5-ht3 Antagonists and the Analgesic Efficacy of Paracetamol Systematic Review and Meta-analysis
Abstruse
Background
The aim of this written report was to assess whatever interaction between ondansetron and paracetamol on a model of postal service-fracture pain in mice.
Methods
In protocol A, afterwards fracture of the tibia, mice were assigned to four groups: paracetamol xxx mg kg−1, paracetamol l mg kg−1, paracetamol 100 mg kg−ane, or a saline vehicle i.p. In protocol B, afterwards fracture of the tibia, mice were randomized to receive either paracetamol (100 mg kg−1) plus saline (vehicle), paracetamol (100 mg kg−1) plus ondansetron (1 mg kg−1), paracetamol (100 mg kg−1) plus ondansetron (2 mg kg−one), saline plus ondansetron (ii mg kg−1), or saline plus saline i.p. Three tests were used to appraise hurting behaviour: von Frey filament application, hot-plate test, and a subjective pain scale. Rescue analgesia with morphine was administered as necessary.
Results
In protocol A, paracetamol (100 mg kg−1)-treated animals had less mechanical nociception, thermal nociception, and a lower subjective hurting calibration rating, when compared with those receiving paracetamol at 30 or fifty mg kg−1 or saline [ED50 paracetamol=46.iii (half-dozen.34) mg kg−1]. No divergence was constitute between paracetamol (xxx mg kg−1) and saline-treated animals. In protocol B, the mechanical withdrawal threshold, the thermal withdrawal latency, and the subjective pain scale were lower afterwards injection of paracetamol (100 mg kg−one)+saline, paracetamol (100 mg kg−1)+ondansetron (1 mg kg−1), and paracetamol (100 mg kg−1)+ondansetron (2 mg kg−one), whereas in mice receiving saline+ondansetron (2 mg kg−1) or saline+saline, in that location was no difference.
Conclusion
We found that paracetamol 100 mg kg−1 blocked the development of hyperalgesia and allodynia afterwards fracture pain and ondansetron did not modify the antinociceptive effect of paracetamol in this model.
Key points
-
Some serotonin receptor blockers interfere with the analgesic consequence of paracetamol in some human studies.
-
The aim of this written report was to asses if ondansetron blocked the effect of paracetamol in a fracture model in mice.
-
Ondansetron did non interfere with the analgesia effect of paracetamol in this model.
-
There are upstanding issues with the utilize of a placebo for fracture hurting in animals, although rescue analgesia was provided.
Postoperative pain management is very important because it is a critical role of the patient'southward recovery. 1–3 Bone injury is often accompanied by acute pain 4,5 that can exist clearly diminished by the apply of morphine. 4–6 However, in clinical practice, paracetamol is frequently used. seven–9 Although paracetamol has been clinically used for more than a century, the mechanism of activeness of paracetamol is still non clearly understood. The analgesic event of paracetamol could exist due to (i) the inhibition of COX in the encephalon, 10 (two) the indirect activation of cannabinoid CB1 receptors, 11,12 and/or (iii) the modulation of the serotoninergic system that has been suggested on the ground of biochemical and behavioural studies supporting an indirect serotoninergic upshot. 13–xvi Paracetamol may stimulate the activeness of descending serotoninergic pathways that inhibit nociceptive signal transmission in the spinal cord. thirteen,14 It was recently shown that coadministration of tropisetron or granisetron with paracetamol completely blocks the analgesic effect of paracetamol in humans. 17 However, in this study, the Pain Matcher auto-evaluation tool, based on electrical stimulation of the median nervus in volunteers, that is, not bodily clinical hurting, was used. Moreover, ondansetron, a serotonin-3 (5-hydroxytryptamine-3, five-HT3) antagonist, is currently used for prophylaxis of postoperative nausea and vomiting in perioperative management, xviii–22 whereas tropisetron and granisetron are used just for chemotherapy nausea.
