Nausea and the quest for the perfect anti-emetic.

European Journal of Pharmacology 722 (2014) 108–121

Contents lists available at ScienceDirect

European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Review

Nausea and the quest for the perfect anti-emetic Paul L.R. Andrews a,n, Gareth J. Sanger b a

Division of Biomedical Sciences, St George's University of London, SW17 0RE, UK National Centre for Bowel Research & Surgical Innovation, Blizard Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, E1 2AT, UK

b

art ic l e i nf o

a b s t r a c t

Article history: Accepted 22 September 2013 Available online 22 October 2013

The discovery of anti-emetic agents is reviewed to illustrate the large database (4 129,000 papers in PubMed) available for potential data mining and to provide a background to the shift in interest to nausea from vomiting. Research on nausea extends to identification of biomarkers for diagnosis/clinical trials and to understanding why nausea is such a common dose-limiting toxicity of diverse therapeutic agents. The lessons learned for translation from animals to humans, from the discovery of the antivomiting effects of 5-HT3 and NK1 receptor antagonists, is discussed in terms of the similarities between the emetic pathways and their pharmacology, and also in terms of the limitations of rodent models of “nausea” (pica, conditioned taste aversion, conditioned gaping and disgust). The review focuses on the established view that anti-emetics are more efficacious against vomiting than nausea. In particular we examine studies of 5-HT3, NK1 and D2 receptor antagonists, gabapentin and various receptor agonists. The potential for targeting anti-nausea agents is then considered, by targeting mechanisms which correct delayed gastric emptying (prokinetics), the rise in plasma vasopressin (AVP) and/or act at central targets revealed by the growing knowledge of cortical regions activated/inhibited in subjects reporting nausea. Modulation of the projections from the brainstem to the cortical areas responsible for the genesis of the sensation of nausea provides the most likely approach to a target at which an anti-nausea drug could be targeted with the expectation that it would affect nausea from multiple causes. & 2013 Elsevier B.V. All rights reserved.

Keywords: Animal model Anti-emetic Prokinetic Nausea Vasopressin Vomiting

Contents 1.

2.

3.

n

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 1.1. How did we get here? A brief survey of the historical literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 1.2. The origins of pharmacological treatments for nausea (and vomiting): seasickness, pregnancy and anaesthesia . . . . . . . . . . . . . . . . . . 109 1.3. The modern era: chemotherapy and radiotherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 1.4. The shift in clinical focus towards nausea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 Why study nausea? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 2.1. In the clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 2.1.1. Diagnosis and measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 2.1.2. Treatments and patient factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 2.1.3. Human models of nausea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 2.1.4. Side-effect of medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 2.2. In the laboratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 2.2.1. Animal models in research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 2.2.2. Animal welfare in research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 2.2.3. Veterinary diagnosis and treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 The physiology of nausea: a brief synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 3.1. Pathways for induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 3.2. Encoding the signals for nausea and vomiting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 3.3. Physiological changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 3.3.1. Plasma AVP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Corresponding author. E-mail address: [email protected] (P.L.R. Andrews).

0014-2999/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2013.09.072

P.L.R. Andrews, G.J. Sanger / European Journal of Pharmacology 722 (2014) 108–121

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3.3.2. The electrogastrogram (EGG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 The wave-like nature of nausea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 Where is the sensation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 3.5.1. How representative is vection induced nausea? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 3.5.2. Regional brain inactivation may be as important as activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 4. Animal models of vomiting: what have they taught us about translation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 4.1. Pathway comparability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 4.2. Pharmacological compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 5. Animal models of nausea: an oxymoron? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 6. The pharmacology of nausea: questions and approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 6.1. The perfect anti-emetic: a myth or realistic possibility? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 6.2. Are current anti-emetics really more efficacious against vomiting as compared to nausea? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 6.3. What do current drugs tell us?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 6.3.1. 5-HT3 and NK1 receptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 6.3.2. Dopamine receptor antagonists and prokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 6.3.3. Receptor agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 Acknowledgement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 3.4. 3.5.

1. Introduction

1.2. The origins of pharmacological treatments for nausea (and vomiting): seasickness, pregnancy and anaesthesia

1.1. How did we get here? A brief survey of the historical literature “The longer you can look back, the further you can look forward” (Winston Churchill, Address to the Royal College of Physicians, March 1944). The “historical” literature on nausea and vomiting spans around 3000 years with the focus being on seasickness, pregnancy sickness and gastrointestinal disorders (reviewed in Stern et al., 2011). Using the search term “nausea” in PubMed reveals over 45,000 publications with the earliest in 1843 (Anon, 1843 ) and using “vomiting” as a search term there are over 57,000 with the earliest in 1814 (Chevalier, 1814). The per annum publication figure has increased steadily and currently there are 4 2200 publications per annum in each topic (Fig. 1a). Curiously, the search term “antiemetic” reveals substantially more publications ( 4129,000) despite the first publication being as recently as 1945. Publications on anti-emetics were stable 3000 per annum between 1983 and 2008 but since then the number has steadily declined and is now 2000 publications per annum, the level in 1978 around the time that studies with domperidone (Motiliums) were in the ascendancy (Fig. 1b). Without more detailed analysis by topic, we must be cautious in drawing conclusions but with such an extensive literature and at least 50 years of relatively well controlled research one could ask “why do we not have a perfect antiemetic?” There is a growing danger that unfamiliarity with “the literature” (especially when much of older key information is in books that can be hard to locate) leads to critical information being overlooked. Further, the published literature represents only a proportion of data generated from human and animal studies on drugs with emetic or anti-emetic activity (especially studies with a negative outcome). This problem can make it difficult to assess translation from laboratory to clinical studies and hence, assess the validity of pre-clinical models and novel research areas (Percie du Sert et al., 2011, 2012). Nevertheless, in the last 30 years, pre-clinical models of anti-cancer chemotherapy-induced emesis played a pivotal role in the identification of two new classes of anti-emetic (5-hydroxytryptamine3 and neurokinin1 receptor antagonists; Percie du Sert and Andrews, in press).

Nausea is a Latin word derived from the Greek word naus for ship and its early use was synonymous for seasickness, reflecting the common form of travel at the time. The Roman statesman and philosopher Cicero (106-43 BCE) is alleged to have exclaimed that he “would rather be killed than again suffer the tortures of nausea maris” (Marti-Ibanez, 1954). Early attempts to treat nausea and the accompanying vomiting were linked either to seasickness or to pregnancy (Stern et al., 2011). For seasickness, the range of active substances is extensive and includes many we recognise today (e.g. opium, bimeconate of morphia, henbane (Hyoscyamus niger, the source of hyoscine), atropine and tincture of ginger; Reason and Brand, 1975) and also sips of iced champagne (Holling, 1947). The discovery of general anaesthesia introduced the problem of post-operative nausea and vomiting, as illustrated by Dr. John Snow (1813–1858) a British physician who developed the first controlled inhalers for volatile anaesthetics (ether and chloroform) “When sickness has continued after the immediate effects of the vapour have subsided, and the stomach has been quite emptied by vomiting, I have generally found that a little wine or weak brandy and water has removed the sickness.” (Ellis, 1994). The desire to treat the nausea and vomiting resulting from volatile anaesthetics may be the first documented example recognising the need for an “antiemetic” to treat a symptom produced by a medical therapy. Today, the large number of operations worldwide indicates that identification of agents to treat post-operative nausea and vomiting (PONV) represents a major opportunity for the pharmaceutical industry, especially when there is now an emphasis on daysurgery. 1.3. The modern era: chemotherapy and radiotherapy The major drivers to identify drugs to treat the side effects of therapies came in the first half of the 20th Century with the identification of chemotherapeutic agents and radiation to treat cancer and antibiotics for infections. For example, in a trial (reported to be the first randomised control trial in humans) of the antibiotic streptomycin for pulmonary tuberculosis, 35% had nausea and vomiting (Bignall and Crofton, 1949). In treatment of cancer, the chemical warfare agent mustine (nitrogen mustard), was used to treat lymphomas following the observation in World War I (1914–1918) that lymphoid aplasia occurred in those

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3500 Vomiting Nausea Antimetic

