Inhaled analgesia- flurane derivatives

A pilot study of 50 labouring patients reported that sevoflurane in sub-anesthetic doses (0.6–0.7 MAC) reduced the mean pain score and was associated with a high satisfaction score. Forty-nine of 50 patients (98%) reported desire to receive the same analgesia in the future [ ]. Apart from drowsiness in 4 parturients (8%), no adverse effects were reported. A subsequent systematic review of 26 randomised controlled trials (RCTs) found flurane derivatives offered better pain relief that nitrous oxide (N ₂ O) in the first stage of labour [ ]. Of note, cross-over design trials were included which may have introduced confounding. Although effective, widespread use of flurane derivatives in a labour room is limited by the need for additional equipment and appropriate scavenging. Further work may help determine an optimal sevoflurane concentration to balance the risk of sedation with the benefit of analgesia.

Inhaled analgesia- nitrous oxide

Inhaled N ₂ O is commonly used as a combination of 50% N ₂ O with 50% oxygen administered by face mask with gas scavenging. Peak analgesic effect takes 30–60 s with rapid clearance through exhalation in the mother. Peak fetal levels are 0.8x maternal levels with diffusion across the placenta and quick respiratory clearance in a newborn. A systematic review found that inhaled N ₂ O offers more pain relief compared to placebo or no treatment, with side effects of vomiting and drowsiness [ ]. However, overall evidence regarding efficacy of N ₂ O for labour pain has been mixed, with systematic reviews demonstrating that N ₂ O reduced pain scores [ ] but provided inferior analgesia than labor epidurals [ ]. More recent small trials have found the analgesic effect of N ₂ O comparable to non-neuraxial meperidine [ ] and transcutaneous electrical nerve stimulation (TENS) [ ] while an observational study found that withholding inhaled N ₂ O during the COVID-19 pandemic increased use of non-neuraxial opioid analgesia [ ].

Despite uncertainty about its efficacy, inhaled N ₂ O continues to be widely used in labour and is described as a valuable option for labour analgesia by both the American Society of Anesthesiologists (ASA) [ ] and the European Society of Anaesthesiology [ ]. The benefits of inhaled N ₂ O extend beyond analgesia as demonstrated by a qualitative analysis of 264 parturients who chose nitrous oxide as their sole labour analgesia [ ]. Although these women described N ₂ O as only transiently or partially effective, it had non-analgesic effects that enhanced coping with labour such as by providing distraction, redirecting their focus towards breathing and promoting relaxation or anxiolysis.

Occupational exposure concerns about inhaled N ₂ O such as reduced fertility, reproductive harm or otherwise can be addressed with the use of appropriate scavenging systems for patients [ ]. There is growing concern about the environmental impact of N ₂ O as a greenhouse gas that traps radiation and heat in the atmosphere. Among labour analgesic options, Entonox (50% N ₂ O with 50% oxygen) is associated with the highest carbon emissions at 237.33 kg CO ₂ e (carbon dioxide equivalency), significantly higher than that of epidural analgesia (1.2 kg CO ₂ e) and remifentanil patient-controlled analgesia (PCA) (0.75 kg CO ₂ e) [ ]. Efforts to mitigate its environmental impact include reducing its use and managing leaks and redundancies within the central gas supply system [ ]. More recently, the use of cracking technology that breaks down nitrous oxide into non-greenhouse gases nitrogen and oxygen was able to reduce median ambient levels by as much as 81%. Although promising, there were many barriers to its implementation including clinical workload [ ]. The successful use of such technology may sustain N ₂ O as an option for labour pain relief without concern for its environmental impact.

Remifentanil

Remifentanil is a potent synthetic opioid with a short context-sensitive half-life. It is ultra-fast acting and whilst it does cross the placenta, it is rapidly metabolized by both maternal and foetal esterases [ ] ^. Therefore, it has unique advantages for the management of contraction pain of labour, has minimal side effects to the foetus, and may be safer than other opioids for the foetus [ ]. Remifentanil for labour is usually in PCA form, which gives women more control as they can time the bolus with their contractions. Observational studies have shown efficacy and maternal satisfaction with remifentanil PCA, with a low incidence of serious maternal or neonatal adverse events [ ].

