Bupivacaine.

Traditionally, the amide local anesthetic bupivacaine has been the most commonly used agent for epidural labor analgesia. Bupivacaine is highly protein-bound, a feature that limits transplacental transfer. The umbilical vein–to–maternal vein concentration ratio is approximately 0.3. After epidural administration of bupivacaine (without opioid) during labor, the patient first perceives pain relief within 8 to 10 minutes, but approximately 20 minutes are required to achieve the peak effect. Duration of analgesia is approximately 90 minutes. Bupivacaine 6.25 to 12.5 mg (e.g., 10 to 20 mL of a 0.0625% solution, or 5 to 10 mL of a 0.125% solution) combined with fentanyl or sufentanil is adequate to initiate labor analgesia in most parturients ( Table 23.2 ).

The potency of local anesthetics for neuraxial labor analgesia is often assessed by determining the median effective concentration of local anesthetic solution when administered as a 20-mL epidural bolus (this concentration is sometimes referred to as the minimum local anesthetic concentration [MLAC]). It is lower for women in early labor than in late labor, and it is also lower when the local anesthetic is combined with a lipid-soluble opioid.

It is important to consider both the local anesthetic dose and concentration for initiation and maintenance of epidural analgesia. Christiaens et al. randomly assigned parturients to receive epidural bupivacaine 20 mg diluted in 4 mL, 10 mL, or 20 mL (0.5%, 0.2%, and 0.1% solutions, respectively). Analgesia in the 10-mL and 20-mL groups was superior to that in the 4-mL group, and duration of analgesia was longest in the 20-mL group. Lyons et al. compared the minimum local anesthetic volume (MLAV) and minimum local anesthetic dose (MLAD) for 0.125% and 0.25% bupivacaine for epidural labor analgesia. Bupivacaine 0.125% produced analgesia equivalent to that provided by bupivacaine 0.25%, with a 50% increase in required volume and a 25% reduction in dose ( Table 23.3 ). Stated differently, a dose-sparing effect is achieved by administering a 0.125% solution of bupivacaine rather than a 0.25% solution. Ginosar et al. randomized parturients to receive maintenance of analgesia with an epidural infusion of either bupivacaine 0.25% at 5 mL/h or bupivacaine 0.0625% at 20 mL/h (10 mg/h in both groups). The median bupivacaine dose was lower and patient satisfaction was greater with bupivacaine 0.0625% than with bupivacaine 0.25%. Together, these data suggest that epidural analgesia and safety are improved with the use of low concentration–high volume local anesthetic solutions.

Ropivacaine.

Ropivacaine, a relatively newer amide local anesthetic, is similar to bupivacaine in structure and pharmacodynamics (see Chapter 13 ). It is a homologue of bupivacaine and mepivacaine, but unlike these other local anesthetics it is formulated as a single-levorotary enantiomer rather than a racemic mixture. Studies of pregnant sheep have demonstrated that clinically relevant plasma concentrations of ropivacaine do not adversely affect uterine blood flow.

Studies in vitro and in vivo have shown that ropivacaine is less cardiodepressant and arrhythmogenic than bupivacaine when doses of equal mass are compared. Ropivacaine is cleared more rapidly than bupivacaine after intravenous administration in both pregnant and nonpregnant sheep. Consequently, a larger dose of drug—but not a higher plasma concentration—is required to produce systemic toxicity. These findings suggest that ropivacaine may have a greater margin of safety than bupivacaine if unintentional intravenous injection occurs in pregnant women. However, many early investigations assumed that ropivacaine and bupivacaine are equipotent; subsequent studies have demonstrated that ropivacaine is 25% to 40% less potent than bupivacaine. In one study that characterized the full dose-response curves, the slope of the bupivacaine and ropivacaine curves were similar, suggesting that the nature of the drug-receptor interaction is not different between the two drugs. When ropivacaine concentrations are adjusted for this difference in potency, there is a less clear advantage for ropivacaine in terms of the risk for systemic toxicity. In reality, systemic toxicity is not a major concern with the contemporary administration of a dilute solution of local anesthetic for epidural labor analgesia.

Several studies that compared equal concentrations of ropivacaine and bupivacaine given by patient-controlled epidural analgesia (PCEA) have not found any significant difference in clinical efficacy between the two local anesthetics. Other studies that adjusted for the potency difference and compared equipotent concentrations (e.g., 0.0625% bupivacaine versus 0.1% ropivacaine) also found no difference in clinical efficacy. It is important to recognize that potency is an unchanging property of a drug, whereas clinical efficacy is influenced by multiple variables. For example, ropivacaine has a longer duration of analgesia than bupivacaine, which may offset its lesser potency when it is administered by continuous epidural infusion.

Early clinical studies suggested that ropivacaine is associated with less motor block than bupivacaine ; avoidance of motor blockade is a desirable characteristic of neuraxial analgesia during labor. However, these studies also compared equal concentrations of ropivacaine and bupivacaine, and the observed lower degree of motor blockade may reflect the lesser potency of ropivacaine. A study of the relative motor-blocking potencies of epidural ropivacaine and bupivacaine showed that ropivacaine was less potent than bupivacaine in terms of motor blockade, a finding that corresponded to the relative analgesic potencies of the two drugs. The differences in potency of motor blockade may not be relevant with the use of low concentrations of local anesthetic. Several clinical studies and a well-conducted meta-analysis of studies that compared epidural ropivacaine and bupivacaine did not demonstrate an advantage for ropivacaine in terms of outcome of labor (see later discussion), although the incidence of motor blockade was less in the ropivacaine groups.

