethacin, phenylbutazone, and aspirin in this condition. GOUT
In a recent 10-patient study (40), ibuprofen in a dose of 2400 mg daily for 3 d successfully treated attacks of gout. Lower doses were thought not to be as useful. ANALGESIA
Ibuprofen has been clearly shown to have analgesic effects in single doses greater than 400 mg in dental extraction pain (41), postpartum pain (42), dysmenorrhea (43), and the pain of soft tissue injury. Its effectiveness in more severe pain has been suggested but not proved. OTHER USES
As a prostaglanding synthesis inhibitor, ibuprofen should be useful in such entities as Bartter's syndrome, patent ductus arteriosus, and some repeated abortion syndromes, all of which are known to be related to increased or inappropriate prostaglandin production. Other nonsteroidal anti-inflammatory drugs are known to improve these conditions, but ibuprofen is well documented to affect only Bartter's syndrome (44). One study has suggested the use of ibuprofen in nephrosis (45), which is paradoxical considering the known effects of the drug in retaining salt and water. Another Kantor • Ibuprofen
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study has suggested its usefulness and safety in Still's disease (46). A D V E R S E EFFECTS
By far the most disturbing adverse effects of all the nonsteroidal anti-inflammatory drugs are gastrointestinal, particularly symptoms of gastritis. We now understand that in addition to the control exerted by the H 2 receptor, the stomach's physiology is also modified by prostaglandins. Their positive presence increases protective mucous production, decreases acid secretion, and increases mucosal blood flow. When their production is inhibited, exactly opposite effects are produced, making perfect conditions for peptic-ulcer formation (47). Ibuprofen, as well as all other inhibitors of prostaglandin production, has been documented to produce ulceration, presumably by this mechanism. Cimetidine is said to be protective (48). Despite their potent prostaglandin inhibition, the propionic-acid derivatives are much less irritating to the stomach than are other agents. Irrespective of their potency as analgesic or anti-inflammatory agents, their reduction in this adverse effect constitutes a real advance in therapeutics. Ibuprofen has between one fifth and one half the gastric irritant capacity of aspirin, depending on the doses. The relative potency of nonsteroidal anti-inflammatory drugs as prostaglandin inhibitors does not seem to be directly related to their capacity to irritate the stomach, which suggests some differential effects on the production of the end products of arachidonic-acid oxidation. In some instances, diarrhea has been a complaint and in others, constipation. Ibuprofen has, however, been used to control idiopathic diarrhea. Originally, some cases of direct retinal or optic nerve toxicity were reported to be related to ibuprofen therapy (49). Later, more definitive prospective studies tended to deny this finding (50), but prudence would dictate withdrawing the drug at any sign of reduced visual acuity. Almost all the nonsteroidal anti-inflammatory drugs have been documented to induce edema formation, presumably due to an effect on salt and water metabolism by the kidney and an enhancing effect on A D H . These effects, which can be shown to cause a significant hypervolemia, are probably related to the effect on prostaglandins. In one reported instance, congestive heart failure has resulted (51). Common diuretics are known to reduce edema caused by nonsteroidal anti-inflammatory drugs. There have been isolated reports of bone marrow and hepatic toxicity, which must be very rare, and as with all drugs a certain low incidence of rash is produced. Several instances have been reported of a sterile meningitis (52) and a nonspecific febrile reaction (53) to ibuprofen in systemic lupus erythematosus. These must also be very rare (54). I have seen a patient with lupus erythematosus treated for 9 months with daily doses of 1600 to 3200 mg of ibuprofen suddenly develop meningitis, which was found to be due to cryptococcus. Although, as noted above, the effect of ibuprofen on blood clotting mechanisms is weak, one would be wise to exercise caution when concurrently treating a patient 8 8 0
