Assessment of Clinical Outcomes in Patients With Osteoarthritis: Analysis From the UK Medical Cannabis Registry.

Osteoarthritis accounts for 0.6% of disability-adjusted life years globally. There is a paucity of research focused on cannabis-based medicinal products (CBMPs) for osteoarthritic chronic pain management. This study aims to assess changes in validated patient-reported outcome measures (PROMs) and CBMP clinical safety in patients with osteoarthritis. A prospective case series from the UK Medical Cannabis Registry was analyzed. Primary outcomes were changes in the Brief Pain Inventory (BPI), McGill Pain Questionnaire (MPQ2), EQ-5D-5L, Generalized Anxiety Disorder-7 (GAD-7) questionnaire, and Single-Item Sleep Quality Scale (SQS) at 1-, 3-, 6-, and 12-month follow-ups from baseline. Common Terminology Criteria for Adverse Events v.4.0 was used for adverse event (AE) analysis. Statistical significance was defined as p < 0.050. Seventy-seven patients met inclusion criteria. CBMP initiation correlated with BPI pain severity (p = 0.004), pain interference (p = 0.005), and MPQ2 (p = 0.017) improvements at all follow-ups compared to baseline. There were improvements in the EQ-5D-5L index (p = 0.026), SQS (p < 0.001), and GAD-7 (p = 0.038) up to 6 and 3 months, respectively. Seventeen participants (22.08%) recorded 76 mild AEs (34.86%), 104 moderate AEs (47.71%), and 38 severe AEs (17.43%). Though causality cannot be assumed in this observational study, results support development of randomized control trials for osteoarthritis pain management with CBMPs.

Patterns of Comorbidities and Prescribing and Dispensing of Non-steroidal Anti-inflammatory Drugs (NSAIDs) Among Patients with Osteoarthritis in the USA: Real-World Study.

BACKGROUND: Osteoarthritis (OA) is a major cause of chronic pain. Non-steroidal anti-inflammatory drugs (NSAIDs) are analgesics commonly used for musculoskeletal pain; however, NSAIDs can increase the risk of certain adverse events, such as gastrointestinal bleeding, edema, heart failure, and hypertension. OBJECTIVE: The objective of this study was to characterize existing comorbidities among patients with OA. For patients with OA with and without a coexisting medical condition of interest (CMCOI), we estimated the prevalence of prescribing and dispensing NSAIDs pre-OA and post-OA diagnosis. METHODS: Data from three large administrative claims databases were used to construct an OA retrospective cohort. Databases leveraged were IBM MarketScan Medicare Supplemental Database (MDCR), IBM MarketScan Commercial Database (CCAE), and Optum's de-identified Clinformatics® Data Mart Database (Optum CDM). The OA study population was defined to be those patients who had an OA diagnosis from an inpatient or outpatient visit with at least 365 days of prior observation time in the database during January 2000 through May 2021. Asthma, cardiovascular disorders, renal impairment, and gastrointestinal bleeding risks were the CMCOI of interest. Patients with OA were then classified as having or not having evidence of a CMCOI. For both groups, NSAID dispensing patterns pre-OA and post-OA diagnosis were identified. Descriptive analysis was performed within the Observational Health Data Sciences and Informatics framework. RESULTS: In each database, the proportion of the OA population with at least one CMCOI was nearly 50% or more (48.0% CCAE; 74.4% MDCR; 68.6% Optum CDM). Cardiovascular disease was the most commonly observed CMCOI in each database, and in two databases, nearly one in four patients with OA had two or more CMCOI (23.2% MDCR; 22.6% Optum CDM). Among the OA population with CMCOI, NSAID utilization post-OA diagnosis ranged from 33.0 to 46.2%. Following diagnosis of OA, an increase in the prescribing and dispensing of NSAIDs was observed in all databases, regardless of patient CMCOI presence. CONCLUSIONS: This study provides real-world evidence of the pattern of prescribing and dispensing of NSAIDs among patients with OA with and without CMCOI, which indicates that at least half of patients with OA in the USA have a coexisting condition. These conditions may increase the risk of side effects commonly associated with NSAIDs. Yet, at least 32% of these patients were prescribed and dispensed NSAIDs. These data support the importance of shared decision making between healthcare professionals and patients when considering NSAIDs for the treatment of OA in patients with NSAID-relevant coexisting medical conditions.

[Clinical comprehensive evaluation of Ruyi Zhenbao Pills in treatment of osteoarthritis].

This study evaluated the clinical effectiveness of Ruyi Zhenbao Pills in the treatment of osteoarthritis, aiming to clarify its clinical advantages and promote rational drug use and related policy transformation. Following the relevant standards in Guidelines for the Comprehensive Evaluation of Drugs in Clinical Practice and Technical Specifications for the Clinical Comprehensive Evaluation of Chinese Patent Medicine, comprehensive research and related data on Ruyi Zhenbao Pills in the treatment of osteoarthritis were collected in the dimensions of safety, effectiveness, economy, innovation, suitability, accessibility, and traditional Chinese medicine(TCM) cha-racteristics(referred to as the "6+1" dimensions). Through evidence-based medicine, questionnaire surveys, health technology assessment, pharmacoeconomic evaluation, and other methods, a multi-criteria decision analysis(MCDA) model and CSC v2.0 software were used to comprehensively evaluate the clinical value of Ruyi Zhenbao Pills. Spontaneous reporting system data on adverse reactions and literature data indicate that the adverse reactions of Ruyi Zhenbao Pills are mostly general adverse reactions, with no reports of se-rious adverse reactions. The known risks are small, and its safety is rated as class A. It has been shown to effectively relieve joint pain and restore joint function in the treatment of osteoarthritis. However, more high-quality, large-sample randomized controlled trials are needed to further validate its effectiveness, which is rated as class B. There is evidence supporting its economic viability, and its economic is rated as class B. It demonstrates good clinical innovation, innovative enterprise service system, and industrial innovation, and innovation is rated as class A. Medical professionals and patients have a favorable perception of the suitability of Ruyi Zhenbao Pills, and further improvement can be made in terms of convenience of administration and promotion to facilitate rational drug use by healthcare professionals and patients. Suitability is rated as class B. The drug has a favorable price level, availability, and affordability, and accessibility is rated as class A. Ruyi Zhenbao Pills are a classic Tibetan medicinal prescription with excellent TCM theoretical characteristics. However, further research is needed on its use in human studies. TCM characteristics are rated as class B. Based on the evaluation results of the "6+1" dimensions, the comprehensive clinical evaluation is rated as grade B. Ruyi Zhenbao Pills have good clinical value in the treatment of osteoarthritis, and it is recommended to undergo the necessary procedures for conditional transformation into a policy for the management of essential clinical drugs.

