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Table of Contents
REVIEW ARTICLE
Year : 2017  |  Volume : 33  |  Issue : 4  |  Page : 441-445

The role of neurokinin-1 (substance P) antagonists in the prevention of postoperative nausea and vomiting


1 Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
2 Department of Anesthesiology; Department of Pharmacology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA
3 Department of Biochemistry, Bowdoin College, Brunswick, ME 04011, USA

Date of Web Publication9-Jan-2018

Correspondence Address:
Richard D Urman
Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Womenfs Hospital, Harvard Medical School, Boston, MA 02115
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9185.222511

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  Abstract 


Postoperative nausea and vomiting (PONV) can be very debilitating for surgical patients, and effective management reduces potential morbidity, aiding in patient satisfaction, and minimizing the need for unintended hospital stays. Risk factors include female sex, nonsmoker, and having a previous history of motion sickness or PONV. Anesthetic risk factors include receiving opioids, not receiving a total intravenous anesthetic (TIVA), exposure to nitrous oxide, and extended length of anesthetic. Many treatments, including serotonin antagonists, dopamine antagonists, corticosteroids, inhaled isopropyl alcohol, and anticholinergics, as well as techniques such as TIVA, have been utilized over recent decades in an attempt to reduce PONV incidence. However, it remains a problem for a significant number of surgical patients. Aprepitant is a neurokinin-1 (substance P) antagonist, which exerts its effects via a final common pathway of the emetic centers after crossing the blood brain barrier. Aprepitant is commonly used in the cancer population to help prevent cancer chemotherapy-induced nausea and vomiting and has shown great promise in both acute and delayed phase PONV. Published data has shown improved efficacy when compared with ondansetron administered prior to surgery. The use of aprepitant in combination with other antiemetics potentially may help decrease unplanned hospital admissions and potentially, reduce costs associated with PONV.

Keywords: Antiemetics, aprepitant, neurokinin-1 (substance P) antagonist, postoperative nausea and vomiting


How to cite this article:
Okafor D, Kaye AD, Kaye RJ, Urman RD. The role of neurokinin-1 (substance P) antagonists in the prevention of postoperative nausea and vomiting. J Anaesthesiol Clin Pharmacol 2017;33:441-5

How to cite this URL:
Okafor D, Kaye AD, Kaye RJ, Urman RD. The role of neurokinin-1 (substance P) antagonists in the prevention of postoperative nausea and vomiting. J Anaesthesiol Clin Pharmacol [serial online] 2017 [cited 2018 Apr 27];33:441-5. Available from: http://www.joacp.org/text.asp?2017/33/4/441/222511




  Introduction Top


Postoperative nausea and vomiting (PONV) is one of the most common morbidities associated with anesthesiology. The incidence is about 30% on the 1st postoperative day.[1] Nausea occurs at an incidence of about 40-50% and vomiting 25-30% depending on surgical population studied.[2] Risk factors associated with PONV can be divided into patient factors, surgical factors, and anesthetic factors. Anesthetic causes of PONV in the post anesthesia care unit (PACU) are most commonly due to the use of postoperative opioids, nitrous oxide (N2O), and volatile anesthetics. From the surgical standpoint, laparoscopic, gynecological surgery, and cholecystectomy are high risk and found to independently increase the risk for PONV.[3]

Patient-related risk factors include female sex, nonsmokers, and having a previous history of motion sickness or PONV. Anesthetic risk factors include receiving opioids, not receiving a total intravenous anesthetic (TIVA), exposure to N2O, and extended length of anesthetic. Nausea and vomiting can be very debilitating for some and when combined with pain from their procedure can make for a miserable experience for our patients. PONV is not only uncomfortable for patients but costly and affects patient satisfaction.[4] Unexpected hospital admissions due to PONV have decreased but are still estimated to occur approximately 0.5-2% of the time.[5],[6] It is, therefore, prudent that as anesthesiologists we identify those at an elevated risk and provide appropriate prophylaxis to all patients.

