Opioids are often added to local anesthetics for neuraxial anesthesia, as this reduces the onset time of spinal block and improves the quality of intraoperative and postoperative analgesia compared with local anesthetic alone.1–4 Moreover, adding an opioid to neuraxial blockade reduces local anesthetic dose, which limits hemodynamic consequences and shortens recovery time.5–9 Given increasing demand for effective, low-dose neuraxial techniques, selection of intrathecal opioid has been the topic of several recent studies.10–13
Fentanyl and sufentanil are lipophilic opioids with similar chemical structure and intrathecal pharmacokinetics.14 They exhibit structural similarities to local anesthetics and exert an effect on sensory C afferent nerve fibers.15 Their short duration of action (4–6 hours) makes them ideal for use in low-dose spinal anesthesia. However, pruritus is an unwanted side effect of intrathecal opioid administration that can decrease patient satisfaction with anesthesia,16 delay postanesthesia care unit discharge, and increase costs.17 The incidence of intrathecal opioid-related pruritus ranges from 30% to 100%,18 depending on the intrathecal opioid used and the patient population.
Among the many medications that have been studied to prevent intrathecal opioid-associated pruritus,18 5-HT3 receptor antagonists have a low toxicity profile with no risk of respiratory depression or effect on coagulation. Although a meta-analysis by Bonnet et al.,19 in 2008, failed to demonstrate an effect of 5-HT3 receptor antagonists on intrathecal opioid-induced pruritus, the study primarily focused on intrathecal morphine and pooled studies of different 5-HT3 receptor antagonists at different doses. To date, the results of single-center trials evaluating prophylactic 5-HT3 receptor antagonists for intrathecal opioid-mediated pruritus have been mixed. Several questions about the potential efficacy of 5-HT3 receptor antagonists to prevent intrathecal opioid-mediated pruritus remain unanswered. We therefore conducted a meta-analysis to assess the efficacy of the prophylactic administration of a unique agent (i.e., IV ondansetron 8 mg) to reduce intrathecal fentanyl- and sufentanil-mediated pruritus and the need for rescue treatment for pruritus.
This meta-analysis of randomized controlled trials assessing the efficacy of prophylactic ondansetron in reducing intrathecal fentanyl- and sufentanil-mediated pruritus was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.20 The primary outcome was the effect of prophylactic ondansetron on the incidence of pruritus, and the secondary outcome was the need for rescue treatment for pruritus. The working hypothesis was that prophylactic ondansetron reduces the incidence of intrathecal fentanyl- or sufentanil-mediated pruritus and patients’ need for rescue medication.
Protocol and Registration
The protocol for this meta-analysis was not registered.
Search Strategy and Eligibility Assessment
PubMed, Medline, and the Cochrane Central Register of Controlled Trials were searched, from January 1, 1994, to January 1, 2014, for studies evaluating the efficacy of prophylactic 5-HT3 antagonists on pruritus associated with intrathecal fentanyl or sufentanil. The search string is given in Appendix 1. The last search was performed on March 29, 2014.
The retrieved articles were screened (by titles and abstracts) for eligibility by one of the investigators. Eligible studies were then analyzed for inclusion by 2 reviewers through full-text review. Studies were included if they fulfilled the following criteria: (1) randomized controlled trials evaluating the efficacy of prophylactic ondansetron on pruritus associated with intrathecal fentanyl or sufentanil; (2) human investigations; and (3) English-language publication. When the incidence of pruritus was not clearly reported, or not calculable from the data reported, authors were contacted to obtain the information. In addition, the reference lists of the eligible studies were hand-searched to identify other potentially eligible studies.
Data were independently extracted from articles by 2 investigators and entered into a database after disagreements between the 2 investigators had been resolved by discussion. If no agreement could be reached, a third investigator decided.
The following data were extracted from each study:
- General characteristics of the study: location of the study, years of inclusion, number of study centers, inclusion/exclusion criteria, and adherence to CONSORT statements.
- Randomization and outcome assessment: method of randomization, method of concealment allocation, type of blinding (single, double, triple), blinding of the assessment of the primary outcome, length of follow-up period.
- Sample size: calculation of a sample size for a specified treatment effect, number of patients planned to be enrolled, number of eligible patients (i.e., with inclusion criteria but not included), number of included patients, and number of patients analyzed.
- Patients and surgery characteristics: sex, age, weight, height, and obstetric or nonobstetric patients.
- Type of neuraxial anesthesia and drugs used for neuraxial anesthesia: spinal, epidural, or combined spinal-epidural anesthesia and type and dose of local anesthetic administered.
