Central
i. Intracranial	Migraine
i. Intracranial	Raised intracranial pressure (tumour, infection, haemorrhage, hydocephalus, etc.)
ii. Labyrinthine Iatrogenic	Labyrinthitis, motion sickness, Ménière’s disease, otitis media
	Cancer chemotherapy
	Many other medicines (e.g. opioids)
	Radiotherapy
	Post-operative
Endocrine/ metabolic	Pregnancy, uraemia, diabetic ketoacidosis, hyperthyroidism, hyperparathyroidism, hypoparathyroidism, Addison’s disease, acute intermittent porpyhria
Infectious	Gastroenteritis (viral or bacterial)
Infectious	Other infections elsewhere
Gastro-intestinal disorders	Mechanical obstruction (gastric outlet or small bowel)
	Organic gastro-intestinal disorders (e.g. cholecystitis, pancreatitis, hepatitis, etc.)
	Functional gastro-intestinal disorders (e.g. non-ulcer dyspepsia, irritable bowel syndrome, etc.)
Psychogenic disorders	Psychogenic vomiting, anxiety, depression
Pain related	Myocardial infarction

(adapted from Quigley et al., 2001)

Pathophysiology

Complex interactions between central and peripheral pathways occur in the production of the clinical features of nausea and vomiting. The most important areas involved peripherally are the gastric mucosa and smooth muscle (the enteric brain) and the afferent pathways of the vagus and sympathetic nerves. Centrally the significant areas involved are the area postrema, the chemoreceptor trigger zone (CTZ), the nucleus tractus solitarus (NTS) and the vomiting centre.

From a pharmacotherapeutic point of view, the most important aspect of this complex pathophysiology is the variety of receptors involved, including histaminergic (H₁), cholinergic (muscarinic M₁), dopaminergic (D2), serotonergic (5HT₃) and neurokinin-1 (NK₁) receptors. In the clinical situation, these become targets for various drugs directed at controlling the symptoms.

There are 10⁸ neurons in the intestine and a complex interaction occurs between these, the mucosa, the smooth muscle in the intestine, the parasympathetic (vagus nerve) and sympathetic nerves and the higher centres in the spinal cord and brain to result in normal gastro-intestinal peristaltic activity. The enteric brain and the vagus nerve monitor stimuli from mucosal irritation and smooth muscle stretch which may result in nausea and/or vomiting.

The area postrema in the floor of the fourth ventricle contains the CTZ and is a special sensory organ rich in dopaminergic, serotonergic, histaminergic and muscarinic receptors. It is located outside the blood–brain barrier (BBB) and it is likely that chemicals, toxins, peptides, drugs and neurotransmitters in the cerebrospinal fluid (CSF) and bloodstream interact with this area to cause nausea and vomiting. However, the precise mechanism is not known.

The vomiting centre is situated in the dorsolateral reticular formation close to the respiratory centre and receives impulses from higher centres, visceral efferents, the eighth (auditory) nerve (the latter two through the nucleus tractus solitarius) and from the CTZ (Fig. 34.1). It includes a number of brainstem nuclei required to integrate the responses of the gastro-intestinal tract, pharyngeal muscles, respiratory muscles and somatic muscles to result in a vomiting episode. The vomiting centre may be stimulated in association with, or in isolation from, the nausea process.

Fig. 34.1 Schematic representation of pathways involved in nausea and vomiting.

The vomiting reflex can be elicited either directly via afferent neuronal connections, especially from the gastro-intestinal tract and is probably dependent on the integrity of the nucleus tractus solitarius, or from humoral factors dependent on the integrity of the area postrema. The sequence of muscle excitation and inhibition necessary for the act of vomiting is probably controlled by a central pattern generator located in the nucleus tractus solitarius, and information from the CTZ and vagus nerve converges at this point.

The central causes of nausea and vomiting include increased intracranial pressure, dilation of cerebral arteries during migraine and stimulation of the labyrinthine mechanism or of the senses of sight, smell and taste.

