Local Anesthetics and Opioids

Neurobehavioral tests have been developed to detect subtle changes in organized behavior in the newborn. These tests include the Brazelton Neonatal Behavioral Assessment Scale (NBAS), the Early Neonatal Neurobehavioral Scale (ENNS), and the Neurologic and Adaptive Capacity Score (NACS). All the tests are subjective and complex and lack specificity.

Other perinatal factors appear to have a more important effect on neonatal test performance than the choice of local anesthetic.²⁰⁸ Indeed, neurobehavioral tests have been shown not to be a reliable measure of drug effect in the newborn.²⁰⁹

Preterm Fetus and Newborn

It has become axiomatic that the preterm infant is more vulnerable than the term infant to the effects of analgesic and anesthetic drugs. Causes of enhanced drug sensitivity in the preterm newborn that have been postulated are as follows: (1) less protein is available for drug binding, (2) higher levels of bilirubin are present and may compete with the drug for protein binding, (3) greater access of the drug to the CNS occurs because of a poorly developed blood-brain barrier, (4) the preterm infant has greater total body water and less fat content, and (5) the preterm infant has a diminished ability to metabolize and excrete drugs. Unfortunately, few systematic studies have determined the maternal and fetal pharmacokinetics and pharmacodynamics of drugs throughout gestation; nevertheless, these deficiencies of the preterm infant may not be as serious as we have been led to believe. Although the plasma albumin and AAG concentrations are lower in the preterm fetus, these factors primarily affect drugs that are highly bound to these proteins. Most local anesthetics, however, exhibit only low to moderate degrees of binding in fetal plasma.⁹⁰^,⁹¹

The placenta efficiently eliminates fetal bilirubin. Thus, the hyperbilirubinemia of prematurity normally occurs in the postpartum period. Bupivacaine has been implicated as a possible cause of neonatal jaundice.²¹⁰^,²¹¹ High affinity of the drug for fetal erythrocyte membranes may lead to a decrease in filterability and deformability, which may render red blood cells more prone to hemolysis.²¹¹ However, increased bilirubin production has not been demonstrated in newborns whose mothers received bupivacaine for epidural anesthesia during labor and cesarean delivery.²¹²^,²¹³

Greater total body water in the preterm fetus results in a larger volume of distribution for drugs. Thus, to achieve equal blood concentrations, the immature fetus must receive a greater amount of drug transplacentally than the mature fetus.

The diminished ability to metabolize or excrete drugs associated with prematurity is certainly not a universal phenomenon. One study of the pharmacokinetics of lidocaine in preterm newborns noted that plasma clearance was similar to that in adults.¹⁹⁶

During anesthesia for preterm labor, concerns about drug effects on the newborn are far less important than the prevention of asphyxia and trauma to the fetus. Indeed, healthy preterm fetal lambs tolerated clinically relevant plasma concentrations of lidocaine (e.g., approximately 1.5 µg/mL) as well as mature ones.¹⁹^,²¹⁴

Asphyxia

Circulatory adaptations important for fetal survival during asphyxia result in increased blood flow and oxygen delivery to vital organs (e.g., heart, brain, adrenal glands).¹⁹⁴ Little information exists about the effects of local anesthetics on these fetal responses. Adaptation to asphyxia was unaffected in mature fetal lambs exposed to lidocaine.¹⁹⁴ In contrast, lidocaine adversely affected asphyxiated preterm fetal lambs, which experienced a further deterioration of acid-base status and a reduction in cardiac output and blood flow to the brain and heart (Figure 13-6).²¹⁵ Also in asphyxiated preterm fetal lambs, exposure to bupivacaine reduced blood flow to vital organs; however, FHR, blood pressure, and acid-base measurements did not change.²¹⁶

FIGURE 13-6 Blood flow to the brain and heart in the preterm fetal lamb before and during asphyxia and during exposure to lidocaine while asphyxiated (mean ± SEM). *Significantly different from control. †Significantly different from asphyxia. (Modified from Morishima HO, Pedersen H, Santos AC, et al. Adverse effects of maternally administered lidocaine on the asphyxiated preterm fetal lamb. Anesthesiology 1989; 71:110-5.)

After performing an in vitro study using perfused human placentas, Johnson et al.²¹⁷ suggested that bupivacaine might be preferable to lidocaine in the presence of fetal acidosis because the greater maternal protein binding of bupivacaine may limit its placental transfer. However, this methodology does not consider the potential for greater fetal tissue uptake of bupivacaine (than of lidocaine) because bupivacaine is more lipid soluble and more protein bound than lidocaine.

In 1997, Santos et al.²¹⁶ reported that the effects of bupivacaine appeared less severe than those of lidocaine in asphyxiated preterm fetal lambs. However, the lidocaine data were generated in a separate experiment reported in 1989.²¹⁵ There are inherent limitations in a historical comparison of two studies performed 8 years apart. Further, it is unclear whether these findings are applicable to humans because both lidocaine and bupivacaine have enjoyed a long history of safe use in obstetric anesthesia practice; prospective clinical studies are required before one drug can be recommended over the other in the setting of fetal asphyxia.

Opioids

Neuraxial opioid administration is unique in that it produces analgesia without loss of sensation or proprioception. Opioids are often co-administered with local anesthetic agents during intrapartum administration of neuraxial analgesia and anesthesia.

The term opioid refers to a series of compounds that are related to opium. These compounds may be classified as follows: (1) naturally occurring (e.g., morphine), (2) semisynthetic compounds (e.g., dihydromorphone), and (3) synthetic compounds (e.g., fentanyl) (Box 13-4). The only three naturally occurring opioids of clinical significance are morphine, codeine, and papaverine. These substances can be obtained from the poppy plant known botanically as Papaver somniferum. Development of synthetic drugs with morphine-like properties has led to development of the broad term opioid. These substances bind to several subpopulations of opioid receptors with resulting morphine-like effects. More than 30 years ago, identification of a dense concentration of opioid receptors in the dorsal horn of the spinal cord led to the use of neuraxial opioids as important adjuncts in obstetric anesthesia.

Molecular Structure

Naturally occurring opioids of significance can be divided into two distinct chemical classes, phenanthrenes (e.g., morphine) and benzylisoquinolines (e.g., papaverine) (Figure 13-7). The phenanthrenes are five-ring structures, and the benzylisoquinolines are three-ring structures. The semisynthetic opioids are morphine derivatives that have undergone relatively simple modification of the morphine molecule. For example, substitution of an ester for the hydroxyl group on carbon 6 of morphine results in hydromorphone (Figure 13-8). Synthetic opioids can be classified into the following four groups: (1) morphinan derivatives (e.g., levorphanol), (2) diphenyl or methadone derivatives (e.g., methadone, D-propoxyphene), (3) benzomorphan derivatives (phenazocine, pentazocine), and (4) phenylpiperidines (e.g., meperidine, fentanyl, sufentanil).

FIGURE 13-7 Naturally occurring opioids: phenanthrenes (e.g., morphine) and benzylisoquinolines (e.g., papaverine).

FIGURE 13-8 Semisynthetic opioids are morphine derivatives. For example, substitution of an ester for the hydroxyl group on carbon 6 of morphine results in hydromorphone.

Structurally, opioids are complex three-dimensional compounds that often exist as two optical isomers (e.g., morphine).²¹⁸ Usually the levorotary isomer is the only isomer capable of producing analgesia. Analgesic activity of the opioid compound depends on its stereochemical structure.²¹⁹ Even relatively minor molecular alterations (e.g., extent of ionization) can produce significant alterations in the pharmacologic activity of the opioid.

Morphine is the prototypical opioid. It is a five-ring structure that conforms to a T shape.²²⁰ Three of the rings lie in one plane, and the other two rings are perpendicular to the plane. This forms the basis for the T (Figure 13-9). Morphine demonstrates several other characteristics that are common to other opioids: (1) a tertiary, positively charged basic nitrogen; (2) a quaternary carbon that is separated from the basic nitrogen by an ethane chain and attached to a phenyl group; (3) a phenolic hydroxyl group (morphine derivatives) or a ketone group (meperidine); and (4) the presence of an aromatic ring.²²⁰

FIGURE 13-9 The T-shaped molecule of morphine.

A phenylpiperidine structure (i.e., an aromatic ring attached to a six-member ring containing five carbons and one nitrogen) is also part of the morphine molecule and is present in some other opioids (e.g., fentanyl) (Figure 13-10).²²⁰ Phenylalanine and tyrosine moieties are structural elements that are important to all opioids, including endogenous neurotransmitters and modulators.²²¹^,²²² The poppy plant synthesizes morphine from two tyrosine molecules; many opioids contain a structure that is similar to alanine.²²⁰

FIGURE 13-10 Chemical structures of phenylpiperidine, meperidine, and the 4-anilinopiperidine derivatives fentanyl, sufentanil, alfentanil, and remifentanil.

