Treatment of nausea and vomiting: Gaps in our knowledge

doi:10.1016/j.autneu.2006.07.009

Autonomic Neuroscience

Volume 129, Issues 1–2, 30 October 2006, Pages 3-16

https://doi.org/10.1016/j.autneu.2006.07.009 Get rights and content

Abstract

The past 20 years have seen notable advances in our understanding of the physiology and pharmacology of the emetic reflex leading to the identification of the anti-emetic effects of 5-hydroxytryptamine₃ (5-HT₃) and neurokinin₁ receptor (NK₁) antagonists. The introduction of 5-HT₃ and NK₁ receptor antagonists into the clinic has had a major impact in alleviating the nausea and vomiting associated with the treatment of cancer and the sequelae to anaesthesia and surgery (post-operative nausea and vomiting, PONV). Despite these advances there are major gaps in our understanding. Interestingly, one of these is the relatively poor ability to treat nausea. Additional gaps in our knowledge are highlighted to provide a framework within which directions for research can be proposed. Particular attention is drawn to: lacunae in knowledge of some currently used anti-emetics such as the source of dopamine required to initiate emesis; the theoretical assumptions and mechanisms underlying the concept of a “universal anti-emetic”; the variety of receptors at which agonists act to have anti-emetic effects (GABA _B, CB₁, 5-HT_1A, ghrelin, opioid); issues of translation from animals to humans and the relationship between the pathways involved in emesis and certain gastrointestinal disorders such as dyspepsia and gastroesophageal reflux, with the latter being of particular interest as some agents affecting reflux are also anti-emetic. Together, the unmet clinical need to adequately control nausea, possibly by new drugs acting within the brainstem, and the significant gaps in understanding key aspects of the emetic reflex, suggest an important need to focus and re-direct research into the distressing and sometimes life-threatening symptoms of nausea and vomiting.

Section snippets

Background and outstanding clinical need

The past 25 years has seen a resurgence of interest in the basic and applied neuropharmacology of emesis since the ground breaking studies of Borison and Wang in the 1950s (see Davis, 1995 for review of early studies). To some extent this resurgence can be traced to the desire to develop efficacious anti-emetic strategies to deal with the intense and protracted nausea and vomiting which accompanied chemo-and radio-therapy. The widespread use of the highly emetic cytotoxic agent cisplatin,

Pathways for nausea and vomiting

These have been described in detail in several recent reviews (e.g. Hornby, 2001, Andrews and Horn, 2006, Rudd and Andrews, 2005) and will only be outlined here as a framework for discussion of the neuropharmacology.

A universal anti-emetic: theoretical or tractable target?

It would be highly desirable to have an agent which can block nausea, retching and vomiting, however caused and to be able to do this either when given prophylactically or as a treatment once nausea and vomiting were established. A theoretical consideration of this issue will form a background to the remainder of this paper which reviews the gaps in our knowledge and barriers to progress to this objective.

Dopamine, histamine and muscarinic receptor antagonists

Dopamine, histamine and muscarinic receptor antagonists are established classes of anti-emetic agent. Their use (e.g. Tonini et al., 2004, Gralla et al., 1999) and pharmacology (Sanger and Andrews, 2001) have been summarised previously. Selective and non-selective dopamine receptor antagonist drugs include thiethylperazine, prochlorperazine, chlorpromazine, fluphenazine, cyclizine, haloperidol, droperidol, domperidone and metoclopramide. Histamine receptor antagonists include cinnarizine,

Relationships between emesis and other disease processes

It is obvious that vomiting and nausea are linked with a reduced appetite, increased reflux of gastric contents into the oesophagus and in addition, to a post-emetic sensation of fatigue. However, the relationships between the pathways which evoke these changes, and the pathways involved in other diseases is less clear.

