Nonspecific Anti-Inflammatory Agents Some Notes on Their Practical Application

Home , Fluprednisolone, Paramethasone

Nonspecific Anti-Inflammatory Agents Some Notes on Their Practical Application. Especially in Rheumatic Disorders EDWARD W. BOLAND, M.D., Los Angeles

* A number of acute and chronic inflammatory acute rheumatic fever. Steroid therapy should be disorders are amenable to varying degrees of reserved for resistant cases and for those with therapeutic control with the administration of significant carditis. Salicylates are mainstays for nonspecific anti-inflammatory drugs. An evalua- pain relief in rheumatoid arthritis, but with the tion of these suppressive agents in the field of analgesic doses usually employed their antirheumatic diseases and practical suggestions re- inflammatory action is slight. garding their administration are presented. Phenylbutazone is a highly useful anti- Eight synthetically modified corticosteroid inflammatory agent, especially in management compounds are available commercially. Each of of acute gouty arthritis and ankylosing (rheu- them exhibits qualitative differences in one or matoid) spondylitis; its metabolite, oxyphenyl- several physiologic actions, each has certain ad- butazone, does not exhibit clear-cut advantages. vantages and disadvantages in therapy, and each Colchicine specifically suppresses acute gouty shares the major deterrent features of cortico- desacetylcolchicine and steroids. Prednisone, prednisolone, methylpred- arthritis. Its analogues, nisolone, fluprednisolone and paramethasone desacetylthiocolchicine, produce fewer unpleas- have similar therapeutic indices, and there is ant gastrointestinal symptoms, but may promote little choice between them for the usual rheu- agranulocytosis and alopecia. matoid patient requiring steroid therapy. Con- A number of indole preparations with anti- versely, the therapeutic indices of dexametha- inflammatory activity have been tested clinically. sone, betamethasone and triamcinolone are lower One of them, indomethacin, has received exten- than that of prednisolone; they are less desirable sive therapeutic trial; with dosages that can be for routine use and should be reserved for spe- tolerated the drug is fairly effective in the cially selected cases. symptomatic control of ankylosing (rheuma- Salicylates are preferred to adrenocortical ste- toid) spondylitis but it is of questionable value in roids in the treatment of the ordinary patient with peripheral rheumatoid arthritis.

MANY DISEASES of obscure cause are characterized by tration of certain hormonal and nonhormonal agents acute or chronic inflammation reactions, and thera- that have the capacity to suppress inflammation in a peutic control of them is dependent on the adminis- nonspecific fashion. Among the anti-inflammatory drugs now available to the physician may be listed From the Department of Medicine. University of Southern Cali- fornia School of Medicine, and St. Vincent's Hospital, Los Angeles. hydrocortisone and cortisone and their synthetic Presented as part of the program, C.M.A. Spotlight on Medicine, derivatives, corticotropin, phenylbutazone and its 1963, at the Third General Meeting at the 92nd Annual Session of the California Medical Association, Los Angeles, March 24-27, 1963. analogues, as well as salicylates and colchicine. Ad-