There is no clear evidence of greater patient safety, lower risk for instrumental vaginal delivery, or other improved outcomes when ropivacaine is used to provide epidural labor analgesia. A 2010 review concluded that there is no advantage to the routine use of ropivacaine compared with bupivacaine for labor analgesia. In contrast, ropivacaine offers greater patient safety in settings in which high concentrations and greater volumes of drugs are administered (e.g., brachial plexus blockade or epidural anesthesia for cesarean delivery).

Like bupivacaine, ropivacaine is often combined with fentanyl or sufentanil for labor analgesia. Ropivacaine concentrations used to initiate epidural analgesia range from 0.08% to 0.2% (see Table 23.2 ). Higher concentrations are used if the drug is administered without an opioid.

Levobupivacaine.

Levobupivacaine is the levorotary enantiomer of bupivacaine (which is a racemic mixture). It is not available in the United States. Both preclinical and clinical studies have suggested that, like ropivacaine, levobupivacaine has less potential for cardiotoxicity than bupivacaine when equal doses of the two drugs are compared. One study found that levobupivacaine was essentially equipotent to bupivacaine with a potency ratio of 0.98; however, the 95% CI was wide (0.67 to 1.41). Other studies have suggested that levobupivacaine and ropivacaine have similar potency. In an MLAC study that compared the motor blocking potency of bupivacaine and levobupivacaine, levobupivacaine was less potent than bupivacaine (potency ratio, 0.87; 95% CI, 0.77 to 0.98). Beilin et al. compared epidural bupivacaine, ropivacaine, and levobupivacaine (0.0625% with fentanyl 2 µg/mL *

* The Institute of Safe Medicine Practices (ISMP) has recommended that health care providers never use µg as an abbreviation for micrograms, but rather they should use mcg ( http://www.ismp.org/tools/errorproneabbreviations.pdf , accessed October 2017). The use of the symbol µg is frequently misinterpreted and involved in harmful medication errors. The abbreviation may be mistaken for mg (milligrams), which would result in a 1000-fold overdose. The symbol µg should never be used when communicating medical information, including pharmacy and prescriber computer order entry screens, computer-generated labels, labels for drug storage bins, and medication administration records. However, most scholarly publications have continued to use the abbreviation µg. The editors have chosen to retain the use of the abbreviation µg throughout this text. However, the editors recommend the use of the abbreviation mcg in clinical practice.

Lidocaine.

Lidocaine is an amide local anesthetic with a duration of action intermediate between those of bupivacaine and 2-chloroprocaine. During labor, the administration of a 0.75% to 1.0% solution of lidocaine typically provides satisfactory analgesia. However, lidocaine is not commonly used for initiation or maintenance of epidural labor analgesia, in part because of its shorter duration of action in comparison with bupivacaine, ropivacaine, and levobupivacaine. Lidocaine is less protein-bound than these other amide local anesthetics, and at delivery, the umbilical vein–to–maternal vein lidocaine concentration ratio is approximately twice that of bupivacaine. Early studies discouraged the epidural administration of lidocaine in pregnant women because epidural lidocaine was associated with abnormal neonatal neurobehavioral findings. Subsequently, larger, more carefully controlled studies have demonstrated that the epidural administration of lidocaine, bupivacaine, and 2-chloroprocaine have similar neonatal outcomes. Although some investigators have observed subtle differences in neurobehavior between infants exposed to lidocaine and those exposed to other local anesthetics, these differences are within the inherent variability of the examinations and are not clinically significant. Other factors (e.g., mode of delivery) appear to be much more important determinants of neonatal condition.

2- Chloroprocaine.

An ester local anesthetic, 2-chloroprocaine has a rapid onset of action. Epidural administration of 10 mL of 2% 2-chloroprocaine provides effective analgesia for approximately 40 minutes. The short duration of action limits its usefulness during labor. In addition, the epidural administration of 2-chloroprocaine may adversely affect the efficacy of subsequently administered epidural bupivacaine and opioids, although it is unclear whether the mechanism is related to pharmacokinetic or pharmacodynamic properties of the drug. In obstetric practice, 2-chloroprocaine is most commonly used for extension of epidural labor analgesia for instrumental vaginal delivery (see later discussion) or emergency cesarean delivery (see Chapter 26 ).

Lipid-soluble opioids: fentanyl and sufentanil.

Morphine was one of the first opioids to be studied for labor analgesia. However, because of its long latency, side effects, and inconsistent analgesia, morphine has largely been replaced by the lipid-soluble opioids fentanyl and sufentanil (see Chapter 13 ). The lipid-soluble agents have a rapid onset of action. Permeability (of the dura-arachnoid) is not a rate-limiting factor, and increasing the concentration gradient (by administration of a larger dose) facilitates faster entry into the spinal cord. The high lipid solubility of these agents also results in a shorter duration of action and greater systemic absorption than occurs with water-soluble drugs.

