Is Ondansetron for Nausea and Vomiting Prophylaxis Necessary with Opioids?

prophylactic ondansetron with opioids example 4+4
Ondansetron is the most documented medication given in emergency departments (ED) 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 mg of 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 opioid.

Logic for giving ondansetron with opioid

This dual therapy seems to make initial sense because all opioids carry a FDA warning that nausea may occur [2]. So why not administer an antiemetic to prevent it? Opioids 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 opioid from exerting emetogenic properties on 5-HT3 receptors in the CTZ and prevent nausea and/or vomiting.

How common is nausea and vomiting associated with IV opioids?

Multiple studies illustrate that morphine-induced nausea and vomiting is low, ranging from 2.0–20.2% in ED patients [4-9]. When discussing with ED nurses, nausea and vomiting are anecdotally associated with how quickly the IV opioid 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 opioids?

Literature Review

StudyInterventionOutcomeConclusion
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 2 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)

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.

 Patients should receive antiemetic therapy only if experience N/V and not as a prophylactic agent with IV opioids.

Patients that received (morphine + placebo) 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 2,574 patients that received IV opioids and randomized 520 patients that developed N/V associated with IV opioids.

Group 1: placebo (n=94)

Group 2: ondansetron 8 mg (n=214)

Group 3: ondansetron 16 mg (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

The best practice seems to treat patients’ N/V after development in patients that receive IV opioids.

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 of the 3 trials concluded that there was no statistical significance in outcomes when adding prophylactic antiemetics with IV opioids. 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.

Prophylactic ondansetron practice

So why is ondansetron still commonly used to pre-treat patients that receive IV opioids in the ED?

The limited literature primarily focused on these anti-emetic agents: metoclopramide, promethazine, and ramosetron (5-HT3 antagonist). Literature related to specifically ondansetron is minimal.

Two randomized, placebo-controlled studies comparing ondansetron, metoclopramide, and saline in ED 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.

Some nerd (me!) put together a prospective multiple-site study (n=133) at 2 academic medical institutions where patients were administered IV opioids, with or without IV ondansetron [14]. Patients were observed for nausea and vomiting at baseline, 5 minutes, and 30 minutes after opioid administration, and then for a total of 2 hours. The results showed that 17.3% of patients developed nausea, with no significant difference in the rate of nausea, emesis, or the need for rescue antiemetics between the group receiving ondansetron and the group receiving opioids alone.

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. It also, not surprisingly, has side effects!

Take Home Point

  1. Concurrent treatment with anti-emetics (including ondansetron) is unnecessary, increases costs, and adds potential for adverse drug reactions.
  2. The next time the request for “4 + 4” comes through, consider holding off on the unnecessary ondansetron with your IV opioid order.
  3. You can use this isopropyl alchohol vapor inhalation trick of the trade for those 2-20% of patients that do develop nausea.

References

  1. National Hospital Ambulatory Medical Care Survey: 2011 Emergency Department Summary. Accessed 19 Dec 2024.
  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 opioid analgesia in the ED. Am J Emerg 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. Am J Emerg 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; 11(4): 240-243.
  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.
  12. Barrett TW, DiPersio DM, Jenkins CA, et al. A randomized, placebo-controlled trial of ondansetron, metoclopramide, and promethazine in adults. Am J Emerg Med. 2011 Mar;29(3):247-55.
  13. Egerton-Warburton D, Meek R, Mee MJ, et al. Antiemetic use for nausea and vomiting in adult emergency department patients: randomized controlled trial comparing ondansetron, metoclopramide, and placebo. Ann Emerg Med. 2014 Nov;64(5):526-532.
  14. Culver MA, Richards EC, Jarrell DH, et al. Use of Prophylactic Ondansetron With Intravenous Opioids in Emergency Department Patients: A Prospective Observational Pilot Study. J Emerg Med. 2017;53(5):629-634. PMID 28987314. DOI

SAEM Clinical Images Series: When it is Not Just a Knot

knot

A 12-year-old male with a history of hydrocephalus status post ventriculoperitoneal (VP) shunt placement presented with an abdominal “knot.” The patient’s mother noticed the knot two days ago, on the right anterolateral thorax, which has steadily been increasing in size. The patient had no known trauma to the area or had been bitten or stung by any insect. He has otherwise been complaining of a headache, generalized, without positional changes, improved with home acetaminophen, ice pack, and rest. There were otherwise no associated vision changes, nausea, vomiting, mental status changes, or fever.

