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

Abstract

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.

KEY POINTS

• Question: Does fentanyl added to intrathecal bupivacaine improve the efficacy of spinal anesthesia and reduce the adverse effects during cesarean delivery?
• Findings: Fentanyl added to intrathecal bupivacaine reduces patients’ need for intraoperative supplemental analgesia by 82% and intraoperative nausea and vomiting by 59%, and it delays the time to the first postoperative analgesic request by 91 minutes; however, the incidence of intraoperative pruritus is increased nearly 6-fold.
• Meaning: Adding fentanyl to intrathecal bupivacaine for cesarean delivery reduces the need for intraoperative supplemental analgesia and nausea/vomiting, but this is at the expense of increased intraoperative pruritus.

Cesarean delivery is the most common major surgical procedure performed worldwide.¹ The use of cesarean delivery has increased dramatically in the past few decades, with Latin America (including Caribbean region) having the highest cesarean delivery rates (40.5%), followed by Northern America (32.3%).² A survey of Society for Obstetric Anesthesia and Perinatology members found that spinal anesthesia is most commonly used for elective cesarean delivery (85% respondents), with 90% of these respondents preferring hyperbaric 0.75% bupivacaine. Further, 79% of responders added fentanyl, 77% added morphine, and 54% added both fentanyl and morphine to the intrathecal bupivacaine for spinal anesthesia.³

There have been many pharmacodynamic and pharmacokinetic studies of intrathecal opioids and the mechanism of action, producing analgesic effects by direct action at the spinal cord level. The addition of intrathecal opioids to bupivacaine for spinal anesthesia may provide clinical advantages such as improved intraoperative conditions and postoperative analgesia. Potential disadvantages of intrathecal opioids include pruritus, sedation, urinary retention, and respiratory depression.^4,5 Approximately 80% of patients receiving intrathecal lipophilic opioid experience pruritus, with 10% describing it as severe and distressing.^6,7

Fentanyl, a lipophilic opioid, has a fast onset and is 10–20 times more potent when administered intrathecally compared to the IV route.⁸ Intrathecal fentanyl, however, has been associated with increased IV opioid requirement in the postoperative period possibly related to subtle opioid tolerance or opioid-induced hyperalgesia.⁹ Furthermore, a “ceiling effect” has been observed in intrathecal doses >0.25 µg/kg, implying that higher doses of intrathecal fentanyl do not improve intraoperative analgesia and may increase side effects.¹⁰

Although the cephalad spread of lipophilic intrathecal fentanyl in cerebrospinal fluid is lower compared with hydrophilic opioids (eg, morphine), several reports of respiratory depression have been described with intrathecal fentanyl. Evidence from animal studies indicates that progesterone potentiates the effect of spinal opioids.¹¹ Therefore, it is vital that we use an evidence-based approach to support and guide the administration of intrathecal opioids for pregnant patients to ensure an ideal balance of risks and benefits.

Despite numerous studies evaluating different doses of fentanyl added to intrathecal bupivacaine, its benefit, harm, and optimal dose remain unclear. Further, the benefit of intrathecal fentanyl, as an additive to bupivacaine in the presence of intrathecal morphine, is uncertain. This study aimed to systematically review the evidence regarding the efficacy (ie, success of spinal anesthesia and need for intraoperative analgesic supplementation) and safety (incidence of adverse effects) of fentanyl used as an additive to intrathecal bupivacaine with and without morphine for cesarean delivery.

METHODS

Registration and Protocol

The study protocol was registered with the International prospective register of systematic reviews (registration number: International prospective register of systematic reviews 2016: CRD42016044075). The review was conducted and is reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.¹²

Eligibility Criteria

We included randomized controlled clinical trials, in adult parturients (>18 years of age) undergoing cesarean delivery under spinal anesthesia, published in the English language. Cluster randomized trials were not included in the review. Included trials compared intrathecal bupivacaine with and without fentanyl, as well as intrathecal bupivacaine–morphine with and without fentanyl. The studies using other additives or mixtures of local anesthetics were excluded to reduce heterogeneity. A study was excluded if it compared different dosages of local anesthetics between each arm, if patients received planned general anesthesia along with spinal anesthesia, or an epidural technique was included with spinal anesthesia (combined spinal-epidural technique).

