Background

Postoperative pain treatment in women undergoing cesarean section (CS) needs to be effective to enable fast and smooth recovery without adverse outcomes and to improve breastfeeding and bonding between mother and child. It is also important that pain treatment should have minimal impact on the newborn.

The overall aim

The overall aim of this thesis was to investigate how to improve pain management in women undergoing cesarean section.

Specific aims were:

* To investigate if a single injection of bupivacaine with adrenaline close to the fascia could decrease opiate consumption and pain in patients undergoing CS in spinal anesthesia and whether the same treatment influences the need for opiates in women operated in general anesthesia (paper 1 and 3).

* To study the overall incidence and risk factors for persistent pain after CS and to characterize the persistent pain, regarding intensity, body location and impact on daily life (paper 2).

* To clarify whether oral oxycodone (OXY) can provide equal/better and safe postoperative pain relief after CS compared to intravenous morphine followed by oral codeine (IVM) (paper 4).

* To study pharmacokinetic aspects of postoperative OXY treatment of mothers after CS and to investigate possible drug exposure through breast milk, including the effects on the newborn (paper 5).

Methods and results:

Study I: Two hundred and sixty women undergoing CS were randomized to receive injection ofeither 40 ml bupivacaine (2.5 mg/ml) with adrenaline (5 μg/ml) (n=130) or 40 ml saline solution (0.9%) (n=130), close to the fascia before closure of the wound. Morphine consumption, pain assessment by Numerical Rating Scale (NRS) and time to mobilization were recorded. Morphine requirements were significantly less for up to 12 h postoperatively and mean and maximum pain intensity lower during the first 6 h in the group receiving local anesthesia (p ≤0.05).

Study II: A prospective follow up study of the women participating in study I. A questionnaire consisting of the Brief Pain Inventory (BPI) was posted to all women at 3, 6 and 12 months after surgery. Women rated pain intensity as well as interference with factors related to general function and quality of life. Women reported pain in one or more locations, in the CS surgical site as well as in other parts of the body. At 3 months 40% had pain and at 6 and 12 months 27% and 21%, still had pain. CS on maternal request i.e. psychological indication as well as a first CS were significant (p ≤0.05) risk factors for persistent pain at 3 months. Severe postoperative pain in the immediate postoperative period (0-48 h) or undergoing a first CS were significant independent risk factors for the development of persistent pain up to 6 months after CS. Parameters related to quality of life such as sleeping difficulties were significantly impaired in women with persistent pain.

Study III: A retrospective study (2008-2014) was conducted at the Karolinska University Hospital, Huddinge where medical records of women who underwent CS in general anesthesia were reviewed. After applying exclusion criteria 250 medical records remained. Information 3 about women receiving local anesthesia in the surgical wound, 20 or 40 ml bupivacaine/adrenaline (36 and 42 women in each group), were collected and data from women receiving no local treatment were identified and served as controls (n=172). A significantly lower morphine consumption during the 6 first postoperative hours was seen in patients receiving 40 ml local anesthetics when compared with controls (p ≤0.05) but no difference was seen for the 20 ml group or between treatment groups.

Study IV: Eighty women scheduled for elective CS were recruited and randomized to receive extended release tablets and short acting OXY (n=40) or IVM (n=40). All patients received a multimodal therapy with ibuprofen and paracetamol and the opiates were administered as needed. Outcome measures were safety parameters for mother and child, opioid requirements, pain intensity by NRS, time to mobilization and time consumption to administer drugs. To evaluate safety for the newborns Apgar scores, acid base status in the umbilical cord, weight development and the Neurological Adaptive Capacity Score were used. A significantly lower postoperative pain intensity measured by NRS was observed 0-6 hours and 25-48 hours in the OXY group (p ≤0.05). Opioid consumption was significantly less in the OXY than in the IVM group 0-5 days postoperatively. Total time to administer analgesics was significantly shorter in the OXY group. There was a significant difference in common opiate related adverse effects between the two groups (3 women in the OXY group compared to 15 in the IVM/codeine group). No negative effects in the newborns related to opioid treatment were observed in either of the two groups.

Study V: The material was obtained in study IV. Maternal blood and breastmilk were sampled at 24 and 48 hours and neonatal blood was collected at 48 hours postpartum. All samples were analyzed for OXY and the metabolites noroxycodone, oxymorphone and noroxymorphone. Detectable plasma levels of OXY and its metabolites were found in all women and even if there were small quantities of breastmilk detectable levels were found also here. In most cases there were low or non-detectable levels of OXY in the plasma of the neonates.

Conclusions: A single injection of bupivacaine with adrenaline in the surgical wound decreases the need for rescue morphine postoperatively and was demonstrated to be a safe and effective pain management in women undergoing CS both in spinal and general anesthesia. Standardized postoperative treatment with oral OXY after CS was shown to be time effective and to give a better pain control, with lower opioid intake than a protocol using IVM/codeine, both as components of a multimodal analgesic regime. Our clinical data and the pharmacokinetic analyses support the view that OXY treatment is safe for mothers and neonates. As severe postoperative pain is a risk factor for long term pain the initial pain relief is crucial and we found that experiences related to quality of life were significantly impaired in women with persistent pain. We suggest that our findings can be of clinical importance, not least in women who have their CS performed in general anesthesia.