Efficacy of Intrathecal Fentanyl for Cesarean Delivery: A Systematic Review and Meta-analysis of Randomized Controlled Trials With Trial Sequential Analysis

BACKGROUND: Fentanyl and morphine are the 2 most commonly added opioids to bupivacaine for spinal anesthesia during cesarean delivery. Numerous clinical trials have assessed efficacy and safety of different doses of fentanyl added to intrathecal bupivacaine for spinal anesthesia, yet its benefit, harm, and optimal dose remain unclear. This study aimed to systematically review the evidence of the efficacy of fentanyl when added to intrathecal bupivacaine alone and when added to bupivacaine with morphine for spinal anesthesia during cesarean delivery. METHODS: Key electronic databases (PubMed, Embase, and Cochrane Library) were searched for randomized controlled trials in the cesarean delivery population. The primary outcome was the failure rate of spinal anesthesia, as assessed by the need for either conversion to general anesthesia or intraoperative analgesic supplementation. Two reviewers independently extracted the data using a standardized electronic form. Results are expressed as relative risks or mean differences with 95% CIs. RESULTS: Seventeen randomized controlled clinical trials (most judged as low or unclear risk of bias) with 1064 participants provided data for the meta-analysis. Fentanyl added to intrathecal bupivacaine alone reduced the need for intraoperative supplemental analgesia (relative risk, 0.18; 95% CI, 0.11–0.27; number needed to treat, 4) and the incidence of nausea/vomiting (relative risk, 0.41; 95% CI, 0.24–0.70; number needed to treat, 6.5), with longer time to first postoperative analgesia request (mean difference, 91 minutes; 95% CI, 69–113). No difference was observed regarding the need for conversion to general anesthesia (relative risk, 0.67; 95% CI, 0.12–3.57), the incidence of hypotension, the onset of sensory block, or the duration of motor block. However, the addition of intrathecal fentanyl was associated with higher incidence of intraoperative pruritus (relative risk, 5.89; 95% CI, 2.07–16.79; number needed to harm, 13.5). The inclusion of fentanyl to intrathecal bupivacaine–morphine compared to intrathecal bupivacaine–morphine alone conferred a similar benefit, with a significantly reduced need for intraoperative supplemental analgesia (relative risk, 0.16; 95% CI, 0.03–0.95; number needed to treat, 9). Analysis using a funnel plot indicated a possibility of publication bias in included studies. CONCLUSIONS: Current evidence suggests a benefit of using fentanyl as both an additive to intrathecal bupivacaine alone and to intrathecal bupivacaine combined with morphine for cesarean delivery under spinal anesthesia. The possibility of publication bias, small sample size, and high risk of bias in some of the included studies warrant treating the results with caution. Accepted for publication November 5, 2018. Funding: This project received a $1200 support from the Department of Anesthesia, Perioperative Medicine and Pain Management, Dalhousie University, Nova Scotia Health Authority, for statistical consultation. Conflicts of Interest: See Disclosures at the end of the article. 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 website (http://bit.ly/KegmMq). Trial registration number: International prospective register of systematic reviews 2016: CRD42016044075. Reprints will not be available from the authors. Address correspondence to Vishal Uppal, FRCA, Department of Anesthesia, Perioperative Medicine and Pain Management, Dalhousie University, Nova Scotia Health Authority and Izaak Walton Killam Health Centre, 5th floor, Halifax Infirmary Site, Rm 5452, 1796, Summer St, Halifax, Nova Scotia, B3H 2Y9, Canada. Address e-mail to v.uppal@dal.ca. © 2019 International Anesthesia Research Society

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