Vitals: T-36.2°C; HR 74 bpm; BP 144/75 mm Hg; RR 20; O2 Sat 96% RA

General: Well-appearing teenager in NAD.

HEENT: NC/AT. PERRL approximately 2-3 mm bilaterally. EOMI.

Neck: Supple, no meningismus.

Chest Wall: Induration to the right anterolateral thorax 5 cm x 4 cm without erythema, fluctuance, or drainage, non-tender to palpation.

Neurological: Alert. No focal neurological deficit observed.

The cause of the knot is subcutaneous cerebrospinal fluid from a shunt malfunction. The ultrasound images show characteristic “cobblestoning,” indicating fluid in the subcutaneous tissue, around a linear hyperechoic object, the catheter of the VP shunt. On the plain film imaging, a disconnect was found between the thoracic and abdominal portions of the VP shunt. Up to 80% of patients with VP shunts will have experienced a shunt malfunction after 12 years, according to one study, with fractured tubing causing shunt failure in around 15% of all cases (1).

Nausea, vomiting, headache, irritability, or decreased mental status are common but nonspecific findings in shunt malfunction. Pediatric patients may present with other signs such as bulging fontanelles, increasing head circumference, or feeding and behavioral changes. An increase in the interval ventricular size can be seen in neuroimaging but can be absent in as many as 20% of patients (2). If there is a high degree of clinical suspicion for shunt malfunction, normal or unchanged neuroimaging should not preclude neurosurgical consultation.

Take-Home Points

  • In the United States, mechanical causes of VP shunt malfunction are the most common presentation, such as catheter obstruction, fracture along the clavicle or ribs, degradation of tubing, and migration of the distal catheter due to changes in height or weight.
  • Rarely, patients can develop an accumulation of CSF at the distal catheter of the VP shunt due to migration into the abdominal wall forming an abdominal pseudocyst.
  • In patients with VP shunts, abdominal complications should be considered as a sign of shunt malfunction.
  • Consider pertinent physical exam findings and POCUS to confirm the diagnosis of shunt malfunction at the distal catheter.

  • Sainte-Rose C, Piatt JH, Renier D, Pierre-Kahn A, Hirsch JF, Hoffman HJ, Humphreys RP, Hendrick EB. Mechanical complications in shunts. Pediatr Neurosurg. 1991-1992;17(1):2-9. doi: 10.1159/000120557. PMID: 1811706.

  • Reynolds RA, Ahluwalia R, Krishnan V, Kelly KA, Lee J, Waldrop RP, Guidry B, Hengartner AC, McCroskey J, Arynchyna A, Staulcup S, Chen H, Hankinson TC, Rocque BG, Shannon CN, Naftel R. Risk factors for unchanged ventricles during pediatric shunt malfunction. J Neurosurg Pediatr. 2021 Sep 24;28(6):703-709. doi: 10.3171/2021.6.PEDS2125. PMID: 34560626.

ACMT Toxicology Visual Pearl: Hiss-teria Averted

snake

What is the predominant clinical effect of envenomation by this snake?

