Morphine

First isolated in 1806 and named morphium after Morpheus, the Greek god of dreams, morphine was introduced and soon abandoned as a labor pain medication because of neonatal depression. Its intrapartum use reappeared in the early 1900s as a component of “twilight sleep,” a combination of morphine and scopolamine; the analgesia produced would often result in maternal sedation and neonatal depression.

Morphine has a high affinity for µ-opioid receptors and is a potent long-acting analgesic. Infrequently used during labor, morphine can be given every 4 hours intravenously (0.05 to 0.1 mg/kg) or intramuscularly (0.1 to 0.2 mg/kg), with a peak effect observed in 10 and 30 min, respectively. The duration of action when given intravenously or intramuscularly is 3 to 4 h.

Morphine is principally metabolized by conjugation in the liver, with up to 70% being transformed into the largely inactive morphine-3-glucuronide. The remainder is transformed into the active metabolite morphine-6-glucuronide, an opioid agonist that is 13 times more potent than morphine and has significant analgesic properties. Both metabolites are excreted in the urine and have elimination half-lives of up to 4.5 hours in the presence of normal renal function. Morphine rapidly crosses the placenta, and a fetal-to-maternal blood concentration ratio of 0.96 is observed at 5 minutes. The elimination half-life of morphine is longer in neonates than in adults.

Maternal side effects include respiratory depression and histamine release, which may result in rash and pruritus. Like many opioids, morphine is emetogenic and is associated with sedation and dysphoria with increasing doses.

The greatest neonatal concern of morphine is that of respiratory depression, which has been attributed to an increased permeability of the neonatal brain. In a small study, Way et al. observed that intramuscular morphine given to newborns seemed to cause greater respiratory depression than an equipotent dose of meperidine when response to carbon dioxide was measured.

Pregnancy alters the pharmacokinetics of morphine. Greater plasma clearance, shorter elimination half-life, and earlier peak metabolite levels occur in pregnant women than in nonpregnant women. In theory, these characteristics should reduce fetal exposure. One study observed no cases of neonatal depression after morphine administration during labor, prompting the researchers to suggest that morphine use in labor should be reevaluated. Subsequently, Olofsson et al. assessed the analgesic efficacy of intravenous morphine during labor (0.05 mg/kg every third contraction, to a maximum dose of 0.2 mg/kg) and observed clinically insignificant reductions in pain intensity. These investigators also compared intravenous morphine (up to 0.15 mg/kg) with intravenous meperidine (up to 1.5 mg/kg) and found that both groups had high pain scores despite high levels of maternal sedation.

A randomized controlled trial comparing morphine (2 mg) to intravenous acetaminophen (1000 mg) for early labor analgesia observed no differences in visual analogue scale (VAS) pain scores before and at 15 minutes and 1 hour. However, within 2 hours of administration, significantly more women receiving acetaminophen required rescue analgesia (52.9% versus 17.6%, P < .01).

Meperidine

In 1947, meperidine (pethidine) was the first synthetic opioid to be used for intrapartum analgesia and quickly displaced morphine as the most common opioid given for labor analgesia in the United Kingdom. An agonist that binds to both µ and κ opioid receptors, meperidine is estimated to provide 10% of the analgesic potency of morphine. The usual dose is 50 to 100 mg intramuscularly, which can be repeated every 4 hours. The onset of analgesia occurs in 10 to 15 minutes, but 45 minutes may be required to reach peak effect. The duration of action is typically 2 to 3 hours.

Meperidine is highly lipid soluble, readily crosses the placenta, and equilibrates between the maternal and fetal compartments within 6 minutes. Meperidine is metabolized in the liver to normeperidine, a pharmacologically active metabolite that may cause prolonged neonatal side effects.

Maternal administration of meperidine may reduce fetal aortic blood flow, fetal muscle activity, and FHR variability. Sosa et al. demonstrated that intravenous meperidine 100 mg, given during the first stage of labor, resulted in an increased incidence of umbilical cord arterial acidemia at delivery compared with a placebo. The risk for neonatal respiratory depression is least with maternal administration of meperidine within 1 hour of delivery, and greatest when administered 3 to 5 hours before delivery.

