TOPIC 2: A Randomised Controlled Trial to investigate the effectiveness of ThOracic Epidural and Paravertebral Blockade In reducing Chronic Post- Thoracotomy Pain: 2

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.