Opioid analgesics for nociceptive cancer pain: A comprehensive review.

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.

Does pain self-efficacy predict, moderate or mediate outcomes in people with chronic headache; an exploratory analysis of the CHESS trial.

BACKGROUND: Chronic headache disorders are disabling. The CHESS trial studied the effects of a short non-pharmacological intervention of education with self-management support for people affected by migraine and/or tension type headache for at least 15 days per month for at least three months. There were no statistically significant effects on the Headache Impact Test-6 (HIT-6) at 12-months. However, we observed improvement in pain self-efficacy questionnaire (PSEQ) and short-term HIT-6. We explored the impact of the CHESS intervention on PSEQ, and subsequently, on the HIT-6 and chronic headache quality of life questionnaire (CH-QLQ) at four, eighth and 12 months. METHODS: We included all 736 participants from the CHESS trial. We used simple linear regression models to explore the change of HIT-6 and CH-QLQ with treatment and PSEQ at baseline (predictor analysis), and the interaction between treatment and baseline PSEQ (moderator analysis). We considered the change of PSEQ from baseline to four months as a mediator in the mediation analysis. RESULTS: Baseline PSEQ neither predicted nor moderated outcomes. The prediction effect on change of HIT-6 from baseline to 12 months was 0.01 (95% CI, -0.03 to 0.04) and the interaction (moderation) effect was -0.07 (95% CI, -0.15 to 0.002). However, the change of PSEQ from baseline to 4-month mediated the HIT-6 (baseline to 8-, and 12-month) and all components of CH-QLQ (baseline to 8-, and 12-month). The CHESS intervention improved the mediated variable, PSEQ, by 2.34 (95% CI, 0.484 to 4.187) units and this corresponds to an increase of 0.21 (95% CI, 0.03 to 0.45) units in HIT-6 at 12-months. The largest mediated effect was observed on the CH-QLQ Emotional Function, an increase of 1.12 (95% CI, 0.22 to 2.20). CONCLUSIONS: PSEQ was not an effective predictor of outcome. However, change of short-term PSEQ mediated all outcomes, albeit minimally. Future behavioural therapy for chronic headache may need to consider how to achieve larger, and more sustained increases level of self-efficacy than that achieved within the CHESS trial. TRIAL REGISTRATION: ISRCTN79708100.

Subacromial balloon spacer for irreparable rotator cuff tears of the shoulder (START:REACTS): a group-sequential, double-blind, multicentre randomised controlled trial.

BACKGROUND: New surgical procedures can expose patients to harm and should be carefully evaluated before widespread use. The InSpace balloon (Stryker, USA) is an innovative surgical device used to treat people with rotator cuff tears that cannot be repaired. We aimed to determine the effectiveness of the InSpace balloon for people with irreparable rotator cuff tears. METHODS: We conducted a double-blind, group-sequential, adaptive randomised controlled trial in 24 hospitals in the UK, comparing arthroscopic debridement of the subacromial space with biceps tenotomy (debridement only group) with the same procedure but including insertion of the InSpace balloon (debridement with device group). Participants had an irreparable rotator cuff tear, which had not resolved with conservative treatment, and they had symptoms warranting surgery. Eligibility was confirmed intraoperatively before randomly assigning (1:1) participants to a treatment group using a remote computer system. Participants and assessors were masked to group assignment. Masking was achieved by using identical incisions for both procedures, blinding the operation note, and a consistent rehabilitation programme was offered regardless of group allocation. The primary outcome was the Oxford Shoulder Score at 12 months. Pre-trial simulations using data from early and late timepoints informed stopping boundaries for two interim analyses. The primary analysis was on a modified intention-to-treat basis, adjusted for the planned interim analysis. The trial was registered with ISRCTN, ISRCTN17825590. FINDINGS: Between June 1, 2018, and July 30, 2020, we assessed 385 people for eligibility, of which 317 were eligible. 249 (79%) people consented for inclusion in the study. 117 participants were randomly allocated to a treatment group, 61 participants to the debridement only group and 56 to the debridement with device group. A predefined stopping boundary was met at the first interim analysis and recruitment stopped with 117 participants randomised. 43% of participants were female, 57% were male. We obtained primary outcome data for 114 (97%) participants. The mean Oxford Shoulder Score at 12 months was 34·3 (SD 11·1) in the debridement only group and 30·3 (10·9) in the debridement with device group (mean difference adjusted for adaptive design -4·2 [95% CI -8·2 to -0·26];p=0·037) favouring control. There was no difference in adverse events between the two groups. INTERPRETATION: In an efficient, adaptive trial design, our results favoured the debridement only group. We do not recommend the InSpace balloon for the treatment of irreparable rotator cuff tears. FUNDING: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health and Care Research partnership.

