Antiemetic therapy for gastroparesis

Gastroparesis is a heterogeneous syndrome with variable clinical manifestations. Some patients present with regurgitation-predominant symptoms suggestive of gastroesophageal reflux disease, but effortless regurgitation of undigested foods after meals and at night should suggest gastroparesis . Other patients may have prominent postprandial epigastric discomfort, early satiety and bloating, distinguishable from functional dyspepsia . The most recognized symptoms of gastroparesis are chronic or episodic nausea, retching, and emesis, which may result in dehydration, weight loss, electrolyte abnormalities, hematemesis, emergency room visits, and hospitalizations . The cause and effect between symptoms and delayed gastric emptying can be difficult to demonstrate. Severity of symptoms does not correlate with severity of delayed gastric emptying, except that emesis is more prevalent in patients with severely delayed gastric emptying (>30% retention at 4-hour) by standardized gastric scintigraphy .

Effective treatment strategy for patients with gastroparesis depends on many factors, such as dietary and lifestyle modifications, treating the underlying cause, preventing complications of dehydration and weight loss, pharmacologic prokinetics to improve gastric emptying, gastric electrical stimulation in selected patients, and promising endoscopic procedures such as per-oral endoscopic myotomy of pylorus. Symptomatic control of nausea and emesis is often the first therapeutic decision by the clinician. This chapter provides an update on antiemetic therapy for gastroparesis.

Mechanisms of nausea and emesis

Nausea is a subjective sensation and difficult to define . Patients often feel they are about to vomit, or use terms such as “sick to the stomach” or “queasy.” Nausea is difficult to measure. Different dimensions of nausea, such as maximal intensity, entity, duration, and quantity have been incorporated in assessing the severity of nausea . In contrast, emesis is a specific event that results in retching and forceful evacuation of gastric contents in retrograde fashion from the stomach up to and out of the mouth.

The pathophysiology of emesis is complex. Induction of emesis may originate from internal signals within our body or from external stimuli from our surrounding environment ( Fig. 25.1 ) . Signals from the pharynx, stomach, and small intestine are transmitted via the parasympathetic and sympathetic visceral afferent pathways to the nucleus tractus solitarius in the medulla to activate the emetic circuitry. This is likely the most common pathophysiology associated with gastroparesis, where gastric distension or other signals stimulate visceral afferent input to the central nervous system (CNS) resulting in emesis. Integrity of the abdominal vagus is essential for the act of emesis . Retching and emesis may be absent if these pathways are not activated, such as in patients with post-vagotomy gastroparesis and gastric bezoars with effortless regurgitation of undigested foods without emesis.

The chemoreceptor trigger zone, which is located in the area postrema on the floor of the fourth ventricle, lies outside the blood-brain barrier and detects endogenous and exogenous toxins which induce emesis. Contrary to the common belief, there is no isolated “vomiting center” that causes emesis, rather it is a group of loosely organized neurons in the medulla that receive signals from the nucleus tractus solitarius and the chemoreceptor trigger zone. Multiple neurotransmitters are integrated in the emetic circuitry, providing multiple targets for potential pharmacologic therapy ( Fig. 25.2 ) . There is an abundance of 5-hydroxytryptamine 3 (5-HT3) receptors in the chemoreceptor trigger zone. Vagal and sympathetic input stimulates the 5-HT3 receptors leading to the release of dopamine. This dopamine surge activates the dopamine-2 (D2) receptors in the medulla. The neurokinin-1 (NK1) receptor, the receptor for tachykinin substance P, are found within the vagal afferents peripherally and within the nucleus tractus solitarus and the chemoreceptor trigger zone centrally . These complex pathways are the basis for the antiemetic properties of the pharmacologic agents which block the 5-HT3, D2, and NK1 receptors.

Nausea and emesis also arise from the vestibular system pathway, which contains numerous histamine-1 and muscarinic-1 receptors. The vestibular center is the prominent mechanism in motion sickness and pregnancy-induced nausea and vomiting, but it plays a less prominent pathophysiologic role in gastroparesis. However, histamine-1 and muscarinic-1 receptor antagonists may be useful as an adjunctive therapy in controlling nausea and emesis in some patients with gastroparesis.

