Birnbach, David J. MD, MPH*†; Ranasinghe, J. Sudharma MD, FFARCS*
The road to discovery of the perfect parenteral labor analgesic has been long and tortuous. As we’ve moved from morphine to twilight sleep (opioid plus scopolamine—a popular choice in the 1950s), to meperidine, and then to fentanyl, some aspects have improved. However, we are still far from the ideal nonneuraxial option that will provide safe and effective analgesia for women in labor, let alone remove neuraxial analgesia techniques from their favored perch.
Unfortunately, despite the many advantages of neuraxial analgesia, complications do occur, and in certain situations, neuraxial labor analgesia may be contraindicated, impossible to perform, not desired, or unavailable. Women in labor have a right to pain management; therefore, a satisfactory alternative to neuraxial blockade should be available. Is remifentanil the Holy Grail that we have so long sought? Probably not, but it may very well depend on finding better and smarter ways to administer this drug.
In this issue of Anesthesia & Analgesia, 2 sets of researchers have evaluated the efficacy of remifentanil as compared with neuraxial analgesia.1,2 Neuraxial blockade is considered to be the most effective and least depressant analgesic option, allowing for an alert, comfortable, and participating parturient and a vigorous neonate.3 Of the opioids that may currently be administered parenterally, IV remifentanil theoretically seems to be the most promising due to its rapid onset of action with short latency to its peak effect and organ-independent elimination. Short elimination is an important advantage in obstetrics since the drug administration to neonatal delivery time is often difficult to predict. Like all opioids, placental transfer of remifentanil does occur, but in the neonate, it appears to be rapidly metabolized, redistributed, or both.4
Previous studies have suggested that remifentanil provides better analgesia than nitrous oxide,5 but few of the U.S. labor floors offer nitrous oxide anyway. A more recent comparative study showed that remifentanil patient-controlled IV analgesia (PCIA) provided better analgesia than IV meperidine or fentanyl via PCIA. However, after the first hour, pain scores started to return toward baseline in all groups, and the efficacy of labor analgesia was only mild to moderate.6
In this issue, Stocki et al.1 present a randomized, nonblinded, single-center, controlled study in 40 healthy women in the active phase of labor comparing PCIA with patient-controlled epidural analgesia (PCEA). Designed to demonstrate that IV remifentanil as an IV labor analgesic is not inferior to epidural analgesia, the study has several strengths including the reported homogeneity of the study population, and unlike most previous studies,6–9 the use of end-tidal CO2 monitoring in addition to oxygen saturation. Of great importance as relates to patient safety, these authors reported that the capnography data showed apnea without desaturation, which suggests that pulse oximetry alone may be inadequate as an early alert to apnea and that CO2 measurement (although rarely performed in this clinical setting) may be beneficial. It should be noted that the investigators intervened in all apnea episodes lasting longer than 40 seconds; therefore, we do not know whether supplemental oxygen protects against apnea-associated oxyhemoglobin desaturation in this setting. The additional monitoring with capnography may be particularly important in the high-risk parturient. This study also brings up another important finding that has been previously reported7: there is no correlation between remifentanil dose (adjusted for body weight) and hypoxemia.
A weakness of the Stocki et al.1 study is the potential bias introduced due to the nonblinded design. An even more important issue relates to the dose and method of remifentanil administration. There is a wide individual variation in the dose required for effective labor analgesia with IV opioids, including remifentanil. Therefore, the results might not have been identical if a different dose of remifentanil and regimen had been used. Unfortunately, the optimal doses and regimens to achieve safe and effective analgesia with IV remifentanil remain unknown and are probably different for different women.
The Stocki et al.1 study design called for the recruiting anesthesiologist to be present in the labor room throughout the remifentanil infusion, maintaining visual contact with the woman’s face and the respiratory monitor. Such a practice is not typically standard, and undoubtedly, there would be a shortage of personnel to allow that degree of monitoring on most labor and delivery suites. Another example of potential nongeneralizability is demonstrated by the statement that the anesthesia provider in the labor room documented causes of artifacts on the monitors, and one of the causes mentioned was eating. While NPO status of women in labor is a topic of heated debate,10 most hospitals in the United States do not allow parturients to ingest solids during labor. It is unclear whether allowing a parturient who is to receive an analgesic that may cause apnea to eat is a safe practice.
Stocki and colleagues1 report that the pain scores (using an 11-point numerical rating scale) were significantly lower than baseline at 30 minutes in both groups. However, assessing the change in pain scores over 6 hours showed that remifentanil was significantly less effective than epidural analgesia. Previous studies have reported similar efficacy. Volmanen et al.11 reported a reduction in pain scores during the first stage of labor by a median of 4.2 points with remifentanil. Another study, however, reported that the pain scores during the second stage of labor remained high in women receiving remifentanil (80 mm on a 100-mm visual analog scale).12
In this issue, Liu et al.2 also evaluate remifentanil in labor. They present a meta-analysis of 5 randomized controlled trials comparing remifentanil PCIA with epidural analgesia. These authors similarly conclude that analgesic efficacy of remifentanil PCIA is not superior to epidural analgesia during labor. They also reported that there was no significant difference in secondary maternal outcomes, namely incidence of nausea, vomiting, and pruritus. As opposed to Stocki et al.,1 they did not evaluate maternal oxygen desaturation or apnea in their analysis.
