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Objective Osteoarthritis (OA) causes significant musculoskeletal pain. This study assessed the efficacy and safety of fasinumab, an investigational nerve growth factor inhibitor, in patients with moderate-to-severe OA pain of the knee/hip. Methods In this Phase 3, randomized, double-blind, placebo- and non-steroidal anti-inflammatory drug (NSAID)-controlled study, patients with OA (Kellgren-Lawrence grade ≥ 2; Western Ontario and McMaster Universities Arthritis Index [WOMAC] pain score ≥ 4) received (2:1:1:1) fasinumab 1 mg every 4 weeks, diclofenac 75 mg twice daily, celecoxib 200 mg daily, or placebo for 24 weeks. Co‑primary endpoints were change in WOMAC pain and physical function scores to Week 24 versus placebo. For safety, joints were imaged in all patients at pre‑specified times, regardless of symptoms. Results Of 4531 patients screened, 1650 were randomized. At Week 24, greater improvements were observed for fasinumab versus placebo; least-squares mean difference: –0.63 ( p  = 0.0003) for WOMAC pain and –0.64 ( p  = 0.0003) for physical function. Improvements were numerically greater for fasinumab versus NSAIDs for physical function (–0.64 versus –0.31; nominal p  < 0.05) and pain (–0.63 versus − 0.39; p  = NS). Adjudicated arthropathies occurred in 1.6% of placebo-treated, 1.5% of NSAID-treated, and 5.6% of fasinumab-treated patients; joint replacements occurred in 3.6% of placebo-treated, 4.8% of NSAID-treated, and 3.4% of fasinumab-treated patients. Conclusion Fasinumab significantly improved WOMAC pain and physical function scores versus placebo in < 24 weeks in difficult-to-treat patients with pain due to OA of the knee/hip. Adjudicated arthropathies were more frequent with fasinumab; there were no differences in the proportions of patients with joint replacements. Trial registration Clinicaltrials.gov NCT03304379. Date of first registration: October 2, 2017.

BackgroundTo date, only a single controlled trial provided evidence that non-steroidal anti-inflammatory drugs (NSAIDs) given continuously reduce radiographic progression compared with an on-demand therapy over 2 years in patients with ankylosing spondylitis (AS). In the current study, we tested whether such an effect of NSAIDs could be confirmed in another randomised trial.MethodsPatients with AS were randomised for treatment with either continuous (150 mg/day) or on-demand diclofenac for 2 years. Tumour necrosis factor-blocker treatment was not allowed during the entire study period. The primary outcome was the difference in radiographic progression in the spine as measured by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) scored by two readers blinded to treatment arm and time point.Results62 of 85 patients enrolled in the continuous arm and 60 of 82 enrolled in the on-demand arm completed the study. The mSASSS progression was numerically higher in the continuous group (1.28 (0.7 to 1.9) vs 0.79 (0.2 to 1.4)) (p=0.39). If only patients were analysed who were either C reactive protein positive or had syndesmophytes at baseline, there was again a higher radiographic progression in the continuous versus the on-demand group: 1.68 (0.7 to 2.6) vs 0.96 (0.0 to 1.9) and 2.11 (1.1 to 3.1) vs 0.95 (0.0 to 1.9), respectively. There was no difference between the two treatment groups regarding adverse events.ConclusionsIn our study, continuous treatment with diclofenac over 2 years did not reduce radiographic progression compared with on-demand treatment in AS.Trial registration numbersEudraCt-no 2007-007637-39; ClinicalTrials.gov NCT00715091.