Screening and Intervention to Prevent Falls and Fractures in Older People.

BACKGROUND: Community screening and therapeutic prevention strategies may reduce the incidence of falls in older people. The effects of these measures on the incidence of fractures, the use of health resources, and health-related quality of life are unknown. METHODS: In a pragmatic, three-group, cluster-randomized, controlled trial, we estimated the effect of advice sent by mail, risk screening for falls, and targeted interventions (multifactorial fall prevention or exercise for people at increased risk for falls) as compared with advice by mail only. The primary outcome was the rate of fractures per 100 person-years over 18 months. Secondary outcomes were falls, health-related quality of life, frailty, and a parallel economic evaluation. RESULTS: We randomly selected 9803 persons 70 years of age or older from 63 general practices across England: 3223 were assigned to advice by mail alone, 3279 to falls-risk screening and targeted exercise in addition to advice by mail, and 3301 to falls-risk screening and targeted multifactorial fall prevention in addition to advice by mail. A falls-risk screening questionnaire was sent to persons assigned to the exercise and multifactorial fall-prevention groups. Completed screening questionnaires were returned by 2925 of the 3279 participants (89%) in the exercise group and by 2854 of the 3301 participants (87%) in the multifactorial fall-prevention group. Of the 5779 participants from both these groups who returned questionnaires, 2153 (37%) were considered to be at increased risk for falls and were invited to receive the intervention. Fracture data were available for 9802 of the 9803 participants. Screening and targeted intervention did not result in lower fracture rates; the rate ratio for fracture with exercise as compared with advice by mail was 1.20 (95% confidence interval [CI], 0.91 to 1.59), and the rate ratio with multifactorial fall prevention as compared with advice by mail was 1.30 (95% CI, 0.99 to 1.71). The exercise strategy was associated with small gains in health-related quality of life and the lowest overall costs. There were three adverse events (one episode of angina, one fall during a multifactorial fall-prevention assessment, and one hip fracture) during the trial period. CONCLUSIONS: Advice by mail, screening for fall risk, and a targeted exercise or multifactorial intervention to prevent falls did not result in fewer fractures than advice by mail alone. (Funded by the National Institute of Health Research; ISRCTN number, ISRCTN71002650.).

Tailored psychological intervention for anxiety or depression in COPD (TANDEM): a randomised controlled trial.

BACKGROUND: The TANDEM multicentre, pragmatic, randomised controlled trial evaluated whether a tailored psychological intervention based on a cognitive behavioural approach for people with COPD and symptoms of anxiety and/or depression improved anxiety or depression compared with usual care (control). METHODS: People with COPD and moderate to very severe airways obstruction and Hospital Anxiety and Depression Scale subscale scores indicating mild to moderate anxiety (HADS-A) and/or depression (HADS-D) were randomised 1.25:1 (242 intervention and 181 control). Respiratory health professionals delivered the intervention face-to-face over 6-8 weeks. Co-primary outcomes were HADS-A and HADS-D measured 6 months post-randomisation. Secondary outcomes at 6 and 12 months included: HADS-A and HADS-D (12 months), Beck Depression Inventory II, Beck Anxiety Inventory, St George's Respiratory Questionnaire, social engagement, the EuroQol instrument five-level version (EQ-5D-5L), smoking status, completion of pulmonary rehabilitation, and health and social care resource use. RESULTS: The intervention did not improve anxiety (HADS-A mean difference -0.60, 95% CI -1.40-0.21) or depression (HADS-D mean difference -0.66, 95% CI -1.39-0.07) at 6 months. The intervention did not improve any secondary outcomes at either time-point, nor did it influence completion of pulmonary rehabilitation or healthcare resource use. Deaths in the intervention arm (13/242; 5%) exceeded those in the control arm (3/181; 2%), but none were associated with the intervention. Health economic analysis found the intervention highly unlikely to be cost-effective. CONCLUSION: This trial has shown, beyond reasonable doubt, that this cognitive behavioural intervention delivered by trained and supervised respiratory health professionals does not improve psychological comorbidity in people with advanced COPD and depression or anxiety.

Comparison of different statistical models for the analysis of fracture events: findings from the Prevention of Falls Injury Trial (PreFIT).

