A discrete-choice experiment of United Kingdom patients' willingness to risk adverse events for improved function and pain control in osteoarthritis.

OBJECTIVE: To assess patient preferences for treatment-related benefits and risks associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the management of osteoarthritis (OA). DESIGN: Using a chronic-illness panel in the United Kingdom, patients 45 years or older with a self-reported diagnosis of OA were eligible to participate in the study. Patient preferences were assessed using a discrete-choice experiment that compared hypothetical treatment profiles of benefits and risks consistent with NSAID use. Benefit outcomes (ambulatory pain, resting pain, stiffness, and difficulty doing daily activities) were presented on a 0-to-100 mm scale. Risk outcomes (bleeding ulcer, stroke, and myocardial infarction [MI]) were expressed as probabilities over a fixed time period. Each patient answered 10 choice tasks comparing different treatment profiles. Preference weights were estimated using a random-parameters logit model. RESULTS: Final sample included 294 patients. Patients ranked reductions in ambulatory pain and difficulty doing daily activities (both: 6.32; 95% confidence interval [CI]: 5.0-7.6) as the most important benefit outcomes, followed by reductions in resting pain (2.80; 95% CI: 1.8-3.8) and stiffness (2.65; 95% CI: 0.9-4.4). Incremental changes (3%) in the risk of MI or stroke were assessed as the most important risk outcomes (10.00; 95% CI: 8.2-11.8; and 8.90; 95% CI: 7.3-10.5, respectively). CONCLUSION: Patients ranked ambulatory pain as a more important benefit than resting pain; likely due to its impact on ability to do daily activities. For a 25-mm reduction, patients were willing to accept four times the risk of MI in ambulatory pain vs resting pain.

Further assessment of the clinically effective dose range of etoricoxib: a randomized, double-blinded, placebo-controlled trial in rheumatoid arthritis.

OBJECTIVE: To further assess the clinically active dose range of etoricoxib, a COX-2 selective inhibitor, in rheumatoid arthritis (RA). METHODS: RA patients were randomized to etoricoxib 10, 30, 60, or 90 mg or placebo in a double-blind, 12-week study. DMARDs (methotrexate, biologics) or low-dose corticosteroids were allowed in stable doses. The primary endpoint was the proportion of patients completing the study and achieving an American College of Rheumatology 20% (ACR20) response. Secondary endpoints included individual components of the ACR index and Patient Global Assessment of Pain. Safety was assessed by physical exam and adverse experiences (AEs) occurrences. RESULTS: Etoricoxib 90 mg was the only dose to reach a statistically significant difference from placebo (p < 0.001) on the primary endpoint; etoricoxib 60 mg approached significance (p = 0.057). Significant pain improvement vs. placebo was observed with etoricoxib 90 mg (p < 0.001), 60 mg (p = 0.018), and 30 mg (p = 0.017). Despite the use of background biologics and corticosteroids, a dose response was still apparent. A higher proportion of etoricoxib 60 and 90 mg patients had renovascular AEs (i.e., edema and hypertension) compared with placebo, although discontinuations for renovascular AEs were rare. Etoricoxib 90 mg had a higher incidence of serious AEs (n = 5; 1 was considered drug-related) versus placebo (n = 0). LIMITATIONS: The present study was not powered to detect differences in cardiovascular or gastrointestinal safety by dose. Additionally, further research is needed to clarify the role of doses less than the etoricoxib 90 mg dose for pain management in RA patients. CONCLUSION: Etoricoxib 90 mg demonstrated statistically superior efficacy (ACR20) compared with placebo and numerical superiority over the other doses of etoricoxib studied. Etoricoxib 30 and 60 mg demonstrated significant pain improvement versus placebo, suggesting utility for some patients.

Safety issues in the development of treatments for osteoarthritis: recommendations of the Safety Considerations Working Group.

OBJECTIVE: The symptomatic treatment of osteoarthritis (OA) remains to be improved, as many patients do not respond well to current palliative therapies and/or suffer unacceptable adverse events. Given the unmet need for innovative, effective and well-tolerated therapies, it is important to develop the means to estimate the ongoing safety profile of novel therapeutic agents over short- and longer term use. DESIGN: Methods are presented to estimate the number of serious adverse events (SAEs) of interest considered as "acceptable" per 1000 patient-years exposure and to estimate the numbers of patient-years needed in a randomized controlled trial (RCT) to meet objectives. As exposure is increased, more evidence is accrued that the overall risk is within study limits. It is equally important that requirements for delineating the safety of promising new therapies not create barriers that would preclude their development. Therefore, ongoing surveillance of occurrence of SAEs of interest during clinical development is proposed, for example after every incremental 500 patient-years exposure are accrued. RESULTS: This paper and others in this special issue focus on identification of safety signals for symptomatic treatments of OA. Much less information is available for agents aimed at slowing/preventing structural progression but it is expected that a higher risk profile might be considered acceptable in the context of more promising benefit. CONCLUSION: This paper provides a proposal and supporting data for a comprehensive approach for assessing ongoing safety during clinical development of both palliative and disease-modifying therapies for OA.

