1. Introduction Currently, a wide variety of nonpharmacologic interventions and pharmacological agents are used to alleviate maternal pain in labour. Non-pharmacological methods can be used as a principal method or complementary to pharmacologic agents. Studies have shown their positive impact on subjective experiences of childbirth. This is emphasized by the fact that worldwide, nearly 73% of women use at least 1 nonpharmacological method during their childbirth.¹ The reported leading methods are breathing techniques, position changes, massage, mental strategies-relaxation. Thus far there is little high-quality evidence as an analgesic method during labour.² Nevertheless, patient satisfaction combined with infrequent incidence of adverse events have led professional societies to acknowledge its utility as an adjunct to pharmacologic agents upon maternal request.³ Pharmacologic options for pain relief during labour can be divided according to route of administration, systemic and regional (epidural). In this section we will focus on systemic pharmacologic agents only.

2. Nitrous oxide (N2O) N2O has been used worldwide for labour analgesia for several decades.⁴ Its analgesic effectiveness is achieved from increasing the release of endogenous endorphins, dopamine, and other natural opioids in the brain and neuromodulation in the spinal cord that offers rapid onset inhaled analgesia.⁵ It also affects several other hormones that are important during labour and birth including prolactin, cortisol, and epinephrine/norepinephrine, but it does nor reduce the relies or effectiveness of endogenous oxytocin and has no effects on uterine contractions or labour progress.⁵ When given in a 1:1 mix with oxygen, N2O has a good safety profile.⁴ Adverse effects associated with N2O use, such as nausea, dizziness, and drowsiness, have been reported. N2O was found to have some analgesic effect, it decreases woman’s perception of pain, and has an anxiolytic effect that may be helpful if women are restless or doubt their ability to cope as commonly occurs near the end of the first stage of labour. Nitrous oxide is eliminated quickly and entirely by the neonatal lungs, with no effect on Apgar and neonatal neurobehavioral scores.⁶

In a study of 1300 Chinese women randomized to inhale either 50% nitrous oxide or 50% oxygen during labour, the women who inhaled N2O had shorter active phases of labour (153 vs. 187min) and fewer caesarean births (11,6% vs 19.3%).⁷ That could be attributed to the inhibition of the excitatory stimulation in the neocortex which inhibits the involuntary physiological processes of birth. Studies comparing nitrous oxide with epidural analgesia found the former less effective.⁸ In a postpartum survey of 2482 parturients, 80% rated EA as very effective, compared with 44% among those who were using nitrous oxide.⁹ Richardson et al., on the other hand, reported a heterogeneity in nitrous oxide analgesic activity. In a postpartum survey in 6507 parturients who delivered vaginally by either EA or nitrous oxide, 50% of those with nitrous oxide reported high analgesic effectiveness scores, the reminder split between intermediate (27%) and low scores (21%). Despite that, the satisfaction scores were uniformly high in all groups and like those who either chose EA from the beginning or swich from nitrous oxide to EA.^{10 11}

The use of nitrous oxide in labour and delivery wards is associated with certain occupational exposure risks. This is due to deactivation of vitamin B_12, which is used by methionine synthase to convert homocysteine into methionine, which uses folate to synthesize myeline and DNA and RNA. When cobalamin is not available, methionine synthase cannot convert homocysteine, and plasma levels of homocysteine rise. After chronic exposure, this can lead to hematologic complications such as megaloblastic anaemia and demyelinating neuronal injury, potentially exerting relevant genotoxicity, which was not detected after exposure to other volatile anaesthetics.^{12 13} Occupational exposure to N2O has been significantly reduced over the last 25 years due to scavenging and ventilation. N2O is a greenhouse gas and is considered an environmental pollutant.

