Effect of prophylactic 5-HT3 receptor antagonists on pruritus induced by neuraxial opioids: a quantitative systematic review^†

Abstract

Pruritus is a frequent adverse event observed after neuraxial administration of opioids. Central 5-hydroxytryptamine subtype 3 (5-HT3) receptors may be activated in this process. This systematic review aimed to evaluate the efficacy of prophylactic 5-HT3 receptor antagonists on neuraxial opioid-induced pruritus. We searched Medline, Embase, and Cochrane Collaboration Library databases. Studies were evaluated with the Oxford Validity Scale. Studies with a score of 3 or more and reporting prophylactic administration of 5-HT3 receptor antagonists vs placebo were included. Fifteen randomized double-blind controlled trials (n=1337) were selected. 5-HT3 antagonists (n=775) significantly reduced pruritus [odds ratio (OR) 0.44 (95% confidence interval, 95% CI, 0.29–0.68), P=0.0002, number-needed-to-treat (NNT) 6 (95% CI, 4–14)], the treatment request for pruritus [OR 0.58 (95% CI, 0.43–0.78), P=0.0003, NNT 10 (95% CI, 7–20)], the intensity of pruritus [weighted mean difference (WMD) −0.35 (95% CI, −0.59 to −0.10), P=0.007], the incidence and the intensity of postoperative nausea and vomiting (PONV), and the need of rescue treatment [respectively, Peto odds ratio (Peto OR) 0.43 (95% CI, 0.31–0.58), P<0.00001, NNT 7 (95% CI, 6–10); WMD −0.12 (95% CI, −0.24 to 0.00), P=0.05 and OR 0.42 (95% CI, 0.20–0.86), P=0.02, NNT 8 (95% CI, 5–35)]. However, the funnel plot was asymmetric, suggesting a risk of publication bias. 5-HT3 receptor antagonists may be an effective strategy in preventing neuraxial opioid-induced pruritus and PONV. Further large randomized controlled trials are required to confirm these findings.

Neuraxial injection of opioids provides effective analgesia in many types of surgery. However, spinal opioids are associated with a wide variety of side-effects such as nausea, vomiting, and pruritus.^4,12 The reported incidence of pruritus varies between 30% and 100%,³⁸ making this the most common side-effect of neuraxial opioids. The exact mechanism of pruritus is unclear. 5-Hydroxytryptamine subtype 3 (5-HT3) receptors are abundant in the dorsal horn of the spinal cord and the spinal tract of the trigeminal nerve in the medulla.^20,41 The interaction between opioids and 5-HT3 receptors¹⁶ may play a role in the generation of neuraxial opioid-induced pruritus. Consequently, specific 5-HT3 receptor antagonists could be an effective prophylactic treatment of neuraxial opioid-induced pruritus.

5-HT3 antagonists, such as ondansetron, have been used to prevent postoperative nausea and vomiting (PONV).² However, there are conflicting results regarding the efficacy of prophylactic 5-HT3 receptor antagonists in neuraxial opioid-induced pruritus prevention.

The purpose of this systematic review was to assess the efficacy of prophylactic 5-HT3 receptor antagonist treatment on neuraxial opioid-induced pruritus in a surgical setting and in labour.

Methods

This study was conducted according to the QUOROM recommendations for improving the quality of meta-analysis.³¹ Three electronic databases, Pubmed^® (MEDLINE/Index Medicus), the Cochrane Central Register of Randomized Controlled Trials, and Embase were searched without language restriction for studies published between January 1966 and May 2007. The MeSH terms ‘pruritus’ or ‘itching’, ‘5-HT3 receptor antagonists’, ‘ondansetron’, ‘tropisetron’, ‘granisetron’, or ‘dolasetron’, and ‘neuraxial opioids’ or ‘intrathecal opioids’ or ‘spinal opioids’ or ‘epidural opioids’ were used for searching. The bibliographies of articles were also screened for additional studies. If original data were missing, authors were contacted.