BACKGROUND: Fractures are rare events and can occur because of a fall. Fracture counts are distinct from other count data in that these data are positively skewed, inflated by excess zero counts, and events can recur over time. Analytical methods used to assess fracture data and account for these characteristics are limited in the literature. METHODS: Commonly used models for count data include Poisson regression, negative binomial regression, hurdle regression, and zero-inflated regression models. In this paper, we compare four alternative statistical models to fit fracture counts using data from a large UK based clinical trial evaluating the clinical and cost-effectiveness of alternative falls prevention interventions in older people (Prevention of Falls Injury Trial; PreFIT). RESULTS: The values of Akaike information criterion and Bayesian information criterion, the goodness-of-fit statistics, were the lowest for negative binomial model. The likelihood ratio test of no dispersion in the data showed strong evidence of dispersion (chi-square = 225.68, p-value < 0.001). This indicates that the negative binomial model fits the data better compared to the Poisson regression model. We also compared the standard negative binomial regression and mixed effects negative binomial models. The LR test showed no gain in fitting the data using mixed effects negative binomial model (chi-square = 1.67, p-value = 0.098) compared to standard negative binomial model. CONCLUSIONS: The negative binomial regression model was the most appropriate and optimal fit model for fracture count analyses. TRIAL REGISTRATION: The PreFIT trial was registered as ISRCTN71002650.

Chronic Headache Education and Self-Management Study (CHESS): a process evaluation.

BACKGROUND: The Chronic Headache Education and Self-Management Study (CHESS) multicentre randomised trial evaluated the impact a group education and self-management support intervention with a best usual care plus relaxation control for people living with chronic headache disorders (tension type headaches or chronic migraine, with or without medication overuse headache). Here we report the process evaluation exploring potential explanations for the lack of positive effects from the CHESS intervention. METHODS: The CHESS trial included 736 (380 intervention: 356 control) people across the Midlands and London UK. We used a mixed methods approach. Our extensive process evaluation looked at context, reach, recruitment, dose delivered, dose received, fidelity and experiences of participating in the trial, and included participants and trial staff. We also looked for evidence in our qualitative data to investigate whether the original causal assumptions underpinning the intervention were realised. RESULTS: The CHESS trial reached out to a large diverse population and recruited a representative sample. Few people with chronic tension type headaches without migraine were identified and recruited. The expected 'dose'of the intervention was delivered to participants and intervention fidelity was high. Attendance ("dose received") fell below expectation, although 261/380 (69%) received at least at least the pre-identified minimum dose. Intervention participants generally enjoyed being in the groups but there was little evidence to support the causal assumptions underpinning the intervention were realised. CONCLUSIONS: From a process evaluation perspective despite our extensive data collection and analysis, we do not have a clear understanding of why the trial outcome was negative as the intervention was delivered as planned. However, the lack of evidence that the intervention causal assumptions brought about the planned behaviour change may provide some insight. Our data suggests only modest changes in managing headache behaviours and some disparity in how participants engaged with components of the intervention within the timeframe of the study. Moving forwards, we need a better understanding of how those who live with chronic headache can be helped to manage this disabling condition more effectively over time. TRIAL REGISTRATION: ISRCTN79708100 .

Falls and fracture risk screening in primary care: update and validation of a postal screening tool for community dwelling older adults recruited to UK Prevention of Falls Injury Trial (PreFIT).

BACKGROUND: Postal screening has not previously been validated as a method for identifying fall and fracture risk in community-dwelling populations. We examined prognostic performance of a postal risk screener used in the UK Prevention of Falls Injury Trial (PreFIT; ISRCTN71002650), to predict any fall, recurrent falls, and fractures over 12 months. We tested whether adding variables would improve screener performance. METHODS: Nine thousand eight hundred and eight community-dwelling participants, aged 70 years and older, and 63 general practices in the UK National Health Service (NHS) were included in a large, pragmatic cluster randomised trial comparing screen and treat fall prevention interventions. The short postal screener was sent to all participants in the trial intervention arms as an A4 sheet to be completed and returned to the GP (n = 6,580). The postal screener items were embedded in the baseline pre-randomisation postal questionnaire for all arms of the trial (n = 9,808). We assessed discrimination and calibration using area under the curve (AUC). We identified additional predictors using data from the control arm and applied these coefficients to internal validation models in the intervention arm participants. We used logistic regression to identify additional predictor variables. FINDINGS: A total of 10,743 falls and 307 fractures were reported over 12 months. Over one third of participants 3,349/8,136 (41%) fell at least once over 12 month follow up. Response to the postal screener was high (5,779/6,580; 88%). Prediction models showed similar discriminatory ability in both control and intervention arms, with discrimination values for any fall AUC 0.67 (95% CI 0.65 to 0.68), and recurrent falls (AUC 0.71; 95% CI 0.69, 0.72) but poorer discrimination for fractures (AUC 0.60; 95% CI 0.56, 0.64). Additional predictor variables improved prediction of falls but had modest effect on fracture, where AUC rose to 0.71 (95% CI 0.67 to 0.74). Calibration slopes were very close to 1. CONCLUSION: A short fall risk postal screener was acceptable for use in primary care but fall prediction was limited, although consistent with other tools. Fracture and fall prediction were only partially reliant on fall risk although were improved with the additional variables.