VOL. 100. NO. 3 * MARCH 1964 145 ditionally, several indole preparations have anti- other physiologic actions. Many of these are unde- inflammatory properties and are under clinical inves- sirable, producing unwanted reactions, sometimes tigation. An attempt will be made herein to review dangerous complications, which serve as obstacles to certain general considerations pertaining to the successful management. (8) A number of pathologic therapeutic application of these compounds, espe- conditions may be aggravated by steroid administra- cially in the field of rheumatic diseases. tion, and when these coexist they set up relative or absolute contraindications for treatment. (9) Pro- ADRENOCORTICAL STEROIDS AND THEIR tracted use of them causes functional depression of SYNTHETIC ANALOGUES the patient's adrenal cortices-and, although rever- sible, this creates a potential hazard that requires The adrenocortical steroids and their synthetic the application of special protective measures dur- analogues are, of course, the most potent antiphlo- ing periods of extraordinary stress. gistic agents now available. An enormous amount Thus, it is obvious that the adrenal cortical of basic research has been accomplished with them hormones have many shortcomings as suppressive during the past 14 years, yet the physiologic mechanisms by which they suppress inflammatory agents for chronic inflammatory diseases. But they processes are not fully understood. It would appear also have distinct attributes and constitute the only that the collagen disorders and a number of other therapeutic weapons now available that have the conditions responsive to steroids may represent capacity to inhibit rapidly the signs and symptoms hypersensitivity reactions of connective tissue and of certain inflammatory disorders. When properly that the steroids or their metabolites operating at prescribed, they allow rehabilitation for useful the tissue level inhibit such excessive reactivity. occupation in a high proportion of patients with Whether their influence is exerted by interfering rheumatoid arthritis and related collagen diseases; with antigen-antibody mechanisms, by blocking and in many such patients successful control can- tissue enzyme systems, by interrupting histamine not be accomplished by other existing means. metabolism, by modifying cellular permeability, or The principles that govern systemic steroid ad- by counteracting a "mineralo-corticoid" type of re- ministration vary with the nature and severity of sponse remain a matter of theoretical consideration. the disease concerned. In acute, self-limited condi- a number tions such as rheumatic fever, for example, large Irrespective of theoretical speculations, doses are necessary for the suppression of the in- of practical considerations are germane in the thera- flammatory process; but the hazards are not great peutic application of anti-inflammatory steroids: because treatment is for a relatively short period. (1) Their influence is not specific against any one Again, during crises of disseminated lupus erythe- disease or group of diseases. Any specificity they matosus, massive doses may be required; but these possess is against some yet unidentified factor com- may be life-saving and the risks from the drug may mon to a number of disease states. (2) They do be distinctly less than the risk of uncontrolled not destroy pathogenic organisms or directly an- disease. The many ramifications of steroid therapy tagonize toxins, allergens or other noxious agents. cannot be discussed in this short communication, Rather, their benefits seem to depend on an ability so my remarks will be confined to prolonged unin- to modify tissue reactions to adverse stimuli. (3) terrupted therapy in chronic disorders such as Their action is not curative, but in responsive self- rheumatoid arthritis. limited conditions they may restrain pathologic processes while the disease runs its course or undergoes The basic policy should be to promote and sustain remission. (4) Most of their effects, favorable and a degree of disease suppression which is optimal for unfavorable, are temporary. In chronic diseases the individual patient-that is, to provide improve- for ment with dosages that are consistent with the such as rheumatoid arthritis, example, therapeu- A tic benefits depend, therefore, on more or less con- avoidance of significant hormonal complications. tinuous administration. (5) Even with continued number of lessons gained from experience and successful control of chronic inflamma- which may serve as helpful guides may be enumer- treatment, as follows: tory or allergic manifestations may not be preserved ated indefinitely because some patients become relatively 1. Satisfactory improvement cannot be expected refractory to the drugs after they have been used for for all patients. The dosage requirements for ade- extended periods. (6) Steroid therapy frequently quate control are often larger than can be tolerated, fails to halt progression of the disease process itself especially when the disease is severe or very active. even while symptomatic relief and increased In such circumstances patients must settle for results functional capacity are being maintained. (7) Each which, although worthwhile, are less than desired. of the available anti-inflammatory steroids promotes, 2. Complete inhibition of the disease should not in addition to its antirheumatic effect, a variety of be sought-rather, both the patient and the physi- 146 CALIFORNIA MEDICINE cian must be satisfied with the improvement which far better than in the presteroid era, the overall re- can be obtained with so-called safe dosage levels. sults left much to be desired. Less than 60 per cent of 3. Initial doses should not be too large or con- cases were considered adequately controlled at the tinued too long. The achievement of rheumatic con- end of two years, and the proportion decreased to trol in a leisurely fashion, with dosages close to the approximately 50 per cent at the end of three years. estimated maintenance level, will often prevent un- As might be expected, results were poorest among wanted reactions from the beginning. It is better to patients with more severe disease whose dosage re- avoid the drama from early "overcharging" than to quirements for good control were greater than could struggle with complications thereafter. be tolerated, and statistically the improvement sta- 4. Reductions from initial suppressive to smaller tus tended to deteriorate as treatment was pro- maintenance doses should be made slowly, and by longed. The major deterrent to more successful man- small decrements. Sudden reductions in dosage often agement was the development of unwanted side- result in loss of clinical control. effects from the hormone, the appearance of which necessitated dosage restriction to suboptimally effec- 5. Dosage should be determined principally on tive levels. the basis of clinical improvement and the occurrence of undesirable side-effects. The erythrocyte sedimen- The obvious limitations of hydrocortisone and tation rate and other laboratory tests are not reliable cortisone as treatment agents led chemists and clini- cians to search for more efficient antiphlogistic gauges. drugs. Since 1953, the molecular structure of the 6. Maintenance doses, once established, should be natural hormones has been modified in many ways considered as relative, not fixed. Disease activity with the hope of fabricating artificial steroids which may wax and wane, and dosages must be altered ac- would possess higher therapeutic indices. That ste- cordingly. Adjustments of dosage should be made roids with superior effectiveness might be synthe- by small changes, not by large or erratic swings in sized was suggested by the knowledge that various dosage. modifications in chemical structure were capable of 7. Maintenance requirements vary in individual altering anti-inflammatory potency of cortisone and cases, but the amounts needed depend more on the hydrocortisone and, more importantly, that certain activity of the process and on the physical or emo- chemical changes could selectively amplify or tional stress to which the patient is subjected than attenuate one or more of those accessory biologic on other factors. Successful management may de- properties that create unwanted and impeding side- pend as much on proper regulation of the patient's effects. activities as on proper manipulation of medication. Some of the ingenious chemical changes that have 8. Steroids should be prescribed in divided doses been made and which have led to the development of because available preparations are absorbed quickly compounds of direct or indirect therapeutic interest and the effects dissipated rapidly. Proper division of are shown in Figure 1. They are: Fluorination at dosage such as two to four times a day (following C-9 and at C-6; dehydrogenation at C-1-C-2 and at meals and at bedtime) provides more even control C-6-C-7; methylation at C-2, at C-6, and C-16, and and minimizes the total daily requirement. C-21; dehydrogenation at C-21; hydroxylation at 9. Some patients who have been well controlled C-16; and desoxygenation at C-21. Many analogues for prolonged periods may eventually become rela- have been fashioned by making one or more of these tively refractory; improvement may deteriorate de- changes. We have tested the effectiveness of 33 dif- spite increasing and finally prohibitive amounts of ferent steroid compounds during the past ten years, steroid. In such instances responsiveness may return and eight of these compounds have been made avail- if the drug is gradually withdrawn and a treatment- free period of two or three months is allowed. TABLE 1.-Analogues of Hydrocortlsone and Cortisone 10. When, for any reason, steroid therapy is dis- Available Commercially continued, the dosage should be tapered off slowly Potency Prudent Times Dosage to prevent withdrawal symptoms (such as weakness, Prednisolone Range fatigue, lowered resistance to stress, sudden flare- (Av.) (MG Per Day) up of joint inflammation, etc.). Generally it is best Prednisone (Meticorten)...... 1.0 2.5-10.0 to gradually wean the patient from treatment over a Prednisolone (Meticortelone) .------1.0 2.5-10.0 Methylprednisolone (Medrol) . . 1.2 2.0- 8.0 period of two to three months. Triamcinolone (Aristocort: Kenacort) 1.2 2.0- 8.0 The results of hydrocortisone therapy in a group Dexamethasone (Decadron: Deronil) 7.0 0.5- 1.5 Betamethasone (Celestone) ...... 7.0 0.5- 1.5 of 150 rheumatoid patients treated continuously for Fluprednisolone (Alphadrol). . 2.5 2.5- 5.0 two years or more were compiled in 1954.1 Although Paramethasone (Haldrone).2.5 2.0- 5.0 VOL. 100, NO. 3 ' MARCH 1964 147 1--- FLUORINATION AT C-9 11. FLUORINATION AT G-6 III. DEHYDROGENATION AT C I-C 2