Some investigators have suggested that the improved analgesia results from a supraspinal action rather than a primary spinal action. However, several studies have refuted this theory, including studies of epidural opioid administration by bolus and continuous infusion. Vella et al. observed that the initiation of epidural analgesia with 0.25% bupivacaine with epidural fentanyl 80 µg resulted in more rapid, complete, and prolonged analgesia than intravenous fentanyl 80 µg, even though plasma fentanyl concentrations were higher in the intravenous group. Similarly, D’Angelo et al. demonstrated that a continuous epidural infusion but not an intravenous infusion of fentanyl reduced epidural bupivacaine requirements in laboring women. Polley et al. determined that the MLAC of epidural bupivacaine administered as a 20-mL bolus in laboring women was reduced from 0.064% to 0.034% when epidural rather than intravenous fentanyl was co-administered with bupivacaine. Ginosar et al. determined that the MLAC of bupivacaine administered by continuous epidural infusion during labor was lower by a factor of three when it was co-administered with an epidural (rather than intravenous) fentanyl infusion. Finally, in a volunteer study, lumbar epidural administration of fentanyl resulted in tolerance to experimental pain at a lumbar but not a cranial dermatome, whereas intravenous fentanyl administration resulted in pain tolerance at both dermatomes. These studies strongly suggest that during labor, epidural fentanyl provides analgesia primarily through a spinal site of action.

Epidural fentanyl alone provides moderate analgesia in early labor, but the dose needed to provide complete analgesia is accompanied by significant side effects (e.g., pruritus, nausea, maternal sedation, perhaps neonatal depression). In addition, epidural administration of an opioid alone provides inadequate analgesia during the late first stage as well as the second stage of labor. In a study comparing sufentanil alone, sufentanil with bupivacaine, and bupivacaine alone, women randomly assigned to the sufentanil-alone (30 µg) group experienced satisfactory analgesia after the initial dose but not after subsequent doses. However, the initial dose was administered after an epidural test dose that contained lidocaine 60 mg. In clinical practice, epidural fentanyl and sufentanil are usually administered with a local anesthetic for the initiation of analgesia (at a minimum, with a local anesthetic–containing epidural test dose).

In clinical practice, either fentanyl or sufentanil is frequently combined with a low-concentration, long-acting amide local anesthetic to initiate epidural labor analgesia. Epidural opioid administration allows the anesthesia provider to use a more dilute solution of local anesthetic to provide epidural labor analgesia. Epidural fentanyl and sufentanil decrease epidural bupivacaine requirements during labor in a dose-dependent fashion ( Fig. 23.2 ). The reduction in MLAC by the addition of fentanyl or sufentanil is observed with levobupivacaine, ropivacaine, and 2-chloroprocaine as well as bupivacaine.

The effect of epidural fentanyl on the minimum local anesthetic concentration (defined as the effective concentration in 50% of subjects [EC ₅₀ ]) for epidural bupivacaine analgesia during labor. Data are expressed as median concentrations with 95% confidence intervals.

(Data from Lyons G, Columb M, Hawthorne L, Dresner M. Extradural pain relief in labour: bupivacaine sparing by extradural fentanyl is dose dependent. Br J Anaesth. 1997;78:493–496.)

The addition of a lipid-soluble opioid to a local anesthetic for neuraxial labor analgesia decreases latency, prolongs the duration of analgesia, and improves the quality of analgesia. For example, Reynolds and O’Sullivan showed that epidural bupivacaine 10 mg combined with fentanyl 100 µg was more effective for the treatment of breakthrough pain and had a faster onset and longer duration of action than either bupivacaine 25 mg or fentanyl 100 µg administered alone. Van Steenberge et al. observed that the mean (± SD) onset of analgesia was 10.3 ± 3.8 minutes in women randomly assigned to receive bupivacaine 12.5 mg without sufentanil, whereas it was 8.7 ± 2.6 minutes in women who received bupivacaine combined with sufentanil 7.5 µg. Duration of analgesia was longer in the sufentanil group (131 minutes versus 86 minutes without sufentanil). In another study, the addition of fentanyl 100 µg to 0.125% bupivacaine prolonged the mean duration of analgesia from 55 minutes to 106 minutes.

The quality of analgesia is also better with the addition of an opioid to the local anesthetic. For example, 86% of women rated their analgesia as excellent after epidural analgesia was initiated with bupivacaine combined with sufentanil, compared with 50% of those who received bupivacaine without sufentanil. The percentage of women who experienced no or short periods of pain during the first stage of labor was 94% in women who received sufentanil and 76% in women who did not. After initiation of analgesia with 0.125% bupivacaine with epinephrine 1.25 µg/mL, 43% of women randomly assigned to receive epidural fentanyl 100 µg rated their analgesia as excellent, compared with 6% in a control group that did not receive fentanyl.

The dose-sparing effects of fentanyl and sufentanil are also evident when the drugs are combined with a low-concentration solution of bupivacaine used for the maintenance of analgesia throughout labor. For example, the total bupivacaine dose (mean ± SD) was 34 ± 17 mg in laboring women who received 0.125% bupivacaine/epinephrine 1.25 µg/mL with sufentanil, compared with 42 ± 19 mg in those who received bupivacaine/epinephrine without sufentanil. Similarly, in women randomly assigned to receive bupivacaine/epinephrine with or without fentanyl 100 µg, the total bupivacaine dose was 55 mg or 110 mg, respectively. Advantages of a lower total dose of local anesthetic include (1) decreased risk for local anesthetic systemic toxicity, (2) decreased risk for high or total spinal anesthesia, (3) decreased plasma concentrations of local anesthetic in the fetus and neonate, and (4) decreased intensity of motor blockade.