There are several antiemetic medications, agents, and techniques in use currently. Many treatments, including serotonin antagonists, dopamine antagonists, corticosteroids, inhaled isopropyl alcohol, and anticholinergics, as well as techniques such as TIVA have been utilized successfully over recent decades in an attempt to reduce PONV incidence. These therapies work mainly by interfering with neurotransmitter receptor signaling in the central nervous system (CNS) and gastrointestinal (GI) tract; however, none are universally effective.[2] More options are becoming available. One such option is a relatively new agent aprepitant, which has been used on cancer patients receiving chemotherapy and has shown great effectiveness for PONV.

Aprepitant and chemotherapy-induced nausea and vomiting

As in the postoperative phase, nausea and vomiting is a major complication after chemotherapy. It is regarded as the most important complication by cancer patients.[7],[8],[9] Chemotherapy-induced nausea and vomiting (CINV), reduces food intake, resulting in malnutrition, weight loss, reduced performance status which increases the incidence of hematoxicity.[10] Without prevention, acute vomiting occurs in close to 100% of patients acutely, and about 70-90% patients in the delayed phase.[11],[12] Aprepitant is, therefore, primarily used in the setting of CINV. The most important effect of neurokinin 1 (NK-1)-receptor antagonists is that they are able to markedly prevent both acute and delayed emesis induced by cisplatin and other chemotherapies in humans. It seems to have particular efficacy in the delayed phase, making it advantageous compared to other antiemetics, as they seem to be only efficacious in the acute phase.[12],[13] According to guidelines of the American Society of Clinical Oncology, the dose for CINV is 125 mg prior to therapy, and then 80 mg on subsequent days.[14] It is given routinely in combination with 5-HT3 receptor antagonists and dexamethasone.[15]

Aprepitant and postoperative nausea and vomiting

Previous studies investigating the use of aprepitant for PONV have demonstrated results which are very promising. In a comparison prophylaxis study, ondansetron 4 mg IV and aprepitant 40 mg PO had similar effectiveness for the first 24 h. However, aprepitant was more effective in the subsequent 24-to 48-h postoperative time period,[16] with an effect on vomiting greater than on nausea.

For those undergoing abdominal surgery under different anesthetic techniques, aprepitant 40 mg or 125 mg was found to be more effective than ondansetron 4 mg IV in reducing nausea and vomiting in first 48 h period.[17] According to a study done by Lim et al., the rate of occurrence of PONV assessed 6 h after surgery was lower for patients who were administered with ondansetron and 125 mg of aprepitant compared to the group that was only administered ondansetron.[18] There were also fewer patients who received rescue treatment in those who had received aprepitant 125 mg. The combination of aprepitant and ondansetron was found to significantly prolong the time to administration of the first rescue antiemetic drug compared with either drug alone, and almost completely prevented the occurrence of emesis.[19] [Table 1] outlines various studies comparing aprepitant and other NK-1 inhibitors to ondansetron and/or placebo.[20]
Table 1: Summarized outcomes of neurokinin-1 inhibitors versus Zofran or placebo studies

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The neurokinin 1 inhibitor drug group

In addition to aprepitant only, fosaprepitant and maropitant are in clinical use. Fosaprepitant is a water-soluable prodrug to aprepitant, used both in CINV and PONV. Maropitant is currently in use for motion sickness and vomiting in cats and dogs. According to a study done by Sedlacek et al., maropitant was effective in preventing vomiting caused by stimulation of either central or peripheral emetic pathways whereas the other drugs examined prevented vomiting caused by central (metoclopramide and chlorpromazine) or peripheral (ondansetron) stimulation but not both.[21] Maropitant is still under investigation for use in humans. Other NK-1 receptor inhibitors include GR205171 (vofopitant, GlaxoSmithKline), CP-122721 (Pfizer), CJ-11974 (Pfizer), casopitant (GlaxoSmithKline), netupitant (Helsinn Healthcare), rolapitant or SCH 619734 (Schering-Plough), T 2328 (Mitsubishi Tanabe Pharma), and vestipitant (GlaxoSmithKline); however, they are still under investigation.[22]