Information Sources

A professional librarian conducted an electronic literature search in MEDLINE (using PubMed platform), Embase, and the Cochrane Central Register of Controlled Trials (May 2017) with no date restriction. The search strategy was modified slightly to suit each database. The search strategy is shown in Supplemental Digital Content 1, Appendix 1, https://links.lww.com/AA/C675.

Study Selection

Two independent reviewers (S.R. and M.C.) performed study selection in 2 stages. Initially, the titles and abstracts were screened, followed by the full-text screening at the second stage. The details of the selection criteria are shown in Supplemental Digital Content 2, Appendix 2, https://links.lww.com/AA/C676. This checklist was used during full-text screening. Discrepancies between the reviewers were settled by agreement or by an arbitrator (V.U.).

Data-Collection Process

Similarly, the 2 reviewers (S.R. and M.C.) independently extracted the data using a standardized electronic form. The extracted items included study characteristics, risk of bias domains, participant, setting, intervention, control, drug doses, and study outcomes.¹³ Supplemental Digital Content 3, Appendix 3, https://links.lww.com/AA/C677 (data-extraction sheet) shows the list of parameters extracted for each study.

Comparisons Conducted

Two different comparisons were performed in this review. During the first comparison, intrathecal bupivacaine (control) was compared to bupivacaine–fentanyl. The second comparison looked at bupivacaine–morphine combination (control) with bupivacaine–morphine–fentanyl for spinal anesthesia in the cesarean delivery population.

Data Items (Outcome Measures Extracted)

The primary outcome for the study was the failure rate of spinal anesthesia, as assessed independently by one of the following definitions: the need for conversion to general anesthesia or need for intraoperative analgesic supplementation or repeat neuraxial procedure or by cancellation of surgery. The secondary outcomes included the following: incidence of intraoperative hypotension, incidence of intraoperative nausea and/or vomiting, and incidence of pruritus. Additionally, block onset time (minutes to reach the fourth thoracic dermatome), duration of motor block (minutes to Bromage scale 1), duration of postoperative analgesia (time to first postoperative analgesia request), and incidence of respiratory depression (as defined within each study) were compared. The unit of measurement was patients, and not the number or episode of events. If a study did not report adverse events, then administration of medications to treat an adverse effect was used as a surrogate marker for the incidence of the adverse event.

Data Synthesis and Analysis of Outcomes

Data analysis and synthesis were performed using Review Manager (RevMan), version 5.3. (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark), and Microsoft Excel (Microsoft Corporation, Redmond, WA). Dichotomous outcomes are reported as relative risks, and continuous outcomes (time of onset, duration of anesthesia, and time to first analgesic request) are reported as the weighted mean differences. Outcomes are reported with their effect estimates along with 95% CI. Pooling of outcomes was performed whenever there were ≥2 studies for an outcome. If a study had multiple intervention groups, the groups were combined to create a single pairwise comparison (recommendation Cochrane handbook section 16.5.4). For time-to-event outcomes, if no log-transformed estimates or hazard ratios were provided, and the studies reported the means and SDs, we made the assumption that the variables were normally distributed, and the data were pooled accordingly.

Pooling was done using a random-effects method by DerSimonian and Laird¹⁴ based on the inverse variance method, rather than using a fixed-effects method. A random-effects meta-analysis model involves an assumption that the effects being estimated in the different studies are not identical but follow the same distribution.¹⁵ Sensitivity analysis was conducted using a fixed-effects model to ensure robustness of significant findings. The unit of analysis from each study was based on the individual patient. Forest plot was used to assess the statistical heterogeneity of studies visually and the χ² test to evaluate the evidence of heterogeneity. A P value of <0.1 was used to determine statistical significance for heterogeneity.¹⁶ The I² statistics were calculated, with I² values >50% indicating substantial to considerable heterogeneity.¹⁵

Meta-regression was performed using Comprehensive meta-analysis software, version 3 (Biostat, Englewood, NJ). Univariate meta-regression using restricted maximum likelihood was used to estimate whether the treatment effect of interest varied across different doses of fentanyl. The treatment effect of fentanyl was explored for 2 outcomes: incidence of pruritus and the need for an intraoperative supplemental analgesic. This exploratory analysis assessed the ideal dose of fentanyl needed to provide clinically acceptable efficacy while minimizing the side effect profile. The findings are reported with measures of relative risk reduction and absolute risk reduction. Studies with shared control arms for different doses had the shared group split into 2 groups of smaller sample size and include ≥2 (reasonably independent) comparisons.¹⁵

Trial sequential analysis was performed for primary outcomes using TSA software 0.9.5.5, beta version (Copenhagen Trial Unit, Copenhagen, Denmark). Trial sequential analysis is a method to interpret meta-analysis results and looks at adjusting the thresholds for significance when required sample size may not have been reached.¹⁷ The optimal information size and O’Brien-Fleming α spending boundaries were calculated using 2-sided 5% type 1 and 10% type 2 error rate (90% power).

