Review Articles

The following article is an Installment In the Drug Therapy Reviews series. The titles of all articles In this series are prefaced with "Drug therapy reviews". Other articles In the Review Articles section of the Journal are riot a part of this series

Am J Hosp Pharm 36:622-633 (May) 1979 Drug therapy reviews; Antirheumatic agents

Ronald P. Evens Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 The pathophysiology, symptoms and drug treatment of rheumatic disease are reviewed. Antirheumatic drugs reviewed are salicylates (including aspirin, sodium salicylate, choline salicylate, choline magnesium salicylate, salsalate), phenylpropionic acid derivatives (fenopro- fen, ihuprofen, naproxen), indole derivatives (sulindac, tolmetin and indomethacin), pyrazo­ lone derivatives (phenylbutazone, oxyphenbutazone), gold compounds, penicillamine, antima­ larials, mefenamic acid, corticosteroids and immunosuppressives. Simple analgesic therapy (acetaminophen, aspirin, propoxyphene) is used in the early stages of the disease. As the disease progre^es, aspirin remains the drug of choice for antiinflamma­ tory activity hut the phenylpropionic acid or indole derivatives may be preferred in patients unable to tolerate salicylates. If such nonsteroidal antiinflammatory agents are not effective, parenteral therapy with gold compounds or oral penicillamine usually is indicated. Indometha­ cin or phenylbutazone, then antimalarials, are resorted to next. Corticosteroids or immunosup­ pressives are reserved for patients who are unsuccessfully controlled or who have major side effects with the other drugs. Mefenamic acid occupies a very secondary place in rheumatoid arthritis treatment. Key words: Analgesics arid antipyretics; Antiinflammatory agents; Antirheumatic agents; Ar­ thritis; Rational therapy

The rheumatic (diseases are a group of polyarthritic dis­ General Therapeutic Principles orders of unknown etiology. They include rheumatoid ar­ thritis, juvenile rheumatoid arthritis, ankylosing spondylitis, The basic pathophysiologic process in rheumatic diseases psoriatic arthritis and Reiter's syndrome. Gouty arthritis is chronic joint inflammation,^-® leading to joint damage, generally is considered separately since the immediate cause destruction of adjacent cartilage and bone and, eventually, of the disease (hyperuricemia) is known and can be con­ joint deformities.®'® Prostaglandins are mediators that am­ trolled with appropriate drug therapy. This paper reviews plify the inflammatory process (Figure 1). Disease activity general therapeutic principles, approaches to monitoring can be assessed,by the degree of inflammation, the,severity drug effects, mechanisms of antiinflammatory drug action and duration of pain, appearance of nocturnal pain and the and pharmacotherapeutic considerations in the use of each degree of morning stiffness. Rheumatic disorders are chronic antirheumatic agent. - * and episodic, with spontaneous exacerbations and remis­ sions, and are progressive with or without therapy. Treat­ ment with drugs and other measures should be individual­ • This is article 79-08 In the AJHP Continuing Education system. See page ized and adjusted as the disease changes. Physiotherapeutic, 581 for learning objectives and test questions: Readers who wish to study this articie are encouraged to first review the learning objectives. smgical, orthopedic, nutritional and psychiatric therapy may be of equal or greater importance than drug therapy, de­ pending on the individual patient. - Goals of drug therapy include pain relief, reduction of Ronald P. Evens, Pharm.D., is Director of the Drug Information Service, University of Texas Health Science Center, San Antonio; Assistant Professor inflammation and preservation of functional capacity of of CHnical Pharmacy, CoUege of Pharmacy, University of Texas; and Assistant joints and adjoining muscles; complete resolution of the Professor, Department of Pharmacology, University of Texas Health Science Uenter. " pathologic process (cure)_is not a reasonable goal. Optimal The assistance of Pamela McMurtray is acknowledged. disease control requires individualization of therapy based Address reprint requests to Dr. Evens at the Department of Pharmacology, on several pharmacotherapeutic principles^'®'®: University of Texas Health Science Center, 7703 Floyd Curl Drive, San An­ tonio, TX 78284, S- • '1. Placebo response is of considerable importance. Over a Copyright © 1979, American Society of Hospital Pharmacists, Inc. All rights tw()-year period, oral or parenteral placebo produced a reserved. satisfactory response in more than 50% of patients in one study.'* .

622 American Journal of Hospital Pharmacy Vol 36 May 1979 0002-9289/79/0501-0622$03.00 Anilrheumatic agents

Figure I.Inflammation scheme; * = sites of action of nonsteroidal antiin­ flammatory agents • The Drug Therapy Reviews column is edited by Russell R. Miller, Pharm.D., IgG + Rh. Factor Ph.D.,' andDavid J. Greenblatt, M.D. The objective of the column is to present critical reviews in pharmacotherapeutics. The principal type of contributionis . papers on the current status of the clinical use of a drug or group of drugs. Ar­ Ag-Ab. Complex ticles on the current status of drug therapy in selected diseases are also pub­ lished. Drug Therapy Reviews is a service of the Department of Pharmacy of the New England Medical Center Hospital, Boston. Redactorial expenses involved in the Complement Chemotaxis pubiication of Drug Therapy Reviews are funded by a grant from the Bingham Associates Fund. Contributions also appear in the Journalof the Maine Medical Association, generally one monthbefore their pubiication in the AmericanJournal 'Neutrophil'# of Hospital Pharmacy. Authors who have prepared papers thought to be ap­ Migration and propriate for this column are invited to submit them to: PG — Phagocytosis Russell R. Miller, Pharm.D., Ph.D. Box 420 New England Medical Center Hospital

Boston, MA 02 111 Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 PG-*— Lysdmal Enzyme -»-Kinihs * Release

\ Synovial Inflammation Membrane flammation in the few involved joints—usually phalangeal -.-PG- ! Hyperplasia - & and carpal joints in the hands, wrists, feet and ankles. As­ Granulation pirin remains the drug of choice since no other nonsteroidal antiinflammatory agent is more effective or less expensive.® However, many patients cannot tolerate large doses of as- Cartilage... DegradationJ and . pirin for long periods. Before prescribing a nonsalicylate Bone Erosion drug, other forms of salicylate should be evaluated. En­ teric-coated aspirin or sodium salicylate tablets and aspirin suppositories are absorbed erratically hut may he useful. Similarly, choline salicylate, choline magnesium salicylate or salsalate may be beneficial. Because they have less gas­ 2. Prior to selection of new treatments, a drug history should trointestinal toxicity than aspirin, phenylpropionic acid be taken to determine response to previous antirheumatic derivatives are being promoted as first choice agents.® drug therapy. However, they probably should be used only after,salicylates 3. Oral antirheumatic drugs should be prescribed singly at first - and assessed in a serial manner in each patient until the have failed or been proved too toxic. If either of these drug optimal drug and dosage is found. categories proves inadequate or too toxic, tolmetin or sul- 4. Response to antirheumatic drugs is highly variable. Some indac (indole drugs chemically related to indomethacin) can patients have the same response to.different drugs, whereas others respond differently to similar drugs within the same be tried. class of compounds. When control of inflammation is not achieved with a 5. A single drug should be continued until sufficient time has nonsteroidal drug and arthritis is moderate to severe, par­ elapsed to permit a full pharmacologic response. For ex­ ample, aspirin or phenylpropionic acid derivatives should enteral therapy with a gold compound or oral penicillamine be given for one month, and penicillamine should be given usually is indicated as a third step. These drugs usually are for four to six months. added to therapy with a nonsteroidal agent and can slow or 6. If treatment failure occurs, the drug dose, frequency of administration and patient compliance should be consid­ arrest the pathogenic process. However, up to six months of ered before a new drug is prescribed. therapy are required before full beneficial effects become 7- When treatment is successful, dosage should be reduced to evident, and these drugs have major dermatologic, renal and maintenance-levels and, if possible, the drug should be discontinued during disease remissions. hematologic effects in many patients. Step four includes indomethacin or phenylbutazone and The less toxic agents should be used in the early disease the antimalarials. Because of their toxicity, antimalarial stages, with the more toxic agents subsequently added as drugs are usually used only after indomethacin or phenyl­ prior drug therapy becomes less effective and the disease butazone have been proved inadequate. Like gold com- progresses^'®'^ (Appendix). The first step frequently involves . pounds and penicillamine, antimalarials slow the progression simple analgesic therapy. Low doses of aspirin (e.g., 2 to 3 of rheumatoid joints. g/day) or acetaminophen may be used. Alternatively, other Step five includes corticosteroids or immunosuppressive salicylates, phenylpropionic acid derivatives (fenoprbfen, agents. These drugs are reserved for patients who are con-, ihuprofen, naproxen) or propoxyphene may be used.^-'' Also, trolled unsuccessfully by other drugs or who have major side a proper balance of rest and exercise should maximize mo­ effects. In patients with asymmetric, single-joint inflam­ bility and control joint trauma in the early stages. mation that has compromised mobility substantially, in­ As the disease progresses, larger doses of aspirin (3.6 to traarticular steroids are given prior to systemic steroid 6.0 g/day) should be used as the second step to reduce in- therapy.

