Factors that affect the choice of opioid include speed of onset, duration of action, efficacy, type and frequency of side effects, and availability. If side effects prevent adequate analgesia, other opioids or nonopioid adjuvants should be used. Patient preferences based on past experiences and desired analgesia should also be considered.

Historically, meperidine (pethidine) has been a popular opioid for postoperative analgesia. However, the American College of Obstetricians and Gynecologists has discouraged the use of meperidine in obstetric patients because of the accumulation of the metabolite normeperidine in the neonate and its subsequent effect on neurobehavioral scores. Table 27.1 shows commonly used alternatives to meperidine with equianalgesic doses.

The use of oral analgesics has been advocated as there is seldom a requirement for a prolonged fasting period after cesarean delivery. Most evidence suggests that intravenous (IV) administration of opioids is not superior to oral opioids for postoperative analgesia. Davis et al. reported that patients randomized to receive oral oxycodone experienced less pain at 6 and 24 hours, and less nausea and drowsiness at 6 hours after cesarean delivery, compared with patients who received morphine by IV patient-controlled analgesia (PCA). Dieterich et al. found IV PCA and oral opioids provided similar satisfaction and pain scores after cesarean delivery. Therefore, when tolerated, oral administration of opioids may be the preferred route. Advantages of this approach are cost savings and facilitation of early mobility. Long-acting oral opioids are not recommended in the immediate postoperative period.

Intramuscular (IM) and subcutaneous opioids are inexpensive, easy to administer, and associated with a long history of safety but are not commonly used in the United States because of the need for repeated painful injections, delayed (and sometimes erratic) absorption of drug, and an inconsistent analgesic response caused by variation in plasma opioid concentration. IV PCA allows patients to control their own pain management by self-administering small doses of IV opioids. A 2015 metaanalysis concluded that PCA is often preferred by patients compared with nurse-administered analgesia on request, and PCA was shown to provide better pain control and increased patient satisfaction compared with non‑patient-controlled methods. The American Society of Anesthesiologists (ASA) Task Force for Acute Pain Management in the Perioperative Setting recommended that “these modalities [epidural or intrathecal opioids, systemic opioid PCA, and peripheral regional techniques] should be used in preference to IM opioids ordered “as needed.” The American Pain Society has recommended the use of IV opioid PCA when parenteral administration of analgesics is necessary and the oral route is not available.

PCA has been used via the IV and epidural routes after cesarean delivery. A study that compared IV and epidural PCA using fentanyl reported higher pain scores and greater fentanyl consumption with the IV route, although patient satisfaction was similar in the two groups. In another study that compared IV versus epidural PCA using hydromorphone , drug requirement was threefold to fourfold higher in the IV group; the two groups had similar pain and sedation scores, but patients in the IV group reported more frequent drowsiness and less pruritus. Studies that compared IV morphine PCA to single-shot epidural morphine administration for postcesarean analgesia showed that analgesia and patient satisfaction were better and sedation was less with epidural morphine, although the incidence of pruritus was higher.

The goal of opioid administration is to achieve maximal analgesia with minimal side effects. It is important to monitor the respiratory rate and sedation level before giving an additional dose or adjusting the PCA bolus dose. Patients with comorbidities such as hepatic or renal dysfunction (e.g., occurring with severe preeclampsia), morbid obesity, and/or obstructive sleep apnea are particularly susceptible to the respiratory depressant effects of opioids; these patients may need special alterations to pain management, including the use of multimodal analgesia (see later discussion).

Healthcare professionals who prescribe PCA should (1) evaluate candidates for PCA (e.g., mental state, level of consciousness, patient understanding); (2) know drug selection criteria, dosing schedules, lockout intervals, and infusion devices; (3) provide patient education on pain management and the use of PCA; (4) understand when to alter PCA settings and when to give or withhold additional (rescue) doses of medications; and (5) be able to respond to side effects and adverse events. Observational studies of nonobstetric patients have reported an incidence of respiratory depression with IV PCA of 0% to 11.5%, which is equivalent to or higher than that reported for neuraxial opioids.

In 2004 The Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) issued a Sentinel Event Alert on PCA “by proxy” (i.e., when other individuals, including family members, become involved in drug administration by PCA). The JCAHO acknowledged that PCA is a safe and effective method of controlling pain when used as prescribed; however, serious adverse events, including oversedation, respiratory depression, and death, can result when analgesia is delivered “by proxy.” The following recommendations were made: (1) develop criteria for selecting appropriate candidates for PCA, (2) carefully monitor patients, (3) teach patients and family members about the proper use of PCA and the dangers of others pressing the button for the patient, (4) alert staff to the dangers of administering a dose outside a prescribed protocol, and (5) consider placing warning tags on all PCA delivery pendants stating “only the patient should press this button.” The PCA settings (drug, demand dose, lockout interval, 4-hour [or other time] limit, and the rate of continuous infusion [if used]) are documented on a flow sheet, and any changes in PCA settings clearly documented.

Programmable PCA parameters include drug choice, bolus dose, maximum dose, and lockout interval ( Table 27.2 ). Owen et al. performed several PCA investigations in patients undergoing abdominal surgery. In an assessment of PCA morphine demand bolus doses (0.5, 1, or 2 mg with a 5-minute lockout interval), more patients in the 0.5-mg group had inadequate pain relief, whereas those in the 2-mg group had more side effects, including respiratory depression (respiratory rate < 10 breaths/min). These outcomes correlated with the total dose of self-administered morphine.

The American Pain Society does not recommend routine use of basal infusions of opioid in opioid-naïve patients; most evidence does not demonstrate improved analgesia compared with patients who receive no basal infusion. Basal infusions of opioids are associated with an increased incidence of nausea and vomiting, and some studies have shown an increased risk for respiratory depression.

During PCA, the ratio of patient demands to delivered bolus doses appears to be a good measure of analgesia and is strongly correlated with pain scores. A high ratio likely reflects patient misunderstanding or inadequate analgesia; a ratio close to 1 signifies adequate pain relief. Analgesia may be improved by an increase in the bolus dose, a shorter lockout interval, or a change of opioid.

Because of the significant morbidity associated with high doses of opioids, use of these drugs should invoke the application of algorithms for pain assessment, management, and monitoring. Acute postoperative pain is limited in duration; therefore, a plan should be devised for the transition from IV opioids to oral analgesic agents when pain is controlled and the patient is able to take medication by mouth.

Acetaminophen is estimated to provide an opioid-sparing effect of approximately 10% to 20%. However, the efficacy of IV perioperative acetaminophen in reducing postoperative opioid utilization has not yet been clearly established. A metaanalysis showed that perioperative IV acetaminophen was associated with similar opioid utilization compared with placebo. The authors concluded that the review was limited by small numbers and heterogeneity, as well as the absence of long-acting neuraxial opioids, which differed from contemporary anesthetic practice. Nonetheless, based on its relative safety, minimal breast milk transfer, and potential opioid-sparing effects, administration of acetaminophen at scheduled intervals is recommended for postcesarean delivery analgesia.

The use of IV acetaminophen is gaining popularity, supported by studies demonstrating faster and higher plasma and cerebrospinal fluid drug levels compared with oral acetaminophen. However, there is little evidence that IV acetaminophen is superior to oral acetaminophen, especially given the additional costs of the IV formulation. A randomized controlled trial reported no significant difference in 24- and 48-hour opioid consumption, time to first opioid rescue, pain scores, satisfaction, side effects, and times to ambulation and discharge after cesarean delivery in patients who received IV acetaminophen at 8-hour intervals compared with those who received the oral formulation, following neuraxial anesthesia with intrathecal fentanyl (15 μg) and morphine (0.2 mg), plus IV ketorolac.

Avoiding opioid/acetaminophen combination medication is recommended to decrease unnecessary opioid use and avoid exceeding recommended maximum doses of acetaminophen. Valentine et al. performed a retrospective medical record review of women who underwent cesarean delivery before and after a change in clinical practice at their institution. All patients received spinal anesthesia with intrathecal morphine 0.2 mg and scheduled NSAIDs for 48 hours postoperatively. After the change, the women received oral acetaminophen 650 mg every 6 hours for 48 hours postoperatively with oral oxycodone administered as needed for breakthrough pain. The scheduled acetaminophen group used less opioid in the first 48 hours than the historical as-needed group ( Fig. 27.2 ).

Opioid use in milligram intravenous morphine equivalents after cesarean delivery in 24-h increments in patients who received scheduled oral acetaminophen with as-needed opioid (dark shading) versus patients who received as-needed combination opioid-acetaminophen (light shading) . Data are mean (bar) and standard deviation (whisker) . *Significant difference between groups ( P <.001).

Redrawn from Valentine AR, Carvalho B, Lazo TA, Riley ET. Scheduled acetaminophen with as-needed opioids compared to as-needed acetaminophen plus opioids for postcesarean pain management. Int J Obstet Anesth . 2015;24:210–216.

NSAIDs suppress inflammation by inhibition of the cyclooxygenase (COX) enzymes and are a key component of multimodal analgesia. They are effective for perineal pain after vaginal delivery and postcesarean abdominal pain; when coadministered with opioids, they produce a 30% to 50% opioid-sparing effect that can reduce opioid-related side effects. A 2016 systematic review and metaanalysis showed that the use of NSAIDs resulted in lower pain scores up to 24 hours postoperatively, less opioid consumption, and less sedation after cesarean delivery. The combination of NSAIDs and acetaminophen has been shown to be more effective than either drug alone, with some evidence for a synergistic interaction. In addition to antiinflammatory, analgesic, and antipyretic properties, nonselective NSAIDs that inhibit both COX-1 and COX-2 isoenzymes also inhibit platelet adhesion and cause renal artery vasoconstriction and gastrointestinal irritation. Therefore, NSAID use in patients at risk for hemorrhage and renal failure warrants caution. Nonetheless, in most parturients without these risk factors, use of NSAIDs is considered safe. Because of limited transfer to breast milk, NSAIDs are particularly beneficial for lactating mothers. The American Academic of Pediatrics considers NSAIDs safe for nursing mothers (see Chapter 16 ).

Ibuprofen is one of the most widely used NSAIDs that is available without prescription. In a small study (oral ibuprofen 400 mg every 6 hours for 24 hours), less than 1 mg of ibuprofen was excreted in breast milk in a 36-hour period. Many centers administer 600 to 800 mg every 6 to 8 hours as a standard dose. Oral naproxen 500 mg every 12 hours has been shown to reduce incisional pain compared with placebo and decrease opioid consumption ( Fig. 27.3 ). Diclofenac has also been extensively studied; rectal suppositories (100 mg twice a day) decreased morphine consumption compared with placebo (14 mg versus 22 mg in 32 hours) after cesarean delivery. A single rectal dose of diclofenac 100 mg prolonged the mean time to first analgesic administration by more than 5 hours in patients who received intrathecal morphine. Patients who received intrathecal morphine doses as small as 25 µg required no rescue analgesic when IM diclofenac 75 mg was administered every 8 hours. Munishankar et al. randomized patients who received spinal anesthesia with bupivacaine and fentanyl to receive one of three analgesic modalities: acetaminophen, diclofenac, or diclofenac plus acetaminophen. Women who received both diclofenac and acetaminophen required less morphine than those who received acetaminophen alone ( Fig. 27.4 ). Lowder et al. showed that ketorolac decreased pain scores at 2, 3, 4, 6, 12, and 24 hours after cesarean delivery and also decreased opioid consumption. Ketorolac previously had a “black box” warning that it was “contraindicated in nursing mothers,” but current recommendations are to use it with caution.