Prescription opioid utilization patterns, and associated outcomes, among privately insured patients prescribed opioids to manage pain associated with osteoarthritis.

OBJECTIVE: To describe utilization patterns, negative clinical outcomes and economic burden of patients diagnosed with osteoarthritis (OA) of the hip and/or knee who received a prescription for tramadol or non-tramadol opioids vs. non-opioid drugs. METHODS: Optum Healthcare Solutions, Inc. commercial claims data were used (1/2012--3/2017). Adults with ≥2 diagnoses of OA of the hip and/or knee, and ≥30 days supply of pain medications were identified during the three-year period from the date of first prescription (index date) after the first OA diagnosis. Drug utilization statistics in the follow-up period were summarized by initial treatment (i.e. tramadol, non-tramadol opioids, non-opioid drugs). Opioid initiators were matched to those initiated on non-opioid treatments using a propensity score model accounting for baseline characteristics. Matched pairs analysis compared outcomes for these cohorts. RESULTS: Of 62,715 total patients, 15,270 (24.3%) initiated treatment with opioids, including 3,513 (5.6%) on tramadol and 11,757 (18.7%) on non-tramadol opioids. Opioid initiators had more comorbidities, higher baseline healthcare costs, and were more likely to have OA of the hip. Among non-opioid initiators, 27.5% switched to tramadol and 63% switched to non-tramadol opioids. Among tramadol initiators, 71% switched to non-tramadol opioids. Patients initiated on opioids had 20.4% (p < .01) higher all-cause healthcare costs and higher percentages experiencing multiple negative clinical outcomes (all p < .01) compared to matched controls. CONCLUSIONS: Most patients with OA of the hip and/or knee either initiate on or switch to opioids for long-term management of OA-related pain despite known risks. This highlights the need for new treatments that delay or prevent use of opioids.

Update on the clinical use of trabecular bone score (TBS) in the management of osteoporosis: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), and the International Osteoporosis Foundation (IOF) under the auspices of WHO Collaborating Center for Epidemiology of Musculoskeletal Health and Aging.

PURPOSE: Trabecular bone score (TBS) is a grey-level textural measurement acquired from dual-energy X-ray absorptiometry lumbar spine images and is a validated index of bone microarchitecture. In 2015, a Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) published a review of the TBS literature, concluding that TBS predicts hip and major osteoporotic fracture, at least partly independent of bone mineral density (BMD) and clinical risk factors. It was also concluded that TBS is potentially amenable to change as a result of pharmacological therapy. Further evidence on the utility of TBS has since accumulated in both primary and secondary osteoporosis, and the introduction of FRAX and BMD T-score adjustment for TBS has accelerated adoption. This position paper therefore presents a review of the updated scientific literature and provides expert consensus statements and corresponding operational guidelines for the use of TBS. METHODS: An Expert Working Group was convened by the ESCEO and a systematic review of the evidence undertaken, with defined search strategies for four key topics with respect to the potential use of TBS: (1) fracture prediction in men and women; (2) initiating and monitoring treatment in postmenopausal osteoporosis; (3) fracture prediction in secondary osteoporosis; and (4) treatment monitoring in secondary osteoporosis. Statements to guide the clinical use of TBS were derived from the review and graded by consensus using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. RESULTS: A total of 96 articles were reviewed and included data on the use of TBS for fracture prediction in men and women, from over 20 countries. The updated evidence shows that TBS enhances fracture risk prediction in both primary and secondary osteoporosis, and can, when taken with BMD and clinical risk factors, inform treatment initiation and the choice of antiosteoporosis treatment. Evidence also indicates that TBS provides useful adjunctive information in monitoring treatment with long-term denosumab and anabolic agents. All expert consensus statements were voted as strongly recommended. CONCLUSION: The addition of TBS assessment to FRAX and/or BMD enhances fracture risk prediction in primary and secondary osteoporosis, adding useful information for treatment decision-making and monitoring. The expert consensus statements provided in this paper can be used to guide the integration of TBS in clinical practice for the assessment and management of osteoporosis. An example of an operational approach is provided in the appendix. This position paper presents an up-to-date review of the evidence base, synthesised through expert consensus statements, which informs the implementation of Trabecular Bone Score in clinical practice.

Biochemical Markers of Musculoskeletal Health and Aging to be Assessed in Clinical Trials of Drugs Aiming at the Treatment of Sarcopenia: Consensus Paper from an Expert Group Meeting Organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) and the Centre Académique de Recherche et d'Expérimentation en Santé (CARES SPRL), Under the Auspices of the World Health Organization Collaborating Center for the Epidemiology of Musculoskeletal Conditions and Aging.

In clinical trials, biochemical markers provide useful information on the drug's mode of action, therapeutic response and side effect monitoring and can act as surrogate endpoints. In pharmacological intervention development for sarcopenia management, there is an urgent need to identify biomarkers to measure in clinical trials and that could be used in the future in clinical practice. The objective of the current consensus paper is to provide a clear list of biochemical markers of musculoskeletal health and aging that can be recommended to be measured in Phase II and Phase III clinical trials evaluating new chemical entities for sarcopenia treatment. A working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) proposed classifying biochemical markers into 2 series: biochemical markers evaluating musculoskeletal status and biochemical markers evaluating causal factors. For series 1, the group agreed on 4 biochemical markers that should be assessed in Phase II or Phase III trials (i.e., Myostatin-Follistatin, Brain Derived Neurotrophic Factor, N-terminal Type III Procollagen and Serum Creatinine to Serum Cystatin C Ratio - or the Sarcopenia Index). For series 2, the group agreed on 6 biochemical markers that should be assessed in Phase II trials (i.e., the hormones insulin-like growth factor-1 (IGF-I), dehydroepiandrosterone sulphate, and cortisol, and the inflammatory markers C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-α), and 2 in Phase III trials (i.e., IGF-I and CRP). The group also proposed optional biochemical markers that may provide insights into the mode of action of pharmacological therapies. Further research and development of new methods for biochemical marker assays may lead to the evolution of these recommendations.

Burden of disease and management of osteoarthritis and chronic low back pain: healthcare utilization and sick leave in Sweden, Norway, Finland and Denmark (BISCUITS): study design and patient characteristics of a real world data study.