Vol 36 May 1979 American Journal of Hospital Pharmacy 623 Antirheumatic agents

Disease Assessment and Response to Ttierapy disproportionately large changes in blood levels.i6 A twofold dosagachange of 1.5 to 3.0 g/day can produce a sixfold ele­ Diagnostic criteria of the American Rheumatism Associ­ vation in blood levels; the plasma half-life may increase from ation allow assessment of the degree of response to treat- two to four hours to 15 to 30 hours." ment.®'i° Common subjective variables include joint pain, The major problems with aspirin therapy are gastroin­ -tenderness, swelling and stiffness; these are tabulated singly testinal and otologic side effects. ^8,14 Gastric intolerance with or together in an articular index of active joints (e.g., dyspepsia and gastritis occurs in at least 30% of arthritic "Lansbury articular index"). Each symptom is evaluated patients. Occult fecal bloodioss, usually 4 to 12 ml/day, is with a rating scale to quantitate improvement in the disease. common. Tinnitus ^d hearing loss usually are observed only Other subjective measures are the duration of morning at high doses and with blood concentrations of 25 to 30 mg/dl stiffness, patient or observer preference for a particular or greater. Other adverse reactions include a twofold to therapy, ancillary analgesic intake and ring size (joint size). threefold prolongation of bleeding time,20.2i hepatotoxi- Functional capacity is quantitated by evaluating grip city,22 skin rashes and asthmatic reactions. strength, time required to walk 50 feet or climb a specific (2) Sodium Salicylate. Sodium salicylate is as effective number of stairs, time for onset of fatigue and range of joint as indomethacin.28 It is absorbed more rapidly than aspirin, Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 movement with flexion and extension. Bone and joint fluid but contains substantial amounts of sodium. A 5-g daily dose changes are assessed by roentgenograms, radioactive isotope provides about 31 mEq pf sodium. uptake in joints, synovial effusion and histologic exam of (3) Choline Salicylate. Choline salicylate (Arthropan) is synovial specimens. Immunologic disease activity is mea­ marketed as a solution containing 870 mg of choline salicy­ sured by erythrocyte sedimentation rate (ESR), serum late, equivalent to 500 mg of salicylate, per 5 ml. This is about rheumatoid factors, antinuclear antibodies and cryoglobu­ the same salicylate content as in 650 mg of aspirin. Absorp­ lins. Subsets of these variables are used to assess drug effi­ tion of choline salicylate is rapid because the drug is already cacy. in solution and tablet dissolution is not necessary. Thus, choline salicylate solution provides peak salicylate blood Individual Antirheumatic Drugs levels more rapidly than does aspirin tablets.24^27 gtoce the overall bioavailability of choline salicylate and aspirin are Salicylates. (1) Aspirin. Aspirin has been the drug of probably similar, these differences are unimportant during choice^for rheumatoid arthritis for over 30 years."-!^ chronic therapy. swelling, mobility of joints, morning stiffness and analgesic Published clinical trials of choline salicylate^'^-^i intake are improved routinely with aspirin therapy. About limited because of many methodologic inadequacies. 50% of patients with mild to moderate disease will be con­ Therefore, the efficacy and toxicity of choline salicylate trolled by aspirin alone.^® The standard dosage range is 3.6 versus aspirin are described and equated only empirically. to 6.0 g/day. The mechanism of action of all nonsteroidal Since choline salicylate is marketed as a solution, gastroin­ antiinflammatory agents like aspirin is inhibition of pros­ testinal side effects probably occur less often. However, bad taglandin synthesis, which interrupts amplification of the taste limits its usefulness. inflammatory process (Figure 1). (4) Choline Magnesium Salicylate. Choline magnesium Aspirin is well absorbed and peak plasma concentrations salicylate (Trilisate) contains 500 mg of salicylate per tablet of salicylate are achieved within 10 to 30 minutes." Although in the form of choline salicylate (293 mg) and magnesium there is not a direct relationship between therapeutic re­ salicylate (362 mg). This salicylate strength is equal to 650 sponse and blood levels, a salicylate concentration of 20 to mg of aspirin. The half-life of choline magnesium salicylate 30 mg/dl generally is considered the therapeutic range for is dose-dependent, as is aspirin's. For example, at 1 g twice antiinflammatory action.i^i® Once an effective daily dose daily, the half-life is 7.6 hours, whereas at 1.5 g twice daily, is found, the frequency of administration can range from it is 18.3 hours.32 Similar serum salicylate levels are produced every four to eight hours with acceptable small interdose by aspirin and choline magnesium salicylate.33 In terms of blood level fluctuations. Steady-state serum levels are duration of morning stiffness and joint involvement, aspirin achieved within approximately one week after starting and choline magnesium salicylate are equally effective 34 chronic dosing. One useful pharmacokinetic scheme" pre­ The side effects of choline magnesium salicylate are dicted that 650 mg given every four hours during waking similar to those of aspirin, but they occur less often at hours plus a 1.3-g bedtime dose will maintian adequate blood equivalent doses.34 The most common reactions in one study levels throughout the 24-hour period. were tinnitus (5.3%), and gastrointestinal distress, nausea In one study, buffered and enteric-coated tablets pro­ and pain (6%).34 Headache and hearing loss also were re­ duced comparable steady-state levels, 14.0 mg/dl versus 17.5 ported. Gastrointestinal blood loss was not evident with mg/dl, respectively,18 but significant bioavailability differ­ choline magnesium salicylate, 1.5 g twice daily.35 ences have been observed between enteric-coated prod- UCtS.18 The efficacy and role of choline magnesium salicylate in rheumatic diseases has not been established completely Aspirin is metabolized in the liver by both first-order and because of the very few published studies. However, pre­ saturable processes. Saturable pathways become important liminary evidence indicates it has effective twice-daily dosing during administration of the large doses required for ar­ and fewer side effects (especially fecal blood loss) than thritis. Small dosing increments (e.g., 325 mg) may cause aspirin.

624 American Journal of Hospital Pharmacy Vol 36 May 1979 Anlirheumatlc agents

(5) Salsalate. Salsdate (Disalcid) is salicylsalicylic acid Table 1. Biopharmaceutics of Phenylpropionic Acid (500 mg/tablet). Its antiinflammatory properties are similar Derivatives to those of aspirin.-'*' It is hydrolyzed to salicylic acid in vivo Steady- more slowly than is aspirin,and has a half-life of about state eight hours.®® The rate of absorption is slower than aspirin Absorp­ Plasma Half- Protein Metabo­ tion Cone. life Binding lism or sodium salicylate. Steady-state salicylate blood levels of Drug (%) (Mg/mi) (ftrs) (%) <%) salsalate and aspirin are about equivalent (13.5 mg/dl at 3 Fenoprofen® 80 30-60 2.5 3 99 90 g/day of salsalate versus 12.9 mg/dl at 3.6 g/day of as­ (24 firs) pirin.®® Ibuprofen'' — 1.9-2 95 93 There are few published clinical trials of salsalate. Com­ Naproxen<= 84 88 30-50 14 99 90 (72 firs) parable relief of joint pain and inflammation and similar patient preference was described for salsalate and indom- ® References 5, 45, 46. '' References 5, 47-49. ethacin in 18 rheumatoid arthritic patients.'*® In 20 os­ " References 5, 50, 51. teoarthritis subjects, salsalate was slightly superior or equal to aspirin in six variables of disease activity.®® An open trial absorption of all three agents and reduces peak plasma Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 showed 73% improvement in joint pain with 66 musculo- concentration (by about 30%) and total absorption (by about skeletal-joint disease subjects. Dosage generally is 3 g/day 20%), as does coadministration of aspirin or antacids.*®"®' in three divided doses, which is a lower daily dose than as­ Concomitant aspirin administration reduces absorption of pirin (3.6 g/day) because of a higher salicylate content. fenoprofen by 46%*® and naproxen by 16%.®® Adverse effects are comparable in scope to other salicy­ Therapeutic dosages are: fenoprofen, 1.2 to 2.4 g/day in lates (e.g., dyspepsia, nausea, abdominal pain and tinnitus). four divided doses; ihuprofen, 1.2 to 2.4 g/day in four divided Precise frequency rates cannot be calculated because of the doses; and naproxen, 0.5 to 1.0 g/day in two divided doses. small number of clinical trials, but rates appear to be less All three drugs are as equally effective as aspirin, indbm- than or equal to aspirin.®®"'*' Gastric erosion and hyperemia ethacin and phenylbutazone (Tables 2 and 3). Even in direct are unusual with salsalate intake, in contrast to their com­ comparisons, consistent differences among the three pro­ mon occurrence with aspirin.^® Gastrointestinal blood loss, pionic acid derivatives are not established.®''-®® Concomitant based on analysis of radioactively tagged red blood cells in steroid doses have been lowered by naproxen administra­ feces,'*® and occult blood loss'*'* were similarly insubstantial tion.''® for salsalate and placebo, but common with aspirin. - Studies comparing these three agents with aspirin have The place of salsalate in salicylate therapy for rheumatic demonstrated a usually lower or similar frequency of adverse diseases is not established. It appears to he as effective as reactions with the phenylpropionic acid derivatives (Table aspirin, and it may have fewer side effects. However, its 4) 55,59,62-68,71-74 -phe frequency of gastrointestinal ulceration safety has not been described completely. and bleeding is significantly lower than with aspirin.'""''® Phenylpropionic Acid Derivatives. Fenoprofen calcium When naproxen was given to recent ulcer disease patients, (Nalfon), ihuprofen (Motrin) and naproxen (Naprosyn) are only one out of 58 subjects had a positive stool occult blood.''® propionic acid derivatives marketed as antirheumatic drugs. However, all three drugs have heen associated with fatal Numerous other drugs of the same chemical class are under gastrointestinal hemorrhage in rare cases.''® investigation (e.g., ketoprofen, flurbiprofen). In usual doses, Tolmetin Sodium. Tolmetin sodium (Tolectin) is chem­ fenoprofen, ibuprofen.and naproxen are well absorbed and ically related to indomethacin and pharmacologically similar rapidly achieve steady-state blood levels (Table 1). All three to phenylpropionic acid derivatives.®®-®® The half-life of drugs are biotransformed in the liver, and the metabolites tolmetin is ahout one hour. Tissue distribution is minimal are excreted in the urine. because of extensive (99%) binding to serum protein.''''-''® The relation between dose and blood levels for naproxen Peak plasma levels occur at 20 to 60 minutes after an oral is linear up to approximately 500 mg/day, where the ab­ dose.''® Repeated drug administration (300 mg three times sorption process becomes saturated. Thus, higher doses daily for 10 days) does not lead to significant drug accumu­ produce smaller increments in hlood level.*® Food delays the lation.'" Clearance is achieved primarily by hepatic bio-

