Systemic Medication (also see Chapter 11 )

Opioids are the most commonly used class of drugs for systemic medication in laboring women. All opioids have various degrees of side effects, including respiratory depression, nausea and vomiting, and mental status changes ranging from euphoria to excessive sedation. All opioids cross to the placental circulation freely because of their physicochemical characteristics, and they may cause respiratory depression in the newborn. However, when used properly, systemic narcotics can be somewhat effective in alleviating labor pain for short periods. Other systemic drugs used in the treatment of labor pain include sedative-tranquilizers and ketamine.

Meperidine

Meperidine is the most commonly used parenteral opioid analgesic during labor. A recent survey carried out in the United States examined the use of parenteral opioids in obstetric units and reported their use in 39% to 56% of patients. In units with over 1500 deliveries per annum, parenteral opioids were administered to 39% of women; units with 500 to 1500 deliveries and units with under 500 per annum reported use in 56% and 50% of women, respectively.^[71] The intramuscular dose ranges from 50 to 100 mg with a peak onset of effect at 40 to 50 minutes; intravenous doses of 25 to 50 mg act within 5 to 10 minutes. The analgesic effect lasts up to 3 to 4 hours. Fetal exposure to meperidine is highest between 2 and 3 hours after maternal administration,^[72] as shown in Figure 58-8 . Meperidine is thought to cause less respiratory depression in the neonate than morphine does; therefore, it is more commonly used.^[73] It may, however, cause loss of beat-to-beat variability of FHR tracings.

Figure 58-8 Effect of time of administration of meperidine before delivery on neonatal depression (Apgar scores of 0 to 6). (Redrawn from Shnider SM, Moya F: Effects of meperidine on the newborn infant. Am J Obstet Gynecol 89:1009–1015, 1964.)

A recent meta-analysis failed to prove that other opioids (tramadol, meptazinol, diamorphine, pentazocine, nalbuphine, and butorphanol) were superior to meperidine for labor analgesia^[74] ; however, several authors have proposed fentanyl and remifentanil as superior choices.^{[75] [76]}

Fentanyl

Fentanyl is an alternative analgesic option for patients in whom regional anesthesia is contraindicated. Its short half-life makes it suitable for prolonged use in labor either as an intravenous bolus or as an analgesic administered by means of a patient-controlled analgesia delivery system.^[77] It provides adequate analgesia with minimal neonatal depression.^[78] Although it is a potent opioid, its use in labor has been limited by side effects and short duration of action. One study that evaluated intravenous fentanyl for labor reported that 4 of 11 fetuses whose mothers received fentanyl for analgesia during labor required naloxone treatment.^[79] The usual dose of fentanyl for labor analgesia is 25 to 50 µg intravenously. The peak effect occurs within 3 to 5 minutes and has a duration of 30 to 60 minutes. Although adverse effects, as measured by acidotic umbilical cord blood gases or lower Apgar scores, have not been demonstrated after doses of 1 µg/kg, placental transfer is rapid.^[80] A study evaluating fentanyl in labor has suggested that mild sedation is apparent after the administration of 50 or 100 µg. In addition, a transient decrease in FHR variability was also noted.^[81]

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Butorphanol and Nalbuphine

Butorphanol and nalbuphine are opioid agonist-antagonists that are structurally related to oxymorphone and naloxone. They have the potential advantages of producing less nausea and vomiting than other opioids do. Butorphanol is a κ-agonist and a μ-antagonist and has minimal affinity for σ receptors. Its dose is 1 to 2 mg intramuscularly or intravenously, and it has a duration of action of up to 4 hours. Nalbuphine is a partial κ-agonist and a potent μ-antagonist with minimal σ receptor activity. A dose of 10 mg intramuscularly or intravenously is equivalent to 10 mg of morphine with an onset of 2 to 3 minutes and 10 to 15 minutes for the intramuscular and intravenous routes, respectively. It offers analgesia for up to 6 hours.

One advantage of these agents over μ-agonists is that they demonstrate a "ceiling effect" whereby increasing doses do not produce further respiratory depression.^[83] Unfortunately, the use of these drugs is limited in clinical practice because they are rapidly transferred across the placenta and have produced ominous sinusoidal FHR patterns.^{[84] [85]} Although it appears that this FHR pattern is often benign and does not signify life-threatening fetal jeopardy as is usually associated with such a pattern, obstetricians are loathe to allow a drug to be used that might produce such a potentially devastating FHR tracing. The use of antagonists or agonist-antagonists may precipitate acute withdrawal syndrome in the mother and the newborn of an opioid-dependent parturient. This syndrome has been reported after parenteral or neuraxial routes of administration.^[86]

Remifentanil

Remifentanil is a potent, short-acting μ-opioid receptor agonist that has been approved for clinical use in the United States since July 1996. It is a piperidine derivative with a normal opioid configuration, but it contains an ester linkage that allows metabolism by nonspecific esterases throughout the blood and muscles. This metabolism gives it a unique pharmacologic profile in comparison to other opioids. Consequently, remifentanil has an extremely rapid plasma clearance and offset of action. Its estimated half-life is 1.3 minutes,^[87] and prolonged administration does not appear to cause accumulation of this drug. Studies have demonstrated an umbilical vein-to-maternal artery ratio of 0.88.^[75] Thus, fetal exposure to the drug is minimized because of its rapid metabolism or redistribution, or both. These properties make it an attractive alternative systemic analgesic in parturients in whom regional anesthesia is contraindicated. Data in the literature from both case series and randomized trials are accumulating with regard to the use of remifentanil in obstetric anesthesia.^{[76] [88]} Dose-response studies using patient-controlled analgesia with intravenous remifentanil suggest that a median effective bolus dose of 0.4 µg/kg with a lockout time of 1 minute^[89] or a continuous infusion of remifentanil at 0.05 µg/kg/min with a bolus of 25 µg and a lockout time of 5 minutes provides satisfactory analgesia.^[76] Prolonged use for 34 hours has also been reported in a complex parturient in whom regional techniques were contraindicated; no adverse effects occurred.^[90] The studies using remifentanil in labor performed thus far have not fully answered whether remifentanil will provide obstetric anesthesiologists with a superior systemic opioid analgesic for parturients.^[91] Although preliminary reports have been promising, it is still somewhat premature to advocate the use of remifentanil until larger studies have fully evaluated its safety.