Supportive Care in Cancer

, Volume 28, Issue 1, pp 13–21 | Cite as

Revisiting the physiology of nausea and vomiting—challenging the paradigm

  • Rita J. WickhamEmail author
Review Article



The predominant neurotransmitters and receptors for acute and delayed chemotherapy-induced nausea and vomiting (CINV) are represented in the current paradigm, which reflects successful control of emesis. However, control of nausea (N) lags behind management of vomiting (V). This review aims to re-examine and incorporate new information about the mechanisms of V and N.


The initial literature search focused on CINV. Keywords in articles led to subsequent discovery of publications focused on N&V in other medical and scientific fields (e.g., gastroenterology, neurology, cannabinoid science, neuropharmacology, and motion sickness). Using keywords to identify other sources continued until no further recent, meaningful publications were found.


More than 86% of references were from recent non-oncology journals and books, suggesting there are many areas for cross-fertilization research into mechanisms and management of N&V—particularly of N, which involves overlapping and dissimilar CNS areas from V. Information from cited articles was incorporated into visual representation of N&V, which is certainly not exhaustive but supports highly complex processes in the stomach and gut, the vagus nerve and spinal cord neurons, the nucleus tractus solitarii, and the anterior insular cortex and anterior cingulate cortex with input from the amygdala.


These data support the idea that mechanisms for N, whatever the cause, must be highly similar. Continued research into nausea, including patient-reported evaluation and outcomes, is important; interventions for nausea could be considered adjuvants to current standard of care antiemetics and be individualized, depending on patient-reported efficacy and adverse effects and preferences.


Nausea Vomiting Gut-brain axis Insular cortex Interoception 


Compliance with ethical standards

Conflict of interest

Rita J. Wickham has received speaker’s honoraria from Insys Therapeutics and advisory board compensation from Helsinn Healthcare SA. There is no primary data associated with this manuscript.