Table 2. Double-blind Clinical Studies of Phenyipropionic Acid Derivatives and Aspirin in Rheumatoid Arthritis

Duration No. of Patients Daily Dose (g) of Studies Drug Drug- Aspirin Drug Aspirin (wk) Efficacy

Fenoprofen® 227 217 0.8-2.4 1.5-6.0 12-52 Fenoprofen equal to aspirin in 4 measures and superior In 2 measures. Aspirin superior to fenoprofen in 3 measures. Ibuprofen'' 1,034 1,034 0.8-1.6 3.0-6.0 4-52 Ibuprofen equal to aspirin in 5 measures. Naproxen'^ 78 78 0.5 3.6-4.0 8-12 Naproxen equal to aspirin in 7 measures and superior in 1 measure. Aspirin superior to naproxen in 4 measures. "" ® References 53-56. " References 57-59. •= References 60-62.

Vol 36 May 1979 American Journal of Hospital Pfiarmacy 625 ' Antirheumatic agents

Table 3. Double-blind Clinical Studies of Phenylproplonic transformation and subsequent urinary excretion of me­ • Acid Derivatives In Osteoarthritis tabolites.''^ Concomitant aspirin therapy reduces tolmetin Mean Daily plasma levels by about 20%, but the interaction probably is Pose (g) Phenyl­ not clinically important.'® butazone In controlled and uncontrolled clinical trials, tobnetin has (Ph) or been consistently superior to placebo.''®-®^ Clinical response , No. Indo­ Of Pa­ methacin Duration is evident after one to two weeks of therapy, but peak effects Drug tients Drug (In) (wk) Efficacy occur at two to three months. Controlled comparisons of Fenoprofen" 17 2.0 0.3 (Ph) 4 Fenoprofen equal to tolmetin with aspirin, phenylbutazone, indomethacin and phenylbutazone In ibuprofen indicate no consistent differences in efficacy pain scores. (Tables).®®-®' ' Ibuprofen® 167 0.9- 0.075- 24 Ibuprofen was similar 1.8 0.150 to indomethacin In The usual effective dose in rheumatoid arthritis is 1,200 (In) 4 measures. mg/day ,in four divided doses.®®''®-®^ Doses of up to 1.6 g®®-®^ Naproxen" 85 0.5 0.1 (In) 4 Naproxen equal to are effective, but one trial found no additional benefit.®® Indomethacin In 3 Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 measures. Therapy usually is initiated at 600 .to 900 mg/day and ti­ trated upward at 200 mg increments approximately once ® Reference 63. weekly. ®2>®® References 92. 9 Reference 64-66. Gastrointestinal reactions are the primary problem in about 25% of patients,®® and they range from transient, mild effects like nausea to more serious reactions requiring ces­ Table 4. Side Effects of Phenylproplonic Acid Derivatives sation of therapy;®® Urticaria, headache, water retention, • versus Aspirin dizziness and hypertension also have been reported.®'-®® In

Fenoprofen vs ASA" Naproxen vs ASA" comparative studies, tolmetin produced fewer side effects (%) (%) than aspirin®®-®® and phenylbutazone.®® However, the side Nausea 20 40 _ . effects of tolmetin are described incompletely to date, Dyspepsia 23 30 46 63 especially the hypertensive reaction. Diarrhea — 46 25 Indomethacin. Indomethacin (Indocin) is an indole Melena — 4 8 compound that is well absorbed by the oral and rectal routes. Tinnitus 17 49 21 89 Hearing change 1 24 46 42 Indomethacin is approximately 90% bound to serum albu­ Dizziness 8 19 min.®® The elimination half-life is about six hours. Hepatic Rash 13 9 21 21 Pruritus — 17 .21 inactivation with both renal and fecal excretion is the major Ecchymoses — 33 63 ftieans of elimination. Headache 26 30 25 38 The clinical efficacy of indomethacin in rheumatic dis­ Drowsiness — 46 25 eases is considerably more impressive in uncontrolled trials " Reference 55; number of patients = 106. (62% good to excellent response) than in controlled studies Reference 62; number of patients = 24. (25% response).®® Indomethacin shows no.consistent supe­ riority over aspirin, the phenylpropionic acids or phenyl­ Table 5. Double-blind Studies of Tolmetln Sodium in butazone for rheumatoid and osteoarthritis (Table 6). The Rheumatoid Arthritis value of indomethacin in ankylosing spondylitis and gout is supported primarily by uncontrolled clinical trials.®®-®® Dally Dally Dose . The usual daily dosage of indomethacin is 150 mg, given No. Dose of in two or three divided doses. This dosage level should be Of of Other Dura­ attained gradually, beginning with 25 mg two or three times Refer-; Pa­ Tolmetin Drug tion ence-- tients (g) (9) (wk) Efficacy a day and adding 25.mg in weekly increments. Daily doses higher than 150 mg usually are associated with unacceptable 83. 20 1.5 Aspirin, 4 Tolmetin equal to aspirin " 4.5 In 4 measures. Neither adverse reactions. Bedtime administration of a large part of drug produced change the daily dose (e.g., 100 mg) is often useful, since it improves In 2 other measures. sleep and reduces morning stiffness and pain.®®-'®® Some 84 , 12 1.6 Phenylbu­ 1 Tolmetin equal to tazone, phenylbutazone In 3 patients may respond after four to six days of treatment, 0.4 measures.Neither drug while others require up to a month of therapy before benefit produced change In 2 is apparent. ' other measures. 85 • 59 0.9 Aspirin, 2 Tolmetin equal to aspirin. The frequency of adverse reactions to indomethacin is 4.5 In 3 measures. Patient high. In one study, 50% of 228 patients reported side effects - preference favored at 1.1 or 2.9 mg/kg/day.'®' Gastrointestinal symptoms and tolmetin. - 87 102 1.2 Ibuprofen, 12 Tolrnetin superior to central nervous system effects are most common. Nausea" Initially, 1.6 to ibuprofen in 4 (12%), diarrhea (10%), abdominal pain (3%), gastrointestinal then 2.115 measures. 1.5 ulcers (2%) and bleeding are the most frequent gastroin­ testinal effects.®® Gastrointestinal blood loss is less than with

