Inhalational Agents: Nitrous Oxide

Entonox (a 50:50 mix of nitrous oxide and oxygen) can be used alone or to supplement other methods of analgesia. A pressure-reducing valve fitted to the Entonox cylinder attaches to a breathing circuit, with a demand valve connected to a mouthpiece for the patient’s use. Inhaled nitrous oxide concentrations equilibrate rapidly with arterial blood concentration, with the peak effect after initiation of Entonox for approximately 50 seconds. Women are encouraged to breathe Entonox only during contractions and room air for in-between rest periods.

The availability and use of nitrous oxide for labor analgesia across the world is very variable. In some countries such as the United Kingdom it is a popular choice for many women, but the evidence supporting its efficacy is mixed.³ Some studies report reductions in pain scores similar to those achieved with systemic opioids,^4–6 but many report no improvement in pain scores, and up to 40 percent of mothers find its use of no benefit. Interestingly despite this, many women would choose to use nitrous oxide again for subsequent labors, suggesting that it is of some help even if not measurable with pain scores.^{3, 7–9}

Inhaled nitrous oxide analgesia for labor displays good safety outcomes for both mother and baby. Side effects include nausea but no increased rate of vomiting, a slight increase in the rate of maternal oxygen desaturation between contractions, and an increase in the rate of maternal drowsiness.^{3, 6, 10, 11} Nitrous oxide administration does not adversely affect uterine activity and does not cause significant neonatal respiratory depression, reduced Apgar scores, or fetal acidosis.^{12, 13}

Nonopioid Analgesics

Acetaminophen (paracetamol) is a widely used and effective antipyretic and analgesic medication. It is administered at a dose of 1 g (if patient weight > 50 kg) orally or intravenously every 4–6 hours, with a maximum of 4 g in 24 hours.^{14, 15}

Oral administration of acetaminophen in labor does not appear to offer significant analgesic benefit, but intravenous acetaminophen has been shown to be more effective than intravenous pethidine, with a duration of action of up to 2 hours.¹⁶ Acetaminophen has many fewer maternal adverse effects than opioids and has a favorable safety profile; when used in pregnancy, it is not associated with an increased risk of fetal morbidity.^{14, 15, 17}

Nonsteroidal anti-inflammatory drugs (NSAIDs) have an anti-inflammatory, analgesic, and antipyretic effect mediated by inhibition of prostaglandin formation. They are not in common use in labor because they do not appear to be effective as sole analgesic agents.¹⁸ As inhibitors of cyclooxygenase, NSAIDs have the potential to prolong labor and to cause constriction of the ductus arteriosus, renal dysfunction, and hemostatic abnormalities in the fetus and neonate.¹⁹

Systemic Opioids (Bolus)

Opioids are the most widely used systemic analgesia in labor but exhibit variable efficacy and a wide range of side effects.^{4, 20} They act by binding to opioid receptors found in the central and peripheral nervous systems and the gastrointestinal tract.

In some countries, such as the United Kingdom, intermittent bolus IM injections have the advantage of being midwife prescribed and delivered and so readily available, but they may be painful, display variable drug absorption depending on the site of injection, and have an inevitable delay between time of injection and onset of action. Intermittent bolus IV injections have the advantage of quicker onset, the ability to titrate to effect, and a more predictable quality and duration of analgesia, but they require the presence of medical staff to prescribe and often administer the dose.²¹

Meperidine (pethidine) is a synthetic opioid and worldwide is the most extensively used and investigated opioid analgesic in labor. The usual dose in labor is 50–100 mg or 1 mg/kg (maximum dose 200 mg) IM (peak effect at 2 hours). Morphine is a mu receptor agonist acting primarily in the CNS. The dose of morphine for maternal analgesia is 2–5 mg IV (peak effect at 10–20 minutes) or 5–10 mg IM (peak effect at 1–2 hours). Diamorphine (heroin) is a prodrug that is converted to the active components of acetylmorphine and morphine by esterases in the liver, plasma, and CNS. Diamorphine is administered intramuscularly at a dose of 2.5–5 mg, half that of morphine (peak effect at 1–2 hours). A second dose of all these drugs can be administered after 3–4 hours. Tramadol (Ultram) can be used at doses of 50–100 mg every 4 hours and can be given orally as well as via the IM or IV route.²²

Despite being in widespread use, published evidence suggests that less than 25 percent of women receive satisfactory pain relief from pethidine administration; morphine and tramadol have not been shown to be any more effective. Both midwives and laboring women rate diamorphine as a more effective analgesic than pethidine, but diamorphine has been associated with significantly longer labors. It has been argued that these drugs often provide sedation rather than direct analgesia.^{4, 23–27}

Maternal side effects of systemic opioids include nausea, vomiting, delayed gastric emptying, sedation, disorientation, pruritus, and respiratory depression. Patient susceptibility to these effects is variable and often dose dependent rather than drug dependent.²¹ Pethidine and tramadol have an added disadvantage of an increased risk of seizure activity in susceptible patients such as those with preeclampsia.²⁸

