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A Comparison of Remifentanil Parturient-Controlled Intravenous Analgesia with Epidural Analgesia: A Meta-Analysis of Randomized Controlled Trials

Liu, Zhi-Qiang MD, PhD*; Chen, Xiu-Bin MD*; Li, Hai-Bing MD*; Qiu, Man-Tang MD, PhD; Duan, Tao MD, PhD

doi: 10.1213/ANE.0000000000000077
Obstetric Anesthesiology: Research Report
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BACKGROUND: Epidural analgesia is generally accepted as the most effective form of pain relief during labor. Remifentanil patient-controlled IV analgesia (PCIA), which is less invasive than epidural analgesia, may be an attractive alternative. In this meta-analysis, we compared the efficacy and safety of the 2 analgesic techniques for labor pain.

METHODS: Databases of PubMed, EMBASE, and Cochrane Library were searched independently by 2 reviewers to retrieve eligible randomized controlled clinical trials. The primary end points were pain scores at 1 and 2 hours, and the secondary end points were nausea, vomiting, pruritus, and umbilical artery pH values. Mean difference (MD) or risk ratio with 95% confidence intervals (CIs) were calculated for each end point. GRADE profiler was applied to assess the quality of evidence.

RESULTS: Five eligible trials were retrieved and analyzed. We found that parturients with remifentanil PCIA had higher visual analog scale (10-cm scale) pain scores than those who received epidural analgesia at 1 hour (MD = 1.9 cm; 95% CI, 0.5–3.3; I2 = 94%) and 2 hours (MD = 3.0 cm; 95% CI, 0.7–5.2; I2 = 89%) after initiation of analgesia. There was no statistical difference between epidural analgesia and remifentanil PCIA in the incidence of nausea, vomiting, pruritus, or umbilical artery pH values. However, the CIs are quite wide and contain clinically significant differences. According to GRADE profiler, most end points had moderate quality except that pain scores at 1 hour were of low quality.

CONCLUSIONS: This meta-analysis suggests that remifentanil PCIA is not superior to epidural analgesia in analgesic efficacy during labor. Given the wide CIs of the pooled results for secondary maternal and neonatal outcomes, definite conclusions cannot be drawn for those outcomes. Further studies are still warranted to validate these conclusions.

Supplemental Digital Content is available in the text.

From the *Department of Anaesthesiology, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai; The Fourth Clinical College of Nanjing Medical University, Nanjing; and Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.

Accepted for publication November 15, 2013.

Funding: This study was supported by Foundation of Shanghai Municipal Health Bureau (no. 2010155).

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site.

Reprints will not be available from the authors.

Address correspondence to Tao Duan, MD, PhD, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, 536 Changle Rd., Shanghai, 200040, China. Address e-mail to tduan@yahoo.com.

Neuraxial analgesia is considered to be the most effective method of pain relief during labor. The American Society of Anesthesiologists and the American College of Obstetricians and Gynecologists believe that parturients requesting neuraxial analgesia should not be deprived of analgesia.1 However, because administration of neuraxial analgesia may be contraindicated in some parturients or parturients may prefer a less invasive method of pain relief, alternative methods of analgesia may be required. From a pharmacokinetic viewpoint, remifentanil parturient-controlled analgesia seems to be an attractive option for labor analgesia.2

Remifentanil is an ultra–short-acting μ1-opioid receptor agonist with an onset time of 30 to 60 seconds and a peak effect at 2.5 minutes.3 Due to rapid metabolism by plasma and tissue esterases, remifentanil offers the advantage of a short half-life. Furthermore, it has a short context-sensitive half-life (3.5 minutes) and can be used over a long period without fear of accumulation.4 Remifentanil rapidly crosses the placenta, but it is metabolized and redistributed quickly by the fetus.5 Due to its unique pharmacodynamic and pharmacokinetic profile, the use of remifentanil PCIA during labor is gaining popularity.6 Recently, several trials7–11 have compared the analgesic efficacy and maternal and neonatal outcomes between remifentanil PCIA and epidural analgesia for labor analgesia, but the results were inconclusive. In addition, a recent case report showed that an obstetric patient using remifentanil PCIA had respiratory arrest and required a brief period of ventilatory support,12 which raised concerns about the efficacy and safety of using remifentanil in labor. Thus, this meta-analysis was designed to compare the efficacy and safety of remifentanil PCIA and epidural analgesia for labor pain relief.