Effect of naproxen on requirement for oral codeine after cesarean delivery: oral codeine use in milligram equivalents (expressed as mean) over time by group.

From Angle PJ, Halpern SH, Leighton BL, et al. A randomized controlled trial examining the effect of naproxen on analgesia during the second day after cesarean delivery. Anesth Analg . 2002;95:741–745.

Morphine consumption in milligrams in consecutive 4-h periods after cesarean delivery in women randomized to receive acetaminophen (paracetamol), diclofenac, or both. Data were analyzed using repeated measures analysis of variance; patients in the acetaminophen/diclofenac group used less morphine per 4-h period than patients in the acetaminophen but not the diclofenac group.

Redrawn from Munishankar B, Fettes P, Moore C, McLeod GA. A double-blind randomised controlled trial of paracetamol, diclofenac, or the combination for pain relief after caesarean section. Int J Obstet Anesth . 2008;17:9–14.

COX-2–selective inhibitors have a potential benefit compared with traditional nonselective NSAIDs in that they have minimal effects on platelet adhesion and thus are less likely to interfere with blood clot formation and contribute to hemorrhage. This category of NSAIDs has similar analgesic effectiveness and opioid dose-sparing compared to traditional NSAIDs in nonobstetric settings. However, in the setting of cesarean delivery, they do not appear to be as effective as nonselective NSAIDs. Additionally, concerns about the potential to increase the risk for cardiovascular and thrombotic events, combined with the baseline elevated risk for these events during pregnancy and postpartum, have prevented COX-2 inhibitors from playing a major role in postpartum analgesia. Celecoxib is the only widely available COX-2–selective inhibitor in the United States. The breast milk content of parecoxib and its primary active metabolite valdecoxib was very low, and neonatal neurologic and adaptive capacity scores were normal, after a single 40-mg IV dose following cesarean delivery.

Alpha ₂ -adrenergic receptor agonists have been used for the treatment of acute and chronic pain in nonobstetric patients. IV dexmedetomidine has been used as an adjunct to opioids as a component of general anesthesia for cesarean delivery. Dexmedetomidine is excreted in breast milk in extremely small concentrations; one study observed a relative infant dose of 0.034%. In a three-arm randomized controlled trial of patients who underwent cesarean delivery under spinal anesthesia without intrathecal morphine, one group received a single IV dexmedetomidine dose perioperatively and sufentanil PCA, a second received the same perioperative dexmedetomidine dose plus postoperative dexmedetomidine added to sufentanil PCA, and a third group received placebo and sufentanil PCA. The group of patients who received both perioperative and postoperative dexmedetomidine had reduced sufentanil PCA requirement compared with the other groups. There was no significant difference in side effects among groups. Neuraxial clonidine has been used for labor analgesia but is not commonly used for postcesarean analgesia. The epidural formulation of clonidine carries a “black box” warning from the US Food and Drug Administration (FDA) because of the risk for hypotension at higher neuraxial doses. Nonetheless, Fernandes et al. compared intrathecal clonidine, IV clonidine, and a placebo in patients undergoing cesarean delivery with intrathecal morphine and found no significant difference in 24-hour dynamic pain scores between the groups, although both clonidine groups had greater maternal sedation.

Peripartum magnesium sulfate therapy is used for tocolysis for preterm labor, seizure prophylaxis in women with preeclampsia, and fetal neuroprotection in women at risk for preterm delivery. Some studies have shown a small (likely not clinically significant) reduction in opioid consumption at 24 hours following magnesium sulfate administration prior to induction of general anesthesia for cesarean delivery, compared with placebo. In patients undergoing cesarean delivery under neuraxial anesthesia without intrathecal morphine, Paech et al. found no difference in pain scores, time to breakthrough analgesic dose, and total opioid consumption following a magnesium sulfate bolus and 24-hour postoperative infusion compared with placebo, although patients who received magnesium sulfate had a 15% to 20% greater median estimated blood loss.

Gabapentin is an anticonvulsant that has analgesic properties, particularly in the setting of neuropathic pain. It has been extensively studied in the management of chronic pain and for postoperative analgesia, where it is associated with more rapid opioid cessation. Gabapentin’s role in opioid-naïve patients undergoing cesarean delivery is less clear. As part of a multimodal analgesic regimen in patients undergoing cesarean delivery, a preoperative dose of oral gabapentin 600 mg was associated with lower pain scores with movement and at rest; however, the incidence of sedation was greater in the gabapentin group than in the placebo group (19% versus 0%). A metaanalysis of six placebo-controlled trials showed significant reduction in 24-hour pain scores with movement (mean difference,–11.58 mm[95% CI,–23.04 to–0.12 mm] [scale: 0 to 100 mm]) in patients who received gabapentin compared with placebo. No significant difference in pain scores at other time points, analgesia consumption, or maternal and neonatal adverse effects were detected. Gabapentin has a high umbilical vein-to-maternal vein ratio and breast milk transfer. Given the lack of clear analgesic benefit and concerns of maternal and neonatal adverse effects, routine use of gabapentin is not recommended for postcesarean analgesia, although it may play a role in patients with chronic pain and those with opioid tolerance.

Ketamine, an N -methyl- d -aspartate (NMDA) antagonist, is a potent analgesic and may play a role in the treatment of acute postoperative pain and prevention or reversal of central sensitization. An evaluation of low-dose ketamine for postcesarean analgesia compared IV ketamine 0.15 mg/kg, intrathecal fentanyl, and a placebo. The study demonstrated prolonged duration of analgesia in both the fentanyl and ketamine groups compared with the placebo group (time to first analgesic request was 145 minutes in the placebo group, 165 minutes in the fentanyl group, and 199 minutes in the ketamine group). Ketamine was superior to fentanyl and placebo for reducing pain scores at 90 and 180 minutes, and for reducing analgesic requirements in the first 24 hours, but not in the second 24 hours, after cesarean delivery. A systematic review and metaanalysis of 20 randomized controlled studies (6 with general anesthesia and 14 with spinal anesthesia) of ketamine use for postcesarean delivery analgesia showed minimally reduced pain scores (mean difference,–1.10 [95% CI,–1.61 to–0.59] [scale: 0 to 10]), decreased morphine consumption (mean difference,–6.11 mg [95% CI,–9.93 to–2.29 mg]), and a longer interval before first analgesia request (mean difference 72.5 minutes [95% CI, 50.9 to 94.1 minutes]) with ketamine compared with controls.

Preservative-free morphine received FDA approval for neuraxial administration in 1984, and subsequently epidural morphine administration has been widely investigated and extensively used. Compared with systemic opioids, epidural morphine provides superior postcesarean analgesia, prolonging the time to first analgesic request, decreasing pain scores, and reducing postoperative analgesic requests during the first 24 hours.

Onset and duration . After epidural administration, plasma morphine concentration is similar to that observed after IM injection. Epidural morphine has a relatively slow onset of action as a result of its low lipid solubility and slower penetration into spinal tissue. The peak analgesic effect is observed 60 to 90 minutes after administration. Many clinicians prefer to delay epidural morphine administration until immediately after delivery of the infant.

Morphine has a prolonged duration, analgesia typically persisting long after plasma concentration has declined to subtherapeutic levels. Epidural morphine provides pain relief for approximately 24 hours after cesarean delivery ; however, there is wide variation in analgesic duration and efficacy among patients. Within the narrow range of doses studied, investigators have not demonstrated a correlation between the dose of morphine and the duration of analgesia.

The volume of the diluent does not appear to affect the pharmacokinetics or clinical activity of epidural morphine. The quality and duration of analgesia, the need for supplemental analgesics, and the incidence of side effects were similar when epidural morphine 4 mg was diluted with saline to a volume of 2, 10, or 20 mL.

In a prospective dose-response study, Palmer et al. observed that postcesarean analgesia (assessed by need for supplemental IV morphine by PCA) improved as the dose of epidural morphine increased from 0 to 3.75 mg. A further increase in dose (to 5 mg) did not significantly improve analgesia or reduce the amount of supplemental IV morphine used in the first 24 postoperative hours ( Fig. 27.6 ). Chumpathong et al. did not observe any difference in pain relief, patient satisfaction, or side effects in women receiving epidural morphine 2.5, 3, or 4 mg for postcesarean analgesia. Rosen et al. found that epidural morphine 5 and 7.5 mg provided similar analgesic efficacy, but a 2-mg dose provided ineffective analgesia. Fuller et al. recommended epidural morphine 3 mg after a large retrospective study of epidural morphine in doses ranging from 2 to 5 mg for postcesarean analgesia.

Random allocation dose-response trial of epidural morphine 0, 1.25, 2.5, 3.75, and 5.0 mg for postcesarean delivery analgesia. Breakthrough pain as assessed by total 24-h patient-controlled analgesia (PCA) morphine use. Data are mean ± 95% confidence interval. Groups were significantly different ( P <.001). *Group 0.0 mg was significantly different from groups 2.5, 3.75, and 5.0 mg. **Group 1.25 mg was significantly different from groups 3.75 and 5.0 mg.

From Palmer CM, Nogami WM, Van Maren G, Alves DM. Postcesarean epidural morphine: a dose-response study. Anesth Analg . 2000;90:887–891.

In contemporary clinical practice, doses of epidural morphine 2 to 4 mg are most commonly used. Lower doses may not provide effective analgesia, and women may require additional supplemental analgesia, whereas higher doses may increase opioid-related side effects without improving analgesia. Singh et al. conducted a randomized, noninferiority trial in which all women received scheduled ketorolac and acetaminophen as well as epidural morphine. Morphine 1.5 mg was noninferior to 3 mg for postcesarean delivery analgesia. They found no difference in 24-hour opioid consumption between the 1.5- and 3-mg epidural morphine groups. Thus, lower epidural morphine doses may be appropriate when multimodal analgesia is used and minimizing side effects is a priority. The Society for Obstetric Anesthesia and Perinatology (SOAP) recommends the use of epidural morphine 1 to 3 mg.

Fentanyl is not approved by the FDA for neuraxial administration, but it is very commonly administered for short-term analgesia. Commercial preparations of fentanyl contain no preservative, are suitable for epidural or intrathecal administration, and have an excellent safety record. Grass et al. reported that the 50% and 95% effective doses (ED ₅₀ and ED ₉₅ , respectively) of epidural fentanyl to reduce postcesarean visual analog scale pain scores to less than 10 mm (scale: 0 to 100 mm) were 33 and 92 µg, respectively. An epidural fentanyl dose of 1 µg/kg has also been suggested to optimize intra operative analgesia. In clinical practice, doses of 50 to 100 µg are given alone or in combination with epidural morphine.

The slow onset of action of morphine limits its ability to provide optimal intraoperative analgesia, and more lipophilic opioids (e.g., fentanyl) with a faster onset of analgesia are more appropriate for supplementation of intraoperative anesthesia (see Table 27.3 ). Although single-dose epidural fentanyl improves intraoperative anesthesia, no meaningful postoperative pain relief occurs beyond 4 hours; duration is variable and dose dependent. A dose-response study of epidural fentanyl 25, 50, 100, and 200 µg, administered at the time of first complaint of postoperative pain following epidural anesthesia using lidocaine (lignocaine) with epinephrine (adrenaline), found that the duration of analgesia ranged from 1 to 2 hours.

