What is the issue
Pain relief during labour can be provided in a number of different ways. These include epidural analgesia, by injection of anaesthetic medication around the nerve roots in the spine, intramuscular or continuous intravenous opioids, and inhalational analgesia such as with nitrous oxide. Remifentanil is a relatively recently introduced potent, short-acting opioid, which gives control over pain relief.
Why is this important
Labour pain may be associated with adverse effects for the mother and her baby and can result in prolonged labour.
This review aimed to compare remifentanil given via a patient-controlled analgesia (PCA) device with other opioids given via the same way or via an intramuscular or intravenous injection, with epidural analgesia, with different regimens of remifentanil (PCA) or with remifentanil as a continuous intravenous infusion, with inhalational analgesia, or with no treatment for women during normal vaginal birth. Our main outcomes of interest were satisfaction with pain relief, pain scores, side effects for the women and their babies, need for additional analgesia and the risk for a caesarean section.
What evidence did we find
A search of the literature was performed in November/December 2015 and updated in December 2016. We found 20 randomised controlled trials with 3569 women. The methodological quality of studies was moderate to poor.
Women who received PCA with remifentanil were more satisfied with their pain relief than women receiving other opioids either by intravenous or intramuscular injection (four trials, 216 women, very low-quality evidence). Remifentanil (PCA) provided stronger pain relief at one hour than the other opioids by intravenous or intramuscular injection (three trials, 180 women) and using PCA (three trials, 215 women), both very low-quality evidence but with moderate-quality evidence that remifentanil (PCA) was associated with a reduced need for additional analgesia compared to other intravenous or intramuscular opioids (three trials, 190 women). The number of women with need for additional analgesia was not different with remifentanil (PCA) or opioids (PCA) (three trials, 215 women, low-quality evidence). Remifentanil (PCA) increased the risk for a maternal respiratory depression compared to other intramuscular opioids (one trial, 36 women, very low-quality evidence). The newborn babies were not more likely to have low Apgar scores at five minutes after birth under remifentanil (PCA) compared to other intravenous or intramuscular opioids (one trial, 88 newborns, very low-quality evidence), but newborns have a lower risk under remifentanil (PCA) compared to other opioids (PCA) (one trial, 17 newborns, very low-quality evidence). Remifentanil (PCA) was not associated with an increased risk for caesarean section when compared with intravenous or intramuscular opioids (four trials, 215 women, low-quality evidence), but compared to other opioids (PCA) (two trials, 143 women, very low-quality evidence).
Women were slightly less satisfied with remifentanil (PCA) compared to an epidural for pain relief (seven trials, 2135 women, very low-quality evidence). Pain intensity was higher in the remifentanil (PCA) group compared to the epidural group (six trials, 235 women, low-quality evidence), with a higher need for additional analgesia (six studies, 1037 women, moderate-quality evidence). Remifentanil (PCA) increased the risk for a maternal respiratory arrest compared to an epidural (one trial, 38 women, very low-quality evidence). Remifentanil (PCA) was not associated with an increased risk of respiratory depression in mothers compared to an epidural (three trials, 687 women, low-quality evidence). The newborn babies were not more likely to have low Apgar scores at five minutes after birth (five trials, 1322 newborns, low-quality evidence). The number of women requiring caesarean section was not different with remifentanil (PCA) or epidural analgesia (moderate-quality evidence).
What does this mean
Our confidence in the results of the current review is limited since the quality of evidence is mostly low. No definite conclusion can be drawn with respect to side effects for women and newborns as well as for the comparators remifentanil given via a continuous infusion or via PCA with a different regimen since there are too few studies with few participants that reported on these. No eligible study examined remifentanil (PCA) versus inhalational analgesia or no treatment. More research is needed, especially on side effects of remifentanil (PCA) for women and newborns.
Based on the current systematic review, there is mostly low-quality evidence to inform practice and future research may significantly alter the current situation. The quality of evidence is mainly limited by poor quality of the studies, inconsistency, and imprecision. More research is needed on maternal and neonatal safety outcomes (maternal apnoea and respiratory depression, Apgar score) and on the optimal mode and regimen of remifentanil administration to provide highest efficacy with reasonable adverse effects for mothers and their newborns.
Multiple analgesic strategies for pain relief during labour are available. Recently remifentanil, a short-acting opioid, has recently been used as an alternative analgesic due to its unique pharmacological properties.
To systematically assess the effectiveness of remifentanil intravenous patient-controlled analgesia (PCA) for labour pain, along with any potential harms to the mother and the newborn.
We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (9 December 2015), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), handsearched congress abstracts (November 2015), and reference lists of retrieved studies.