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METHODS

Searching Strategy

Eligible trials were retrieved by electronic search of databases and manual search of references of related reviews or meta-analysis. Databases of PubMed, EMBASE, and Cochrane Library were searched using the following key words: “remifentanil,” “epidural analgesia,” and “patient-controlled analgesia.” Alternative spellings were also used, and there was no limitation of languages, publication time, or article types. Trials listed at ClinicalTrials.gov and conference proceedings of the American Society of Anesthesiologists annual meetings (from October 1997 to November 2012) were also searched. The last search was performed on November 29, 2012.

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Inclusion and Exclusion Criteria

Trials meeting the following criteria were included: (1) randomized controlled trials (RCTs); (2) comparison of PCIA and epidural analgesia for labor analgesia; (3) full-text articles available; and (4) presence of detailed clinical data. Only healthy parturients were included, and trials with abnormal pregnancies were excluded. Two investigators (Z-QL and M-TQ) retrieved eligible trials independently and reached consensus on each citation.

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Data Collection

Two reviewers (Z-QL and M-TQ) collected data from eligible trials in duplicate using a standard data collection form. The following data were collected: name of first author, year of publication, number of participants, age, height, weight, technical details of epidural analgesia and PCIA, pain scores at 1 and 2 hours after administration of analgesic, nausea, pruritus, vomiting, Apgar scores, and umbilical artery pH values. The 2 reviewers reached consensus on each item. In the trial reported by Ismail and Hassanin8 and Tveit et al.,9 pain scores reported using a visual analog scale (VAS) of 0 to 100 mm were transformed to a 0- to 10-cm scale. In the trial of Stourac et al.,7 means and SDs of pain scores were obtained from the authors. In the trial of Volmanen et al.,11 means and SDs of pain scores were estimated according to the procedures described in the Cochrane Handbook (http://www.mrc-bsu.cam.ac.uk/cochrane/handbook502/).

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Validity Assessment

Methodological quality of eligible trials was assessed with the “risk of bias” tool recommended by the Cochrane Handbook (http://www.cochrane.org/training/cochrane-handbook). Seven items were assessed: “random sequence generation,” “allocation concealment,” “blinding of participants and personnel,” “blinding of outcome assessment,” “incomplete outcome data,” “selective reporting,” and “other bias.” Two investigators (Z-QL and M-TQ) assessed the quality of trials independently, and disagreement was solved by discussion with another investigator (X-BC).

GRADE profiler (version 3.6, the GRADE Working Group, http://www.gradeworkinggroup.org) was used to assess the quality of evidence for each end point. Factors that would downgrade the quality (risk of bias, inconsistency, indirectness, imprecision, and publication bias) or upgrade the quality (large effect, plausible confounding, and dose response) were assessed. Quality of evidence was assessed as “low,” “moderate,” and “high.”

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Statistical Analysis

The primary end points were pain scores at 1 and 2 hours; secondary end points were maternal adverse effects (nausea, vomiting, and pruritus) and umbilical artery pH values. Risk ratios and 95% confidence intervals (CIs) were calculated for nausea, vomiting, and pruritus. Mean differences (MDs) and 95% CIs were calculated for VAS pain scores and umbilical artery pH values. CIs were used for statistical test, and a 95% CI without 1 for risk ratio or without 0 for MD indicated a significant difference. A random-effects model was used for data synthesis in the presence of significant heterogeneity, while a fixed-effects model was used when there was no significant heterogeneity. Heterogeneity across trials was assessed with I2 test, and an I2 >50% suggested there was significant heterogeneity. Sensitivity analysis was performed to explore the impact of an individual study by deleting 1 study each time. Publication bias was visually examined by funnel plots. Due to the limited number of trials, subgroup analysis was not conducted. All statistical analyses were performed by Reviewer Manager (version 5.2.1 for Windows; the Cochrane Collaboration, 2011, http://ims.cochrane.org/revman/, Oxford, United Kingdom).

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RESULTS

Flowchart

The process of trial selection is shown in Figure 1. Twelve full-text articles7–11,13–19 were further examined for eligibility after screening the titles and abstracts. Seven articles were excluded; 5 RCTs7–11 were retrieved and analyzed in this meta-analysis.