The fetal effects of opioids can be direct (because the low molecular weight and high lipid solubility of opioids allow for placental transfer) or indirect (via effects on the mother, for example, such as altered minute ventilation or uterine tone).^{29, 30} Opioids are associated with decreased beat-to-beat fetal heart rate variability, neonatal respiratory depression, and a delay in effective feeding due to the inhibition of sucking reflexes.^{24, 31, 32} Diamorphine and tramadol produce less neonatal respiratory depression than pethidine or morphine.^{25, 33} Naloxone (an opioid antagonist) may be administered directly to the neonate if required.³⁴

Codeine is not commonly the opioid of choice in active labor owing to poor-quality analgesia, but it is worth mentioning that its use in children and in breast-feeding mothers has recently been discouraged by the European Medicines Agency and Medicines and Healthcare Products Regulatory Agency. Although no new recommendations have as yet been made regarding its use in pregnancy, there may be a risk of neonatal respiratory depression in babies of individuals who are ultrarapid metabolizers of codeine via the enzyme CYP2D6. It would be sensible to consider this potential effect if prescribing codeine to a laboring woman.³⁵

Systemic Opioids: Intravenous Patient-Controlled Analgesia

Patient-controlled analgesia (PCA) systems require prescription and often must be set up by medical staff, but they can achieve good analgesia with lower drug doses than intermittent boluses. PCA systems have the added benefit of giving patients an increased sense of control during labor. Remifentanil (Ultiva), the most commonly used opioid in PCA for labor, is an ultra-short-acting synthetic pure mu agonist. Its rapid onset and rapid metabolism by tissue and plasma esterases mean that it has a context-sensitive half-life of 3 minutes and no accumulation.³⁶ The efficacy of remifentanil depends on both the dose and the manner in which it is administered. The most popular regimens used in clinical practice are either 0.5 µg/kg or 40-µg boluses with a 2- to 3-minute lockout time. The onset of effect is at around 30 seconds, and peak effect occurs at 2.5 minutes. With an average uterine contraction time of 70 seconds, it therefore can be difficult initially for women to time dose delivery so as to coincide the peak drug effect with the peak of each uterine contraction, but with tutoring from midwives, women are able to learn to anticipate the next contraction and make an early, effective demand.^37–40

Remifentanil PCA has been shown to significantly reduce pain scores of women in labor compared with baseline^41–43 and provides superior analgesia and higher patient satisfaction than bolus administration of pethidine with a comparable degree of adverse events.⁴⁴ However, the analgesia provided by remifentanil PCA is inferior to epidural analgesia.^45–49

The potential for maternal sedation, respiratory depression, and oxygen desaturation is significant with remifentanil PCA, and there have been a number of articles published recently questioning its safety profile.^{50, 51} An appraisal of the evidence suggests that 32 percent of patients experience respiratory depression,⁵² but this is usually transient and easily corrected with stimulation, nasal oxygen, or a reduction in dose. The rate of nausea and vomiting is difficult to distinguish as a true opioid effect because it is common in laboring women, but remifentanil PCA does not appear to cause a significantly higher rate of nausea than other opioids.⁵³

Due to the high incidence of maternal sedation and desaturation, remifentanil should not be started in women who have had other opioids administered in the preceding 4 hours, and it is imperative that there is appropriate monitoring and supervision. To date, there have been four case reports describing respiratory arrest with remifentanil PCA.^53–57 While each has its own set of circumstances and potentially confounding factors, their existence cannot and should not be ignored. High standards of supervision must be maintained, with trained midwives or nurses providing constant one-to-one care with a protocol that includes continuous oxygen saturation monitoring; regular documentation of pain scores, respiratory rate, and sedation level; and use of a dedicated cannula with an antisyphon valve. As with all areas where strong parenteral opioids are administered, full resuscitation equipment must be immediately available, with supplemental oxygen and a bag-valve/mask apparatus in the room⁵⁸ (Table 9.2). Caregivers must be trained to recognize and manage the potential adverse events. Maternity departments choosing to use remifentanil should have stringent guidelines in place to ensure appropriate safeguards for women and regular audit processes to ensure compliance, and if this cannot be guaranteed at all times, then units should not offer remifentanil as an option for laboring women.⁵⁹ Remifentanil should not be viewed as a “poor woman’s epidural.”⁶⁰

Table 9.2 Guidelines for the Safe Administration of Remifentanil PCA

Prescription and training	Prescribed by an anesthetist Only nurses/midwives who have undergone a period of supervised practice and have been deemed competent may administer this infusion
Eligibility	36 weeks’ gestation In established labor Informed consent
Contraindications	Other opioid use in preceding 4 hours Allergy to opioids Multiple pregnancy Preeclampsia
Supervision and monitoring	Continuous one-to-one nursing/midwifery supervision Continuous SaO2 pulse oximetry established prior to first administration 30-minute observations: respiratory rate, sedation score, pain score
Equipment	Dedicated IV cannula Dedicated PCA administration pump Unidirectional antisyphon valve on administration set
Indications for contacting anesthetist	Excessive sedation score (not responding to voice) Respiratory rate < 8 breaths/min SaO2 < 90 percent despite oxygen via nasal specs

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