Cyclic Vomiting Syndrome

Updated: Oct 20, 2023
Author: Thangam Venkatesan, MD; Chief Editor: Carmen Cuffari, MD 


Practice Essentials

Cyclic vomiting syndrome (CVS), first described in children by Samuel Gee in 1882, is a chronic functional disorder of unknown etiology that is characterized by paroxysmal, recurrent episodes of vomiting. (See the image below.)

Cyclic versus chronic temporal patterns of recurre Cyclic versus chronic temporal patterns of recurrent vomiting. Number of emeses is plotted over 2-month period. Chronic pattern, represented by thin dashed line, has low grade on nearly daily basis (eg, gastroesophageal reflux). Cyclic pattern, represented by heavy solid line, involves high-intensity episodes intermittently once every several weeks (eg, cyclic vomiting syndrome).

The pathophysiology is unknown (see Pathophysiology and Etiology), but data suggest a strong genetic component in children with CVS, with evidence of mitochondrial heteroplasmies that predispose to CVS and other related disorders (eg, migraine and chronic fatigue syndrome). Other theories include autonomic dysfunction and, possibly, corticotropin-releasing factor (CRF) because stress is known to be a trigger for these episodes. The possible role of cannabis in causing CVS has been examined, though it remains controversial.

Signs and symptoms

CVS is characterized by recurrent, discrete, stereotypical episodes of rapid-fire vomiting between varying periods of completely normal health. This on-and-off stereotypical pattern of vomiting is nearly pathognomonic.

See Presentation for more detail.


Because no biochemical markers for CVS have been identified, physicians must initially look for alarming symptoms and then tailor the subsequent workup accordingly. Depending on the presenting symptoms and signs other than vomiting, different diagnostic approaches are recommended.

See Workup for more detail.


In the absence of known pathophysiology, treatment of CVS remains empiric.

See Treatment and Medication for more detail.

Patient education

For ongoing support and information, families are encouraged to contact the Cyclic Vomiting Syndrome Association, which is an international voluntary organization that serves the needs of patients in the United States and Canada.

Pathophysiology and Etiology

The etiology and pathophysiology of CVS are not known. However, studies have suggested several potential brain-gut mechanisms.

Migraine-related mechanisms have been proposed.[1, 2] In one study, patients with CVS have a significantly higher prevalence of family members with migraine headaches (82% vs 14% of control subjects with a chronic vomiting pattern). Furthermore, 28% of patients with CVS whose vomiting subsequently resolved developed migraine headaches. Approximately 80% of affected patients with family histories positive for migraine respond to antimigraine therapy.[1, 2]

Mitochondrial DNA (mtDNA) mutations may be involved in the pathogenesis of CVS. Boles et al demonstrated that 86% of children with CVS and neuromuscular disease had a history of migraines on the matrilineal side. In children with CVS, 2 mtDNA polymorphisms (16519T and 3010A) are expressed with a high degree of frequency and may serve as a surrogate marker for predisposition to the disease.[3]

The 16519T polymorphism is 6 times more common in pediatric CVS patients than in control populations.[4] The 3010A polymorphism increases the likelihood of CVS in subjects with 16519T by as much as 17 times. These mtDNA polymorphisms may account for the clustering of functional conditions and symptoms in the same individuals and families. One small (and possibly underpowered) study found that adult-onset CVS, unlike pediatric CVS, CVS is not associated with these polymorphisms, suggesting a degree of genetic distinction.[2]

Sympathetic hyperresponsiveness and autonomic dysfunction also appear to contribute to the pathogenesis of CVS.[5] Many associated symptoms, such as pallor, flushing, fever, lethargy, salivation, and diarrhea, are mediated by the autonomic nervous system.[6, 7] Several studies support altered autonomic function in CVS.

Rashed et al[8] and To et al[9] demonstrated heightened sympathetic cardiovascular tone in patients with CVS. Kasawinah et al reported the successful use of dexmedetomidine, an alpha2-adrenergic agonist, to treat CVS.[10] In a small study involving 6 children with CVS, all patients had sympathetic autonomic dysfunction, affecting mainly the vasomotor and sudomotor systems. Symptoms developed during tilt testing in half of these patients, suggesting that these findings may play a role in the pathophysiology of CVS.[11]

To evaluate this association with autonomic dysfunction, a cross-sectional study was performed in which the Ohio dysautonomia (ODYSA) questionnaire was administered to 21 patients with CVS (3 children) and 46 patients with migraines.[12] The 2 patient groups had similar comorbid conditions, with fibromyalgia noted in 38% of subjects with CVS, orthostatic intolerance in 47% of subjects with CVS, functional dyspepsia in 9.5% of subjects with CVS, and complex regional pain syndrome in 24% of subjects with CVS.

The main limitation of this study was that the findings were not corroborated by means of either a physical examination or standard autonomic function testing.[12] However, the findings of orthostatic intolerance are of clinical significance because the use of pharmacologic therapy (eg, fludrocortisone and beta-blockers) may be considered in these patients.

In a prospective trial in adult CVS patients, Venkatesan et al found that most subjects with CVS (90%) had impairment of the sympathetic nervous system with postural tachycardia or sudomotor dysfunction while parasympathetic nerve function was intact.[13]

In this study, 17 (85%) of 20 adult CVS subjects and 2 (10%) of 20 control subjects had abnormalities on thermoregulatory sweat testing.[13] A total of 7 (35%) patients and 1 control subject had evidence of postural tachycardia with an increase of more than 30 beats/min in heart rate (HR) on standing. Of the subjects, 18 (90%) had abnormal sudomotor function, postural tachycardia, or both. The HR response to deep breathing was normal in 19 (95%) subjects with CVS and 18 (95%) controls.

