Opioids may be administered intermittently by subcutaneous (SC), intramuscular (IM) or intravenous (IV) administration,
and the route and timing of this administration influence both maternal uptake and placental transfer. SC and IM injections have the advantage of relative safety and simplicity but can be painful and are associated with a variable absorption depending on the site of the injection. The injection itself is inevitably followed by a delay in the onset of analgesia. Therefore, delivery via SC or IM injection results in analgesia of variable onset, quality, and duration. The IV route of administration offers several advantages. Firstly, there is less variability in the peak plasma concentration of the drug; secondly, there is a faster onset of analgesia; and thirdly, the ability to titrate dose to effect tends to be much more achievable.

Patient-controlled intravenous analgesia (PCIA) is widely and effectively used in the management of postoperative pain and has also been applied to the management of labor analgesia, with a recent survey of UK practice showing that 49% obstetric units offer PCIA for labor analgesia (6). Advantages of the PCIA technique over that of intermittent boluses have been shown to be plentiful with smaller, more frequent dosing resulting in a more stable plasma drug concentration and having a more consistent analgesic effect (7). Other advantages include superior pain relief with lower doses of drug, less risk of maternal respiratory depression, less placental transfer of drug, less need for antiemetic agents, and higher patient satisfaction (7).

PCIA can offer an attractive alternative for labor analgesia in hospitals when epidural anesthesia is unavailable or when contraindicated or unsuccessful. The mother can theoretically adjust the analgesic dose to her individual needs and achieve a greater perceived control over the situation. PCIA use has resulted in higher patient satisfaction scores than other methods of opioid administration. However, studies have not concurrently demonstrated either a reduced use of drug or improved analgesia with PCIA as compared with intravenous administration of an opioid by the obstetric nurse (8).

PCIA use for labor does have some limitations, as even frequent administration of small doses of opioid proves to not always be effective for the fluctuating intensity of labor pains, especially in the late first or second stage of labor (7). Many of the studies in this area have used variable, non-comparable methods to assess the risks to the neonate making the true risks to the fetus and neonate difficult to assess. In addition, variable doses and dosing intervals have also been used, including both the use of a background infusion with an added PCIA bolus as well as PCIA bolus alone, which can make comparison across different studies using a variety of opioids difficult. The most appropriate drug, drug dose, and dosing schedules have not necessarily yet been thoroughly defined with a wide variety being used (Table 7-2).

Meperidine (pethidine, Demerol™) is the most widely used opioid for labor analgesia worldwide, with 84% of UK units prescribing meperidine for labor analgesia (9), usually at a dose of 100 mg IM 4 hourly for 2 doses. Onset of analgesia is 30 to 45 minutes with a 2- to 3-hour duration. Its popularity and widespread use are perpetuated by familiarity, ease of administration, low cost and until recently perhaps, a lack of extensive evidence that alternative opioids showed any significant superiority.

The use of meperidine has been investigated by Tsui et al. (10), who conducted the first double-blind, randomized, placebo-controlled study of IM meperidine for labor analgesia. The study was terminated prematurely when interim analysis revealed significantly greater reduction in visual analog scale
(VAS) pain scores with 100 mg IM meperidine versus saline control. The analgesic effect was found to be modest, however, with a median change in VAS pain score of 11 mm (95% CI 2 to 26 mm) at 30 minutes.

Maternal, fetal, and neonatal side effects are ongoing concerns with meperidine use. Maternal nausea, vomiting, and sedation all occur frequently. Fetal and neonatal effects relate to the pharmacokinetic properties of meperidine and are shown in Table 7-3, as well as being discussed below. It is a synthetic opioid which readily crosses the placenta by passive diffusion, equilibrating between materno-fetal compartments in 6 minutes (11). Decreased FHR variability occurs 25 to 40 minutes after administration and resolves within an hour (12). Maternal half-life is 2.5 to 3 hours but neonatal half-life is prolonged at 18 to 23 hours (13). It is metabolized in the liver to produce normeperidine, a pharmacologically active metabolite which is a potent respiratory depressant. This crosses the placenta and is also produced by the neonate’s own metabolism of meperidine.

Normeperidine has a half-life of 60 hours in the neonate (14). Neonatal complications relate to the total dose and dose-delivery time. Maximal fetal uptake of meperidine occurs 2 to 3 hours after maternal IM administration and studies have shown that infants born within this time have increased risk of respiratory depression (15,16). Normeperidine accumulates after multiple doses or after prolonged dose–delivery interval (17) and may be associated with altered neonatal neurobehavior including reduced duration of wakefulness, reduced attentiveness, and impaired breast feeding (18,19,20).