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with coumarin derivatives. Even though there is no direct interaction with coumarins per se, the irritative effect on the stomach and the inhibition of secondary platelet aggregation could be associated with severe gastrointestinal hemorrhage. The bleeding and clotting times of hemophiliac patients, however, are reportedly unaffected (55). In pregnant patients at term, nonsteroidal anti-inflammatory drugs theoretically prolong labor, which is partially under prostaglandin control, and promote excess bleeding. Similarly, these drugs may reduce the mild inflammation caused by intrauterine devices, which is quite possibly related to their effectiveness. In children, there is some fear that all nonsteroidal anti-inflammatory drugs may be toxic to the liver, and indeed this has been reported with ibuprofen (56). Mild effects on liver function tests, however, may not be clinically important, which is also true for adults. Some believe that prostaglandin-synthesis-inhibiting drugs in general may cross-react in patients with aspirin hypersensitivity syndrome (nasal polyps and asthma). Some patients who develop hives on aspirin therapy, and who may or may not be iodide sensitive, are also sensitive to ibuprofen (57). The former group are not infrequently sensitive to tetrazine, a dye used in the original preparation of the "Motrin" tablet. At any rate, patients who have either condition are sensitive to ibuprofen. Certain asthmatic patients improve with nonsteroidal anti-inflammatory drugs, including ibuprofen (58). Ibuprofen appears not to be mutagenic (59). Conclusion
Ibuprofen is a mild but effective anti-inflammatory and analgesic drug whose salient clinical property is reduced symptoms of gastric irritation. In an individual patient, when indicated, its effect is unpredictable, and the drug is probably not as immediately anti-inflammatory as aspirin or corticosteroids. It should be given a trial of 14 to 21 d before abandonment. It is becoming obvious that failure to achieve a beneficial effect with one propionic-acid derivative does not imply failure with others. This suggests genetic or environmental differences between subjects that are unknown at present. As with other drugs with short-term plasma half-lives, dosing must be frequent (three or four times daily), a feature that reduces patient compliance, especially in the long-term problems for which ibuprofen is indicated. In the 12 years since its introduction in England, ibuprofen has shown no serious long-term adverse effects, nor has tolerance been noted to its action. The gradual increase in its suggested dose over the years reflects not only the crudity of our present methods of determining clinical anti-inflammatory effects but also ibuprofen's relative lack of toxicity. Rheumatologists are increasingly sanguine about using the drug in doses greater than 1600 mg/d. It remains to be seen whether the reduced gastrointestinal toxicity of ibuprofen, as compared with salicylates, phenylacetic, and pyrazole drugs, will continue as doses are raised. The apparent capriciousness of clinical effect in the individual patient will no doubt be resolved as our under-
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standing of the pharmacology of anti-inflammatory drugs improves. Except for the infectious arthritides, rheumatology is plagued with a group of diseases without known cause and therefore no rational treatment. Nonsteroidal antiinflammatory drugs provide symptomatic relief and aid in rehabilitative efforts but do not at all affect the cause or suspected pathogenesis of the rheumatic disease entities. Because of cost differentials that may be as much as $1000/year, aspirin has been the drug of choice for the initial treatment of arthritis. If it cannot be tolerated or can be tolerated only at an ineffective dose, I believe that ibuprofen should be the next drug in line, because its cost is not much different and its therapeutic index established over the years is somewhat better than that of many other nonsteroidal anti-inflammatory drugs. • Requests for reprints should be addressed to Thomas G. Kantor, M.D.; New York University Medical Center, 550 First Avenue; New York, N Y 10016. Received 9 April 1979; revision accepted 26 July 1979.
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Ther. 1978;24:616-21. 56. STEMPEL DA, M I L L E R JJ. Lymphopenia and hepatic toxicity with ibuprofen. JPediatr. 1977;90:657-8. 57. FISHERMAN EW, C O H E N G N . Hypersensitivity to five non-steroidal anti-inflammatory agents: ibuprofen, fenoprofen, indomethacin, naproxen and tolmetin. Ann Allergy. 1978;41:75-7. 58. K O R D A N S K Y D, A D K I N S O N N F J R , N O R M A N PS, R O S E N T H A L RR.
Asthma improved by nonsteroidal anti-inflammatory drugs. Ann Intern Med. 1978;88:508-11. 59. K R I C K G, C O N N O R T, K A P L A N SR. Studies of the mutagenic potential
of drugs used in the treatment of rheumatic diseases. Arthritis 1975;18:409-10.
55. M C I N T Y R E BA, P H I L P RB, I N W O O D MJ. Effect of ibuprofen on platelet
function in normal subjects and hemophiliac patients. Clin
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Rheum.
