nausea

What are causes of nausea

Nausea is a feeling of sickness or unpleasant painless subjective feeling or discomfort characterized by a loss of appetite and the sensation of impending vomiting 1). Nausea is considered to function as a protective mechanism, warning the organism to avoid potential toxic ingestion 2). Less adaptive circumstances are also associated with nausea, including post-operative nausea, chemotherapy-induced nausea and motion sickness.

Nausea is a commonly encountered symptom with a broad list of possible causes (see Table 1). While nausea and vomiting are often thought to exist on a temporal continuum, this is not always the case. There are situations when severe nausea may be present without vomiting and less frequently, when vomiting may be present without preceding nausea. Most individuals report that nausea is more common, more disabling, feels worse and lasts longer than vomiting 3).

In the Diagnosis and Management of Nausea – Key Clinical Questions are 4):

  • Is the nausea symptom acute (less than 4 weeks) or chronic (longer than 4 weeks) ?
  • Are warning signs present ?
  • Is this related to the GI (gastrointestinal) tract or to another organ system ?
  • Are special conditions present ?
  • What tests have been performed ?
  • What treatment options are available ?

Is the Nause Acute or Chronic ?

  • Acute less than 4 weeks in duration
    • Infectious, toxins, medications, recent surgery, obstruction, inner ear disorders.
  • Chronic longer than 4 weeks in duration
    • Gastroparesis
    • Chronic intestinal pseudo-obstruction
    • Dyspepsia
    • Hepatobiliary
    • Medications
    • Functional abdominal pain
    • Narcotic bowel syndrome
    • Psychogenic/psychological (bulimia)
    • Other (renal, cardiac, urinary, CNS, endocrine).

Are warning signs present ?

  • Persistent vomiting/hematemesis
  • Odynophagia: Pain on swallowing food and fluids
  • Dysphagia: Difficulty or discomfort in swallowing food and fluids
  • Unintentional weight loss
  • Significant abdominal pain (out of proportion)
  • Evidence of obstruction (distention)
  • Associated headaches/CNS findings
  • Change in mental status/vision
  • Adverse events of chronic nausea & vomiting
  • Dehydration, hypokalemia, metabolic alkalosis
  • Fever
  • Reduce consciousness
  • Severe headache with neck stiffness

Table 1. Common causes of nausea

Medications and toxic etiologiesDisorders of the gut and peritoneum
Cancer chemotherapyMechanical obstruction
AnalgesicsGastric outlet obstruction
Cardiovascular medicationsSmall bowel obstruction
DigoxinFunctional gastrointestinal disorders
AntiarrhythmicsFunctional dyspepsia
AntihypertensivesChronic idiopathic nausea
β-BlockersCyclic Vomiting Syndrome
Calcium-channel antagonistsIdiopathic vomiting
Hormonal preparations/therapies
Oral antidiabeticsNon-ulcer dyspepsia
Oral contraceptivesIrritable bowel syndrome
Antibiotics/antiviralsOrganic gastrointestinal disorders
ErythromycinPancreatic adenocarcinoma
TetracyclinePeptic ulcer disease
SulfonamidesCholecystitis
Antituberculous drugsPancreatitis
AcyclovirHepatitis
Gastrointestinal medicationsCrohn’s disease
SulfasalazineNeuromuscular disorders of the gastrointestinal tract
AzathioprineGastroperesis
NicotinePost-operative nausea and vomiting
CNS activeChronic intestinal pseudo-obstruction
NarcoticsCNS causes
Antiparkinsonian drugsMigraine
AnticonvulsantsIncreased intracranial pressure
Malignancy
Radiation therapyHemorrhage
Infarction
Ethanol abuseAbscess
Meningitis
Infectious causesCongenital malformation
GastroenteritisHydrocephalus
Otitis mediaPseudotumor cerebri
Acute intermittent porphyriaSeizure disorders
Demyelinating disorders
Miscellaneous causesPsychiatric disease
Cardiac diseasePsychogenic vomiting
Myocardial infarctionAnxiety disorders
Congestive heart failureDepression
Radiofrequency ablationPain
StarvationEating disorders
Labyrinthine disorders
Motion sickness
Labyrinthitis
Tumors
Meniere’s disease
Iatrogenic
Endocrinological and metabolic causes
Pregnancy
Other endocrine and metabolic
Uremia
Diabetic ketoacidosis
Hyperparathyroidism
Hypoparathyroidism
Hyperthyroidism
Addison’s disease
[Source 5)]

