Ondansetron vs Placebo vs Metoclopramide: Normal saline as an antiemetic?

This week we review an article comparing ondasetron, metoclopramide and placebo (normal saline).

Title: Antiemetic use for nausea and vomiting in adult emergency department patients: randomized controlled trial comparing ondansetron, metoclopramide, and placebo. PMID: 24818542

Background

Why is this paper important?

Nausea and/or vomiting are common emergency department (ED) presentations. While investigating underlying cause and establishing a diagnosis are important, so too is the goal of relieving the patient’s symptoms. This paper evaluates two commonly prescribed anti-emetic medications and placebo in a head-to-head comparison for the treatment of ED patients with nausea and/or vomiting.

Catching Up

The success of pharmacologic anti-emetic strategies in oncology and post-operative patients (1, 2) was extrapolated to support use in patients with un-differentiated nausea and vomiting in the ED. Four studies (3, 4, 5, 6) have shown success of metoclopramide and/or ondansetron in reducing the severity of nausea in the ED, but the only two placebo controlled studies showed no benefit of these medications over placebo (3, 4). Severity of nausea and vomiting is frequently measured using a visual analogue scale (VAS) and a minimally significant change has previously been defined as 15mm (7). This topic was previously covered by Ryan Radecki in a post “Nausea? We’ve got placebo for that” on EM Literature of Note.

The Study: Ondansetron vs Placebo vs Metoclopramide

Bottom Line

IV ondansetron and metoclopramide are no better than placebo at improving patient perceptions of nausea and vomiting along a visual analogue scale but all three provide a clinically significant improvement in symptoms.

The PICO Question

Population: Adult patients with nausea and vomiting during ED care for which the physician prescribed IV anti emetics.

Exclusions: hemodynamic instability, critical intervention needed, pregnancy or lactation, Parkinson’s disease, restless leg syndrome, use of antemtic in last 8 hours, previous IV fluids during ED stay, N/V related to vertigo/chemo/radiotherapy, previous allergy to a study medication

Intervention:

Metoclopramide 20mg IV (10mg/2ml x 2-2ml syringes)
Ondansetron 4mg IV (4mg/2ml x 1-2ml syringe + 0.9% saline x 1-2ml syringe )

Control:

0.9% Saline 4ml (0.9% saline x 2-2ml syringes)

Outcomes:

Primary: mean change in severity rating on the VAS 30 minutes after administration of study drug
Secondary:
- Median change in severity on the numeric rating scale
- Adjectival description of change
- Change in number of vomiting episodes
- Need for rescue medication
- Patient satisfaction
- Adverse Events

Results

Of 744 patients screened, 385 were eligible for enrollment (see exclusion criteria above) and 270 underwent randomization. Data on 258 patients (96%) was available for analysis. The results after 30 minutes were:

Less need for rescue medication in the metoclopramide group (18%) compared to ondansetron (35%) and placebo (36%). No statistically significant differences in the other secondary outcomes.
Nine adverse events were reported (3.5%) with six were in the metoclopramide group. Of those, two had akathisia, two had restlessness, one had muscle twitching, and one was diaphoretic. There were also two minor adverse events with ondansetron and one with placebo.

Appraisal

Internal Validity

This study met most of the criteria for high internal validity:

Randomisation was centralized and computer generated.
Treatment groups were similar at baseline on important factors such as gender, age, clinical cause, number of vomiting episodes and initial VAS score.
Patients, care-givers and data collectors were blinded to the intervention through rather elaborate measures to conceal delivered medications. In this case, blinding was particularly important because all other factors of treatment were not perfectly controlled. Physicians were free to implement treatments other than antiemetics at their discretion. We have no data on whether opioids/steroids/other medications were given differently to each group. Since there is no guarantee in the protocol that groups remained similar throughout ED stay, we are left to hope that proper blinding prevented against any systematic confounding bias towards or against a specific treatment.
Follow-up was near complete (96%). The 4% lost to follow-up were excluded but the remaining were included analyzed using the intention-to-treat principle. Ideally it would have been nice to see a “best and worse” case scenario analysis with the missing results, but it is still unlikely that this small missing cohort would change the conclusion.
The study endpoint was symptoms at 30 minutes, however, nausea often comes in waves rather than being a persistent phenomenon. As such, it would have been helpful to see comparison at a number of different evaluation time points (ie. 60 minutes, 120 minutes) to account for more realistic symptomatology and provide information that may be relevant when considering patient discharge.