I. DEHDROGENATION AT C-6,C-7 3Z. METHYLATION AT C-2

VARIABLE EFFECT

ZI METHYLATION AT C-6 7I. METHYLATION AT C-21

INCREASE DECREASE

HYDROXYLATION AT C-16 I. DESOXYGENATION N,N AT C-21 --OHI

DECREASE 1 J DECREASE

Figure 1.-Influence of certain individual structural alterations on antirheumatic potency (general). able commercially. In general, each of them pro- solone and paramethasone occupy intermediate posi- motes a similar pattern of improvement when given tions, having potencies that are roughly two and one in doses of comparable antirheumatic potency. They half times greater than that of prednisolone.2 differ in antirheumatic activity, and they display But antirheumatic potency is not synonymous qualitative differences in one or several physiologic with therapeutic efficiency. This depends on the properties. But no one preparation exhibits consist- maintenance of adequate improvement in relation ent advantages, and none is divested of the major to the development of undesirable effects and com- inherent limitations of corticosteroid therapy. (See plications, not on the number of milligrams required Figure 2. ) per day. Hence a word is in order regarding the The compounds which have been marketed and relative merits of each of these steroids, based on their relative antirheumatic strengths per milligram long-term treatment studies.3 are shown in Table 1. The potencies of prednisone Prednisolone and Prednisone: These analogues and prednisolone are similar and, on average, are differ from hydrocortisone and cortisone, respect- approximately four times greater than hydrocorti- ively, by the presence of a double bond between the sone. -Methylprednisolone and triamcinolone are ap- first and second carbon positions. This change en- proximately 20 per cent more potent than predniso- hances anti-inflammatory potency and glycogen dep- lone, and the strengths of dexamethasone and beta- osition without causing a corresponding increase in methasone are about seven times greater. Flupredni- electrolyte activity. Of interest is the fact that each 148 CALIFORNIA MEDICINE synthetic analogue that has been marketed has con- over a five-year period indicate that their therapeu- tained this modification. tic indices are greater than those of the parent com- Our observations with prednisone and predniso- pounds. Their antirheumatic potency per milligram lone in a series of 400 rheumatoid patients treated is approximately four times greater than that of hy-

CS2OH C 2OH C:O C:O O,"

HYDROCORTISONE CORTISONE

CH20 I: C -OH

PREDNISOLONE CH3 (A - hydroemiw"e ) METHYL PREDNISONE PREDNISOLONE (6 ) (W -csrtisu j -methylpreduisolone

CH20H CH20H CH2OH C O C O Is 0 N O OH C-ONH3

I. 10# 0

TRIAMCINOLONE KEXAMETHASONE BETAMETHASONE (16. -hydrexy, 9. flIworedris.e. ) (16. -methyl, 90.flwp soslo"n) (16b mthyi, 9. flompredflsolomn) CH2 Om I C O.

