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.
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.
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.
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).
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.
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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