The relief of pain in labour and the role of remifentanil.

This Invited Commentary accompanies the following article: Tveit TO, Seiler S, Halvorsen A, Rosland JH. Labour analgesia: a randomised, controlled trial comparing intravenous remifentanil and epidural analgesia with ropivacaine and fentanyl. Eur J Anaesthesiol 2012; 29:129–136. For centuries, labour has been portrayed as a dangerous and painful event. The pain might perhaps have been tackled earlier if the clergy had not preached, and male society believed, that if God had wished labour to be painless, he would have created it so. This was the case long after James Young Simpson (1811–1870) wrote, in his report of chloroform anaesthesia in obstetrics, that ‘all pain is per se and especially in excess, destructive and ultimately fatal in its nature and effects’.1,2 He had already used diethyl ether to relieve labour pain, but was dissatisfied with its performance. He won his argument later, when John Snow, by royal invitation, used chloroform on Queen Victoria during the delivery of Prince Leopold on 7 April 1853. The medical establishment, in view of the reported side-effects, and with an innate resistance to clinical advances, still commented in the Lancet3: ‘intense astonishment, therefore, has been excited throughout the profession by the rumour that Her Majesty during her last labour was placed under the influence of chloroform, an agent which has unquestionably caused instantaneous death in a considerable number of cases. Doubts on this subject cannot exist’. They concluded ‘… we could not imagine that anyone had incurred the awful responsibility of advising the administration of chloroform to Her Majesty during a perfectly natural labour with a seventh child’. These caveats are nicely illustrated by a story about Mr Gladstone, who was Prime Minister at the time of Prince Leopold's birth. It is the custom for the Prime Minister to visit the sovereign once a week to discuss affairs of state. On this occasion, Gladstone congratulated the Queen on the addition to her family, and then asked her how she liked Dr Snow's chloroform. The Queen replied ‘very well, Mr Gladstone’. He replied ’the bishops are not pleased Ma’am’. ‘Then let the bishops have the babies Mr Gladstone’ she answered. Queen Victoria's request for an ‘off-label’ intervention for labour pain using a method that had no recognised place in management, and after six normal labours, may be viewed as early evidence of maternal participation and choice in medical decision making. Even in the 1940s, long after the clergy's influence had diminished, it remained the firm belief of some obstetricians that labour pain was a valuable regulator of muscular activity during labour and delivery, and that minimising its intensity would be at best counterproductive. Later in 1981, Melzack et al.,4 using modern pain questionnaires, identified birth pain as the most intensely painful experience which is still true even after careful preparation for birth by techniques that teach self-control. They argued that ‘… prepared childbirth training and epidural anaesthesia should be regarded as compatible, complementary procedures’. This all-encompassing viewpoint takes into account that individual perception and preference may vary to a large extent. It was some years later that the acknowledgement that ‘there is no other circumstance in which it is considered acceptable for a person to experience untreated severe pain, amenable to safe intervention, while under a physician's care. In the absence of a medical contraindication, maternal request is a sufficient medical indication for pain relief during labour’, eventually appeared.5 The mere fact that in 2002 it was felt necessary to publish a justification of pain relief in labour underlines the failure of recognition that this human right should be exercised in delivery rooms around the world. This was true even in high-income countries that should have been able and willing to afford pain relief in this dedicated setting. Even today, disinformation and prejudice are widespread, although now disseminated by women. In 2010, an article concluded that ‘in many ways, epidurals are the drug trip of the current generation. … Women get epidurals for one of the main reasons so many women smoked pot in the 1970s – their friends are doing it’. No further comments are needed to demonstrate that the road to unbiased decision making is long and difficult.6 Obstetric analgesia has seen a tremendous evolution in recent years and, at the same time, childbirth has never been safer for both the mother and the baby in the developed world.7,8 Following the expansion of epidural pain relief in the 1970s, the reduction of dose and toxicity of local anaesthetics used in the 1980s and the development of motor sparing analgesia in the 1990s have all served to refine the technique. The latest step in this evolution is the development of analgesic alternatives to neuraxial techniques which not only are effective in the context of labour pain but also allow the mother to retain control. Patient-controlled intravenous analgesia with opioids has been intensively studied and has shown promise, especially since the ultra-short-acting opioid remifentanil became available (Fig. 1). However, despite the liberal use of pethidine, meptazinol and other long-lasting opioids with proven disadvantages,9 remifentanil patient-controlled intravenous analgesia is still underrepresented in many European delivery rooms.10–12Fig. 1: no caption available.Old habits die hard! This is perhaps why, for many years, the mainstay of pain relief in labour has been older drugs that have largely been abandoned for pain relief outside delivery rooms. For some time we have known that those opioids still in frequent use for labour pain do not perform particular well, and pethidine's detrimental effects may extend beyond the immediate peripartum period due to its metabolite norpethidine.13,14 A Cochrane Review summarised the situation: ‘parenteral opioids provide some relief from pain in labour but are associated with adverse effects. Maternal satisfaction with opioid analgesia was largely unreported but appeared moderate at best’.15 Due to the pharmacokinetic properties of pethidine, restricting its use to an early stage in labour will not avoid its detrimental effects and may even prove counterproductive with respect to neonatal outcome.16 Single trials make the case against the use of long-acting opioids, especially pethidine, even more dramatically: ‘it is concluded that labour pain is not sensitive to systemically administered morphine or pethidine. These drugs only cause heavy sedation. It therefore seems unethical and medically incorrect to meet parturients’ requests for pain relief by giving them sedation. Considering the well documented negative effects on newborn infants we also believe systemic pethidine should be avoided in labour’.17 The failure to provide adequate analgesia applies also to other analgesics such as tramadol18 or meptazinol,19 so that as early as 1987 it was suggested that ‘the critical reassessment of traditional drugs for analgesia in labour’ is urgently needed.20 However, at that time – aside from epidural analgesia – no promising pharmacological approaches were at hand. Epidural analgesia in its present form is best characterised in terms of the pain relief that can be obtained by dilute local anaesthetics in conjunction with lipophilic opioids. Despite refinement, the effects of neuraxial labour analgesia on the progress of labour have generated considerable controversy even among its proponents. There is no advantage withholding epidural analgesia because current evidence indicates that effective labour analgesia given early in labour does not increase the rate of caesarean delivery,21 and is not associated with an increased risk of instrumental delivery, compared with more advanced labour.22 However, compared with other forms of analgesia, it may prolong the second stage of labour and may also increase the rate of instrumental vaginal delivery.23,24 On the basis of these considerations and the risk versus benefit analysis that each woman inevitably will perform, there should be consensus that labour analgesia must be tailored to the individual need; there is no ‘one size fits all’ solution in peripartum analgesia. No matter how good the information provided, a significant proportion of women, when they prepare for childbirth, will not want epidural analgesia. Sometimes, this choice is based on disinformation. We know that most women and their families derive their information from non-medical sources25 and it falls to the anaesthesiologist to balance misconceptions. We also know that a woman's intentions may not be constant26 and can change radically once real labour pain begins to bite. It is important to cater for the customer, not the cook! If maternal satisfaction is a goal, then patient choice and participation in decision making constitute a key element in the process of informed consent. Effective analgesia tends to make fathers happy by reducing paternal anxiety and stress and increasing paternal involvement, participation and satisfaction with the experience of childbirth.27 Analgesia is just one of several factors related to increased maternal satisfaction. A systematic review revealed that ‘ … four factors – personal expectations, the amount of support from caregivers, the quality of the caregiver–patient relationship, and involvement in decision making – appear to be so important that they override the influences of age, socioeconomic status, ethnicity, childbirth preparation, the physical birth environment, pain, immobility, medical interventions, and continuity of care, when women evaluate their childbirth experiences’.28 This clearly represents a strong vote in favour of patient choice and autonomy in this dedicated area of medical care. These findings might also explain in part why women consider remifentanil frequently as helpful as an epidural, based on the pain relief score, the proportion who discontinue due to poor analgesia, the proportion who would have liked to continue and those who recommend the given medication at the end of the study, when pain scores markedly differ.29,30 This is the situation described in the study in this issue of the European Journal of Anaesthesiology.31 The authors reported that 100% of patients would recommend remifentanil patient controlled intravenous analgesia (PCIA) (versus 95% in the epidural group), 