The peripheral causes of nausea and vomiting include motion sickness, delayed gastric emptying and gastric mucosal irritation (ulceration, NSAIDs). These mechanisms are all mediated through the vagal afferent neurons. The vomiting associated with distension or obstruction of the gastro-intestinal tract is mediated through both the sympathetic and vagal afferent neurons.

Patient management

Management of the patient with nausea and vomiting is approached in three steps.

1. Recognise and correct any complications. This includes correction of dehydration, hypokalaemia and metabolic alkalosis in the acute situation with symptoms of less than 4 weeks duration. Weight loss and malnutrition are features of chronic nausea/vomiting, that is, when symptoms have been present for 4 weeks or longer.

2. Where possible, identify the underlying cause (see Table 34.1) and institute appropriate treatment. Here it is important to be aware that metabolic or endocrine conditions such as hypercalcaemia, hyponatraemia and hyperthyroidism can result in vomiting.

3. Implement therapeutic strategies to suppress or eliminate symptoms (these depend on the severity and clinical context). Ideally, antiemetic drugs are prescribed only when the cause of the nausea and/or vomiting is known, since by suppressing symptoms, they may otherwise delay diagnosis. This is especially true in children. However, they may sometimes be necessary temporarily in situations when directly addressing the underlying cause will not bring symptom relief sufficiently rapidly.

Some scenarios illustrating common therapeutic problems in the management of nausea and vomiting are outlined in Table 34.2.

Table 34.2 Common therapeutic problems in managing patients with nausea and vomiting

Problem	Possible cause/solution
Persistent nausea and vomiting despite treatment	Is the cause correctly diagnosed?
Persistent nausea and vomiting despite treatment	Review the antiemetic agent and the dose: if both correct, change to or add a second agent
Patient with PONV is vomiting despite suitable antiemetic regimen	Check analgesia: pain may be causing nausea and vomiting, or patient-controlled analgesia may require adjustment downwards to reduce analgesic dose
Patient with bowel obstruction is passing flatus	Prokinetic drug is first-choice antiemetic. 5HT₃ antagonists may also be effective
Patient with bowel obstruction is not passing flatus	Spasmolytic drug is first choice. Prokinetic drugs are contraindicated. Similarly, bulk-forming, osmotic and stimulant laxatives are inappropriate; phosphate enemas and faecal softeners are better
A terminally ill patient receiving diamorphine is vomiting, despite use of haloperidol	Levomepromazine given as a 24-h subcutaneous infusion can be very effective
A patient with renal failure (uraemia) is vomiting	Consider a 5HT₃ antagonist
A patient develops an acute dystonic reaction to metoclopramide	Give an intramuscular injection of an antihistamine. Such extrapyramidal reactions to metoclopramide are more common in young adults (especially females) and this agent is best avoided in this group

PONV, post-operative nausea and vomiting.

Antiemetic drugs

Several classes of antiemetic drugs are available that antagonise the neurotransmitter receptors involved in the pathophysiology of nausea and vomiting. These classes of drugs are generally distinguished from each other by the identity of their main target receptor, although some act at more than one receptor.

Antihistamines

This group of medicines includes cinnarizine, cyclizine, diphenhydramine, diphenhydrinate and promethazine. They have some efficacy in nausea and vomiting caused by a wide range of conditions, including motion sickness and post-operative nausea and vomiting (PONV). They are thought to block H₁ receptors in the CTZ and possibly elsewhere. However, several of these agents also have potent anticholinergic (M₁) receptor antagonist activity, which may contribute significantly to their efficacy as well as their adverse effect profile (see Section ‘Anticholinergics’). The sedative effects of some antihistamines may also contribute to antiemetic activity, although this property appears not to be essential and it can be a particular problem when skilled tasks, such as driving, need to be performed. Nevertheless, the newer non-sedating antihistamines, for example, fexofenadine, are of limited value in nausea and vomiting.