Antiemetics

The use of antiemetic medications is very common in clinical practice. Antiemetics reduce emesis by acting on a number of receptors in the peripheral and central nervous systems that control emesis as stated above. Efficacy of antiemetics has been demonstrated by multiple randomized controlled trials (RCTs) for nausea and vomiting associated with chemotherapy, perioperative periods, pregnancy, and motion sickness. However, data supporting the efficacy of antiemetic agents in gastroparesis are very limited. Classifications of the antiemetic therapies and their available formulations are provided in Table 25.1 .

Table 25.1

Therapies for nausea and emesis.

Antiemetic classes	Medications	Formulations
Antiemetic classes	Medications	Tablet or Capsule	Suspension	ODT ^aor OSF ^b	Transdermal	Rectal suppository	Sub-cutaneous	Transnasal	Intra-muscular	Intravenous
Phenothiazines ^f	Promethazine	X	X			X			X	X
	Prochlorperazine	X				X			X	X
	Chlorpromazine	X							X	X
	Perphenazine	X
Histamine-1 receptor antagonist	Diphenhydramine ^c	X	X	X					X	X
	Dimenhydrinate ^c	X							X	X
	Meclizine ^c	X
	Hydroxyzine	X							X
	Doxylamine ^c	X
Dopamine receptor antagonist	Metoclopramide	X	X	X		X	X	X	X	X
	Domperidone ^d	X	X			X			X
	Experimental ^e a. TAK-906 b. CIN-102 c. NG 101
Muscarinic receptor antagonist	Scopolamine				X
5-Hyroxytryptamine-3 receptor antagonist	Ondansetron	X	X	X					X	X
	Dolasetron	X								X
	Palonosetron									X
	Granisetron	X	X				X			X
Neurokinin-1 receptor antagonist	Aprepitant	X	X							X
	Netupitant ^e	X
	Fosaprepitant									X
	Rolapitant	X								X
	Tradipitant ^f	X
Tricyclic antidepressant	Amitriptyline	X
	Nortriptyline	X	X
	Imipramine	X
	Desipramine	X
Butyrophenones ^f	Haloperidol	X	X						X	X
Butyrophenones ^f	Droperidol								X	X
Benzodiazepines	Midazolam		X					X		X
Benzodiazepines	Lorazepam	X	X						X	X
Others	Olanzapine	X	X						X
	Mirtazapine	X		X
	Cannabinoids a. Dronabinol	X	X
	a. Nabilone	X
	Gastric neurostimulation
	Alternative and complementary medications

a Oral disintegrating tablet.

b Oral soluble film.

c Available over-the-counter.

d Not available in the US and not FDA-approved.

e Not FDA-approved, in clinical trials.

f Available only in combination with palonosetron.

Phenothiazines

Phenothiazines are the most commonly prescribed antiemetics ( Table 25.1 ). They exert an antiemetic effect by blocking dopamine-2 and 5-HT receptors in the chemoreceptor trigger zone, as well as having weak histamine-1 and muscranic-1 receptor blocking activity. The most commonly used phenothiazines as antiemetics are promethazine and prochlorperazine. Chlorpromazine and perphenazine are first generation antipsychotic medications for bipolar disorder and schizophrenia, and they are used much less as antiemetic agents. Promethazine is commonly dosed at 12.5–25 mg oral tablet every four to six hours as needed for nausea and emesis. Promethazine is inexpensive and widely available. It can be given as a suppository, intramuscular injection, and intravenous infusion. These alternatives to the oral preparation are useful in patients during periods of emesis. Prochlorperazine is usually dosed at 5–10 mg every six to eight hours as needed. Prochlorperazine can be given as oral tablets, intramuscular injection, and intravenous infusion ( Table 25.1 ).