This study was undertaken to assess a possible pharmacological interaction of ondansetron and paracetamol in an fauna model of post-fracture pain. four,23
Methods
Animals
This study, including care of the animals involved, was conducted according to the official edict presented by the French Ministry of Agronomics (Paris, French republic) and the recommendations of the Helsinki Declaration. These experiments were approved by our Institutional Creature Care and Use Committee, and the written report was conducted in accordance with the International Association for the Study of Hurting guidelines on the use of animals in experimental enquiry. 24 Adult C57 BL/6 male mice (The Jackson Laboratories, Bar Harbor, ME, USA) were used in all experiments. The animals were housed individually in isolator cages with solid flooring covered with 3 cm of soft bedding and were fed and watered advertizement libitum. Animals were on a 12 h light–nighttime bicycle. The rescue analgesia protocol for animals in pain was v mg kg−1 i.p. morphine. At the cease of the experiment, animals were killed with CO2.
Surgery
All mice were anaesthetized with ii–iii% sevoflurane. Adequate anaesthesia was ascertained by an absent pedal withdrawal reflex after hard pinching of the toe. Closed fracture of the tibia was performed as previously described. 4 Briefly, after antiseptic preparation of the right paw with povidone iodée, a unilateral airtight fracture was produced in the correct tibia using a particularly designed fracture appliance (edgeless guillotine). For the intramedullary pinning using a sterile technique, a hole was fabricated above the tibial tuberosity percutaneously using a 27 G needle (BD, Drogheda, Ireland). Then, the needle was directed straight into the medullary canal. By rotating the needle, the canal was reamed to 5 mm upwardly to the ankle articulation. The end of the needle was cut every bit brusque as possible so that the skin could curl over and cover information technology. No suture was performed. The mouse was then placed with the leg on the anvil in order to line up the blunt guillotine with the proximal tertiary of the tibia. A 300 k weight was decreased from a height of 9 to x cm, fracturing the tibia shaft. No movement response to injury occurred under these weather condition.
Experimental groups
Protocol A: effects of paracetamol on fracture pain
20-four mice were randomized. Surgery was performed as described above. Testing (mechanical stimulation, hot-plate exam, and pain rating scale) was performed before the surgery and 2 h after the surgery (T0). And then, mice were randomly assigned to receive either paracetamol 30 mg kg−1 (n=half dozen) i.p., paracetamol 50 mg kg−1 i.p. (n=vi), paracetamol 100 mg kg−1 i.p. (north=6), or a saline vehicle i.p. (n=half-dozen). Responses to mechanical, heat stimuli, and pain rating calibration were determined every 30 min until 240 min afterwards drug administration. Experiments were conducted using a blind protocol.
Protocol B: furnishings of ondansetron on paracetamol effect on fracture pain
The aim of this second part was to assess the effect of systemic ondansetron administration on paracetamol-enhanced responses to postoperative testing.
Thirty other mice were randomized. Surgery was performed every bit described above. Testing (mechanical stimulation, hot-plate test, and pain rating scale) was performed before the surgery and 2 h after the surgery (T0). Then, mice were randomly assigned to receive i.p. either paracetamol (100 mg kg−1 body weight) plus saline (vehicle), paracetamol (100 mg kg−one body weight) plus ondansetron (ane mg kg−1), 25,26 paracetamol (100 mg kg−1 body weight) plus ondansetron (ii mg kg−1), saline plus ondansetron (2 mg kg−ane), or saline plus saline. Responses to mechanical, heat stimuli, and pain rating scale were adamant every thirty min until 240 min afterward the assistants. Experiments were conducted using a blind protocol.
Behavioural measurements
Three tests were used to assess pain behaviour: (i) mechanical nociception assessed by the withdrawal response to von Frey filament application, (two) thermal nociception assessed past the withdrawal response to thermal stimulus (hot-plate test), and (iii) subjective hurting determined using a pain rating scale as described by Attal and colleagues. 27
Mechanical nociception
Unrestrained mice were placed beneath a clear plastic sleeping accommodation on an elevated mesh flooring and were allowed to acclimatize. Withdrawal responses to mechanical stimulation were adamant using calibrated von Frey filaments applied from underneath the cage through openings in the plastic mesh floor on the hindpaw plantar skin, approximately at the heart of the fractured leg. The filament was pushed until it slightly bowed and then it was maintained in that position for 6 due south. Each von Frey filament was applied once, starting with 0.008 g and increasing until a withdrawal response was reached which was considered a positive response. The test was repeated iii times. The lowest force from the iii tests producing a response was considered every bit the withdrawal threshold.
