Cyclic vomiting syndrome

INTRODUCTION — Cyclic vomiting syndrome (CVS) is an idiopathic disorder characterized by recurrent, stereotypical bouts of vomiting with intervening periods of normal or baseline health [1]. Both children and adults are affected, although the clinical presentation and natural history vary somewhat with age [2-6].

CVS was first described in the late 1800s [7,8]. The key features are [9,10]:

●Recurrent discrete episodes of vomiting

●Varying intervals of normal (or baseline) health between episodes

●Episodes are stereotypical with regard to timing of onset, symptoms, and duration

●The vomiting is not attributable to other disorders

This topic review will provide an overview of CVS in children and adults. Treatment guidelines have been published for children [9] and adults [10]. Overviews of other causes of vomiting are presented separately. (See "Approach to the infant or child with nausea and vomiting" and "Approach to the adult with nausea and vomiting".)

EPIDEMIOLOGY — CVS is no longer considered to be rare in children or adults.

The prevalence of CVS in children is estimated at 1.9 to 2.3 percent, with an incidence of 3.2 per 100,000 population, based on studies in predominantly White populations [11-13]. The average age was 9.6 years at the time of diagnosis, while the average age at the onset of symptoms was 5.3 years. CVS appears to be more common in girls than boys, with a ratio of 55:45 [1,9,14-18]. CVS is highly associated with a history of migraines, either in the patient or (especially in children) a maternal family member (72 to 82 percent) [19]. A family in which CVS appears to be inherited has been described [20].

The prevalence of CVS in adults appears to be slightly lower than that in children. In a multinational survey of functional disorders conducted in 33 countries, the overall prevalence was 1.2 percent, equal across sex with similar proportions in males and females and higher (1.6 percent) in younger adults ages 18 to 39 years compared with older adults [21]. CVS represented 10.8 percent of functional gastrointestinal disorders seen in an adult gastroenterology clinic and 2 percent in a population survey of English-speaking patients [22,23]. In one of the largest studies of 101 adults, patients could be divided into subgroups with pediatric-onset or adult-onset of CVS, in which symptoms began at a mean age of 13 versus 32 years, respectively [2,24]. These groups differed significantly in sex predominance (86 percent female in pediatric-onset versus 57 percent female in adult-onset disease). Another study found that the CVS began at an average age of 35 (range 14 to 73 years) but was not diagnosed until patients were on average 41 years old [25]. Compared with children, adults with CVS tend to have less frequent episodes but with far longer duration. (See 'Adults' below.)

PATHOGENESIS — The pathogenesis of CVS remains unknown; however, it appears to be multifactorial, with several potential pathways. An association between CVS and migraine headaches has been most consistently described in children and adults, suggesting that there may be a common pathophysiologic process. However, CVS has also been linked to autonomic abnormalities (elevated sympathetic tone and impaired parasympathetic regulation), hypothalamic-pituitary-adrenal activation (Sato variant), mitochondrial dysfunction, menses (estrogen sensitivity), food allergy, and cannabis use [1,26]. One review notes that chronic migraine, epilepsy, panic disorder, and CVS have similar temporal patterns and triggers and posits a neuroexcitability threshold, which when exceeded (due to enhanced susceptibility plus acute stressors), triggers episodic attacks of vomiting [26].

Association with migraines — CVS has been linked to migraine headaches and abdominal migraine (table 1) [27,28]. This association is based upon the discreteness of episodes, the progression from cyclic vomiting to migraine headaches in many patients, the presence of a strong family history of migraine headaches in affected children (approximately 80 percent), and the response to antimigraine therapy in up to 80 percent of children [9,19]. In adults, CVS is also associated with a personal history (43 percent) or family history (64 percent) of migraines and often responds to antimigraine therapy [2]. Underlying autonomic sympathetic and parasympathetic dysfunction may predispose children and adults to both CVS and migraine headaches [24,29,30]. (See "Pathophysiology, clinical features, and diagnosis of migraine in children".)

Cross-sectional prevalence data suggest that CVS (which predominates at a mean age of five years) often progresses to abdominal migraines (mean age nine years), which in turn lead to migraine headaches (mean age 11 years) [11]. However, many children progress directly from CVS to migraines. (See 'Natural history' below.)

Mitochondrial dysfunction — Mitochondrial disorders of fatty acid oxidation (eg, medium-chain acyl-coenzyme A dehydrogenase deficiency), respiratory chain defects (eg, MELAS [mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes]), and mitochondrial DNA deletions can be associated with episodes of metabolic crisis and vomiting, usually triggered by infection or prolonged fasting [31]. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Mitochondrial myopathies: Clinical features and diagnosis".)

The hypothesis that mitochondrial dysfunction contributes to CVS in some patients is suggested by findings of maternal inheritance of two common mitochondrial DNA polymorphisms, 16519T and 3010A, reported in approximately one-half of White children with CVS with haplotype H [32,33]. This association appears to be common in children but not in adults. Further support comes from clinical observations of the efficacy of mitochondrial-targeted therapies, coenzyme Q10 [34,35] and L-carnitine [34-36], in CVS. This hypothesis is further strengthened by an association of both CVS and migraine headache with the same two mitochondrial DNA polymorphisms [37]. Sequencing of nuclear DNA suggests that there may be synergistic polymorphisms in some genes (RYR2, SCN4A) that impact cellular stress responses in CVS [38].

Autonomic dysfunction — Children and adults with CVS have been found to have augmented sympathetic tone with low to normal parasympathetic tone [24,29]. In one small series, 47 percent of affected adolescents were found to meet criteria for postural orthostatic tachycardia syndrome (POTS) and treatment of that comorbid condition helped prevent episodes of vomiting [30,39]. In two small series of adult patients, 23 to 35 percent had postural tachycardia or orthostatic hypotension [40,41]. Patients who have a hereditary sensory autonomic neuropathy (such as Riley-Day syndrome) sometimes have clinical episodes resembling CVS. (See "Hereditary sensory and autonomic neuropathies".)

Hypothalamic-pituitary-adrenal axis hyperreactivity — A subset of children with CVS have prolonged and severe episodes, associated with profound lethargy and intra-episodic hypertension, known as the Sato variant [42]. These children also have intra-episodic elevations of corticotropin, cortisol, vasopressin, prostaglandin E2, and catecholamines, suggesting hypothalamic-pituitary-adrenal axis hyperreactivity. Animal studies suggest that CVS may be a brain-gut disorder in which corticotropin-releasing factor triggers gastric stasis and vomiting by vagal stimulation [43].

Association with rapid gastric emptying or gastroparesis — In adults, gastric emptying may be accelerated or sometimes delayed in CVS, but any association with symptoms is controversial. One hypothesis is that rapid gastric emptying is a marker for underlying dysautonomia [24,44]. Paradoxically, there may be an overlap between CVS and idiopathic gastroparesis in adults. Testing of gastric emptying to exclude gastroparesis may be considered if cyclic vomiting symptoms are refractory to therapy [44,45] (see 'Adults' below). Gastric emptying is generally normal in children with CVS [46].