Each study was evaluated qualitatively and independently by two investigators (M.-P.B. and J.J.) who were not blind to authors and results. Discrepancies were resolved by discussion with a third investigator (E.M.). Studies were scored according to the Oxford Validity Scale,²⁵ based on a five-point evaluation with three items: randomization, double-blinding, and completeness of patient follow-up. One point was attributed if the study was described as randomized. A supplementary point was given if the randomization was described and appropriate (e.g. computer-generated table of random numbers), whereas no supplemental point was given if the randomization method was not described or inappropriate (e.g. alternate allocation or allocation by date of birth). Similarly, one point was assigned to studies described as double-blind, an additional point if the double-blinding method was described and adequate (identical placebo, active placebo, double-dummy). A final point was given if the article specified the numbers of and reasons for withdrawals. If no patients were excluded from the study, one point was also awarded. Thus, the highest possible score was 5.

Criteria for study selection were as follows: prospective randomized double-blind trials, quality assessment score of 3 or more, and the study evaluating the efficacy of a prophylactic treatment with i.v. 5-HT3 receptor antagonist compared with placebo after spinal, epidural, or both opioid administration. All surgical settings and labour were considered. Water-soluble (morphine) and lipid-soluble (fentanyl and sufentanil) opioids were assessed. Patients receiving lipid-soluble opioids along with neuraxial morphine were included in the morphine group. When two different doses of the same 5-HT3 receptor antagonist or two different 5-HT3 receptor antagonists were compared with each other and with placebo, data from the treatment groups were combined for analysis. I.V. 5-HT3 antagonists could be administered either before or after the neuraxial opioid injection.

Criteria for study exclusion were: trials studying curative treatment of pruritus with 5-HT3 receptor antagonists; non-randomized trials; patients <18 yr; absence of a placebo group; studies with more than one injection of 5-HT3 receptor antagonist and association with other anti-pruritus agents.

The primary evaluation criterion was the incidence of pruritus, defined by the number of patients with pruritus during the first 24 h after operation. The other endpoints were: the request for treatment of pruritus; pruritus severity score (from 1, no pruritus, to 4, severe pruritus; all scores were converted to a four-point scale); the incidence and the severity score of PONV during the first 24 h after operation and the request for treatment of PONV. The regimen of curative treatment of pruritus was also extracted when available.

Data were obtained from values reported in the manuscripts or the tables of the selected trials, or were extracted from the figures. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated for dichotomous data and the results were expressed graphically. All criteria were analysed separately. When the authors reported zero event, the Peto odds ratio (Peto OR) was then calculated.⁴⁷ Results are reported as the median value with the corresponding 95% CI, or as the mean value with standard deviation (sd). For the intensity scores of pruritus and PONV, weighted means differences (WMDs) were calculated, taking into account study samples size and sd as reported in the included trials. Forest plots were constructed to represent the effects of 5HT-3 antagonists on the different studied outcomes. All analyses were performed using RevMan software (version 4.2, Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen, Denmark), with calculation of number-needed-to-treat (NNT) for the significant criteria (http://www.nntonline.com). When the test of heterogeneity (Cochran Q test) was significant (P<0.1), a random effect analysis was carried out.

A subgroup analysis was performed in groups of patients who received hydrosoluble opioids alone or in association with lipid-soluble opioids or lipid-soluble opioids alone, and in groups of patients undergoing Caesarean section. To assess whether the studies were affected by publication bias, a funnel plot was constructed.¹⁵ All tests were two-sided, and P-values of <0.05 were considered statistically significant.

Results

Twenty-four studies were identified by the Medline, Cochrane database, and Embase search. Ten studies were excluded for the following reasons: five were case reports,^{3,13,22,30,33} one was a systematic review,²⁶ one was a randomized study without a placebo group,³⁷ two trials studied the efficacy of a curative treatment with ondansetron on neuraxial opioid-induced pruritus,^5,9 and one study evaluated the efficacy of prophylactic treatment with ondansetron on pruritus induced by i.v. opioid.²⁹ A manual search of cross-references from the manuscripts identified one additional study, only published as an abstract.²¹ Finally, 15 randomized controlled double-blind studies comparing the efficacy of a prophylactic treatment with 5-HT3 antagonist to placebo on neuraxial opioid-induced pruritus were included in this systematic review (Fig. 1).

