Can Medical Cannabis Therapies be Cost-Effective in the Non-Surgical Management of Chronic Knee Pain?

INTRODUCTION: Chronic knee pain is a common musculoskeletal condition, which usually leads to decreased quality of life and a substantial financial burden. Various non-surgical treatments have been developed to relieve pain, restore function and delay surgical intervention. Research on the benefits of medical cannabis (MC) is emerging supporting its use for chronic pain conditions. The purpose of this study was to evaluate the cost-effectiveness of MC compared to current non-surgical therapies for chronic knee pain conditions. METHODS: We conducted a cost-utility analysis from a Canadian, single payer perspective and compared various MC therapies (oils, soft gels and dried flowers at different daily doses) to bracing, glucosamine, pharmaceutical-grade chondroitin oral non-steroidal anti-inflammatory drugs (NSAIDs), and opioids. We estimated the quality-adjusted life years (QALYs) gained with each treatment over 1 year and calculated incremental cost-utility ratios (ICURs) using both the mean and median estimates for costs and utilities gained across the range of reported values. The final ICURs were compared to willingness-to-pay (WTP) thresholds of $66 714, $133 428 and $200 141 Canadian dollars (CAD) per QALY gained. RESULTS: Regardless of the estimates used (mean or median), both MC oils and soft gels at both the minimal and maximal recommended daily doses were cost-effective compared to all current knee pain therapies at the lowest WTP threshold. Dried flowers were only cost-effective up to a certain dosage (0.75 and 1 g/day based on mean and median estimates, respectively), but all dosages were cost-effective when the WTP was increased to $133 428/QALY gained. CONCLUSION: Our study showed that MC may be a cost-effective strategy in the management of chronic knee pain; however, the evidence on the medical use of cannabis is limited and predominantly low-quality. Additional trials on MC are definitely needed, specifically in patients with chronic knee pain.

Direct comparative effectiveness and safety between non-vitamin K antagonist oral anticoagulants for stroke prevention in nonvalvular atrial fibrillation: a systematic review and meta-analysis of observational studies.

The non-vitamin K antagonist oral anticoagulants (NOACs) have been increasingly prescribed in clinical practice for stroke prevention in patients with nonvalvular atrial fibrillation (AF). Direct comparisons between NOACs in trials are lacking, leaving an important clinical decision-making gap. We aimed to perform a systematic review and meta-analysis to summarize the evidence of observational studies for direct comparative effectiveness and safety amongst NOACs in patients with AF. Conference proceedings and electronic databases including MEDLINE, CINAHL, EMBASE and PUBMED were systematically searched. We included observational studies directly comparing individual NOACs in patients with nonvalvular AF who were aged ≥ 18 years for stroke prevention. Primary outcome included effectiveness outcome (stroke or systemic embolism) and safety outcome (major bleeding). Data were extracted in duplicated by two reviewers independently. A random-effects meta-analysis was conducted to synthesize the data from included observational studies. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to rate the overall quality of evidence for each outcome. Fifteen studies were included for qualitative synthesis, twelve studies for meta-analyses. It was found that rivaroxaban and dabigatran were similar with regard to risk of stroke or systemic embolism (Hazard ratio [HR] = 1.00, 95% CI 0.91-1.10; evidence quality: low), but rivaroxaban was associated with higher risk of major bleeding (HR = 1.39, 95% CI 1.28-1.50; evidence quality: moderate). Compared with apixaban, a significantly higher risk of major bleeding was observed with rivaroxaban (HR = 1.71, 95% CI 1.51-1.94; evidence quality: low). Apixaban was associated with lower risk of major bleeding, in comparison with dabigatran (HR = 0.80, 95% CI 0.68-0.95; evidence quality: low). No differences in risk of stroke or systemic embolism was observed between rivaroxaban versus apixaban, and apixaban versus dabigatran. In this study, apixaban was found to have the most favorable safety profile amongst the three NOACs. No significant difference was observed in risk of stroke or systemic embolism between the NOACs. Such findings may provide some decision-making support for physicians regarding their choices amongst NOACs in patients with AF.Registration PROSPERO (identifier: CRD42016052908).

