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.

Supportive Self-Management Program for People With Chronic Headaches and Migraine: A Randomized Controlled Trial and Economic Evaluation.

BACKGROUND AND OBJECTIVES: Chronic headache disorders are a major cause of pain and disability. Education and supportive self-management approaches could reduce the burden of headache disability. We tested the effectiveness of a group educational and supportive self-management program for people living with chronic headaches. METHODS: This was a pragmatic randomized controlled trial. Participants were aged 18 years or older with chronic migraine or chronic tension-type headache, with or without medication overuse headache. We primarily recruited from general practices. Participants were assigned to either a 2-day group education and self-management program, a one-to-one nurse interview, and telephone support or to usual care plus relaxation material. The primary outcome was headache related-quality of life using the Headache Impact Test (HIT)-6 at 12 months. The primary analysis used intention-to-treat principles for participants with migraine and both baseline and 12-month HIT-6 data. RESULTS: Between April 2017 and March 2019, we randomized 736 participants. Because only 9 participants just had tension-type headache, our main analyses were on the 727 participants with migraine. Of them, 376 were allocated to the self-management intervention and 351 to usual care. Data from 586 (81%) participants were analyzed for primary outcome. There was no between-group difference in HIT-6 (adjusted mean difference = -0.3, 95% CI -1.23 to 0.67) or headache days (0.9, 95% CI -0.29 to 2.05) at 12 months. The Chronic Headache Education and Self-management Study intervention generated incremental adjusted costs of £268 (95% CI, £176-£377) (USD383 [95% CI USD252-USD539]) and incremental adjusted quality-adjusted life years (QALYs) of 0.031 (95% CI -0.005 to 0.063). The incremental cost-effectiveness ratio was £8,617 (USD12,322) per QALY gained. DISCUSSION: These findings conclusively show a lack of benefit for quality of life or monthly headache days from a brief group education and supportive self-management program for people living with chronic migraine or chronic tension-type headache with episodic migraine. TRIAL REGISTRATION INFORMATION: Registered on the International Standard Randomized Controlled Trial Number registry, ISRCTN79708100 16th December 2015 doi.org/10.1186/ISRCTN79708100. The first enrollment was April 24, 2017. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a brief group education and self-management program does not increase the probability of improvement in headache-related quality of life in people with chronic migraine.

The TANDEM trial: protocol for the process evaluation of a randomised trial of a complex intervention for anxiety and/or depression in people living with chronic obstructive pulmonary disease (COPD).

BACKGROUND: TANDEM is a randomised controlled trial of a complex healthcare intervention to improve the psychological and physical health of people living with chronic obstructive pulmonary disease (COPD) and anxiety and/or depression. Based on health psychology theory set out in a logic model, respiratory health professionals were recruited and trained to deliver a cognitive behavioural approach intervention (The TANDEM intervention) under the supervision of senior cognitive behavioural practitioners. Here, we describe the protocol for the process evaluation commissioned alongside the trial. A realist approach that includes attention to describing contexts and mechanisms has been adopted. METHODS: We set up a multi-disciplinary team to develop and deliver the process evaluation. The mixed-methods design incorporates quantitative process data; monitoring of intervention fidelity; qualitative interviews with patients, carers, health professionals (facilitators) and clinical supervisors about their perspectives on acceptability of the intervention; and exploration with all stakeholders (including management/policy-makers) on future implementation. Normalisation process theory (NPT) will inform data collection and interpretation with a focus on implementation. Quantitative process data will be analysed descriptively. Qualitative interview data will be analysed before the trial outcomes are known using analytic induction and constant comparison to develop themes. Findings from the different elements will be reported separately and then integrated. CONCLUSION: Detailed description and analysis of study processes in a research trial such as TANDEM enables research teams to describe study contexts and mechanisms and to examine the relationship with outcomes. In this way, learning from the trial goes beyond the randomised control trial (RCT) model where effectiveness is prioritised and makes it possible to explore issues arising for post-trial study implementation. TRIAL REGISTRATION: ISRCTN ISRCTN59537391 . Registered on 20 March 2017. Trial protocol version 6.0, 22 April 2018. Process evaluation protocol version 4.0, 1 November 2020.

MEMPHIS: a smartphone app using psychological approaches for women with chronic pelvic pain presenting to gynaecology clinics: a randomised feasibility trial.