The median quality score was 4 (range, 3–5). All 15 studies were published in or after 1999. All of the studies reported a single i.v. 5-HT3 antagonist administration with an i.v. saline placebo-control. The number of patients in each group ranged from 13 to 75. Seven hundred and seventy-five patients were treated with a 5-HT3 antagonist and 562 patients received placebo. The different procedures were: Caesarean section (n=608),^{8,18,35,36,45,46} labour (n=103),^21,44 abdominal hysterectomy,⁴⁰ minor elective surgery (inguinal hernia, cord hydrocoele, and pilonidal sinus),³⁴ orthopaedic surgery,¹⁴ knee arthroscopy,²⁷ knee arthroscopy or urologic surgery,¹⁹ urologic, vascular, or orthopaedic surgery,²⁴ and ambulatory surgery.⁴³ All patients received a neuraxial anaesthesia: spinal anaesthesia in 10 studies,^{8,14,19,24,27,34,36,43,45,46} combined spinal–epidural anaesthesia in four studies,^18,21,35,44 and epidural anaesthesia.⁴⁰ The opioids used were intrathecal morphine alone in six studies,^{8,14,24,34,36,46} epidural morphine (3 mg) in one study,⁴⁰ intrathecal fentanyl alone in five studies,^{18,19,21,27,44} and intrathecal sufentanil alone in one study.⁴³ In two studies, intrathecal morphine was combined with either intrathecal sufentanil⁴⁵ or intrathecal fentanyl.³⁵ The intrathecal morphine dose varied between 150 and 300 µg, the fentanyl dose between 10 and 25 µg, and the sufentanil dose between 2.5 and 10 µg. The local anaesthetics associated were intrathecal bupivacaine (2–15 mg),^{8,14,18,19,21,24,27,34–36,44–46} intrathecal lidocaine (15–100 mg),⁴³ or epidural lidocaine 2% with 1:100 000 epinephrine (0.3 ml kg⁻¹).⁴⁰

Ondansetron was used in all studies at a dose of 4,^14,24,40 8 mg,^{8,18,19,21,27,34–36,43–45} or 0.1 mg kg⁻¹.⁴⁶ The other 5-HT3 receptor antagonists were tropisetron (5 mg),³⁵ granisetron (3 mg),³⁶ and dolasetron (12.5 mg) (Table 1).²⁴ In all trial studies of Caesarean section, a single dose of 5-HT3 receptor antagonist or saline was administered by i.v. route after neuraxial opioid injection and delivery.^{8,18,35,36,45,46} In other studies, 5-HT3 receptor antagonists or saline were injected either at the time of²¹ or before neuraxial opioid injection.^{14,19,24,27,34,40,43,44}

The incidence of pruritus was the primary outcome in 12 trials. The incidence of PONV was the primary aim in two studies^40,45 and the treatment request for pruritus was the primary aim in another investigation (Table 1).⁸

Pruritus after neuraxial opioids was reported in all trials. The incidence of pruritus was 78% (range, 57–100%) in the control group, 80% with neuraxial morphine (range, 57–93%), and 74% with lipid-soluble opioids (range, 57–100%).

5-HT3 receptor antagonists reduced the risk of pruritus from 78% to 66% (range, 25–95%) [OR 0.44 (95% CI, 0.29–0.68), P=0.0002, NNT 6 (95% CI, 4–14), Fig. 2]; a l'Abbé plot of the risk of pruritus for 5-HT3 antagonists vs placebo was constructed (Fig. 3). Eight studies showed a significant decrease in the incidence of pruritus with 5-HT3 receptor antagonists vs placebo,^{8,18,19,21,24,34,40,46} and seven studies showed no significant differences.^{14,27,35,36,43–45}

A subgroup analysis was performed taking into account morphine administration. In patients receiving spinal or epidural morphine, a significant reduction in the incidence of pruritus was observed in the 5-HT3 receptor antagonist group from 80% to 66% (range, 25–88%) [OR 0.41 (95% CI, 0.26–0.65), P=0.0002, NNT 6 (95% CI, 4–13), Fig. 2]. In contrast, no significant difference was observed when patients received neuraxial lipid-soluble opioids alone (Fig. 2). Another subgroup analysis was conducted to evaluate the effect of 5-HT3 receptor antagonists to prevent pruritus induced by neuraxial opioid after Caesarean section. The incidence of pruritus was 74% (range, 25–88%) in patients undergoing Caesarean section receiving 5-HT3 receptor antagonist (n=368) and 83% (range, 67–93%) in the control group (n=240). This difference was statistically significant [OR 0.42 (95% CI, 0.21–0.84), P=0.01, NNT 7 (95% CI, 4–39), Fig. 4]. However, the funnel plot was not symmetrical around the mean, suggesting a risk of publication bias (Fig. 5).