Thermal nociception
Thermal nociception was measured by a modified hot-plate test. 28 The time that a mouse would get out its hind paw on a hot plate at 52°C reflected thermal nociception (thermal latency). The manus was removed from the plate after a maximal fourth dimension of 12 s by the investigator to avoid thermal injury and thermal hyperalgesia. 28 This examination was repeated 3 times on each hind hand for each mouse.
Subjective pain scale
A subjective pain rating scale (0–five) modified from that described by Attal and colleagues 27 was used to quantify the pain, where: 0 is normal, one is curling of the toes, 2 is eversion of the paw, iii is fractional weight bearing, 4 is non-weight bearing and guarding, and 5 is avoidance with whatever contact with the hind limb.
Statistical analysis
On the ground of previous studies, 4,17 an expected 80% deviation in the consequence of paracetamol with a coefficient of variation of 40% based on a Cohen d >2.8 with ketoprofen iv yielded a minimum sample size of five mice for each grouping (probability level of 0.05 and power of 0.eighty). The values for results of behavioural testing were not normally distributed and thus were analysed not-parametrically. To appraise whether the withdrawal responses inverse over time, Friedman's test was used. When Friedman's examination was significant (P<0.05), pairwise comparisons were made using Wilcoxon's signed-rank test. Fourth dimension points' comparisons between the groups were fabricated using kickoff a non-parametric Kruskal–Wallis. When a Kruskal–Wallis test was significant (P<0.05), pairwise comparisons were made using the Mann–Whitney U-test. The effect sizes were also estimated using Cohen'due south d values. Cohen'due south d values are considered a minor event size at 0.2, a moderate effect size at 0.five, and a large effect size at >0.8. A dose–effect relationship was tested for both the mechanical and thermal responses using a unproblematic Hill equation: (Eastward=E max Dose/EDfifty+Dose), where E max is the maximum theoretical effect, EDl the dose of paracetamol leading to one-half Eastward max, and Dose the dose of paracetamol. We used the software NONMEM (version Half dozen, level i). 27 The upshot of the time elapsed between drug assistants and pain measurement (sixty, 90, and 120 min) was tested using the Akaike benchmark. Nosotros also tested whether the ED50 was different between mechanical and thermal responses. Because nosotros did not include whatsoever interindividual variability gene, we used the FO method and the results are given as the fitted value (standard difference). P<0.01 was considered as the limit of significance.
Results
Protocol A: effects of paracetamol on fracture pain
No difference in the measured parameters was observed in any of the groups after fracture and before treatment. Thermal nociception, mechanical nociception, and subjective pain scale were significantly modified in mice receiving paracetamol at a dose of 100 mg kg−ane compared with those receiving paracetamol at 30 or 50 mg kg−i or saline only. Effect sizes (Cohen'due south d) for mechanical and thermal stimulation are shown in Tables 1 and 2 respectively. When compared with saline, paracetamol (100 mg kg−one) provided a reduction of mechanical nociception from 30 to 120 min (Fig. 1a), of thermal nociception from 30 to 240 min (Fig. 1b), and of subjective hurting scale from 30 to 120 min (Fig. 1c). No divergence was plant between paracetamol (xxx mg kg−1) and saline-treated animals. The effect of time between administration and measurement was not meaning. Similarly, ED50 was not dissimilar betwixt the two experiments (von Frey hairs and hot plate): E max VF=4.72 (3.01) one thousand, E max HP=xiii.7 (20.8) s, and ED50=46.three (6.34) mg kg−1.
Table 1.
Effect sizes (Cohen's d) later on mechanical stimulation in protocol A. Effect sizes (Cohen's d) for paracetamol (30 mg kg−1) and paracetamol (100 mg kg−1) compared with saline, in terms of the response to mechanical stimulation (von Frey filaments) in protocol A. Cohen's d<0.2 small-scale event, 0.5 moderate effect, and >0.viii large effect
| Fourth dimension (min) | Paracetamol (30 mg kg−1) | Paracetamol (100 mg kg−ane) |
|---|---|---|
| thirty | 0.72 | 1.40 |
| 60 | 0.49 | ane.97 |
| 90 | 1.03 | 3.04 |
| 120 | ane.80 | 2.19 |
| 150 | 0.47 | 0.90 |
| 180 | 0.72 | 0.72 |
| 240 | 0.29 | 0.72 |
| Time (min) | Paracetamol (30 mg kg−1) | Paracetamol (100 mg kg−ane) |
|---|---|---|
| 30 | 0.72 | one.40 |
| 60 | 0.49 | 1.97 |
| 90 | ane.03 | three.04 |
| 120 | i.eighty | 2.19 |
| 150 | 0.47 | 0.90 |
| 180 | 0.72 | 0.72 |
| 240 | 0.29 | 0.72 |
Table 1.
