Labor pain has been described as one of the most intense forms of pain that can be experienced1 and epidural analgesia is generally accepted as the most effective form of pain relief.2 However, in certain circumstances, neuraxial analgesia may be contraindicated, unavailable, or very difficult to perform. Some parturients may also elect for alternative forms of analgesia.
An alternative to neuraxial analgesia is systemic opioids (e.g., meperidine, fentanyl). Meperidine seems to be the most frequently used opioid for labor analgesia3 despite evidence to suggest that it has limited efficacy and multiple side effects.4
Remifentanil is an ultrashort-acting μ receptor agonist first synthesized in the early 1990s.5 Its use in obstetrics followed a landmark study by Kan et al.6 that detailed the effects of remifentanil on maternal and neonatal well-being, thus paving the way for use of remifentanil in pregnancy. The first observational study, by Olufolabi et al.7 in 2000, found that remifentanil was ineffective in reducing labor pain and instead resulted in significant opioid-related side effects. However, several letters to the editor after that publication provided anecdotal evidence that remifentanil could indeed reduce labor pain if an appropriate dose regimen was given.8,9
Remifentanil as a labor analgesic has since been a controversial topic with several dose-finding10–12 and comparative studies being performed.13–26 It has also been a subject of several editorials,27–31 narrative reviews,32–35 and a university dissertation.36
A systematic review attempting to analyze all data involving remifentanil as a labor analgesic was published in a Spanish journal in 2009.37 The authors included all case reports, observational studies, comparative studies, and data that had been described within reviews or editorials. However, they were unable to quantitatively analyze their data because of the heterogeneous nature of the studies, and they omitted several studies.17,18 Furthermore, several new trials have been published since this review.19,22
The remifentanil controversy lies with the potentially serious side-effect profile of opioids, especially maternal sedation, respiratory depression, and possible maternal-fetal transfer of the drug. Despite favorable pharmacokinetic properties, many still remain unconvinced of the efficacy and safety of remifentanil in the labor ward.
The objective of this systematic review was to evaluate studies comparing remifentanil with meperidine for the treatment of labor pain. The primary outcome was pain scores. We also aimed to examine treatment side effects in the mother, labor process, and in neonatal outcome.
Institutional review board approval was not required for this systematic review. The study was performed using a prespecified protocol that outlined the aim, search strategy, eligibility criteria, data extraction strategy, and statistical analysis. The reporting of the study's findings is in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement.38
The patient population included laboring parturients who received labor analgesia. Randomized controlled trials that compared the use of remifentanil with meperidine and that reported pain scores as an outcome were selected.
We searched, without language restriction, for randomized controlled trials comparing remifentanil with meperidine until November 2010 using the electronic databases of MEDLINE, CINAHL, Embase, Cochrane CENTRAL, and Maternity and Infant Care using multiple keywords for labor analgesia, remifentanil, and meperidine (online Appendix 1, see Supplemental Digital Content 1, http://links.lww.com/AA/A297). Electronic databases from MDConsult,a Science Direct, b and an online registry of clinical trials c were also searched using the keywords “remifentan*l” AND “labo*r” AND “(pethidine OR meperidine).”
We also manually searched through published abstracts from January 1998 to November 2010 of the following meetings, if available: American Society of Anesthesiologists, International Anesthesia Research Society, Society for Obstetric Anesthesia and Perinatology, Obstetric Anesthetists' Association, and Society for Maternal-Fetal Medicine to identify further relevant studies. Because remifentanil is a relatively new opioid that has only been used in the obstetric population since 1998, searching the literature from this year forward allowed us to capture all possible relevant studies. The references of all retrieved articles were examined to identify additional articles. Studies were excluded if they were duplicate studies or did not compare remifentanil with meperidine.
Risk of Bias Assessment
We assessed the methods used in each study for the risk of bias using criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions.39 We assessed for adequacy of sequence generation, allocation sequence concealment, blinding, and the completeness of follow-up. For studies that were judged to be at higher risk of bias, a sensitivity analysis was performed to assess whether the inclusion of these studies significantly biased the result.
Extraction of Data
Two reviewers extracted the data independently using a data collection form (online Appendix 2, see Supplemental Digital Content 2, http://links.lww.com/AA/A298). Any disagreements that arose between the 2 independent reviewers were resolved by a third reviewer. Sample size and inclusion/exclusion criteria were recorded and baseline data were examined for adequacy of randomization. Methods and the specifics of the interventions (dosage regimens used, details of each study group, and numbers recruited in each study group, including the number that had dropped out) were abstracted as well as the need for alternative/ breakthrough medication. Details of the pain scores and other outcome variables were collated and adverse outcomes were recorded if they occurred.