Ibuprofen THOMAS G. KANTOR, M.D.; New York, New York
Ibuprofen was introduced in England in 1 9 6 7 and in the United States in 1974 as an anti-inflammatory drug in humans. It has weak but definite anit-inflammatory properties similar to those of aspirin, milligram for milligram, but with considerably less adverse effect on the stomach. Ibuprofen is chemically related to fenoprofen and naproxen, but lack of effect for any one in this chemical class of propionic-acid derivatives does not necessarily mean lack of effect for any other in an individual patient. The drug has analgesic properties, probably related to its anti-inflammatory effect. It inhibits prostaglandin synthesis and has no effect on the adrenopituitary axis, making it a nonsteroidal agent. Ibuprofen has been shown to be efffective in rheumatoid arthritis and osteoarthritis and is probably effective in ankylosing spondylitis, gout, and Bartter's syndrome.
IBUPROFEN (Motrin® [Upjohn Co., Kalamazoo, Michigan] in the United States; Brufen [Boots Pure Drug Co. Ltd., Nottingham, England] elsewhere) is a 2-phenylpropionic acid and the chemical relative of a group of substituted phenylalkanoic acids prepared during the early 1960s. The drug ibufenac, introduced in England and proven hepatotoxic, was shown before its removal from the market to have useful anti-inflammatory properties. This engendered a search for safer, equally potent drugs of the same general class, culminating in the introduction of ibuprofen or 2 (4-isobutylphenyl) propionic acid. Ibuprofen was the first of three propionic acid compounds introduced into the United States, the others being fenoprofen and naproxen. The proven anti-inflammatory effect of, and the relative gastrointestinal tolerance to, the drug have been discussed in several excellent reviews (1, 2), and there was a wide experience with ibuprofen in Europe before its introduction here. Ibuprofen was introduced in England in 1967 and in the United States in 1974. Pharmacology
Animal screens have shown a moderately potent antiinflammatory effect for ibuprofen clearly not due to either a direct or indirect effect on the adrenal production of corticosteroids. The drug, therefore, is a prominent class member of the so-called nonsteroidal anti-inflammatory drugs. EFFECT O N M E D I A T O R S OF I N F L A M M A T I O N
As with others in its class, ibuprofen interferes with the • From the N e w York University Study Group on Rheumatic Diseases, and Section of Clinical Pharmacology, Department of Medicine, N e w York University School of Medicine; N e w York, New York.
metabolism of arachidonic acid by inhibiting the enzyme cyclo-oxygenase. This inhibits the subsequent production of the short-lived endoperoxides and the stable inflammation-mediating prostaglandins PGE 2 and PGF 2a (3). Superoxide production is a consequence of endoperoxide metabolism and is also inhibited. These effects are time dependent and, in pharmacologically achievable doses, reversible, unlike the effect of aspirin. Aspirin donates its acetyl group to cyclo-oxygenase and in so doing irrevocably destroys the enzyme (4). The time-effect action of ibuprofen on prostaglandins is clearly related to its pharmacokinetics, whereas that of aspirin may depend on the rate of replacement of the enzyme. Through its effect on prostaglandins, ibuprofen also affects the kinin and histamine (5) systems of inflammation mediation. The production of slow-reacting substance-A may also be affected (6). Lysosomal enzymes are known to amplify the inflammatory state by production of mediators in situ. Ibuprofen has a slight effect as a lysosomal membrane stabilizer (7). OTHER EFFECTS R E L A T E D TO I N F L A M M A T I O N
Ibuprofen has been tested for its interference with mitochondrial oxidative phosphorylation, an effect widely held to relate to anti-inflammation by reduction of the energy required to mount the inflammatory state. Here ibuprofen was less potent than aspirin and far more potent than flufenamic acid. In the same system, phenylbutazone and indomethacin were also active but reduced the energy needed for inflammation by other, more potent means (8). Leukocyte motility and phagocytosis are partially suppressed by ibuprofen (9). Sulfate uptake in human cartilage tissue culture is inhibited (10), an effect that may modify the connective tissue milieu of inflammation. I M M U N O L O G I C EFFECTS
Immune mechanisms may be affected by ibuprofen. Although humoral mechanisms do not appear to be directly affected, high concentrations of ibuprofen do perturb cell membranes of peripheral lymphocytes and thymocytes, which may confound receptor-site recognition at lower concentrations (11). Phenylbutazone, indomethacin, and ibuprofen all inhibit phytohemagglutinin lymphocyte stimulation, ibuprofen at a concentration greater than 5 jug/dL. Two hundred milligrams of ibuprofen given orally three times