Figure 1

Figure 1

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Characteristics of Included Trials

Table 1 shows detailed characteristics of eligible trials, and Figure 2 shows “risk of bias” assessment results. A total of 886 healthy participants were included in the data synthesis; 443 were randomly assigned to receive remifentanil PCIA. For epidural analgesia, fentanyl or sufentanil combined with bupivacaine, levobupivacaine, or ropivacaine was used. The dose of analgesics varied among trials.

Table 1

Table 1

Figure 2

Figure 2

Methodological quality of eligible trials was moderate, and the included RCTs had a low risk of bias in general, except the trial reported by Stourac et al.7 In this trial, randomization was conducted “by the parturient,” which was assessed as “unknown risk of bias.” Blinding of the parturients and the primary and secondary outcomes were not mentioned in most reports, which suggested that the results of VAS pain scores might be affected by performance bias and detection bias.

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Primary End Points

VAS pain scores at 1 hour were reported by all eligible RCTs, and the pooled result showed that at the first hour after administration, there was a trend for superiority of epidural analgesia (MD = 1.9 cm; 95% CI, 0.5–3.3; I2 = 94%; Fig. S1A, see Supplemental Digital Content 1, http://links.lww.com/AA/A702, Table 2). Sensitivity analysis found that no individual study significantly affected the pooled result or heterogeneity. VAS pain scores at 2 hours were recorded in 3 trials, and the pooled result suggested that parturients with epidural analgesia had lower pain scores than those with remifentanil (MD = 3.0 cm; 95% CI, 0.7–5.2; I2 = 89%; Fig. S1B, see Supplemental Digital Content 1, http://links.lww.com/AA/A702, Table 2). Sensitivity analysis revealed that the trial reported by Douma et al.10 was the source heterogeneity, but the trial did not significantly affect the pooled result.

Table 2

Table 2

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Secondary End Points

The incidence of nausea, vomiting, and pruritus among patients with remifentanil PCIA and epidural analgesia were compared. By pooled analysis, we did not find any statistically significant difference between remifentanil PCIA and epidural analgesia in the incidence of nausea, vomiting, or pruritus. However, the CIs are quite wide and contain clinically significant differences. For the comparison of vomiting, the trial reported by Ismail and Hassanin8 was responsible for heterogeneity and significantly affected the result. The only neonatal outcome suitable for data synthesis was umbilical artery pH. Pooled results showed a trend that parturients who received remifentanil PCIA had slightly higher umbilical artery pH values than those who received epidural analgesia (Fig. S2, see Supplemental Digital Content 2, http://links.lww.com/AA/A703). Apgar scores at 1 and 5 minutes were reported; however, the data were not appropriate for synthesis. No trial reported significant differences in Apgar scores or neonatal outcomes between remifentanil PCIA and epidural analgesia.

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Publication Bias and Quality of Evidence

We examined publication bias for the 3 end points with significant differences (Fig. S3, see Supplemental Digital Content 3, http://links.lww.com/AA/A704, Fig. S4, see Supplemental Digital Content 4, http://links.lww.com/AA/A705, and Fig. S5, see Supplemental Digital Content 5, http://links.lww.com/AA/A706). No obvious asymmetry was detected in the funnel plots of pain scores at 2 hours (Fig. S4, see Supplemental Digital Content 4, http://links.lww.com/AA/A705) or umbilical artery pH values (Fig. S5, see Supplemental Digital Content 5, http://links.lww.com/AA/A706). Asymmetry was present in the funnel plot of pain scores at 1 hour (Fig. S3, see Supplemental Digital Content 3, http://links.lww.com/AA/A704); the trial by Volmanen et al.11 was responsible for the asymmetry.

The quality of the evidence was assessed with GRADE profiler. Most of the end points had moderate quality due to imprecision or risk of bias, except for pain scores at 1 hour, which were downgraded for potential bias. The detailed GRADE profiler is described in the Table S1 (see Supple mental Digital Content 6, http://links.lww.com/AA/A867).

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DISCUSSION

In this meta-analysis, we included 5 RCTs comparing the analgesic efficacy and safety of remifentanil PCIA and epidural analgesia. GRADE profiler suggested that the quality of the evidence is moderate.

