OBJECTIVE: Current global guidelines regarding the first-line analgesics (acetaminophen, topical or oral non-steroidal anti-inflammatory drugs [NSAIDs]) for knee osteoarthritis remain controversial and their comparative risk-benefit profiles have yet to be adequately assessed.
DESIGN: Pubmed, Embase, Cochrane Library, and Web of Science were searched from database inception to March 2021 for randomized controlled trials (RCTs) comparing acetaminophen, topical NSAIDs and oral NSAIDs directly or indirectly in knee osteoarthritis. Bayesian network meta-analyses were conducted. A propensity-score matched cohort study was also conducted among patients with knee osteoarthritis in The Health Improvement Network database.
RESULTS: 122 RCTs (47,113 participants) were networked. Topical NSAIDs were superior to acetaminophen (standardized mean difference [SMD]=-0.29, 95% credible interval [CrI]: -0.52 to -0.06) and not statistically different from oral NSAIDs (SMD=0.03, 95% CrI: -0.16 to 0.22) for function. It had lower risk of gastrointestinal adverse effects (AEs) than acetaminophen (relative risk [RR]=0.52, 95%CrI: 0.35 to 0.76) and oral NSAIDs (RR=0.46, 95%CrI: 0.34 to 0.61) in RCTs. In real-world data, topical NSAIDs showed lower risks of all-cause mortality (hazard ratio [HR]=0.59, 95% confidence interval [CI]: 0.52 to 0.68), cardiovascular diseases (HR=0.73, 95%CI: 0.63 to 0.85) and gastrointestinal bleeding (HR=0.53, 95%CI: 0.41 to 0.69) than acetaminophen during the one-year follow-up (n=22,158 participants/group). A better safety profile was also observed for topical than oral NSAIDs (n=14,218 participants/group).
CONCLUSIONS: Topical NSAIDs are more effective than acetaminophen but not oral NSAIDs for function improvement in people with knee osteoarthritis. Topical NSAIDs are safer than acetaminophen or oral NSAIDs in trials and real-world data.
BACKGROUND: Pine bark (Pinus spp.) extract is rich in bioflavonoids, predominantly proanthocyanidins, which are antioxidants. Commercially-available extract supplements are marketed for preventing or treating various chronic conditions associated with oxidative stress. This is an update of a previously published review.
OBJECTIVES: To assess the efficacy and safety of pine bark extract supplements for treating chronic disorders.
SEARCH METHODS: We searched three databases and three trial registries; latest search: 30 September 2019. We contacted the manufacturers of pine bark extracts to identify additional studies and hand-searched bibliographies of included studies.
SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating pine bark extract supplements in adults or children with any chronic disorder.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility, extracted data and assessed risk of bias. Where possible, we pooled data in meta-analyses. We used GRADE to evaluate the certainty of evidence. Primary outcomes were participant- and investigator-reported clinical outcomes directly related to each disorder and all-cause mortality. We also assessed adverse events and biomarkers of oxidative stress.