Phenothiazines are effective therapies for acute nausea and vomiting associated with elective surgery, vertigo, motion sickness, and migraine based on randomized controlled trials . However, there are no efficacy data on the use of phenothiazines in chronic nausea and vomiting associated with gastroparesis. Short term, intermittent use of phenothiazines is a reasonable approach. Frequent daily use or high doses of phenothiazines, especially with intravenous dosing, should be avoided. Promethazine has been recognized for its potential for abuse and intentional misuse . It can increase the “high” sensation one gets from opiates .

Phenothiazines penetrate the CNS and frequently cause drowsiness, sedation, and confusion. Patients should be warned against driving, operating machinery, and strenuous activity. Concurrent intake of alcohol and other sedatives should be avoided. Lower doses of promethazine should be used whenever possible, especially in the elderly. Furthermore, both promethazine and prochlorperazine may cause extrapyramidal side effects, such as tardive dyskinesia and dystonia, due to their dopamine antagonism in the basal ganglia . Phenothiazines should be used with caution in patients with dementia, due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and cognitive decompensation.

Venous scarring with promethazine is a well-known adverse event. FDA issued a patient safety bulletin in 2006 for the potential of severe tissue injury due to extravasation of intravenous promethazine. Promethazine should be infused only through a large-bore vein, and the patency of the access site should be checked before administering. The patient should be instructed to report burning or pain during and after the injection. An intravenous port or peripherally inserted central catheter line should be considered if promethazine is ordered for home health use in patients with recurring nausea and vomiting. Subcutaneous injection of promethazine is contraindicated.

Histamine-1 (H1) receptor antagonist

Antihistamines inhibit the action of histamine at the H1 receptor, blocking the stimulation of the emesis pathway that originates from the histamine rich vestibular system. The currently available H1 receptor antagonists for nausea and emesis are listed in Table 25.1 . Dimenhydrinate and meclizine are pure H1 receptor antagonists, while diphenhydramine and hydroxyzine have mixed actions on other receptor subtypes. Diphenhydramine, dimenhydrinate, and meclizine are available over-the-counter. H1 receptor antagonists have been shown to be efficacious in the treatment of acute nausea and vomiting associated with motion sickness and in the postoperative period . There are no data regarding efficacy of H1 receptor antagonist for chronic nausea and emesis associated with gastroparesis. These agents are generally less helpful than other emetics in gastroparesis, since the vestibular system does not play a prominent role in the pathophysiology of emesis associated with gastroparesis. However, the sedative and antiemetic properties of intravenous histamine receptor antagonists may be helpful in the hospitalized patients. Potential side effects of H1 receptor antagonists are usually minor, but include sedation, dizziness, fatigue, and tremor.

Dopamine-2 (D2) receptor antagonist

Two D2 receptor antagonists commonly used in the treatment of gastroparesis are metoclopramide and domperidone, though only metoclopramide is approved in the United States. Dopamine-2 receptor antagonists work on both central (antiemetic effect) and peripheral (prokinetic effect) dopamine receptors. They promote their peripheral prokinetic effects through the blockade of enteric D2 receptors, thereby facilitating the release of acetylcholine known to increase gastric motility by directly mediating smooth muscle contraction . In this chapter, we will focus on the anti-emetic effects of D2 receptor antagonist, as the prokinetic effects will be addressed in a separate chapter of this book.