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Year Fig. 1. The upper panel plots the number of publications from 1945 to 2012, using the search terms “nausea”, “vomiting” and “anti-emetic” on PubMed. Note that whilst there is a steady increase in publications on both nausea and vomiting which track each other closely, the number of publications using the search term “antiemetic” after a long plateau is now showing a decline. The lower panel shows the number of publications in PubMed for selected anti-emetic agents. Note the similar pattern for domperidone, ondansetron and metoclopramide with a similarly rapid rise in publications followed by a decline and a plateau. The slow in rise years of publications on aprepitant over a 15 year period is in marked contrast to ondansetron and may account for the recent decline in publications on anti-emesis seen in the upper panel.

exposed to mustard gas (Beswick, 1983), but it is also a potent and rapid acting emetic. With the introduction of additional anticancer chemotherapy agents to the clinic (e.g. cyclophosphamide, 5-fluorouracil) and particularly following the trials with cisplatin in the 1970s (see Christie and Tansey, 2007), the necessity for drugs to alleviate the dose limiting toxicity of chemotherapyinduced nausea and vomiting (CINV) became a clinical priority. Emesis caused by radiation was similarly recognised as early as 1897, after accidental exposure to ionising radiation (Walsh, 1897) followed by observations of exposure in clinical, industrial and military contexts (leading to the definition of the acute radiation syndrome, in which nausea was one of the symptoms; Court-Brown, 1953). Attempts to block nausea and vomiting prior to World War II (1939–1945) were empirical; the substances selected were based on traditional, historic remedies for seasickness and pregnancy sickness (Wang, 1965). Atropine was shown to be effective against seasickness in 1880 (Beard, 1880) but it was not until the 1940s that formal trials occurred at sea and demonstrated the efficacy of belladonna-scopolamine drugs (Holling, 1947). These studies combined with the knowledge that the vestibular system was essential for the genesis of “motion sickness” (a term first coined by Irwin (1881), led to the identification of the central anti-

cholinergic action of belladonna-scopolamine family of drugs and to the first neuropharmacologically-defined mechanism of emesis. The second transmitter/receptor located in an emetic pathway was the histamine (H1) receptor. The newly introduced antihistamine dimenhydrinate was used in 1949 to treat allergic urticaria in a pregnant woman sensitive to car sickness and an incidental observation was that her motion sickness was also controlled (Gay and Carliner, 1949). In the same year an older but related antihistamine (diphenhydramine, Benadryls) was shown to alleviate nausea and vomiting induced by streptomycin in patients with pulmonary tuberculosis (Bignall and Crofton, 1949). Screening for antihistamine properties of phenothiazine compounds begun in 1946 identified chlorpromazine, prochlorperazine and thiethylperazine. Interestingly, anti-emetic activity was investigated by testing against vomiting induced in dogs by the nonselective dopamine D2 receptor agonist apomorphine (Wyant, 1962). It is perhaps not surprising, therefore, that several of the resultant compounds have mixed pharmacological activity at both D2 and H1 receptors (Sanger and Andrews, 2006). Although apomorphine had often been used experimentally to induce emesis in the late 19th century (e.g. Mellinger, 1881, cited by Hatcher, 1924) it was the seminal paper by Wang and Borison (1952) that firmly established apomorphine as a prototypical agent to investigate central sites of emetic activation, along with copper sulphate for investigation of peripheral pathways. Blockade of apomorphine-induced emesis became regarded as an indication of an anti-emetic effect on the chemoreceptor trigger zone (CTZ) in the area postrema which was then considered to be the site at which apomorphine and all other substances in the circulation acted to induce emesis. Of the three phenothiazines, chlorpromazine has since been shown to be approximately equipotent at D2 and H1 receptors whereas prochlorperazine is 10 more selective for D2 vs. H1 receptors (Table 1). These drugs (particularly prochlorperazine) were rapidly adopted in a number of clinical settings including anti-cancer chemotherapy and became the comparator for newer agents (e.g. metoclopramide, cannabinoids) in later studies (see Harris and Cantwell, 1986). A drug discovery programme at DeLaGrange in the mid-1950s, to improve the anti-dysrhythmic properties of procainamide, led to the identification in 1964 of metoclopramide as a D2 receptor antagonist, anti-emetic and gastric prokinetic. Later, metoclopramide was shown to stimulate gastric motility by activating 5-hydroxytryptamine4 (5-HT4) receptors and at higher concentrations, to act as a 5-HT3 receptor antagonist (Sanger, 2009). Further, a screening programme at Janssen Pharmaceutica for neuroleptic drugs (originating in the mid-1950s, studying 5000 compounds) identified the anti-emetic drug domperidone (1974) again utilising apomorphine-induced emesis in the dog as a screen. Metoclopramide and domperidone entered clinical studies, including anticancer chemotherapy, initially in placebo-controlled studies (no longer permitted) and then compared with prochlorperazine or each other. Interestingly, both drugs, in addition to having “direct” anti-emetic effects also stimulate gastric motility either directly or indirectly (gastric prokinetic effect-see Section 6.3.2) and are used in disorders where gastric emptying is delayed (e.g. diabetic gastroparesis) and often accompanied by nausea (Sanger et al., 2013). Cannabinoids (δ-9-tetrahydrocannabinol, nabilone, levonantrodol) were investigated as anti-emetics in anti-cancer chemotherapy in the late 1970s and early 1980s and although superior to placebo and prochlorperazine, they were not pursued because of side effects and probably also because of the discovery of the anti-emetic efficacy of 5-HT3 receptors antagonists a few years later. Pre-clinical studies of the pharmacology of metoclopramide, combined with observations of increased anti-emetic efficacy


111

Table 1 Selectivity and non-selectivity of common anti-emetic drugs for the D2 receptor (adapted from Andrews and Sanger, 2001). Values are given for the dopamine D2 and D3 receptors, the α1-adrenoceptors, histamine H1, muscarinic (M; subtype not specified) and 5-HT3 receptors, and are derived from the summary of Ki values obtained using native and/or cloned rat and human receptors, as listed in Sanger and Andrews, 2006. Additional data (*) is included from Moreland et al. (2004), using human receptor stable cell lines. These authors also give data to suggest an affinity of haloperidol and domperidone for the D4 receptor, although for domperidone, the Ki values were 25 times higher than that for the D2 receptor. Bymaster et al. (1996) þ used human cell lines and the data shown here represent the range for muscarinic M1–4 receptors; additional data for olanzapine and haloperidol at other 5-HT receptors are to be found in Bymaster et al. (1996). Little information is known about thiethylperazine, but Clarke and Dundee (1971) describe significant drowsiness associated with this drug. Compound

D2

D3

α1

H1

M

Estimated increase in concentration required to bind to the receptor, relative to that which binds to the D2 receptor (given as 1) Thiethylperazine 1 21 Prochlorperazine 1 7 21 11 225 Chlorpromazine 1 Fluphenazine 1 2 0.4 1 6 Haloperidol 1 2 14 80 6–46 þ 3630 þ 1600 þ Droperidol 1 4–12 þ Domperidone 1 0.6 1179 4 10,000 Metoclopramide 1 5n–32 32 Metopimozine 1 57 6 4 10,000 þ Olanzapine 1 1 1 Weak