- Spinal opioids: drugs and doses used.
- Intervention and control antipruritic drugs and rescue medication: drugs, dose, route, timing relative to spinal medication defined as before or after spinal administration of opioids, and use of any medications in addition to interventional and control antipruritic drugs.
- Methods of assessment of pruritus: scales and observation of scratching.
- Other outcomes examined by the study in addition to pruritus (i.e., postoperative nausea or vomiting, pain).
- Statistical methods including the intention to treat.
The 2 data extraction authors performed quality assessments separately. The quality of each study was scored using a modified Jadad scale21 in which the randomization, allocation concealment, and blinding method were evaluated. A 3-point scale was used, with 0 indicating a low risk of bias, 1 indicating a moderate risk of bias, and 2 indicating a high risk of bias.
Results were analyzed using Review Manager 5.2 (Cochrane Collaboration, Oxford, UK) and Microsoft Excel 2008 for Mac (version 12.3.2). The risk ratio (RR) was used as the statistical measure for the primary and secondary outcomes. The RRs were calculated from the original data, and meta-analysis was performed using the Mantel-Haenszel method. The RR represents the probability of an adverse event (i.e., pruritus) occurring in the experimental group (i.e., those given prophylactic ondansetron) versus the control group (i.e., those given placebo). P < 0.01 was considered significant for all analyses.
Because the effects of administering prophylactic 5-HT3 receptor antagonists to prevent pruritus may differ across different surgical populations and settings, we decided a priori to perform a random-effect analysis for all end points. Meta-analysis of the dichotomous primary and secondary outcome was performed. The a priori subgroup analyses to explain heterogeneity among studies were (1) patient population (nonobstetric surgery patients versus parturients) and (2) ondansetron before or after intrathecal opioid administration.
Cochrane χ2 test and I2 test for heterogeneity were used to assess interstudy heterogeneity. The χ2 test measures whether observed differences are compatible with chance alone, and the I2 assesses the percentage of the effect variability estimates that is because of heterogeneity rather than sampling error. The between-study variance (τ) was estimated with the method of moments (DerSimonian-Laird). Statistically significant heterogeneity was considered present at I2 > 50% with P < 0.01. We chose a P value <0.01 for statistical significance because no correction was made when the number of included studies was small. Publication bias was assessed by visually inspecting a funnel plot.
The flow diagram of the study search and selection is presented in Figure 1. Six randomized controlled trials met the inclusion criteria and were included in the final analysis (Table 1). Four studies were excluded after full-text review, 1 for not reporting necessary data, 1 for not including a control group, and 2 for administration of intrathecal morphine. No study was excluded from the analysis because of low quality based on the Jadad scale quality assessment (Appendix 2). No evidence of publication bias was evident by visual inspection of the funnel plot (Appendix 3).
Characteristics of Included Studies
The included studies were published from 2002 to 2007 and all were single-center prospective, randomized controlled trials (Table 1). Among them, 3 were conducted in Europe, 1 in North America, 1 in South America, and 1 in Australia. The studies included a total of 555 patients undergoing elective cesarean section (n = 108), labor analgesia (n = 73), or nonobstetric surgical procedures (n = 374). All study patients received intrathecal fentanyl or sufentanil (10–25 μg fentanyl; 10 μg sufentanil). Follow-up assessment of pruritus varied from 90 minutes to 7 days.
Study Intervention and Pruritus Assessment
The dose of IV ondansetron was 8 mg in all studies. Administration of ondansetron was performed before neuraxial anesthesia in 4 studies22–25 and intraoperatively after neuraxial anesthesia in 2 studies.26–29 Placebo or control treatment was the administration of IV normal saline in 5 studies, and no intervention in 1 study.29 Intrathecal opioids were administered as part of combined spinal-epidural anesthesia in the 2 studies involving obstetric patients22,26,27 and as part of spinal injection in 4 studies.23–25,28,29
All patients were blinded to the study intervention. Pruritus was assessed by a blinded investigator in 5 of the 6 studies.29 Assessment intervals ranged from every 5 to 10 minutes to hourly to daily. Pruritus was subjectively ranked by patients on a 0 to 3 scale (0 absent symptoms, 1 mild, 2 moderate, 3 severe) in 2 studies,25,26 on a 0 to 4 scale (0 absent, 1 mild, 2 moderate, 3 severe, 4 refractory to rescue treatment) in 1 study,29 on a 0 to 10 scale (0 absent symptoms, 10 worst possible) in 2 studies,23,24,27 and on a 0 to 100 scale (0 absent symptoms, 100 worst possible) in 1 study.22 One study assessed patients for signs of scratching.22 For the purpose of the study, pruritus was categorized as present or absent, with absence defined as a value of zero on any of the scales used.