Event sizes (Cohen's d) after mechanical stimulation in protocol A. Effect sizes (Cohen's d) for paracetamol (30 mg kg−1) and paracetamol (100 mg kg−one) compared with saline, in terms of the response to mechanical stimulation (von Frey filaments) in protocol A. Cohen's d<0.two small result, 0.v moderate effect, and >0.viii large effect
| Fourth dimension (min) | Paracetamol (30 mg kg−one) | Paracetamol (100 mg kg−one) |
|---|---|---|
| 30 | 0.72 | i.40 |
| 60 | 0.49 | i.97 |
| xc | one.03 | three.04 |
| 120 | 1.lxxx | 2.19 |
| 150 | 0.47 | 0.xc |
| 180 | 0.72 | 0.72 |
| 240 | 0.29 | 0.72 |
| Fourth dimension (min) | Paracetamol (xxx mg kg−1) | Paracetamol (100 mg kg−1) |
|---|---|---|
| 30 | 0.72 | 1.40 |
| 60 | 0.49 | one.97 |
| 90 | 1.03 | 3.04 |
| 120 | 1.eighty | two.19 |
| 150 | 0.47 | 0.90 |
| 180 | 0.72 | 0.72 |
| 240 | 0.29 | 0.72 |
Table 2.
Effect sizes (Cohen'south d) afterwards thermal stimulation in protocol A. Event sizes (Cohen's d) for paracetamol (30 mg kg−i) and paracetamol (100 mg kg−ane) compared with saline, in terms of the response to thermal stimulation (hot-plate test) in protocol A. Cohen's d<0.2 pocket-size effect, 0.5 moderate result, and >0.8 large result
| Time (min) | Paracetamol (30 mg kg−one) | Paracetamol (100 mg kg−one) |
|---|---|---|
| thirty | 0.46 | three.05 |
| lx | 0.35 | iv.65 |
| ninety | 0.47 | 4.71 |
| 120 | 0.44 | 4.34 |
| 150 | 0.06 | 2.eight |
| 180 | 0.38 | 2.46 |
| 240 | 0.35 | 2.32 |
| Time (min) | Paracetamol (xxx mg kg−1) | Paracetamol (100 mg kg−1) |
|---|---|---|
| thirty | 0.46 | 3.05 |
| 60 | 0.35 | 4.65 |
| 90 | 0.47 | 4.71 |
| 120 | 0.44 | 4.34 |
| 150 | 0.06 | ii.8 |
| 180 | 0.38 | two.46 |
| 240 | 0.35 | two.32 |
Table ii.
Consequence sizes (Cohen'due south d) after thermal stimulation in protocol A. Effect sizes (Cohen's d) for paracetamol (30 mg kg−1) and paracetamol (100 mg kg−1) compared with saline, in terms of the response to thermal stimulation (hot-plate test) in protocol A. Cohen's d<0.two small upshot, 0.5 moderate effect, and >0.8 large outcome
| Time (min) | Paracetamol (30 mg kg−one) | Paracetamol (100 mg kg−1) |
|---|---|---|
| 30 | 0.46 | iii.05 |
| 60 | 0.35 | 4.65 |
| 90 | 0.47 | 4.71 |
| 120 | 0.44 | 4.34 |
| 150 | 0.06 | 2.viii |
| 180 | 0.38 | two.46 |
| 240 | 0.35 | 2.32 |
| Fourth dimension (min) | Paracetamol (30 mg kg−i) | Paracetamol (100 mg kg−1) |
|---|---|---|
| 30 | 0.46 | 3.05 |
| threescore | 0.35 | iv.65 |
| 90 | 0.47 | 4.71 |
| 120 | 0.44 | 4.34 |
| 150 | 0.06 | 2.8 |
| 180 | 0.38 | 2.46 |
| 240 | 0.35 | ii.32 |
Fig ane.