of high-dose metoclopramide, led to the discovery of the antiemetic actions of 5-HT3 receptor antagonists (Miner and Sanger, 1986) and development of selective antagonists at this receptor (e.g. granisetron and ondansetron) for prevention of emesis evoked by anti-cancer chemo- and radio-therapy. Notably, the in vivo screening cascade differed from all previous compounds in that it included cisplatin-induced emesis in ferrets; this was the first time a new class of drug was specifically developed for a clinical indication by testing in a model of their intended clinical use. The significance of this should not be underestimated, because if apomorphine had still been used, 5-HT3 receptor antagonists would have been excluded from further study as they do not block apomorphine-induced emesis (Sanger et al., 1987). Subsequently, the ferret cisplatin-emesis model played a key role in identification of the anti-emetic effect of neurokinin1 (NK1) receptor antagonists in the delayed phase of emesis (Tattersall et al., 2000). For both 5-HT3 and NK1 receptor antagonists, initial clinical studies were in anti-cancer chemotherapy with studies in PONV following, and then “off label” investigations in pregnancy, motion and miscellaneous clinical problems (e.g. cyclical vomiting syndrome). In 100 years of research the following neurotransmitter receptors are established to play important roles in the mechanisms of human emesis: muscarinic, probably M3/M5; H1; D2; 5-HT3; NK1. In addition, a diversity of other mechanisms is implicated from studies of emesis in animals. For example, in the acute phase of cisplatin-induced emesis in ferrets the following receptors have been implicated: ACTH, adrenoceptors, cortisol, D2, D3, GABAA, glucocorticoid, 5-HT1A, 5-HT3, 5-HT4, NK1 (but not NK3) NMDA, non-NMDA, m and δ opioid, prostaglandin, TRPV1 (see Percie du Sert and Andrews, in press). However, the translation of some of these mechanisms to humans remains to be established. 1.4. The shift in clinical focus towards nausea It is not surprising that retching and vomiting were the initial focus of anti-emetic research; this is dramatic, externally visible and can result in physical injury to patients. The sight of vomit causes disgust (see Allegories of the senses; the sense of smell (reaction to vomiting), Wellcome Images L0019338; images.wellcome.ac.uk) perhaps reflecting concern that in a communal setting with food sharing, the observer may be next and in more recent times, vomit is a route of infection (e.g. Helicobacter pylori, Norovirus; Stern et al., 2011). Vomit needs to be cleared up and in hospitals the cost of doing this was assessed as part of the pharmacoeconomic assessment of the 5-HT3 receptor antagonist

5-HT3

193 91 410,000 1953 410,000 1 410,000

ondansetron. The perceived secondary importance of nausea is also reflected in some trials with 5-HT3 receptor antagonists where “complete response” is defined by the absence of vomiting but allows for the occurrence of “mild to moderate” nausea. This is further emphasised in a recent quote from the MASCC and ESMO guidelines: “It has also been recognized that the standard primary endpoint for emetogenic trials, complete response is defined as ‘no vomiting and no use of rescue medication' and does not specifically refer to nausea or protection form nausea at all.” (Roila et al., 2010). Nevertheless, the success of the 5-HT3 receptor antagonists in treatment of vomiting has highlighted their lower efficacy against nausea (but see Section 6.2). For example, the three symptoms most feared by cancer patients in response to treatment changed from ‘being sick’, ‘feeling sick’ and ‘loss of hair’ in 1983 to ‘feeling sick’, ‘loss of hair’ and ‘being sick’ in 1995 (De Boer-Dennert et al., 1997). Several papers began to draw attention to nausea as the “neglected symptom” (Foubert and Vaessen, 2005), reinforced by increased interest in patient quality of life. The shift is reflected by the recently revised MASCC and ESMO Guidelines:“Control of vomiting has markedly improved during the last years. Therefore in future attention should shift to control of nausea, at present the greatest remaining emetogenic challenge.” (Roila et al., 2010). Clinical trials are responding to this challenge by now reporting data on nausea and vomiting separately (e.g. Navari et al., 2011). Whilst the focus on treating nausea is in the areas of CINV and PONV, there are multiple other types of patient who experience nausea (e.g. patients with diabetic gastroparesis, migraine or following therapeutic drug use). One particularly difficult (and growing) area is the persistent nausea and vomiting in palliative care as illustrated by the following quote: “I was nauseous all of the time and throwing up. My energy level was really low, and I was dropping weight… I really just couldn't eat or drink anything. Even feeding through a J-tube… was making me nauseous” (Wood et al., 2007).

2. Why study nausea? 2.1. In the clinic 2.1.1. Diagnosis and measurement The primary, and some would argue, the only way that nausea is diagnosed is by patient self-reporting, preferably aided by a standardised definition of nausea (e.g. “the feeling that you might vomit” MASCC, 2004). Standardising the definition is essential to achieve reproducibility of data (e.g. when comparing different

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drugs) and to differentiate between related symptoms such as dyspepsia, early satiety, bloating and visceral pain, which can occur together with nausea and are used in diagnosis of functional bowel diseases (Sanger et al., 2013). There are also no objective biomarkers to independently verify the diagnosis or measure the intensity and temporal pattern. A biomarker is required for clinical situations where the patient may be unable to report nausea, such as in stroke and dementia. In young children food refusal has been proposed as surrogate marker for nausea (Richards and Andrews, 2004). 2.1.2. Treatments and patient factors Treatment of vomiting (and nausea) associated with CINV has been the main focus of anti-emetic research, with successful agents then being used in radiotherapy and PONV. Progress has been made to identify patient-related risk factors (e.g. patients with particular isoforms of the 5-HT3 receptor may be less likely to benefit from 5-HT3 receptor antagonism and more recently, mu-opioid receptor polymorphism has been linked with variations in morphine-induced analgesia and side-effects, including vomiting; Tremblay et al., 2003; Skorpen et al., 2008) but little is known about how these factors influence vomiting or nausea separately. 2.1.3. Human models of nausea The majority of studies into nausea in healthy volunteers have used variants of motion sickness, usually in the form of vection (illusory self-motion). Whilst such studies have provided important insights, it is unclear how generalisable the findings are to nausea induced by other mechanisms (see Section 3.5.1). Other methods of evoking nausea in healthy volunteers have included gastric antral distension (vagal afferent pathway; Ladabaum et al., 1998), apomorphine (Isaacs and MacArthur, 1954) and oral ipecacuanha (e.g. Minton et al., 1993). These models require further investigation particularly to compare the patterns of brain activation with that evoked by vection to identify if there is a “nausea cortex”. 2.1.4. Side-effect of medication Nausea is one of the most commonly reported side-effects of prescribed medications and is frequently encountered when a new chemical entity is given for the first time to healthy volunteers (Holmes et al., 2009); a method for early recognition of nausea and vomiting is therefore required before a potential new drug enters human trials. Examples of such methods could involve the use of a microorganism (e.g. Dictyosetelium discoideum, Robery et al., 2011), in silico (Parkinson et al., 2012) or in vitro methodology using human tissue (e.g. Broad et al., 2012). Identification of mechanisms and sites by which a diverse range of compounds induce nausea will also give important insights into novel approaches to antinausea drugs. 2.2. In the laboratory 2.2.1. Animal models in research Animal models for patient reported symptoms such as pain, depression, anxiety and nausea are fraught with problems of interpretation. For nausea, a consensus also needs to be reached about the translational value (if any) of the various models (see Section 5 below). 2.2.2. Animal welfare in research Identification of pain, suffering, distress and lasting harm is an essential aspect of research involving the use of animals. In species such as non-human primates, cats, dogs, ferrets, house musk and least shrews the observation that the animal is vomiting could

be used to argue that a particular procedure was also likely to be causing an additional unpleasant experience, recognised by humans as nausea (see Section 5 below, for discussion on this assumption). However, in rodents and lagomorphs where vomiting does not occur, a similar argument cannot be made and hence if these animals do experience “nausea” (or a similarly unpleasant sensation), this may represent an unrecognised source of suffering. 2.2.3. Veterinary diagnosis and treatment The diagnosis of “nausea” (or similarly unpleasant sensation) in companion and farm animals presents a challenge that is similar to that for laboratory animals. In the veterinary context there is also a requirement for treatment to follow diagnosis. It is often overlooked that the data gathered during animal experimentation to identify drugs for use in humans also identifies approaches for use in veterinary practice with examples including chlorpromazine, metoclopramide, granisetron and maropitant (Sedlacek et al., 2008).