The primary outcome was pain scores assessed using the visual analog scale (VAS) (0- to 100-mm scale). Scores at 1 hour were used for comparison because this was the most frequently reported time point at which data were collected in most of the studies. When incomplete data were encountered, we attempted to contact the authors to obtain additional data and to clarify details.
If appropriate, meta-analyses were conducted with RevMan 5 software (Cochrane Library, Oxford, UK). For continuous data, mean differences with 95% confidence intervals were calculated using the random-effects model. Odds ratios and 95% confidence intervals were calculated for dichotomous data using the Mantel-Haenszel random-effects method. Statistical heterogeneity was tested by the Cochran Q test, with P values <0.10 considered significant. Heterogeneity was quantified with the I2 statistic, with values >50% consistent with significant heterogeneity. Substantial heterogeneity was expected among studies because different regimens of remifentanil and meperidine had been used. If meta-analytic methods of maternal and neonatal outcomes were not possible, results were tabulated and discussed qualitatively. We had planned to assess for publication bias using a funnel plot. However, because the number of included studies was small, this was not feasible. Furthermore, it is unlikely that major studies would have been missed by this review based on the strategy of literature search performed.
The search strategy initially yielded 605 publications (Fig. 1). The titles were scrutinized and 544 were discarded because they were not relevant (e.g., studies not involving remifentanil as a comparator). The titles and abstracts of the remaining 61 were examined and a further 52 discarded (narrative reviews, editorials, observational studies, case series/ reports, and 4 duplicate studies),40–43 leaving 9 eligible publications. Two further studies were excluded24,25 because both arms of the studies were comparing different doses of remifentanil.
The remaining 7 studies comparing remifentanil with meperidine, with a total of 349 subjects, were included in the analysis (Table 1).13–19 One study had 3 arms comparing remifentanil with meperidine and fentanyl.19 Only subjects in the remifentanil and meperidine groups were included in this review. The results of 1 study were also included even though study recruitment was terminated early because of the high number of adverse effects in the meperidine group.13
All of the studies had adequate descriptions of baseline data. One study had significantly more parturients receiving oxytocin infusions in the remifentanil (67%) versus meperidine (25%) groups.13 The distribution of patients with respect to oxytocin infusion and parity seemed uniform in the remainder of the studies.
Risk of Bias Assessment
Details of the risk of bias assessment are listed in Table 2. One study was analyzed using per-protocol analysis.19
A sensitivity analysis excluding studies that had inadequate blinding showed no significant difference in the summary statistic (VAS score: 24 vs 25 mm) with overlapping 95% confidence intervals. Another sensitivity analysis excluding the study that analyzed using per-protocol analysis also showed a similar treatment effect (VAS score: 26 vs 25 mm) with overlapping 95% confidence intervals (online Appendix 3, see Supplemental Digital Content 3, http://links.lww.com/AA/A299; and online Appendix 4, see Supplemental Digital Content 4, http://links.lww.com/AA/A300).Thus, inclusion of these studies did not bias the results significantly.
All 7 studies evaluated the pain scores using the VAS, a linear scale of scores between 0 and 100 mm (Table 3). Three studies were included in the meta-analysis.15,18,19 Three studies were excluded because the VAS data were presented graphically.13,16,17 A fourth study was excluded because pain scores were presented using median and interquartile ranges.14 All 4 excluded studies found a significant reduction in VAS scores with remifentanil compared with meperidine (P < 0.05).13,14,16,17 We attempted to contact the authors of these reports but no further information was forthcoming.
The results of the 3 studies that reported using the means and standard deviations of VAS scores were quantitatively combined in a forest plot15,18,19 (Fig. 2). There was a further reduction of mean VAS score at 1 hour of 25 mm for remifentanil compared with meperidine (P < 0.001, 95% confidence interval = 19–31 mm). However, significant heterogeneity was found among the studies.
We performed a sensitivity analysis including the 4 studies that were excluded in the forest plot.13,14,16,17 The means were estimated to be equal to the median and interquartile ranges were converted to standard deviation by dividing by 1.35 (as described in the Cochrane Handbook44). Enlarged copies of graphically presented data were used to estimate data points with a ruler. When all 7 studies were included in the meta-analysis, remifentanil reduced the mean VAS scores at 1 hour by 25 mm compared with meperidine (95% confidence interval = 20–29 mm) (online Appendix 5, see Supplemental Digital Content 5, http://links.lww.com/AA/A301). Compared with the 7-study sensitivity analysis, the summary estimate of the 3-study meta-analysis was unchanged, although the precision was reduced, as reflected by a wider confidence interval.