Mechanism of Action

Since first described in 1979,²²³ neuraxial opioid administration has become a mainstay in obstetric anesthesia practice. Clinical and laboratory research has focused on the mechanisms of synaptic transmission as well as the study of opioids and neurotransmitters that modulate this transmission.

Pain perception involves a complex series of nociceptive transmissions that begin with stimulation of sensory nerves in the periphery, resulting in generation of action potentials within the spinal cord and synaptic transmission to other supraspinal sites. Intraspinal administration of an opioid exploits the pharmacology of pain-modulating and pain-relieving systems that exist within the spinal cord (see Figure 20-9). In early studies, Yaksh²²⁴ demonstrated that morphine could produce selective suppression of nociceptive processing without affecting motor function, sympathetic tone, or proprioception when it was administered to the superficial layers of the dorsal horn of the spinal cord. However, when small amounts of opioid were administered to the cortex, the effects on nociceptive processing were negligible. Collectively, this work demonstrated that small doses of opioid can be selectively administered to a receptor site (i.e., spinal cord) and produce profound analgesia. In contrast, systemic administration of a much larger dose of opioid results in activation of multiple central and peripheral receptors to produce analgesia, but with unwanted side effects.

All opioids produce analgesia by binding to G protein–coupled opioid receptors. Activation of opioid receptors subsequently inhibits both adenylate cyclase– and voltage-gated calcium channels. Inhibition of these calcium channels inhibits the release of excitatory afferent neurotransmitters, including glutamate, substance P, and other tachykinins.²²⁵^,²²⁶ The result is inhibition of ascending nociceptive stimuli from the dorsal horn of the spinal cord.

Opioid receptors are nonuniformly distributed throughout the CNS. Although parenterally administered opioids most likely have both direct spinal and supraspinal effects, neuraxially administered opioids block the transmission of pain-related information by binding at presynaptic and postsynaptic receptor sites in the dorsal horn of the spinal cord (i.e., Rexed laminae I, II, V) (Figure 13-11). However, the rate and extent of neuraxial analgesia depends largely on the specific drug's physicochemical properties and ability to reach the opioid receptors in the spinal cord.

FIGURE 13-11 Architecture of the spinal cord, showing the gray matter nuclei (left) and Rexed laminae (right). (From Ross BK, Hughes SC. Epidural and spinal narcotic analgesia. Clin Obstet Gynecol 1987; 30:552-65.)

The following three broad classes of opioid receptors have been identified: (1) mu (μ) receptor for morphine type, (2) kappa (κ) receptor for ketocyclazocine type, and (3) delta (δ) receptor.²²⁵ A fourth receptor, the opioid receptor–like-1 (ORL-1) receptor, has structural homology to the classic opioid receptors, but its endogenous ligand, orphanin (OFQ) (also called nociceptin [N]), binds poorly to the classic opioid receptors.²²⁷ Its role in pain modulation is not well characterized but appears distinctive from that of the classic opioid system.²²⁵ Each opioid receptor is encoded by a different gene and mediates different physiologic effects (Table 13-3). Although all of these receptors may be involved with pain processing, the μ or κ receptors have the most important clinical pharmacologic effects.

TABLE 13-3

Subtypes of Opioid Receptors

The distinct receptor subtypes have significance in neuraxial opioid administration and drug development. Common pharmacologic effects (e.g., analgesia, respiratory depression) of morphine are mediated by μ-opioid receptors. Functional subclasses of μ-opioid receptors have been characterized; however, only one gene has been identified for the μ-opioid receptor. Some specific functions have been ascribed to μ-opioid receptor subtypes, including mediation of respiratory depression and spinal opioid analgesia by μ₂ receptors and production of supraspinal analgesia by μ₁ receptors.²²⁸ Although subtype-specific μ agonists may have greater efficacy and less toxicity, no receptor-specific agents have been developed for clinical use.

Morphine also has effects at κ- and δ-opioid receptors when higher doses are administered. Responsible for analgesic, sedative, dysphoric, and diuretic effects,²²⁵ κ receptors are located both within the CNS and peripherally.²²⁹ Peripheral κ-opioid receptor agonists have been shown to modulate visceral pain, particularly in conditions that involve inflammation.²²⁹

The δ receptor is responsible for mediating some of the analgesic effects of the endogenous opioids (e.g., enkephalins, prodynorphan, pro-opiomelanocortin, pro-orphanin, endomorphins) in the spinal cord.²³⁰ Few of the opioids have effects at the δ receptor in clinically relevant doses, but if a μ agonist is administered in a high enough dose to treat an opioid-tolerant patient, the drug may be less selective and produce δ effects.

Pharmacokinetics and Pharmacodynamics

Many of the pharmacologic differences observed among neuraxially administered opioids depend on an opioid's ability to reach opioid receptors. An opioid's physicochemical properties, especially lipophilicity or hydrophilicity, largely determine the bioavailability of neuraxially administered opioids as well as the drug's ability to produce spinally mediated analgesia.

Before G protein–receptor activation can occur, the opioid must undergo a series of complex processes. Although several mechanisms have been proposed to explain the movement of opioids from the epidural space to the spinal cord, studies demonstrate that the only relevant mechanism is diffusion through the spinal meninges.²³¹^-²³³ The opioid must traverse the dura and arachnoid membranes, diffuse through the CSF, and cross the pia membrane to reach the spinal cord (Figure 13-12). Once the drug reaches the surface of the spinal cord, it must diffuse through the white matter and then the gray matter to reach the site of action, the dorsal horn.²³⁴ The rate and extent of opioid transfer to receptors largely depend on a drug's physicochemical properties, particularly lipid solubility, because competing processes (e.g., uptake into the epidural fat or systemic circulation) limit the agent's diffusion to opioid receptors. Greater lipid solubility of a drug results in more rapid onset of analgesia. For example, fentanyl is a highly lipid-soluble opioid (i.e., 600 times more lipid soluble than morphine); therefore, it has a more rapid onset of action than morphine (Table 13-4).

FIGURE 13-12 Epidural opioids traverse the dura and arachnoid membranes, diffuse through cerebrospinal fluid, and cross the pia membrane before reaching the spinal cord. Several factors, including physicochemical properties (e.g., pKa), affect the distribution of opioids within the neuraxis. (From Ross BK, Hughes SC. Epidural and spinal narcotic analgesia. Clin Obstet Gynecol 1987; 30:552-65.)

TABLE 13-4

Physicochemical Properties of Opioids Used for Neuraxial Analgesia

^* Octanol-water partition coefficient.

Data from Camu F, Vanlersberghe C. Pharmacology of systemic analgesics. Best Pract Res Clin Anaesthesiol 2002; 16:475-88; and McLeod GA, Munishankar B, Columb MO. Is the clinical efficacy of epidural diamorphine concentration-dependent when used as analgesia for labour? Br J Anaesth 2005; 94:229-33.

Latency, potency, and duration are also affected by other physicochemical properties, including molecular weight, pKa, and protein binding. For example, the lower the pKa, the greater the percentage of opioid existing in uncharged form (i.e., the anionic base) at a pH of 7.4. In the uncharged form, opioids penetrate the dura mater and dorsal horn more easily, resulting in a more rapid onset of analgesia.

The boundaries of the epidural space are the vertebral bodies, ligaments, and spinal meninges. Fat and the epidural venous plexus account for a large volume of the epidural space. The spinal meninges consist of the dura, arachnoid, and pia mater. Of these membranes, the arachnoid is the primary barrier for drug transfer from the epidural space to the spinal cord.²³⁵ The arachnoid mater has multiple layers of overlapping cells that represent both a hydrophilic domain (consisting of extracellular and intracellular fluid) and a hydrophobic domain (the cell membranes).²³² For an opioid to navigate the arachnoid, it must diffuse through both domains before entering the CSF. Therefore, drugs of intermediate hydrophobicity move most readily across the arachnoid. Other physical characteristics of drugs (e.g., molecular weight) do not appear to play an important role in determining redistribution from the epidural space to the subarachnoid space.²³²

The efficacy of a drug also depends on its physicochemical properties, particularly lipid solubility. For example, the amount of drug that is sequestered in the epidural fat is entirely dependent on the drug's octanol-to-buffer distribution coefficient.²³⁶ Consequently, lipophilic drugs (e.g., fentanyl) with a high octanol-to-buffer coefficient may never reach the arachnoid membrane and may partition in epidural fat. This lack of drug transfer across the meninges results in poor CSF bioavailability. To evaluate movement of opioids from the epidural to the subarachnoid space, Bernards et al.²³⁶ used a porcine model to continuously sample opioid concentrations in the epidural and intrathecal spaces. Using microdialysis techniques, the investigators measured the redistribution of morphine, alfentanil, fentanyl, and sufentanil out of the epidural space. (These opioids were administered by epidural bolus injection.) Opioid concentrations were measured over time in the epidural space, subarachnoid space, systemic venous plasma, and epidural venous plasma. Results suggested that there was a strong linear relationship between lipid solubility and mean residence time, indicating that more lipid-soluble opioids spent a longer time in the epidural space. Consequently, these drugs partition themselves into the epidural fat with ongoing slow release back into the epidural space. Because of their long residence time in the epidural space, more lipid-soluble drugs are found in lower concentrations in the CSF (i.e., decreased bioavailability to opioid receptors in the dorsal horn).

