Nausea is a commonly encountered symptom in healthcare, one that is difficult for any patient. Causes may be as simple as the body's defense against an ingested toxin, to a complex association set of signals activated my motion, medications, anesthesia, position, stress, pregnancy, psychiatric disorder, and/or fear. Multiple or single neurohumoral pathways may be involved. Indications for the treatment of symptoms require astute evaluation by the treating provider. Therapy to treat chronic nausea stemming from chemotherapeutic agents and doses will vary from the treatment of postoperative nausea (a relatively common side effect of general anesthesia) and vomiting. Acute onset nausea/emesis is more likely related to a defined insult or problem and may require a minimal or short duration of treatment. Chronic nausea is more likely to be multi-factorial, necessitate more prolonged therapy, and might be more challenging to treat. No rule of thumb can be applied when treating nausea. Empiric treatment of nausea in the absence of a clear diagnosis is typically well-tolerated and may result in a significant benefit to the patient. Practitioners should be wary of overlooking surgical emergencies such as small bowel obstructions, perforated viscus, and acute appendicitis, among others. Pregnancy merits consideration in women of child-bearing age.
There are multiple pathways and causes of nausea and vomiting. Specific areas in the brain include the area postrema in the floor of the fourth ventricle, the nucleus tractus solitarius in the medulla, and various motor nuclei that make up a central pattern generator. A complex interaction of vagal afferents and efferents to the cortex, hypothalamus, and limbic regions also play a role in how the brain perceives nausea. Multiple chemoreceptors are involved in these pathways and include the muscarinic M1, dopaminergic D2, serotonin 5-HT3, neurokinin-1, and histamine H1. As such, most of the anti-emetics can broadly fit into the following classes based on the mechanism of action:
The setting and clinical presentation will dictate the type of medication prescribed, the dosing, and the route of administration. A careful review of the symptoms and past medical history, allergies, and prior exposure to/uses of these medications will lead to a better outcome for the patient.
Serotonin-receptor antagonists: Ondansetron, granisetron, dolasetron, palonosetron. The mechanism of action is to block serotonin from interacting with the 5-HT3 receptor. Of these, ondansetron and granisetron are the most frequently encountered. Intravenous (IV) and oral (PO) preparations are available. Side effects include headache, dizziness, and constipation. The most worrisome side effect is QTc-prolongation, and clinicians should avoid these medications in patients with known prolonged QTc.
Glucocorticoids: The mechanism of action is not clearly understood. Possible mechanisms are changes in the blood-brain barrier and decrease synthesis of prostaglandin messengers. Dexamethasone has been the topic of extensive study in chemotherapy and the prevention of postoperative nausea and vomiting literature. Side effects are mild when used short-term and include insomnia, excitation, and changes in mood. PO and IV formulations are available.
Anticholinergics: Scopolamine is the most commonly encountered medication in this class. It works by antagonizing the M1 muscarinic receptor. It is predominantly used to treat motion sickness or prophylactically in the perioperative setting. Side effects are typically mild but include dry mouth, vision changes, or drowsiness. The administration is transdermal.
Neurokinin receptor antagonists: Aprepitant (PO) and fosaprepitant (IV) highlight this class of medications that involve antagonism of the NK-1 receptor, preventing the release of substance-P, which is an inducer of vomiting. As with many medications, side effects include headache and dizziness, but case reports have been published noting significant hypersensitivity reactions to include anaphylaxis and anaphylactic shock.
Dopamine receptor antagonists: Phenothiazines antagonize the D2 receptor, most notably in the area postrema in the brain. Prochlorperazine and chlorpromazine are examples of this class of medication. IV, PO, and rectal (PR) formulations are available. Side effects include dizziness, headache, and extrapyramidal symptoms to include dystonia and tardive dyskinesia.
Butyrophenones also work to antagonize the D2 receptor. Droperidol and Haloperidol have proven to be very efficacious anti-emetics, but due to the side effect profiles have fallen out of favor in many environments. Intramuscular (IM) and IV are effective routes of administration. In addition to more typical side effect profiles, these medications can cause dose-dependent QTc prolongation and require caution in those with known or suspected QTc prolongation.
Benzamides antagonize the D2 receptor at low doses but also antagonizes the 5-HT3 receptor at higher doses. Metoclopramide is the most common medicine in this class and is typically used as a pro-motility agent to reduce nausea and vomiting. PO and IV formulations are available. This medication can cross the blood-brain barrier. As with other dopamine antagonists, this medication can cause dystonia, tardive dyskinesia, and akathisia. An FDA “Boxed” warning cautions against repeated and long-term use as it can cause irreversible tardive dyskinesia.
Cannabinoids therapy is relatively new and somewhat controversial. Nabilone and dronabinol have been studied and show some benefit, though significant side-effects such as vertigo, hypotension, and dysphoria have limited their use in some populations. IV and PO formulations are available.
Antihistamines act to antagonize the histamine (H1, H2) receptors. Diphenhydramine, meclizine, promethazine are common medications in this class. They are widely available, generally well-tolerated, and there are PO, IV, IM, PR formulations available. Sedation is a widely reported, common side effect.