OBJECTIVES: Osteoarthritis (OA) and chronic low back pain (CLBP) are common musculoskeletal disorders with substantial patient and societal burden. Nordic administrative registers offer a unique opportunity to study the impact of these conditions in the real-world setting. The Burden of Disease and Management of Osteoarthritis and Chronic Low Back Pain: Health Care Utilization and Sick Leave in Sweden, Norway, Finland and Denmark (BISCUITS) study was designed to study disease prevalence and the societal and economic burden in broad OA and CLBP populations. METHODS: Patients in Sweden, Norway, Finland and Denmark with diagnoses of OA or CLBP (low back pain record plus ≥2 pain relief prescriptions to indicate chronicity) were identified in specialty care, in primary care (Sweden and Finland) and in a quality-of-care register (Sweden). Matched controls were identified for the specialty care cohort. Longitudinal data were extracted on prevalence, treatment patterns, patient-reported outcomes, social and economic burden. RESULTS: Almost 1.4 million patients with OA and 0.4 million with CLBP were identified in specialty care, corresponding to a prevalence in the Nordic countries of 6.3 and 1.9%, respectively. The prevalence increased to 11-14% for OA and almost 6% for CLBP when adding patients identified in primary care. OA patients had a higher Elixhauser comorbidity index (0.66 vs. 0.46) and were using opioids (44.7 vs. 10.2%) or long-term nonsteroidal anti-inflammatory drug (NSAIDs) (20.9 vs. 4.5%) more than four times as often as compared to controls. The differences were even larger for CLBP patients compared to their controls (comorbidity index 0.89 vs. 0.39, opioid use 77.7 vs. 9.4%, and long-term NSAID use 37.2 vs. 4.8%). CONCLUSIONS: The BISCUITS study offers an unprecedented, longitudinal healthcare data source to quantify the real-world burden of more than 1.8 million patients with OA or CLBP across four countries. In subsequent papers we aim to explore among others additional outcomes and subgroups of patients, primarily those patients who may benefit most from better healthcare management.

Opioid Utility and Hospital Outcomes Among Inpatients Admitted With Osteoarthritis and Spine Disorders.

OBJECTIVE: The aim of the study is to evaluate opioid analgesic utilization and predictors for adverse events during hospitalization and discharge disposition among patients admitted with osteoarthritis or spine disorders. DESIGN: This is a retrospective study of 12,747 adult patients admitted to six private community hospitals from 2017 to 2020. Opioid use during hospitalization and risk factors for hospital-acquired adverse events and nonhome discharge were investigated. RESULTS: The total number of patients using opioids decreased; however, the daily morphine milligram equivalent use for patients on opioids increased from 2017 to 2020. Increased odds of nonhome discharge were associated with older age, Medicaid, Medicare insurance, and increased lengths of stay, increased body mass index, daily morphine milligram equivalent, and electrolyte replacement in the osteoarthritis group. In the spine group, older age, Black race, Medicaid, Medicare, no insurance, increased Charlson Comorbidity Index, lengths of stay, polypharmacy, and heparin use were associated with nonhome discharge. Adverse events were associated with increased age, lengths of stay, Medicare, polypharmacy, antiemetic, and benzodiazepine use in the osteoarthritis group and increased Charlson Comorbidity Index, lengths of stay, and electrolyte replacement in the spine group. CONCLUSIONS: Despite the decreasing number of patients using opioids over the years, patients on opioids had an increased daily morphine milligram equivalent over the same period.

Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group.

Vitamin D is a key component for optimal growth and for calcium-phosphate homeostasis. Skin photosynthesis is the main source of vitamin D. Limited sun exposure and insufficient dietary vitamin D supply justify vitamin D supplementation in certain age groups. In older adults, recommended doses for vitamin D supplementation vary between 200 and 2000 IU/day, to achieve a goal of circulating 25-hydroxyvitamin D (calcifediol) of at least 50 nmol/L. The target level depends on the population being supplemented, the assessed system, and the outcome. Several recent large randomized trials with oral vitamin D regimens varying between 2000 and 100,000 IU/month and mostly conducted in vitamin D-replete and healthy individuals have failed to detect any efficacy of these approaches for the prevention of fracture and falls. Considering the well-recognized major musculoskeletal disorders associated with severe vitamin D deficiency and taking into account a possible biphasic effects of vitamin D on fracture and fall risks, an European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group convened, carefully reviewed, and analyzed the meta-analyses of randomized controlled trials on the effects of vitamin D on fracture risk, falls or osteoarthritis, and came to the conclusion that 1000 IU daily should be recommended in patients at increased risk of vitamin D deficiency. The group also addressed the identification of patients possibly benefitting from a vitamin D loading dose to achieve early 25-hydroxyvitamin D therapeutic level or from calcifediol administration.

Assessment of functional roles and therapeutic potential of integrin receptors in osteoarthritis: A systematic review and meta-analysis of preclinical studies.

BACKGROUND: Integrins are heterodimeric transmembrane receptors that mediate a variety of biological function and plays a critical role in osteoarthritis (OA) pathogenesis, which may provide new targets for the development of OA therapies. However, the roles of integrins in different stages of OA remain elusive. OBJECTIVES: This study aimed to synthesize all published preclinical evidence on the roles of integrin receptors in different stages of OA to identify the potential target for drug development in alleviating OA pathogenesis. METHODS: Major electronic databases were used to identify related original articles. The methodological quality of all included studies was appraised using the SYRCLE risk of bias tool. We used the generic inverse variance with random effects model to calculate standardized mean differences (SMDs) and 95% confidence interval (CI). RESULTS: Seventeen studies were included in this systematic review. Integrin α5ß1 activation increases the histopathological score both in early [SMD, 6.39; 95%CI (2.90, 9.87); p = 0.0003] and late [SMD, 3.41; 95%CI (2.44, 4.38); p < 0.00001] stage of OA. Integrin α5ß1 also increased the core catabolic factors like MMP-3, IL-1ß, and TNF-α. Interestingly, the inactivation of α5ß1 integrin did not change the histopathological score (p = 0.84). Similarly, ß1 integrin notably increased histopathological score at both stages of OA [early; SMD, 7.13; 95%CI (2.01, 12.24); p = 0.006]; [late; SMD, 10.25; 95%CI (5.11, 15.39); p < 0.0001], and increased the MMP-13 levels. However, integrin ß1 was upregulated at the early stage and downregulated at the late stage of OA. Furthermore, α2ß1 integrin significantly increased histopathological score [SMD, 3.14; 95%CI (2.18, 4.10); p < 0.00001] and MMP-13 [SMD, 2.24; 95%CI (0.07, 4.41); p = 0.04]. Deactivating integrin α1ß1 increased histopathological score in late [SMD, 1.53; 95%CI (0.80, 2.26); p < 0.0001], but not in early [SMD, 0.90; 95%CI (-1.65, 3.45); p = 0.49] stage of OA. CONCLUSION: This study provides evidence that α5ß1, α2ß1, and α1ß1 integrin might be the potential target for future drug development in alleviating OA pathogenesis. Further work is required to establish our findings through activating/deactivating these receptors in different stages of OA.

