The relative efficacy of topical non-steroidal anti-inflammatory drugs and capsaicin in osteoarthritis

Background Pain is often the most troubling issue for people with osteoarthritis (OA) and is typically the focus of pharmacological management. A multitude of treatment options are available for OA, but these produce, on average, only small to moderate reductions in pain. Often the modest reductions in pain do not outweigh the safety concerns of traditional analgesics. Topical non-steroidal anti-inflammatory drugs (NSAIDs) and capsaicin are safe alternatives, with different mechanisms of action, that are widely used for knee and hand OA. However, there is a paucity of evidence to guide the choice between the treatments. Their relative efficacies are unknown and it is unclear if certain people would benefit more from one treatment than the other. The identification of predictors of response to the treatments is essential in order to maximise treatment effects and implement a precision medicine approach in OA care. Objectives [1] To determine the relative efficacy of topical NSAIDs and capsaicin in OA, [2] to identify predictors of response that may allow topical therapy to be tailored to the individual, and [3] to implement and appraise methods that guide precision medicine in OA. Methods Systematic literature searches were conducted for randomised controlled trials (RCTs) of topical NSAIDs or capsaicin in OA and neuropathic pain (NP). NP was chosen as a surrogate for phenotypes with predominantly neuropathic-like pain. Average treatment effects were examined using aggregate data, extracted from eligible publications. Placebo-controlled RCTs were pooled in random-effects conventional meta-analyses (CMA) for the specific (difference between treatment and placebo) and overall (improvement from baseline in the treatment group) treatment effects. Network meta-analysis (NMA) compared the treatments using placebo as a common comparator. Aggregate data effect sizes (ES) were presented as Hedges' g. Predictors of response were examined using individual patient data meta-analysis (IPD MA) and a pilot n-of-1 trial series. Raw IPD from eligible RCTs, acquired through author contact and direct enquiry to pharmaceutical companies, were pooled in IPD MA. Predictors of the specific (treatment-by-covariate interactions) and overall (prognostic factors) treatment effect were investigated. Participants with radiographic, painful knee OA were recruited to an open label pilot n-of-1 trial series. Participants were randomly allocated to three treatment cycles consisting of alternating periods of 5% ibuprofen gel and 0.025% capsaicin (Zacin) cream. Treatment periods were four weeks. Treatment preferences were determined at an individual level and responses were pooled across participants to examine the variation in responses and potential predictors of response. Results Of 63 topical NSAID and 10 capsaicin RCTs identified in the systematic literature search, CMA and NMA were based on 21 (n=6,191) and five (n=415) RCTs for topical NSAIDs and capsaicin, respectively. Moderate level evidence suggested that topical NSAIDs were effective for pain relief in OA (21 RCTs, ES: 0.31, 95% confidence interval [CI] 0.20 to 0.41). Very low level evidence suggested that capsaicin was only effective when used at the 0.025% concentration (4 RCTs, ES 0.41, 95%CI 0.17 to 0.64; ES of all capsaicin RCTs: 5 RCTs, ES 0.28, 95%CI -0.04 to 0.60). Absolute levels of pain relief from the treatments, compared to baseline, were substantial (overall effect: topical NSAIDs ES 1.23, 95%CI 1.06 to 1.41; capsaicin ES 1.05, 95%CI 0.52 to 1.57). Very low level evidence in NMA indicated that, on average, topical NSAIDs and capsaicin were equally effective (ES 0.04, 95% credible interval [CrI] -0.29 to 0.37). IPD were provided for 15 (n=3,889) topical NSAID RCTs, including 11 (n=3,140) placebo-controlled trials. No IPD were obtained for capsaicin. Nine potential predictors of response to topical NSAIDs were examined. A significant but small interaction was observed between sex and topical NSAID use, with women reporting a greater effect (11 RCTs, 2,939 participants, p=0.023). Women also reported larger overall levels of pain relief on topical NSAIDs (15 RCTs, 1,857 participants, p=0.008), but this could be explained by baseline pain severity. Twenty-two participants enrolled in the pilot n-of-1 trial series and completed 104 treatment periods. Clinically important pain relief (≥1 point on 0-10 numeric rating scale) was achieved in 64% of the completed periods. Women reported greater pain reduction from baseline irrespective of treatment (p=0.031), but this could be explained by baseline pain severity. No difference in pain relief was observed, on average, between topical ibuprofen and capsaicin (p=0.271). Individual responses to treatment varied, with approximately 60% of people preferring one treatment over the other, but without clear predictors for the preference. Twenty-five potential predictors of response were examined, of which fibromyalgia severity, distal pressure pain thresholds, temporal summation, synovial hypertrophy, and quadriceps strength inconsistently associated with a preference for one treatment over the other. Very low level evidence suggested that low-dose capsaicin cream was not effective for NP (7 RCTs, ES -0.18, 95%CI -0.90 to 0.53). No data were available for the CMA of topical NSAIDs in NP. In addition, insufficient IPD were received for NP participants and it was not possible to examine for predictors of response to topical NSAIDs or capsaicin in NP. Conclusion Topical NSAIDs and capsaicin may both effectively relieve OA pain, but treatment effects from group comparisons do not directly translate to treatment outcomes at the individual level. Patients with different pain mechanisms may respond differently to these two agents, but definitive trial evidence is still needed. Presently, patients may benefit from trying both treatments to determine which is better for them. To better guide the care of an individual, evidence synthesis should encompass a spectrum of methods, from study-level to participant-level evidence. Further development of IPD MA and n-of-1 trial series methodology is required to successfully guide precision medicine

