Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial.

BACKGROUND: In recent studies of acute pain and primary dysmenorrhea, rofecoxib, a nonsteroidal anti-inflammatory drug that selectively targets the cyclooxygenase-2 enzyme, was found to be similar in efficacy to ibuprofen and naproxen sodium. OBJECTIVE: The purpose of this study was to determine the analgesic efficacy of a single oral dose of rofecoxib 50 mg compared with the combination of codeine 60 mg/acetaminophen 600 mg in a model of postsurgical dental pain. METHODS: In this double-blind, placebo- and active comparator-controlled, parallel-group study, patients experiencing moderate or severe pain after the surgical extraction of > or = 2 third molars, at least 1 of which was a mandibular impaction, were randomized to receive placebo, rofecoxib 50 mg, or codeine 60 mg/acetaminophen 600 mg. Patient evaluations of pain intensity, pain relief, and global assessments were recorded throughout the 24-hour period after dosing. The 2-stopwatch method was used to determine time to confirmed perceptible pain relief. The primary end point assessing overall analgesic effect was total pain relief over 6 hours (TOPAR6). Secondary end points were patient global assessment of response to therapy (PGART) at 6 hours, onset of analgesia, peak analgesic effect, and duration of analgesia. RESULTS: A total of 393 patients were enrolled; 182 received rofecoxib, 180 received codeine/acetaminophen, and 31 received placebo. The overall analgesic effect of rofecoxib 50 mg was greater than that of codeine 60 mg/acetaminophen 600 mg for TOPAR6 (12.4 vs 7.0; P < 0.001) and PGART at 6 hours (P < 0.001). The onset of analgesic effect was similar for rofecoxib and codeine/acetaminophen. Peak analgesic effect as measured by peak pain relief scores during the first 6 hours was significantly greater in the rofecoxib group compared with the codeine/acetaminophen group (P < 0.001), as was the duration of analgesic effect measured by the time to rescue analgesia (9.6 hours vs 2.3 hours, P < 0.001). Adverse events were reported in 33.0%, 46.1%, and 32.3% of patients treated with rofecoxib, codeine/acetaminophen, and placebo, respectively. The most common adverse events were nausea (6.0%, 25.0%, and 9.7%, respectively) and vomiting (3.8%, 18.3%, and 6.5%, respectively). Significantly more patients in the codeine/acetaminophen group than in the rofecoxib group experienced adverse events overall (P < 0.050) and nausea in particular (P < 0.001). CONCLUSION: In this study of moderate to severe postoperative dental pain, the analgesic efficacy of rofecoxib 50 mg was greater than that of codeine/acetaminophen, with a lower incidence of adverse events and nausea.

Effects of modulators of the renin-angiotensin-aldosterone system on cough. Losartan Cough Study Group.

OBJECTIVE: To compare the incidence of cough in patients with a history of angiotensin converting enzyme (ACE) inhibitor-related cough who received losartan [a type 1 angiotensin II (Ang II) receptor antagonist], lisinopril (an ACE inhibitor) or hydrochlorothiazide (a diuretic). DESIGN: An international, multicentre, randomized double-blind, parallel-group controlled trial. SETTING: Outpatient clinics at 20 tertiary care medical centres in 11 countries. PATIENTS: One hundred and thirty-five patients with uncomplicated primary hypertension with a history of ACE inhibitor-related cough were randomly assigned to the double-blind treatment phase and completed the study. INTERVENTION: After confirming that the cough was ACE inhibitor-related by a single-blind rechallenge, followed by a placebo washout period, patients were randomly assigned to receive 50mg losartan, 20mg lisinopril or 25mg hydrochlorothiazide once a day for 8 weeks. MAIN OUTCOME MEASURES: Cough incidence, severity and frequency were assessed by a self-administered questionnaire and a visual analogue scale. RESULTS: The percentage of patients who complained of cough was significantly higher with lisinopril than with losartan or hydrochlorothiazide. The mean visual analogue scale scores for patients treated with lisinopril demonstrated that these patients coughed more frequently than those who received losartan or hydrochlorothiazide. CONCLUSION: The incidence of cough related to the type 1 Ang II receptor antagonist losartan is significantly lower than that observed with lisinopril, and similar to that observed with hydrochlorothiazide in patients with a rechallenged ACE inhibitor cough. Type 1 Ang II receptor antagonists represent a potential new treatment for hypertensive patients in whom ACE inhibitors are indicated, but who develop a cough with these agents.

A retrospective assessment of the 75/75 rule in bioequivalence.

The 75/75 rule was originally proposed by the U.S. Food and Drug Administration (FDA) as an alternative means of testing the bioequivalence of two formulations of a pharmaceutical agent. The rule specified that the ratio of test-to-reference formulation of a bioavailability measure arising in a bioequivalence study must be between 75 and 125 per cent of unity in at least 75 per cent of subjects to declare two formulations bioequivalent. The rule has garnered criticism in the literature and the FDA no longer uses the rule formally in assessing bioequivalence. The basis, however, for all criticism of the rule has been simulation arguments. In this paper, we derive the sampling model implied by the rule and place the rule in the framework of a statistical hypothesis test. We show how the significance level of the test depends upon variability of the formulations, and thus why the rule performs in the way that has received criticism.

Identification of an optimal subgroup for treatment evaluation of patients with brain metastases using RTOG study 7916.

The overall poor prognosis of brain metastases patients has complicated the evaluation of treatment effectiveness in previous clinical trials involving radiation therapy. Therapy has not been seen to alter survival, which is generally short in these patients. Possible benefits of the treatments tested may be better assessed using a favorable group of patients who are at lower risk of dying quickly from cancer. The determination of a patient subgroup having prolonged survival allows for improvement in the design and analysis of subsequent clinical trials. An optimal patient group was identified in an RTOG study (7916) that evaluated two fractionation schedules (30 Gy/10 fractions/2 weeks and 20 Gy/6 fractions/3 weeks) with or without the administration of misonidazole (MISO) in the treatment of brain metastases. A Cox regression model was used to identify the pretreatment characteristics associated with a favorable prognosis for survival: Karnofsky Performance Status (KPS) of 70-100, an absent/controlled primary tumor, age less than 60 years, and metastatic spread limited to the brain. A logistic model confirmed that the odds of surviving at least 200 days depend on these pretreatment characteristics. Patients with all four favorable characteristics constitute 11% of the evaluable study population and have a predicted 200 day survival of 52%. Prognostically favorable subgroups have been identified as patients having at least three of these four favorable characteristics. These patients have predicted probabilities of 200 day survival between 33 and 52%. Conversely, unfavorable subgroups are defined as patients having two or less favorable characteristics. Subsequent verification of these results by a second data set is warranted. The prognostically favorable characteristics have been used to define the patient population in a current RTOG study evaluating accelerated radiation therapy in patients with brain metastases.