What evidence supports the use of neurokinin‐1 receptor antagonists for gastroparesis-related nausea and vomiting?

Introduction
Gastroparesis is a chronic motility disorder characterized by delayed gastric emptying with no known mechanical obstruction.1,2 A recent study reported that the prevalence of gastroparesis is 268 per 100,000 American adults, with the highest prevalence among those aged between 58 and 64 years.3 The pathophysiology of gastroparesis is complex and not fully understood, although recent studies have described altered central processing and autonomic dysfunction as important pathogenic factors.4

The etiology of gastroparesis is diverse.5 The largest etiologic group is idiopathic, accounting for more than 50% of gastroparesis cases.2,5 Diabetes accounts for 25% of cases, and other causative factors include vascular disorders, certain medications (e.g., opioids, glucagon-like peptide-1 agonists), connective tissue disorders, autoimmune diseases, and postsurgical causes. Symptoms of gastroparesis include postprandial fullness, early satiety, nausea, vomiting, upper abdominal pain, and bloating.1,6 The severity of symptoms can vary from mild to debilitating; severe cases may lead to malnutrition and/or dehydration resulting in increased morbidity and mortality.2

Nausea and vomiting are generally the predominant persistent symptoms.5 Symptom profiling from patients enrolled in the National Institutes of Health Gastroparesis Clinical Research Consortium demonstrated that 95% of patients with gastroparesis experience nausea.1 Patients with diabetic gastroparesis experience more severe nausea and prolonged episodes of vomiting (lasting several hours to nearly the entire day) compared to patients with idiopathic gastroparesis. Management of these symptoms is essential to improve quality of life and prevent complications.

To date, metoclopramide, a dopamine receptor antagonist, is the only drug approved by the U.S. Food and Drug Administration (FDA) for treatment of gastroparesis.5-7 Metoclopramide exerts both prokinetic and antiemetic effects.1 However, its duration of use is restricted to 12 weeks (despite the chronicity of gastroparesis) and there are safety concerns, especially in the elderly.6,7 These limitations suggest that there is a need for more safe and effective treatments.7 Several pharmacological agents are prescribed off-label for gastroparesis-related nausea and vomiting, including but not limited to, other dopamine receptor antagonists (e.g., domperidone), serotonin type 3 (5-HT3) receptor antagonists, serotonin type 4 (5-HT4) receptor agonists, histamine receptor antagonists, motilin agonists, tricyclic antidepressants, and neurokinin-1 (NK-1) receptor antagonists.

Neurokinin-1 receptor antagonists are a class of antiemetic drugs indicated for suppression of chemotherapy-induced nausea and vomiting.8 Examples of NK-1 receptor antagonists include aprepitant, fosaprepitant, rolapitant, casopitant, and tradipitant; the first 3 agents are FDA-approved. These agents prevent the emetic signal being transmitted by blocking the interaction of the neuropeptide substance P at the NK-1 receptors. These receptors are expressed in both the visceral abdominal afferent nerves and the brain/brainstem (area postrema and nucleus tractus solitarius); thus, NK-1 antagonists prevent both central and peripheral stimulation of emesis centers. Due to this distinctive mechanism, there has been interest in the utility of these agents in the management of gastroparesis-related nausea and vomiting.7

Guidelines on the treatment of gastroparesis
Several recently published guidelines on the management of gastroparesis discuss the role of NK-1 receptor antagonists in treating gastroparesis-related nausea and vomiting.5,6,9

In 2022, the American Gastroenterological Association (AGA) published a clinical practice update on the management of medically refractory gastroparesis.5 Medically refractory gastroparesis is characterized by persistent symptoms despite dietary adjustments and first-line treatment with metoclopramide. Management goals include the identification and improvement of predominant symptoms, reduction of complications, and improvement in quality of life. For patients with nausea and vomiting who fail metoclopramide, the AGA lists a variety of off-label treatment options without stating a preference for any particular agent(s): ondansetron, granisetron, prochlorperazine, chlorpromazine, meclizine, scopolamine, dimenhydrinate, diphenhydramine, trimethobenzamide, aprepitant (80 mg/day), and ginger. The brief discussion on NK-1 receptor antagonists focus on 2 randomized controlled trials (RCTs) that have assessed the efficacy of tradipitant and aprepitant in patients with gastroparesis; these RCTs are described in the following section.5,10,11 The guideline comments that although NK-1 receptor antagonists seem to alleviate nausea and vomiting, these symptoms improved regardless of the presence or absence of significantly delayed gastric emptying in patients with gastroparesis or functional dyspepsia, respectively, and symptoms do not necessarily correlate with emptying time in several patients.5 Nonetheless, up to one-third of patients with nausea may benefit from NK-1 receptor antagonists, provided that treatment costs are reasonable.

