Safety Assessment of a Novel Intravenous Diclofenac Sodium Formulation Following 28-Day Repeated Administration in Wistar Rats.

These toxicity studies aimed to assess the safety and tolerability of a novel intravenous diclofenac sodium (37.5 mg/mL) formulation containing povidone K12 (80 mg/mL) as the key excipient in Wistar rats. This formulation was tested at doses of 3, 7, and 15 mg/kg/day and was administered daily for 28 days by intravenous route. Toxicokinetic estimation revealed a dose-proportional increase in plasma exposure to diclofenac. The formulation was well tolerated in males; however, mortality was observed in females (2/15) at the highest dose (15 mg/kg/day). Adverse gastrointestinal events related to NSAIDS and a few other treatment-related effects on clinical and anatomic pathology were noted at the 15 mg/kg/day dose, which normalized at the end of the 2-week recovery period. In addition, the excipient povidone K12 was present in a higher amount than the approved Inactive Ingredient Database (IID) limit in the proposed novel formulation. It was qualified through a separate 28-day repeated dose toxicity study by intravenous route in Wistar rats. Povidone K12 was found to be well tolerated and safe up to a dose of 165 mg/kg/day. No treatment-related adverse effects were observed in this study. In conclusion, repeated administration of a novel intravenous formulation containing diclofenac sodium was found to be safe up to the dose of 7 mg/kg/day in female rats and 15 mg/kg/day in male rats.

Design, synthesis and anti-inflammatory assessment of certain substituted 1,2,4-triazoles bearing tetrahydroisoquinoline scaffold as COX 1/2-inhibitors.

Aiming to discover effective and safe non-steroidal anti-inflammatory agents, a new set of 1,2,4-triazole tetrahydroisoquinoline hybrids 9a-g, 11a-g and 12a-g was synthesized and evaluated as inhibitors of COX-1 and COX-2. In order to overcome the adverse effects of highly selective COX-2 and non-selective COX-2 inhibitors, the compounds of this study were designed with the goal of obtaining moderately selective COX-2 inhibitors. In this study compounds 9e, 9g and 11f are the most effective derivatives against COX-2 with IC50 values 0.87, 1.27 and 0.58 µM, respectively which are better than or comparable to the standard drug celecoxib (IC50 = 0.82 µM) but with lower selectivity indices as required by our goal design. The results of the in vivo anti-inflammatory inhibition test revealed that compounds 9e, 9g and 11f displayed a higher significant anti-inflammatory activity than celecoxib at all-time intervals. In addition, these compounds significantly decreased the production of inflammatory mediators PGE-2, TNF-ɑ and IL-6. Compounds 9e, 9g and 11f had a safe gastric profile compared to indomethacin, also compound 11f (ulcerogenic index = 1.33) was less ulcerous than the safe celecoxib (ulcerogenic index = 3). Moreover, histopathological investigations revealed a normal architecture of both paw skin and gastric mucosa after oral treatment of rats with compound 11f. Furthermore, molecular docking studies were performed on COX-1 and COX-2 to study the binding pattern of compounds 9e, 9g and 11f on both isoenzymes.

Incidence of Surgically Managed Post-Tonsillectomy Hemorrhage Associated With NSAID Prescribing for Postoperative Pain Management.

INTRODUCTION: Tonsillectomy ranks high among the most common pediatric surgical procedures in the United States. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), such as ibuprofen, are routinely prescribed to manage post-tonsillectomy pain, but may carry the risk of hemorrhage. MATERIALS AND METHODS: This retrospective, longitudinal, secondary-data analysis study compared the incidence of surgically managed post-tonsillectomy hemorrhage (sPTH) in pediatric patients prescribed ibuprofen at Brooke Army Medical Center (BAMC) after tonsillectomy compared to a similar cohort of pediatric patients at the Children's Hospital of Philadelphia (CHOP) not prescribed ibuprofen. Additional regression analysis examined predictors of sPTH at BAMC. RESULTS: The odds of sPTH was lower in patients who were prescribed ibuprofen at BAMC, relative to patients who were not at CHOP (OR 0.57, 95% CI, 0.37, 0.87; P < 0.01). In a generalized linear model evaluating BAMC patient data, there was a lack of a relationship between reason for tonsillectomy (tonsillitis versus tonsillar obstruction), primary procedure (tonsillectomy-only versus tonsillectomy with adenoidectomy), and presence of a co-occurring procedure. CONCLUSIONS: Post-tonsillectomy ibuprofen prescribing practices were not associated with an elevated risk of sPTH, relative to patients at CHOP not exposed to ibuprofen.