Details of maternal outcomes reported in the studies are summarized in Table 4 with further details in online Appendix 6 (see Supplemental Digital Content 6, http://links.lww.com/AA/A302).
Of the 5 studies that reported maternal sedation, 3 studies16–18 did not show any significant difference between remifentanil and meperidine. One study found more sedation in the remifentanil group19 and 1 in the meperidine group.15 Four studies compared the rates of oxygen desaturation to <95%; 1 study found a significantly higher rate of desaturation with remifentanil,19 1 with meperidine,15 whereas 2 other studies14,18 found no significant difference between the groups. All 6 studies evaluating maternal satisfaction found higher satisfaction scores with remifentanil compared with meperidine.14–19 Two studies15,19 reported the conversion rates for remifentanil to epidural analgesia as half that for meperidine and 2 other studies13,14 showed no differences.
Neonatal outcomes are summarized in Table 5 with further details in online Appendix 6 (see Supplemental Digital Content 6, http://links.lww.com/AA/A302). Six14–19 of 7 studies reported no significant difference in Apgar scores at 1 and 5 minutes between remifentanil and meperidine, and the remaining study13 was terminated early because of significantly lower Apgar scores in the meperidine group. All 3 studies that reported on cord pH15,16,19 reported no significant difference between the mean cord pH in the remifentanil and the meperidine groups. Neurologic and Adaptive Capacity Score was measured in 2 studies16,19; 1 study16 reported lower Neurologic and Adaptive Capacity Scores with meperidine 30 minutes after delivery and no significant difference at 120 minutes. Three studies15,16,19 reported fetal heart rate changes; 1 study15 found that remifentanil was associated with better reactivity, lower rates of loss of variability, and fewer variable decelerations or loss of variability and reactivity. A single study13 reported the use of naloxone and admission to the neonatal intensive care unit for 1 neonate in the meperidine group. There were no other recorded incidences of naloxone use among the other studies.
This systematic review suggests that remifentanil is more effective than meperidine in reducing pain scores for parturients in labor. Remifentanil reduces mean VAS scores at 1 hour by 25 mm more than meperidine. Although incomplete, the analgesia provided by remifentanil was still modest. Conversion rates to epidural analgesia were generally <10%, and most studies reported high maternal satisfaction scores, implying that this modest pain reduction may be clinically relevant.34 Indeed, in an editorial, Volmanen and Alahuhta28 suggested that many parturients do not expect complete pain relief and the median level of pain that parturients would consider acceptable during labor was 4 (range, 0–7; scale, 0–10). When Volmanen et al.20 compared remifentanil with epidural analgesia, they found that although epidural analgesia led to superior pain relief, remifentanil was also able to make labor pain more acceptable. Additionally, in their comparative study of remifentanil and meperidine, Blair et al.16 found that although VAS scores were similar, patient satisfaction scores were higher with remifentanil.
Indeed, pain is very subjective and pain scores are not necessarily related linearly with satisfaction scores. In a systematic review evaluating maternal satisfaction,45 analgesia is only 1 component of a satisfactory birth experience and complete analgesia is not listed as an important factor. All 6 studies within this systematic review that reported satisfaction scores as an outcome rated remifentanil as the better analgesic (compared with meperidine). It seems that having some degree of control is important to laboring women.35 This finding suggests that having patient-controlled analgesia is, by itself, a factor in improving maternal satisfaction. Also, in a feasibility study12 of 21 patients, 62% chose to continue using remifentanil as a labor analgesic if given the choice.
Limited conclusions can be drawn for the side-effects profile of remifentanil as compared with meperidine because of insufficient data. Remarkably, there was no significant difference between the oxygen desaturation rates of <95% between remifentanil and meperidine. However, if maternal desaturation does occur with remifentanil, it is arguably not significantly different from desaturation that occurs with meperidine or even when no analgesia is prescribed.36,46 Of note, the study by Evron et al.15 found no episodes of desaturation <95% in the remifentanil group whereas 17% of subjects had desaturation of <95% when a continuous infusion of meperidine was used. These investigators used escalating patient-controlled bolus doses of remifentanil from 20 to 70 μg with an average of 270 μg/kg/h. We also did not find a difference in the rates of bradypnea between parturients who received remifentanil versus meperidine.