Local anesthetics may have a synergistic interaction with neuraxial opioids. The concurrent administration of local anesthetic reduces epidural fentanyl dose requirements after cesarean delivery. Epidural fentanyl, administered either as a single dose or as a continuous or patient-controlled infusion, generally has fewer side effects than epidural morphine. Some investigators have suggested that the administration of epidural fentanyl before incision may provide preemptive analgesia and improve postoperative analgesia.

Epidural administration of the lipid-soluble opioid sufentanil provides a rapid onset of effective postcesarean analgesia. The potency ratio of epidural sufentanil to epidural fentanyl is approximately 5:1. No differences in onset, quality, or duration of analgesia were found after epidural administration of equianalgesic doses of sufentanil and fentanyl. Like fentanyl, epidural sufentanil does not provide postoperative analgesia of long duration. Rosen et al. compared epidural morphine 5 mg with epidural sufentanil 30, 45, or 60 µg. Although most patients who received sufentanil reported pain relief within 15 minutes, the duration of analgesia was 4 to 5 hours, in contrast to 26 hours of analgesia with epidural morphine. The duration of analgesia is dose-dependent; an epidural bolus of sufentanil 25 µg produced less than 2 hours of analgesia, whereas 60 µg provided 5 hours of pain relief.

Meperidine is an opioid agonist that also has local anesthetic properties at usual clinical doses. Epidural meperidine has been used for postcesarean analgesia. Two clinical trials compared the safety and efficacy of epidural meperidine 50 mg and IM meperidine 100 mg administered to patients after cesarean delivery. Epidural meperidine provided a faster onset of analgesia with a duration (2 to 4 hours) similar to that provided by IM meperidine. Paech evaluated the quality of analgesia and side effects produced by a single epidural bolus of meperidine 50 mg or fentanyl 100 µg. The onset of pain relief was slightly faster with fentanyl; however, the duration of analgesia was longer with meperidine. Ngan Kee et al. compared different doses of epidural meperidine (12.5, 25, 50, 75, and 100 mg) and concluded that meperidine 25 mg was superior to 12.5 mg and that doses > 50 mg offered no improvement in the quality or duration of analgesia. Studies that have compared a single bolus dose of epidural or intrathecal morphine with PCEA meperidine have reported superior analgesia with morphine, but with a higher incidence of opioid-related side effects such as nausea, pruritus, and sedation.

Hydromorphone is a hydroxylated derivative of morphine with a lipid solubility intermediate between that of morphine and meperidine. The quality of epidural hydromorphone analgesia after cesarean delivery appears to be similar to that observed with epidural morphine; however, its onset is faster and its duration shorter. Evidence suggests a potency ratio of 3:1 to 5:1 between epidural morphine and epidural hydromorphone. Halpern et al. found no overall difference in quality of postcesarean analgesia or severity of side effects between patients who received epidural hydromorphone 0.6 mg or epidural morphine 3 mg. A metaanalysis suggested that epidural morphine and hydromorphone provide analgesia with similar efficacy and side effects when given for the treatment of acute or chronic pain.

Diamorphine (heroin) is a lipid-soluble diacetylated derivative of morphine that is commonly administered neuraxially in the United Kingdom. The lipid solubility of diamorphine provides rapid-onset analgesia, and its principal metabolite (morphine) facilitates prolonged duration of analgesia, although less than that of morphine. Roulson et al. found that epidural diamorphine 2.5 mg provided postcesarean analgesia for 16 hours. Other investigators have found a duration of postcesarean analgesia of 6 to 12 hours after epidural diamorphine 5 mg. In the United Kingdom, the National Institute for Health and Care Excellence (NICE) recommends doses of epidural diamorphine up to 3 mg for postcesarean analgesia.

Theoretically, the epidural administration of a lipophilic opioid combined with morphine should provide analgesia of rapid onset and prolonged duration. The use of a lipophilic opioid administered intrathecally (e.g., fentanyl 15 µg) or epidurally (e.g., fentanyl 100 µg) in combination with epidural morphine 3.5 mg improves intraoperative anesthesia and reduces nausea and vomiting during cesarean delivery. Some investigators have expressed concern that opioid interactions might reduce analgesic efficacy after epidural administration and that neuraxial fentanyl might initiate acute tolerance or affect the pharmacokinetic and receptor-binding characteristics of morphine. However, these concerns have not been confirmed in subsequent studies. Epidural fentanyl, administered immediately after delivery of the infant, improved the quality of intraoperative analgesia without worsening epidural morphine analgesia after cesarean delivery.

Studies of combined epidural morphine and sufentanil have produced mixed results. Dottrens et al. compared a single epidural dose of either morphine 4 mg, sufentanil 50 µg, or morphine 2 mg with sufentanil 25 µg. The addition of sufentanil to epidural morphine provided a more rapid onset and similar duration of postcesarean analgesia than morphine alone. In another study, morphine alone or in combination with sufentanil provided analgesia of longer duration than sufentanil alone. Sinatra et al. were unable to show any potentiation when epidural sufentanil 30 µg was added to morphine 3 mg, and the duration of this combination was shorter than that of epidural morphine 5 mg alone.

Better analgesia at rest and with movement has been reported in reviews of studies that compared continuous epidural analgesia with IV PCA after nonobstetric surgery. However, PCEA is less frequently used for analgesia after cesarean delivery compared with single-dose epidural morphine.

Fanshawe compared PCEA meperidine with single-dose epidural morphine and found that postoperative pain scores were better with epidural morphine at 6, 8, and 24 hours. However, lipophilic opioids have been widely evaluated for PCEA after cesarean delivery and can be used when requirement for long-lasting analgesia is anticipated. Epidural morphine’s prolonged latency and risk for delayed respiratory depression make it a less safe option for CEI. Previous investigations have compared meperidine PCEA with other routes of parenteral administration (PCA, IM). Paech et al. performed a crossover study comparing PCEA with IV PCA meperidine after cesarean delivery; patients were randomly assigned to either PCEA or IV PCA for 12 hours before crossing over to the other route of drug administration for the next 12 hours. The PCEA and PCA meperidine protocols in this study were identical (20-mg bolus, 5-minute lockout interval). Patients receiving meperidine PCEA had lower pain scores at rest and with coughing than patients receiving IV PCA. Ngan Kee et al. observed that PCEA (fentanyl or meperidine) regimens were associated with lower pain scores compared with the respective IV PCA regimens. Goh et al. observed similar analgesic profiles among patients receiving fentanyl and meperidine PCEA but noted more favorable side-effect profiles and better patient satisfaction among patients receiving meperidine PCEA.

Cooper et al. postulated that the combination of epidural fentanyl with local anesthetic (fentanyl 2 µg/mL with 0.05% bupivacaine) would provide better analgesia than that provided by a single-drug PCEA regimen (fentanyl 4 µg/mL or 0.1% bupivacaine). The combination drug regimen was associated with lower pain scores at rest and significantly lower total drug requirements. However, no significant differences in pain scores during coughing were reported among the three groups. Cohen et al. compared four different concentrations of ropivacaine (0.025%, 0.05%, 0.1%, 0.2%) with fentanyl 3 µg/mL and epinephrine 0.5 µg/mL. The lowest-dose group (0.025%) received the largest volume in the epidural space and had the lowest 24-hour pain scores and highest satisfaction scores with no immobility or urinary retention.

Parker and White compared hydromorphone PCEA with IV PCA; no differences in pain scores were found between the two treatment groups. In a follow-up study, these investigators assessed hydromorphone PCEA, with and without a background infusion, and hydromorphone combined with 0.08% bupivacaine, with and without a background infusion. No differences in pain scores, PCEA usage, or 24-hour PCEA requirements were noted, and the combination of hydromorphone-bupivacaine PCEA with a background infusion was associated with a greater degree of lower extremity numbness and weakness.

Cohen et al. compared PCEA using 0.01% bupivacaine and epinephrine 0.5 µg/mL with either fentanyl 2 µg/mL or sufentanil 0.8 µg/mL after cesarean delivery. Pain scores and side effects (nausea, pruritus, and sedation) were similar in the two groups; however, vomiting occurred more commonly in the sufentanil group. Vercauteren et al. compared sufentanil PCEA (bolus 5 µg, lockout 10 minutes) with or without a background infusion of sufentanil 4 µg/h. Pain was lower at 6 hours in the group receiving a background infusion, but no other differences in analgesia were reported between 6 and 24 hours. The background infusion group received considerably more sufentanil and had a higher incidence and severity of sedation.

Chang et al. reported a network metaanalysis of 23 studies that compared opioids administered via IV PCA or PCEA for postcesarean delivery analgesia. They found that, in general, delivery of opioids via PCEA was associated with better analgesic outcomes than delivery via IV PCA. In particular, PCEA fentanyl was associated with significantly lower pain scores at 4 and 8 hours, and it reduced the odds of developing nausea/vomiting and sedation/drowsiness compared with IV PCA morphine, but at the cost of increased odds of developing pruritus.

Although CEI or PCEA can provide satisfactory postoperative analgesia, these techniques may diminish maternal satisfaction because of local anesthetic–induced motor block in lower limbs and the lack of physical independence from infusion devices in the postpartum period. They increase cost and potentially increase the risk for catheter-related complications (e.g., hematoma, infection) in comparison with single-dose administration of neuraxial morphine. In contrast, a single dose of neuraxial morphine may facilitate early discharge after elective cesarean delivery, a strategy suggested by the NICE guidelines, which state that “women who are recovering well, are apyrexial and do not have complications following cesarean should be offered early discharge.”

Extended-release epidural morphine (EREM) is an FDA-approved preparation that delivers standard morphine sulfate via DepoFoam (Pacira Pharmaceuticals, Inc., San Diego, CA). DepoFoam is a drug-delivery system composed of multivesicular lipid particles containing nonconcentric aqueous chambers that encapsulate the active drug. These naturally occurring lipids are broken down by erosion and reorganization, resulting in a sustained release of morphine for up to 48 hours after epidural administration of a single dose. After treatment with EREM, lower pain scores and lower requirement for supplemental analgesia over 48 hours were reported compared with standard epidural morphine. Supplemental analgesia consumption was reduced by 60% in women who received a single dose of EREM 10 mg compared with standard epidural morphine 4 mg after cesarean delivery. However, caution is required, as pooled data from EREM studies for nonobstetric surgery suggest that EREM is associated with more opioid-related side effects, especially with higher doses, including a significantly higher risk for respiratory depression compared with IV opioid PCA (odds ratio [OR], 5.8; 95% CI, 1.1 to 31.9; P =.04). Use of EREM requires extended monitoring for respiratory depression (48 hours compared with 24 hours with standard epidural morphine). Any analgesic advantage must be weighed against the potential risk for serious side effects associated with EREM administration.

Several studies have compared the analgesic efficacy of epidural and intrathecal administration of opioids. Sarvela et al. compared epidural morphine 3 mg with intrathecal morphine 0.1 and 0.2 mg; the two routes of administration provided postcesarean analgesia with similar efficacy and equal duration. Duale et al. observed modest improvements in pain scores and lower morphine consumption with epidural morphine 2 mg compared with intrathecal morphine 0.075 mg. In both studies, the incidence of side effects (e.g., sedation, pruritus, nausea, and vomiting) was not different between the epidural and intrathecal routes. A metaanalysis concluded that both epidural and intrathecal techniques provide effective postcesarean analgesia and neither technique is superior in terms of analgesic efficacy. However, intrathecal administration results in less systemic drug exposure and less potential fetal drug exposure and has a faster onset of action than epidural administration of morphine. Profound sedation and respiratory depression requiring opioid reversal and intensive care monitoring have been reported after unintentional subdural or intrathecal administration of a dose intended for epidural administration. If a CSE anesthetic is planned, intrathecal administration of the opioid may be preferable.