Normeperidine accumulation is associated with altered neonatal behavior, manifesting as reduced duration of wakefulness, attentiveness, and breast-feeding. Meperidine administration is associated with lower Apgar scores and muscle tone in the neonate. Maternal side effects are of less clinical concern, although there is a high incidence of nausea, vomiting, and dysphoria.

The maternal half-life of meperidine is 2.5 to 3 hours, whereas that of normeperidine is 14 to 21 hours. The half-life of both compounds is increased by up to three times in the neonate as a result of reduced clearance, resulting in adverse effects up to 72 hours after delivery. The action of meperidine, but not normeperidine, is reversed by naloxone; consequently, antagonism with naloxone may exacerbate normeperidine-induced seizures owing to suppression of the anticonvulsant effect of meperidine.

The quality of labor analgesia produced by meperidine 50 mg is comparable to that of intravenous acetaminophen 1000 mg; a greater incidence of adverse effects has been observed (64% versus 0%).

The effect of meperidine on the progress of labor is unclear. Historically, meperidine has been given to decrease the length of the first stage of labor in cases of dystocia. However in 407 parturients diagnosed with dystocia, Sosa et al. found no differences in the duration of active labor or operative delivery rates, but significantly greater need for oxytocin augmentation (RR 2.24, 95% CI, 1.13 to 4.43), with the administration of intravenous meperidine 100 mg compared with saline-placebo.

Despite these concerns, meperidine is the most common opioid given for labor analgesia worldwide; this is most likely the result of its familiarity, ease of administration, availability, and low cost.

Diamorphine

Diamorphine (3,6-diacetylmorphine, heroin) is a synthetic morphine derivative used for labor analgesia in 34% of obstetric units in the United Kingdom. Diamorphine is twice as potent as morphine. As a prodrug, diamorphine has no direct affinity for opioid receptors, but it is rapidly hydrolyzed by plasma esterases to active metabolites, which are responsible for its clinical effect. The metabolite 6-monoacetylmorphine is responsible for a significant proportion of analgesic activity, and it is further metabolized to morphine.

Although diamorphine 5 to 10 mg can be given intravenously, the same dose given intramuscularly results in approximately 90 minutes of labor analgesia. Both diamorphine and its active metabolite 6-monoacetylmorphine are more lipid soluble than morphine, resulting in a faster onset of analgesia with more euphoria but less nausea and vomiting. These pharmacokinetic properties may predispose to maternal respiratory depression. Because of rapid placental transfer, neonatal respiratory depression may also occur, although this is often associated with high doses of diamorphine.

Rawal et al. investigated the relationship between a single intramuscular dose of diamorphine 7.5 mg, the umbilical cord blood concentration of free morphine, and neonatal outcomes. A significant negative correlation between the dose-delivery interval and umbilical cord blood morphine levels was observed, with no correlation between higher free morphine concentrations and lower 1-minute Apgar scores (and the need for neonatal resuscitation). These findings suggest that infants born shortly after diamorphine administration are at greater risk for respiratory depression.

In 133 pregnant women randomized to receive intramuscular diamorphine 7.5 mg or meperidine 150 mg, Fairlie et al. found significantly greater reports of poor or no pain relief at 60 minutes in the group receiving meperidine, although approximately 40% of women in both groups requested a second-line analgesic agent. The incidence of maternal sedation was comparable, but the diamorphine group had less vomiting and higher neonatal Apgar scores at 1 minute.

Wee et al. conducted a two-center double-blinded randomized controlled trial of 484 women receiving intramuscular diamorphine 7.5 mg or intramuscular meperidine 150 mg for labor analgesia. The analgesia with diamorphine was modestly better, despite the average length of labor being 82 minutes longer (95% CI, 39 to 124). No differences in maternal sedation, nausea and vomiting, or primary neonatal outcomes were observed.

Fentanyl

Fentanyl is a synthetic opioid that is highly lipid-soluble, protein-bound, and selective for the µ-opioid receptor, with an analgesic potency 100 times that of morphine and 800 times that of meperidine. Its rapid onset (peak effect, 2 to 4 minutes), short duration of action (30 to 60 minutes), and lack of active metabolites make it attractive for labor analgesia. Although intramuscular and intranasal routes are available, fentanyl is most commonly administered via the intravenous route and titrated to effect, often with a patient-controlled device.

