Title: A systematic review with mixed treatment comparisons meta analysis of anti-depressant treatment for adults with chronic pain
Funder: Department of Health and Social Care

Abstract: People with chronic pain often feel frustrated, sad, exhausted and distressed. Although these symptoms look like clinical depression they might be different, because they result from the challenges of living with pain daily. In most cases, people living with pain who are also distressed will be prescribed antidepressants, but it is not currently known how effective these are, and there is a possibility that long term use might be harmful. It is important to find out if antidepressants are effective in improving mood and sleep, and reducing pain and disability in people living with chronic pain. We also need to know if some groups of people with pain should get antidepressants, while others might do better with other treatments. To find this out we will do a systematic review with meta analysis. We will identify all of the published trials in which antidepressants were tested in adults with chronic pain. We will assess how well these trials were carried out, and we will analyse the results across all the trials. This method overcomes problems that occur when single trials are too small, and produces an overall estimate of how well antidepressants do in the treatment of people with chronic pain. We will examine each type of drug separately, and look for groups of people who do well and who do poorly on antidepressants. This research is important because it will help doctors decide whether antidepressants are a suitable treatment for people who have chronic pain and who are distressed.

Lay abstract: Research question: What is the comparative efficacy and safety for antidepressant medicines in the treatment of pain, mood, and sleep in adults with chronic pain?_x000D_ Background: People with chronic pain often feel frustrated, sad, exhausted and distressed. Although these symptoms look like clinical depression they might result from the challenges of living with pain daily. In most cases, people living with pain who are also distressed will be prescribed antidepressants, but it is not currently known how effective these are, and there is a possibility that long term use might be harmful. _x000D_ Aims and objectives: We aim to compare the efficacy and safety of different antidepressants (including different classes of antidepressants, different types of antidepressants, and different dose regimes) within homogeneously defined populations of people living with chronic pain. To achieve this aim, we will do a systematic review and mixed treatment comparisons meta- analysis to inform clinical practice by comparing different antidepressants for treatment of adults with chronic pain. If data is sufficient, we aim to identify sub-groups of responders to antidepressants._x000D_ Methods: We will compare the efficacy and safety of different antidepressants (including different classes of antidepressants, different types of antidepressants, and different dose regimes) within homogeneously defined populations of people living with chronic pain. We will include only double blind randomised controlled trials against placebo, or head to head trials, including all active controls in primary analysis. We will test the following outcomes: pain intensity, mood (anxiety and depression) and sleep._x000D_ _x000D_ We propose to carry out network meta-analysis separately for each outcome. If sufficient data exist the NMA will be extended to a multivariate NMA examining pain and depression concurrently. Dose of drug, class of drug and diagnostic groupings will be explored as reasons for heterogeneity, and will be tested as moderators. We will assess heterogeneity using the I² statistic, calculated for each pairwise comparison on each outcome. Estimates of variation from the NMA will also be utilised. We will summarise results using effect estimates, their confidence intervals, and probability of best treatment from NMA. We will use forest plots and SUCRA for data visualisation. Number needed to treat values will be calculated from the results of the meta-analysis to detect any contrast between the results of NMA indirect comparison and standard pairwise comparison. We will identify RCTs that carried out sub-group analysis, and those that included data suitable for a meta-regression for treatment moderation. We will also utilise observational data where it improves connectivity in NMA and threshold analysis indicates sensitivity._x000D_ Timelines for delivery: The project will be completed in 18 months_x000D_ Anticipated impact and dissemination: The project will lead to better understanding of the effectiveness of antidepressants for people living with chronic pain. It is novel and timely and has the potential to save patients receiving unnecessary treatment, and save costs to the NHS through the reduction in prescribing, and associated side-effects and consultations. Findings may also lead to the development of more appropriate care pathways. We will aim to publish in a high impact journal, present our findings at international conferences, and work with our PPI networks to disseminate findings.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: GENERIC HEALTH RELEVANCE