Remifentanil was originally reserved for patients with contraindications to neuraxial anaesthesia. However, it has evolved to become a viable routine analgesic choice in many units. Although it provides inferior pain relief to neuraxial techniques, it compares favourably with other systemic opioids [ ]. A systematic review comparing remifentanil to fentanyl PCA with respect to pain scores found remifentanil provided superior analgesia [ ]. In a multi-centre UK RCT (RESPITE trial) comparing remifentanil PCA to IM pethidine for labour analgesia, remifentanil provided superior maternal analgesia and satisfaction [ ]. There was also no difference in maternal respiratory rate below 8 breaths per minute, a similar rate of caesarean delivery and no difference in breastfeeding rates within the first hour after birth [ ]. Remifentanil use in labour is also associated with a lower rate of conversion to epidural analgesia compared to other opioids [ , ]. In a large study analysing almost 40,000 births in a single unit over a ten-year period with >11,000 women using remifentanil PCA for labour analgesia, remifentanil was associated with high maternal satisfaction and a low rate of conversion to epidural. Over 85% who used remifentanil stated they would choose this option for future deliveries [ ]. Most recently in the UK, the National Institute for Clinical and Health Excellence (NICE) guidance on Intrapartum Care [NG235] [ ] advises that, compared to pethidine, remifentanil PCA was associated with reduced need for epidural analgesia and instrumental delivery, but increased need for supplemental oxygen. The authors recommended that remifentanil PCA should be considered as an analgesic option for labour pain but only in obstetric units due to the risk of respiratory depression and potential need for anesthetic support.

There is debate regarding the optimal PCA bolus dose, with ranges from 10 to 40mcg proposed. Some studies have looked at increasing the dose with progression of labour.

A lower bolus dose may also reduce the risk of respiratory complications while maintaining analgesia. This is an evolving area of research.

A systematic review of 36 papers on remifentanil for labour analgesia found an association between remifentanil and significant respiratory depressant effects, including respiratory arrest in one case [ ]. A number of adverse incidents have been reported when remifentanil was used in cases of intrauterine death, including respiratory and cardiac arrest [ , ]. Such safety concerns about remifentanil for labour analgesia-maternal hypoxia, apnoea and cardiorespiratory arrest-have limited its use in some centers. Melber et al. reported that among 5740 patients who used remifentanil PCA, 27% had a decrease in maternal oxygen saturation without a requirement for ventilation or cardiopulmonary resuscitation [ ]. Ronel et al. noted that serious adverse events relating to remifentanil use are rare, and with robust safety guidelines in place, the risk is significantly reduced [ ]. Adverse incidents may relate to inadequate supervision and lack of monitoring. Labour analgesia with remifentanil PCA should be considered on a case-by-case basis, and remifentanil may be an option provided adequate staff training and levels of observation and monitoring to ensure safety. Oversedation or significant respiratory depression are uncommon side effects but if they do occur, it is likely to be early in the use of a remifentanil PCA. Therefore, the anaesthetist prescribing and starting the PCA should remain with the patient or be immediately available on the labour ward for the initial period of use to maximise safety [ ].

Other required safety measures include continuous pulse oximetry and availability to provide supplemental oxygen in the labour room [ , ]. Apnoea monitoring and end tidal carbon dioxide monitoring have also been suggested [ ], although in practice this may be impractical. A dedicated cannula for the remifentanil is advised to reduce the risk of incidents involving inadvertent bolus of remifentanil with the coadministration of other fluids or medications. Only one standardized concentration of remifentanil should be available on labour wards, or a premade solution used to eliminate the risk of dosing error [ ]. The use of specific remifentanil infusion pumps pre-programmed with dosing regimens can also lower the risk of dosing error. Midwives should have specific training on remifentanil and maintain familiarity with the technique and its associated risks. Staffing should be appropriate for one-to-one continuous supervision at all times [ ]. The requirement for one-to-one midwifery care has limited the widespread implementation of remifentanil PCAs [ ]. Overall remifentanil PCA is a safe, effective labour analgesic and provides an alternative for women who have contraindications to, or do not want, an epidural.