Rating of the quality of evidence with confidence in effect estimates is reported using the Grading of Recommendations Assessment, Development, and Evaluation approach.

RESULTS

Results of Literature Search (Study Selection)

Figure 1.: Preferred Reporting Items for Systematic Reviews and Meta-analyses 2009 flow diagram showing literature search results. Randomized controlled clinical trials were included in the analysis.

Figure 1 (Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart) shows the results of the search. There were 3592 studies identified between 1946 and 2017. After the screening, 18 randomized controlled clinical trials met the inclusion criteria. One study was retracted by the authors after publication, leaving 17 studies and 1064 participants to provide data for the meta-analysis.¹⁸ None of the studies provided log-transformed estimates or hazard ratios for outcomes “onset time,” “duration of the block,” and “duration of analgesia.” Each study reported the mean and SD assuming the outcomes followed a normal distribution. Therefore, we have made the same assumption and pooled the data accordingly.

Study Characteristics

Population, intervention control, and other details of the study are included in Table 1. All the studies were conducted in an elective cesarean delivery population with 1 exception: the semiurgent population.²⁰ The sample size ranged from 24 to 100 subjects. Fourteen studies used hyperbaric bupivacaine, and 3 studies did not specify the baricity used.

Table 1.: Study Characteristics and Groups

Table 2.: Outcome Definitions Used in Each Study

Subgroup analysis was not performed for baricity because previous reviews have not found any significant difference in primary outcome with different baricity.^35,36 The dose range of bupivacaine across studies was 7.5–13.75 mg, and fentanyl was 5–25 µg. However, the same doses of bupivacaine and fentanyl/morphine were administered in each intervention arm for the included studies. Most studies used Ringer’s lactate solution for fluid preloading, and none of the studies used prophylactic vasopressors. Outcome definitions used in individual studies are shown in Table 2.

Risk of Bias Within Studies

Forest plots show the risk of bias for each study. Most studies (except 4) were judged as a low or unclear risk of bias. Sensitivity analysis performed for the primary outcome by excluding the studies with high risk of bias did not affect the final conclusion.

Comparison 1: Bupivacaine (Control) Versus Bupivacaine Fentanyl

Primary Outcome (Failure of Spinal Anesthesia).

Conversion to General Anesthesia.

Fifteen randomized controlled clinical trials with a total population of 759 participants reported data regarding conversion to general anesthesia. Only 1 study, Ngiam and Chong,²⁹ reported positive events, with 2 events reported in the intrathecal fentanyl group and 3 events reported in the control group. The reason for conversion to general anesthesia in this particular study appears to be related to the use of a 27-gauge spinal needle and the inability to obtain a free flow of cerebrospinal fluid during the spinal injection. There was no difference between intrathecal fentanyl and control group regarding the need for conversion to general anesthesia (relative risk, 0.67; 95% CI, 0.12–3.57; P = .64; I² = not applicable). Considering the low frequency of this event, the sample size may not be powered to detect the difference between the groups. Further, the quality of evidence was low considering the few events in both groups and the high risk of bias in 3 included studies. The trial sequential analysis could not be conducted due to the low event rate in the control arm.

Repeat Neuraxial Procedure or the Cancellation of Surgery After Spinal Anesthesia.

None of the studies repeated neuraxial anesthesia or canceled surgery. Therefore, no further analysis could be conducted using this outcome definition.

Need for Intraoperative Analgesic Supplementation.

Fourteen randomized controlled clinical trials with a total population of 694 participants reported data regarding the need for supplemental intraoperative analgesia. Figure 2 shows a forest plot of the outcome. Seventeen of 370 (4.6%) participants in the intrathecal fentanyl group and 96 of 324 (29.6%) participants in the control group needed supplemental intraoperative analgesia. The need for intraoperative supplemental analgesia was significantly lower in the intrathecal fentanyl group compared to the control group (relative risk, 0.18; 95% CI, 0.11–0.27; P < .001; I² = 0%; number needed to treat, 4). Sensitivity analysis without the studies with high risk of bias did not alter the conclusion (relative risk, 0.19; 95% CI, 0.12–0.29; P < .001; I² = 0%).