FDA/Arthritis Foundation osteoarthritis drug development workshop recap: Assessment of long-term benefit.

OBJECTIVE: To summarize proceedings of a workshop convened to discuss the current state of science in the disease of osteoarthritis (OA), identify the knowledge gaps, and examine the developmental and regulatory challenges in bringing these products to market. DESIGN: Summary of the one-day workshop held virtually on June 22nd, 2021. RESULTS: Speakers selected by the Planning Committee presented data on the current approach to assessment of OA therapies, biomarkers in OA drug development, and the assessment of disease progression and long-term benefit. CONCLUSIONS: Demonstrated by numerous failed clinical trials, OA is a challenging disease for which to develop therapeutics. The challenge is magnified by the slow time of onset of disease and the need for clinical trials of long duration and/or large sample size to demonstrate the effect of an intervention. The OA science community, including academia, pharmaceutical companies, regulatory agencies, and patient communities, must continue to develop and test better clinical endpoints that meaningfully reflect disease modification related to long-term patient benefit.

Assessment of joint pharmacokinetics and consequences for the intraarticular delivery of biologics.

Intraarticular (IA) injections provide the opportunity to deliver biologics directly to their site of action for a local and efficient treatment of osteoarthritis. However, the synovial joint is a challenging site of administration since the drug is rapidly eliminated across the synovial membrane and has limited distribution into cartilage, resulting in unsatisfactory therapeutic efficacy. In order to rationally develop appropriate drug delivery systems, it is essential to thoroughly understand the unique biopharmaceutical environments and kinetics in the joint to adequately simulate them in relevant experimental models. This review presents a detailed view on articular kinetics and drug-tissue interplay of IA administered drugs and summarizes how these can be translated into reasonable formulation strategies by identification of key factors through which the joint residence time can be prolonged and specific structures can be targeted. In this way, pros and cons of the delivery approaches for biologics will be evaluated and the extent to which biorelevant models are applicable to gain mechanistic insights and ameliorate formulation design is discussed.

Multimethod quantitative benefit-risk assessment of treatments for moderate-to-severe osteoarthritis.

OBJECTIVE: Demonstrate how benefit-risk profiles of systemic treatments for moderate-to-severe osteoarthritis (OA) can be compared using a quantitative approach accounting for patient preference. STUDY DESIGN AND SETTING: This study used a multimethod benefit-risk modelling approach to quantifiably compare treatments of moderate-to-severe OA. In total four treatments and placebo were compared. Comparisons were based on four attributes identified as most important to patients. Patient Global Assessment of Osteoarthritis was included as a favourable effect. Unfavourable effects, or risks, included opioid dependence, nonfatal myocardial infarction and rapidly progressive OA leading to total joint replacement. Clinical data from randomized clinical trials, a meta-analysis of opioid dependence and a long-term study of celecoxib were mapped into value functions and weighted with patient preferences from a discrete choice experiment. RESULTS: Lower-dose NGFi had the highest weighted net benefit-risk score (0.901), followed by higher-dose NGFi (0.889) and NSAIDs (0.852), and the lowest score was for opioids (0.762). Lower-dose NGFi was the highest-ranked treatment option even when assuming a low incidence (0.34% instead of 4.7%) of opioid dependence (ie, opioid benefit-risk score 808) and accounting for both the uncertainty in clinical effect estimates (first rank probability 46% vs 20% for NSAIDs) and imprecision in patient preference estimates (predicted choice probability 0.26, 95% confidence interval [CI] 0.25-0.28 vs 0.21, 95% CI 0.19-0.23 for NSAIDs). CONCLUSION: The multimethod approach to quantitative benefit-risk modelling allowed the interpretation of clinical data from the patient perspective while accounting for uncertainties in the clinical effect estimates and imprecision in patient preferences.

Cost Effectiveness of Pharmacological Management for Osteoarthritis: A Systematic Review.

BACKGROUND AND OBJECTIVE: Osteoarthritis (OA) is a highly prevalent, disabling disease requiring chronic management that is associated with an enormous individual and societal burden. This systematic review provides a global cost-effectiveness evaluation of pharmacological therapy for the management of OA. METHODS: Following Center for Reviews and Dissemination (CRD) guidance, a literature search strategy was undertaken using PubMed, EMBASE, Cochrane Library, Health Technology Assessment (HTA) database, and National Health Service Economic Evaluation database (NHS EED) to identify original articles containing cost-effectiveness evaluation of OA pharmacological treatment published before 4 November 2021. Risk of bias was assessed by two independent reviewers using the Joanna Briggs Institute (JBI) critical appraisal checklist for economic evaluations. The Quality of Health Economic Studies (QHES) instrument was used to assess the reporting quality of included articles. RESULTS: Database searches identified 43 cost-effectiveness analysis studies (CEAs) on pharmacological management of OA that were conducted in 18 countries and four continents, with one study containing multiple continents. A total of four classes of drugs were assessed, including non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, symptomatic slow-acting drugs for osteoarthritis (SYSADOAs), and intra-articular (IA) injections. The methodological approaches of these studies showed substantial heterogeneity. The incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) were (in 2021 US dollars) US$44.40 to US$307,013.56 for NSAIDS, US$11,984.84 to US$128,028.74 for opioids, US$10,930.17 to US$27,799.73 for SYSADOAs, and US$258.36 to US$58,447.97 for IA injections in different continents. The key drivers of cost effectiveness included medical resources, productivity, relative risks, and selected comparators. CONCLUSION: This review showed substantial heterogeneity among studies, ranging from a finding of dominance to very high ICERs, but most studies found interventions to be cost effective based on specific ICER thresholds. Important challenges in the analysis were related to the standardization and methodological quality of studies, as well as the presentation of results.

Cost-effectiveness of hydroxychloroquine versus placebo for hand osteoarthritis: economic evaluation of the HERO trial.