Reducing Opioid Use for Chronic Pain With a Group-Based Intervention: A Randomized Clinical Trial.

Importance: Opioid use for chronic nonmalignant pain can be harmful. Objective: To test whether a multicomponent, group-based, self-management intervention reduced opioid use and improved pain-related disability compared with usual care. Design, Setting, and Participants: Multicentered, randomized clinical trial of 608 adults taking strong opioids (buprenorphine, dipipanone, morphine, diamorphine, fentanyl, hydromorphone, methadone, oxycodone, papaveretum, pentazocine, pethidine, tapentadol, and tramadol) to treat chronic nonmalignant pain. The study was conducted in 191 primary care centers in England between May 17, 2017, and January 30, 2019. Final follow-up occurred March 18, 2020. Intervention: Participants were randomized 1:1 to either usual care or 3-day-long group sessions that emphasized skill-based learning and education, supplemented by 1-on-1 support delivered by a nurse and lay person for 12 months. Main Outcomes and Measures: The 2 primary outcomes were Patient-Reported Outcomes Measurement Information System Pain Interference Short Form 8a (PROMIS-PI-SF-8a) score (T-score range, 40.7-77; 77 indicates worst pain interference; minimal clinically important difference, 3.5) and the proportion of participants who discontinued opioids at 12 months, measured by self-report. Results: Of 608 participants randomized (mean age, 61 years; 362 female [60%]; median daily morphine equivalent dose, 46 mg [IQR, 25 to 79]), 440 (72%) completed 12-month follow-up. There was no statistically significant difference in PROMIS-PI-SF-8a scores between the 2 groups at 12-month follow-up (-4.1 in the intervention and -3.17 in the usual care groups; between-group difference: mean difference, -0.52 [95% CI, -1.94 to 0.89]; P = .15). At 12 months, opioid discontinuation occurred in 65 of 225 participants (29%) in the intervention group and 15 of 208 participants (7%) in the usual care group (odds ratio, 5.55 [95% CI, 2.80 to 10.99]; absolute difference, 21.7% [95% CI, 14.8% to 28.6%]; P < .001). Serious adverse events occurred in 8% (25/305) of the participants in the intervention group and 5% (16/303) of the participants in the usual care group. The most common serious adverse events were gastrointestinal (2% in the intervention group and 0% in the usual care group) and locomotor/musculoskeletal (2% in the intervention group and 1% in the usual care group). Four people (1%) in the intervention group received additional medical care for possible or probable symptoms of opioid withdrawal (shortness of breath, hot flushes, fever and pain, small intestinal bleed, and an overdose suicide attempt). Conclusions and Relevance: In people with chronic pain due to nonmalignant causes, compared with usual care, a group-based educational intervention that included group and individual support and skill-based learning significantly reduced patient-reported use of opioids, but had no effect on perceived pain interference with daily life activities. Trial Registration: isrctn.org Identifier: ISRCTN49470934.

What's important for recovery after a total knee replacement? A systematic review of mixed methods studies.

BACKGROUND: Understanding how patients perceive and prioritise various aspects of recovery following total knee replacement, including pain, function and return to activity, will help clinicians in pre-operative consultations by ensuring they effectively address patient concerns and managing their expectations. AIMS: The aim of this study is to identify aspects of recovery that are important to people after a total knee replacement. METHODS: Studies were identified from Medline, Embase, PsycInfo, Cochrane Library and Web of Science. This mixed methods review included all original study types (quantitative, qualitative, discrete choice experiments and mixed methods design). Reviews and non-peer-reviewed publications were excluded. Studies with participants (age ≥ 18 years) who had a primary TKR for osteoarthritis were included. Studies of people with unicompartmental knee, patella-femoral or revision knee replacement were excluded. Recovery attributes were extracted from individual papers and grouped into recovery themes. RESULTS: A total of 23 studies with 8404 participants and 18 recovery themes were developed. The most frequently identified overarching theme was pain, followed by activities of daily living, mobility (walking), recreational activities, specific functional movements of the knee, use of walking aids, sexual activity and range of motion of the knee. Medical complications were an infrequently reported theme, however, was deemed to be high importance. CONCLUSIONS: Reducing pain, returning of activities and daily living and mobility are the three most frequently reported recovery domains for people after TKR. Clinicians should be aware of recovery themes, to ensure they are explored sufficiently when consenting for a TKR. Future research should aim to determine the relative importance of these attributes compared to each other. Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021253699.

Competing treatments for migraine: a headache for decision-makers.