The American College of Gastroenterology (ACG) also published an update to their clinical guideline on gastroparesis in 2022.6 The guideline conditionally recommends the use of pharmacological treatment to improve symptoms in patients with gastroparesis with consideration of risks and benefits. The use of metoclopramide is suggested over no treatment for management of refractory symptoms (conditional recommendation, low quality of evidence). Regarding use of NK-1 antagonists, similarly to the AGA guideline, findings from the 2 RCTs on aprepitant and tradipitant are summarized. The guideline suggests the use of antiemetic agents, including NK-1 receptor antagonists, for improved symptom control although these agents do not improve gastric emptying (conditional recommendation, low quality of evidence). No preference is given for any particular antiemetic agent(s).

Lastly, the United European Gastroenterology and European Society for Neurogastroenterology and Motility released a consensus guideline on gastroparesis in 2020.9 Nausea and vomiting were identified as cardinal symptoms of gastroparesis and only dietary therapy, dopamine-2 antagonists, and 5-HT4 receptor agonists were considered appropriate therapies. There was no consensus on the use of other therapies, including other classes of prokinetics or antiemetics, including NK-1 antagonists. Neither the statement that antiemetic therapy is effective for gastroparesis, nor the statement that antiemetic therapy is the most appropriate first-line therapy for gastroparesis, was endorsed. The guideline mentioned the same RCT as the other guidelines on the efficacy on aprepitant for management of nausea in patients with gastroparesis. Of note, the RCT on tradipitant was published after the release of this guideline.

Studies of NK-1 receptor antagonists for management of gastroparesis-related nausea and vomiting
Overall, studies on NK-1 receptor antagonists for management of gastroparesis-related nausea and vomiting are limited. A review of literature identified 2 RCTs and 3 case reports, which are summarized in Table 1.10-14

The phase 2 RCT by Carlin et al (2021) assessed the safety and efficacy of oral tradipitant to treat gastroparesis symptoms in adults with idiopathic or diabetic gastroparesis and moderate to severe nausea.10 The mean patient age was 45.9 years; approximately 90% of patients were female and approximately 86.2% were White. Tradipitant demonstrated statistically significant improvements in nausea severity and overall gastroparesis symptoms compared to placebo at 4 weeks. Tradipitant was also well-tolerated, with an adverse event profile similar to placebo. However, since gastroparesis is a chronic condition, authors noted that efficacy and safety of treatment beyond 4 weeks would be more useful. Notably, the ongoing phase 3 RCT assessing the efficacy and safety of tradipitant compared to placebo failed to meet its prespecified primary endpoint, the change in nausea severity from baseline to 12 weeks of treatment.15,16 Initial exploratory analysis suggest that this may have occurred due to potential confounders, including a baseline imbalance of rescue medication use between the treatments groups and poor adherence to tradipitant.15 After restricting the analysis to patients who did not use rescue medications at baseline and adjusting for poor compliance, the manufacturer reported a significant effect favoring tradipitant for the primary outcome. Tradipitant also continued to be safe and well-tolerated. The manufacturer plans for further data analyses in order to pursue FDA approval of tradipitant for the indication of gastroparesis.

All guidelines discussed above cite another 4-week RCT, by Pasricha et al (2019), that evaluated use of oral aprepitant in adults with chronic nausea and vomiting due to gastroparesis or gastroparesis-like syndrome.11 The mean patient age was 44.8 years; 80% of patients were female and 80% were White. Nausea was the major target symptom in the study. While aprepitant failed to reduce symptoms of nausea (the visual analog scale [VAS]-based primary outcome measure), significant reductions were observed in secondary outcomes for nausea, vomiting, and overall symptoms. The trialists noted that the VAS may not be the optimal measure for assessing nausea improvement when it comes to chronic symptoms observed in this population. Another study limitation that may have led to the negative results is the heterogeneity in the patient population, which consisted of patients with both normal and delayed emptying.