Comment on: Conventional and biologic disease-modifying anti-rheumatic drugs for osteoarthritis: a meta-analysis of randomized controlled trials: Reply

MD reports a grant from AstraZeneca funding a non-drug PI-led study in Nottingham (Sons of Gout study) and honoraria for Advisory boards on osteoarthritis and gout for AstraZeneca, Grunenthal, Mallinckrodt, and Roche, outside the submitted work. WZ reports honoraria for Grunenthal and speaker fees for Bioiberica and Hisun, outside the submitted work. All other authors have declared no conflicts of interest

Comment on: Conventional and biologic disease-modifying anti-rheumatic drugs for osteoarthritis: a meta-analysis of randomized controlled trials: Reply

MD reports a grant from AstraZeneca funding a non-drug PI-led study in Nottingham (Sons of Gout study) and honoraria for Advisory boards on osteoarthritis and gout for AstraZeneca, Grunenthal, Mallinckrodt, and Roche, outside the submitted work. WZ reports honoraria for Grunenthal and speaker fees for Bioiberica and Hisun, outside the submitted work. All other authors have declared no conflicts of interest

Individual responses to topical ibuprofen gel or capsaicin cream for painful knee osteoarthritis: a series of n-of-1 trials

OBJECTIVES: To determine individual responses to ibuprofen gel or capsaicin cream for painful, radiographic knee OA using a series of n-of-1 trials. METHODS: Twenty-two participants were allocated 5% ibuprofen gel (A) and 0.025% capsaicin cream (B) in random sequence (AB or BA). Patients underwent up to 3 treatment cycles, each comprising one treatment for 4 weeks, an individualized washout period (maximum 4 weeks), then the other treatment for 4 weeks. Differential (ibuprofen or capsaicin) response was defined when change-from-baseline pain intensity scores (0-10 NRS) differed by ≥1 between treatments in ≥2 cycles within a participant. RESULTS: A total of 104 treatment periods were aggregated. Mean pain reduction was 1.2 (95% CI: 0.5, 1.8) on ibuprofen and 1.6 (95% CI: 0.9, 2.4) on capsaicin (P = 0.221). Of 22 participants, 4 (18%) had a greater response to ibuprofen, 9 (41%) to capsaicin, 4 (18%) had similar responses, and 5 (23%) were undetermined. CONCLUSION: Irrespective of equal efficacy overall, 59% of people displayed a greater response to one treatment over the other. Patients who do not benefit from one type of topical treatment should be offered to try another, which may be more effective. N-of-1 trials are useful to identify individual response to treatment. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, NCT03146689