Metoclopramide has been available in the US since 1974 and is indicated for the treatment of diabetic gastroparesis and symptomatic gastroesophageal reflux disease. It is the only drug approved by the FDA for the management of symptoms related to diabetic gastroparesis. It has a short half-life (60–90 minutes), has a rapid onset of action within minutes when given intravenously or intramuscularly, and it is well-absorbed. It can be administered orally in either tablet or solution form with 5–10 mg BID to QID 30 minutes prior to meals and at bedtime. It is recommend to titrate to the lowest effective dose with a maximum not to exceed 40 mg/day in 4 divided doses . Intramuscular (IM), intravenous (IV), intranasal, and rectal formulations are available ( Table 25.1 ). For IV administration, a maximum of 30 mg/day in 3 divided doses is recommended. An intraperitoneal formulation has been utilized for patients on peritoneal dialysis . For patients with refractory nausea and vomiting limiting any absorption by oral administration, subcutaneous (sc) injections of metoclopramide 10 mg (2 mL) administered every 6 hours for 3 days resulted in subjective and objective improvement in both GI symptoms and gastric stasis in patients with gastroparesis . Additionally, administering metoclopramide sq provided peak levels at 30 minutes with serum concentration levels comparable to that of IV administration. Subcutaneous metoclopramide use is recommended for patients who have demonstrated no side effects in the past but whose nausea and vomiting is not being adequately controlled. Subcutaneous metoclopramide at 5–10 mg doses (1–2 cc’s) BID or TID can supplement oral metoclopramide and guarantee absorption to gain symptom control thus avoiding emergency room visits and their accompanying economic burden. Side effect potential does need to be monitored.

Metoclopramide readily crosses the blood-brain barrier and has inhibitory effects on 5-HT3 and D2 receptors on the medullary chemoreceptor trigger zone in the brain which explains its antiemetic activity . Blocking D2 receptors in the striatopallidal and nigrostriatal pathways may lead to extrapyramidal movements similar to those seen in patients with Parkinson’s disease known as tardive dyskinesias. Tardive dyskinesia, a potentially irreversible clinical manifestation, is characterized by involuntary movements of the face, tongue, lips, extremities, and choreoathetoid movements of the body . Consequently, prolonged use of metoclopramide is limited by its CNS side effects. Because of this, the FDA issued a black box warning in 2009 and limited its use to no more than 12 weeks . Metoclopramide should be avoided in patients with Parkinson’s as it may exacerbate Parkinsonian symptoms, and it is contraindicated in patients with seizures since metoclopramide lowers the seizure threshold. It is estimated that the risk of developing tardive dyskinesia is rare and can develop in <1% of patients with onset usually seen within 24–48 hours after starting metoclopramide (mostly parenterally) . The risk is greater in the elderly, females, and patients with renal impairment. Interestingly, genetic factors may play a role in the development of this side effect, and should be avoided if there is a family history of metoclopramide-induced movement disorder . If an acute dystonic reaction develops, administration of anticholinergics (i.e. diphenhydramine 25–50 mg IV or IM) in combination with benzodiazepines (i.e. diazepam 2–10 mg IV or IM) may provide immediate relief . Other side effects reported in up to 35% of patients, include fatigue, drowsiness, irritability, and depression . Galactorrhea, irregular menses, and breast tenderness can also develop related to prolactin release. In diabetic gastroparesis, it is recommended limiting the use of metoclopramide to severe refractory cases since there are now safer alternatives for control of nausea and emesis such as 5-HT3 or NK1 receptor antagonists . Additionally, clinicians should always discuss with their patients all expected side effects expected with metoclopramide along with documentation of this discussion in the medical record.

Domperidone is another D2 receptor antagonist with both central and peripheral effects. However, domperidone does not have the significant CNS side effects seen with metoclopramide because it does not readily crosses the blood-brain barrier – nor does it have cholinergic effects, a side effect seen in other prokinetic agents . Another difference is that domperidone is not a 5-HT4 agonist. Although extensively utilized throughout the world for treatment of gastroparesis since it was first developed in 1978, domperidone is not approved in the U.S. due to rare reports of cardiotoxicity from QTc prolongation after IV administration of high doses . To put this into perspective, because of the low oral bioavailability of domperidone (13–17%) , oral doses over 1000 mg/day would correlate with the IV doses administered to patients when cardiotoxicity was reported . Currently, domperidone is no longer available in IV form. When the FDA evaluated domperidone in 1989, they determined that there were not enough patients enrolled in controlled clinical trials to make a statistically significant evaluation, and therefore the agency withheld approval of this drug without attempt to pursue further trials . Physicians may prescribe domperidone only if they apply for an FDA-approved Investigational New Drug (IND) protocol, a compassionate clearance program for patients with refractory GI symptoms of gastroparesis or other functional GI disorders who have failed standard treatment .