Figure 2.: Forest plot showing the comparison of outcome: the need for analgesic supplementation during surgery for intrathecal fentanyl versus control. Evaluation of bias risk items for each included study. Green indicates low risk of bias; red indicates high risk of bias; and yellow indicates unclear risk of bias. df indicates degrees of freedom.

Meta-regression was conducted looking at how the treatment effect varies with the fentanyl dose that showed a dose coefficient of −0.1085 (95% CI, 0.2179–0.0008). Thus, for every (1) μg increase in fentanyl dose, the log risk ratio decreases by 0.1085 for intraoperative supplemental analgesia (Supplemental Digital Content 4, Figure 1, https://links.lww.com/AA/C678). The analysis showed goodness-of-fit Q value of 6.70 (degrees of freedom [Q] = 11; P = .8231; I² = 0). Therefore, we cannot reject the fit of the model. The overall quality of evidence was moderate considering strong association.

Trial sequential analysis of the need for supplemental intraoperative analgesia showed statistical significance in favor of the intrathecal fentanyl group (Supplemental Digital Content 4, Figure 2, https://links.lww.com/AA/C678) because the cumulative Z score crossed the trial sequential monitoring boundary. Thus, the accumulated evidence is sufficient to make the finding conclusive, and no further studies are warranted to assess the benefit of intrathecal fentanyl on the need for supplemental intraoperative analgesia.

Secondary Outcomes.

Incidence of Intraoperative Hypotension.

Eleven randomized controlled clinical trials with a total population of 554 participants reported data regarding hypotension. Ninety of the 300 (30%) participants in the intrathecal fentanyl group and 88 of 254 (34.6%) participants in the control group reported hypotension. There was no difference between intrathecal fentanyl and control group regarding incidence of hypotension (relative risk, 1.00; 95% CI, 0.87–1.15; P = .95; I² = 0). The overall quality of evidence was downgraded to moderate because some of the included studies had a high risk of bias.^20,21,29

Incidence of Intraoperative Nausea and Vomiting.

Figure 3.: Forest plot showing the comparison of outcome: the incidence of intraoperative nausea and vomiting for intrathecal fentanyl versus control. Evaluation of bias risk items for each included study. Green indicates low risk of bias; red indicates high risk of bias; and yellow indicates unclear risk of bias. df indicates degrees of freedom.

Twelve studies with a total population of 580 participants reported data related to this outcome (Figure 3). Thirty-one of 298 (10.4%) participants in the intrathecal fentanyl and 73 of 282 (25.9%) participants in the control group suffered intraoperative nausea/vomiting. The addition of intrathecal fentanyl reduced the incidence of intraoperative nausea/vomiting (relative risk, 0.41; 95% CI, 0.24–0.70; P < .001; I² = 35%; number needed to treat, 6.5) compared to the control group. The overall quality of evidence was downgraded to moderate considering that 3 included studies that had a high risk of bias.^20,21,29

Incidence of Intraoperative Pruritus.

Figure 4.: Forest plot showing the comparison of outcome: the incidence of pruritus for intrathecal fentanyl versus control. Evaluation of bias risk items for each included study. Green indicates low risk of bias; red indicates high risk of bias; and yellow indicates unclear risk of bias. df indicates degrees of freedom.

Thirteen studies with a total population of 604 participants reported data regarding pruritus (Figure 4). Twenty-five of 310 (8.1%) participants in the intrathecal fentanyl and 2 of 294 (0.7%) participants in the control group suffered pruritus. The incidence of intraoperative pruritus was significantly higher in the intrathecal fentanyl group compared to control (relative risk, 5.89; 95% CI, 2.0–16.8; P < .001; I² = 0%; number needed to harm, 13.5). The overall quality of evidence was high given a strong association. Meta-regression looking at how the effect size varies with the fentanyl dose showed a dose coefficient of 0.03 (95% CI, −0.1964 to 0.2564; P = .7940). Therefore, there is not enough evidence to suggest that dose may be related to effect size.

Onset Time.