BACKGROUND: Migraine is the world's second most common disabling disorder, affecting 15% of UK adults and costing the UK over £1.5 billion per year. Several costly new drugs have been approved by National Institute for Health and Care Excellence. AIM: To assess the cost-effectiveness of drugs used to treat adults with chronic migraine. METHODS: We did a systematic review of placebo-controlled trials of preventive drugs for chronic migraine. We then assessed the cost-effectiveness of the currently prescribable drugs included in the review: Onabotulinum toxin A (BTA), Eptinezumab (100mg or 300mg), Fremanezumab (monthly or quarterly dose), Galcanezumab or Topiramate, each compared to placebo, and we evaluated them jointly. We developed a Markov (state-transition) model with a three-month cycle length to estimate the costs and quality-adjusted life years (QALYs) for the different medications from a UK NHS and Personal Social Services perspective. We used a two-year time horizon with a starting age of 30 years for the patient cohort. We estimated transition probabilities based on monthly headache days using a network meta-analysis (NMA) developed by us, and from published literature. We obtained costs from published sources and applied discount rates of 3.5% to both costs and outcomes. RESULTS: Deterministic results suggest Topiramate was the least costly option and generated slightly more QALYs than the placebo, whereas Eptinezumab 300mg was the more costly option and generated the most QALYs. After excluding dominated options, the incremental cost-effectiveness ratio (ICER) between BTA and Topiramate was £68,000 per QALY gained and the ICER between Eptinezumab 300mg and BTA was not within plausible cost-effectiveness thresholds. The cost-effectiveness acceptability frontier showed that Topiramate is the most cost-effective medication for any amount the decision maker is willing-to-pay per QALY. CONCLUSIONS: Among the various prophylactic medications for managing chronic migraine, only Topiramate was within typical cost-effectiveness threshold ranges. Further research is needed, ideally an economic evaluation alongside a randomised trial, to compare these newer, expensive CGRP MAbs with the cheaper oral medications.

Clinical effectiveness of pharmacological interventions for managing chronic migraine in adults: a systematic review and network meta-analysis.

BACKGROUND: Chronic migraine can be a profoundly disabling disorder that may be treated with preventive medications. However, uncertainty remains as to which preventive medication is the most effective. We present a network meta-analysis to determine the effectiveness and rank of preventive drugs for chronic migraine in adults. METHODS: We identified, reviewed, and extracted data from randomised controlled trials (RCTs) of preventive drugs for chronic migraine with at least 200 participants. Data were analysed using network meta-analysis. FINDINGS: We included 12 RCTs of six medications (Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Onabotulinumtoxin A, and Topiramate) compared to placebo or each other. All drugs effectively reduced monthly headache and migraine days compared with placebo. The most effective drug for monthly headache days was Eptinezumab 300mg, with a mean difference of -2.46 days, 95% Credible Interval (CrI): -3.23 to -1.69. On the Surface Under the Cumulative Ranking Area (SUCRA) analysis, the probability that Eptinezumab 300mg was ranked highest was 0.82. For monthly migraine days, the most effective medication was Fremanezumab-monthly, with a mean difference: -2.77 days, 95% CrI: -3.36 to -2.17, and 0.98 probability of being ranked the highest. All included drugs, except Topiramate, improved headache-related quality of life. No eligible studies were identified for the other common preventive oral medications such as Amitriptyline, Candesartan, and Propranolol. The main reasons were that the studies did not define chronic migraine, were undertaken before the definition of chronic migraine, or were too small. INTERPRETATION: All six medications were more effective than the placebo on monthly headache and migraine days. The absolute differences in the number of headache/migraine days are, at best, modest. No evidence was found to determine the relative effectiveness of the six included drugs with other oral preventive medications. REGISTRATION: PROSPERO (number CRD42021265990).

Mapping between headache specific and generic preference-based health-related quality of life measures.

BACKGROUND: The Headache Impact Test (HIT-6) and the Chronic Headache Questionnaire (CH-QLQ) measure headache-related quality of life but are not preference-based and therefore cannot be used to generate health utilities for cost-effectiveness analyses. There are currently no established algorithms for mapping between the HIT-6 or CH-QLQ and preference-based health-related quality-of-life measures for chronic headache population. METHODS: We developed algorithms for generating EQ-5D-5L and SF-6D utilities from the HIT-6 and the CHQLQ using both direct and response mapping approaches. A multi-stage model selection process was used to assess the predictive accuracy of the models. The estimated mapping algorithms were derived to generate UK tariffs and was validated using the Chronic Headache Education and Self-management Study (CHESS) trial dataset. RESULTS: Several models were developed that reasonably accurately predict health utilities in this context. The best performing model for predicting EQ-5D-5L utility scores from the HIT-6 scores was a Censored Least Absolute Deviations (CLAD) (1) model that only included the HIT-6 score as the covariate (mean squared error (MSE) 0.0550). The selected model for CH-QLQ to EQ-5D-5L was the CLAD (3) model that included CH-QLQ summary scores, age, and gender, squared terms and interaction terms as covariates (MSE 0.0583). The best performing model for predicting SF-6D utility scores from the HIT-6 scores was the CLAD (2) model that included the HIT-6 score and age and gender as covariates (MSE 0.0102). The selected model for CH-QLQ to SF-6D was the OLS (2) model that included CH-QLQ summary scores, age, and gender as covariates (MSE 0.0086). CONCLUSION: The developed algorithms enable the estimation of EQ-5D-5L and SF-6D utilities from two headache-specific questionnaires where preference-based health-related quality of life data are missing. However, further work is needed to help define the best approach to measuring health utilities in headache studies.