Several human studies have evaluated whether epidurally administered fentanyl produces analgesia by a selective spinal mechanism or by systemic absorption and redistribution. Results of studies of lipophilic opioids (administered by epidural infusion) have suggested that low concentrations of lipophilic opioids are subject to rapid vascular uptake from the epidural space or sequestration in epidural fat, thereby limiting access to the spinal cord.²³⁷^-²³⁹ However, other studies have suggested the occurrence of a spinal effect when lipophilic opioids are administered by epidural bolus injection²⁴⁰ or by epidural infusion of short duration.²⁴¹ Ginosar et al.²⁴² compared the analgesic effects of epidural bolus injection and epidural infusion of fentanyl in human volunteers. Study results suggested that epidural fentanyl infusion produced analgesia by uptake into the systemic circulation with redistribution to brain and peripheral opioid receptors. However, epidural bolus administration of fentanyl produced analgesia by selective spinal mechanisms. These results were consistent with previous reports that an epidural fentanyl bolus results in a larger amount of fentanyl in the epidural space than occurs at any time during an epidural infusion, leading to the greater availability of drug to activate opioid receptors in the dorsal horn of the spinal cord.

Although hydrophilic drugs (e.g., morphine) are subject to less systemic and epidural fat uptake than lipophilic drugs, the transfer of the former into the CSF is an inefficient process because they have difficulty in crossing the lipid bilayer of the arachnoid. However, despite these inefficiencies, morphine content in the spinal cord is significantly greater than lipophilic drug (e.g., fentanyl) content,²⁴³ and morphine has much greater bioavailability in the spinal cord than do fentanyl and sufentanil.²³⁶^,²⁴³ In summary, although morphine clearly produces analgesia via a spinal mechanism, the extent of spinal analgesia produced by the neuraxial administration of fentanyl is less clear.

After a drug reaches the subarachnoid space, either by diffusion across the meninges or by direct injection into the CSF, its effects depend on its lipid solubility. All opioids produce at least some analgesia by spinal-specific mechanisms. Movement of these drugs within the CSF depends on their physicochemical properties. Drugs can diffuse within the CSF in either a cephalad or a caudad direction. Both morphine and fentanyl have been shown to move rapidly within the CSF.²⁴⁴ Lipophilic drugs can also return to the epidural space by traversing previously mentioned structures.

Ummenhofer et al.²⁴³ used a porcine model to investigate intrathecal administration of opioids. These investigators found that lipophilic opioids have a very large volume of distribution compared with hydrophilic drugs; the volume of distribution of sufentanil was 40 times greater than that of morphine. The reason is sufentanil's extreme lipid solubility, with the drug rapidly leaving the CSF and entering the epidural fat, from which it is absorbed systemically.²⁴⁵

The ultimate goal of neuraxial opioid administration is for the drug to penetrate the dorsal horn of the spinal cord and activate μ-opioid receptors. A drug's ability to move from the CSF to the dorsal horn depends on its physicochemical properties. Of the clinically relevant opioids, morphine has the most favorable physicochemical properties to allow penetration of the dorsal horn of the spinal cord (i.e., gray matter). Because of its extreme lipid solubility, sufentanil redistributes itself or partitions itself on the superficial layer (i.e., white matter) of the spinal cord.²⁴³ Data suggest that the spinal bioavailability of the hydrophilic drugs (e.g., morphine, hydromorphone) is greater than that of hydrophobic opioids (e.g., fentanyl, sufentanil).

An extended-release formulation of morphine has been developed to prolong the duration of a single epidural injection of morphine or obviate the need for a continuous catheter. Multivesicular liposomal preparations gradually release morphine so that a larger epidural dose can be administered, providing analgesia for up to 48 hours (see Chapter 28). Studies that have compared extended-release epidural morphine (EREM) 10 to 15 mg with conventional epidural morphine for provision of analgesia after cesarean delivery have determined that EREM provided superior and prolonged analgesia.²⁴⁶^,²⁴⁷ The most recent American Society of Anesthesiologists Practice Guidelines for the Prevention, Detection, and Management of Respiratory Depression Associated with Neuraxial Opioid Administration state that “the literature reports no significant difference in the frequency of respiratory depression when [EREM] is compared with conventional (i.e., immediate release) epidural morphine.”²⁴⁸ However, in a study of patients undergoing cesarean delivery, Atkinson Ralls et al.¹⁴⁹ observed that epidural administration of 20 to 35 mL of epidural lidocaine 2% with fentanyl 1 hour before administration of EREM (8 mg) increased the mean (± SD) peak plasma concentration (C_max) in the EREM group (11.1 ± 4.9 ng/mL) compared with a group that received a CSE anesthetic technique without epidural medication (8.3 ± 7.1 ng/mL) (P = .038). Further, the EREM group had an increased incidence of vomiting, hypotension, and use of supplemental oxygen. Patients who receive EREM should be monitored at least once every hour during the first 12 hours after administration and at least once every 2 hours for the next 12 hours (i.e., from 12 to 24 hours).²⁴⁸ After 24 hours, monitoring should be performed at least once every 4 hours for a minimum of 48 hours. Increased intensity and duration of monitoring should be considered in patients at increased risk for respiratory depression (e.g., obesity) or in the setting of concomitant administration of opioid analgesics or sedative-hypnotics by other routes. Extra precautions should be taken when patients receive EREM within 1 hour of large doses of local anesthetic ¹⁴⁹ or when unintentional spinal administration occurs.²⁴⁹

In summary, the onset and duration of analgesia as well as side effects produced by neuraxial opioid administration depend on the specific type of opioid receptor that is activated as well as the dose, lipid solubility, and rate of movement and clearance of the opioid in the CSF.

Pharmacogenetics

Pain associated with labor and delivery is influenced by a multitude of physiologic, psychosocial, and environmental factors. However, genetic variations have also been suggested to alter a patient's sensation, experience, and perception of pain. Recent advances in genomic research have led to identification of more than 100 variants (polymorphisms) in the μ-opioid receptor gene (OPRM1).²⁵⁰ Although inconsistent, results of some studies suggest that a single-nucleotide polymorphism (SNP) in OPRM1 at position 118 (initially known as 118A>G, now annotated 304A>G; rs1799971) may influence responses to opioid analgesics.²⁵¹ The allelic frequency of the 304A>G polymorphism is population dependent; it is more common in Asians and less frequent in whites and blacks.

The role of the 304A>G polymorphism has been investigated in obstetric anesthesia. Using both up-down sequential allocation and random allocation methods, Landau et al.²⁵² estimated the ED₅₀ of intrathecal fentanyl, administered as part of a CSE technique for labor analgesia in nulliparous women with and without the 304A>G variant. The ED₅₀ of intrathecal fentanyl in women with the variant allele was lower than in women without the allele (1.5- to 2-fold difference). However, when Wong et al.²⁵³ investigated the effect of the 304A>G allele on the duration of intrathecal fentanyl labor analgesia (25 µg), they found no significant difference in the duration of analgesia or in the treatment of breakthrough pain in women with the variant allele. Camorcia et al.²⁵⁴ examined the effect of the 304A>G variant on the ED₅₀ of epidural sufentanil in nulliparous women. Similar to the findings of the Landau et al. study,²⁵² the estimated ED₅₀ was significantly lower in women with the variant allele (20.2 µg; 95% CI, 14.2 to 23.6) compared with women without the variant (25.2 µg; 95% CI, 23.2 to 26.4) (P = .03).