Tramadol/Diclofenac Fixed-Dose Combination for Acute Pain Management: Bioavailability Assessment of a Generic Product.

The multimodal analgesia strategy for acute pain involves using 2 or more analgesic medications with distinct mechanisms of action. This study assessed the bioavailability and tolerability of 2 tramadol hydrochloride (50 mg)/diclofenac sodium (50 mg) fixed-dose combination formulations under fed conditions to attend the Brazilian regulatory requirements for generic product registration. An open-label, randomized, single-dose, 2-period, 2-way crossover trial was conducted, including healthy subjects of both sexes. Subjects received a single dose of either the test or reference formulation of tramadol/diclofenac fixed-dose combination tablets with a 7-day washout period. Blood samples were collected up to 36 hours after dosing for tramadol and 12 hours for diclofenac and quantified using a validated liquid chromatography-tandem mass spectrometry method. Of 56 subjects enrolled, 53 completed the study. The 90% confidence intervals for maximum plasma concentration and area under the concentration-time curve from time 0 to the last quantifiable concentration were within acceptable bioequivalence limits of 80%-125%. Considering the results presented in this study, the test formulation is bioequivalent to the reference formulation and could be interchangeable in medical practice.

Re-assessment of monoclonal antibodies against diclofenac for their application in the analysis of environmental waters.

The non-steroidal anti-inflammatory drug (NSAID) diclofenac (DCF) is an important environmental contaminant occurring in surface waters all over the world, because, after excretion, it is not adequately removed from wastewater in sewage treatment plants. To be able to monitor this pollutant, highly efficient analytical methods are needed, including immunoassays. In a medical research project, monoclonal antibodies against diclofenac and its metabolites had been produced. Based on this monoclonal anti-DCF antibody, a new indirect competitive enzyme-linked immunosorbent assay (ELISA) was developed and applied for environmental samples. The introduction of a spacer between diclofenac and the carrier protein in the coating conjugate led to higher sensitivity. With a test midpoint of 3 µg L-1 and a measurement range of 1-30 µg L-1, the system is not sensitive enough for direct analysis of surface water. However, this assay is quite robust against matrix influences and can be used for wastewater. Without adjustment of the calibration, organic solvents up to 5%, natural organic matter (NOM) up to 10 mg L-1, humic acids up to 2.5 mg L-1, and salt concentrations up to 6 g L-1 NaCl and 75 mg L-1 CaCl2 are tolerated. The antibody is also stable in a pH range from 3 to 12. Cross-reactivity (CR) of 1% or less was determined for the metabolites 4'-hydroxydiclofenac (4'-OH-DCF), 5-hydroxydiclofenac (5-OH-DCF), DCF lactam, and other NSAIDs. Relevant cross-reactivity occurred only with an amide derivative of DCF, 6-aminohexanoic acid (DCF-Ahx), aceclofenac (ACF) and DCF methyl ester (DCF-Me) with 150%, 61% and 44%, respectively. These substances, however, have not been found in samples. Only DCF-acyl glucuronide with a cross-reactivity of 57% is of some relevance. For the first time, photodegradation products were tested for cross-reactivity. With the ELISA based on this antibody, water samples were analysed. In sewage treatment plant effluents, concentrations in the range of 1.9-5.2 µg L-1 were determined directly, with recoveries compared to HPLC-MS/MS averaging 136%. Concentrations in lakes ranged from 3 to 4.4 ng L-1 and were, after pre-concentration, determined with an average recovery of 100%.

Electrochemical degradation of diclofenac generates unexpected thyroidogenic transformation products: Implications for environmental risk assessment.