The efficacy of meperidine use in labor with variable administration techniques was investigated by Isenor and Penny-McGillivray (21), who compared intermittent bolus IM meperidine (50 to 100 mg 2 hourly) and PCIA meperidine with background infusion 60 mg/h and bolus 25 mg up to a maximum of 200 mg. They found that pain scores were significantly lower in the PCIA group and that there was no difference in maternal side effects, FHR or neonatal Apgars in this small group. However, when meperidine PCIA is compared with shorter acting opioids, it has been shown to have disadvantages. Volikas et al. (22) compared 10 mg meperidine with 5-minute lockout to 0.5 μg/kg remifentanil with a 2-minute lockout. The study was terminated after 17 subjects due to concern about poor neonatal Apgar scores in the meperidine group (median score 5.5 at 1 minute, and 7.5 at 5 minutes). Blair et al. (23) also compared meperidine PCIA (15 mg, 10-minute lockout) to remifentanil PCIA (40 μg, 2-minute lockout). VAS pain scores were similar in both groups but neurologic and adaptive capacity scores were significantly lower in the meperidine group. These studies show a clear advantage to the use of shorter acting opioids, such as remifentanil, in the PCIA technique as compared to meperidine.

Historically, morphine had been administered in combination with scopolamine to provide “twilight sleep” during labor and delivery, with good analgesia being obtained at the expense of excessive maternal sedation and neonatal depression. Morphine is also used in the present day in some North American hospitals as a single agent in early labor, at doses of 5 to 10 mg IM or 2 to 5 mg IV with a time of onset at 20 to 40 minutes or 3 to 5 minutes, respectively, and a duration of 3 to 4 hours (24).

Morphine is metabolized by conjugation to its major inactive and active metabolites. Morphine-3-glucuronide is the major inactive metabolite and is excreted in the urine with 66% clearance in 6 hours if renal function is normal (24,25). Morphine-6-glucuronide is the active metabolite, which is produced in smaller amounts (1:4). This has significant analgesic properties but also a respiratory depressant effect (26,27). Morphine rapidly crosses the placenta with a fetal to maternal blood concentration ratio of 0.96 at 5 minutes (28). The elimination half-life is increased in neonates (at 6.5 +/- 2.8 hours) as compared to adults (at 2.0 +/- 1.8 hours) (28,29). FHR variability decreases as with other opioids.

Oloffson et al. (30) assessed the analgesic efficacy of IV morphine during labor (0.05 mg/kg every third contraction to a maximum of 0.2 mg/kg) and found clinically insignificant reductions in pain intensity. The group’s further work (31) compared IV morphine (up to 0.15 mg/kg) to IV meperidine (up to 1.5 mg/kg) and found high pain scores were maintained in both groups despite high levels of sedation. Way et al. (32) showed that IM morphine given to newborns caused greater respiratory depression than an equipotent dose of meperidine when response to CO₂ was measured, and attributed it to an increased permeability of the neonatal brain to morphine.

The concern regarding using morphine PCIA in labor is the accumulation of the active metabolite, morphine-6-glucuronide, a respiratory depressant, which may increase the incidence of neonatal adverse events. There are no studies to compare modes of administration of morphine in labor. Morphine PCIA is not routinely used in labor when there is a viable fetus.

Diamorphine (3,6-diacetylmorphine, heroin) is a synthetic derivative of morphine used as a labor analgesic and has been reported to provide rapid, effective analgesia with euphoria and reduced nausea and vomiting. Although it is not available legally anywhere other than the UK, it is used in 34% UK obstetric units, and in some areas of the country, it is used more frequently than meperidine (9). Diamorphine is rapidly metabolized to 6 monoacetylmorphine via hydrolytic ester cleavage (33). The greater lipid solubility as compared to morphine accounts for its rapid onset. A significant proportion of analgesic activity is due to the metabolite 6-monoacetylmorphine, which crosses the placenta and is associated with respiratory depression. Further breakdown to morphine occurs and this is metabolized by conjugation as already described (34). Typically, a dose of 5 to 7.5 mg IM diamorphine is used, with the administration of higher doses being linked to neonatal respiratory depression (35).

Rawal et al. (35) investigated the effects of a single dose of diamorphine on free morphine concentrations in the umbilical cord at delivery. Following diamorphine 7.5 mg IM, they
found evidence of rapid fetal exposure to morphine and a significant correlation between dose–delivery interval and umbilical cord morphine levels. There was a trend toward lower 1-minute Apgar scores, the need for resuscitation, and higher morphine concentrations in those infants born after a short dose–delivery interval.

In 1999, Fairlie et al. (36) compared IM meperidine (150 mg) to IM diamorphine (7.5 mg) and found significantly more of the meperidine group reported no or poor pain relief at 60 minutes. The trial was small, but suggested that diamorphine conferred some benefits over meperidine with regard to maternal side effects, notably vomiting, and neonatal condition as assessed by Apgar scores at 1 minute. High numbers in both groups required analgesia in addition to meperidine though, suggesting poor efficacy of analgesia achieved by both meperidine and diamorphine.

