The effect of intra-abdominal local anaesthetics following major gynaecological surgery. Clinical and experimental studies

Abstract: Background: Local anaesthetics (LA), in addition to inhibition of pain signalling, also have anti-inflammatory properties. In vitro studies have demonstrated anti-proliferative and cytotoxic effect of LAs on cancer cells when administered in therapeutic concentrations. Intraperitoneal administrated LA is shown to reduce pain, improve surgical recovery and to blunt the postsurgical inflammatory response. Retrospective studies have indicated beneficial oncological outcome of regional anaesthesia on cancer recurrence when used in cancer surgery. Abdominal hysterectomy causes moderate to severe pain, and assessing new tools for pain treatment is crucial. The postoperative period of extensive surgery for advanced ovarian cancer is associated with high morbidity. When the patients have recovered from cancer surgery, chemotherapy can be initiated. New therapeutic approaches to enhanced recovery with reduced postoperative pain and inflammation is of great interest. Methods and aim: The thesis aimed to evaluate the efficacy of intra-abdominal local anaesthetics on pain, inflammatory response, serum concentration of LA and patient recovery after gynaecological surgery (study I, II and III). The aim of study IV was to determine the effects of LA on ovarian cancer cells in vitro. The clinical studies were prospective, double blind, randomized and placebo-controlled. In study I, women scheduled for abdominal hysterectomy, were randomised to local infiltration analgesia (Group LIA) or placebo (group C). Rescue analgesic consumption and opioid related side effects were analysed. In study II and III, women undergoing cytoreductive surgery for advanced ovarian cancer were randomised to receive either intraperitoneal ropivacaine (Group IPLA) or saline (Group Control) peroperatively. Inflammatory markers in serum, LA concentrations (study II), and objective measures of patient comfort, postoperative complications, pain, home readiness and time to initiation of chemotherapy (study III) were analysed. In study IV proliferation and migration in two ovarian cancer cell lines, exposed to LA in concentrations corresponding to doses used in study II and III, were analysed. Analysis of cancer stem cells (CSC) phenotypes were performed. Results: The median supplemental requirements of morphine during 0–24 hours after abdominal hysterectomy was significantly lower in group LIA compared to group C (18 mg vs. 27 mg, p = 0.028) and the median time to first analgesic injection was significantly longer in group LIA (40 min vs. 20 min, p = 0.005) (Study I). Perioperative intraperitoneal LA resulted in significantly decreased serum cortisol levels. Serum concentrations of ropivacaine were well below toxic concentrations (study II). Time to initiation of chemotherapy was significantly shorter in group IPLA (Median 21, IQR 19-29 vs. 29 days, IQR 21-40, p = 0.021). No differences in standardised recovery endpoints were found between the groups (Study III) . The laboratory study showed a significantly reduced cell number and an inhibited cell migration. Cell size were significantly increased and CSC phenotype analysis showed a reduction in all cells by up to 50% (Study IV). Discussion: Local infiltration analgesia results in a significantly lower rescue morphine consumption following abdominal hysterectomy. Intraperitoneal local anestetics can be administered in ovarian cancer cytoreductive surgery safely, without achieving toxic doses. Although IPLA do not provide further anti-inflammatory effects, the stress response is briefly blunted and there might be positive effects such as earlier start of chemotherapy. LA reduce the ability of cancer cells to metastasise. Intra-abdominal LA offers a potential to have beneficial effects on pain, recovery and circulating tumour cells after gynaecological surgery.