Parenteral opioids for maternal pain relief in labour
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness, safety and acceptability to women of different types, doses and modes of administration of parenteral opioid analgesia in labour. A second objective is to assess the effects of opioids in labour on the baby in terms of safety, condition at birth and early feeding.
Background
Description of the condition
Introduction
Pain during labour is a normal event, being one of the few examples of pain which does not signal pathology or harm. This does not make the experience of pain any less, but it may alter the way pain is perceived, both by the woman in labour and those providing care. For some women, labour pain is something to 'work with', coping with the pain of labour, rather than seeking to relieve it (Olayemi 2003). For others, the pain has no positive component and the woman may look to diminish or remove the pain altogether (Hodnett 2002; Leap 2000). This latter stance has only been possible since the acceptance of the use of pain relieving drugs during labour, a change which was accelerated following the use of chloroform by Queen Victoria when she gave birth to her eighth child in 1853 (Camann 2005). The use of pain‐relieving drugs during labour is now perceived as standard care in many countries throughout the world (Findley 1999; Olayemi 2003).
Characteristics of labour pain
Pain during labour is intermittent, accompanying uterine contractions (Findley 1999; Lowe 2002). Characteristically the pain intensifies as the contraction increases, reaching a peak when the contraction is at its strongest, then diminishing as the uterus relaxes. Between contractions the uterus is at rest and there is usually no associated pain. As labour progresses the uterine contractions grow stronger, more frequent and longer lasting; at the same time they become more painful. Typically the strongest, most frequent, and most painful, uterine contractions occur at the end of the first stage of labour as the cervix reaches full dilatation. While the vast majority of women will describe at least some stages of labour as painful, the severity of reported pain varies considerably (Findley 1999).
Physiology
Women’s responses to pain often change as labour progresses. The cause of labour pain is not fully understood, but is thought to be related primarily to the dilatation of the cervix and the distension of the lower uterine segment (Hawkins 2003). The build up of lactate in the uterine walls may also contribute to pain levels as labour progresses. A woman may experience labour pain in her abdomen, lower back or thighs (Melzack 1984). Pain may be experienced in more than one site at any given time, and as labour progresses the pain sites may vary. If a woman is afraid and anxious during labour, it is thought that this results in a release of adrenaline and an increase in perceived pain. Conversely, if a woman feels secure and well‐cared for, this may help her to be more relaxed and confident during labour, which may lower the perception of pain (Fletcher 2001).
Effects on the baby
It is not known whether labour is experienced as painful by the baby. Although it has been generally accepted that the baby does not find labour painful, some authors have argued that this is not the case (Bradford 1995). There is some evidence from studies comparing babies born following labour and those delivered by elective caesarean section that experiencing labour is of benefit to the baby. The physiological changes taking place during labour, while experienced as painful by the mother, are thought to assist in preparing the baby's lungs for birth and thus decrease the risk of neonatal respiratory problems. It has been suggested that the hormonal surge that occurs with the spontaneous rupture of the membranes and during labour (that is absent when caesarean sections are carried out without labour) improve babies' lung function (Hansen 2008).
The use of analgesics during labour are known to have some effects on the baby before and after birth. The effects of analgesic drugs on fetal heart rate patterns have caused concern, but while the use of opioid analgesia during labour is associated with fetal sinusoidal heart rate patterns, these changes are temporary and are not thought to be harmful (Theard 1984). Such drugs do, however, have a sedative effect on both the mother and baby and this may have negative implications for early infant feeding (NICE 2007). There is evidence that the use of pethidine (meperidine) during labour (and especially close to the time of delivery) is associated with poor or no sucking in newborn babies particularly during the first hour after birth, and that the failure to establish successful breastfeeding at this early stage relates to the success and duration of later breastfeeding (Rajan 1994; Righard 1990).
Pain relief in labour
The extent of use of parenteral opioids during labour has not been well documented. What is known is that where it is available, and not contraindicated, the use of epidural analgesia has increased while the use of pethidine and other parenteral opioids has decreased (Leeman 2003). Nevertheless, parenteral opioids remain widely available and widely used. In several countries (including the UK) several parenteral opoid drugs can be prescribed and administered by midwives without the need for a doctor to be present (Dimond 2003). Most obstetric units in developed countries offer intramuscular pethidine or other opioids, or both, along with facilities for epidural analgesia. In developing countries, parenteral opioids may be the only form of pharmacological analgesia available. Recent surveys in New Zealand and the UK revealed more than 95% of hospitals surveyed routinely offered intramuscular pethidine (Lee 2004; Saravanakumar 2007). In the UK study, approximately half (49%) of the units surveyed offered patient‐controlled intravenous opioid analgesia for use in labour (Saravanakumar 2007).