Estrogen sensitivity (catamenial cyclic vomiting syndrome) — Similar to menstrual migraine headaches, some adolescent girls (22 percent) develop CVS at the onset of their menstrual periods (catamenial CVS). This phenomenon is postulated to be the result of the premenstrual decline in estrogen, and many patients with this pattern respond to treatment with low-dose estrogen, progesterone-only oral contraceptives, or a medroxyprogesterone acetate intramuscular injection every three months. An association between CVS and menses has also been described in adults [25]. (See 'Catamenial cyclic vomiting syndrome' below.)

Chronic cannabis use — Cannabis hyperemesis syndrome (CHS) is characterized by episodic vomiting associated with prolonged, high-dose (nearly daily) recreational cannabis use and that resolves with cannabis cessation [5,47]. This disorder primarily affects young adult and adolescent males, as described in growing numbers of case series [23,48-54]. Among people with cannabis use disorder, almost one-half experience withdrawal symptoms when tapering use [55].

Circumstantial evidence suggests that CHS is a subset of CVS that is triggered by chronic (eg, >2 years), frequent (eg, ≥4 times/week), high-dose cannabis use, although it can be difficult to distinguish between these disorders [10,54,55]. Both CHS and CVS are associated with characteristic, repetitive hot-water bathing behavior, which is seen during cannabis-associated vomiting cycles [47,51] as well as in typical CVS attacks in both adults (48 percent) and children who have not been exposed to cannabis [56]. However, reverse causality is also possible since many adults with CVS self-medicate with cannabis to alleviate their daily nausea, and this can be a source of diagnostic confusion. Patients with classic CVS symptoms and modest, intermittent therapeutic use of cannabis are frequently mislabeled as having CHS.

For patients with CVS-like symptoms who have a history of chronic frequent cannabis use, we suggest a trial of prolonged abstinence from cannabis. The duration of cannabis cessation needed to exclude a diagnosis of CHS is not well defined in the literature. A report from experts in CVS suggests that symptom resolution with cannabis abstinence for six months or three typical CVS cycles is needed for diagnosis of CHS. A presumptive diagnosis of CHS can also be made for patients unable to abstain from cannabis products [54]. Of note, patients who do not experience long-term resolution of symptoms following prolonged abstention from cannabis should be diagnosed with CVS rather than CHS. If emetic episodes persist despite abstention from cannabis, then further work-up for CVS should be undertaken and corresponding treatment trialed. (See "Cannabinoid hyperemesis syndrome".)

Food sensitivity — Foods that trigger CVS in some patients include chocolate, cheese, and monosodium glutamate, similar to the triggers that have been reported for migraines. However, the commonly-held association with dietary triggers has been called into question in blinded provocative trials [57]. If a causal association has not been established, we suggest a trial of avoidance only if the clinical history suggests that a food is a trigger for an individual patient (see "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Precipitating and exacerbating factors'). Sensitivity to cow's milk, soy, and egg white protein has also been reported to trigger CVS attacks in some children [14].

CLINICAL MANIFESTATIONS — The essential features of CVS are recurring episodes of vomiting with a stereotypical pattern regarding time of onset and duration (hours to days), accompanying symptoms and signs (eg, pallor, lethargy), and the absence of vomiting between episodes (table 2). Other common features include a history in the patient or family history of migraine headaches; the self-limited nature of the attacks; associated symptoms of nausea, abdominal pain, headache, motion sickness, and photophobia; and associated signs of profound lethargy and pallor (especially in children), excess salivation, diarrhea, dehydration, and social withdrawal. (See 'Diagnosis' below.)

Children and adolescents — In children and adolescents, the specific pattern of vomiting episodes is variable but usually remains stereotypical for an individual patient [1,4]. In general, CVS episodes tend to begin in the early morning hours (2:00 to 7:00 AM) and last approximately the same duration. Most have a prodromal period of pallor, anorexia, nausea, abdominal pain, and/or lethargy (table 2). The attacks usually last an average of 24 to 48 hours, although they may last up to 7 to 10 days. Approximately one-half of children have attacks at regular intervals, commonly occurring every two to four weeks, while the remainder have unpredictable intervals between episodes. Approximately three-quarters of parents can identify triggers, which are usually psychological (typically more excitement, eg, birthdays, rather than negative stressors) or infectious (eg, upper respiratory) events [58].

The clinical picture of CVS has gradually expanded to recognize that the recurring vomiting is often accompanied by multiple comorbid conditions that affect the patient even between vomiting episodes:

●Anxiety – The most prevalent comorbidity is anxiety, which affects 47 percent of (59 percent of school-aged) children with CVS [59]. In fact, the lower health-related quality of life in CVS patients correlated with trait anxiety and coping abilities rather than with medical severity (frequency, duration of episodes) [59].

●Postural orthostatic tachycardia syndrome (POTS) – POTS is common in adolescents with CVS (14 percent in one pediatric case series and 38 percent of screened adolescents [60]). There is evidence of altered autonomic tone at baseline with elevated sympathetic tone and low to normal parasympathetic tone [29,30] (see 'Autonomic dysfunction' above). Management of POTS in adolescents with CVS, consisting of fluid and salt supplementation, fludrocortisone and low-dose propranolol, can reduce the frequency of vomiting episodes [30].

●Coalescent CVS – Some pediatric patients initially have a typical episodic pattern of CVS but later develop chronic daily nausea between vomiting episodes. The nausea typically peaks in the morning, affects approximately 12 percent of pediatric patients with CVS, and is most common in adolescent girls [34,60]. Some may outgrow the episodic vomiting entirely, and the persisting nausea may be then diagnosed as functional nausea. In the absence of an effective antinausea agent, it is difficult to treat. Anecdotally, amitriptyline and doxylamine-pyridoxine improve symptoms for some patients [61]. The term "coalescent" CVS has been used to classify this pattern in pediatric patients, although the term is imprecise.

Adults — In adults, 93 percent described a prodrome of nausea, epigastric pain, or headache; early morning onset of vomiting; abdominal pain during episodes; and a high peak rate of vomiting of eight emeses per hour during the emetic phase [56]. Other common features include erosive esophagitis during or shortly after a vomiting episode, association with menstrual cycles or pregnancy, and a history of migraine headaches in self or family [2,24,25]. Postural orthostatic tachycardia may be present. In two series of adults with CVS, approximately one-third experienced either orthostatic tachycardia or hypotension [24,44].

Although there are similarities in CVS across age groups [15], some key differences between adults and children have been observed (table 2) [25]:

●Frequency – Adult patients with adult-onset CVS tend to have less frequent symptoms compared with adult patients with pediatric-onset CVS (approximately four cycles per year, compared with 12 cycles per year, respectively) [56].

●Duration – Adults tend have longer episodes of CVS compared with children (mean duration six versus two days).

●Age of onset – The age of onset is highly variable in adults, while in children, the age of onset is predominantly in the toddler or preschool years. In those whose episodes begin in adolescence, episodes persist well into adulthood [24].

●Triggers – Triggering events may be less common in adults.

