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Department of Anesthesiology, State University of New York at Stony Brook, Health Sciences Center, Stony Brook, New York
Address correspondence to Tracie A. Saunders, MD, Department of Anesthesiology, State University of New York at Stony Brook, Health Sciences Center, L4–060, Stony Brook, NY 11794–8480. Address e-mail to tsaunders{at}anesthes.sunysb.edu
Epidural analgesia provides superior relief of labor pain compared to any parenteral opioid analgesic, regardless of the delivery system (1). Neuraxial analgesia, however, may not always be available or may be contraindicated. In Third World countries, lack of experienced personnel and excessive costs preclude the use of neuraxial techniques, and even in industrialized nations these techniques are not always available. Although nonpharmacologic options for labor analgesia (e.g., hypnosis, acupuncture, aromatherapy, massage therapy) have been used, the efficacy of these methods is variable, unreliable, and depend heavily upon the parturient’s expectations for her labor experience. It is therefore imperative that safe and effective options for systemic labor analgesia be developed.
The challenge is to develop a simple, uncomplicated system that provides adequate pain control during labor while minimizing associated maternal or fetal adverse effects. Optimal therapy should also be simple to administer and not require the constant availability of an anesthesiologist. In addition, this analgesic should not affect the laboring woman’s ability to participate in her labor experience. A further challenge to any systemic opiate is that it must match the unique time course of labor pain, being intermittent and increasing in intensity over time.
Is it possible to create a systemic opioid that meets these requirements? The ideal parenteral analgesic for labor must have unique pharmacokinetic properties with a rapid onset and rapid offset of effect, irrespective of the duration of its administration.
Commonly used parenteral opioids for labor analgesia include meperidine, morphine, fentanyl, nalbuphine, and butorphanol. Because of the delayed onset and the prolonged duration of action of morphine in the parturient, it has very limited labor analgesic effects and causes maternal sedation (2). Morphine, if used at all, should be reserved for use in very early prodromal labor. Worldwide, meperidine, probably because of its familiarity and minimal cost, is the most commonly used parenteral opiate for labor analgesia (3) despite the fact that it has been associated with many adverse fetal and neonatal effects (4).
Do any of the newer piperidine derivatives approach the ideal labor analgesic and provide advantages over meperidine? Several investigators have determined that IV fentanyl is preferable to meperidine as a labor analgesic (4,5). Fentanyl has a time to peak effect of 3–4 min, but after repeated use has an increasing context-sensitive decrement time (6). In two different studies where patient-controlled analgesia (PCA) fentanyl was given during labor for 2 to 5 h, there were no newborn neurobehavioral changes noted (7,8). In one of the studies, however, 4 of the 11 fetuses required naloxone (7). Alfentanil has a very rapid onset of effect (1 min) and a much briefer context-sensitive decrement than fentanyl when given for longer than an hour. Thus one might expect that alfentanil would be a superior analgesic during labor. However, in a randomized trial, Morley-Forster et al. (7) compared PCA fentanyl with PCA alfentanil for labor analgesia and found that PCA fentanyl provided superior labor analgesia with no difference in maternal side effects. Fentanyl also offers diversity as it can be administered in various ways in addition to parenterally such as via patch, orally, or subcutaneously. The data validating fentanyl’s acceptable analgesic effects in this unique patient population are encouraging and should motivate further prospective studies.
Sufentanil has a slower time to peak effect (4–6 min), but has a brief context-sensitive decrement time, even after several hours of administration (6). Thus sufentanil may provide some advantages for labor analgesia. A potential problem with using sufentanil for labor analgesia is that the placenta acts as a depot. The placenta takes up sufentanil and it becomes highly protein bound. There has been very limited work evaluating the role of IV sufentanil as a labor analgesic.
The newest opiate to be used for labor analgesia is remifentanil. Remifentanil is an ultra-short-acting drug that was specifically synthesized to be a potent µ-opioid receptor agonist subject to esterase metabolism. It is a piperidine derivative with the normal opioid configuration, but it contains an ester linkage that makes the compound susceptible to metabolism by nonspecific esterases in blood and other tissues. It has rapid onset (time to peak effect of 60 to 90 s) and rapid offset times irrespective of the duration of its administration. The context-sensitive half-time for remifentanil irrespective of the duration of administration is approximately 3 min (9) in nonpregnant patients. When administered to parturients as a continuous IV infusion, remifentanil rapidly crosses the placenta and it is quickly metabolized and redistributed in the fetus, however, there have been no reports of associated increases in newborn respiratory depression or lower Apgar scores (10). With these properties, remifentanil appears to be a very titratable opioid suitable for administration when analgesia is required for either very brief periods or over prolonged periods, without the concern for prolonged recovery. It therefore resembles our description of an ideal systemic analgesic for use during labor.