Intrathecal morphine 0.075 to 0.2 mg is equivalent to epidural morphine 2 to 3 mg. The analgesic efficacy, duration of action, and side-effect profile of intrathecal morphine are similar to that of epidural morphine (see earlier discussion). A systematic review and metaanalysis found that the median time to first analgesic request after cesarean delivery was 27 hours (range, 11 to 29 hours) after intrathecal morphine administration. The duration of analgesia is dose-dependent. A 2016 metaanalysis comparing low-dose (0.05 to 0.1 mg) and high-dose (>0.1 to 0.25 mg) intrathecal morphine found mean time to first analgesic request was longer (mean difference, 4.5 hours; 95% CI, 1.8 to 7.1 hours; P =.0008) for the high-dose group compared with the low-dose group.

Dose . Several studies have attempted to determine the optimal dose of intrathecal morphine for postcesarean analgesia. Palmer et al. assessed IV PCA morphine use after doses of intrathecal morphine ranging from 0.025 to 0.5 mg and found no decrease in PCA morphine use with morphine doses >0.075 mg. Uchiyama et al. performed a dose-response study with intrathecal morphine 0, 0.05, 0.1, and 0.2 mg. They observed that 0.1 mg and 0.2 mg provided comparable and effective postcesarean analgesia for 28 hours. The 0.05-mg dose was less effective, and the incidence of side effects was greater with the 0.2-mg dose; therefore, the investigators concluded that intrathecal morphine 0.1 mg is the optimal dose for postcesarean analgesia. Berger et al. compared 0.05, 0.1, and 0.15 mg of intrathecal morphine in women who received multimodal analgesia with IV ketorolac; all doses provided similar analgesia after cesarean delivery. There were no differences in 24-hour morphine consumption or reported pain or nausea scores, but pruritus scores were lower at 6 and 12 hours in the 0.05-mg group. Sultan et al. performed a metaanalysis to determine whether low-dose (0.05 to 0.1 mg) intrathecal morphine provides comparable duration and quality of analgesia with fewer side effects than a high-dose (>0.1 to 0.25 mg). Pain scores at 12 hours and morphine consumption at 24 hours were not significantly different, but duration of analgesia was longer with the higher doses. The incidence of opioid-related side effects, including nausea or vomiting (OR 0.4; 95% CI, 0.3 to 0.7) and pruritus (OR 0.3; 95% CI, 0.2 to 0.6) were lower in the low-dose group. Thus, there is a trade-off between incidence of side effects and duration of analgesia.

The analgesic efficacy and side-effect profile of intrathecal morphine with those of PCEA after cesarean delivery have been compared. Vercauteren et al. reported that intrathecal morphine 0.15 mg provided superior analgesia and fewer side effects compared with PCEA using 0.06% bupivacaine and sufentanil 1 µg/mL. Paech et al. reported that patients who received intrathecal morphine 0.2 mg had lower pain scores, offset by a higher incidence of pruritus, nausea, and drowsiness, compared with patient who received PCEA meperidine. In another study in which intrathecal morphine (0, 0.05, and 0.1 mg) was combined with CEI (0.2% ropivacaine at 6 mL/h), inclusion of intrathecal morphine improved postcesarean analgesia compared with placebo.

In summary, the intrathecal administration of a small dose of morphine (0.05 to 0.2 mg) provides effective analgesia for 14 to 36 hours after cesarean delivery. Higher doses (>0.1 mg) may slightly increase the duration of analgesia but are associated with increasing side effects and limited improvement in analgesic quality in the typical patient. Because of the variability in patient response to intrathecal morphine, some patients treated with low doses may experience inadequate postoperative analgesia and/or opioid-related side effects. Thus, the use of low-dose intrathecal morphine as a component of multimodal analgesia may provide optimal analgesia with a low risk for side effects. SOAP recommends the use of a long-acting opioid such as intrathecal morphine 0.05 to 0.15 mg (50 to 150 μg) whenever feasible.

There is a need for more study of the relationship between patients’ expectations for pain after cesarean delivery and their analgesic needs and use. Carvalho et al. investigated the relationship between patients’ choice of dose of intrathecal morphine, postcesarean pain scores, and opioid use. Patients were randomly assigned to a choice of 0.1 or 0.2 mg of intrathecal morphine or no choice. Women assigned a choice were read a standardized script that discussed the trade-off of pain relief with increased risk for the most common intrathecal morphine side effects (nausea, vomiting, and pruritus). Participants who requested the larger dose of intrathecal morphine required more supplemental opioids and reported more pain with movement regardless of the intrathecal morphine dose they actually received. Thus, patients may correctly anticipate a greater postoperative opioid need. Using a higher dose of intrathecal morphine in patients predicted to be at risk for high acute postpartum pain after cesarean delivery may result in less acute postoperative pain. Shared decision-making, involvement of both the patient and anesthesia provider in a sharing of information to build a consensus about preferred dose, and reaching an agreement about which dose to use may result in improved analgesia.

Intrathecal fentanyl improves intraoperative anesthesia (especially during uterine exteriorization), reduces intraoperative nausea and vomiting (IONV), decreases local anesthetic dose requirement, and provides a better postoperative transition to other pain medications during recovery from spinal anesthesia for cesarean delivery. However, intrathecal fentanyl provides a limited duration of postoperative analgesia, with a median time to first request for additional analgesia of 4 hours (range, 2 to 13 hours). A study that compared intrathecal morphine 0.1 mg with fentanyl 25 µg found that morphine provided better and longer postoperative analgesia after cesarean delivery.

The analgesic effects, duration of analgesia, and side effects after intrathecal fentanyl are dose-related. Belzarena found that the mean duration of postcesarean analgesia ranged from 305 to 787 minutes with intrathecal fentanyl doses of 0.25 to 0.75 µg/kg; however, patients who received the higher doses experienced decreased respiratory rate and a high incidence of side effects (e.g., pruritus, nausea). Dahlgren et al. reported that intrathecal fentanyl 10 µg added to bupivacaine increased the mean time of effective analgesia from 121 to 181 minutes. Similarly, Wilwerth et al. found that intrathecal fentanyl 25 µg added to bupivacaine resulted in a median duration of analgesia of 187 minutes (interquartile range [IQR], 151 to 230 minutes). Hunt et al. compared intrathecal fentanyl doses of 2.5 to 50 µg combined with intrathecal bupivacaine for cesarean delivery and found that doses greater than 6.25 µg were associated with better intraoperative anesthesia and a longer time to first request for additional analgesia than administration of bupivacaine alone (72 minutes versus 192 minutes, respectively). Chu et al. found that fentanyl doses of 12.5 to 15 µg were required to increase the duration of effective analgesia.

In summary, intrathecal fentanyl optimizes intraoperative anesthesia and provides immediate postoperative analgesia. However, intrathecal fentanyl (10 to 25 µg) provides a limited duration of postcesarean analgesia (2 to 4 hours) and does not decrease subsequent postoperative analgesic requirements.

Sufentanil has a fast onset of action, which may improve intraoperative anesthesia and reduce the dose of local anesthetic required for cesarean anesthesia. However, its pharmacokinetic properties limit the duration of effective postoperative analgesia after intrathecal administration. Courtney et al. found that intrathecal sufentanil 10, 15, or 20 µg resulted in a mean duration of postcesarean analgesia of approximately 3 hours. More than 90% of patients reported pruritus, but only one patient required treatment. Dahlgren et al. compared the safety and efficacy of sufentanil 2.5 or 5 µg, fentanyl 10 µg, or placebo added to hyperbaric bupivacaine 12.5 mg for cesarean delivery and found that the duration of effective analgesia was longer with inclusion of opioids and was longest with sufentanil 5 µg, although this dose also had the highest incidence of pruritus. Patients receiving intrathecal sufentanil had lower requirements for intraoperative antiemetics and postoperative IV morphine rescue. In another study, increasing the dose of intrathecal sufentanil to 7.5 µg did not increase the duration of postoperative analgesia compared with 5 µg but increased the incidence of pruritus. Karaman et al. found that intrathecal sufentanil 5 µg delayed the time to first analgesic request to 6 hours, compared with 20 hours for intrathecal morphine 0.2 mg. A study that compared intrathecal fentanyl 20 µg and sufentanil 2.5 µg added to bupivacaine found no difference in the quality of intraoperative and postoperative analgesia, as well as no difference in the frequency of nausea and pruritus. Wilwerth et al. added intrathecal fentanyl 25 µg, sufentanil 2.5 µg, or sufentanil 5 µg to hyperbaric bupivacaine 10 mg. Effective analgesia was defined as time from spinal injection to first IV morphine administered. Median duration of analgesia was longer with sufentanil 2.5 µg (214 minutes) and 5 µg (236 minutes) compared with fentanyl 25 µg (187 minutes). The incidence of pruritus and postoperative nausea and vomiting (PONV) was similar among groups.

In summary, intrathecal sufentanil, similar to fentanyl, enhances intraoperative anesthesia and provides postoperative analgesia of limited duration. The duration of analgesia is not prolonged with doses > 5 µg and higher doses are associated with greater pruritus.

Intrathecal meperidine reduces the intensity of pain associated with the regression of spinal anesthesia and provides postoperative analgesia of intermediate duration (4 to 5 hours). Yu et al. found that the addition of meperidine 10 mg to hyperbaric bupivacaine 10 mg prolonged the mean duration of postcesarean analgesia (234 minutes for meperidine versus 125 minutes for placebo); however, the incidence of IONV was greater in the meperidine group. Imarengiaye et al. reported that meperidine 7.5 mg added to bupivacaine 10 mg resulted in mean duration of postoperative analgesia of 257 minutes compared with 161 minutes with saline-placebo. Unlike other opioids, meperidine possesses local anesthetic properties at usual clinical doses. Although the use of larger intrathecal meperidine doses (e.g., 1 mg/kg) as the sole agent for spinal anesthesia for cesarean delivery has been described, experience with this technique is limited.

Diamorphine has physicochemical properties that are of value in providing intrathecal analgesia as well as epidural analgesia. A high lipophilicity (octanol-water partition coefficient, 280) results in a rapid onset of analgesia, and diamorphine’s active metabolite (morphine) provides prolonged duration of analgesia. The rapid onset of diamorphine is an advantage in the provision of intraoperative as well as postoperative analgesia. Saravanan et al. concluded that the ED ₉₅ for intrathecal diamorphine to prevent intraoperative discomfort was 0.4 mg when combined with hyperbaric bupivacaine 12.5 mg.

Kelly et al. compared intrathecal diamorphine 0.125, 0.25, and 0.375 mg for postcesarean analgesia. The 0.25- and 0.375-mg doses provided effective analgesia; the incidence of both vomiting and pruritus was dose-related. Stacey et al. reported that the duration of analgesia was dose-dependent and found that intrathecal diamorphine 1 mg provided 10 hours of postcesarean analgesia, compared with 7 hours for 0.5 mg. A dose-response study of intrathecal diamorphine 0.1, 0.2, or 0.3 mg reported a dose-dependent enhancement of analgesia and an increase in pruritus. Husaini and Russell observed that intrathecal diamorphine 0.2 mg and intrathecal morphine 0.2 mg provided similar postcesarean analgesia as assessed by rescue postoperative IV PCA morphine requirement. However, the patients who received intrathecal morphine had a higher incidence of pruritus and drowsiness. Hallworth et al. reported that intrathecal diamorphine 0.25 mg produced the same duration and quality of postcesarean analgesia as epidural diamorphine 5 mg, with less nausea and vomiting.