●Interepisodic nausea – Nausea between episodes is more common in adults compared with children (40 to 63 percent versus 12 percent) (figure 1) [56].

●Behavioral symptoms – Two notable behaviors are more common in adults than in children: the use of hot-water showers or bathing to attenuate the nausea (56 percent), even in the absence of cannabis use, and rapid drinking of fluids followed by vomiting (apparently to dilute the bitterness of the bile). These behaviors do not indicate a factitious or psychiatric etiology [62]. Nearly one-half (44 percent) of adults with CVS had a history of physical or sexual abuse as a child, and two-thirds have had panic anxiety [4].

Case series of adult patients with CVS reflect difficulty and delays in establishing the diagnosis, often with repeat imaging and endoscopic studies and sometimes with surgical procedures such as cholecystectomy, pyloroplasty, or fundoplication without improvement [2,25,56]. This may reflect the frequent presence of interepisodic symptoms between acute vomiting episodes in adults with CVS and the limited awareness of CVS among clinicians caring for adults.

There may be an overlap between CVS and idiopathic gastroparesis in adults. Approximately 11 percent of adults with idiopathic gastroparesis have a cyclic pattern of symptoms and some respond to tricyclic antidepressants, similar to patients with CVS [63]. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis".)

NATURAL HISTORY — Many children outgrow CVS by their preteen or early teenage years [64]. However, we have estimated that up to 75 percent of children with CVS will then develop migraine headaches by age 18 [1,19]. Some children who progress from CVS to migraine headaches will first pass through a phase of abdominal migraines [65]. Abdominal migraines can be distinguished from CVS in that the core symptom of abdominal migraines is abdominal pain, with little or no vomiting. Both syndromes may have headache as a feature and respond to antimigraine therapy [1]. One retrospective study of 51 children followed for up to 13 years found that vomiting resolved in 60 percent [66]. However, despite resolution of vomiting, 42 percent continued to have regular headaches and 37 percent had abdominal pain.

The natural history in adults has not been well studied. In the series of 17 adults described above [25], 13 had at least a partial response to tricyclic antidepressant therapy, while an additional three responded to other types of treatment. One patient had resolution off of medication during two years of follow-up. Nonresponders to tricyclic antidepressants compared with responders were more likely to have coalescent symptoms, have poor compliance, use narcotics, have more severe symptoms with longer episodes, and have more emergency department visits [2,24].

DIAGNOSIS — The diagnosis of CVS is based on the clinical history and exclusion of alternative diagnoses (table 3). Two sets of criteria have been proposed based upon a consensus of experts:

Pediatric criteria — The pediatric criteria for diagnosis of CVS developed by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) require all of the following [6,9,67]:

●At least five attacks in any interval or a minimum of three attacks during a six-month period

●Episodic attacks of intense nausea and vomiting lasting one hour to 10 days and occurring at least one week apart

●Stereotypical pattern and symptoms in the individual patient

●Vomiting during attacks occurs at least four times per hour for at least one hour

●Return to baseline health between episodes

●Not attributed to another disorder

The NASPGHAN guideline summarizes the diagnostic process in an algorithm (algorithm 1) [9].

A separate set of diagnostic criteria for CVS were developed in 2016 (pediatric Rome IV criteria) [6,67]. These differ from the NASPGHAN criteria by including those children with a minimum of two episodes and eliminating the quantitative severity of vomiting of as least four times per hour at the peak. These criteria could result in a higher sensitivity but possibly lower specificity than the NASPGHAN criteria.

Adult criteria — Criteria for diagnosis of CVS in adults (adult Rome IV criteria) are [5]:

●Stereotypical episodes of vomiting regarding onset (acute) and duration (less than one week)

●Three or more discrete episodes in the prior year and two episodes in the past six months, occurring at least one week apart

●Absence of vomiting between episodes, but other milder symptoms can be present between cycles

A history or family history of migraine headaches further supports the diagnosis.

Exclusion of other causes of vomiting — CVS should be considered among other diagnoses in patients presenting with nausea and vomiting. (See "Approach to the adult with nausea and vomiting" and "Approach to the infant or child with nausea and vomiting".)

Alarm symptoms and signs — Alarm symptoms and signs alerting the clinician to a diagnosis other than CVS include the following; these were developed in the pediatric consensus statement but generally apply to adults as well [9]:

●Gastrointestinal

•Gastrointestinal bleeding (other than mild hematemesis developing during an episode of vomiting, which suggests a prolapse gastropathy or Mallory-Weiss tear)

•Unilateral abdominal pain

•Bilious vomiting (bilious vomiting is quite common in CVS but warrants further evaluation to exclude intestinal obstruction)

•Weight loss

●Metabolic

•In toddlers, episodes triggered by fasting, illness, or high-protein meal, or by marked anion gap acidosis, hypoglycemia, or hyperammonemia

●Neurologic

•Severe headaches (especially if continuous or worsening rather than episodic)

•Altered mental status

•Gait disturbances or other new neurologic signs

●Other

•Severe clinical course characterized by failure to respond to treatment, progressive worsening, prolonged episodes requiring hospitalization

•A change in the vomiting pattern or symptoms

Considerations for children — Further steps depend upon the absence or presence of warning signs:

●Alarm signs absent – Children who present with the typical symptoms of CVS as outlined above and with no warning symptoms require only a limited screening evaluation to exclude other disorders:

•Imaging – An upper gastrointestinal series to the ligament of Treitz should be performed in all children to exclude intestinal malrotation or nonfixation with possible intermittent volvulus [68]. (See "Intestinal malrotation in children".)

•Laboratory testing – During at least one episode, laboratory testing should be performed, consisting of electrolytes, glucose, blood urea nitrogen (BUN), creatinine, and urinalysis. The primary purpose of these tests is to monitor for hypovolemia and electrolyte disturbances that can result from protracted vomiting, and chronic renal or Addison disease. Mild metabolic acidosis, hypoglycemia, and ketosis are consistent with CVS. Severe acidosis or hypoglycemia warrant further evaluation for an inborn error of metabolism, especially in infants and toddlers. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management".)

•Trial of prophylactic therapy – For patients whose symptoms warrant a trial of prophylactic therapy, the diagnosis of CVS is further supported if the CVS improves. Children who do not respond to prophylactic therapy may warrant further evaluation to identify other possible causes of the symptoms. (See 'Prophylactic medications' below.)

For children with no alarm signs and typical symptoms, a provisional diagnosis of CVS can be made on the basis of the clinical history and basic testing outlined above. An extensive evaluation is not recommended because of low yield and high costs [1,69]. As an example, among 225 children with recurring cyclical episodes of vomiting who were evaluated extensively, only one in eight were found to have an underlying disorder that required intervention [70]. In a separate study, the results of systematic laboratory, radiographic, and endoscopic testing (cost of $6125 per child) altered management in only 4 percent [69]. A cost-decision analysis concluded that a more cost-effective diagnostic strategy in children was to obtain an upper gastrointestinal series to rule out malrotation and the possibility of subsequent volvulus, followed by a two-month trial of antimigraine therapy, with further studies reserved for those with continued symptoms [68].