No other completed or ongoing RCTs were identified on the use of NK-1 antagonists in patients with gastroparesis. An RCT by Jacob et al (2017) found that aprepitant increases fasting, postprandial, and accommodation gastric volumes, as well as volume to fullness, in healthy adults.17 The study investigators discuss that these findings could be beneficial in patients with gastroparesis; aprepitant may enhance gastric accommodation and, in turn, improve appetite in patients with this condition and other related disorders.

The remaining literature on NK-1 antagonists for management of gastroparesis-related nausea and vomiting are limited to older case reports.12-14 Overall, these reports describe successful treatment with aprepitant in 4 adults with refractory gastroparesis (3 diabetic etiology, 1 idiopathic etiology) who had failed to tolerate and/or respond to various prior treatments. All patients experienced improvements in nausea and vomiting without any reports of treatment-related adverse effects.

Table 1: Studies of NK-1 receptor antagonists for treatment of gastroparesis-related nausea and vomiting10-14
Study Design and Setting
Subjects
Duration
Interventions
Results
Carlin et al (2021)10
 
Phase 2, multicenter, double-blind, placebo-controlled RCT
 
U.S. (47 sites)
N=152 patients ≥18 years of age with IG (n=90) or DG (n=61) with delayed gastric emptying and moderate to
severe nausea
4 weeks
Randomized 1:1 to receive:
 
Tradipitant 86 mg PO twice daily (n=77)
 
OR
 
Matching placebo (n=75)
 
 
Results reported for ITT population (patients treated for ≥14 days [n=141])
 
Primary Outcome: tradipitant vs. placebo group:
 
Change in average nausea severity from baseline at week 4, measured by the Gastroparesis Core Symptom Daily Diary:a -1.25 point improvement vs. -0.73 point improvement (p=0.0099)
 
Secondary Outcomes: tradipitant vs. placebo group:
 
Nausea-free days: 28.81% of patients vs. 15.00% of patients (p=0.0160)
 
Gastroparesis Cardinal Symptom Index total score:b -0.93 point improvement vs. -0.58 point improvement (p=0.0223) 

Nausea responders (defined as an average nausea score of very mild or better [≤1] at days 22 to 28): 32.9% of patients vs. 11.8% of patients (p=0.0013)
 
Safety: tradipitant vs. placebo group:
 
Treatment-emergent AEs: 40.3% vs. 26.7%
 
Most common AEs: diarrhea, nausea, abdominal pain, dizziness, headache; these were similarly reported between groups
Pasricha et al
(2019)11
 
APRON trial
 
Multicenter, placebo-controlled, double-masked RCT
 
 
U.S.
N=126 patients ≥18 years of age with at least moderate symptoms of chronic nausea and vomiting of presumed gastric origin for ≥6 months
4 weeks
Randomized 1:1 to receive:
 
Aprepitant 125 mg PO daily (n=63)
 
OR
 
Matching placebo (n=63)
Primary Outcome:
aprepitant vs. placebo group:
 
Reduction in VAS score for nausea severity:c 46% reduction vs. 40% reduction; relative risk, 1.2; 95% CI, 0.8 to 1.7, p=NS
 
Secondary Outcomes:
aprepitant vs. placebo group:
 
Reduction in symptom severity (measured by the Gastroparesis Clinical Symptom Index): nausea (1.8 vs. 1.0; p=0.005), vomiting (1.6 vs. 0.5; p=0.001), and overall symptoms (1.3 vs. 0.7; p=0.001)
 
Safety:
aprepitant vs. placebo group:
 
AEs: predominantly mild or moderate in severity grade; 35% vs. 17%; p=0.04
Fountoulakis et al (2017)12
 
Case report
 
U.K.
Case 1: 73-year-old male (with DM II and ESRD on dialysis) and severe symptoms of refractory GP; failed treatment with metoclopramide, cyclizine, domperidone, erythromycin, and ondansetron
 
Case 2: 44-year-old male (with DM I and pancreatic transplant recipient) with refractory GP; failure treatment with domperidone, metoclopramide, ondansetron, promethazine, linaclotide, and prucalopride
Case 1: 18 months of treatment
 
Case 2: 12 months of treatment 
 
 
 
 
 
 
 
 
Aprepitant 80 mg PO daily
Case 1:
Before treatment vs. after treatment for 12 months:

Patient weight: 83 kg vs. 89 kg
 
Vomiting episodes per day: 15 to 20 vs. 0
 
Hospital admissions due to GP: 6 vs. 0
 
WHO performance status: 3 vs. 2
 
Benefits were continued at 18 months; no treatment-related AEs

Case 2:
Before treatment vs. after treatment for 12 months
 
Patient weight: 66 kg vs. 69 kg
 
Vomiting episodes per day: 10 to 15 vs. 2 to 3
 
Hospital admissions due to GP: 5 vs. 1
 
WHO performance status: 2 vs. 1
 
No treatment- related AEs
Fahler et al
(2012)13
 
Case report
 
U.S.
41-year-old female with refractory IG; failed treatment with numerous agents including  metoclopramide, ondansetron, and promethazine
2 months of treatment; follow-up 4 months after treatment discontinuation
Aprepitant 40 mg PO daily
Within 48 hours of starting treatment (2 doses): significantly decreased nausea, able to tolerate oral feeding, decreased need for outpatient IV hydration
 
During 2 months of treatment:  improvement in GP symptoms; no treatment-related AEs
 
After aprepitant discontinuation (due to cost): symptoms worsened but did not return to initial severity
 
At 4 months after treatment discontinuation: no daily nausea/vomiting but receiving high-dose promethazine and occasional outpatient IV hydration
Chong and Dhatariya
(2009)14
 
Case report
 
U.K.
31-year-old female admitted to the hospital with severe vomiting and ketoacidosis due to severe DG refractory to other treatments
4 months of treatment
Aprepitant
80 mg PO daily (slowly weaned off over a few weeks; stopped approximately 1 month after insertion of gastric electrical stimulation device)
Stopped vomiting within 24 hours of first dose of aprepitant
 
During 4 months of treatment: remained free of nausea and vomiting, able to tolerate oral food and drink for the first time in 2 months
Abbreviations: AE=adverse event, CI=confidence interval, DG=diabetic gastroparesis, DM I=diabetes mellitus type 1, DM II=diabetes mellitus type 2, ESRD=end-stage renal disease, GP=gastroparesis, IG=idiopathic gastroparesis, IV=intravenous, ITT=intention-to-treat, RCT=randomized controlled trial, NK-1=neurokinin-1, NS=not significant, PO=by mouth, U.K.=United Kingdom, U.S.=United States, VAS=visual analog score, WHO=World Health Organization.
aThe Gastroparesis Core Symptom Daily Diary is used by patients to rate the worst occurrence of each cardinal symptom of gastroparesis in the past 1 day; the scale ranges from 0 (no symptoms) to 5 (very severe).
bThe Gastroparesis Cardinal Symptom Index assesses the core symptoms of gastroparesis, with symptoms graded from 0 (no symptoms) to 5 (very severe); the total score is the average of the following subscores: nausea/vomiting (3 items), fullness/early satiety (4 items), and bloating (2 items).
cReduction in nausea was defined as a decrease of ≥25 mm, or absolute level <25 mm, on a daily patient-reported visual analog scale (0 to 100) of nausea severity.

Conclusion
Neurokinin-1 receptor antagonists, although not currently approved for the treatment of gastroparesis-related nausea and vomiting, may be potentially beneficial in the management of this condition. The phase 2 trial on tradipitant reported favorable findings; however, the approval of the drug for the indication of gastroparesis is contingent upon full phase 3 study findings and additional analyses.10,15 While the RCT on aprepitant did not meet its VAS-based primary endpoint of nausea improvement, the drug was effective in relieving nausea as assessed by a variety of secondary outcome measures (including validated scales).11 Additional RCTs of aprepitant with different primary endpoints are warranted. A few case reports have described successful management of refractory symptoms of gastroparesis with aprepitant, although there were differences in gastroparesis etiology, patient comorbidities, and treatment dosages/duration.12-14

If the overall benefit-risk profile for the NK-1 antagonists is confirmed in patients with gastroparesis, these agents may offer advantages over both approved and off-label treatments currently used.11 The ability of these agents to not only relieve nausea but also improve overall symptoms suggest a disease-modifying effect through their action both centrally in the emesis centers of the brain and peripherally in the smooth muscle of the intestines. However, future studies are needed to determine the exact mechanisms by which NK-1 antagonists reduce nausea and vomiting. Additional studies should determine optimal dosages, investigate comparative efficacy of agents, assess long-term use, and study different etiologic groups.