Small doses of fentanyl undergo rapid redistribution, but large or repeated doses may accumulate. Importantly, clearance of fentanyl by elimination represents only 20% of that occurring by redistribution, resulting in a rapid increase in context-sensitive half-time with an increased duration of infusion. Fentanyl has a longer elimination half-life than morphine, but it is metabolized to several inactive metabolites in the liver that are excreted in the urine.

Fentanyl readily crosses the placenta as it is lipophilic; however, the average umbilical vein/maternal vein ratio remains low, most likely owing to a significant degree of maternal protein binding and drug redistribution. In a chronically instrumented sheep model, Craft et al. detected fentanyl in fetal plasma as early as 1 minute after maternal administration; however, maternal plasma levels were approximately 2.5 times greater than fetal plasma levels.

Rayburn et al. compared women receiving intravenous fentanyl (50 to 100 µg every hour at maternal request) with those who did not receive analgesia. All patients receiving fentanyl (mean 140 µg; range 50 to 600 µg) experienced brief analgesia (mean 45 minutes), sedation, and a transient reduction in FHR variability (mean 30 minutes). There were no differences between groups in neonatal Apgar scores, respiratory status, or Neurologic and Adaptive Capacity Scores (NACS). In a similar comparison of intravenous fentanyl (50 to 100 µg every hour) with an equianalgesic dose of meperidine (25 to 50 mg every 2 to 3 hours), Rayburn et al. observed less sedation, vomiting, and neonatal naloxone administration with fentanyl, but no difference in NACS. The two groups experienced similarly high pain scores, suggesting that both drugs have poor analgesic efficacy at the studied doses.

Rezk et al randomized 80 parturients in active labor to receive intravenous fentanyl or intramuscular pethidine. A mild to moderate decrease in pain scores in both groups, but a return to baseline scores, was observed within 3 hours of fentanyl administration. Meperidine was associated with more maternal nausea and vomiting ( P < .05), but less need for neonatal resuscitation and naloxone administration ( P < .05).

A randomized controlled trial of 156 parturients investigated the efficacy of intranasal (i.n.) fentanyl, subcutaneous (s.c.) fentanyl, and intramuscular (i.m.) meperidine. Significant, similar reductions in pain scores were observed in all groups at 30 minutes; however, greater satisfaction (i.n. fentanyl 82.9%, s.c. fentanyl 80.6%, and i.m. meperidine 44%, P < .05) and less sedation (i.n. fentanyl 7.3%, s.c. fentanyl 2.9%, and i.m. meperidine 44%) were observed in the fentanyl groups. In a pilot study aimed at assessing the practicality and tolerability of patient-controlled analgesia with i.n. fentanyl (54 µg, lockout interval 3 min) for providing ongoing labor analgesia, most women reported satisfactory analgesia (78.2%), with a mean fentanyl dose of 734 µg over 3.5 hours, and a willingness to use it again (84.4%). However, 12.5% of neonates ( n = 4) required bag-and-mask ventilation at birth.

Nalbuphine

Nalbuphine is a mixed agonist-antagonist opioid analgesic with agonist activity at κ-opioid receptors, thereby producing analgesia, and partial agonist activity at µ-opioid receptors, thus resulting in less respiratory depression. A partial agonist is a drug that has receptor affinity but produces a submaximal effect compared with a full agonist, even when given at very high doses.

Nalbuphine can be administered by intramuscular, intravenous, or subcutaneous injection, with a usual dose of 10 to 20 mg every 4 to 6 hours. The onset of analgesia occurs within 2 to 3 minutes of intravenous administration and within 15 minutes of intramuscular or subcutaneous administration. The drug is metabolized in the liver to inactive compounds that are then secreted into bile and excreted in feces.

Nalbuphine and morphine are of equal analgesic potency and result in sedation and respiratory depression at similar doses. However, because of its mixed receptor affinity, nalbuphine demonstrates a ceiling effect for respiratory depression at a dose of 0.5 mg/kg. Nalbuphine causes less nausea, vomiting, and dysphoria than morphine. Concerns that it may have an antianalgesic effect, particularly in men, led to the withdrawal of nalbuphine in the United Kingdom in 2003.