Responder analysis for pain relief and numbers needed to treat in a meta-analysis of etoricoxib osteoarthritis trials: bridging a gap between clinical trials and clinical practice.

BACKGROUND: Population mean changes from clinical trials are difficult to apply to individuals in clinical practice. Responder analysis may be better, but needs validating for level of response and treatment duration. METHODS: The numbers of patients with pain relief over baseline (> or =15%, > or =30%, > or =50%, > or =70%) at 2, 4, 8 and 12 weeks of treatment were obtained using the WOMAC 100 mm visual analogue pain subscale score for each treatment group in seven randomised placebo-controlled trials of etoricoxib in osteoarthritis lasting > or =6 weeks. Dropouts were assigned 0% improvement from baseline from then on. The numbers needed to treat (NNTs) were calculated at each level of response and time point. RESULTS: 3554 patients were treated with placebo, etoricoxib 30 mg and 60 mg, celecoxib 200 mg, naproxen 1000 mg or ibuprofen 2400 mg daily. Response rates fell with increasing pain relief: 60-80% experienced minimally important pain relief (> or =15%), 50-60% moderate pain relief (> or =30%), 40-50% substantial pain relief (> or =50%) and 20-30% extensive pain relief (> or =70%). NNTs for etoricoxib, celecoxib and naproxen were stable over 2-12 weeks. Ibuprofen showed lessening of effectiveness with time. CONCLUSION: Responder rates and NNTs are reproducible for different levels of response over 12 weeks and have relevance for clinical practice at the individual patient level. An average 10 mm improvement in pain equates to almost one in two patients having substantial benefit.

Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial.

OBJECTIVE: The present study was a randomized, parallel, double-blind comparison between controlled-release (CR) tramadol and sustained-release (SR) diclofenac in patients with chronic pain due to osteoarthritis of the hips and/or knees. METHODS: Patients with at least moderate pain intensity, and having received analgesics over the past three months, underwent a two- to seven-day washout of current analgesics before initiation of 200 mg CR tramadol or 75 mg SR diclofenac. During the eight-week study, patients returned to the clinic biweekly. CR tramadol doses were titrated to a maximum of 200 mg, 300 mg or 400 mg per day. SR diclofenac doses were titrated to 75 mg or 100 mg once daily, or 75 mg twice a day based on pain relief and the presence of side effects. For rescue analgesic, patients took acetaminophen as needed, up to 650 mg three times a day. RESULTS: Forty-five patients on CR tramadol and 52 patients on SR diclofenac were evaluable. Significant improvements from prestudy treatment were shown for visual analogue scale pain (P=0.0001), stiffness (P<0.0005) and physical function (P=0.0001) scores for both treatments. There were no significant differences between the two treatments in the Western Ontario and McMaster Universities subscales, overall pain, pain and sleep, or the clinical effectiveness evaluation. Overall incidence of adverse events was similar in both groups, with more opioid-related adverse events with CR tramadol, and two serious adverse events occurring with the use of SR diclofenac. CONCLUSIONS: CR tramadol is as effective as SR diclofenac in the treatment of pain due to knee or hip osteoarthritis, with the potential for fewer of the serious side effects that characterize nonsteroidal anti-inflammatory drug administration.

Exercise for treating fibromyalgia syndrome.