The stress response, mediated by the hypothalamic-pituitary-adrenal (HPA) axis, can also potentially induce episodes of CVS. Infectious, psychological, and physical stressors are known triggers of episodes.[14, 15, 16, 17, 18] Sato et al documented increased levels of adrenocorticotropic hormone (ACTH) and cortisol, associated with extreme lethargy and hypertension, before the onset of vomiting.[19, 20, 21, 22] Furthermore, Taché showed that central CRF induced gastric stasis, emesis, or both in animals.[23]

Therefore, CRF may be a brain-gut mediator of CVS that directly connects stress and vomiting.[24] If this theory holds true, CRF receptor antagonists currently in development could theoretically ablate vomiting by blocking the CRF receptor’s vagally mediated actions.[25]

Cannabis use in CVS has received considerable attention. Chronic marijuana use has been associated with hot showers or compulsive hot water bathing and CVS, though a cause-and-effect relation has not been confirmed. The endocannabinoid system (ECS) consists of the ligands 2-AG and anandamide and the cannabinoid receptors CB1 and CB2. This system is thought to play a role in nausea and vomiting and in coping with stress.

There is considerable evidence that activation of central and peripheral CB1 cannabinoid receptors inhibits nausea and vomiting; conversely, both nausea and vomiting are frequent adverse effects accompanying CB1 receptor antagonist use in humans. These and other data strongly suggest that the tone of the ECS regulates nausea and vomiting; further studies are needed to explore this possibility more fully.[26, 27]

That CVS has a central component has been suggested by functional magnetic resonance imaging (MRI) studies using whole-brain seed-based analysis. Patients with CVS exhibited a distinct alteration in resting state functional connectivity involving connections from the cingulate and inferior frontal gyrus (IFG), a known neural correlate of nausea.[28]

In conclusion, the pathogenesis of CVS is likely to be multifactorial, with multiple genetic, autonomic, central, and environmental factors playing a role. Further studies are needed to elucidate the exact mechanisms underlying this disorder.


United States statistics

The true incidence and prevalence of CVS in the United States are unknown, although a prevalence of about 2% among US children and adults has been estimated.[29]  In central Ohio, amid a predominantly White population, the prevalence of CVS in children (evaluated by the sole pediatric gastroenterology referral center) was 0.04%.[30]

International statistics

On the basis of limited epidemiologic data, Cullen and MacDonald estimated the prevalence of periodic vomiting in western Australia to be 2.3%.[6] Similarly, Abu-Arafeh and Russell observed a prevalence of 1.9% in school-aged children in Aberdeen, Scotland.[31] Both of these figures are derived from White populations and may not accurately reflect prevalence in all races or ethnic populations.

In a study performed at KEM Hospital in Pune, India, CVS accounted for 0.5% of admissions to pediatric wards during 1998-2000. In a retrospective study conducted in Japan, Chang et al found that the prevalence of CVS among children was 2.10 per 1000 population, and the prevalence among adults was 0.05 per 1000 population.[32]

In a population-based study from Ireland, the incidence of CVS was relatively high at 3.15 cases per 100,000 children. This incidence is comparable to those of other major GI diseases of childhood (eg, Crohn disease) in Ireland.[33]

Age-, sex-, and race-related demographics

The median age at onset is 4.8 years; however, CVS has been observed in infants as young as 6 days and in adults as old as 73 years.[1] The typical interval from onset of symptoms to diagnosis is 2.7 years.[1] In adults, the average age of onset is 21 years and the average age of evaluation for recurrent vomiting 34 years.[7] Females show a slight predominance over males (female-to-male ratio, 57:43). CVS occurs in all races but seems to affect White persons disproportionately.


Most published series indicate that CVS lasts an average of 2.5-5.5 years, resolving in late childhood or early adolescence. A few patients continue to be symptomatic through adulthood.

As early as 1898, clinicians observed that some patients went on to develop migraine headaches. That some children with CVS progress to abdominal migraines and then to migraine headaches implies that there may be a sequential progression of age-dependent manifestations of migraine.

A survey by Abu-Arafeh et al found the mean ages of children with CVS, abdominal migraines, and migraine headaches to be 5.3 years, 10.3 years, and 11.5 years, respectively.[31] This finding supports the developmental progression from vomiting to abdominal pain to headache. In unpublished data, Li and Hayes determined that nearly one third of patients develop migraines after resolution of CVS and predicted that nearly 75% would develop migraines by age 18 years.

A study of 31 patients with CVS by Hikita et al found that the median overall duration of the disorder was 66 months and that 44% of the patients seen for follow-up (25 patients) developed migraine. The authors also found abnormally high adrenocorticotropic hormone and antidiuretic hormone levels among the 25 patients for whom follow-up data were available. Significant correlations between attack duration and adrenocorticotropic hormone levels and attack duration and antidiuretic hormone levels were noted.[34]

Although patients are well about 90% of the time, CVS can be medically and socially disabling. More than 50% of patients require intravenous (IV) fluids, compared with less than 1% of patients with rotavirus gastroenteritis. The average annual cost of testing, treatment, and absenteeism totals $17,000. Children miss an average of 24 school days per year and often need home tutoring or, occasionally, home schooling. Additionally, because of its frequency during times of excitement, CVS has ruined many birthdays, holidays, and vacations.[30]

In adults, substantial morbidity is associated with CVS, perhaps because of lack of awareness and resultant delays in diagnosis. In a study of 41 CVS patients, Fleisher found that 32% were completely disabled at the time of diagnosis.[7] A total of 293 procedures were performed in the 41 patients, and none were indicative of organic etiology. In addition, 17 surgical procedures, including 10 cholecystectomies, appendectomies, exploratory laparotomies, a pyloroplasty, and a hysterectomy, were performed without any therapeutic benefit.