Table 2. Presentations of Nausea and Vomiting That Suggest Specific Diagnoses

Clinical presentationSuggested diagnosesSuggested tests
Acute onset

  • Cholecystitis,

  • Gastroenteritis,

  • Medication-related effect,

  • Pancreatitis

Cholecystitis: right upper-quadrant ultrasonography
Pancreatitis: amylase and lipase levels, ultrasonography to assess for gallstones, contrast-enhanced abdominal computed tomography in patients with severe illness
Associated with diarrhea, headache, and myalgiasViral gastroenteritisNone
Bilious vomitingSmall bowel obstructionAbdominal radiography or computed tomography
Continuous vomitingConversion disordersElectrolyte levels
Delayed vomiting (more than one hour after meals)

  • Gastric outlet obstruction,

  • Gastroparesis

Obstruction: abdominal radiography
Gastroparesis: gastric emptying study
Feculent or foul odor to vomitusIntestinal obstructionAbdominal radiography
Habitual postprandial, irregular vomitingMajor depressionPatient Health Questionnaire-9, Beck Depression Inventory
Insidious onset

  • Gastroesophageal reflux,

  • Gastroparesis,

  • Medication-related effect,

  • Metabolic disorders,

  • Pregnancy

Gastroesophageal reflux: esophagogastroduodenoscopy if patient has warning signs or does not improve with empiric therapy
Gastroparesis: gastric emptying study
Metabolic disorders: pulse oximetry, arterial blood gases, serum chemistries, chest radiography
Pregnancy: pregnancy test in women of childbearing age, with pelvic ultrasonography if ectopic pregnancy is suspected
Patient report of previous organic or functional gastrointestinal illnessChronic psychogenic vomitingElectrolyte levels, further evaluation if organic cause is suspected
Projectile vomiting, may not be preceded by nauseaIntracranial disorders, increased intracranial pressure (also associated with normal emesis)
Brain computed tomography
Regurgitation of undigested food

  • Achalasia,

  • Esophageal stricture,

  • Zenker diverticulum

Esophagogastroduodenoscopy, upper gastrointestinal barium study
Vomiting before breakfast

  • Alcohol ingestion,

  • Increased intracranial pressure,

  • Pregnancy,

  • Uremia

Increased intracranial pressure: brain computed tomography
Pregnancy: pregnancy test in women of childbearing age, with pelvic ultrasonography if ectopic pregnancy is suspected
Uremia: renal function testing, electrolyte levels
Vomiting during or soon after meals

  • Anorexia,

  • Bulimia

Electrolyte levels
Vomiting partly digested food or chyme several hours after meals

  • Gastric outlet obstruction (no bile),

  • Gastroparesis

Obstruction: abdominal radiography
[Source 6)]

In population studies, more than 50% of adults reported at least one episode of nausea, and more than 30% of adults reported one episode of vomiting within the preceding 12 months, with women reporting more episodes of nausea than men 7). In a large population based study of 62,651 individuals, 12.5% of the individuals reported nausea as ‘minor or major complaint’ in the last 12 months with the prevalence of nausea being three times higher in women than in men 8). Similar results have been reported in other epidemiological studies 9). In addition, race has also been shown to be associated with differential rates of the experience of nausea with White/African-Americans experiencing less nausea than Asian/Asian-American subjects 10).

Chronic, unexplained nausea alone or with vomiting occurs less commonly but is associated with significant comorbidity and poses a therapeutic challenge to health care providers 11). The exact prevalence of chronic idiopathic nausea or functional vomiting is not well studied and population-based studies are needed to estimate the disease burden.

Pathophysiology of nausea

The underlying mechanisms involved in nausea are complex and encompass psychological states, the central nervous system, autonomic nervous system, gastric dysrhythmias, and the endocrine system (see Figure 1).

Central and peripheral pathways involved in pathogenesis of nausea. Afferent information from various stimuli are relayed to nucleus tractus solitarius via four pathways: vestibular and cerebellar, cerebral cortex and limbic system, area postrema and gastrointestinal tract via vagus nerve.*

*Once any of these neural pathways are activated, it culminates into sensation of nausea with or without vomiting. The efferent information from nucleus tractus solitarius is also responsible for activation of autonomic nervous response via vagal pathways. Nausea is also associated with gastric dysrhythmia and release of vasopressin. However, the cause–effect relationship of this triad is not very well understood and warrants further studying.

In order to understand the pathophysiology underlying nausea, it is important to introduce the concept of the dynamic threshold 12). It is proposed that each individual has a threshold for nausea that changes minute by minute. At any given moment, the threshold depends on the interaction of certain inherent factors of the individual with the more changeable psychological states of anxiety, anticipation, expectation and adaptation 13). This dynamic interaction likely explains the inter- and intra-individual variability that is typically encountered in the face of a nauseogenic stimulus 14).

Stimuli giving rise to nausea and vomiting originate from visceral, vestibular, and chemoreceptor trigger zone inputs which are mediated by serotonin/dopamine, histamine/acetylcholine and serotonin/dopamine, respectively. These relationships serve as the basis on which current pharmacological therapy for nausea and vomiting is recommended 15).

