Opioids are often used for managing labor pain. Limitations to their use include unwanted maternal effects, such as sedation, vomiting, and pruritus, and neonatal complications, such as depressed respiration and impaired neuroadaptive capability (1). In addition, animal studies have suggested that some opioids may alter the spontaneous contractility of uterine muscle. For example, in the rat uterus, morphine exerts an inhibitory effect (2), whereas meperidine has an excitatory effect on uterine contractility (3,4). These findings may explain previous observations that patients who received meperidine had shorter labors than those who received morphine (5) and that meperidine increased the duration and frequency of uterine contractions in the active phase of labor (6). Although the uterine responses to opioids may vary with the species of animals, little is known about these responses in humans.
We investigated the effects of opioids—specifically fentanyl, sufentanil, morphine, and meperidine—on the spontaneous contractility of the human pregnant uterus. Segments of human uterus were taken from patients undergoing elective lower-segment cesarean delivery, and their isometric tension was recorded.
The protocol of the study was approved by the IRB. Written informed consent was obtained from 46 ASA physical status I and II full-term parturients undergoing elective lower-segment cesarean delivery. All patients had epidural anesthesia and received 17–22 mL of 0.5% bupivacaine. None was in labor. A small segment of myometrium was excised from the upper incisional surface of the lower uterine segment after delivery of the infant and placenta. The specimen was placed in cold physiological salt solution (PSS) and immediately transferred to the laboratory.
Longitudinal muscle strips (12 × 2 × 2 mm) were cut and mounted vertically and individually in 10-mL tissue chambers. They were connected to isometric force transducers (Grass FT03; Grass, Quincy, MA) to record their active tension on a polygraph (Grass 7D). A resting tension of 0.25 g was placed as in previous investigations (7). PSS in the chamber was maintained at 37°C and aerated with a gas mixture of 95% oxygen and 5% CO2 (pH = 7.4). The PSS had the following composition (in mM): NaCl, 112; KCl, 5; NaHCO3, 25; KH2PO4, 1; MgSO4, 1.2; CaCl2, 2.5; and glucose, 11.5.
Muscle strips developed spontaneous contractions in the tissue chamber approximately 90 min after being mounted. Among the preparations examined, 89% developed regular contractions. Strips showing the contractile amplitude of 1.5 g or more were used. Opioids were added cumulatively at 15-min intervals, and the resultant contractile activities during the last 10 min were averaged to yield a datum at each concentration. In a preliminary study, the contraction lasted without fading up to 5–7 h. However, each series of concentration-response curves was completed within 2 h. Different strips from one subject were tested for different opioids.
Experiments were further performed to explore possible mechanisms by which opioids alter the uterine contractility. To examine whether opioid receptors, nitric oxides, β-adrenoceptors, or prostaglandins are involved in the uterine response to opioids, the concentration-response curves were obtained in the presence of their antagonists. Muscle strips were treated with either naloxone (10−5M), NG-nitro-l-arginine methyl ester (L-NAME) (10−5M), atenolol (10−4M), or indomethacin (10−5M) at least 30 min before applying the opioid. The experiments using these antagonists were performed only for fentanyl and meperidine, because these two opioids showed apparent inhibitory effects on the uterine contractility.
Fentanyl citrate, sufentanil citrate, morphine hydrochloride, and meperidine hydrochloride were donated by Hana Company (Seoul, Korea). Naloxone hydrochloride, L-NAME, atenolol, and indomethacin were purchased from the Sigma Chemical Company (St. Louis, MO). They were dissolved in distilled water, except indomethacin, which was dissolved in 5% wt/vol Na2CO3.
Results are expressed as mean ± sem. Differences in muscular tension were tested by analysis of var-iance with a repeated measures factor, followed by Dunnett’s t-test. Probability values <0.05 were considered statistically significant.
Figure 1 depicts typical traces showing spontaneous contractions of the isolated uterine strip in the control condition and in the presence of incremental doses of fentanyl. The contraction lasted without fading up to several hours in the control condition, but was progressively attenuated during application of increasing doses of fentanyl. Fentanyl (3.5 × 10−8 to 3.5 × 10−5M) caused concentration-dependent decreases of contractility, whereas sufentanil (3.5 × 10−8 to 3.5 × 10−5M) had minimal effects (Fig. 2). Meperidine (3.5 × 10−5 to 3.5 × 10−3M) also caused concentration-dependent decreases of contractility, whereas morphine (3.5 × 10−5 to 3.5 × 10−3M) was without significant effects (Fig. 3). IC50 (concentrations causing 50% inhibition of the contractile amplitude) for fentanyl and meperidine were 2.3 × 10−6 and 1.0 × 10−3M, respectively.
Naloxone (10−5M), indomethacin (10−5M), atenolol (10−4M), or L-NAME (10−4M) alone did not significantly affect the basal contractility, nor did they alter the uterine responses to fentanyl or meperidine (n = 12–17, data not shown).