Background: An economic evaluation alongside the Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis (HERO) trial was undertaken to assess the cost-effectiveness of hydroxychloroquine compared with placebo for symptomatic treatment of hand osteoarthritis for patients with at least moderate hand pain and inadequate response to current therapies. Methods: A trial-based cost-utility analysis was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time horizon, using evidence from 248 participants included in the HERO trial, conducted in England. Patient-level data were collected prospectively over a 12-month period, using participant-completed questionnaires and investigator forms, to collect healthcare utilisation, costs and quality-adjusted life years (QALYs) using the EQ-5D-5L. The base-case analysis was conducted on an intention-to-treat basis and used multiple imputation methods to deal with missing data. Results were presented in terms of incremental cost-effectiveness ratios (incremental cost per QALY) and net health benefit, with uncertainty surrounding the findings explored using cost-effectiveness acceptability curves. Results: The base-case analysis estimated slightly lower costs on average (-£11.80; 95% confidence interval (CI) -£15.60 to -£8.00) and marginally fewer QALYs (-0.0052; 95% CI -0.0057 to -0.0047) for participants in the hydroxychloroquine group versus placebo group at 12 months. The resulting incremental cost-effectiveness ratio of £2,267 per QALY lost indicated that although costs were saved, health-related quality of life was lost. Even assuming symmetrical preferences regarding losses and gains for health benefits, the findings do not fall within the cost-effective region. Similar findings arose for analyses conducted from the societal perspective and using complete cases only. Conclusions: This economic evaluation indicates that hydroxychloroquine is unlikely to provide a cost-effective pain relief option for improving health-related quality of life in adult patients with moderate-to-severe hand osteoarthritis.

Anti-inflamatórios não esteroides tópicos para dor crônica musculoesquelética ou por osteoartrite / Topical non-steroidal anti-inflammatory drugs for pain chronic musculoskeletal or osteoarthritis

INTRODUÇÃO: Considera-se que, no Brasil, a dor crônica é umas das principais razões de atendimento ambulatorial. Conceitualmente, trata-se da dor que persiste além de três meses. Referências brasileiras estimam a prevalência de dor crônica entre 28,70 e 76,16% em diferentes cidades. Não há AINEs de administração tópica padronizados na Relação Nacional de Medicamentos Essenciais, apenas aqueles de via oral ou parenteral. A via de administração oral possibilita que o medicamento esteja disponível em altas concentrações plasmáticas no sítio de ação, o que pode gerar eventos adversos, como dispepsia, sangramento gastrointestinal e eventos adversos cardiovasculares. O objetivo de se empregar AINEs tópicos seria minimizar eventos adversos sistêmicos e encorajar a adesão ao tratamento pela comodidade. TECNOLOGIA: Anti-inflamatórios não esteroides (AINEs) tópicos, especificamente o diclofenaco dietilamônio. PERGUNTA: Os anti-inflamatórios não esteroides tópicos são eficazes e seguros para o tratamento de dor crônica derivada de agravo musculoesquelético ou osteoartrite? Evidências clínicas: Com o objetivo de responder à pergunta clínica, foram avaliadas três comparações, a saber: AINEs tópicos versus placebo tópico (Comparação 1); AINES tópicos versus AINES orais (Comparação 2); diferentes AINES tópicos (Comparação 3). A Comparação 1 teve estudos com baixo (dois estudos), algumas preocupações (onze estudos) e alto (quatro estudos) risco de viés. O desfecho dor mensurado pela escala WOMAC teve diferença de médias padronizadas (DMP) de -0,34 (IC 95%: -0,53 a 0,14) demonstrando que AINE tópico foi mais efetivo para redução de dor. Já considerando a mensuração da dor pela escala visual analógica (EVA), a DMP foi de -0,21 (IC 95%: -0,30 a -0,12), favorecendo também AINE tópico para redução de dor. Ao realizar comparação de todas as estimativas em meta-análise de efeitos randômicos, a DMP foi de -0,28 (IC 95%: -0,43 a -0,14), favorecendo mais uma vez AINEs tópicos. Especificamente para o diclofenaco tópico, a DMP foi de -0,30 (IC 95%: -0,39 a -0,21), favorecendo a intervenção para redução da dor Os resultados para o desfecho de proporção de respondedores favoreceram o AINE tópico para redução de sintomas, com RR=1,15 (IC 95%: 1,05 a 1,27). Com relação aos desfechos de segurança, não houve diferença entre os grupos quanto ao risco de eventos adversos gerais, OR=1,15 (IC 85%: 1,00 a 1,32), locais, com OR=1,43 (IC 95%: 0,99 a 2,06), ou gastrointestinais, OR=1,05 (IC 95%: 0,75 a 1,48). Especificamente para o diclofenaco tópico, houve maior incidência de eventos adversos locais na intervenção, com OR=2,03 (IC 95%: 1,36 a 3,05). A Comparação 2 teve estudos com algumas preocupações (dois estudos) e alto (seis estudos) risco de viés. Para o desfecho dor, mensurado pela escala WOMAC, a DMP foi de 0,11 (IC 95%: -0,01 a 0,24), favorecendo o uso de AINE oral, porém sem significância estatística. Apesar de não ser possível realizar metaanálise da proporção de respondedores, os estudos relataram haver maior proporção no grupo diclofenaco oral em comparação ao diclofenaco tópico, além de não haver diferença para esse desfecho entre loxoprofeno oral e tópico. No que se refere aos desfechos de segurança, para incidência de eventos adversos, a RR=0,89 (IC 95%: 0,71 a 1,13) não mostrou diferença significativa entre os grupos. Quanto à incidência