Figure 1. Pathogenesis of nausea

Pathogenesis of nausea
[Source 16)]

Central nervous system (brain & spinal cord)

Despite the prevalence and importance of nausea, surprisingly little is known regarding the central mechanisms underlying this sensation 17). The neurocircuitry involved in vomiting is better characterized. Associated autonomic changes which occur during nausea and emesis (e.g. salivation, sweating) are coordinated at the level of the medulla oblongata 18). Chemosensitive receptors detect the presence of emetic agents in the blood and this information is relayed via the area postrema to the nucleus tractus solitarius (NTS) 19). Abdominal vagal afferents which detect gastric tone and contents also project to the NTS 20). Neurons from the nucleus tractus solitarius (NTS) then project to a central-pattern generator which coordinates the various actions involved in the act of emesis in addition to directly projecting to neurons in the ventral medulla and hypothalamus, from which higher brain areas can be reached 21).

Many studies have suggested that the cerberal cortex is also involved in pathways of nausea 22). Recent investigations using functional magnetic resonance imaging (fMRI) techniques in healthy adults have shown that the medial prefrontal cortex and the pregenual anterior cingulate cortex, areas of the brain involved in higher cognitive function and emotion, are positively correlated with an increase in heart rate during nausea, suggesting the importance of cognitive and emotional centers in modulating the parasympathetic to sympathetic shift associated with nausea 23). Napadow and colleagues 24) studied humans predisposed to motion sickness and suggested that nauseogenic stimulus causes activation of amygdala, putamen and locus ceruleus which translates into fear conditioning and emotional triggering. This ultimately leads to the sensation of strong nausea 25). This is followed by continued, sustained activation in cortical areas such as insula, anterior cingulated cortex, nucleus accumbens, orbitofrontal, somatosensory and prefrontal cortex. These areas are involved in the interoceptive, limbic, somatosensory and cognitive network which alerts the suffering individual of the changes in interoceptive signaling so that appropriate autonomic and motor responses are initiated in a timely manner 26). Many of these areas involved in the nausea circuit specifically anterior cingulate cortex, insular cortex, nucleus accumbens and amygdala are known to be involved in processing of acute as well as chronic painful stimulus 27). Furthermore, the medial prefrontal cortex, which appears to be much more involved in chronic pain than acute pain perception, was also found to be a part of the nausea circuit 28). It is plausible that the brain perceives peripheral noxious stimuli through similar pathways, which in some cases lead to chronic pain and in others to chronic nausea. Understanding the central mechanisms of nausea, especially chronic unexplained nausea will be important for the development of therapies in the treatment of chronic nausea.

Autonomic nervous system

Characteristic physiological changes (sweating, pallor, salivation, increase in blood pressure, tachycardia, cutaneous vasoconstriction, decreased gastrointestinal motility) occurring before vomiting are mediated by the autonomic nervous system (ANS) and are well described 29). Afferent signaling arises from vagal inputs, reflecting mechanical or chemical stimuli 30). Several studies have now shown that increasing nausea perception is associated with decreased parasympathetic and increased sympathetic modulation which accounts for majority of above mentioned symptoms 31). In addition, LaCount and colleagues 32) have shown that bursts of cardiovagal modulation precedes transition to a higher level of nausea, perhaps by prompting interoceptive re-evaluation by the subject culminating in rating nausea at a higher level. This autonomic outflow during nausea is likely modulated by the central nervous system (CNS). While some areas of the brain, such as insula appear to be modulating both sympathetic as well as parasympathetic response, there also appears to be a divergent central control for autonomic response of nausea 33). Thus, ANS outflow and the CNS network controlling it could be determinant of overall nausea intensity, and understanding them in more detail could be of therapeutic importance.

Endocrine

Several hormones have been studied in the pathogenesis of nausea with the most important being vasopressin [also called antidiuretic hormone (ADH)]. Increase in antidiuretic hormone (ADH) secretion in various emetogenic situations is clear evidence that the rise in antidiuretic hormone (ADH) level precedes emesis, indicating that this rise does not appear in response to volume depletion or hyperosmolarity 34). Studies have also reported a positive correlation between serum antidiuretic hormone (ADH) level and nausea intensity 35). However, the cause–effect relationship between nausea and antidiuretic hormone (ADH) is still not clear. Although some studies have shown that supra-physiological levels of antidiuretic hormone (ADH) can induce gastric dysrhythmias and nausea whether this happens under normal physiological circumstances is not clear 36). The precise temporal relationship between vasopressin, gastric dysrhythmias and nausea should be studied in order to give us insight into pathogenesis of acute and chronic nausea syndromes. In addition to vasopressin, corticotropin-releasing factor has been established as brain–gut mediator in foregut function and can stimulate inhibitory motor nerves in the dorsal motor nucleus of the vagus, causing delayed gastric emptying and nausea 37).