Group sequential designs in pragmatic trials: feasibility and assessment of utility using data from a number of recent surgical RCTs.

BACKGROUND: Assessing the long term effects of many surgical interventions tested in pragmatic RCTs may require extended periods of participant follow-up to assess effectiveness and use patient-reported outcomes that require large sample sizes. Consequently the RCTs are often perceived as being expensive and time-consuming, particularly if the results show the test intervention is not effective. Adaptive, and particularly group sequential, designs have great potential to improve the efficiency and cost of testing new and existing surgical interventions. As a means to assess the potential utility of group sequential designs, we re-analyse data from a number of recent high-profile RCTs and assess whether using such a design would have caused the trial to stop early. METHODS: Many pragmatic RCTs monitor participants at a number of occasions (e.g. at 6, 12 and 24 months after surgery) during follow-up as a means to assess recovery and also to keep participants engaged with the trial process. Conventionally one of the outcomes is selected as the primary (final) outcome, for clinical reasons, with others designated as either early or late outcomes. In such settings, novel group sequential designs that use data from not only the final outcome but also from early outcomes at interim analyses can be used to inform stopping decisions. We describe data from seven recent surgical RCTs (WAT, DRAFFT, WOLLF, FASHION, CSAW, FIXDT, TOPKAT), and outline possible group sequential designs that could plausibly have been proposed at the design stage. We then simulate how these group sequential designs could have proceeded, by using the observed data and dates to replicate how information could have accumulated and decisions been made for each RCT. RESULTS: The results of the simulated group sequential designs showed that for two of the RCTs it was highly likely that they would have stopped for futility at interim analyses, potentially saving considerable time (15 and 23 months) and costs and avoiding patients being exposed to interventions that were either ineffective or no better than standard care. We discuss the characteristics of RCTs that are important in order to use the methodology we describe, particularly the value of early outcomes and the window of opportunity when early stopping decisions can be made and how it is related to the length of recruitment period and follow-up. CONCLUSIONS: The results for five of the RCTs tested showed that group sequential designs using early outcome data would have been feasible and likely to provide designs that were at least as efficient, and possibly more efficient, than the original fixed sample size designs. In general, the amount of information provided by the early outcomes was surprisingly large, due to the strength of correlations with the primary outcome. This suggests that the methods described here are likely to provide benefits more generally across the range of surgical trials and more widely in other application areas where trial designs, outcomes and follow-up patterns are structured and behave similarly.

A systematic review of economic evaluations of pharmacological treatments for adults with chronic migraine.

BACKGROUND AND AIMS: Chronic migraine is a common neurovascular brain disorder with substantial economic costs. We performed a systematic review to identify economic evaluations of pharmacological treatments for adults with chronic migraine. METHODS: We undertook systematic literature searches using terms for migraine/headache and prophylactic drug interventions, combined with economic/cost terms where appropriate. Using inclusion and exclusion criteria, two reviewers independently assessed the citations and abstracts, and full-text articles were retrieved. A review of study characteristics and methodological quality was assessed. RESULTS: Sixteen citations met the inclusion criteria and were model-based cost-utility studies evaluating: Botox (n = 6); Erenumab (n = 8); Fremanezumab (n = 2); and Galcanezumab (n = 1) as the main treatment. They varied in their use of comparators, perspective, and model type. Botox was cost-effective compared to placebo with an incremental cost-effectiveness ratio (ICER) ranging between £15,028 (€17,720) and £16,598 (€19,572). Erenumab, Fremanezumab and Galcanezumab when compared to Botox, was associated with ICERs ranging between £59,712 ($81,080) and £182,128 (€218,870), with the ICERs above the most common willingness-to-pay thresholds (WTPs). But they were cost-effective within the commonly used WTPs among the population for whom the previous treatments including Botox were failed. Three studies compared the cost-effectiveness of Erenumab against the placebo and found that Erenumab was dominant. All studies performed sensitivity analyses to check the robustness of their results. None of the findings from the included articles were generalisable and none of the included studies fulfilled all the criteria mentioned in the CHEERS 2022 reporting checklist and Phillips's checklist for economic models. CONCLUSIONS: Evidence to support the cost-effectiveness of pharmacological treatments of chronic migraine in the adult population using Botox and Erenumab were identified. Our findings suggest that both Botox and Erenumab, are cost-effective compared to placebo; although Erenumab had more incremental economic benefits compared to Botox, the ICERs were above the most common willingness-to-pay thresholds. Hence, Erenumab might be an acceptable treatment for chronic migraine for patients whom other treatments such as Botox do not work. Further research is needed to help characterise the data to adequately structure and parameterise an economic model to support decision-making for chronic migraine therapies.