Diclofenac (DCF) is an environmentally persistent, nonsteroidal anti-inflammatory drug (NSAID) with thyroid disrupting properties. Electrochemical advanced oxidation processes (eAOPs) can efficiently remove NSAIDs from wastewater. However, eAOPs can generate transformation products (TPs) with unknown chemical and biological characteristics. In this study, DCF was electrochemically degraded using a boron-doped diamond anode. Ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry was used to analyze the TPs of DCF and elucidate its potential degradation pathways. The biological impact of DCF and its TPs was evaluated using the Xenopus Eleutheroembryo Thyroid Assay, employing a transgenic amphibian model to assess thyroid axis activity. As DCF degradation progressed, in vivo thyroid activity transitioned from anti-thyroid in non-treated samples to pro-thyroid in intermediately treated samples, implying the emergence of thyroid-active TPs with distinct modes of action compared to DCF. Molecular docking analysis revealed that certain TPs bind to the thyroid receptor, potentially triggering thyroid hormone-like responses. Moreover, acute toxicity occurred in intermediately degraded samples, indicating the generation of TPs exhibiting higher toxicity than DCF. Both acute toxicity and thyroid effects were mitigated with a prolonged degradation time. This study highlights the importance of integrating in vivo bioassays in the environmental risk assessment of novel degradation processes.

The prevalence, incidence and management of low back pain with radiating leg pain in Dutch general practice: A population-based cohort study in the Rijnmond Primary Care Database.

BACKGROUND: Radiating leg pain is common in patients with low back pain (LBP). In this study, we aimed to determine the prevalence and incidence of LBP with radiating leg pain in Dutch general practice, and to describe the prescribed medications and requested imaging diagnostics. METHODS: The Rijnmond Primary Care Database containing over 500,000 primary care patients was used to select patients ≥18 years with LBP with radiating leg pain between 2013 and 2021. Data on patient characteristics, LBP episodes, prescribed medication and requested imaging in the first 3 months of an episode was extracted. Descriptive statistics were used to present patient characteristics and diagnostic/therapeutic interventions. RESULTS: A total of 27,695 patients were included. The total number of LBP with radiating leg pain episodes in these patients was 36,268. In 2021, the incidence and prevalence were 19.1 and 25.7 per 1000 patient years, respectively. In 60% of patients, the episode duration was shorter than 1 month. In 62% of the episodes, patients visited the general practitioner (GP) one to two times. In 59% of the episodes, at least one medication was prescribed, non-steroidal anti-inflammatory drugs (NSAIDs) being the most common one (45%). In approximately 11% of the episodes, additional diagnostic imaging was requested. CONCLUSION: LBP with radiating leg pain is common in Dutch general practice patients. About 2/3rd were prescribed pain medications. Dutch request few to none diagnostic imaging for these patients which is in line with clinical practice guidelines. SIGNIFICANCE: In this new study, we have gained insights into the incidence and prevalence of LBP with radiating leg pain in Dutch general practice. Both remained fairly stable over the study period of 9 years (2013-2021). Overall, the care burden regarding seeking contact with the GPs and the requested diagnostics seem not to be that high. In 62% of the care episodes, there were one or two consultations with the GP, and in 11% of the episodes a diagnostic imaging was requested. Pain medications frequently prescribed (i.e. 2/3rd of the episodes), with NSAIDs being the most common ones.

Trends and prescribing patterns of antimigraine medicines in nine major cities in China from 2018 to 2022: a retrospective prescription analysis.

BACKGROUND: The objective of this study was to investigate the trends and prescribing patterns of antimigraine medicines in China. METHODS: The prescription data of outpatients diagnosed with migraine between 2018 and 2022 were extracted from the Hospital Prescription Analysis Cooperative Project of China. The demographic characteristics of migraine patients, prescription trends, and corresponding expenditures on antimigraine medicines were analyzed. We also investigated prescribing patterns of combination therapy and medicine overuse. RESULTS: A total of 32,246 outpatients who were diagnosed with migraine at 103 hospitals were included in this study. There were no significant trend changes in total outpatient visits, migraine prescriptions, or corresponding expenditures during the study period. Of the patients who were prescribed therapeutic medicines, 70.23% received analgesics, and 26.41% received migraine-specific agents. Nonsteroidal anti-inflammatory drugs (NSAIDs; 28.03%), caffeine-containing agents (22.15%), and opioids (16.00%) were the most commonly prescribed analgesics, with corresponding cost proportions of 11.35%, 4.08%, and 19.61%, respectively. Oral triptans (26.12%) were the most commonly prescribed migraine-specific agents and accounted for 62.21% of the total therapeutic expenditures. The proportion of patients receiving analgesic prescriptions increased from 65.25% in 2018 to 75.68% in 2022, and the proportion of patients receiving concomitant triptans decreased from 29.54% in 2018 to 21.55% in 2022 (both P <  0.001). The most frequently prescribed preventive medication classes were calcium channel blockers (CCBs; 51.59%), followed by antidepressants (20.59%) and anticonvulsants (15.82%), which accounted for 21.90%, 34.18%, and 24.15%, respectively, of the total preventive expenditures. Flunarizine (51.41%) was the most commonly prescribed preventive drug. Flupentixol/melitracen (7.53%) was the most commonly prescribed antidepressant. The most commonly prescribed anticonvulsant was topiramate (9.33%), which increased from 6.26% to 12.75% (both P <  0.001). A total of 3.88% of the patients received combined therapy for acute migraine treatment, and 18.63% received combined therapy for prevention. The prescriptions for 69.21% of opioids, 38.53% of caffeine-containing agents, 26.61% of NSAIDs, 13.97% of acetaminophen, and 6.03% of triptans were considered written medicine overuse. CONCLUSIONS: Migraine treatment gradually converges toward evidence-based and guideline-recommended treatment. Attention should be given to opioid prescribing, weak evidence-based antidepressant use, and medication overuse in migraine treatment.