BACKGROUND: Fibromyalgia (FMS) is a syndrome expressed by chronic widespread body pain which leads to reduced physical function and frequent use of health care services. Exercise training is commonly recommended as a treatment. This is an update of a review published in Issue 2, 2002. OBJECTIVES: The primary objective of this systematic review was to evaluate the effects of exercise training including cardiorespiratory (aerobic), muscle strengthening, and/or flexibility exercise on global well-being, selected signs and symptoms, and physical function in individuals with FMS. SEARCH STRATEGY: We searched MEDLINE, EMBASE, CINAHL, SportDiscus, PubMed, PEDro, and the Cochrane Central Register for Controlled Trials (CENTRAL, Issue 3, 2005) up to and including July 2005. We also reviewed reference lists from reviews and meta-analyses of treatment studies. SELECTION CRITERIA: Randomized trials focused on cardiorespiratory endurance, muscle strength and/or flexibility as treatment for FMS were selected. DATA COLLECTION AND ANALYSIS: Two of four reviewers independently extracted data for each study. All discrepancies were rechecked and consensus achieved by discussion. Methodological quality was assessed by two instruments: the van Tulder and the Jadad methodological quality criteria. We used the American College of Sport Medicine (ACSM) guidelines to evaluate whether interventions had provided a training stimulus that would effect changes in physical fitness. Due to significant clinical heterogeneity among the studies we were only able to meta-analyze six aerobic-only studies and two strength-only studies. MAIN RESULTS: There were a total of 2276 subjects across the 34 included studies; 1264 subjects were assigned to exercise interventions. The 34 studies comprised 47 interventions that included exercise. Effects of several disparate interventions on global well-being, selected signs and symptoms, and physical function in individuals with FMS were summarized using standardized mean differences (SMD). There is moderate quality evidence that aerobic-only exercise training at recommended intensity levels has positive effects global well-being (SMD 0.44, 95% confidence interval (CI 0.13 to 0.75) and physical function (SMD 0.68, 95% CI 0.41 to 0.95) and possibly on pain (SMD 0.94, 95% CI -0.15 to 2.03) and tender points (SMD 0.26, 95% CI -0.28 to 0.79). Strength and flexibility remain under-evaluated. AUTHORS' CONCLUSIONS: There is 'gold' level evidence (www.cochranemsk.org) that supervised aerobic exercise training has beneficial effects on physical capacity and FMS symptoms. Strength training may also have benefits on some FMS symptoms. Further studies on muscle strengthening and flexibility are needed. Research on the long-term benefit of exercise for FMS is needed.

Massage for mechanical neck disorders.

BACKGROUND: Mechanical neck disorders (MND) are common, disabling and costly. Massage is a commonly used modality for the treatment of neck pain. OBJECTIVES: To assess the effects of massage on pain, function, patient satisfaction and cost of care in adults with neck pain. To document adverse effects of treatment. SEARCH STRATEGY: Cochrane CENTRAL, MEDLINE, EMBASE, MANTIS, CINAHL, and ICL databases were electronically searched, without language restriction, from their inception to September 2004 SELECTION CRITERIA: Studies using random or quasi-random assignment were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently conducted citation identification, study selection, data abstraction and methodological quality assessment. Using a random-effects model, we calculated the relative risk and standardized mean difference. MAIN RESULTS: Nineteen trials met the inclusion criteria. Overall, the methodological quality was low, with 12/19 assessed as low-quality studies. Trials could not be statistically pooled because of heterogeneity in treatment and control groups. Therefore, a levels-of-evidence approach was used to synthesize results. Assessment of the clinical applicability of the trials showed that the participant characteristics were well reported, but neither the descriptions of the massage intervention nor the credentials or experience of the massage professionals were well reported. Six trials examined massage as a stand-alone treatment. The results were inconsistent. Of the 14 trials that used massage as part of a multimodal intervention, none were designed such that the relative contribution of massage could be ascertained. Therefore, the role of massage in multimodal treatments remains unclear. AUTHORS' CONCLUSIONS: No recommendations for practice can be made at this time because the effectiveness of massage for neck pain remains uncertain. Pilot studies are needed to characterize massage treatment (frequency, duration, number of sessions, and massage technique) and establish the optimal treatment to be used in subsequent larger trials that examine the effect of massage as either a stand-alone treatment or part of a multimodal intervention. For multimodal interventions, factorial designs are needed to determine the relative contribution of massage. Future reports of trials should improve reporting of the concealment of allocation, blinding of outcome assessor, adverse events and massage characteristics. Standards of reporting for massage interventions, similar to CONSORT, are needed. Both short- and long-term follow-up are needed.

Exercise for treating fibromyalgia syndrome.