Adults and children with CVS also have multiple emergency department (ED) visits (see Table 1 below), and the diagnosis is often unrecognized.[35]

Table 1. Characteristics of Emergency Department Visits in Patients With Cyclic Vomiting Syndrome (Open Table in a new window)



(n = 104)


(n = 147)

Number of ED visits per patient with CVS (median)

15 (range, 1-200)

10 (range, 1-175)

Number of ED visits before diagnosis of CVS (median)

7 (range, 1-150)

5 (range, 0-65)

Diagnosis not made in ED

89 (93%)

119 (93%)

Diagnosis not recognized in ED in patients with established diagnosis of CVS

84 (88%)

97 (80%)

Number of different EDs visited (mean ± SD)

4.69 ± 4.72

2.6 ± 2.42

CVS = cyclic vomiting syndrome; ED = emergency department; SD = standard deviation.


A study that evaluated the relationship between anxiety and health-related quality of life in children and adolescents with cyclic vomiting syndrome (CVS) reported that children and adolescents with CVS appear to be at increased risk for anxiety. Anxiety symptoms are a stronger predictor of health-related quality of life than disease characteristics in children and adolescents with CVS. Assessment and treatment of anxiety in children and adolescents with CVS may have a positive impact on health-related quality of life.[36]




Cycling vomiting syndrome (CVS) is characterized by recurrent, discrete, stereotypical episodes of rapid-fire vomiting between varying periods of completely normal health (see the image below). This on-and-off stereotypical pattern of vomiting is nearly pathognomonic of CVS.

Cyclic versus chronic temporal patterns of recurre Cyclic versus chronic temporal patterns of recurrent vomiting. Number of emeses is plotted over 2-month period. Chronic pattern, represented by thin dashed line, has low grade on nearly daily basis (eg, gastroesophageal reflux). Cyclic pattern, represented by heavy solid line, involves high-intensity episodes intermittently once every several weeks (eg, cyclic vomiting syndrome).

Although periods of complete normality typically occur between episodes, many adult patients lose the cyclic pattern of symptoms over time, and 63% of them develop inter episodic symptoms (often nausea) between episodes; this pattern is termed coalescence.[7]

The Rome IV diagnostic criteria for CVS in children include of the following, both of which must be met[37] :

  • At least 2 periods of unremitting vomiting with or without retching, lasting hours to days within a 6-month period

  • A return to the usual state of health that lasts weeks to months

Because this 2-episode cutoff resulted in a significant number of misdiagnoses, the guidelines were modified by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) as follows (all criteria must be met)[38] :

  • At least 5 episodes, or a minimum of 3 over a 6-month period

  • Episodic attacks of intense nausea and vomiting lasting 1 hour to 10 days, occurring at least 1 week apart

  • Stereotypical pattern and symptoms in the individual patient

  • Vomiting during episodes occurs at least 4 times an hour for at least 1 hour

  • A return to baseline health during episodes

  • Symptoms cannot be attributed to another disorder

The Rome IV criteria left the minimum number of 2 episodes to diagnose CVS unchanged to promote early diagnosis. The Rome IV criteria also removed the word “nausea” from the guideline as it was difficult to assess.[37]

The Rome III criteria for CVS in adults include the following:

  • Stereotypical episodes of vomiting regarding onset (acute) and duration (< 1 week)

  • A minimum of 3 discrete episodes in the preceding year

  • Absence of nausea and vomiting between episodes

  • No metabolic, gastrointestinal (GI), or central nervous system (CNS) structural or biochemical disorders

Supportive criteria include a history of migraine headaches and a family history of migraine headaches.

The vomiting in CVS is typically much more severe and intermittent than that observed in gastroesophageal reflux. When children with CVS were compared with children with chronic vomiting, they had a much higher peak rate of emeses per hour (12.6 vs 1.9) but far fewer episodes per month (1.5 vs 36).[1] A cutoff criterion of at least 4 emeses per hour at peak and fewer than 2 episodes per week was 92% sensitive and 100% specific for the final diagnosis of CVS.[39]

With a larger cohort, the median peak rate of emeses was still 6 times per hour.[14] Only Bacillus cereus food poisoning matches this high intensity of emesis.[30] This singularly severe vomiting (so-called cyclic vomiting pattern) typifies patients with CVS and helps point toward a disorder that is localized outside the GI tract.

The stereotypical “on-off” pattern often begins with a prodrome of nausea and pallor. Vomiting peaks in the first hour and then begins to decline over the ensuing 4-8 hours, lasting a mean of 24 hours (median, 43 hours). Episodes commonly occur in the early morning (2:00-4:00 AM) or upon awakening (6:00-8:00 AM). The recovery period from the end of vomiting to the point of being able to eat and play lasts a mere 5 hours. Despite the implication of the term “cyclic,” only one half of patients have a stable periodicity; the rest have sporadic episodes.[30]

Besides vomiting, patients may also experience other GI symptoms. Abdominal pain is present in 80% of patients and may initially be severe enough to mimic acute abdomen and result in a laparotomy.[14] Patients may also have epigastric pain secondary to peptic injury of the esophagus.

Most patients experience retching (79%) and nausea (82%). They typically describe the nausea as the most distressing symptom[1] : It is unrelenting, is completely unrelieved by vomiting, and disappears only when the child is asleep or the episode is over. Many of the behavioral symptoms commonly observed in patients with CVS (eg, fetal positioning, social withdrawal, and turning off lights and televisions) are attempts to lessen this severe nausea.[30]

Fever, diarrhea, or both are noted in approximately one third of CVS patients, complicating the differentiation of this condition from gastroenteritis. These findings are likely due to associated autonomic symptoms, which are also common, particularly lethargy (93%) and pallor (91%).[1] Lethargy may be profound, and patients may be unable to walk or talk or may appear comatose. Excessive salivation (27%) can also be dramatic.[1]

Many patients with CVS have neurologic symptoms, which support the relation between migraines and CVS. Symptoms include headache (42%), photophobia (38%), phonophobia (30%), and vertigo (26%). Because less than half the patients with CVS have classic migraine symptoms, these symptoms cannot be used as diagnostic criteria for a migraine variant.[1]

Approximately 68% of families are able to identify events that appear to precipitate a patient’s episode.[6, 14, 17, 40] The most common precipitating event is infection (41%), particularly chronic sinusitis.[30] Psychological stresses (34%) and food products, including chocolate, cheese, and monosodium glutamate (MSG), rank close behind chronic sinusitis. Positive excitement, such as birthdays, holidays, vacations, and school outings, appear to trigger more episodes than do negative stresses.