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daily will lead to a blood level of about 2 to 5 jag/dL; thus the inhibitory blood level is pharmacologically achievable (12). OTHER EFFECTS
Related to the effect on prostaglandin synthesis by ibuprofen is an inhibition of secondary platelet aggregation, which in turn prolongs bleeding time. Prothrombin production, and therefore clotting time, is not interfered with. Interference with platelet aggregation triggered by contact with bare collagen fibers is more potent with aspirin and naproxen than with ibuprofen (13). Also apparently related to the effect on prostaglandin synthesis is the retention of salt and water by the kidney and an enhanced effect of antidiuretic hormone ( A D H ) . Although this effect is weaker than that of other nonsteroidal anti-inflammatory drugs, it has clinical applicability (see below). In animal screening procedures, ibuprofen has had no analgesic effects despite its moderately potent pain-reducing effects in humans. Antipyretic effects have also been noted. Clinical Pharmacology
Clinical testing for anti-inflammatory effect in humans is extraordinarily difficult, and despite a plethora of clinical trial methods, dosage estimates are often widely off the mark when such a drug is first introduced. Phenylbutazone, for example, was introduced into this country with a 300-mg tablet and suggested daily dose of 1200 mg. Indomethacin was introduced as a 25-mg capsule and a year later, as a 25- and 50- mg tablet. Ibuprofen was first used in England as a 200-mg tablet with a suggested total daily dose of 600 mg. When introduced into the United States 7 years later, both a 300-and 400-mg tablet were marketed with a suggested daily dose of 1200 to 1600 mg. Some of the early controversy in England on the efficacy of ibuprofen as an anti-inflammatory drug can be laid to confusion as to its optimal dose. Until clinical trial methods become more precise, using bioassay comparison with known standards, confusion in dosage at the initial stages of new nonsteroidal anti-inflammatory drug introduction will probably continue. Several English (1, 14) and one American (15) review considered ibuprofen to be mainly analgesic, not anti-inflammatory, before dose levels were raised. I believe that these two effects are merely two parts of a continuum and that much confusion in the categorization of nonsteroidal anti-inflammatory drugs, especially by regulatory agencies, might be resolved if this philosophy were more widespread. In fact, all nonsteroidal anti-innflammatory drugs tested in pain models such as postoperative, postpartum, and postdental extraction pain and headache pain are clearly analgesic. "Dolor" is, after all, one of the cardinal signs of inflammation. The definitive studies of Lim (16) showed that those nonsteroidal anti-inflammatory drugs tested worked as analgesics peripherally, presumably at the point of inflammation, as contrasted with narcotics, whose analge373
sic effects are in the central nervous system. In these experiments, acetaminophen was also shown to work peripherally. This was considered to be paradoxical at the time, since acetaminophen was not believed to have antiinflammatory properties. Recent evidence suggests, however, that it does act as an anti-inflammatory in high dosage (17). Therefore, the spectrum of these two effects suggests that all anti-inflammatory drugs, including ibuprofen, are analgesic in low dose, with the anti-inflammatory effect becoming clinically apparent at higher, more prolonged dosage. Possibly one or more chemical mediators of pain are also mediators of inflammation, the latter being a more complex process requiring more prolonged effect by the drug. Bradykinin fulfills some of the requirements for such a mediator. Pharmacokinetics
Ibuprofen is readily absorbed by mouth and does not seem to accumulate in tissues that are not in equilibrium with the plasma. It has two metabolites, both pharmacologically inactive, and urinary excretion of a single dose of the drug and its metabolites is complete in 24 h (18). In healthy female volunteers, 600 mg of ibuprofen every 6 h produced a steady state with a blood level of 20 to 30 jitg/dL (19). Plasma half-life of the drug is between 1 and 3 h in humans, and in a comparison of normal and adjuvant arthritic rats the half-life was the same for the two groups. Drug Interaction