3. Opioids Opioids are commonly used for pain relief during labour, as they are widely available, easy to use and are of low cost. Their main advantage is that they produce analgesia with milder effect on sensation and proprioception. They act through opioid receptors distributed throughout the CNS including brain structures (thalamus, nucleus raphe, locus coeruleus and limbic system), and the dorsal horn of the spinal cord where their action is pre-and postsynaptic. Given systematically, opioids act through all sites simultaneously with the supraspinal systems being most sensitive. Opioid use during labour is associated with maternal side effects including nausea, vomiting, pruritus, sedation, and respiratory depression. After crossing the placenta, opioids may lead to reduced baseline foetal heart rate and foetal heart rate variability, neonatal respiratory depression, lower Apgar scores, neurobehavior alternations, and decreased early breastfeeding.¹⁴

A. Meperidine/pethidine Meperidine is the most frequently used systemic opioid. Onset of action is 5-10 min after iv. injection and up to 45 min after im. injection with a half-life of 2-4 hours. Meperidine is metabolized to an active longer lasting normeperidine, which has a prolonged half-life in adults and a half-life of up to 72 hours in neonates. Maximal foetal exposure, and hence neonatal respiratory depression and metabolic acidosis are seen if pethidine was given between 1-4 hours before birth.¹⁴ The neonatal side effects are dose- and time dependant, and comprise of depressed respiration, Apgar scores, neurobehavioral scores, muscle tone and suckling and detrimental effect on breast feeding. Meperidine provides only mild pain relief. It is equally effective than nitrous oxide and less effective than neuraxial analgesia. A recently published RCT compared the efficacy of intravenous (IV) meperidine and inhaled N2O for intrapartum pain relief among multiparous, term, singleton gestations. The results showed that pain intensity after 20 to 30 minutes of analgesic administration, as assessed by VAS score, was comparable between the groups (primary outcome). The mean VAS scores that were between 7 and 8 in both groups at baseline, and at 20 and 30 minutes after analgesia administration, suggests that neither technique provided adequate analgesia. Secondary outcomes, which included rate of additional analgesic use, labour length, mode of delivery, breastfeeding, satisfaction, and maternal and neonatal adverse effects, were similar between the groups. The authors concluded that pain intensity and adverse effects were comparable between the 2 analgesic methods.¹⁵ Douma et al. compared pethidine PCA with remifentanil PCA and reported two main findings. The rate of crossovers to EA was higher for pethidine, and pain relief was greater with remifentanil, but this difference disappeared after one hour.¹⁶

Pethidine is still very popular among midwifes and obstetricians due to belief of its effect on labour duration and cervical ripening. Various reports described the mechanism underlying these effects. During cervical ripening, pethidine increases urokinase activity which converts plasminogen into active plasmin, which further converts pro-collagenase into active collagenase. Sosa and colleagues conducted a randomized controlled trial to examine meperidine use in the management of women with dystocia during the first stage of labour. The authors found no differences between the intervention and placebo groups in duration of labour or in any of the maternal secondary outcomes.¹⁷

B. Remifentanil patient-controlled analgesia (remifentanil-PCA) From the pharmacological viewpoint, remifentanil-PCA provides advantages in comparison with other opioids. Remifentanil is a potent synthetic μ-opioid receptor agonist with a rapid onset and ultrashort duration of action making it suitable for labour analgesia. When administered by patient-controlled analgesia (PCA), it can mimic the intermittent profile of labour contractions. Remifentanil is rapidly metabolized by plasma esterizes into inactive metabolites, independently of renal and liver function. With a very short context sensitive half-life of 3.5 min, it does not accumulate even when administered during prolonged infusion. Remifentanil crosses the placenta and is quickly redistributed and metabolized by the neonate. The potential side effects for mother and child are therefore very short-lived, which makes it extremely well steerable.¹⁸