BackgroundRecent meta-analyses suggested diclofenac may be superior to indomethacin in preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). The aim of our study was to compare the efficacy of 100 mg rectal indomethacin versus diclofenac on PEP incidences.DesignThis multicentre, double-blinded, randomised controlled trial was conducted in nine tertiary centres in China. Patients with low and high risk for PEP and native papilla were randomly allocated (1:1) to receive 100 mg diclofenac or 100 mg indomethacin rectally before ERCP. The primary outcome was the occurrence of PEP defined by the Cotton consensus. The intention-to-treat principle was conducted for the analysis.ResultsThe trial was terminated early for futility after the predetermined first interim analysis. Between June 2023 and May 2024, 1204 patients were randomised into the diclofenac group (n=600) or indomethacin group (n=604). Baseline characteristics were balanced. The primary outcome occurred in 53 patients (8.8%) of 600 patients allocated to the diclofenac group and 37 patients (6.1%) of 604 patients allocated to the indomethacin group (relative risk 1.44; 95% CI 0.96 to 2.16, p=0.074). PEP occurred in 35 (14.2%) of 247 high-risk patients in the diclofenac group and 26 (9.8%) of 266 high-risk patients in the indomethacin group (p=0.124). PEP incidences were also comparable in low-risk patients between the two groups (18/353 (5.1%) vs 11/338 (3.3%), p=0.227). Other ERCP-related complications did not differ between the two groups.ConclusionPre-procedure 100 mg rectal diclofenac was not superior to the same dose of rectal indomethacin regarding preventing PEP. These findings supported current clinical practice guidelines of 100 mg indomethacin or diclofenac for PEP prophylaxis in patients without contraindications.Trial registration numberClinicalTrials.gov (NCT05947461).

This study compared the pharmacokinetic properties and safety profile of low-dose (18- and 35-mg) diclofenac capsules manufactured using SoluMatrix Fine Particle Technology (Trademark of iCeutica Inc. (Philadelphia, Pennsylvania), and the technology is licensed to Iroko Pharmaceuticals, LLC (Philadelphia, Pennsylvania) for exclusive use in NSAIDs), which produces submicron-sized drug particles with enhanced dissolution properties, to those of diclofenac potassium immediate-release (IR) 50-mg tablets. This Phase 1, single-center, randomized, open-label, single-dose crossover study was conducted in 40 healthy volunteers. Subjects received, in randomized order, SoluMatrix diclofenac 18- or 35-mg capsules in the fasting condition, SoluMatrix diclofenac 35-mg capsules under fed conditions, and diclofenac potassium IR 50-mg tablets under fasting and fed conditions. Pharmacokinetic parameters (Tmax, Cmax, AUC0–t, AUC0–∞) were calculated from the concentrations of diclofenac in the plasma. Absorption, food effect, and dose proportionality were determined using a mixed-model ANOVA for Cmax, AUC0–t, and AUC0–∞. Tolerability was assessed by recording adverse events, physical examination findings, vital sign measurements: clinical laboratory test results. Overall, 35 healthy volunteers aged 18 to 52 years completed the study. The mean age of the subjects was 33.4 years, and approximately half were men (47.5%). Median Tmax values were similar between the low-dose SoluMatrix diclofenac 35-mg capsules and the diclofenac potassium IR 50-mg tablets (both, ~1.0 hour). The mean maximum plasma concentration (Cmax) after the administration of low-dose SoluMatrix diclofenac 35-mg capsules was 26% lower than that with diclofenac potassium IR 50-mg tablets under fasting conditions (868.72 vs 1194.21 ng/mL). The administration of low-dose SoluMatrix diclofenac 35-mg capsules was associated with a 23% lower overall systemic exposure compared with that of diclofenac potassium IR 50-mg tablets under fasting conditions. Food decreased the rate but not the overall extent of absorption of SoluMatrix diclofenac. No serious AEs and no clinically significant abnormalities in physical examination findings, including vital sign measurements, or clinical laboratory test results, were noted during this study. The pharmacokinetic properties of low-dose SoluMatrix diclofenac capsules in the healthy volunteers in this study suggest rapid diclofenac absorption as measured by Tmax. Low-dose SoluMatrix diclofenac capsules represent a potential option for the management of acute and osteoarthritis-related pain.