I u I F~~~~~~~~~~~~ f FLUPREONISOLONE PARAMETHASONE (6. - fluoropr3dnisolone) (16.- methyl, 6. flvoropWednesolone) Figure 2.-Chemically modified adrenocortical steroids of therapeutic interest for systemic administration. VOL. 100. NO. 3 * MARCH 1964 149 drocortisone, and, accordingly, substantially smaller that it did not exhibit clear-cut advantages or dis- milligram dosages are required. It has been clearly advantages over prednisolone. Its antirheumatic po- demonstrated that prednisone and prednisolone are tency is approximately 20 per cent greater than that capable of maintaining satisfactory response among of prednisolone, and therefore proportionately patients who are amenable to hydrocortisone ther- smaller milligram doses are required. However, apy. Furthermore, a substantial number of patients when equivalently potent doses of the two drugs are in whom improvement had deteriorated during hy- given, clinical improvement is upheld equally well drocortisone therapy regained and maintained ade- on long-term administration, and the unwanted re- quate improvement status after a switch was made ductions that intrude are similar in kind and degree. to prednisolone. The attainment of higher levels of Triamcinolone: In 1956 another series of com- improvement with the analogues can be attributed pounds were introduced, and these contained a hy- in many, but not all patients, to the fact that an ab- droxyl group at the sixteenth carbon position. This sence of salt and water retention permits the use of modification lessened anti-inflammatory potency but more effective doses. reduced electrolyte activity much more drastically. Prednisone and prednisolone differ from hydro- Importantly, it eliminated the severe sodium reten- cortisone in their proclivity for individual unwanted tion that results from adding a fluorine atom at C-9 effects. The incidence of salt and water retention and and allowed 9-fluorinated compounds to be used raised blood pressure are distinctly less. Conversely, therapeutically for the first time. Triamcinolone is a digestive complaints, peptic ulcers, vasomotor symp- complex steroid which differs chemically from pred- toms, and cutaneous ecchymoses develop more fre- nisolone in two details: the addition of an hydroxyl quently. Other undesirable reactions, such as facial radical at C-16 and of a fluorine atom at C-9. mooning, fat pads, nervous excitation, hypertricho- On a weight for weight basis, the antirheumatic sis, acne, skin tags, disturbances in glucose toler- potency of triamcinolone is somewhat greater ance and osteoporosis, seem to appear with similar (about 20 per cent, on average) than the potency of frequency when comparable antirheumatic doses are prednisolone, and is about equal to that of methyl- prescribed. It has been shown that the incidence of prednisolone. At dosage levels up to 12 mg a day, digestive complaints and of roentgenographically the compound does not cause sodium retention-in identified ulcers is substantially reduced when non- fact, it may induce sodium and water diuresis. absorbable antacids are taken with each dose of the Edema of even a slight degree is rarely seen-and drugs, and with combined administration the inci- the drug does not tend to produce or aggravate ar- dences are then no greater than during hydrocorti- terial hypertension. It has less tendency than other sone administration. steroid preparations to appetite stimulation, and it Like most investigators, we prefer prednisone or frequently causes anorexia and loss of weight. prednisolone to hydrocortisone and cortisone for In our experience, the proportion of patients who rheumatoid patients requiring steroid therapy. The are maintained satisfactorily for long periods on reasons for this choice are their lower tendency to triamcinolone is distinctly smaller than with prednis- produce salt and water retention and potassium loss, olone and methylprednisolone. This is due princi- their ability to restore improvement in a significant pally to the fact that troublesome side-effects pecu- percentage of patients after improvement from hy- liar to the drug frequently intrude during the course drocortisone has deteriorated, and the better statis- of treatment and make the transfer to another ste- tical results on long-term administration. roid necessary or prudent. Actually it was found ad- Methylprednisolone: In 1955 a series of steroids visable to discoitinue triamcinolone in approxi- containing a methyl grouping at the sixth carbon mately 25 per cent of our patients who received the atom were synthesized. The substitution was found drug as initial treatment and in over 30 per cent to potentiate anti-inflammatory activity as measured of those who were switched to it from prednisolone. by the granuloma pouch technique and without in- Among the unique unwanted effects of triamcino- creasing electrolyte activity. One of these com- lone are anorexia, loss of weight (sometimes with pounds, 6-methylprednisolone, was subsequently in- notable wasting of subcutaneous and muscle tissue), troduced commercially. Its structure differs from muscle weakness, leg cramps, nausea, cutaneous ery- prednisolone only by the presence of a methyl radi- thema, dryness and burning sensations, generalized cal at C-6. fatigue, and dizziness. The occurrence rates for some During 1956 and 1957, in collaboration with Doc- of these have been considerable: Anorexia in 10 per tor Grant Liddle of Vanderbilt University, we ap- cent, muscle weakness in 16 per cent, and pronoun- praised the metabolic and antirheumatic effects of ced loss of weight in 18 per cent. These peculiar methylprednisolone. Our conclusions were that the