Title: A Randomised Controlled Trial to investigate the clinical and cost-effectiveness of Paravertebral Blockade compared with Thoracic Epidural Blockade in reducing Chronic Post-Thoracotomy Pain (TOPIC 2)
Funder: Department of Health and Social Care

Abstract: Design: Multi-centre randomised trial with internal pilot & economic evaluation. Setting: At least twenty large adult UK thoracic centres with a track record of successful recruitment to clinical trials and typical patient case mix. Target population: Consenting adults undergoing elective open thoracotomy. Inclusion criteria: Aged over 18 years; ASA physical status I-IV. Exclusion Criteria: Contraindication to TEB/PVB; infection near proposed puncture site; coagulation/thoracic spine disorders; chest wall resection; emergency surgery; previous thoracotomy. Health technologies being assessed: Two existing peri-operative analgesic techniques: i) PVB: multiple injections followed by placement of catheter; ii) TEB: usual practice. Measurement of outcomes: Our outcomes set is based on the IMMPACT recommendations for core outcomes in chronic pain. Primary outcome: Incidence of Chronic Post-Thoracotomy Pain (CPTP) at 6 months post-randomisation. Participants will be asked to indicate their ‘worst chest pain over the last week at the site of their thoracotomy operation’ on a visual analogue scale (0-100). Incidence will be taken to be a score greater or equal to 40 indicating at least a moderate level of pain. Secondary outcomes: Brief Pain Inventory (BPI) interference score, Short Form McGill Pain Scale (SF-MPQ-2) Generic health related quality of life (EQ-5D-5L), Hospital Anxiety and Depression Scale (HADS) collected at baseline, 3, 6 and 12 months. Analgesic use, pain post-surgery and discharge, mortality, complications, days in Intensive Care Unit/High Dependence Unit (ICU/HDU) and patient satisfaction. Resource use and costs: Data on use of health care resources and relevant costs will be collected as part of the trial. These will include the cost of the procedures, post-operative and post-discharge resource use, private costs and productivity loss. Sample size: Assuming a 30% incidence of CPTP in the TEB group (similar to our TOPIC-pilot results and systematic review 2), 392 patients in each group will give 90% power (p=0.05) to detect a 10% absolute reduction (i.e. down to 20%) in the PVB group. Assuming a 10% rate of death and a further 15% loss to follow-up at 6 months we will recruit 1026 participants. Project timetables including recruitment rate: Our data suggest 3400 operations take place in the 20 identified centres per year. The total trial duration is 54 months; 6 months set-up, 30 months recruitment (assuming the majority of centres will recruit around 3 patients every 2 months), 12 months follow-up and 6 months for analysis. Expertise in team: We have an outstanding track record in conducting large multi-centre RCTs. FG, NIHR Senior Investigator, MW, NIHR Clinician Scientist, BS & NM, thoracic consultant anaesthetists, are experienced clinician trialists in anaesthesia and pain in the roles of Chief Investigator; BN is an experienced thoracic consultant surgeon and trialist. JY, NIHR Post-Doctoral Fellow, has expertise in teaching and training; AG is a pain expert with an international reputation in pain research; LM, senior statistician and experienced methodologist; LJ is a health economist who is a co-applicant on two large HTA-funded trials; TM and AK provide expertise in clinical trials delivery. MJ has expertise in QuiteT Research Intervention model; AW provides PPI voice and CS leads trainee network. The trial will be co-ordinated and supported by the BCTU HJ with 17 years clinical trials experience.

Lay abstract: Aim:To conduct a multi-centre randomised controlled trial to evaluate the effects of using paravertebral blockade vs thoracic epidural blockade for peri-operative pain relief in terms of the development of chronic pain. Background: Surgery through the side of the chest (thoracotomy), usually to treat lung cancer, can cause pain post-operatively that can last months or years in up to half of patients. This Chronic Post-Thoracotomy Pain (CPTP) can be severe and debilitating to patients, leading to more frequent GP visits, anxiety, depression, time off sick and unemployment. CPTP is a burden to the NHS that is set to increase as lung operations over the last decade have gone up by 60%. Thoracic epidural block (TEB), which numbs both sides of the chest, and paravertebral block (PVB), targeting pain relief only on the side of the surgery, are two common techniques that provide good pain relief, but crucially PVB may reduce the likelihood of chronic pain developing afterwards. Practice varies across the NHS and we do not currently know which is better, particularly in preventing the number of people who later develop chronic pain. This study is trying to find out which technique results in less incidence of chronic pain at 6-month. Design and Methods: People experience pain differently to one another and to be sure that the trial answers the question definitively we are proposing to conduct a large clinical trial of 1026 participants in at least 20 UK thoracic centres. The patients receiving TEB need to be similar to those receiving the PVB; to do this we will randomly assign consenting patients to receive either one at the time of operation (randomisation). There will be no other changes to their operative care. Patients will be followed up for up to 12 months and asked questions about their pain levels, quality of life, use of NHS care and out-of-pocket payments. The data will be analysed and used to establish which is the most effective and cost-effective type of analgesic. PPI: We have included two laypersons (AW a co-applicant; SG advisor) of our study team who are experienced in PPI activity and have experienced post-surgery chronic pain. They have reviewed and advised on study design and outcome measurements, and will contribute to the writing of patient information sheet, consent form & dissemination. We are also liaising with the Patient, Carer & Public Involvement & Engagement (PCPIE) group, National Institute of Academic Anaesthesia, to strengthen TOPIC 2-PPI elements for patients recruitment. Dissemination: We’ll take advice from our PPI representatives, Breathe Easy, Cancer Research UK, British Lung Foundation & British Pain Society on developing ‘plain English’ summary of the trial for clear and meaningful information to bring it to a lay audience. We’ll inform the participants of the findings, present at the INVOLVE conference and to NHS national electronic Library for Health (NHS Evidence, NHS Choices) webpage. We’ll present our findings at local, national & international anaesthetic and cardiothoracic surgery educational meetings and thoracic training events. We’ll publish the full trial protocol and findings of TOPIC2 in peer reviewed journals, an HTA monograph, high impact international journals or revisions of Cochrane review as appropriate. We will directly feedback the conclusions of TOPIC2 and its impact to the Royal Colleges of Surgeons & Anaesthetists and NICE for their future recommendations in open thoracic surgery.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: NEUROLOGICAL