Fentanyl

Fentanyl is a potent, short acting synthetic opioid. It has no active metabolites, and is associated with less sedation and nausea than other opioids used during labour [ , ]. A study comparing remifentanil, pethidine and fentanyl PCA demonstrated that remifentanil was superior for analgesia but produced more sedation than the others [ ]. A RCT comparing pethidine and fentanyl demonstrated that IV fentanyl was associated with decreased nausea and vomiting and reduced requirement for naloxone in neonates when compared to pethidine [ ]. Other trials have shown that remifentanil may provide superior analgesia to fentanyl for the first hour of labour, but this levels out for subsequent hours [ ]. There have been no large RCTs directly comparing the use of remifentanil and fentanyl PCAs to date.

Fentanyl can be given via a variety of routes for labour analgesia including intranasal, subcutaneous and via an epidural but systemically, is most commonly used as an IV bolus or PCA. One trial comparing nurse administered IV bolus versus PCA demonstrated no significant difference in maternal analgesia or maternal or foetal side effects [ ]. The dose for PCA fentanyl is usually 20 mcg with a lockout time of 5 min although this may vary across institutions. A short onset time and a duration of action of around 30 min make fentanyl a good option for labour analgesia. However, repeated doses may result in accumulation in the mother and foetus [ ].

Overall, fentanyl is a good opioid analgesic option for labour but there are concerns similar to remifentanil PCAs, namely the risks of sedation and respiratory depression in the parturient and foetus. Fentanyl PCA has been shown to be inferior to neuraxial analgesia. In a large RCT comparing both modalities, fentanyl was associated with increased sedation, higher pain scores, decreased satisfaction and increased use of anti-emetics when compared to epidural [ ].

Pethidine

Pethidine (meperidine) is a synthetic phenylpiperidine derivative metabolized to the active metabolite normeperidine and is given in a dose of 1 mg/kg IM(40). Pethidine was, until recently, the mainstay of opioid analgesia for labour in the UK since its introduction more than 70 years ago. It is also still the most used opioid worldwide for labour analgesia [ ]. However, its use in recent years has declined due to alternative options and its potential side effects on the mother and the foetus. Over the last 15 years, numerous trials have demonstrated inferior analgesia with pethidine compared to other systemic opioids such as fentanyl, morphine & remifentanil. One concern with the use of pethidine is that while it has a half-life of 2–3 h in the maternal circulation, the conversion to an active metabolite normeperidine can have a prolonged effect in the foetus. This phenomenon can lead to sedation, respiratory depression and decreased Apgar score at birth [ ]. The prolonged effect of pethidine can also lead to poor muscle tone and suckling in the newborn, therefore impacting breast feeding [ ]. Despite the concerns regarding efficacy and side effect profile, the use of pethidine globally is likely to remain high, particularly in low resource countries.

Diamorphine & morphine

Diamorphine is a semi-synthetic opioid produced by the acetylation of morphine [ ]. It is converted to two active metabolites, morphine and 6-monoacetyl morphine which are responsible for its analgesic effect [ ] ^. Diamorphine IM has been a popular analgesic option in the UK for many years, and has begun to overtake pethidine as the IM opioid of choice [ ]. A large RCT directly comparing IM pethidine to IM diamorphine conducted in the UK found that diamorphine provides superior pain relief to pethidine [ ]. However, its use is limited in other countries worldwide. Due to shortages of diamorphine in recent years, a number of UK units have moved to the use of IM morphine in labour but this practice is not widespread.

One trial reported less nausea and vomiting and improved Apgar scores in patients who received diamorphine compared to pethidine [ ] but these findings have not been replicated in larger studies. While diamorphine perhaps provides superior analgesia to pethidine, there remains the problems of IM administration, notably that it is a single injection which is non-titratable. There is also concern that due to supply issues, diamorphine may become unavailable in the near future.

Non-pharmacological methods for labor analgesia

Various non-pharmacological methods for labour analgesia have been studied. In addition to effectively reducing labour pain, other advantages of such methods include their accessibility and lack of adverse side effects. Such methods are often non-invasive and can have other beneficial features including reduced duration of labour. Importantly, maternal empowerment of choice and perceived greater sense of control with use of these methods may improve satisfaction with the birth experience. Many of these methods can be used in combination with other nonpharmacological or pharmacological approaches. However, such heterogeneity has made it difficult to demonstrate efficacy of nonpharmacological methods for labour analgesia.