Pharmacological properties

Substance P, a member of the tachykinin family of bioactive peptides, is a neurotransmitter in the afferent pathway of the emetic reflex.[23] The presence of substance P in regions of the brainstem involved in emesis in humans has been demonstrated.[24] The NK-1 receptor is the preferential site of action of the neuropeptide substance P in regions of the brainstem believed to mediate the emesis reflex.[25],[26],[27] Substance P is the natural ligand for the NK-1 receptor found to trigger its signaling and cause nausea and vomiting. NK-1 is widely expressed in the GI vagal afferents and brain areas involved in the vomiting reflex such as the nucleus solitary tract,[26],[27],[28] the area postrema of the CNS, as well as in the peripheral nervous system.[19]

Aprepitant is a NK-1 receptor antagonist which is highly selective and centrally acting, with a half-life of 9-12 h.[28],[29] It has a bioavailability of 65%.[30] Aprepitant has the chemical name 5-([2R, 3S]-2-[1R]-1- [3,5-bis [trifluoromethyl] phenyl] ethoxy]-3-[4-fluorophenyl]-4 morpholinyl]methyl)-1,2-dihydro-3H-1, 2, 4-triazol-3-one.

Aprepitant undergoes oxidation at the morpholine ring and its side chains, and it is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. It is also found to be a weak inhibitor of CYP2C19 and CYP2C9, a moderate inhibitor of CYP3A4 and an inducer of CYP2C9; therefore, there is potential for drug interactions.[30] Aprepitant is eliminated mainly by excretion of metabolites in feces and urine.[31]

Aprepitant dosing, side effects, and cost

Aprepitant, which is made in capsular form, is administered orally, 1-2 h preoperatively, for PONV prophylaxis.[2] A typical dose is 40 mg, although doses up to 125 mg for PONV have been studied. Fosaprepitant, a pro-drug is available for intravenous administration, with a typical dose of 115 mg.[30] Fosaprepitant, is only Food and Drug Administration approved for use in CINV although it has been shown to more effective than ondansetron in reducing vomiting in gynecologic, neurological, and lower limb surgeries.[32],[33],[34] Aprepitant is relatively safe; however, common side effects include dizziness, constipation, and hypotension, especially when used in the setting of PONV prophylaxis. In the setting of CINV prophylaxis, common side effects are fatigue, diarrhea, weakness, indigestion, abdominal pain, hiccups, leukopenia, dehydration and altered liver function tests, cough, and hiccups.[35]

The cost of a 80 mg capsule is approximately US$100 and a 125 mg capsule is about US$110.[36] There is no generic form available; so it is considerably costly compared to other antiemetics, such as ondansetron, which became generic in 2007.[31]


  Conclusion Top


Aprepitant, a NK 1 receptor antagonist, exerts its effects via a common pathway of the emetic centers after crossing the blood brain barrier. Aprepitant is a drug with limited side effect profile and works very efficiently for PONV. Dosed alone or in combination with other antiemetics, this medication has shown tremendous relief of symptoms and for a prolonged period of time. The novel drug has addressed both acute and delayed onset of nausea and vomiting, which is very useful in the postoperative population because it decreases the need for rescue doses later in the postoperative period. It should be noted that aprepitant has been found to be more effective than ondansetron at preventing PONV in the perioperative period.[37]

The major drawback and limitation of aprepitant for its use is that it is expensive, making it difficult to justify its use outside of very severe symptoms or potential risk factors for nausea and vomiting. Hopefully, prices will become more competitive in the future and allow for the integration of this effective medication for everyday use of prophylaxis for PONV.

All classes of antiemetics, including aprepitant, have demonstrated efficacy for the treatment of nausea and vomiting. However, much of the data is contradictory given the complex multifactorial nature of PONV, and thus, no one agent is likely to prevent PONV in all patients. Ongoing and future large studies are warranted to best sort out the role for aprepitant vis-à -vis individual variables and best practice strategies in high-risk patients, which ultimately increase patient comfort, satisfaction, and minimize morbidity associated with extended PACU times and unplanned hospital stays.

Financial support and sponsorship

Nil.

Conflicts of interest

Dr. Urman received research funding from Premier Research.



 
  References Top

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