The potential role of the 304A>G polymorphism in influencing opioid analgesic requirements after cesarean delivery has been investigated in several studies. Wong et al.,²⁵³ in a mixed race/ethnicity population, found no difference in duration of intrathecal morphine analgesia or need for supplemental analgesia in women carrying the variant allele. In contrast, Sia et al.²⁵⁵ reported that Asian women with the variant allele had increased breakthrough pain (as assessed by patient-controlled intravenous morphine requirements) after intrathecal administration of morphine compared with women without the variant allele. In a second study, the variant allele was found to independently predict increased postoperative morphine use in women undergoing cesarean delivery.²⁵⁶

The results of these studies are difficult to reconcile.²⁵⁷ Although genetic components may influence patients' responses to nociceptive stimuli, current evidence suggests that genetic polymorphism in OPRM1 plays a minor role, if any, in opioid pain management.²⁵¹^,²⁵⁷ A recent meta-analysis examining the 304A>G variant of OPRM1 failed to identify a strong association between this variant allele and the response to opioids in different clinical settings.²⁵¹

Toxicity

Any agent that is injected into the epidural or subarachnoid space should be administered with caution owing to the potential for neurotoxicity and permanent neurologic damage. Although there is concern about injecting any type of medication into the neuraxis, the epidural space is more forgiving than the subarachnoid space (see Chapter 32). In many cases, clinicians have injected medications that were not well tested in animal models. Yaksh and Collins²⁵⁸ have urged careful administration of neuraxial drugs, stating that “studies in animals should precede human use of spinally administered drugs.”

The most commonly administered neuraxial opioids in obstetric patients are preservative-free morphine, fentanyl, and sufentanil. Preservative-free morphine is commercially available for both epidural and intrathecal administration. To evaluate preservative-free morphine for potential neurotoxicity, Abouleish et al.²⁵⁹ examined the short- and long-term effects of intrathecal morphine injection in monkeys. The meninges, nerve roots, and dorsal root ganglia were examined macroscopically and microscopically in both the study and the control groups. The researchers found no evidence of demyelination, arachnoiditis, or necrosis in either group.

Fentanyl is also available in a preservative-free formulation. Despite its widespread clinical use, few studies have assessed the histologic, physiologic, or clinical evidence of neurotoxicity with spinally administered fentanyl. One in vitro study evaluated the effects of fentanyl administration on nerve conduction.²⁶⁰ Histopathologic studies of isolated rabbit vagus nerve axons did not show localized nerve damage after nerves were bathed in an isotonic solution of fentanyl. When axons were bathed in a hypotonic solution of fentanyl, permanent conduction deficits were noted. However, in vivo, relatively large doses of fentanyl would be required to create a hypotonic intrathecal environment.

Although no formal neurotoxicology studies have evaluated sufentanil administration in humans, there are no clinical reports of neurotoxicity despite its widespread use. In one study, sufentanil was administered to cats through an indwelling intrathecal catheter over 5 days.²⁶¹ Sabbe et al.²⁶² administered clinically relevant doses of intrathecal sufentanil to dogs over several weeks and reported no histopathologic changes. In a sheep model, Rawal et al.²⁶³ demonstrated dose-dependent spinal cord histopathologic changes after intrathecal administration of sufentanil (50 to 100 µg) every 6 hours for 72 hours. These doses are much larger than those used in clinical practice. It is possible that these findings reflect an artifact of experimental design (e.g., the frequent administration of a large-volume, hypotonic preparation).

Despite the paucity of data about possible neurotoxicity, both fentanyl and sufentanil are widely used in clinical practice. These drugs are not approved by the FDA for neuraxial use. However, there are no published reports of neurologic deficits after epidural or intrathecal administration of either agent in humans, and these drugs appear to be safe for neuraxial administration. In general, anesthesia providers should exercise extreme caution before injecting any untested agent into the spinal or epidural space, in order to prevent irritation or damage to neural structures.

Side Effects

Neuraxial opioid administration is associated with beneficial effects as well as potential complications and side effects. Intrathecal administration of relatively large doses of morphine is associated with a high incidence of side effects, including somnolence, nausea and vomiting, pruritus, and respiratory depression (Table 13-5). However, epidural and intrathecal injection of more lipid-soluble opioids have fewer side effects.

TABLE 13-5

Incidence of Adverse Side Effects after Intrathecal Injection of 0.5 or 1.0 mg of Morphine

Modified from Abboud TK, Shnider SM, Dailey PA, et al. Intrathecal administration of hyperbaric morphine for the relief of pain in labour. Br J Anaesth 1984; 56:1351-60.

Sensory Changes

An early study evaluating intrathecal sufentanil in laboring women reported sensory changes and hypotension, although no local anesthetics were administered.²⁶⁴ Other investigators have reported high cervical sensory blockade associated with mental status changes, dysphagia, dyspnea, and automatisms after intrathecal sufentanil injection.²⁶⁵^-²⁶⁸ These symptoms are likely to be related to a dose-dependent opioid effect rather than neuraxial blockade–induced sympathectomy.²⁶⁹ Further, these changes do not predict the quality or duration of analgesia or degree of hemodynamic change.²⁶⁹ These sensory changes can be clinically significant, especially when they extend to the cervical dermatomes. Patients may feel that they cannot breathe or swallow, an effect that can be distressing. Fortunately, neither intrathecal sufentanil nor fentanyl affects the efferent limb of the nervous system, and motor function is not impaired. Patients should be reassured that their respiratory efforts are not impaired and that these symptoms will subside in 30 to 60 minutes. One report described the use of naloxone to treat the sensory changes associated with intrathecal sufentanil.²⁶⁵

Nausea and Vomiting

Nausea and vomiting are common during labor and delivery. Intrapartum nausea and vomiting can occur from a variety of causes, including pregnancy, physiology of labor itself, pain associated with labor, and parenteral administration of an opioid that may have preceded the neuraxial opioid administration. Therefore, it is difficult to determine the incidence of nausea and vomiting as direct side effects of neuraxial analgesia. Although the mechanism of neuraxial opioid–mediated nausea is unclear, there are suggestions that it may be caused by modulation of afferent input to the area postrema (i.e., the chemoreceptor trigger zone) or at the nucleus of the tractus solitarius, a key relay station in the visceral sensory network.²⁷⁰ Interestingly, nausea is more common after intrathecal administration of opioids to patients who have undergone cesarean delivery than in patients who received the same intrathecal regimen during labor and delivery. Norris et al.²⁷¹ reported that women receiving epidural or intrathecal opioid analgesia during labor had an incidence of nausea and vomiting of only 1.0% and 2.4%, respectively.

A number of treatments are available with minimal side effects. A meta-analysis suggested that metoclopramide administration (10 mg) before initiation of spinal anesthesia or after delivery resulted in a significant reduction in intraoperative nausea and vomiting as well as early postoperative nausea and vomiting.²⁷² One explanation for metoclopramide's efficacy is that it promotes gastric emptying. Ondansetron is also used in many centers for prophylaxis and treatment of opioid-induced nausea. In a study comparing transdermal scopolamine 1.5 mg, intravenous ondansetron 4 mg, and placebo, scopolamine was an effective prophylactic medication against nausea in parturients who received intrathecal morphine for analgesia after cesarean delivery.²⁷³ However, the use of scopolamine may be limited by bothersome side effects, including dry mouth, drowsiness, and blurred vision. George et al.²⁷⁴ performed a systematic review of randomized, controlled trials comparing prophylaxis or treatment of nausea and vomiting using one of the 5-hydroxytryptamine-3 (5-HT₃) receptor antagonists or placebo in women receiving spinal anesthesia with intrathecal morphine for cesarean delivery. The authors determined that 5-HT₃ receptor antagonists reduced the incidence of postoperative nausea and vomiting as well as the need for postoperative rescue antiemetic therapy when compared with placebo.

Although droperidol is effective for the treatment of nausea, the FDA has issued a “black box” warning against its use because of concern for QT-interval prolongation in association with droperidol administration. Intravenous cyclizine 50 mg was shown to be superior to dexamethasone 8 mg in reducing nausea after intrathecal morphine administration for cesarean delivery.²⁷⁵ Another systematic review of randomized controlled trials compared dexamethasone with placebo for the prevention of postoperative nausea and vomiting in patients receiving neuraxial morphine as part of a neuraxial technique.²⁷⁶ Results suggested that dexamethasone is an effective antiemetic agent, and doses used for antiemetic prophylaxis enhanced postoperative analgesia compared with placebo.

Pruritus

Pruritus is the most common side effect of neuraxial opioid administration.²⁶⁴^,²⁷⁷ Presentation is highly variable, but the incidence and severity seem to be dose dependent, especially with epidural opioid administration.²⁷⁸ Onset of the pruritus occurs shortly after analgesia develops, and even small doses of intrathecal sufentanil may produce significant pruritus.²⁷⁹ Some observers have noted a segmental pruritus, especially with lipophilic opioids. For example, patients often complain of perineal and truncal pruritus after intrathecal sufentanil injection.²⁶⁴ Pruritus occurs more commonly with intrathecal opioid administration than with epidural administration (in one study,²⁷¹ 41.4% versus 1.3%, respectively). The incidence and severity of pruritus may be reduced by administration of a lower dose of opioid²⁷⁹^,²⁸⁰ or co-administration of the opioid with a local anesthetic.²⁸¹ Many patients do not complain about the pruritus and appear asymptomatic; however, when questioned, they acknowledge the symptom.