Eleven studies with a total population of 524 participants recorded onset time. There was no difference between intrathecal fentanyl and control group regarding onset of sensory block (mean difference, −0.24 minutes; 95% CI, −0.47 to 0.00; P = .05; I² = 71%). The overall evidence was “very low” considering 2 studies had a high risk of bias, unexplained heterogeneity, and low precision (wide CI).

Duration of Motor Block.

Seven studies with a total population of 309 participants recorded the duration of motor block. There was no difference between the intrathecal fentanyl and control group regarding the duration of motor block (mean difference, 1.3 minutes; 95% CI, −10.9 to 13.6; P = .83; I² = 93%). The overall quality of evidence was assessed as low due to 2 studies with high risk of bias, high heterogeneity, and low precision.

Duration of Analgesia.

Twelve studies with a total population of 574 participants recorded the duration of analgesia as per a priori definition (time to first postoperative analgesic request). The time to first postoperative analgesia request was longer in the intrathecal fentanyl group compared to the control group (mean difference, 91 minutes; 95% CI, 69–113; P < .001; I² = 97%). The overall quality of evidence was “low,” with 3 included studies assessed as high risk of bias and unexplained heterogeneity.

Incidence of Respiratory Depression.

Thirteen randomized controlled clinical trials with a total population of 690 participants reported data regarding respiratory depression. There were 4 events from 368 participants noted in the intrathecal fentanyl group and no events from 322 participants recorded in the control group.^29,33 None of the studies reported any serious harm because of respiratory depression. Furthermore, the different incidence of respiratory depression between the intrathecal fentanyl and control groups was not found to be statistically significant (relative risk, 3.20; 95% CI, 0.38–27.26; P = .29; I² = 0%). Overall quality of evidence was low considering 3 included studies assessed as high risk of bias and the low event rate.

Comparison 2: Bupivacaine–Morphine (Control) Versus Bupivacaine–Morphine–Fentanyl

Need for Intraoperative Analgesic Supplementation.

Two randomized controlled clinical trials with a total population of 100 participants reported data for this outcome.^9,34 One of 60 (1.6%) participants in the intrathecal bupivacaine–morphine–fentanyl group and 5 of 40 (12.5%) participants in the control group needed supplemental analgesia intraoperatively. The need for supplemental analgesia was significantly lower in the intrathecal bupivacaine–morphine–fentanyl group compared to the bupivacaine–morphine only group (relative risk, 0.16; 95% CI, 0.03–0.95; P = .04; I² = 0%; number needed to treat, 9). Overall, the quality of evidence was low considering that 2 studies had low event rates and 1 had a high risk of bias.

Incidence of Intraoperative Nausea and Vomiting.

Eight of the 60 (13.3%) participants in the intrathecal bupivacaine–morphine–fentanyl group and 10 of 40 (25.0%) participants in the control group suffered intraoperative nausea/vomiting. The incidence of intraoperative nausea/vomiting was not found to be significantly different between the groups (relative risk, 0.45; 95% CI, 0.08–2.58; P = .37; I² = 72%).

The data from the other outcomes of interest were limited and therefore could not be pooled. No conversion to general anesthesia was reported in the 2 studies. One study (Techanivate et al³⁴) reported outcome “intraoperative hypotension” with no significant difference in the incidence of intraoperative hypotension between the intrathecal bupivacaine–morphine–fentanyl group (15/30 [50%]) and the bupivacaine–morphine group (11/30 [37%]; P = .192). Regarding outcome “intraoperative pruritus,” 1 event was reported in the bupivacaine–morphine–fentanyl group and 1 event in the bupivacaine–morphine group. Thus, further analysis was not conducted. Techanivate et al³⁴ reported onset time with no significant difference in mean (SD) onset time between the bupivacaine–morphine–fentanyl group (5.3 [0.1] minutes) and the bupivacaine–morphine group (5.8 [0.1]; P = .354).

Neither of the 2 included studies reported “duration of the motor block” or “duration of analgesia” outcomes. Finally, none of the studies reported any events of respiratory depression.

Additional Analysis

Funnel plots for the primary outcome (need for supplemental analgesia) with the use of intrathecal fentanyl showed a possibility of publication bias in the published literature (Supplemental Digital Content 4, Figure 3, https://links.lww.com/AA/C678).