There is some evidence that remifentanil is sedative in parturients, although not more so than meperidine. However, sedation was not found to be excessive and parturients were rousable to a verbal stimulus. Because of its rapid offset, remifentanil-induced sedation is likely to quickly resolve and may not require the use of a reversal drug. Moreover, the inherent safety of patient-controlled devices without background infusions may also be protective against excessive sedation.
None of the studies evaluated in our systematic review reported any neonatal adverse outcomes caused by remifentanil. Even though remifentanil crosses the placenta, it is metabolized rapidly by the fetus with an umbilical artery to umbilical vein ratio of 0.29 (implying rapid metabolism and redistribution in the fetus6). However, vigilance is still advised, because there are several case reports cautioning on perinatal adverse effects after the use of remifentanil. One such case47 reported neonatal chest wall rigidity after a high bolus dose of remifentanil (2.5 mg/kg given at induction of anesthesia, 9 minutes before delivery, followed by a background of 0.1–0.15 mg/kg/min infusion) in a patient undergoing cesarean delivery under general anesthesia. Also, a case series48 of 10 patients who received a 0.5 mg/kg remifentanil bolus with 0.2 mg/kg/min infusion reported a 60% incidence of neonatal respiratory depression at birth after a cesarean delivery. As an added precaution, we suggest that appropriate supervision (1-to-1 midwifery), supplemental oxygen, and respiratory and oxygen saturation monitoring should still be made available so that patients can be safely monitored and adverse consequences avoided.
Limitations of the Study
There is substantial clinical heterogeneity found in these studies with remifentanil and meperidine drug regimens varying greatly, with different bolus doses, background infusions, lockout times, and different modes of administration. Because few dose-response studies have been done with either medication, studies may not have compared equipotent doses.
Comparative studies are not sufficiently powered to conclusively quantify the side-effect risks of remifentanil in labor. Most studies have reported on these side effects as secondary outcomes. Moreover, in all of these studies, there is no mention that P values had been adjusted for multiplicity.
The number of comparative studies performed in which data can be pooled is limited. Even so, there is some evidence that remifentanil is a better labor analgesic than meperidine. This systematic review supports the view of the previous systematic review37 that remifentanil might be considered the best alternative analgesia technique after neuraxial techniques.
Although we included all studies involving laboring parturients, most studies excluded high-risk patients with obstetric complications, multiple gestation, and preterm labor. Thus, the results from our systematic review may not be generalized to these populations. Also, we primarily evaluated VAS pain scores at 1 hour; further studies are needed to evaluate the effectiveness of remifentanil beyond this hour.
Future Research Directions
The “ideal” parenteral labor analgesic may not exist. However, remifentanil has the pharmacokinetic properties to give it the best potential. The optimal drug-delivery doses and regimens remain to be determined.
Training the parturient in timing the bolus injection is important8 and it is necessary to coach the parturient to press the button in anticipation of her contractions.33 Remifentanil has a rapid onset of analgesia that starts at 30 to 60 seconds and peaks at approximately 2.5 minutes. Thus, an IV bolus delivered at the beginning of a contraction lasting an average of 70 seconds is likely to provide analgesia for the following contraction.34 In a series of repeated patient-controlled analgesia boluses, a fluctuating level of remifentanil will be available at the effect site during both the contractions and the intervening pauses.28 A method to couple the remifentanil pump with the cardiotocograph may improve analgesia by “anticipating” or predicting each contraction based on features of each patient's cardiotocograph.49
In conclusion, this systematic review found that for parturients in labor, remifentanil reduces pain scores more than meperidine after 1 hour of analgesia. Remifentanil seems to have a comparable side-effect profile to meperidine, although limited conclusions may be drawn from this analysis. Thus, it seems to be a viable alternative to meperidine, especially in cases in which neuraxial analgesia is contraindicated, unavailable, or very difficult to perform. To better quantify the side-effect profile and determine optimal dose regimens, large, well-conducted, randomized controlled trials comparing remifentanil with meperidine or other labor analgesics are needed.
Name: Wan Ling Leong, MBBS, FANZCA.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Wan Ling Leong has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Ban Leong Sng, MBBS, MMed(Anaes), FANZCA, FFPMANZCA.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Ban Leong Sng has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Alex Tiong Heng Sia, MBBS, MMed(Anaes).
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Alex Tiong Heng Sia has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
We would like to thank Dr. Ben Tang, Sydney School of Public Health, University of Sydney, for advice and assistance with the methodology of this report.
a In-Depth and Quick Reference Medical Content. Available at: http://www.mdconsult.com/php/257615941-41/homepage. Accessed June 9, 2011.
b Science Direct. Available at: http://www.sciencedirect.com. Accessed June 9, 2011.
c ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed June 9, 2011.
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