Systemic drugs have been used to decrease the pain of childbirth since 1847, when James Young Simpson used diethyl ether to anesthetize a parturient with a deformed pelvis. Since that time, the provision of labor analgesia has advanced significantly. The growth of labor analgesia owes its progress to the heightened awareness of the neonatal effects of sedating medications or general anesthesia administered during vaginal delivery and a greater desire of parturients to actively participate in their childbirth experience.
In the modern era, systemic drug administration provides less effective labor analgesia with greater side effects compared with neuraxial techniques (epidural, spinal, combined spinal-epidural, dural-puncture epidural). As a consequence, a significant and growing number of parturients receive neuraxial labor analgesia globally, particularly in North America (60% to 75% rate of use).
However, the use of systemic analgesia remains the most common practice worldwide. Many parturients labor and deliver in an environment where safe neuraxial analgesia is not available. Some parturients decline neuraxial analgesia or choose to receive systemic analgesia. Finally, some parturients may have a medical condition that contraindicates a neuraxial procedure (e.g., coagulopathy) or presents technical challenges (e.g., severe scoliosis, the presence of spinal hardware).
PARENTERAL OPIOIDS
Opioids are the most widely used systemic medications for labor analgesia owing to their low cost, ease of use, and the lack of need for specialized equipment and personnel. These drugs act at opioid receptors ( Table 23.1 ). Although associated with a high frequency of maternal side effects (e.g., nausea, vomiting, delayed gastric emptying, dysphoria, drowsiness, hypoventilation) and the potential for adverse neonatal effects, opioid use has been augmented by the availability of patient-controlled delivery systems.
Table 23.1
Opioid Receptor Type Classification
| Classification | Effects |
|---|---|
| μ 1 , μ 2 , μ 3 | Analgesia, miosis, euphoria, respiratory depression, bradycardia |
| κ | Analgesia, sedation, miosis |
| δ | Analgesia, respiratory depression |
| Nociception | Inhibition of opioid analgesia |
| ζ | Tissue growth, embryonic development |
There is little scientific evidence to suggest that one opioid is superior to another, as analgesia and side effects are largely dose-dependent rather than drug-dependent; most often, drug selection is based on local policies and provider preferences ( Table 23.2 ). As a result of their high lipid solubility and low molecular weight (<500 Da), all opioids readily cross the placenta by diffusion and are associated with the risk for neonatal respiratory depression and neurobehavioral changes. Opioids may also affect the fetus in utero and neonate, who are particularly susceptible to opioid-induced side effects for several reasons. The metabolism and elimination of these drugs are prolonged compared with adults, and the blood-brain barrier is less well developed, allowing for greater central effects. Opioids may result in decreased variability of the fetal heart rate (FHR), although this change usually does not reflect a worsening of fetal oxygenation or acid-base status. The likelihood of neonatal respiratory depression depends on the dose and timing of opioid administration, as well as the presence of active metabolites. In a multicenter randomized trial, Halpern et al. demonstrated an increased need for active neonatal resuscitation in a group that received parenteral opioid via patient-controlled analgesia (PCA) compared with a group that received local anesthetic plus opioid via patient-controlled epidural analgesia (PCEA) (52% versus 31%).
Table 23.2
Systemic Opioids for Labor Analgesia
| Drug | Usual Dose (IV/IM) | Time to Peak Effect (IV/IM) | Duration of Action | Comments |
|---|---|---|---|---|
| Meperidine (Pethidine) |
|
|
2–3 h |
|
| Morphine |
|
|
3–4 h |
|
| Diamorphine |
|
|
90 min |
|
| Fentanyl | 25–50 µg IV | 2–4 min IV | 30–60 min |
|
| Nalbuphine |
|
|
3–6 h |
|
| Butorphanol |
|
|
4–6 h |
|
| Meptazinol | 50–100 mg IM | 30 min IM | 2–3 h |
|
| Pentazocine |
|
|
3–4 h |
|
| Tramadol |
|
10 min IM | 2–4 h |
|
IM , Intramuscular; IV , intravenous; PCA , patient-controlled analgesia; SC , subcutaneous.
Intermittent Bolus Parenteral Opioids
Opioids may be given intermittently by subcutaneous (SC), intramuscular (IM), or intravenous (IV) injection. The route and timing of administration influence maternal uptake and placental transfer to the fetus. The SC and IM routes have the advantage of ease of administration but are painful. Absorption varies with the site of injection and depends on local and regional blood flow; consequently, the onset, quality, and duration of analgesia are highly variable. IV administration is generally preferred when available, as it offers several advantages: the onset of analgesia is fast, the timing and magnitude of the peak plasma concentration of the drug are predictable, and titration to desired effect is possible.
Morphine
First isolated in 1806 and named after Morpheus , the Greek god of dreams, morphine was used only briefly for labor analgesia because of associated neonatal depression. In the early 1900s, morphine reappeared in combination with scopolamine (“twilight sleep”), but its use would often result in maternal sedation and neonatal depression.
With a high affinity for µ-opioid receptors, morphine is a potent long-acting analgesic. Morphine is principally metabolized by conjugation in the liver, with up to 70% transformed into largely inactive morphine-3-glucuronide. The remainder is transformed into the active metabolite morphine-6-glucuronide, an opioid agonist that is 13 times more potent than morphine. Both metabolites are excreted in the urine and have elimination half-lives of up to 4.5 hours in the presence of normal renal function. Morphine rapidly crosses the placenta, and a fetal-to-maternal blood concentration ratio of 0.96 is observed at 5 minutes. The elimination half-life of morphine is longer in neonates than in adults.