Several investigators have evaluated the use of remifentanil for labor analgesia. Two reports are featured in this edition of Anesthesia & Analgesia (12,13). Surprisingly, the results of these and other studies have not been consistent and this has led to some controversy (11). Are there possible explanations for these discrepancies? Owen et al. (12) describe the successful use of remifentanil in a case in which a 34-h remifentanil infusion was administered for labor analgesia in a parturient with contraindications to regional analgesia. They used standard monitoring plus capnography, administered supplemental oxygen, and a labor nurse was continuously present. This case report is interesting in that it used a continuous infusion rather than bolus doses, thus not exploiting the rapid onset feature of remifentanil. It does, however, demonstrate that it is possible to achieve effective analgesia using remifentanil for prolonged labor, and thus its rapid offset provides a unique advantage. Volmanen et al. (13) studied 17 healthy parturients administered remifentanil PCA for 60 min during the first stage of labor and measured the time to adequate analgesia, amount of drug used, and patient satisfaction while monitoring for adverse maternal and fetal effects. They measured the individual effective dose defined as the largest bolus dose during which the patient did not want to have more analgesia. The median effective PCA dose was 0.4 µg/kg with a range of 0.2–0.8 µg/kg. The median consumption was 0.066 µg · kg-1 · min-1 (range 0.046–0.1 µg · kg-1 · min-1). This dose of remifentanil provided a visual analog pain score between 3 and 5 on an 11-point numerical rating scale. This dosing resulted in episodes of desaturation below 94% in 10 of the 17 parturients that was readily corrected with verbal prompting or 2 L/min nasal oxygen. No parturients had signs of utero-placental insufficiency during remifentanil administration. Unfortunately, this study was not continued until the second stage of labor. Thus the impact of remifentanil on the fetus cannot be determined from this study. Jones et al. (14) had similarly positive results with the prolonged use (4–12 h) of remifentanil bolus administration until the second stage of labor in a limited number of parturients with no adverse fetal effects. These studies contrast with the study by Olufolabi et al. (10) who abandoned their study, as they were unable to provide adequate analgesia using remifentanil in four consecutive patients. In these patients, remifentanil was associated with a frequent incidence of adverse effects including respiratory depression (as evidenced by peripheral oxygen desaturation), nausea and vomiting, sedation, and facial pruritus. In this study the remifentanil was not administered by the patient but rather by a separate individual at the beginning of a contraction. This is certainly not ideal. The maximal dose of remifentanil was limited to 0.5 µg/kg, close to the median effective dose established by Volmanen et al. (13). The episodes of respiratory depression were also readily treated using supplemental oxygen. Thus, the studies of remifentanil performed thus far have not fully answered whether remifentanil will provide obstetric anesthesiologists with a superior systemic analgesic for parturients.
In attempting to establish the value of any systemic analgesic during labor one must not only consider the drug but also the delivery system. This is because the ability to predict the minute-to-minute conduct of the pain associated with the labor process will ultimately result in failure. Also, to depend upon a parturient, during perhaps the most vulnerable time in her life, to press a button at the right time is unrealistic. As noted above, Owens et al. (12) provided successful analgesia using a simple infusion. Our own experience with fentanyl has demonstrated that for the laboring patient fentanyl is ideally administered as both a small-dose continuous infusion (e.g., 0.25 µg · kg-1 · min-1) plus bolus dose (0.2–0.4 µg/kg) administered by the patient via a PCA. It would appear from the studies performed thus far that the most effective means of administering remifentanil to optimize its ideal pharmacokinetic profile is to provide basal analgesia via a small-dose continuous infusion to which small additions of rescue analgesia are provided during the peak of the contraction. It would also make sense that as the parturient increases her demands (and thus indicates the progression of labor) the infusion rate is appropriately increased.
The controversies generated by the use of remifentanil for labor analgesia should stimulate us to perform more extensive controlled studies comparing the newer opioid analgesics and with different delivery systems with the goal of finding the ideal parenteral opioid and delivery system for labor analgesia. We must also not forget that there are at least two different populations; the ideal labor analgesic for Third World countries may be different from that of a parturient in a major city in the industrialized world. We need to seek the best form of pain relief for all of our patients. Just as the labor process is dynamic and progressive, so is this challenge for obstetric anesthesiologists.
References
This article has been cited by other articles:
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  J. Waring, S. K. Mahboobi, K. Tyagaraj, and D. Eddi Use of Remifentanil for Labor Analgesia: The Good and the Bad Anesth. Analg., June 1, 2007; 104(6): 1616 - 1617. [Full Text] [PDF]
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 I. Volikas, A. Butwick, C. Wilkinson, A. Pleming, and G. Nicholson Maternal and neonatal side-effects of remifentanil patient-controlled analgesia in labour Br. J. Anaesth., October 1, 2005; 95(4): 504 - 509. [Abstract] [Full Text] [PDF]
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S. Evron, M. Glezerman, O. Sadan, M. Boaz, and T. Ezri Remifentanil: A Novel Systemic Analgesic for Labor Pain Anesth. Analg., January 1, 2005; 100(1): 233 - 238. [Abstract] [Full Text] [PDF]
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 J. Littleford Effects on the fetus and newborn of maternal analgesia and anesthesia: a review: [Les effets de l'analgesie et de l'anesthesie de la mere sur le foetus et le nouveau-ne: une revue] Can J Anesth, June 1, 2004; 51(6): 586 - 609. [Abstract] [Full Text] [PDF]
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