Skip to main content

Revisiting the physiology of nausea and vomiting—challenging the paradigm

Supportive Care in Cancer volume 28, pages 13–21 (2020)Cite this article

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Aapro M (2018) CINV: still troubling patients after all these years. Support Care Cancer 26(suppl 1):S5–S9. https://doi.org/10.1007/s00520-018-4131-3

    Article  Google Scholar 

  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. https://doi.org/10.1007/s00520-018-4323-x

    Article  PubMed  Google Scholar 

  3. Singh P, Yoon SS, Kuo B (2016) Nausea: a review of pathophysiology and therapeutics. Ther Adv Gastroenterol 9:98–112. https://doi.org/10.1177/1756283X15618131

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1007/s00520-015-3071-4

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ng TL, Hutton B, Clemons M (2015) Chemotherapy-induced nausea and vomiting: time for more emphasis on nausea? Oncologist 20:576–583. https://doi.org/10.1634/theoncologist.2014-0438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s00520-018-4326-7

    Article  PubMed  Google Scholar 

  7. Horn CC (2014) The medical implications of gastrointestinal vagal afferent pathways in nausea and vomiting. Curr Pharm Des 20:2703–2712. https://doi.org/10.2174/13816128113199990568

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00520-015-2801-y

    Article  Google Scholar 

  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). https://doi.org/10.1523/ENEURO.0256-18.2018

    Article  Google Scholar 

  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. https://doi.org/10.3389/fphar.2018.00913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Balaban CD, Yates BJ (2017) What is nausea? A historical analysis of changing views. Auton Neurosci 202:5–17. https://doi.org/10.1016/j.autneu.2016.07.003

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1093/cercor/bhs073

    Article  PubMed  Google Scholar 

  13. Koch KL (2014) Gastric dysrhythmias: a potential objective measure of nausea. Exp Brain Res 232:2553–2561. https://doi.org/10.1007/s00221-014-4007-9

    Article  PubMed  Google Scholar 

  14. Müller TD, Nogueiras R, Andermann ML (2015) Ghrelin. Molecular Metabolism 4:437–460. https://doi.org/10.1016/j.molmet.2015.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s10147-011-0289-0

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1365-2036.2010.04567.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.3389/fphar.2018.00869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/j.1365-2982.2010.01483.x

    Article  CAS  PubMed  Google Scholar 

  19. Rock EM, Sticht MA, Limebeer CL, Parker LA (2016) Cannabinoid regulation of acute and anticipatory nausea. Cannabis Cannabinoid Res 1:113–121. https://doi.org/10.1089/can.2016.0006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/nyas.13969

    Article  PubMed  Google Scholar 

  21. Schemann M (2005) Control of gastrointestinal motility by the “gut brain” — the enteric nervous system. J Pediatr Gastroenterol Nutr 41:S4–S6

    Article  Google Scholar 

  22. Critchley HD, Harrison NA (2013) Visceral influences on brain and behavior. Neuron 77:624–638. https://doi.org/10.1016/j.neuron.2013.02.008

    Article  CAS  PubMed  Google Scholar 

  23. Ahlman H, Nilsson O (2001) The gut as the largest endocrine organ in the body. Ann Oncol 12(Suppl 2):S63–S68

    Article  Google Scholar 

  24. Nezami BG, Srinivasan S (2010) Enteric nervous system in the small intestine: pathophysiology and clinical implications. Curr Gastroenterol Rep 12:358–365. https://doi.org/10.1007/s11894-010-0129-9

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.cell.2017.05.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1111/nmo.13101

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1007/s00210-018-1493-5

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1073/pnas.1804938115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Babic T, Browning KN (2014) The role of vagal neurocircuits in the regulation of nausea and vomiting. Eur J Pharmacol 722:38–47. https://doi.org/10.1016/j.ejphar.2013.08.047

    Article  CAS  PubMed  Google Scholar 

  30. Zhong W, Picca AJ, Lee AS, Darmani NA (2017) Ca2+ signaling and emesis: recent progress and new perspectives. Auton Neurosci 202:18–27. https://doi.org/10.1016/j.autneu.2016.07.006

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/bph.12629

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.ejphar.2008.04.050

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.jphs.2017.02.009

    Article  CAS  PubMed  Google Scholar 

  34. Travagli RA, Anselmi L (2016) Vagal neurocircuitry and its influence on gastric motility. Nat Rev Gastroenterol Hepatol 13:389–401. https://doi.org/10.1038/nrgastro.2016.76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Muth ER (2006) Motion and space sickness: intestinal and autonomic correlates. Auton Neurosci 129(1-2):58–66. https://doi.org/10.1016/j.autneu.2006.07.020

