Clinical Assessment of Osteoarthritis Pain: Contemporary Scenario, Challenges, and Future Perspectives.

The multifaceted nature of osteoarthritis (OA) pain presents a challenge in understanding and managing the condition. The diverse pain experiences, progression rates, individual responses to treatments, and complex disease mechanisms contribute to heterogeneity in the clinical studies outcomes. The lack of a standardized methodology for assessing and classifying OA pain challenges healthcare practitioners. This complicates the establishment of universally applicable protocols or standardized guidelines for treatment. This article explores the heterogeneity observed in clinical studies evaluating OA pain treatments, highlighting the necessity for refined methodologies, personalized patient categorization, and consistent outcome measures. It discusses the role of the multidimensional nature of OA pain, underlying pain mechanisms, and other contributing factors to the heterogeneity in outcome measures. Addressing these variations is crucial to establishing a more consistent framework for evidence-based treatments and advancing care of the patient with OA pain.

Evidence-Based Opinions from Multidisciplinary Experts on Use of Naturopathic Herbal Remedies in Pain Management.

Background: Pharmacological approaches to acute and chronic pain management, including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids, are respectively associated with adverse reactions (such as gastrointestinal, cardiovascular, and renal effects) that might limit their use in patients with comorbidities and controversy related to inappropriate use. Naturopathic remedies might offer patients alternative and integrative treatments with minimal side effects. Objective: To explore the regional variation in the acceptance and use of naturopathic remedies in pain management. Methods: Two expert panel discussions were held by GlaxoSmithKline Consumer Healthcare (now Haleon Pte. Ltd.) over 9 and 12 hours in 2020 and 2021, respectively, and attended by multidisciplinary experts in naturopathy, Ayurvedic medicine, community pharmacy, physiotherapy, clinical pharmacy, Western medicine, academics, and naturopathic pain relief. Experts shared and discussed their experiences of naturopathic treatments and relevant clinical evidence related to different types of pain (including joint and muscle pain, migraine, sleeplessness due to pain, and general pain) and examined barriers to providing support to patients. Results: Experts agreed on the potential for curcumin (2020, 71.4% [5/7]; 2021, 91.7% [11/12]) and fish oil (2020, 100% [7/7]) for management of osteoarthritic joint pain although these are not uniformly recommended in osteoarthritis treatment guidelines. In treatment of migraines, coenzyme Q10 and magnesium were favored by experts (2021, 90.9% [10/11] and 63.6% [7/11], respectively). Conclusion: The need was emphasized for more and higher quality clinical studies to support naturopathic remedies, which might not be reflected in the latest treatment guidelines. The expert panel also highlighted missed opportunities for physicians and pharmacists to recommend effective naturopathic treatments.

Model-Based Assessment of the Liver Safety Profile of Acetaminophen to Support its Combination Use with Topical Diclofenac in Mild-to-Moderate Osteoarthritis Pain.

INTRODUCTION: The use of combination therapy of oral acetaminophen and topical diclofenac, having complementary mechanisms of action, is an attractive strategy to enhance the analgesic response in osteoarthritis (OA) pain. While topical diclofenac is considered as well tolerated due to its low systemic exposure, concerns of liver toxicity with acetaminophen at standard analgesic doses remain. Thus, this study aimed to assess the liver safety profile of acetaminophen, particularly in OA management, using a model-based meta-analysis (MBMA). METHODS: A literature review was conducted using the MEDLINE database to identify randomized clinical trials (RCTs) reporting liver toxicity on acetaminophen use. An MBMA was implemented to assess the deviation from the upper limit of normal (ULN) of alanine aminotransferase or aspartate aminotransferase, namely > 0-1 × ULN, > 1.5-2 × ULN, and > 3 × ULN representing mild, moderate, and severe risk of liver abnormality, respectively. RESULTS: A total of 15 RCTs were included in the MBMA, encompassing over 4800 subjects and exposure to acetaminophen ranging from 2 to 26 weeks. Of the 15 included studies, eight involved patients with OA pain, four involved healthy subjects and three were in patients with conditions such as asthma, glaucoma, chronic pain, and cardiovascular disease. Acetaminophen 1500-4000 mg/day was found to exhibit 23% (95% confidence interval (CI): 17.74-29.20), 1.35% (95% CI: 0.17-2.51) and 0.01% (95% CI: 0.00-0.32) increased risk for mild, moderate, and severe liver injury, respectively, versus placebo. Moreover, at therapeutic doses, no correlation was identified between acetaminophen intake and liver abnormality risk. CONCLUSIONS: Overall, our analysis shows that short-term (~ 8-16 weeks) acetaminophen use at therapeutically recommended doses is associated with a low risk of clinically relevant changes in liver enzymes. Given the good tolerability of topical diclofenac, the findings support the safety of the combination of acetaminophen and topical diclofenac, at least over the short term, as treatment for mild-to-moderate OA pain.