  1. Acute hepatic failure leading to coagulopathy
  2. Direct cardiotoxicity leading to arrhythmias
  3. Profound neuromuscular paralysis
  4. Rapid onset of shock and multisystem organ failure

[Image courtesy of iStock. ID: 1311554579]

(more…)

SAEM Clinical Images Series: A Curious Case of Anisocoria

anisicoria

A 3-month-old male with no past medical history was brought to the emergency department for evaluation of newly asymmetric pupils. The infant appeared to be asymptomatic per parents, without any behavior changes or associated symptoms noted. The patient’s mother noticed her son’s left pupil was dilated and unresponsive to light the morning of presentation. The father had applied a prescription antiperspirant containing glycopyrronium to his axillae the previous evening but denied any known exposure to the infant.

Vitals: BP 85/66; HR 143; RR 42; SpO2 100%; T 98.3°F

Constitutional: No distress, well appearing.

HENT: Left pupil fixed and dilated to 7 mm in the light and the dark; right pupil 2 mm and reactive in the light, 5 mm in the dark. EOM intact bilaterally. No stigmata of trauma. Normal TMs bilaterally.

Neck: Normal range of motion.

Cardiovascular: Normal rate, regular rhythm and normal heart sounds.

Pulmonary: Breath sounds normal, no respiratory distress.

Abdominal: Soft, nontender, nondistended.

Neurological: Alert. Moving all 4 extremities spontaneously. Normal muscle tone. Normal suck and Moro reflexes.

Skin: Normal. No piloerection or sweating. No bruising or lesions.

No labs drawn. Head CT was obtained, which showed no acute intracranial pathology.

Ophthalmology consultation was sought, and an ophthalmologic exam demonstrated unremarkable slit lamp and fundal exams, with no afferent pupillary defect by reverse. The patient’s anisocoria was ultimately attributed to inadvertent glycopyrronium exposure from his father’s prescription antiperspirant, Qbrexza. The patient’s father later noted that he cradled the patient against his chest after applying the antiperspirant, and was not wearing a shirt at the time

Pilocarpine, a cholinergic antagonist that stimulates pupillary constriction, can be used to test mydriatic pupils. Pilocarpine drops will not reverse pharmacologically-induced anisocoria (1). Conversely, it will correct mydriasis caused by tonic pupil or third nerve palsy (2). In our patient’s case, pilocarpine administration did not result in pupillary constriction, supporting the diagnosis of drug-induced anisocoria.

Take-Home Points

  • Evaluation of acute anisocoria in the pediatric population can be challenging due to its wide range of potential etiologies including traumatic, neurologic, inflammatory, and pharmacologic causes. Though most commonly physiologic, anisocoria may represent a pediatric emergency due to the potential for underlying trauma or neurovascular compromise and thus a thorough neurologic exam and history is crucial (1, 20).

  • Inadvertent exposure to drugs such as glycopyrronium, a topical antiperspirant with anticholinergic properties, has been implicated in the pathogenesis of anisocoria in both adult and pediatric patients via inhibition of acetylcholine at the pupillary sphincter muscle (3-13). Other documented pharmacological causes of anisocoria include nebulized ipratropium bromide and scopolamine (14-19).

  • EM Clinicians should consider exposure-related anisocoria in the differential diagnosis of infant patients with acutely asymmetric pupils. In the absence of concerning neurologic findings, identification of potential drug exposures may help to minimize unnecessary testing and radiation exposure, sparing certain patients from time-intensive and costly interventions.

  • 1. Falardeau J. Anisocoria. Int Ophthalmol Clin. 2019;59(3):125-39.

  • 2. Payne WN, Blair K, Barrett MJ. Anisocoria. StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2023, StatPearls Publishing LLC.; 2023.

  • 3. Pecha JD, Yen KG, Moisiuc A, et al. Anisocoria secondary to antiperspirant wipes in a pediatric population: a case series. J aapos. 2022;26(1):42-3.

  • 4. Chabicovsky M, Winkler S, Soeberdt M, et al. Pharmacology, toxicology and clinical safety of glycopyrrolate. Toxicol Appl Pharmacol. 2019;370:154-69.

  • 5. Coleman MJ, Tomsak RL. A 15-year-old girl with variable anisocoria. Digit J Ophthalmol. 2014;20(1):13-4.

