NIHR DC Discover

Woman in labour attached to monitor

NIHR Signal Better pain relief for women in labour

Published on 9 October 2018

doi: 10.3310/signal-000659

Women in labour, who had the short acting strong painkiller remifentanil, rather than pethidine, had less need for further pain relief. Only 19% of women given remifentanil received a subsequent epidural compared with 41% given pethidine. Remifentanil was given intravenously, using a patient-controlled delivery device, and pethidine given by intramuscular injection.

This NIHR-funded study is the first large trial to compare intravenous remifentanil (administered via a patient-controlled delivery device) with intramuscular pethidine for women requesting opioid pain relief in labour. Opioid drugs can cause maternal sedation and depression of the baby's breathing but this trial found no difference in adverse maternal or neonatal outcomes between drugs.  

One caution is the potential for subjective bias. A quarter of women allocated to pethidine who converted to epidural requested this before they had even received the drug

Nevertheless, this study could pave the way for patient-controlled remifentanil to have more widespread use in the UK.

Share your views on the research.

Why was this study needed?

Effective pain management during labour is important. Pethidine is widely used and given to an estimated 250,000 women per year in the UK.  It makes many mothers feel sleepy or nauseated and also crosses the placenta making babies sleepy and occasionally causing dangerous depression of breathing. Pethidine in recommended doses is not always very effective, and many women need a subsequent epidural.

Although epidurals are highly effective, they may prolong labour and increase the risk of assisted delivery. They also incur administration and monitoring costs and are not always available when the woman requests. Intravenous remifentanil given via patient-controlled analgesia is a newer alternative but is not available in all UK maternity departments.  

A 2017 Cochrane Review compared remifentanil with other methods and found mostly low-quality and inconsistent evidence, particularly around maternal and neonatal safety outcomes. In this review, no large trials had compared remifentanil with intramuscular pethidine or looked at conversion to epidural as the main outcome. This trial aimed to close this evidence gap.

What did this study do?

The RESPITE randomised controlled trial was conducted across 14 UK maternity units and included women in term labour (at 37 weeks or later) with a single, head-down baby, intending vaginal birth and requesting opioid pain-relief. A total 401 women were assigned to either patient-controlled intravenous remifentanil or intramuscular pethidine.

The pump delivered a dose of 40µg remifentanil on demand with a lockout interval of 2 minutes, during which time further doses were withheld. If maternal sedation was observed the dose was reduced to 30µg. Pethidine was given in a 100mg injection every four hours (maximum 400mg in 24 hours).

Randomisation was balanced according to mother’s age, ethnicity, previous births and onset of labour (spontaneous or induced). The trial was open-label meaning that women and healthcare providers were aware of treatment allocation.

What did it find?

  • Patient-controlled remifentanil, via a pump, halved the number of women needing subsequent epidural: 19% (39/201) compared with 41% (81/199) for pethidine (relative risk [RR] 0.48, 95% confidence interval [CI] 0.34 to 0.66). Twenty-two women in the pethidine group requested an epidural before receiving pethidine compared with none in the remifentanil group.
  • Median pain scores on a 100-point visual analogue scale were lower in the remifentanil group (difference -13.91 points, 95% CI -21.40 to -6.43). Women also reported greater satisfaction with pain management when given remifentanil.
  • There were fewer instrumental deliveries in the remifentanil group (15% vs 26% with pethidine; RR 0.59, 95% CI 0.40 to 0.88) but there was no difference in the number of caesareans.
  • There was no difference in rates of excessive maternal sedation or respiratory depression which were rare in both groups (sedation recorded for 1% given remifentanil and 2% given pethidine; respiratory depression for 1% given pethidine). However, more women given remifentanil had low blood oxygen saturation (14% vs 5% with pethidine) and required supplemental oxygen.  
  • There was no difference between groups in neonatal Apgar scores or the number of babies who required resuscitation (10% with remifentanil and 11% with pethidine).

What does current guidance say on this issue?

NICE guidelines on care during labour (updated 2017) cover non-drug methods of pain relief such as use of water, massage and relaxation techniques. Drug options include inhalation pain-relief (Entonox), regional pain-relief (epidural/spinal) and intravenous or intramuscular opioids. NICE specifies that "pethidine, diamorphine or other opioids" are available in all birth settings, but the guideline doesn’t specify remifentanil.

Some local NHS hospital protocols cover criteria for use of patient-controlled remifentanil, mostly when pethidine or an epidural are unsuitable.

What are the implications?

This study indicates that the use of patient-controlled remifentanil has a place in the care of women in labour and its use may become more widespread across maternity units.

It was considered ethically inappropriate to administer double sham/placebo interventions (requiring inactive injections or infusions). This does raise the possibility that preconceptions around pethidine could have influenced epidural requests. However, the low rates of maternal or neonatal sedation or respiratory depression and decreased assisted delivery rate with remifentanil are promising objective findings.