Model-Based Meta-Analysis Supporting the Combination of Acetaminophen and Topical Diclofenac in Acute Pain: A Therapy for Mild-to-Moderate Osteoarthritis Pain?

INTRODUCTION: Acetaminophen and topical diclofenac (AtopD) have complementary mechanisms of action and are therefore candidates for combination use in osteoarthritis (OA) pain. However, an evidence gap exists on their combination use in OA pain. This study aimed to assess the effects of this combination and compare its performance relative to monotherapies on pain score reduction and opioid-sparing effect by leveraging evidence from acute pain setting using a model-based meta-analysis (MBMA). METHODS: A literature search was conducted using the MEDLINE database to identify randomized controlled trials (RCTs) studying the combination for acute pain. Subsequently, an MBMA of RCTs was implemented in conjunction with extrapolation principles to infer efficacy in the population of interest. Pain score reduction and opioid-sparing effect (OSE) were selected as the measures of efficacy. RESULTS: A total of 11 RCTs encompassing 1396 patients were included. Exploratory evaluation revealed AtopD combination to show greater pain score reduction versus acetaminophen monotherapy. However, pain score reduction was more susceptible to confounding by opioid patient-controlled analgesia (PCA) than OSE. Therefore, a parsimonious MBMA evaluating OSE was developed from 5 of the 11 RCTs (n = 353 patients). The analysis revealed a statistically significant interaction coefficient, suggesting a reduction of 32% in opioid use with the combination versus acetaminophen monotherapy. Differences in the effect size of the combination were less conclusive versus diclofenac monotherapy. CONCLUSION: Our results indicate greater pain reduction and opioid-sparing efficacy for the AtopD combination versus acetaminophen monotherapy. Given the similar pain pathways and mechanisms of action of the two drugs in acute and mild-to-moderate OA pain, comparable beneficial effects from the combination therapy may be anticipated following extrapolation to chronic OA pain. Prospective RCTs and real-world studies in OA pain are needed to confirm the differences in the efficacy of the combination treatment observed in our study.

Patients' experience and utilization patterns of diclofenac gel in Germany: a real-world study with a prospective longitudinal survey and a retrospective analysis of pharmacy data.

OBJECTIVE: Describe and characterize treatment patterns, satisfaction, improvement in pain and functional impairment (health-related quality of life [HRQoL]) in users of over the counter (OTC) Voltaren gel diclofenac (VGD) 2.32% and 1.16% in a real-world setting. METHODS: This observational real-world German study had prospective and retrospective components. The prospective data were collected from electronic surveys completed by adults who purchased VGD to treat their musculoskeletal pain at baseline and 4 and 12 weeks after baseline. Retrospective data were from a 12-month (March 2019 to February 2020) abstraction from dispensing software platforms used in select German pharmacies. RESULTS: Surveys from 467 participants (mean age 60.8 years) were analyzed. Average pain severity at baseline was 6.0 on an 11-point Numeric Rating Scale (0 = no pain, 10 = worst possible pain), improving by 0.8 and 1.2 points at Weeks 4 and 12, respectively. Performance of functional activities (daily/physical/social activities and errands/chores) improved and the proportion of participants with at least moderate interference decreased at both follow-up timepoints. Retrospective analyses indicated that majority of patients receiving VGD (n = 95,085) were ≥65 years old (67.9%), had one dispensed tube (70.8%) and did not switch to another topical treatment (including other NSAIDs) (77.3%), and were co-prescribed at least one cardiovascular medication (74.3%). CONCLUSIONS: This study provides the first real-world insights into OTC VGD use in Germany. The participants using VGD reported a decrease in pain severity and an improvement of HRQoL while under treatment, as well as resulting satisfaction with treatment. Patients infrequently switched to alternate topical therapies/NSAIDs.

Potential complementary and/or synergistic effects of curcumin and boswellic acids for management of osteoarthritis.