Anticholinergics

This is one of the oldest classes of antiemetics, of which many members are potent inhibitors of muscarinic receptor (M₁) activity both peripherally and centrally. Anticholinergic drugs such as atropine, hyoscine and glycopyrronium have been used preoperatively to inhibit salivation and excessive respiratory secretions during anaesthesia. Anticholinergics act by inhibiting cholinergic transmission from the vestibular nuclei to higher centres within the cerebral cortex, thereby explaining their predominant use in the treatment of motion sickness. Hyoscine hydrobromide (scopolamine hydrobromide) is the most widely used agent and it can be given orally, by subcutaneous or intramuscular injection, or transdermally for motion sickness. Inhibition of peripheral muscarinic receptors can cause drowsiness, dry mouth, dilated pupils and blurred vision, decreased sweating, gastro-intestinal motility and gastro-intestinal secretions and difficulty with micturition. Anticholinergic agents may also precipitate closed-angle glaucoma in susceptible individuals.

Antidopaminergics

Selective 5HT₃-receptor antagonists

Serotonin or 5-hydroxytryptamine (5HT) plays an important role in nausea and vomiting. The subtype 5HT₃-receptors, which mediate the vomiting pathway, are located peripherally on vagal nerve endings in the gastro-intestinal tract and centrally in the brain, with high concentrations found in the area postrema and nucleus tractus solitarius. Highly emetogenic agents such as cisplastin are thought to disrupt gastric mucosa and initiate the release of 5HT from enterochromaffin cells, which stimulate the 5HT₃-receptors on afferent vagal nerve endings and thus trigger the emetic reflex. Selective 5HT₃-receptor antagonists that act centrally and peripherally are now commonly used to treat or prevent CINV (with drugs of moderate to high emetogenic potential) and PONV. They are also effective in radiotherapy-induced nausea and vomiting. Selective 5HT₃ antagonists are generally well tolerated, with the most common adverse effects being constipation, headache, dizziness and sensation of warmth or flushing. Some available agents include granisetron, ondansetron and palonosetron. They are all more expensive than antihistamines, phenothiazines, anticholinergics or dopamine antagonists.

Neurokinin-1 (NK₁) receptor antagonists

Substance P is a bioactive peptide that shares a common amino acid sequence with other bioactive peptides known as tachykinins. It appears to play an important role as a neurotransmitter in emesis as well as in pain and a number of other inflammatory processes. Substance P binds to the subtype neurokinin-1, or NK₁ receptors, which are found in the area postrema and nucleus tractus solitarius. Selective NK₁ receptor antagonists, aprepitant and fosaprepitant (a prodrug of aprepitant), are now available for use as an adjunct to dexametasone and a 5HT₃ antagonist in preventing, but not treating, nausea and vomiting associated with moderately and highly emetogenic chemotherapy. They appear to be well tolerated but it is an inhibitor (and sometimes inducer) of cytochrome P450 (CYP3A4) and inducer of CYP2C9 and glucuronidation, so potential drug interactions with chemotherapeutic agents as well as other concomitantly administered agents, for example, possibly warfarin, may occur.

Cannabinoids

It is likely that the antiemetic activity of cannabinoids is related to stimulation of central and peripheral cannabinoid (CB1) receptors. Cannabinoids have modest antiemetic activity that is of similar magnitude to prochlorperazine in CINV, but they can cause a range of central nervous adverse effects, including drowsiness and sometimes behavioural disturbances, which may at times be severe. Thus, while the synthetic cannabinoid nabilone is indicated for nausea and vomiting caused by cytotoxic chemotherapy unresponsive to conventional antiemetics, it is recommended that patients are made aware of possible changes in their mood and other unwanted effects on their behaviour. In addition, nabilone should be used under close supervision, preferably in a hospital setting.

Corticosteroids

Corticosteroids are known to have antiemetic effects. Their mechanism of action is unclear but steroid receptors are thought to exist in the area postrema. As single agents, they appear to be at least as effective as prochlorperazine in preventing nausea and vomiting associated with mild to moderately emetogenic cytotoxic chemotherapy. Dexametasone, the most widely used corticosteroid in this context, improves the antiemetic activity of prochlorperazine and metoclopramide and may reduce some of the side effects associated with the latter. When combined with 5HT₃ antagonists, corticosteroids are particularly effective in CINV associated with moderately emetogenic chemotherapy, or when used in delayed emesis. The same combination of dexametasone and a 5HT₃ antagonist, and sometimes with aprepitant, may also be effective in CINV associated with highly emetogenic chemotherapy regimens.

