Included studies

Five studies were included in this review: 4 randomised controlled trials (RCTs) (Gunes 2014, Ng 2011, Thurlow 2002 and Wilson 2018) and 1 retrospective cohort study (Murray 2019).

Four RCTs compared IV remifentanil PCA to IM pethidine (Gunes 2014, Ng 2011, Thurlow 2002 and Wilson 2018). One of these studies included a third arm which compared IV remifentanil PCA with a background infusion of remifentanil to IM pethidine (Gunes 2014). The retrospective cohort study compared IV remifentanil PCA to IM diamorphine (Murray 2019).

The bolus dose of remifentanil administered by the PCA device varied between studies: 2 studies used a 40 microgram bolus of remifentanil (Murray 2019 and Wilson 2002); 1 study used a 20 microgram bolus (Thurlow 2002); and 2 studies used a bolus dose which accounted for the weight of the woman (Gunes 2014 and Ng 2011). The Thurlow 2002 study was a very small pilot study with a low (20 micrograms) dose of remifentanil, and for this reason the results from this study were not meta-analysed with other studies with higher dose of remifentanil. The rate of delivery and lockout period for each bolus varied between studies.

The included studies were conducted in Ireland, Hong Kong, Turkey and the UK

The included studies are summarised in Table 2.

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies not included in this review are listed, and reasons for their exclusion are provided in appendix J.

Summary of included studies

Summaries of the studies that were included in this review are presented in Table 2.

Table 2

Summary of included studies.

See the full evidence tables in appendix D and the forest plots in appendix E.

Remifentanil PCA (20 to 40 microgram) versus IM pethidine

Evidence from one RCT suggested that there was an important benefit for the use of rescue analgesia with remifentanil PCA at a dose of 40 micrograms but no evidence of an important difference at a dose of 20 micrograms. For spontaneous vaginal birth there was an important benefit for remifentanil PCA at a dose of 25 to 40 micrograms (2 RCTs) but evidence of an important harm at a dose of 20 micrograms (1 RCT). For instrumental vaginal birth there was an important benefit for remifentanil PCA at 25-40 micrograms (2 RCTs) but no evidence of an important difference at a dose of 20 micrograms (1 RCT). For caesarean birth there was no evidence of an important difference for remifentanil PCA at 25-40 micrograms (2 RCTs) or 20 micrograms (1 RCT). This evidence was graded as low to very low quality.

Evidence from one large RCT suggested that there was an important harm for remifentanil PCA (40 micrograms) when compared to IM pethidine for the outcome of respiratory depression, measured by the requirement for supplemental oxygen for the mother. There was possible important harm for remifentanil PCA (40 micrograms) when compared to IM pethidine for the outcome respiratory depression measured by oxygen saturation <94%. There was no evidence of important difference in terms of respiratory depression in the mother measured by respiratory rate < 8 breaths per minute, maternal satisfaction, neonatal admission, pain in labour and breastfeeding within first hour of birth for remifentanil PCA (40 micrograms) versus IM pethidine. This evidence was graded as moderate to low quality.

Evidence from one RCT comparing remifentanil PCA (0.25 micrograms/kg) versus IM pethidine, suggested that remifentanil PCA had an important benefit on pain in labour (measured by a verbal rating scale). There was no important difference for remifentanil PCA (0.25 microgram/kg) when compared to IM pethidine for respiratory depression in mother measured by oxygen saturation (threshold undefined) and neonatal respiratory depression. The overall quality of the evidence for these outcomes was considered to be moderate to low quality.

No important benefits of remifentanil PCA (remifentanil 25 microgram bolus if <60kg, 30 micrograms if >60kg) versus IM pethidine were found for the outcome maternal satisfaction. The quality of the evidence contributing to this outcome was considered to be moderate quality.

Remifentanil PCA (0.25 micrograms/kg) plus background infusion versus IM pethidine

For the comparison of remifentanil PCA (0.25 micrograms/kg) with a background infusion versus IM pethidine, one RCT found that remifentanil PCA had an important benefit on pain (measured by a verbal rating scale). The study also reported respiratory depression in the mother and neonatal respiratory depression, however, no important differences were found. Evidence for these outcomes was from a single study with a small sample size and the outcomes were considered moderate to low quality. No other critical or important outcomes were reported for this comparison.

Remifentanil PCA (40 microgram) versus IM diamorphine

For the comparison of remifentanil PCA (40 microgram) versus intramuscular diamorphine, remifentanil PCA had an important benefit on neonatal admission. The quality of the evidence from this observational study was low. No other critical or important outcomes were reported for this comparison.

See appendix F for full GRADE tables.

Included studies

A systematic review of the economic literature was conducted but no economic studies were identified which were applicable to this review question.

Excluded studies

Economic studies not included in this review are listed and reasons for their exclusion are provided in appendix K.