de eventos adversos gastrointestinais, a RR=0,54 (IC 95%: 0,33 a 0,87) mostrou que o uso de AINEs tópicos está associado a menos eventos, especialmente no subgrupo diclofenaco, RR=0,32 (IC 95%: 0,11 a 0,91). Como esperado, houve menor chance de desenvolver eventos adversos cutâneos com o uso de AINE oral, OR=3,43 (IC 95%: 1,90 a 6,21). A Comparação 3 incluiu quatro estudos com alto risco de viés. Como foram quatro comparações diferentes nos estudos, não foi realizada meta-análise. Ao comparar Sflurbiprofeno e flurbiprofeno adesivos, o primeiro proporcionou redução da dor, porém com mais eventos adversos, principalmente locais. Considerando flurbiprofeno adesivo e piroxicam gel, o primeiro teve melhor resultado em redução da dor, sem diferenças na incidência de eventos adversos. As comparações piroxicam adesivo versus piroxicam creme e diclofenaco spray versus diclofenaco gel não tiveram diferenças significativas em desfechos de eficácia e segurança. AVALIAÇÃO ECONÔMICA: A análise de custo-efetividade demonstrou que a incorporação do diclofenaco tópico, seja em monoterapia, seja em terapia combinada, não promove ganho de QALY e aumenta o custo do tratamento. Na análise de sensibilidade, foi confirmado a ausência de ganho de QALY, mas houve a possibilidade de redução de custo. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Para o caso base, considerou-se que indivíduos com dor crônica atendidos pelo SUS estão fazendo uso de ibuprofeno ou naproxeno, e 36,6% delesterão eventos adversos gastrointestinais leves, e, portanto, estarão em uso concomitante de omeprazol. O cenário proposto considerou a população dividida em três partes: uso de AINE oral somente (maior proporção), associação de AINE oral e tópico (proporção intermediária) e AINE tópico somente (parcela menor). Dessa forma, estima-se que o custo incremental acumulado em cinco anos com a incorporação do diclofenaco dietilamônio ao SUS seja de R$ 71.170.946,00, sendo o aporte dividido entre as populações atendidas pelos Componentes Básico e Especializado da Assistência Farmacêutica. Uma vez que existem limitações da análise no que diz respeito às incertezas associadas à estimativa populacional elegível e às proporções de utilização de medicamentos, sugere-se cautela na interpretação e consideração desses dados para a tomada de decisão por parte do gestor. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Não foram localizados medicamentos tópicos potenciais para as indicações clínicas consideradas. Com relação ao diclofenaco dietilamônio gel, não foram identificadas patentes vigentes depositadas no Instituto Nacional da Propriedade Industrial (INPI). CONSIDERAÇÕES FINAIS: A comparação entre AINE tópico e placebo tópico favoreceu o primeiro quanto à eficácia. Entre AINE tópico e AINE oral, o último reduz mais a dor e produz mais eventos adversos gastrointestinais, esse resultado geral se aplica também para o diclofenaco tópico, embora houvesse poucos estudos específicos dessa intervenção. Entre diferentes AINE tópicos, um estudo favorece S-flurbiprofeno adesivo ao flurbiprofeno adesivo convencional; e outro, favorece o flurbiprofeno adesivo e relação ao piroxicam gel. Cabe destacar que a maior parte dos estudos teve alto risco de viés e baixa ou muito baixa qualidade da evidência. O uso de AINEs tópicos pode representar uma opção terapêutica nos casos de intolerância por eventos adversos, sobretudo aqueles de natureza gastrointestinal. Por meio da análise de impacto orçamentário proposta, estima-se que sua incorporação resulte em custo incremental ao SUS. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O relatório foi apreciado na 97ª Reunião Ordinária da Conitec, ocorrida nos dias 5 e 6 de maio de 2021. O Plenário deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação dos anti-inflamatórios não esteroides (AINEs) tópicos, incluindo o diclofenaco dietilamônio gel, para o tratamento da dor crônica musculoesquelética ou por osteoartrite em razão de não ser superior em eficácia a anti-inflamatórios orais, tais como o ibuprofeno, já incorporado ao SUS, além do incremento orçamentário em um cenário de possível incorporação. CONSULTA PÚBLICA: A Consulta Pública nº 46 foi realizada entre os dias 27/05/2021 e 15/06/2021. Foram recebidas oito contribuições, sendo três pelo formulário para contribuições técnico-científicas e cinco pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Apenas 25% (dois de oito) foram a favor da recomendação da Conitec, 12,5% (um de oito) não foi nem contra nem a favor e a maioria foi contra a recomendação inicial (62,5%, cinco de oito). As contribuições versaram sobre a necessidade de uma alternativa terapêutica para pacientes que tenham alguma contraindicação à via de administração oral e sobre a sua eficácia para o controle da dor. Não foram apresentadas novas evidências científicas, tampouco novas considerações de custo. RECOMENDAÇÃO FINAL: Diante do exposto, os membros presentes na 99ª Reunião Ordinária, no dia 01 de julho de 2021, deliberaram em unanimidade pela não incorporação dos anti-inflamatórios não esteroides tópicos para dor crônica musculoesquelética ou por osteoartrite no SUS. O Plenário entendeu que a consulta pública não agregou informações adicionais a esse relatório que pudessem alterar a recomendação preliminar. Foi assinado o Registro de Deliberação nº 638/2021. DECISÃO: Não incorporar os anti-inflamatórios não esteroides tópicos para dor crônica musculoesquelética ou por osteoartrite, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 48, publicada no Diário Oficial da União nº 137, seção 1, página 76, em 22 de julho de 2021.