626 American Journal of Hospital Pharmacy Vol 36 May 1979 Antirheumatic agents aspirin. Central nervous system effects include headache Sulindac is the most recently marketed nonsteroidal, (25%), vertigo and dizziness (15%), depression, psychosis and antiinflammatory agent. Its similar antirheumatic activity hallucinations.®® Toxicity is dose related. At daily doses of and lower frequency of adverse effects in comparison to as­ less than 150 mg, 36% of patients have adverse reactions; at pirin make it similar to the phenylpropionic acid derivatives 150 to 200 mg, the frequency is 60% to 70%.®®-!®! About 70% and tolmetin. The twice-daily dosing is a convenience factor, of these effects occur within 48 hours of initiation of hut aspirin remains the least expensive mainstay of therapy therapy. as long as its side effects are tolerated. Sulindac. Sulindac (Clinoril) is an indomethacin deriva­ Phenylbutazone. Phenylbutazone (Butazolidin) is a tive with antiinflammatory, analgesic and antipyretic ac­ pyrazolone derivative with a half-life of 37 to 76 hours.**® tions.^®® Absorption is about 90% complete, and peak serum Protein binding is about 98%.* As the dose increases, plasma levels are attained in two to three hours with single levels increase, but not linearly. Plasma levels do not cor­ doses.^®®"^®® This sulfoxide compound primarily is metab­ relate with clinical response,!**'**® but higher doses provide olized to a sulforie and its conjugates and a sulfide, which is greater relief than lower doses.**® Phenylbutazone is bio- an active irietabolite.^®®'^®® Enterohepatic recirculation is transformed in the liver to several products, including an significant with both fecal (23% to 28%) and urinary (44% to active metabolite, oxyphenbutazone.* The clinical effects Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 52%) excretion, based on 96:hour collections.!®®'!®®'^®® Sul- of oxyphenbutazone (Tandearil) are almost identical to indac's half-life is seven hours, but its active sulfide has an those of phenylbutazone.**'* 18-hour half-life.!®®'!®® This sulfide is considered to provide Phenylbutazone is not consistently more effective than the majority of sulindac's action.!®'* other antirheumatic agents, with the possible exception of At doses of 200 to 400 mg/day, sulindac has antirheumatic aspirin in osteoarthritis (Tables 6 and 7). activity equal or superior to 3.6 to 4.8 g/day of aspirin in both Phenylbutazone usually is given in a daily dose of 200 to rheumatoid and osteoarthritis, and to 0.6 to 1.2 g/day of 400 mg, divided into two to four doses. As with other orally ibuprofen in osteoarthritis.!®*'!®'^'!®® However, these are administered antirheumatic drugs, dosing with meals re­ moderate to low. doses of aspirin and very low doses of ibu­ duces gastrointestinal side effects. profen. Sulindac is given in twice-daily doses. Phenylbutazone often is compared to indomethacin with Side effects occur at a 25% incidence rate, but they are regard to side effects. The overall frequency of unwanted generally less severe than aspirin-related reactions.!®* effects is lower with phenylbutazone, primarily because it Gastrointestinal reactions (18%) include abdominal pain, causes few central nervous system problems.®®'®'* However, nausea and constipation; the latter occurs more frequently phenylbutazone and oxyphenbutazone do cause significant than with aspirin.*®*'!®® Gastric mucosal erythema, edema, gastrointestinal irritation (5.9%), including nausea, pain, hemorrhage and erosion were minimal with sulindac, but stomatitis and ulceration.**'*'*®® Edema has been reported common with aspirin in one study.*®® Fecal blood loss with in several studies,*®*-*®® and phenylbutazone should be used 240 to 400 mg of sulindac was similar to placebo (0.9 ml/day) cautiously in patients with heart or renal disease. and lower than aspirin (3.6 ml/day).**® Neurologic reactions The most serious adverse reaction is bone marrow de­ are Common and include dizziness, drowsiness, tiredness and pression (e.g., leukopenia, pancytopenia, agranulocytosis, headache.!®*'!®® Dry mouth also has been reported fre­ aplastic anemia); the estimated frequency of bone marrow quently.*®® Platelet aggregation is inhibited, but this persists depression is one in 80,000 to 150,000 patient-months of for only about 24 hours.*** Bleeding time is variably reported treatment.**® Aplastic anemia occurs primarily in older as normal or prolonged with sulindac use.!®*'!** Coadmin­ patients (older than 50 years) after three months of therapy. istration with tolbutamide did not alter peak serum levels Agranulocytosis occurs in younger patients, usually within or half-life of the hypoglycemic agent.**® the first three months of therapy. Regular blood counts are

Table 6. Double-blind Studies of Indomethacin In Rheumatoid and Osteoarthritis

Dally Dose of Type of , No. of Indomethacin Dally Dose of Reference Arthritis Patients (mg) Other Drug (g) Duration Efficacy 90 . Rheumatoid 2.1 50-200 Aspirin, 1.6-6.4 1 mo Indomethacin equal to aspirin in 4 measures. 91 Rheumatoid 19 100 Aspirin, 5.0 1 wk indomethacin equal to aspirin in 3 measures. 92 Osteo- 167. 75-150 Ibuprofen, 6.9-1.8 6 mo Indomethacin prefemed by 54 %; ibuprofen, 45 %. Indomethacin provided pain relief in 63%; ibuprofen, 70%. Range of motion improved 76% among ibuprofen recipients • and 68% among indomethacin recipients. Use of propoxyphene as supplemental analgesic was similar. 93 Rheumatoid 30 150 Naproxen, 0.75 4wk Indomethacin equal to naproxen in 6 measures. Indomethacin preferred by 9 patients; naproxen by 11. 66 Rheumatoid 35 100 Naproxen, 0.5 4wk Indomethacin equal to naproxen in 3 measures. 65 Osteo- 50 100 Naproxen, 0.5 8wk Indomethacin equal to naproxen in 4 measures. 94 Rheumatoid 24 200 Phenylbutazone, 0.3 2 wk Indomethacin equal to phenylbutazone In 2 measures. 95 Rheumatoid 26 75 Phenylbutazone, 0.3 4wk Indomethacin equal to phenylbutazone in 4 measures. 96 Rheumatoid 24 150 Phenylbutazone, 0.3 4wk Indomethacin equal to phenylbutazone in 8 measures. 97 Rheumatoid 18 50 initially, 150 Phenylbutazone, 0.3 12 wk Indomethacin equal to phenylbutazone in 5 measures. maintenance

Vol Se May 1979 American Journal of Hospital Pharmacy 627 Antirheumatic agenti

Table 7. Double-blind Studies of Phenylbutazone In Rheumatoid Arthritis and Osteoarthritis Dally Dose of Type of No. of Phenylbutazone Dally Dose ot Duration Reference Arthritis Patients (mg) Other Drug (g) (wkj Efficacy 118 Osteo- 20 400 Aspirin, 3.9 2 Phenylbutazone superior to aspirin In 4 measures and favorable In 1 measure. 119 Osteo- 75 400 Aspirin, 3.9 2 Phenylbutazone showed slight superiority over aspirin In 4 measures. 120 Rheumatold 100 600 Ibuprofen, 1.2 2 Phenylbutazone and Ibuprofen equivalent In 6 measures. 121 Osteo- 159 400 Ibuprofen, 1.2 4 Phenylbutazone equal to ibuprofen In 4 measures. (Alka) 122 Rheumatold 24 400 Tolmetin, 1.6 2 Phenylbutazone equal to tolmetin In 4 measures. Slightly less use of acetaminophen by tolmetin recipients. No clear differences In patient preference.