The pruritus intensity score was reported in 13 studies. It was measured with a four-point scale in seven studies;^{8,14,18,19,24,36,44} with a three-point scale in two studies;^45,46 with a verbal analogue scale ranging from 0 to 10 in two studies;^27,43 and with a 10 cm visual analogue scale in two studies.^21,34 All the pruritus intensity scores were converted to a four-point scale. 5-HT3 receptor antagonists significantly reduced the intensity of pruritus (Fig. 6).

The request for treatment of pruritus was reported in 13 studies. The treatments used for pruritus were naloxone,^{27,35,36,43,44} hydroxizine,³⁵ propofol,^8,19,46 diphenhydramine,^{18,34,36,43,45} or nalbuphine.^21,24 Treatment was requested by 24% (range, 0–49%) of the patients in the 5-HT3 receptor antagonists group and by 31% (range, 3–72%) of the patients in the control group. Thus, prophylactic administration of 5-HT3 antagonists significantly decreased the request for curative treatment of pruritus [OR 0.58 (95% CI, 0.43–78), P=0.0003, NNT 10 (95% CI, 7–20), Fig. 7].

PONV was reported in 11 studies^{8,18,21,24,27,34–36,40,44,45} and was observed in 32% (range, 0–58%) of patients in the control group and 17% (range, 0–40%) of patients in the 5-HT3 receptor antagonists group. This difference was statistically significant [Peto OR 0.43, (95% CI, 0.31–0.58), P<0.00001, NNT 7 (95% CI, 6–10)] (Table 2). 5-HT3 receptor antagonists also decreased the request for treatment^34–36,45 with an incidence of 12% (range, 8–24%) compared with 27% (range, 10–39%) in the control group [OR 0.42 (95% CI, 0.20–0.86), P=0.02, NNT 8 (95% CI, 5–35)]. Finally, the intensity score for PONV was reported in six studies.^{8,18,34,36,44,45} When all scores were converted in a four-point scale, 5-HT3 receptor antagonists reduced the severity of PONV [WMD −0.12 (95% CI, −0.24 to 0.00), P=0.05] (Table 2).

No adverse effects of 5-HT3 receptor antagonists, such as headache, cardiac arrhythmia, or extrapyramidal signs, were reported in the studies.

Discussion

This systematic review of 15 randomized controlled trials indicates that prophylactic treatment with a single i.v. bolus of 5-HT3 receptor antagonists may provide a significant decrease in the incidence and the intensity score of pruritus after neuraxial opioid administration, particularly when morphine is used. It also suggests a significant decrease in the requirement for treatment of pruritus. Moreover, 5-HT3 receptor antagonists provide a significant decrease in incidence and intensity score of PONV and in treatment request for PONV. However, the asymmetrical funnel plot suggests a risk of publication bias for the current meta-analysis.

The quality of the trials included in a systematic review may affect the results. Indeed, low-quality trials overestimate the benefits of the studied treatment.³² Therefore, only high-quality trials were included in this systematic review. These studies were randomized controlled double-blind trials, with an Oxford Validity Scale score of at least 3 (median, 4; range, 3–5). However, the funnel plot we performed suggests a potential reporting bias.¹⁵ Reporting bias tends to occur when statistically significant or ‘positive’ studies are more likely to be published (publication bias) or published in English (language bias). In meta-analyses of studies prone to this bias, the overall effect might be exaggerated. In the current systematic review, abstracts and published studies were included and there was no language restriction. Small positive studies are more likely to be published than small negative trials which may explain the funnel plot.