DISCUSSION

Main Findings

This review is the first to objectively assess and summarize the available evidence regarding the efficacy of intrathecal fentanyl for cesarean delivery. With the addition of fentanyl to intrathecal bupivacaine, the patient’s need for intraoperative supplemental analgesia is reduced by 82%, and the incidence of intraoperative nausea–vomiting is reduced by 59%. In addition, fentanyl added to bupivacaine delays the time to the first postoperative analgesic request by 91 minutes. No difference was observed regarding the need for conversion to general anesthesia, the incidence of hypotension, the onset of sensory block, or the duration of motor block. However, the incidence of intraoperative pruritus is increased nearly 6-fold (ie, an increase of 489%).

Last, fentanyl, when added to the combination of intrathecal bupivacaine–morphine, similarly reduces a patient’s need for intraoperative supplemental analgesia by 84% (a similar benefit to when intrathecal fentanyl was added to bupivacaine alone).

Summary of Evidence

In 1999, Dahl et al³⁷ published a review of perioperative analgesic efficacy and the adverse effects of intrathecal opioids for the cesarean delivery. The review included trials that used different types of local anesthetics (lidocaine and tetracaine) and different doses of bupivacaine between the groups. The authors concluded that intrathecal morphine produced a clinically relevant reduction in postoperative pain and analgesic consumption. There was evidence for a small effect with fentanyl and sufentanil. Pooling results from all opioids and doses, they observed a median number needed to treat to prevent the need for supplemental analgesics intraoperatively to be 4.9 with no significant differences among the various opioids. Further, they did not observe any dose–response relationship.

In 1999, Hamber and Viscomi⁸ also reviewed the literature on intrathecal fentanyl and sufentanil, including both cesarean delivery and the general surgical population, which showed enhancement of quality of spinal anesthesia without prolongation of motor block. Since these reviews, several clinical studies have been added to the literature. We therefore aimed to synthesize the current clinical evidence to guide practicing clinicians on the use of intrathecal fentanyl for cesarean delivery.

This current review shows that the addition of fentanyl to intrathecal bupivacaine reduced the risk of need for intraoperative supplemental analgesia compared to bupivacaine alone. Trial sequential analysis (Supplemental Digital Content 4, Figure 2, https://links.lww.com/AA/C678) showed that the accumulated evidence from included studies is sufficient to make the finding conclusive. The effect was observed across all studies consistently, irrespective of the dose used. A significant dose–effect response was not established (P = .057) using meta-regression model, but the P value nears significance.

In this current review, 2 randomized controlled clinical trials with 100 participants assessed the effect of adding fentanyl to the combination of intrathecal bupivacaine and morphine. Interestingly, the pooled data showed improved “intraoperative analgesia,” as indicated by the reduced requirement of intraoperative supplemental analgesia. Therefore, the inclusion of fentanyl to the spinal bupivacaine and morphine combination confers an additive benefit, reducing the risk of need for intraoperative supplemental analgesia (relative risk, 0.16; 95% CI, 0.03–0.95) compared to bupivacaine–morphine alone. The sample size was too small to draw any meaningful conclusion regarding other side effects. We can postulate that the faster onset time of a lipophilic opioid such as fentanyl compared to the slower onset time of hydrophobic intrathecal morphine alone is not adequate for any clinically important intraoperative effect. Therefore, combining the 2 opioids is desirable in clinical practice. However, the recommendation is supported by data from 2 small studies.

This review found that the addition of intrathecal fentanyl also increased the time to first postoperative analgesia request. When intrathecal fentanyl is given without morphine, there is an observed prolongation of analgesia by 1.5 hours (91 minutes). This finding may be clinically useful for patients who do not get intrathecal morphine. However, for “postoperative analgesia,” the evidence supporting the addition of fentanyl when intrathecal morphine is used is conflicting.

Carvalho et al⁹ observed that total IV morphine use over the 24-hour postspinal was similar among intrathecal fentanyl and no fentanyl group. Postoperative pain scores were higher in patients receiving intrathecal fentanyl 5, 10, and 25 µg compared to the no fentanyl control group. However, Techanivate et al³⁴ Found that in the second hour and the third hour after spinal anesthesia, all patients in the fentanyl group still had no pain, whereas 24 patients (80%) at 2 hours and 23 patients (76.7%) at 3 hours in the control group experienced significant pain.

In the context of intrathecal morphine (12–18 hours duration of postoperative analgesia), the addition of intrathecal fentanyl could be argued as less important for postoperative analgesia.³⁸ Interestingly, Techanivate et al³⁴ also observed that the incidence of intraoperative and postoperative shivering was also lower when fentanyl was added to intrathecal hyperbaric bupivacaine and morphine compared to the “no fentanyl” group.