Morphine can be given every 4 hours IV (0.05 to 0.1 mg/kg) or IM (0.1 to 0.2 mg/kg), with a peak effect observed in 10 and 30 minutes, respectively. The duration of action when given IV or IM is 3 to 4 hours. As an intrapartum opioid analgesic, morphine is infrequently used owing to its long half-life and maternal side effects such as respiratory depression and histamine release, which may result in rash and pruritus. Like many opioids, morphine is emetogenic and is associated with sedation and dysphoria with increasing doses. Despite these limitations, IM morphine 10 to 15 mg is sometimes used in early labor, concomitantly with an antiemetic (e.g., IM dimenhydrinate 25 mg), to provide analgesia with sedation.
Olofsson et al. assessed the analgesic efficacy of IV morphine (0.05 mg/kg every third contraction, to a maximum dose of 0.2 mg/kg) and observed clinically insignificant reductions in labor pain intensity. The same investigators also compared IV morphine (up to 0.15 mg/kg) with IV meperidine (pethidine) (up to 1.5 mg/kg) and found that both groups had high pain scores despite high levels of maternal sedation. A randomized controlled trial that compared morphine 2 mg with IV acetaminophen (paracetamol) 1000 mg for early labor analgesia observed no differences in visual analog scale (VAS) pain scores at baseline and at 15 and 60 minutes. However, within 2 hours of administration, more patients receiving acetaminophen required rescue analgesia (52.9% versus 17.6%; P <.01).
Pregnancy alters the pharmacokinetics of morphine, with greater plasma clearance, shorter elimination half-life, and earlier peak metabolite levels. In theory, these characteristics should reduce fetal exposure. Possible neonatal respiratory depression has been attributed to an increased permeability of the neonatal brain. In a small study, Way et al. observed that IV morphine given to newborns appeared to cause greater respiratory depression than an equipotent dose of meperidine when response to carbon dioxide was measured. However, no cases of neonatal depression after morphine administration during labor were observed in one study.
Meperidine
In 1947 meperidine (pethidine) was the first synthetic opioid used for labor analgesia and quickly displaced morphine in the United Kingdom. An agonist that binds to both µ- and κ-opioid receptors, meperidine is estimated to have 10% of the analgesic potency of morphine. The usual dose is 50 to 100 mg IM, which can be repeated every 4 hours. The onset of analgesia occurs in 10 to 15 minutes, but 45 minutes may be required to reach peak effect. The duration of action is typically 2 to 3 hours.
Meperidine is highly lipid soluble, readily crosses the placenta, and equilibrates between the maternal and fetal compartments within 6 minutes. Meperidine is metabolized in the liver to normeperidine ( norpethidine ), a pharmacologically active metabolite that may cause prolonged neonatal side effects. The action of meperidine, but not normeperidine, is reversed by naloxone; consequently, antagonism with naloxone may exacerbate normeperidine-induced seizures owing to suppression of the anticonvulsant effect of meperidine.
Historically, meperidine was given to decrease the length of the first stage of labor in cases of dystocia. However, Sosa et al. reported that, compared with placebo, meperidine 100 mg given IV was associated with no differences in the duration of active labor or operative delivery rate, but greater requirement for oxytocin augmentation (relative risk [RR] 2.24, 95% confidence interval [CI], 1.13 to 4.43). Moreover, maternal administration of meperidine has been associated with increased umbilical cord arterial acidemia, altered neonatal behavior, and lower Apgar scores and neonatal muscle tone. Maternal side effects include a high incidence of nausea, vomiting, and dysphoria.
Elbohoty et al. reported that IV meperidine 50 mg produced labor analgesia that was comparable to that produced by IV acetaminophen 1000 mg but with a greater incidence of adverse effects (64% versus 0%). Zuarez-Easton et al. reported that labor pain intensity, side effects, and maternal satisfaction did not differ after IV meperidine 50 mg or inhaled nitrous oxide . A review of 62 randomized controlled trials from 1972 to 2018 found that meperidine had similar or inferior analgesic efficacy compared with other analgesics for acute postoperative or labor pain and was associated with more sedation and respiratory depression. Despite the availability of newer and more effective analgesics with fewer side effects, meperidine remains commonly administered for labor analgesia, most likely because of familiarity, ease of administration, availability, and low cost.
Diamorphine
Diamorphine (3,6-diacetylmorphine, heroin) is a synthetic derivative twice as potent as its parent morphine and used in some countries for labor analgesia. As a prodrug, diamorphine has no direct affinity for opioid receptors; however, when rapidly hydrolyzed by plasma esterases, the active metabolites provide faster analgesia onset with more euphoria and less nausea and vomiting than morphine. These pharmacokinetic properties may predispose to maternal, as well as neonatal, respiratory depression owing to rapid placental transfer.
In a two-center double-blind randomized controlled trial that compared IM diamorphine 7.5 mg with IM meperidine 150 mg for labor analgesia in 484 parturients, Wee et al. found that analgesia was modestly better but the mean length of labor was 82 (95% CI, 39 to 124) minutes longer with diamorphine. No differences in maternal sedation, nausea and vomiting, or primary neonatal outcomes were observed. In a single-center retrospective observational safety study, patients who chose PCA remifentanil, IM diamorphine, or epidural analgesia, experienced similar neonatal adverse events.
Despite the risk of maternal and neonatal respiratory depression, diamorphine is still used for labor analgesia in some developed countries with low epidural analgesia rates, such as the United Kingdom, but it is seldom used in the United States or Canada.
Nalbuphine
Nalbuphine is a mixed agonist-antagonist opioid analgesic with agonist activity at κ-opioid receptors, thereby producing analgesia, and partial agonist activity at µ-opioid receptors, thus resulting in less respiratory depression. A partial agonist is a drug that has receptor affinity but produces a submaximal effect compared with a full agonist, even when given at very high doses.