Maternity services need to ensure that women understand the risks and benefits of different pain relief options. Potentially higher initial drug and equipment costs of PCA remifentanil need to be weighed against the costs of midwives' and anaesthetists' time and patients' satisfaction.  

Citation and Funding

Wilson M, MacArthur C, Hewitt CA, et al; RESPITE Trial Collaborative Group. Intravenous remifentanil patient-controlled analgesia versus intramuscular pethidine for pain relief in labour (RESPITE): an open-label, multicentre, randomised controlled trial. Lancet. 2018; 392(10148):662-72.

This project was independent research funded by the National Institute for Health Research (NIHR). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Bibliography

Corfe, J. Management of remifentanil patient controlled analgesia for labour. Norwich: Norfolk and Norwich University Hospitals NHS Foundation Trust; 2017. 

Jackson G. Remifentanil PCA for labour guidelines (GL769). Reading: Royal Berkshire NHS Trust; 2017.

NICE. Intrapartum care for healthy women and babies. CG190. London: National Institute for Health and Care Excellence; 2014, updated 2017.

Weibel S, Jelting Y, Afshari A, et al. Patient-controlled analgesia with remifentanil versus alternative parenteral methods for pain management in labour. Cochrane Database Syst Rev. 2017;4:CD011989.

Why was this study needed?

Effective pain management during labour is important. Pethidine is widely used and given to an estimated 250,000 women per year in the UK.  It makes many mothers feel sleepy or nauseated and also crosses the placenta making babies sleepy and occasionally causing dangerous depression of breathing. Pethidine in recommended doses is not always very effective, and many women need a subsequent epidural.

Although epidurals are highly effective, they may prolong labour and increase the risk of assisted delivery. They also incur administration and monitoring costs and are not always available when the woman requests. Intravenous remifentanil given via patient-controlled analgesia is a newer alternative but is not available in all UK maternity departments.  

A 2017 Cochrane Review compared remifentanil with other methods and found mostly low-quality and inconsistent evidence, particularly around maternal and neonatal safety outcomes. In this review, no large trials had compared remifentanil with intramuscular pethidine or looked at conversion to epidural as the main outcome. This trial aimed to close this evidence gap.

What did this study do?

The RESPITE randomised controlled trial was conducted across 14 UK maternity units and included women in term labour (at 37 weeks or later) with a single, head-down baby, intending vaginal birth and requesting opioid pain-relief. A total 401 women were assigned to either patient-controlled intravenous remifentanil or intramuscular pethidine.

The pump delivered a dose of 40µg remifentanil on demand with a lockout interval of 2 minutes, during which time further doses were withheld. If maternal sedation was observed the dose was reduced to 30µg. Pethidine was given in a 100mg injection every four hours (maximum 400mg in 24 hours).

Randomisation was balanced according to mother’s age, ethnicity, previous births and onset of labour (spontaneous or induced). The trial was open-label meaning that women and healthcare providers were aware of treatment allocation.

What did it find?

  • Patient-controlled remifentanil, via a pump, halved the number of women needing subsequent epidural: 19% (39/201) compared with 41% (81/199) for pethidine (relative risk [RR] 0.48, 95% confidence interval [CI] 0.34 to 0.66). Twenty-two women in the pethidine group requested an epidural before receiving pethidine compared with none in the remifentanil group.
  • Median pain scores on a 100-point visual analogue scale were lower in the remifentanil group (difference -13.91 points, 95% CI -21.40 to -6.43). Women also reported greater satisfaction with pain management when given remifentanil.
  • There were fewer instrumental deliveries in the remifentanil group (15% vs 26% with pethidine; RR 0.59, 95% CI 0.40 to 0.88) but there was no difference in the number of caesareans.
  • There was no difference in rates of excessive maternal sedation or respiratory depression which were rare in both groups (sedation recorded for 1% given remifentanil and 2% given pethidine; respiratory depression for 1% given pethidine). However, more women given remifentanil had low blood oxygen saturation (14% vs 5% with pethidine) and required supplemental oxygen.  
  • There was no difference between groups in neonatal Apgar scores or the number of babies who required resuscitation (10% with remifentanil and 11% with pethidine).

What does current guidance say on this issue?

NICE guidelines on care during labour (updated 2017) cover non-drug methods of pain relief such as use of water, massage and relaxation techniques. Drug options include inhalation pain-relief (Entonox), regional pain-relief (epidural/spinal) and intravenous or intramuscular opioids. NICE specifies that "pethidine, diamorphine or other opioids" are available in all birth settings, but the guideline doesn’t specify remifentanil.

Some local NHS hospital protocols cover criteria for use of patient-controlled remifentanil, mostly when pethidine or an epidural are unsuitable.

What are the implications?