Identifying predictors of response to oral non-steroidal anti-inflammatory drugs and paracetamol in osteoarthritis: a hypothesis-driven protocol for an OA Trial Bank individual participant data meta-analysis

Introduction Symptomatic treatments for osteoarthritis (OA) provide only small-to-moderate efficacy over placebo in randomised controlled trials (RCTs). Treatment guidelines therefore have emphasised the need to identify predictors of treatment response through subgroup and multiple regression analysis. Individual participant data (IPD) meta-analysis is recommended as an efficient approach for this purpose. To our knowledge, this has not been undertaken for oral non-steroidal anti-inflammatory drugs (NSAIDs), including paracetamol, in OA. In this IPD meta-analysis, we aim to identify RCTs with specific mechanistic features related to OA pain, such as joint inflammation. We hypothesise that NSAIDs may work better for participants with joint inflammation, whereas paracetamol may not. Methods and analysis A comprehensive literature search will be conducted on the databases of Web of Science, Embase, Medline, CINAHL, AMED and the Cochrane Library from 1 January 1998 to 1 December 2020. All RCTs related to oral NSAIDs or paracetamol including placebo-controlled trials in people with OA that have evaluated pain-related peripheral risk factors (eg, clinically detected knee effusion, synovial hypertrophy or effusion on imaging, knee morning stiffness, elevated serum C-reactive protein (CRP) level) and/or central pain risk factors (eg, pain elsewhere, depression, anxiety, sleep disturbance) will be retrieved. The outcome will be change in pain from baseline. Change in function and patient global assessment will also be included as outcomes if available. Investigators of all eligible trials will be contacted for IPD. Multilevel regression models will be used to identify predictors for the specific (active-placebo) and the overall treatment effect (change from baseline in active group). Ethics and dissemination No identifiable data will be included in this study and no formal ethics approval is required as no new data collection will be processed. Results of this hypothesis-driven IPD meta-analysis will be disseminated through conference presentations and publication in peer-reviewed journals. PROSPERO registration number CRD42020165098

Relative efficacy of different exercises for pain, function, performance and quality of life in knee and hip osteoarthritis: systematic review and network meta-analysis

Background: Guidelines recommend exercise as a core treatment for osteoarthritis (OA). However, it is unclear which type of exercise is most effective, leading to inconsistency between different recommendations. Objectives: To investigate the relative efficacy of different exercises (aerobic, mind-body, strengthening, flexibility/skill, or mixed) for improving pain, function, performance and quality of life (Qol) for knee and hip OA at, or nearest to, 8 weeks. Methods: We searched nine electronic databases up until December 2017 for randomised controlled trials that compared exercise with usual care or with another exercise type. Bayesian network meta–analysis was used to estimate the relative effect size (ES) and corresponding 95% credibility interval (CrI) (PROSPERO registration: CRD42016033865) Findings: We identified and analysed 103 trials (9,134 participants). Aerobic exercise was most beneficial for pain (ES 1.11; 95%CrI 0.69, 1.54) and performance (1.05; 0.63, 1.48). Mind–body exercise, which had pain benefit equivalent to that of aerobic exercise (1.11; 0.63, 1.59), was the best for function (0.81; 0.27, 1.36). Strengthening and flexibility/skill exercises improved multiple outcomes at a moderate level. Mixed exercise was the least effective for all outcomes and had significantly less pain relief than aerobic and mind–body exercises. Trend for exercise hierarchy was significant for pain (p=0.01), but not for function (p=0.07), performance (p=0.06) or QoL (p=0.65) Conclusion:The effect of exercise varies according to the type of exercise and target outcome. Aerobic or mind–body exercise may be the best for pain and function improvements

Comparative efficacy of exercise therapy and oral non-steroidal anti-inflammatory drugs and paracetamol for knee or hip osteoarthritis: a network meta-analysis of randomised controlled trials