MAIN RESULTS: This review included 27 RCTs (22 parallel and five cross-over designs; 1641 participants) evaluating pine bark extract supplements across 10 chronic disorders: asthma (two studies; 86 participants); attention deficit hyperactivity disorder (ADHD) (one study; 61 participants), cardiovascular disease (CVD) and risk factors (seven studies; 338 participants), chronic venous insufficiency (CVI) (two studies; 60 participants), diabetes mellitus (DM) (six studies; 339 participants), erectile dysfunction (three studies; 277 participants), female sexual dysfunction (one study; 83 participants), osteoarthritis (three studies; 293 participants), osteopenia (one study; 44 participants) and traumatic brain injury (one study; 60 participants). Two studies exclusively recruited children; the remainder recruited adults. Trials lasted between four weeks and six months. Placebo was the control in 24 studies. Overall risk of bias was low for four, high for one and unclear for 22 studies. In adults with asthma, we do not know whether pine bark extract increases change in forced expiratory volume in one second (FEV1) % predicted/forced vital capacity (FVC) (mean difference (MD) 7.70, 95% confidence interval (CI) 3.19 to 12.21; one study; 44 participants; very low-certainty evidence), increases change in FEV1 % predicted (MD 7.00, 95% CI 0.10 to 13.90; one study; 44 participants; very low-certainty evidence), improves asthma symptoms (risk ratio (RR) 1.85, 95% CI 1.32 to 2.58; one study; 60 participants; very low-certainty evidence) or increases the number of people able to stop using albuterol inhalers (RR 6.00, 95% CI 1.97 to 18.25; one study; 60 participants; very low-certainty evidence). In children with ADHD, we do not know whether pine bark extract decreases inattention and hyperactivity assessed by parent- and teacher-rating scales (narrative synthesis; one study; 57 participants; very low-certainty evidence) or increases the change in visual-motoric coordination and concentration (MD 3.37, 95% CI 2.41 to 4.33; one study; 57 participants; very low-certainty evidence). In participants with CVD, we do not know whether pine bark extract decreases diastolic blood pressure (MD -3.00 mm Hg, 95% CI -4.51 to -1.49; one study; 61 participants; very low-certainty evidence); increases HDL cholesterol (MD 0.05 mmol/L, 95% CI -0.01 to 0.11; one study; 61 participants; very low-certainty evidence) or decreases LDL cholesterol (MD -0.03 mmol/L, 95% CI -0.05 to 0.00; one study; 61 participants; very low-certainty evidence). In participants with CVI, we do not know whether pine bark extract decreases pain scores (MD -0.59, 95% CI -1.02 to -0.16; one study; 40 participants; very low-certainty evidence), increases the disappearance of pain (RR 25.0, 95% CI 1.58 to 395.48; one study; 40 participants; very low-certainty evidence) or increases physician-judged treatment efficacy (RR 4.75, 95% CI 1.97 to 11.48; 1 study; 40 participants; very low-certainty evidence). In type 2 DM, we do not know whether pine bark extract leads to a greater reduction in fasting blood glucose (MD 1.0 mmol/L, 95% CI 0.91 to 1.09; one study; 48 participants;very low-certainty evidence) or decreases HbA1c (MD -0.90 %, 95% CI -1.78 to -0.02; 1 study; 48 participants; very low-certainty evidence). In a mixed group of participants with type 1 and type 2 DM we do not know whether pine bark extract decreases HbA1c (MD -0.20 %, 95% CI -1.83 to 1.43; one study; 67 participants; very low-certainty evidence). In men with erectile dysfunction, we do not know whether pine bark extract supplements increase International Index of Erectile Function-5 scores (not pooled; two studies; 147 participants; very low-certainty evidence). In women with sexual dysfunction, we do not know whether pine bark extract increases satisfaction as measured by the Female Sexual Function Index (MD 5.10, 95% CI 3.49 to 6.71; one study; 75 participants; very low-certainty evidence) or leads to a greater reduction of pain scores (MD 4.30, 95% CI 2.69 to 5.91; one study; 75 participants; very low-certainty evidence). In adults with osteoarthritis of the knee, we do not know whether pine bark extract decreases composite Western Ontario and McMaster Universities Osteoarthritis Index scores (MD -730.00, 95% CI -1011.95 to -448.05; one study; 37 participants; very low-certainty evidence) or the use of non-steroidal anti-inflammatory medication (MD -18.30, 95% CI -25.14 to -11.46; one study; 35 participants; very low-certainty evidence). We do not know whether pine bark extract increases bone alkaline phosphatase in post-menopausal women with osteopenia (MD 1.16 ug/L, 95% CI -2.37 to 4.69; one study; 40 participants; very low-certainty evidence). In individuals with traumatic brain injury, we do not know whether pine bark extract decreases cognitive failure scores (MD -2.24, 95% CI -11.17 to 6.69; one study; 56 participants; very low-certainty evidence) or post-concussion symptoms (MD -0.76, 95% CI -5.39 to 3.87; one study; 56 participants; very low-certainty evidence). For most comparisons, studies did not report outcomes of hospital admissions or serious adverse events.