Conclusions: a way forward

Current status: Research into anti-emetic agents has in general attempted to identify neurotransmitters involved at key points in the pathway activated by the emetic stimulus of interest and finding ways of interfering selectively with this transmission. This approach has identified the key transmitters and receptors involved in the emetic reflex (i.e. D₂, H₁, M₃/M₅, 5-HT₃, NK₁) and have led to the development of drugs with significant clinical impact. An underlying assumption of this approach

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The results suggest that SCL exerted a dose-dependent anti-emetic effect on the chicks. Pretreatment with SCL-10 significantly minimized the number of retches and lengthened the emesis tendency of the experimental animals. SCL-10 significantly increased the anti-emetic effects of ODN and DOM. However, compared to the ODN-treated group, (SCL-10 + ODN) group considerably (p < 0.0001) extended the latency duration (109.40 ± 1.03 s) and significantly (p < 0.01) decreased the number of retches (20.00 ± 0.70), indicating an anti-emetic effect on the test animals. In in-silico analysis, SCL exhibited promising binding affinities with suggesting receptors.
SCL-10 exerted an inhibitory-like effect on emetic chicks, probably through the interaction of the 5HT₃ and D₂ receptors. Further studies are highly appreciated to validate this study and determine the precise mechanism(s) behind the anti-emetic effects of SCL. We expect that SCL-10 may be utilized as an antiemetic treatment in a single dosage form or that it may function as a synergist with other traditional medicines.
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ReviewTreatment of nausea and vomiting: Gaps in our knowledge

Abstract

Section snippets

Background and outstanding clinical need

Pathways for nausea and vomiting

A universal anti-emetic: theoretical or tractable target?

Dopamine, histamine and muscarinic receptor antagonists

Relationships between emesis and other disease processes

Conclusions: a way forward

Auton. Neurosci.

Auton. Neurosci. Basic Clin.

Eur. J. Pharmacol.

Neuropharmacology

Neuropsychopharmacology

Neuroscience

Neuropharmacology

Eur. J. Oncol. Nurs.

Neuropharmacology

Auton. Neurosci.

Eur. J. Cancer

Trends Pharmacol. Sci.

Gastroenterology

Gastroenterology

Gastroenterol. Clin. North Am.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Biochem. Pharmacol.

Gene

Jpn. J. Pharmacol.

Pharmacol. Biochem. Behav.

Neurosci.

Gastroenterology

Lancet

Gynecol. Oncol.

Eur. J. Pharmacol.

Neurosci. Lett.

Eur. J. Pharmacol.

J. Affect. Disord.

Eur. J. Cancer

Neuropharmacology

Eur. J. Cancer

Gastroenterology

5-HT3-receptor antagonists in the management of nausea and vomiting in cancer and cancer treatment

Oncology

High-dose dexamethasone for prevention of cisplatin-induced vomiting

Cancer Chemother. Pharmacol.

Vomiting and reflex vagal relaxation of the stomach elicited from heart receptors in the cat

Acta Physiol. Scand.

Comparative efficacy of a single oral dose of ondansetron and of buspirone against cisplatin-induced emesis in cancer patients

Br. J. Cancer

The role of tachykinins and the tachykinin NK1 receptor in nausea and emesis

Emesis and Anti-cancer Therapy: Mechanisms and Treatment

Mechanisms and models of fatigue associated with cancer and its treatment: evidence from preclinical and clinical studies

A factorial trial of six interventions for the prevention of postoperative nausea and vomiting

N. Engl. J. Med.

Betamethasone does not prevent nausea and vomiting induced by ipecacuanha

Acta Anaesthesiol. Scand.

Letter

N. Engl. J. Med.

Excitation of area postrema neurons by transmitters, peptides and cyclic nucleotides

J. Neurophysiol.

Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health

Am. J. Physiol.

Naloxone antagonizes narcotic self blockade of emesis in the cat

J. Pharmacol. Exp. Ther.

The role of D2 and D3 dopamine receptors in the mediation of emesis in Cryptotis parva (the least shrew)

J. Neural Transm.

Review
Treatment of nausea and vomiting: Gaps in our knowledge

5-HT₃-receptor antagonists in the management of nausea and vomiting in cancer and cancer treatment

The role of tachykinins and the tachykinin NK₁ receptor in nausea and emesis

The role of D₂ and D₃ dopamine receptors in the mediation of emesis in Cryptotis parva (the least shrew)