(a) Withdrawal response (chiliad) to von Frey filaments assessing mechanical hyperalgesia in the fractured hind paw in protocol A. (b) Thermal nociceptive withdrawal latency (s) assessing thermal hyperalgesia in the fractured hind paw in protocol A. (c) Subjective pain scale assessing pain in the fractured hind paw in protocol A. B, before fracture; T, treatment; P, paracetamol. The symbols represent the mean (confidence intervals). *P<0.05 when compared with Group saline; § P<0.05 when compared with Group paracetamol (30 mg kg−i); ¤ P<0.05 when compared with group paracetamol (50 mg kg−i); + P<0.05 when compared with T0.
Fig 1.
(a) Withdrawal response (g) to von Frey filaments assessing mechanical hyperalgesia in the fractured hind paw in protocol A. (b) Thermal nociceptive withdrawal latency (southward) assessing thermal hyperalgesia in the fractured hind hand in protocol A. (c) Subjective pain scale assessing pain in the fractured hind paw in protocol A. B, before fracture; T, handling; P, paracetamol. The symbols represent the mean (confidence intervals). *P<0.05 when compared with Group saline; § P<0.05 when compared with Group paracetamol (30 mg kg−one); ¤ P<0.05 when compared with group paracetamol (50 mg kg−one); + P<0.05 when compared with T0.
In protocol A, all mice receiving paracetamol at a dose of 30 mg kg−i or saline were given rescue analgesia.
Protocol B: effects of ondansetron on the paracetamol effect on fracture hurting
No difference in the measured parameters was observed in any of the groups later fracture and before treatment. Equally shown in Figure 2a and b, withdrawal responses and thermal responses increased similarly and transiently afterwards a single injection of paracetamol at 100 mg kg−1, regardless of whether ondansetron was administered or not. No change was seen in animals receiving only saline plus ondansetron or saline alone. The subjective hurting calibration (Fig. twoc) was similarly and transiently reduced afterward paracetamol 100 mg kg−one, with and without ondansetron.
Fig 2.
(a) Withdrawal response (g) to von Frey filaments assessing mechanical hyperalgesia in the fractured hind paw in protocol B. (b) Thermal nociceptive withdrawal latency (s) assessing thermal hyperalgesia in the fractured hind manus in protocol B. (c) Subjective pain scale in protocol B. B, earlier fracture; T, handling; P, paracetamol; S, saline; O, ondansetron. The symbols stand for the hateful (confidence intervals). *P<0.05 vs Grouping saline+ondansetron (two mg kg−1).
Fig ii.
(a) Withdrawal response (thou) to von Frey filaments assessing mechanical hyperalgesia in the fractured hind paw in protocol B. (b) Thermal nociceptive withdrawal latency (s) assessing thermal hyperalgesia in the fractured hind hand in protocol B. (c) Subjective pain scale in protocol B. B, before fracture; T, handling; P, paracetamol; S, saline; O, ondansetron. The symbols represent the mean (conviction intervals). *P<0.05 vs Grouping saline+ondansetron (ii mg kg−1).
In protocol B, all animals which did non receive paracetamol were given rescue analgesia.
Discussion
This is the first report showing that an acute assistants of paracetamol exhibits an antinociceptive upshot in mice subjected to fracture pain. Moreover, we likewise observed no antagonistic interaction between paracetamol and ondansetron on antinociception. Paracetamol is ofttimes used in the clinical do to care for bone pain. 7,8 It appears to be efficient in different models of pain in mice, xv,29–32 but to appointment, its effect in a post-fracture pain model in mice was not known. Indeed, paracetamol efficiency is surgical procedure-dependent. 33,34 The nowadays study underscores the involvement of paracetamol in pain direction afterward bone fracture, even if its effects seem lower than those of morphine or ketoprophen. 4 Nonetheless, in clinical practice, it is rarely used alone to treat bone hurting. 34 It was necessary to acquit out this study in mice first, before cess of ondansetron/paracetamol interactions in patients. A human study can now be started in the calorie-free of our results in mice.