BACKGROUND: Fibromyalgia (FMS) is a syndrome expressed by chronic widespread body pain which leads to reduced physical function and frequent use of health care services. Exercise training is commonly recommended as a treatment. OBJECTIVES: The objective of this systematic review was to examine the efficacy of exercise training as an treatment for FMS. SEARCH STRATEGY: We searched 6 electronic bibliographies for studies of exercise training in FMS: MEDLINE (1966-12/2000), CINAHL (1982-12/2000), HealthSTAR (1990-12/2000), Sports Discus (1975-05/2000), EMBASE (1974-05/2000) and the Cochrane Controlled Trials Register (2000, issue 4). We also reviewed the reference lists from identified articles including reviews and meta-analyses of treatment studies. SELECTION CRITERIA: Randomized trials focused on cardiorespiratory endurance, muscle strength and/or flexibility as treatment for FMS were selected. DATA COLLECTION AND ANALYSIS: Two reviewers independently identified trials meeting inclusion criteria, rated the methodologic quality using 2 standardized validated instruments, evaluated the adequacy of the exercise training stimulus using the American College of Sports Medicine (ACSM) criteria and evaluated the results. Disagreements were resolved through active discussion and consensus. High quality training studies had scores of 50% or greater on van Tulder methodologic criteria and met the minimum training standards of ACSM. Outcome variables were grouped into 7 constructs: pain, tender points, physical function, global well being, self efficacy, fatigue & sleep, and psychological function. Two reviewers independently extracted data on study characteristics, results and point estimates for selected variables, and used consensus to address discrepancies. MAIN RESULTS: Sixteen trials involving a total of 724 participants were assigned at random to: exercise intervention groups (n=379), control groups (n=277), or groups receiving an alternate treatment (n=68). Seven studies were high quality training studies: 4 aerobic training, 1 a mixture of aerobic, strength and flexibility training, 1 strength training and 2 with exercise training as part of a composite treatment. Flexibility protocols were never described in sufficient detail to allow evaluation. The four high quality aerobic training studies reported significantly greater improvements in the exercise groups versus control groups in aerobic performance (17.1% increase in aerobic performance with exercise versus 0.5% increase in the control groups), tender point pain pressure threshold (28.1% increase versus 7.0% decrease) and improvements in pain (11.4% decrease in pain versus 1.6% increase). Poor description of exercise protocols was common, with insufficient information on intensity, duration, frequency and mode of exercise. Adverse events were also poorly reported. REVIEWER'S CONCLUSIONS: Supervised aerobic exercise training has beneficial effects on physical capacity and FMS symptoms. Strength training may also have benefits on some FMS symptoms. Further studies on muscle strengthening and flexibility are needed. Research on the long-term benefit of exercise for FMS is needed.

The economic implications of cyclooxygenase-2-specific inhibitors.

Rheumatoid arthritis and osteoarthritis are prevalent and costly conditions. A large proportion of the direct costs associated with these conditions relates to management of iatrogenic side effects. The cyclooxygenase (COX)-2-specific inhibitors lead to equivalent control of pain and disability compared with traditional NSAIDs. However, the COX-2-specific inhibitors have significant potential to reduce health-care costs, principally through the reduction of side effects. These cost savings are most likely to be realized through reductions in costs associated with dyspepsia and upper gastrointestinal ulcers and bleeding. Reduced indirect costs through improved disability scores and improved health-related quality of life are also predictable with the use of COX-2-specific inhibitors. This is accomplished without the attendant increase in risk to the gastrointestinal tract associated with traditional NSAIDs.

An evidence-based approach to prescribing NSAIDs in the treatment of osteoarthritis and rheumatoid arthritis: The Second Canadian Consensus Conference.

The Second Canadian Consensus Conference was convened to discuss the latest developments in the management of osteoarthritis (OA) and rheumatoid arthritis (RA), and to make evidence-based recommendations, specifically regarding the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for these indications in primary care practice. The recent availability of cyclo-oxygenase-2-specific inhibitors has raised questions as to their role in the pharmacological management of OA and RA, particularly in relation to conventional treatments such as acetaminophen and nonspecific NSAIDs (with or without misoprostol or proton pump inhibitors). The recommendations in this document, which were arrived at through critical review of data from published randomized, clinical trials, deal with treatments of choice, information to discuss with patients, use of NSAIDs in patients at risk for serious upper gastrointestinal complications, renal or hepatic impairment or congestive heart failure, appropriate follow-up, and the use of NSAIDs with anti- hypertensives, warfarin, low dose acetylsalicylic acid and other medications. The goal of these recommendations is to improve patient outcomes in the primary care setting by maximizing treatment efficacy and minimizing rates of adverse events.

An evidence-based review of ACE inhibitors in incipient diabetic nephropathy.

