Response to expression of concern regarding VIGOR study.
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Arthritis, Rheumatoid↗
Biomedical subjects
Alise Reicin
Publications and source records attributed to Alise Reicin.
Dental impaction pain model as a potential tool to evaluate drugs with efficacy in neuropathic pain.
Intravenous lidocaine, a nonspecific Na-channel blocker, was used to assess the dental impaction model for evaluation of neuropathic pain drugs. Sixty patients, experiencing moderate or severe pain after removal of > or = 2 third molars, were randomized (2:2:1:1) to lidocaine (4 mg/kg; maximal dose 300 mg), oxycodone/acetaminophen (10/650 mg), placebo, and active placebo (diphenhydramine, 50 mg). Lidocaine provided a modest degree of pain relief. Predefined endpoints of total pain relief and sum of pain intensity at 2, 4, and 6 hours showed numerically, not statistically significantly, greater pain relief versus placebo. A significantly greater effect over placebo was observed in peak effect and at shorter time points (30 minutes and 1 hour), consistent with the pharmacokinetic profile (plasma concentration of approximately 2 mug/mL). Oxycodone/acetaminophen provided significantly greater analgesia versus placebo, validating study conduct, and significantly greater pain relief was observed versus lidocaine, which is consistent with a smaller portion of dental extraction pain being of neuropathic origin.
Acetaminophen↗
The analgesic effect of etoricoxib relative to that of cetaminophen analgesics: a randomized, controlled single-dose study in acute dental impaction pain.
BACKGROUND: To compare the analgesic effect of single doses of etoricoxib 120 mg, oxycodone/ acetaminophen 10 mg/650 mg and codeine/ acetaminophen 60 mg/600 mg in acute pain using the dental impaction model. METHODS: In this randomized, double-blind, placebo-controlled, parallel-group study, patients reported pain intensity and pain relief (16 times) and global scores (twice) during a 24-h period. The primary endpoint was the overall analgesic effect, total pain relief over 6 h (TOPAR6). Other endpoints were patient global evaluation, time to onset (2-stopwatch method), duration of analgesic effect (median time to and amount of rescue medication use). Tolerability was evaluated by overall and opioid-related (nausea and vomiting) adverse experiences. RESULTS: 302 patients (mean age 23; 63% women; 63 % White) were randomized to etoricoxib 120 mg, oxycodone/acetaminophen 10 mg/650 mg, codeine/acetaminophen 60 mg/600 mg, and placebo (2:2:1:1). Etoricoxib demonstrated significantly greater overall analgesic efficacy (TOPAR6) (13.2 units) versus oxycodone/acetaminophen (10.2 units); and codeine/acetaminophen (6.0 units); p < 0.001 for all. All active treatments were superior to placebo. Median time to onset was significantly (p < 0.001) shorter for oxycodone/acetaminophen (20 min) and numerically but not significantly shorter (p = 0.259) for codeine/acetaminophen (26 min) compared with etoricoxib (40 min). Etoricoxib (24 h) had a significantly longer lasting analgesic effect than oxycodone/acetaminophen (5.3 h), codeine/acetaminophen (2.7 h), and placebo (1.7 h) (p < 0.001 for all). Etoricoxib patients experienced fewer clinical adverse experiences than patients on oxycodone/acetaminophen and codeine/acetaminophen, specifically, significantly (p < 0.05) fewer episodes of nausea. CONCLUSION: Etoricoxib 120 mg provided superior overall analgesic effect with a smaller percentage of patients experiencing nausea versus both oxycodone/acetaminophen 10 mg/650 mg and codeine/acetaminophen 60 mg/600 mg.
Acetaminophen↗
Onset of pain relief with rofecoxib in chronic low back pain: results of two four-week, randomized, placebo-controlled trials.