Several studies have directly compared the administration of epidural fentanyl or sufentanil combined with a local anesthetic for the initiation of labor analgesia. There were no differences in analgesia in women in early labor randomly assigned to receive either fentanyl 100 µg or sufentanil 20 µg immediately after a lidocaine 45-mg/epinephrine 15-µg test dose. In contrast, a second study demonstrated slightly better analgesia 20 minutes after injection of 0.125% bupivacaine (15 mg) with sufentanil 15 µg than after the same dose of bupivacaine with fentanyl 75 µg.

In the United States, fentanyl is more commonly used because historically it had a lower acquisition cost than sufentanil. Additionally, the concentration of the commercially available sufentanil preparation (50 µg/mL) may make drug errors more likely with sufentanil than with fentanyl because sufentanil doses significantly lower than 50 µg are used for initiation of epidural analgesia.

There are few rigorous dose-response studies of epidural fentanyl or sufentanil combined with bupivacaine for initiation of epidural labor analgesia. Herman et al. randomly assigned 100 laboring women with a cervical dilation of 5 cm or less to receive 0.125% bupivacaine 10 mL, combined with fentanyl 0 to 100 µg (in 25-µg increments) or sufentanil 0 to 25 µg (in 5-µg increments), injected after a negative epidural test dose (bupivacaine 7.5 mg with epinephrine 15 µg). Using a probit dose-response analysis, these researchers calculated the effective dose in 95% of subjects (ED ₉₅ ) to be 50 µg for fentanyl and 8 µg for sufentanil; these figures equate to a sufentanil-to-fentanyl potency ratio of 6.3 : 1. Capogna et al. sought to determine the median effective analgesic dose (ED ₅₀ ) of epidural fentanyl and sufentanil alone (no local anesthetic) for the initiation of epidural analgesia in nulliparous women with a cervical dilation between 2 and 4 cm. The ED ₅₀ of fentanyl was 124 µg (95% CI, 118 to 131), and the ED ₅₀ of sufentanil was 21 µg (95% CI, 20 to 22), with a potency ratio of 5.9 : 1. The potency ratio in volunteers subjected to an electrical stimulus was approximately 5 : 1. Taken together, these data suggest that the potency ratio of sufentanil to fentanyl administered into the epidural space is approximately 6 : 1.

Several studies have compared bupivacaine combined with fentanyl 50 µg and 100 µg. No differences in the onset, duration, and quality of analgesia were noted in Asian women randomly assigned to receive 0.125% bupivacaine (10 mg) combined with either 50 or 100 µg of fentanyl. In contrast, when 0.125% bupivacaine (15 mg) with epinephrine 15 µg was administered to laboring Italian women with either 50 or 100 µg of fentanyl, there was no difference in the onset or duration of analgesia, but more women in the 100-µg group had excellent analgesia.

There were no differences in latency, duration of analgesia, and quality of analgesia when analgesia was induced with 0.125% bupivacaine (12.5 mg)/epinephrine 12.5 µg and either 7.5 or 15 µg of sufentanil. Similarly, after injection of a lidocaine 60-mg/epinephrine 15-µg test dose, another study found no differences in latency and quality of analgesia among epidural sufentanil doses of 5, 10, 20, 30, 40, and 50 µg. However, the duration of analgesia was longer after the higher doses of sufentanil.

The range of fentanyl and sufentanil doses used for the initiation of epidural labor analgesia is shown in Table 23.2 . Pain and analgesic requirements vary depending on several factors, including parity, stage of labor, presence of ruptured membranes, oxytocin augmentation, and whether the opioid is administered in combination with a local anesthetic. One study reported that the ED ₅₀ of epidural sufentanil was higher in women undergoing prostaglandin induction of labor than in women with spontaneous labor. Conell-Price et al. developed a model of labor pain in nulliparous women and found that the use of oxytocin was associated with 48% more pain at the start of labor. Preliminary evidence suggests that pharmacogenetics may also play a role in dose requirements. Camorcia et al. reported that nulliparous women who were heterozygous or homozygous for the single nucleotide polymorphism (SNP) A118G (substitution of guanine for adenine at position 118) of the gene encoding the µ-opioid receptor (OPRM1) had a lower ED ₅₀ for epidural sufentanil administered for labor analgesia.

Several early studies suggested that the duration of epidural and spinal analgesia may exhibit circadian rhythm (chronobiology), possibly secondary to human biologic rhythms. However, in a secondary analysis of data from a large study, Scavone et al. found no evidence of a circadian response to intrathecal fentanyl or intravenous opioid labor analgesia. In a detailed analysis of data from a study designed to test whether parturient response to intrathecal bupivacaine exhibited a circadian rhythm, Shafer et al. demonstrated that external daily rhythms, such as nursing shifts, may contribute to the appearance of biologic rhythm. Thus, whether a circadian response to neuraxial local anesthetic or opioid exists, or is clinically significant, requires further study.

