RESEARCH/PRACTICE REPORTS

FLURBIPROFEN VERSUS DICWFENAC FOR THE TREATMENT OF OSTEOARTHRITIS OF THE KNEE Edgar Atra, Craig A. Metz, Bruce L. Brown, and Kok-wah Teoh

ABSTRACf: Seventy-four patientswereenrolledin this double-blind, randomized single-eenterstudy to evaluatethe therapeutic effectiveness of 50 mg tid regimensof flurbiprofen or diclofenac sodium in patients with osteoarthritisof the knee. By chance, the flurbiprofen patientshad a significantly more advanceddiseasestatusat baselinethan their diclofenac-treated counterparts. However, at subsequentfollow-up evaluations, both treatment groupsexperienceda significant reduction in diseaseseverityregardless of the baselinedifferences. No serious safety problemswereassociated with either investigational therapy. The frequency of reported medicalevents weredistributedequally betweenthe flurbiprofen and diclofenac groups. Althoughthe imbalance in diseaseseveritybetweentreatmentgroups made a rigorousstatistical interpretation of the resultsvery difficult,the data from this clinicaltrial tend to support the equiefficacy of 50 mg tid regimensof flurbiprofen versusdiclofenac for treatingosteoarthritisof the knee.

otcr Ann Pharmacother 1990;24:920-3. ALTHOUGH NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDs) are thought to have the same basic mechanism of

action (i.e., prostaglandin synthetase inhibition), there appear to be ranges in efficacy, tolerance, and toxicity among the various agents. Flurbiprofen is a NSAID which, in clinical studies in the U. S. and other countries, has been shown to be effective therapy in the treatment of osteoarthritis.v' rheumatoid arthritis," general pain," and related musculoskeletal conditions.?" The primary objective of this study was to compare the efficacy, tolerance, and safety of a six-week regimen of flurbiprofen 50 mg tid with an identical regimen of another NSAID (diclofenac) with regard to subjective evaluations of disease status in patients with osteoarthritis of the knee. EDGAR ATKA, M.D., is with the Rheumatology Department, Escola Pscola Paulista de Medicina, San Paula, Brazil; and CRAIG A. METZ, Ph.D., BRUCE L. BROWN, M.D., and KOK·WAH TEOH, Ph.D., are Anti-Inflammatory Clinical Researchers, The Upjohn Company, Kalamazoo, MI 49001. ReprInts: Craig A. Metz, Ph.D.

Methods Seventy-four patientswere enrolled in a single-center, double-blind, randomized clinicaltrial. Patients eligiblefor study inclusion met all of the following criteria: (I) activeosteoarthritisof at leastone knee (only one joint was evaluated in this study); (2) after a drug-free washout periodof one week,the patient'sarthritis wasmorepainfulon subjective evaluation or demonstrated at least one other indicatorof inflammation (i.e., redness,heat, swelling, tendernesson pressure,and/orpainon passive motion);(3) X-rayevidenceshowedjoint changes typicalof osteoarthritis (withinnine monthsprior to studyadmission); (4)diseasedurationwasat leasttwomonths;(5) patientswerebetween 30and75 yearsof age; and (6) patientsgave informedconsent. Patients were excluded from the study if any of the following were present: (I) hypersensitivity or intolerance to f1urbiprofen, diclofenac, acetaminophen, and/or related compounds; (2) presence or history (within three years) of gastrointestinal (GI) ulceration with or without concurrentbleeding; (3) significant hematologic, renal, hepatic, or cardiac impairment; (4) pregnancy, possiblepregnancy, or nursing; (5) serious medical conditions other than those previously described; (6) previousstudyparticipation; and (7) no worsening of arthritisduringthe one-week,drug-free washoutperiod. Patients satisfyingthe studyinclusion criteria received treatment with a 50 mg tid regimenof flurbiprofen or diclofenac according to a computer-generated randomization scheme. Investigational therapies wereadministered for six consecutive weeks. The following endpointswereevaluated at baselineand follow-up at weeks2, 4, and6: (I) tendernesson pressure(yes/no); (2)painon passive motion (five-point scale ranging from none [I) to severe [5)); (3) joint rednessor swelling (four-point scalerangingfromnone[I) to severe[4)); and (4) physicianand patientglobal assessments of arthritis (five-point scale ranging from inactive [I) to incapacitating [5)). To limit interobserver variability, the same person from the study staff performed the subjectiveevaluations. Vitalsigns (blood pressure, pulse, respiration, and temperature), hematology (hemoglobin, hematocrit, red blood cell count, white blood cellcountand differential, plateletcount, anderythrocytesedimentation rate),urinalysis,and serum chemistries(alkalinephosphatase, bilirubin, alanineaminotransferase [ALT) , aspartateaminotransferase [AST ,and bloodureanitrogen[BUN))wererecordedat baselineand studyweeks2, 4, and6. Additional safetyinformation in theformofroutinestoolhemoccult tests wascollectedwith the aforementioned assays.