The outcomes that matter most

As the aim of this review was to determine the effectiveness of remifentanil patient-controlled analgesia for pain relief in labour, the committee agreed that use of epidural analgesia was a critical outcome as the need for escalation to regional analgesia is a good measure of the direct effectiveness of the intervention. The committee agreed that respiratory depression in the mother and the baby were critical outcomes for this review as opioids can lead to respiratory depression and so this captures the safety of the intervention. Evidence was available for all of the above 3 critical protocol outcomes.

The committee agreed that mode of birth and women’s experience of labour and birth were important outcomes as they wanted to find out whether remifentanil patient-controlled analgesia would reduce the need for interventions during labour and whether this method could improve subjective scores of pain and satisfaction during labour. The committee recognised the great importance of women’s experience of labour and birth, including pain, for this review, but they were aware that data on this outcome was likely to be sparse and unlikely to inform decision-making in a meaningful way, so they prioritised other outcomes as critical. The majority of women and babies would have been healthy prior to birth and the committee agreed that neonatal admission should be included as an important outcome to capture any adverse effects on the baby associated with the intervention. The committee agreed that breastfeeding was an important outcome for this review as it may be impacted by the method of pain relief used in labour and it has important consequences for the long-term health of the mother and baby.

The quality of the evidence

The quality of the evidence ranged from low to moderate with most of the evidence being of low quality. The main issues were around the indirectness of the evidence. Most of the studies did not report the risk status of the women or whether the labour was induced. Some of the studies included women who had been induced, and some did not report the proportion of those out of the whole sample who had been induced. There were some concerns with risk of bias in the evidence. This was mainly due to missing data, for example excluding women who were escalated to rescue epidural analgesia. With the exception of one study which included a saline IM injection or saline PCA bolus, there was a risk of bias across studies due to participants not being blinded to the intervention. Whilst there is no clear evidence of the effectiveness of IV remifentanil PCA over intramuscular opioid on pain relief in labour, it is possible that participants in the PCA arms may have had better perceived control over pain as they could self-administer their analgesic. There were concerns over imprecision of the evidence for several outcomes due to the size of the confidence intervals around the estimate of effect and due to the low number of participants in each arm.

It was not possible to carry out the pre-planned stratification by BMI at booking as no data were available to inform this subgrouping.

Benefits and harms

The committee discussed the evidence around remifentanil PCA and used this alongside their expert opinion and clinical knowledge to make recommendations. The committee noted that the studies used included different doses of remifentanil and that this may impact on the results seen so considered the evidence in terms of doses. They also noted that one study, (Thurlow 2002) was a very small pilot study with a low (20 micrograms) dose of remifentanil and that the results from this study were very different to those seen in other larger studies. The committee therefore considered it was not appropriate to meta-analyse these results (using a random effects model due to the heterogeneity) with the results from the larger studies, and instead considered the results from this study separately.

For the comparison of remifentanil PCA (25 to 40 micrograms) with IM pethidine, there was evidence to suggest that remifentanil reduced the need for rescue epidural analgesia, increased the rate of spontaneous vaginal birth and reduced instrumental vaginal birth. However, there was no important difference in terms of caesarean birth, respiratory depression in the mother measured by respiratory rate < 8 breaths per minute, maternal satisfaction, neonatal unit admission, pain in labour and breastfeeding within first hour of birth for remifentanil compared to IM pethidine. However, remifentanil 25 to 40 micrograms increased the requirement for supplemental oxygen compared to IM pethidine. There was a possible increased respiratory depression measured by oxygen saturation <94% saturation with remifentanil 40 micrograms compared to IM pethidine. Remifentanil PCA (0.25 microgram/kg) was associated with reduction in pain in labour (measured by a verbal rating scale) compared to IM pethidine, but there was no important difference in maternal or neonatal respiratory depression.

Low dose remifentanil PCA (20 micrograms) when compared to IM pethidine was found to be associated with a reduction in the rate of spontaneous vaginal birth but there was no important difference for instrumental vaginal birth. There was no clinically important difference between remifentanil PCA 20 micrograms and IM pethidine for use of rescue epidural analgesia and caesarean birth.

The committee noted that the evidence for remifentanil 40 micrograms compared to diamorphine showed a reduction in neonatal admission, but the committee noted this was based on low quality evidence from the cohort study. Looking at the raw data reported by the study in detail (Murray 2019, data not reported as part of the evidence review), the committee noted that the rate of neonatal admission for women receiving IM diamorphine was higher than PCA remifentanil in 2011 (3.5% vs 1.1%) but by 2013 and 2014 was very similar (1.7% and 1.8% respectively in 2013 and 2.3% and 1.9% respectively in 2014). Furthermore, there was no important difference in terms of neonatal unit admission for the comparison of remifentanil PCA versus IM pethidine. They therefore agreed that it was difficult to conclude that remifentanil reduced neonatal unit admission, and so did not include this in their summary of the risks and benefits for women.

The committee discussed the inconclusive evidence in terms of women’s experience of labour and birth for remifentanil PCA versus IM pethidine: there was evidence of an important benefit of remifentanil PCA on pain in labour (when measured by verbal rating scale) from one small RCT using remifentanil 0.25 micrograms/kg (with and without a background infusion), and no important difference on pain in labour (when measured by a visual analogue scale) from a larger RCT using remifentanil 40 micrograms.