Current evidence supports the administration of epidural opioid doses at the lower end of the dose range for nulliparous women, for women in early labor, or when the opioid is co-administered with a local anesthetic. Higher doses are associated with a higher incidence of maternal side effects and the potential for neonatal depression (see later discussion). The major maternal side effect of epidural fentanyl and sufentanil for labor analgesia is pruritus. Neonatal outcomes do not appear to be adversely affected by the addition of fentanyl or sufentanil to a local anesthetic for epidural analgesia (see later discussion). In fact, the combination of drugs allows lower doses of both drugs to be administered, resulting in lower concentrations of both drugs in the neonate.

Two studies found that the diluent volume (2 to 20 mL) did not affect the onset and duration of epidural labor analgesia when fentanyl was injected into the epidural space after the injection of a local anesthetic solution.

Other opioids.

Morphine was one of the first opioids used for labor analgesia. Hughes et al. compared analgesia using epidural administration of morphine (2.0, 5.0, and 7.5 mg) with that using epidural bupivacaine 0.5%. Morphine was effective in 7 of 11 parturients until the end of the first stage of labor, but all parturients required bupivacaine for adequate analgesia during the second stage of labor. Subsequently, investigators combined morphine with bupivacaine and observed a longer duration of analgesia compared with that for bupivacaine alone. However, the inconsistent analgesia, long latency (30 to 60 minutes), and high incidence of side effects of morphine (which continued after delivery), along with the introduction of lipid-soluble opioids and epidural infusion pumps into clinical practice, have made the use of epidural morphine for labor analgesia largely obsolete.

Several studies described the use of alfentanil with bupivacaine for labor analgesia. Alfentanil has lower lipid solubility than both fentanyl and sufentanil. Only a few small studies have compared alfentanil with other opioids for labor analgesia.

Several groups of investigators have reported the use of epidural hydromorphone for labor analgesia. The lipid solubility of hydromorphone lies between those of morphine and fentanyl, but is closer to that of morphine. In a large prospective observational study, effective labor analgesia was obtained by initiating analgesia with 0.25% bupivacaine (20 to 25 mg) with epinephrine (40 to 50 µg), followed by hydromorphone 100 µg. However, Mhyre observed that effective labor analgesia could not be provided by 0.035% bupivacaine (7 mg) with hydromorphone 100 to 110 µg. In another trial, parturients were randomly assigned to receive either epidural hydromorphone 300 µg or saline-control immediately after the initiation of analgesia with lidocaine 45 mg, epinephrine 15 µg, and fentanyl 100 µg. Duration of analgesia and side effects were similar in the two groups. At the current time, further investigation is required before hydromorphone can be recommended for epidural labor analgesia.

Meperidine may be used effectively alone (without a local anesthetic), in part because it possesses local anesthetic properties. When given during labor, epidural meperidine 100 mg provides analgesia similar to that provided by 0.25% bupivacaine, with less motor blockade. However, this dose of epidural meperidine produces more sedation, nausea, and pruritus than epidural bupivacaine. Handley and Perkins observed that the addition of meperidine 25 mg to 0.125%, 0.187%, or 0.25% bupivacaine (10 mL) provided adequate analgesia for the first stage of labor. Epidural administration of meperidine effectively prevents or treats the shivering that often occurs during labor. Investigators from Saudi Arabia randomly allocated women to receive 0.1% bupivacaine with either meperidine 1 mg/mL or fentanyl 2 µg/mL. No differences were noted between groups in analgesic characteristics, except that women in the meperidine group had a higher incidence of nausea and vomiting. Currently there is no evidence that meperidine alone or in combination with bupivacaine has any advantages over a combination of a long-acting amide local anesthetic and a lipid-soluble opioid.

Butorphanol is a lipid-soluble opioid agonist-antagonist, with weak µ-receptor and strong κ-receptor activity. Because κ-opioid receptors appear to be involved in the modulation of visceral pain, κ-receptor agonists should be useful agents for the relief of labor pain, which has a significant visceral component (see Chapter 20 ). Somnolence is the most prominent side effect of epidural butorphanol. The addition of butorphanol 1, 2, or 3 mg to 0.25% bupivacaine (25 mg) shortened latency and prolonged the duration of analgesia in comparison with epidural bupivacaine alone in one study. The investigators concluded that the optimal dose of butorphanol was 2 mg. Of concern was the observation of a transient sinusoidal FHR pattern in the 3-mg group that was not unlike that seen after the intravenous administration of butorphanol. However, there was no difference among groups in Apgar scores, umbilical cord blood gas and pH measurements, or neurobehavioral scores. Similarly, Abboud et al. observed that the addition of butorphanol 1 or 2 mg to 0.25% bupivacaine resulted in better quality and longer duration of analgesia than the epidural administration of bupivacaine alone, without maternal or neonatal side effects. However, some anesthesia providers have noted that the epidural administration of butorphanol results in somnolence and occasional dysphoria, which are side effects of κ-receptor stimulation.

Diamorphine (heroin) is available for epidural analgesia in the United Kingdom. Using isobolographic analysis, McLeod et al. concluded that the combination of diamorphine and levobupivacaine is additive when used for first-stage labor analgesia. Several studies from the United Kingdom have reported diamorphine doses between 250 and 500 µg/h (i.e., diamorphine 25 to 50 µg/mL combined with a low concentration of bupivacaine). Whether diamorphine offers any advantages over fentanyl or sufentanil has not been studied. It is not available for clinical administration in the United States.

Epinephrine.