Generally, anti-emetic medications are well tolerated. As indicated above, side effects range from more common (mild headaches and dizziness) to rare (anaphylaxis, hypersensitivity.) The list of all side effects is beyond the scope of this document, and the practitioner should review all possible side-effects (common and uncommon) before prescribing these medications. However, as noted, extrapyramidal symptoms to include tardive dyskinesia, akathisia, and dystonia, are well described. QTc prolongation and subsequent Torsades de Pointes can also be a life-threatening complication and should be a consideration when prescribing these medications.
Contraindications will vary based on class and mechanism of medication:
Monitoring considerations will be dependent on the clinical environment and patient presentation. It is not typical to measure or use blood concentrations of any of these medications. Patient-specific monitoring relating to side effects will be specific to the patient the medication received.
An interprofessional approach to antiemetics is the best course of action. As described above, nausea and vomiting is a common symptom and part of a complex pathway. Selecting the appropriate treatment option will require coordination across all areas of healthcare to include nurses, physicians, pharmacists, and other health professionals. The prescriber would do well to include the pharmacist during agent selection, and have the pharmacist perform thorough medication reconciliation as well as verify dosing and duration. The nursing staff can provide counsel on administration, warn about potential side effects (reinforced by the pharmacist), and answer patient questions. They can also verify therapeutic effectiveness on follow-up visits. This interprofessional team methodology will benefit the patient by increasing positive outcomes and minimizing adverse effects. [Level V]
The current level of evidence for treatment varies for each class and specific drug. Some medications have been thoroughly tested through RCTs, sometimes alone, and sometimes, in conjunction with other therapies. Other medications, for example, the cannabinoids, lack an in-depth level of testing and investigation. Interprofessional teams and thoughtful, appropriate, prescribing methods will increase patient safety and improve outcomes.
|||Gan TJ,Diemunsch P,Habib AS,Kovac A,Kranke P,Meyer TA,Watcha M,Chung F,Angus S,Apfel CC,Bergese SD,Candiotti KA,Chan MT,Davis PJ,Hooper VD,Lagoo-Deenadayalan S,Myles P,Nezat G,Philip BK,Tramèr MR, Consensus guidelines for the management of postoperative nausea and vomiting. Anesthesia and analgesia. 2014 Jan [PubMed PMID: 24356162]|
|||Abdelsayed GG, Management of radiation-induced nausea and vomiting. Experimental hematology. 2007 Apr [PubMed PMID: 17379085]|
|||Flake ZA,Linn BS,Hornecker JR, Practical selection of antiemetics in the ambulatory setting. American family physician. 2015 Mar 1 [PubMed PMID: 25822385]|
|||Hornby PJ, Central neurocircuitry associated with emesis. The American journal of medicine. 2001 Dec 3 [PubMed PMID: 11749934]|
|||Horn CC,Wallisch WJ,Homanics GE,Williams JP, Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting. European journal of pharmacology. 2014 Jan 5 [PubMed PMID: 24495419]|
|||Jordan K,Schmoll HJ,Aapro MS, Comparative activity of antiemetic drugs. Critical reviews in oncology/hematology. 2007 Feb [PubMed PMID: 17208005]|
|||Tavorath R,Hesketh PJ, Drug treatment of chemotherapy-induced delayed emesis. Drugs. 1996 Nov [PubMed PMID: 9118814]|
|||Clissold SP,Heel RC, Transdermal hyoscine (Scopolamine). A preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs. 1985 Mar [PubMed PMID: 3886352]|
|||dos Santos LV,Souza FH,Brunetto AT,Sasse AD,da Silveira Nogueira Lima JP, Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting: a systematic review. Journal of the National Cancer Institute. 2012 Sep 5 [PubMed PMID: 22911671]|
|||Rao AS,Camilleri M, Review article: metoclopramide and tardive dyskinesia. Alimentary pharmacology [PubMed PMID: 19886950]|
|||Kassel L,Nelson M,Shine J,Jones LR,Kassel C, Scopolamine Use in the Perioperative Patient: A Systematic Review. AORN journal. 2018 Sep [PubMed PMID: 30156728]|
|||McParlin C,O'Donnell A,Robson SC,Beyer F,Moloney E,Bryant A,Bradley J,Muirhead CR,Nelson-Piercy C,Newbury-Birch D,Norman J,Shaw C,Simpson E,Swallow B,Yates L,Vale L, Treatments for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy: A Systematic Review. JAMA. 2016 Oct 4 [PubMed PMID: 27701665]|
|||Hendren G,Aponte-Feliciano A,Kovac A, Safety and efficacy of commonly used antiemetics. Expert opinion on drug metabolism [PubMed PMID: 26293198]|
|||Keller GA,Ponte ML,Di Girolamo G, Other drugs acting on nervous system associated with QT-interval prolongation. Current drug safety. 2010 Jan [PubMed PMID: 20210727]|