Although the cause of opioid-induced pruritus is unknown, it appears to be unrelated to histamine release.²⁸² Some investigators have suggested that pruritus results from a perturbation of sensory input resulting from rostral spread of the opioid within the CSF to the trigeminal nucleus or subnucleus caudalis.²⁸² Itch-specific neuronal pathways may interact with pain pathways so that continuing activity of the pain-processing system suppresses activity in the spinal itch-processing neurons. Consequently, if pain is inhibited, pruritus can be unmasked (e.g., intrathecal morphine–induced pruritus). Pruritus can also be inhibited by pain (e.g., antipruritic effect of scratching).²⁸³

The serotoninergic system may contribute to modulation of pain by providing a balance between nociception and anti-nociception in the network of pain-processing neurons.²⁸⁴^,²⁸⁵ The dorsal horn of the spinal cord and the spinal tract of the trigeminal nerve are abundant in 5-HT₃ receptors. Because morphine is known to activate 5-HT₃ receptors by a mechanism independent of opioid receptors,²⁸⁶ it is postulated that morphine may directly stimulate 5-HT₃ receptors and may cause intrathecal morphine–induced pruritus. Consequently, occupation of 5-HT₃ receptors by a 5-HT₃–receptor antagonist potentially prevents the pruritus.

Iatrou et al.²⁸⁷ performed a randomized, double-blind, placebo-controlled study to evaluate the prophylactic effects of ondansetron and dolasetron in the treatment of intrathecal morphine–induced pruritus. Study results demonstrated that patients who received preemptive 5-HT₃–receptor antagonists reported significantly less pruritus and pruritus of less severity during the first 8 postoperative hours than patients who received placebo. The frequency of pruritus was reduced by 48% and 70% for ondansetron and dolasetron, respectively, compared with placebo. A quantitative systematic review evaluated the efficacy of prophylactic 5-HT₃ receptor antagonists for the prophylaxis and treatment of neuraxial opioid-induced pruritus. The investigators determined that prophylactic 5-HT₃ receptor antagonists did not alter the incidence of pruritus compared with placebo but did reduce the incidence of severe pruritus and the need for therapy.²⁷⁴ Additionally, 5-HT₃ receptor antagonists were efficacious for the treatment of established pruritus.

Other treatments of intrathecal opioid–induced pruritus include administration of intravenous naloxone (40 to 80 µg) or diphenhydramine (25 mg). Despite the probability that the pruritus is unrelated to histamine release, there may be some benefit from the modest sedation that follows diphenhydramine administration. Administration of nalbuphine (2.5 to 5 mg intravenously²⁸⁸^,²⁸⁹ or 10 mg subcutaneously²⁸⁸^,²⁹⁰) may also be helpful in reducing symptoms. The advantage of nalbuphine compared with naloxone is that it is less likely to reverse neuraxial opioid analgesia.²⁸⁹ Although propofol 10 to 20 mg was found effective for the treatment of pruritus in several studies in nonobstetric patients, its efficacy was no better than placebo in an obstetric study.²⁹¹ Regardless of the chosen treatment, pruritus can contribute significantly to patient dissatisfaction and should be treated promptly upon request.

Hypotension

Decreased blood pressure was reported in early studies that evaluated intrathecal opioid administration.²⁶⁴^,²⁶⁹ Although hypotension occurs in 5% to 10% of parturients who receive intrathecal opioids,²⁶⁴^,²⁶⁹ the incidence is higher when a local anesthetic or clonidine is added to the opioid. Early reports suggested that hypotension was due to a sympathectomy, but later work suggests that hypotension results from pain relief²⁹² and decreased maternal levels of catecholamines, especially epinephrine.²⁹³ Wang et al.²⁹⁴ demonstrated that intrathecal opioids block the afferent information from A-delta and C-fibers to the spinal cord but that efferent nerve impulses (e.g., sympathetic efferents) are not directly blocked.

Respiratory Depression

All opioids can cause respiratory depression regardless of their route of administration. When opioids are administered either epidurally or intrathecally, the following factors affect the risk for respiratory depression: (1) choice of drug and its pharmacokinetics, (2) drug dose, and (3) concomitantly administered CNS depressants. The most important factor affecting the onset time of respiratory depression induced by intrathecal opioids is lipid solubility.²⁷⁰ Respiratory depression may occur within minutes after the administration of a lipophilic opioid (e.g., fentanyl, sufentanil) because of rapid absorption of the opioid from the CSF to lipophilic tissues.²³⁴ Its subsequent clearance and elimination are similar to those of the drug when injected intravenously; thus the “time frame” for respiratory depression is short. In contrast, hydrophilic drugs (e.g., morphine, hydromorphone) are associated with a delayed onset of respiratory depression. This potentially serious side effect occurs because these hydrophilic opioids remain in the CSF for several hours. Although this characteristic improves the bioavailability of these opioids, rostral migration and absorption of the drug into the respiratory centers in the brainstem can produce respiratory depression 6 to 12 hours after injection (Figure 13-13).

FIGURE 13-13 Respiratory rate of an obstetric patient who received 5 mg of morphine after cesarean delivery and who experienced delayed respiratory depression. (From Leicht CH, Hughes SC, Dailey PA, et al. Epidural morphine sulfate for analgesia after cesarean section: a prospective report of 1000 patients [abstract]. Anesthesiology 1986; 65:A366.)

The dose of opioid has also been shown to be an important factor in the occurrence of respiratory depression. The usual dose of intrathecal morphine for analgesia after cesarean delivery is 0.1 to 0.2 mg. Not surprisingly, an early report of respiratory depression occurred after administration of intrathecal morphine 1 mg.²⁹⁵ In a dose-response study, Palmer et al.²⁹⁶ concluded that there was little justification for giving more than 0.1 mg of intrathecal morphine for analgesia after cesarean delivery. In a dose-response study of epidural morphine administration after cesarean delivery, investigators concluded that the quality of analgesia increases as the dose of epidural morphine increases to 3.75 mg but that increasing the dose to 5 mg does not improve analgesia.²⁹⁷

Studies in nonobstetric surgical patients suggest that the risk for respiratory depression after the epidural administration of EREM is also dose related.²⁹⁸^,²⁹⁹ Carvalho et al.²⁴⁷ compared EREM (10 mg) administration with standard epidural morphine (4 mg) administration in healthy women undergoing cesarean delivery and found that EREM reduced opioid consumption for 48 hours without significant risk for respiratory depression. However, the authors cautioned that the study's small sample size may not accurately reflect the true incidence of respiratory depression in obstetric patients who have received the extended-release preparation.

Although most cases of respiratory depression associated with sufentanil administration occur with larger doses, respiratory depression has also been reported with as little as 10 µg of intrathecal sufentanil administered for labor analgesia.³⁰⁰^,³⁰¹ Larger doses (e.g., 15 µg) have not been found to produce better or more prolonged analgesia but do result in increased plasma opioid concentrations and a higher risk for respiratory depression. In a female volunteer study, Lu et al.²⁴⁵ reported that doses of intrathecal sufentanil larger than 12.5 µg did not produce a proportionate increase in intensity or duration of analgesia. Similarly, there is little benefit to increasing the dose of intrathecal fentanyl beyond 25 µg when it is used as the sole agent for labor analgesia. These higher doses (i.e., more than 10 µg of sufentanil or more than 25 µg of fentanyl) should not be used in routine clinical practice. Respiratory depression has been reported with as little as 100 µg of epidural fentanyl.³⁰²

Several case reports have implicated previous parenteral administration of opioid as a contributing factor in respiratory arrest associated with intrathecal sufentanil administration in laboring women.³⁰³^,³⁰⁴ For example, Jaffee et al.³⁰⁵ reported a case of apnea and unresponsiveness in a parturient who had received several doses of intravenous fentanyl in the 4 hours before intrathecal sufentanil administration. Although the pregnancy-induced increase in respiratory drive continues throughout labor and into the postpartum period and may provide some protection against respiratory depression, respiratory depression is the most serious side effect of neuraxial opioid administration.