3. The physiology of nausea: a brief synthesis Rational identification of novel approaches to therapies for nausea rely on an understanding of the pathways responsible for the genesis of the sensation and associated physiological changes, combined with a knowledge of the neurotransmitters and receptors in these pathways in humans. In this section selected aspects of the physiology of nausea in humans are reviewed and the subsequent section examines the pharmacology. 3.1. Pathways for induction Precise knowledge of the pathways by which vomiting can be induced in humans is based largely upon extrapolation from animal studies, usually involving lesion studies. In rare cases, data are available showing the same lesion (area postrema ablation) in a human and an animal blocks the response to the same stimulus (e.g. apomorphine, Lindstrom and Brizzee, 1962). Further, the efficacy of many anti-emetics in humans and animals against the same stimulus supports the view that similar pathways are involved in the induction of vomiting. These include the brainstem pathways capable of generating the somatomotor and autonomic responses of retching and vomiting and the vestibular system, the area postrema, the cardiac and digestive tract vagal afferents. Vomiting can also be induced from “higher” brain regions in response to unpleasant sights, smells or tastes but components of this may be learned rather than reflex. Each of these pathways has also been shown in humans to be capable of induction of nausea as well as vomiting, by adjusting the dose or stimulus intensity (Fig. 2). For example nausea can be induced by activation of the area postrema by apomorphine (Lee and Feldman, 1993), by activation of cardiac vagal afferents during myocardial infarct (Gnecchi Ruscone et al., 1986), abdominal visceral afferents by gastric antral distension (Ladabaum et al., 1998), or by ingested ipecacuanha (Minton et al., 1993), by vestibular system activation by terrestrial motion (Stott et al., 1989) and labyrinthitis and the vestibulo-visual system by vection (Stern et al., 2011), by gustatory pathways by bitter tasting substances (Peyrot des Gachons et al., 2011) and via sites such as the frontal lobe, anterior cingulate cortex, lateral primary somatosensory cortex in the human cerebral hemispheres following electrical stimulation (Penfield and Rasumssen, 1950; Sem-Jacobsen, 1968; Devinsky et al., 1995), and probably migraine and some forms of epilepsy. One or more of these cerebral sites are likely to be the region(s) where the sensation of nausea is ultimately generated. However, any stimulus acting in these regions or closely connected pathways


Vestibular Sy em Area Postrema Gut afferents

1 2

6 NAUSEA

4

Vestibular System

3 5

BRAIN STEM

VP

VOMITING

Area Postrema

Probability of vomiting

Nausea intensity

Parasymp dominant

Symp dominant t

Plasma [AVP]

EGG dysrhythmia

Gut afferents ANS OUTPUTS TO SKIN, HEART& GUT

1

EGG normogastria

Fig. 2. A summary of the key physiological changes associated with nausea (lower left) and the pathways by which nausea is induced (right hand side). The upper panel shows potential sites at which pharmacological interventions (antagonists or agonists) could be targeted to treat nausea: (1) Blockade of input pathways to the brainstem either at their origin or primary termination in the brainstem would block nausea (and vomiting) when induced by that input but if for example both the area postrema and gut afferents were activated by a stimulus then both would need to be blocked to be effective. In the case of the gut afferents correcting motility disturbances could also be effective; (2) Blockade at a common point of afferent information convergence within the brainstem integrative circuitry (probably the nucleus tractus solitarius) would potentially block both nausea and vomiting irrespective of the pathway activated and this is also the case for site 3 where the block is at the point in the integrative circuitry prior to the output pathways for induction nausea and vomiting diverging. Blockade at points 4 and 6 would in principle block nausea without affecting vomiting and it is unclear what the effect would be on nausea of blocking secretion of AVP (5) secretion but again vomiting would be unaffected.

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than vomiting, but there is also a temporal element to the signal, as even at a steady intensity of stimulus, the intensity of nausea increases with time of exposure as the probability of vomiting increases; this is especially obvious using motion stimuli. Studies with apomorphine in humans show that nausea can be induced rapidly, beginning a few minutes after dosing (Lee and Feldman, 1993). For both the area postrema and the abdominal vagal afferents, we also need to consider that both structures are capable of reducing food intake in response to circulating substances (e.g. CCK, GLP-1; Sanger et al., 2013). In the case of gastric distension and the vagus, the threshold for satiety is below that for either nausea or vomiting. One additional indication of a relationship between these two events is that the threshold for satiety can be increased by administration of the 5-HT3 receptor antagonist ondansetron (Janssen et al., 2011). After a threshold dose for an emetic agent has been reached, the latency of onset of retching and vomiting usually decreases as the dose is increased. This occurs with drugs (e.g. cisplatin) and with total body ionising radiation. Similarly, at an ED100 dose of an emetic agent incremental doses of anti-emetic agents often (but not always) manifest their anti-emetic potential by an initial increase in latency perhaps with only a small initial reduction in number of retches and vomits (e.g. Stables et al., 1987; Andrews and Bhandari, 1993a). Both of these observations support the view that encoding of stimulus intensity is important in determining which events occur and also when they will occur. To produce an effective anti-nausea and anti-vomiting agent it may therefore be necessary to disrupt the afferent signal so that it never reaches threshold intensity. 3.3. Physiological changes

could evoke nausea and such stimuli would include tumours, reduced regional cortical blood flow and drugs acting on neurotransmitter systems in these areas. The latter could be one of the reasons why selective serotonin/noradrenaline reuptake inhibitors (e.g. venlafaxine, Huang et al., 2013) and multi-modal antidepressants (e.g. vortioxetine, Baldwin et al., 2012) have nausea as an adverse event; understanding their effect on cortical transmitter systems should give insights for the development of specific anti-nausea agents. Overall there is good concordance between the sites from which vomiting can be initiated in gyrencephalic mammals that vomit and the sites from which nausea can be evoked in humans, providing a framework for identifying targets to block nausea. We now need to consider the nature of the afferent signals responsible for induction of nausea and vomiting as these are the signals we are attempting to disrupt; it is notable that anti-emetics drugs act (at H1, M3/5, 5-HT3 and NK1 receptors) primarily (but not necessarily only) on the “input” side of emetic pathways. 3.2. Encoding the signals for nausea and vomiting Understanding the relationship between stimulus intensity and the genesis of either nausea or vomiting is critical. There is a diversity of evidence indicating that nausea is produced by lower intensity activation of the same pathways that when activated with a stimulus of higher intensity or longer duration, induce vomiting. This is clear for activation of the vestibular system by graded motion (e.g. Mowrey and Clayson, 1982), for the dose-related effect of apomorphine acting on the area postrema (Lee and Feldman, 1993), for graded distension of the stomach (Ladabaum et al., 1998), and when administering different concentrations of intragastric copper sulphate (Araya et al., 2001), or hypertonic solutions (Barker et al., 1974). Not only is nausea induced at a lower threshold

A diverse range of physiological changes have been recorded in subjects reporting nausea (e.g. tachycardia, regionally specific sweating and vasoconstriction, yawning, delayed gastric emptying), but the large increase in plasma vasopressin (arginine vasopressin; AVP) and change in pattern of tachygastria/dysrhythmia in the electrogastrogram (EGG) have probably been the subject of most intense study (Stern et al., 2011). Do these changes provide a target for anti-nausea drugs? 3.3.1. Plasma AVP A rise in plasma vasopressin in anticipation of vomiting is perhaps not unexpected because of the expected water loss, but the rise in vasopressin has also been implicated in reduction of gut blood flow, disruption of gastric motility and genesis of nausea, possibly via area postrema activation. As vasopressin stimulates adrenocorticotrpic hormone (ACTH) secretion from the anterior pituitary, it is possible that this helps to alleviate nausea as for both vection and ipecac, the elevation of AVP occurs prior to cortisol ACTH and cortisol outlasts it (Xu et al., 1993). Nevertheless, poor temporal resolution of the plasma changes in AVP makes correlation with symptoms and other physiological measurements difficult. Overall it appears that whilst there is often a correlation between nausea score and plasma concentrations of AVP, the onset of nausea is coincident with the concentration rise. There is wide range of published plasma vasopressin values in subjects reporting nausea but the peak levels achieved are either at the levels required for maximal antidiuresis (6–10 pg/ml) or substantially higher (e.g. 93–555 pg/ml) (see Stern et al., 2011 for details). Similar fold changes are reported in animals (e.g. cynomologous monkey, dog, ferret). In animal studies it is not necessary for the animal to be conscious for emetic stimuli to raise vasopressin (Hawthorn et al., 1988). In humans, vasopressin infusion induces