Anti-inflamatórios não esteroides tópicos para dor crônica musculoesquelética ou por osteoartrite / Topical non-steroidal anti-inflammatory drugs for pain chronic musculoskeletal or osteoarthritis

INTRODUÇÃO: Considera-se que, no Brasil, a dor crônica é umas das principais razões de atendimento ambulatorial. Conceitualmente, trata-se da dor que persiste além de três meses. Referências brasileiras estimam a prevalência de dor crônica entre 28,70 e 76,16% em diferentes cidades. Não há AINEs de administração tópica padronizados na Relação Nacional de Medicamentos Essenciais, apenas aqueles de via oral ou parenteral. A via de administração oral possibilita que o medicamento esteja disponível em altas concentrações plasmáticas no sítio de ação, o que pode gerar eventos adversos, como dispepsia, sangramento gastrointestinal e eventos adversos cardiovasculares. O objetivo de se empregar AINEs tópicos seria minimizar eventos adversos sistêmicos e encorajar a adesão ao tratamento pela comodidade. TECNOLOGIA: Anti-inflamatórios não esteroides (AINEs) tópicos, especificamente o diclofenaco dietilamônio. PERGUNTA: Os anti-inflamatórios não esteroides tópicos são eficazes e seguros para o tratamento de dor crônica derivada de agravo musculoesquelético ou osteoartrite? EVIDÊNCIAS CLÍNICAS: Com o objetivo de responder à pergunta clínica, foram avaliadas três comparações, a saber: AINEs tópicos versus placebo tópico (Comparação 1); AINES tópicos versus AINES orais (Comparação 2); diferentes AINES tópicos (Comparação 3). A Comparação 1 teve estudos com baixo (dois estudos), algumas preocupações (onze estudos) e alto (quatro estudos) risco de viés. O desfecho dor mensurado pela escala WOMAC teve diferença de médias padronizadas (DMP) de -0,34 (IC 95%: -0,53 a 0,14) demonstrando que AINE tópico foi mais efetivo para redução de dor. Já considerando a mensuração da dor pela escala visual analógica (EVA), a DMP foi de -0,21 (IC 95%: -0,30 a -0,12), favorecendo também AINE tópico para redução de dor. Ao realizar comparação de todas as estimativas em meta-análise de efeitos randômicos, a DMP foi de -0,28 (IC 95%: -0,43 a -0,14), favorecendo mais uma vez AINEs tópicos. Especificamente para o diclofenaco tópico, a DMP foi de -0,30 (IC 95%: -0,39 a -0,21), favorecendo a intervenção para redução da dor. Os resultados para o desfecho de proporção de respondedores favoreceram o AINE tópico para redução de sintomas, com RR=1,15 (IC 95%: 1,05 a 1,27). Com relação aos desfechos de segurança, não houve diferença entre os grupos quanto ao risco de eventos adversos gerais, OR=1,15 (IC 85%: 1,00 a 1,32), locais, com OR=1,43 (IC 95%: 0,99 a 2,06), ou gastrointestinais, OR=1,05 (IC 95%: 0,75 a 1,48). Especificamente para o diclofenaco tópico, houve maior incidência de eventos adversos locais na intervenção, com OR=2,03 (IC 95%: 1,36 a 3,05). A Comparação 2 teve estudos com algumas preocupações (dois estudos) e alto (seis estudos) risco de viés. Para o desfecho dor, mensurado pela escala WOMAC, a DMP foi de 0,11 (IC 95%: -0,01 a 0,24), favorecendo o uso de AINE oral, porém sem significância estatística. Apesar de não ser possível realizar metaanálise da proporção de respondedores, os estudos relataram haver maior proporção no grupo diclofenaco oral em comparação ao diclofenaco tópico, além de não haver diferença para esse desfecho entre loxoprofeno oral e tópico. No que se refere aos desfechos de segurança, para incidência de eventos adversos, a RR=0,89 (IC 95%: 0,71 a 1,13) não mostrou diferença significativa entre os grupos. Quanto à incidência de eventos adversos gastrointestinais, a RR=0,54 (IC 95%: 0,33 a 0,87) mostrou que o uso de AINEs tópicos está associado a menos eventos, especialmente no subgrupo diclofenaco, RR=0,32 (IC 95%: 0,11 a 0,91). Como esperado, houve menor chance de desenvolver eventos adversos cutâneos com o uso de AINE oral, OR=3,43 (IC 95%: 1,90 a 6,21). A Comparação 3 incluiu quatro estudos com alto risco de viés. Como foram quatro comparações diferentes nos estudos, não foi realizada meta-análise. Ao comparar Sflurbiprofeno e flurbiprofeno adesivos, o primeiro proporcionou redução da dor, porém com mais eventos adversos, principalmente locais. Considerando flurbiprofeno adesivo e piroxicam gel, o primeiro teve melhor resultado em redução da dor, sem diferenças na incidência de eventos adversos. As comparações piroxicam adesivo versus piroxicam creme e diclofenaco spray versus diclofenaco gel não tiveram diferenças significativas em desfechos de eficácia e segurança. AVALIAÇÃO ECONÔMICA: A análise de custo-efetividade demonstrou que a incorporação do diclofenaco tópico, seja em monoterapia, seja em terapia combinada, não promove ganho de QALY e aumenta o custo do tratamento. Na análise de sensibilidade, foi confirmado a ausência de ganho de QALY, mas houve a possibilidade de redução de custo. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Para o caso base, considerou-se que indivíduos com dor crônica atendidos pelo SUS estão fazendo uso de ibuprofeno ou naproxeno, e 36,6% delesterão eventos adversos gastrointestinais leves, e, portanto, estarão em uso concomitante de omeprazol. O cenário proposto considerou a população dividida em três partes: uso de AINE oral somente (maior proporção), associação de AINE oral e tópico (proporção intermediária) e AINE tópico somente (parcela menor). Dessa forma, estima-se que o custo incremental acumulado em cinco anos com a incorporação do diclofenaco dietilamônio ao SUS seja de R$ 71.170.946,00, sendo o aporte dividido entre as populações atendidas pelos Componentes Básico e Especializado da Assistência Farmacêutica. Uma vez que existem limitações da análise no que diz respeito às incertezas associadas à estimativa populacional elegível e às proporções de utilização de medicamentos, sugere-se cautela na interpretação e consideração desses dados para a tomada de decisão por parte do gestor. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Não foram localizados medicamentos tópicos potenciais para as indicações clínicas consideradas. Com relação ao diclofenaco dietilamônio gel, não foram identificadas patentes vigentes depositadas no Instituto Nacional da Propriedade Industrial (INPI). CONSIDERAÇÕES FINAIS: A comparação entre AINE tópico e placebo tópico favoreceu o primeiro quanto à eficácia. Entre AINE tópico e AINE oral, o último reduz mais a dor e produz mais eventos adversos gastrointestinais, esse resultado geral se aplica também para o diclofenaco tópico, embora houvesse poucos estudos específicos dessa intervenção. Entre diferentes AINE tópicos, um estudo favorece S-flurbiprofeno adesivo ao flurbiprofeno adesivo convencional; e outro, favorece o flurbiprofeno adesivo e relação ao piroxicam gel. Cabe destacar que a maior parte dos estudos teve alto risco de viés e baixa ou muito baixa qualidade da evidência. O uso de AINEs tópicos pode representar uma opção terapêutica nos casos de intolerância por eventos adversos, sobretudo aqueles de natureza gastrointestinal. Por meio da análise de impacto orçamentário proposta, estima-se que sua incorporação resulte em custo incremental ao SUS. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O relatório foi apreciado na 97ª Reunião Ordinária da Conitec, ocorrida nos dias 5 e 6 de maio de 2021. O Plenário deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação dos anti-inflamatórios não esteroides (AINEs) tópicos, incluindo o diclofenaco dietilamônio gel, para o tratamento da dor crônica musculoesquelética ou por osteoartrite em razão de não ser superior em eficácia a anti-inflamatórios orais, tais como o ibuprofeno, já incorporado ao SUS, além do incremento orçamentário em um cenário de possível incorporação. CONSULTA PÚBLICA: A Consulta Pública nº 46 foi realizada entre os dias 27/05/2021 e 15/06/2021. Foram recebidas oito contribuições, sendo três pelo formulário para contribuições técnico-científicas e cinco pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Apenas 25% (dois de oito) foram a favor da recomendação da Conitec, 12,5% (um de oito) não foi nem contra nem a favor e a maioria foi contra a recomendação inicial (62,5%, cinco de oito). As contribuições versaram sobre a necessidade de uma alternativa terapêutica para pacientes que tenham alguma contraindicação à via de administração oral e sobre a sua eficácia para o controle da dor. Não foram apresentadas novas evidências científicas, tampouco novas considerações de custo. RECOMENDAÇÃO FINAL: Diante do exposto, os membros presentes na 99ª Reunião Ordinária, no dia 01 de julho de 2021, deliberaram em unanimidade pela não incorporação dos anti-inflamatórios não esteroides tópicos para dor crônica musculoesquelética ou por osteoartrite no SUS. O Plenário entendeu que a consulta pública não agregou informações adicionais a esse relatório que pudessem alterar a recomendação preliminar. Foi assinado o Registro de Deliberação nº 638/2021. DECISÃO: Não incorporar os anti-inflamatórios não esteroides tópicos para dor crônica musculoesquelética ou por osteoartrite, no âmbito do Sistema Único de Saúde ­ SUS, conforme a Portaria nº 48, publicada no Diário Oficial da União nº 137, seção 1, página 76, em 22 de julho de 2021.