Wilson et al. performed a randomized, double-blinded comparison of intramuscular nalbuphine 20 mg and meperidine 100 mg for labor analgesia. Nalbuphine was associated with less nausea and vomiting but more maternal sedation. Analgesia was comparable between the groups. Neonatal neurobehavioral scores were lower in the nalbuphine group at 2 to 4 hours, but there was no difference between groups at 24 hours. The umbilical vein-to-maternal vein concentration ratio was higher with nalbuphine (mean ± SEM, 0.78 ± 0.03) than with meperidine (0.61 ± 0.02). A subsequent study failed to demonstrate an analgesic advantage with either drug but again reported transient neonatal neurologic depression with nalbuphine.

Amin et al. compared the neonatal outcome for women who received either nalbuphine or saline-control before elective cesarean delivery. They found lower 1-minute Apgar scores and a significantly longer time to sustained respiration in the nalbuphine group. However, 5-minute Apgar scores and umbilical cord blood gas measurements were similar between groups.

Nicolle et al. evaluated the transplacental transfer and neonatal pharmacokinetics of nalbuphine administered intramuscularly or intravenously in 28 laboring women. The investigators found a high umbilical vein-to-maternal vein concentration ratio of 0.74, which did not correlate with the administered dose. The estimated neonatal half-life was 4.1 hours, which is greater than the adult half-life and, more importantly, longer than the half-life of naloxone. There was a transient reduction in FHR variability in 54% of the fetuses, which was not associated with the plasma concentration of nalbuphine. Analgesia was rated as effective by 54% of parturients.

Giannina et al. compared the effects of intravenous nalbuphine and meperidine on intrapartum FHR tracings. Nalbuphine significantly reduced both the number of FHR accelerations and FHR variability, whereas meperidine had little effect.

A prospective pilot study of 302 nulliparous parturients (57 women who received nalbuphine, and a control group of 245 women who received neither nalbuphine nor epidural analgesia) reported a marked reduction in duration of the active phase of the first stage of labor in the nalbuphine group (75 minutes versus 160 minutes in the control group); this effect appeared to be independent of oxytocin use. Additional investigations are needed to verify this finding.

Butorphanol

Butorphanol is a synthetic opioid with κ-opioid receptor agonist and µ-opioid receptor antagonist properties that resemble those of nalbuphine. It is five times more potent than morphine and 40 times more potent than meperidine. The typical dose during labor is 1 to 2 mg intravenously or intramuscularly. Butorphanol is 95% metabolized in the liver to inactive metabolites. Excretion is primarily renal. A plateau effect for analgesia and respiratory depression is noted, where butorphanol 2 mg produces respiratory depression similar to that of morphine 10 mg or meperidine 70 mg. However, butorphanol 4 mg results in less respiratory depression than morphine 20 mg or meperidine 140 mg. Higher doses do not provide any additional pain relief or respiratory depression but will increase the likelihood of other side effects.

Maduska and Hajghassemali compared intramuscular butorphanol (1 to 2 mg) with meperidine (40 to 80 mg) and found comparable labor analgesia; similar umbilical vein-to-maternal vein concentration ratios (0.84 and 0.89, respectively); and no differences in FHR tracings, Apgar scores, time to sustained respiration, or umbilical cord blood gas measurements at delivery. Conversely, in a double-blinded comparison of intravenous butorphanol (1 or 2 mg) and meperidine (40 or 80 mg) during labor, Quilligan et al. noted lower pain scores at 30 minutes and 1 hour after the administration of butorphanol. There was no significant difference in Apgar scores between the two groups of infants; however, the mean FHR was noted to be higher among those fetuses whose mothers received butorphanol.

Nelson and Eisenach investigated the possible synergistic effect of giving both intravenous butorphanol and meperidine. Women received intravenous butorphanol 1 mg, meperidine 50 mg, or butorphanol 0.5 mg with meperidine 25 mg. All three groups reported a similar reduction in pain intensity; however, only 29% of the women achieved clinically significant pain relief. There was no difference among groups in maternal side effects or neonatal Apgar scores. The investigators concluded that there was no therapeutic benefit to combining the two drugs.

Atkinson et al. performed a double-blinded trial of intravenous butorphanol (1 to 2 mg) and fentanyl (50 to 100 µg) administered hourly on maternal request. They found that butorphanol provided better analgesia initially, with fewer requests for additional drug doses or progression to epidural analgesia. There was no difference in adverse maternal or neonatal effects between the two groups.