Domperidone is rapidly absorbed with peak plasma concentrations occurring at approximately 10 for oral formulations . The pharmacokinetics are linear over a dose range of 10–40 mg . Its half-life is 7–9 hours in healthy subjects . Domperidone has low bioavailability by oral route (13–17%) and high by IM route (90%) likely due to first-pass effect in the liver and gut wall metabolism . It has a short half-life (60–90 minutes). The pharmacodynamics that explain its effective prokinetic effects includes its ability to enhance antroduodenal contractions, improve esophageal motor function, accelerate gastric emptying, and improve peristalsis across the pylorus . Dosing normally begins at 10 mg before meals and at bedtime and can be titrated up to 80–120 mg/day until symptom control is achieved. The most common side effects are due to hyperprolactinemia (i.e. galactorrhea, irregular menses, breast tenderness).

The clinical efficacy of domperidone has been well documented in the literature. American Gastroenterology Association recognizes domperidone as an important treatment option for gastroparesis . Long term treatment with domperidone 20 mg QID for an average of 23 months has resulted in significant reduction in GI symptoms and hospitalizations, accelerated gastric emptying to normal, and enhanced quality of life . In a multicenter, two-phase withdrawal study involving over 200 insulin-dependent diabetic patients showed that domperidone 20 mg QID provided significant improvement in upper GI symptoms and quality of life with a good tolerability profile . Other studies have shown clinical effectiveness of domperidone in patients with gastroparesis . In a recent study by McCallum et al. to assess the cardiac safety and clinical efficacy of high dose domperidone in 21 patients with refractory gastroparesis followed over a median of 12 months, treatment response was positive with 80% reporting >50% improvement in symptoms . Average dose was 65 mg daily and 33% of patient received doses ≥80 mg/day titrated up to 120 mg/day. At 120 mg/day, three patients had a prolonged QTc interval on EKG without adverse cardiac effects. Two of these patients did not meet criteria for treatment response and therefore domperidone was discontinued, while the other patient continued at 80 mg/day without recurrence of QTc prolongation for 20 more months. High-dose domperidone was deemed a safe and effective treatment in patients with refractory gastroparesis. These data are consistent with a recent comprehensive literature review on domperidone which concluded that overall studies do not substantiate cardiac adverse events in patients receiving oral domperidone, even at higher doses .

Clinical trials are currently in process for future dopamine antagonists without cardiac toxicity. TAK-906 is a promising D2/D3 antagonist compound currently in phase 2 trials, and its efficacy and safety are being tested on patients with symptomatic idiopathic or diabetic gastroparesis . TAK-906 does not have any evidence of cardiac toxicity based on animal and phase IA studies in normal subjects providing an advantage over domperidone. A multi-center, double-blind, placebo-controlled trial is to be conducted worldwide with plans to enroll approximately 280 patients who will be followed for approximately 17 weeks with completion date of study estimated to be in late 2020.

CIN-102 is another domperidone-like agent currently undergoing randomized, double-blind clinical trials to evaluate its safety, tolerability, and effect on gastric emptying in adults with diabetic gastroparesis . CIN-102 is a deuterated form of domperidone in which 4 hydrogen atoms on the aromatic ring have been substituted with deuterium atoms. This change in molecular structure lowers its peak plasma concentration and allows for similar antiemetic effects to those of domperidone but without QTc prolonging consequences. A phase 2 trial plans to enroll 60 participants who will be given three different oral doses of CIN-102 twice daily for 14 days versus placebo in three separate cohorts with estimated study completion date later in 2020.

NG 101 is another potent, selective, peripherally-restrictive dopamine D2/D3 receptor antagonist under development for the treatment of gastroparesis. For decades, this agent has been safely used in Europe for the treatment of acute nausea. Clinical trials to date shows that NG 101 has potent antiemetic properties and also increases gastric motility but does not cross the blood-brain barrier nor alter cardiac rhythms . These domperidone-like agents currently under investigation are exciting novel therapies that show potential promise and will hopefully positively benefit the lives of many patients with intractable gastroparesis in the near future.