A Retrospective Database Study of Gastrointestinal Events and Medical Costs Associated with Nonsteroidal Anti-Inflammatory Drugs in Japanese Patients of Working Age with Osteoarthritis and Chronic Low Back Pain.

CONTEXT: The real-world burden of gastrointestinal (GI) events associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in Japanese patients with osteoarthritis (OA) and/or chronic low back pain (CLBP) remains unreported. OBJECTIVE: To assess the incidence and economic burden of NSAID-induced GI events by using data from large-scale real-world databases. METHODS: We used the Japanese Medical Data Center database to retrospectively evaluate anonymized claims data of medical insurance beneficiaries employed by middle- to large-size Japanese companies who were prescribed NSAIDs for OA and/or CLBP between 2009 and 2018. RESULTS: Overall, 180,371 patients were included in the analysis, of whom 32.9% had OA, 53.8% had CLBP, and 13.4% had both OA and CLBP. NSAIDs were administered as first-line analgesics to 161,152 (89.3%) of the patients in the sample, in oral form to 90.3% and as topical patches to 80.4%. A total of 65.1% used combined oral/topical patches. Of the 21.0% of patients consistently using NSAIDs (percentage of days supplied ≥70%), 54.5% received patches. A total of 51.5% patients used NSAIDs for >1 to ≤6 months. The incidence of GI events was 9.97 per 10,000 person-years (95% confidence interval: 8.92-11.03). The risk of developing GI events was high in elderly patients and patients with comorbidities and remained similar for patients receiving oral vs. topical NSAIDs. Longer treatment duration and consistent NSAID use increased the risk of GI events. The cost (median [interquartile range]) of medications (n = 327) was US$ 80.70 ($14.10, $201.40), that of hospitalization (n = 33) was US$ 2,035.50 ($1,517.80, $2,431.90), and that of endoscopic surgery (n = 52) was US$ 418.20 ($418.20, $418.20). CONCLUSION: NSAID-associated GI toxicity imposes a significant health and economic burden on patients with OA and/or CLBP, irrespective of whether oral or topical NSAIDs are used.

Use of non-steroidal anti-inflammatory drugs and risk of death from COVID-19: an OpenSAFELY cohort analysis based on two cohorts.

OBJECTIVES: To assess the association between routinely prescribed non-steroidal anti-inflammatory drugs (NSAIDs) and deaths from COVID-19 using OpenSAFELY, a secure analytical platform. METHODS: We conducted two cohort studies from 1 March to 14 June 2020. Working on behalf of National Health Service England, we used routine clinical data in England linked to death data. In study 1, we identified people with an NSAID prescription in the last 3 years from the general population. In study 2, we identified people with rheumatoid arthritis/osteoarthritis. We defined exposure as current NSAID prescription within the 4 months before 1 March 2020. We used Cox regression to estimate HRs for COVID-19 related death in people currently prescribed NSAIDs, compared with those not currently prescribed NSAIDs, accounting for age, sex, comorbidities, other medications and geographical region. RESULTS: In study 1, we included 536 423 current NSAID users and 1 927 284 non-users in the general population. We observed no evidence of difference in risk of COVID-19 related death associated with current use (HR 0.96, 95% CI 0.80 to 1.14) in the multivariable-adjusted model. In study 2, we included 1 708 781 people with rheumatoid arthritis/osteoarthritis, of whom 175 495 (10%) were current NSAID users. In the multivariable-adjusted model, we observed a lower risk of COVID-19 related death (HR 0.78, 95% CI 0.64 to 0.94) associated with current use of NSAID versus non-use. CONCLUSIONS: We found no evidence of a harmful effect of routinely prescribed NSAIDs on COVID-19 related deaths. Risks of COVID-19 do not need to influence decisions about the routine therapeutic use of NSAIDs.

Are pain severity and current pharmacotherapies associated with quality of life, work productivity, and healthcare utilisation for people with osteoarthritis in five large European countries?

OBJECTIVES: Although the osteoarthritis (OA) burden is well-recognised, the benefit of currently available OA pharmacological therapy is not clear. This study aimed to assess whether the impact of OA pain on health-related quality of life (HRQoL), work, and healthcare resource utilisation (HRU) differed by both pain severity and prescription medication status. METHODS: This cross-sectional study used pooled data from the 2016/2017 European National Health and Wellness Survey. Respondents with self-reported physician-diagnosed OA and pain were included. Outcomes examined included HRQoL, health utility, health status, work productivity and activity impairment, and HRU. Groups derived from self-reported pain severity and prescription medication use were compared using chi-square tests, analysis of variance, and generalised linear models controlling for socio-demographics, health behaviours, and health status. RESULTS: Respondents with OA (n=2417) reported mild (40.4%, of which 44.9% prescription-treated) and moderate to severe pain (59.6%, of which 54.0% prescription-treated). HRQoL, health utility, health status, and work and activity impairment were substantially worse among the moderate/severe pain prescription-treated group compared to the rest (e.g. SF-12v2 physical component score [PCS] for moderate/severe pain prescription-treated=34.5 versus mild pain prescription-treated =39.3, moderate/severe pain prescription-untreated=40.6, and mild pain prescription-untreated=45.6; p<0.01). HRU such as the mean number of emergency room visits for >6 months was higher in the prescription-treated groups (0.51-0.52, 95% CI 0.437-0.71) than the prescription-untreated groups (0.30-0.34, 95% CI 0.21-0.46; p<0.05). CONCLUSIONS: Persons with moderate to severe OA pain treated with available prescription medications have poor health status and HRQoL and increased HRU compared to those not receiving prescription medications.