Nalbuphine can be administered by IM, IV, or SC injection, with a usual dose of 10 to 20 mg every 4 to 6 hours. The onset of analgesia occurs within 2 to 3 minutes of IV administration and within 15 minutes of IM or SC administration. The drug is metabolized in the liver to inactive compounds that are then secreted into bile and excreted in feces.
Nalbuphine and morphine are of equal analgesic potency and result in sedation and respiratory depression at similar doses. However, because of its mixed receptor affinity, nalbuphine demonstrates a ceiling effect for respiratory depression at a dose of 0.5 mg/kg. Nalbuphine causes less nausea, vomiting, and dysphoria than morphine.
Wilson et al. performed a randomized, double-blind comparison of IM nalbuphine 20 mg and meperidine 100 mg for labor analgesia. Nalbuphine was associated with less nausea and vomiting but more maternal sedation. Analgesia was comparable between the groups. Neonatal neurobehavioral scores were lower in the nalbuphine group at 2 to 4 hours, but there was no difference between groups at 24 hours. The mean umbilical vein-to-maternal vein concentration ratio was higher with nalbuphine (0.78) than with meperidine (0.61). A subsequent study failed to demonstrate an analgesic advantage with either drug but again reported transient neonatal neurologic depression with nalbuphine.
Nicolle et al., evaluating the transplacental transfer and neonatal pharmacokinetics of IM or IV nalbuphine in 28 laboring parturients, found a high umbilical vein-to-maternal vein concentration ratio of 0.74, which did not correlate with the administered dose. The estimated neonatal half-life was 4.1 hours, which is greater than the adult half-life and, more importantly, longer than the half-life of naloxone. There was a transient reduction in FHR variability in 54% of the fetuses, which was not associated with the plasma concentration of nalbuphine. Analgesia was rated as effective by only 54% of parturients.
Like morphine, nalbuphine is occasionally used for early labor analgesia; more commonly, its antagonistic properties are employed to treat pruritus from neuraxial or IV opioids.
Fentanyl
Fentanyl is a synthetic opioid that is highly lipid-soluble, protein-bound, and selective for the µ-opioid receptor, with an analgesic potency 100 times that of morphine. Its rapid onset (peak effect 2 to 4 minutes), short duration of action (30 to 60 minutes), and lack of active metabolites make it attractive for labor analgesia. Fentanyl is most commonly administered via PCA.
Small doses of fentanyl undergo rapid redistribution, but large or repeated doses may accumulate. Importantly, clearance of fentanyl by elimination represents only 20% of that occurring by redistribution, resulting in a rapid increase in context-sensitive half-time when using an infusion over 2 hours of duration. In contrast to morphine, fentanyl is metabolized to several inactive metabolites in the liver that are excreted in the urine. After 2 hours of infusion, it takes at least 50 minutes for plasma concentration to decrease by 50%. Thus, to avoid neonatal effects, in many labor analgesia studies fentanyl was stopped before the second stage of labor.
Fentanyl readily crosses the placenta; however, the average umbilical vein-to-maternal vein ratio remains low, most likely owing to a significant degree of maternal protein binding and drug redistribution. In a chronically instrumented sheep model, Craft et al. detected fentanyl in fetal plasma as early as 1 minute after maternal administration; however, maternal plasma levels were approximately 2.5 times greater than fetal plasma levels.
Rayburn et al. compared parturients receiving IV fentanyl (50 to 100 µg every hour at maternal request) with those who did not receive analgesia. All patients receiving fentanyl (mean dose 140 [range 50 to 600] µg) experienced brief analgesia (mean 45 minutes), sedation, and a transient reduction in FHR variability (mean 30 minutes). There were no differences between groups in neonatal Apgar scores, respiratory status, or Neurologic and Adaptive Capacity Scores (NACS). In a similar comparison of IV fentanyl (50 to 100 µg every hour) with an equianalgesic dose of meperidine (25 to 50 mg every 2 to 3 hours), Rayburn et al. observed less sedation, vomiting, and neonatal naloxone administration with fentanyl, but no difference in NACS. The two groups experienced similarly high pain scores, suggesting that both drugs have poor analgesic efficacy at the studied doses.
Fentanyl boluses administered during labor are most often used as a bridge to neuraxial analgesia or opioid PCA but can also be used for analgesia throughout labor. When fentanyl is used throughout labor, naloxone should be readily available for administration to the mother or neonate, and oxygen saturation monitoring for the neonate should be considered.
Other Opioids
Compared with meperidine, butorphanol , meptazinol , and pentazocine provide similar or less analgesia, with greater cost or side effects. Butorphanol does not confer additional analgesic benefit compared with meperidine. Meptazinol is costly, confers similar benefit to meperidine, is rarely used in the United Kingdom, and unavailable in the United States and Canada. Pentazocine provides similar analgesia to meperidine, but psychomimetic effects such as dysphoria and hallucinations complicate its use.
Tramadol , an atypical racemic mixture of two enantiomers, is a weak, synthetic drug that has affinity for all opioid receptors, but particularly the µ-opioid subtype. Administered orally, IM, or IV at a dose of 50 to 100 mg every 4 to 6 hours in adults, the analgesic potency of tramadol is equal to that of meperidine and one-fifth to one-tenth that of morphine. Tramadol and its active M1 metabolite O -desmethyltramadol readily cross the placenta, and an umbilical vein-to-maternal vein ratio of 0.94 has been observed at delivery. In a comparison of IM tramadol 100 mg and meperidine 100 mg for labor analgesia, Keskin et al. observed greater pain relief and a lower incidence of nausea and fatigue with meperidine. By contrast, Viegas et al. conducted a randomized, double-blind trial to compare IM administration of tramadol 50 mg, tramadol 100 mg, and meperidine 75 mg. Tramadol and meperidine provided similar labor analgesia; however, a higher incidence of maternal and neonatal adverse effects was observed with meperidine.
