A Randomized, Double-Blind, Sham-Controlled, Clinical Trial of Auricular Vagus Nerve Stimulation for the Treatment of Active Rheumatoid Arthritis.

OBJECTIVE: Preliminary evidence suggests that vagus nerve stimulation (VNS) may have some benefit in patients with rheumatoid arthritis (RA); however, prior studies have been small and/or uncontrolled; this study aimed to address that gap. METHODS: This randomized, double-blind, sham-controlled trial enrolled patients aged 18 to 75 years with active RA who had failed conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and were naïve to biologic and/or targeted synthetic DMARDs. All patients received an auricular vagus nerve stimulator and were randomized 1:1 to active stimulation or sham. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Secondary endpoints included mean changes in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI). RESULTS: A total of 113 patients (mean age 54 years; 82% female) enrolled, and 101 patients (89.4%) completed week 12. ACR20 response at week 12 was 25.0% for active stimulation versus 26.9% for sham (difference vs. sham, -1.9; 95% CI, -18.8, 14.9, P = 0.823). The least square mean ± SE change in DAS28-CRP was -0.95 ± 0.16 for active stimulation and -0.66 ± 0.16 for sham (P = 0.201); in HAQ-DI it was -0.19 ± 0.06 for active stimulation and -0.02 ± 0.06 for sham (P = 0.044). Adverse events occurred in 17 patients (15%); all were mild or moderate. CONCLUSION: Auricular VNS did not meaningfully improve RA disease activity. If VNS with other modalities is pursued in the future for the treatment of RA, larger, controlled studies will be needed to understand its utility.

Oral extended-release oxymorphone: a new choice for chronic pain relief.

Opana ER (oxymorphone extended release [ER]) is a new oral long-acting formulation indicated for the treatment of moderate to severe chronic pain. Because the ER matrix slowly releases oxymorphone over 12 h, consistent plasma levels are produced with low peak-to-trough fluctuations. Oxymorphone ER is the only long-acting opioid that contains oxymorphone, which exhibits some distinct pharmacologic properties compared with most other opioids, including a longer half-life, higher affinity for the micro-opioid receptor, and lack of interaction with the CYPP450 drug-metabolizing system. With a safety and tolerability profile similar to other opioids and documented efficacy in several models of chronic pain (low back, cancer, and osteoarthritis), oxymorphone ER provides a new option for clinicians and patients in the treatment of chronic pain.

Oxymorphone extended-release tablets relieve moderate to severe pain and improve physical function in osteoarthritis: results of a randomized, double-blind, placebo- and active-controlled phase III trial.

OBJECTIVE: To compare oxymorphone extended release (ER) and placebo on indices of pain, function, and safety in patients with chronic osteoarthritis (OA) pain. DESIGN: In this multicenter, double-blind, placebo- and active-controlled, parallel-group, dose-ranging study, patients were randomized to oxymorphone ER 20 mg (N = 121), oxymorphone ER 40 mg (N = 121), oxycodone controlled release 20 mg (N = 125), or placebo (N = 124) every 12 hours. The primary efficacy end point was change in arthritis pain intensity (visual analog scale, 0-100) from baseline to week 3 for the oxymorphone ER 40 mg group versus placebo. RESULTS: The primary end point was achieved: the week 3 oxymorphone ER least squares mean difference (LSMD) from placebo was -9.0 (95% confidence interval [CI]: -16.2 to -1.8; P = 0.015). Secondary efficacy analysis showed similar improvements at week 4 (LSMD from placebo, -10.3 [95% CI: -17.7 to -2.8]; P = 0.007) and with oxymorphone ER 20 mg at week 3 (LSMD from placebo, -7.7 [95% CI: -15.0 to -0.4]; P = 0.039) and week 4 (LSMD from placebo, -7.5 [95% CI: -15.0 to 0.0]; P = 0.050). Weeks 3 and 4 pain intensity decreased by approximately 30-40%. Oxymorphone ER 20 and 40 mg improved from baseline on the Western Ontario and McMaster Universities Osteoarthritis Composite Index and pain and physical function subscales at week 4. Adverse events in all opioid groups included mild to moderate nausea, constipation, and somnolence. CONCLUSIONS: In this short-term study, oxymorphone ER was superior to placebo for relieving pain and improving function in patients with moderate to severe chronic OA pain, and is an alternative to other sustained-release opioids.