There is some interaction of ibuprofen with aspirin, and the package insert supplied with the drug suggests that the two not be given together (both drugs are bound to serum albumin, aspirin with the higher affinity). There is a slight reduction of ibuprofen peak blood levels when given with aspirin (20). The clinical effect of this is as uncertain as the mechanism. With naproxen, another propionic acid, this effect has also been observed, but a clinical study suggests that the two drugs are additive (21). In an in-vitro study of human serum, added ibuprofen increased the amount of free salicylate when salicylate had been previously added. Empirically, many rheumatologists believe that adding ibuprofen to a tolerated dose of aspirin gives an increased clincial effect without added penalty of adverse reaction (22). Protein-binding considerations are complex, and clinical inferences cannot be made with certainty. In one study, ibuprofen displaced indomethacin from its albumin binding site even though indomethacin's binding affinity is much stronger. As an explanation, two binding sites were postulated and the hypothesis presented that ibuprofen, binding at a secondary binding site, perturbed the primary site for indomethacin in such a way that the latter drug was displaced (23). Much work on drug interaction in this field remains to be done. In terms of metabolic interaction, there is some evidence that phenobarbital induces the metabolism of ibuprofen and that ibuprofen itself inhibits those enzyme systems responsible for JV-demethylation (24). In the for-
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mer circumstance, barbiturates might reduce the effectiveness of ibuprofen and in the latter, the effect of aminopyrine and narcotics might be increased. There have been no clinical studies to prove or disprove either possiblity. Ibuprofen enhances the toxicity of oubain in dogs, an effect partially reversed by guanethidine (25). The authors of this study doubted any clinical consequence. Interaction with coumarin derivatives has been examined. In 36 normal male volunteers receiving 1200 to 1600 mg of ibuprofen daily and 7.5 mg of coumarin for 14 d, no effect was noted on Coumadin binding to albumin, on prothrombin and partial thromboplastin times, or on levels of coagulation factors II, V, VII, and IX (26). In rats given enormous doses of ibuprofen, however, slight displacement of warfarin from the albumin binding site was observed. Neither prothrombin production nor its effect was reduced. Clinical Effects R H E U M A T O I D ARTHRITIS
A considerable number of clinical trials of ibuprofen have been done, the earliest by J. J. R. Duthie in Scotland in 1967 (27). Those that I consider adequate are reviewed here. Among those trials comparing ibuprofen to placebo or other marketed nonsteroidal anti-inflammatory drugs, and using less than 1000 mg daily, there is general agreement that some analgesia has been conferred but some doubt that a true anti-inflammatory effect, in the sense of reduction in joint swelling and tenderness, has been produced. In general, there are statistically significant differences between ibuprofen and placebo in analgesic variables but little or none between the two in a distressingly large number of studies for anti-inflammatory variables (28-30). In most instances where ibuprofen was compared to standard nonsteroidal anti-inflammatory drugs in relatively short-term ( < 6 weeks) clinical studies, there were no significant differences between ibuprofen and aspirin (31) or phenylbutazone (32). In some cases, other nonsteroidal anti-inflammatory drugs fared better, though rarely by statistically significant margins (P < 0.05) (33). As more propionic-acid derivatives were introduced into the British market, comparative evaluations between them often put ibuprofen behind, especially in regard to patient and observer total assessment (28). With the added experience of the late 1960s and early 1970s, the relative safety of ibuprofen seemed well established and higher doses began to be used. Even here, ibuprofen in doses higher than 1000 mg seemed to have similar characteristics to studies using lower doses (34, 35). A study purporting to show a dose-response relation in rheumatoid arthritis between 1200 mg and 2400 mg (36) has been severely criticized as inadequate. With its introduction into the United States in a suggested dose of 1600 mg daily, a similar situation has developed. While the larger doses seem safe, little if any advantage over other drugs in anti-inflammatory effect has been noted. In a recent well-performed study using
parallel, double-blind conditions in 83 patients treated with either 4 g of aspirin or 3200 mg of ibuprofen daily for 6 weeks, ibuprofen again showed similar analgesic effects, but aspirin was clearly superior in measurements of swollen joints. Although the adverse effects of ibuprofen, especially with respect to the gastrointestinal tract, were less than those of aspirin in this study, ibuprofen's advantage was by no means as great as in studies using the lower doses (37). One wonders if a milligram-for-milligram comparison between aspirin and ibuprofen would show differences between them in any respect. OSTEOARTHRITIS