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No concomitant aspirin, corticosteroid, nonstudy NSAID, or anticoagulant therapy was allowed either during the washout period or the courseof the study. Othermedications wereallowedwiththe provisothat they be recorded. Furthermore, patientswere specifically queried concerning acetaminophen use during the two-week period precedingthat particularclinic visit. Patientswere allowedto withdraw from the study at their discretion. Any patientswhosesignsor symptomswerenot controlledby investigational therapyor who experiencedsignificant intolerance to study medication were also eligible for withdrawal from the study. Times and reasons for study termination were recordedby the investigator. For inclusionin theefficacyanalysis,a patienthad to remainon investigational therapyfor a minimumof two consecutiveweeks. Continuousand discrete ordinal variableswere analyzed using twosample r-tests, In order to detect significant changes from baseline, within-group, pairedr-testswereused to comparefollow-up valueswith baselinevalues.If significant differences betweentreatmentgroupswere presentat baseline, an analysisof covariancewas used to adjust for the potentialeffectsof suchdifferences. Generally, discretecategoricalvariableswereanalyzedusingchi-squareand/orFisher'sexacttestsof homogeneity of distributions. Differences werestatistically significant if the correspondingp-value was ~0.05. A differencewasmarginally significant if the corresponding p-valuewas >0.05 but ~O.IO.

each treatment group improved significantly (pCD

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Figure2. Joint pain with motion. 'Decrease from baselineindicatesimprovement.

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DICP, The Annals of Pharmacotherapy •

I. MENA H. Long-term treatment of osteoarthritis with f1urbiprofen and aspirin (protocol 3208). Upjohn Company technical report 7244/ 75/7244/018, March 1975. 2. RACHID A. Pesquisa Clinica Comparativa com lIurbiprofeno versus fentiazaco em processos de osteoartrose. Rev Bras Med 1986;43(9):259. 3. FlZSMAN P, PERFETUSJBR. Estudo comparativo com lIurbiprofeno versus diclofenac em osteoartrose. FoliaMed 1986;93:43-7. 4. GRANT M, WALTER J, WOJTULEWSKI JA. A double-blind paralled group comparison of f1urbiprofen and indomethacin in the long term treatment of osteoarthrosis of the knee. Br J Clin Pract 1980;37 (Suppl 9):92-4. 5. MENA H. Long-term treatment of rheumatoid arthritis with lIurbiprofen and aspirin (protocol 3207). Upjohn Company technical report 7244/7517244/024, March 1975.

episiotomy pain. Pharmacotherapy 1983;3:177-817. MENA H, STILES DM, LAMBORN K. Treatment of acute gout with lIurbiprofen and indomethacin (protocol 3204). Upjohn Company technical report 7244/76/7244/062, August 1976. 8. MENA H, STILES DM, ABOLINS KA. Treatment of acute shoulder syn-

1990 October, Volume 24

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Research/Practice drome (bursitis/tendonitis) with flurbiprofen (protocol 3261). Upjohn Company technical report 724417617244/037, May 1976.