Pruritus is the most common side effect attributed to intrathecal lipophilic opioid use. Intrathecal fentanyl does appear to significantly increase the incidence of intraoperative pruritus (relative risk, 5.89; 95% CI, 2.07–16.79). Pooled data from 14 studies showed an incidence of pruritus to be 8% when intrathecal fentanyl was used compared to 0.6% in the placebo group. The incidence of pruritus is similar to with the previously quoted rate (10%) in the intrathecal fentanyl group.⁶ Meta-regression did not establish a dose-effect relationship for this adverse event. Nevertheless, we note that none of the studies using low-dose fentanyl (10 µg) reported “pruritus needing treatment” in the intrathecal fentanyl group.

The additional benefit conferred by intrathecal fentanyl was reduced intraoperative nausea/vomiting. The findings of this review regarding the incidence of nausea/vomiting are consistent with the report by Hamber and Viscomi,⁸ who pointed out that the use of intrathecal fentanyl reduces intraoperative nausea/vomiting after spinal anesthesia.⁸ This finding is contrary to the belief of some clinicians. There are 2 plausible explanations for this effect. First, pain is a direct stimulus that may cause nausea and vomiting. Intrathecal fentanyl may inhibit visceral pain impulses thus reducing nausea and vomiting. Second, as evidenced in this review, an absence of fentanyl in spinal anesthesia leads to increased need for supplemental intraoperative parenteral opioids, which may contribute to nausea and vomiting.

We did not find evidence for a higher incidence of respiratory depression with the use of intrathecal fentanyl, with only 4 events in the intrathecal fentanyl group and no events in the control group. Thus, considering the rarity of this event, this review is underpowered to detect a difference.³⁹ We do note that, similar to pruritus, no respiratory events were reported in 3 studies that used 10 μg of intrathecal fentanyl.^24,26,30

Urinary retention is a side effect observed with the use of intrathecal opioids. Most studies included in this review used a urinary catheter in the immediate postoperative period. Therefore, it was not possible to synthesize the evidence regarding this outcome.

It is widely believed that the intrathecal fentanyl shortens the onset time of spinal anesthesia.⁸ However, pooled data from multiple randomized controlled clinical trials refute this belief. The onset time of sensory block was similar with or without intrathecal fentanyl. Similarly, the duration of the motor block did not appear to be affected by the addition of intrathecal fentanyl.

Relevance to Anesthesiologists

Fentanyl and morphine are the commonly used additives to bupivacaine for spinal anesthesia for cesarean delivery. Fentanyl alone added to intrathecal bupivacaine reduced the need for intraoperative supplemental analgesia (number needed to treat, 4) and the incidence of intraoperative nausea/vomiting (number needed to treat, 6.5). However, the addition of intrathecal fentanyl was associated with a higher incidence of intraoperative pruritus (number needed to harm, 13.5). No difference was observed regarding the need for conversion to general anesthesia, the incidence of hypotension, the onset of sensory block, or the duration of motor block. Intrathecal fentanyl prolonged the time to first postoperative analgesia request by 91 minutes. The inclusion of fentanyl to intrathecal bupivacaine–morphine conferred a similar benefit, with significantly reduced the need for intraoperative supplemental analgesia compared to intrathecal bupivacaine–morphine alone (number needed to treat, 9).

This current review supports utilizing the combination of both opioids (Fentanyl and Morphine) intrathecally for cesarean delivery. Fentanyl for intraoperative analgesia and reduction in nausea/vomiting and morphine for postoperative analgesia benefit. The benefit of reduction in the need for intraoperative supplemental analgesia and intraoperative nausea–vomiting with the addition of intrathecal fentanyl outweighs the risk of pruritus.

The ideal intrathecal fentanyl dose is still a matter of debate. We were unable to conclusively show a fentanyl dose–effect relationship regarding the outcome “need for intraoperative supplemental analgesia” using meta-regression. However, we note that the studies that used a dose of 10 µg of intrathecal fentanyl did not report any significant pruritus or respiratory depression events and the event rate was very low for treated pruritus in the studies that used 12.5 µg intrathecal fentanyl dose. Thus, the dose of 10–12.5 µg might provide right balance for reducing the need for supplemental intraoperative analgesia and need for treatment of intraoperative nausea/vomiting or pruritus. Because these were 2 small studies using this 10-µg dose and only 2 studies evaluated the use of intrathecal fentanyl to bupivacaine-morphine, we suggest future studies could confirm these observations.