Others recognize physical exhaustion or lack of sleep (18%), atopic events (13%), motion sickness (9%), and menses (13%) as triggers.[30] Many patients experience remission in the summer, when the number of infections and school stressors decline.[41]

The terms “cyclic vomiting syndrome” and “abdominal migraine” have often been used interchangeably because of the considerable overlap in clinical criteria. Indeed, except for vomiting, the key criteria for abdominal migraines are identical to those for CVS and include the following:

  • Recurrent, stereotypical, and severe episodes of abdominal pain

  • Punctuating well periods

  • Autonomic symptoms (eg, pallor, lethargy)

  • Family history of migraine headaches

Because 80% of children with CVS have abdominal pain, and 50% of those with abdominal pain vomit, many children can be diagnosed with either CVS or abdominal migraine. When both symptoms are present, the authors use the predominant or more consistent symptom as the primary label.

The following 3 additional criteria help strengthen the diagnosis of CVS[30] :

  • Negative screening test results to exclude common GI, hepatobiliary, renal, metabolic, and endocrine disorders

  • Subsequent development of migraine headaches

  • A positive response to antimigraine medications

Clinical features of CVS are summarized in Table 2 below.[42]

Table 2. Clinical Features in Adults and Children with Cyclic Vomiting Syndrome (Open Table in a new window)




Age of onset

4.8 years (earliest, 6 days)

35 years (latest, 73 years)

Delay in diagnosis

2.6 years

8 years

Female-to-male ratio




Every 2-4 weeks

Every 3 months

Duration (mean)

1-2 days (range, 1-10 days)

6 days (range, 1-21 days)



Not reported

Early morning onset



Stereotypical episodes




72%, 1.5 hours



Nausea, anorexia, pallor

Nausea, epigastric pain

Recovery to oral feeding

6 hours

24 hours

Relieving factors

Deep sleep

Hot bath or shower (56%)

Precipitating factors

Stress (47%), infection (31%)

Menses (57%), anxiety

Comorbid conditions


Not reported

Inter episodic nausea

< 6%


Coalescence of episodes




6 episodes/hr at peak, bile (81%)

8.5 episodes/hr

Systemic symptoms

Pallor, salivation, listlessness

Intense thirst (33%)

GI symptoms

Anorexia, nausea, diarrhea, abdominal pain

Abdominal pain, diarrhea

Neurologic symptoms

Headache, photophobia, phonophobia, abdominal pain

Irritability, confusion

Natural history

=28% progress to migraine

Not reported

Family history




Dehydration, esophagitis

Dehydration, esophagitis, laparotomy (18%)


14-25 days of missed school per year

32% completely disabled



Diagnostic Considerations

In addition to the conditions listed in the differential diagnosis, a number of other disorders should be considered in suspected cases of cyclic vomiting syndrome (CVS).

Gastrointestinal (GI) disorders to be considered include the following:

  • Gastroesophageal reflux disease (peptic esophagitis)

  • Peptic disorders (gastritis, duodenitis, and Helicobacter pylori infection)

  • Inflammatory bowel disease (Crohn disease and ulcerative colitis)

  • Anatomic obstruction (malrotation with intermittent volvulus)

  • Hirschsprung disease

  • Intestinal pseudo-obstruction

  • Cholelithiasis (gallbladder dyskinesia)

  • Choledochal cyst

  • Chronic appendicitis

  • Recurrent pancreatitis

Neurologic disorders to be considered include the following:

  • Abdominal migraine with vomiting

  • Migraine headaches with vomiting

  • Chronic sinusitis

  • Subtentorial neoplasm (cerebellar medulloblastoma or brainstem glioma)

  • Chiari malformation

  • Familial dysautonomia (Riley-Day syndrome)

Renal disorders to be considered include the following:

  • Acute hydronephrosis secondary to uteropelvic junction obstruction

  • Nephrolithiasis

Metabolic disorders to be considered include the following:

  • Disorders of fatty acid oxidation

  • Urea cycle defects

  • Mitochondriopathy

  • Acute intermittent porphyria

Endocrine disorders to be considered include the following:

  • Addison disease

  • Diabetes mellitus with ketoacidosis

  • Pheochromocytoma

  • Hyperemesis gravidarum

Psychological disorders to be considered include the following:

  • Munchausen syndrome by proxy

  • Anxiety

  • Depression

  • Bulimia

Other conditions to be considered include the following:

  • Pregnancy

  • Cannabinoid hyperemesis

Allen et al reported 19 CVS cases associated with chronic cannabis use; 10 of the 19 were not included in follow-up, but most of the remaining 9 who abstained from marijuana experienced symptomatic relief.[43] Other cases of cannabinoid hyperemesis have been published, though no long-term follow-up is reported for most of them.[44]

Evidence implicating marijuana use as the actual cause of vomiting is insufficient; no clear temporal relation between the onset of vomiting and the actual initiation of marijuana use has been established. It is possible that these patients already have CVS and are using marijuana for its antiemetic properties.