Codeine seldom has been studied for labor analgesia and produces limited analgesic benefit. Tramadol and codeine are not widely available in parenteral formulation. In addition, the US Federal Drug Administration issued a strong warning against the use of codeine and tramadol for lactating women because of the risk of serious adverse reactions (sedation, hypopnea or apnea, breastfeeding difficulties, and death) in breastfed infants born to mothers who are CYP2D6 ultrametabolizers.
Patient-Controlled Analgesia
First described in parturients with thrombocytopenia who were unable to receive neuraxial analgesia, the use of PCA has grown in availability and popularity. Suggested advantages of PCA include: (1) superior pain relief with lower doses of drug, (2) less risk for maternal respiratory depression compared with bolus IV administration, (3) less placental transfer of drug, (4) less need for antiemetic agents, and (5) greater patient satisfaction. For these reasons, PCA is a common method of labor analgesia when neuraxial analgesia is not available, contraindicated, or unsuccessful. The parturient can tailor the administration of analgesia according to individual needs; furthermore, with some regimens, the bolus dose can be titrated as labor progresses. The smaller, more frequent dosing of PCA may result in a more stable plasma drug concentration and thus a more consistent analgesic effect compared with that of intermittent bolus administration regimens.
However, PCA for labor analgesia is not without limitations. Despite the frequency of dose administration, the coordination of peak opioid concentrations with uterine contractions can be difficult and may result in suboptimal analgesia. In addition, the relatively small doses of opioid may be less effective at controlling pain as labor progresses. A variety of drugs, doses, and regimens for PCA have been studied, including comparisons with and without a continuous IV infusion ( Table 23.3 ). The safest and most effective opioids used for PCA for labor analgesia are fentanyl and remifentanil . Rarely administered by PCA for labor analgesia in parturients with a live fetus, morphine , diamorphine , and meperidine are options for those with intrauterine fetal demise.
Table 23.3
Opioids Used for Intravenous Patient-Controlled Analgesia in Labor
| Drug | Bolus Dose | Lockout Interval (min) |
|---|---|---|
| Fentanyl | 10–25 µg | 5–12 |
| Remifentanil (bolusonly) | 0.2–0.5 µg/kg (low dose initially, then titrated to effect) | 2–3 |
| Remifentanil (background infusion with bolusdose) |
|
2–3 |
Fentanyl
The pharmacologic profile of fentanyl (e.g., rapid onset, high potency, short duration of action, absence of active metabolites) has resulted in its selection as one of the most commonly used opioids for PCA during labor and delivery since the early 1990s.
Rayburn et al. compared fentanyl PCA (bolus 10 µg, lockout interval 12 minutes) with intermittent IV nurse-administered boluses (50 to 100 µg every hour, on demand). The degree of analgesia, adverse maternal effects, and neonatal outcomes (e.g., Apgar scores, naloxone requirement, neurobehavioral scores) were similar between the two groups. The two groups used a similar total amount of fentanyl, had comparable umbilical serum concentrations of fentanyl, and had incomplete analgesia during late labor.
Nikkola et al. observed that fentanyl PCA (loading dose 50 µg, bolus 20 µg, lockout interval 5 minutes) provided a moderate reduction in labor pain in 50% of parturients; however, less overall pain relief was experienced compared with parturients who received epidural analgesia. The use of fentanyl was also associated with a higher incidence of maternal dizziness and sedation.
Morley-Forster and Weberpals observed a 44% incidence of moderate neonatal depression (1-minute Apgar score < 6) in a retrospective review of 32 neonates whose mothers had received fentanyl PCA using various regimens during labor. A total of 9.4% of the neonates required naloxone; the total dose of fentanyl was higher in the mothers of neonates who required naloxone than in those who did not (mean 770 [SD 233] µg versus 298 [287] µg, respectively). By contrast, in a retrospective evaluation of fentanyl PCA (loading dose 50 µg, bolus 20 µg, lockout interval 5 minutes) compared with no analgesia during labor, Miyakoshi et al. observed comparable Apgar scores, similar mean umbilical arterial blood pH measurements, and no requirement for naloxone in 258 neonates exposed to fentanyl PCA. Maternal pain scores with PCA fentanyl were decreased significantly from baseline for the first 3 hours after initiation, with 6.2% experiencing nausea, but none exhibiting maternal respiratory depression or excessive sedation.
Halpern et al. randomized 242 laboring patients to receive either PCA fentanyl (loading dose 100 µg plus additional doses of 50 µg until adequate pain relief, bolus 25 to 50 µg, lockout interval 10 minutes) or epidural analgesia. There were no differences in rates of cesarean delivery or instrumentation, however, the PCA fentanyl group had greater use of antiemetics (17% versus 6.4%; P =.01); experienced more sedation (39% versus 5%; P <.001); and had more pain, lower maternal satisfaction, and more neonates requiring active resuscitation (52% versus 31%; P =.001) and naloxone (17% versus 3%; P <.001). Some 33% of the parturients in the PCA fentanyl group requested epidural analgesia.