AUTHORS' CONCLUSIONS: Small sample sizes, limited numbers of RCTs per condition, variation in outcome measures, and poor reporting of the included RCTs mean no definitive conclusions regarding the efficacy or safety of pine bark extract supplements are possible.
OBJECTIVE: Despite an extensive body of research on NSAIDs in osteoarthritis, the duration of their efficacy and timeline of adverse event (AE) onset have been understudied. We conducted a systematic review and meta-analyses from 2 to 26 weeks to characterize the efficacy and AE trajectories of oral NSAIDs in knee osteoarthritis.
METHODS: We searched MEDLINE, EMBASE, Web of Science, Google Scholar, and the Cochrane Database from inception to May 2018. RCTs assessing the efficacy and/or safety of FDA-approved NSAIDs in knee osteoarthritis patients were included. Two independent reviewers assessed quality and extracted data. We calculated standardized mean differences and risk ratios with 95% confidence intervals.
RESULTS: We included 72 RCTs (26,424 participants). NSAIDs demonstrated moderate, statistically significant effects on pain that peaked at 2 weeks (SMD -0.43 [-0.48, -0.38]), but the magnitude of the effects decreased over time. The results for function were similar. The incidence of GI AEs was significantly higher in NSAID users than placebo users as early as 4 weeks (RR 1.38 [1.21, 1.57]). The incidence of CV AEs in NSAID users was not significantly different from placebo. Most GI and CV AEs were transient and of minor severity.
CONCLUSION: NSAIDs produced significant pain and function improvements that peaked at 2 weeks but decreased over time. The incidence of minor GI and CV AEs consistently rose, reaching significance as early as 4 weeks. Clinicians should weigh the durability of efficacy with the early onset of minor AEs along with patient tolerability and preferences when formulating an NSAID regimen. This article is protected by copyright. All rights reserved.
OBJECTIVE: Despite an extensive body of research on nonsteroidal antiinflammatory drugs (NSAIDs) in osteoarthritis, the duration of their efficacy and timeline of adverse event (AE) onset have been understudied. We conducted a systematic review and meta-analyses from 2 to 26 weeks to characterize the efficacy and AE trajectories of oral NSAIDs in knee osteoarthritis.METHODS: We searched MEDLINE, Embase, Web of Science, Google Scholar, and the Cochrane Database from inception to May 2018. Randomized controlled trials assessing the efficacy and/or safety of Federal Drug Administration-approved NSAIDs in knee osteoarthritis patients were included. Two independent reviewers assessed quality and extracted data. We calculated standardized mean differences (SMDs) and risk ratios (RRs) with 95% confidence intervals (95% CIs).RESULTS: We included 72 randomized controlled trials (26,424 participants). NSAIDs demonstrated moderate, statistically significant effects on pain that peaked at 2 weeks (SMD -0.43 [95% CI -0.48, -0.38]), but the magnitude of the effects decreased over time. The results for function were similar. The incidence of gastrointestinal (GI) AEs was significantly higher in NSAID users than placebo users as early as 4 weeks (RR 1.38 [95% CI 1.21, 1.57]). The incidence of cardiovascular (CV) AEs in NSAID users was not significantly different from placebo. Most GI and CV AEs were transient and of minor severity.CONCLUSION: NSAIDs produced significant pain and function improvements that peaked at 2 weeks but decreased over time. The incidence of minor GI and CV AEs consistently rose, reaching significance as early as 4 weeks. Clinicians should weigh the durability of efficacy with the early onset of minor AEs along with patient tolerability and preferences when formulating an NSAID regimen.
OBJECTIVES: To identify predictors of the specific (difference between treatment and placebo) and overall (change from baseline in treatment arm) treatment effects of topical NSAIDs in OA.
METHODS: Randomized controlled trials (RCTs) of topical NSAIDs in OA were identified through systematic literature searching and inquiry to pharmaceutical companies. The raw, de-identified data were analysed in one-stage individual patient data meta-analysis (IPD-MA). Negative values for treatment effects (0-100 scale) indicate pain reduction.