advisable during prolonged therapy, but the insidiousness frequency of injections can be further reduced to every three aiid spontaneity of the blood dyscrasias limit their predictive or four weeks. Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 value. Patients should he advised to stop the drug and notify , Adyerse reactions to gold compounds are often major and their physician immediately if they develop fever, sore throat can be life-threatening.112-145 fhey are dose-related—at 25 or stomatitis. mg/week, 18% of recipients have an adverse reaction; this Gold Compounds. Following the very early clinical sup­ increases to 40% at 100 mg/week. Dermatitis is the most port for gold,^^'^ the long-standing controversy over the common adverse reaction with 20% to 30% incidence! This safety and effectiveness of gold compounds was settled by usually begins as pruritus, then progresses to almost any type a 30-month, double-blind, placebo-controlled trial' in of skin lesion (e.g., urticaria, maculopapular, vesicular or 1960^25.126. tjjeir efficacy has been confirmed further in more purpuric rash). Concomitant stomatitis or eosinophilia, or recent reports.i27-i3o GQIJ compounds produce a favorable both, are common. The reactions are reversible within a few response in about 75% of patients, with disease remission in weeks if the drug is discontinued. Otherwise, rash may 20 to 25% and lesser improvement in about 55%.i2i progress to fatal exfoliative dermatitis. Thus, gold therapy All gold compounds have similar antiarthritic efficacy in should be discontinued immediately when rash occurs. Gold adult and juvenile rheumatoid arthritis, as well as similar dermatitis may be related to the vehicle; in retrospective toxicity.123.126,131-136 Aurothioglucose (Solganal) is more studies of gold compounds administered in aqueous or oily difficult to administer accurately than is gold sodium vehicles, patients who received the aqueous preparation had thiomalate (Myochrysine) because the former is marketed a higher frequency of dermatitis.n^'Hi as a suspension in oil that requires warming and agitation Nephrotoxicity has been observed in up to 17% of gold to resuspend. therapy patients. ii2-i45 Albuminuria and proteinuria are Single 60-mg doses of gold sodium thiomalate produce found initially, and they may progress to nephrotic syndrome peak blood levels of 700 Mg/dl at two to eight hours.i2v-i39 and eventually to membranous glomerulonephritis and acute Steady-state gold levels of 75 to 125 pg/dl are maintained tubular necrosis. Blood dyscrasias can result from bone with 50-mg doses given intramuscularly every three to four marrow suppression and may involve platelets; neutrophils weeks.. However, a correlation between serum levels and or erythrocytes, or all of these. Ocular toxicity includes effectiveness or toxicity is not established.i2i Gold is ap­ corneal chrysiasis with reversible gold deposition when the proximately 92% bound to serum albumin.^o Tissue dis­ total dose exceeds 1 g. More serious cataracts, corneal ul­ tribution is prominent, and includes the liver, skin, bone, ceration and retinopathy also have occurred.!"*® bone marrow, eyes and recticuloendothelial system.i^o D-Penicillamine. D-Penicillamine (Cuprimine) has Synovial concentrations are about one-half those of serum. chelating activity and has been used for many years in the Excretion is very slow, progressing from a half-life of about treatment of Wilson's disease, heavy metal poisoning and one week; low blood levels (10 to 30 Mg/dl) persist for many cystinuria. More recently, it has been used to treat rheu­ months.i28.i39,141,142 routes of excretion are urine (70%) matoid arthritis, but the mechanism of its antiarthritic ac­ and feces (30%). tion is not known.!42 An adequate trial of chrysotherapy requires four to five Clinical improvement with penicillamine occurs in more months because of the need to assess carefully toxicity,,as than 50% of patients,5^^ t^e duration of therapy well as the slow onset of effect (eight to 12 weeks).ii2.i43 preceding improvement varies from six weeks to six Therapy should begin with an i.m. injection of 10 mg of ei­ months.*22.157 ^ direct comparison, penicillamine had ther gold compound as a test dose. If no toxicity occurs, 25 efficacy similar to that of gold compounds.*®® mg is given one week later. Weekly 50-mg doses are given , Penicillamine causes adverse reactions more often (greater until a total of 0.5 to 1.0 g has been administered. If there is than 60% incidence) than gold compounds, but they are less no response by the time 1 g has been given, the drug should likely to require drug discontinuation.*®® Adverse effects to be discontinued. If the patient has improved and no toxic penicillamine include rash (26%), thrombocytopenia (17%), effects have developed, dosage can be reduced to 50 mg every proteinuria, loss of taste (28%), anorexia (12%) and nausea two weeks. In patients who have prolonged remissions, the and vomiting (22%).*22-'®® Other side effects include sore lips

628 American Journal of Hospital Pharmacy Vol 36 May 1979 Antirheumatic agents and swollen legs. Proteinuria is common and can progress analgesic and antiinflammatory action similar to aspirin. to the nephrotic syridrome.i^i'i®'''!®^ Urinary protein above However, it has no advantage with respect to side effects. 2 to 5 g/day necessitates drug discontinuation. Agranulo­ Common adverse reactions include dyspepsia (33%), diar­ cytosis,i®2.i53 myasthenia gravis,1®° and Goodpasture's rhea (10 to 15%), maculopapular rashes, headache, dizziness syndrome^®! are rare complications of treatment. Skin re­ and drowsiness. Gastrointestinal blood loss and hemolytic actions are divided into early and late manifesta- anemia are unusual effects. tions.^®®'^®^'^®®'^®'''^®^'!®® The early rash is a reversible, allergic, Corticosteroids. Systemic corticosteroids should be one pruritic, morbilliform eruption, occurring within three of the last therapeutic alternatives because of their many months. The late rash occurs after five months and is a serious side effects. ^"®4®® They should he used only as pal­ papular, scaly lesion, resistant to steroids. liative, adjunctive treatment in patients with very resistant The dosage range of penicillamine for adults with rheu­ disease, and should he given in physiologic doses (e.g., matoid arthritis is between 0.75 to 1.5 g/day.^®®'!®'' The drug prednisone, 5 to 7.5 mg/day, with a 10 to 12-mg maximum). should be given after meals in divided doses, starting at low Steroids'are given in single morning doses to minimize in­ levels. A recommended regimen is 0.25 g daily for the first terference with the normal diurnal adrenal secretion. Al­

14 days, followed by increases of 0.25 g daily at bimonthly ternate-day doses generally are unsuccessful in rheumatoid Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 intervals so that an average maintenance dose of 0.75 to 1.5 disease. g/day is achieved in 12 to 14 weeks. Clinical effects may re­ A summary of untoward reactions attributable to corti­ quire six to eight weeks to be seen; therefore, longer intervals costeroids is as followsi®''468; (1) endocrine—adrenal sup­ between adjustments may be appropriate. If no improve­ pression, hyperglycemia, Cushing's syndrome; (2) muscu­ ment is seen after six months, the patient will probably not loskeletal—osteoporosis, myopathy; (3) cardiovascular— respond. fluid and electrolyte imbalances; (4) hematologic—super­ Penicillamine should be considered as an alternative to infection; (5) ocular—glaucoma, posterior subcapsular cat­ gold and should not he used before an adequate trial of more aracts; (6) cutaneous—bruises, acne, striae; (7) neuro­ conventional modes of treatment. Downward adjustment logic—euphoria, dependence, psychosis; and (8) gastroin­ in dosage of other antiinflammatory drugs, especially ste­ testinal—gastritis. roids, is often possible after the addition of penicillamine to Intraarticular corticosteroids are administered for specific the drug regimen.i®^'!®® Renal function and hematologic asymmetric joint inflammation that restricts mobility, i®® variables must be monitored closely during treatment be­ Response is apparent within 24 hours of injection, with re­ cause of the severe toxicity of the drug. duction of swelling and pain. Long-acting steroid suspen­ Antimalarials. Chloroquine and hydroxychloroquine sions, like triamcinolone hexacetonide or prednisolone te- sulfate (Plaquenil) are used almost always in combination butate, provide effects lasting two to four weeks following with other nonsteroidal drugs when prior therapy is inade­ single injections. The dose is dependent on the joint size (e.g., quate, or parenteral treatment is not feasible.^®^-^®® Onset of knee, 1 ml; ankle, 0.5 ml; phalangeal, 0.1 ml). Activity of the improvement is gradual, with initial changes after at least joint should be limited for about 48 hours after injection to four weeks and maximal benefit at three to six months. minimize damage caused by premature mobilization. The Therapy usually is initiated with loading doses (e.g., chlo­ injection procedure consists of an adjunctive topical anes­ roquine, 250 mg daily at bedtime or hydroxychloroquine, 200 thetic, withdrawal of excess fluid and a flushing of the needle mg one to three times a day). Maintenance doses are lower in situ to prevent placement of crystals in synovial mem­ (e.g., chloroquine, 250 mg two to three times a week). branes. If repeated at all, at least six to eight weeks should Ocular toxicity is the major complication of antimalarial elapse between injections. Complications of intraarticular therapy. These drugs concentrate in the eyes at levels lOO corticosteroid injections can be acute (e.g., septic arthritis, times greater than those in plasma. Diplopia and loss of ac­ crystal-induced synovitis) or delayed (e.g., destructive ar­ commodation are reversible reactions. Reversible corneal thropathy, cutaneous atrophy). opacities occur with chronic administration but they are Immunosuppressives. Cyclophosphamide (Cytoxan) and asymptomatic. Retinal toxicity is the most serious effect, azathioprine (Imuran) are highly effective agents that pro­ since antimalarials accumulate in pigmented ocular tissues. vide partial or complete remissions in up to 75% of severely The incidence ranges from 0.1 to 15%. High cumulative doses arthritic patients. However, hematologic toxicity diminishes (e.g., 550 g over 3 to 4 years) are associated with retinal their value. Immunosuppressives usually are given toxicity. Fundascopic diagnosis reveals edema and pig­ together with corticosteroids, which permits lower steroid mentary changes. Blindness may result. doses. Response follows a latent period of three to six months Central nervous system and neurologic effects include after initiation of therapy. Dosage of cyclophosphamide headache, dizziness and neuromyopathy. Gastrointestinal ranges from 1.0 to 2.5 mg/kg/day in one or two divided effects (diarrhea and nausea) and cutaneous reactions (li­ doses. chenoid patches, hyperpigmentation and exfoliative der­ Major toxicity precludes routine use of these drugs in matitis) can also occur. rheumatoid arthritis. Leukopenia (WBC count of 2,000 to Fenemates. Mefenamic acid (Ponstel) occupies a very 4,000/cmm) is produced routinely by therapeutic doses. secondary place in rheumatoid arthritis therapy.^''*'® At doses Secondary infection, especially with herpes zoster and pro­ of 750 to 1,000 mg/day in three divided doses, it possesses tozoa, is another significant limitation of immunosuppressive