Practice guidelines from the American Society of Anesthesiologists recommend that all patients who receive neuraxial opioids should be monitored for adequacy of ventilation (e.g., respiratory rate, depth of respiration), oxygenation (e.g., pulse oximetry when appropriate), and level of consciousness.²⁴⁸ In patients who receive a single neuraxial injection of a lipophilic opioid (e.g., fentanyl), monitoring should be continual for the first 20 minutes after administration, followed by monitoring at least once per hour until 2 hours have passed. In patients who receive a single neuraxial injection of a hydrophilic opioid (e.g., morphine), monitoring should be performed at least hourly for the first 12 hours and then at least every 2 hours for the next 12 hours after opioid administration (and then every 4 hours for another 24 hours in patients who receive epidural EREM). For patients who receive a continuous infusion of a neuraxial opioid, monitoring should be performed hourly during the first 12 hours, every 2 hours for the next 12 hours, and then every 4 hours for the duration of the opioid infusion. In addition, the guidelines state that greater duration and intensity of monitoring and/or additional methods of monitoring may be indicated in patients at increased risk for respiratory depression (e.g., obesity, obstructive sleep apnea, concomitant administration of opioid analgesics by other routes).

Urinary Retention

Urinary retention is a bothersome side effect of intraspinal opioid administration. The incidence varies widely. It is more common with neuraxial opioid administration than with intramuscular or intravenous administration of equivalent doses. Urinary retention is unrelated to systemic absorption and is dose independent. The onset of urinary retention appears to parallel the onset of analgesia. Evidence suggests that the rapid onset of this side effect is produced by relaxation of the detrusor muscle (Figure 13-14),³⁰⁶ which most likely results from the sacral spinal action of opioids. Urinary retention can be treated with naloxone; however, because many parturients require catheterization for other reasons, urinary retention is often treated with bladder catheterization.

FIGURE 13-14 Urodynamic effects of epidural (Ep.), intramuscular (I.M.), and intravenous (I.V.) morphine administration in male volunteers. Depression of detrusor muscle function persisted for many hours after epidural morphine administration. This did not occur with parenteral opioids and may represent a local spinal cause (i.e., opioid receptors). (From Rawal N, Mollefors K, Axelsson K, et al. An experimental study of urodynamic effects of epidural morphine and of naloxone reversal. Anesth Analg 1983; 62:641-7.)

Delayed Gastric Emptying

Labor may delay gastric emptying, and opioids may further exacerbate this delay (see Chapter 29). Parenterally administered opioids are known to delay gastric emptying in laboring women.³⁰⁷ However, clinically useful doses of epidural fentanyl have minimal effects on gastric emptying. Intrathecal administration of fentanyl produces greater delays in gastric emptying than epidural administration.³⁰⁸ Delays in gastric emptying may increase the risk for nausea and vomiting and also increase the risk for aspiration if general anesthesia is necessary for emergency cesarean delivery.

Recrudescence of Herpes Simplex Virus Infections

Genital herpes infection (herpes simplex virus [HSV]) is the most common type of herpes-virus infection during pregnancy³⁰⁹; however, oral HSV infections (common cold sore or fever blister) resulting from reactivation of latent HSV infection also occur during pregnancy. Reports have suggested a relationship between neuraxial opioid administration and reactivation of oral herpes infection.³¹⁰ Crone et al.³¹¹ reported a 10% incidence of reactivation after cesarean delivery in patients who had received epidural morphine, compared with a 1% incidence in similar patients who did not receive epidural morphine. These observations have been confirmed in two prospective studies.³¹²^,³¹³ Davies et al.³¹⁴ reported an increased incidence of postpartum herpes infection in patients with a history of HSV-1 who had received intrathecal morphine. Two case reports have reported an association between intraspinal administration of fentanyl and meperidine and reactivation of oral herpes infection.³¹⁵^,³¹⁶

The mechanism of herpes reaction is unknown.³¹⁰ Viral reactivation is known to occur with exposure to ultraviolet light, immunosuppression, trauma, and fever. Proposed causes include (1) a skin trigger mechanism, whereby pruritus and scratching trigger reactivation; (2) an altered immunologic response³¹⁷; and (3) a ganglion trigger mechanism, whereby the intraspinal opioid spreads rostrally and binds to the trigeminal nerve.³¹⁸ The ganglion trigger mechanism involves an alteration of sensory modulation that results in reactivation. We are unaware of any serious maternal or neonatal complications that have resulted from neuraxial administration of an opioid and reactivation of oral herpes infection.

Placental Transfer and Fetal and Neonatal Effects

Neuraxial opioid administration may have a direct effect on the infant (i.e., respiratory depression at delivery) that results from systemic absorption of the opioid followed by transplacental transfer. The fetus may also be affected indirectly by opioid-related maternal side effects (i.e., hypoxemia, respiratory depression).

Neonatal Depression

Systemic opioid absorption can result in neonatal respiratory depression, which is sometimes observed after systemic opioid administration during labor.³¹⁹^,³²⁰ Neuraxial opioid analgesia techniques may result in better Apgar scores and umbilical cord blood gas and pH measurements at delivery. Despite the rapid systemic uptake of intrathecally administered opioids, the neuraxial analgesia requires the administration of smaller doses of opioid.

Several studies have evaluated neonatal outcome after continuous maternal epidural infusion of opioids and local anesthetics.³²¹^-³²³ Collectively, these studies have demonstrated that maternal epidural opioid administration by continuous infusion rarely results in drug accumulation and subsequent neonatal depression. Reynolds et al.³²⁴ performed a systematic review of randomized and nonrandomized studies comparing epidural with systemic opioid analgesia. They reviewed 12 trials with a total study population of 2102 parturients. Epidural analgesia was associated with better umbilical cord blood acid-base measurements than systemic opioids, suggesting that placental perfusion and gas exchange was well preserved despite maternal sympathetic blockade and effective analgesia. Although not all of the studies used neuraxial opioid infusions, the researchers suggested that replacement of systemic opioids with modest doses of neuraxial opioids not only produces superior analgesia but also may have a favorable effect on neonatal outcome.³²⁴

Fetal Heart Rate Abnormalities

Although epidural or intrathecal opioid administration has little direct effect on FHR,³²⁵ worrisome abnormalities such as late decelerations and fetal bradycardia have been observed after intrathecal lipophilic opioid administration. Several reports have described the abrupt onset of fetal bradycardia after intrathecal administration of fentanyl or sufentanil.³²⁶^-³²⁸ Clarke et al.³²⁷ suggested that the bradycardia is an indirect effect of decreased circulating maternal epinephrine associated with the rapid onset of analgesia. Epinephrine has a tocolytic effect and causes uterine relaxation by stimulating β₂-adrenergic receptors. Consequently, reduced epinephrine levels may lead to increased uterine tone. Because uteroplacental perfusion occurs during periods of uterine diastole (i.e., uterine relaxation), uterine tachysystole may result in diminished uteroplacental perfusion and fetal hypoxia. Norepinephrine is known to have a uterine-stimulating effect³²⁹; thus the decrease in epinephrine concentration alongside an unchanged norepinephrine concentration may produce uterine hyperactivity and fetal compromise.

Other mechanisms may also be relevant. Van de Velde et al.³³⁰ questioned the catecholamine imbalance theory, because intrathecal bupivacaine combined with low-dose sufentanil (1.5 µg) produced analgesia similar to that provided by intrathecal sufentanil (7.5 µg), but the incidence of fetal bradycardia was higher with sufentanil 7.5 µg. Russell et al.³³¹ demonstrated that intravenous opioids have central effects, altering the release of oxytocin and vasopressin and inducing uterine hyperactivity. Lipid-soluble opioids undergo rapid systemic redistribution after neuraxial injection; therefore, even neuraxial opioids may have central effects.

Initial reports indicated that the incidence of FHR abnormalities with intrathecal opioid analgesia was 15% to 20%.²⁶⁴^,³³² One published report suggests that uterine tachysystole and fetal bradycardia may follow administration of either intrathecal or epidural analgesia during labor.³³³ FHR tracings were assessed after administration of either intrathecal sufentanil or epidural bupivacaine. There were no observed differences in the incidence of FHR abnormalities (i.e., recurrent late decelerations and/or bradycardia) between groups (22% in the intrathecal sufentanil group versus 23% in the epidural bupivacaine group).³³³ In contrast, Mardirosoff et al.³³⁴ performed a systematic review of all randomized trials comparing intrathecal with non-intrathecal administration of opioids in laboring women. Twenty-four trials met criteria; the study population included 3513 women. The relative risk for FHR abnormalities in patients receiving spinal opioids was 1.81 (95% CI, 1.04 to 3.14). The risks of cesarean delivery for FHR abnormalities were similar in the two groups (6.0% for intrathecal administration versus 7.8% for other methods).