Pruritus is an unpleasant and uncomfortable sensation on the skin. Epidural and intrathecal opioid injections are very often associated with pruritus^1,10 and the incidence of pruritus varies between 30% and 100%, depending on the nature of the opioid.³⁸ The symptoms typically spread from the site of opioid injection to the trunk and facial region. Itching on the nose and around the eyes is common.⁷ Pruritus may require treatment, which can be ineffective or can reverse the analgesic effect of the opioid.^4,23 The mechanisms of pruritus induced by a drug or secondary to a systemic disease are complex and still not fully understood.⁴² Neuraxial opioid-induced pruritus is probably not related to histamine release, because anti-histamines are ineffective.²⁸ Supraspinal and spinal opioid receptors activated by opioids are involved. Neuraxial opioids may induce pruritus by acting on central 5-HT3 receptors, which are concentrated in the dorsal horn of the spinal cord and in the trigeminal nucleus of the medulla, an area thought to be associated with facial itching.^4,16 Thus, 5-HT3 receptor antagonists may be a preventive treatment for neuraxial opioid-induced pruritus.

In our systematic review, the reduction of the incidence of pruritus secondary to prophylactic treatment with 5-HT3 antagonists could seem to be modest [NNT 6 (95% CI, 4–14)]. However, as the incidence of pruritus after neuraxial opioids is high, a substantial number of patients are involved. The beneficial effect on the incidence of PONV and the safety profile of 5-HT3 antagonists increase the interest of using these drugs as a preventive treatment of neuraxial opioid-induced pruritus.

5-HT3 receptor antagonists reduced the incidence of pruritus after neuraxial morphine injection, but not after neuraxial lipid-soluble opioids injection. Fentanyl and sufentanil are highly lipid-soluble opioids, which promote rapid onset and minimal residual opioid concentration in cerebrospinal fluid. Morphine is less lipid-soluble, slowing the onset of analgesia, and giving higher residual opioid concentration in the cerebrospinal fluid and a greater cephalic migration.¹² As the peak concentration of ondansetron occurs around 15 min, 5-HT3 antagonists may reach 5-HT3 receptors in the spinal cord before morphine but after the lipid-soluble drugs. This mechanism may be supported by the two trials where both lipid-soluble and hydrosoluble opioids were administered for neuraxial anaesthesia.^35,45 In these trials, both including patients undergoing Caesarean section, the 5-HT3 receptor antagonists had no effect on the incidence of pruritus (OR close to 1, Fig. 2).

Patients in labour were included for several reasons. First, they compose a large proportion of the patients receiving neuraxial opioids and are similar to pregnant patients undergoing Caesarean section. Pregnant women seem to be more susceptible to pruritus after neuraxial opioids administration than other populations, with an incidence of 60–100%.³⁸ In contrast, after orthopaedic surgery, the incidence of pruritus after intrathecal opioid ranges from 30% to 60%.^11,39 In our systematic review, the mean incidence of pruritus is 83% in the parturients and 69% in the non-pregnant population when administered placebo. This difference is statistically significant but less pronounced than previously reported.^38,39 This vulnerability to pruritus could be explained by the interaction of oestrogen with opioid receptors.⁶ In the current systematic review, 5-HT3 receptor antagonists were significantly effective on neuraxial opioid-induced pruritus in obstetric patients. Currently, parturients undergoing Caesarean section receive lipid-soluble associated hydrosoluble neuraxial opioids.¹⁷ 5-HT3 receptor antagonists were given after neuraxial opioid administration, due to the necessity of clamping the umbilical cord as required by licensing regulations. One may speculate that 5-HT3 receptor antagonists may have been effective in the obstetric population receiving lipid-soluble and hydrosoluble neuraxial opioids, if the administration could have been performed before the procedure. Owing to the potential publication bias observed between the included studies, further large randomized controlled trials are needed to confirm these results, in particular in patients undergoing Caesarean section under spinal anaesthesia with hydrosoluble and lipid-soluble opioids and with 5-HT3 antagonists given before spinal anaesthesia.

In conclusion, the current systematic review showed potential benefits with 5-HT3 antagonists on the incidence and intensity of hydrosoluble opioid-induced pruritus and PONV.

Acknowledgement

The authors would like to express their acknowledgement to M.J.P. Harnett for supplying unpublished personal data.

References

Author notes