Although the role of marijuana in CVS has not been well established, a report by McCallum et al found chronic marijuana use to be a risk factor for lack of response to the tricyclic antidepressants used to treat this disorder. Thus, complete abstinence from marijuana may be recommended in patients with CVS.[45]

In a study comparing patients with CVS and those with functional vomiting, patients with CVS were more likely to be younger and male and used marijuana more frequently.[46] In a retrospective review of 31 published case reports and a case series of 98 patients with CVS, cyclic vomiting was associated with chronic daily marijuana use.[47, 48] However, the long duration (2-10 years) of marijuana use before the onset of symptoms and the short follow-up (< 3 months) argued against marijuana as a cause of the vomiting.

Differential Diagnoses



Approach Considerations

Because no biochemical markers for cyclic vomiting syndrome (CVS) have been identified, the guidelines formulated by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) suggest that physicians must initially look for alarming symptoms and then tailor the workup accordingly. Suspicious symptoms include the following:

  • Bilious vomiting, abdominal tenderness, or severe abdominal pain

  • Attacks precipitated by intercurrent illness, fasting, or a high-protein meal

  • Abnormal neurologic examination findings, such as severe alteration of mental status, abnormal eye movements, papilledema, motor asymmetry, or gait abnormality (ataxia)

  • Progressively worsening episodes or conversion to a continuous or chronic pattern

Depending on the presenting symptoms and signs other than vomiting, different diagnostic approaches are recommended. In addition, certain subgroups of patients are thought to be at high risk for metabolic disorders. If the following conditions are met, early referral to a metabolic specialist or neurologist should be considered:

  • Presentation before the age of 2 years (with cyclic vomiting or comorbidities below)

  • Vomiting episodes associated with intercurrent illnesses, prior fasting, or increased protein intake

  • Any neurologic finding, such as ataxia, dystonia, or another gait disturbance; mental retardation; or seizure disorder or acute encephalopathy (including true lethargy, severe irritability, confusion, psychosis, or rapidly changing or unstable mental status)

  • Laboratory findings suggestive of a metabolic disorder, such as hypoglycemia, substantial anion gap metabolic acidosis (see the Anion Gap calculator), respiratory alkalosis, or hyperammonemia

A heterogeneous group of disorders can mimic CVS, and these disorders must be excluded with systematic laboratory and radiographic testing. An analysis by Li et al identified 3 main categories to be considered in the differential diagnosis[49] :

  • Gastrointestinal (GI) disorders

  • Extraintestinal disorders

  • Idiopathic CVS

A psychological evaluation may reveal ongoing panic, anxiety, and eating disorders, and stress management may attenuate the stress triggers.[50]

Laboratory Studies

In the evaluation of the patient for possible GI disease, screening blood work should include a complete blood count (CBC) with differential, assessment of the erythrocyte sedimentation rate (ESR), and measurement of levels of hepatic transaminases, pancreatic amylase, and lipase. Nonanatomic renal disease can be detected by means of serum blood urea nitrogen (BUN) and creatinine tests, urinalysis, and urine calcium-to-creatinine ratio.[50]

Screening for multiple metabolic and endocrine disorders can be accomplished by assessing pH and measuring levels of electrolytes, glucose, lactic acid, ammonia, amino acids, adrenocorticotropic hormone (ACTH), and antidiuretic hormone (ADH).

Urinary ketones, organic acids, ester-to-free carnitine ratio, porphobilinogen, and aminolevulinic acid may also guide diagnosis in the correct direction.[50] These metabolic and endocrine tests must be obtained during the vomiting episode to detect intermittent disorders (eg, disorder of fatty acid oxidation) or heterozygote disorders (eg, partial ornithine transcarbamylase deficiency).

All blood and urine tests must be performed before the administration of intravenous (IV) fluids containing glucose or other medical treatments.

In a postmenarchal girl, the physician must consider a beta human chorionic gonadotropin (beta-hCG) test for pregnancy.[50]

Radiography, Endoscopy, US, CT, and MRI

Imaging studies may be indicated as follows.

In evaluation for GI diseases, upper GI (UGI) radiography with small-bowel follow-through (SBFT), esophagogastroduodenoscopy (EGD), abdominal ultrasonography (US), or computed tomography (CT) and gastric-emptying scanning may provide definitive information.[50] In evaluation for neurologic or otolaryngologic diseases, sinus CT or brain MRI should be considered. CT scans may not adequately visualize the subtentorial region. Obstructive renal disease can be revealed with renal ultrasonography or CT imaging.

With a broad array of possible diagnoses and possible diagnostic approaches, an extensive evaluation may appear cumbersome. Olson and Li reported that UGI radiography followed by empiric antimigraine therapy for 2 months is the most cost-effective approach ($1600) for the initial treatment of recurrent episodic vomiting in children ($3020 for extensive diagnostic evaluation, and $1830 for empiric treatment alone).[51]

Until prospective trials are conducted, the authors’ current approach generally includes initial blood and urine screens, including metabolic screening and UGI radiography at initial presentation.

The presence of specific symptoms such as hematemesis, bilious vomiting, persistent headache, flank pain, acidosis, or uncharacteristically severe or atypical vomiting episodes should raise the clinician’s index of suspicion of an underlying disorder and should warrant a prompt and more extensive or repeat evaluation.[51] The 4 tests with the highest yield are endoscopy, sinus radiography or CT imaging, small-bowel radiography, and head CT or MRI.[50]



Approach Considerations

In the absence of known pathophysiology, treatment of cyclic vomiting syndrome (CVS) remains empiric.[14, 52] The following management strategies are used for CVS[30, 53] :

  • Avoidance of triggers

  • Prophylactic and abortive therapy

  • Supportive care during acute episodes

  • Family support

Consultation with a sympathetic gastroenterologist without drug therapy may decrease the frequency of vomiting episodes by as much as 70%.[50]