Diamorphine PCIA has been found to be associated with higher pain scores and lower satisfaction scores when compared to intermittent IM bolus in labor (37). As is the case for morphine, diamorphine PCIA is also not frequently used for labor.

Fentanyl is a highly lipid soluble, highly protein bound synthetic opioid with an analgesic potency 100 times that of morphine and 800 times that of meperidine. Its rapid onset (peak effect 3 to 4 minutes), short duration of action and lack of active metabolites make it attractive for labor analgesia. However, large doses of fentanyl may accumulate, and the context sensitive half-time (the time for plasma concentration to decrease by 50% after stopping an infusion which had achieved steady-state plasma concentration) of fentanyl increases with the length of infusion.

Fentanyl readily crosses the placenta but the average umbilical to maternal concentration ratio remains low at 0.31. Eisele et al. (38) found that 1 μg/kg fentanyl provided good analgesia without significant hemodynamic effect and with no adverse effect on Apgar scores, acid–base status or neurobehavioral scores at 2 and 24 hours. Rayburn et al. (39) administered 50 to 100 μg fentanyl IV as often as hourly at maternal request during labor. All patients experienced transient analgesia and sedation. Reduced FHR variability occurred but there was no difference, when compared with a group of infants unexposed to analgesia, with regard to Apgar scores, respiratory depression, or neurologic and adaptive capacity scores at 2 to 4 hours or 24 hours. Rayburn et al. (40) also compared fentanyl (50 to 100 μg IV hourly) and an equi-analgesic dose of meperidine (25 to 50 mg IV 2 to 3 hourly). The authors found less sedation, vomiting, and significantly less naloxone use for neonatal respiratory depression with fentanyl but no difference in neurologic and adaptive capacity scores. Unfortunately, both groups had similarly high pain scores, suggesting poor efficacy of both analgesics.

The pharmacokinetic profile of fentanyl with rapid onset, high potency, short duration, and absence of active metabolites makes it particularly suitable for PCIA mode of delivery and because of this is one of the most common opioids for labor PCIA. In the UK it was found to be used in 26% of the units which offer PCIA for labor (6).

Rayburn et al. (40) compared PCIA fentanyl (10 μg, 12-minute lockout) to intermittent IV fentanyl (50 to 100 μg hourly) and found equivalent analgesia and sedation between the groups. Unfortunately, however, both groups had incomplete analgesia in late labor. Neonatal Apgar scores, naloxone requirement, and neuroadaptive tests were comparable. Morley-Forster and Weberpals (41) found a 44% incidence of moderate neonatal depression (1-minute Apgar <6) in a retrospective review of 32 neonates after maternal fentanyl PCIA. They found a significant difference in total dose of fentanyl in the mothers of neonates who required naloxone (mean 770 ± SD 233 μg vs. 298 ± 287 μg).

Alfentanil is a fentanyl derivative with reduced potency (10 times less than fentanyl). Alfentanil is less lipophilic and more protein bound, so has a low volume of distribution, which results in a rapid onset (within 1 minute), short duration of action, and rapid clearance (elimination half-life is only 90 minutes). It has a shorter context sensitive half-life than fentanyl. It has, however, been associated with greater depression of neonatal scores than meperidine (42). Morley-Forster et al. (43) compared PCIA alfentanil (200 μg bolus, 5-minute lockout and 200 μg/h basal infusion) to PCIA fentanyl (20 μg bolus, 5-minute lockout and 20 μg/h basal rate). PCIA alfentanil failed to provide adequate analgesia late in labor as compared to fentanyl. There were no significant differences in maternal side effects or neonatal outcome. They concluded that alfentanil was less effective as PCIA than fentanyl.

Remifentanil is a novel ultra-short acting mu-receptor agonist with a rapid onset of action (brain–blood equilibration occurs in 1.2 to 1.4 minutes) and is rapidly metabolized by plasma and tissue esterases to an inactive metabolite (44). It has a constant context sensitive half-life of 3.5 minutes, which is independent of the duration of infusion. The effective analgesia half-life is longer at 6 minutes allowing effective analgesia for several consecutive painful uterine contractions (45).

Plasma concentrations in pregnancy are about half that of the non-pregnant state. This may be due to the increased volume of distribution, with higher blood volume and reduced protein binding, and greater clearance due to increased cardiac output and renal perfusion with higher esterase activity. Remifentanil crosses the placenta rapidly; the umbilical vein to maternal blood ratio is 0.85. However, umbilical artery to vein concentration ratio is low, at 0.29, demonstrating that the drug is rapidly redistributed and metabolized by the fetus (46). Remifentanil was introduced into obstetric analgesia at the end of the 1990s and has many advantages as an opioid PCIA for this purpose. In 2007, 33% of UK obstetric units that offered labor PCIA were using remifentanil (47) and this is likely to increase as clinical confidence with the technique grows.