RESULTS: Of 63 eligible RCTs, 15 provided IPD (n = 1951 on topical NSAID), including 11 placebo-controlled RCTs (n = 1587 on topical NSAIDs, 1553 on placebo). Seven potential predictors of response were examined. Topical NSAIDs were superior to placebo [-6 (95% CI -9, -4)], with a small, but statistically significant greater effect in women than men [difference -4 (95% CI -8, -1)]. The overall treatment effect was 4-fold larger than the specific effect [-25 (95% CI -31, -19)] and increased with greater baseline pain severity (P < 0.001). No differences in efficacy were observed for age, BMI, features of inflammation, duration of complaints or radiographic OA severity.
CONCLUSION: Topical NSAIDs are effective for OA pain relief. Greater overall pain relief in individuals with more baseline pain might be due to contextual and non-specific effects, including regression to the mean. Additional factors that have been linked either mechanistically or through empirical evidence to outcomes should be selected for inclusion across future RCTs in order to facilitate the identification of response predictors through IPD-MA.
OBJECTIVES: To summarize all good quality randomized controlled trials (RCTs) using complementary and alternative medicine (CAM) interventions in patients with rheumatic diseases.
METHODS: A systematic literature review guided by the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) was performed. We excluded non-English language articles and abstract-only publications. Due to the large number of RCTs identified, we only include "good quality" RCTs with Jadad score of five.
RESULTS: We identified 60 good quality RCTs using CAM as intervention for patients with rheumatic diseases: acupuncture (9), Ayurvedic treatment (3), homeopathic treatment (3), electricity (2), natural products (31), megavitamin therapies (8), chiropractic or osteopathic manipulation (3), and energy healing therapy (1). The studies do not seem to suggest a particular type of CAM is effective for all types for rheumatic diseases. However, some CAM interventions appear to be more effective for certain types of rheumatic diseases. Acupuncture appears to be beneficial for osteoarthritis but not rheumatoid arthritis. For the other therapeutic modalities, the evidence base either contains too few trials or contains trials with contradictory findings which preclude any definitive summary. There were only minor adverse reactions observed for CAM interventions presented.
CONCLUSION: We identified 60 good quality RCTs which were heterogenous in terms of interventions, disease, measures used to assess outcomes, and efficacy of CAM interventions. Evidence indicates that some CAM therapies may be useful for rheumatic diseases, such as acupuncture for osteoarthritis. Further research with larger sample size is required for more conclusive evidence regarding efficacy of CAM interventions.
OBJECTIVE: To compare the efficacy of topical non-steroidal anti-inflammatory drugs (NSAIDs) with topical capsaicin for pain relief in osteoarthritis (OA).
DESIGN: A systematic literature search was conducted for randomised controlled trials (RCTs) examining any topical NSAID or capsaicin in OA. Pain relief at or nearest to four weeks was pooled using a random-effects network meta-analysis (NMA) in a Frequentist and Bayesian setting. Analysis was conducted for all trials and for trials using drugs listed as licenced for OA in the British National Formulary (BNF).
RESULTS: The trial network comprised 28 RCTs (7372 participants), of which 17 RCTs (3174 participants) were included in the as licensed analyses. No RCTs directly compared topical NSAIDs with capsaicin. Placebo was the only common comparator for topical NSAIDs and capsaicin. Frequentist and Bayesian effect size (ES) estimates were in agreement. Topical NSAIDs were statistically superior to placebo overall (ES 0.30, 95% confidence interval [CI] 0.19 to 0.41) and as licensed (ES 0.32, 95% CI 0.24 to 0.39). However, capsaicin was only statistically superior to placebo when used at licensed doses (ES 0.41, 95% CI 0.17 to 0.64). No significant differences were observed in pain relief between topical NSAIDs and capsaicin (overall: ES 0.04, 95% CI -0.26 to 0.33; as licensed: ES-0.09, 95% CI -0.34 to 0.16).
CONCLUSIONS: Current evidence indicates that topical NSAIDs and capsaicin in licensed doses may be equally effective for pain relief in OA. Whether the equivalence varies between individuals remains unknown.