Clinical guidelines recommend exercise as a core treatment for knee or hip osteoarthritis (OA). However, how its analgesic effect compares to analgesics, for example, oral non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol-the most commonly used analgesics for OA, remains unknown. Network meta-analysis. PubMed, Embase, Scopus, Cochrane Library and Web of Science from database inception to January 2022. Randomised controlled trials (RCTs) comparing exercise therapy with oral NSAIDs and paracetamol directly or indirectly in knee or hip OA. A total of n=152 RCTs (17 431 participants) were included. For pain relief, there was no difference between exercise and oral NSAIDs and paracetamol at or nearest to 4 (standardised mean difference (SMD)=-0.12, 95% credibility interval (CrI) -1.74 to 1.50; n=47 RCTs), 8 (SMD=0.22, 95% CrI -0.05 to 0.49; n=2 RCTs) and 24 weeks (SMD=0.17, 95% CrI -0.77 to 1.12; n=9 RCTs). Similarly, there was no difference between exercise and oral NSAIDs and paracetamol in functional improvement at or nearest to 4 (SMD=0.09, 95% CrI -1.69 to 1.85; n=40 RCTs), 8 (SMD=0.06, 95% CrI -0.20 to 0.33; n=2 RCTs) and 24 weeks (SMD=0.05, 95% CrI -1.15 to 1.24; n=9 RCTs). Exercise has similar effects on pain and function to that of oral NSAIDs and paracetamol. Given its excellent safety profile, exercise should be given more prominence in clinical care, especially in older people with comorbidity or at higher risk of adverse events related to NSAIDs and paracetamol. CRD42019135166

The relative efficacy of topical non-steroidal anti-inflammatory drugs and capsaicin in osteoarthritis