All studies offered rescue treatment for persistent pruritus, including 4 to 100 µg IV or IV naloxone,22–24,27,29 10 mg IV propofol,25 or 25 mg IV diphenhydramine,23,26,28 at patient request.
Although the precise timing of follow-up assessment varied, all studies provided data on the primary end point within 4 hours of spinal opioid administration. One study did not provide data on the secondary end point and was excluded from secondary end point analyses.26 For the purpose of the study, analysis of the occurrence of pruritus was limited to the first 4 hours after opioid administration.
Overall, 117 (59%) of 199 patients who received 8 mg ondansetron reported pruritus versus 138 (70%) of 196 control patients. Prophylactic ondansetron did not significantly decrease the incidence of pruritus in the overall analysis (RR, 0.90; 95% CI, 0.72–1.13; I2 = 67%; P = 0.38). Exploratory subgroup analysis did not demonstrate a reduction in the incidence of pruritus among obstetric or nonobstetric surgery patients or among those who received ondansetron before versus after spinal opioid administration (Fig. 2; Supplemental Digital Content, Supplemental Figure 1, https://links.lww.com/AA/B270).
Overall, 19 (12%) of 163 patients who received 8 mg ondansetron requested rescue medication for pruritus versus 34 (21%) of 160 control patients. There was a trend toward reduced rescue medication use in the overall analysis (RR, 0.57; 95% CI, 0.35–0.91; I2 = 0%; P = 0.02). Exploratory subgroup analyses also demonstrated a trend toward less rescue medication use among nonobstetric surgery patients (RR, 0.47; 95% CI, 0.26–0.85; I2 = 0%; P = 0.01) and in patients who received ondansetron before spinal opioid administration (RR, 0.62; 95% CI, 0.38–1.00; I2 = 0%; P = 0.05; Fig. 3; Supplemental Digital Content 2, Supplemental Figure 2, https://links.lww.com/AA/B271).
This meta-analysis indicates that prophylactic ondansetron does not decrease the incidence of pruritus after intrathecal fentanyl or sufentanil. However, these findings suggest that it may decrease the need for rescue medication, especially in certain subgroups of patients: nonobstetric surgery patients and patients who receive ondansetron before spinal anesthesia. These findings suggest new potential questions and research areas related to intrathecal lipophilic opioids.
Although many studies have explored the incidence and prevention of pruritus associated with neuraxial morphine, relatively few have focused on lipophilic opioids. Despite differences in pharmacokinetics and pharmacodynamics between opioids,30 a recent meta-analysis by Youssef et al.31 demonstrated that the incidence of pruritus with neuraxial fentanyl is as high as that with neuraxial morphine. The incidence of pruritus in nonobstetric surgery patients after intrathecal morphine ranges from 15% to 70%32–34 and after intrathecal fentanyl or sufentanil, from 53% to 79%.23–25,29 A meta-analysis of 28 trials by Pöpping et al.9 demonstrated that intrathecal fentanyl and sufentanil allowed for a lower dose of intrathecal local anesthetic and hastening recovery from motor block but at the price of an increased risk of pruritus (RR, 11.8; 95% CI, 6.2–21.9).
The need for rescue medication may serve as a proxy for severity of pruritus, as suggested by previous studies focusing on intrathecal morphine. In a systematic review and meta-analysis, George et al.35 found that prophylactic 5-HT3 receptor antagonists reduced the severity of pruritus and the need for rescue medication among parturients receiving spinal morphine for cesarean delivery. Likewise, Bonnet et al.19 found that prophylactic 5-HT3 receptor antagonists (including ondansetron, tropisetron, granisetron, and dolasetron) lead to decreased need for pruritus rescue medication after spinal opioid (morphine, sufentanil, or fentanyl). Our analysis also suggests a reduced need for rescue treatment in patients receiving intrathecal fentanyl or sufentanil, especially in nonobstetric patients and when the treatment is initiated before spinal opiate administration.
The mechanisms responsible for an effect of ondansetron in these 2 subgroups remain hypothetical. Although the pathophysiology of intrathecal opioid-mediated pruritus is unclear, activation of 5-HT3 receptors in the dorsal horn has been implicated.36 By blocking this interaction, 5-HT3 receptor antagonists may prevent associated pruritus. The timing of ondansetron administration relative to intrathecal opioid may therefore determine which agent reaches the 5-HT3 receptors first.19 This may explain why patients who received ondansetron before intrathecal opioid required less frequent rescue medication for pruritus. Although local guidelines sometimes require that 5-HT3 receptor antagonists administration be delayed until after umbilical cord clamping, both groups in this analysis included a mix of nonobstetric and obstetric patients.