Antenatal education

A systematic review and meta-analysis of 23 studies including 14 controlled trials found antenatal education on childbirth preparation, mindfulness-based childbirth or parenting skills can reduce maternal stress, improve self-efficacy (belief in one’s ability to complete a task) and decrease the use of epidural anaesthesia [ ]. However, the use of analgesics was not reduced in the patients exposed to antenatal education. Additional studies to clarify the effect of antenatal education on labour analgesia choices and effectiveness are required. Diversity of the interventions for labour analgesia in the available meta-analysis was limiting, and remains a barrier for further research to understand the impact of antenatal education on analgesia requirement.

Acupuncture and acupressure

Acupuncture involves the insertion of fine needles into specific points called acupoints. Acupressure is based on similar principles but stimulates acupoints using a constant and firm pressure with hands or a suitable tool. Compared to acupuncture, acupressure has the benefit of being a non-invasive technique that can be administered with less certification than acupuncture.

A large meta-analysis of 28 trials included 13 acupuncture trials and 15 acupressure trials [ ]. There was some evidence that acupuncture may increase satisfaction with pain relief compared to sham acupuncture and reduce the use of pharmacological analgesia. However, these favourable findings were not found in a comparison of acupuncture to usual care or no treatment. The same meta-analysis found evidence with moderate certainty that acupressure slightly reduces the intensity of pain during labour compared with a combined control (usual care, TENS, breathing group, sterile water injections, or no intervention). Another meta-analysis similarly reported that acupressure significantly reduces labour pain in the active and transitional phases of the first stage of labour and was superior to no intervention [ ]. Despite promising results and the appeal of an easily administered technique, it has been difficult to compare and consolidate findings due to the risk of bias for blinding and considerable heterogeneity in study design, methodology, skill of practitioner and acupressure point used.

Aromatherapy

In aromatherapy, aromatic extracts of plants are administered through inhalation or massage. Theories for its mechanism of action include stimulation of the limbic system and the relief of anxiety and hence pain by lowering cortisol and increasing serotonin levels [ ]. There have been multiple systematic reviews demonstrating that aromatherapy reduces anxiety and pain in labour [ , ]. These reviews are limited by heterogeneity in the type of essential oil used and method of application. A recent RCT compared pain scores in women who received lavender essential oil aromatherapy by either inhalation or massage therapy to controls. Pain scores were significantly lower in both intervention groups compared to the control group. Inhalation had the most favourable results in the latent phase while massage therapy was more effective in the active and transition phases [ ]. Many other types of essential oils have been used including Neroli oil and geranium [ ]. Although difficult to standardize for research purposes, aromatherapy provides a non-invasive method of analgesia that is unlikely to have adverse effects.

Breathing techniques

Breathing exercises can be conducted with the support of nursing and midwifery staff. Such exercises stimulate the parasympathetic nervous system and increase the release of endorphins [ ]. A meta-analysis of 22 RCTs studied the effect of Lamaze breathing training with nursing intervention [ ]. Accompanying nurse interventions included position change, delivery ball, doula nursing, massage, and psychological nursing. Eleven of these studies evaluated the effect on labour pain and found reduction in pain and had other benefits including increasing the rate of natural delivery and shorter length of labour. A recent meta-analysis found that although there was not a difference in length of labour between the intervention group and the control group, breathing exercises did reduce the duration of the second stage of labour [ ]. Only two of the trials in this review evaluated the effect of breathing exercises on pain and they had conflicting results. There have been RCTs demonstrating the benefits of breathing exercises in reducing pain [ ], some in combination with other modalities such as massage [ ]. Although the evidence for the analgesic effect of breathing exercises is mixed, it is easy to conduct and could have benefits in other outcomes such as duration of labour.