In a prospective study, Van de Velde et al.³³⁰ investigated whether intrathecal sufentanil 7.5 µg produced more FHR abnormalities than either conventional epidural analgesia or intrathecal bupivacaine combined with sufentanil 1.5 µg. The high-dose sufentanil group had more FHR abnormalities (i.e., late decelerations, fetal bradycardia) but less hypotension than the low-dose sufentanil/bupivacaine group. The incidence of FHR abnormalities was similar in the low-dose sufentanil/bupivacaine and conventional epidural analgesia groups. The rates of cesarean delivery for FHR abnormalities were similar in the three groups. Although FHR abnormalities are worrisome, most published trials have not reported a higher risk for emergency cesarean delivery with intrathecal opioid analgesia.³³⁰^,³³⁴^,³³⁵ However, Gambling et al.³³⁶ reported more operative deliveries for nonreassuring fetal status after administration of intrathecal sufentanil 10 µg than with parenteral meperidine analgesia. The study's conclusions, however, were limited in that the two study groups differed in frequency of FHR assessment.

In a randomized trial, Abrao et al.³³⁷ evaluated the effects of CSE versus traditional epidural analgesia on basal uterine tone and the occurrence of FHR abnormalities. Use of the CSE technique was the only independent predictor of an increase in basal intrauterine pressure of 10 mm Hg or more (OR, 3.53; 95% CI, 1.21 to 10.36; P = .022). The authors also demonstrated that the only predictor of FHR abnormalities was an increase in intrauterine pressure after initiation of analgesia (OR, 18.62; 95% CI, 4.46 to 77.72). A decrease in visual analog scale pain scores immediately after administration of analgesia was also correlated with an increased probability of increased intrauterine pressure and FHR abnormalities. Although there were no emergency cesarean deliveries that resulted from either neuraxial technique, the authors concluded that more studies are needed to better understand the effects of the CSE technique on labor progress and fetal physiology.³³⁷ However, in a letter-to-the-editor, Landau et al.³³⁸ suggested that the analgesic techniques were not equipotent. Additionally, monitoring for FHR abnormalities was only performed for 15 minutes. Given that the onset of analgesia is slower with epidural compared with CSE techniques, FHR abnormalities may occur earlier after intrathecal analgesia.

Given the potential risk for fetal bradycardia after neuraxial analgesia in laboring women, the FHR should be monitored before and after the initiation of epidural and intrathecal analgesia. FHR changes are usually transient and may be managed successfully with conservative measures, including (1) supplemental oxygen administration, (2) position changes to relieve aortocaval compression, (3) vasopressor therapy to treat hypotension, (4) discontinuation of oxytocin infusion, (5) intravenous fluid bolus administration, and (6) administration of a tocolytic agent for persistent uterine tachysystole.

Historically, intravenous or subcutaneous terbutaline was used to treat persistent uterine tachysystole. More recently, nitroglycerin has been used with some success. Nitroglycerin has several advantages compared with terbutaline. First, nitroglycerin has a short duration of action and labor resumes shortly after the period of tachysystole. In addition, nitroglycerin rarely produces significant hypotension, and if hypotension occurs, it is easily treated. Several studies have evaluated nitroglycerin for the treatment of uterine hypertonus. Mercier et al.³³⁹ described consistent success in treating FHR abnormalities resulting from uterine tachysystole after the administration of one or two doses of nitroglycerin (60 to 90 µg), and Bell³⁴⁰ described the successful use of sublingual nitroglycerin (400 µg) in the treatment of uterine tachysystole. In a randomized trial comparing intravenous terbutaline 250 µg to nitroglycerin 400 µg for the treatment of intrapartum tachysystole and nonreassuring FHR tracings, acute intrauterine resuscitation success rates were similar between the two groups (72% versus 64% for terbutaline and nitroglycerin, respectively; P = .38), but the incidence of tachysystole 10 minutes after drug administration was lower in the terbutaline group.³⁴¹ Therefore, if there is no response within 2 to 3 minutes of nitroglycerin administration, terbutaline 0.25 mg (250 µg) should be administered and preparations should be made for emergency cesarean delivery if the fetal bradycardia does not resolve.

Adjuvants

Epinephrine

Epinephrine is often added to epidural and spinal local anesthetic solutions to increase the duration of anesthesia, reduce peak plasma drug concentrations, improve block reliability, and intensify analgesia/anesthesia.³⁴²^-³⁴⁴ Uptake of epinephrine varies with the choice and concentration of local anesthetic as well as the concentration of epinephrine. The effect of epinephrine is greater when it is combined with lidocaine than when it is combined with bupivacaine.¹⁵⁹^,¹⁹⁸ Even concentrations of epinephrine as low as 3.3 µg/mL (1 : 300,000) have been shown to be effective in reducing the plasma concentrations of lidocaine.³⁴⁴

The efficacy of epinephrine depends on the specific local anesthetic as well as the site of injection. Epinephrine prolongs the duration of epidural lidocaine anesthesia by reducing uptake of local anesthetic into the systemic circulation through constriction of the epidural venous plexus. This effect helps maintain the concentration of local anesthetic at the site of injection. During epidural administration, epinephrine provides optimal results when added to lidocaine in a concentration of 5 µg/mL (1 : 200,000); this concentration of epinephrine nearly doubles the duration of epidural lidocaine anesthesia.³⁴⁵ In contrast to lidocaine, the addition of epinephrine 3.3 µg/mL to epidural bupivacaine 0.5% had no effect on maternal venous plasma concentrations of drug in laboring women.³⁴⁶ Similarly, Reynolds et al.³⁴⁷ observed no effect when epinephrine 5 µg/mL was added to bupivacaine during administration of epidural anesthesia for cesarean delivery. Epinephrine did not prolong the epidural anesthesia produced by ropivacaine,³⁴⁸ nor did it alter absorption of lidocaine after subarachnoid injection.³⁴⁹ In contrast, one group reported that the addition of epinephrine to bupivacaine resulted in a 50% decrease in maternal plasma concentrations of bupivacaine after paracervical block.³⁵⁰

Greater reliability and intensity of the block are sometimes observed when epinephrine is added to epidurally administered local anesthetics. Epinephrine has intrinsic analgesic effects that are produced by stimulation of α₂-adrenergic receptors. These presynaptic adrenergic receptors are found at the terminals of primary afferent neurons. They can also be found centrally on neurons in superficial laminae of the spinal cord and in several brainstem nuclei.

In addition to the intrinsic analgesic effects of epinephrine, the inherent lipid solubility of each local anesthetic affects the degree of sensory blockade. Each local anesthetic has a lipid-to-water partition coefficient that determines the drug uptake between the aqueous and lipid phases within the spinal canal. The outcome of competition between these lipid and aqueous phases depends on the lipid solubility of the local anesthetic. If a local anesthetic is more lipid soluble, the advantage of adding epinephrine to the local anesthetic is less significant. For example, the lipid-to-water partition coefficient of lidocaine is 2.7. When epinephrine is added to lidocaine, there is marked improvement in the intensity of the block. However, because bupivacaine has a lipid-to-water partition coefficient 10 times greater than that of lidocaine, the effect of epinephrine on a bupivacaine block is less pronounced. Because ropivacaine has a lipid-to-water partition coefficient similar to that of lidocaine, epinephrine will intensify a ropivacaine block. However, the duration of the block remains unchanged.

Despite the advantages of epinephrine, concern remains about the effects of epinephrine on uterine blood flow and the maternal cardiovascular system. In healthy fetuses, epidural administration of epinephrine does not affect umbilical cord blood flow. However, in fetuses with increased vascular resistance, epidural epinephrine administration can increase the umbilical artery S/D ratio.³⁵¹ Studies of the effects of epinephrine on the placental transfer of local anesthetics have yielded contradictory results. In rabbits, epinephrine did not affect the F/M ratio of bupivacaine.³⁵² As a result of the addition of epinephrine, the F/M ratio for bupivacaine has been found to be increased³⁵³ or unchanged.³⁴⁶^,³⁵⁰^,³⁵⁴ For lidocaine, the F/M ratio has variously been reported to be increased,¹⁹⁸^,³⁵⁵ decreased,³⁴⁴ or unchanged.³⁵⁶

Bicarbonate

The addition of sodium bicarbonate to a local anesthetic solution increases the pH closer to the pKa of the local anesthetic. This change increases the proportion of drug in un-ionized form that is available to penetrate the nerve sheath and membrane, thereby accelerating the onset of the block and decreasing the minimum concentration required for conduction blockade.³⁵⁷ Most studies have demonstrated that the addition of sodium bicarbonate to lidocaine, bupivacaine, or 2-chloroprocaine hastens the onset of epidural blockade by as much as 10 minutes.¹⁴⁸^,³⁵⁸^-³⁶⁰ The speed of onset of a ropivacaine block does not seem to be affected by alkalinization, but as with the other local anesthetics, evidence suggests that alkalinization intensifies epidural ropivacaine anesthesia and improves spread to sacral dermatomes.³⁶¹ The effects of alkalinization are most pronounced in epinephrine-containing solutions, particularly commercially prepared epinephrine-containing formulations. These solutions are prepared at a lower pH, ranging from 3.2 to 4.2.³⁶² The lower pH of these solutions helps preserve the epinephrine but increases the latency of onset.