Gastric dysrhythmias

The stomach is a neuromuscular organ, the myoelectrical activity of which can be measured by a number of techniques including electrogastrography. Normal gastric myoelectrical activity reflects the balance of the intrinsic pacemaker activity of the stomach, smooth muscle, the enteric nervous system, the autonomic nervous system and hormone levels 38). Activity frequency slower than the intrinsic rate is termed bradygastria; a faster frequency is termed tachygastria. There are numerous studies demonstrating the relationship of nausea with the onset of dysrhythmias in individuals with motion sickness, pregnant females, drug-induced nausea and gastroparesis 39). Xu and colleagues 40) have shown that in individuals experiencing vection-induced nausea, experienced tachygastria a few minutes beforehand, suggesting a relationship between gastric dysrhythmias and nausea. Interestingly, medications and interventions that promote normalization of myoelectrical activity from tachygastria decrease nausea, and conversely, stimuli that decrease normal myoelectrical activity and increase dysrhythmias promote the sensation of nausea 41). Whether activation of sympathetic nervous system precedes onset of gastric dysrhythmias or vice versa is not clear and needs to be studied in future 42). High amplitude, retrograde persistaltic contractions of small intestine from the distal to the proximal part on antroduodenal manometry has been shown to precede vomiting episodes 43). However, the causal relationship between gastric dysrhythmias or small intestinal dysmotility and nausea is not well established.

Diagnosis of Nausea

Detailed history and physical exam forms the cornerstone of evaluating patients with the chief complaint of nausea. History and physical exam help to rule out the non-gastrointestinal causes of nausea such as CNS, endocrinological and psychiatric diagnoses, which might be the primary cause or could be a contributing factor (see Table 1 above). The mainstay of diagnostic evaluation of the patient with nausea and vomiting is correcting any symptom consequences (electrolyte abnormalities, dehydration, malnutrition), identifying the cause of the symptoms and initiating targeted therapy, and lastly, if no cause is found, initiating therapy directed at suppressing the symptoms 44). There are no well-designed, controlled trials to guide diagnostic evaluation in patients with acute or chronic nausea. Basic blood work, including electrolytes, liver function tests, pancreatic enzymes and pregnancy test (wherever applicable) should be performed to help establish etiology. If mechanical obstruction is suggested by clinical presentation, radiological investigations such as abdominal X-ray and abdominal CT scan are typically the first-line investigations 45). If mucosal diseases such as ulcer or mass are suspected, esophagogastroduodenoscopy remains the most sensitive and specific investigation to study the esophageal, gastric and duodenal mucosa. If needed, small bowel mucosa can be studied by small bowel follow through and enteroclysis.

Scintigraphic measures of solid phase gastric emptying (such as 99mTc-sulfur colloid in egg) are commonly used to evaluate gastric motion function in suspected gastroparesis 46). Following the test for four instead of two hours has been shown to improve accuracy in diagnosing gastroparesis 47). One should remember that these studies do not establish cause–effect relationship in patients with nausea. Their utility is further limited by the finding that symptoms are not well correlated with abnormalities of gastric emptying and medications to improve motility have been shown to improve symptoms without changing emptying delay 48). In general, most health providers would advocate an empirical trial of antiemetic or prokinetic medications prior to specialized testing 49). Moreover, many of these patients need to be on antiemetics to be able to tolerate these tests. However, many of these agents, specifically prokinetics, can alter gut motility. Thus, it is important to interpret the results in the context of being on or off medication. Investigations such as cutaneous electrogastrography and antroduodenal manometry to study gastric motor functions are not widely available, are expensive and their role in the diagnostic algorithm of patients with chronic nausea is not well established 50). A reduction or decrease of expected postprandial electrogastric amplitude has been shown to correlate with delayed gastric emptying 51). Similarly, postprandial antral hypomotility on atroduodenal manometry is a common finding in patients with unexplained nausea, as well as gastroparesis, and could be used if other tests for gastric motility are normal in a patient with persistent symptoms despite empirical treatment 52). It aids in the diagnosis of motor disorders in such cases but when normal, helps to rule out dysmotility as a cause of nausea.

Patients with unexplained chronic nausea (even after thorough investigation including normal gastric emptying studies) pose a diagnostic dilemma and they remain indistinguishable from those with documented gastric delay with respect to demographics, stability of symptoms over time, healthcare utilization and health-related quality of life 53). In the absence of an identifiable cause, Rome III criteria for functional gastroduodenal disorders can be utilized to diagnose functional disorders related to nausea and vomiting, including chronic idiopathic nausea, functional vomiting, cyclical vomiting syndrome and rumination syndrome. Pasricha and colleagues showed that current Rome III diagnostic criteria may be inadequate for differentiating this group of patients, with significant overlap of diagnoses; many patients met diagnostic criteria for functional dyspepsia, irritable bowel syndrome and chronic idiopathic nausea/functional vomiting 54). Further refinement will be guided by evolving experience and knowledge of this specific group of patients.