●Alarm signs present – In the presence of alarm signs, further evaluation is recommended:

•Acute-onset unilateral or flank pain – Perform an abdominal ultrasound to exclude acute hydronephrosis (so-called Dietl crisis). In a case series of four children, acute hydronephrosis caused by ureteropelvic junction obstruction closely mimicked symptoms of CVS [71]. (See "Congenital ureteropelvic junction obstruction", section on 'Clinical presentation'.)

•Metabolic warning signs – For young children with characteristics suggesting metabolic disease (eg, episodes triggered by fasting, illness or a high-protein meal), measure serum concentrations of lactate, pyruvate, ammonia and serum amino acids, and urine organic acids. These tests should be performed during the early part of the episode, prior to administration of intravenous fluids.

•Neurologic signs – Perform a magnetic resonance imaging scan of the brain and/or evaluation for epilepsy [72].

•Upper gastrointestinal bleeding – If upper gastrointestinal bleeding is severe or persistent, perform an endoscopic evaluation. Patients with CVS may have endoscopic evidence of prolapse gastropathy or Mallory-Weiss tear due to repetitive forceful vomiting.

•Upper gastrointestinal symptoms that persist between episodes – Perform an upper endoscopy between episodes. If endoscopy is performed during or shortly after an episode of CVS, the presence of esophagitis does not imply that reflux is an underlying cause, since one-half of patients with CVS may have esophageal inflammation that does not require chronic antireflux treatment.

Considerations for adults — In adults, guidelines recommend biochemical, endoscopic, and sometimes radiographic assessments [10]:

●Biochemical testing is recommended to include a complete blood count, serum electrolytes, glucose, hepatic aminotransferases and pancreatic lipase, and urinalysis.

●An esophagogastroduodenoscopy is also recommended, even though common findings of Mallory-Weiss tear and mild esophagitis are likely to be epiphenomenon.

●Imaging may be considered for very selected patients who have localized pain or other symptoms suggesting an organic cause.

MANAGEMENT — Management of CVS involves:

●Lifestyle interventions to reduce the risk of inducing an attack and improve self-efficacy and quality of life.

●Supportive care, provided during any severe bout of cyclic vomiting. This may include admission to the emergency department and/or hospital, intravenous fluids, antiemetics (including those with beneficial sedating effects), and analgesics. (See 'Supportive care and antiemetics' below.)

●Abortive medication used during the prodrome to prevent or attenuate the attack. This approach may be sufficient for patients with relatively mild or infrequent symptoms and, if possible, should be initiated at home. (See 'Abortive medications (for prodrome)' below.)

●Prophylactic medication for selected patients, given daily to prevent further episodes. This approach is generally reserved for patients with frequent prolonged or severe symptoms. (See 'Prophylactic medications' below.)

The recommendations for management are summarized in the tables (table 4A-C). Referral to a pediatric consultant, pediatric gastroenterologist, neurologist, or metabolic specialist is indicated for children with frequent or severe disabling episodes or mild episodes that persist despite lifestyle changes, supportive care, and a therapeutic trial. Similarly, adults should be referred to a specialist familiar with CVS if episodes are severe or disabling and initial interventions are not effective. Management of CVS in adults is outlined in the algorithm (algorithm 2).

Lifestyle interventions — Lifestyle modifications to reduce the risk of inducing an attack include adequate fluid intake, avoidance of fasting, using long-acting caloric snacks, good sleep hygiene, and regular exercise. Recognized precipitating factors should be avoided whenever feasible. In children, common triggers include physical exhaustion from lack of sleep, stressors such as bullying at school, motion (car rides, amusement park rides), fasting, and certain foods (eg, chocolate, cheese, cow's milk). In adults, precipitating factors are somewhat less common than in children but may include sleep disruptors (shift work, extended travel across time zones) and psychological stressors related to interpersonal conflict at work or home. If there as a history or prolonged and frequent cannabis use, total abstention can clarify whether this is cannabis hyperemesis syndrome (CHS) or CVS.

Management should address comorbid conditions as well. First among them is anxiety, panic attacks, or depression, which are present in 30 to 50 percent of children or adults with CVS [10,73-75]. Referral to a medical psychologist for cognitive behavioral therapy is an integral part of our program's treatment plan, and behavioral intervention can result in reduced disease severity. In more severe cases, the addition of anxiolytic agents (eg, citalopram, sertraline) may be necessary. If school absenteeism fails to respond to a graded school-reentry plan, a comprehensive biobehavioral rehabilitation program may be needed for recovery.

Understanding of and adherence to the treatment plan can be aided by a visual chart of the overall action plan, suitable for patients or caregivers with low literacy [76]. A sample can be accessed at the Darnall Medical Library.

Supportive care and antiemetics — Supportive or rescue care is provided during an episode of vomiting to alleviate symptoms and complications. Once the vomiting becomes well established after several hours, the episode typically cannot be aborted and must run its usual course. The goal then becomes one of alleviating symptoms including vomiting, nausea, abdominal pain, and headache and replenishing fluid, energy, and electrolytes. A single-center review of pediatric visits for CVS found that delayed presentation to the emergency department >24 hours after onset of symptoms and delay in administration of antiemetics in the emergency department were associated with higher rates of hospitalization [77]. This confirms the clinical observation that prompt intervention helps to attenuate the severity of episodes.

For supportive care of patients with CVS, the following strategies are often used, based on limited evidence (table 4B) [10,78]:

●Intravenous hydration – Intravenous hydration can decrease the frequency of vomiting and duration of episodes [79] in approximately one-half of patients, based on clinical experience [78].

•First, hypovolemia should be corrected with one or more fluid boluses (eg, isotonic saline 10 to 20 mL/kg, or 1 L in adults) as needed.

•Subsequently or simultaneously (piggy-backed), additional intravenous hydration should be given using half-normal saline (0.45% NaCl) with 10% dextrose for children and normal saline (0.9% NaCl) with 5% dextrose for adults [10]. The solution should be infused at 1.5 times the maintenance rate. The rationale for including dextrose is that this may attenuate the catabolic state and ketosis induced by the acute CVS episode, which can prolong vomiting. For patients with significant electrolyte derangements (hypokalemia, hypochloremia, and hyponatremia), adjustments to intravenous fluids are discussed separately. (See "Treatment of hypovolemia (dehydration) in children in resource-abundant settings" and "Maintenance and replacement fluid therapy in adults".)

In children, persistent moderate to severe anion gap acidosis or hypoglycemia should prompt further evaluation for a metabolic disorder, even though striking elevations of urinary acetoacetate and beta-hydroxybutyrate (on organic acid profiles) can be found during episodes of CVS. (See 'Considerations for children' above.)

●Environment – Some patients benefit from staying in a quiet, dark room with limited vital sign checks to reduce sensory stimulation, which can exacerbate episodes.

●Feeding – Provision of calories during the emetic phase is thought to help children with mitochondrial variants of CVS and suspected disorders of carbohydrate or fat metabolism. However, most children can only tolerate delivery by parenteral or jejunal routes, which is usually not feasible unless the patient has a jejunal access device in place. Once vomiting has ceased during the recovery, initiation of frequent small feedings with low-fat foods is important for nutritional recovery. (See 'Mitochondrial dysfunction' above.)