94% of patients would use the same analgesia next labour (versus 90% in the epidural group) and 76% reported to be ‘very satisfied’ with analgesia (versus 75% in the epidural group), although pain scores (not reduction in pain scores) differed at various time points during labour. The advantages of remifentanil include ultra-short elimination and titratability to individual needs. The administration modes studied in the available trials differ, but have not substantially changed since the first description of its use in thrombocytopaenic patients.32 Although it readily crosses the placenta,33,34 the short elimination time constitutes an important safety feature in that the rapid elimination of remifentanil is sufficiently swift to minimise the risk for the newborn. It is also possible to adapt the supplied boluses – within certain limits – to the individual need of the women, as this is known to vary during the course of the labour.32 It may be reassuring to some that remifentanil is already used in the neonatal setting, for painful procedures and for sedation during mechanical ventilation,35–37 a scenario that seems unconceivable with pethidine.38 Following remifentanil administration, functional MRI indicates an onset time of 20–30 s, with a maximum between 80 and 90 s in the fastest loci in the brain.39 A lag between the peak blood concentration and the peak concentration at the effect site would make it impossible to provide analgesia at the peak of the contraction from an earlier PCA request, even when anticipated administration is encouraged. If peak efficacy from a single bolus of remifentanil given at the beginning of a contraction follows the peak of the contraction, there may still be drug active at the time of the next contraction. However, these are academic interests at best, as labouring women seem to cherish the temporary control remifentanil PCIA offers to them. The discrepancies between pain relief, satisfaction with the applied method and pain scores, give rise to the assumption that placebo effects, in addition to any genuine analgesic effect, may play a role.30 All this adds to the debate about what exactly maternal satisfaction is, and whether it should be measured in analgesic trials. However, the fact that usually there is ‘no difference between the groups in the proportion of parturients who discontinued due to ineffective analgesia, nor in the proportion of parturients who would have liked to continue the given medication at the end of the study’, even when compared with epidural analgesia, could mean that these analgesic techniques meet the expectations of many women. Our own experiences support these findings,40,41 and the notion that remifentanil may represent significant progress for those women who either do not want, cannot have or do not need epidural analgesia.42 The routine use of remifentanil for labour pain is already established in many units.42,43 The main lesson is that the availability of remifentanil PCIA decreases the uptake of other methods of pain relief. It may also finally lead to a decline in the rate of epidural analgesia in settings in which this method is widely used, as it offers a real choice between two options that, in the patient's eyes, may seem equivalent and may also meet their ‘ideal birth experience’. Perhaps it is more important that it removes the need to choose between traditional but rather ineffective methods44,45 and an epidural that is effective, but not (yet) wanted. Although in the author's institutions, remifentanil PCIA is (still) not as routine as epidural analgesia or CSE techniques, having it as an option removes any pressure to put in an epidural at all costs. It may be that the availability of remifentanil PCA helps epidural analgesia retain its place as the best option by replacing it for those patients who are in a higher risk category because of relative contraindications such as impaired coagulation. In this way, the safety record of epidural analgesia will not be threatened. However, despite encouraging experiences with safety and efficacy, we are doubtful whether ‘labour analgesia can (or should) once again be removed from the hands of the anaesthetist and back into the hands of the patient and her midwife’.42 Notwithstanding its exciting pharmacology and suitability for labour pain, remifentanil is a respiratory depressant and has potential for harm.46,47 For this reason, it is important that appropriate safety precautions are defined. We firmly believe that this emerging indication will not render the anaesthesiologist superfluous, given the extensive experience we have with remifentanil (an excellent safety backup), but give more women access to effective pain relief. This will help bring this human right to all delivery suites and finally render obsolete statements about the justification for pain relief.5 Acknowledgements This work was supported by the Department of Anaesthesia and Critical Care, University Hospitals of Würzburg, Germany. There are no conflicts of interest. The authors would like to thank Dr Andrea Melber, Salem-Spital, Bern (Switzerland) for inspiring comments and discussion. This article has been edited by the European Journal of Anaesthesiology, but has not been sent for peer review.