The mechanism of action of paracetamol is notwithstanding not clearly understood. Unlike morphine, for example, paracetamol has no known endogenous high-affinity binding sites. xiii,xiv Paracetamol is mostly considered to be a weak inhibitor of the synthesis of prostaglandins. 10 Modulation of the serotoninergic system has also been suggested on the basis of biochemical and behavioural studies supporting an indirect serotoninergic result. Paracetamol may stimulate the activity of descending serotoninergic pathways that inhibit nociceptive betoken transmission in the spinal cord. 13,xiv This is the reason why the interaction between paracetamol and 5-HT antagonists has been frequently assessed in animals 14,15,35 and in humans. 17 It has been shown in human that both tropisetron and granisetron completely cake the analgesic event of paracetamol. 17 These authors suggested that the outcome of v-HT antagonists results from a pharmacodynamic interaction, implying that the central serotoninergic system might be involved in the mechanism of action of paracetamol. 17 Paracetamol allows endogenous serotonin to exert its antinociceptive effect. Tropisetron is more strong than granisetron as the latter is antinociceptive only at high doses. 14,36 Yet, we but found one report describing an interaction between ondansetron and paracetamol, where it was reported that paracetamol antinociception was blocked by ondansetron in the formalin exam. 35 Nevertheless, this is yet far removed from clinical perioperative hurting. In our written report, no change in the nociceptive outcome of paracetamol was seen when ondansetron was co-administered. Our pain model may involve several mechanisms such as peripheral tissue injury and inflammation, where paracetamol is effective, whereas ondansetron possibly only inhibits paracetamol effects centrally. However, fifty-fifty if the analgesic effect of paracetamol is central and at least partially involves activation of descending serotoninergic pathways, other sites of activity are involved such as the inhibition of prostaglandin synthesis 37 or the indirect activation of CB1 receptors. 11,12,16 Moreover, although the involvement of the serotoninergic system in the analgesic effect of paracetamol has been demonstrated, the detailed machinery by which serotonin acts, together with the exact nature of the receptor subtypes involved, has non all the same been elucidated. 38 The lack of the antagonistic upshot of ondansetron on the antinociception exerted past paracetamol has already been demonstrated using a rat model of pain [paw pressure test (Randall and Selitto) and hot-plate test]. 38,39 Sandrini and colleagues 38 showed that 5-HT1B, but non v-HT3, receptors are involved in the antinociceptive effect of paracetamol. Libert and colleagues 39 demonstrated that, unlike tropisetron, other v-HT3 receptor antagonists, such as ondansetron and granisetron injected intrathecally, were unable to opposite the antinociceptive effect of paracetamol. The serotoninergic arrangement implicated in the analgesia induced by paracetamol may therefore involve only specific serotonin receptors (5-HT1B) but not all (e.g. v-HT3), suggesting that ondansetron could be associated with paracetamol in clinical practice. Moreover, in normal circumstances, ondansetron is actively pumped out of the fundamental nervous system and other protein-1 p-glycoprotein-expressing tissues (run into below). forty Lastly, another caption for the lack of antagonistic consequence of ondansetron on the antinociception exerted by paracetamol could be that the analgesic effect of paracetamol is mainly due to the indirect activation of cannabinoid CB1 receptors every bit recently described. 11,12,16
Regarding ondansetron, we are non aware of any studies in the literature showing that this drug exerts antihyperalgesic effects in wild-type mice. Withal, information technology has been shown to exist anti-allodynic in rats 41 and to reduce nociception in patients with neuropathic pain after a single i.v. injection. 42 Nonetheless, in our study, nosotros plant no analgesic event later ondansetron administration alone in os fracture pain. Directly (intrathecal) application of ondansetron can remove tonic inhibitory tone mediated past 5-HT3 receptors and increase pain sensitivity; but systemic treatment of an animate being with intact multidrug resistance protein-1 protein does not cause this phenotype, near likely considering of insufficient central nervous system levels. 40 A possible limit of our paper could be that a central administration has not been tested and thus the newspaper is based on negative findings. However, we wished to mimic the clinical use of drugs that are never administered intrathecally. Lastly, this could also be explained because this is a different model of pain. Indeed, it has already been shown that antiemetics induce antinociception in the presence of chemic but not thermal stimuli, so not in all types of stimulus. 43
In summary, in this model, the pain threshold levels of mice given paracetamol solitary or with ondansetron appear to be like. Our results signal that ondansetron does not decrease the analgesic effectiveness of paracetamol on post-fracture pain in mice. Because ondansetron is oft used concomitantly with paracetamol after functioning in patients with bone pain, the results of our experimental study need to be evaluated in clinical practice with ondansetron as well as with ramosetron, the new selective 5-HT3 receptor antagonist. 44
Conflict of interest
None declared.
Funding
Support was provided solely from institutional and department sources.
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