OBJECTIVE: We recently reported the efficacy of rofecoxib in two randomized controlled trials in chronic low back pain (CLBP). The objectives of this report are to present data regarding the onset of efficacy of rofecoxib from these trials and propose methods for reporting onset. RESEARCH DESIGN AND METHODS: Patients were aged 18-75, with non-radicular CLBP for >or= 3 months. Patients were randomized to rofecoxib 25mg, 50 mg, or placebo once daily for 4 weeks. Assessments included Low Back Pain and Bothersomeness scales every morning and Relief from Starting Pain after the first dose at 0.5, 1, 2, 3, 4 h, bedtime, and next morning. Onset of meaningful relief was measured by Time to Confirmed 50% Reduction in Pain and Time to Confirmed 'Slightly' or 'Not At All' Bothersome Pain. Onset of perceptible pain relief was measured by Time to At Least 'A Little' Confirmed Pain Relief. RESULTS: 690 patients entered. Significantly more patients treated with rofecoxib had compared with 1/3 receiving placebo. Median meaningful relief compared to placebo: 60.4, 58.4, and 34.7% for rofecoxib 25mg, 50 mg, and placebo (p< 0.001). Median time to meaningful relief for rofecoxib was 2 days, 1 day sooner than placebo. Rofecoxib was superior to placebo by bedtime after the first dose. CONCLUSIONS: Approximately 2/3 of patients achieved meaningful pain relief with rofecoxib time to onset of meaningful relief was about 2 days, but superior relief over placebo was seen by bedtime after the first dose. Onset of perceptible pain relief was within 2 h. We propose that measures of onset of analgesic effect include the proportion of patients who achieve meaningful pain relief and in this subgroup, the time-to-onset of confirmed meaningful reduction in pain intensity, time-to-onset of confirmed pain relief, and time to first separation from placebo in the proportion of patients who achieve meaningful pain relief.
Adolescent↗
Selective COX-2 inhibition and cardiovascular effects: a review of the rofecoxib development program.
See related Editorials on pages 561 and 563. Cyclo-oxygenase-2 (COX-2) inhibitors appear to alter the balance of vasoactive eicosanoids (prostacyclin and thromboxane) and to suppress the inflammatory mediators implicated in the progression of atherogenesis and ischemic myocardial injury. Neutral, harmful, and beneficial cardiovascular (CV) effects have all been postulated to result from these changes. Investigations conducted with rofecoxib, a selective COX-2 inhibitor, have substantially contributed to our understanding of this scientific area. Rofecoxib had little or no effect on platelet aggregation or platelet-derived thromboxane synthesis but reduced systemic prostacyclin synthesis by 50% to 60%. These findings prompted extensive analyses of CV thrombotic events within the rofecoxib development program. Among 5435 osteoarthritis trial participants, similar rates of CV thrombotic events were reported with rofecoxib, placebo, and comparator, nonselective NSAIDs (ibuprofen, diclofenac, and nabumetone). In the VIGOR gastrointestinal outcomes trial of >8000 patients, naproxen (an NSAID with aspirin-like sustained antiplatelet effects throughout its dosing interval) was associated with a significantly lower risk of CV events than was rofecoxib. A subsequent pooled analysis from 23 studies (including VIGOR) encompassing multiple disease states and including more than 14,000 patient-years at risk also demonstrated that rofecoxib was not associated with excess CV thrombotic events compared with either placebo or nonnaproxen NSAIDs. Again, naproxen appeared to be the outlier, suggesting a cardioprotective benefit of naproxen. Finally, among the predominantly elderly, male population participating in Alzheimer trials, both rofecoxib- and placebo-treated patients had similar rates of CV thrombotic events. The totality of data is not consistent with an increased CV risk among patients taking rofecoxib.
Alzheimer Disease↗
Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use.
BACKGROUND & AIMS: Epidemiologic studies suggest nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for lower gastrointestinal (GI) clinical events, but data from prospective trials are lacking. Cyclooxygenase (COX)-2-selective inhibitors decrease upper GI clinical events but the effect on lower GI events has not been determined. We performed a post hoc analysis of serious lower GI clinical events with a nonselective NSAID and a COX-2-selective agent in a prospective, double-blind, randomized GI outcomes trial. METHODS: A total of 8076 rheumatoid arthritis patients 50 years or older (or 40 years or older on corticosteroid therapy) expected to require NSAIDs for 1 year or greater were randomly assigned to naproxen 500 mg twice daily or rofecoxib 50 mg daily. The rate of serious lower GI clinical events, defined as bleeding with a 2 g/dL drop in hemoglobin or hospitalization, or hospitalization for perforation, obstruction, ulceration, or diverticulitis, was determined. RESULTS: The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (relative risk, 0.46; 95% confidence interval [CI], 0.22-0.93; P = 0.032). Serious lower GI events accounted for 39.4% of all serious GI events (complicated upper GI event or lower GI event) among patients taking naproxen and 42.7% among those taking rofecoxib. CONCLUSIONS: Serious lower GI events occurred at a rate of 0.9% per year in rheumatoid arthritis patients taking the nonselective NSAID naproxen, accounting for nearly 40% of the serious GI events that developed in these patients. Serious lower GI events were 54% lower with the use of the selective COX-2 inhibitor rofecoxib.