effects have been troublesome enough to discourage analogue was a satisfactory antirheumatic agent, but routine use of triamcinolone for rheumatoid patients ISO CALIFORNIA MEDICINE requiring steroid therapy. In our opinion, the drug ranging from 2 to 5 mg a day, the steroid has may be employed to best advantage as a "special proved to be a satisfactory antirheumatic agent. Its purpose" steroid. It should be reserved for selected therapeutic index is at least equal to that of pred- situations, such as when salt and water retention nisolone: It appears to have even less proclivity for develops from other steroids or from cardiac de- salt and water retention, and perhaps has slightly compensation, or when excessive appetite and weight less tendency to promote appetite stimulation, gain are problems in management. weight gain and abnormal fat deposition. Dexamethasone and Betamethasone: In 1958 a Paramethasone: Paramethasone is the last syn- family of analogues containing in common a methyl thetic analogue that has been marketed. It differs grouping at C-16 was synthesized. This substitution, chemically from fluprednisolone only by the addi- like 16-hydroxylation, decidedly reduces the salt re- tion of a methyl radical at C-16. Paramethasone is taining property of 9-fluorinated compounds; but, slightly more potent than fluprednisolone, but other- unlike 16-hydroxylation, the methyl substitution wise its effects are similar. In our experience it ap- does not reduce anti-inflammatory potency. Dexa- pears to have a slightly greater tendency than methasone differs from prednisolone by the presence fluprednisolone or prednisolone to bring about of a methyl group at C-16 and a fluorine at C-9. The weight gain and abnormal fat deposition. methyl group is attached at the alpha position of C-16; a point is made of this because subsequently In summary, our experience with the eight anti- another steroid, betamethasone, was introduced rheumatic modified corticosteroid analogues now which has the grouping placed at the beta position. available would indicate that none of them satisfies Despite claims to the contrary, betamethasone does the criteria for an ideal suppressive agent for rheu- not, in our clinical experience, differ significantly in matoid arthritis and other steroid-responsive con- any respect from dexamethasone. ditions. Some of the compounds exhibit qualitative Dexamethasone is approximately seven times as differences in one or another physiological action, potent as prednisolone in anti-inflammatory activity but the major deterrent features of corticosteroids and is effective in remarkably small milligram doses are shared by each of them. Prednisone, predniso- -amounts ranging from 0.5 to 1.5 mg a day. lone, methylprednisolone, fluprednisolone, and para- The overall incidence of adverse reactions from methasone seem to have similar therapeutic indices; the drug is considerably higher than from predniso- and there appears to be little to choose between lone, and certain unwanted effects are frequent and them for the ordinary patient who requires steroid troublesome. The drug is more inclined than prednis- therapy. Conversely; because they produce unique olone to cause excessive appetite, excessive gain in reactions of their own and because they have greater weight, increased abdominal girth, abdominal bloat- proclivity to promote certain troublesome hormonal ing and distention, ecchymotic skin lesions and thin- side-effects, the therapeutic indices of dexametha- ning of the skin. These unwanted effects were suffi- sone, betamethasone, and triamcinolone are lower ciently pronounced to warrant switching to another than that of prednisolone; they are less desirable for steroid in over one-third of our patients. routine use and are best employed for selected cases Although dexamethasone has greater biologic po- as "special purpose" steroids. tency than prednisolone, our observations made dur- Most adverse reactions (weight gain, abnormal ing the past five years have led us to the conclusion fat deposits, hypertrichosis, and the like) are that its general therapeutic efficiency is distinctly less avoided or kept to within acceptable degrees by than that of prednisolone and methylprednisolone. using minimally effective dosages, and in rheu- We do not employ it as a general purpose steroid, matoid arthritis we rarely exceed 5.0 mg of prednis- but, instead, restrict its use to a very few special sit- olone a day in moderate cases, 7.5 mg in moder- uations-as when refractoriness may prompt a ately severe cases or 10.0 mg in severe cases. The change of medication to another steroid or when appearance of edema is usually readily controlled appetite stimulation and weight gain are desired and by. dietary sodium restriction or administration of cannot be obtained with other compounds. chlorothiazide. Digestive complications usually can Fluprednisolone: In 1958 a number of compounds be avoided by giving the drugs after meals and containing 6-fluoro substitutions were synthesized. combined with nonabsorbable alkalis. Symptoms of This modification intensifies anti-inflammatory ac- hypokalemia (weakness, fatigue, mental aberra- tivity, but unlike 9-fluorination it does not disturb tions) are rarely encountered and may be combated electrolyte metabolism. One of these compounds, by the administration of potassium salts in dosages fluprednisolone, has antirheumatic activity which is of 3 to 5 gm a day. Shock resulting from adrenal approximately two and a half times greater than insufficiency during periods of stress, such as a that of prednisolone. With maintenance dosages major surgical procedure or acute infection, may