  1. 1.
    Aapro M (2018) CINV: still troubling patients after all these years. Support Care Cancer 26(suppl 1):S5–S9. CrossRefGoogle Scholar
  2. 2.
    Childs DS, Looker S, Le-Rademacher J et al (2019) What occurs in the other 20% of cancer patients with chemotherapy-induced nausea and vomiting (CINV)? A single-institution qualitative study. Support Care Cancer 27:249–255. CrossRefPubMedGoogle Scholar
  3. 3.
    Singh P, Yoon SS, Kuo B (2016) Nausea: a review of pathophysiology and therapeutics. Ther Adv Gastroenterol 9:98–112. CrossRefGoogle Scholar
  4. 4.
    Donovan HS, Hagan TL, Campbell GB, Boisen MM, Rosenblum LM, Edwards RP, Bovbjerg DH, Horn CC (2016) Nausea as a sentinel symptom for cytotoxic chemotherapy effects on the gut-brain axis among women receiving treatment for recurrent ovarian cancer: an exploratory analysis. Support Care Cancer 24:2635–2642. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Ng TL, Hutton B, Clemons M (2015) Chemotherapy-induced nausea and vomiting: time for more emphasis on nausea? Oncologist 20:576–583. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Harder SL, Groenvold M, Herrstedt J, Johnsen AT (2019) Nausea in advanced cancer: relationships between intensity, burden, and the need for help. Support Care Cancer 27:265–273. CrossRefPubMedGoogle Scholar
  7. 7.
    Horn CC (2014) The medical implications of gastrointestinal vagal afferent pathways in nausea and vomiting. Curr Pharm Des 20:2703–2712. CrossRefPubMedGoogle Scholar
  8. 8.
    Torres CH, Mazzarello S, Ng T et al (2015) Defining optimal control of chemotherapy-induced nausea and vomiting—based on patients’ experience. Support Care Cancer 23:3341–3359. CrossRefGoogle Scholar
  9. 9.
    Limebeer CL, Rock EM, Sharkey KA, Parker LA (2018) Nausea-induced 5-HT release in the interoceptive insular cortex and regulation by monoacylglycerol lipase (MAGL) inhibition and cannabidiol. eNeuro 5(4). CrossRefGoogle Scholar
  10. 10.
    Sanger GJ, Andrews PLR (2018) A history of drug discovery for treatment of nausea and vomiting and the implications for future research. Front Pharmacol 9:913. Published online Sept 4, 2018. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Balaban CD, Yates BJ (2017) What is nausea? A historical analysis of changing views. Auton Neurosci 202:5–17. CrossRefPubMedGoogle Scholar
  12. 12.
    Napadow V, Sheehan JD, Kim J, LaCount LT, Park K, Kaptchuk TJ, Rosen BR, Kuo B (2013) The brain circuitry underlying the temporal evolution of nausea in humans. Cereb Cortex 23:806–813. CrossRefPubMedGoogle Scholar
  13. 13.
    Koch KL (2014) Gastric dysrhythmias: a potential objective measure of nausea. Exp Brain Res 232:2553–2561. CrossRefPubMedGoogle Scholar
  14. 14.
    Müller TD, Nogueiras R, Andermann ML (2015) Ghrelin. Molecular Metabolism 4:437–460. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hiura Y, Takiguchi S, Yamamoto K, Kurokawa Y, Yamasaki M, Nakajima K, Miyata H, Fujiwara Y, Mori M, Doki Y (2012) Fall in plasma ghrelin concentrations after cisplatin-based chemotherapy in esophageal cancer patients. Int J Clin Oncol 17:316–323. CrossRefPubMedGoogle Scholar
  16. 16.
    Wo JM, Ejskjaer N, Hellstrom PM et al (2011) Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting – randomised clinical study subset data. Aliment Pharmacol Ther 33:679–688. CrossRefPubMedGoogle Scholar
  17. 17.
    Rudd JA, Chan SW, Ngan MP, Tu L, Lu Z, Giuliano C, Lovati E, Pietra C (2018) Anti-emetic action of the brain-penetrating new ghrelin agonist, HM01, alone and in combination with the 5-HT3 antagonist, palonosetron and with the NK1 antagonist, netupitant, against cisplatin- and motion-induced emesis in Suncus murinus (house musk shrew). Front Pharmacol 9:869. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Cabezos PA, Vera G, Martin-Fontelles MI et al (2010) Cisplatin-induced gastrointestinal dysmotility is aggravated after chronic administration in the rat. Comparison with pica. Neurogastroenterol Motil 22:797–805, 797-e225. CrossRefPubMedGoogle Scholar
  19. 19.
    Rock EM, Sticht MA, Limebeer CL, Parker LA (2016) Cannabinoid regulation of acute and anticipatory nausea. Cannabis Cannabinoid Res 1:113–121. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Weltens N, Iven J, Van Oudenhove L, Kano M (2018) The gut–brain axis in health neuroscience: implications for functional gastrointestinal disorders and appetite regulation. Ann N Y Acad Sci 1428:129–150. CrossRefPubMedGoogle Scholar
  21. 21.