Meperidine has an excitatory effect in pregnant and nonpregnant rat uterine muscles (3,4). Morphine, however, inhibits the nonpregnant rat uterus (2,8) but has no effects on the pregnant uterus (9). This study, using isolated human pregnant uterine muscle strips, demonstrates that fentanyl and meperidine inhibit spontaneous contractility, whereas morphine and sufentanil do not. Although opioids are often administered to provide labor analgesia, this is the first report to examine their direct effect on human uterine contractility.
It has been suggested that the effects of opioids on uterine muscle vary according to the species, the hormonal status, and the opioid examined. The mechanisms by which opioids may alter uterine contractility have not been fully determined. In this study, the inhibitory effects of opioids on uterine contractility were not affected by naloxone, a μ-opioid receptor antagonist. This finding concurs with previous data that suggested that naloxone had no significant effects on either the stimulatory action of meperidine or the inhibitory action of morphine in the isolated rat uterus (3,8). Furthermore, the inhibitory potency of opioids did not correlate with their known analgesic potency mediated through the opioid receptors. Although the pharmacological potency of sufentanil on the μ receptor is 5- to 10-fold more than that of fentanyl (10), the magnitude of tocolytic effects of the former was much smaller than that of the latter. Therefore, an opioid receptor-mediated mechanism is unlikely to be involved in any inhibitory effects of these agonists.
Nitric oxide (11), β-adrenergic activities (12), and prostaglandins (13) modulate the myometrial contractility during pregnancy in humans. Therefore, we evaluated whether they are responsible for the inhibitory effects of opioids on uterine contractility. The uterine responses to fentanyl or meperidine were not affected by either L-NAME, atenolol, or indomethacin at concentrations that block the respective receptors or enzyme systems in the rat uterus (14) or in the isolated human pregnant uterus (12,15). These findings suggest that the products generated by nitric oxides, β-adrenergic nerve activity, or cyclooxygenase do not play a key role in the uterine response to these opioids.
Spontaneous uterine contraction is closely dependent on the cytoplasmic concentration of free Ca2+(16). Drugs that reduce the intracellular availability of Ca2+ depress the contractile activity of isolated uterine muscles in rats (4) and in pregnant humans (15). The effects of opioids on intracellular Ca2+ have been demonstrated in other tissues. In rat ventricular myocytes, fentanyl depresses myocardial contractility in association with decreases of intracellular availability and myofilament sensitivity of Ca2+, whereas morphine acts primarily by decreasing myofilament sensitivity to Ca2+(17). Leucine enkephalin, an opioid receptor agonist, also reduces L-type Ca2+ channel current in rat ventricular myocytes (18). It is likely that the inhibitory effect of opioids on the human uterine muscle is also associated with their modulating effects on Ca2+ behavior. Further studies will be needed to clarify this possibility.
Regional differences have been demonstrated in the uterine response to various drugs. Prostaglandin E2 contracted strips of myometrium from the fundus with no significant effects on those from the lower uterine segment in pregnant baboons (19). The relaxant effect of vasoactive intestinal peptide is more effective in the outer layer of human nonpregnant uterus than in the inner layer (20). This study examined the muscle preparations excised from the middle layer of lower uterine segment. Those from the fundus may react differently to opioids. In addition, the circulating levels of oxytocin may vary in different stages of labor, which in turn may also affect the uterine responses to opioids. In this context, effective concentrations of opioids to inhibit the uterine contractions in parturients cannot be easily extrapolated. Further studies are necessary to reveal any differential effects that opioids might have in different segments of the uterus.
Whether the opioids administered epidurally or IV would affect the uterine contraction during labor and delivery is not clear. In parturients receiving epidural or IV patient-controlled analgesia, plasma concentrations of fentanyl range from 0.4 ng/mL (approximately 1.2 × 10−9 molar) to 0.8 ng/mL (2.4 × 10−9 molar), and those of meperidine range from 0.2 μg/mL (approximately 0.8 × 10−6 molar) to 0.5 μg/mL (2.0 × 10−6 molar) (21,22). In this study, IC50 for fentanyl and meperidine was 2.3 × 10−6 and 1.0 × 10−3 molar, respectively; the concentrations were approximately three orders larger than those clinically encountered. Furthermore, a significant amount of opioids is bound to plasma proteins in the circulation (23). It is unlikely that clinically appropriate doses of opioids would actually delay the progress of labor or increase blood loss by decreasing the contractile tone during labor and delivery. Indeed, a tocometric study has shown that epidural analgesia during labor with a bupivacaine-fentanyl combination had little effect on uterine contractility (24). In addition, a recent study has also demonstrated that epidural as well as IV analgesia using meperidine during the first stage of labor had no effects on the frequency of uterine activity (25).
In summary, fentanyl and meperidine inhibited the spontaneous contraction of human pregnant uterine muscle in an isolated preparation. However, the concentrations of these opioids required to reduce the uterine muscle tone were much larger than their clinically relevant plasma levels obtained during labor analgesia.
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