Taking a Systems Neuroscience Approach to Persistent Postsurgical Pain: Mechanisms, Prediction Tools and Preventive Strategies

Abstract

Background: Persistent postsurgical pain (PPP) is an increasingly recognised complication of surgery. Various putative risk factors have been identified over the last ten years. However the prevention of this phenomenon has proven difficult. I studied PPP following cardiac surgery to identify both means of prediction and prevention. Methods: With ethics committee approval, I followed up 312 patients undergoing cardiac surgery over a six-month period in our hospitals. This established pilot data and allowed power calculation for the following prospective studies: 1. Randomised controlled trial (RCT) of pregabalin alone (P) or pregabalin combined with ketamine (PK), as compared to usual care (UC) for the prevention of PPP. 2. Quantitative Sensory testing before and after surgery, to identify central nervous system changes predictive of PPP, as well as any protective effect of P and PK in the active arms. Patients were risk stratified into vulnerable and resilient phenotypes, with the use of dynamic pain assessments of Conditioned Pain Modulation (CPM), Temporal Summation (TS) and Zone of Hyperalgesia (ZoH.) Results: In the observational pilot cohort, 39.7% of patients described PPP following elective first-time cardiac surgery. The age of the patient, duration of surgery and acute pain during the recovery period all seemed to act as strong predictors for the development of PPP in this cohort study. In the prospective RCT, pregabalin was protective for future PPP. The study demonstrated a significant improvement in PPP; OR= 0.11 and 0.046, for groups P and PK respectively at three months, as compared to the UC group. The addition of ketamine to pregabalin, as part of a multimodal regimen, had no significant effect on PPP outcomes in this trial. Tolerability of both drugs on the first day of treatment was an issue. As an example, NNH (Number Needed to Harm) for diplopia was equal to 6.3 and 4.5, in P and PK respectively. This failed to impact on recovery, however, with improvements in median length of stay of 1 and 1.5 days respectively (p=0.023 and 0.002.) The powerful and protective effects of pregabalin in the perioperative period are demonstrated by: 1. Increases in pressure pain threshold (PPT) at a site remote to the incision 2. Prevention of the development of new TS 3. Reduction in the zone of peri-incisional hyperalgesia The likelihood of developing PPP in any cardiac surgical patient may be predicted by a combination of the following perioperative risk factors: 1. Perioperative QST markers of new TS and increased ZoH, at the site of surgical incision, as well as decreased PPT remote to the incision. 2. Inefficiency of CPM 3. Poor preoperative quality of life, measured with EQ-5D 4. Increased levels of state anxiety and catastrophising 5. Young age 6. Surgical risk factors of increased duration of surgery and poorly managed acute pain - but not surgical technique and extent of dissection. Conclusion: This study suggests a potential to risk-stratify cardiac surgery patients and allow targeted preventive intervention for PPP.