The clinical efficacy of ibuprofen in osteoarthritis is somewhat similar to the experience in rheumatoid arthritis, although the overall advantage of ibuprofen in the therapeutic ratio of effectiveness to toxicity seems slightly better (38). On theoretical grounds, an analgesic effect in osteoarthritis might seem more advantageous than an anti-inflammatory one, although cautions against a tendency to joint overuse have already been voiced (39). Again, there is little to choose in effectiveness between ibuprofen in doses greater than 1000 mg daily and other nonsteroidal anti-inflammatory drugs in conventional doses. Differences in side effects, however, clearly favor ibuprofen. A N K Y L O S I N G SPONDYLITIS
A sparse literature suggests that ibuprofen has no clinical advantage over other nonsteroidal anti-inflammatory drugs except with respect to gastrointestinal adverse effects. Here the therapeutic ratio of ibuprofen is less than with the previously discussed diseases, primarily because of the effectiveness of indomethacin, phenylbutazone, and aspirin in this condition. GOUT
In a recent 10-patient study (40), ibuprofen in a dose of 2400 mg daily for 3 d successfully treated attacks of gout. Lower doses were thought not to be as useful. ANALGESIA
Ibuprofen has been clearly shown to have analgesic effects in single doses greater than 400 mg in dental extraction pain (41), postpartum pain (42), dysmenorrhea (43), and the pain of soft tissue injury. Its effectiveness in more severe pain has been suggested but not proved. OTHER USES
As a prostaglanding synthesis inhibitor, ibuprofen should be useful in such entities as Bartter's syndrome, patent ductus arteriosus, and some repeated abortion syndromes, all of which are known to be related to increased or inappropriate prostaglandin production. Other nonsteroidal anti-inflammatory drugs are known to improve these conditions, but ibuprofen is well documented to affect only Bartter's syndrome (44). One study has suggested the use of ibuprofen in nephrosis (45), which is paradoxical considering the known effects of the drug in retaining salt and water. Another Kantor • Ibuprofen
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study has suggested its usefulness and safety in Still's disease (46). A D V E R S E EFFECTS
By far the most disturbing adverse effects of all the nonsteroidal anti-inflammatory drugs are gastrointestinal, particularly symptoms of gastritis. We now understand that in addition to the control exerted by the H 2 receptor, the stomach's physiology is also modified by prostaglandins. Their positive presence increases protective mucous production, decreases acid secretion, and increases mucosal blood flow. When their production is inhibited, exactly opposite effects are produced, making perfect conditions for peptic-ulcer formation (47). Ibuprofen, as well as all other inhibitors of prostaglandin production, has been documented to produce ulceration, presumably by this mechanism. Cimetidine is said to be protective (48). Despite their potent prostaglandin inhibition, the propionic-acid derivatives are much less irritating to the stomach than are other agents. Irrespective of their potency as analgesic or anti-inflammatory agents, their reduction in this adverse effect constitutes a real advance in therapeutics. Ibuprofen has between one fifth and one half the gastric irritant capacity of aspirin, depending on the doses. The relative potency of nonsteroidal anti-inflammatory drugs as prostaglandin inhibitors does not seem to be directly related to their capacity to irritate the stomach, which suggests some differential effects on the production of the end products of arachidonic-acid oxidation. In some instances, diarrhea has been a complaint and in others, constipation. Ibuprofen has, however, been used to control idiopathic diarrhea. Originally, some cases of direct retinal or optic nerve toxicity were reported to be related to ibuprofen therapy (49). Later, more definitive prospective studies tended to deny this finding (50), but prudence would dictate withdrawing the drug at any sign of reduced visual acuity. Almost all the nonsteroidal anti-inflammatory drugs have been documented to induce edema formation, presumably due to an effect on salt and water metabolism by the kidney and an enhancing effect on A D H . These effects, which can be shown to cause a significant hypervolemia, are probably related to the effect on prostaglandins. In one reported instance, congestive heart failure has resulted (51). Common diuretics are known to reduce edema caused by nonsteroidal anti-inflammatory drugs. There have been isolated reports of bone marrow and hepatic toxicity, which must be very rare, and as with all drugs a certain low incidence of rash is produced. Several instances have been reported of a sterile meningitis (52) and a nonspecific febrile reaction (53) to ibuprofen in systemic lupus erythematosus. These must also be very rare (54). I have seen a patient with lupus erythematosus treated for 9 months with daily doses of 1600 to 3200 mg of ibuprofen suddenly develop meningitis, which was found to be due to cryptococcus. Although, as noted above, the effect of ibuprofen on blood clotting mechanisms is weak, one would be wise to exercise caution when concurrently treating a patient 8 8 0