What helps nausea

A distinction should be made with respect to management of acute (less than 4 weeks) versus chronic (greater than 4 weeks) symptoms as they are likely entirely different entities and response to therapeutics differ between the two. There is a paucity of literature evaluating the pharmacological therapy of chronic, unexplained nausea 55). This is likely related to the fact that most clinically encountered episodes of nausea and vomiting are typically short lived and self-limited 56). Most of the literature is focused on those clinical situations where the risk of nausea and vomiting is high, such as in pregnancy, the post-operative time period, post chemotherapy, and post radiation 57). It is important to realize the inconsistent effect on the relief of nausea compared with vomiting, with nausea being more resistant to interventions. This finding likely reflects the different physiology of these two distinct symptoms 58). Effect of various antiemetics on different types of nausea, e.g. benzodiazepines for anticipatory nausea and serotonin antagonists for chemotherapy-induced nausea again highlights the complex pathophysiology of nausea.

Current medical therapy generally falls into two categories:

  1. Agents directed at suppressing nausea and preventing vomiting (antiemetic) which typically act centrally in the brain, and
  2. Agents directed at modulating gastrointestinal motility (prokinetic).

Commonly utilized antiemetics are listed (see Table 3).

Table 3. Common anti nausea medications

MedicationsTypical dosageSide effectsRoute of administration
Anticholinergics
Scopolamine0.3–0.6 mg q24 hoursTachycardia, confusion, dry mouth, constipation, urinary retention, blurred visionSL, IV, IM, transdermal
Antihistamines
Meclizine
Diphenhydramine
Cinnarizine
Cyclizine
Hydroxyzine
25–50 mg q24 hours
25–50 mg q6–8 hours
25–75 mg q8 hours
25–50 mg q4–6 hours
25–100 mg q6–8 hours
Drowsiness, confusion, blurred vision, constipation, urinary retentionOral
Oral, IM, IV
Oral
Oral
Oral, IM
Phenothiazines
Prochlorperazine
Promethazine
Chlorpromazine
Perphenazine
5–10 mg q6–8 hours
12.5 –25 mg q4–6 hours
10–25 mg q4–6 hours
4–8 mg q8–12 hours
Extrapyramidal side effects, tardive dyskinesias, neuroleptic malignant syndrome, hyperprolactinemia, QT prolongationOral, IM, IV, rectal
Oral, IM, IV, rectal
Oral, IM, IV
Oral
Benzamides
Metoclopramide
Domperidone
10–20 mg q6–8 hours
10 mg q8–24 hours
Sedation
Anxiety
Mood disturbances
Sleep disruption
Dystonic reactions
Tardive dyskinesia
Galactorrhea
Sexual dysfunction
Oral, IM, IV
Oral
5-HT3 antagonists
Ondansetron
Granisetron
Palonosetron
4–8 mg q4–8 hours
1–2 mg q24 hours
0.075–0.25 mg q24 hours
Headache, fatigue,
malaise, constipation
Oral, IV
Oral, IV, transdermal
IV
Cannabinoids
Dronabinol
Nabilone
2.5–10 mg q6–8 hours
1–2 mg q8–12 hours
Palpitations, tachycardia, vasodilation/facial flushing, euphoria, abnormal thinking, dizziness, paranoia, depersonalization, hallucinations, visual changesOral
Oral
Benzodiazepines
Lorazepam
Alprazolam
0.5–2 mg
0.25–1 mg
Ataxia, cognitive dysfunction, depression, dizziness, drowsiness, dysarthria, fatigue, irritability, memory impairment, sedationOral, SL, IM, IV
Oral
Corticosteroids
Dexamethasone4–8 mg q4–6 hoursEmotional instability, acne, bruising, hyperglycemia, adrenal suppression, Cushing’s syndromeOral, IM, IV
Droperidol0.625–1.25 mg q24hoursQTc prolongation, orthostatic hypotension, extrapyramidal symptoms, CNS effectsIM, IV
NK-1 Receptor Antagonists
Aprepitant80–125 mg q24 hoursFatigue, constipation, hiccupsOral

SL, sublingual; IV, intravenous; IM, intramuscular; CNS, central nervous system.