Complementary and alternative medicines

Systematic reviews support the use of stimulating wrist acupuncture point P6 for preventing PONV in combination with, or as an alternative to, conventional antiemetics (Lee and Done, 2004). A systematic review of randomised trials has also demonstrated the efficacy of ginger (at least 1 g preoperatively) in PONV. Ginger has also been claimed to be beneficial in motion sickness and pregnancy-associated nausea, but the evidence for each is limited to single randomised trials (Ernst and Pittler, 2000).

Drug treatment in selected circumstances

Post-operative nausea and vomiting

Around 25% of patients experience PONV within 24 h of surgery (Gan et al., 2003). The aetiology is complex and multifactorial and includes patient-, medical-, surgical- and anaesthetic-related factors. Management is multimodal and involves strategies to reduce baseline risk such as using less emetogenic induction agents, anaesthetic agents and analgesics, consideration of the use of regional rather than general anaesthesia, adequate hydration and intraoperative supplemental oxygen use and avoidance of high-dose neostigmine.

Many antiemetic agents have some efficacy in post-operative nausea and vomiting but combination therapy with drugs from different classes may be needed in patients at high risk, such as those with a previous history of post-operative nausea and vomiting or motion sickness, or after high-risk procedures, for example, prolonged operations. Prophylactic treatments include dexametasone before induction or 5HT₃ antagonists, antihistamines or phenothiazines at the end of surgery. Metoclopramide and cannabinoids appear to be of limited value in the management of post-operative nausea and vomiting.

Premedication with opioids increases the incidence of post-operative nausea and vomiting and this may be reduced by concurrent administration of either atropine or hyoscine, which are primarily used as anti-secretory drugs at premedication.

Risk scores

Prophylaxis is preferable to treatment and this can often be achieved not only by use of antiemetic drugs but also by suitable planning. For example, not all patients undergoing surgery will experience post-operative nausea and vomiting and universal prophylaxis is not cost-effective (Habib and Gan, 2004). A simple risk scoring system has been devised in which the score increases relative to the presence or absence of four factors:

• female gender

• history of motion sickness or PONV

• non-smoker

• opioid use during operation.

The incidence of post-operative nausea and vomiting with the presence of none, one, two, three or all four of these risk factors has been shown to be 10%, 20%, 40%, 60% and 80%, respectively (Apfel et al., 1999). Use of risk scores based on these criteria helps to appropriately tailor antiemetic use and can significantly reduce the incidence of nausea and vomiting in clinical practice (Apfel et al., 2002; Pierre et al., 2004).

Chemotherapy-induced nausea and vomiting

Three different types of CINV have been identified: acute, delayed and anticipatory. Acute emesis begins within 1 or 2 h of treatment and peaks in the first 4–6 h. Delayed emesis occurs more than 24 h after treatment, peaks at 48–72 h and then subsides over 2–3 days. It occurs characteristically after high-dose cisplatin but may also occur after the related agent carboplatin, as well as cyclophosphamide or an anthracycline. Anticipatory emesis occurs in patients who have developed significant CINV during previous cycles of therapy. Acute CINV is often associated with an increase in plasma serotonin concentrations for the most emetogenic agents, while delayed and anticipatory vomiting seem to be mediated by serotonin-independent pathways.

Management of CINV depends on the emetogenicity of the chemotherapy regimen and the use of combinations of antiemetic drugs based on their varying target receptors. Chemotherapy agents are divided into four emetogenic levels (Table 34.3) defined by expected frequency of emesis (Kris et al., 2006).

