Introduction

JOHN J. CALABRO, M.D., F.A.C.P. and GEORGE E. EHRLICH, M.D., F.A.C.P.

his supplement features the proceedings of an inter- tries, nonsteroidal anti-inflammatory drugs number in the
T national syrhposium on inflammatory disease and
the role of diclofenac sodium held in Tahiti on May 14 and
thirties and forties [S]. However, in the United States,
there are only a dozen available, ftif fewer than in any
15, 1985. It serves as a natural sequence to an earlier other country in the world.
symposium on this phenylacetic acid derivative that was After more than 30 years of experience with a host of
held in Jamaica Worn November 30th to December 2nd, anti-inflammatory drugs, on& mightwonder what features
1984 [l]. constitute the ideal nonsteroidal &&inflammatory drug. In
The purpose of this supplement is to provide an over- fact, the chemical structure of diclofenac sodium wqs de-
view of diclofenac sodium, a nonsteroidal anti-inflamma- signed through information gleaKe$ irom the structure-
tory drug that has undergone extensive, worldwide clinical activity relationships of other nb$eroidal anti-inflamma-
trials in rheumatoid arthritis, osteoarthritis, and ankylosing tory drugs [a. Critical factors include drug transport
spondylitis. The reports that follow represent numerous through biologic membranes, the atomic and spatial strut-
controlled trials of diclqfenac sodium conducted both io ture of the molecule, which governs its attachment to the
the United States and in other parts of the world. These receptor, and the electronic structure, which controls the
are preceded by reviews of the pathogenesis of rheuma- interactiori between ttie drug and the receptor [8]. More-
toid arthritis and osteoarthritis, the role of the arachidonic over, it has beei postulated that the ideal npnsteroidal
acid cascade in inflammatory disease, and the history, anti-inflammatory drug should have an acidity co&ant df
chemistry, and pharmacology of diclofenac sodium. 4 to 5, a partition ctifficient (n-octanol/aqueous buffer, pH
The introduction of pheriylbutazone in the 1950s 7.4) of approxim&ely 10, and iwd aromatic rjngs twisted in
brought recognition to a therapeutic class of drugs now relationship to each other. df riiore than 200 analogues
known collectively as the nonsteroidal anti-inflammatory surveyed by CIBA-GEIGY Pliarmaceuticals, it was diclo-
drugs. Clearly, the discovery of phenylbutazone prottfded fenac sodium that satisf&d 1II.bf ihese ariteria [Si.
the impetus for worldwide research. As a result, there has After 12 years of worldWid+ex$erience, diclofenac so-
been a steady proliferation of these drugs in the past three dium has proved to be a pote&anti-inflammatqry, analge-
decades. To fully appreciate the impact of this therapeutic sic, and antipyretic agent with .a Safety profile that is more
advance, one need only to take a retrospective look at the than satisfactory. The drug’s ‘mode of action includes po-
state of the art of rheumatology in the era before phenyl- tent cycle-oxygenape irihibition and enhanced uptake of
butazone. arachidanic acid into cellular triglyceride pools (as demon-
Until 1974, when ibuprofen was first marketed, only a strated in vitro), resulting in a dual effect on the cyclo-
handful of nonsteroidal anti-inflammatory drugs were oxygenase and lipoxygenas,e pathways [a. Diclofenac
available. These’ included aspirin, phenylbutazone, oxy- effectively counteracts the clinical signs and symptoms of
phenbutazone, and indomethacin. Since then, a number inflammation and affects a wide range of inflammatioh-
of other nonsteroidal anti-inflammatory drugs have related mediators and cell functions.
emerged and the chemical classes of these drugs have The serum half-life of diclofenac s;odium is only two
broadened considerably [2-51 (Table I). In some coun- hours. In long-term administration, diclofenac does not

From the University of Massachusetts Medical School and Saint Vincent Hospital, Mrcester, Massachu-
setts, and New York University School of Medicine. New York, and CBA-GEIGY Corpor&n, Summit, New
Jersey. Requests for reprints should be addressed to Dr. John J. Cal?bro, Saint Viriceni Hospitaf, 25 Win-
throp Street, Worcester, Massachusetts 01604