Bioequivalence risk assessment of oral formulations containing racemic ibuprofen through a chiral physiologically based pharmacokinetic model of ibuprofen enantiomers.

The characterization of the time course of ibuprofen enantiomers can be useful in the selection of the most sensitive analyte in bioequivalence studies. Physiologically based pharmacokinetic (PBPK) modelling and simulation represents the most efficient methodology to virtually assess bioequivalence outcomes. In this work, we aim to develop and verify a PBPK model for ibuprofen enantiomers administered as a racemic mixture with different immediate release dosage forms to anticipate bioequivalence outcomes based on different particle size distributions. A PBPK model incorporating stereoselectivity and non-linearity in plasma protein binding and metabolism as well as R-to-S unidirectional inversion has been developed in Simcyp®. A dataset composed of 11 Phase I clinical trials with 54 scenarios (27 per enantiomer) and 14,452 observations (7129 for R-ibuprofen and 7323 for S-ibuprofen) was used. Prediction errors for AUC0-t and Cmax for both enantiomers fell within the 0.8-1.25 range in 50/54 (93 %) and 42/54 (78 %) of scenarios, respectively. Outstanding model performance, with 10/10 (100 %) of Cmax and 9/10 (90 %) of AUC0-t within the 0.9-1.1 range, was demonstrated for oral suspensions, which strongly supported its use for bioequivalence risk assessment. The deterministic bioequivalence risk assessment has revealed R-ibuprofen as the most sensitive analyte to detect differences in particle size distribution for oral suspensions containing 400 mg of racemic ibuprofen, suggesting that achiral bioanalytical methods would increase type II error and declare non-bioequivalence for formulations that are bioequivalent for the eutomer.

Ixequizumabe para o tratamento de adultos com espondiloartrite axial radiográfica e não radiográfica que não responderam à terapia convencional (antiinflamatórios não esteroides) / Ixequizumabe for the treatment of adults with radiographic and non-radiographic axial spondyloarthritis who do not respond to conventional therapy (anti-inflammatory drugs or steroids)