In terms of analgesic efficacy, remifentanil-PCA provides only mild pain relief which helps women better coping with pain. The reduction of pain spans from severe-unbearable (VAS 8-10) to intermediate-bearable (VAS 5-7), lasting up to one hour. The RESPITE study compared remifentanil IV-PCA to intramuscular meperidine in a non- blinded, 1:1 randomized controlled trial. Remifentanil-PCA was associated with a significantly lower proportion of women requesting epidural analgesia (19% vs. 41%). The mean VAS scores were significantly lower with remifentanil as compared to meperidine (50 vs. 65), while the reduction in VAS scores was similar in both groups. Women in the remifentanil group were more satisfied with their pain relief as compared to those in the meperidine group, while no differences were observed in the overall birth satisfaction between the groups.¹⁹Compared to neuraxial analgesia, several randomized controlled trials and 2 meta-analyses reported higher pain scores and shorter duration of pain relief with remifentanil-PCA.^{20 21} Consequently, neuraxial analgesia was associated with greater satisfaction with pain relief as compared to remifentanil-PCA.^{22 23} In 2019, two large audits were published, one from Ulster hospital and another from Remi-PCA SAFE Network with over 13000 remifentanil-PCA applications, which by 2022 counted for over 25000 documented cases. REMI-PCA Network with over 13000 remifentanil-PCA applications.^{24 25} For comparison, in our institution (Dpt. of Perinatology, UMC Ljubljana, Slovenia), the remifentanil-PCA has been used routinely for labour analgesia since 2013 per the standard operative protocol of the Department of Anaesthesiology and Intensive Therapy, University Medical Centre Ljubljana. By 2023, our institution alone reached over 13000 remifentanil applications. Indications for remifentanil-PCA are parturient request, when EA is contraindicated, after unsuccessful epidural administration, accidental dural puncture or technical failure, in an advanced labour or rapidly progressing labour and for obstetric indications such as breech or tween vaginal deliveries and a trial of labour after CS. During this 10-year period, no severe maternal complications in terms of cardiorespiratory arrest or respiratory depression requiring mask ventilation have been observed in any of our parturient. That could be attributed to the established safe operative standards which have been constantly reviewed and adjusted during the extensive routine use of remifentanil-PCA in our institution.

Nevertheless, several RCT and meta-analysis reported a higher incidence of respiratory depression associated with remifentanil-PCA as compared to neuraxial analgesia.^{20 21} However, this incidence of respiratory adverse effects associated with remifentanil-PCA does not appear to be significantly different from hypoxic episodes during labour with nitrous oxide and or long-acting opioids.²⁶ Hypoxic episodes can also occur during labour with epidural analgesia or without any analgesic treatment. Continuous care by the midwife, who intervenes immediately in the event of mild hypoxia or sedation, prevents the escalation of a benign, self-limiting situation and is one major aspects of safe administration. The short half-life of remifentanil contributes significantly to the fact that the regime settings can be adjusted quickly and efficiently in case of adverse reactions. Regular training of the personnel, clear standards for critical values and appropriate interventions are paramount for a high level of safety, while the parturient additionally benefit from the continuous professional care which contributes significantly to overall satisfaction with labour experience.^{27 28} In addition, since the expectations of women also depend on the cultural and personal environment and their personality, careful information about the benefits and drawbacks of remifentanil or any other method of pain relief is of great importance when counselling patient to be sure that their labour experience will meet their expectations as much as possible.²⁹

In terms of labour progress and outcomes, no differences in the rate of spontaneous delivery were reported by meta-analysis of 9 RCT trials comparing remifentanil-PCA with epidural analgesia.²⁰ On the other hand, a cohort study with more than 10000 deliveries comparing epidural vs remifentanil analgesia found remifentanil-PCA to be associated with lower CS and OVD rates in nulliparous women with spontaneous and induced labour and in multiparous women with spontaneous onset of labour, respectively. No differences in neonatal outcomes were recorded between the two analgesic techniques within any of the studied groups.³⁰ However, the associations observed in that study may not necessarily imply a causal relationship. Favourable results of non-operative delivery with Remifentanil-PCA may also point to the fact that more complicated labours require EA to assist in their management. On the other hand, the women with normal labour progress or expectations of faster labour are more likely to choose remifentanil-PCA to avoid the potential adverse/side effects of EA.³¹ This is particularly true of multiparous women who can combine a fast delivery with rapid availability and a short use of pain relief.²⁸ Additionally, certain obstetric conditions, such as a history of previous CD, twin gestation, or a breech presentation, may pose heightened risks with epidural analgesia, prompting a preference for alternative analgesic approaches.^{32 33} In a retrospective analysis of 127 planned vaginal breech and 244 twin deliveries obtained from the Slovenian National Perinatal Information System, no statistically significant nor clinically relevant differences between the EA and remifentanil-PCA groups were observed in the rates of CS in labour and neonatal outcomes suggesting that both EA and remifentanil-PCA are safe and comparable in terms of labour outcomes in singleton breech and twin deliveries.³⁴

In conclusion, given the increasing environmental issues of nitrous oxide and disadvantageous pharmacokinetic/dynamic of meperidine as compared to remifentanil-PCA, the routine use of remifentanil-PCA for labour analgesia should be seriously considered in all labour wards to increase the confidence with its usage while reducing potential for complications.

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