External Validity

After confirming that a study internally valid it is important to think about whether or not the results are generalizable. This study is generalizable with a few considerations to keep in mind when applying to your patients.

First, the exclusion criteria eliminate (with good reason) a significant number of patients with nausea and vomiting. Before you think about applying the results of this study by skipping on IV anti-emetics make sure that the patient does not meet one of these exclusion criteria.
Second, the dosing of medications must also be considered. The recommended dose of ondansetron is 0.15mg/kg so it could be argued that patients were actually underdosed in this trial by receiving 4mg. Conversely, metoclopramide is most often dosed at 10mg (rather than 20mg) so the increased number of side effects may have been attributable to that.
Unfortunately this trial did not include anti-emetics delivered PO, IM or SL. We often administer medications this way to avoid an IV. We can’t extrapolate the results from this study for those alternate antiemetic strategies.

Implications

So What?

Is normal saline the new ondansetron? This study demonstrates that there was no difference between IV anti-emetics (ondansetron and metoclopromide) and an IV placebo of 0.9% saline in the reduction of undifferentiated nausea &/or vomiting in a convenience sample of ED patients. Given the possible adverse effects and costs associated with antiemetics, should we re-evaluate their role in this patient population? Or is this another study that will not be replicated?

The not so boring question

If it does turn out that ondansetron is no better than placebo,should doctors be able to prescribe a placebo medication? Is it unethical if it works? Why? Why not? What do you think the results would have been for a fourth group with no intervention? Or perhaps the 4ml of 0.9% saline is not actually a placebo. After all, we know normal saline isn’t so normal after all.

Please comment below.

This post was reviewed by Dr. Andrew Petrosoniak (@petrosoniak).
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References

1. Carlisle J., & Stevenson C. (2006). Drugs for preventing post operative nausea and vomiting. Cochrane Anesthesia Group. Accessed online: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD004125.pub2/abstract;jsessionid=55EBBAA09E9A3009F704B0C0A22FC995.f01t04

2. Billio A., Morello E., & Clarke M. (2009). Serotonin receptor antagonists for highly emaetogenic chemotherapy in adults. Cochrane Pain, Palliative and Supportive Care Group. Accesed online: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006272.pub3/abstract

3. Braude, D., Soliz, T., Crandall, C., Hendey, G., Andrews, J., & Weichenthal, L. (2006). Antiemetics in the ED: a randomized controlled trial comparing 3 common agents. The American journal of emergency medicine, 24(2), 177-182.

4. Barrett, T. W., DiPersio, D. M., Jenkins, C. A., Jack, M., McCoin, N. S., Storrow, A. B., … & Slovis, C. M. (2011). A randomized, placebo-controlled trial of ondansetron, metoclopramide, and promethazine in adults. The American journal of emergency medicine, 29(3), 247-255.

5. Braude, D., & Crandall, C. (2008). Ondansetron versus Promethazine to Treat Acute Undifferentiated Nausea in the Emergency Department: A Randomized, Double‐blind, Noninferiority Trial. Academic Emergency Medicine, 15(3), 209-215.

6. Chae, J., McD Taylor, D., & Frauman, A. G. (2011). Tropisetron versus metoclopramide for the treatment of nausea and vomiting in the emergency department: A randomized, double‐blinded, clinical trial. Emergency Medicine Australasia, 23(5), 554-561.
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