VOL. 100. NO. 3 * MARCH 1964 1.51 provoked by a variety of irritants. The mechanisms by which salicylates exert anti-inflammatory action are not entirely known, but presumably they involve the inhibition of certain enzyme systems and the N N suppression of vascular reactivity. NN C=O H3C-N -0 A number of authorities still prefer salicylates to adrenocortical steroids in the treatment of the ordi- O-C-CK2-CNCHMCH3 H3C- NCH nary patient with rheumatic fever. Steroid therapy is reserved by them for patients whose articular and PHENYLBUTAZONE AMINOPYRINE febrile reactions cannot be symptomatically con- (DIMETHYLAMINOANTIPYRIN) trolled by full doses of salicylates and for patients Figure 3.-Chemical structure of phenylbutazone and with clinical evidence of significant carditis. Ninety aminopyrine. per cent of patients without signs of carditis during the acute attack recover without having clinical evi- be avoided by fortifying the patient with extra dence of rheumatic heart disease. These are patients steroid medication. It is our custom, for example, to whose predominant manifestations are acute poly- administer 100 mg of cortisone acetate intramus- arthritis and they usually respond adequately to cularly 24 hours before and again on the day of the large oral doses of salicylates. Initial doses of 10 surgical operation to all patients who are on steroid gm (150 grains) of acetylsalicylic acid per day are therapy. With such a schedule we have had no recommended for patients weighing 70 kilograms deaths due to adrenal insufficiency in over 70 pa- (150 pounds) or more, and proportionately smaller tients subjected to major surgical procedures. doses for patients weighing less. It is important that Among our rheumatoid patients who have re- the total daily amount be divided into six doses ceived steroid therapy continuously for years, the given every four hours in order to maintain ade- most troublesome complications have consisted of quate blood levels of salicylate. Large doses should osteoporosis and pathologic fractures (especially of be continued until there is complete relief from the the spine), increased capillary fragility and ecchy- arthritis and until the temperature has returned to motic lesions,thinning and friability of the skin, and normal; dosage should then be reduced gradually delayed wound healing. We have found no satis- over a period of days or weeks. Toxic symptoms factory way of combating these complications of (tinnitus, coloring of vision, nausea, impaired hear- cellular catabolism other than withdrawing steroids ing, mental confusion) are not uncommon with or reducing the dosage. High protein diets, comple- high dosage and may force reduction in dosage be- mental calcium, and the administration of anabolic fore the desired response has occurred. In such cir- sex hormones may be of value, but the effects of cumstances the substitution or the addition of adre- these measures are most difficult to measure. Rarely nocortical steroid therapy is in order. has vasculitis or peripheral neuropathy developed in Salicylates are the mainstays for the relief of pain patients we were treating, which is fortunate be- in patients with rheumatoid arthritis. Aspirin or cause these complications are serious and partic- sodium salicylate is usually prescribed in doses of ularly refractory to treatment. 0.3 to 0.6 gm (5 to 10 grains) four to six times a day. In these amounts it is probable that the anti- SALICYLATES inflammatory effect is slight, but larger doses are not recommended for prolonged continuous use in a Salicylates, and particularly acetylsalicylic acid or chronic disease such as rheumatoid arthritis. The aspirin, are the most commonly employed analgesic concomitant ingestion of nonabsorbable antacids and antipyretic drugs in medicine. For the past 75 and the taking of the drug after meals or with milk years they have been universally employed for the reduces the incidence of gastritis and activation of relief of the pain, aching and stiffness that charac- peptic ulcers. There is no good evidence that various terize many rheumatic disorders. It has been amply combinations with antacids increase the effectiveness demonstrated that salicylates administered in large or rate of absorption of salicylates. doses have anti-inflammatory activity but not so much as adrenocortical hormones and their ana- PHENYLBUTAZONE AND OXYPHENYLBUTAZONE logues, corticotropin and phenylbutazone. In animals acetylsalicylic acid will delay the erythema in- Since its clinical introduction in 1951, phenylbu- duced by ultra-violet light, will inhibit the exuda- tazone has established itself as a successful anti-in- tive reaction of turpentine-induced pleurisy, and will flammatory and analgesic agent in several condi- lessen the capillary permeability that is ordinarily tions affecting the musculoskeletal system, especially

