Title: SPAARK: Study of Peri-Articular Anaesthetic for Replacement of the Knee
Funder: Department of Health and Social Care

Abstract: Background Around 100,000 knee replacements (KR) are performed per year across the UK with a 600% rise expected by 2030 [1]. Although successful in treating end-stage osteoarthritis; KR remains a painful procedure and despite the introduction of enhanced recovery programmes (ERP), aimed at reducing surgical stress and optimising recovery, around 40% patients report severe pain peri-operatively [2]. ERPs use multi-modal techniques, including local anaesthetic (LA) infiltration around the knee at the time of surgery, to reduce pain, promote mobilisation and minimise opiates and opiate related side effects including nausea, itching, constipation and hypotension which effect up to half of patients. A limitation of current ERPs is that existing LAs, including bupivacaine hydrochloride, only provide clinically significant analgesia for the initial 12-24 hours post-surgery resulting in patients having significant breakthrough pain the morning after surgery when they are encouraged to mobilise their knee and get out of bed. Breakthrough pain and the subsequent use of opioids delays mobilisation, increasing the risk of chest infection and venous thromboembolism and delays discharge [9]. Any medication that can prolong the duration of analgesia without the systemic side effects has the potential to revolutionise the way KR patients are managed within the NHS. Liposomal bupivacaine (LB; Exparel, Pacira, San Diego) is a LA encapsulated in a biodegradable fat matrix effective for 72 hours. Approved by FDA (2011); LB is routinely used in the USA to reduce post-operative pain, minimise opioid usage and facilitate early discharge [7, 10]. In many centres in the USA; typical hospital stay after a KR is 4-6 hours in contrast to the NHS average of 4.5 days with each inpatient day costing around 717 pounds [11, 20]. Whilst a systematic review of all RCTs has provided evidence of superiority of LB compared with bupivacaine hydrochloride, subgroup analysis of trials of knee replacement have failed to demonstrate an effect. The variance in results and large body of evidence of superiority from non-RCTs suggest that existing trials may not be adequately powered to detect a small but true difference. Whether this difference clinically or economically justifies the use of LB as part of a multi-modal ERP within the NHS remains to be proven and hence there is a need for an appropriately powered RCT. Aim To assess the clinical & cost-effectiveness of peri-articular liposomal bupivacaine compared with peri-articular bupivacaine hydrochloride in patients undergoing KR. Investigation plan A blinded multi-centre prospective RCT is planned. A sample size of 500 (250/arm) would provide 90% power & 5% significance (two sided) to detect a five point difference in Quality-of-Recovery-40 (QoR-40) score (SD 15.5) allowing for a 15% loss to follow-up. The study will be conducted across five NHS hospitals with recruitment completed over 18 months. The primary outcome will be recovery measured at 72 hours post-surgery using the QoR-40, a six-dimension validated patient reported peri-operative recovery score which is widely used across different specialities including KR [12]. An important secondary outcome, (which the study is also powered to detect) is a joint specific cumulative pain score with activity. Other outcomes include patient reported quality of life (EQ-5D-5L), analgesia requirements and fitness for discharge with functional outcomes at 6 weeks, 6 months and one year. Benefits This trial will assess the clinical and cost-effectiveness of liposomal bupivacaine compared to peri-articular bupivacaine hydrochloride in patients undergoing KR. If effective, it will provide better pain control, reduce complications and make significant savings by facilitating early patient discharge from the hospital. If ineffective this first independent trial will convincingly show that LB is not beneficial in KR and should not be introduced in the NHS.

Lay abstract: Knee replacement is highly successful for treating severe arthritis, however the surgery is painful and nearly half of patients report severe pain post-operatively. If pain is not controlled, it slows recovery and can lead to complications such as chest infection, heart attack, and blood-clots. In addition, experiencing pain after surgery leads to longer hospital stays and patient dissatisfaction. Typically, pain control is provided by using local anaesthetic (LA) injected around the knee during surgery. Following knee replacement, the pain is worst over the first 72 hours. Current LAs provide good pain relief for 12 to 24 hours but the worst pain experienced is typically the next morning when the patients are encouraged to bend their knee and get out of bed. A new formulation of LA, liposomal bupivacaine, has been widely used in the USA since 2011 but is not yet licensed in the UK. It is reported to give pain relief over 72 hours and across a range of surgeries has been reported to improve pain control, reduce the need for additional pain killers and result in a shorter hospital stays compared to current LAs. There is a need to assess how effective this drug is in knee replacement surgery within the NHS, as if it is better; it has the potential to significantly improve outcomes as well as result in cost-savings. Across five NHS hospitals we will conduct a study to investigate how well liposomal bupivacaine works compared to bupivacaine hydrochloride, the current standard LA, and whether it has the potential to save the NHS money. The results of this study can be directly applied across the NHS and it would represent a landmark study improving patient experience after knee replacement and informing anaesthetists and surgeons about whether it can bring benefits to around 100,000 patients every year.

Research activity codes: 6.4 SURGERY
Health categories: MUSCULOSKELETAL