ANTECEDENTES:

El etodolac es un inhibidor selectivo de la ciclooxigenasa 2 (COX-2), con pruebas de eficacia para la osteoartritis y la artritis reumatoide. No se ha establecido claramente su eficacia analgésica para el dolor posoperatorio. No se hallaron revisiones sistemáticas sobre el uso de etodolac en esta afección.

OBJETIVOS:

Evaluar la eficacia analgésica del etodolac en dosis orales únicas para el dolor posoperatorio moderado e intenso.

ESTRATEGIA DE BÚSQUEDA:

Se hicieron búsquedas en Cochrane CENTRAL, MEDLINE, EMBASE y en la Oxford Pain Relief Database hasta mayo 2009.

CRITERIOS DE SELECCIÓN:

Ensayos aleatorios doble ciego controlados con placebo de una dosis única oral de etodolac (cualquier formulación) en adultos con dolor posoperatorio agudo de moderado a intenso.

RECOPILACIÓN Y ANÁLISIS DE DATOS:

Dos autores de la revisión evaluaron de forma independiente la calidad de los ensayos y extrajeron los datos. Se extrajeron datos sobre el alivio del dolor o la intensidad del dolor, y se convirtieron en resultados dicotómicos sobre el número de participantes con al menos 50% de alivio del dolor a las cuatro a seis horas, con los que se calculó el riesgo relativo (RR) y el número necesario a tratar (NNT) para causar un beneficio. El número de participantes con medicación de rescate durante períodos específicos, y el momento adecuado para el uso de medicación de rescate, se buscaron como medidas adicionales de eficacia. Se recopiló información sobre los retiros y los eventos adversos.

RESULTADOS PRINCIPALES:

Nueve estudios (1459 participantes) compararon etodolac con placebo. La calidad de la información de los estudios fue adecuada; además, la mayoría de los participantes presentaron dolor luego de extracciones dentales. La dosis de etodolac utilizada fue de 25 mg a 1200 mg, con amplia información para las dosis de 100 mg y 200 mg. Para al menos 50% de alivio del dolor de cuatro a seis horas en comparación con placebo, el NNT para el etodolac 100 mg (498 participantes) fue de 4,8 (3,5 a 7,8) y para el etodolac 200 mg (670 participantes) fue de 3,3 (2,7 a 4,2). La información limitada sobre la formulación de liberación prolongada no indicó beneficios superiores para este resultado.


La proporción de participantes con al menos el 50% de alivio del dolor fue del 41% con 100 mg y del 44% con 200 mg. Fue necesario volver a medicar a los pacientes en casi el 60% con etodolac 200 mg o 400 mg durante seis u ocho horas en comparación con casi el 80% con placebo.


Los eventos adversos fueron poco frecuentes y diferentes a los del placebo.

CONCLUSIONES DE LOS AUTORES:

El etodolac 200 mg puede ser un analgésico útil para el dolor posoperatorio, con eficacia similar al paracetamol 1000 mg y celecoxib 200 mg. Las dosis más altas pueden brindar una analgesia equivalente a los fármacos usados con mayor frecuencia, como ibuprofeno 400 mg, naproxeno 500 mg y diclofenac 50 mg.

Etodolac is a new nonsteroidal anti-inflammatory drug (NSAID) with potent analgesic and antiarthritic properties. The purpose of these randomized, double-blind, parallel-group studies was to compare etodolac with other standard NSAIDs or placebo for the treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Results of rheumatoid arthritis and osteoarthritis studies showed etodolac (200 to 300 mg b.i.d. or 200 mg t.i.d.) to be comparable to naproxen (500 mg b.i.d.), piroxicam (20 mg once daily), and diclofenac (50 mg t.i.d.). Key efficacy variables improved significantly (p less than or equal to 0.05) in all treatment groups, and there were no significant between-group differences. Studies comparing etodolac (200 mg b.i.d.) with indomethacin (50 mg t.i.d.) for treatment of ankylosing spondylitis showed significant improvement from baseline in both the patient's and physician's global assessments for both treatments. Titrated-dose studies compared etodolac (50 to 200 mg b.i.d.) with naproxen (250 to 375 mg b.i.d.) and placebo for the treatment of ankylosing spondylitis. Both active drugs resulted in greater improvement than did placebo in the patient's and investigator's global assessments. These results indicate that etodolac is as effective as naproxen, piroxicam, and diclofenac for the treatment of rheumatoid arthritis and osteoarthritis. Moreover, it is comparable to naproxen and indomethacin and superior to placebo for the treatment of ankylosing spondylitis.