[Source 59)]

Table 4. Treatment of Nausea and Vomiting in Adults according to disease condition

CauseTreatment
Benign positional vertigoMeclizine (Antivert)
Benign, self-limited, no alarm signsCola, ginger ale, mints, oral rehydration, supportive therapy, treatment of underlying cause
GastroenteritisOndansetron (Zofran), promethazine
Gastroesophageal reflux disease, gastritisHistamine H2 antagonist, proton pump inhibitor
GastroparesisErythromycin, metoclopramide (Reglan)
MigraineMetoclopramide, nonsteroidal anti-inflammatory drugs, prochlorperazine plus antihistamines (NNT = 5)
Motion sicknessAntihistamines, scopolamine
Peptic ulcer diseaseProton pump inhibitor (NNT = 3)
PregnancyDoxylamine (Unisom), ginger, vitamin B6
Renal colicIntravenous or intramuscular nonsteroidal anti-inflammatory drugs, with or without opioids (NNT = 16)

NNT = number needed to treat.

[Source 60)]

Anti nausea medicines

Serotonin 5-HT3 antagonists

Serotonin 5-HT3 antagonists such as granisetron and ondansetron have utility in post-operative vomiting, post-radiation therapy, and in preventing chemotherapy-related emesis 61). Their mechanism of action is mediated primarily though central 5-HT3 receptor blockade (mainly in the chemoreceptor trigger zone) and peripheral blockade of 5-HT3 receptors on intestinal vagal and spinal afferent nerves 62). Their effect in relieving nausea is less robust and prevalence of chemotherapy-induced nausea has increased despite the introduction of potent 5-HT3 antagonists 63). Its utility in other forms of nausea, such as gastroparesis and functional vomiting, is not well studied and it has not been shown to be superior to metaclopramide or promethazine in a double-blinded randomized controlled trial in controlling nausea symptoms in adults visiting the emergency department 64).

Antihistamines

Antihistamines have a therapeutic role in motion sickness and labrynthitis and exert their antiemetic action through central anticholinergic (M1 receptor) and antihistamine (H1 receptor) effects 65). These drugs suppress labyrinthine and vestibular stimulation and that of the chemoreceptor zone in the brainstem 66).

Anticholinergic agents

Anticholinergic agents act centrally via the muscarinic receptors and block the pathway from the inner ear to the brainstem and the ‘vomiting center’ 67). Scopolamine is the most widely used anticholinergic and is administered as a transdermal patch for both prophylaxis and treatment of motion sickness, but its use in other forms of nausea are not well established 68). Selective M3 and M5 antagonist (Zamifenacin) appears to be equally effective implicating these two receptor subtypes 69).

Phenothiazines

Phenothiazines are antidopaminergic agents which act via nonselective inhibition of mainly D2 and D3 receptors in the region of the area postrema, but also muscarinic and H1 receptors 70). They have demonstrated efficacy in treating nausea related to migraine, motion sickness and vertigo, as well as post-operative and post-chemotherapy nausea and vomiting 71). The butyrophenone, droperidol, is only available as a restricted use drug by the FDA, primarily due to its effects on QT prolongation. Its efficacy is well documented in post-operative and chemotherapy-associated nausea and vomiting and like phenothiazines, the mechanism of action is primarily via antidopaminergic activity in the chemoreceptor zone 72).

Cannabinoids

Cannabinoids have been investigated in chemotherapy-related nausea and vomiting 73). They are thought to act primarily via the cannabinoid receptor (CB1) in the ‘vomiting center’ of the medulla and the area subpostrema of the NTS, although potential to modulate 5-HT3 activation in nodose ganglions and substance P release in the spinal cord could also contribute to their antiemesic activity 74). Like many of the other antiemetic agents, the antinausea effect of cannabinoids is not as well established as their antiemetic effect 75).

Benzodiazepines

Benzodiazepines have been investigated as adjunctive therapy in post-operative nausea and small reports have shown that its use reduces anticipatory nausea associated with chemotherapy 76). It is postulated that the antiemetic mechanism of action involves dopamine in the chemoreceptor trigger zone 77). Its primary mode of action is via its sedative, anxiolytic, and amnestic properties in reducing the anticipatory component of nausea 78).

Corticosteroids

Corticosteroids are often used concomitantly with 5-HT3 antagonists and other agents for acute, as well as delayed chemotherapy-induced nausea and vomiting. They have also been shown to have efficacy equivalent to ondansetron and droperidol in post-operative nausea 79). The mechanism of action is unclear but most likely involves its effect on prostaglandin formation and inflammation 80).

Tachykinin peptides

The role of tachykinin peptides such as substance P in the vomiting reflex has been exploited therapeutically, with aprepitant, an antagonist of the tachykinin receptor NK1. Aprepitant is FDA approved for the prevention of both acute, as well as delayed chemotherapy-induced nausea and vomiting and has been showed to potentiate the effects of 5-HT3 receptor antagonists and corticosteroids 81). Case reports have demonstrated the use of aprepitant in the treatment of gastroparesis-associated nausea and vomiting with no demonstrated change in gastric emptying 82). Formal investigation into the efficacy of aprepitant in the treatment of chronic, refractory nausea and vomiting is needed.

