Nauseating Evidence 1/3 (Ondansetron)
I would imagine ondansetron to be one of the most commonly administered medications in emergency medicine. For whatever reason, it has never much interested me to look into what the evidence says regarding best practice in antiemetic choice and dose until a few days ago.
At my shop we carry both metoclopramide and ondansetron. The typical progression I see these administered is to start with ondansetron and if nausea doesn't improve, switch therapies to metoclopramide. However, if someone were to ask me why - I'm not sure I would have a satisfying answer. The truth is, there is limited evidence when it comes to antiemetic therapy in the emergency setting. The majority of the studies examining antiemetic therapy, are based on cancer patients being treated with chemotherapy, and prevention of post operative nausea and vomiting (PONV).
I thought I would start a small series on examining the pathophysiology and evidence behind why we get nauseous and best practices in symptom relief. This blog will be open edited. Meaning I will actively edit as you comment on additional thoughts, ideas, and studies. This will allow us to all be able to reference back to this content in the future, and serve as a hub for all research and data that we come across.
Let's start off by looking at the pathophysiology.
There is this little guy named the Medulla Oblongata located at the distal end of the brainstem.
Within the Medulla Oblongata (would make a great name for a roller coaster) is the vomiting center. Muscurinic receptors surround the vomiting center and will cause a vomiting reflex when stimulated. Right next to the vomiting center is the Chemoreceptor Trigger Zone (CTZ). The two receptors on the CTZ include dopamine and serotonin (5-HT). When you stimulate the CTZ, it will then stimulate the vomiting center... and then you get to see what the circus peanuts taste like for a second time.
The CTZ sits outside the blood brain barrier and is a real sensitive little $%^% to certain circulating chemicals. One of these being cytotoxins used in chemotherapy.
Motion sickness originates in the labyrinth within the inner ear. The vestibulocochlear nerve will stimulate the vestibular nuclei's histamine and muscurinic receptors. This in turn will stimulate the CTZ and is passed along to the vomiting center.
Farts, Fear, and Pain
When the higher brain centers are over-stimulated (smells, emotions, disturbing sights, or pain), they can trigger the muscurinic receptors of the vomiting center. This direct sensory track makes it nearly impossible to pharmaceutically prevent nausea when you open up that old maggot filled lunch box in the back of your Prius you forgot about last year..
The stomach has gastric pits which are lined enterochromaffin cells (its like muffin, but with a Jersey accent). These cells when irritated will secrete histamine and serotonin. The vagus nerve will pass long these messages to the vomiting center, and TA-DA!
So basically all causes of vomiting come back to the same place of the brain.
There are multiple types of antiemetic agents in the world. It would not be helpful for us to cover each one, so we will focus on the agents most popular in the EMS setting. In part one of this series we will look at ondansetron.
Serotonin 5-HT3 receptor antagonists
Cheap, safe, and usually effective makes this drug very popular. We commonly see this given in aliquots of 4 mg's. You can probably feel safe knowing that there has been no statistical difference noted in the dosing between 4 mg's and 8 mg's. "Yah, but one time.... blah blah blah." As you will see further down, the placebo of 0.9% saline improved symptoms in some patients. Self reporting can be very interesting.
This systematic review looked at dosing regimens of ondansetron for prevention of post operative nausea and vomiting within the first six hours of the procedure. I realize the limitations to this study and understand that we are discussing prevention of nausea as opposed to treating active nausea, which is probably more applicable to our setting in emergency and critical care medicine. The issue is as mentioned earlier, there is not much high quality literature looking at antiemetics in emergency medicine.
I did come across an emergency department study in which 270 patients were randomized to either ondansetron, metoclopramide, or placebo. The patients were asked to rate their nausea using a visual analog scale (VAS) upon enrollment and at the 30 minute mark after receiving the closed label intervention.
Interesting enough, there was no statistical difference between the three groups. I believe that a self reporting measurement is very difficult to avoid biases such as a Hawthorne Effect. Discussing these cases amongst peers has brought up many good points, such as:
1. How many of these patients would have a reduction in VAS score if no intervention was performed.
2. Did an episode of vomiting relieve their symptoms (it has for me).
Secondary endpoints were even more interesting. The placebo actually had a higher percentage of satisfied patients than ondansetron. Metoclopramide out performed both, however the difference was not statistically significant.
I noticed that the majority of the diagnostic group was opioid induced. The reason opioids cause nausea is very similar to the reason chemotherapy causes nausea. The metabolites and active circulating opioid can cause a direct stimulation to the CTZ sitting outside the blood brain barrier.
Do all patients who get ondansetron need to be placed on the monitor?
Unless your planning on giving a single 32 mg dose IV... No! The 32 mg dosing range was removed from the ondansetron label in 2012 by the FDA. People can get ondansetron OTC and aren't sent home with holter monitors. However, I would argue that all patients who are sick enough to be airlifted or call 911 should at least be placed on the monitor during transport. We can debate this in another blog :).
Does ondansetron work for motion sickness?
No. As mentioned earlier, motion sickness is mostly driven by histamine1. So the whole "let's give you some Zofran for the ride," probably has been more of a placebo effect. If you truly want to help with motion sickness, consider diphenhydramine. After all that is the main ingredient in Dramamine ;)
Does ondansetron only work if you give it before they puke?
1.Nausea/Vomiting can be caused by many factors but all comes back to the same place in the brain.
2.There is no proven benefit in giving 8mg of Ondansetron vs. 4mg.
3.With the doses we use..we probably overstate prolonged Q-T as a concern for Ondansetron.
4. Ondansetron is not the choice for motion sickness.