Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.

BACKGROUND: Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP. METHODS: OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443. FINDINGS: Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway. INTERPRETATION: To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment programme.

PLEASANT: Preventing and Lessening Exacerbations of Asthma in School-age children Associated with a New Term - a cluster randomised controlled trial and economic evaluation.

BACKGROUND: Asthma episodes and deaths are known to be seasonal. A number of reports have shown peaks in asthma episodes in school-aged children associated with the return to school following the summer vacation. A fall in prescription collection in the month of August has been observed, and was associated with an increase in the number of unscheduled contacts after the return to school in September. OBJECTIVE: The primary objective of the study was to assess whether or not a NHS-delivered public health intervention reduces the September peak in unscheduled medical contacts. DESIGN: Cluster randomised trial, with the unit of randomisation being 142 NHS general practices, and trial-based economic evaluation. SETTING: Primary care. INTERVENTION: A letter sent (n = 70 practices) in July from their general practitioner (GP) to parents/carers of school-aged children with asthma to remind them of the importance of taking their medication, and to ensure that they have sufficient medication prior to the start of the new school year in September. The control group received usual care. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of children aged 5-16 years who had an unscheduled medical contact in September 2013. Supporting end points included the proportion of children who collected prescriptions in August 2013 and unscheduled contacts through the following 12 months. Economic end points were quality-adjusted life-years (QALYs) gained and costs from an NHS and Personal Social Services perspective. RESULTS: There is no evidence of effect in terms of unscheduled contacts in September. Among children aged 5-16 years, the odds ratio (OR) was 1.09 [95% confidence interval (CI) 0.96 to 1.25] against the intervention. The intervention did increase the proportion of children collecting a prescription in August (OR 1.43, 95% CI 1.24 to 1.64) as well as scheduled contacts in the same month (OR 1.13, 95% CI 0.84 to 1.52). For the wider time intervals (September-December 2013 and September-August 2014), there is weak evidence of the intervention reducing unscheduled contacts. The intervention did not reduce unscheduled care in September, although it succeeded in increasing the proportion of children collecting prescriptions in August as well as having scheduled contacts in the same month. These unscheduled contacts in September could be a result of the intervention, as GPs may have wanted to see patients before issuing a prescription. The economic analysis estimated a high probability that the intervention was cost-saving, for baseline-adjusted costs, across both base-case and sensitivity analyses. There was no increase in QALYs. LIMITATION: The use of routine data led to uncertainty in the coding of medical contacts. The uncertainty was mitigated by advice from a GP adjudication panel. CONCLUSIONS: The intervention did not reduce unscheduled care in September, although it succeeded in increasing the proportion of children both collecting prescriptions and having scheduled contacts in August. After September there is weak evidence in favour of the intervention. The intervention had a favourable impact on costs but did not demonstrate any impact on QALYs. The results of the trial indicate that further work is required on assessing and understanding adherence, both in terms of using routine data to make quantitative assessments, and through additional qualitative interviews with key stakeholders such as practice nurses, GPs and a wider group of children with asthma. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03000938. FUNDING DETAILS: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 93. See the HTA programme website for further project information.

A systematic review of fish-oil supplements for the prevention and treatment of hypertension.

AIMS: Fish oils are widely believed to promote cardiovascular health by lowering blood pressure (BP) but the evidence supporting this is not conclusive. We aimed to systematically review existing evidence. METHOD: We undertook a systematic review of randomized controlled trials and crossover trials that evaluated the effectiveness of fish-oil supplements. We included trials enrolling adults who were given fish-oil supplements with at least 8 weeks' follow up. Effects on systolic and diastolic BP were assessed using meta-analysis. Meta-regression was undertaken to explore the relationship between dose of fish oil and BP outcomes. RESULTS: We included 17 studies, with a total of 1524 participants. We explored the effects of fish-oil supplements in both normotensive and hypertensive participants with BP 140/85 mmHg at least. Meta-analyses were performed using the inverse-variance method. Data from eight studies in hypertensive participants found a statistically significant reduction in systolic and diastolic BP; 2.56 mmHg (95% CI 0.58 to 4.53) and 1.47 mmHg (95% CI 0.41 to 2.53), respectively. Nine studies in normotensive participants showed a non-significant reduction in both systolic and diastolic BP. Meta-regression showed no significant relationship between dose of fish oil and the effect on BP. CONCLUSION: The small but statistically significant effects of fish-oil supplements in hypertensive participants in this review have important implications for population health and lowering the risk of stroke and ischaemic heart disease. Their modest effects, however, mean that they should not be recommended as an alternative to BP-lowering drugs where guidelines recommend treatment.