Measuring health-related quality of life in chronic headache: A comparative evaluation of the Chronic Headache Quality of Life Questionnaire and Headache Impact Test (HIT-6).

OBJECTIVE: To compare the quality and acceptability of a new headache-specific patient-reported measure, the Chronic Headache Quality of Life Questionnaire (CHQLQ) with the six-item Headache Impact Test (HIT-6), in people meeting an epidemiological definition of chronic headaches. METHODS: Participants in the feasibility stage of the Chronic Headache Education and Self-management Study (CHESS) (n = 130) completed measures three times during a 12-week prospective cohort study. Data quality, measurement acceptability, reliability, validity, responsiveness to change, and score interpretation were determined. Semi-structured cognitive interviews explored measurement relevance, acceptability, clarity, and comprehensiveness. RESULTS: Both measures were well completed with few missing items. The CHQLQ's inclusion of emotional wellbeing items increased its relevance to participant's experience of chronic headache. End effects were present at item level only for both measures. Structural assessment supported the three and one-factor solutions of the CHQLQ and HIT-6, respectively. Both the CHQLQ (range 0.87 to 0.94) and HIT-6 (0.90) were internally consistent, with acceptable temporal stability over 2 weeks (CHQLQ range 0.74 to 0.80; HIT-6 0.86). Both measures responded to change in headache-specific health at 12 weeks (CHQLQ smallest detectable change (improvement) range 3 to 5; HIT-6 2.1). CONCLUSIONS: While both measures are structurally valid, internally consistent, temporally stable, and responsive to change, the CHQLQ has greater relevance to the patient experience of chronic headache.Trial registration number: ISRCTN79708100. Registered 16th December 2015, http://www.isrctn.com/ISRCTN79708100.

The Prevalence of Opioid Analgesic Use in People with Chronic Noncancer Pain: Systematic Review and Meta-Analysis of Observational Studies.

OBJECTIVE: To review studies examining the proportion of people with chronic noncancer pain who report consuming opioids and characteristics associated with their use. DESIGN: Systematic review. METHODS: We searched databases from inception to February 8, 2020, and conducted citation tracking. We included observational studies reporting the proportion of adults with chronic noncancer pain who used opioid analgesics. Opioids were categorized as weak (e.g., codeine) or strong (e.g., oxycodone). Study risk of bias was assessed, and Grading of Recommendations Assessment, Development and Evaluations provided a summary of the overall quality. Results were pooled using a random-effects model. Meta-regression determined factors associated with opioid use. RESULTS: Sixty studies (N=3,961,739) reported data on opioid use in people with chronic noncancer pain from 1990 to 2017. Of these 46, 77% had moderate risk of bias. Opioid use was reported by 26.8% (95% confidence interval [CI], 23.1-30.8; moderate-quality evidence) of people with chronic noncancer pain. The use of weak opioids (17.3%; 95% CI 11.9-24.4; moderate-quality evidence) was more common than the use of strong opioids (9.8%; 95% CI, 6.8-14.0; low-quality evidence). Meta-regression determined that opioid use was associated with geographic region (P=0.02; lower in Europe than North America), but not sampling year (P=0.77), setting (P=0.06), diagnosis (P=0.34), or disclosure of funding (P=0.77). CONCLUSIONS: Our review summarized data from over 3.9 million people with chronic noncancer pain reporting their opioid use. Between 1990 and 2017, one-quarter of people with chronic noncancer pain reported taking opioids, and this proportion did not change over time.

Identification of subgroup effect with an individual participant data meta-analysis of randomised controlled trials of three different types of therapist-delivered care in low back pain.