INTRODUÇÃO: A espondiloartrite axial é uma doença inflamatória crônica, de origem autoimune, que acomete preferencialmente a coluna vertebral. O tratamento da doença tem por objetivo aliviar os sintomas, melhorar a capacidade funcional, manter a capacidade laboral e/ou escolar, diminuir as complicações e prevenir ao máximo o dano esquelético do indivíduo, e inclui drogas de diferentes classes (anti-inflamatórios não esteroidais ­ AINE, glicocorticoides e medicamentos modificadores do curso da doença) que são utilizadas de acordo com a gravidade da doença. PERGUNTA: Em relação aos medicamentos biológicos disponíveis no SUS, ixequizumabe é eficaz e seguro em pacientes com espondiloartrite axial, radiográfica ou não radiográfica, que não tenham respondido à terapia convencional (anti-inflamatórios não esteroides)? SÍNTESE DAS EVIDÊNCIAS: A evidência encontrada para a população diagnosticada com a forma radiográfica da doença foi composta por um ensaio clínico e três revisões sistemáticas. Observouse que não há diferença estatisticamente significativa quando são comparados os efeitos dos tratamentos de todos os biológicos já incorporados ao SUS com ixequizumabe. Para o desfecho ASAS40, na comparação entre ixequizumabe e as outras tecnologias não foram observadas diferenças estatísticas: ixequizumabe versus certolizumabe (risco relativo 1,49 [IC95% 0,88- 2,52]), infliximabe (1,51 [IC95% 0,84-2,72]), golimumabe (1,06 [0,67-1,64]), adalimumabe (0,98 [0,67-1,45]), etanercepte (1,07 [IC95% 0,70-1,63]). Resultados semelhantes foram observados para a população com a forma não radiográfica em metanálises indiretas conduzidas pelos autores deste relatório. Para essa população foi identificado um único ensaio clínico randomizado no qual se comparou ixequizumabe com placebo. Para o desfecho ASAS40, o tratamento com ixequizumabe foi associado a melhor resultado (risco relativo 1,99 [IC95% 1,29-3,07]). Em relação à segurança para ambas as populações, não houve diferença estatisticamente significativa entre as intervenções, a não ser na incidência de infecções. A certeza da evidência foi baixa na comparação entre ixequizumabe e os demais comparadores ativos, e moderada na comparação com placebo. AVALIAÇÃO ECONÔMICA (AE): O tratamento com ixequizumabe foi associado a desempenho semelhante em termos de eficácia e segurança em relação aos demais medicamentos biológicos (adalimumabe, etanercepte, infliximabe, golimumabe e certolizumabe), e, portanto, foi desenvolvida uma análise de custo-minimização. O horizonte temporal foi de 2 anos, sendo calculados os custos dos medicamentos para o primeiro e ano subsequente, pelo fato de que alguns dos comparadores possuem dose inicial e de manutenção diferentes. Foi considerado apenas o custo de aquisição dos medicamentos. Como resultado da análise principal observouse que o custo de ixequizumabe, tanto no primeiro ano, como no ano subsequente, foi superior a todos os demais medicamentos biológicos em comparação, com a diferença de custo anual variando entre 44 mil reais e 54 mil reais (a depender do comparador). Análise de Impacto Orçamentário (AIO): Por demanda aferida, foi identificado que para o primeiro ano de análise, o número de pacientes em uso de medicamentos biológicos para o tratamento de espondilite anquilosantes seria de 38.806 pacientes; para os anos subsequentes, considerou-se uma incidência de 3 mil novos usuários de medicamentos biológicos a cada ano. Para a definição do market share do cenário alternativo também foram consideradas essas informações. O market share do ixequizumabe foi de 3% no primeiro ano, chegando a 10% no quinto ano de análise (market share dos comparadores no cenário alternativo variou entre: 42-45% para o adalimumabe, 18-19,5% etanercepte, 8-9,5% infliximabe, 13-14,5% golimumabe, e 9-9,5% certolizumabe). Utilizando os dados da análise principal, observa-se que a incorporação de ixequizumabe no SUS para indicação proposta tem como resultado um incremento de custos. O impacto orçamentário incremental foi de R$ 58 milhões no primeiro ano, chegando a R$ 105 milhões no quinto ano de análise, totalizando R$ 436 milhões em cinco anos. Perspectiva do paciente: Foi aberta a chamada pública nº 42/2023 para inscrição de participantes para a perspectiva do paciente, durante o período de 10/11/2023 a 20/11/2023, e 18 pessoas se inscreveram. A seleção dos representantes titular e suplente ocorreu por meio de sorteio realizado em plataforma digital, com transmissão em tempo real e com gravação enviada posteriormente para todos os inscritos. Durante o seu relato, a representante, diagnosticada com espondilite anquilosante há cinco anos, relatou que o uso do ixequizumabe controlou os sintomas e teve impactos positivos na sua qualidade de vida, permitindo-lhe, atualmente, retomar suas atividades diárias, como caminhar e trabalhar. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectadas 4 (quatro) tecnologias para compor o esquema terapêutico de pacientes diagnosticados com adultos com EpA radiográfica e não radiográfica que não responderam à terapia convencional (AINE). Um inibidor de IL-17 (bimequizumabe) e três inibidores da Jak: filgotinibe, tofacitinibe e upadacitinibe. Estes dois últimos possuem registro na Anvisa e EMA, enquanto o bimequizumabe na EMA para a população deste relatório. RECOMENDAÇÕES INTERNACIONAIS: Foram encontradas recomendações do NICE (National Institute for Health and Care Excellence - Reino Unido) e CADTH (Canadian Agency for Drugs and Technologies in Health - Canadá) recomendando o ixequizumabe para tratamento da espondiloartrite. Não foram encontradas avaliações da ixequizumabe na SMC (Scottish Medicines Consortium ­ SMC - Escócia) e PBAC (Pharmaceutical Benefits Advisory Committee - Austrália) para a indicação em questão. CONSIDERAÇÕES FINAIS: De forma geral, não foram identificadas diferenças em termos de eficácia e segurança na comparação entre ixequizumabe e outros biológicos disponíveis no SUS. O resultado da análise de custo-minimização demonstrou que o custo de ixequizumabe, tanto no primeiro ano, como no ano subsequente, foi superior a todos os demais medicamentos biológicos em comparação, com a diferença de custo anual variando entre 44 mil reais e 54 mil reais (a depender do comparador). Além disso, o impacto orçamentário incremental foi de R$ 58 milhões no primeiro ano, chegando a R$ 105 milhões no quinto ano de análise, totalizando R$ 436 milhões em cinco anos. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Comitê de Medicamentos presentes na 128ª Reunião Ordinária, realizada no dia 11 de abril de 2024, deliberaram por unanimidade encaminhar o tema para consulta pública com recomendação preliminar desfavorável à incorporação do ixequizumabe para o tratamento de adultos com espondiloartrite axial radiográfica e não radiográfica que não responderam à terapia convencional (anti-inflamatórios não esteroides). Consideraram-se elevadas as estimativas de custo incrementais nas análises de custo-minimização e de impacto orçamentário.