In summary, domperidone is considered a safe, effective, and well-tolerated antiemetic and prokinetic agent in the management of patients with gastroparesis who have exhausted other therapeutic options. Although domperidone has the potential to prolong QTc with increased risk of arrhythmias, so too do other approved therapies for gastroparesis such as ondansetron, promethazine, and azithromycin as well as many other medications used in non-GI areas. One recommendation is to obtain a baseline electrocardiogram and serum potassium prior to starting domperidone, as well as at 3-month intervals during treatment, with a QTc of >450 ms in males and >470 ms in females and/or significant sustained hypokalemia serving as contraindications to either starting this drug or continuing therapy .

Muscarinic receptor antagonist

Similar to H1 receptor antagonist, muscarinic receptor antagonist blocks the stimulation of the emesis pathway that originates from the vestibular system. Scopolamine is a nonselective muscarinic antagonist, producing both peripheral and central effects. Oral and intravenous administration of scopolamine is limited by very short half-life and does-dependent adverse side effects . Transdermal scopolamine is the only formulation available in the US. When transdermal scopolamine patch is applied to the postauricular skin, an initial priming dose saturates the skin and plasma level can be detected within 4 hours, and subsequent scopolamine is delivered at an approximately constant rate over 3 days .

Efficacy of scopolamine has been demonstrated in meta-analysis of randomized controlled trials for the prevention of motion sickness and postoperative nausea and vomiting . There are no prospective study utilizing scopolamine for nausea and emesis associated with gastroparesis. It’s reasonable to try a short course of transdermal scopolamine patch in selected patients with daily emesis who are unable to tolerate an oral antiemetic. However, adverse side effects of scopolamine are common, related to its central and peripheral anticholinergic effects, such as drowsiness, blurred vision, dry mouth, dizziness, bradycardia and urinary retention. Additionally, scopolamine as an anticholinergic agent, may have a very small effect – if any at all – in delaying gastric emptying .

5-Hydroxytryptamine-3 (5-HT3) receptor antagonists

In response to toxic substances and formation of free radicals, large amounts of 5-HT are released from the enterochromaffin cells in the gastrointestinal mucosa. This circulating serotonin stimulates the 5-HT3 receptors on the surface of vagal afferents in the GI tract and triggers the chemoreceptor trigger zone within the CNS resulting in emesis . Pharmacologic use of 5-HT3 receptor antagonist exerts a diffuse blockade of the 5-HT3 receptors in the small intestine, chemoreceptor trigger zone, and nucleus tractus solitarius.

The currently available 5-HT3 receptor antagonists are listed in Table 25.1 . Genetic polymorphisms in the cytochrome P450 mono-oxygenase system, 5-HT3 receptor subtypes, and drug transporter P-glycoprotein account for the variable inter-individual’s response to the different 5-HT3 receptor antagonists . Ondansetron is metabolized by multiple cytochrome P450 enzymes such as CYP3A4, CYP1A2 and CYP2D6. There are evidence linking the CYP2D6 allele genotypes with variability in drug efficacy in patients receiving ondansetron for nausea and vomiting associated with chemotherapy, surgery, and pregnancy . CYP2D6 rapid metabolizers increases ondansetron metabolism resulting in decreased drug efficacy. Several single nucleotide polymorphisms (SNPs) for 5-HT3A, 5-HT3B, and 5-HT3C receptor genes have been identified that can affect efficacy . Polymorphism for the drug transporter P-glycoprotein ABCB1 was associated with antiemetic efficacy of ondansetron in chemotherapy induced nausea and vomiting . Based on these pharmcogenetic studies, it is reasonable to switch a patient from one 5-HT3 receptor antagonist to another, if the medication administered initially is not providing the desired symptom control. Currently, genotyping for these polymorphisms have not been utilized for 5HT-3 RA efficacy in nausea and vomiting associated with gastroparesis.