A major problem of IV opioids for labor pain relief is incomplete analgesia. This, unfortunately, has not been totally overcome by the PCIA mode of administration. In addition, opioids provide predominantly visceral pain relief and therefore will be less effective in the second stage of labor, when the pain is predominantly somatic. The timing of the bolus dose, its rate of administration, and the lockout time are all critical elements for providing effective pain management. It was originally thought that due to the rapid onset and offset of remifentanil, it could be given in tandem with the cyclic pain of uterine contractions.13 However, even when the parturient is reminded to “press the button” as soon as they feel the start of a contraction, it is difficult to match the unique time course of labor pain. The pain caused by uterine contractions is episodic in nature and increasing in intensity over time. To depend on a laboring woman to press a button at just the right time before or during each contraction is also somewhat unrealistic.
Remifentanil has some ideal characteristics for patient-controlled analgesia, namely rapid onset and offset. However, potentially serious side effects, such as maternal oxygen desaturation, sedation, and reduced fetal heart rate beat-to-beat variability that may occur during extended periods of remifentanil analgesia, may ultimately limit the use of remifentanil in obstetrics. In determining the minimal effective dose of remifentanil PCIA for labor analgesia, Volmanen et al.8 reported that there was wide individual variation in the dose required for effective labor analgesia (0.2–0.8 mcg/kg). This makes the therapeutic window surprisingly narrow. The requirement for analgesia usually increases as labor progresses. The decrease in oxygen saturation was shown to be significantly greater with remifentanil when compared with meperidine.6 Significantly, more sedation has also been seen with remifentanil when compared with fentanyl or meperidine.6
Although many opioid-induced side effects are minimized with short-acting remifentanil, high degrees of sedation and periods of apnea with desaturation are very concerning. In the study by Stocki et al,1 there were a total of 27 apnea events occurring in 9 women receiving remifentanil versus none receiving PCEA. This finding highlights the importance of appropriate respiratory monitoring as suggested by previous studies5,6 and brings up potential manpower issues when administering remifentanil during labor.
On a positive note, Stocki et al.1 reported no differences in neonatal outcome between the groups. Liu et al.2 and others have similarly reported no significant difference in the neonatal outcomes. A previous study9 that compared remifentanil with meperidine was also encouraging, reporting fewer nonreassuring fetal heart rate tracings and better neurobehavioral scores in the neonates whose mothers received remifentanil. By way of comparison, maternal fentanyl PCIA during labor has been found to result in lower oxygen saturation in newborns for up to 12 hours.14
What about different methods of administration of remifentanil? Recently, attempts have been made to improve the efficacy and safety of remifentanil for labor analgesia by modifying the way it is administered. Volmanen et al.15 designed a study to optimize the timing of a remifentanil bolus in the uterine contraction cycle (at the beginning of contraction versus delayed to coincide with contraction pause), thereby increasing the analgesia effect or reducing the side effects of the drug. They hypothesized that administering a remifentanil bolus during the contraction pause would improve analgesia in early labor but found that administering a remifentanil bolus during the uterine contraction pause does not improve pain relief.
Use of a background infusion of remifentanil is also controversial. In a dose finding study, Blair et al.12 found that the addition of a background infusion did not improve analgesia but increased the side effects such as maternal oxygen desaturation and sedation.
When attempting to establish an effective systemic analgesia method during labor, one must consider the drug in tandem with the system that delivers the IV medication. The inevitable delay and slow administration of the bolus adds to the inadequate pain relief. An average uterine contraction lasts approximately 70 seconds.16 Because of the delay in recognizing a contraction, it is likely that a bolus of remifentanil may not achieve its peak effect during the current contraction if administered at its start, and to date, there are no reported data to define the optimum bolus and infusion rate.
A possible explanation for the excessive side effects is that the peak effect of the remifentanil bolus occurs during uterine diastole when no pain relief is needed. Preemptive administration of parenteral analgesia by anticipating or predicting contractions by using an automated smart-pump coupled with the cardiotocograph may improve analgesia, allowing maximal efficacy during contractions, little opioid effect between contractions, and minimal impact on the fetus. This would require development of a smart algorithm to make real-time predictions about when the next contraction will occur, as well as development of an infusion device that would administer an automatic bolus of remifentanil approximately 60 seconds before a contraction. Although not commercially available, this technology is being studied.17,18
The low conversion rate from remifentanil to epidural analgesia and satisfaction scores similar to the PCEA group, as reported by Stocki et al,1 suggest that most women were satisfied with the less-than-perfect pain relief provided with remifentanil. Comparable maternal satisfaction scores between remifentanil PCIA and epidural analgesia techniques have also been reported in previous studies.7,8
The optimal drug delivery system, doses, and regimens for remifentanil remain to be determined. At the current time, however, according to the current scientific evidence presented in the 2 papers published in this issue, remifentanil via conventional PCIA cannot be considered an effective and safe analgesia method to be used routinely for labor analgesia or as an optimal replacement for neuraxial analgesia. Future development of new analgesic agents and improved methods of administration are essential. So what’s the bottom line? No Holy Grail at this time! Women who cannot receive neuraxial analgesia because of preexisting conditions or who have a preference for analgesic options other than neuraxial blockade have to make the best of an imperfect situation, at least for now.
Name: David J. Birnbach, MD, MPH.
Contribution: This author helped write the manuscript.
Attestation: David J. Birnbach approved the final manuscript.
Name: JS. Ranasinghe, MD.
Contribution: This author helped write the manuscript.
Attestation: JS. Ranasinghe approved the final manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
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