References

  1. Grover M, Farrugia G, Stanghellini V. Gastroparesis: a turning point in understanding and treatment. Gut. 2019;68(12):2238-2250. doi:10.1136/gutjnl-2019-318712
  2. Naing LY, Heckroth M, Mathur P, Abell TL. Gastroparesis syndromes: emerging drug targets and potential therapeutic opportunities. Expert Opin Investig Drugs. 2023;32(3):245-262. doi:10.1080/13543784.2023.2186222
  3. Ye Y, Yin Y, Huh SY, Almansa C, Bennett D, Camilleri M. Epidemiology, etiology, and treatment of gastroparesis: real-world evidence from a large US national claims database. Gastroenterology. 2022;162(1):109-121.e5. doi:10.1053/j.gastro.2021.09.064
  4. Cangemi DJ, Lacy BE. Gastroparesis. Curr Opin Gastroenterol. 2021;37(6):596-601. doi:10.1097/MOG.0000000000000782
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  6. Camilleri M, Kuo B, Nguyen L, et al. ACG Clinical Guideline: Gastroparesis. Am J Gastroenterol. 2022;117(8):1197-1220. doi:10.14309/ajg.0000000000001874
  7. Sanger GJ, Andrews PLR. Review article: An analysis of the pharmacological rationale for selecting drugs to inhibit vomiting or increase gastric emptying during treatment of gastroparesis [published online ahead of print, 2023 Mar 14]. Aliment Pharmacol Ther. 2023;10.1111/apt.17466. doi:10.1111/apt.17466
  8. Ibrahim MA, Preuss CV. Antiemetic neurokinin-1 receptor blockers. In: StatPearls. Treasure Island (FL): StatPearls Publishing; September 21, 2022.
  9. Schol J, Wauters L, Dickman R, et al. United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis. United European Gastroenterol J. 2021;9(3):287-306. doi:10.1002/ueg2.12060
  10. Carlin JL, Lieberman VR, Dahal A, et al. Efficacy and safety of tradipitant in patients with diabetic and idiopathic gastroparesis in a randomized, placebo-controlled trial. Gastroenterology. 2021;160(1):76-87.e4. doi:10.1053/j.gastro.2020.07.029
  11. Pasricha PJ, Yates KP, Sarosiek I, et al. Aprepitant has mixed effects on nausea and reduces other symptoms in patients with gastroparesis and related disorders. Gastroenterology. 2018;154(1):65-76.e11. doi:10.1053/j.gastro.2017.08.033
  12. Fountoulakis N, Dunn J, Thomas S, Karalliedde J. Successful management of refractory diabetic gastroparesis with long-term Aprepitant treatment. Diabet Med. 2017;34(10):1483-1486. doi:10.1111/dme.13413
  13. Fahler J, Wall GC, Leman BI. Gastroparesis-associated refractory nausea treated with aprepitant. Ann Pharmacother. 2012;46(12):e38. doi:10.1345/aph.1R484
  14. Chong K, Dhatariya K. A case of severe, refractory diabetic gastroparesis managed by prolonged use of aprepitant. Nat Rev Endocrinol. 2009;5(5):285-288. doi:10.1038/nrendo.2009.50
  15. Vanda Pharmaceuticals reports results from the phase iii study of tradipitant in gastroparesis. BioSpace. February 4, 2022. Accessed April 20, 2023. https://www.biospace.com/article/releases/vanda-pharmaceuticals-reports-results-from-the-phase-iii-study-of-tradipitant-in-gastroparesis/
  16. VP-VLY-686-3301: A multicenter, randomized, double-blind, placebo-controlled phase Iii study to assess the efficacy of tradipitant in relieving symptoms of gastroparesis. govidentifier: NCT04028492. Updated March 3, 2021. Accessed April 20, 2023. https://clinicaltrials.gov/ct2/show/NCT04028492?term=NCT04028492&draw=2&rank=1
  17. Jacob D, Busciglio I, Burton D, et al. Effects of NK1 receptors on gastric motor functions and satiation in healthy humans: results from a controlled trial with the NK1 antagonist aprepitant. Am J Physiol Gastrointest Liver Physiol. 2017;313(5):G505-G510. doi:10.1152/ajpgi.00197.2017

Prepared by:
Saira Jatoi
PharmD Candidate Class of 2023
University of Illinois at Chicago College of Pharmacy

Honey Joseph, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

June 2023

The information presented is current as April 4, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.