Pain management in osteoarthritis: a focus on onset of efficacy--a comparison of rofecoxib, celecoxib, acetaminophen, and nabumetone across four clinical trials.

UNLABELLED: We compared onset of efficacy (during days 1 to 6) of 2 coxibs (rofecoxib, celecoxib) with acetaminophen and nabumetone by using a prespecified approach to data from 4 similarly designed 6-week randomized osteoarthritis trials. In 2 trials, rofecoxib (12.5 mg and 25 mg once daily) was compared with celecoxib (200 mg once daily) and acetaminophen (4000 mg daily). In the other 2 trials, rofecoxib (12.5 mg) was compared with nabumetone (1000 mg once daily) and placebo. Efficacy end points included Patient Global Response to Therapy and Western Ontario and McMaster Osteoarthritis Index scores. Rofecoxib (12.5- and 25-mg doses) consistently demonstrated a faster onset of osteoarthritis (OA) efficacy than the comparator drugs during the first 6 days of therapy of OA patients experiencing "flare." Acetaminophen resulted in the slowest onset of efficacy. There was a strong correlation (0.7) between efficacy response during days 1 to 6 and that averaged over 6 weeks. Rates of discontinuation as a result of lack of efficacy were significantly lower (P < .02) for each of the coxib-treated groups compared with acetaminophen and for rofecoxib 12.5 mg (P = .01) compared with nabumetone. Rofecoxib treatment, with its faster onset of OA efficacy and lower rates of related discontinuations, might provide efficacy advantages in the treatment of OA pain. PERSPECTIVE: The efficacy of rofecoxib, celecoxib, nabumetone, and acetaminophen is established for the majority of OA patients within the first 6 days of therapy, and this predicts efficacy during the longer term. Rofecoxib provides significantly faster time to onset of efficacy and better improvement on multiple measures versus the comparators.

Etoricoxib.

Etoricoxib (Arcoxia, Merck & Co., Inc.) is a selective inhibitor of cyclooxygenase-2 (COX-2), an enzyme involved in pain and inflammation. It is a member of the COX-2-selective (coxib) class of nonsteroidal antiinflammatory drugs (NSAIDs). Extensive clinical trials have confirmed its analgesic and antiinflammatory efficacy to be at least as good as and in some cases superior to nonselective NSAIDs in a number of disease and patient treatment settings. Etoricoxib displays improved gastrointestinal safety compared with nonselective NSAIDs and has a favorable overall safety and tolerability profile. It is rapidly and completely absorbed following oral administration providing a rapid onset of action. Its long plasma half-life allows for once-daily dosing. Etoricoxib is currently approved in a number of countries for various indications including the treatment of acute pain, acute gouty arthritis, chronic low back pain, primary dysmenorrhea, and chronic treatment for the signs and symptoms of osteoarthritis and rheumatoid arthritis. In countries where it is approved, the highest recommended daily dose for chronic use is 90 mg for rheumatoid arthritis and 60 mg for osteoarthritis and chronic low back pain. The recommended daily dose for acute pain relief treatment from primary dysmenorrhea and acute gouty arthritis is 120 mg. This review summarizes the published preclinical and clinical data relevant to the use of etoricoxib in clinical practice.

Efficacy and safety of rofecoxib 12.5 mg versus nabumetone 1,000 mg in patients with osteoarthritis of the knee: a randomized controlled trial.