Table 34.3 Relative emetogenicity of chemotherapy drugs

Emetic risk (incidence of emesis without antiemetics)	Agent
High (>90%)	Cisplatin
	Mechlorethamine
	Streptozotocin
	Cyclophosphamide ≥1500 mg/m²
	Carmustine
	Dacarbazine
	Dactinomycin
Moderate (30–90%)	Oxaliplatin
	Cytarabine >1000 mg/m²
	Carboplatin
	Ifosfamide
	Cyclophosphamide <1500 mg/m²
	Doxorubicin
	Daunorubicin
	Epirubicin
	Idarubicin
	Irinotecan
Low (10–30%)	Paclitaxel
	Docetaxel
	Mitoxantrone
	Topotecan
	Etoposide
	Pemetrexed
	Methotrexate
	Mitomycin
	Gemcitabine
	Cytarabine ≤1000 mg/m²
	Flurouracil
	Bortezomib
	Cetuximab
	Trastuzumab
Minimal (<10%)	Bevacizumab
	Bleomycin
	Busulfan
	2-Chlorodeoxyadenosine
	Fludarabine
	Rituximab
	Vinblastine
	Vincristine
	Vinrelbine

(from Kris et al., 2006)

In high-level acute emesis, a single dose of a 5HT₃ antagonist given before chemotherapy is therapeutically equivalent to a multidose regimen with these agents. Odansetron and granisetron appear to be equally effective in CINV and only one study suggests palonosetron is superior to granisetron when given in combination with dexametasone (Billio et al., 2010). Oral formulations of antiemetics are often as effective as intravenous ones. In lower level acute emesis, the cost of the 5HT₃ antagonists is prohibitive and metoclopramide or prochlorperazine are commonly used and are sufficiently effective.

Dexametasone is the most extensively evaluated steroid in the management of CINV. Used alone, it is not sufficiently potent in CINV. However, it enhances the effect of other agents such as 5HT₃ antagonists in high-risk situations and, together with metoclopramide, it also appears to be useful in treating delayed emesis.

The best management for anticipatory emesis is the avoidance of acute and delayed emesis during previous cycles. However, when anticipatory nausea and vomiting are a problem, a low dose of a benzodiazepine such as lorazepam is often effective.

When apparently appropriate antiemesis regimens fail, consideration should be given to the possibility of other underlying disease- and medication-related issues (Box 34.1).

Box 34.1 Factors that cause nausea and vomiting in their own right and may contribute to the failure of apparently appropriate prophylactic regimens for chemotherapy-induced nausea and vomiting (CINV)

Hypercalcaemia or other metabolic or endocrine disturbance

CNS metastases

Antibiotics such as erythromycin/clarithromycin

Gastro-intestinal obstruction

Radiotherapy enteropathy

Pregnancy-associated nausea and vomiting

Pregnancy-associated nausea and/or vomiting occurs in about 70% of women during the first trimester. Risk factors for vomiting include a personal history of previous pregnancy-associated nausea/vomiting or motion sickness or migraine-associated nausea/vomiting, a family history of hyperemesis gravidarum or a large placental mass, for example, due to multiple pregnancy. Symptoms usually begin 4 weeks after the last menses and in 80% of cases end at 12 weeks, having peaked at 9 weeks. In some women, the problem may persist until 16–20 weeks. First-trimester nausea and vomiting are not usually harmful to either the fetus or the mother and is not generally associated with a poor pregnancy outcome.

In contrast, hyperemesis gravidarum is a condition of intractable vomiting complicating between 1% and 5% of pregnancies and sometimes resulting in serious fluid and electrolyte disturbance and nutritional deficits.

In first-trimester nausea and vomiting, simple measures such as small frequent carbohydrate-rich meals and reassurance are sufficient to control symptoms. Ginger and P6 acupressure have also been advocated, although the evidence base is equivocal in early pregnancy (Jewell and Young, 2003). More recent studies on the use of acupuncture in pregnancy-associated nausea and vomiting remain unclear (King and Murphy, 2009). It is important to avoid antiemetic drugs when possible, but promethazine has been recommended in severe vomiting, with prochorperazine or metoclopramide as second line agents. In Canada and the USA, a combination of pyridoxine (vitamin B₆) and an antihistamine (doxylamine) is approved for the treatment of nausea in pregnancy but this combination treatment appears to be less effective for controlling vomiting.