Diamorphine is commonly used in the United Kingdom, but it is not available for clinical use in the United States and Canada. In the United Kingdom, NICE recommends the use of an intrathecal diamorphine dose up to 0.3 mg (300 µg) for postcesarean analgesia.

Intrathecal hydromorphone has been used to provide analgesia following cesarean delivery as an alternative to morphine; its use increased with shortages of intrathecal morphine in the United States. Two retrospective studies found an analgesic advantage in favor of intrathecal morphine. Marroquin et al. retrospectively compared intrathecal morphine 0.2 mg or epidural morphine 3 mg with intrathecal hydromorphone 60 µg or epidural hydromorphone 0.6 mg. Time to first opioid request was 17 to 21 hours with neuraxial morphine compared with 13 to 15 hours for neuraxial hydromorphone. Beatty et al. compared intrathecal morphine 0.1 mg with intrathecal hydromorphone 40 µg and found 24-hour supplemental opioid use favored intrathecal morphine (8 versus 33 mg). The side effects of intrathecal morphine and hydromorphone are similar.

The optimal intrathecal hydromorphone dose has not been fully elucidated. Using an up-down sequential allocation method, Lynde estimated that the ED ₅₀ of intrathecal hydromorphone was 4.6 µg. In a dose-response study, Sviggum et al. randomized 80 participants to intrathecal morphine or intrathecal hydromorphone in a biased-coin, up-down sequential allocation study. The ED ₉₀ for achieving a numeric pain score (scale, 0 to 10) ≤ 3 for a duration of 12 hours was 75 µg for intrathecal hydromorphone compared with 150 µg for intrathecal morphine. Further research is needed to help refine the optimal dose of intrathecal hydromorphone for postcesarean analgesia.

Intrathecal administration of morphine in combination with a lipophilic opioid (e.g., fentanyl, sufentanil) may offer some advantages, similar to their combination in the epidural space. Intrathecal morphine has a delayed onset; therefore, the coadministration of a lipophilic opioid may serve to improve intraoperative anesthesia and reduce the intensity of pain associated with the regression of spinal anesthesia in the postanesthesia care unit. Chung et al. found that the combination of intrathecal meperidine 10 mg and morphine 0.15 mg provided better intraoperative analgesia, less need for supplemental analgesia, and greater satisfaction than intrathecal morphine alone following cesarean delivery. Intrathecal sufentanil 5 µg coadministrated with morphine 0.15 mg provided better and longer pain relief than intrathecal sufentanil plus a single injection of subcutaneous morphine; however, a higher incidence of side effects, such as nausea and vomiting, was observed with intrathecal morphine.

Some investigators have suggested that intrathecal morphine may be less effective when concurrently administered with intrathecal fentanyl, suggesting acute spinal opioid tolerance. This claim is controversial, and study results are inconsistent. Cooper et al. reported that patients who received intrathecal fentanyl 25 µg with bupivacaine had higher postoperative IV morphine PCA requirements than patients who received bupivacaine alone. By contrast, Sibilla et al. found that the intrathecal combination of fentanyl 25 µg and morphine 0.1 mg provided similar postoperative analgesia to that provided by intrathecal morphine alone. Carvalho et al. found no difference in postoperative analgesia requirements but small increases in postoperative pain scores with the addition of increasing doses of intrathecal fentanyl (5, 10, or 25 µg) to intrathecal morphine 0.2 mg for cesarean delivery. The authors suggested that intrathecal fentanyl may induce subtle acute tolerance to intrathecal morphine. The clinical significance of this finding is unclear, however, especially because of widespread evidence that intrathecal lipid-soluble opioids decrease the incidence of intraoperative visceral pain and nausea. Many anesthesia providers currently administer both intrathecal morphine and fentanyl with a local anesthetic for spinal anesthesia for cesarean delivery (see Chapter 26 ). The coadministration of intrathecal fentanyl does not appear to significantly compromise the postoperative analgesia provided by intrathecal morphine.

Despite the administration of neuraxial opioid analgesia, the quality and duration of analgesia after cesarean delivery are often incomplete. Thus, neuraxial opioid analgesia is rarely the sole analgesic technique used for postcesarean analgesia. Rather, neuraxial opioids should be considered as part of a multimodal analgesic approach for the treatment of postcesarean pain.

Neurotoxicity (safety) studies suggest that morphine , fentanyl , sufentanil , hydromorphone , meperidine , clonidine , and neostigmine are safe for neuraxial administration. Morphine and clonidine are approved by the FDA for neuraxial administration. Although unlicensed for neuraxial administration, fentanyl and sufentanil have been used for many years without evidence of neurotoxicity. Studies in sheep have reported potential neurotoxicity with intrathecal butorphanol . Culebras et al. reported potential toxic interactions with the coadministration of nalbuphine and local anesthetic. However, Rawal et al. evaluated the behavioral and histopathologic effects of butorphanol, sufentanil, and nalbuphine after intrathecal administration in sheep and found that nalbuphine caused the least evidence of neural tissue damage.

Clinicians should avoid neuraxial administration of any agent before adequate evaluation for potential neurotoxicity has been completed. Drugs and diluents that are proven safe for parenteral use may have adverse effects when administered intrathecally. Despite these valid concerns, a number of opioid analgesics, including fentanyl and sufentanil, have been administered intrathecally to healthy obstetric patients without prior adequate investigation of their safety profile in animal and clinical volunteer studies.

Preservatives added to many commercial preparations may be hazardous if administered to the neuraxis. Examples are sodium (meta)bisulfite and disodium ethylenediaminetetraacetic acid (EDTA) , which are known to incite inflammatory and fibrotic changes in pia-arachnoid and spinal tissue after intrathecal administration. Dezocine has been shown to cause neuropathologic changes in the dog spinal cord. Similarly, glycine , a neurotransmitter, is added as a preservative to remifentanil preparations and is specifically contraindicated for neuraxial injection.

All opioids have the potential for placental transfer and neonatal effects. Minimal neonatal effects have been found after the administration of epidural morphine 2 to 7.5 mg for cesarean delivery. This is not surprising given the slow increase in plasma concentration after epidural administration and active transport of morphine out of the blood-brain barrier and placenta by P-glycoproteins. Some clinicians prefer to administer neuraxial opioids after umbilical cord clamping to avoid placental transfer, although it is minimal. Lipophilic opioids are associated with faster systemic uptake; if indicated (e.g., for treatment of intraoperative pain before delivery), the smallest necessary dose should be administered. Courtney et al. found that intrathecal sufentanil (10, 15, or 20 µg) did not affect neonatal outcome as assessed by umbilical cord blood gas measurements and Apgar and neurobehavioral scores. Smaller doses of intrathecal opioids are associated with less neonatal drug transfer than epidural or IV opioid administration.

Neuraxial opioids can depress the respiratory center in the brainstem via direct and/or indirect mechanisms. Respiratory depression after neuraxial morphine administration is biphasic. Early respiratory depression can occur 30 to 90 minutes after epidural morphine administration following systemic vascular absorption from the epidural space, whereas delayed respiratory depression can occur 6 to 18 hours after epidural or intrathecal morphine administration following rostral spread in CSF and slow penetration into the brainstem. In contrast, lipophilic opioids do not cause delayed respiratory depression but may cause early respiratory depression, typically within 30 minutes, because of vascular uptake and rostral spread in CSF and, potentially, direct transit in epidural veins.

The incidence of respiratory depression, which can lead to death or permanent brain damage, after neuraxial morphine administration in obstetric patients is very low, with a reported range from 8.67 per 10,000 to 5.96 per 10,000. The Serious Complication Repository project of SOAP systematically tracked complications related to obstetric anesthesia between 2004 and 2009. Among 90,795 reported cases of neuraxial anesthesia for cesarean delivery, no cases of respiratory arrest secondary to neuraxial opioid administration were reported. No studies in the obstetric setting have reported serious morbidity, although some patients have required naloxone administration for treatment of respiratory depression. Early reports suggested that intrathecal morphine was more likely to cause delayed respiratory depression than epidural morphine. However, this likely reflected the relatively high intrathecal morphine doses (1 to 10 mg) used in early clinical studies. Subsequently, lower doses of intrathecal morphine have been found to provide effective analgesia with a low risk for clinically significant respiratory depression. No maternal deaths attributable to maternal neuraxial opioid administration were reported in the United Kingdom and Ireland Confidential Enquiries into Maternal Deaths and Morbidity 2018–2020. In a retrospective study of 5036 postpartum women who received low-dose neuraxial morphine for cesarean delivery, no instances of respiratory depression were identified (defined as clinically relevant episodes of respiratory depression requiring naloxone administration or a rapid-response team call). Thus, clinicians have concluded that the analgesic benefits derived from neuraxial opioids outweigh the risks associated with respiratory depression in most patients. The incidence of respiratory depression associated with systemic (IV or IM) opioids is likely to be equivalent or higher than that observed with neuraxial opioids.

There are very few case reports of respiratory depression after neuraxial administration of lipophilic opioids in the obstetric setting. In one report, respiratory depression occurred 25 minutes after intrathecal fentanyl 15 µg and morphine 0.2 mg and required reversal with naloxone. Respiratory depression has been described after administration of epidural fentanyl 90 to 100 µg for cesarean delivery. Cohen et al. reported that epidural sufentanil 30 to 50 µg depressed the ventilatory response to CO ₂ after cesarean delivery. Although overt respiratory depression did not occur, the highest sedation scores and depression of CO ₂ response occurred 45 minutes after administration. Another group reported that epidural fentanyl 100 µg or sufentanil 10 to 50 µg added to lidocaine for cesarean delivery caused significant changes in respiratory rate and end-tidal CO ₂ but no adverse clinical events.

Historically, respiratory depression was more common because patients received greater doses of neuraxial opioid than those currently used in modern practice. For cesarean delivery, neuraxial morphine appears to have a limit or “ceiling” in analgesic efficacy. More specifically, effective doses of intrathecal and epidural morphine are 0.075 to 0.2 mg and 2 to 4 mg, respectively, in opioid-naïve patients. Sultan et al. performed a systematic review of studies of low-dose compared with high-dose intrathecal morphine administered for postoperative analgesia following elective cesarean delivery; there were no reported episodes of respiratory depression. Thus, avoiding high doses of neuraxial morphine may improve safety without compromising analgesia.

All patients who receive neuraxial opioids should be monitored for adequacy of ventilation, oxygenation, and level of consciousness. Opioid effects on respiration include reduced minute ventilation (decrease in respiratory rate, tidal volume, or both) and decreased response to hypoxemia and changes in PaCO ₂ . In nearly two-thirds of cases of respiratory depression following general anesthesia in the Anesthesia Closed Claims Project database, somnolence was present, but not addressed, before the respiratory depression event.

Guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration have been published by the ASA and the American Society of Regional Anesthesia and Pain Medicine (ASRA). The duration of respiratory monitoring corresponds to the expected duration of action of the administered opioid. The onset of respiratory depression after neuraxial opioids is variable and has been reported to range from 2 to 12 hours. CO ₂ responsiveness is depressed for up to 24 hours after the administration of epidural morphine 5 mg. The ASA recommends that respiratory monitoring after neuraxial administration of morphine should occur at least every hour for the first 12 hours and then every 2 hours for the next 12 hours. However, these guidelines do not specifically address obstetric patients and are likely overly prescriptive given the low risk for clinically significant neuraxial opioid–induced respiratory depression with conventional dosing in this patient population. The SOAP has commissioned a consensus statement specific to the obstetric population following cesarean delivery, whereby the frequency and modality of respiratory monitoring should be based on patient risk stratification and neuraxial morphine dose. In summary, patients who receive high-dose neuraxial morphine (intrathecal > 0.15 mg or epidural > 3 mg) or those with risk factors, including cardiopulmonary or neurological comorbidity, body mass index (BMI) ≥ 40 kg/m ² , obstructive sleep apnea, chronic opioid use, hypertension, general anesthesia, supplemental IV opioid, concomitant use of sedating medications or magnesium, and postanesthesia desaturation, should be monitored according to the ASA guidelines. In contrast, patients without these risk factors who receive ultra-low-dose neuraxial morphine (intrathecal ≤ 0.05 mg or epidural ≤ 1 mg) do not require additional respiratory monitoring apart from routine postoperative vital sign assessments. Respiratory rate and sedation assessments should be performed every 2 hours for 12 hours in patients who received low-dose neuraxial morphine (intrathecal 0.05 to 0.15 mg or epidural 1 to 3 mg).

Early-onset respiratory depression associated with lipophilic opioids usually occurs within 30 minutes of administration and is likely to occur in a high-visibility, controlled setting (e.g., operating or labor room). The ASA and ASRA recommend that respiratory monitoring after administration of neuraxial fentanyl should continue for a minimum of 2 hours.

Nausea and vomiting are common complaints after cesarean delivery, and the causes are likely multifactorial. It was hypothesized that neuraxial opioids increase the risk for PONV after cesarean delivery in a non–dose-dependent manner via rostral spread of opioid in the CSF to the brainstem or from vascular uptake and delivery to the vomiting center and chemoreceptor trigger zone. However, the link between intrathecal opioids and PONV after cesarean delivery is unclear. Palmer et al. found no difference in PONV between intrathecal morphine (0.025 to 0.5 mg) and placebo, nor a relationship between PONV and morphine dose. A similar study by the same group found no difference in the severity of PONV in patients receiving increasing doses of epidural morphine (1.25 to 5 mg). However, neither study was adequately powered to investigate the absence of PONV as a primary outcome measure. A 2021 network metaanalysis investigating the effects of intrathecal morphine, morphine and fentanyl combination, fentanyl, diamorphine, sufentanil, and meperidine for cesarean delivery found that, compared with a placebo, intrathecal opioids did not significantly increase the incidence of nausea or vomiting when assessed as separate outcomes. When assessed as a combined outcome of PONV, only meperidine was associated with increased risk for nausea and vomiting.

Many studies have investigated different regimens to reduce PONV in patients receiving neuraxial opioids for cesarean delivery, but these studies did not standardize PONV outcome measures and did not stratify patients according to risk for PONV. It is notable that PONV is mainly triggered by the emetogenic effects of opioids and severe pain, hence underscoring the importance of optimal neuraxial opioid dosing and the use of a multimodal opioid-sparing strategy to provide adequate analgesia while minimizing opioid use.

Single antiemetic agents . Older antiemetics, such as metoclopramide and droperidol , have been used to prevent or treat neuraxial opioid–induced emesis in the obstetric setting. Metoclopramide antagonizes dopamine receptors in the chemoreceptor trigger zone. It is often administered preoperatively owing to its favorable gut prokinetic properties. In a metaanalysis of studies that assessed efficacy of antiemetic prophylaxis, metoclopramide was associated with a reduced incidence of IONV and early PONV compared with placebo.

The use of a transdermal scopolamine patch may also lower the incidence of PONV after cesarean delivery. A transdermal scopolamine patch (1.5 mg) provided efficacy similar to that provided by ondansetron 4 mg in reducing emesis among parturients receiving spinal anesthesia (incidence of 40% and 42%, respectively, versus 59% in the control group). However, transdermal scopolamine has a latency period of 3 to 4 hours, and side effects, including dry mouth, visual disturbances, dizziness, and agitation, are common.

Serotonin (5-HT ₃ ) receptor antagonists have been used for both prophylaxis and treatment of PONV. These drugs bind to 5-HT ₃ receptors in the chemoreceptor trigger zone and at vagal afferents in the gastrointestinal tract. Prophylactic administration of ondansetron 4 to 8 mg has been shown to have a better antiemetic profile in the first 24 hours after intrathecal and epidural opioid administration compared with placebo ( Fig. 27.7 ). A metaanalysis of six trials found that the use of serotonin receptor antagonists reduced the incidence of PONV and the need for rescue antiemetic treatment in women who received intrathecal opioids for cesarean delivery.

Randomized trial of postoperative nausea and emesis in patients undergoing cesarean delivery with epidural anesthesia (2% lidocaine with epinephrine and fentanyl) who received prophylactic ondansetron, metoclopramide, or placebo. Distribution of nausea and emesis episodes (0 [nausea or emesis free] or 1 or less) in the first 24 h. Values are given as percentages of each patient group. #Group metoclopramide versus ondansetron; P <.05. *Group metoclopramide versus placebo; P <.05. †Group metoclopramide versus placebo; P <.005. ‡Group ondansetron versus placebo; P <.005.

Data from Pan PH, Moore CM. Comparing the efficacy of prophylactic metoclopramide, ondansetron, and placebo in cesarean section patients given epidural anesthesia. J Clin Anesth . 2001;13:430–435.

Corticosteroid receptors have been identified in areas important to the signal processing of nausea and vomiting, including the nucleus of the solitary tract, the nucleus of raphe, and the area postrema. Tzeng et al. reported that IV dexamethasone 8 mg and droperidol 1.25 mg provided similar efficacy in the prevention of PONV. Wang et al. suggested that dexamethasone 5 mg is the minimum effective dose for preventing PONV. In both studies, patients received epidural morphine 3 mg. In a 2012 metaanalysis of studies of obstetric and gynecologic patients who received neuraxial morphine, prophylactic dexamethasone (2.5 to 10 mg) was associated with a reduced risk for PONV and need for antiemetic rescue therapy compared with placebo. Administration of cyclizine 50 mg has been reported to be associated with fewer episodes of PONV (0 to 12 hours after cesarean delivery) than administration of dexamethasone 8 mg after intrathecal opioid (fentanyl and morphine) administration.

Combination antiemetic regimens . Administration of drugs acting at more than one different receptor sites may improve antiemetic efficacy through additivity or synergism. Drug combinations may also facilitate a concomitant reduction in drug doses limiting individual side effects. Wu et al. reported lower rates of PONV after intrathecal morphine administration with use of a combination of dexamethasone 8 mg and droperidol 0.625 mg than with the use of dexamethasone 8 mg or droperidol 1.25 mg alone. In a multicenter study, Habib et al. randomized women to one of three groups: placebo, metoclopramide 10 mg plus placebo, or a combination of metoclopramide 10 mg plus ondansetron 4 mg. Spinal anesthesia–induced hypotension was managed prophylactically with a phenylephrine infusion to maintain the systolic blood pressure within 20% of baseline or more than 90 mm Hg. The combination of metoclopramide and ondansetron reduced IONV and PONV compared with placebo.

Nonpharmacologic techniques . Several studies have investigated the prophylactic use of acupressure (using wrist bands with a plastic bead placed bilaterally on the P6 [HG-6] acupoint) for reducing PONV after neuraxial anesthesia for cesarean delivery. A metaanalysis of six studies (649 patients) that assessed the effect of P6 stimulation versus placebo to reduce IONV and PONV revealed inconsistent results, thereby limiting any definitive conclusions regarding the efficacy of this intervention. Based on very limited evidence in patients undergoing cesarean delivery, supplemental oxygen and generous IV fluid administration do not appear to reduce IONV or PONV.

Pruritus is a common side effect of neuraxial opioids. In a retrospective review of 4880 patients undergoing cesarean delivery who received epidural morphine 2 to 5 mg, pruritus was reported by 58% of patients. However, a sample of patients who received spinal anesthesia for cesarean delivery ranked pain, nausea, and vomiting as more undesirable than pruritus. The incidence and severity of pruritus are likely influenced by the opioid dose, route of administration (more common after intrathecal administration), and method of assessment. The incidence of pruritus after intrathecal morphine is as high as 70% to 90%, with approximately 25% to 40% of patients requesting treatment.

Pruritus may manifest in the dermatomal distribution of neuraxial opioid spread as well as nonspecific areas of the head and neck; specific symptoms and severity vary among patients. Opioid-induced histamine release from mast cells does not appear to be the causative mechanism for pruritus after neuraxial opioid administration. Plasma opioid and histamine levels are clinically insignificant at the time of symptom presentation (3 to 6 hours after intraspinal morphine administration). At present, the mechanisms of spinal and epidural opioid–induced pruritus remain unclear. Postulated theories include: (1) direct or indirect excitatory effects on central µ-opioid receptors; (2) cephalad migration of the opioid within the CSF to the trigeminal nucleus (which contains the subnucleus caudalis, integrates facial sensory input, and exhibits high opioid receptor density); (3) excitatory effects on dorsal or ventral horn neurons; and (4) other mechanisms (e.g., effects on dopamine-2 [D ₂ ] receptors, prostaglandin system, serotonin receptors, and CNS gamma-aminobutyric acid and glycine receptors). Pregnant patients may be more susceptible as a result of estrogen interaction with opioid receptors. The incidence of moderate-to-severe pruritus with epidural morphine administered for postcesarean analgesia has been reported to be lower in patients homozygous for the G118G polymorphism in the µ-opioid receptor gene (OPRM1) than in patients with the A118G or A118A genotype (incidence 5%, 42%, and 53%, respectively). In a study of 63 women who received morphine 0.1 mg during spinal anesthesia for elective cesarean delivery, Pettini et al. reported an incidence of pruritus of 50% in patients homozygous for the G118G polymorphism and 82% in patients with the A118G or A118A genotype.

There is little consensus regarding the prevention and treatment of neuraxial opioid–induced pruritus after cesarean delivery. Further, there are currently no validated or consistent methods for assessing pruritus, which limits the analysis of data from studies investigating the efficacy of antipruritic regimens.

Studies comparing opioid antagonists for the treatment of pruritus have demonstrated mixed results. Nalbuphine (5 mg) significantly reduced the severity of pruritus after epidural morphine, and fewer patients required additional treatment of persistent pruritus. Smaller doses of nalbuphine (2 to 3 mg) were effective for treating moderate-to-severe pruritus after intrathecal morphine administration. Wu et al. found that butorphanol 1 mg followed by an infusion of 0.2 mg/h was associated with reduced pruritus compared with a saline-control group in patients who received intrathecal morphine.