OBJECTIVES: To evaluate the feasibility of a randomised trial of a modified, pre-existing, mindfulness meditation smartphone app for women with chronic pelvic pain. DESIGN: Three arm randomised feasibility trial. SETTING: Women were recruited at two gynaecology clinics in the UK. Interventions were delivered via smartphone or computer at a location of participants choosing. PARTICIPANTS: Women were eligible for the study if they were over 18, had been experiencing organic or non-organic chronic pelvic pain for 6 months or more, and had access to a computer or smartphone. 90 women were randomised. INTERVENTIONS: Daily mindfulness meditation delivered by smartphone app, an active control app which delivered muscle relaxation techniques, and usual care without app. Interventions were delivered over 60 days. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcomes included length of recruitment, follow-up rates, adherence to the app interventions, and clinical outcomes measured at baseline, two, three and 6 months. RESULTS: The target sample size was recruited in 145 days. Adherence to the app interventions was extremely low (mean app use 1.8 days mindfulness meditation group, 7.0 days active control). Fifty-seven (63%) women completed 6-month follow-up, and 75 (83%) women completed at least one postrandomisation follow-up. The 95% CIs for clinical outcomes were consistent with no benefit from the mindfulness meditation app; for example, mean differences in pain acceptance scores at 60 days (higher scores are better) were -2.3 (mindfulness meditation vs usual care, 95% CI: -6.6 to 2.0) and -4.0 (mindfulness meditation vs active control, 95% CI: -8.1 to 0.1). CONCLUSIONS: Despite high recruitment and adequate follow-up rates, demonstrating feasibility, the extremely low adherence suggests a definitive randomised trial of the mindfulness meditation app used in this study is not warranted. Future research should focus on improving patient engagement. TRIAL REGISTRATION NUMBERS: NCT02721108; ISRCTN10925965; Results.

mHealth: providing a mindfulness app for women with chronic pelvic pain in gynaecology outpatient clinics: qualitative data analysis of user experience and lessons learnt.

OBJECTIVES: To determine whether a pre-existing smartphone app to teach mindfulness meditation is acceptable to women with chronic pelvic pain (CPP) and can be integrated into clinical practice within the National Health Service (NHS) CPP pathways, and to inform the design of a potential randomised clinical trial. DESIGN: A prestudy patient and public involvement (PPI) group to collect feedback on the acceptability of the existing app and study design was followed by a three-arm randomised feasibility trial. In addition, we undertook interviews and focus groups with patients and staff to explore app usability and acceptability. We also obtained participant comments on the research process, such as acceptability of the study questionnaires. SETTING: Two gynaecology clinics within Barts Health NHS, London, UK. PARTICIPANTS: Patients with CPP lasting ≥6 months with access to smartphone or personal computer and understanding of basic English. INTERVENTION: The intervention was mindfulness meditation content plus additional pain module delivered by a smartphone app. Active controls received muscle relaxation content from the same app. Passive (waiting list) controls received usual care. MAIN OUTCOME MEASURES: Themes on user feedback, app usability and integration, and reasons for using/not using the app. RESULTS: The use of the app was low in both active groups. Patients in the prestudy PPI group, all volunteers, were enthusiastic about the app (convenience, content, portability, flexibility, ease of use). Women contributing to the interview or focus group data (n=14), from a 'real world' clinic (some not regular app users), were less positive, citing as barriers lack of opportunities/motivation to use the app and lack of familiarity and capabilities with technology. Staff (n=7) were concerned about the potential need for extra support for them and for the patients, and considered the app needed organisational backing and peer acceptance. CONCLUSION: The opinions of prestudy PPI volunteers meeting in their private time may not represent those of patients recruited at a routine clinic appointment. It may be more successful to codesign/codevelop an app with typical users than to adapt existing apps for use in real-world clinical populations. TRIAL REGISTRATION NUMBER: ISRCTN10925965.

Research prioritization of interventions for the primary prevention of preterm birth: An international survey.

OBJECTIVE: To identify research priorities of interventions for the primary prevention of preterm birth (PTB), by conducting an international stakeholder survey. STUDY DESIGN: A prospective cross-sectional online survey was conducted in November 2016. Fifteen interventions to prevent spontaneous PTB were identified and ranked by stakeholders (n = 159) in the field of maternal and perinatal health research, using nine equally weighted criteria. Medians and interquartile ranges (IQRs) were calculated and the interventions ranked accordingly. RESULTS: Respondents to the survey were from 46 different countries, mostly from low and middle-income countries (62%, 99/159) and were mainly clinicians (80%, 127/159). Of the fifteen interventions ranked, the following five were identified as research priorities in the primary prevention of PTB: dietary counselling and nutritional education, risk scoring, vitamin D supplementation, exercise and antioxidant supplementation. CONCLUSION: We have identified research priorities of interventions to prevent spontaneous PTB through a global stakeholder survey. The interventions prioritized in this exercise can be used by researchers, grant funding bodies and research-policy decision makers to inform calls on future clinical trials or individual patient data meta-analyses on the primary prevention of PTB.

AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies.

BACKGROUND: Pregnant women with epilepsy on antiepileptic drugs (AEDs) may experience a reduction in serum AED levels. This has the potential to worsen seizure control. OBJECTIVE: To determine if, in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels. DESIGN: A double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out. SETTING: Fifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK. PARTICIPANTS: Pregnant women with epilepsy on one or more of the following AEDs: lamotrigine, carbamazepine, phenytoin or levetiracetam. Women with a ≥ 25% decrease in serum AED level from baseline were randomised to therapeutic drug monitoring or clinical features monitoring strategies. INTERVENTIONS: In the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features. MAIN OUTCOME MEASURES: Primary outcome - seizure deterioration, defined as time to first seizure and to all seizures after randomisation per woman until 6 weeks post partum. Secondary outcomes - pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable serum AED level, AED dose exposure and adverse events related to AEDs. ANALYSIS: Analysis of time to first and to all seizures after randomisation was performed using a Cox proportional hazards model, and multivariate failure time analysis by the Andersen-Gill model. The effects were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes were reported as mean differences (MDs) or odds ratios. RESULTS: A total of 130 women were randomised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group; 294 women did not have a reduction in serum AED level. A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group (98% of complete data) were included in the primary analysis. There were no significant differences in the time to first seizure (HR 0.82, 95% CI 0.55 to 1.2) or timing of all seizures after randomisation (HR 1.3, 95% CI 0.7 to 2.5) between both trial groups. In comparison with the group with stable serum AED levels, there were no significant increases in seizures in the clinical features monitoring (odds ratio 0.93, 95% CI 0.56 to 1.5) or therapeutic drug monitoring group (odds ratio 0.93, 95% CI 0.56 to 1.5) associated with a reduction in serum AED levels. Maternal and neonatal outcomes were similar in both groups, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l, 95% CI 0.11 to 1 mg/l) or levetiracetam (MD 7.8 mg/l, 95% CI 0.86 to 14.8 mg/l) in the therapeutic drug monitoring group than in the clinical features monitoring group. There were no differences between the groups on daily AED exposure or quality of life. An increase in exposure to lamotrigine, levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs, but not maternal or fetal complications. Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs. LIMITATIONS: Fewer women than the original target were recruited. CONCLUSION: There is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes. FUTURE WORK RECOMMENDATIONS: Further evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both randomised groups is needed. An individualised prediction model will help to identify those women who need close monitoring in pregnancy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN01253916. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 23. See the NIHR Journals Library website for further project information.

Smartphone App Using Mindfulness Meditation for Women With Chronic Pelvic Pain (MEMPHIS): Protocol for a Randomized Feasibility Trial.

BACKGROUND: Female chronic pelvic pain (CPP) is defined as intermittent or constant pelvic or lower abdominal pain occurring in a woman for at least 6 months. Up to a quarter of women are estimated to be affected by CPP worldwide and it is responsible for one fifth of specialist gynecological referrals in the United Kingdom. Psychological interventions are commonly utilized. As waiting times and funding capacity impede access to face-to-face consultations, supported self-management (SSM) has emerged as a viable alternative. Mindfulness meditation is a potentially valuable SSM tool, and in the era of mobile technology, this can be delivered to the individual user via a smartphone app. OBJECTIVE: To assess the feasibility of conducting a trial of a mindfulness meditation intervention delivered by a mobile phone app for patients with CPP. The main feasibility objectives were to assess patient recruitment and app adherence, to obtain information to be used in the sample size estimate of a future trial, and to receive feedback on usability of the app. METHODS: Mindfulness Meditation for Women With Chronic Pelvic Pain (MEMPHIS) is a three-arm feasibility trial, that took place in two hospitals in the United Kingdom. Eligible participants were randomized in a 1:1:1 ratio to one of three treatment arms: (1) the intervention arm, consisting of a guided, spoken mindfulness meditation app; (2) an active control arm, consisting of a progressive muscle relaxation app; and (3) usual care (no app). Participants were followed-up for 6 months. Key feasibility outcomes included the time taken to recruit all patients for the study, adherence, and estimates to be used in the sample size calculation for a subsequent full-scale trial. Upon completion of the feasibility trial we will conduct focus groups to explore app usability and reasons for noncompliance. RESULTS: Recruitment for MEMPHIS took place between May 2016 and September 2016. The study was closed March 2017 and the report was submitted to the NIHR on October 26, 2017. CONCLUSIONS: This feasibility trial will inform the design of a large multicentered trial to assess the clinical effectiveness of mindfulness meditation delivered via a smartphone app for the treatment of CPP. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02721108; https://clinicaltrials.gov/ct2/show/NCT02721108 (Archived by WebCite at http://www.webcitation.org/6wLMAkuaU); BioMed Central: ISRCTN10925965; https://www.isrctn.com/ISRCTN10925965 (Archived by WebCite at http://www.webcitation.org/6wLMVLuys).