Introduction Osteoarthritis (OA) is a chronic, progressive joint disease characterized by the degradation of articular cartilage, subchondral bone remodeling, synovial inflammation, and osteophyte formation. Despite being a leading cause of disability in older people, effective long-term management of OA remains a significant challenge. Current treatment strategies primarily focus on symptom control, with both non-pharmacological and pharmacological interventions. Materials and methods A systematic literature review followed by a structured Delphi survey was conducted, involving an international Technical Expert Panel (TEP) of OA specialists. The panel evaluated the efficacy, safety, and clinical utility of combining low dose diclofenac and chondroitin sulfate in OA management. Results The analysis of expert consensus indicated that the combination of low dose diclofenac and chondroitin sulfate may be effective in reducing pain and improving joint function in patients with knee OA. Additionally, this combination could reduce the need for higher doses of NSAIDs, thereby minimizing systemic adverse effects. Conclusion The combination of low dose diclofenac and chondroitin sulfate represents a promising therapeutic strategy for managing knee OA. Further studies are needed to confirm these findings and optimize therapeutic strategies to improve patient outcomes.

This study investigated the ability of rhodococci to biodegrade diclofenac (DCF), one of the polycyclic non-steroidal anti-inflammatory drugs (NSAIDs) most frequently detected in the environment. Rhodococcus ruber strain IEGM 346 capable of complete DCF biodegradation (50 µg/L) over 6 days was selected. It is distinguished by the ability to degrade DCF at high (50 mg/L) concentrations unlike other known biodegraders. The DCF decomposition process was accelerated by adding glucose and due to short-term cell adaptation to 5 µg/L DCF. The most typical responses to DCF exposure observed were the changed ζ-potential of bacterial cells; increased cell hydrophobicity and total cell lipid content; multi-cellular conglomerates formed; and the changed surface-to-volume ratio. The obtained findings are considered as mechanisms of rhodococcal adaptation and hence their increased resistance to toxic effects of this pharmaceutical pollutant. The proposed pathways of bacterial DCF metabolisation were described. The data confirming the C-N bond cleavage and aromatic ring opening in the DCF structure were obtained.

This study aimed to compare the effects of oral pre-operative aceclofenac and supplemental intra-ligamentary mepivacaine and articaine injection on the anaesthetic efficacy of failed inferior alveolar nerve block (IANB) in patients with symptomatic irreversible pulpitis in mandibular molars. A total of 126 patients who fulfilled the inclusion criteria were selected for the study intervention. The study design was a prospective, randomised, double-blinded clinical trial. Pre-operative medication was administered 15 minutes before the patients received the standard IANB. Subsequently, the endodontic therapy was started. Pain felt at any time during the procedure was recorded on a 170 mm Heft-Parker visual analogue scale (VAS), and a supplemental intra-ligamentary injection was administered. Based on the pre-operative medication and the intra-ligamentary injection received, the patients were categorized into the following four groups: two groups received 4% articaine with 1:100,000 epinephrine as an intra-ligamentary injection with or without aceclofenac as the pre-operative medication (Group 1 and Group 2, respectively), and two other groups received 3% plain mepivacaine with or without aceclofenac (Group 3 and Group 4, respectively). The VAS scores were determined pre-operatively, following access preparation and/or instrumentation within the dentin, the pulpal space, and the instrumentation of canals. Data were analyzed using Pearson's chi-square test and independent -test. A -value < 0.05 was considered statistically significant. Concerning the supplemental intra-ligamentary injection, 4% articaine with 1:100,000 epinephrine showed a higher success rate than 3% plain mepivacaine, irrespective of the pre-operative medication used, and the difference was statistically significant (  < 0.05). In addition, if the supplemental intra-ligamentary injection was complemented with pre-operative medication such as aceclofenac 100 mg, the anaesthetic efficacy improved compared to groups receiving a placebo as pre-operative medication (  > 0.05). The anesthetic efficacies of the four groups were as follows: Group 1 (87.1%) > Group 2 (66.7%) > Group 3 (60.6%) > Group 4 (53.1%). In patients with symptomatic irreversible pulpitis of mandibular molars, an intraligamentary injection of 4% articaine combined with 1:100,000 epinephrine can significantly aid in achieving anesthesia in situations where primary IANB is unsuccessful. Mandibular molars with symptomatic irreversible pulpitis are associated with a high anaesthetic failure rate of a single primary IANB injection during endodontic treatment. Adding an oral pre-operative aceclofenac medication and a supplemental intra-ligamentary injection, augments the anaesthetic efficacy in such cases.

