Vomiting – what’s coming up next?

Professor Paul Andrews,
Professor of Physiology,
St George’s Hospital Medical School.

Biography
Studied Physiology at undergraduate and postgraduate levels at the University of Sheffield, prior to obtaining lectureships at the University of Edinburgh and St George’s, University of London, where he is Professor of Comparative Physiology and Dean of Postgraduate Studies.

His research over the past 25 years has focused on the pre-clinical neuropharmacology of emesis, with particular emphasis on anti-cancer chemotherapy and the role of the vagus.  He has worked on the site(s) of action of 5-HT3 and NK1 receptor antagonists in conjunction with colleagues in Industry.

He is co-author of a book on Nausea for Oxford University Press and this is due to be published next year.  He has had a long standing interest in comparative physiology of the digestive tract and has published on octopus, sharks and crocodiles as well as studies in mammals including humans.

He gave the 2008 Paget Lecture of the Research Defence Society on the topic of  “Translating the 3Rs in complex physiological systems” and in October gave the 2009 Sydenham Lecture of the Society of Apothecaries on “A brief history of vomiting: The fist 700million years”.

Currently he is working on non-animal methodologies to investigate the emetic liability of potential new drugs.

Abstract

Vomiting is the forceful oral expulsion of upper gastrointestinal contents and in mammals is brought about primarily by compression of the stomach by forceful contraction of the diaphragm (the crural fibres are inactive during vomiting, but not during retching) and anterior abdominal muscles.  Prior to the onset of retching and vomiting the proximal stomach is relaxed (vagal efferent activation of inhibitory NO/VIP neurones) and a retrograde giant contraction (RGC) sweeps intestinal contents from the lower small intestine to the stomach-the RGC is under vagal cholinergic control.  These motor events and associated prodromata (e.g. salivation, swallowing, cutaneous vasoconstriction) are coordinated in the brainstem and vomiting can be elicited in decerebrate and anaesthetised animals.  Vomiting is evoked by activation of one of the following inputs: cerebral inputs (sight, smell, vision); vestibular system (motion sickness); area postrema (a circumventricular organ located at the caudal extremity of the fourth venbtricle where the blood-brain-barrier is relatively permeable); cardiac and abdominal vagal afferents.  Although splanchnic (“pain”) afferents are unable to trigger reflex emesis, pain and nausea are related possibly via the release of adrenaline.  Each of the above sites and indirect effects leading to activation of one or more of the above pathways (e.g. gastric stasis, release of hormones with emetic potential ) is a potential target for the emetic effects of anaesthetics, drugs used in the peri-operative period (e.g. opioids) or surgical procedures.

Broadly speaking anti-emetics may be targeted at correcting underlying disordered gut motility (e.g. conventional doses of metoclopramide), blocking a key step in abdominal vagal afferent activation (e.g. one of the sites of action of 5-HT3 receptor antagonists) or blocking the effect of a transmitter at a key step in the central pathways (e.g. NK1 receptor antagonists, H1/M3/5 antagonists for motion sickness).

In contrast, nausea is a self-reported unpleasant sensation associated with the urge to vomit of the feeling that vomiting is imminent.  It is relatively poorly understood from a mechanistic perspective although a large rise in plasma ADH (vasopressin) and EGG (electrogastrogram) rhythm changes are arguably reliable biomarkers and the brain pathways (insular cortex) involved in processing visceral sensations are beginning to be identified.  Nausea is relatively poorly treated in contrast to vomiting.  This is curious as the conventional view of nausea is that it serves as a “warning” induced by “low” level activation of pathways which if more intensely/continuously stimulated would lead to vomiting.  Nausea is usually of more concern to patients and although it is a less visible sign of distress than is vomiting its impact upon recovery (e.g.  resumption of food intake) should not be underestimated.

The above framework will provide a background against which gaps in our current knowledge of nausea and vomiting will be discussed in particular relation to PONV and drugs used to treat pain.  Future therapeutic approaches especially to the treatment of nausea will be considered.

References

1. Andrews, P.L.R. (1999). Postoperative nausea and vomiting. In M.K. Herbert, P. Holzer and N. Roewer (eds.) Problems of the gastrointestinal tract in anesthesia, the perioperative period, and intensive care, (pp. 267-288). Berlin and Heidelberg: Springer Verlag
   
   
2. Andrews, P.L.R. and Rudd, J.A. (2004). The role of tachykinins and the tachykinin NK1 receptor in nausea and emesis. In P. Holzer, Handbook of Experimental Pharmacology (pp. 359-440). Berlin: Springer-Verlag.
   
   
3. Apfel., C.C. (2009) Postoperative nausea and vomiting. In Young,W.L., (Ed) Miller’s Anaesthesia. Churchill Livingstone/Elsevier.

4. Apfel, C.C., Kranke, P., Eberhart, l.H., Roos, A. and Roewer, N. (2002) Comparison of predictive models for postoperative nausea and vomiting.  Br J Anaesthesiol, 89, 339-340.
   
   
5. Apfel, C.C., Kortilla, K., Abdalla, M., Kerger, H., Turan, A., Vedder, I., Zernak, C., Danner, K., Jokela, R., Pocock, S.J., Trenkler, S., Kredel, M., Biedler, A., Sessler, D.I., Roewer, N. And IMPACT Investigators (2004). A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med, 350, 2441-2451.
   
   
6. Apfel, C.C., Malhotra, A. and Leslie, J.B. (2008). The role of neurokinin-1 receptor antagonists for the management of postoperative nausea and vomiting. Curr Opinion in Anesth,21, 427-432.

7. Gan, T.J. (2006). Risk factors for postoperative nausea and vomiting.  Anesth Analg, 102, 1884-1898.
   
   
8. Gan, T.J., Apfel, C.C., Kovac, A., Philip, B.K., Singla, N., Minkowitz, H., Habib, A.S., Knighton, J., Carides, A.D., Zhang, H., Horgan, K.J., Evans, J.K., Lawson, F.C., The Aprepitant-PONV Study Group (2007). A Randomized, Double-Blind Comparison of the NK1Antagonist, Aprepitant, Versus Ondansetron for the Prevention of Postoperative Nausea and Vomiting. Anesth Analg, 104, 1082-1089.
   
   
9. Gan, T.J., Jiao, K.R., Zenn, M. and Georgiade, G. (2004). A randomized controlled comparison of electro-acupoint stimulation or ondansetron versus placebo for the prevention of postoperative nausea and vomiting. Anesth Analg, 99, 1070-1075.
   
   
10. Gan, T.J., Meyer, T., Apfel, C.C., Chung, F., Davis, P.J., Eubanks, S., Kovac, A., Philip, B.K., Sessler, D.I., Temo, J., Tramèr, M.R. and Watcha, M. (2003). Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg, 97, 62-71.
    
    
11. Sanger, G.J. and Andrews, P.L.R. (2006). Treatment of nausea and vomiting: Gaps in our knowledge. Auton Neurosci, 129, 3-16.
    
    
12. Stern, R.M., Andrews. P.L.R. & Koch, K.  (2010).  Nausea.  Oxford University Press.  To be published in mid 2010.