Avoidance of Triggers

In some cases of CVS, avoiding identified dietary triggers such as chocolate, cheese, and monosodium glutamate (MSG) can prevent episodes without the use of medication.[30] If psychological stressors trigger episodes, stress management techniques or benzodiazepine anxiolytics (eg, lorazepam or diazepam) may help to abort attacks in the early stages. However, avoiding common triggers such as car rides and infection may be impractical or impossible. Keeping a detailed diary that records the frequency of vomiting episodes, the type of meal consumed before each episode, and potentially aggravating life events can help patients identify and avoid triggers.[54]

Sleep deprivation is also cited as a common trigger for patients with CVS, and proper sleep hygiene should be emphasized. Interestingly, a 70% decrease in frequency of episodes (placebo effect) on consultation and lifestyle changes without drug therapy has been noted.[55]

Prophylactic and Abortive Pharmacologic Therapy

Pharmacologic therapy is used to prevent episodes of vomiting or to decrease their frequency and also to abort or attenuate episodes once they begin.[56, 57, 58] Preventive medications are normally used in patients with more than a single episode of CVS per month. The mainstays of prophylactic therapy include the following:

  • Cyproheptadine

  • Amitriptyline

  • Anticonvulsants such as topiramate, zonisamide, and levetiracetam

  • Propranolol

  • Phenobarbital

  • Erythromycin

Medications used for aborting episodes include the following:

  • Ondansetron

  • Promethazine

  • Prochlorperazine

  • Triptans

Agents used in migraines, such as triptans, have also been effective in aborting attacks. If abortive therapy fails, supportive combinations such as ondansetron plus lorazepam or chlorpromazine plus diphenhydramine may attenuate an attack of cyclic vomiting in progress.[59] In September 2011, the US Food and Drug Administration (FDA) released an alert about the possibility of an increase in cardiac arrhythmias with the use of ondansetron, and monitoring the QT interval is recommended.

Daily prophylactic pharmacotherapy may be used to prevent episodes that occur more than once a month or if they are extremely severe and disabling (eg, lasting 3 days or longer).[60, 61] Most of these drugs are non-GI medications, such as antimigraine agents, anticonvulsants, neuroleptics, and prokinetic drugs. A family history positive for migraines predicts a high response rate (80%) to antimigraine medications; therefore, these agents are a logical first choice.[30]

The guidelines formulated by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) recommend cyproheptadine as first-line therapy in children younger than 5 years. However, cyproheptadine can cause substantial weight gain because of an increase in appetite. Amitriptyline is the first-line choice in children older than 5 years and adolescents.[30]

Although no randomized control trials have examined medications used in CVS, several open-label trials and retrospective studies support the use of amitriptyline as first-line therapy in patients with CVS who are older than 5 years. In an open-label study of 41 patients with CVS who were followed up for 1-2 years, long-term therapy with tricyclic antidepressants (TCAs) significantly reduced the frequency and duration of episodes and the number of emergency department (ED) visits and hospitalizations.[62]

In this study, 80% of patients reported overall improvement of symptoms; however, one third of the patients reported mild adverse effects that did not lead to discontinuance of the medication.[62] After 2 years of treatment, the frequency of episodes was reduced from 17.8 episodes per year to 3.3 episodes, and the duration of an episode decreased from 6.7 days to 2.2 days. The mean number of ED visits and hospitalizations decreased from 15 to 3.3 over 2 years.

In a study of 132 patients with CVS who had been monitored for 4 years, 17 subjects were identified as nonresponders to TCA therapy.[45] When compared with responders, nonresponders were significantly more likely to have a history of migraine, coexisting psychological disorders, chronic marijuana use, and reliance on narcotics for pain control between CVS episodes. These findings favor a multidisciplinary approach to these patients, with aggressive treatment of other comorbid illnesses.

One study used an Internet-based survey completed by subjects with CVS or their parents to assess the efficacy of coenzyme Q10 and amitriptyline.[63] In all, 72% of the 162 patients receiving amitriptyline and 68% of the 22 patients receiving coenzyme Q10 reported at least a 50% reduction in the frequency, duration, or severity of episodes. Patients receiving coenzyme Q10 did not have any side effects, whereas one half of the patients receiving amitriptyline reported side effects.

In this study, 21% of patients on amitriptyline discontinued treatment because of side effects.[63] The same author reported a high degree of efficacy with monitoring drug levels and titrating medications to achieve therapeutic levels in a small series of patients.[64] Combination therapy with amitriptyline and mitochondrial supplements such as coenzyme Q10 and L-carnitine were used in most of these patients.

In another study, 20 adult patients with CVS received zonisamide (median dosage, 400 mg/day) or levetiracetam (median dosage, 1000 mg/day) because TCAs alone were unsatisfactory as maintenance medications; at least moderate clinical response was reported in 15 subjects (75%), and 4 of these (20%) reported symptomatic remission during 9.5 ± 1.8 months of follow-up.[65] Newer antiepileptic agents appeared beneficial as maintenance medications for nearly three fourths of adults with CVS.

In a retrospective study of 101 adults with CVS, most patients (86%) responded to treatment with TCAs, anticonvulsants (topiramate), coenzyme Q10, and L-carnitine.[66] Nonresponse to therapy was associated with coalescence of symptoms, chronic opiate use, and more severe disease as characterized by longer episodes, a greater number of ED visits in the year before presentation, the presence of disability, and noncompliance on univariate analysis. On multivariate analysis, only compliance to therapy was associated with a response.