●Antiemetics

•Ondansetron – Use of ondansetron, a 5-hydroxytryptamine (5-HT₃) receptor antagonist, is recommended for use in emergency and inpatient settings to reduce the frequency of emesis and fluid requirements [78]. Parenteral ondansetron, even if administered early, may attenuate the vomiting but usually does not abort the episode and does not reduce the unrelenting nausea. In the available cases series, 50 to 75 percent of patients reported improvement with intravenous ondansetron [19,78,79].

Dosing for ondansetron is:

-Children – 0.3 mg/kg/dose, up to a maximum of 8 mg. May give an additional dose every four to six hours, with a maximum total dose of 32 mg/24 hours.

-Adults – 8 mg intravenously. May give an additional 8 mg dose every four to six hours, with a maximum total dose of 32 mg/24 hours [80].

Use with caution in patients with risk factors for QT_c prolongation, including other medications that also prolong the QT interval, such as tricyclic antidepressants and phenothiazine antiemetics or family history of sudden death.

•Fosaprepitant – Our program uses intravenous fosaprepitant as an alternative to intravenous ondansetron as it appears to be more effective with fewer side effects, based on our anecdotal experience. We use the following dosing:

-Children 2 to <12 years – 3 to 4 mg/kg intravenously over 60 minutes (maximum dose 150 mg). If needed, administer 2 mg/kg intravenously (fosaprepitant) or orally (aprepitant) on days 2 and 3.

-Children ≥12 years and adults – 150 mg intravenously over 30 minutes. If needed, administer 80 mg intravenously (fosaprepitant) or orally (aprepitant) on days 2 and 3.

Fosaprepitant has a large evidence base from treatment of chemotherapy-induced nausea and vomiting [81]. Dosing for CVS is not standardized and varies among centers but is generally similar to that used for chemotherapy-induced vomiting, with minor variations for days 2 and 3 including route of administration and as-needed dosing.

Triptan therapy (eg, sumatriptan) may be useful if the patient presents to the emergency department in the very early phases of the episode (ie, within one hour of the onset of vomiting), but this is rarely the case [10]. (See 'Abortive medications (for prodrome)' below.)

●Sedating agents – Because vomiting is not completely controlled by a 5-HT₃ antagonist therapy alone, we usually add a medication with both antiemetic and sedating effects (eg, diphenhydramine or lorazepam).

Data on the use of these medications in this setting are extremely limited. The practice of using medications with a sedating effect is based largely on clinical observations that induction of deep sleep may alleviate both nausea and vomiting in some cases or stop episodes already in progress. Occasionally, administration of benzodiazepines or use of closely monitored general anesthesia using dexmedetomidine will terminate an episode [82]. The efficacy of these medications for severe and intractable vomiting is also supported by experience with these drugs in other settings (eg, chemotherapy-induced nausea and vomiting, postoperative nausea and vomiting, cannabinoid hyperemesis) [51]. In pediatric practice, we often begin with diphenhydramine and if sedation is inadequate, we switch to lorazepam. Adult guidelines are similar but suggest initiating treatment with lorazepam [10]. (See "Prevention of chemotherapy-induced nausea and vomiting in adults" and "Postoperative nausea and vomiting" and "Cannabinoid hyperemesis syndrome".)

●Antihypertensives – Most patients with mild hypertension during an acute CVS episode do not require antihypertensive therapy, since the hypertension usually resolves as the patient's discomfort improves. A small subset of patients (those with the Sato variant of CVS) may present with more severe and persistent hypertension (see 'Hypothalamic-pituitary-adrenal axis hyperreactivity' above). If pharmacologic therapy is needed for such patients, short-acting antihypertensives can be used as needed during the episode. Prolonged use of antihypertensives is not necessary, because the hypertension abates with resolution of the CVS episode.

●Other medications – Management of abdominal and headache pain usually begins with the nonsteroidal antiinflammatory drug intravenous ketorolac. This approach is supported by our clinical experience and the theoretical mechanism that it reduces elevated prostaglandin E2. Oral or intravenous acetaminophen also may be trialed but may be less effective than ketorolac, based on anecdotal clinical experience. If possible, narcotics should be avoided as they can worsen vomiting and induce dependence over time.

For adults, there is only anecdotal experience on the efficacy of the above antiemetics, sedating agents, and analgesics used for supportive care [40,83,84]. A variety of other antiemetic medications have been used, including high-dose dexamethasone, metoclopramide, and naloxone, but these are usually unsuccessful [83].

Abortive medications (for prodrome) — Abortive medications should be administered to any patient with known CVS if they can be given during the prodrome or shortly after the vomiting begins. The medications should be administered promptly after the patient presents to the emergency department. Patients with delayed intervention (especially >24 hours after symptom onset) are more likely to require hospital admission [77].

Abortive therapy alone is generally suggested for patients with relatively mild or infrequent episodes. For those with frequent or severe symptoms, abortive therapy may be used in conjunction with ongoing prophylactic therapy. (See 'Prophylactic medications' below.)

The primary choices for abortive medication in both children and adults are sumatriptan and aprepitant (a neurokinin 1 antagonist) (table 4B).

Children and adolescents

●Sumatriptan – For children with migraine-associated CVS, sumatriptan is moderately effective if given early in the prodromal phase and may have some effect if given within one hour after onset of vomiting. In one small case series, sumatriptan had a 54 percent response rate when given subcutaneously and 33 percent when given intranasally [41]. It may be tried in those without a family history of migraines because it can be effective in some. It appears to be more effective when the episodes are shorter in duration (<1 day) in children. Our approach is to first do a trial by the intranasal route. If symptoms persist, the dose can be repeated once in two hours. However, if intranasal administration fails to alleviate symptoms, we may proceed to a trial of a subcutaneous sumatriptan injection during the next episode of vomiting. In general, sumatriptan either is completely effective or wholly ineffective in terminating an episode.

Sumatriptan dosing is not well established, especially for young children. We use the following doses for CVS, based on clinical experience and a few published case series [39,41]:

•Age 5 to 11 years, or weight 20 to 39 kg – Intranasal dose 5 to 10 mg or subcutaneous dose 2 to 3 mg

•Age 12 to 17 years, or weight 40 to 59 kg – Intranasal dose 20 mg or subcutaneous dose 3 to 6 mg

•Age ≥18 years, or weight ≥60 kg – Intranasal dose 20 mg or subcutaneous dose 6 mg

A repeat dose may be given in two hours for intranasal administration and one hour for subcutaneous administration. The nasal form causes a bitter aftertaste, which can be lessened by flexing the head forward to avoid dripping spray into the nasopharynx. The subcutaneous dose can induce a pronounced transient burning in the chest and neck region. Triptans are contraindicated in those with known coronary or peripheral vascular disease and those with complex (eg, basilar) migraines.