Meptazinol

Meptazinol is a partial opioid agonist specific to µ-opioid receptors with a rapid onset of action (15 minutes after intramuscular administration). The intramuscular dose (50 to 100 mg) and duration of action for labor analgesia are similar to those for meperidine, with an adult half-life of 2.2 hours, and a neonatal half-life of 3.4 hours. Its partial agonist activity is thought to result in less sedation, respiratory depression, and risk for dependence compared with other opioid agonists. Meptazinol is metabolized by glucuronidation in the liver and then excreted in the urine. This process is more mature in the neonate than is the metabolic pathway of meperidine.

Theoretically, this rapid elimination should confer a lower incidence of adverse neonatal effects than occurs with meperidine. In a single-blinded study, Jackson and Robson compared the same dose (100 mg if maternal weight was ≤ 60 kg, 125 mg if 61 to 70 kg, and 150 mg if ≥ 70 kg) of intramuscular meptazinol or meperidine. Meptazinol provided significantly better analgesia than meperidine but resulted in a similar frequency of maternal side effects.

Nicholas and Robson subsequently compared intramuscular meptazinol 100 mg with meperidine 100 mg in a randomized, double-blinded trial in 358 parturients. Meptazinol provided significantly better pain relief at 45 and 60 minutes, but the two drugs provided a similar duration of analgesia, and there was no significant difference between groups in maternal side effects. Neonatal outcomes were similar between groups, except significantly more infants whose mothers had received meptazinol had an Apgar score of 8 or higher at 1 minute.

Other investigators have reported little difference in analgesic efficacy, maternal side effects, or neonatal outcomes between meptazinol and meperidine. In a study of 1100 patients, Morrison et al. found that neither drug given at equal doses (150 mg in patients weighing > 70 kg, 100 mg in those weighing ≤ 70 kg) was effective at relieving pain. Maternal drowsiness was significantly less pronounced with meptazinol, but the incidence of vomiting was higher. FHR changes and neonatal outcomes, including Apgar scores, need for resuscitation, and suckling ability, were comparable. The overall use of naloxone was similar in the two groups, but if the dose-delivery interval exceeded 180 minutes, significantly more neonates in the meperidine group required naloxone.

De Boer et al. assessed neonatal blood gas and acid-base measurements after maternal intramuscular administration of meptazinol (1.5 mg/kg) or meperidine (1.5 mg/kg) during labor. Capillary blood gas measurements at 10 minutes of life showed a significantly lower pH and a higher Pa co ₂ in the meperidine group, although this difference resolved by 60 minutes. These findings suggest that meptazinol causes less neonatal respiratory depression.

Meptazinol may confer some benefits over meperidine in early neonatal outcome, but it is not widely used. A recent survey indicated that it is the intramuscular labor analgesic of choice in only 14% of obstetric units in the United Kingdom. The cost of meptazinol is considerably higher than that of meperidine. Meptazinol is not available in the United States.

Pentazocine

Pentazocine is a selective κ-opioid receptor agonist with some weak antagonist activity at µ-opioid receptors. It may be given orally or systemically by intramuscular or intravenous injection. The typical parenteral adult dose is 30 to 60 mg, which is equivalent to morphine 10 mg. Onset of action occurs within 2 minutes when given intravenously and within 20 minutes if given by the intramuscular route. Metabolism occurs in the liver by oxidation and glucuronidation; metabolites are then excreted in the urine.

Pentazocine causes similar respiratory depression to that seen with equipotent doses of morphine and meperidine, but it exhibits a ceiling effect with doses in excess of 60 mg. Psychomimetic effects (e.g., dysphoria, hallucinations) may complicate its use, particularly with increasing doses.

In a double-blinded study of 94 laboring women who received intramuscular administration of pentazocine (up to 60 mg) and meperidine (up to 150 mg), Mowat and Garrey observed equivalent and adequate analgesia for approximately 40% of women in each group. The incidence of sedation was comparable between groups, and fewer women in the pentazocine group complained of nausea and vomiting.