Knee arthroscopy versus conservative management in patients with degenerative knee disease: a systematic review.

OBJECTIVE: To determine the effects and complications of arthroscopic surgery compared with conservative management strategies in patients with degenerative knee disease. DESIGN: Systematic review. MAIN OUTCOME MEASURES: Pain, function, adverse events. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Google Scholar and Open Grey up to August 2016. ELIGIBILITY CRITERIA: For effects, randomised clinical trials (RCTs) comparing arthroscopic surgery with a conservative management strategy (including sham surgery) in patients with degenerative knee disease. For complications, RCTs and observational studies. REVIEW METHODS: Two reviewers independently extracted data and assessed risk of bias for patient-important outcomes. A parallel guideline committee (BMJ Rapid Recommendations) provided input on the design and interpretation of the systematic review, including selection of patient-important outcomes. We used the GRADE approach to rate the certainty (quality) of the evidence. RESULTS: We included 13 RCTs and 12 observational studies. With respect to pain, the review identified high-certainty evidence that knee arthroscopy results in a very small reduction in pain up to 3 months (mean difference =5.4 on a 100-point scale, 95% CI 2.0 to 8.8) and very small or no pain reduction up to 2 years (mean difference =3.1, 95% CI -0.2 to 6.4) when compared with conservative management. With respect to function, the review identified moderate-certainty evidence that knee arthroscopy results in a very small improvement in the short term (mean difference =4.9 on a 100-point scale, 95% CI 1.5 to 8.4) and very small or no improved function up to 2 years (mean difference =3.2, 95% CI -0.5 to 6.8). Alternative presentations of magnitude of effect, and associated sensitivity analyses, were consistent with the findings of the primary analysis. Low-quality evidence suggested a very low probability of serious complications after knee arthroscopy. CONCLUSIONS: Over the long term, patients who undergo knee arthroscopy versus those who receive conservative management strategies do not have important benefits in pain or function. TRIAL REGISTRATION NUMBER: PROSPERO CRD42016046242.

Activation of RAW264.7 mouse macrophage cells in vitro through treatment with recombinant ricin toxin-binding subunit B: involvement of protein tyrosine, NF-κB and JAK-STAT kinase signaling pathways.

Ricin toxin-binding subunit B (RTB) is a galactose-binding lectin protein. In the present study, we investigated the effects of RTB on inducible nitric oxide (NO) synthase (iNOS), interleukin (IL)-6 and tumor necrosis factor (TNF)-α, as well as the signal transduction mechanisms involved in recombinant RTB-induced macrophage activation. RAW264.7 macrophages were treated with RTB. The results revealed that the mRNA and protein expression of iNOS was increased in the recombinant RTB-treated macrophages. TNF-α production was observed to peak at 20 h, whereas the production of IL-6 peaked at 24 h. In another set of cultures, the cells were co-incubated with RTB and the tyrosine kinase inhibitor, genistein, the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, the p42/44 inhibitor, PD98059, the p38 inhibitor, SB203580, the JNK inhibitor, SP600125, the protein kinase C (PKC) inhibitor, staurosporine, the JAK2 inhibitor, tyrphostin (AG490), or the NOS inhibitor, L-NMMA. The recombinant RTB-induced production of NO, TNF-α and IL-6 was inhibited in the macrophages treated with the pharmacological inhibitors genistein, LY294002, staurosporine, AG490, SB203580 and BAY 11-7082, indicating the possible involvement of protein tyrosine kinases, PI3K, PKC, JAK2, p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB in the above processes. A phosphoprotein analysis identified tyrosine phosphorylation targets that were uniquely induced by recombinant RTB and inhibited following treatment with genistein; some of these proteins are associated with the downstream cascades of activated JAK-STAT and NF-κB receptors. Our data may help to identify the most important target molecules for the development of novel drug therapies.