Some anesthesia providers add a low dose of epinephrine (1.25 to 5 µg/mL [1 : 800,000 to 1 : 200,000]) to the local anesthetic solution ( Table 23.4 ). The addition of epinephrine shortens the latency and prolongs the duration of epidural bupivacaine analgesia. The MLAC of bupivacaine with epinephrine (66 µg) is 29% lower than that of bupivacaine without epinephrine, perhaps as a result of the stimulation of alpha-adrenergic receptors in the spinal cord.

The addition of epinephrine to the local anesthetic has a variable effect on the systemic uptake of the local anesthetic in obstetric patients. The systemic absorption of epinephrine may increase maternal heart rate and transiently decrease uterine activity as a result of beta-adrenergic receptor stimulation. However, some studies have shown that the addition of epinephrine to bupivacaine, lidocaine, or levobupivacaine does not result in longer labor than the epidural administration of bupivacaine or lidocaine without epinephrine or levobupivacaine-sufentanil without epinephrine. Epidural administration of an epinephrine-containing local anesthetic solution does not adversely affect intervillous blood flow or neonatal outcome. One disadvantage of the use of epinephrine is that it increases the intensity of motor blockade. The addition of epinephrine may improve the efficacy of epidural opioids, but the enhanced effect is insufficient to make use of epidural opioids (without local anesthetic) an attractive regimen for the duration of labor. Finally, the addition of a third drug to the local anesthetic/opioid solution may increase the risk for drug error and contamination. For these reasons, at our institution my colleagues and I do not routinely administer epinephrine-containing local anesthetic solutions during labor. However, other anesthesia providers have a different view, and some consider epinephrine a useful adjuvant, especially when added to a very dilute solution of local anesthetic with an opioid.

Clonidine.

Analgesia is enhanced by the direct stimulation of alpha ₂ -adrenergic receptors and the inhibition of neurotransmitter release in the dorsal horn of the spinal cord (see Chapter 20 ). Epidural administration of clonidine alone provides modest analgesia. Studies have evaluated the epidural administration of clonidine as an adjuvant to a local anesthetic alone, to local anesthetic and opioid combinations, to fentanyl, and to neostigmine (see later discussion). In an MLAC study, clonidine 60 µg, but not 30 µg, decreased the MLAC of ropivacaine by approximately two-thirds. In another study, clonidine 75 µg and sufentanil 5 µg both reduced the MLAC of ropivacaine by about two-thirds. Unlike epinephrine, clonidine does not increase the motor blockade that results from the epidural administration of a local anesthetic, but it does potentiate both the quality and duration of analgesia. However, in a “black box” warning on the package insert, the manufacturer of Duraclon (the epidural clonidine formulation approved by the U.S. Food and Drug Administration [FDA]) recommends against its use in obstetric patients because of the risk for hypotension and bradycardia. Most studies, however, have found that the hypotension is readily amenable to treatment. An additional side effect is maternal sedation. High doses (greater than 150 µg) may be associated with FHR changes, although no adverse fetal effects have been observed with lower doses.

Clonidine is not often used for labor analgesia in North America, but it is more widely used in some European countries. It may be particularly useful in women in whom other epidural analgesics are contraindicated or in those who have breakthrough pain with standard local anesthetic/opioid solutions, despite a functioning epidural catheter. In this circumstance, additional local anesthetic will result in motor blockade but clonidine will not.

Neostigmine.

Neostigmine inhibits the breakdown of acetylcholine within the spinal cord. Acetylcholine binds to muscarinic receptors, leading to a reduction in neurotransmitter release and subsequent analgesia. Roelants et al. randomly assigned parturients to receive either epidural ropivacaine (20 mg) alone or epidural neostigmine (4 µg/kg) combined with ropivacaine 10 mg, with or without sufentanil 10 µg. The magnitude and duration of analgesia in the ropivacaine/neostigmine group were similar to that of the plain ropivacaine group but less than in the ropivacaine/sufentanil group. Neostigmine is hydrophilic, and the researchers hypothesized that only a small portion of the epidural dose penetrates the spinal cord. In a subsequent study, the same researchers compared epidural sufentanil 20 µg with sufentanil 10 µg combined with neostigmine 250, 500, or 750 µg. Neostigmine 250 µg with sufentanil was ineffective, but both 500 and 750 µg of neostigmine produced effective analgesia similar in duration to that obtained with sufentanil alone.

In another study, maintenance of epidural analgesia with a solution of neostigmine 4 µg/mL combined with bupivacaine 0.125% resulted in a 19% reduction in bupivacaine consumption compared with administration of bupivacaine alone. However, maternal sedation was noted in the neostigmine group in the first 5 to 20 minutes after initiation of epidural analgesia with bupivacaine and neostigmine 60 µg. Booth et al. randomized laboring women to receive initiation and maintenance of epidural analgesia with 0.125% bupivacaine, combined with fentanyl 2 µg/mL or neostigmine 2, 4, or 8 µg/mL. The primary outcome, hourly bupivacaine consumption, did not differ among groups, nor did patient satisfaction. Pruritus was less common in the neostigmine groups, but other adverse effects did not differ, suggesting that there is no advantage to replacing the lipid-soluble opioid with neostigmine when combined with a local anesthetic.