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nausea in a dose-related manner but the concentrations required are at the higher end of those measured in subjects with nausea from other causes (especially vection; see Stern et al., 2011). Nevertheless, there are vection studies where nausea is reported in the absence of a rise in AVP and inspection of individual data in other studies shows a wide range of values with no change in concentrations of AVP in some individuals reporting nausea (see Stern et al., 2011 for references). Perhaps the differences and the large individual variations in the AVP response can be explained by the absence of detailed dose–response information and poor temporal resolution of the measurements. Thus, good dose– response data is available for the anti-diuretic effect of AVP and this relationship is not linear, with small increases from basal having a larger effect than subsequent equivalent changes. Finally, nausea can be induced in patients with congenital diabetes insipidus (Nussey et al., 1988) showing that AVP is not essential for the induction of nausea. The involvement of vasopressin in the genesis of nausea will be determined when selective antagonists and agonists for each of the three vasopressin receptors (V1: mainly vascular; V2: mainly renal; V3: mainly CNS) are available for human studies. Early studies in squirrel monkey and piglet with a V1 receptor antagonist were equivocal (Cheung et al., 1994; Grelot et al., 2001). Of particular interest will be studies of the effects of such antagonists on brain activity and gastric motility in subjects reporting nausea. In humans reporting nausea, the plasma concentrations of AVP (10–200 pM) are within the range of concentrations (100 pM– 100 nM) of vasopressin which caused a concentration-dependent increase in muscle tension of human isolated gastric antrum and fundus (Broad et al., 2012). This indicates a potential direct role of vasopressin in modulating gastric motility, contributing to genesis of nausea.

3.3.2. The electrogastrogram (EGG) The EGG continuously records the electrical activity of the stomach on the abdominal surface in humans although it can also be recorded in animals by telemetry using implanted electrodes (Percie du Sert et al., 2009a, 2010a,b). Deviations from the normal frequency in humans (2.5–3.6 cycles/min) in the form of bradygastria (1–2.5 cycles/min) or tachygastria (3.6–10 cycles/min) are classified as dysrhythmic activity and it is this which is usually (but not universally) observed in subjects reporting nausea. Dysrhthmias are induced by a variety of stimuli (e.g. vection, vasopressin, glucagon, morphine) and clinical settings (e.g. post-surgery, diabetic gastroparesis; Stern et al., 2011 for references).The onset of dysrhythmia (particularly tachygastria) coincident with the report of the onset of nausea and the intensity of nausea related to the degree of dysrhythmia (e.g. in motion: Hasler et al., 1995) (Fig. 2). Anti-emetic and gastric prokinetic drugs, such as domperidone, can alleviate the nausea, the EGG disruption and delay in gastric emptying (Stern et al., 2011). However, as is the case with AVP, it is possible to experience nausea in the absence of changes in the EGG. Although there are multiple mechanisms which if disrupted can produce gastric dysrhythmias (e.g. enteric neuropathies, damage to Interstitial Cells of Cajal), the major mechanism proposed, based mainly on studies of vection-induced nausea, is an increase in gastric sympathetic activity accompanied by a decrease in parasympthatic activity (Stern et al., 2011). The mechanical correlate of dysrhythmias is perhaps surprisingly a decrease/inhibition of antral contractile activity and this is consistent with the long standing observation that nausea is accompanied by a delay in gastric emptying (e.g. Wolf, 1943). It is still unclear if the delay in gastric emptying is “cause” or “effect” or a combination of both giving rise to a vicious cycle (see Stern et al., 2011; Sanger et al., 2013). Regardless, correcting the disruption of the EGG and the reduction of gastric contractile activity and emptying,

would be expected to alleviate symptoms to some degree which is the rationale underlying the treatment of nausea with gastric prokinetic agents (Sanger et al., 2013, see Section 6.3.2). 3.4. The wave-like nature of nausea One of the puzzling and least well characterised aspects of nausea is its “wave like” nature, a phenomenon which may also confound accurate reporting by patients but is well described by the following quotation relating to motion sickness: “Once firmly established, the nausea syndrome takes on – like Frankenstein's monster – a separate existence of its own, waxing and waning (our italics) independently of the circumstances which originally elicited it” (Reason and Brand, 1975). This wave-like nature implies either some change in arousal levels, making the subject more or less aware, and/or a change in the underlying cause(s). Kim et al. (2011) and La Count et al. (2011) recently provided evidence by studying the autonomic outflow to the cardiovascular system and the skin, suggesting increased perception of nausea is associated with increased sympathetic and decreased parasympathetic outflow (Fig. 2). Although they did not monitor the EGG, the same pattern of autonomic outflow is associated with dysrhythmic/ tachygastric changes temporally linked with nausea (see above). These autonomic changes are likely to result from activation of the central “emotional” pathways and it will be important to determine whether agents affecting the reporting of nausea also modify these associated autonomic changes. Autonomic outflow can also be recorded in animal studies and could assist in interpretation of the significance of the behavioural changes argued to be induced by nausea in some animal models (see Section 5). 3.5. Where is the sensation? Identification of the ultimate site at which the sensation of nausea is generated, presumed to be in the cerebral cortex, is an important research goal; key transmitters and receptors could then be isolated prior to reverse translation in animal models for the identification of new treatments of nausea (without interference to other, critical brain functions). Identification of this area will also enable accurate identification of the route(s) by which information from the vagal afferents, area postrema and vestibular system reaches the cortex; this is important as hypothetically interruption at any point of this pathway could block nausea. Progress has been made in recent years using brain imaging in humans with the following structures most often implicated: anterior insula, anterior cingulate, orbitofrontal, prefrontal and inferior frontal gyrus (Fredrikson et al., 1995; Kim et al., 2011; Napadow et al., 2012, 2013; Ng et al., 2012). Two points should be noted: 3.5.1. How representative is vection induced nausea? Because of the technical issues associated with controlled induction of nausea in an MRI scanner (Stern et al., 2011), most studies have used visually-induced motion sickness (vection). However, this method involves primary activation of the visual system and it is therefore possible that the results are not representative of nausea evoked by vestibular, area postrema or vagal afferent activation. The evolutionary significance of the induction of nausea and vomiting via the abdominal vagal afferents and the area postrema for ingested toxin detection are clear (Davis et al., 1986). However, the significance of motion sickness (and especially that induced by vection as opposed to “real” motion) remains elusive, and proposals that it may also be part of the toxin detection system are debated (see Oman, 2012 for recent review). Thus, caution needs to be exercised about placing


too much reliance on using vection to investigate anti-nausea drugs until similar data on brain pathways are available for activation of other input pathways. Nevertheless, limited studies using gastric distension, apomorphine and ipecacuanha have demonstrated activation of broadly the same areas as are activated by vection (Stern et al. 2011 for review). More detailed analysis of the role of gastrointestinal mucosal vagal afferents are now required as in evolutionary terms, this is the most important pathway for detection of toxins ingested with food and subsequent induction of nausea and vomiting. 3.5.2. Regional brain inactivation may be as important as activation A consistent finding is that while many regions are activated, others are inactivated (e.g. declive and parahippocampal gyrus, Ng et al., 2012). It would therefore be unwise to focus solely on blocking a pathway as it is possible that reactivating one of the inactivated areas may provide the best solution.

