OFFICIAL JOURNAL OF THE CALIFORNIA MEDICAL ASSOCIATION © 1964, by the California Medical Association Volume 100 MARCH 1964 Number 3 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 anti- rheumatic 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 proc- esses 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