Clinical management of pain in labour
The clinical management of pain during labour involves much more than simply the provision of a pharmacological intervention. Related Cochrane reviews have demonstrated the value of continuous support and non‐pharmacological approaches to managing pain in labour (Cluett 2002; Hodnett 2007; Hunter 2007; Smith 2006).
Good communication and sensitive support from carers improves a woman’s experience of labour, and her overall satisfaction with care, regardless of her choice of pain relief or levels of reported pain (Hodnett 2002). It is vital that each woman feels in control of what happens in terms of management of labour and that decisions for coping with the pain of labour are based on informed choice (Green 2003; Hawkins 2003).
This review will focus on use of parenteral opioids for analgesia in labour. Pethidine has become widely used in labour since the 1950s. It was introduced without prior evaluation by randomised controlled trials however, and it is thought its perceived analgesic efficacy may be due, at least in part, to its sedative effects (NICE 2007). Two other opioids have also been introduced into use in England and Wales, namely diamorphine and meptazinol. At present, the choice of opioid for analgesia in labour depends on what is available in different hospitals. However, no matter what facilities and drugs are available, women often have no choice as to which drug is used, and healthcare professionals have little information to guide decision‐making. This review will examine the evidence from randomised controlled trials of the effectiveness, safety and acceptability of opioids used in labour.
Why it is important to do this review
There remains uncertainty amongst practitioners as to which opioid provides the most effective pain relief in labour, and whether opioids used during labour are acceptable to women. The most effective and acceptable mode of administration also remains unknown. In addition, there are concerns about the potential adverse effects associated with the use of opioids in labour, particularly the effects on the baby in relation to infant feeding. Whilst there have been reviews on this topic in the past, this review would provide an up‐to‐date summary of existing knowledge (Bricker 2002; Elbourne 2006).
Objectives
To assess the effectiveness, safety and acceptability to women of different types, doses and modes of administration of parenteral opioid analgesia in labour. A second objective is to assess the effects of opioids in labour on the baby in terms of safety, condition at birth and early feeding.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials.
Types of participants
Women in labour. We will exclude studies focusing exclusively on women in high‐risk groups, or women in premature labour (before 37 weeks' gestation), but will include studies which include such women as part of a broader sample.
Types of interventions
Parenteral opioids (including intramuscular and intravenous drugs). This potentially allows for a large number of possible comparisons (where different drugs, doses (or patient‐controlled analgesia (PCA) lock‐out times) and modes of delivery have been compared); for example, intramuscular opioid versus no intervention, placebo, nitrous oxide, other opioids, same opioid at a different dose or the same drug administered intravenously (either as a bolus or via a PCA system).
We will carry out separate analyses where two drugs are compared or where a drug is compared with a placebo, no intervention or another type of analgesic. We will carry out separate analyses for comparisons of different doses of the same drug. We will use trialists' definitions of higher and lower doses of the same drugs as high and low doses are different for different opioids. We will carry out separate analyses where different modes of administration for the same drug and dose are compared.
Where different doses of the same drug are compared with the same comparator (e.g. 40 mg pethidine versus placebo, and 80 mg pethidine versus placebo), we will use subgroup analyses to examine findings.
We will not include comparisons with epidural analgesia as this has been covered in a related Cochrane review (Anim‐Somuah 2005).
Drugs for comparison include pethidine or meperidine, nalbuphanol, butanophol, diamorphine, buprenorphine, meptazinol, pentazocine, tramadol, oxycodone, alfentanyl, sufentanil, remifentanyl and fentanyl.
Types of outcome measures
Primary outcomes
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Maternal satisfaction with analgesia measured during labour
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Maternal satisfaction with analgesia in labour measured during the postnatal period
Secondary outcomes
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Maternal pain score or presence or absence of severe pain measured in labour
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Assisted vaginal delivery
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Caesarean section
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Maternal sleepiness during labour
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Additional analgesia required: epidural
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Postpartum haemorrhage (as defined by the trial authors)
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Naloxone administration
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Neonatal resuscitation
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Admission to neonatal unit
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Breastfeeding at discharge
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Breastfeeding in the postnatal period (four to six weeks)
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Apgar score less than seven at one minute
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Apgar score less than seven at five minutes
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Apgar score less than seven at ten minutes
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Fetal heart rate changes (persistent decelerations or tachycardia)
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Neonatal neurobehavioural scores
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Neurodevelopment outcomes during infancy
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Cost
Search methods for identification of studies
Electronic searches
We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register.
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE;
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
Searching other resources
In addition, we will handsearch the reference lists of background review articles and the reference lists of papers retrieved by the search described above.
We will not apply any language restrictions.
Data collection and analysis
Selection of studies
Two review authors (R Ullman and T Dowswell) will independently assess for inclusion all the studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult the third author (R Mori).
Data extraction and management
We will design a form to extract data. At least two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult the third author. We will enter data into Review Manager software (RevMan 2008) and check them for accuracy.