Randomised controlled trials (RCTs) and cluster-randomised trials comparing remifentanil (PCA) with another opioid (intravenous (IV)/intramuscular (IM)), or with another opioid (PCA), or with epidural analgesia, or with remifentanil (continuous IV), or with remifentanil (PCA, different regimen), or with inhalational analgesia, or with placebo/no treatment in all women in labour including high-risk groups with planned vaginal delivery.
Two review authors independently assessed trials for inclusion, extracted data, and appraised study quality.
We contacted study authors for additional information other than incomplete outcome data. We performed random-effects meta-analysis.
To reduce the risk of random error in meta-analysis we performed trial sequential analysis. We included total zero event trials and used a constant continuity correction of 0.01 (ccc 0.01) for meta-analysis. We applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach to assess the quality of evidence.
Twenty RCTs with 3569 women were included. Of those, 10 trials (2983 participants) compared remifentanil (PCA) to an epidural, four trials (216 participants) to another opioid (IV/IM), three trials (215 participants) to another opioid (PCA), two trials (135 participants) to remifentanil (continuous IV), and one trial (20 participants) to remifentanil (PCA, different regimen). No trials were identified for the remaining comparisons.
Methodological quality of studies was moderate to poor. We assessed risk of bias as high for blinding issues and incomplete outcome data in 65% and 45% of the included studies, respectively.
There is evidence of effect that women in the remifentanil (PCA) group were more satisfied with pain relief than women in the other opioids (IV/IM) group (standardised mean difference (SMD) 2.11, 95% confidence interval (CI) 0.72 to 3.49, four trials, very low-quality evidence), and that women were less satisfied compared to women in the epidural group (SMD -0.22, 95% CI -0.40 to -0.04, seven trials, very low-quality evidence).
There is evidence of effect that remifentanil (PCA) provided stronger pain relief at one hour than other opioids administered IV/IM (SMD -1.58, 95% CI -2.69 to -0.48, three trials, very low-quality evidence) or via PCA (SMD -0.51, 95% CI -1.01 to -0.00, three trials, very low-quality evidence). Pain intensity was higher in the remifentanil (PCA) group compared to the epidural group (SMD 0.57, 95% CI 0.31 to 0.84, six trials, low-quality evidence).
Data were limited on safety aspects for both the women and the newborns. Only one study analysed maternal apnoea in a comparison of remifentanil (PCA) versus epidural and reported that half of the women in the remifentanil and none in the epidural group had an apnoea (very low-quality evidence). There is no evidence of effect that remifentanil (PCA) was associated with an increased risk for maternal respiratory depression when compared to epidural analgesia (RR 0.91, 95% CI 0.51 to 1.62, ccc 0.01, three trials, low-quality evidence) and no reliable conclusion might be reached compared to remifentanil (continuous IV) (all study arms included zero events, two trials, low-quality evidence). In one trial of remifentanil (PCA) versus another opioid (IM) three out of 18 women in the remifentanil and none out of 18 in the control group had a respiratory depression (very low-quality evidence).
There is no evidence of effect that remifentanil (PCA) was associated with an increased risk for newborns with Apgar scores less than seven at five minutes compared to epidural analgesia (RR 1.26, 95% CI 0.62 to 2.57, ccc 0.01, five trials, low-quality evidence) and no reliable conclusion might be reached compared to another opioid (IV) and compared to remifentanil (PCA, different regimen) both with zero events in all study arms (one trial, very-low quality evidence). In one trial of remifentanil (PCA) versus another opioid (PCA) none out of nine newborns in the remifentanil and three out of eight in the opioid (PCA) group had Apgar scores less than seven (very-low quality evidence).
There is evidence that remifentanil (PCA) was associated with a lower risk for the requirement of additional analgesia when compared to other opioids (IV/IM) (RR 0.57, 95% CI 0.40 to 0.81, three trials, moderate-quality evidence) and that it was associated with a higher risk compared to epidural analgesia (RR 9.27, 95% CI 3.73 to 23.03, ccc 0.01, six trials, moderate-quality evidence). There is no evidence of effect that remifentanil (PCA) reduced the requirement for additional analgesia compared to other opioids (PCA) (RR 0.76, 95% CI 0.45 to 1.28, three trials, low-quality evidence).
There is evidence that there was no difference in the risk for caesarean delivery between remifentanil (PCA) and other opioids (IV/IM) (RR 0.63, 95% CI 0.30 to 1.32, ccc 0.01, four trials, low-quality evidence) and epidural analgesia (RR 1.0, 95% CI 0.82 to 1.22, ccc 0.01, nine trials, moderate-quality evidence), respectively. Pooled meta-analysis revealed an increased risk for caesarean section under remifentanil (PCA) compared to other opioids (PCA) (RR 2.78, 95% CI 0.99 to 7.82, two trials, very low-quality evidence). However, a wide range of clinically relevant and non-relevant treatment effects is compatible with this result.