Adult↗
Cox-2 inhibitors and fracture healing: an argument against such an effect.
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Animals↗
Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis.
BACKGROUND & AIMS: Epidemiologic data indicate that the risk of nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) clinical events varies based on patients' clinical characteristics. The authors determined risk factors for NSAID-related clinical upper GI events and the event rates, absolute risk reductions, and numbers needed to treat for individual risk factors for a nonselective NSAID and a selective cyclooxygenase 2 inhibitor in a double-blind outcomes trial. METHODS: Eight thousand seventy-six rheumatoid arthritis patients aged >or=50 years (or >or=40 on corticosteroid therapy) were randomly assigned to rofecoxib 50 mg daily or naproxen 500 mg twice daily for a median of 9 months. The development of clinical upper GI events (bleeding, perforation, obstruction, and symptomatic ulcer identified on clinically indicated work-up) was assessed. RESULTS: Significant risk factors included prior upper GI events, age >or=65, and severe rheumatoid arthritis (RR, 2.3-3.9). Patients administered naproxen who had prior upper GI complications or who were aged >or=75 years had 18.84 or 14.46 events per 100 patient-years, and the risk of events remained constant over time. The reduction in events with rofecoxib was similar in high- and low-risk subgroups (RR, 0.31-0.68). The number needed to treat with rofecoxib instead of naproxen to avert 1 GI event was 10-12 in highest risk patients (prior event, age >or=75 years, or severe rheumatoid arthritis), 17-33 in patients with other risk factors, and 42-106 in low-risk patients. CONCLUSIONS: NSAID-related GI events increase dramatically with risk factors such as prior events or older age. Ten to twelve high-risk patients need to be treated with a protective strategy such as the selective cyclooxygenase 2 inhibitor, rofecoxib, to avert a clinical GI event.
Adrenal Cortex Hormones↗
A comparison of adverse renovascular experiences among osteoarthritis patients treated with rofecoxib and comparator non-selective non-steroidal anti-inflammatory agents.
BACKGROUND: Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclo-oxygenase (COX) isoenzymes, i.e. COX-1 and COX-2. Rofecoxib, an agent that selectively inhibits COX-2, has been shown to provide equivalent anti-inflammatory and analgesic efficacy to comparator non-selective NSAIDs in osteoarthritis (OA) and other pain models with a significant improvement in gastrointestinal (GI) safety and tolerability. Based on renal physiology studies, it was predicted that rofecoxib would have renovascular effects similar to those observed with non-selective NSAIDs--specifically edema, blood pressure elevation, attenuation of the effects of ACE inhibitors, and (in rare circumstances), acute renal failure might be manifest in a small percentage of patients. OBJECTIVE: To assess the renovascular safety profile of rofecoxib in OA patients compared to that of non-selective NSAID comparators. METHODS: Renovascular adverse experiences (AEs) in over 5,000 participants in Phase IIb/III OA clinical trials were reviewed and compared between rofecoxib and non-selective NSAID comparators (ibuprofen 800mg tid, diclofenac 50 mg tid, nabumetone 1,500 mg qd). RESULTS: The incidence of lower extremity edema (LEE) AEs was generally similar between rofecoxib 12.5 mg/day, rofecoxib 25 mg/day, and non-selective comparator NSAIDs. Treatment discontinuations due to LEE AEs and clinically significant weight gain (> or = 2 kg) associated with LEE AEs were infrequent and generally similar in all active treatment groups. Congestive heart failure (CHF) was rare in all treatment groups. The incidence of hypertension AEs was low in all active treatment groups. Discontinuations due to hypertension AEs and hypertension AEs requiring a change or adjustment in blood pressure medications were similar and uncommon in all treatment groups. There was only a single report of acute renal failure (in the ibuprofen treatment group). CONCLUSIONS: In the rofecoxib phase IIb/III OA database, the renal safety profile for rofecoxib, a selective inhibitor of COX-2, was generally similar to that of the comparator, non-selective NSAIDs which were studied.
Aged↗