Remifentanil
Remifentanil is an ultra-short-acting, synthetic anilinopiperidine derivative with selective activity at the µ-opioid receptor, and a small volume of distribution (0.39 L/kg). Functional brain magnetic resonance imaging revealed an onset time of 20 to 30 seconds, peak concentration within 80 to 90 seconds at the cortical loci, and a blood-brain equilibration time of 1.2 to 1.4 minutes. Remifentanil undergoes rapid hydrolysis by nonspecific plasma and tissue esterases to inactive metabolites, independent of organ metabolism, resulting in a short elimination half-life of approximately 9.5 minutes. The context-sensitive half-time is 3.5 minutes, irrespective of the duration of infusion. The effective analgesic half-life is 6 minutes, thus allowing effective analgesia for consecutive uterine contractions. Plasma concentrations of remifentanil in pregnant patients are approximately half those found in nonpregnant patients. This difference may be caused by the greater volume of distribution (increased blood volume and reduced protein binding), greater clearance (increased cardiac output and renal perfusion), and higher esterase activity during pregnancy.
Remifentanil is rapidly titratable, allowing for dose adjustments with labor progress or in response to side effects. Termination of a continuous remifentanil infusion results in a 50% recovery in minute ventilation within 5.4 minutes. Although remifentanil readily crosses the placenta, resulting in a fetal-to-maternal blood ratio of 0.88, the lower umbilical artery-to-vein concentration ratio of 0.29 demonstrates that the drug is extensively redistributed and/or metabolized by the fetus. Kan et al. also found no adverse neonatal effects after a remifentanil infusion during cesarean delivery.
With ultrarapid pharmacokinetics, remifentanil does not accumulate with time and can be used during the second stage of labor with less concern for neonatal side effects. However, the rapid onset and offset of remifentanil, with peak effect-site concentrations at 1 to 2 minutes, may not provide adequate or sustained analgesia for the desired or subsequent uterine contraction, respectively. Thus, the use of PCA remifentanil requires training of patients to appropriately time the bolus dose with contractions.
Efficacy and Optimal Regimen.
Owing to its ultra-short action, delivery of remifentanil is limited to PCA bolus, a continuous infusion, or a combination of the two. Although a number of studies have compared remifentanil with other opioids using fixed, nontitratable PCA doses, Volmanen et al. attempted to determine the minimum effective dose of remifentanil for labor analgesia during the first stage of labor. Using an initial bolus dose of 0.2 µg/kg, and dose increases of 0.2 µg/kg (lockout interval 1 minute) over a 1-hour study period, the median effective bolus dose was observed to be 0.4 µg/kg (range 0.2 to 0.8 µg/kg). However, frequent episodes of maternal oxygen saturation < 94% (10 of 17 subjects), maternal sedation, and reduced FHR variability were observed.
Balki et al. compared the effect of a fixed remifentanil bolus dose with a titratable background infusion versus a fixed background infusion with a titratable bolus dose. Both groups started with a remifentanil bolus dose of 0.25 µg/kg (lockout interval 2 minutes) and a background infusion rate of 0.025 µg/kg/min. If analgesia was inadequate, either the background infusion or bolus dose was increased in a stepwise manner to a maximum of 0.1 µg/kg/min or 1 µg/kg, respectively. The mean pain scores, satisfaction scores, and cumulative remifentanil doses were similar in the two groups; only one patient eventually requested epidural analgesia. The incidence of maternal side effects was higher in the escalating bolus dose group, including drowsiness (100% versus 30%) and frequency of oxygen saturation < 95% (60% versus 40%). There was no difference in the incidence of adverse neonatal effects. The investigators advocated the use of a titrated background infusion (range, 0.025 to 0.1 µg/kg/min) with a constant PCA bolus dose (0.25 µg/kg, lockout interval 2 minutes).
D’Onofrio et al. conducted an observational study of 205 parturients in whom a continuous infusion of remifentanil was titrated (initial to maximum dose range, 0.025 to 0.15 µg/kg/min) with a goal of achieving pain scores ≤ 4/10 during contractions. Adequate analgesia was achieved within 30 minutes but required a median remifentanil infusion dose of 0.075 µg/kg/min. The oxygen saturation remained greater than 95% in all patients without supplemental oxygen, and there were no reported neonatal side effects.
Together, these studies suggest that fixed-dose remifentanil PCA protocols are less effective than titratable regimens, with the potential for low doses resulting in poor analgesia, underdosing, and maternal dissatisfaction, and high doses resulting in adverse effects such as maternal sedation, respiratory depression, and oxygen desaturation. Evidence is conflicting as to whether the use of a background infusion confers additional benefits, particularly given the greater risk for maternal sedation and respiratory depression.
Rehberg et al. sought to improve labor analgesia and reduce side effects by altering the timing of the remifentanil PCA bolus. A handheld dynamometer was used to determine the peak effect of the next contraction; however, because of contraction variability, analgesia was not substantially improved. The analgesic benefit of remifentanil may be best optimized by instructing parturients to press the PCA button at the first perception of a contraction, given that the peak analgesic effect occurs within 1 to 3 minutes.
Leong et al. devised an automated closed interactive feedback system (“step-up–step-down” regimen) with the input of continuous monitoring devices (pulse oximeter and heart rate) to modulate drug delivery and improve labor analgesia and safety. The vital sign–controlled, patient-assisted IV analgesia prototype initially administered small boluses of remifentanil, with dosing alterations based on the presence or absence of patient demands over a predefined period. In the 29 parturients who used the device, despite all using supplemental oxygen, 52% experienced oxygen desaturation < 95% for more than 60 seconds, and 24% experienced a heart rate < 60 beats/min for more than 60 seconds. The median dose of remifentanil was 0.07 µg/kg/min, and the system automatically reduced dosages and temporarily halted remifentanil administration when desaturation and bradycardia thresholds were achieved. Additional analgesia, including nitrous oxide or an epidural technique, was required by 31% of parturients.
Side effects.