Prophylactic treatment with opioid antagonists has also been investigated as a method of reducing the incidence of opioid-induced pruritus. Morgan et al. reported that pretreatment with IV nalbuphine (20 mg at skin closure) with subsequent postoperative administration (20 mg in divided doses) was ineffective in reducing pruritus in patients receiving epidural morphine. Similarly, pretreatment with subcutaneous naloxone (0.4 mg) did not reduce the incidence of pruritus in patients receiving intrathecal fentanyl and morphine for elective cesarean delivery. This is not surprising given the short half-life of naloxone. However, naloxone and nalbuphine administered via patient-controlled bolus doses with a continuous background infusion have been found to reduce the incidence of pruritus after cesarean delivery in patients who received epidural morphine 5 mg. The long-acting oral opioid antagonist naltrexone reduced pruritus compared with placebo after cesarean delivery in patients who received epidural or intrathecal morphine. Paech et al. compared methylnaltrexone , a peripherally acting µ-opioid receptor antagonist developed to antagonize the peripheral side effects of opioids while preserving centrally mediated analgesia, with placebo. Women undergoing elective cesarean delivery under spinal anesthesia with intrathecal morphine 0.1 mg were randomized to receive subcutaneous methylnaltrexone 12 mg or placebo after delivery. The incidence and severity of pruritus were not statistically different between groups, although the study may have been underpowered to identify a small effect. Pentazocine , a κ-opioid receptor agonist and partial µ-opioid receptor agonist, may be a useful drug for treating opioid-induced pruritus. Hirabayashi et al. randomized women scheduled for cesarean delivery with spinal anesthesia containing fentanyl 10 µg and morphine 0.1 mg to receive pentazocine 15 mg or saline-placebo. Pentazocine reduced the overall incidence of pruritus within the first 24 hours compared with saline.

The effects of neuraxially administered opioid antagonists have also been investigated. Jeon et al. reported less pruritus in patients who received epidural naloxone (1.2 mg over 48 hours) with epidural 0.1% bupivacaine and morphine (6 mg over 48 hours) than in patients in a control group. Similarly, Culebras et al. investigated the effects of three different doses of intrathecal nalbuphine (0.2, 0.8, and 1.6 mg) and found a significantly lower incidence of pruritus in all of the nalbuphine groups compared with a control group that received intrathecal morphine without nalbuphine. However, the duration of analgesia was shorter among patients in the nalbuphine groups. It is not clear whether an optimal dose of µ-opioid receptor antagonists can be found that prevents pruritus without reducing analgesia. These drugs are not approved for administration into the neuraxial canal.

Propofol has been reported to relieve pruritus caused by neuraxial opioids in nonobstetric patients after a single 10-mg bolus dose and after a 10-mg bolus dose followed by a 30 mg/24 hour infusion. The mechanism of the antipruritic effect of propofol is unknown, and these results have not been replicated in obstetric patients who received subhypnotic doses of propofol (10 to 20 mg) for treatment of intrathecal morphine–induced pruritus. A comparative study demonstrated that IV nalbuphine 3 mg is superior to propofol 20 mg for treating pruritus after administration of intrathecal morphine.

Stimulation of 5-HT ₃ receptors found in the dorsal horn of the spinal cord and in the nucleus of the spinal tract of the trigeminal nerve in the medulla may occur after subarachnoid opioid administration. A metaanalysis of studies of surgical patients receiving neuraxial opioids concluded that prophylaxis with a 5-HT ₃ antagonist results in a reduced risk for postoperative pruritus compared with placebo (OR, 0.44; 95% CI, 0.29 to 0.68). IV ondansetron 4 to 8 mg has been shown to be more effective than placebo for reducing the incidence of postcesarean pruritus after intrathecal administration of morphine 0.15 to 0.2 mg. However, other studies that compared ondansetron 8 mg with placebo found no significant reduction in pruritus after intrathecal administration of morphine (0.1 to 0.2 mg) alone or in combination with a lipophilic opioid (sufentanil or fentanyl). The lack of antipruritic effect in these studies may be caused by the peak effect of ondansetron occurring sooner (15 minutes after IV administration) than that of intrathecal morphine. The antipruritic effects associated with ondansetron may depend on the dose, lipophilicity, and duration of action of the intrathecal opioid. Siddik-Sayyid et al. found no significant difference in the incidence or severity of pruritus among patients who received granisetron 3 mg or ondansetron 8 mg or saline. In contrast, Tan et al. observed that the severity of pruritus was reduced at 8 and 24 hours after cesarean delivery in patients who received granisetron 3 mg compared with those who received ondansetron 8 mg.

George et al. reported a metaanalysis of studies of women who received spinal anesthesia with morphine for cesarean delivery; prophylactic administration of a 5-HT ₃ antagonist did not reduce the risk for pruritus compared with the placebo-control group. However, administration of a 5-HT ₃ antagonist reduced the severity of pruritus and the need for rescue treatment compared with a placebo. Heterogeneity and small sample sizes in the studies included in this systematic review limited detailed analysis of the efficacy of prophylactic administration of a 5-HT ₃ antagonist. Few studies have assessed the therapeutic effect of 5-HT ₃ antagonists for managing postcesarean pruritus induced by neuraxial opioids. In one study, ondansetron 4 mg had a high rate of success for the treatment of moderate-to-severe pruritus compared with placebo (80% and 36%, respectively).

Historically, antihistamines have been a popular first choice for treatment of pruritus. However, the efficacy of these agents has been questioned in patients receiving neuraxial opioids, as histamine release is not the mechanism of pruritus. Alhashemi et al. demonstrated that diphenhydramine was less effective than nalbuphine (higher itching scores and more treatment failures) after administration of intrathecal morphine 0.2 mg. Yeh et al. found that the incidence of pruritus was comparable among patients receiving diphenhydramine 30 mg and placebo (80% and 85%, respectively); however, both groups had a higher incidence of pruritus compared with a group that received ondansetron 0.1 mg/kg (25%). In contrast, Siddik-Sayyid et al. found that the therapeutic success rates for ondansetron 4 mg and diphenhydramine 25 mg were identical (70% for each drug), with similar recurrence rates in successfully treated patients (28% versus 35%, respectively). Differences in study methodology and antihistamine-induced sedation may explain the inconsistent antipruritic effect of diphenhydramine observed in these studies.

The mechanisms by which neuraxial opioids affect specific components of micturition (urge sensation, detrusor and sphincter function) are not fully understood, although spinal and supraspinal sites of action are likely to be involved. Kuipers et al. performed urodynamic studies in healthy male volunteers who received intrathecal sufentanil or morphine. Both opioids caused dose-dependent decreases in detrusor contractility and the urgency to void. Volunteers who received intrathecal sufentanil had earlier recovery of lower urinary tract function than those who received intrathecal morphine. Intrathecal local anesthetics (bupivacaine and lidocaine) have also been shown to ablate detrusor contractility and urge sensation until the dermatomal block regresses to the S2 to S3 level, with no partial recovery until this regression has occurred.

Evron et al. performed an observational study investigating the urinary effects of epidural morphine and methadone in 120 women undergoing cesarean delivery. Not surprisingly given the longer duration of action, difficulty in micturition and need for bladder catheterization were greater in the morphine group (58%) compared with the methadone group (3%). A similar study by Liang et al. reported a higher incidence of postcesarean urinary retention and urinary catheterization (22%) among patients receiving epidural morphine compared with other analgesia modalities (PCEA with ropivacaine-fentanyl [7%] and IV meperidine [3%]). In a study of male volunteers, naloxone reversed the impact of neuraxial morphine on urodynamic function.

To avoid impairment of bladder/detrusor function, urinary catheterization should be considered if voiding has not occurred within 6 hours. Risk factors for postcesarean urinary retention include low BMI, multiparity, emergency cesarean delivery, prolonged operation time, perineal injury, and postoperative analgesia. Transient postpartum voiding difficulty is not detrimental to urinary function and does not subsequently lead to voiding difficulties. Reversal with systemic naloxone may be considered in problematic cases.

Epidural and intrathecal alpha ₂ -adrenergic receptor agonists provide analgesia by activating the descending noradrenergic system, binding to presynaptic and postsynaptic alpha ₂ -adrenergic receptors at the spinal dorsal horn. This process subsequently leads to norepinephrine release, which in turn modulates pain processing in the dorsal horn by inhibiting the release of substance P and increasing acetylcholine levels to produce analgesia. Clonidine , an alpha ₂ -adrenergic receptor agonist, provides a more potent analgesic response with fewer side effects when administered neuraxially than systemically. Clonidine also potentiates sensory and motor block when administered with epidural local anesthetics and acts additively or synergistically with intraspinal opioids. Pregnancy may enhance the analgesic effects of alpha ₂ -adrenergic receptor agonists, thus making them particularly valuable in this setting. In combination with an intrathecal local anesthetic, intrathecal clonidine may prolong the regression of sensory block, improve postoperative analgesia, and decrease intraoperative pain. However, a combination of intrathecal clonidine and local anesthetic may also increase the risk for hypotension in a non–dose-dependent manner. Mendez et al. compared the analgesic efficacy of low-dose epidural clonidine (400-µg bolus) versus high-dose clonidine (800-µg bolus), followed by epidural infusion at 10 or 20 µg/h after cesarean delivery. They observed short-lived, dose-dependent analgesia and sedation, and prolonged motor block, which might lead to delays in the discharge of patients from the postanesthesia care unit.

Several studies have investigated epidural clonidine in combination with epidural opioids for optimizing postcesarean analgesia. An isobolographic evaluation of epidural clonidine (in doses ranging from 50 to 400 µg) with fentanyl (15 to 135 µg) demonstrated nonsynergistic, additive effects between clonidine and fentanyl in patients recovering from cesarean delivery. However, marked variability in drug response and failure of high doses to produce complete analgesia limited the validity of dose-response and ED ₅₀ analyses. Capogna et al. observed that the addition of clonidine 75 to 50 µg to epidural morphine 2 mg lengthened the duration of postcesarean analgesia without increasing the incidence of side effects.

A number of studies have evaluated the potential role of intrathecal clonidine for postcesarean analgesia. Ginosar et al. administered intrathecal clonidine (0 to 100 µg) to healthy volunteers to assess the analgesic effect of doses less than 100 µg; analgesia to experimental heat pain was detected for doses greater than 25 µg. Van Tuijl et al. assessed postcesarean analgesia in patients who received intrathecal clonidine 75 µg combined with bupivacaine compared with intrathecal bupivacaine alone. Early postoperative analgesia (for 1 to 2 hours) was improved in patients who received clonidine; however, no difference was found in 24-hour morphine consumption between the groups, likely reflecting the short duration of action of a bolus dose of clonidine.

Interaction studies of intrathecal opioids combined with clonidine have investigated the contribution of each drug to analgesia and side effects. Benhamou et al. evaluated postcesarean analgesic outcomes in patients who received hyperbaric bupivacaine alone, or bupivacaine and clonidine 75 µg, or bupivacaine with clonidine and fentanyl 12.5 µg. Patients who received the bupivacaine-clonidine-fentanyl combination reported less intraoperative pain and more prolonged postcesarean analgesia (time to first analgesia request 215 minutes) than those who received bupivacaine-clonidine and bupivacaine alone (183 and 137 minutes, respectively). However, higher rates of pruritus and sedation were reported for the bupivacaine-clonidine-fentanyl group. Paech et al. performed a six-arm study assessing postcesarean analgesia after intrathecal bupivacaine 12.5 mg with fentanyl 15 µg and one of the following regimens: clonidine 150 µg; morphine 0.1 mg; morphine 0.1 mg with clonidine 30, 60, 90, or 150 µg. They concluded that the morphine-clonidine regimens provided optimal analgesia with lower pain scores at rest and with coughing in the first 4 hours. The minimum effective intrathecal dose of clonidine was 30 to 60 µg combined with bupivacaine, fentanyl 15 µg, and morphine 0.1 mg. However, an increase in intraoperative sedation was observed in all groups receiving clonidine.