●Aprepitant – As an alternative, aprepitant, an oral neurokinin 1 antagonist antiemetic, can be used if it can be given during the prodrome at least 30 minutes before the onset of vomiting with subsequent dosing on days 2 and 3. Aprepitant is particularly appropriate for patients with no family history of migraine or who failed to respond to triptans.

Abortive dosing of aprepitant varies by body weight:

•Children <15 kg – 80 mg orally on day 1 and 40 mg on days 2 and 3

•Children 15 to 20 kg – 80 mg orally once daily for three days

•Children >20 kg – 125 mg orally on day 1 and 80 mg on days 2 and 3

Among 25 children who were able to take oral aprepitant 30 minutes before vomiting, 76 percent achieved at least a partial response [85].

Adults — We suggest sumatriptan as the first-line abortive agent, using an intranasal dose of 20 mg or subcutaneous dose of 6 mg (algorithm 2). Based upon experience from treating migraines, the subcutaneous route is likely more effective than the nasal one. If sumatriptan is not effective, the second-line choice is a trial of aprepitant, using 125 mg orally on day 1 and 80 mg on days 2 and 3. These suggestions reflect expert opinion, based on low-quality evidence from case reports and clinical experience, as reviewed in the adult guideline [10].

Ondansetron administered orally before vomiting, beginning at home or intravenously in the emergency department, rarely aborts an episode but can reduce the pace and amount of vomiting and may circumvent the need for parenteral fluids [9]. (See 'Supportive care and antiemetics' above.)

Prophylactic medications — The decision to use prophylactic medications depends upon the frequency and severity of the attacks, similar to the principles that guide treatment of patients with migraine headaches [31]. In general, prophylactic therapy is warranted if attacks occur more than monthly or last more than one to two days in a child or adolescent, or >4 episodes/year or last >2 days in an adult, or are severe enough to require hospitalization or cause substantial school absenteeism or work disability. Abortive therapy may be used in addition to prophylactic therapy for patients who continue to have breakthrough vomiting episodes. (See 'Abortive medications (for prodrome)' above.)

Children and adolescents — In children, prophylactic agents that have been used with variable success include antimigraine agents (cyproheptadine, pizotifen, propranolol, amitriptyline, nortriptyline, mirtazapine), antiemetics (ondansetron, aprepitant), and anticonvulsants (topiramate, phenobarbital) [85-87]. Adjunctive treatment with mitochondrial supplements (coenzyme Q10, L-carnitine, riboflavin) is often added to the preventative regimen, based on limited evidence and with wide variation in practice [9,34-36,88].

We use the following approach to selecting prophylactic medications, consistent with the 2008 North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) Consensus Statement [9]. The limited evidence for the use of these medications for CVS suggests similar efficacy, so selection among these medications is guided primarily by side effects and toxicities, differences in clinician experience with use of each drug for CVS within a specific age group, and indirect experience from their use for migraine.

●First-line – As the initial first-line choice for prophylactic therapy, we suggest the following (table 4C):

•Children <5 years – Cyproheptadine or pizotifen. Pizotifen is similar to cyproheptadine and is available outside of the United States.

•Children ≥5 years – Amitriptyline.

The use of cyproheptadine for prophylactic therapy in patients with CVS is supported by several case series. Response rates (ie, at least partial reduction in the frequency and/or severity of episodes compared with baseline) reported in the available series range from 41 to 83 percent [19,79,86,89,90]. Its use for CVS is also supported by indirect experience of its use for migraine headaches in children. The recommendation favoring cyproheptadine over amitriptyline in younger children was based primarily upon expert experience and respective side effect profiles. Cyproheptadine is generally well tolerated by young children; side effects may include excessive weight gain and sedation. Children should be monitored for these effects, and an alternative agent should be considered in children who are already overweight. In some cases, tachyphylaxis may arise and can be countered by intermittent dosing, achieved by either skipping this medication on weekends or skipping one week per month. Outside of the United States, pizotifen, a similar agent, may be used as first–line therapy, based on limited evidence [91]. (See "Preventive treatment of migraine in children", section on 'Cyproheptadine'.)

The evidence supporting amitriptyline as a first-line agent includes several large case series in children and adults, in which amitriptyline was the single most effective agent [2,9,19,86,92]; response rates in the available case series range from 70 to 90 percent [19,25,34,79,86,90]. Amitriptyline may be more effective for those with a personal or family history of migraine but should be tried in those without a migraine association. In one case series, amitriptyline and other antimigraine agents were effective in 79 percent of children with a history of migraines in the family or patient, compared with 36 percent in those with no history of migraines [19]. Nortriptyline, a less sedating alternative to amitriptyline, has also been successfully used in this population. (See "Preventive treatment of migraine in children", section on 'Tricyclic medications'.)

Optimal tolerance of amitriptyline requires gradual titration, monitoring (ie, electrocardiogram [ECG]), and, in some cases, obtaining therapeutic blood levels, especially in children on higher doses. A common starting dose is 0.2 to 0.3 mg/kg per day at bedtime, followed by increases in increments of 5 to 10 mg at weekly intervals to a higher dose, often 1 to 1.5 mg/kg per day at bedtime. This incremental dose increase allows for adaptation to side effects (eg, morning tiredness). Up to 50 percent of patients may experience anticholinergic (dry mouth, constipation) and sedative side effects (morning tiredness). ECG monitoring should be performed before starting and again 10 days after reaching the peak dose; cardiotoxicity (tachyarrhythmia) can be avoided by maintaining the QTc interval <460 msec. It typically takes up to one to two months for the effects of amitriptyline to become fully evident once the target dose is reached. In some individuals, higher doses may be needed to control the CVS, but this should be approached with caution. (See 'Nonresponders' below.)

●Second-line – If the first-line agents are not effective after optimal titration, the next step is a trial of either aprepitant or propranolol (table 4C).

Aprepitant is a newer antiemetic agent that has good efficacy based on limited but increasing clinical experience in adults and children. When aprepitant is used for prophylaxis, it is administered at the following doses [85]:

•Children <40 kg – 40 mg orally twice weekly

•Children 40 to 60 kg – 80 mg orally twice weekly

•Children >60 kg and adults – 125 mg orally twice weekly

Aprepitant is also used for abortive therapy, at higher doses, as described above. (See 'Abortive medications (for prodrome)' above.)

In one retrospective series of 16 children treated prophylactically with aprepitant, three (19 percent) achieved a complete response and 10 (62 percent) achieved a partial response [85]. For propranolol, response rates in the available case series range from 46 to 83 percent [9,19,79,89]. Propranolol was recommended as the second-line agent in the NASPGHAN consensus statement, which was written in 2008 before data on aprepitant became available [9]. Other agents that may be effective include the anticonvulsants phenobarbital or topiramate, or the antidepressant mirtazapine [87,93,94]. Although all have similar rates of efficacy, we suggest aprepitant or propranolol because of the substantive but reversible cognitive side effects associated with the use of anticonvulsants.

●Adjunctive therapy – In addition to the first- or second-line therapies described above, we suggest a trial in children of adjunctive treatment with coenzyme Q10 and/or L-carnitine supplements and riboflavin for at least four months. All of these supplements are also used for mitochondrial disorders in children [9]. In some milder cases of CVS, these supplements may be effective as sole therapy rather than as adjuncts to other medications. Anecdotally, some children with limited physical stamina or chronic fatigue experience marked improvement on mitochondrial supplements, sometimes recognized only in hindsight.