RESUME

Los autores lIevan a cabo un estudio con el proposito de evaluar la efectividad y seguridad de flurbiprofen en comparacion con diclofenac, ambos en dosis de 50 mg po tid en el tratamiento de osteoartritis de la rodilla. EI estudio fue doble ciego y se asignaron los pacientes a sus respectivos tratamientos utilizando un rnetodo aleatoreo. La duraci6n del estudio fue de seis semanas. No se informaron reacciones adversas severas con el uso de los farmacos estudiados y la frecuencia de efectos secundarios fue similar para ambos grupos. AI cvaluar los pacientes, fue evidente que los pacientes asignados a recibir flurbiprofen tenian un grado de enfermedad mas avanzado al comenzar el estudio. Al evaluar los grupos durante eI estudio. sin embargo, ambos grupos lograron el mismo grado de reducci6n en la severidad de la condici6n. Aunque el desbalance en la severidad de la condici6n entre los grupos hizo que la interpretacion del analisis estadistico fuera dificil de realizar, los autores indican que la data sf tiende a apoyar que flurbiprofen y diclofenac 50 mg po tid fueron igualmente de efectivos en este grupo de pacientes.

L'objectif premier de cette etude randomisee a double-insu consistait a evaluer l' efficacite therapeutique et Ie profil de toxicite d'un regime de flurbiprofene et de diclofenac, tous deux adrninistres a raison de 50 mg tid pour six semaines, a 74 patients atteints d'osteoarthrite localisee a un ou deux genou(x). L'evaluation pre-traitement des patients assignes au flurbiprofene a revele une osteoarthrite significativement plus severe par rapport a celie des patients recevant Ie diclofenac, En depit de cette difference, les trois evaluations subsequentes effectuees pendant la therapie ont demontre une reduction similaire de la seve rite de la maladie chez les deux groupes traites. Le flurbiprofene et Ie diclofenac ont ete bien toleres et aucune difference significative quant a la frequence et a la nature des effets secondaires des deux anti-inflammatoires n'a ete rapportee. Une analyse statistique rigoureuse des resultats est en partie limitee par la difference pre-traitement de l'evaluation subjective de la severite de l'osteoarthrite. De plus, l'utilisation d'une dose maximale de diclofenac (150 rug/jour) versus une dose nonmaximale de flurbiprofene (rnaximale 200-300 mg/jour) do it etre tenu en consideration. Les auteurs concluent que Ie flurbiprofene 50 mg tid est aussi efficace que Ie diclofenac 50 mg tid dans Ie traitement palliatif de l'osteoarthrite localisee au(x) genou(x).

WANDA T. MALDONADO

SYLVIE ROBERT

EXTRACTO

CORRELATION OF FREE PHENTYOIN TO SERUM ALBUMIN INCANCER PATIENTS Greg S, Umstead and Kurt H. Neumann

ABSTRACT: The objectives of this study were to compare the total and free phenytoin serum concentrations of cancer patients with hypoalbuminemia with those of cancer patients with normal serum albumin and to correlate the percentage of free phenytoin with the albumin concentration. A total of 22 patients were studied, 13 with normal albumin concentration and 9 with low albumin. The mean free phenytoin in the normal albumin group was 9.9 (± 1.3) percent and 17.6 (±4.6) percent in the low albumin group. With the groups combined, the mean free phenytoin was 13.1 percent (range 8.3-22.2) with the albumin range of 20-45 giL. There was a significant negative correlation (r=-0.9, p 15- 20 percent. 1,5-7 Another factor affecting the free fraction of phenytoin is the concentration of serum albumin, The Boston Collaborative Drug Surveillance Program reported an increased incidence of adverse effects among patients with hypoalbu-

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Flurbiprofen versus diclofenac for the treatment of osteoarthritis of the knee.

Seventy-four patients were enrolled in this double-blind, randomized single-center study to evaluate the therapeutic effectiveness of 50 mg tid regime...
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