Patients who received remifentanil PCIA had higher VAS pain scores at 1 and 2 hours. In 3 trials published in 2012, the pain scores at 1 hour did not differ between PCIA and epidural analgesia; however, 2 previous studies revealed a significant difference. In addition, there was significant heterogeneity in the comparison of 1 hour pain scores. No individual study was responsible for heterogeneity; we hypothesize that the heterogeneity is attributable to different analgesic doses among the studies. In addition, because of the potential for bias, the quality of this outcome was assessed as “low” by the GRADE profiler. The funnel plot of pain scores at 1 hour was asymmetrical, which indicated potential publication bias. Since only 5 trials were included, this asymmetry may have been a result of “small study effects.”20

Pain scores at 2 hours were also higher in participants receiving PCIA than parturients receiving epidural analgesia, and the quality of this evidence was moderate. Douma et al.10 noticed that 2 hours after administration, the pain scores of participants receiving PCIA increased and were no longer statistically different from baseline. In addition, this trial was also responsible for heterogeneity of pain scores at 2 hours. A possible explanation is that the PCIA administration methods led to drug tolerance. Participants in the Douma et al.10 study were relatively older than in the other trials.

No statistical difference between remifentanil PCIA and epidural analgesia was detected in the incidence of nausea, vomiting, or pruritus. However, the wide CIs of pruritus and vomiting preclude us from drawing definite conclusions from the pooled results.21 For instance, the lower 95% CI of pruritus was 0.20, which was a clinically significant end point and showed a tendency that remifentanil PCIA might be associated with a lower incidence of pruritus than epidural analgesia. Volmanen et al.11 observed more nausea in parturients receiving PCIA than those receiving epidural analgesia; however, our meta-analysis results suggested that there was no difference in nausea between PCIA and epidural analgesia. In addition, Volmanen et al.11 also found that the nausea scores during PCIA decreased compared with baseline. Intriguingly, we found a trend that PCIA was associated with a slightly higher umbilical artery pH value. Since the CIs for nausea, vomiting, and pruritus were wide and included clinically significant end points, no definite conclusion can be drawn, and further trials with large sample sizes are warranted to clarify these issues. Although no quantitative synthesis was conducted, other neonatal outcomes did not appear to differ between the 2 groups.

Although significant statistical differences in pain scores were identified in this meta-analysis, these differences may not reflect clinically significant differences. Pain perception is individual and is impacted by parturients’ tolerance, progression of labor, human influences (e.g., psychological influence from doctors or nurses), analgesic dose, and other factors. Thus, the pain score by itself may not reflect pain relief efficacy. In the 5 included trials, maternal clinical outcomes (pain, nausea, vomiting, and pruritus) did not differ significantly between PCIA and epidural analgesia.

There are some limitations of this meta-analysis. First, the number of eligible trials was small, thus statistical power was low, and results were likely biased. Second, there was significant heterogeneity in the comparison of primary end points. Clinical application of our results should be cautious, since our meta-analysis was based on small-sized trials. Notably, in a published protocol, Freeman et al.15 conducted a large-sized RCT (with at least 568 parturients) to comprehensively compare the efficacy, safety, and cost of remifentanil PCIA and epidural analgesia. This trial is expected to greatly improve our knowledge about the definitive role of using remifentanil for labor analgesia.

In summary, we conducted a meta-analysis of 5 trials to compare remifentanil PCIA and epidural analgesia; the results showed that remifentanil PCIA did not provide better analgesic efficacy than epidural analgesia during labor, but could be an optional effective alternative for pain relief to epidural analgesia. There is no doubt that the safety of remifentanil PCIA remains a controversial question. It has been reported that maternal sedation and respiratory depression may occur during labor with the use of PCIA12; therefore, PCIA requires careful monitoring, one-on-one nursing care throughout labor, and supplemental oxygen in some parturients. Considering its advantages of less-invasive treatment, easier performance, and possible lower costs, we believe remifentanil PCIA may be an attractive alternative to epidural analgesia. Further well-designed clinical studies with large sample sizes are warranted to evaluate the efficacy and safety of using this mode of analgesia in labor.

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DISCLOSURES

Name: Zhi-Qiang Liu, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Zhi-Qiang Liu has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Xiu-Bin Chen, MD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Xiu-Bin Chen has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Hai-Bing Li, MD.

Contribution: This author helped conduct the study and analyze the data.

Attestation: Hai-Bing Li has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Man-Tang Qiu, MD, PhD.

Contribution: This author helped analyze the data and write the manuscript.

Attestation: Man-Tang Qiu has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Tao Duan, MD, PhD.

Contribution: This author helped design the study.

Attestation: Tao Duan 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.

This manuscript was handled by: Cynthia A. Wong, MD.

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