Remifentanil can cause respiratory depression through reductions in the ventilatory rate and tidal volume. Although the safety profile of remifentanil PCA in labor has been specifically evaluated, the data are conflicting. Volikas et al. investigated the maternal and neonatal effects of remifentanil PCA (bolus dose 0.5 µg/kg, lockout interval 2 minutes) in 50 parturients. Effective analgesia was reported in 86% of study participants, and 44% experienced slight drowsiness (but were rousable to voice and maintained oxygen saturation > 93%). Mild itching and FHR changes occurred in the first 20 minutes of remifentanil PCA but did not require treatment. Umbilical cord blood gas measurements and neonatal Apgar scores and neurologic examinations were all within normal limits.
A survey of 61 Dutch hospitals reviewed 27 maternal and 2 neonatal serious adverse events related to remifentanil PCA. The majority of maternal serious adverse events were oxygen desaturation (23 cases), followed by apnea (6 cases), bradycardia (4 cases), and 1 maternal cardiac arrest; the 2 neonatal adverse events were respiratory depression. In five cases of maternal apnea, a background infusion was used in addition to PCA boluses.
With the use of oxygen saturation and end-tidal CO 2 monitoring, Stocki et al. reported a moderate number of apneic events (respiratory arrest greater than 20 seconds), low respiratory rates, and hypoxemic events in laboring parturients who received remifentanil PCA, compared with none in those who received epidural analgesia. These findings suggest that the analgesia onset from a bolus dose of remifentanil may occur after the cessation of uterine contractions (which have an average duration of 60 to 70 seconds). Although Thurlow et al. encouraged parturients to activate a bolus dose at the very first detection of a contraction, or even between contractions, Volmanen et al. indicated that the onset of electroencephalographic depression and subsequent onset of peak respiratory depression does not happen until approximately 2.5 minutes after bolus injection. Consequently, bolus administration can frequently miss the uterine contraction.
Weiniger et al. evaluated candidate variables (i.e., respiratory rate, end-tidal CO 2 , pulse oximetry, heart rate, and integrated pulmonary index) to serve as early warning apnea alerts (defined as any variable value below a prespecified threshold for 15 seconds). A total of 331 immediate early warning alerts and 62 episodes of apnea (defined as maximal CO 2 < 5 mm Hg for at least 30 consecutive seconds) occurred among 10 of 19 patients (56.2%) who received remifentanil PCA. Alerts for end-tidal CO 2 , respiratory rate, and integrated pulmonary index detected most episodes of apnea, pulse oximetry alerts missed the majority of apneic episodes, and all variables had a low positive predictive rate, indicating the limitations of respiratory monitors for early warning apnea surveillance in this setting.
The use of remifentanil PCA during labor results in a variable range in the incidences of maternal sedation, dizziness, nausea, vomiting, and pruritus. The wide incidence of nausea (0% to 60%) may reflect an opioid-induced increase in vagal activity, which can decrease mean arterial pressure and heart rate; however, this has not been reported in laboring patients receiving remifentanil PCA, perhaps reflecting the doses administered and/or the high maternal sympathetic activity during labor. Pruritus occurs in approximately 16% of parturients. In 140 parturients randomly assigned to either remifentanil PCA or epidural analgesia, Douma et al. observed fever (temperature > 38°C) in 10% of remifentanil PCA patients compared with 37% in epidural analgesia patients.
Opioid-induced loss of FHR variability, a potential indicator of fetal compromise, may create diagnostic confusion in a labor setting. Comparison studies have reported a lower incidence of FHR abnormalities with remifentanil than with meperidine. However, similar to other opioids, available data suggest that remifentanil might induce fetal and neonatal acidosis.
Many studies have suggested that continuous patient monitoring is required with remifentanil use during labor. Van de Velde and Carvalho suggested that monitoring for respiratory depression should ideally evaluate respiratory rate and sedation (one-to-one nursing or midwifery care), determine the adequacy of ventilation (capnography, apnea monitor), and evaluate oxygenation (pulse oximetry). Routine use of supplemental oxygen may increase the duration of apnea and reduce the sensitivity of pulse oximetry for detecting hypoventilation. A method for assisting ventilation (e.g., a self-inflating ventilating bag) should be immediately available.
The RemiPCA SAFE Network ( https://www.remipca.org/php/en/index.php ), which currently over 40 international hospital centers, was established to create international standards and monitor maternal and neonatal outcomes associated with the use of remifentanil PCA for labor. Melber et al. published findings from the self-reported RemiPCA network database from 2010 to 2015, which included 5740 pregnant patients; the most frequent maternal side effects were hypoxemia (Sp o 2 < 94%) (27%), sedation (26%), nausea/vomiting (17%), and pruritus (3%). Although no parturients required assisted ventilation or cardiopulmonary resuscitation, neonatal oxygen supplementation was required in 7% of neonates, and cardiopulmonary resuscitation potentially related to remifentanil was required in 0.3% of neonates. Of interest, no complications were reported in centers that used remifentanil PCA at least 10 times per year, suggesting the value of familiarity with use. To decrease maternal adverse events, three operational changes were adopted by the RemiPCA network in 2013: (1) use of a 4-hour minimum time interval between the administration of long-acting opioids and the initiation of remifentanil PCA, (2) reduction of the bolus dose maximum to 30 µg (ideal range 10 to 30 µg), and (3) use of a supplemental oxygen administration threshold of Sp o 2 < 94%.
To date, the studies of remifentanil administration for labor analgesia have included only healthy parturients with low-risk singleton pregnancies. Given the significant risk for maternal and neonatal sedation, respiratory depression, and oxygen desaturation with remifentanil PCA, the use of continuous pulse oximetry and continuous (or near continuous) one-to-one nursing care is critical for its safe use. An anesthesia provider should be notified if excess sedation, respiratory rate < 8 breaths/min, and/or oxygen saturation < 94%, despite supplemental oxygen, occurs.