Retrospective studies support the efficacy of coenzyme Q10, L-carnitine, and riboflavin in children with CVS [34-36,88]. In one report based on surveys of parents, the response to coenzyme Q10 alone appeared similar to that of amitriptyline [34]. In another retrospective study of 30 patients treated with a protocol consisting of fasting avoidance, coenzyme Q10 and L-carnitine supplementation, and, in refractory cases, with added amitriptyline or cyproheptadine, 90 percent achieved at least a 50 percent reduction in vomiting episodes [35].

•For coenzyme Q10, a common starting dose is 10 mg/kg per day or 200 mg twice daily and target blood levels are >3 to 4 microgram/mL. If blood levels of coenzyme Q10 are low, this may be the result of poor bioavailability and indicate the need for a higher dose or different preparation.

•Alternatively or in addition, L-carnitine can be used. A typical starting dose for L-carnitine supplements is 50 or 100 mg/kg per day or 1 g twice daily. Higher doses (eg, up to 4 g/day) have been used if needed based on laboratory testing of blood carnitine levels (target free carnitine level >40 micromol/L) [35]. However, high doses should be approached with caution and careful monitoring for adverse events, including dose-related diarrhea.

•The suggested dosing for riboflavin is approximately 10 mg/kg per day divided into two daily doses; most often, doses of 100 or 200 mg twice daily are used [88].

If there is no apparent therapeutic benefit during a trial of at least four months, the supplements may be discontinued. These supplements are available without prescription. There are some combination powdered preparations that are easier for children to take and avoid the burden of multiple supplement pills (eg, Spectrum Needs brand).

●Stopping treatment – In children, CVS tends to persist for three to five years [1,64]. CVS often begins to improve around age 10 years and resolves by 18 years in approximately 75 percent of individuals, although the vomiting symptoms are often replaced by migraine headaches [60,64] (see 'Natural history' above). Therefore, we typically attempt weaning off of prophylactic medication for adolescents who have had no episodes for one to two years or done well with few episodes for three years. For practical reasons, we tend to wean the medication during the summer holidays when school is in recess.

Adults — The approach to prophylactic therapy in adults is similar to that in older children, with slight differences in priorities (table 4C and algorithm 2):

●First-line – For adults who require prophylactic therapy for CVS, the first-line choice is amitriptyline, using doses of 75 to 100 mg per day [2,25,84,92]. Amitriptyline is more likely to be effective for patients with a personal or family history of migraines but also appears to be effective in those without such a history. A typical approach is to initiate a low dose of 10 to 25 mg at night and, if well tolerated, titrate upward based upon tolerance [95]. Its use may be limited by common side effects such as fatigue or sedation, confusion, headache, poor concentration, weight gain, constipation, palpitations, and lightheadedness, which may be dose-limiting. If these occur and are intolerable, treatment may be switched to alternative tricyclic antidepressants (nortriptyline, doxepin) [10,84,92]. For some individuals, higher doses may be needed to control the CVS, but this should be approached with caution. (See 'Nonresponders' below.)

This recommendation is based on evidence from open-label and retrospective studies. In a review of 14 studies that included 600 adult and pediatric patients with CVS treated with amitriptyline or other tricyclic antidepressants, 70 percent reported complete or partial improvement with a decrease in frequency, duration, or severity of CVS symptoms [10]. Similarly, in an open-label study of 46 patients followed for two years, treatment with a tricyclic antidepressant was associated with marked reductions in the number of CVS episodes (from 17 to 3), duration of a CVS episode (from six to two days), and in the number of emergency department visits/hospitalizations (from 15 to 3) [92].

●Second–line – When tricyclic antidepressants fail to control attacks or are not tolerated, the anticonvulsants topiramate (100 mg), zonisamide (400 mg), and levetiracetam (1000 mg) may be used [2,10,96]. In a retrospective review of 136 adults, 88 responded to topiramate with a significant 50 to 66 percent reduction in annual number of CVS episodes and CVS-related emergency department visits and hospitalizations [97]. Potential adverse effects of topiramate include cognitive dysfunction (8 to 12 percent at migraine dosages), paresthesia, headache, fatigue, dizziness, mood problems, and loss of appetite [98,99]. Alternatively, it is reasonable to do a trial of aprepitant 125 mg twice a week, as suggested in guidelines based largely on the collective clinical experience of the panel [10]. There is minimal experience to support or refute the use of propranolol for prophylaxis of CVS in adults, although indirect evidence from its use for migraines suggests that it might be effective for CVS. Further details on these drugs are discussed in separate topic reviews. (See "Preventive treatment of episodic migraine in adults" and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Zonisamide' and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Levetiracetam'.)

●Adjunctive therapy – Mitochondrial supplements (coenzyme Q10, sometimes with riboflavin) are sometimes used as adjuncts to other prophylactic agents in adults and are discussed as options in the adult guideline [10]. Doses for adults are coenzyme Q10 200 mg orally twice daily and riboflavin 200 mg orally twice daily. This is based primarily upon very limited and indirect evidence for efficacy in prophylaxis of migraines in adults and prophylaxis of CVS in children. (See 'Children and adolescents' above and "Preventive treatment of episodic migraine in adults".)

Catamenial cyclic vomiting syndrome — For adolescent or adult women with catamenial CVS (ie, when onset of episodes coincide with the onset of menses), addition or adjustment of hormonal contraceptives is an early consideration. Options include oral contraceptives (with either low doses of estrogen or progesterone-only) or intramuscular medroxyprogesterone acetate every three months. In contrast, oral contraceptives with high doses of estrogen can also exacerbate symptoms in CVS patients [9,100]. The strategy is similar to that used for estrogen-associated menstrual migraine. (See "Estrogen-associated migraine headache, including menstrual migraine".)

Nonresponders — In children, adolescents, and adults who remain refractory to the therapies recommended above, we suggest the following approach [60]:

●First, reevaluate for the possibility of a recurring trigger such as school (eg, bully), work, or family stressors (eg, divorce). In children, an indolent infection such as chronic sinusitis can be a hidden trigger. In adults, chronic unrevealed use of cannabis or reliance on opioids for pain management may be triggers. (See 'Lifestyle interventions' above.)

●Second, in children, consider alternative causes of vomiting and screen for acute hydronephrosis or small bowel obstruction (volvulus) during the vomiting episode with an abdominal ultrasound or abdominal computed tomography. Some adolescents may evolve from CVS into a postprandial pattern of rumination or "coalescent" daily morning nausea and occasional vomiting that is much milder than that in a CVS episode. Adolescents and adults should avoid cannabis and opioids. Adults may benefit from an evaluation for gastroparesis. (See 'Exclusion of other causes of vomiting' above.)