152 CALIFORNIA MEDICINE acute gouty arthritis and ankylosing (rheumatoid) spond well during the first six months of admini- spondylitis. The drug, better known as Butazoli- stration usually continue to do so over long periods. din,® is a pyrazol and is related to aminopyrine In our experience the results in peripheral rheuma- (Figure 3). Actually it was first employed as a toid arthritis from the small doses (100 to 200 mg solubolizing agent for aminopyrine and only later a day) of phenylbutazone that can be tolerated on was found to have inherent therapeutic effects of its continued administration are unimpressive; rarely own. Like other pyrazole compounds it exerts sev- is a true anti-inflammatory response noted, and the eral biologic effects. The anti-inflammatory quality degree of analgesia that results is usually not suffi- of phenylbutazone has been amply demonstrated in cient to warrant the risks involved. laboratory animals: it delays or inhibits the ery- With long-term phenylbutazone therapy, total thema that follows exposure to ultraviolet light, and daily doses should not exceed 200 to 300 mg, as the it inhibits the edema which normally follows the in- incidence of toxic reactions is decidedly greaterwhen jection of formalin or egg albumin into the paw of higher dosage is used. Some spondylitic patients re- a rat. The drug is also capable of causing sodium spond symptomatically to doses of 100 mg a day. If retention and it exerts uricosuric action in both larger amounts (400 to 800 mg a day) are required to normal and gouty subjects.4 quell a temporary exacerbation, they should be em- The anti-inflammatory action of phenylbutazone ployed for only a few days at a time. The physician is best exemplified in acute gouty arthritis, and dur- must be thoroughly familiar with the drug's poten- ing the past few years it has made a fair bid to re- tial toxic effects and be ready to discontinue its ad- place colchicine in treatment of an acute episode. ministration or to lower the dosage if they appear. Given early in an attack and in adequate dosage, it He must be particularly vigilant for such reactions causes the pain of acute gouty arthritis to subside as skin rash, indigestion and symptoms of peptic dramatically within a few hours (within 24 hours ulcer (including bleeding), fluid retention, suppres- in 95 per cent of early cases), and the signs of in- sion of hemopoiesis (agranulocytosis, aplastic ane- flammation usually resolve within 24 to 72 hours. mia) and hepatitis. Blood cell examination should In well established attacks, when the synovitis has be done routinely each month during continuous existed for several days, the response is slower and therapy, and nonabsorbable alkalis should be in- may not be complete for seven to fourteen days. gested with each dose of the drug. Our usual program for administering phenylbuta- Favorable anti-inflammatory action from phenyl- zone orally in acute gouty arthritis is to prescribe a butazone has been reported in acute rheumatic fever large initial dose of 400 to 600 mg, followed by 200 and in superficial thrombophlebitis, but we have had mg every two hours for two or three doses, so that no personal experience with the drug in the first a total of 1,000 mg is given during the first 24-hour and very limited experience in the second condi- period. Beginning on the second day and continuing tion. until the inflammation has subsided, 100 mg is pre- During the past four years, oxyphenylbutazone, a scribed two to four times a day, depending on the metabolite of phenylbutazone, has been introduced severity of the attack and the response to the drug. commercially under the trade name of Tandearil.@ Noxious side effects (diarrhea, nausea and vomit- It was hoped that fewer unwanted side-effects would ing) which occur so commonly with full therapeu- be produced by the derivative, but the results of tic doses of colchicine, are not a problem with phe- carefully controlled studies indicate that phenylbuta. nylbutazone. An occasional patient experiences gas- zone and oxyphenylbutazone do not differ signifi- tric irritation from large initial doses, and in such cantly in either their ameliorating effects or tox- circumstances the drug may be administered intra- icity. muscularly. The intragluteal injection of 500 to 1,000 mg early in an attack dramatically aborts or COLCHICINE suppresses the inflammatory reaction. Given infre- Colchicum is perhaps the oldest anti-inflamma- quently and for short periods, such as for an acute tory drug in medicine, having been used by Byzan- gouty attack, phenylbutazone rarely produces toxic tine physicians as early as the fifth century. Its alka- reactions. loid, colchicine, acts specifically in suppressing the The drug has proved to be very useful in the inflammatory reaction of acute gouty arthritis, and symptomatic control of ankylosing (rheumatoid) the drug does not antagonize any other form of in- spondylitis, and here again it appears to exert anti- flammation. The mechanism of its action in acute inflammatory action. It is much more effective in gouty arthritis is unknown: it exerts no effect on spondylitis than in peripheral rheumatoid arthritis, the production or excretion of uric acid; it does not and may even afford worthwhile relief in advanced influence the solubility of sodium urate in the cases in which ankylosis is present. Patients who re- plasma; it has no effect on adrenocortical function; VOL. 100, NO. 3 * MARCH 1964 153 EXPERIMENTAL NONSTEROIDAL ANTI-INFLAMMATORY AGENTS CH30 CHCOOH COOH CFF During the past five years a number of nonste- CHo roidal compounds with anti-inflammatory activity, as demonstrated by animal testing, have been tried clin- FLUFENAMIC ACID ically in patients with rheumatic disease. The most promising of these has been a series of indole prep- cI N-(°e,°s,°c-trifluoro-m-tolyl ) INDOMETHACIN anthronilic acid. arations, one of which, known as indomethacin I1p-chlorobenzoyl)-5 methoxy- (MK-615), has been investigated extensively in 2-methyllndole-3-acetic acid many centers. Another family of compounds which Figure 4.-Chemical structure of indomethacin and flu- is now being assessed for anti-inflammatory, an- fenamic acid. algesic and antipyretic properties is represented by flufenamic acid (Figure 4). and, insofar as can be determined, its anti-gout activity is unrelated to its antimytotic properties. Indomethacin has shown anti-inflammatory activ- The response of acute gouty arthritis is usually ity in rats by the cotton-pellet granuloma-inhibition dramatic if the drug is given early and in proper test and by its capacity to suppress the edema that dosage. The specificity of its action makes colchicine usually results from the subplantar injection of irri- of value both diagnostically and therapeutically. tating agents. The level of its activity may be com- Joint pain, tenderness, redness and swelling usually pared with that of phenylbutazone, and toxic effects begin to subside within 12 hours after therapy is from oral administration to animals have consisted begun, and in most instances pain is completely re- of gastrointestinal irritation for the most part. lieved after 24 to 72 hours. Acute bouts are con- Chemically, indomethacin is 1-(p-chlorobenzoyl) -5- siderably diminished in 80 or 85 per cent of cases methoxy-2-methylindol-3-acetic acid (Figure 4). by a single course of the drug, but the response rate Our clinical experience with indomethacin em- is considerably less if treatment is delayed for sev- braces a total of 119 patients with various types of eral days after an attack has been established. To- rheumatic disease who were treated for varying pe- day authorities are divided in their preference of riods (from 1 to 18 months) and with oral dosage colchicine or phenylbutazone for treatment of the ranging from 50 to 200 mg a day. Among patients acute attack. Suffice it to say that phenylbutazone with osteoarthritis, chronic tendinitis and bursitis, has successfully rivaled colchicine as the drug of the results have been disappointing, and the major- choice in recent years, and phenylbutazone is usually ity so afflicted have noticed no difference when effective in those cases that do not respond to col- placebos were given. Among 51 patients with active chicine. peripheral rheumatoid arthritis, most of whom received 100 to 200 mg per day, the influence of the *For an acute attack we usually advise that 0.65 drug on subjective complaints as well as on lessen- mg (1/100 grain) of colchicine be given orally ing of the measurable objective manifestations of every hour for 8 to 12 doses or until the occurrence the disease has been inconclusive. An occasional of nausea, vomiting or diarrhea. Many patients patient with mild or moderate disease activity has learn by experience the optimum number of tablets responded well, but even among these less severe necessary to relieve an attack, and by taking one or cases objective evidences of significant antirheu- two tablets short of toxic effects they avoid unde- matic action have been witnessed irregularly and sirable gastrointestinal symptoms. unpredictably. Among corticosteroid-treated patients For patients who, for one reason or another, can- the concomitant administration of indomethacin has not take the drug orally, colchicine may be given only occasionally allowed reduction of maintenance intravenously. If the dosage by this route does not dosage of the steroid. Conversely, indomethacin in exceed 3 mg, gastrointestinal symptoms are usually dosages of 100 to 200 mg a day has proved to be obviated. It is our custom to give a second intrave- quite effective in reducing the subjective complaints nous dose of 3 or 2 mg after 12 or 24 hours. of ankylosing (rheumatoid) spondylitis, and its During the past few years a number of colchicine ameliorating influence might eventually prove com- analogues have been prepared and evaluated. Of parable to that of phenylbutazone in this condition. these, desacetylmethylcolchicine and desacetylthio- In the experience of some investigators, attacks colchicine are effective for acute gouty episodes and of acute gouty arthritis respond rapidly to indo- have considerably less gastrointestinal toxicity. These methacin given in dosages of 400 to 600 mg during drugs should not be considered as satisfactory alter- the first 24 hours. Reportedly, the benefits derived native agents, however, because they have much compare favorably with those observed from phe- greater tendency than colchicine to produce agranu- nylbutazone and colchicine. We have had no expe- locytosis and loss of hair. rience with the drug in acute gouty arthritis because