For several thousand years (~4000) Boswellia serrata and Curcuma longa have been used in Aryuvedic medicine for treatment of various illnesses, including asthma, peptic ulcers, and rheumatoid arthritis, all of which are mediated through pathways associated with inflammation and pain. Although the in vivo pharmacology of both these natural ingredients is difficult to study because of poor bioavailability, in vitro data suggest that both influence gene expression mediated through nuclear factor kappa B (NF-κB). Therefore, the activity of pathways associated with inflammation (including NF-κB and lipoxygenase- and cyclooxygenase-mediated reduction in leukotrienes/prostaglandins) and those involved in matrix degradation and apoptosis are reduced, resulting in a reduction in pain. Additive activity of boswellic acids and curcumin was observed in preclinical models and synergism was suggested in clinical trials for the management of osteoarthritis (OA) pain. Overall, studies of these natural ingredients, alone or in combination, revealed that these extracts relieved pain from OA and other inflammatory conditions. This may present an opportunity to improve patient care by offering alternatives for patients and physicians, and potentially reducing nonsteroidal anti-inflammatory or other pharmacologic agent use. Additional research is needed on the effects of curcumin on the microbiome and the influence of intestinal metabolism on the activity of curcuminoids to further enhance formulations to ensure sufficient anti-inflammatory and antinociceptive activity. This narrative review includes evidence from in vitro and preclinical studies, and clinical trials that have evaluated the mechanism of action, pharmacokinetics, efficacy, and safety of curcumin and boswellic acids individually and in combination for the management of OA pain.

Perspectives of Healthcare Professionals Towards Combination Use of Oral Paracetamol and Topical Non-Steroidal Inflammatory Drugs in Managing Mild-to-Moderate Pain for Osteoarthritis in a Clinical Setting: An Exploratory Study.

Purpose: To seek indicative evidence on clinical prescription practice and perspectives regarding combined oral paracetamol (APAP) and/or topical non-steroidal anti-inflammatory drugs (NSAIDs) therapy for managing mild-to-moderate osteoarthritis (OA) pain. Participants and Methods: An exploratory qualitative study to investigate the perspectives towards using APAP and/or topical NSAIDs for OA pain management and whether current clinical practices are aligned with OA guidelines was conducted using a two-round modified Delphi methodology among three general practitioners, three orthopedists, and two pharmacists from Australia, Malaysia, and Sweden during January-June 2021. In the first round, 60-minute virtual in-depth interviews were conducted individually; in the second round, summary of the key findings was shared with the panel to seek clarity on the level of consensus (≥70% unanimity) and disagreement. Results: The healthcare professionals (HCPs) agreed that APAP was considered as a universally accepted pharmacologic for most OA patients except those with contraindications or allergies. Consensus was achieved towards APAP combination with topical NSAIDs being a safer alternative than with oral NSAIDs. However, prescription uptake of combined therapy APAP with topical NSAIDs was low among the panel due to lack of strong scientific evidence on efficacy and awareness. Differences in clinical practice across and within countries could be due to different reference sources for OA pain - clinical practice experience or local/international guidelines/medical products handbooks. Conclusion: The study suggests an opportunity to raise awareness of the suitability and potential benefits for adjuvant topical NSAIDs to APAP for effective OA pain management as well as a need for universal OA guidelines.

A Randomized, Double-Blind Study Assessing Changes in Cognitive Function in Indian School Children Receiving a Combination of Bacopa monnieri and Micronutrient Supplementation vs. Placebo.

Several studies have indicated a chronic cognitive enhancing effect of Bacopa monnieri across different ages and cognitive impairment associated with vitamin and mineral deficiencies in children. Therefore, we investigated the effects of 4-month supplementation with a combination of B. monnieri extract and multiple micronutrients on cognitive functions in Indian school children aged 7-12 years. This was a randomized, double-blind, parallel design, single-center study in which 300 children were randomized to receive a beverage either fortified with B. monnieri and multiple micronutrients ("fortified") or a non-fortified isocaloric equivalent ("control") twice-daily for 4 months. Cognitive function was assessed by the Cambridge Neuropsychological Automated Test Battery (CANTAB) administered at baseline, Day 60 and Day 121. The primary endpoint was change in short-term memory (working memory) from baseline in subjects receiving "fortified" vs. "control" beverages after 4 months. Secondary endpoints included sustained attention, episodic memory, and executive function. The "fortified" beverage did not significantly improve short-term memory or any of the secondary outcomes tested relative to the "control" beverage. However, the spatial working memory "strategy" score showed significant improvement on Day 60 (difference between groups in change from baseline: -0.55; p < 0.05), but not on Day 121 due to the active intervention. Study products were well-tolerated. Reasons for these unexpected findings are discussed.