In the serious condition of hyperemesis gravidarum, drug therapy may be used, although no trials have shown clear benefit (Jewell and Young, 2003). Fluid and electrolyte replacement, rest and if necessary postpyloric or parenteral feeding to provide nutritional support and vitamins (e.g. thiamine to reduce the risk of Wernicke’s encephalopathy) supplementation should be considered. There are few safety or efficacy data on which to select the most appropriate treatments so the agents recommended for vomiting of pregnancy mentioned above are generally used in the first instance in the UK.

Migraine

Migraine is a paroxysmal disorder with attacks of headaches, nausea, vomiting, photophobia and malaise. Treatment is directed at:

• prophylaxis: avoid triggers, try β-blockers, pizotifen and in severe cases a 5HT_1B/D-receptor agonist such as sumatriptan

• analgesia, including aspirin, paracetamol, opioids, NSAIDs

• antiemetics.

Nausea and vomiting in migraine are associated with headache intensity, and the concomitant gastric stasis aggravates the nausea and vomiting and may also delay absorption of oral analgesics. Metoclopramide and domperidone attenuate the autonomic dysfunction and promote gastric emptying but the risk of acute dystonic crisis, especially with metoclopramide therapy should be borne in mind, especially in young women and children, but also in the elderly.

Labyrinthitis

Labyrinthine dysfunction results in vertigo, nausea and vomiting. Episodes may last a few hours or days. Causes include labyrinth viral infections, tumours and Ménière’s disease. The onset of episodes is often unpredictable and disabling. Betahistine sometimes has some benefit. The anticholinergics, antihistamines, phenothiazines or benzodiazepines can be used to suppress the vestibular system. Usually hyoscine is sufficient but if there is severe vomiting, prochlorperazine or metoclopramide may be of value.

Motion sickness

Motion sickness is a syndrome, a collection of symptoms without an identifiable cause. It is brought on by chronic repetitive movements which stimulate afferent pathways to the vestibular nuclei and lead to activation of the brainstem nuclei. Histaminergic and muscarinic pathways are involved. The symptoms include vague epigastric discomfort, headache, cold sweating and nausea which may culminate in vomiting. This is often followed by marked fatigue which can last hours or days. Onset of symptoms may be abrupt or gradual.

The anticholinergic agent hyoscine is the prophylactic drug of choice, although there is no evidence of its benefit once motion sickness is established (Spinks et al., 2004). Antihistamine drugs may also be effective. The less sedating antihistamines cinnarizine or cyclizine are used. Promethazine, an antihistamine with sedative effects, is also effective but phenothiazines, domperidone, metoclopramide and 5HT₃-receptor antagonists appear to be ineffective in this situation. Treatment should be started before travel; for long journeys, promethazine or transdermal hyoscine may be preferred for their longer duration (24 h and 3 days, respectively). Otherwise, repeated doses will be needed.

The most important adverse effect of many drugs used is sedation, whilst for anticholinergic drugs it is blurred vision, urinary retention and constipation. In laboratory studies, the degree to which these effects impair performance, for example, driving a car, is highly variable but subjects who take anti-motion sickness drugs should normally be deemed unfit for such tasks. These drugs also potentiate the effects of alcohol.

Many non-drug treatments have been advocated for alleviation of motion sickness, including wristbands, which act on acupuncture points, variously positioned pieces of coloured paper or card, as well as plant extracts such as ginger. The evidence base for these interventions remains very limited.

Drug-associated nausea and vomiting

As well as chemotherapeutic agents, many commonly used medications for other disorders can cause nausea and vomiting (Quigley et al., 2001). Opioids are perhaps the most important group clinically, but dopamine agonists (used in Parkinson’s disease), theophylline, digoxin and macrolide antibiotics such as erythromycin can all cause nausea and/or vomiting, often in a dose-related manner (Type A toxicity). High-dose oestrogen, used in postcoital contraception, can produce these symptoms. Consideration should be given to altering the dose of the offending agent when possible, and administering the medication with food. With some agents, tolerance may develop. Thus, tolerance to the emetic effects of opioids often develops within 5–10 days and, therefore, antiemetic therapy is not generally needed for long-term opioid use.