Because animal studies suggest a synergistic antinociceptive effect of spinal alpha ₂ -adrenergic agonists and cholinesterase inhibitors, researchers have also investigated epidural neostigmine combined with clonidine. The combination of clonidine 75 µg with neostigmine 500 or 750 µg provided acceptable analgesia (visual analogue scale pain score less than 30/100 mm in 30 minutes) in approximately 80% of parturients. Epidural neostigmine 500 µg combined with clonidine 75 µg prolonged labor analgesia initiated with spinal ropivacaine and sufentanil. In a follow-up study, the same investigators initiated analgesia with spinal ropivacaine and sufentanil and maintained analgesia with ropivacaine/sufentanil PCEA. Study subjects were randomized to receive a 10-mL epidural bolus injection of a solution containing neostigmine 500 µg combined with clonidine 75 µg or placebo saline solution 15 minutes after the intrathecal injection. Hourly ropivacaine use and the incidence of breakthrough pain were less in the group that received the epidural neostigmine/clonidine bolus. Systolic blood pressures were lower in the treatment group, but the incidence of hypotension did not differ.

Taken together, the studies have not identified any significant adverse maternal or neonatal effects; however, the number of studies is small and further study is required to determine the role of epidural neostigmine for routine labor analgesia. Neostigmine is not approved for neuraxial injection in the United States.

Fentanyl and sufentanil.

The two opioids most commonly used for initiation of spinal labor analgesia are fentanyl and sufentanil. When administered alone in early labor, intrathecal fentanyl and sufentanil provide complete analgesia without a sympathectomy or motor blockade. This is a particularly useful technique for patients in whom a sudden decrease in preload (secondary to neuraxial local anesthetic–induced sympathectomy) might not be well tolerated (e.g., patient with a stenotic heart lesion).

Studies suggest that the ED ₅₀ of intrathecal fentanyl varies from 5.5 to 18 µg. The wide range of published values may be explained by differences in patient population (e.g., parity), cervical dilation at initiation of analgesia, and definition of successful analgesia. Nelson et al. hypothesized that acute mixing of fentanyl in cerebrospinal fluid (CSF) may explain the large interindividual variability observed after the injection of intrathecal opioid. In an elegant study, the investigators determined CSF fentanyl concentration at the site of the lumbar injection 60 seconds after the fentanyl injection. CSF fentanyl concentration did not correlate with onset, sensory level, or duration of analgesia. Instead, decreased diastolic and increased systolic blood pressure correlated with duration of analgesia. The authors hypothesized that hemodynamic characteristics may influence the distribution of drug in the CSF and, hence, block characteristics.

Herman et al. determined that the ED ₉₅ of intrathecal fentanyl for parturients of mixed parity in early labor (cervical dilation less than or equal to 5 cm) was 17.4 µg (95% CI, 13.8 to 27.1). The duration of analgesia is dose dependent but plateaus at 80 to 90 minutes after administration of 15 to 25 µg of fentanyl ( Fig. 23.3 ). There does not appear to be any reason to administer doses higher than 25 µg, because side effects (e.g., pruritus, respiratory depression) are also dose dependent.

Duration of intrathecal fentanyl analgesia (mean ± SD) among nulliparous women in active labor who received 5, 10, 15, 20, 25, 35, or 45 µg. Duration of analgesia (time from intrathecal dose to first request for additional analgesia) differed significantly among the groups (analysis of variance [ANOVA], P < .005). * P < .05 versus groups 15 to 45 µg; ** P < .05 versus groups 25 to 45 µg.

(From Palmer CM, Cork RC, Hays R, et al. The dose-response relationship of intrathecal fentanyl for labor analgesia. Anesthesiology. 1998;88:355–361.)

The reported ED ₅₀ of intrathecal sufentanil varies from 1.8 to 4.1 µg, and the ED ₉₅ is 8 to 10 µg. A comparison of the potencies of fentanyl and sufentanil using ED ₅₀ estimates from different studies is difficult because of differences in patient populations and the definition of efficacy. In a single-center study, the relative potency ratio of intrathecal sufentanil to fentanyl for labor analgesia was estimated to be 4.4 : 1. When the drugs were administered at twice the ED ₅₀ (fentanyl 36 µg, sufentanil 8 µg), the duration of sufentanil analgesia was 25 minutes longer than that of fentanyl analgesia (104 versus 79 minutes), although the incidence of side effects was not different.

Landau et al. investigated the influence of genetic variability of the µ-opioid receptor OPRM1 on the ED ₅₀ of intrathecal fentanyl for labor analgesia. Nulliparous women who were heterozygous or homozygous for A118G had a lower ED ₅₀ for intrathecal fentanyl (18 µg, 95% CI, 13 to 22) than women homozygous for the wild-type allele (A118) (27 µg, 95% CI, 23 to 31). Additionally, women in the group with the A118G allele requested analgesia at a more advanced cervical dilation. However, in two other studies assessing duration of intrathecal fentanyl labor analgesia, there was no difference in the duration of analgesia in women with the A118G allele compared with women who were homozygous for the wild-type allele. Thus, the clinical implications of genetic polymorphisms of OPRM1 on labor analgesia remain unclear.