Use of metamizole and other non-opioid analgesics in Switzerland between 2014 and 2019: an observational study using a large health insurance claims database.

OBJECTIVE: To investigate claims patterns for metamizole and other non-opioid analgesics in Switzerland. To characterise users of these non-opioid analgesics regarding sex, age, comedications and canton of residence. METHODS: We conducted a retrospective descriptive study using administrative claims data of outpatient prescribed non-opioid analgesics of the Swiss health insurance company Helsana between January 2014 and December 2019. First, we evaluated the number of claims and defined daily doses  per year of metamizole, ibuprofen, diclofenac and paracetamol in adults aged 18 years or over. Second, we characterised new users of these non-opioid analgesics in terms of sex, age, claimed comedications and canton of residence. RESULTS: From 2014 to 2019, among the investigated non-opioid analgesics, metamizole showed the highest increase in claims (+9545 claims, +50%) and defined daily doses (+86,869 defined daily doses, +84%) per 100,000 adults. Metamizole users had the highest median age (62 years [IQR: 44-77]) compared to ibuprofen (47 years [IQR: 33-62]), diclofenac (57 years [IQR: 43-71]) and paracetamol (58 years [IQR: 39-75]) users. Metamizole users also more frequently claimed proton pump inhibitors, anticoagulants, platelet aggregation inhibitors and antihypertensive drugs than users of other non-opioid analgesics. While metamizole was most frequently claimed in German-speaking regions of Switzerland, ibuprofen and paracetamol were most frequently claimed in the French-speaking regions and diclofenac in German- and Italian-speaking regions. CONCLUSION: In Switzerland, metamizole was increasingly claimed between 2014 and 2019. Metamizole was most frequently claimed by older adults and patients with comedications suggestive of underlying conditions, which can be worsened or caused by use of nonsteroidal anti-inflammatory drugs. The lack of studies regarding the effectiveness and safety of metamizole in this population warrants further investigation.

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.

Patient information leaflets and package inserts of ibuprofen provided in the UK and Thailand: a comparative assessment.

OBJECTIVES: Written medicine information (WMI) is important for ensuring patients understand and use their medicines optimally, but relatively little research has assessed the quality of available WMI. This study assessed the quality of WMI using a sample of leaflets for ibuprofen in the UK and Thailand. METHODS: Leaflets were obtained by purchasing a product from retail outlets or community pharmacies, 18 from each country. In the UK, these were patient information leaflets (PILs); in Thailand, they were package inserts PIs not specifically designed for patients. Leaflets were assessed for content, layout, and readability using standard methods and compared to relevant guidelines. KEY FINDINGS: The UK PILs were uniform and conformed to EU regulatory requirements for content, whereas Thai PIs varied considerably, many failing to include important information required by Thai regulations. Several forms of Thai PIs were found, including some very short leaflets, containing minimal information. The readability of both was rated as poor, all used small font size and had less than desirable white space. Fewer Thai PIs than UK PILs met the Keystone Criteria for ibuprofen. CONCLUSIONS: The extent of variation in format and content of Thai WMI could potentially cause confusion and reduce willingness to read it. PILs, conforming to Thai regulatory guidelines, should be provided with medicines instead. Leaflets in both countries would benefit from improved readability and layout.