    Schemann M (2005) Control of gastrointestinal motility by the “gut brain” — the enteric nervous system. J Pediatr Gastroenterol Nutr 41:S4–S6CrossRefGoogle Scholar
  22. 22.
    Critchley HD, Harrison NA (2013) Visceral influences on brain and behavior. Neuron 77:624–638. CrossRefPubMedGoogle Scholar
  23. 23.
    Ahlman H, Nilsson O (2001) The gut as the largest endocrine organ in the body. Ann Oncol 12(Suppl 2):S63–S68CrossRefGoogle Scholar
  24. 24.
    Nezami BG, Srinivasan S (2010) Enteric nervous system in the small intestine: pathophysiology and clinical implications. Curr Gastroenterol Rep 12:358–365. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bellono NW, Bayrer JR, Leitch DB, Castro J, Zhang C, O’Donnell TA, Brierley SM, Ingraham HA, Julius D (2017) Enterochromaffin cells are gut chemosensors that couple to sensory neural pathways. Cell 170:185–198. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Diwakarla S, Fothergill LJ, Fakhry J, Callaghan B, Furness JB (2017) Heterogeneity of enterochromaffin cells within the gastrointestinal tract. Neurogastroenterol Motil 29:e13101–ee1315. CrossRefGoogle Scholar
  27. 27.
    Obara Y, Machida T, Takano Y, Shiga S, Suzuki A, Hamaue N, Iizuka K, Hirafuji M (2018) Cisplatin increases the number of enterochromaffin cells containing substance P in rat intestine. Naunyn Schmiedeberg's Arch Pharmacol 391:847–858. CrossRefGoogle Scholar
  28. 28.
    Alcaino C, Knutson KR, Treichel AJ, Yildiz G, Strege PR, Linden DR, Li JH, Leiter AB, Szurszewski JH, Farrugia G, Beyder A (2018) A population of gut epithelial enterochromaffin cells is mechanosensitive and requires Piezo2 to convert force into serotonin release. Proc Natl Acad Sci U S A 115(32):E7632–E7641. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Babic T, Browning KN (2014) The role of vagal neurocircuits in the regulation of nausea and vomiting. Eur J Pharmacol 722:38–47. CrossRefPubMedGoogle Scholar
  30. 30.
    Zhong W, Picca AJ, Lee AS, Darmani NA (2017) Ca2+ signaling and emesis: recent progress and new perspectives. Auton Neurosci 202:18–27. CrossRefPubMedGoogle Scholar
  31. 31.
    Yamamoto K, Asano K, Tasaka A, Ogura Y, Kim S, Ito Y, Yamatodani A (2014) Involvement of substance P in the development of cisplatin-induced acute and delayed pica in rats. Brit J Pharmacol 171:2888–2899. CrossRefGoogle Scholar
  32. 32.
    Ju C, Hamaue N, Machida T, Liu Y, Iizuka K, Wang Y, Minami M, Hirafuji M (2008) Anti-inflammatory drugs ameliorate opposite enzymatic changes in ileal 5-hydroxytryptamine metabolism in the delayed phase after cisplatin administration to rats. Eur J Pharmacol 589:281–287. CrossRefPubMedGoogle Scholar
  33. 33.
    Machida T, Takano Y, Iizuka K, Machida M, Hirafuji M (2017) Methotrexate causes acute hyperplasia of enterochromaffin cells containing substance P in the intestinal mucosa of rats. J Pharmacol Sci 133:190–193. CrossRefPubMedGoogle Scholar
  34. 34.
    Travagli RA, Anselmi L (2016) Vagal neurocircuitry and its influence on gastric motility. Nat Rev Gastroenterol Hepatol 13:389–401. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Muth ER (2006) Motion and space sickness: intestinal and autonomic correlates. Auton Neurosci 129(1-2):58–66. CrossRefPubMedGoogle Scholar
  36. 36.
    Lackner JR (2014) Motion sickness: more than nausea and vomiting. Exp Brain Res 232:2493–2510. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Toschi N, Kim J, Sclocco R, Duggento A, Barbieri R, Kuo B, Napadow V (2017) Motion sickness increases functional connectivity between visual motion and nausea-associated brain regions. Auton Neurosci 202:108–113. CrossRefPubMedGoogle Scholar
  38. 38.
    Cutsforth-Gregory JK, Benarroch EE (2017) Nucleus of the solitary tract, medullary reflexes, and clinical implications. Neurology 88:1187–1196. CrossRefPubMedGoogle Scholar
  39. 39.
    Kaur C, Ling E-A (2017) The circumventricular organs. Histol Histopathol 32:879–892. CrossRefPubMedGoogle Scholar
  40. 40.
    Price CJ, Hoyda TD, Ferguson AV (2008) The area postrema: a brain monitor and integrator of systemic autonomic state. Neuroscientist 14:182–194. CrossRefPubMedGoogle Scholar
  41. 41.
    Miyata S (2015) New aspects in fenestrated capillary and tissue dynamics in the sensory circumventricular organs of adult brains. Front Neurosci 9:–390.
  42. 42.
    Wang Q-P, Guan J-L, Pan W, Kastin AJ, Shioda S (2008) A diffusion barrier between the area postrema and nucleus tractus solitarius. Neurochem Res 33:2035–2043. CrossRefPubMedGoogle Scholar
  43. 43.