  • 6. Micieli R, Micieli JA. Dilated Pupil in a Patient With Hyperhidrosis. JAMA. 2019;322(3):264-5.

  • 7. Radotra A, Baneke A, Paul B. Mydriasis secondary to use of glycopyrrolate cream. Br J Hosp Med (Lond). 2019;80(12):736.

  • 8. Pashaei-Marandi A, Assam JH, Arnold A, et al. Reversible anisocoria due to inadvertent ocular exposure to topical anticholinergic treatment for primary axillary hyperhidrosis. Can J Ophthalmol. 2019;54(6):e300-e2.

  • 9. Siscos SM, Figenshau K, Rajpara A. Use of gloves when applying topical glycopyrronium for treatment of primary axillary hyperhidrosis. J Am Acad Dermatol. 2020;83(4):e275.

  • 10. Kaufman AR, Gulati S, Curnyn KM. Pharmacologic anisocoria secondary to topical glycopyrronium for axillary hyperhidrosis: an emerging clinical presentation. Can J Ophthalmol. 2020;55(5):464.

  • 11. Al-Holou SN, Lipsky SN, Wasserman BN. Don’t Sweat the Blown Pupil: Anisocoria in Patients Using Qbrexza. Ophthalmology. 2020;127(10):1381.

  • 12. Kaufman AR, Gulati S, Pula JH, et al. Pharmacologic Mydriasis Secondary to Topical Glycopyrronium Tosylate Cloths: Clinical Characterization From a Multicenter Analysis. J Neuroophthalmol. 2022;42(4):530-4.

  • 13. Sandhu M, Eisenstein K. Mydriasis and anisocoria in a pediatric hyperhidrosis patient with interesting findings in the family cat. Pediatr Dermatol. 2023;40(1):210-1.

  • 14. Derinoz-Guleryuz O, Fidanci İ, Men-Atmaca Y. Nebulized Ipratropium Bromide-induced Anisocoria: Why Is Anisocoria Observed?. Iran J Allergy Asthma Immunol. 2021;20(1):125-128.

  • 15. Kokulu K, Öner H, Özen C, Eroğlu SE, Altunok İ, Akça HŞ. Pharmacologic anisocoria due to nebulized ipratropium bromide: A diagnostic challenge. Am J Emerg Med. 2019;37(6):1217.e3-1217.e4.

  • 16. Pejic R, Klaric B. Transient anisocoria in a patient treated with nebulized ipratropium bromide. Am J Ophthalmol Case Rep. 2017;7:11-13. Published 2017 Apr 12.

  • 17. Thiele EA, Riviello JJ. Scopolamine patchinduced unilateral mydriasis. Pediatrics. 1995;96(3 Pt 1):525.

  • 18. Rodor F, Cottin C, Jouglard J. Transdermal scopolamine and mydriasis. Therapie. 1989;44(6):447-448.

  • 19. Rubin MM, Sadoff RS, Cozzi GM. Unilateral mydriasis caused by transdermal scopolamine. Oral Surg Oral Med Oral Pathol. 1990;70(5):569-570.

  • 20. Gross JR, McClelland CM, Lee MS. An approach to anisocoria. Curr Opin Ophthalmol. 2016;27(6):486-492.

SAEM Clinical Images Series: Pediatric Forehead Swelling

puffy

A 12-year-old male with a history of autism spectrum disorder and chronic sinusitis presented for forehead swelling. His mother reported that she noticed progressive forehead swelling for about one month. She had followed up with the patient’s pediatrician and ENT and was given oral cephalexin and fluticasone nasal spray which did not make any changes in his symptoms. The patient denied any fevers or headaches.

Vitals: Temp 97.4°F; BP 100/58; HR 90; RR 18; SpO2 98%.

General: Patient is comfortable appearing, in no acute distress.

ENT: 3×3 cm area of fluctuance centrally located over the forehead with no drainage or surrounding erythema that is minimally tender to palpation. No nasal drainage.