When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Any disagreement will be resolved by discussion or by involving a third assessor.
(1) Sequence generation (checking for possible selection bias)
We will describe for each included study the methods used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We will assess the methods as:
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adequate (e.g. random‐number table; computer random‐number generator);
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inadequate (odd or even date of birth; hospital or clinic record number); or,
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unclear.
(2) Allocation concealment (checking for possible selection bias)
We will describe for each included study the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during, recruitment.
We will assess the methods as:
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adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
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inadequate (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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unclear.
(3) Blinding (checking for possible performance bias)
We will describe for each included study all the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will also provide any information relating to whether the intended blinding was effective and note where there has been partial blinding.
We will assess the methods as:
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adequate, inadequate or unclear for participants;
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adequate, inadequate or unclear for personnel;
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adequate inadequate or unclear for outcome assessors.
(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
We will describe for each included study the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported, the numbers (compared with the total randomised participants), reasons for attrition or exclusion where reported, and any re‐inclusions in analyses which we undertake.
We will assess the methods as:
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adequate (e.g. where there was no missing data or low levels and where reasons for missing data are balanced across groups); as the intervention is during labour and as most outcomes will be measured during, or just after labour, we would expect low levels of missing data (less than 10%) for methods to be assessed as adequate;
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inadequate (e.g. where there are high levels of attrition or where missing data or are not balanced across groups);
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unclear (e.g. where there is insufficient reporting of attrition or exclusions to permit a judgement to be made).
(5) Selective reporting bias
We will describe for each included study how the possibility of selective outcome reporting bias was examined by us and what we found.
We will assess the methods as:
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adequate (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review have been reported);
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inadequate (where not all the study’s prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
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unclear.
(6) Other sources of bias
We will describe for each included study any important concerns we have about other possible sources of bias; for example, where there a potential source of bias related to a specific study design or where a trial was stopped early due to some data‐dependent process.
We will assess whether each study was free of other problems that could put it at risk of bias:
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yes;
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no;
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unclear.
(7) Overall risk of bias
We will make explicit judgements about risk of bias for important outcomes both within and across studies. With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses, see 'Sensitivity analysis'.
Measures of treatment effect
We will carry out statistical analysis using the Review Manager software (RevMan 2008). We will use fixed‐effect meta‐analysis for combining data where trials are examining the same intervention, and the trials' populations and methods are judged to be sufficiently similar. Where there is clinical or statistical heterogeneity between studies, sufficient to suggest that treatment effects may differ between trials, we will use random‐effects meta‐analysis.
Dichotomous data
For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals.
Continuous data
For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.
Unit of analysis issues
Cluster‐randomised trials
We will include cluster‐randomised trials in the analyses along with individually randomised trials using the methods described in the Handbook (Higgins 2008). Their sample sizes will be adjusted using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources are used, this will be reported and sensitivity analyses conducted to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.
Cross‐over trials
We will not include cross‐over trials.
Dealing with missing data
For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analyses .
Where data are not reported for some outcomes or groups, we will attempt to contact the study authors for further information.
We will analyse data on all participants with available data in the group to which they are allocated, regardless of whether or not they received the allocated intervention. If in the original reports participants are not analysed in the group to which they were randomised, and there is sufficient information in the trial report, we will attempt to restore them to the correct group.
Assessment of heterogeneity
We will apply tests of heterogeneity between trials using the I² statistic. If we identify heterogeneity among the trials, we will explore it by prespecified subgroup analysis and perform sensitivity analysis. A random‐effects meta‐analysis will be used as an overall summary if this is considered appropriate.
Assessment of reporting biases
Where we suspect reporting bias (see 'Selective reporting bias' above), we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing are data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.
Subgroup analysis and investigation of heterogeneity
We will conduct planned subgroup analysis using the methods described by Deeks 2001 and set out in the Cochrane Handbook for Systematic Reviews (Higgins 2008).
We plan to carry out the following subgroup analyses.
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By parity (nulliparous versus multiparous women).
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By spontaneous versus induced or augmented labour.
Where different doses of the same drug versus the same comparator have been examined (e.g. pethidine 40 mg or pethidine 80 mg versus a placebo), we will separate analyses into subgroups to examine the impact of different doses.
For fixed‐effect meta‐analyses we will conduct planned subgroup analyses classifying whole trials by interaction tests. For random‐effects meta‐analyses we will assess differences between subgroups by inspection of the subgroups' confidence intervals: non‐overlapping confidence intervals indicate a statistically significant difference in treatment effect between the subgroups.
Sensitivity analysis
We will carry out sensitivity analyses to explore the effect of trial quality for important outcomes in the review. Where there is risk of bias associated with a particular aspect of study quality (e.g. inadequate allocation concealment), we will explore this by sensitivity analyses.