Typically, an intrathecal opioid injection for labor analgesia is administered as part of a CSE technique. Maintenance epidural analgesia is usually initiated soon after initiation of spinal analgesia. Therefore, the duration of intrathecal analgesia is relatively less important. Nelson et al. concluded, and we concur, that the longer duration of sufentanil analgesia in comparison with fentanyl analgesia does not necessarily justify the former’s use. Other factors, such as cost and the greater risk for a drug dose error with sufentanil (because of its greater potency), should be considered. In some European countries sufentanil is available in a dilute concentration (5 µg/mL), possibly making it easier and safer to use.

Intrathecal fentanyl (or sufentanil) is often co-administered with an amide local anesthetic (see later discussion), most commonly bupivacaine (see Table 23.2 ). The addition of a local anesthetic to intrathecal fentanyl or sufentanil markedly decreases the dose of opioid necessary to produce analgesia. Wong et al. randomly assigned parous women to receive intrathecal bupivacaine 2.5 mg and intrathecal sufentanil 0, 2.5, 5, 7.5, or 10 µg, followed by a standard epidural test dose. There were no differences among the sufentanil groups in quality and duration of analgesia. These results suggest that a sufentanil dose as small as 2.5 µg is effective when combined with bupivacaine 2.5 mg. In current clinical practice, it is common to combine bupivacaine 2.5 mg with sufentanil 1.5 to 2 µg. Stocks at al. demonstrated that three different doses of intrathecal fentanyl (5, 15, and 25 µg) led to similar reductions in the ED ₅₀ of intrathecal bupivacaine, although both the duration of analgesia and the incidence of pruritus were dose dependent. As with sufentanil, the dose of intrathecal fentanyl is usually reduced when combined with bupivacaine. Intrathecal fentanyl 10 to 15 µg, combined with bupivacaine 2.5 mg, provides effective analgesia for most parturients.

Other opioids.

Early studies demonstrated that the intrathecal administration of 0.5 to 2 mg of morphine reliably produced analgesia during the first stage of labor, but the analgesia was less reliable during the second stage of labor and during instrumental vaginal delivery. However, intrathecal administration of these relatively large doses of morphine resulted in a high incidence of side effects, including somnolence, nausea and vomiting, pruritus, and respiratory depression. In addition, the onset of analgesia is slower with intrathecal morphine than with lipid-soluble opioids, and the long duration of action may be a disadvantage (i.e., the parturient may deliver before the regression of side effects). Abouleish reported a case of life-threatening respiratory depression 1 hour after delivery and 7 hours after the administration of 1 mg of hyperbaric intrathecal morphine.

In several studies, low-dose morphine (0.1 to 0.25 mg) was successfully combined with intrathecal bupivacaine (2 to 2.5 mg) and fentanyl (12.5 to 25 µg); the combination resulted in short latency of onset and a prolonged duration of analgesia. In contrast, a single study from Sweden found no advantage to adding morphine 0.05 or 0.1 mg to bupivacaine 1.25 mg and sufentanil 5 µg. The addition of low-dose morphine to intrathecal bupivacaine and a lipid-soluble opioid may be useful in low-resource settings in which continuous epidural infusion techniques are impractical. When used as part of a CSE technique, the addition of intrathecal morphine to bupivacaine and fentanyl has been shown to result in less breakthrough pain during labor as well as decreased analgesic use in the first 24 hours postpartum, compared with intrathecal bupivacaine and fentanyl without morphine. The incidence of intrapartum side effects was similar ; however, the morphine group had a higher incidence of postpartum nausea (17% versus 0% for no morphine).

An alternative drug is meperidine. Meperidine is unique among the opioids in that it possesses weak local anesthetic properties, and it has been used in large doses (e.g., 1 mg/kg) as the sole agent to provide spinal anesthesia for surgical procedures. Intrathecal administration of meperidine (10 to 20 mg) results in effective labor analgesia within 2 to 12 minutes, with a duration of 1 to 3 hours. Honet et al. compared the efficacy of intrathecal meperidine 10 mg, fentanyl 10 µg, and sufentanil 5 µg in 65 laboring women. The three drugs were similar in onset of analgesia (less than 5 minutes) and duration of effective analgesia (80 to 100 minutes). However, the meperidine group had significantly lower pain scores after cervical dilation had progressed beyond 6 cm. As labor advances, the nature of pain becomes increasingly somatic; only meperidine also functions as a local anesthetic. This fact helps explain why meperidine provided more effective analgesia during advanced labor, including the second stage. Booth et al. observed that intrathecal meperidine was associated with a significantly higher incidence of nausea and vomiting than a combination of fentanyl and bupivacaine for labor analgesia. Therefore, intrathecal meperidine does not seem to offer any advantages over bupivacaine-fentanyl for routine intrathecal analgesia, although it may be useful for the rare patient with a contraindication to bupivacaine-fentanyl administration.

In the United Kingdom, some anesthesia providers have advocated the intrathecal administration of diamorphine (heroin) for labor analgesia, although it is not commonly used for this purpose. This drug is not available for clinical use in the United States. Kestin et al. observed that the intrathecal administration of diamorphine (0.2 to 0.5 mg) provided good to excellent analgesia in 90% of laboring women. The mean duration of analgesia was approximately 100 minutes. However, 75% of patients had pruritus, nausea, and vomiting. In contrast, Vaughan et al. randomly assigned parturients to receive intrathecal bupivacaine 2.5 mg with either fentanyl 25 µg or diamorphine 0.25 mg. Duration of analgesia was longer in the diamorphine group, but the incidence of side effects was low in both groups.