4. Animal models of vomiting: what have they taught us about translation? There are several key points that we can derive from the relative success in translation of the 5-HT3 and NK1 receptor antagonists in CINV. Whilst interpretation of animal studies claiming to investigate nausea is contentious (see Section 5), there is agreement that the phenomena of retching and vomiting are broadly the same in laboratory mammals and humans, as is the underlying physiology involving brainstem coordination of the respiratory and gastrointestinal systems. The main inputs of the area postrema, abdominal vagal afferents and vestibular system responsible for induction of vomiting, are also conserved and are present even in the rat which in common with other rodents lacks the ability to vomit (Sanger et al., 2011; Horn et al., 2013). Nevertheless, although the brainstem of the rat is superficially similar to other mammals, functional studies have identified differences in brainstem physiology (Horn et al., 2013), gut endocrinology (e.g. absence of a motilin system in rodents) and anatomy (e.g. gastric morphology), which may provide a partial explanation for the absence of vomiting in rodents (Sanger et al., 2011). The ability to vomit has been lost in rodents but we do not yet know if this has had an impact on systems thought to be involved in behaviours induced by procedures which cause vomiting in other species (e.g. is CTA/CFA particularly well developed in the rat because of the lack of vomiting?). Rodents, as exemplified by the rat, respond to stimuli that would evoke vomiting in other species by pica (ingestion of a non-nutritive substance such as kaolin; note pica may either not occur in mice or may not be a very robust phenomenon), markedly delayed gastric emptying, conditioned taste/flavour aversion, conditioned gaping (see Stern et al., 2011, chapter 8 for review). In one sense it is immaterial whether these responses are indices of vomiting, nausea or something else, but what is important is that these behavioural responses occur in response to stimuli capable of inducing vomiting in other laboratory species and nausea and vomiting in humans. If this is the case then non-vomiting species have some utility in both identification of novel chemical entities (NCE) which may have an emetic liability in humans (Percie du Sert et al., 2012), and in the understanding the pathways by which emetic agents have their effects (e.g. investigating the possible role of hepatic vagal afferents in cisplatin-induced emesis, Horn et al., 2004) as well as in identification of anti-emetic agents. In addition since the dose is the primary parameter separating nausea from vomiting and if the readout from the model equates to either of these, then it is valid for identification of emetic liability of NCEs. However, the

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problems inherent in all animal models aimed at identification of novel anti-nausea drugs can be illustrated by reference to cisplatin-induced emesis in the ferret. This is discussed below because it is relatively well understood, with a large body of comparable quantitative animal data in a single species and good data on translation. 4.1. Pathway comparability Although the ferret and human have both an acute and delayed phase of retching and vomiting in response to cisplatin, in humans emesis in the acute phase is more severe than the delayed phase whereas in the ferret the reverse is true. In the ferret it has been possible to show that the acute phase is highly dependent upon the integrity of the abdominal vagus and this is also the case in monkey, dog and Suncus murinus where abdominal vagotomy was combined with section of the greater splanchnic nerves (see Andrews and Davis, 1995 and Rudd and Andrews, 2005 for discussion of problems of interpretation of vagal and area postrema lesions and species differences). In the least shrew (Cryptotis parva), studies of Fos-immunoreactivity have implicated the area postrema in the acute phase of cisplatin-induced emesis (Ray et al., 2009). The area postrema is implicated in the delayed phase of cisplatin-induced emesis in the ferret by lesion studies (Percie du Sert et al., 2009b). These studies, together with other data provide a workable model of cisplatin-induced emesis (and to some extent other forms of CINV), but the evidence that the same pathways operate in humans must remain largely circumstantial. 4.2. Pharmacological compatibility If we assume the same pathways are operative in the ferret and human, then for a candidate anti-vomiting/anti-nausea drug to translate to humans it is necessary that the same transmitter (s) and receptor(s) are also operative at the same critical point (s) in the pathway(s). In the ferret we are in the fortunate position of having good pre-clinical data against cisplatin-induced emesis for two drug classes (5-HT3 and NK1 receptor antagonists) that continued into use in humans. A meta-analysis (Percie du Sert et al., 2011) reveals that the ferret accurately predicted the efficacy of ondansetron in the acute phase of cisplatin-induced emesis but the reduction of 60% in the delayed phase in the ferret overestimated the efficacy in humans. Similarly the efficacy of the NK1 receptor antagonist aprepitant in both the acute and delayed phase is overestimated in the ferret. The reasons for such differences are discussed in detail elsewhere (Percie du Sert and Andrews, in press), including the difference that healthy ferrets were used, as opposed to cancer patients. These observations illustrate the difficulty in translation even when the end-point is readily quantified and mechanistically well understood. Mapping the relationship between various emetic stimuli and receptor/ transmitter systems in animal models will therefore be critical for reverse translation of studies of nausea as information becomes available from brain imaging studies in humans (e.g. Napadow et al., 2012; Ng et al., 2012). It is arguable whether the cerebral architecture in lissencephalic (e.g. rat, mouse) as opposed to gyrencephalic laboratory species (e.g. non-human primate, dog, pig, ferret) will allow such studies.

5. Animal models of nausea: an oxymoron? Selected views about the issue of nausea in animal models are summarised in Table 2 to illustrate that this is a contentious issue. We take the view that there are “no validated animal models of nausea” and propose that journals should look critically at paper

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Table 2 Selected quotations from 60 years of literature to illustrate the controversial nature of studying nausea in animal models. Selected quotations about animal models of nausea

Reference

It is impossible to determine whether nausea is experienced by experimental animals. However, experimental identification of nausea requires a leap of faith to interpret the feelings of animals, which is not the case when recording the forces of vomiting. As there is no way to directly validate the appropriateness of this behavioural model as an analogue to nausea, it remains an article of faith that taste aversion in the rat is an analogue to nausea in man. Nausea is a sensation and as such can only be studied with assurance only in human subjects. One immediate discrepancy between studies in human subjects and those with animal subjects is that there is nothing that can only be measured in an animal as nausea. Nausea cannot be studied in nonhumans Investigating nausea in laboratory rodents is difficult because of the subjective nature of this sensation; however, behavioural models do exist

Borison and Wang (1953), p194 Borison and McCarthy (1981) Morrow (1984), p2271 Stricker et al. (1998), p295. Lucot (1998), p63. Hornby (2001). p106S Izzo and Sharkey (2010). p22

Table 3 Examples of measurements used to investigate “nausea” in animals. See text and Stern et al. (2011) for detailed references and discussion of the issues. Model

Exemplar species

References

Pica (as indicated by kaolin consumption) Conditioned taste aversion/conditioned food avoidance Conditioned gaping (disgust reactions)

Rat (not present in house musk shrew and not reliably demonstrated in mouse) Rat, mouse, house musk shrew, cat, dog, ferret, guinea-pig, hamster, quoll, monkey. Rat, house musk shrew

Yamamoto et al. (2010), Liu et al. (2005) and Stern et al. (2011) Garcia and Hankins, (1977) and Stern et al. (2011)

Context aversion conditioning Unconditioned lying-on-belly Reduced food intake

Rat Rat Rat, house musk shrew, mouse, ferret

Delayed gastric emptying Peri-emetic behaviours

Rat, mouse House musk shrew, ferret, cat, piglet, marmoset

titles implying that nausea has been induced/measured/modelled in an animal or at least, a question mark should be included in the title. We suggest that phrases like “nausea-induced behaviour in rats” and that comments such as “…the insular cortex which is an area involved in the sensation of nausea in humans and other animals” (Tuerke et al., 2012b) are avoided and that studies of nausea other than in humans include the animal species in the title (e.g. “The anti-nausea effects of CB1 agonists are mediated by an action at the visceral insular cortex” – this is a rat study of conditioned gaping, Limebeer et al., 2012). As we do not currently have a substance that blocks nausea in humans without affecting vomiting, we are unable to test directly whether any of the behaviours/effects observed in rodents (or other species) claimed to represent nausea actually do so, assuming the rodents employ the same transmitters/receptors in the same “nausea” pathway (s) as humans (but see Sanger et al., 2011, 2013, in which important differences in neurotransmitter receptor types and affinities are discussed in relation to human and rodent GI functions). However, we qualify the above views by the following comments: i) Rats do appear to have an ability to generate aversive, rejection, avoidance responses and pica in response to a range of substances capable of causing nausea and often vomiting in humans and retching/vomiting in other species. ii) It is likely (but not essential) that the drive for a rat to ingest kaolin in response to a toxin is a conscious sensation and that the genesis of conditioned taste aversion/flavour avoidance, conditioned gaping and context aversion conditioning also involve a conscious sensation. However, the sensation does not have to be the same as the human sensation; it merely needs to serve the same function.