Vol 36 May 1979 American Journal of Hospital Pharmacy 629 Anllrheumatlc agents

therapy. Hemorrhagic cystitis caused by a cyclophos­ rheumatoid arthritis, Br Med J 3:278-280 (Aug 2) 1969. phamide metabolite occurs frequently (up to 40% incidence) 24. Broh-Kahn RH: Choline salicylate: a new, effective and well- and can range from microscopic hematuria to overt bleeding. tolerated analgesic, anti-inflammatory and antipyretic agent, Int Rec Med Gen Pract Clin 173:217-232 (Apr) 1960. Bedtime dosing should be avoided to prevent retention of 25. Wolf J and Aboody R: Choline salicylate: a new and more the-metabolites overnight in the bladder. Adequate hydra­ rapidly absorbed drug for salicylate therapy, Int Rec Med Gen tion and frequent bladder emptying are useful means to Pract Clin 173:234-241 (Apr) 1960. 26. Leary JF: Preliminary pharmacological comparison of choline minimize this toxicity. 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630 American Journal of Hospital Pharmacy Vol 36 May 1979 Antlrheumallc agents k Rheumatol (suppl 2):29-36 (May) 197S. of tolmetin in man, Clin Pharmacol Ther 77:599-605 (May) 51. Segre EJ: Naproxen metabolism in man, J Clin Pharmacol 1975. 15:316-323 (Apr) 1975. ' 78. Cressman WA, Wortham GE and Plostnieks J: Pharmacoki­ 52. Segre E, Sevelins H, Chaplin M et al: Interaction of naproxen netics of tolmetin, a new antiinflammatory agent (abstract), and aspirin in the rotund man, Scand J Rheumatol (suppl Ciin Pharmacol Ther 75:203-204 (Feb) 1974. 2):37-42,1973. 79. Berkowitz SS, Bernhard G, Bilka PJ et al: Tolmetin versus 53. HuskissoA EC, Wojtulewski JA, Berry H et al: Treatment of placebo for the treatment of rheumatoid arthritis: a sequential * rheumatoid arthritis with fenoprofen: cdmparisoii with aspirin, double-blind clinical trial, Curr Ther Res 76:442-456 (May) Br Med J 1:176-180 (Feb 2) 1974. 1974.- 54. Zuckner J and Auclair RJ: Fenoprofen calcium' therapy in 80. Brooks PM, Watkins CF, Sturrock RD et al: Clinical evaluation rheumatoid arthritis, J Rheumatol 3{suppl 2):18-25,1976. of tolmetin, Curr Med Res Opin 2:323-328,1^74. 55. Gum OB: Fenoprofen in rheumatoid arthritis: a controlled 81. Brown JH, Hull J and Biundo JJ: Results of a one-year trial crossover multicenter study, t/Rheumatol 3(suppl 2):26-31, of tolmetin in patients with rheumatoid arthritis, J Clin 1976; , . Pharmacol 75:455-463 (May) 1975. 56. Sigler JW-, Ridolfo AS and Bluhm GB: Comparison of benefit 82. Cordrey LJ: Tolmetin in sodium, a new anti-arthritis drug: to risk ratios of aspirin and fenoprofen: controlled multicenter double-blind and long term studies, J Am Geriatr Soc 24: . study in rheumatoid arthritis, J Rheumatol 3(suppl 2):49-60, 440^46 (Oct) 1976. 1976.' ' - 83. Bain LS, El-Ghobarey AF, Collins RM et al: Tolmetin: an 57. Dornan J md Reynolds WJ: Comparison of ibuprofen and evaluation of a new preparation in the treatment of rheumatoid acetylsalicylic acid in treatment of rheumatoid arthritis. Can arthritis, Br J Clin Pract 29:208-210 (Aug) 1975. Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 Med Assoc J 110:1370-1372 (Jun) 1974. 84. Huskisson EC, Berry H, Scott J et al: Tolectin for rheumatoid 58. Brooks CD, Schmid FR, Biundo J et al:Aspirin and ibuprofen arthritis, Rheumatol Rehabil 73:132-134 (Aug) 1974. in the treatment of rheumatoid arthritis, Rheumatol Physical 85. Muller FO, Gosling JA Erdmann GH: A comparison of tol­ Med 10(suppl):9-14,1970. metin with aspirin in the treatment of osteoarthritis of the 59. Blechman WJ, Schmid FR, April PA et al: Ibuprofen or aspirin knee, S Afr Med J 51:794-796 (May) 1977. in rheumatoid arthritis therapy, J Am Med Assoc 233:336-340 86. Maibach E: European experiences with tolmetin in the treat­ (Jul 28) 1975. ment of rheumatic diseases, Curr Ther Res 79:350-362 (Mar) 60. Diamond H, Alexander S, Kuzell W et al: A multicenter dou­ 1976. ble-blind crossover comparison study of naproxen and aspirin 87.• McMillen JI: Tolmetin sodium vs. ibuprofen in rheumatoid in patients with rheumatoid arthritis, Scand J Rheumatol arthritis patients previously untreated with either drug: a (suppl 2):17l-175 (May) 1973. . double-blind crossover study, Curr Ther Res 22:266-275 (Aug) 61. HiU HFH, Hill AGS, Mowat AG et al: Naproxen: a new non- 1977. hormonal anti-inflammatory agent, Ann Rheum Dis 33:12-14 88. Hvidberg E, Lausen HH and Jemsen JA: Indomethacin: plasma (Jan) 1974. concentrations and protein binding in man, Eur J Clin Phar­ 62. Alexander SJ: Clinical experience with naproxen in rheumatoid macol 4:119-124,1972. arthritis. Arch Intern Med 735:1429-1435 (Nov) 1975. 89. O'Brien WM: Indomethacin: a survey of clinical trials, Clin 63. Wojtulewski JA: Fenoprofen in the treatment of osteoarthritis. Pharmacol Ther 9:94-107 (Jan) 1968. Cure Med Res 0pm 2:551-555,1974. 90. Pinais RS and Frank S: Relative efficacy of indomethacin and 64. Clarke AK, Barnes CG, Goodman HV et al: A double-blind acetylsalicylic acid in rheumatoid arthritis, N Engl J Med comparison of naproxen against indomethacin in osteoaftbritis, 276:512-514 (Mar 2) 1967. Arzneim Forsch 25:302-304 (Feb) 1975. 91. Haslock I, Omar AS and Wright V: A comparison of microen­ 65. Barnes CG, Goodman HV, Eade AWT et al: A double-blind capsulated aspirin and indomethacin in the treatment of comparison of naproxen witb indomethacin in osteoarthritis, rheumatoid arthritis, Br J Clin Pract 29:311-314 (Nov) J Chn Pharmacol 75:347-354 (Apr) 1975. 1975. 66. Cochrane GM: A double blind comparison of naproxen with 92. Royer GL Jr, Moxley TE, Hearron MS et al: A six month indomethacin in osteoarthritis, Scand J Rheumatol (suppl double blind trial of ibuprofen and indomethacin in osteoar­ 2):89-93 (May) 1973. thritis, Curr Ther Res 77:234-248 (Mar) 1975. 67. Reynolds PMG and Whorwell PJ: A single blind crossover 93. Kogstad 0: A double-blind crossover study of naproxen ahd comparison of fenoprofen, ibuprofen, and naproxen .in rheu­ indomethacin in patients with rheumatoid arthritis, Scand J matoid arthritis, Curr Med Res Opin 2:461-464,1974. Rheumatol (suppl 2):159-163 (May) 1973. 68. Huskisson EC, Woolf DL, Balme HW et al: Four naw anti- 94. Percy JS, Stephenson P and Thompson M: Indomethacin in inflammatory drugs: responses and variations, Br Med J I: the treatment of rheumatic diseases, Ann Rheum Dis 23: 1048-1049 (May 1) 1976. . 226-231 (May) 1964. 69. Lewis JR: New rheumatic agents: fenoprofen calcium (Nalifon), 95. Hart FD and Boardman PL: Indomethacin and phenylbuta­ naproxen (Naprosyn), and tolmetin sodium (Tolectin), J Am zone: a comparison, Br Med J 2:1281-1284 (Nov 27) 1965. . Med Assoc 237:1260-1261 (Mar 21) 1977, 96. Wright V, Walker WC and McGuire RJ: Indomethacin in the 70. Floras JJB and Rojas SV: Naproxen: corticosteroid-sparing treatment of rheumatoid arthritis; a controlled trial comparing effect in rheumatoid arthritis, J Clin Pharmacol 75:373-377 indomethacin, phenylbutazone and placebo, Ann Rheum Dis^ (Apr) 1975. 28:157-162 (Mar) 1969. 71. Loebl DH; Craig RM, Culic DD et al: Gastrointestinal blood 97. Hahn K-J: A comparison of phenylbutazone and indomethacin loss: effect of aspirin, fenoprofen and acetaminophen, J Am in the treatment of rheumatoid arthritis, Arzneim Forsch Med Assoc 237:976-981 (Mar 7) 1977. 23:851-854 (Jun) 1973. 72. Schmid FR and Culic DD: Antiinflammatory drugs and gas- 98. Smyth CJ and Percy JS: Comparison of indomethacin and trointestinal bleeding: a comparison of aspirin and ibuprofen, phenylbutazone in acute gout, Ann Rheum Dis 32:351-353 J C/m Pharmacol 76:418-425 (Aug) 1976. (Jul) 1973. 73. Arsenault A, Varady J, LeBel E et al: Effect of naproxen on 99. Huskisson EC, Taylor RT, Burston D et al: Evening indom­ gastrointestinal microbleeding following acetylsalicylate ethacin in tbe treatment of rheumatoid arthritis, Ann Rheum medication, J Clin Pharmacol 75:340-346 (Apr) 1975. Dts 29:393-396 (Jul) 1970. 74. Halvorsen L, Dotevall G and Sevelius H: Comparative effects 100. Hobkirk D, Rhodes M and Haslock 1: Night medication in of aspirin and naproxen on gastric mucosa, Scand J Rheumatol rheumatoid arthritis, part ii, combined therapy with,indom­ (suppi2):43-47 (May) 1973. ethacin and diazepam, Rheumatol Rehabil 76:125-127 (May) 75. Roth SH and Boost G: An open trial of naproxen in rheumatoid 1977. arthritis patients with significant esophageal, gastric and du- 101. Boardman PL and Hart FD: Side effects of indomethacin, Ann odenal lesions, J Clin Pharmacol 75:378-384 (Apr) 1975. Rheum Dis 26:127-132 (Mar) 1967. 76. Cuthbert.MF: Adverse reactions to non-steroidal antirheu- • 102. Beirne JA, Bianchine JR, Johnson PC et al: Gastrointestinal matic drugs, Curr Med Res Opin 2:600-610,1974. blood loss caused by tolmetin, aspirin and indomethacin, Clin 77. Selley ML, Glass J, Triggs EJ et al: Pharmacokinetic studies Pharrhacol Ther 76:821-825 (Nov) 1974.