Lavand’homme et al. compared antihyperalgesic effects in patients receiving intrathecal clonidine 150 µg with bupivacaine, clonidine 75 µg with bupivacaine-sufentanil, or bupivacaine-sufentanil. The bupivacaine-clonidine 150-µg group had a smaller area of periincisional hyperalgesia and a lower incidence of hyperalgesia compared with the other study groups. However, no between-group differences were observed in postoperative morphine consumption or in pain scores before and after discharge. Carvalho et al. randomized 195 women to receive intrathecal hyperbaric bupivacaine with morphine 0.05 mg, morphine 0.1 mg, or morphine 0.05 mg combined with clonidine 75 µg for surgical anesthesia. Pain intensity at rest or while coughing did not differ among groups. During recovery, the incidences of hypotension, bradycardia, and sedation were similar among groups.

Allen et al. performed a systematic review and metaanalysis evaluating the effect of neuraxial clonidine on 24-hour morphine consumption and time to first analgesic request in women undergoing elective cesarean delivery. Eighteen studies were included in the analysis (12 intrathecal administration, 6 epidural administration). Neuraxial clonidine reduced 24-hour morphine consumption by 7.2 mg and prolonged time to first analgesic request by 135 minutes compared with the control group. Intraoperative hypotension and intraoperative sedation were more frequent with neuraxial clonidine.

In summary, neuraxial clonidine may offer a small improvement in postcesarean analgesia in addition to that provided by neuraxial morphine. Epidural clonidine (150 to 800 µg) may prolong postcesarean analgesia when given in combination with epidural opioids. Intrathecal clonidine (75 to 450 µg) has modest efficacy and a relatively short duration of action. Ongoing concern about the adverse side-effect profile of epidural and intrathecal clonidine—notably sedation and hypotension—limit the neuraxial administration of this agent in most patients undergoing cesarean delivery. Additionally, in the United States, epidural clonidine has a “black box” warning stating that it is not recommended for obstetric, postpartum, or perioperative pain management because of the risk for hypotension and bradycardia that were identified after high doses. In selected cases, the anesthesia provider may conclude that the potential benefits outweigh the risks.

Dexmedetomidine is a highly selective alpha ₂ -adrenergic receptor agonist that provides some analgesic effects mediated at the spinal level. Its systemic administration is widespread in anesthesia and critical care; however, its use in peripheral nerve blocks and neuraxial anesthesia is off-label. In one of the few studies evaluating neuraxial dexmedetomidine, 80 healthy women were randomly assigned to a control group (intrathecal hyperbaric bupivacaine 5 mg and an epidural mixture of 10 mL plain bupivacaine 0.25% and fentanyl 50 µg) or a study group who received the same drugs with the addition of epidural dexmedetomidine (0.5 µg/kg). The dexmedetomidine group required less intraoperative and postoperative fentanyl than the control group (4/40 and 18/40, respectively). There was no difference between the groups in block characteristics or sedation. In a study of intrathecal dexmedetomidine for cesarean anesthesia, Qi et al. compared bupivacaine 10 mg, bupivacaine 10 mg combined with dexmedetomidine 5 µg, and bupivacaine 10 mg combined with morphine 0.1 mg. Sensory blockade was longer in the dexmedetomidine group than in other groups. Intrathecal dexmedetomidine provided similar analgesia and less pruritus and shivering compared with morphine. Dexmedetomidine via the neuraxial route is currently not approved by any regulatory body.

Epinephrine has a direct analgesic effect by activating alpha ₂ -adrenergic receptors and may potentiate local anesthetics by inducing local vasoconstriction through alpha ₁ -adrenergic activation, resulting in slower drug clearance. Several clinical studies have investigated epinephrine as a spinal or epidural adjunct. Robertson et al. reported that epidural epinephrine 25 µg prolonged the duration of analgesia with epidural fentanyl 100 µg but increased the incidence of pruritus. Similar prolongation of analgesia has been observed when epinephrine (5 to 30 µg/mL) was combined with epidural diamorphine or sufentanil; however, the incidence of side effects (including vomiting that required treatment) was also increased. In contrast, McMorland et al. did not replicate this finding, although their study was not powered to demonstrate noninferiority. Importantly, studies of the addition of epidural epinephrine (5 µg/mL) to 2% lidocaine or 0.5% bupivacaine have not demonstrated any detrimental effects of epinephrine on umbilical artery blood-flow velocity waveforms, uteroplacental or fetal vascular resistance, fetal myocardial function, or fetal heart rate or neonatal outcomes.

The use of intrathecal epinephrine as an adjuvant to local anesthetics, with or without opioids, has been evaluated in several studies. The addition of epinephrine 200 µg to hyperbaric spinal bupivacaine improved perioperative analgesia but was associated with a longer duration of residual sensory and motor block. In a separate study, a combined intrathecal regimen of epinephrine 200 µg with morphine 0.2 mg improved intra- and postoperative analgesia compared with intrathecal morphine 0.2 mg alone. Zakowski et al. found earlier and higher peak plasma bupivacaine concentrations with the addition of spinal epinephrine 200 µg to spinal bupivacaine in patients undergoing cesarean delivery. In contrast, plasma levels of morphine were approximately 66% lower in the epinephrine group than in the control group. The investigators concluded that the enhanced efficacy of intrathecal bupivacaine combined with morphine and epinephrine was not caused by vasoconstriction alone.

In summary, the use of epidural epinephrine (2.5 to 30 µg/mL) seems to prolong the duration of analgesia with epidural opioids but may increase side effects. The use of intrathecal epinephrine 200 µg does seem to enhance neuraxial opioid analgesia but is associated with prolonged sensory and motor block.

By interfering with the breakdown of acetylcholine, neostigmine indirectly stimulates spinal nicotinic and muscarinic receptors and the release of nitric oxide. As both nicotinic and muscarinic receptors are important to central and peripheral pain transmission, the resulting analgesia may be caused by central and/or peripheral alterations in pain modulation and transmission. Initial studies of intrathecal neostigmine in animals and human volunteers have demonstrated analgesic effects without neurotoxic effects. However, despite producing dose-dependent analgesia, intrathecal neostigmine results in nausea that is particularly resistant to traditional antiemetic treatment, and therefore the use of intrathecal neostigmine is generally not recommended.

Kaya et al. assessed the analgesic efficacy of epidural neostigmine administration after cesarean delivery. A CSE technique was employed with intrathecal bupivacaine 8 mg and fentanyl 10 µg, and patients subsequently received epidural neostigmine doses of 75, 150, or 300 µg after delivery. The investigators reported modest, short-lived, and dose-independent reductions in postoperative pain in the neostigmine groups. No differences among groups in 24-hour morphine consumption after surgery were observed.

Epidural neostigmine is not currently recommended for routine use until additional studies substantiate clinically significant postcesarean analgesic benefits with fewer side effects compared with alternatives. Data regarding the maternal and fetal safety profile of epidural neostigmine are reassuring.

Ketamine . Limited data exist regarding the role of neuraxial ketamine in the provision of postcesarean analgesia. Anesthetic and subanesthetic doses of ketamine have analgesic properties via noncompetitive antagonism of NMDA receptors. In patients undergoing cesarean delivery randomly assigned to receive intrathecal bupivacaine alone or in combination with S(+) ketamine 0.05 mg/kg or fentanyl 25 µg, significantly prolonged and better quality analgesia was observed in the fentanyl group. It is unclear whether the S(+) or R(-) isomers of ketamine have analgesic advantages over the racemate. No published studies have evaluated perioperative epidural ketamine administration in patients undergoing cesarean delivery. At this time, neuraxial use cannot be recommended for patients undergoing cesarean delivery because there is a lack of data regarding the safety of neuraxial administration.

Magnesium . Magnesium is a noncompetitive antagonist of the NMDA receptor and may alter pain signaling by preventing central sensitization after nociceptive stimulation. Magnesium blocks NMDA ion channels in a voltage-dependent manner. Studies investigating intrathecal and epidural magnesium have shown variable analgesic effects after cesarean delivery. Sun et al. compared the postcesarean analgesic profile of four different epidural solutions administered in the perioperative period. All patients received 0.1% bupivacaine 10 mL with one of the following: morphine 1.5 mg, magnesium 500 mg, morphine 1.5 mg and magnesium 500 mg, or placebo. Patients who received magnesium and morphine had lower postoperative pain scores at rest and with movement, an increased time to first analgesic request, and increased satisfaction at 24 hours after surgery compared with women who received only one drug or placebo. Albrecht et al. reviewed 18 trials (including some trials in women undergoing cesarean delivery) of the efficacy and safety of neuraxial magnesium sulfate for postoperative analgesia. They observed an overall increase in the interval to first analgesic request (mean difference of 40 minutes after intrathecal administration and 110 minutes after epidural administration). However, only four trials assessed neurologic complications, and the authors concluded that there were not enough patients ( n = 140) to evaluate the risk for neurologic complications.

Intrathecal magnesium sulfate 50 mg prolonged the duration of spinal anesthesia and improved postoperative analgesia in patients undergoing nonobstetric surgery with bupivacaine and fentanyl spinal anesthesia. In women undergoing cesarean delivery, no difference in the first request for postcesarean analgesia was found among patients who were randomized to receive intrathecal magnesium sulfate 50 mg compared with placebo (median time, 100 versus 105 minutes, respectively); patients who received intrathecal fentanyl 25 µg had a longer time to first request for analgesia (132 minutes) compared with those who received magnesium.

In summary, neuraxial administration of magnesium may have a favorable analgesic effect in patients after cesarean delivery. However, more research, including dose-response studies and comparison with systemic administration, are needed to formally assess the analgesic efficacy of epidural and intrathecal magnesium.

In the future, newer agents and adjuvants may enhance postoperative pain management strategies in patients receiving neuraxial anesthesia for cesarean delivery. Adenosine (and adenosine analogues) have been proposed to have antinociceptive activity related to activation of spinal adenosine A ₁ receptors. However, studies have not demonstrated improved analgesia with intrathecal adenosine administration in patients undergoing hysterectomy or for labor analgesia.

Intrathecal midazolam may have a favorable pharmacologic profile for cesarean anesthesia. After cesarean delivery, patients who received intrathecal midazolam 2 mg (without neuraxial opioids) had prolonged postoperative analgesia, reduced requirement for rescue analgesic, and lower pain scores for 6 hours after surgery compared with patients who received either intrathecal midazolam 1 mg or no midazolam. Dodawad et al. randomly assigned 60 women with pregnancy-induced hypertension undergoing cesarean delivery to receive intrathecal bupivacaine 10 mg (control group) or bupivacaine combined with midazolam 2 mg (study group). Postoperative analgesia was longer in the midazolam group than in the control group (202 and 358 minutes, respectively). A systematic review and metaanalysis by Hung et al. demonstrated that adjuvant intrathecal midazolam prolonged the time to the first analgesic and decreased perioperative maternal nausea and vomiting but with more sedation. It is unknown whether intrathecal midazolam has any benefit compared with intrathecal morphine or in addition to morphine.

Several neuraxially administered drugs have been shown to produce antinociceptive effects by altering calcium channel conductance in the spinal cord. Intrathecal gabapentin reduced incision-induced allodynia in rats, and epidural verapamil lowered postoperative opioid consumption after lower abdominal surgery. Ziconotide , a neuronal N-type-selective voltage-sensitive calcium entry–blocking agent, has been shown to have analgesic effects after intrathecal administration in chronic pain patients.

Before recommendations can be made about the potential use of new adjunct agents, neurotoxicity studies are necessary to ensure these agents’ safety for neuraxial administration. In addition, studies assessing analgesic efficacy, side effects, and toxicity must demonstrate that these agents result in significant improvement over the neuraxial local anesthetic and opioid regimens currently used in clinical practice.