    Article  PubMed  Google Scholar 

  36. Lackner JR (2014) Motion sickness: more than nausea and vomiting. Exp Brain Res 232:2493–2510. https://doi.org/10.1007/s00221-014-4008-8

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.autneu.2016.10.003

    Article  PubMed  Google Scholar 

  38. Cutsforth-Gregory JK, Benarroch EE (2017) Nucleus of the solitary tract, medullary reflexes, and clinical implications. Neurology 88:1187–1196. https://doi.org/10.1212/WNL.0000000000003751

    Article  PubMed  Google Scholar 

  39. Kaur C, Ling E-A (2017) The circumventricular organs. Histol Histopathol 32:879–892. https://doi.org/10.14670/HH-11-881

    Article  PubMed  Google Scholar 

  40. Price CJ, Hoyda TD, Ferguson AV (2008) The area postrema: a brain monitor and integrator of systemic autonomic state. Neuroscientist 14:182–194. https://doi.org/10.1177/1073858407311100

    Article  PubMed  Google Scholar 

  41. Miyata S (2015) New aspects in fenestrated capillary and tissue dynamics in the sensory circumventricular organs of adult brains. Front Neurosci 9:–390. https://doi.org/10.3389/fnins.2015.00390

  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. https://doi.org/10.1007/s11064-008-9676-y

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1124/jpet.111.188797

    Article  CAS  PubMed  Google Scholar 

  44. Craig AD (2015) How do you feel? (pp 130–181). Princeton University Press

  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. https://doi.org/10.1111/nmo.13096

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.neuropharm.2015.10.039

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1113/jphysiol.2014.284240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1093/cercor/bhu172

    Article  PubMed  Google Scholar 

  49. Uddin LQ, Nomi JS, Hebert-Seropian B et al (2017) Structure and function of the human insula. J Clin Neurophysiol 34:300–306. https://doi.org/10.1097/WNP.0000000000000377

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.tins.2017.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gogolla N (2017) The insular cortex. Curr Biol 27:R573–R591. https://doi.org/10.1016/j.cub.2017.05.010

    Article  CAS  Google Scholar 

  52. Craig AD (2009) How do you feel — now? The anterior insula and human awareness. Nat Rev Neurosci 10:59–70. https://doi.org/10.1038/nrn2555

    Article  CAS  PubMed  Google Scholar 

  53. Janak PH, Tye KM (2015) From circuits to behaviour in the amygdala. Nature 517(7534):284–292. https://doi.org/10.1038/nature14188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Benarroch EE (2016) Parabrachial nuclear complex: multiple functions and potential clinical implications. Neurology 86:676–683. https://doi.org/10.1212/WNL.0000000000002393

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00520-012-1574-9

    Article  PubMed  Google Scholar 

  56. Lu Y, Anderson HD (2017) Cannabinoid signaling in health and disease. Can J Physiol Pharmacol 95:311–327. https://doi.org/10.1139/cjpp-2016-0346

    Article  CAS  PubMed  Google Scholar 

  57. Mechoulam R, Parker LA (2013) The endocannabinoid system and the brain. Annu Rev Psychol 64:21–47. https://doi.org/10.1146/annurev-psych-113011-143739

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ejphar.2013.09.068

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ejphar.2014.01.047

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/14651858.CD009464.pub2

  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. https://doi.org/10.1016/j.ejim.2018.01.003

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00520-012-1493-9

    Article  PubMed  Google Scholar 

  63. Andrews PLR, Sanger GJ (2014) Nausea and the quest for the perfect anti-emetic. Eur J Pharmacol 722:108–121. https://doi.org/10.1016/j.ejphar.2013.09.072

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2147/DDDT.S125743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Rush University College of Nursing, 8039 Garth Point Lane, Rapid River, MI, 49878, USA

    Rita J. Wickham

Authors
  1. Rita J. Wickham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rita J. Wickham.

Ethics declarations

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

If you always do what you always did, you’ll always get what you always got.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wickham, R.J. Revisiting the physiology of nausea and vomiting—challenging the paradigm. Support Care Cancer 28, 13–21 (2020). https://doi.org/10.1007/s00520-019-05012-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00520-019-05012-8

Keywords

  • Nausea
  • Vomiting
  • Gut-brain axis
  • Insular cortex
  • Interoception