Parker and Kemp (2001), Tuerke et al. (2012b) and Limebeer et al. (2012) Rodriguez et al. (2000) and Bolognini et al. (2013) Tuerke et al. (2012a) Liu et al. (2005), Yamamoto et al. (2007) and Stern et al. (2011) Bradner and Schurig (1981) and Cabezos et al. (2008) Horn et al. (2011) and Stern et al. (2011)

iii) Rodents in general and rats specifically lack the ability to vomit (Sanger et al., 2011; Horn et al., 2013). One commonly used clinical definition of nausea is a “symptom typified by epigastric discomfort with the urge to vomit” (La Count et al., 2011). The lack of vomiting in rats has two practical implications for the “rat models”. Firstly, if rats do not vomit then it follows that they cannot have an “urge to vomit”, although there is some evidence for gastroesophageal reflux in rats (Hultin et al., 2005), and if evoked reliably by emetic agents it could give rise to a sensation from the oesophagus but this need not be nausea. Secondly, nausea is usually (but not always) temporally linked to vomiting and hence investigation of peri-emetic behaviour or biomarkers for nausea in humans (e.g. plasma AVP and EGG) using fully emetic stimuli may support an argument that an animal is experiencing a sensation associated with the forthcoming retching and vomiting. However, in rodents there is no event around which such measurements could be based (although the period prior to initiation of kaolin consumption may provide an opportunity). In emetic species (e.g. cynomologous monkey, ferret, pig, cat, dog) as in humans, fully emetic or sub–emetic doses of several agents (e.g. CCK, apomorphine) cause large increases in plasma concentrations of AVP (Stern et al., 2011 for references). In the rat it is plasma oxytocin which increases in response to “emetic” stimuli so it is difficult to be confident about this as a potential biomarker for “nausea” in rodents. iv) Studies in rodents of the central pathways and transmitters involved in visceral sickness induced by cisplatin (e.g. Horn, 2009), conditioned disgust and taste avoidance (e.g. Tuerke et al., 2012a,b) provide important insights into the processing of information from vagal and gustatory afferents and the ways in which they interact to form aversive memories. The latter may be particularly relevant to understanding anticipatory


nausea and vomiting following chemotherapy which is particularly difficult to treat (Janselsins et al., 2013). In particular rodent brain pathway studies may show potential sites at which interventions may be targeted and identify regions of interest for fMRI and PET studies in humans. In Table 3 we summarise some of the measurements claimed as indicators of nausea in animals. The reader is referred to Stern et al. (2011) Chapter 8 for a detailed analysis of these models. Overall, we urge caution when attempting to translate data from these models to identification of drugs to treat nausea in humans; lessons learned from the poor translation of rodent pain studies to humans (Borsook et al., 2012) should be taken into account. The following quotation encapsulates the problem “Remember that all models are wrong; the practical question is how wrong do they have to be to not be useful” (Box and Draper, 1987).

6. The pharmacology of nausea: questions and approaches 6.1. The perfect anti-emetic: a myth or realistic possibility? Irrespective of their effects against nausea, the clinical efficacy of the 5-HT3 and NK1 receptor antagonists in combination with dexamethasone has set a high bar for novel compounds to demonstrate superiority over current gold-standard therapies in CINV and PONV. Ideally, the next development should be a drug (or combination of drugs) that blocks both nausea and vomiting irrespective of the cause (including the many ‘non-cancer’ conditions in which nausea occurs, such as those associated with delayed gastric emptying). Nevertheless, a drug with complete efficacy against nausea (or vomiting) in a specific clinical setting (e.g. anticipatory nausea and vomiting from chemotherapy, PONV, delayed gastric emptying, terminal care) would be clinically useful. Although this may seem like an impossible challenge, it should be recalled that in 1984 a 5 drug regime acting on 6 transmitter systems (thiethylperazine: D2 receptor antagonist; metoclopramide: D2 antagonist and 5-HT4 receptor agonist; diphenhydramine: H1 antagonist 4M receptor antagonist; diazepam: allosteric modulation of GABAA; dexamethasone: corticosteroid) was required to block ongoing vomiting induced by cisplatin (Plezia et al., 1984), but within 4 years it was possible to do the same with just a 5-HT3 receptor antagonist (Cassidy et al., 1988). Thus, once pivotal receptors and transmitters are identified, progress can be rapid and dramatic. No drug has been specifically designed or registered for the treatment of nausea. So is a universally effective anti-nausea agent possible and where would a discovery research programme begin? Fig. 2 summarises some of the sites that could be targeted. Notably, recent research has highlighted areas of the brain which increase or decrease in activity during nausea (see 3.5.2 above), but extensive research is still needed to determine if this information can be used to identify sites at which “anti-nausea” drugs might act selectively without affecting cerebral functioning and reflexes, particularly those associated with the cardio-respiratory system. 6.2. Are current anti-emetics really more efficacious against vomiting as compared to nausea? Anti-emetic drugs were designed to inhibit vomiting and even though it may have then been assumed that nausea would also be affected, any ability to act in this way was incidental. There is a perception primarily originating from the CINV and PONV literature that vomiting is treated more effectively than nausea (see Roila et al., 2010; Jokela et al., 2009), however, the data is

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complicated not just by the descriptions used by patients to describe nausea but also by the methods used to quantify the efficacy (e.g. a reduction in magnitude in an individual vs number of patients not reporting nausea). Knowledge of the precise efficacy of existing drugs against nausea in comparison to vomiting is therefore essential for identifying clues to new anti-nausea approaches. Nevertheless, this approach is confounded by different methodologies used to assess efficacy. For example, a systematic review showed that in PONV ondansetron was more effective against vomiting than nausea (Tramer et al., 1997) but Relative Risk analysis showed similar efficacy (Jokela et al., 2009). In addition, in PONV droperidol may be more effective against nausea than vomiting (Heinzi et al., 2000) but Relative Risk analysis showed similar efficacy (Apfel et al., 2001). Nevertheless, it is possible to search for unusual profiles within study comparisons. An open label study in 2003, for example, showed that gabapentin (which binds to the alpha2-delta subunit of L-type voltage-regulated calcium channels) had the potential to reduce nausea in patients treated for breast cancer (Guttuso et al., 2003) and more recently a pilot study investigated gabapentin added to a control regime of ondansetron, dexamethasone and ranitidine in moderately emetogenic chemotherapy for breast cancer (Cruz et al., 2012). This revealed that in the delayed phase, the control regime achieved complete control of vomiting in 75% of patients and nausea in 60.7% whereas addition of gabapentin increased the complete response rate and evened out the difference between nausea and vomiting (blocked in 89.3% and 92.8% of patients respectively). This suggests that gabapentin has greater efficacy against nausea compared to vomiting, an unusual profile perhaps related to the various roles for alpha2-delta subunits in neuropathic and visceral pain, seizures, anxiety and even enteric neurotransmission (Gale and Houghton, 2011). 6.3. What do current drugs tell us? 6.3.1. 5-HT3 and NK1 receptor antagonists Overall, studies with 5-HT3 receptor antagonists show a similar pattern of efficacy in the acute phase (first 24 h) of CINV, with the percentage of patients free of nausea being lower than those free of vomiting. This is illustrated by selected examples from different types of chemotherapy study; the percentage differences in number of patients protected for granisetron is 14.4% (Soukop 1990), for ondansetron/dolasetron combination is 15.1% and for palonosetron is 24.1% (Aapro, 2007). The significance of this for understanding mechanisms becomes clear by looking in detail at the granisteron study (Soukop, 1990). Against highly emetogenic cisplatin, granisetron (40 mg/kg i.v.) completely blocked acute phase vomiting in 62% of patients showing that in those patients activation of the 5-HT3 receptor was the critical step for induction of vomiting and that removal of that effect was sufficient to ensure that the threshold for induction of emesis was not reached in the subsequent 24 h. For nausea the argument is the same except that only 48% had their nausea driven via a mechanism involving 5-HT3 receptor activation. This was not dependent upon dose as similar results were obtained by quadrupling the dose of granisetron. Thus, in about 50% of this population both acute nausea and vomiting were blocked by a drug acting at a single receptor making the point that if the correct receptor in the pathway activated by the stimulus is targeted, then in principle both nausea and vomiting can be blocked – the challenge is now to identify a critical point at which all pathways for induction of nausea and vomiting converge. Recent studies utilising a second generation 5-HT3 receptor antagonist palonosetron (Aapro, 2007) and NK1 receptor antagonists (e.g. aprepitant, Dos Santos et al., 2012) illustrate additional points. Palonosetron was superior to ondansetron/dolasetron in