Vol 36 May 1979 American Journal of Hospital Pharmacy 631 Antlrtieumattc agenti

- 1031. Shen T-Y and Winter CA: Chemical and biological studies on 3:461-466 (Oct) 1973. indomethacin, sulindac, and their analogs, Adv Drug Res 131. AUegretti JE: TTie role of chrysotherapy in active rheumatoid 12:89-245,1977. arthritis. Postgrad Med 28:623-626 (Dec) 1960. 104. Brogden RN, Heel RC, Speight TM et al: Sulindac: a review 132. Freyberg RH: Gold salts in the treatment of chronic arthritis: of its pharmacological properties and therapeutic efficacy in metabolic and clinical studies, Proc Staff Meet Mayo Clin rheumatic diseases. Drugs 16:97-114 (Aug) 1978. 17:534-541 (Oct) 1942. 105.i. Huskisson EC: Antiinflammatory drugs, Semin Arthritis 133. Adams CH and Cecil RL: Gold therapy in early rheumatoid Rheum 7:1-20 (Aug) 1977. arthritis, Ann Intern Med 33:163-167 (Jul) 1950. 106. Duggan DE, Hare LE, Ditzler CA et al: The disposition of su­ 134. Hill DF: Gold therapy for rheumatoid arthritis, Med Clin lindac, Clin Pharmacol Ther 21:326-335 (Mar) 1977. North Am 52:733^738 (May) 1968. 107. Dieppe PA, Hurry HC, Grahame R et al:Sulindac in osteoar­ 135. Bland JH: Drug treatment of rheumatoid arthritis, Semin throsis of the hip, Rheumatol Rehabil 15:112-115 (May) Drug Treat 1:93-118 (Sep) 1971. -1976. 136. Myers AR: Chrysotherapy in rheumatoid arthritis. Mod Treat 108. Huskisson EC and Scott J: Sulindac: trials of a new antiin­ 8:761-768 (Nov) 1971. flammatory drug, Ann Rheum Dis 37:89-92 (Feb) 1978. 137. Gerber RC, Paulus HE, Jenririch RI et al: Gold kinetics fol­ 109. Bianchi-Porro G, Petrillo M, Caruso E et al: Sulindac and lowing aurothiomalate therapy, J Lab Clin Med 83:778-789 gastric mucosa. Lancet 1:1152-1153 (May 28) 1977. (May) 1974. 110. Cohen A: Intestinal blood loss after a new anti-inflammatory 138. Gottlieb NL: Chrysotherapy, Bull Rheum Dis 27:912-917, drug, sulindac, Clin Pharmacol Ther 20:238-240 (Aug) 1977. , 1976. 139. Gottlieb NL, Smith PM and Smith EM: Pharmacodynamics Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 111. Green D, Ts-ao C and Ross EC: Sulindac, Lancet 1:804 (Apr of Au labeled aurothiomalate in blood;^correlation with course 9) 1977. of rheumatoid arthritis, gold toxicity, and gold excretion. Ar­ 112. Ryan JR, Jain AK, McMahon FG et al: On the question of an thritis Rheum 17:171-183 (Mar) 1974. interaction between sulindac and tolbutamide in the control 140. Gottlieb NL, Smith PM and Smith EM: Tissue gold in a of diabetes, Clin Pharmacol Ther 21:231-233 (Feb) 1977. rheumatoid arthritic receiving chrysotherapy. Arthritis 113. Dick WC, Brooks PM and Buchanan WW: Phenylbutazone Rheum 15:16-32 (Jan) 1972. dose response in patients with rheumatoid arthritis, JInt.Med 141. Mascarhenes BR, Grand JL and Freyberg RH: Gold metabo­ Res 5(suppl 2):48-51 (Mar) 1977. lism in patients with rheumatoid arthritis treated with gold . 114. Orme M, Holt PJL, Hughes GRV et al: Plasma concentration compounds—reinvestigated. Arthritis Rheum 15:391-402 of phenylbutazpne and its therapeutic effects—studies in (Jul) 1972. , patients with rheumatoid arthritis, Br J Clin Pharmacol 3: 142. Gottlieb NL, Smith PM and Smith EM: Gold excretion cor­ 185-191 (Feb) 1976. related with clinical course during chrysotherapy in rheuma­ 115. Brooks PM, Walker JJ, Dick WC et al: Phenylbutazone: a toid arthritis. Arthritis Rheum 15:582-592 (Nov) 1972. clinico-pharmacological study in rheumatoid arthritis, Br J 143. Bluhm GB: The treatment.of rheumatoid arthritis with gold, Clin Pharmacol 2:437-442 (Jul) 1975. Semin Arthritis Rheum 5:147-166 (Nov) 1975. 116. Orme MLE: Phenylbutazone: plasma concentrations and ef­ 144. Rothermich NO, Philips VK, Bergen W et al: Chrysotherapy; fectiveness in patients with rheumatoid arthritis, J/rat Med a prospective study. Arthritis Rheum 19:1321-1327 (Nov) Re.s 5(supp/2):4(5-47 (Mar) 1977. 1976. 117. Committee on the Review of Medicines: Recommendations 145. Anon: Gold for rheumatoid arthritis (editorial), Br Med J1: on phenylbutazone, oxyphenbutazone, feprazone, allopurinol, 471-472 (Feb 27) 1971. colchicine, probenecid, and sulfinpyrazone, Br Med J 1- 146. Lawrence JS: Comparative toxicity of gold preparations in 1466-1467 (Jun 3) 1978. treatment of rheumatoid arthritis, Ann Rheum Dis 35:171-173 118. Scharff EU: A doubleblind comparison of phenylbutazone and (Apr) 1976. aspirin in osteoarthritis, Curr Ther Res 16:1264-1269 (Dec) 147. Lawence JS: Factors in gold dosage and toxicity in rheumatoid 1974. arthritis,. Ann Rheum Dis 12:129-135 (Jun) 1953., 119. Rotstein J: Phenylbutazone and aspirin in osteoarthritis: a 148. Gottlieb NL and Major JC: Ocular chrysiasis correlated with controlled study, Curr Ther Res 17:444-451 (May) 1975. gold concentrations in the crystalline lens during chrysoth­ 120.,.Pavelka K, Susta A, Vojtisek 0 et al: Double-blind comparison erapy, Arthritis Rheum 21:704-708 (Jul-Aug) 1978. of ibuprofen and phenylbutazone in a short term treatment 149. Huskisson EC: Penicillamine and the rheumatologist: a review, of rheumatoid arthritis, Arzneim Forsch 23:842-846 (Jun) Pharmacotherapeutics 1:24-39 (Jan) 1976. 1973. 150. Multicenter Trial Group: ControUed trial of D(-)penicillamine 121. Moxley TE, Royer GL, Hearron MS et al: Ibuprofen versus in severe rheumatoid arthritis. Lancet 1:275-280 (Feb 10) buffered phenylbutazone in the treatment of osteoarthritis, 1973. J Am Geriatr Soc 23:343-348 (Aug) 1975. 151. 122. Day AT, Golding JR, Lee PN et al: Penicillamine in rheuma­ Cardoe N and Steele CE: A doubleblind crossover comparison toid disease; a long term study, Br Med J 1:180-183 (Feb 2) of tolmetin sodium and phenylbutazone in the treatment of 1974. rheumatoid arthritis, Curr Med Res Opin 4:688-694,1977. 152. 123. Zuckiier J, Ramsey RH, Dorner RW et al: D-penidllamine in Sperling IL: Adverse reactions with long-term use of phenyl­ rheumatoid arthritis. Arthritis Rheum 13:131-138 (Mar) butazone and oxyphenbutazone. Lancet 2:535-537 (Sep 6) 1970. 1969. 153. 124. Golding JR, Wilson JV and Day AT: Observations on the Forestier J: Rheumatoid arthritis and its treatment by gold treatment of rheumatoid disease with penicillamine. Postgrad salts,y Lab Clin Med 20:827-840 (Apr) 1935. Med J 46:599-605 (Oct) 1970. ,125.. Empire Rheumatism Council: Gold therapy in rheumatoid 154. Huskisson EC and Hart DF: Penicillamine in the treatment arthritis; report of a multi-center controlled trial, Ann Rheum of rheumatoid arthritis, Ann Rheum Dis 31:402-404 (Sep) Dis 19:95-119 (Jun) 1960. 1972.' . 126s Freyberg RH, Block WD and Wells GS: Gold therapy for 155. Hill HLH: Selection of patients with rheumatoid arthritis to rheumatoid arthritis. Clinics 1:537-570 (Oct) 1942. 127. . be "treated with penicillamine and their management, Ciirr Anon: Gold revalued (editorial). Lancet 1:789-790 (Apr 27) Med Res Opin 2:573-580,1974. 1974. 156. 128. Jaffe lA: The effect of penicillamine on the laboratory pa­ Sigler JW, Bluhm GB, Duncan H et al: Gold salts in the rameters in rheumatoid arthritis. Arthritis Rheum 8:1064- treatment of rheumatoid arthritis, Ann Intern Med 80:21-26 1069 (Dec) 1965. ii (Jan) 1974. 157. .129. Jaffe lA:TEe treatment of rheumatoid arthritis and necrotizing American Rheumatism Council: A controlled trial of gold salt vasculitis with penicillamine. Arthritis Rheum 13:436-443 therapy in rheumatoid arthritis, Arlhritis Rheum 16:353-358 (Jul) 1970. (May) 1973. 158. 130. Huskisson EC, Gibson TJ, Balme HW et al: Trial comparing Palmer DG and Dunckley JV: Gold levels in serum during D-penicillamine and gold in rheumatoid arthritis, Ann Rheum treatment of rheumatoid arthritis with gold, Aust NZJ Med Dis 33:532-535 (Jul) 1974.