Due to concerns over the quality of the evidence and the heterogeneity of the evidence, the committee agreed that they could not make a strong recommendation. However, based on the evidence that higher doses of remifentanil PCA had benefits for use of rescue epidural analgesia and spontaneous vaginal birth when compared to other IM opioids and there was no evidence of inferiority on pain outcomes, they agreed that remifentanil PCA should be considered instead of intramuscular opioids for women who want ongoing pain relief during labour but who do not want an epidural.

The committee discussed the dose of remifentanil that should be used. They were aware that remifentanil is currently used at a dose of 40 micrograms in a number of obstetric units, and this was in line with the doses used in the two largest and most recent studies (Murray 2018, Wilson 2018). However, the committee noted that it was at this dose that an increase in maternal respiratory depression had been seen. Hence the committee agreed that it was important the recommendations highlighted the need for all units to have clear guidelines in place in responding to respiratory depression if using remifentanil PCA. The committee discussed appropriate settings for using remifentanil PCA and based on their experience and expertise, they agreed that it should only be offered on obstetric units where the risk of respiratory depression could be appropriately managed. Based on this rationale, the committee agreed that intramuscular opioids remain the most appropriate opioid-based pain analgesia in midwifery-led units or for home births.

The committee discussed the benefits and harms of remifentanil PCA using both the evidence and their own experience, and agreed that it was important for healthcare professionals to explain these to women to inform decision making about pain relief in labour. Based on the evidence, the committee agreed that women should be informed which outcomes are more and less likely for remifentanil PCA compared to IM pethidine.

There was evidence showing no increase in neonatal respiratory depression compared to IM opioids, and the committee agreed that this was expected based on the fact that remifentanil is metabolised by ubiquitous pseudocholinesterase enzymes in the neonate to an inactive compound and so can be given throughout labour and birth. The comparison with diamorphine also showed that remifentanil reduced neonatal unit admission, but the committee noted this was based on low quality evidence from the cohort study. Looking at the raw data reported by the study in detail (Murray 2019, data not reported as part of the evidence review), the committee noted that the rate of neonatal admission for women receiving IM diamorphine was higher than PCA remifentanil in 2011 (3.5% vs 1.1%) but by 2013 and 2014 was very similar (1.7% and 1.8% respectively in 2013 and 2.3% and 1.9% respectively in 2014). Furthermore, there was no important difference in terms of neonatal unit admission for the comparison of remifentanil PCA versus IM pethidine. They therefore agreed that it was difficult to conclude that remifentanil reduced neonatal unit admission, and so did not include this in their summary of the risks and benefits for women.

The committee agreed that the recommendations should be explicit in outlining additional monitoring needed to ensure the woman’s safety if using remifentanil PCA. Based on the evidence and their own experience and knowledge, the committee agreed it was important that women using remifentanil PCA had continuous one-to-one midwifery care from a midwife who was trained in the care of women receiving a remifentanil PCA and their respiratory function was monitored, both via observation of breathing and continuous pulse oximetry. In addition, the committee discussed the importance of having supplemental oxygen readily accessible so women would not have to discontinue their pain relief in response to a drop in oxygen saturation. The committee agreed that units should also ensure access to an anaesthetist for all women using remifentanil PCA in order to manage cases of respiratory depression. Based on the evidence and their experience, the committee also agreed that continuous cardiotocography (CTG) monitoring would be required for women using remifentanil PCA. The committee were aware of a large observational study (Melber 2019) in the public domain which was designed to monitor maternal and neonatal outcomes when using remifentanil PCA and inform standards of care. Although this study was not included in this review because it did not include a comparator arm, the committee highlighted that this was an important source of information relevant to guide decisions on standard procedures.

Cost effectiveness and resource use

Remifentanil PCA is more expensive than IM opioids because of higher drug costs and the more intensive staffing requirements for drug administration and monitoring. However, a health economic model developed for this guideline, which compared remifentanil PCA with IM pethidine, suggested that these additional treatment costs for remifentanil could be more than offset by downstream savings resulting from a reduced need for rescue analgesia and antiemetics, lower costs of birth and lower neonatal admission costs. The committee recognised that this cost saving finding was small and sensitive to assumptions about staff tasks, timings, and grade in the administration of the respective drugs as well as the risk of neonatal admission.

The model also suggested that remifentanil PCA would generate small QALY gains when compared to IM pethidine meaning that remifentanil dominated IM pethidine in the deterministic analysis, albeit the net incremental monetary benefit was small in absolute terms. Probabilistic sensitivity analysis suggested that there was a 55% probability that remifentanil PCA was more cost-effective than IM pethidine.

Therefore, the committee considered there was cost-effectiveness evidence to support a consider recommendation for intravenous remifentanil patient-controlled analgesia (PCA) instead of intramuscular opioids as an option for women who want ongoing pain relief during labour, but who do not want an epidural.