Prokinetics

Prokinetic medications are listed (Table 5) and include agents that act primarily as a prokinetic (e.g. erythromycin) versus those that have both prokinetic and antiemetic properties (e.g. metoclopramide). Erythromycin exerts its effects via activation of motilin receptors present on gut smooth muscle, possibly leading to modulation of vagal nerve pathways involved in emesis 83). At low doses of 50–100 mg before meals, it has been shown to be efficacious in controlling nausea and vomiting in patients with delayed gastric emptying. However, when used as antibiotic at higher doses (250–500 mg, 2–4 times a day), it induces nausea, possibly with vomiting 84). At higher concentrations it probably promotes nausea by contracting the gastric fundus and thus inducing gastric dysrythmias and prolonged, nonpropulsive hypermotility of the antrum 85). Recently, ghrelin has been shown to increase gastric emptying in patients with diabetic gastroparesis 86). It has also been shown to control nausea in ferrets exposed to cisplatin; but its effect on nausea in humans is not yet studied 87). However, it is important to realize that nausea likely has both peripheral and central components, and the prokinetic mechanism of action is likely restricted to the periphery. Metoclopramide and domperidone are benzamides with potent antiemetic and prokinetic properties. Their mechanism of action is complex and involves vagal and central 5-HT3 and D2 receptor antagonism with prokinetic properties via gut dopamine receptor antagonism and 5-HT4-receptor agonist activity. They are differentiated by the fact that domperidone does not cross blood–brain barrier and is thus free of extrapyramidal side effects which are common with metaclopramide. Domperidone is not available in the US but metaclopramide is manufactured for both oral and parenteral use. These drugs have been shown to be efficacious in post-chemotherapy vomiting and gastroparesis. Clinically, the use of prokinetic agents is unfortunately limited by numerous side effects, some of which may be irreversible.

Table 5. Prokinetic medications

AgentTypical DosageSide EffectsRoute of administration
Metoclopramide10–20 mg q6–8 hoursSedation
Anxiety
Mood disturbances
Sleep disruption
Dystonic reactions
Tardive dyskinesia
Galactorrhea
Sexual dysfunction
Oral, IM, IV
Domperidone10mg q8–24 hoursGalactorrhea/gynecomastia
Sexual dysfunction
Oral
Erythromycin250–500mg q8 hoursNausea and vomiting
Diarrhea
Oral, IV

IV, intravenous; IM, intramuscular.

[Source 88)]

Novel therapies

Novel and nontraditional medical therapies for nausea and vomiting have been studied (Table 6), and include low-dose antidepressants such as tricyclic antidepressants (TCAs). Retrospective studies have showed moderate symptom reduction in patients with chronic nausea and vomiting including cyclical vomiting syndrome in both diabetic and non-diabetic population; however, given lack of good prospective studies, their use is typically reserved for those with moderate to severe or refractory symptoms 89). In a retrospective study of 37 patients with chronic functional nausea, 51% patients had a complete response and an additional 33% had at least moderate symptoms reduction with low dose TCAs 90). TCAs such as amitriptyline have been shown to have some benefit in functional upper gastrointestinal symptoms such as painful dyspepsia in patients who do not have prolonged gastric emptying 91). This is likely true for other symptoms such as chronic nausea where TCAs are likely to benefit only those patients without delayed gastric emptying.

Table 6. Novel and non-traditional therapies for nausea

AgentMechanism of actionTypical dosageSide effectsRoute of administration
Tricyclic antidepressants
Amitriptyline
Nortriptyline
Doxepin
Desipramine
Imipramine
Antihistaminic and muscarinic activity10–100 mg/day is the common range for most of theseConstipation, gastric emptying delay, agitation, sedationOral
GabapentinMitigation of calcium currents and tachykinin in areas such as the area postrema300–900 mg thrice daily
For sensitive patients, consider starting at between 12.5 to 25 mg daily
Clumsiness, somnolenceOral
OlanzapineTargets dopaminergic (D1, D2, D3 and D4), serotonergic (5-HT2A, 5-HT2C, 5-HT3, 5-HT6), histaminic and muscarinic receptor5–10 mg/daySomnolence, postural hypotension, dizziness, dyspepsia, restlessness, weight gain and rarely extrapyramidal symptomsOral
[Source 92)]

Gabapentin

Gabapentin, a γ-aminobutyric acid analog has been shown to be efficacious in preventing post-operative nausea and vomiting in multiple randomized controlled trials 93). There is also some use of gabapentin in preventing acute and delayed chemotherapy-associated nausea and vomiting, hyperemesis gravidarum, and life-threatening refractory emesis following posterior fossa surgery 94). It is suggested that the mechanism of action involves mitigation of calcium currents in areas such as area postrema 95). Future studies should explore its use in patients with chronic functional nausea vomiting.

