Persistent postsurgical pain (PPSP) is reported as recurrent and frequently disabling complication of many surgical procedures. The consequences for PPSP not only reduce the quality of life for patients but also financially tax the health care system, considering the volume of surgical procedures performed annually. Development of chronic pain has been proposed to involve a complex pathophysiology combined with pre-, intra-, and post-operative risk factors. There is no definite recommendation on which factor to assess (in which surgery) and what tools to utilize for conducting a study on PPSP, since many recognized risk factors for PPSP are contradictory. For a comprehensive overview of major PPSP risk factors for identification and possible prevention, we conducted a systematic review and meta-analysis of the published literature on the risk factors across six major surgical groups: breast surgery, chest/thoracic surgery, total hip arthroplasty/total knee arthroplasty (THA/TKA), gynecologic surgery, iliac crest bone harvest (ICBH), and groin hernia repair. Furthermore, to assess the generalizability of the meta-analysis results, we sought to conduct a retrospective, cross-sectional study examining the prevalence and major risk factors of PPSP after cystectomy for bladder cancer. The meta-analysis found that no single risk factor was associated with PPSP across all surgical groups. Age and previous surgery were found to be risk factors for PPSP in gynecologic surgery. For thoracic surgery, male sex and BMI were found as risk factors for PPSP. Surgical duration, presurgical chronic pain, and BMI were risk factors for groin hernia repair. The prevalence of PPSP in our cystectomy study was 22.1%. Female sex and presurgical chronic pain were risk factors significantly associated with PPSP after cystectomy. No risk factors were universally associated with PPSP. Persistent pain after each type of surgical procedure appear to have separate set risk factors among age, BMI, sex, previous surgery, and presurgical pain.

In this thesis, rodent models of chronic pain were used to explore analgesic mechanisms that may potentially be engaged in spinal and peripheral compartments by systemically-administered amitriptyline, a tricyclic antidepressant. The first project (Chapter 2) identified the roles of spinal adenosine A1 and serotonin 5-HT7 receptors, as well as of peripheral adenosine A1 receptors, in the acute antinociceptive effects of amitriptyline in mice. The second project (Chapter 3) examined the potential utility of amitriptyline as a preventive analgesic against persistent post-surgical pain, and involved perioperative administration of amitriptyline after peripheral nerve injury in rats. Changes in post-injury behavioural outcomes, as well as spinal noradrenergic sprouting, were assessed. Overall, spinal serotonergic pathways linked to adenosine A1 receptors, as well as peripheral adenosine A1 receptors, appear to be important in antinociception by amitriptyline. Preventive analgesia by this drug does not appear to result from anatomical changes in spinal noradrenergic pathways.