When prophylactic medication fails or is not taken because of the sporadic and infrequent occurrence of cyclic vomiting episodes (< 1/month), abortive agents may be taken at the onset of an attack to stop progression. These antinausea and antimigraine agents are best administered nasally, rectally, or parenterally because they are not usually tolerated by mouth during intractable emesis.[50]

Sumatriptan, a 5-hydroxytryptamine receptor 1B/1D (5-HT1B/1D) agonist used off label, has a 46% efficacy rate when administered either intranasally or subcutaneously. The subcutaneous route has fallen out of favor because of a severe associated burning sensation in the chest and neck.[67, 68]

Ondansetron, a 5-HT3 antagonist, is a potent and effective antiemetic that acts on the chemoreceptor zone in the brainstem. In CVS, it is more effective at a higher dose of 0.3-0.4 mg/kg every 6 hours and is rendered more effective in severe episodes with the use of a benzodiazepine or diphenhydramine as an adjunctive antinausea agent.[1] High-dose intravenous (IV) ondansetron has a 59% efficacy rate and ameliorates episodes more often than it aborts them.

Aprepitant, a promising tachykinin (NK-1)–receptor antagonist, is used for chemotherapy-induced emesis and could be of benefit for patients with CVS.[50]

Guidelines on the management of CVS in adults from the American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association strongly recommend a tricyclic antidepressant, such as amitriptyline, as a first‐line prophylactic medication for adults with moderate to severe CVS.[69] Topiramate or aprepitant can be considered as alternatives. Zonisamide or levetiracetam and mitochondrial supplements (coenzyme Q10, L‐carnitine, and riboflavin) are conditionally recommended as alternative prophylactic medications. For acute attacks, the guidelines conditionally recommend serotonin antagonists, such as ondansetron, and/or triptans, such as sumatriptan, or aprepitant.

Supportive Pharmacologic Therapy

When both prophylactic and abortive therapy fails, supportive care becomes an essential aspect of treatment during acute episodes.

IV glucose-containing fluids may diminish the severity of episodes by as much as 42%.[50] Glucose may serve as the active ingredient by truncating the ketosis. However, the abdominal pain may be severe enough to necessitate the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or narcotics once a surgical abdomen has been excluded. Caution must be exercised when narcotics are administered for moderate to severe pain and patients must be monitored to ensure that they do not become dependent on or addicted to these agents.

Chronic opiate use can result in hyperalgesia, for which various mechanisms have been proposed. Sustained morphine administration increased substance P (SP) and NK-1 receptor expression in the spinal dorsal. Morphine-induced hyperalgesia was reversed by spinal administration of NK-1 receptor antagonists in rats and mice and was observed in wild-type NK-1 receptor positive mice but not in NK-1 receptor knockout (KO) mice.[70]

The transient receptor potential vanilloid 1 (TRPV1) receptor, a molecular sensor of noxious heat, also plays an important role in the development of hyperalgesia. Administration of morphine via subcutaneously implanted morphine pellets elicited both thermal and tactile hypersensitivity in TRPV1 wild-type mice but not in TRPV1 KO mice.[71] Moreover, oral administration of a TRPV1 antagonist reversed both thermal and tactile hypersensitivity induced by sustained morphine administration in mice and rats.

Sedatives such as diphenhydramine, lorazepam, and chlorpromazine have been administered to permit sleep and to provide temporary respite from unrelenting nausea.[50] The combination of lorazepam and ondansetron appears to be more effective than ondansetron alone.

Family Support

Families are encouraged to contact the Cyclic Vomiting Syndrome Association, which is an international voluntary organization that serves the needs of CVS patients in the United States and Canada, for ongoing support and information. Various resources, including local support groups and scientific and family conferences, are available to help families understand this disorder and to provide them with coping mechanisms for battling this often disabling illness.


A study that evaluated the relationship between anxiety and health-related quality of life in children and adolescents with cyclic vomiting syndrome (CVS) reported that children and adolescents with CVS appear to be at increased risk for anxiety. Anxiety symptoms are a stronger predictor of health-related quality of life than disease characteristics in children and adolescents with CVS. Assessment and treatment of anxiety in children and adolescents with CVS may have a positive impact on health-related quality of life.[36]



Medication Summary

Medications used to prevent, ameliorate, or abort vomiting episodes include cyproheptadine, amitriptyline, topiramate, zonisamide, levetiracetam, propranolol, phenobarbital, erythromycin, ondansetron, promethazine, and prochlorperazine.

Antiemetic Agents

Class Summary

The vomiting center (VC) of the central nervous system (CNS) may be stimulated directly by gastrointestinal (GI) irritation, motion sickness, or vestibular neuritis. Increased activity of central neurotransmitters, such as dopamine in the chemoreceptor trigger zone (CTZ) or acetylcholine in the VC, appear to be major mediators of vomiting.

An emetogenic episode may initiate the release of serotonin (5-HT) from enterochromaffin cells in the GI tract. 5-HT then binds to 5-HT3 receptors, which stimulate vagal neurons that transmit signals to the VC, resulting in nausea and vomiting. Pharmacologic agents are directed to the particular etiology or mechanism that stimulates the vomiting response.

Ondansetron (Zofran)

The 5-HT3 antagonist ondansetron directly acts at the CTZ and vagal afferents from the GI tract. It attenuates or, occasionally, aborts an active episode of CVS. High doses are more effective in patients with CVS.

Promethazine (Phenergan, Phenadoz)

Promethazine is a phenothiazine derivative that possesses antihistaminic, sedative, antimotion sickness, antiemetic, and anticholinergic effects.

Prochlorperazine (Compro)

Prochlorperazine may relieve nausea and vomiting by blocking postsynaptic mesolimbic dopamine receptors through its anticholinergic effects and depressing the reticular activating system.

Antihistamines, 1st Generation

Class Summary

Antihistamines may be used to prevent nausea rather than treating vomiting, though antihistamines appear to be the best of all classes in treating it once it has begun. Their effectiveness is likely due to their central anticholinergic properties that reduce activity in the vestibular nuclei. The nonsedating antihistamines (ie, those that do not cross the blood-brain barrier) do not appear to be effective in either preventing or treating nausea and vomiting. Common adverse effects can include dry mouth/nose/throat, drowsiness, and sensitivity to bright light (secondary to mydriasis). Less common adverse effects include palpitations, urinary retention, bloating, constipation, headache, and confusion. They should be taken 1 hour prior to departure.