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treatment of both nausea and vomiting in the delayed phase of moderately emetogenic chemotherapy (Aapro, 2007). It is unclear if this is contributed to by the longer plasma half-life of palonosetron in comparison to other 5-HT3 receptor antagonists or if this is due to additional pharmacological actions such as the promotion of 5-HT3 receptor internalisation or NK1 receptor antagonism (Rojas et al., 2010a,b). Studies with selective NK1 receptor antagonists (e.g. aprepitant) show that their addition to a 5-HT3 receptor antagonist regime improved the control of both nausea and vomiting, with the effect being much more marked in the delayed compared to the acute phase (Dos Santos et al., 2012). Using a combination of palonosteron, aprepitant and dexamethasone in highly emetogenic chemotherapy the response rates were; acute phase no vomiting 87% and no nausea 87% (note parity-see above) and delayed phase no vomiting 73% and no nausea 38% (note the disparity) (Navari et al., 2011). From this we conclude that in the acute phase in 90% of the patient population the vomiting and nausea is driven by 5-HT3 and/or NK1 receptor activation, with the peripheral vagal afferent-enteroendocrine cell unit and the nucleus tractus solitarius being the most likely sites (Andrews and Rudd, 2004). In the delayed phase whilst NK1 and 5-HT3 (NK1 45-HT3) receptors have a role in vomiting in the majority of patients (4 70%), this is not the case for nausea implying that 60% of patients have other mechanisms operating. However, adding the atypical antipsychotic olanzapine to the treatment regime, although without additional benefit on nausea in the acute phase, increased anti-vomiting efficacy to 97% and in the delayed phase had a marginal effect on vomiting (77%) but increased the number of patients with no nausea to 69% from 38%. Clinically, this is a positive step. We should now consider the receptors implicated: 5HT3 (palonosetron), NK1 (aprepitant), glucocorticoid (dexamethasone, mechanism not discussed here but see Rudd and Andrews (2005)), D2, H1, M1, α1 adrenoceptor (olanzapine, depending upon dose, see Table 1 and Torigoe et al., 2012). This regime is reminiscent of the “5 drug” regime (Plezia et al., 1984) acting on 6 receptors, used to treat cisplatin-induced vomiting and superseded a few years later by selective 5-HT3 receptor anatagonists.

6.3.2. Dopamine receptor antagonists and prokinetics Although it is at least 60 years since the first antagonists implicated dopamine in emesis using apomorphine as challenge, we still do not know the source of the dopamine acting on the central D2 receptors (see Andrews and Sanger, 2006), or the precise role of D2 receptors in the prokinetic effects of agents such as domperidone. Drugs which antagonise at dopamine receptors (often non-selectively) remain widely used. For example, in a comparator study in moderately emetogenic chemotherapy total control of nausea and vomiting in the acute phase was achieved in 33% of patients with prochlorperazine (Burris et al., 1996). Prochlorperazine also has some indications of broader spectrum effects with efficacy against motion sickness and opioid induced nausea and vomiting. Our poor understanding of exactly how dopamine receptor antagonists exert their anti-emetic effects represents a major gap in our knowledge of emetic pathways. Domperidone and metoclopramide are D2 receptor antagonists but they are also gastric prokinetics (in the case of metoclopramide this is via 5-HT4 agonism, Sanger 2009) and this action has been argued to contribute to their anti-nausea effect as a delay in gastric emptying and inhibition of gastric motility is frequently (but not inevitably) associated with nausea and reduced food intake or early satiety (see Sanger et al., 2013 for detailed discussion). The relationship between delayed gastric emptying, reduced food intake and nausea is not well understood. Irrespective of the origin of the delay in gastric emptying the use of prokinetic agents to alleviate this could treat both the reduced food intake and the nausea. Interestingly, ingestion of high protein

meals reduced nausea during motion sickness (and reduced EGG dysrhythmia, Levine et al., 2004) and in chemotherapy patients (Levine et al., 2008), so the act of eating may of itself contribute to treatment of nausea.

6.3.3. Receptor agonists Recent approaches to the design of gastric prokinetics has moved away from the non-selective 5-HT4 receptor agonists (metoclopramide, cisapride, mosapride), to identify selective agonists at this receptor (e.g. prucalopride) and non-peptide agonists of the motilin (e.g. erythromycin and GSK962040) and ghrelin (e.g. TZP-101) receptors. For ghrelin the effects on gastric motility in rodent studies has not clearly translated to symptomatic benefit in the clinic, although in a pilot and phase IIa (but not phase IIb) study, there was some relief in patients with diabetic gastroparesis (Ejskjaer et al., 2010, 2013). The anti-emetic potential of ghrelin identified in the ferret (Rudd et al., 2006) has not been investigated in the clinic, in spite of the marked fall in blood plasma ghrelin concentrations (and appetite) in patients receiving anticancer chemotherapy (Hiura et al., 2012). Low doses of erythromycin and certain other macrolide structures such as azithromycin (Broad and Sanger., 2013) non-selectively activate motilin receptors and stimulate gastric emptying by facilitating enteric cholinergic nerve activity and in patients with delayed gastric emptying, reduce nausea and early satiety (see Sanger et al., 2013 for references). Studies in Suncus murinus (Javid et al., 2013) also show that low doses of erythromycin have antiemetic activity and stimulate vagal afferent activity (modality not identified). The more selective motilin receptor agonist GSK962040 (Sanger et al., 2009) is currently undergoing clinical investigation in patients with delayed gastric emptying. Other examples where agents with an agonist activity have been shown to have anti-emetic effects in pre-clinical studies (often against more than one pathway) include the cannabinoid CB1 (Van Sickle et al., 2001) gamma amino butyric acid GABAB (Suzuki, et al., 2005; Andrews and Sanger, 2006), 5-HT1A (Lucot, 1998), TRPVI (Andrews and Bhandari, 1993b) and m opioid receptors (Johnston, 2010). In the case of cannabinoids and opioids there is additional evidence, including data from humans, that blockade of the same receptors can either induce nausea/vomiting or reduce the threshold for induction of nausea/vomiting. These studies provide compelling evidence that as is the case with pain, there is an endogenous system capable of modulating nausea and vomiting. Pharmacological manipulation of this system offers an attractive approach to therapies for nausea and vomiting and the cannabinoid system has been the one most investigated (see Parker et al., 2011 for review). The availability of agonists for CB1 receptors including cannabidiolic acid has provided proof that these agents have the potential to block vomiting and rat studies have shown an ability to reduce lithium chloride and contextinduced conditioned gaping (see Bolognini et al., 2013; Limebeer et al., 2012; Parker et al., 2011). An interesting aspect of the Bolognini et al. (2013) study is the evidence suggesting the effects of cannabidiolic acid are mediated by 5-HT1A receptor activation, one of the receptors previously implicated in emesis by agonist studies. Studies in humans measuring the effects of CB1 agonists on nausea are required and in addition, their potential to inhibit gastric motility, as the latter is normally associated with induction, rather than treatment, of nausea (Sanger et al., 2013). Reduced antral pacemaker frequency was observed in response to cannabinoid in ferrets (Percie du Sert et al., 2010a). An interesting feature of most of the receptors listed above is that in addition to an anti-emetic effect they have been shown to have effects in humans and/or animal models against gastroesophageal reflux, which utilises very similar mechanisms to vomiting.


These agonists also stimulate food intake in humans and/or animal models (see Andrews and Sanger, 2006) and this in itself may be beneficial for treatment of nausea (see above).

7. Conclusions There is now a recognition of nausea as a specific clinical problem which is often not optimally treated in a number of clinical settings. Examination of the anti-nausea effects of several anti-emetic agents used to control CINV supports the view that nausea is a tractable target, at least in this group of patients. In addition, when nausea can be linked to delayed gastric emptying, there is a case for further exploration of prokinetic agents (e.g. motilin, ghrelin receptor agonists) particularly if they also stimulate food intake. Identification of an anti-nausea agent with the potential to affect nausea from a wide range of causes requires more detailed knowledge from humans of pathways linking the brainstem and cortex and their transmitters. Although further research is still needed to explore the role of vasopressin, a more promising approach may be to investigate the mechanisms by which signals for nausea are translated within the brain itself.

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