Olanzapine

Olanzapine is a known antagonist for dopamine and serotonin receptors. Clinical trials have demonstrated the efficacy of olanzapine in the control of both acute and delayed chemotherapy induced nausea and vomiting 96). In animal studies, olanzapine has been shown to be effective for the control of narcotic-induced nausea and sleep disturbance associated with chronic pain 97).

Gastric electrical stimulation (GES)

Gastric electrical stimulation (GES) is a technique used for refractory gastroparesis. A recent analysis of a large series at one institution demonstrated symptomatic improvement after GES but a need for additional surgical procedures and complications after GES implant 98). Symptomatic improvement achieved by GES in patients with gastroparesis is best explained by activation of vagal afferent pathways to influence CNS control mechanisms for nausea and vomiting, accompanied by enhanced vagal efferent autonomic function and decreased gastric sensitivity to volume distention which enhances postprandial gastric accommodation 99). GES with short pulses can improve gastroparesis symptoms such as nausea and vomiting and GES with long pulses has been shown to improve gastric motility 100). Evidence for the efficacy of GES in patients without demonstrated gastric-emptying delay (such as patients with functional dyspepsia and chronic, refractory, idiopathic nausea and vomiting) is evolving 101).

Home remedies for nausea

With respect to dietary recommendations in the management of nausea and vomiting, a low-fat, low-fiber diet with small frequent meals is typically recommended if patients are able to tolerate oral intake. A short-term liquid diet in extreme cases of patients not tolerating a solid diet is also routinely recommended 102). For patients with chronic, unexplained symptoms, dietary recommendations typically follow those routinely recommended for patients with documented gastric emptying delay, although there are no large, well-designed trials evaluating this strategy.

Dietary manipulation and supplements have also been investigated for the management of nausea and vomiting. Use over-the-counter (OTC) motion sickness medicines. If you’re planning a trip, OTC motion sickness drugs, such as dimenhydrinate (Dramamine) or meclizine (Rugby Travel Sickness) may help calm your queasy stomach. For longer journeys, such as a cruise, ask your doctor about prescription motion sickness adhesive patches, such as scopolamine (Transderm Scop). Ginger is a herbal supplement that has been shown to have some efficacy in small studies to reduce severity of post-operative nausea and vomiting, morning sickness and motion sickness 103). Studies involving the use of ginger in prevention of chemotherapy-induced nausea and vomiting are conflicting and do not support its use 104). Its mechanism of action is largely unknown but improvements in gastric motility, anti-5-hydroxytryptamine activity and central antiemetic effects have been postulated 105). Rieber and colleagues investigated human subjects, looking at the effect of acute tryptophan depletion when subjected to a rotational procedure intended to induce nausea and found that it increased 106). Interestingly, acute tryptophan depletion was also shown to slow gastric emptying time in females 107). These findings suggest a potential role of diet and supplements in modulating the sensation of pain and nausea, which would be important to pursue with further research.

Alternative and complementary approaches to the management of nausea and vomiting include hypnosis, acupressure and acupuncture. In a systematic review, P6 acupoint stimulation significantly reduced nausea, vomiting and the need for rescue medications in the post-operative setting 108). Another randomized controlled trial involving 63 subjects with post-surgical gastroparesis showed that P6-acupoint stimulation was superior to metaclopramide in achieving complete recovery rate 109). Marchioro and colleagues 110) have also shown efficacy of hypnosis in preventing chemotherapy-induced anticipatory nausea and vomiting in 16 patients.

Summary

Acute nausea (e.g. related to chemotherapy) is easier to control than chronic unexplained nausea. Clinically, patients with chronic and refractory symptoms in the absence of an identifiable cause pose a significant challenge and should be the focus of clinical investigation. Antiemetics such as antihistaminics, antidopaminergics and 5-HT3 antagonists are often the first-line agents used for common causes of acute nausea. Other agents such as steroids and aprepitant are most commonly used for acute and delayed phase of chemotherapy-induced nausea. Benzodiazepines are best suited for the anticipatory component of post-operative or chemotherapy-induced nausea.

Chronic nausea is much more difficult to control and poses a therapeutic challenge for most health care providers. As discussed above, the central pathways of chronic nausea are very close to chronic neuropathic pain and thus therapeutic options are also directed towards the same. The first line therapeutic options for these patients are neuromodulators such as TCAs, olanzapine, gabapentin and possibly cannabinoids and benzodiazepines. However, if a patient is found to have delayed gastric emptying, prokinetics are the agents of choice. For patients with chronic nausea, we recommend starting with the lowest possible dose of antinausea agents and titrating slowly, as most of these types of patient are sensitive to triggers such as food and medications, which could worsen their symptoms.

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