BACKGROUND: Osteoarthritis (OA) is a disorder involving deterioration of articular cartilage and underlying bone and is associated with symptoms of pain and disability. Glucosamine is a component of articular cartilage naturally synthesized in the body from glucose and incorporated into substances contained in the cartilage. It has been suggested that consumption of glucosamine may reduce the pain of OA and may have favorable effects on structural changes in the cartilage. This article presents a systematic review and meta-analysis of the effectiveness of orally consumed glucosamine sulfate (GS) on OA-related pain and joint structural changes.
METHODS: PubMed and Ovid Embase were searched using specific search terms to find randomized, double-blinded, placebo-controlled trials on the effects of GS on pain and/or joint-space narrowing. The outcome measure was the standardized mean difference (SMD), which was the improvement in the placebo groups minus the improvement in the GS groups divided by the pooled standard deviation.
RESULTS: There were 17 studies meeting the review criteria for pain, and the summary SMD was -0.35, with a 95% confidence interval (95% CI) = -0.54 to -0.16 (negative SMD is in favor of GS). Of the 17 studies, 7 showed a statistically significant reduction in pain from GS use. Four studies met the review criteria for joint space narrowing with a summary SMD = -0.10 (95% CI = -0.23 to +0.04). Studies without involvement of the commercial glucosamine industry had a lower (but still significant) pain reduction efficacy (summary SMD = -0.19, 95% CI = -0.39 to -0.02) than those with industry involvement. Several smaller dosages throughout the day had larger pain reduction effects than a single daily large dose (1500 mg).
CONCLUSION: These data indicate that GS may have a small to moderate effect in reducing OA-related pain but little effect on joint-space narrowing. Until there is more definitive evidence, healthcare providers should be cautious in recommending use of GS to their patients. Because GS dosages used in studies to date resulted in mild and transient adverse effects, and these were similar to that experienced by patients receiving placebos, larger GS doses possibly could be investigated in future studies.
BACKGROUND: Osteoarthritis (OA) has a high prevalence in Western societies and can affect an individual's life in a number of domains, including work. In our experience, treatment trials on OA, however, rarely report work-related outcomes. Here we conducted a systematic review to assess the reporting of work-related outcomes in randomized, double blind, placebo-controlled trials in OA. Our systematic review also compared two search strategies for identifying eligible publications, one where work-related terms were included in the database search string (A) and one where this was not the case and work-related outcomes were identified by searches of full text Portable Document Formats (PDFs) (B). Search strategy A would conventionally be used and would only identify publications where work-related terms were mentioned in the title or abstract. Search strategy B presents the innovation of full text PDF searching and would identify publications were work-related terms were reported in the full text, regardless of whether they are mentioned in the title and abstract or not. We hypothesize that search strategy B identifies more relevant publications than search strategy A.
METHODS: Electronic database searching was performed in Medline (Pubmed) from database inception to February 23, 2017 to identify peer-reviewed articles of randomized, double blind, placebo-controlled treatment trials in OA of the hand, hip, or knee, available as full-text PDFs. For search strategy A, search terms to identify work-related outcomes were included in the database search string, while search strategy B did not have these terms included in the database search string, but instead involved full text PDF searching. We included English language articles only and only those articles where searchable PDFs were available, to enable a comparison between search strategies A and B. Additionally, included studies also needed to report on pain intensity in relation to the work-related outcomes.
RESULTS: Search strategy A yielded 50 hits combined for hand, hip or knee OA that mentioned some work-related concept in the title or abstract; 12 articles had to be excluded because they were not available as searchable PDFs. Screening of the remaining 38 articles resulted in only two articles that satisfied our inclusion criteria. Search strategy B yielded 986 hits, out of which 201 articles were excluded because searchable full text PDFs were not available. PDF full text searching and further screening resulted in 10 articles that were considered eligible for our review.
CONCLUSIONS: Work-related outcomes are rarely reported in journal publication on randomized, double blind, placebo-controlled trials of hand, hip or knee OA. Searching full text PDFs yields more eligible articles than searching titles and abstracts only.