154 CALIFORNIA MEDICINE we have been unwilling to risk dosages that exceed REFERENCES 200 mg a day. 1. Boland, E. W.: Present status of hydrocortisone as a Adverse effects from indomethacin are frequent, therapeutic agent in rheumatoid arthritis, Ann. New York and their occurrence limits the usefulness of the Acad. Sc. 61:349, 1955. drug. With daily dosages of 100 to 200 mg a day, 2. Boland, E. W.: Antirheumatic potency of chemically modified adrenocortical steroids, Am. J. of Med. 31:581, headaches, dizziness or drowsiness have been the 1961. most common side effects noticed.5 Gastric irritation 3. Boland, E. W.: Clinical comparison of the newer anti- has been common, and in five of our patients roent- inflammatory corticosteroids, Ann. of Rheum. Dis. 21:176, genographically demonstrable gastric ulcers devel- 1962. oped. Four of the five were treated simultaneously 4. Freyberg, R. H.: Phenylbutazone (Butazolidin®) in the treatment of acute arthritis. Progress in Arthritis, pp. with oral adrenocortical steroids while one patient 177-184, Ed. Talbott and Lockie, Grune and Stratton, 1958. with a severe hemorrhagic ulcer received indometha- 5. Hart, F. Dudley and Boardman, M. B.: Indomethacin: cin only. a new non-steroid anti-inflammatory agent. Brit. Med. 2210 West Third Street, Los Angeles, California 90057. Journal, pp. 965-970, Oct. 19, 1963.

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