April 28, 19843 The American Joumrl of Medicine Volume 60 (suppl4B) 1

TABLE I Nonsteroidal Anti-Inflammatory Drugs by acute reductions in glomerular filtration rate include those
Chemical Class, United States Marketing with congestive heart failure, chronic glomerulonephritis,
Year, and qlasma Half-Life systemic lupus erythematosus, hepatic failure with asci-
Year Fin! Plasma Half-life tes, the elderly, and patients receiving diuretics. Conse-
Chemical Class Marketed, U.S. (hoW quently, in prescribing nonsteroidal anti-inflammatory
drugs in susceptible patients, it is critical to monitor them
Salicylates for potential adverse renal effects with serial determina-
Aspirin’ 1915 9-16’
1976
tions of serum creatinine and electrolyte levels, as well as
Nonacetylated forms 12
Pyrazoles blood pressure and body weight [16].
Phenylbutazone 1952 64 Renal insufficiency can influence the dispqsition of non-
Oxyph,enbutazone* 1961 72 steroidal anti-inflammatory drugs by displacing them from
lndole acetic acids protein-binding sites due to decreases in s&urn a!bumin
Indomethacin 1965 4-5
Indomethacin-SR 1961 12 concentration and/or competition for binding with accumu-
Tolmetin’ 1976 6 lated endogenous organic acids [17]. In addition, renal
Sullndac 1978 16 insuffiency may result in decreased drug clearance.
Propionic acids Theiefore, in patienis with renal insufficiency, half or less
Ibuprofen 1974 2 of the normal dose must,be prescribed for certain drugs,
Ferioprofen 1976 4
Naproxen 1976 13 such as naproxen, oxaprozin, and azapropazone. With
jWoprofen 1986 2-4 diclofenac, however, unbound concentrations of the drug
Fenamic acids do not change in patients with renal insufficiency, so no
Meclofenamate 1960 4 dosage adjustment is required [17]. Patients with severe
Oxicams renal insufficiency, however, should rgmain under close
Piroxicam 1982 38
Phenylacetic acid medical surveillance.
Diclofenac sodium To be determined 2 Diclofenac sodium belongs to an entirely new chemical
*Only aspirin and tolmetin are approved for children under age 15. class of nonsteroidal anti-inflammatory drugs (Table I).
tOnly when administered in anti-inflammatory quantities. filthough not yet tiarketed in the United States, /t is not a
*Although still available in other countries, oxyphenbutazane is no drug with limited marketing experience [l]. On the con-
longer manufactured in the United States. trary, it has been approved for,marketing in more than 100
countries, has been commercially available for 12 years
appear to accumulate in the plasma, with peak levels ob- (since lg74), and has approximately 10 million patient-
served at about two hours [9]. That tpe biaavailability of years of use. If drug sales reflect physician and patient
diclofenac is much more F[olonged than the serum half- acceptance of a nonsteroidal anti-inflammatory drug, di-
life is shown by sjrnovial fl‘uid studies [lo]. Peak synovial clofenac is a leader. In fact, it is the eighth largest-selling
fluid lev+ of diclofenac have been observed up to fdur drug in the world [l]. Moreover, in most European coun-
hours after peak plasma levels. Moreotier,‘the elimination tries, it ranks either first or second in terms of nonsterpidal
half-life is three times longer for synovial ,fluid than for anti-inflammatory drug usage.
plasma, and, in fact, ?4 hours after doSing, the concentra- As with tither nonsteroidal anti-inflammatory drugs, cer-
tion of drug is higher in synovial fluid than in plasrqa. tain precautions must be taken when prescribing diclo-
These findings ari! support/ve of clinical studies attesting fenac sqdium:
to the drug’s efficacy when administered once or twice l It should not be used in conjunction with anti-inflamma-

daily. The importance of significant levels of other nonste- tory dosages of other nonsteroidal anti-inflammatory
rpidal anti-inlamm8tory drugs at the site of inflammation drugs, including aspirin.
has been discussed by a number of investigators [l l-l 41. l Safe conditions for its use in pregnant women have not
The rple of renal prostaglandins and nephrotoxicity due been established [ 181. Nor is diclofenac sodium recom-
to nansteroidai anti-inflammatory drugs has been re- mended for use in nursing mothers, since it is excreted
viewed recently [15]. All nonsteroidal anti-inflammatory iv the milk [19].
drugs, without exception, may adversely affect renal per- l As with all nonsteroidal anti-inflammatory drugs, diclo-

fusion, electrolyte balance, and blood pressure in suscep- fenac sodium must be used with special care in the el-
tible patients [16]. Hyperkalemia, the most frequent ad- derly [20].
verse renal effect, occurs most commonly in patients with l The manufacturer’s product circular should be con-
diabetes mellitus or renal insufficiency, and in those re- sulted for a complete listing of precautions and adverse
ceiving beta blockers, angiotensin-converting enzyme reactions.
inhibitors, or potassium-sparing agents. Moreover, pa- Finally, we wish to thank our associates for their excel-
tients at risk for the development of fluid retention and lent contributions in making this publication a reality.