This study compared the efficacy and safety of etodolac, a new nonsteroidal anti-inflammatory drug of the pyranocarboxylic class, with that of diclofenac in patients with osteoarthritis of the knee. A total of 172 patients entered this double-blind, parallel study and were randomly assigned to receive etodolac 600 mg/day (n = 85) or diclofenac 150 mg/day (n = 87) for 8 weeks. Both treatment groups showed a statistically significant reduction in pain at the second week and significant improvement (P < or = 0.05) from baseline in all efficacy assessments for the remainder of the study. Seventeen (20%) patients in the etodolac group and 21 (24%) patients in the diclofenac group reported at least one adverse event. Seven (8%) patients treated with etodolac and eight (9%) of those receiving diclofenac withdrew prematurely from the trial. One diclofenac-treated patient had a significant increase in alanine aminotransferase at the final evaluation. The results of this study indicate that etodolac was well tolerated and as effective as diclofenac in relieving the signs and symptoms of osteoarthritis.

A double-blind, parallel group study was carried out in 61 patients suffering from acute gouty arthritis to compare the effectiveness of etodolac and naproxen in the relief of symptoms. Patients were allocated at random to receive either 300 mg etodolac twice daily (31 patients) or 500 mg naproxen twice daily (30 patients) for 7 days. Both groups were comparable for sex, age and weight of patients, but there was a tendency for patients in the etodolac group to have more severe gout as shown by baseline clinical assessment scores. The variables assessed on entry and on Days 2, 4 and 7 of treatment were pain intensity, swelling, tenderness, erythema, joint heat, range of motion, and physician's and patients' overall evaluation of the condition. The results showed that there was a significant improvement from baseline in all of the variables at each time point in both treatment groups. However, more etodolac-treated patients (81%) than naproxen-treated patients (53%) showed overall improvement at Day 2, and etodolac was significantly better than naproxen on the Day 2 evaluation of joint swelling and at the Day 4 evaluations of joint tenderness, range of motion and the physician's global assessment. At the final evaluation on Day 7, 97% of the etodolac group reported that their condition had improved as compared to 93% of the naproxen group. Both drugs were well tolerated and only a few mild side-effects were reported.

This double-masked, parallel-group, randomized study compared the analgesic efficacy and tolerability of a single investigational 1200-mg dose of extended-release etodolac with those of a single 400-mg dose of extended-release etodolac and twice-daily doses of conventional etodolac 200 and 400 mg and placebo given 8 hours apart in 237 patients with moderate or severe postoperative pain following surgical removal of > or = 2 impacted third molars. Both doses of conventional etodolac and the 1200-mg dose of extended-release etodolac were significantly more effective on all summary analgesic measures than placebo (P < 0.05). Conventional etodolac had an onset of analgesic activity within 45 (400 mg) to 60 (200 mg) minutes and an analgesic duration of 5 to 6 hours. Extended-release etodolac 1200 mg had an onset of action within 60 minutes and an analgesic duration of 12 to 24 hours. At hours 2 and 3, conventional etodolac 400 mg was significantly more effective than the other treatments; from hours 6 through 12, extended-release etodolac 1200 mg was significantly more effective than the other treatments (both, P < 0.05). No serious adverse events were observed in this study, with an incidence of side effects in the active etodolac groups no different than that with placebo. Extended-release etodolac 1200 mg has a prolonged analgesic duration and an acceptable side-effect profile in the oral surgery pain model.

OBJECTIVE:

To determine if the pharmacokinetics of methotrexate (MTX) is modified by the coadministration of etodolac.

METHODS:

MTX (10 mg) was administered intramuscularly in the absence and presence of steady state levels of etodolac in 19 patients with rheumatoid arthritis. MTX levels were assayed by fluorescence polarization immunoassay. Concentrations of 7-hydroxymethotrexate (7-OH-MTX) were assayed by a reverse phase high performance liquid chromatography method. The unbound fraction was determined by ultrafiltration.

RESULTS:

When etodolac was coadministered with MTX, the highest observed concentration decreased and the mean residence time increased to become statistically significant. However, these differences are not of great clinical importance especially given that the area under the curve and clearances were unchanged. There were no significant differences in binding protein and 7-OH-MTX concentrations between MTX with and without etodolac administration.

CONCLUSION:

The pharmacokinetics of MTX is slightly modified by coadministration of etodolac. Moreover, no clinical toxicity was observed.