Protocol for diaphragm pacing in patients with respiratory muscle weakness due to motor neurone disease (DiPALS): a randomised controlled trial.

BACKGROUND: Motor neurone disease (MND) is a devastating illness which leads to muscle weakness and death, usually within 2-3 years of symptom onset. Respiratory insufficiency is a common cause of morbidity, particularly in later stages of MND and respiratory complications are the leading cause of mortality in MND patients. Non Invasive Ventilation (NIV) is the current standard therapy to manage respiratory insufficiency. Some MND patients however do not tolerate NIV due to a number of issues including mask interface problems and claustrophobia. In those that do tolerate NIV, eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. The NeuRx RA/4 Diaphragm Pacing System was originally developed for patients with respiratory insufficiency and diaphragm paralysis secondary to stable high spinal cord injuries. The DiPALS study will assess the effect of diaphragm pacing (DP) when used to treat patients with MND and respiratory insufficiency. METHOD/DESIGN: 108 patients will be recruited to the study at 5 sites in the UK. Patients will be randomised to either receive NIV (current standard care) or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 follow up time points (2, 3, 6, 9 and 12 months) plus an additional surgery and 1 week post operative visit for those in the DP group. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews. DISCUSSION: The primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND with respiratory muscle weakness. The project is funded by the National Institute for Health Research, Health Technology Assessment (HTA) Programme (project number 09/55/33) and the Motor Neurone Disease Association and the Henry Smith Charity. TRIAL REGISTRATION: Current controlled trials ISRCTN53817913. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

The effectiveness of routinely delivered cognitive behavioural therapy for obsessive-compulsive disorder: a benchmarking study.

OBJECTIVES: There is often difficulty in generalizing the results of randomized controlled trials (RCTs) to routine clinical practice given the rigid design features of such studies. The purpose of this study is to describe the effectiveness of routinely delivered, formulation-based cognitive behavioural therapy (CBT) within a publicly funded clinic for adults with obsessive-compulsive disorder (OCD) and offer a comparison against the outcomes achieved in efficacy studies for the same population. METHOD: Practice-based prospective study. Routine data collected from a National Health Service out-patient clinic for adult clients with OCD is benchmarked against the findings of RCTs. The comparison RCTs were identified using a systematic review methodology. RESULTS: The mean (95% confidence interval) change in Yale-Brown Obsessive Compulsive Scale score pre- to post-therapy in the Sheffield clinic was 10.2 (7.1 - 13.3), which compares well with changes of 11.4 (10.5 - 12.2) for exposure and response prevention trials, 12.9 (11.2 - 14.7) for cognitive therapy trials, and 10.6 (8.5 - 12.8) for CBT trials. The Sheffield results fell within the benchmarks derived from the included RCTs. CONCLUSION: These results indicate that CBT for adults with OCD delivered outside the constraints of a clinical trial is equivalently effective but that this conclusion should be tested further on a larger group of patients.

Looking inside the black box of community rehabilitation and intermediate care teams in the United Kingdom: an audit of service and staffing.

OBJECTIVE: To generate a picture of the range, configuration and staffing of community and intermediate care services in the United Kingdom (UK) and to ascertain whether any relationships exist between service configuration and staffing models. METHOD: A service audit tool was sent to members of the Community Therapist's Network (CTN) and to chief executives of primary care and National Health Service trusts in the UK. Data were collected from the CTN and chief executives of primary care trusts (PCTs) and NHS trusts between late 2005 and early 2006. RESULTS: The overall response rate to the two audits was 37% (n = 243), with 77% of these responses (n = 186) useable. Services varied greatly in terms of their organisation and staffing configurations. Skill mix varied according to the location of service delivery, with home-based services utilising more therapy and support staff than inpatient services. Two clusters of service emerged, based on the number of referrals per year, support staff in the team and the level of care provided by the service. CONCLUSION: There are no clear patterns to the structure and organisation of community and intermediate care services in relation to their purpose, and it remains unclear how different staffing configurations impact on service costs and patient outcomes. The amount of variation observed indicates that there is likely to be considerable variability in service costs and outcomes for the teams. Further evidence is required to determine the impact of different staffing models, and to identify approaches that optimise both effectiveness and efficiency.