The reduced need for rescue medication among nonobstetric surgery patients versus obstetric patients may be related to obstetric patients’ baseline predisposition to pruritus (e.g., conditions such as pruritic urticarial papules and plaques of pregnancy), as well as the limitation that the obstetric trials included only females, whereas the nonobstetric trials included both sexes. Females may be predisposed to pruritus through modulation of keratinocyte receptors by estrogen.37 As ondansetron is specific for 5-HT3 receptors, it is not necessarily applicable in the prevention of other types of pruritus. Future trials may consider controlling for baseline pruritic conditions and for sex.
The pathophysiology of intrathecal lipophilic opioid-mediated pruritus remains under investigation. Hypotheses include activation of spinal serotonergic systems,36 prostaglandins,38 medullary dorsal horn activation,39 and antagonism of inhibitory neurotransmitters.40 Further research in this arena may clarify the time course of pruritus and the mechanism of prevention by ondansetron.
There are several limitations to our study: (1) Because of variation in trial design and patient assessment, we were only able to assess pruritus that occurred within 4 hours of neuraxial anesthesia. However, pruritus associated with lipophilic opioids is generally thought to occur earlier and to be of shorter duration than that associated with hydrophilic opioids,18 which suggests that our analysis included the clinically relevant time frame. (2) There was variability in the surgical populations, which introduced heterogeneity into our analysis. This was particularly evident among the nonobstetric surgery trials, which included orthopedic, urologic, and various nonobstetric ambulatory procedures. These trials included a mix of male and female patients, but this was not always done equitably. For example, in Waxler et al.,23 the control group was completely male. These differences may have affected our results. (3) All subgroup analyses included <5 studies, which limits the statistical power of the results. Given this limitation and the exploratory nature of these analyses, we would avoid drawing definitive conclusions from the results. Rather, this meta-analysis is intended to identify potential subgroups for future clinical trials.
This study also included both obstetric and nonobstetric patients which, while introducing heterogeneity into the analysis, also increases the power of the analysis; this is critical, given the low number of trials focusing on neuraxial lipophilic opioids. Furthermore, this population represents a large proportion of patients likely to receive neuraxial anesthesia, which improves the external validity of these findings.
Low-dose spinal anesthesia is increasingly being explored for a variety of surgical procedures.41–43 Given the increasing proportion of anesthesia administered in the ambulatory setting,44,45 there is demand for anesthetic techniques which allow for rapid recovery with minimal side effects.46,47 The demand for low-dose spinal techniques in ambulatory surgery highlights the need for additional studies focusing on nonobstetric populations. Low-dose spinal anesthesia is also of interest for those obstetric patients who may not tolerate spinal hypotension.7 Further research in the prevention of pruritus associated with intrathecal fentanyl and sufentanil may allow for more widespread use of low-dose spinal anesthesia in various target populations.
In conclusion, ondansetron did not significantly reduce the incidence of pruritus after administration of intrathecal fentanyl or sufentanil but may decrease the need for rescue medication, particularly among nonobstetric surgery patients and those who received the intervention before administration of intrathecal opioid. Preventing the incidence and severity of pruritus is an important part of patient care, which may affect patient satisfaction. Future studies may focus on these target populations.
((((((“Ondansetron”) OR “5-HT3”) AND “spinal”) OR “intrathecal”) AND “fentanyl”) OR “opiate”) OR "pruritus" AND ((“1994/01/01”[PDat]: “2014/01/01”[PDat]) AND Humans[Mesh] AND English[lang] AND medline[sb] AND adult[MeSH]).
APPENDIX 2. Study Quality Scores
Name: Meghan Prin, MD.
Contribution: This author conceived the project, contributed to project design, performed data collection and analysis, and helped write the manuscript.
Attestation: Meghan Prin approved the final manuscript and is the archival author.
Name: Jean Guglielminotti, MD, PhD.
Contribution: This author contributed to the project design, performed data collection and analysis, and helped write the manuscript.
Attestation: Jean Guglielminotti approved the final manuscript.
Name: Vivek Moitra, MD.
Contribution: This author helped write the manuscript.
Attestation: Vivek Moitra approved the final manuscript.
Name: Guohua Li, MD, DrPH.
Contribution: This author helped with statistical analysis and to write the manuscript.
Attestation: Guohua Li approved the final manuscript.
This manuscript was handled by: Ken B. Johnson, MD.
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