Comparison with other forms of labor analgesia.
The efficacy of remifentanil PCA has been compared with that of other labor analgesic agents and regimens ( Table 23.4 ).
Table 23.4
Trials Comparing Remifentanil Patient-Controlled Analgesia With Alternative Labor Analgesia With Analgesia as a Primary Outcome
| Reference | Number of Subjects | Study Design | Groups; Drugs; Doses | Primary Data | Comments |
|---|---|---|---|---|---|
| Volikas and Male 2001 | 17 | Double-blinded, randomized |
|
|
|
| Thurlow et al. 2002 | 36 | Unblinded, randomized |
|
|
|
| Blair et al. 2005 | 39 | Double-blinded, randomized |
|
|
Similar VAPS in labor and overall between groups (overall pain score 63.6 mm with remifentanil versus 68.6 mm with meperidine) ( P = NS) |
| Evron et al. 2005 | 88 | Double-blinded, randomized |
|
|
|
| Douma et al. 2010 | 159 | Double-blinded, randomized |
|
VAPS hourly |
|
| Ng et al. 2011 | 68 | Double-blind, randomized |
|
VAPS hourly |
|
| Marwah et al. 2012 | 98 | Retrospective cohort |
|
Hourly verbal pain score scale 0–10 |
|
| Wilson et al. 2018 | 401 | Open-label multicenter randomized controlled trial |
|
Request for epidural analgesia | 41% requested epidural analgesia with meperidine versus 19% with remifentanil (RR, 0.48; 95% CI, 0.34 to 0.66; P <.0001) |
| Volmanen et al. 2005 | 15 | Double-blind, randomized, crossover |
|
Pain intensity difference (PID=mean pain score without analgesia minus mean pain score with analgesia) | Higher PID with remifentanil (1.5 versus 0.5, P =.01) |
| Volmanen et al. 2008 | 45 | Double-blind, randomized |
|
Pain after each contraction (0–10) | Higher median pain scores with remifentanil (7.3 versus 5.2, P =.009) |
| Douma et al. 2011 | 20 | Randomized unblinded controlled |
|
VAPS hourly | Greater decrease in pain scores with epidural atall time intervals ( n = 6 per group analyzed) |
| Stocki et al. 2014 | 39 | Randomized unblinded controlled noninferiority study |
|
Mean NRS pain scores assessed hourly | Mean NRS reduction at 30 min with remifentanil 4.5 versus 7.1 with PCEA, pain score at 30 min 3.7 with remifentanil versus 1.5 with PCEA |
| Freeman et al. 2015 | 1414 | Multicenter randomized controlled equivalence trial |
|
Hourly satisfaction scores for pain relief | Area under the curve for satisfaction scores lower with remifentanil |
| Tveit et al. 2012 | 37 | Unblinded, randomized |
|
VAPS every 15 min |
|
CI , Confidence interval; IM , intramuscular; NRS , numeric rating scale; NS , nonsignificant; PCA , patient-controlled analgesia; PCEA , patient-controlled epidural analgesia; RR , relative risk; VAPS , visual analog pain score.
Remifentanil versus fentanyl.
Douma et al. compared remifentanil PCA (loading dose 40 µg, bolus 40 µg, lockout interval 2 minutes), fentanyl PCA (loading dose 50 µg, bolus 20 µg, lockout interval 5 minutes), and meperidine PCA (loading dose 49.5 mg, bolus 5 mg, lockout interval 10 minutes) in 159 laboring patients. The decrease in pain scores was mild to moderate and similar in all groups, except after 1 hour of initiation, when the remifentanil group had better analgesia. Patients receiving meperidine had the highest crossover rate to epidural analgesia. Remifentanil PCA had greater sedation and pruritus than the other two groups. Compared with PCA meperidine, PCA remifentanil had more oxygen desaturation, but greater overall satisfaction. Neonatal outcomes were similar in all groups.
In a retrospective observation study, Marwah et al. compared 98 laboring parturients who had received PCA fentanyl (bolus 25 to 50 µg, lockout interval 3 to 6 minutes) or PCA remifentanil (bolus 0.25 µg/kg, lockout interval 2 minutes, infusion 0.025 to 0.05 µg/kg/min). Decreases in pain scores were similar and moderate in both groups. Maternal sedation and desaturation were higher in the PCA remifentanil group, while the PCA fentanyl group had greater need for neonatal resuscitation (excluding confounders, 44% versus 8%; OR, 8.56; 95% CI, 2.17 to 33.77), and a greater percentage of neonates with 1-minute Apgar score < 7 (39% versus 18%; OR 2.83; 95% CI, 1.07 to 7.53). No neonate required naloxone and the umbilical cord gas measurements were similar between groups and within normal range.
Overall, remifentanil PCA offers similar or marginally better analgesia and satisfaction than fentanyl PCA, with significantly more maternal side effects of sedation, respiratory depression, and hypoxemia. Conversely, fentanyl PCA accumulates with repeated doses, especially after 2 hours duration, and pharmacodynamically mimics an infusion. The advantage of such an accumulation diminishes the need to time the PCA bolus with contractions compared with remifentanil PCA. However, fentanyl accumulation has been shown to impact neonatal outcomes with an increased need for neonatal resuscitation and decreased Apgar scores at 1 minute. Thus, the choice of opioid PCA for each healthcare center should consider available labor resources for maternal monitoring and patient education, proximity of anesthesia providers to the labor and delivery ward, and in-house availability of specialized neonatal healthcare personnel, such as pediatricians.
Remifentanil versus meperidine.