Neuro: Intact with no deficits.

WBC: 14.35

ESR: 23 mm/h

CRP: 0.74 mg/dL

CT demonstrates osteomyelitis of the frontal bone with osseous destruction with a 5 cm bifrontal complex loculated anterior epidural abscess as well as a 3 cm midline frontal subgaleal extracranial scalp abscess.

Findings are consistent with Pott’s Puffy Tumor.

Take-Home Points

  • Pott’s puffy tumor is a rare, life-threatening complication of frontal sinusitis characterized by osteomyelitis of the frontal bone with associated subperiosteal abscess causing swelling and edema over the forehead and scalp. It can be found in all age groups but is most common in adolescents.
  • MRI brain with and without contrast is the preferred imaging modality due to increased sensitivity to detect early intracranial and osseous abnormalities.
  • Treatment is typically surgical intervention with at least 6 weeks of intravenous antibiotics. The infection is typically polymicrobial warranting gram-positive, gram-negative, and anaerobic antibiotic coverage.

  • Sharma P, Sharma S, Gupta N, Kochar P, Kumar Y. Pott puffy tumor. Proc (Bayl Univ Med Cent). 2017 Apr;30(2):179-181. doi: 10.1080/08998280.2017.11929575. PMID: 28405074; PMCID: PMC5349820.
  • Masterson L, Leong P. Pott’s puffy tumour: a forgotten complication of frontal sinus disease. Oral Maxillofac Surg. 2009 Jun;13(2):115-7. doi: 10.1007/s10006-009-0155-7. PMID: 19352731.

SAEM Clinical Images Series: Rectal Bulge

rectal bulge

A 13-month-old, full-term male presented due to intermittent emesis over a 3-week period. He and his parents had COVID one week prior to presentation. He had multiple episodes of non-bloody, non-bilious vomit the day before and the day of presentation. Parents noted he had been listless and unable to tolerate food. The mother was also concerned that he was straining to have bowel movements and that a mass was coming out of his bottom on the ride to the hospital. Parents reported decreased activity, decreased appetite, and decreased urine output. He was born via cesarean section due to breech presentation but had an otherwise uncomplicated prenatal history.

Constitutional: Fatigued.

Gastrointestinal: Diffuse abdominal tenderness. Reducible rectal bulge.

Skin: Pale.

Anion Gap: 19

COVID-19: Positive

WBC: 11.9

Limited Abdominal Ultrasound: A large intussusception is noted, which appears to extend at least to the descending/sigmoid colon.

XR Abdomen: Few prominent, featureless bowel loops with air-fluid levels. No gastric distention.

Air or hydrostatic enemas have a 70-85% success rate in current literature. These are often done under either fluoroscopic or ultrasound guidance. A delayed repeat enema can be done in cases where the initial enema resolved some of the intussusception. If the initial measures are unsuccessful, the patient is unstable, or the patient is exhibiting signs of peritonitis or bowel perforation, surgical management is the next step. This can either be done laparoscopically or open. In this patient’s case, an air enema was attempted but he ultimately required surgery. The surgery was laparoscopic, and he was discharged the same day.

Take-Home Points

  • Consider intussusception in any child with a URI (including COVID-19) and a rectal bulge.
  • Although this patient had a formal ultrasound, POCUS can be a useful tool in the ED to identify and expedite intussusception treatment. The classic “bullseye sign” was seen on this patient’s ultrasound.

  • Mandeville K, Chien M, Willyerd FA, Mandell G, Hostetler MA, Bulloch B. Intussusception: clinical presentations and imaging characteristics. Pediatr Emerg Care. 2012 Sep;28(9):842-4. doi: 10.1097/PEC.0b013e318267a75e. PMID: 22929138.
  • Siafakas C, Vottler TP, Andersen JM. Rectal prolapse in pediatrics. Clin Pediatr (Phila). 1999 Feb;38(2):63-72. doi: 10.1177/000992289903800201. PMID: 10047938.

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