Background Pain is often the most troubling issue for people with osteoarthritis (OA) and is typically the focus of pharmacological management. A multitude of treatment options are available for OA, but these produce, on average, only small to moderate reductions in pain. Often the modest reductions in pain do not outweigh the safety concerns of traditional analgesics. Topical non-steroidal anti-inflammatory drugs (NSAIDs) and capsaicin are safe alternatives, with different mechanisms of action, that are widely used for knee and hand OA. However, there is a paucity of evidence to guide the choice between the treatments. Their relative efficacies are unknown and it is unclear if certain people would benefit more from one treatment than the other. The identification of predictors of response to the treatments is essential in order to maximise treatment effects and implement a precision medicine approach in OA care. Objectives [1] To determine the relative efficacy of topical NSAIDs and capsaicin in OA, [2] to identify predictors of response that may allow topical therapy to be tailored to the individual, and [3] to implement and appraise methods that guide precision medicine in OA. Methods Systematic literature searches were conducted for randomised controlled trials (RCTs) of topical NSAIDs or capsaicin in OA and neuropathic pain (NP). NP was chosen as a surrogate for phenotypes with predominantly neuropathic-like pain. Average treatment effects were examined using aggregate data, extracted from eligible publications. Placebo-controlled RCTs were pooled in random-effects conventional meta-analyses (CMA) for the specific (difference between treatment and placebo) and overall (improvement from baseline in the treatment group) treatment effects. Network meta-analysis (NMA) compared the treatments using placebo as a common comparator. Aggregate data effect sizes (ES) were presented as Hedges' g. Predictors of response were examined using individual patient data meta-analysis (IPD MA) and a pilot n-of-1 trial series. Raw IPD from eligible RCTs, acquired through author contact and direct enquiry to pharmaceutical companies, were pooled in IPD MA. Predictors of the specific (treatment-by-covariate interactions) and overall (prognostic factors) treatment effect were investigated. Participants with radiographic, painful knee OA were recruited to an open label pilot n-of-1 trial series. Participants were randomly allocated to three treatment cycles consisting of alternating periods of 5% ibuprofen gel and 0.025% capsaicin (Zacin) cream. Treatment periods were four weeks. Treatment preferences were determined at an individual level and responses were pooled across participants to examine the variation in responses and potential predictors of response. Results Of 63 topical NSAID and 10 capsaicin RCTs identified in the systematic literature search, CMA and NMA were based on 21 (n=6,191) and five (n=415) RCTs for topical NSAIDs and capsaicin, respectively. Moderate level evidence suggested that topical NSAIDs were effective for pain relief in OA (21 RCTs, ES: 0.31, 95% confidence interval [CI] 0.20 to 0.41). Very low level evidence suggested that capsaicin was only effective when used at the 0.025% concentration (4 RCTs, ES 0.41, 95%CI 0.17 to 0.64; ES of all capsaicin RCTs: 5 RCTs, ES 0.28, 95%CI -0.04 to 0.60). Absolute levels of pain relief from the treatments, compared to baseline, were substantial (overall effect: topical NSAIDs ES 1.23, 95%CI 1.06 to 1.41; capsaicin ES 1.05, 95%CI 0.52 to 1.57). Very low level evidence in NMA indicated that, on average, topical NSAIDs and capsaicin were equally effective (ES 0.04, 95% credible interval [CrI] -0.29 to 0.37). IPD were provided for 15 (n=3,889) topical NSAID RCTs, including 11 (n=3,140) placebo-controlled trials. No IPD were obtained for capsaicin. Nine potential predictors of response to topical NSAIDs were examined. A significant but small interaction was observed between sex and topical NSAID use, with women reporting a greater effect (11 RCTs, 2,939 participants, p=0.023). Women also reported larger overall levels of pain relief on topical NSAIDs (15 RCTs, 1,857 participants, p=0.008), but this could be explained by baseline pain severity. Twenty-two participants enrolled in the pilot n-of-1 trial series and completed 104 treatment periods. Clinically important pain relief (≥1 point on 0-10 numeric rating scale) was achieved in 64% of the completed periods. Women reported greater pain reduction from baseline irrespective of treatment (p=0.031), but this could be explained by baseline pain severity. No difference in pain relief was observed, on average, between topical ibuprofen and capsaicin (p=0.271). Individual responses to treatment varied, with approximately 60% of people preferring one treatment over the other, but without clear predictors for the preference. Twenty-five potential predictors of response were examined, of which fibromyalgia severity, distal pressure pain thresholds, temporal summation, synovial hypertrophy, and quadriceps strength inconsistently associated with a preference for one treatment over the other. Very low level evidence suggested that low-dose capsaicin cream was not effective for NP (7 RCTs, ES -0.18, 95%CI -0.90 to 0.53). No data were available for the CMA of topical NSAIDs in NP. In addition, insufficient IPD were received for NP participants and it was not possible to examine for predictors of response to topical NSAIDs or capsaicin in NP. Conclusion Topical NSAIDs and capsaicin may both effectively relieve OA pain, but treatment effects from group comparisons do not directly translate to treatment outcomes at the individual level. Patients with different pain mechanisms may respond differently to these two agents, but definitive trial evidence is still needed. Presently, patients may benefit from trying both treatments to determine which is better for them. To better guide the care of an individual, evidence synthesis should encompass a spectrum of methods, from study-level to participant-level evidence. Further development of IPD MA and n-of-1 trial series methodology is required to successfully guide precision medicine

Identifying predictors of response to oral non-steroidal anti-inflammatory drugs and paracetamol in osteoarthritis

Introduction Symptomatic treatments for osteoarthritis (OA) provide only small-to-moderate efficacy over placebo in randomised cont

Relative efficacy of topical non-steroidal anti-inflammatory drugs and topical capsaicin in osteoarthritis: Protocol for an individual patient data meta-analysis

Background: Pain is the most troubling issue to patients with osteoarthritis (OA), yet current pharmacological treatments offer only small-to-moderate pain reduction. Current guidelines therefore emphasise the need to identify predictors of treatment response. In line with these recommendations, an individual patient data (IPD) meta-analysis will be conducted. The study aims to investigate the relative treatment effects of topical non-steroidal anti-inflammatory drugs (NSAIDs) and topical capsaicin in OA and to identify patient-level predictors of treatment response. Methods: IPD will be collected from randomised controlled trials (RCTs) of topical NSAIDs and capsaicin in OA. Multilevel regression modelling will be conducted to determine predictors for the specific and the overall treatment effect. Discussion: Through the identification of treatment responders, this IPD meta-analysis may improve the current understanding of the pain mechanisms in OA and guide clinical decision-making. Identifying and prescribing the treatment most likely to be beneficial for an individual with OA will improve the efficiency of patient management