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with coumarin derivatives. Even though there is no direct interaction with coumarins per se, the irritative effect on the stomach and the inhibition of secondary platelet aggregation could be associated with severe gastrointestinal hemorrhage. The bleeding and clotting times of hemophiliac patients, however, are reportedly unaffected (55). In pregnant patients at term, nonsteroidal anti-inflammatory drugs theoretically prolong labor, which is partially under prostaglandin control, and promote excess bleeding. Similarly, these drugs may reduce the mild inflammation caused by intrauterine devices, which is quite possibly related to their effectiveness. In children, there is some fear that all nonsteroidal anti-inflammatory drugs may be toxic to the liver, and indeed this has been reported with ibuprofen (56). Mild effects on liver function tests, however, may not be clinically important, which is also true for adults. Some believe that prostaglandin-synthesis-inhibiting drugs in general may cross-react in patients with aspirin hypersensitivity syndrome (nasal polyps and asthma). Some patients who develop hives on aspirin therapy, and who may or may not be iodide sensitive, are also sensitive to ibuprofen (57). The former group are not infrequently sensitive to tetrazine, a dye used in the original preparation of the "Motrin" tablet. At any rate, patients who have either condition are sensitive to ibuprofen. Certain asthmatic patients improve with nonsteroidal anti-inflammatory drugs, including ibuprofen (58). Ibuprofen appears not to be mutagenic (59). Conclusion
Ibuprofen is a mild but effective anti-inflammatory and analgesic drug whose salient clinical property is reduced symptoms of gastric irritation. In an individual patient, when indicated, its effect is unpredictable, and the drug is probably not as immediately anti-inflammatory as aspirin or corticosteroids. It should be given a trial of 14 to 21 d before abandonment. It is becoming obvious that failure to achieve a beneficial effect with one propionic-acid derivative does not imply failure with others. This suggests genetic or environmental differences between subjects that are unknown at present. As with other drugs with short-term plasma half-lives, dosing must be frequent (three or four times daily), a feature that reduces patient compliance, especially in the long-term problems for which ibuprofen is indicated. In the 12 years since its introduction in England, ibuprofen has shown no serious long-term adverse effects, nor has tolerance been noted to its action. The gradual increase in its suggested dose over the years reflects not only the crudity of our present methods of determining clinical anti-inflammatory effects but also ibuprofen's relative lack of toxicity. Rheumatologists are increasingly sanguine about using the drug in doses greater than 1600 mg/d. It remains to be seen whether the reduced gastrointestinal toxicity of ibuprofen, as compared with salicylates, phenylacetic, and pyrazole drugs, will continue as doses are raised. The apparent capriciousness of clinical effect in the individual patient will no doubt be resolved as our under-
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standing of the pharmacology of anti-inflammatory drugs improves. Except for the infectious arthritides, rheumatology is plagued with a group of diseases without known cause and therefore no rational treatment. Nonsteroidal antiinflammatory drugs provide symptomatic relief and aid in rehabilitative efforts but do not at all affect the cause or suspected pathogenesis of the rheumatic disease entities. Because of cost differentials that may be as much as $1000/year, aspirin has been the drug of choice for the initial treatment of arthritis. If it cannot be tolerated or can be tolerated only at an ineffective dose, I believe that ibuprofen should be the next drug in line, because its cost is not much different and its therapeutic index established over the years is somewhat better than that of many other nonsteroidal anti-inflammatory drugs. • Requests for reprints should be addressed to Thomas G. Kantor, M.D.; New York University Medical Center, 550 First Avenue; New York, N Y 10016. Received 9 April 1979; revision accepted 26 July 1979.
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