Cyproheptadine is a nonselective antihistamine effective against CVS and migraines. It is also an appetite stimulant. Therapeutic effects are observed within 1-2 weeks. This agent is an excellent choice for children younger than 5 years.

Diphenhydramine (Benadryl)

Diphenhydramine is used for treatment and prophylaxis of vestibular disorders that may cause nausea and vomiting. It provides mild sedation, as well as antinausea and antiemetic actions synergistic with those of 5-HT3 antagonists.

Antidepressants, TCAs

Class Summary

Tricyclic antidepressants are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects. They may block the active reuptake of norepinephrine and serotonin.


Tricyclic antidepressants (TCAs) such as amitriptyline are excellent first-line choices in children older than 5 years. Amitriptyline has anticholinergic and sedating side effects and thus is best administered at bedtime. Cardiac arrhythmia, especially in overdose, has been described; monitoring the QTc interval both before therapy is initiated and after the target level has been reached is advised. Up to 1 month may be needed for clinical effects to become evident.

Beta-Adrenergic Blocking Agents

Class Summary

Beta-blockers may reduce the frequency and severity of episodes. Propranolol is usually recommended because of its CNS penetration.

Propranolol (Inderal LA, InnoPran XL)

Propranolol is a beta-adrenergic blocker and an excellent first-line agent for prophylaxis when used at low doses. It has a 57% efficacy rate, with efficacy defined as a 50% reduction in the frequency and severity of episodes. It requires 1 week for efficacy and requires gradual withdrawal over 1 week. Dosing may be monitored on the basis of a fall in presleep resting pulse from baseline; a decline of less than 15-20 beats/min indicates that the dose may be further increased.


Class Summary

Agents that inhibit brain glutamate decarboxylase, which causes a decrease in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), may help reduce the frequency and severity of episodes.


Phenobarbital may be used in patients with or without electroencephalographic (EEG) changes. A 79% response rate has been observed in patients with CVS.

Topiramate (Topamax)

Topiramate is a sulfamate-substituted monosaccharide with a broad spectrum of antiepileptic activity; it may have state-dependent sodium channel blocking action. It potentiates the inhibitory activity of the neurotransmitter GABA. In addition, topiramate may block glutamate activity and, in turn, help reduce the frequency and severity of episodes.

Zonisamide (Zonegran)

Zonegran blocks T-type calcium channels, prolongs sodium channel inactivation, and is a carbonic anhydrase inhibitor.

Levetiracetam (Keppra, Keppra XR)

Levetiracetam may facilitate GABAergic inhibitory transmission through displacement of negative modulators.


Class Summary

Antibiotics with prokinetic activity in the stomach may be used.

Erythromycin (E.E.S., Ery-Tab, Erythrocin)

Erythromycin is a gastric prokinetic that stimulates coordinated gastric emptying. A 75% response rate has been demonstrated in patients with CVS.

Sumatriptan (Imitrex, Sumavel DosePro)

The 5-HT1B/1D agonist sumatriptan may effectively terminate an episode of CVS by constricting the cerebral vasculature. High doses are more effective in patients with CVS.

Anxiolytics, Benzodiazepines

Class Summary

Some agents in this class may be used for the treatment of nausea.

Lorazepam (Ativan)

Because of both their sedative properties and their antinausea effects, sedatives may be helpful. Lorazepam induces sedation and anxiolysis through central inhibition of gamma-aminobutyric acid (GABA). Its effects appear to be synergistic with the antinausea and antiemetic effects of 5-HT3 antagonists. Concomitant sedation and induction of sleep provide sustained relief from intractable nausea.


Questions & Answers


What is cyclic vomiting syndrome (CVS)?

What is the pathogenesis of cyclic vomiting syndrome (CVS)?

What is the US prevalence of cyclic vomiting syndrome (CVS)?

What is the global prevalence of cyclic vomiting syndrome (CVS)?

Which patient groups have the highest prevalence of cyclic vomiting syndrome (CVS)?

What is the prognosis of cyclic vomiting syndrome (CVS)?


Which clinical history findings are characteristic of cyclic vomiting syndrome (CVS)?


Which conditions are included in the differential diagnoses of cyclic vomiting syndrome?

What are the differential diagnoses for Cyclic Vomiting Syndrome?


How is cyclic vomiting syndrome diagnosed?

What is the role of lab tests in the workup of cyclic vomiting syndrome?

What is the role of imaging studies in the workup of cyclic vomiting syndrome?


How is cyclic vomiting syndrome treated?

Which factors may trigger cyclic vomiting syndrome?

What is the role of medications in the treatment of cyclic vomiting syndrome?

What is supportive care for cyclic vomiting syndrome

What support and patient education resources are available for families and patients with cyclic vomiting syndrome?

What are the possible complications of cyclic vomiting syndrome?


Which medications are used in the treatment of cyclic vomiting syndrome?

Which medications in the drug class Anxiolytics, Benzodiazepines are used in the treatment of Cyclic Vomiting Syndrome?

Which medications in the drug class Antibiotics are used in the treatment of Cyclic Vomiting Syndrome?

Which medications in the drug class Anticonvulsants are used in the treatment of Cyclic Vomiting Syndrome?

Which medications in the drug class Beta-Adrenergic Blocking Agents are used in the treatment of Cyclic Vomiting Syndrome?

Which medications in the drug class Antidepressants, TCAs are used in the treatment of Cyclic Vomiting Syndrome?

Which medications in the drug class Antihistamines, 1st Generation are used in the treatment of Cyclic Vomiting Syndrome?

Which medications in the drug class Antiemetic Agents are used in the treatment of Cyclic Vomiting Syndrome?