632 American Journal of Hospital Pharmacy Vol 36 May 1979 Antirheumatic agents/Phenothlazlna analgesia

159. Jaffe lA, Treser G, Suzuki Y et al: Nephropathy induced by 169. Urowitz MB: Immunosuppressive therapy in rheumatoid ar­ penicillamine, Ann Intern Med 69:549-556 (Sep) 1968. thritis, J Rheumatol 1:364-373 (Dec) 1974. 160. Bucknall RC, Dixon ASJ, Glick EN et al: Myasthenia gravis 170. Andreis M: Immunosuppression in the treatment of rheuma­ associated with penicillamine treatment for rheumatoid ar­ toid arthritis, Adv Clin Pharmacol 6:81-88,1974. thritis, Br Med J 1:600-602 (Mar 15) 1975.' 171. DeSeze S and Kahn MF: Immunosuppressive drugs in rheu­ 161. Sternlieb I, Bennett B and Scheinberg IH: D-penicillamine matoid arthritis: clinical results, Adv Clin Pharmacol 6:89-97, induced Goodpasture's syndrome in Wilson's disease, Ann 1974. Intern Med 82:673-676 (May) 1975. 172. Currey HLF: Immunosuppressive drugs in rheumatoid ar­ 162. Jaffe lA; Rheumatoid arthritis with arteritis; report of a case thritis—toxicity, Adv Clin Pharmacol 6:98-104,1974. . treated with penicillamine, Ann Intern Med 61:556-560 (Sep) 1964. 163. Jaffe lA and Smith RW: Rheumatoid vasculitis—report of a second case treated with penicillamine. Arthritis Rheum 11:585-592 (Aug) 1968. Appendix 164. Popert AJ: Chloroquine: a review, Rheumatol Rehabil 15: 235-238 (Aug) 1976. Steps In the Drug Treatment of Rlieumatic Disease^ - 165. Zvaifler NJ: Antimalarials in the treatment of rheumatoid arthritis. Mod Treat 8:769-777 (Nov) 1971. Step 1. Analgesia with aspirin (2 to 3 g/day) or acetaminophen; 166. Gifford RH: Corticosteroid therapy in rheumatoid arthritis, alternative drugs: phenylpropionic acid derivatives or Med Clin North Am 57:1179-1190 (Sep) 1973. propoxyphene. Downloaded from https://academic.oup.com/ajhp/article/36/5/622/5196005 by guest on 02 October 2021 167. David DS, Grieco MH and Cushman P: Adrenal glucocorti­ Step 2. Salicylates, phenylpropionic acid or indole derivatives. coids after twenty years; a review of their clinically relevant Step 3. Gold compounds or penicillamine. consequences, J C/ironic D(s 22:637-711,1970. Step 4. Indomethacin or phenylbutazone; alternative drugs: 168. Thompson EB and Lippman ME: Mechanism of action of antimalarials. glucocorticoids. Metabolism 23:159-202 (Feb) 1974. Step 5. Adrenal corticosteroids or immunosuppressives.

Am J Hosp Pharm 36:633-640 (May) 1979 Phenothiazine analgesia—fact or fantasy?

Jackie L. n/lcGee and Micftael R. Alexander

Double-blind clinical trials involving the use of phenothiazines as analgesics or potentiators of analgesics (aspirin, meperidine, mo .-phine sulfate) and adverse effects of phenothiazines are reviewed and evaluated. Promethazine, promazine and. propiomazine were not found to possess analgesic or poten­ tiating properties. One chlorpromazine study contained important design and reporting defi­ ciencies which precluded a recommendation for use of chlorpromazine in the treatment of pain. Methotrimeprazine was determined by numerous authors to have analgesic properties; how­ ever, most of the studies also were deficient in design or data presented, or both. Adverse reac­ tions to phenothiazines, including hypotension, sedation, drowsiness, extrapyramidal symp­ toms, tardive dyskinesia, cardiac toxicity and agranulocytosis, are often more common and se­ vere than those attributed to narcotic analgesics. Because of the lack of data supportive of analgesic activity and the adverse reactions associ-' ated with phenothiazines, use of these agents in the management of pain should be discour­ aged. The prophylactic use of phenothiazine for narcotic analgesic-induced emesis also is, in most cases, a questionable practice. Key words: Analgesics and antipyretics; Aspirin; Drug interactions; Drugs, adverse reactions; Meperidine; Morphine sulfate; Phenothiazines; Rational therapy

Pain is frequently one of the earliest signs of disease and The use of pharmacological agents to alleviate pain can is valuable for that purpose. On the other hand, the per­ be traced back to ancient times when the juice of the poppy ception of pain is usually an undesirable sensation in a pa­ was administered to suffering patients. The opium alkaloid tient and it can, at times, be debilitating and intolerable. morphine, obtained from the poppy plant (Papauer som- niferuni), is a potent, effective analgesic which remains the standard against which other analgesics are compared.

This is article 79-09 in the AJHP Continuing Education system. See page However, morphine and other opioid analgesics have nu­ 582 for learning objectives and test questions. Readers who wish to study this merous undesirable characteristics which make the man­ article are encouraged to first review the learning objectives. agement of pain a unique challenge for the clinician. Some of the greatest concerns have been their potential for ad­ diction and tolerance which has led to the use of antihista­ mines,antidepressants^-'' and antipsychotics®-® for pain Jackie .L. McGee is a Pharinacy Intern, Veterans Administration Hospital, Iowa Gity, lA. IMiehael R. Alexander, M.S., is Clinical Pharmacy Coordi­ relief. The phenothiazines, such as those included in the nator, Veterans Administration Hospital, and Clinical Assistant Professor, recently popularized Brompton's mixture,''-® are the most College of Pharmacy, University of Iowa, Iowa City .52242. widely used of these agents, however, owing to the lack of Copyright © 1979, American Society of Hospital Pharmacists, Inc. All rights consensus concerning their efficacy, it is important to ex­ reserved. amine the data on which these claims are based.

0002-9289/79/0501-0633$02.00 Vol 36 May 1979 American Journal of Hospital Pharmacy 633