Birthweight and risk markers for type 2 diabetes and cardiovascular disease in childhood: the Child Heart and Health Study in England (CHASE).

AIMS/HYPOTHESIS: Lower birthweight (a marker of fetal undernutrition) is associated with higher risks of type 2 diabetes and cardiovascular disease (CVD) and could explain ethnic differences in these diseases. We examined associations between birthweight and risk markers for diabetes and CVD in UK-resident white European, South Asian and black African-Caribbean children. METHODS: In a cross-sectional study of risk markers for diabetes and CVD in 9- to 10-year-old children of different ethnic origins, birthweight was obtained from health records and/or parental recall. Associations between birthweight and risk markers were estimated using multilevel linear regression to account for clustering in children from the same school. RESULTS: Key data were available for 3,744 (66%) singleton study participants. In analyses adjusted for age, sex and ethnicity, birthweight was inversely associated with serum urate and positively associated with systolic BP. After additional height adjustment, lower birthweight (per 100 g) was associated with higher serum urate (0.52%; 95% CI 0.38, 0.66), fasting serum insulin (0.41%; 95% CI 0.08, 0.74), HbA1c (0.04%; 95% CI 0.00, 0.08), plasma glucose (0.06%; 95% CI 0.02, 0.10) and serum triacylglycerol (0.30%; 95% CI 0.09, 0.51) but not with BP or blood cholesterol. Birthweight was lower among children of South Asian (231 g lower; 95% CI 183, 280) and black African-Caribbean origin (81 g lower; 95% CI 30, 132). However, adjustment for birthweight had no effect on ethnic differences in risk markers. CONCLUSIONS/INTERPRETATION: Birthweight was inversely associated with urate and with insulin and glycaemia after adjustment for current height. Lower birthweight does not appear to explain emerging ethnic difference in risk markers for diabetes.

Are ethnic and gender specific equations needed to derive fat free mass from bioelectrical impedance in children of South asian, black african-Caribbean and white European origin? Results of the assessment of body composition in children study.

BACKGROUND: Bioelectrical impedance analysis (BIA) is a potentially valuable method for assessing lean mass and body fat levels in children from different ethnic groups. We examined the need for ethnic- and gender-specific equations for estimating fat free mass (FFM) from BIA in children from different ethnic groups and examined their effects on the assessment of ethnic differences in body fat. METHODS: Cross-sectional study of children aged 8-10 years in London Primary schools including 325 South Asians, 250 black African-Caribbeans and 289 white Europeans with measurements of height, weight and arm-leg impedance (Z; Bodystat 1500). Total body water was estimated from deuterium dilution and converted to FFM. Multilevel models were used to derive three types of equation {A: FFM = linear combination(height+weight+Z); B: FFM = linear combination(height(2)/Z); C: FFM = linear combination(height(2)/Z+weight)}. RESULTS: Ethnicity and gender were important predictors of FFM and improved model fit in all equations. The models of best fit were ethnicity and gender specific versions of equation A, followed by equation C; these provided accurate assessments of ethnic differences in FFM and FM. In contrast, the use of generic equations led to underestimation of both the negative South Asian-white European FFM difference and the positive black African-Caribbean-white European FFM difference (by 0.53 kg and by 0.73 kg respectively for equation A). The use of generic equations underestimated the positive South Asian-white European difference in fat mass (FM) and overestimated the positive black African-Caribbean-white European difference in FM (by 4.7% and 10.1% respectively for equation A). Consistent results were observed when the equations were applied to a large external data set. CONCLUSIONS: Ethnic- and gender-specific equations for predicting FFM from BIA provide better estimates of ethnic differences in FFM and FM in children, while generic equations can misrepresent these ethnic differences.