OBJECTIVES: To evaluate the use of starting doses of rofecoxib and nabumetone in patients with osteoarthritis (OA) of the knee. DESIGN: A 6-week, randomized, parallel-group, double-blind, placebo-controlled study. SETTING: One hundred thirteen outpatient sites in the United States. PARTICIPANTS: A total of 1,042 male and female patients aged 40 and older with OA of the knee (>6 months). INTERVENTIONS: Rofecoxib 12.5 mg once a day (n=424), nabumetone 1,000 mg once a day (n=410), or placebo (n=208) for 6 weeks. MEASUREMENTS: The primary efficacy endpoint was patient global assessment of response to therapy (PGART) over 6 weeks, which was also specifically evaluated over the first 6 days. The main safety measure was adverse events during the 6 weeks of treatment. RESULTS: The percentage of patients with a good or excellent response to therapy as assessed using PGART at Week 6 was significantly higher with rofecoxib (55.4%) than nabumetone (47.5%; P=.018) or placebo (26.7%; P<.001 vs rofecoxib or nabumetone). Median time to first report of a good or excellent PGART response was significantly shorter in patients treated with rofecoxib (2 days) than with nabumetone (4 days, P=.002) and placebo (>5 days, P<.001) (nabumetone vs placebo; P=.007). The safety profiles of rofecoxib and nabumetone were generally similar, including gastrointestinal, hypertensive, and renal adverse events. CONCLUSION: Rofecoxib 12.5 mg daily demonstrated better efficacy over 6 weeks of treatment and quicker onset of OA efficacy over the first 6 days than nabumetone 1,000 mg daily. Both therapies were generally well tolerated.

Spirituality, well-being, and quality of life in people with rheumatoid arthritis.

OBJECTIVE: To evaluate spirituality, well-being, and quality of life (QOL) among people with rheumatoid arthritis (RA). METHODS: Questionnaires assessing positive and negative affect, depression, QOL and spirituality were completed. Disease activity was assessed by rheumatologic examination. RESULTS: Women (n = 62) had a mean (+/- SD) age of 53.0 (+/- 13.0) years with 12 (+/- 13) swollen and tender joints (STJ). Men (n = 15) were 61.9 (+/- 13.0) years with 7 (+/- 11) STJ. Disease activity was associated (P < 0.05) positively with depression (r = 0.23), pain (r = 0.26), poorer self-ratings of health (r = 0.29) and physical role limitations (r = 0.26). Spirituality was associated directly with positive affect (r = 0.26) and higher health perceptions (r = 0.29). In multiple regression, spirituality was an independent predictor of happiness and positive health perceptions, even after controlling disease activity and physical functioning, for age and mood. CONCLUSION: Spirituality may facilitate emotional adjustment and resilience in people with RA by experiencing more positive feelings and attending to positive elements of their lives.

A randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy and tolerability of the highly selective cyclooxygenase-2 (COX-2) inhibitor etoricoxib for the treatment of rheumatoid arthritis (RA). METHODS: A double blind, randomized, placebo and active comparator controlled, 12 week study conducted at 88 US sites. Eligible patients were chronic nonsteroidal antiinflammatory drug (NSAID) users with clinical worsening of RA upon withdrawal of prestudy NSAID. Patients received either placebo, etoricoxib 90 mg once daily, or naproxen 500 mg twice daily (2:2:1 allocation ratio). Primary efficacy measures: patient and investigator global assessments of disease activity and direct assessment of arthritis by counts of tender and swollen joints. Key secondary measures: patient global assessment of pain, the Stanford Health Assessment Questionnaire, and the percentage of patients both completing the study and meeting the ACR20 criteria. Tolerability was assessed by tabulation of adverse events and routine laboratory evaluations. RESULTS: In all, 816 patients were randomized (placebo = 323, etoricoxib = 323, naproxen = 170), and 448 completed 12 weeks of treatment (placebo = 122, etoricoxib = 230, naproxen = 96). Compared with patients receiving placebo, patients receiving etoricoxib and naproxen showed significant improvements in all efficacy endpoints (p < 0.01). Compared with patients receiving naproxen, patients receiving etoricoxib demonstrated significant improvements (p < 0.05) on all primary endpoints and most other endpoints including ACR20 criteria. The percentage of patients who achieved an ACR20 response and who completed the study was 21%, 53%, and 39% in the placebo, etoricoxib and naproxen groups, respectively. Etoricoxib and naproxen were both generally well tolerated. CONCLUSION: In this study, etoricoxib 90 mg once daily was more effective than either placebo or naproxen 500 mg twice daily for treating patients with RA over 12 weeks. Etoricoxib 90 mg was generally well tolerated in patients with RA.