Continuous labour support

Continuous support from a companion of choice has been advocated for women in labour by the World Health Organization (WHO) [ ]. A Cochrane review of 26 trials in 17 countries found that continuous companion support reduced the use of any type of intrapartum analgesia and suggested further benefits including reducing the rate of cesarean delivery, duration of labour and negative feelings about childbirth [ ]. However, subgroup analysis suggested that the benefits may be greater settings where epidural analgesia was not routinely available. Hence, the measurable benefits of continuous companion support must be considered in appropriate context. This has been illustrated in recent studies with mixed results. An observational study comparing 446 women with continuous companion support to 340 women without continuous companion support showed no difference in the use epidural analgesia or other modalities [ ]. In contrast, a subgroup analysis of a cluster randomised trial demonstrated that parturients who received one-to-one midwifery care were less likely to have an epidural or be given nitrous oxide. They were also less likely to have a cesarean delivery or an operative vaginal birth [ ]. Despite the mixed evidence, continuous labour support is non-invasive with no harm and should be readily encouraged.

Heat and cold therapy

The administration of heat and cold to different parts of the body has been proposed to reduce labour pain. Based on the gate control theory, cold can block neural transmission in sensory fibers and increase the pain threshold. Local heat application stimulates receptors in cutaneous and deeper tissues that neutralize and impede neural impulses to the brain [ ]. A RCT with 64 patients found that intermittent placement of a cold pack over the abdomen, back and perineum reduced the degree of pain during all parts of the active phase and second stage of labour with no adverse effects [ ]. A recent meta-analysis including 10 RCTs demonstrated that heat therapy significantly reduced pain intensity in the first stage of labour and the duration of first stage of labour. In the presence of a sensorimotor block from concurrent epidural analgesia, extremes of temperature therapy should be avoided for safety.

Hypnosis

The use of hypnosis aims to control pain through suggestion of pain relief and reinterpretation of pain perception. The goal is to reframe the birthing experience into a non-threatening one and increase the pain threshold during labour [ ]. A systematic review found that hypnosis reduced the overall use of analgesia but not epidural analgesia during labour [ ]. There were no differences in other outcomes including maternal satisfaction with pain relief and ability to cope with labour [ ]. A separate systematic review found that hypnosis-based interventions had a positive impact on labour analgesia in all but one study [ ]. Three studies reported lower pain scores in the hypnosis group compared to usual care. More positive childbirth experience and shorter duration of labour was also reported in the hypnosis group. Both systematic reviews were limited by poor quality of included studies and significant heterogeneity. Although evidence about the analgesic effects of hypnosis is likely to remain limited, the beneficial psychological impact of hypnosis including alleviating anxiety and fear towards birth [ ] add value to this technique.

Hydrotherapy

Immersion in water can reduce anxiety and pain perception in labour [ ]. Hydrotherapy can be used during either or both the first and second stage of labour. A previous systematic review found a small reduction in the use of regional analgesia in the first stage of labour [ ]. However, there are concerns related to use of hydrotherapy at the time of delivery and neonatal complications, including infection and water aspiration. A separate systematic review of case reports on neonatal outcomes did not support concerns of water aspiration or cord rupture but identified other risks including infection and neonatal hyponatraemia [ ]. A third systematic review on this topic including 36 papers reported outcomes for 157,546 women and echoed the previous findings on the analgesic effect of hydrotherapy with a reduced use of epidural and injected opioids and an increase in maternal satisfaction. Immersion during the second stage of labour and subsequent waterbirth was associated with increased risk of cord avulsion [ ]. There were no differences in other reported neonatal outcomes including newborn infection, resuscitation or respiratory distress of the newborn. The authors concluded that water immersion may provide benefits for the mother and advised that clinicians should minimize traction on the umbilical cord when bringing the newborn to the surface of the water. Notably, inconsistencies in birth setting, care practices, interventions and outcomes precluded meta-regression analysis for outcomes related to analgesia or neonatal outcomes.