Sodium bicarbonate 1 mEq/mL (8.4%) may be freshly added to local anesthetic solutions shortly before use (Table 13-6). Alkalinization of bupivacaine must be performed carefully because the margin between satisfactory alkalinization and complete precipitation is very narrow. All local anesthetics have a tendency to precipitate, so solutions containing bicarbonate should be inspected for precipitation before being administered.

TABLE 13-6

Alkalinization of Local Anesthetic Solutions

Local Anesthetic	Sodium Bicarbonate (mL)*
Lidocaine	1.0
Bupivacaine	0.1
2-Chloroprocaine	0.3

^* Sodium bicarbonate 8.4% (1 mEq/mL) added to 10 mL local anesthetic solution. Suggested doses are from Warren DT, Neal JM, Bernards CM. Neuraxial anesthesia. In Longnecker DE, Newman MF, Brown DL, Zapol WM, editors. Anesthesiology. 2nd edition. New York, McGraw-Hill, 2012. Available at http://www.accessanesthesiology.com/content/56638559. Accessed August 2013..

Hypotension occurs more frequently with epidural administration of an alkalinized local anesthetic than with administration of an unbuffered solution.³⁶³ This likely results from an accelerated onset of sympathetic blockade. Carbonated salts of local anesthetics can also be administered for a rapid onset of epidural blockade. However, these drugs have limited availability. Like alkalinized local anesthetics, these preparations are more likely to produce hypotension.

Clonidine

α₂-Adrenergic agonists (e.g., clonidine) have been investigated as adjuvants to local anesthetics and opioids to improve analgesic efficacy without increasing side effects. The advantage of clonidine is its ability to provide analgesia without affecting sensation or producing motor blockade.³⁶⁴ However, epidural and intrathecal administration of α₂-adrenergic agonists are known to produce hypotension, probably by acting on α₂-adrenergic receptors on preganglionic cholinergic neurons.³⁶⁵ In addition, α₂-adrenergic agonists produce dose-dependent sedation, which results from α₂-adrenergic stimulation in the locus ceruleus.³⁶⁶

Neuraxial clonidine has been administered for labor as well as analgesia after cesarean delivery. It exerts its effects by binding to α₂-adrenergic receptors located on primary afferent terminals of the spinal cord, substantia gelatinosa, and brainstem nuclei³⁶⁷ as well as via a cholinergic mechanism.³⁶⁸ Conduction blockade is produced by increases in potassium conductance and in acetylcholine and norepinephrine in the CSF, leading to decreased release of substance P and subsequent analgesia.³⁶⁹

Approximately 70% of alpha-adrenergic receptors on human myometrium are α₂-adrenergic receptors³⁷⁰; therefore, the potential effects of clonidine on labor and delivery have been evaluated. In an in vitro study, clonidine directly enhanced the frequency and amplitude of human myometrial contraction.³⁷¹ α₂-Adrenergic receptor stimulation in the uterus could theoretically enhance uterine contractions and decrease uterine blood flow.³⁶⁵ Indeed, in animal studies, large doses of clonidine produced a decrease in FHR.³⁷² This effect probably resulted from direct fetal transfer of drug and from direct and indirect effects on baroreflexes. However, this effect is unlikely to occur with clinical doses of neuraxial clonidine.

Multiple studies have evaluated neuraxial clonidine administration in humans as an analgesic adjunct during labor and delivery (see Chapter 23). When combined with local anesthetics and opioids, lower doses may be used, resulting in less hypotension and sedation. The FDA has issued a “black box” warning against its use in obstetric patients because of concerns about hemodynamic instability after its use. Therefore, clonidine is rarely used for labor analgesia in North America; however, it is more widely used in some European countries. Clonidine 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 setting, the bolus administration of clonidine 75 µg without a local anesthetic is not usually associated with hypotension. It appears safe to add small doses of intrathecal clonidine (15 to 30 µg) to opioids or local anesthetics, but side effects must be treated promptly to avoid fetal compromise.

Epidural clonidine has been administered for analgesia after cesarean delivery. One study suggested that epidural clonidine (400 to 800 µg) provided postoperative analgesia, but a continuous infusion was required after 6 hours.³⁷³ Others have demonstrated that epidural clonidine (75 to 150 µg) lengthens the duration of postoperative analgesia without increasing the incidence of side effects.³⁷⁴^,³⁷⁵

Neostigmine

Both nicotinic and muscarinic cholinergic receptors are present in the dorsal horn of the spinal cord. Neostigmine prevents breakdown of acetylcholine in the spinal cord. The acetylcholine then binds to muscarinic and nicotinic receptors of the spinal cord.³⁷⁶^-³⁷⁸ Stimulation of muscarinic receptors facilitates release of gamma-aminobutyric acid (GABA) in the dorsal horn of the spinal cord, resulting in analgesia.³⁶⁸^,³⁷⁹ Neostigmine and clonidine use a common pathway to produce analgesia mediated through acetylcholine release.

Several studies have evaluated the addition of neostigmine to intrathecal labor analgesics. Although results of these studies were inconsistent in terms of prolonging the duration of labor analgesia, all studies found that intrathecal administration of neostigmine produced severe nausea unresponsive to standard antiemetics.³⁸⁰^,³⁸¹ These important gastrointestinal side effects limit its clinical use despite its ability to potentiate the analgesic effects of intrathecal opioids and clonidine.

Epidural neostigmine alone has limited efficacy. Neostigmine appears to be more effective at alleviating somatic pain than visceral pain.³⁸²^,³⁸³ Visceral afferents are located deep within the spinal cord. Because neostigmine has low lipid solubility, it has a limited ability to traverse biologic membranes. When it is administered without other agents, it is unable to reach these visceral afferents responsible for much of labor pain.³⁸⁴ This accounts for the limited efficacy of neostigmine epidurally administered as the sole agent. However, when combined with epidural sufentanil or clonidine for initiation of analgesia, neostigmine produces selective analgesia without side effects.³⁸⁵^,³⁸⁶ Large doses of neostigmine can potentially reduce uteroplacental blood flow by CNS activation and direct stimulation of uterine contractions.³⁸⁷ When administered for analgesia after cesarean delivery, epidural neostigmine (75 to 300 µg) produced modest analgesia without nausea or vomiting, but the incidence of sedation was increased.³⁸⁸ Neostigmine is not routinely used in clinical practice, and its neuraxial administration is not approved by the FDA.

Key Points

• Pregnancy enhances the effect of local anesthetic agents.

• Appropriate administration of epidural anesthesia does not adversely affect uterine tone or uterine or umbilical blood flow.

• Bupivacaine has greater cardiotoxicity than lidocaine because of its greater electrophysiologic effects, which predispose to ventricular arrhythmias.

• Single (levorotary) isomer formulations of amide local anesthetics, such as ropivacaine and levobupivacaine, have a lower potential for cardiotoxicity than racemic bupivacaine.

• The decision to initiate lipid therapy for treatment of local anesthetic systemic toxicity should be based on clinical severity and rate of progression of symptoms.

• Fetal acidosis results in a greater accumulation of amide local anesthetic in the fetus.

• Local anesthetics, as used clinically, are not teratogenic.

• The elimination half-life of amide local anesthetics is longer in the newborn than in the adult because the former has a greater volume of distribution.

• The fetus and newborn seem to be no more vulnerable to the toxic effects of local anesthetics than the adult.

• Neonatal neurobehavior depends on many factors other than the choice of local anesthetic.

• Alkalinization of a local anesthetic solution shortens the latency of neural blockade but increases the risk for hypotension during administration of epidural anesthesia.

• Neuraxial opioid administration produces analgesia without loss of sensation or proprioception.

• The combination of a neuraxial local anesthetic and an opioid increases block density and allows for administration of a lower total dose of local anesthetic and a lower incidence of side effects.

• Spinal bioavailability of the hydrophilic drugs (e.g., morphine, hydromorphone) is greater than that of hydrophobic (lipophilic) opioids (e.g., fentanyl, sufentanil).

• The most common side effects of neuraxial opioid administration are pruritus and nausea and vomiting. Fetal bradycardia and maternal respiratory depression are the most serious complications.

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