BACKGROUND: Proven treatments for low back pain, at best, only provide modest overall benefits. Matching people to treatments that are likely to be most effective for them may improve clinical outcomes and makes better use of health care resources. METHODS: We conducted an individual participant data meta-analysis of randomised controlled trials of three types of therapist delivered interventions for low back pain (active physical, passive physical and psychological treatments). We applied two statistical methods (recursive partitioning and adaptive risk group refinement) to identify potential subgroups who might gain greater benefits from different treatments from our individual participant data meta-analysis. RESULTS: We pooled data from 19 randomised controlled trials, totalling 9328 participants. There were 5349 (57%) females with similar ratios of females in control and intervention arms. The average age was 49 years (standard deviation, SD, 14). Participants with greater psychological distress and physical disability gained most benefit in improving on the mental component scale (MCS) of SF-12/36 from passive physical treatment than non-active usual care (treatment effects, 4.3; 95% confidence interval, CI, 3.39 to 5.15). Recursive partitioning method found that participants with worse disability at baseline gained most benefit in improving the disability (Roland Morris Disability Questionnaire) outcome from psychological treatment than non-active usual care (treatment effects, 1.7; 95% CI, 1.1 to 2.31). Adaptive risk group refinement did not find any subgroup that would gain much treatment effect between psychological and non-active usual care. Neither statistical method identified any subgroups who would gain an additional benefit from active physical treatment compared to non-active usual care. CONCLUSIONS: Our methodological approaches worked well and may have applicability in other clinical areas. Passive physical treatments were most likely to help people who were younger with higher levels of disability and low levels of psychological distress. Psychological treatments were more likely to help those with severe disability. Despite this, the clinical importance of identifying these subgroups is limited. The sizes of sub-groups more likely to benefit and the additional effect sizes observed are small. Our analyses provide no evidence to support the use of sub-grouping for people with low back pain.

Once daily 300 mg aspirin with compression versus compression alone in patients with chronic venous leg ulcers (ASPiVLU): A randomised, double-blinded, multicentre, placebo-controlled, clinical trial.

AIM: Venous leg ulcers are lower limb skin ulcers characterised by a cycle of healing and recurrence due to underlying chronic venous insufficiency. While compression improves healing outcomes, many ulcers do not heal. As a daily 300 mg oral dose of aspirin in conjunction with compression may improve healing outcomes, we investigated the effect of adjuvant aspirin on venous leg ulcer healing in participants already receiving compression. MATERIALS AND METHODS: We conducted a prospective, randomised, double-blinded, placebo-controlled, clinical trial (known as ASPiVLU). Participants were recruited from six wound clinics in Australia. We screened 844 participants. Community-dwelling adult participants identified at six hospital outpatient clinics and clinically diagnosed with a venous leg ulcer present for 6+ weeks were eligible between April 13, 2015 to June 30, 2018. We randomised 40 participants (n = 19 aspirin, n = 21 placebo) and evaluated against the primary outcome. There were no dropouts. Ten serious adverse events in six participants were recorded. None were study related. The primary outcome measure was healing at 12 weeks based on blinded assessment. RESULTS: We found no difference in the number of ulcers healed at 12 weeks between the intervention and control groups. CONCLUSION: This study could not detect whether or not aspirin affected VLU healing speed. This is likely because we recruited fewer participants than expected due to the high number of people with venous leg ulcers in Australia who were already taking Aspirin; future research should investigate other adjuvant therapies or different study designs.

The risks associated with tourniquet use in lower limb trauma surgery: a systematic review and meta-analysis.

PURPOSE: Tourniquet use in lower limb fracture surgery may reduce intra-operative bleeding, improve surgical field of view and reduce length of procedure. However, tourniquets may result in pain and the production of harmful metabolites cause complications or affect functional outcomes. This systematic review aimed to compare outcomes following lower limb fracture surgery performed with or without tourniquet. METHODS: We searched databases for RCTs comparing lower limb fracture surgery performed with versus without tourniquet reporting on outcomes pain, physical function, health-related quality of life, complications, cognitive function, blood loss, length of stay, length of procedure, swelling, time to union, surgical field of view, volume of anaesthetic agent, biochemical markers of inflammation and injury, and electrolyte and acid-base balance. Random-effects meta-analysis was performed. PROSPERO ID CRD42020209310. RESULTS: Six RCTs enabled inclusion of 552 procedures. Pooled analysis demonstrated that tourniquet use reduced length of procedure by 6 minutes (95% CI -10.12 to -1.87; p < 0.010). We were unable to exclude increased harms from tourniquet use. Pooled analysis showed post-operative pain score was higher in tourniquet group by 12.88 on 100-point scale (95% CI -1.25-27.02; p = 0.070). Risk differences for wound infection, deep venous thrombosis and re-operation were 0.06 (95% CI -0.00-0.12; p = 0.070), 0.05 (95% CI -0.02-0.11; p = 0.150) and 0.03 (95% CI -0.03-0.09; p = 0.340). CONCLUSION: Tourniquet use was associated with a reduced length of procedure. It is possible that tourniquets also increase incidence of important complications, but the data are too sparse to draw firm conclusions. Methodological weaknesses of the included RCTs prevent any solid conclusions being drawn for outcomes investigated. Further studies are required to address these limitations.