●Third, revisit the possibility of treatment with amitriptyline, with further dose escalation (>1.5 mg/kg dose) using careful titration, ECG monitoring, and therapeutic monitoring. In some children or adults, these higher doses may be needed to control the CVS, especially if the individual is a rapid metabolizer. Such patients may not respond to standard doses of amitriptyline (1 to 1.5 mg/kg per day) and have very low or undetectable blood levels of amitriptyline but may respond when the amitriptyline dose is further increased and blood levels reach therapeutic levels of 100 to 150 micrograms/L [35]. As a general rule, an ECG and blood amitriptyline level should be obtained before attempting to exceed 1.5 mg/kg per day. To avoid cardiotoxicity (tachyarrhythmia), the QTc interval should be maintained below a safe threshold (eg, <460 msec for children and adolescents [101], <470 msec for women, and <450 msec for men [10]).

●Finally, combination medical therapy may be effective, such as [60,102]:

•Amitriptyline and an anticonvulsant (eg, topiramate)

•Amitriptyline and aprepitant

•Amitriptyline and propranolol

•Propranolol and erythromycin

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nausea and vomiting".)

ADDITIONAL RESOURCES FOR PATIENTS — Support and counseling may be helpful for selected patients. The Cyclic Vomiting Syndrome Association (CVSA), an international organization, was established in 1993 to provide support to patients with CVS. This and other resources that may be useful for patients are listed in the table (table 5).

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Nausea and vomiting in adults (The Basics)" and "Patient education: Cannabis hyperemesis syndrome (The Basics)")

●Beyond the Basics topic (see "Patient education: Nausea and vomiting in infants and children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical features – Cyclic vomiting syndrome (CVS) is an idiopathic disorder characterized by recurrent, stereotypical bouts of vomiting with intervening periods of normal or baseline health. Both children and adults are affected. (See 'Introduction' above.)

●Pathogenesis – The pathogenesis of CVS remains unknown, and CVS may represent a heterogeneous group of disorders. An association between CVS and migraine headaches has been consistently described in the majority of patients, suggesting that there may be a common pathophysiologic process, but other mechanisms have been implicated, including, in some cases, chronic high-dose cannabis use. (See 'Pathogenesis' above.)

●Diagnosis – Diagnostic criteria have been proposed based upon consensus of experts by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) for children (algorithm 1) and Rome IV Committees for children and adults. The specific pattern, severity, and duration of vomiting episodes varies among patients but is usually stereotypical for an individual patient. CVS is diagnosed based primarily upon the history and exclusion of alternative diagnoses (table 3). (See 'Diagnosis' above.)

●Acute management – Management of CVS includes addressing lifestyle modifications and comorbidities, especially anxiety. Specific interventions depend on age of patient, severity of symptoms, timing of presentation, and setting. Our general approach is as follows (see 'Lifestyle interventions' above and 'Management' above):

•Prodromal and early symptoms (home management) – For patients with an episode of CVS that can be identified during the prodrome or shortly after the vomiting begins, we suggest treatment with an abortive agent such as intranasal or subcutaneous sumatriptan or oral aprepitant (Grade 2C). The choice between these options is based largely on patient and provider preference (table 4B). Aprepitant is particularly appropriate for patients without a personal or family history of migraine and those who have failed to respond to triptans.

Abortive treatments are most effective if they are given early in the prodrome and should be prescribed to have at home for timely use by the patient. (See 'Abortive medications (for prodrome)' above.)

•Acute vomiting episodes (emergency department management) – For patients who present to the emergency department with moderate to severe vomiting episodes, supportive care includes the following measures (table 4B). Supportive care is more effective when the patient presents to the emergency department earlier, especially within six hours of onset, compared with waiting 24 or more hours from onset (see 'Supportive care and antiemetics' above):

-Intravenous hydration – Intravenous fluids should be given to replace fluid losses. Hypovolemia is initially corrected with fluid boluses (eg, 10 to 20 mL/kg of isotonic saline). For ongoing maintenance fluid therapy in children, we suggest a half-normal saline (0.45% sodium chloride) with 10% dextrose rather than lower dextrose concentrations (Grade 2C). For adults, we typically use isotonic saline (0.9% sodium chloride) with 5% dextrose. This dextrose infusion may lessen the catabolic state and ketosis, which can prolong vomiting.

-Antiemetic therapy – For patients presenting with acute vomiting episodes, we suggest initial treatment with high-dose 5-hydroxytryptamine (5-HT₃) receptor antagonist (eg, ondansetron, granisetron) (Grade 2C). A possible alternative is intravenous fosaprepitant. In addition, we suggest concomitant treatment with an agent with both antiemetic and sedating effects (eg, diphenhydramine or lorazepam) (Grade 2C). The sedating agent provides additional symptom relief, which is valuable because control of nausea and vomiting is often incomplete with 5-HT₃ receptor antagonist therapy.

Triptan therapy (eg, sumatriptan) may be useful if the patient presents to the emergency department in the very early phases of the episode (ie, within one hour of the onset of vomiting), but this is rarely the case. (See 'Abortive medications (for prodrome)' above.)

-Environmental measures – Whenever possible, the patient should be kept in a dark, quiet, low-stimulation environment because any disturbance of the hyperesthetic patient typically incites more nausea and vomiting.

-Treatment of pain (if present) – Management of abdominal and headache pain usually begins with an intravenous nonsteroidal antiinflammatory drug (eg, ketorolac). If the pain has a midepigastric or dyspeptic quality, an antireflux medication (eg, histamine type 2 receptor antagonist or proton pump inhibitor) is reasonable adjunctive therapy.

●Prophylactic therapy – For patients who experience CVS episodes that are frequent, prolonged, or debilitating, or that result in recurrent emergency department or hospital admissions, we suggest prophylactic therapy (Grade 2C). Selection of medication is based primarily upon side effects and toxicities, as well as differences in the amount of clinical experience with use of each drug for CVS within each age group. (See 'Prophylactic medications' above.)

•For children <5 years, we suggest prophylactic treatment with cyproheptadine or pizotifen rather than other agents (Grade 2C). This preference is based primarily on a more favorable side effect profile in younger children and is supported by an expert panel. Potential side effects of cyproheptadine include weight gain and sedation.

•For children ≥5 years and adults, we (and an expert panel) suggest amitriptyline or other tricyclic antidepressant (Grade 2C). This preference is based upon the greater clinical experience with amitriptyline for CVS compared with alternative agents (aprepitant, topiramate) and overall higher level of effectiveness, despite frequent but tolerable side effects.

Alternatives include aprepitant, propranolol (typically used only for children), or selected anticonvulsants. Dosing, side effects, and alternatives are outlined in the table (table 4C). In addition, for most children who warrant prophylaxis, we suggest a trial of concomitant treatment with coenzyme Q10, with or without L-carnitine and riboflavin supplementation (Grade 2C). Coenzyme Q10, sometimes with riboflavin, is sometimes used as an adjunct to other prophylactic agents in adults, based upon indirect and limited evidence for efficacy in prophylaxis of migraines. (See 'Children and adolescents' above and 'Adults' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Emily Dulude, MD, Richard G Boles, MD, and David J Desilets, MD, PhD, who contributed to earlier versions of this topic review.