Massage

Massage involves the systematic manipulation of soft tissues, with pressure applied thought to block transmission of pain impulses to the brain while stimulating local release of endorphins [ ]. RCTs on the analgesic effect of intrapartum massage have produced conflicting results and a recent Cochrane review found that although massage may reduce pain intensity during the first stage of labour, there was no clear benefit in other outcomes such as length of labour or use of pharmacological analgesics [ ]. However, massage may have other benefits including sense of control and satisfaction with the childbirth experience. Optimal duration and site of intrapartum massage is unknown, nor is whether skill of the practitioner impacts effectiveness. Massage therapy is often used in combination with other non-pharmacological approaches such as aromatherapy or breathing techniques and benefit of such combined techniques has been demonstrated in RCTs [ , ].

Virtual reality

Virtual reality (VR) has an emerging role for both analgesia and as an adjunct to sedation and anaesthesia [ ]. In non-obstetric populations, results have been mixed regarding its analgesic efficacy [ , ] but higher satisfaction scores have been reported [ ]. VR is hypothesized to directly modulate pain-related brain activity through a mechanism of distraction [ ]. A systematic review and meta-analysis of 8 RCTs with a total of 466 patients found VR significantly reduced labour pain score [ ]. Anxiety was evaluated in 3 of 8 studies and was reduced while satisfaction evaluated in 2 of 8 studies was increased. Although promising, larger multicentre RCTs are required to verify these conclusions and explore the optimal duration and frequency of the VR system. The cost of VR systems previously restricted their widespread application but declining costs over time may make VR more feasible as a scalable option for non-neuraxial analgesia [ ].

Music therapy

A recent meta-analysis highlighted the benefits of music therapy on labour pain and anxiety levels [ ], reducing VAS scores during both the latent and active phases of labour. However, the evidence was of low to moderate quality due to heterogeneity and risk of bias as masking and randomization procedures were generally not described. Another meta-analysis of 13 RCTs involving 2387 patients found similar benefits of music therapy on labour pain and anxiety but was similarly limited by the quality of included studies [ ].

Transcutaneous electrical nerve stimulation

The TENS technique involves the administration of low voltage electrical impulses through electrodes placed on the skin, typically on a paravertebral T10-L1 and S2–S4 bilateral position. A proposed mechanism of action is via the gate control theory of pain where stimulation of afferent nerve fibres by electrical impulses closes the pathway for other painful stimuli. A meta-analysis of RCTs found that TENS significantly reduced pain intensity but the strength of the conclusion was limited by poor quality of included studies [ ]. Compared to other methods, a RCT found TENS to be comparable to inhaled Entonox in reducing pain scores [ ] while another RCT found TENS to be superior to aromatherapy [ ]. A prospective study comparing epidural analgesia with TENS showed that there was no difference in more favourable reporting of either technique, though more parturients in the epidural group were highly satisfied with analgesia [ ].

Sterile water injection

Sterile water injections involve either intradermal or subdermal injections with a mechanism of action is based on the gate control theory [ ]. Meta-analyses of the efficacy of sterile water injections have been mixed. A Cochrane review of seven RCTs with 766 participants did not find robust evidence that sterile water injections were effective [ ]. However, a more recent meta-analysis including nine RCTs with 2102 participants found that both intradermal and subdermal sterile water injections were associated with pain reduction between 30 and 90 min after injection [ ]. Nonetheless, only 2 additional RCTs were added in this study, and most subgroup analyses were limited by heterogeneity and a small number of trials.

Other factors to consider include the acceptability and specific technique of sterile water injection. A review exploring the experiences of midwives and women showed that barriers to use of sterile water injection included midwives feeling conflicted about providing an invasive procedure and the requirement to learn the skill. However, women appreciated sterile water injection for its rapid onset of pain relief and lack of side effects [ ]. There is no consensus on the ideal technique of injection. Within the meta-analysis demonstrating efficacy, subdermal sterile water injections produced better pain relief than intradermal injections at 10 min but not at 30–45 min. Of note, only 2 RCTs were compared for this analysis [ ]. Uncertainty also exists in the optimal number of injections for labour analgesia. The most common approach involves 4 injections but a recent multicenter randomised equivalence trial demonstrated that 4 injections provided only marginal benefit over 2 injections for amount and duration of analgesia. Both techniques were able to achieve at least 30% reduction in pain in over 75% of participants [ ]. Further work is warranted to study the acceptability and feasibility of this technique as well as the best approach for optimal analgesia.