Diabetic nephropathy develops in approximately 35% of diabetics and is the leading cause of end-stage renal disease in North America. End-stage renal disease is associated with increased morbidity and mortality, and a large economic burden. Treatments that can prevent or postpone diabetic nephropathy are important therapeutic advances. Interventional studies in type I diabetes and type II diabetes have demonstrated a beneficial effect of improved glycemic control and good blood pressure control in delaying the progression of diabetic nephropathy. Angiotensin-converting enzyme (ACE) inhibitors have been found to be effective in delaying the progression of diabetic nephropathy in hypertensive as well as normotensive diabetics with early and advanced nephropathy. Microalbuminuria or incipient diabetic nephropathy is the earliest clinical expression of diabetic nephropathy and identifies patients at risk of further progression. Advanced or overt nephropathy is associated with a greater risk for coronary artery disease and mortality. It is possible that interventions aimed earlier in the cascade at preventing the development of overt nephropathy may result in greater clinical benefit. There is compelling evidence of the benefit of ACE inhibitors in preventing the progression of incipient diabetic nephropathy to overt diabetic nephropathy in normotensive diabetics.

Double blind randomized placebo control trial of controlled release codeine in the treatment of osteoarthritis of the hip or knee.

OBJECTIVE: Pain is the cardinal feature of osteoarthritis (OA), and with advancing disease there is loss of function and increasing pain even at times of joint rest. Few studies have evaluated the role of opioid analgesics in treating the pain of OA. METHODS: This randomized, double blind, parallel group study compared the efficacy and safety of a 12 hourly controlled release codeine formulation (Codeine Contin) with placebo in patients with chronic pain due to OA of the hips and/or knees. The 4 week treatment period, following an analgesic washout phase of 2-7 days, included weekly clinic evaluations, at which the dose was escalated as appropriate, and daily patient diary completion. Pain (daily), stiffness, and physical function (weekly) were assessed using the multidimensional, self-administered WOMAC (visual analog scale version) questionnaire. RESULTS: Sixty-six eligible patients completed the study. The mean initial and final daily doses of controlled release codeine were 50 mg every 12 h at baseline and 159 mg every 12 h at the final assessment. All variables in the efficacy analysis indicated superiority of controlled release codeine over placebo. The WOMAC pain scale showed an improvement of 44.8% over baseline in the controlled release codeine group compared with 12.3% taking placebo (p = 0.0004). For the WOMAC stiffness and physical function scales the improvements over baseline on controlled release codeine were 47.7% and 49.3%, respectively compared with 17.0% and 17.0%, respectively, with placebo (p = 0.003; p = 0.0007). Controlled release codeine was also significantly better than placebo on measures of sleep quality and requirement for supplemental acetaminophen. CONCLUSION: Single entity controlled release codeine is an effective treatment for pain due to OA of the hip or knee.

Small-group format for continuing medical education: a report from the field.

BACKGROUND: For continuing medical education (CME) to be effective, several key features must be realized. These include a learner-directed agenda of topics, presentation of information by trusted peers or local experts, and opportunity for practice and feedback. If the information comes from several sources--printed materials, peer discussion, patient questions, and presentation from the specialist community--the perception of need for and the durability of change are enhanced. Finally, motivation for change must be high enough for change to occur, yet not overwhelming. METHOD: Facilitated small-group discussion among general practitioner colleagues with an expert specialist around clinic-based problems meets many of these requirements. When followed up by relevant literature, key concepts and practice changes are reinforced. RESULTS: We discuss our 3-year experience with the small-group format, comprising more than 25 sessions as either learners or facilitators. We describe the maturation of our group. We highlight the benefits to learners, including the relevance to clinical practice and the opportunity to ascertain the standard of care of peers. The benefits to the specialist are also discussed, including opportunities to learn which suggestions are difficult to implement. IMPLICATIONS: Our experience demonstrates that this format is sustainable over the long term. The success of the small-group format at improving CME and patient outcomes deserves further evaluation.

Two Less Common Causes of Headache in Systemic Lupus Erythematosus that May Require Specific Measures.

Headache is a frequent occurrence in patients with systemic lupus erythematosus (SLE). We present two cases of young women with headache and papilledema. One patient had this as a presenting manifestation of SLE, and the other had known active SLE. The first patient had a diagnosis of cerebral venous thrombosis, and the other pseudotumor cerebri. Both of these conditions are rare but have known associations with lupus. In the lupus patient with headache, it is essential that the clinician rule out these potentially treatable conditions by carefully taking a history and performing a physical examination as well as using ancillary investigations, including lumbar puncture, computed tomograph and magnetic resonance imaging as required. These uncommon causes of headache in the lupus patient must not be missed, because there is significant potential for morbidity, such as visual loss, or even mortality.