Limitations

All studies included in the review were conducted in the opioid naive population so the results cannot be extrapolated to opioid-tolerant subjects. Second, the pooled sample size was not large enough to make any definite conclusion about rare adverse events such as respiratory depression. The included studies were heterogeneous regarding the dose and type of bupivacaine formulation. However, 2 recent reviews have found that the kind of bupivacaine formulation (hyperbaric or isobaric) does not impact the success rate of spinal anesthesia.^35,36

The current review shows that, if the same dose of bupivacaine is used, intrathecal fentanyl did not affect the incidence of hypotension. The anesthesiologists may reduce the dose of bupivacaine in an attempt to lessen the incidence of adverse effect such as hypotension, which is more likely attributable to the local anesthetic dose.⁴⁰ However, reducing the dose of intrathecal bupivacaine may be associated with the increased need for intraoperative supplemental analgesia.⁴¹ This review excluded studies that used different doses of bupivacaine to reduce heterogeneity because we felt that it is challenging to tease out the difference of outcomes attributable to opioid type and dose if different doses of bupivacaine were used within a study.

CONCLUSIONS

This review supports using the combination of both opioids for spinal anesthesia in the cesarean delivery population. The addition of intrathecal fentanyl to bupivacaine reduces the need for intraoperative supplemental analgesia, reduces the incidence of intraoperative nausea/vomiting, and increases the time to first analgesic request. The accumulated evidence showing the reduction in need for intraoperative supplemental analgesia with the addition of intrathecal fentanyl to bupivacaine is sufficient to make the finding conclusive. No further studies are warranted to assess the benefit of intrathecal fentanyl on the need for supplemental intraoperative analgesia. Intrathecal fentanyl does not appear to affect the incidence of hypotension, onset of sensory block, or duration of motor block. The inclusion of fentanyl to intrathecal morphine–bupivacaine conferred similar benefit with a significant reduction in the need for supplemental analgesia intraoperatively.

Small sample size, low precision, and high risk of bias in some of the included studies warrant that the results should be treated with caution especially with the possibility of “publication bias” in the published literature.

ACKNOWLEDGMENTS

The authors thank Darlene Chapman (Manager, Library Services), and Pamela Parker (Library Assistant) from Izaak Walton Killam Health Centre (Halifax), and Leah Boulos (Evidence Synthesis Coordinator, Maritime SPOR SUPPORT Unit-Research Services, Halifax) for helping us with the literature search.

DISCLOSURES

Name: Vishal Uppal, FRCA.

Contribution: This author helped conceive/design the study, design the search strategy, perform the data analysis, create the figures/tables, and prepare the manuscript.

Conflicts of Interest: V. Uppal has been a principal investigator for Recro Pharma (Devault, PA), which funded a clinical trial on IV meloxicam. However, it does not directly or indirectly affect the conduct or reporting of this study.

Name: Susanne Retter, MD.

Contribution: This author helped select/screen the study, extract the data, assess risk of bias, analyze the data, create the tables/figures, and prepare the manuscript.

Conflicts of Interest: None.

Name: Margaret Casey, MD.

Contribution: This author helped develop protocol, select/screen the study, extract the data, assess the risk of bias, and critically revise the manuscript.

Conflicts of Interest: None.

Name: Sushil Sancheti, FRCPC.

Contribution: This author helped select/screen the study, extract the data, assess the risk of bias, and critically revise the manuscript.

Conflicts of Interest: None.

Name: Kara Matheson, MSc.

Contribution: This author helped analyze the data; create the 2 figures, bubble plot, and trial sequential analysis graph; and critically revise the manuscript.

Conflicts of Interest: None.

Name: Dolores M. McKeen, FRCPC.

Contribution: This author helped conceive/design the study; analyze the data; and prepare, critical review, and revise the manuscript.

Conflicts of Interest: D. M. McKeen has received payments and travel funding for lectures from Merck Canada Inc. She conducted a clinical trial in 2012 that was funded by Merck Canada. Total funding approximately $130,000 CAD. She has acted as a consultant for Merck Canada Inc.

This manuscript was handled by: Jill M. Mhyre, MD.