2 AprU ~a,1986 The American Journal of Wlci~ yolume~ 60 @uPPi 48)

REFERENCES
1. Gottlieb NL: Introduction: the art and science of nonsteroidal trations of diclofenac iti patients with rheumatoid arthritis or
anti-inflammatoq drug selection. Semih Arthritis Rheum osteoarthritis. Semin Arthritis Rheum 1986; 15 (‘SuppI 1): 65-
1985; 15 (sbppl 1): l-3. 67.
2. Calabro JJ, Londino AV Jr: Drug therapy in rheumatojd arthritis 11. Emori HW, Champion GD, ‘Bluestone R, et al: Simultaneous
based on an understanding bf its natural history: part Il. Clin pharmacokinetics of ivdomethacin in serum and synovial
Rheumatol Prac 1985; 3: 4-13. fluid. Ann Rheum Dis 1973; 32: 433-455.
3. Calabro JJ: Dmg therapy of juvenile rheumatoid arthritis and of 12. Makela AL, Lempiainen M, Ylijoki H: Ibuprofen levels in serum
the seronegative spondyloarthropathies. In: Roth SH, ed. and synovial fluid. Stand J Rheumatol 1981; 39 (suppl): 15-
Handbook of drug therapy In, rheumatology. Llttleton, MA: 17.
PSG Publishing Co; 1985; 115-180. 13. Furst DE, Drqmgoole SM, Desiraju RK, et al: Clinical pharma-
4. Paulus HE, SieQel M, Mongan E, et al: Variations of serum cdn- cology of tolmetin: comparisons in rheumatoid arthritis pa-
centrations and half-life of salicylate in patients with rheurria- tients and normal volunteers. J Clin Pharmacoll983; 23: 329-
toid arthritis. Arthritis Rheum 1971; 14: 527-532. 335.
5. Calabro JJ: Status of oxyphenbutazone (letter). Clin Rheumatol 14. Jalava S, Saarimaa H, Anttilh M, et al: Naproxen concentrations
Prac 1985; 3: 279. in serum, synovial fluid, and synovium. Stand J Rheumatol
6. Husklsson EC: Practical aspbcts in selecting and prescrit$g 1977; 6t i55-i57.
antirheumatic dnigs. In: Roth SH, ed. Handbook of drug th&- 15. Epstein M: Preface. Ah J Med ‘1986; 80 (suppl 1A): 1-2.
apy in rhellmatology. Littletdn, MA: PSG Publishing Co, 1985; 16. Zip!+r RD, Henrich WL: Imp&cations of nonsteroidal antl-
79-113. inflammatory drug therapy. Am J Med 1986; 80 (suppl 1A):
7. Scholer DW, Boett&er I, Ku EC, et al: Pharmacolbgy of diclo- 78-84.
fenac sodium (Voltaien). Semin Arthritis Rheum 1985; 15 17. Brater DC: Drug-drug and drug-disease interactions with non-
(suppl 1): 61-64. steroidal anti-inflammatory drugs. Am J Med 1986; BO (suppl
8. Sallman AR: The history of diclofenac. Semin Arthritis Rheum 1 A): 62-77.
1985; 15 (suppl 1): 57-60. 18. Needs CJ, Brooks PM: Antirheumatic medicatioh in pregnancy.
9. Fowler PD, Shadforth MF, Crook PR, dt al: Plasma and synovial Br J Rheumatol 1985; 24: 282-290.
fluid corlcentrations of diclofenac sodium and its major hy- 19. Needs CJ, Brooks PM: Antirtibumatic medication during lacta-
droxylated metabolites during long-term treatment of rheuma- tion. Br J Rheumatol 1985; 24: 291-297.
toid arthritis. Eur J Clin Pharmacol 1983; 25: 389-394. 20. Calabro JJ: Analgesic and anti-inflammatory therapy in the el-
IO. Benson MD, Aldo-Benson M, Brandt KD: Synovial fluid concen- derly. Am J Med 1985; 79 (suppl 48): 33-34.

April 28. 1986 The Amerlcen Journal of Medicine Volumh SO (suppl 4B) 3