Numerous clinical trials have shown etodolac to be an effective analgesic. The purpose of the present report is to review results of 14 studies that demonstrate the effectiveness of etodolac in a variety of painful conditions. Presented are the results of four postsurgical pain studies, one study of acute gouty arthritis and nine studies of acute musculoskeletal disorders: acute low back pain, acute painful shoulder, tendinitis and bursitis, and acute sports injuries. A single oral dose of etodolac (25, 50, 100, 200, or 400 mg) was compared with aspirin (650 mg) or a combination of acetaminophen (600 mg) plus codeine (60 mg) for the relief of pain up to 12 h following oral, urogenital or orthopedic surgery. In multiple dose studies of acute gouty arthritis and musculoskeletal conditions, etodolac 200 or 300 mg twice a day (b.i.d.) or 200 mg three times a day (t.i.d.) was compared with naproxen 500 mg b.i.d. or t.i.d., diclofenac 50 mg b.i.d. or t.i.d., and piroxicam 20 or 40 mg once a day (o.d.) administered over 5 to 14 days. The efficacy of etodolac was at least equal and in some ways superior to aspirin and acetaminophen plus codeine in the relief of postsurgical pain. In studies of acute gouty arthritis, significant improvement from baseline were seen for all efficacy parameters evaluated for both the etodolac- and naproxen-treated patients. All the present studies of musculoskeletal conditions have shown etodolac to be effective and comparable in analgesic efficacy to naproxen, diclofenac or piroxicam. In summary, etodolac therapy for pain following surgery, in acute gouty arthritis and in acute musculoskeletal conditions resulted in analgesia comparable to that provided by several well-established analgesic or anti-inflammatory agents.

The analgesic efficacy of etodolac for 161 patients reporting moderate to severe pain after oral surgery was evaluated. The patients were given single oral doses of one of the following test drugs--aspirin, 650 mg; etodolac, 50 mg; or etodolac, 200 mg--or placebo. There were at least 39 patients in each drug group. After medication, patients recorded pain intensity and pain relief at half-hour intervals for the first hour and then hourly for up to eight hours. Pain intensity differences, total pain relief, onset of analgesia, and each patient's overall opinion of the drug were analyzed. Time--effect curves were derived from the pain relief and pain intensity difference scores. Analgesic effects produced by both doses of etodolac were comparable with those of 650 mg of aspirin. All active drugs were significantly more effective than placebo, and the 200-mg dose of etodolac provided an earlier onset and longer duration of analgesia than the other test drugs.

The efficacy and tolerability of etodolac and piroxicam were compared in patients with osteoarthritis of the knee. Two hundred and twenty patients entered a double-blind, parallel group trial and were randomly assigned to receive 300 mg etodolac twice daily (n = 112) or 20 mg piroxicam once daily (n = 108) for 8 weeks. The etodolac group showed significant improvement (p less than 0.05) from baseline in all efficacy assessments at all evaluations. The piroxicam group showed improvement from baseline in all efficacy assessments at all evaluations except for erythema at Week 2. While mean change from baseline was similar for both groups, the patients' and physicians' final overall evaluations showed that the etodolac-treated patients improved slightly more from baseline than the piroxicam-treated patients. Twenty (18%) patients in the etodolac group reported at least one drug-related study event. In the piroxicam group, 16 (15%) patients reported at least one drug-related study event. Twelve (11%) etodolac-treated patients prematurely withdrew from the study. Of these, 7 had at least one adverse reaction. Two of the 12 patients withdrew because of lack of efficacy. Withdrawals from the piroxicam group were comparable. Thirteen (12%) patients withdrew, 6 of whom had at least one adverse reaction. One of these patients suffered a cardiovascular accident and died. Three patients withdrew because of lack of efficacy. The results of this study indicate that etodolac and piroxicam are comparable in efficacy and tolerability for the treatment of patients with osteoarthritis.

Single oral doses of etodolac 50, 100 and 200 mg were compared with aspirin 650 mg and placebo in a double-blind, parallel group study of 189 outpatients reporting moderate or severe pain after oral surgery. Overall efficacy of test drugs was evaluated by sum of pain intensity difference (SPID) scores and total pain relief (TOTPAR) scores over 0.5-3, 0.5-6, 0.5-8 and 0.5-12 hours. Etodolac 200 mg provided significantly greater analgesia than aspirin by these measurements over all SPID and all but one TOTPAR interval, and was significantly more effective than placebo over all intervals. Etodolac 100 mg was superior to aspirin for SPID 0.5-8 and 0.5-12 hours, and superior to placebo for both SPID and TOTPAR over all time intervals. Onset of analgesia for etodolac 100 mg, 200 mg and aspirin was 1 hour or less for the majority of patients in each group; 42% receiving etodolac 200 mg reported onset of analgesia within 0.5 hour. Duration of analgesia for etodolac 200 mg appeared twice that of aspirin. A significant positive dose-response relationship was obtained for the three doses of etodolac. A low frequency of side effects was observed in all treatment groups.