Deprescribing potential of commonly used medications among community-dwelling older adults: insights from a pharmacist's geriatric assessment.

Pharmacist's geriatric assessment can provide valuable insights into potential deprescribing targets, while including important information on various health-related domains. Data collected from a geriatric assessment questionnaire, for 388 patients, from the Croatian cohort of the EuroAgeism H2020 ESR 7 international project, along with guideline-based deprescribing criteria, were used to analyse potentially inappropriate prescribing of four medication groups (benzodiazepines (BZN), proton pump inhibitors (PPI), opioids, and non-steroidal anti-inflammatory drugs (NSAID)), and to assess the deprescribing potential. Binary logistic regression was used to explore the effects of age, gender, number of medicines and diagnoses, self-reported health, frailty score, and healthcare utilization on the likelihood of needing deprescribing. More than half of participants (n = 216, 55.2%) are candidates for deprescribing, with 31.1% of PPI, 74.8% of NSAID, 75% of opioid, and 96.1% of BZN users meeting at least one criterion. Most common criteria for deprescribing were inappropriately long use and safety concerns. Women (aOR = 2.58; p < 0.001), those reporting poor self-reported health (aOR = 5.14; p < 0.001), and those exposed to polypharmacy (aOR = 1.29; p < 0.001) had higher odds of needing to have medicines deprescribed. The high rate of deprescribing potential warrants prompt action to increase patient safety and decrease polypharmacy. Pharmacist's geriatric assessment and deprescribing-focused medication review could be used to lead a personalised approach.

Patient characteristics, treatment patterns, healthcare resource utilization, and costs among patients diagnosed with neurofibromatosis type 1 with and without plexiform neurofibromas in Japan.

OBJECTIVES: The objectives of this study were to retrospectively investigate the patient characteristics, treatment patterns, healthcare resource utilization (HCRU), and healthcare costs related to management of neurofibromatosis type 1 (NF1) in Japan. METHODS: Cohorts of NF1 patients with or without plexiform neurofibromas (PN) were identified from the Medical Data Vision database in 2008-2019. Baseline characteristics, NF1 medications, HCRU, and associated costs were assessed using descriptive statistics. All-cause HCRU and costs following the first confirmed NF1 diagnosis date were analyzed per patient per year (PPPY) in Japanese Yen (JPY) and United States Dollar (USD). RESULTS: A total of 4394 NF1 patients without PN and 370 NF1 patients with PN were identified. The mean age was 35.0 and 36.9 years, respectively. The proportion of patients with PN treated with medications was higher than that in patients without PN (except for antirheumatic/immunologic agents). Analgesics/non-steroidal anti-inflammatory drugs were the most frequently prescribed NF1 medications (44.3% and 56.0% in patients without and with PN, respectively), followed by inpatient prescriptions of opioids/opioid-like agents (17.8% and 27.6%, respectively). Inpatient admissions accounted for the highest costs in both cohorts with the average cost PPPY being JPY 2,133,277 (USD 19,861) for patients without PN and JPY 1,052,868 (USD 9802) for patients with PN. CONCLUSIONS: NF1 is treated primarily with supportive care with analgesics/non-steroidal anti-inflammatory drugs being the most frequently prescribed NF1 medications in Japan. Findings underscored the unmet need and substantial economic burden among patients with NF1 and highlighted the need for new treatment options for patients with this disease.

Drug-drug interaction assessment based on a large-scale spontaneous reporting system for hepato- and renal-toxicity, and thrombocytopenia with concomitant low-dose methotrexate and analgesics use.

BACKGROUND: Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment. METHODS: We used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA. RESULTS: After identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω025 = 0.08) and piroxicam (Ω025 = 0.46), and ibuprofen (Ω025 = 0.74) and ketorolac (Ω025 = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs. CONCLUSIONS: Studies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment.

National Trends in Orthopaedic Pain Management from 2016 to 2020.

