Pain relief during labour and following obstetric and gynaecological surgery with special reference to neuroaxial morphine

Abstract: Background: Pain is a major clinical problem during childbirth and postoperatively after caesarean section (CS) and hysterectomy. There are several reasons why pain should be minimized; pain is indeed a negative sensation, it affects the birth-experience and the entire post-operative recovery, with reduced wellbeing and extended time in hospital. Inadequately treated pain is a risk factor for persistent pain. Multimodal pain treatment, combining different analgesics with different mode of action to reach additive or synergistic analgesic effect; thereby gain effective pain management but a lower incident of side effects has become praxis. Adding small amounts of morphine to local anaesthetic for spinal anaesthesia is an attractive combination improving intraoperative anaesthesia and postoperative analgesia. The use of intrathecal morphine (ITM) is however associated to side effects, where respiratory depression is the most feared adverse effect, which restricted its use. Obesity per se is associated with risk for respiratory complications e.g. sleep apnoea and hypoventilation. Thus obesity, ITM and pregnancy may act additive increasing risk for respiratory depression and the risk for respiratory depression has been seen more commonly in obese mothers after caesarean section CS. The aim of this thesis was to study morphine as adjunct to bupivacaine in neuroaxial anaesthesia in different perspectives; ITM used in spinal labour analgesia, ITM used in spinal for post hysterectomy pain, the use of neuroaxial administered morphine in Sweden, the role of polygraphic registration in obese mothers after CS in spinal anaesthesia including ITM and finally the use of general and regional anaesthesia ITM in emergent CS. Methods and Main Results: Study I and II are randomized double-blinded placebocontrolled trials investigating the effects of different doses of morphine added to local anaesthetic intrathecally. In Study I we compared the addition of morphine 50, 100 µg or saline to intrathecal bupivacaine (1.25 mg) and sufentanil (5 µg) to evaluate the impact on duration of labour analgesia as part of a combined spinal-epidural technique in 90 nulliparous labouring women. Duration of analgesia was defined as the time from intrathecal injection to the return of pain VAS >4. No significant differences were seen in onset or duration of analgesia, obstetric and neonatal outcome or side effects, between the groups. In Study II ASA I-II women (n=144) scheduled for abdominal hysterectomy in combined general and spinal anaesthesia were randomised to spinal anaesthesia with 12 mg of hyperbaric bupivacaine combined with 100, 200, and 300 µg morphine or saline. Primary outcome was 24 h used nurse administered and patient controlled analgesia (PCA)-morphine. ITM reduced accumulated 24 h post-operative morphine consumption. Morphine 100 µg reduced morphine consumption significantly vs. placebo at 0–6 h, 6–12 h, and for the entire 0–24 h after operation. Morphine 200 µg further reduced morphine consumption significantly vs. morphine 100 µg at 0–6 h and for the entire 0–24 h after operation. Morphine 300 µg did not further reduce the morphine consumption. Emesis was experienced similar in all groups, and pruritus occurred only in the morphine groups. No serious side effects were observed. In Study III we investigated the use of intrathecal and epidural opioids in mainly CS, and hysterectomies in Sweden by a questionnaire to anaesthetists in charge of obstetric anaesthesia units. We had 68% of units responding and found in CS spinal anaesthesia, 20/32 units use ITM, the most common dose was 100 µg (17/21). Addition of intrathecal fentanyl (10-20 µg) or sufentanil (2.5-10 µg), was used by 21 and 9 units respectively. In CS epidural anaesthesia 12/32 clinics used epidural morphine, the majority of units used a 2 mg dose while use of fentanyl (50-100 µg) or sufentanil (5-25 µg) was more common, in 10 and 15 units respectively. For hysterectomy ITM was used by 20/32 units (80-200 µg), the majority used 200 µg dose (9/32). Risk of respiratory depression and difficult to monitor postoperatively was the main reason for withholding intrathecal opioids in 7/12 units. Study IV is a prospective observational study to explore the occurrence of sleep disorder breathing in obese mothers and use of portable sleep apnoea polygraphy for respiratory monitoring the first night after CS with bupivacaine/morphine/fentanyl spinal anaesthesia, assessing the occurrence of apnoea/hypopnea index (AHI) and oxygen desaturation index (ODI). Among the 20 mothers that completed polygraphic registration: 11 had normal apnoea-hypopnea index (AHI <5) 7 had mild; AHI ≥5 and <15; and 2 had moderate; AHI ≥15 (15.3 and 18.2) but no one had severe obstructive sleep apnoea, OSA (AHI ≥30). Those mothers with moderate OSA did not show high ODI or signs of hypercapnia on transcutaneous CO2 registration. The ODI was on average 4.4, eight mothers had an ODI >5. Mean saturation was 94% (91-96%), and four mothers had mean saturation between 90-94%, but none had a mean SpO2 <90%. None of the mothers showed clinical signs or symptoms of severe respiratory depression, registered by routine clinical monitoring. Study V is a retrospective chart review of emergency CS (ECS) at Danderyd Hospital between January and October 2016 with the aim to assess the decision to delivery interval (DDI) and the impact of chosen anaesthetic technique, general anaesthesia (GA), spinal anaesthesia (SA) with opioid supplementation, or “top-up” of labour epidural analgesia (tEDA) with local anaesthesia and fentanyl mixture, and work shift for ECS at Danderyd Hospital, Sweden. In total, 135 ECS were analysed: 92% were delivered within 30 minutes. Mean DDI for all CS was 17.3 ± 8.1 minutes. With GA DDI was shortened by 10 and 13 minutes compared to SA and tEDA (p<0.0005). DDI for SA and tEDA was similar. No difference in DDI was seen regarding time of day or weekday. Apgar <7 at 5 min. was found more commonly in ECS having GA (11/64) vs. SA (2/30) and tEDA (1/41)(p<0.05). Conclusions: Low dose ITM has an important role mainly in a fast track concept to minimize systemic opioid consumption and still optimize postoperative analgesia in elective and emergent CS in recommended dose of 100 µg and hysterectomy 200 µg. If spinal labour analgesia is chosen addition of ITM doses 100 µg or less seems of no value to prolong the duration. ITM is widely used in Sweden in mainly CS and hysterectomy, although still restricted in some units due to fear of respiratory depression and/or difficulties monitoring postoperatively. Respiratory monitoring with polygraphy in obese mothers after CS ITM anaesthesia did not reveal severe sleep disorder breathing and seems to be of limited value in the postoperative period after CS performed in spinal anaesthesia including morphine. We found 92% of ECS, were delivered within 30 min. and DDI was shortened with GA by 10 and 13 minutes compared to SA and tEDA but with no difference between SA and tEDA