The first drug of this class was ondansetron, approved by the FDA in 1991 for chemotherapy induced nausea and vomiting. Meta-analysis studies of the multiple RCTs of ondansetron, dolasetron, palonosetron, granisetron, and tropisetron have shown that all agents were superior to placebo for chemotherapy-induced nausea and vomiting . There is no RCT of 5-HT3 receptor antagonist for chronic nausea and emesis associated with gastroparesis. Use of 5HT3 antagonist is helpful in relieving intermittent nausea and emesis in gastroparesis. 5HT-3 RAs are available in multiple formulations ( Table 25.1 ). Oral disintegrating tablet (ODT) formulation of ondansetron, an oral freeze-dried formulation of the 5-HT3 antagonist, may be helpful in patients not tolerating oral medications. Transdermal granisetron for gastroparesis has been studied in an open label prescription study of patients with gastroparesis . Of the 55 patients who started transdermal granisetron, 76% reported positive global response and improvement of nausea and emesis by gastroparesis cardinal symptom index (GCSI). Patients with a severe delay in gastric scintigraphy, defined by >30% gastric retention at 4 hours, tend to have a less favorable response. Ondansetron has minimal effects on gastric emptying and may therefore be given prior to a gastric emptying test to help relieve any symptoms of nausea or vomiting .

The 5-HT3 receptor antagonists are generally well tolerated. Potential adverse side effects are headache, constipation, and dizziness. Although electrocardiogram changes have been attributed to 5-HT3 receptor antagonists as a class, serious cardiac events such as of torsade de pointes have not been reported . In a meta-analysis of RCTs of 5HT-3 receptor antagonists for postoperative nausea and vomiting, patients receiving granisetron plus dexamethasone experienced more arrhythmia compared to other agents, but there were no differences for QT prolongation or cardiac mortality between all 5HT3 antagonists versus placebo . Electrocardiogram monitoring of chemotherapy patients receiving 5-HT3 receptor antagonists did not reveal increase incidence of clinically significant arrhythmia .

Neurokinin-1 (NK1) receptor antagonist

Substance P is a neurotransmitter involved in many physiologic functions within the central and enteric nervous systems . The neurokinin-1 (NK1) receptor, the receptor for tachykinin substance P, is found within the peripheral vagal afferents and within the central nucleus tractus solitarus and the chemoreceptor trigger zone. Substance P is stored in enteroendocrine cells and is released to stimulate vagal afferent fibers through NK1 receptors to modulate nausea and emesis in the emetic circuitry in the hindbrain . NK1 receptors are also involved in the control of gastric volume and postprandial satiation and affect symptoms by increasing fasting, postprandial, and accommodation gastric volumes .

Currently available NK1 receptor antagonists are provided in Table 25.1 . They are highly specific for NK1 receptors and are effective in preventing chemotherapy and postoperative emesis . Efficacy of aprepitant for gastroparesis was studied by the National Institute of Health (NIH) sponsored Gastroparesis Clinical Research Consortium (GpCRC) in a multicenter randomized controlled trial . One hundred and twenty-six patients (57% with gastroparesis and 43% with chronic unexplained nausea and emesis) with at least moderate nausea and emesis, were randomized to oral aprepitant 125 mg versus placebo for 4 weeks. The results were mixed. There were no differences in the primary outcome of reduction of nausea severity measured by visual analog scale between aprepitant and placebo. Aprepitant did reduce nausea, vomiting, and retching severity by GCSI in secondary outcome measurement ( Fig. 25.3 ). There were no significant differences in responses between patients with and without delayed gastric emptying. Authors concluded that additional trials for aprepitant for gastroparesis are warranted . Currently, the high cost of both the oral and intravenous NK1 receptor antagonist limits its use, but it should be considered in the refractory cases of nausea and emesis. Side effects of aprepitant are minimal, and there were no significant differences in adverse events between aprepitant and placebo in patients with gastroparesis . Benefits and adverse side effects of chronic use of NK1 receptor antagonist are unknown.