Background Neck pain (NP) is a common musculoskeletal disorder in primary care that frequently causes discomfort. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used to reduce neck pain and associated inflammation and facilitate earlier recovery. Topical diclofenac diethylamine (DDEA) 1.16% gel is clinically proven to be effective and well tolerated in acute and chronic musculoskeletal conditions, but until now no clinical data existed for its use in acute NP. The aim of this study was to assess the efficacy and safety of DDEA 1.16% gel compared with placebo gel in acute NP. Methods In a randomized, double-blind, placebo-controlled study, patients with acute NP (n = 72) were treated with DDEA 1.16% gel (2 g, 4x/day, for 5 days) or placebo. Efficacy assessments included pain-on-movement (POM), pain-at-rest (PAR), functional neck disability index (NDI) and response to treatment (decrease in POM by 50% after 48 h). Adverse events (AEs) were recorded throughout the study. Results The primary outcome, POM at 48 h, was statistically significantly lower with DDEA gel (19.5 mm) vs. placebo (56.9 mm) (p < 0.0001), representing a clinically relevant decrease from baseline (75% vs. 23%, respectively). All POM scores were significantly lower with DDEA gel vs. placebo from 1 h, as were PAR and NDI scores from first assessment (24 h) onwards (all p < 0.0001). Response to treatment was significantly higher with DDEA gel (94.4%) vs. placebo (8.3%) (p < 0.0001). There were no AEs with DDEA gel. Conclusions DDEA 1.16% gel, which is available over-the-counter, was effective and well tolerated in the treatment of acute neck pain. The tools used to assess efficacy suggest that it quickly reduced neck pain and improved neck function. However, questions remain regarding the comparability and validity of such tools. Further studies will help ascertain whether DDEA 1.16% gel offers an alternative treatment option in this common, often debilitating condition. Trial registration ClinicalTrials.gov identifier: NCT01335724

Cyclo-oxygenase (COX)-2-selective non-steroidal anti-inflammatory drugs (NSAIDs) and non-selective NSAIDs plus a proton-pump inhibitor (PPI) have similar upper gastrointestinal outcomes, but risk of clinical outcomes across the entire gastrointestinal tract might be lower with selective drugs than with non-selective drugs. We aimed to compare risk of gastrointestinal events associated with celecoxib versus diclofenac slow release plus omeprazole. We undertook a 6-month, double-blind, randomised trial in patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk at 196 centres in 32 countries or territories. Patients tested negative for Helicobacter pylori and were aged 60 years and older or 18 years and older with previous gastroduodenal ulceration. We used a computer-generated randomisation schedule to assign patients in a 1:1 ratio to receive celecoxib 200 mg twice a day or diclofenac slow release 75 mg twice a day plus omeprazole 20 mg once a day. Patients and investigators were masked to treatment allocation. The primary endpoint was a composite of clinically significant upper or lower gastrointestinal events adjudicated by an independent committee. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00141102. 4484 patients were randomly allocated to treatment (2238 celecoxib; 2246 diclofenac plus omeprazole) and were included in intention-to-treat analyses. 20 (0·9%) patients receiving celecoxib and 81 (3·8%) receiving diclofenac plus omeprazole met criteria for the primary endpoint (hazard ratio 4·3, 95% CI 2·6–7·0; p<0·0001). 114 (6%) patients taking celecoxib versus 167 (8%) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events (p=0·0006). Risk of clinical outcomes throughout the gastrointestinal tract was lower in patients treated with a COX-2-selective NSAID than in those receiving a non-selective NSAID plus a PPI. These findings should encourage review of approaches to reduce risk of NSAID treatment. Pfizer Inc.