Thurlow et al. conducted a randomized unblinded study in 36 patients that compared remifentanil PCA (bolus 20 µg, lockout interval 3 minutes) with IM meperidine 100 mg. The remifentanil group had lower pain scores (median maximum pain score 66/100 mm versus 82/100 mm, P =.009) within the first 2 hours of commencing analgesia. However, parturients in the remifentanil group also used nitrous oxide analgesia (56%) and experienced more sedation and episodes of oxygen saturation < 94%. No difference in Apgar scores was found.
Ng et al. conducted a randomized, double-blind study in which 69 patients used a PCA device containing either remifentanil (PCA group) or 0.9% saline (meperidine group), and also received an IM injection of either saline (PCA group) or meperidine (meperidine group). The doses administered depended on patient weight; parturients < 60 or ≥ 60 kg were given a bolus dose of remifentanil of 25 or 30 µg, respectively. Similarly, the dose of meperidine was either 50 or 75 mg. The PCA lockout interval was 3.75 to 4.5 minutes with no background infusion. Maternal analgesia was greater (particularly in the first 2 hours after initiation), the median time to first rescue analgesic request was longer (8.0 versus 4.9 hours), and maternal satisfaction scores were higher in the remifentanil PCA group compared with the meperidine group. There was no difference between groups in maternal sedation, nausea, oxygen saturation, and neonatal outcomes.
Blair et al. observed that the use of remifentanil PCA (bolus 40 µg, lockout interval 2 minutes) resulted in higher maternal satisfaction scores and modest analgesic benefit compared with meperidine PCA (bolus 15 mg, lockout interval 10 minutes).
In a systematic review of seven randomized controlled trials ( n = 349), Leong et al. evaluated the administration of remifentanil versus meperidine via a variety of drug delivery methods (e.g., PCA, continuous infusion, IM) for labor analgesia. The use of remifentanil reduced mean VAS pain scores by 25 mm more than meperidine in the first hour, and was associated with a conversion rate to epidural analgesia of less than 10%. Similarly, Schnabel et al., in a metaanalysis comparing PCA remifentanil, PCA meperidine, and epidural analgesia, reported that parturients who received remifentanil PCA had lower mean pain scores after 1 hour, a lower crossover rate to epidural analgesia, and higher satisfaction scores than those who received meperidine.
In the 2018 RESPITE study comparing IM meperidine with PCA remifentanil in 400 laboring parturients, 41% and 19% of parturients in the meperidine and remifentanil groups, respectively, requested epidural analgesia (RR 0.48; 95% CI, 0.34 to 0.66; P <.0001). Parturients in the remifentanil group also had fewer operative vaginal deliveries, lower pain scores, and higher satisfaction compared with those in the meperidine group. A subsequent qualitative exploration study by the same authors interviewed 49 patients from the original RESPITE study. Those who received PCA remifentanil reported feeling more effective analgesia, alert, and in control during their birth experience compared with the meperidine group. Side effects including nausea and cognitive effects were present in both groups. Overall, compared with meperidine, PCA remifentanil has been shown to provide better analgesia, less conversion to epidural analgesia, and higher maternal satisfaction.
Remifentanil versus nitrous oxide.
Volmanen et al. performed a double-blind crossover trial that compared remifentanil (bolus 0.4 µg/kg, lockout interval 1 minute) with 50% nitrous oxide during the first stage of labor. The 20 patients used both analgesics in a random order for 20 minutes, with an intervening washout period of 20 minutes. Pain relief (although modest), maternal sedation, and patient satisfaction were greater in the remifentanil group. No difference in the incidence of FHR changes was observed between the two groups.
Remifentanil versus epidural analgesia.
A large metaanalysis found that PCA fentanyl and remifentanil provided inferior labor analgesia at 30, 60, 120, and 180 minutes, and greater sedation, nausea, and vomiting compared with various epidural techniques; the analgesia curves further diverged as labor progressed. A Cochrane review concluded that PCA remifentanil compared with epidural analgesia was associated with less maternal satisfaction (seven trials) and higher pain intensity (four trials) and no differences in delivery mode (nine trials) or assisted birth (eight trials). Two additional metaanalyses concluded that PCA remifentanil provides inferior labor analgesia (mean difference in effect size 3.0 cm/10 cm [95% CI, 0.7 to 5.2] at 2 hours) and satisfaction compared with epidural analgesia.
In a randomized, double-blind trial, Volmanen et al. compared PCA remifentanil (mean effective bolus 0.5 [range 0.3 to 0.7] µg/kg, lockout interval 1 minute) with lumbar epidural analgesia (20-mL levobupivacaine 0.0625% with fentanyl 2 µg/mL). All patients received an epidural technique and PCA remifentanil or saline. Parturients receiving epidural analgesia had a more significant and rapid reduction in pain scores than those receiving remifentanil (10 versus 40 minutes to reach the individual effective dose), but median “pain relief” scores were similar between the two groups. The investigators postulated that high maternal satisfaction with PCA remifentanil may be the result of factors other than the degree of analgesia produced.
Stocki et al. conducted an unblinded controlled noninferiority study in 39 healthy parturients randomized to receive PCA remifentanil (titrated from 20 to 60 µg, lockout interval 1 to 2 minutes), or PCEA (0.1% bupivacaine with 2 µg/mL fentanyl). Analgesia with remifentanil was inferior to the epidural technique at all time points, but maternal satisfaction was similar. All apnea events occurred in the patients receiving remifentanil, who also had lower mean respiratory rates and oxygen saturation. In a multicenter trial of 1414 parturients randomized to receive PCA remifentanil or epidural analgesia, Freeman et al. found higher satisfaction and analgesia in parturients who received epidural analgesia.
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