In a randomized study comparing intramuscular administration of pentazocine 30 mg with tramadol 100 mg in 100 laboring women, Kuti et al. observed greater analgesia in the pentazocine group at 1 hour, with a longer time to subsequent request for additional analgesia (181 minutes versus 113 minutes, P < .05). The overall analgesic effect of both drugs was modest, with only 30% to 50% of women reporting satisfactory pain relief. More women in the pentazocine group were drowsy, but the result did not achieve statistical significance. There were no cases of maternal respiratory depression, and there was no difference between groups in neonatal outcomes. The investigators concluded that pentazocine provides better labor analgesia than tramadol.

Tramadol

Tramadol is an atypical, weak, synthetic opioid that has affinity for all opioid receptors, but particularly the µ-opioid subtype. A racemic mixture of two enantiomers, the analgesic properties of tramadol (+) are mediated via inhibition of the central neuronal reuptake of serotonin, while tramadol (−) inhibits norepinephrine reuptake. Tramadol can be administered orally or by intramuscular or intravenous injection at a dose of 50 to 100 mg every 4 to 6 hours in adults.

The analgesic potency of tramadol is equal to that of meperidine and one-fifth to one-tenth that of morphine. In equianalgesic doses, tramadol causes less respiratory depression than morphine; at usual doses, no clinically significant respiratory depression occurs. The onset of analgesia is within 10 minutes of intramuscular administration, with an effective duration of 2 to 4 hours.

Tramadol is metabolized by demethylation and glucuronidation in the liver to several metabolites, one of which has independent analgesic activity (O-desmethyltramadol [M1]). The metabolites are almost entirely excreted in the urine. The elimination half-life is approximately 5 to 6 hours, whereas that of the active metabolite is 9 hours. Clinical experience in its use over 30 years is substantial. Since pregnant and breast-feeding women were excluded from randomized phase 1 to 3 clinical trials before marketing, research into its use in pregnancy and lactation is limited, and it is now difficult to conduct postmarketing clinical research in these populations.

Tramadol and its active metabolite M1 readily cross the placenta, and an umbilical vein-to-maternal vein ratio of 0.94 has been observed at delivery. Neonates possess complete hepatic capacity for metabolism of tramadol to its active metabolite M1. The elimination profile of M1 suggests a terminal half-life of 85 hours because of its requirement for renal elimination, which is an immature process in neonates. An observational study of women given intramuscular tramadol in doses up to 250 mg for labor analgesia resulted in normal Apgar scores and NACS, with no correlation with tramadol or M1 concentrations. However, the single neonate who required naloxone had the highest plasma concentration of tramadol.

Tramadol for maternal pain relief in labor produces limited analgesic benefit. In a comparison of intramuscular tramadol 100 mg and meperidine 100 mg for labor analgesia, Keskin et al. observed greater pain relief and a lower incidence of nausea and fatigue with meperidine. There was no significant difference between groups in neonatal outcome, but more infants in the tramadol group required supplemental oxygen for respiratory distress and hypoxemia. The investigators concluded that meperidine provided superior analgesia and was associated with a better side-effect profile.

By contrast, Viegas et al. conducted a randomized, double-blinded trial to compare intramuscular administration of tramadol 50 mg, tramadol 100 mg, and meperidine 75 mg. Tramadol 100 mg and meperidine 75 mg provided similar labor analgesia; however, a higher incidence of maternal and neonatal adverse effects was observed with meperidine.

Khooshideh and Shahriari evaluated the intramuscular administration of tramadol 100 mg or meperidine 50 mg on labor duration and analgesic efficacy in 160 parturients. The investigators observed that tramadol was associated with a reduced duration of both the first stage (140 versus 190 minutes, P < .001) and the second stage of labor (25 versus 33 minutes, P = .001). There was no difference in median and maximum pain scores between groups 1 hour after drug administration; however, lower pain scores were observed during the second stage of labor in the meperidine group. Nausea, vomiting, and drowsiness occurred less frequently in the tramadol group.

Shetty et al. observed no difference with the intramuscular injection of tramadol 1 mg/kg compared with pentazocine 30 mg for labor analgesia; however, by the end of the first stage of labor, 55% and 60% of women rated their pain as severe and very severe, respectively. The mean injection to delivery interval was significantly shorter in the tramadol group compared with the pentazocine group.