Wednesday, November 25, 2015

4 & 4 Por Favor: Prophylactic Ondansetron + Intravenous Opiate - Is It Necessary?

Ondansetron is the most documented medication given in emergency departments throughout the United States.1 We have all heard someone ask, “Can I get an order for 4 and 4 for this patient?” in reference to 4 milligram (mg) of intravenous (IV) morphine and 4 mg of IV ondansetron. It has become common practice in many institutions to provide a prophylactic antiemetic prior to administering an IV opiate. All opiates carry a FDA warning that nausea may occur, 2 so why not administer an antiemetic to prevent it? Opiates cause nausea and vomiting due to its interaction on the chemoreceptor trigger zone (CTZ), increased vestibular sensitivity, and hindered gastric emptying.3 The logic is to provide these patients with a 5-HT3 antagonist (i.e. ondansetron) to inhibit the opiate from exerting emetogenic properties on 5-HT3 receptors in the CTZ and prevent nausea and/or vomiting.
Of note, ondansetron is not FDA approved for the treatment or prophylaxis of acute nausea and/or vomiting (N/V) outside of chemotherapy, radiation, and postoperative use.

But how common is nausea and vomiting associated with IV opiates? Multiple studies illustrate that morphine-induced N/V is low, ranging from 2.0 – 20.2% in emergency department (ED) patients.4-9 When discussing with nurses in the ED, N/V is anecdotally associated with how quickly the IV opiate is administered and generally occurs within 5 minutes of administration. So we should give IV ondansetron to prevent this, right? A common misconception with IV ondansetron is its onset of action. In fact, it can take anywhere between 27-34 minutes before there is a 50% decrease in nausea severity following the administration of ondansetron.10,11 This begs the question, does it really make sense to provide prophylactic antiemetics with IV opiates?

We review the literature below:
Bradshaw et al.5
RCT- double blinded
Performed in United Kingdom

IV Morphine + placebo (n = 136)
IV Morphine + metoclopramide 10 mg (n = 123)
N/V between the two groups was not statistically significant (p = 0.3).
Overall incidence of N/V was low in both treatment groups (3.7% in placebo and 1.6% metoclopramide)
Determined pre-treating patients with metoclopramide was not necessary. 
Overall N/V associated with IV morphine was very low and recommended using antiemetics for patients who develop N/V
Bhowmik et al. 8
RCT- double blinded
Performed in India

IV Morphine + placebo (n = 53)
IV Morphine + promethazine (n = 54)
IV Morphine + ramosetron     (n = 54)
IV Morphine + metoclopramide (n=54)
Overall incidence of N/V was low in all treatment groups (9.4% ramosetron, 18.5% metoclopramide, 10.2% in promethazine and 6.2% in placebo)
Rate of N/V was not statistically significant between any of the groups.
Incidence of N/V in patients was low in all treatment groups. Trial concluded that patients should receive antiemetic therapy only if experience N/V and not as a prophylactic agent with IV opiates.  
Per results patients that received placebo + morphine had less N/V compared to other treatment groups; however, NOT statistically significant. 
Sussan et al 9
Randomized Double masked multicenter trial
Performed in 9 countries
Investigated 2574 patients that received IV opiates and randomized 520 patients that developed N/V associated with IV opiates.
Group 1: placebo               (n = 94)
Group 2: ondansetron 8 mg (n = 214)
Group 3: ondansetron 16mg (n = 211)
Resolution of N/V was statistically more significant (p < 0.001) when comparing ondansetron therapy with placebo.                                                                     
Group 1:  45.7% N/V resolved
Group 2:  62.3% N/V resolved
Group 3:  68.7% N/V resolved

Concluded the best practice would be to treat patients’ N/V after development in patients that receive IV opiates.
Trial determined the prevalence of N/V is minimal and exposing patients to medication they do not need puts them at risk for additional adverse drug reactions. 

Each trial concluded that there was no statistical significance in outcomes when adding prophylactic antiemetics with IV opiates. After these institutions analyzed their findings, the investigators at their respective institutions made it common practice for patients to only receive antiemetics after a patient developed nausea or vomiting. So why is ondansetron still commonly used to pre-treat patients that receive IV opiates in the ED? The current available literature examines metoclopramide, promethazine, and ramosetron (5-HT3 antagonist), but literature related to prophylactic ondansetron is lacking. Even the literature to support the use of ondansetron for N/V in the emergency department could be challenged. Two randomized, placebo-controlled studies comparing ondansetron, metoclopramide, and saline in emergency department patients complaining of nausea showed no clinically important difference in the reduction of nausea between treatments and placebo.12,13  Yet in the ED, we still order ondansetron more than any other medication.
Currently, the prophylactic use of IV ondansetron with IV opiates is unproven. Previous literature has shown us that prophylactic antiemetic therapy with IV opiates is unnecessary, increases costs, and adds potential for adverse drug reactions. Our institution is currently undergoing a prospective study designed to determine the prophylactic utility of ondansetron with IV opiates in the ED. Perhaps, in the near future, there will be evidence to either cease the use of prophylactic IV ondansetron or evidence that validates its use.
Emily Richards, PharmD (@EmilyPharmD)
Pharmacy Practice Resident (PGY1)
Banner - University Medical Center Phoenix
Phoenix, Arizona

Mark Culver, PharmD, BCPS (@EMdruggist)
Emergency Medicine Pharmacist
Banner - University Medical Center Phoenix
Phoenix, Arizona

Peer reviewed by Craig Cocchio, PharmD, BCPS (@iEMPharmD) and Nadia Awad, PharmD, BCPS (@Nadia_EMPharmD)
1.National Hospital Ambulatory Medical Care Survey: 2011 Emergency Department Summary. Available at Accessed 22 Nov 2015.
2. Red Book: pharmacy’s fundamental reference. Montvale, NJ: Thompson Healthcare Inc.; 2010
3. Smith H, Smith J, Seidner P. Opioid-induced nausea and vomiting. Annals of Palliative Medicine 2012;1(2):121-129
4. Paoloni R, Talbot-Stern J. Low incidence of nausea and vomiting with intravenous opiate analgesia in the ED. Amr J Emer Med 2002;20:604-608
5. Bradshaw M, A Sen. Use of prophylactic antiemetic with morphine in acute pain: randomized controlled trial. Emerg med J 2006; 23:210-212
6. Talbot-Stern J, Paoloni R. Prophylactic metoclopramide is unnecessary with intravenous analgesia in the ED. Amr J Emr Med 2000;18(6):653-7
7. Lambie B, Chambers J, Herbison P. The role of prophylactic anti-emetic therapy in emergency department patients receiving intravenous morphine for musculoskeletal trauma. Emer Med 1990; 
8. Bhowmik A, Dasgupta I, Barua S, et al. Evaluation of the need of prophylactic antiemetic with injection morphine in treating acute musculoskeletal pain in the Indian population. IJAR 2014;2:53-58
9. Sussan G, Shurman J, Creed M, et al. Intravenous ondansetron for the control of opioid-induced nausea and vomiting. Clinical Therapeutic. 1999; 21:1216-1227
10. Cotton J, Rowell L, Hood R, et al. A comparative analysis of isopropyl alcohol and ondansetron in the treatment of postoperative nausea and vomiting from the hospital setting to the home. AANA J. 2007; 75(1):21-6
11. Winston A, Rinehart R, Riley G, et al. Comparison of inhaled isopropyl alcohol and intravenous ondansetron for treatment of postoperative nausea. AANA J. 2003; 71(2):127-32