INTRODUCTION: Effective pain management is vital in orthopaedic care, impacting postoperative recovery and patient well-being. This study aimed to discern national and regional pain prescription trends among orthopaedic surgeons through Medicare claims data, using geospatial analysis to ascertain opioid and nonopioid usage patterns across the United States. METHODS: Physician-level Medicare prescription databases from 2016 to 2020 were filtered to orthopaedic surgeons, and medications were categorized into opioids, muscle relaxants, anticonvulsants, and NSAIDs. Patient demographics were extracted from a Medicare provider demographic data set, while county-level socioeconomic metrics were obtained primarily from the American Community Survey. Geospatial analysis was conducted using Geoda software, using Moran I statistic for cluster analysis of pain medication metrics. Statistical trends were analyzed using linear regression, Mann-Whitney U test, and multivariate logistic regression, focusing on prescribing rates and hotspot/coldspot identification. RESULTS: Analysis encompassed 16,505 orthopaedic surgeons, documenting more than 396 million days of pain medication prescriptions: 57.42% NSAIDs, 28.57% opioids, 9.84% anticonvulsants, and 4.17% muscle relaxants. Annually, opioid prescriptions declined by 4.43% ( P < 0.01), while NSAIDs rose by 3.29% ( P < 0.01). Opioid prescriptions dropped by 210.73 days yearly per surgeon ( P < 0.005), whereas NSAIDs increased by 148.86 days ( P < 0.005). Opioid prescriptions were most prevalent in the West Coast and Northern Midwest regions, and NSAID prescriptions were most prevalent in the Northeast and South regions. Regression pinpointed spine as the highest and hand as the lowest predictor for pain prescriptions. DISCUSSION: On average, orthopaedic surgeons markedly decreased both the percentage of patients receiving opioids and the duration of prescription. Simultaneously, the fraction of patients receiving NSAIDs dramatically increased, without change in the average duration of prescription. Opioid hotspots were located in the West Coast, Utah, Colorado, Arizona, Idaho, the Northern Midwest, Vermont, New Hampshire, and Maine. Future directions could include similar examinations using non-Medicare databases.

Randomized controlled trial demonstrates novel tools to assess patient outcomes of Indigenous cultural safety training.

BACKGROUND: Health care routinely fails Indigenous peoples and anti-Indigenous racism is common in clinical encounters. Clinical training programs aimed to enhance Indigenous cultural safety (ICS) rely on learner reported impact assessment even though clinician self-assessment is poorly correlated with observational or patient outcome reporting. We aimed to compare the clinical impacts of intensive and brief ICS training to control, and to assess the feasibility of ICS training evaluation tools, including unannounced Indigenous standardized patient (UISP) visits. METHOD: Using a prospective parallel group three-arm randomized controlled trial design and masked standardized patients, we compared the clinical impacts of the intensive interactive, professionally facilitated, 8- to10-h Sanyas ICS training; a brief 1-h anti-bias training adapted to address anti-Indigenous bias; and control continuing medical education time-attention matched to the intensive training. Participants included 58 non-Indigenous staff physicians, resident physicians and nurse practitioners from family practice clinics, and one emergency department across four teaching hospitals in Toronto, Canada. Main outcome measures were the quality of care provided during UISP visits including adjusted odds that clinician would be recommended by the UISP to a friend or family member; mean item scores on patient experience of care measure; and clinical practice guideline adherence for NSAID renewal and pain assessment. RESULTS: Clinicians in the intensive or brief ICS groups had higher adjusted odds of being highly recommended to friends and family by standardized patients (OR 6.88, 95% CI 1.17 to 40.45 and OR 7.78, 95% CI 1.05 to 58.03, respectively). Adjusted mean item patient experience scores were 46% (95% CI 12% to 80%) and 40% (95% CI 2% to 78%) higher for clinicians enrolled in the intensive and brief training programs, respectively, compared to control. Small sample size precluded detection of training impacts on clinical practice guideline adherence; 100% of UISP visits were undetected by participating clinicians. CONCLUSIONS: Patient-oriented evaluation design and tools including UISPs were demonstrated as feasible and effective. Results show potential impact of cultural safety training on patient recommendation of clinician and improved patient experience. A larger trial to further ascertain impact on clinical practice is needed. TRIAL REGISTRATION: Clinicaltrials.org NCT05890144. Retrospectively registered on June 5, 2023.