This study indicates that the use of patient-controlled remifentanil has a place in the care of women in labour and its use may become more widespread across maternity units.

It was considered ethically inappropriate to administer double sham/placebo interventions (requiring inactive injections or infusions). This does raise the possibility that preconceptions around pethidine could have influenced epidural requests. However, the low rates of maternal or neonatal sedation or respiratory depression and decreased assisted delivery rate with remifentanil are promising objective findings.

Maternity services need to ensure that women understand the risks and benefits of different pain relief options. Potentially higher initial drug and equipment costs of PCA remifentanil need to be weighed against the costs of midwives' and anaesthetists' time and patients' satisfaction.  

Citation and Funding

Wilson M, MacArthur C, Hewitt CA, et al; RESPITE Trial Collaborative Group. Intravenous remifentanil patient-controlled analgesia versus intramuscular pethidine for pain relief in labour (RESPITE): an open-label, multicentre, randomised controlled trial. Lancet. 2018; 392(10148):662-72.

This project was independent research funded by the National Institute for Health Research (NIHR). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Bibliography

Corfe, J. Management of remifentanil patient controlled analgesia for labour. Norwich: Norfolk and Norwich University Hospitals NHS Foundation Trust; 2017. 

Jackson G. Remifentanil PCA for labour guidelines (GL769). Reading: Royal Berkshire NHS Trust; 2017.

NICE. Intrapartum care for healthy women and babies. CG190. London: National Institute for Health and Care Excellence; 2014, updated 2017.

Weibel S, Jelting Y, Afshari A, et al. Patient-controlled analgesia with remifentanil versus alternative parenteral methods for pain management in labour. Cochrane Database Syst Rev. 2017;4:CD011989.

Intravenous remifentanil patient-controlled analgesia versus intramuscular pethidine for pain relief in labour (RESPITE): an open-label, multicentre, randomised controlled trial

Published on 13 August 2018

Matthew J A Wilson, Christine MacArthur, Catherine A Hewitt, Kelly Handley, Fang Gao, Leanne Beeson, Jane Daniels, on behalf of the RESPITE Trial Collaborative Group*

The Lancet , 2018

Summary Background About a third of women receiving pethidine for labour pain subsequently require an epidural, which provides effective pain relief but increases the risk of instrumental vaginal delivery. Remifentanil patient-controlled analgesia (PCA) in labour is an alternative to pethidine, but is not widely used. We aimed to evaluate epidural analgesia progression among women using remifentanil PCA compared with pethidine. Methods We did an open-label, multicentre, randomised controlled trial in 14 UK maternity units. We included women aged 16 years or older, beyond 37 weeks’ gestation, in labour with a singleton cephalic presentation, and who requested opioid pain relief. We randomly assigned eligible participants (1:1) to either the intravenous remifentanil PCA group (40 µg bolus on demand with a 2 min lockout) or the intramuscular pethidine group (100 mg every 4 h, up to 400 mg in 24 h), using a web-based or telephone randomisation service with a minimisation algorithm for parity, maternal age, ethnicity, and mode of labour onset. Because of the differences in routes of drug administration, study participants and health-care providers were not masked to the group allocation. The primary outcome was the proportion of women who received epidural analgesia after enrolment for pain relief in labour. Primary analyses were unadjusted and analysed by the intention-to-treat principle. This study is registered with the ISRCTN registry, number ISRCTN29654603. Findings Between May 13, 2014, and Sept 2, 2016, 201 women were randomly assigned to the remifentanil PCA group and 200 to the pethidine group. One participant in the pethidine group withdrew consent, leaving 199 for analyses. The proportions of epidural conversion were 19% (39 of 201) in the remifentanil PCA group and 41% (81 of 199) in the pethidine group (risk ratio 0·48, 95% CI 0·34–0·66; p<0·0001). There were no serious adverse events or drug reactions directly attributable to either analgesic during the study. Interpretation Intravenous remifentanil PCA halved the proportion of epidural conversions compared with intramuscular pethidine. This finding challenges routine pethidine use as standard of care in labour. Funding National Institute for Health Research Clinician Scientist Award.

Expert commentary

Labour is a painful experience for women. Surprisingly in a world of progressive health technology, the analgesic options available in labour remain limited and mostly inadequate.

The perceived inevitability of labour pain can lead to anxiety and fear for pregnant women. Pain can disrupt normal birth processes and may have longer-term psychological effects.

Compared with pethidine, patient-controlled dosing of remifentanil halves the need for an epidural, suggesting it is a more effective analgesia. The availability of remifentanil is not widespread in UK maternity units, however, given what is currently available and the findings of this trial, it should be. 

Diane Farrar, NIHR Post-doctoral Research Fellow and Maternal Health Research Programme Manager, Bradford Institute for Health Research, Bradford Teaching Hospitals

The commentator declares involvement in recruitment for this study