    Chin C-L, Fox GB, Hradil VP et al (2006) Pharmacological MRI in awake rats reveals neural activity in area postrema and nucleus tractus solitarius: relevance as a potential biomarker for detecting drug-induced emesis. NeuroImage 33:1152–1160. CrossRefPubMedGoogle Scholar
  44. 44.
    Craig AD (2015) How do you feel? (pp 130–181). Princeton University PressGoogle Scholar
  45. 45.
    Sun X, Xu L, Guo F, Luo W, Gao S, Luan X (2017) Neurokinin-1 receptor blocker CP-99 94 improved emesis induced by cisplatin via regulating the activity of gastric distention responsive neurons in the dorsal motor nucleus of vagus and enhancing gastric motility in rats. Neurogastroenterol Motil 29(10):1–11. CrossRefPubMedGoogle Scholar
  46. 46.
    Stich MA, Limebeer CL, Rafla BR et al (2016) Endocannabinoid regulation of nausea is mediated by 2-arachidonoylglycerol (2-AG) in the rat visceral insular cortex. Neuropharmacol 102:92–102. CrossRefGoogle Scholar
  47. 47.
    Farmer AD, Ban VF, Coen SJ, Sanger GJ, Barker GJ, Gresty MA, Giampietro VP, Williams SC, Webb DL, Hellström PM, Andrews PLR, Aziz Q (2015) Visually induced nausea causes characteristic changes in cerebral, autonomic and endocrine function in humans. J Physiol 593(5):1183–1196. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Sclocco R, Kim J, Garcia RG, Sheehan JD, Beissner F, Bianchi AM, Cerutti S, Kuo B, Barbieri R, Napadow V (2016) Brain circuitry supporting multi-organ autonomic outflow in response to nausea. Cereb Cortex 26:485–497. CrossRefPubMedGoogle Scholar
  49. 49.
    Uddin LQ, Nomi JS, Hebert-Seropian B et al (2017) Structure and function of the human insula. J Clin Neurophysiol 34:300–306. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Namkung H, Kim S-H, Sawa A (2017) The insula: an underestimated brain area in clinical neuroscience, psychiatry, and neurology. Trends Neurosci 40:200–207. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Gogolla N (2017) The insular cortex. Curr Biol 27:R573–R591. CrossRefGoogle Scholar
  52. 52.
    Craig AD (2009) How do you feel — now? The anterior insula and human awareness. Nat Rev Neurosci 10:59–70. CrossRefPubMedGoogle Scholar
  53. 53.
    Janak PH, Tye KM (2015) From circuits to behaviour in the amygdala. Nature 517(7534):284–292. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Benarroch EE (2016) Parabrachial nuclear complex: multiple functions and potential clinical implications. Neurology 86:676–683. CrossRefPubMedGoogle Scholar
  55. 55.
    Pirri C, Bayliss E, Trotter J, Olver IN, Katris P, Drummond P, Bennett R (2013) Nausea still the poor relation in antiemetic therapy? The impact on cancer patients’ quality of life and psychological adjustment of nausea, vomiting and appetite loss, individually and concurrently as part of a symptom cluster. Support Care Cancer 21:735–748. CrossRefPubMedGoogle Scholar
  56. 56.
    Lu Y, Anderson HD (2017) Cannabinoid signaling in health and disease. Can J Physiol Pharmacol 95:311–327. CrossRefPubMedGoogle Scholar
  57. 57.
    Mechoulam R, Parker LA (2013) The endocannabinoid system and the brain. Annu Rev Psychol 64:21–47. CrossRefPubMedGoogle Scholar
  58. 58.
    Sharkey KA, Darmani NA, Parker LA (2014) Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol 722:134–146. CrossRefPubMedGoogle Scholar
  59. 59.
    Zheng Y, Wang X-L, Moa F-F, Li M (2014) Dexamethasone alleviates motion sickness in rats in part by enhancing the endocannabinoid system. Eur J Pharmacol 727:99–105. CrossRefPubMedGoogle Scholar
  60. 60.
    Smith LA, Azariah F, Lavender VTC, et al (2015). Cannabinoids for nausea and vomiting in adults with cancer receiving chemotherapy. Cochrane Database of Systematic Reviews Issue 11. Art. No.: CD009464.
  61. 61.
    Abrams DI (2018) The therapeutic effects of Cannabis and cannabinoids: an update from the National Academies of Sciences, Engineering and Medicine report. Eur J Intern Med 49:7–11. CrossRefPubMedGoogle Scholar
  62. 62.
    Farrell C, Brearley SG, Pilling M, Molassiotis A (2013) The impact of chemotherapy-related nausea on patients’ nutritional status, psychological distress and quality of life. Support Care Cancer 21:59–66. CrossRefPubMedGoogle Scholar
  63. 63.
    Andrews PLR, Sanger GJ (2014) Nausea and the quest for the perfect anti-emetic. Eur J Pharmacol 722:108–121. CrossRefPubMedGoogle Scholar
  64. 64.
    Malamood M, Roberts A, Kataria R, Parkman H, Schey R (2017) Mirtazapine for symptom control in refractory gastroparesis. Drug Des Devel Ther 11:1035–1041. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Rush University College of NursingRapid RiverUSA

Personalised recommendations