INTRODUCTION
Cyclic vomiting syndrome (CVS) is a disorder of gut-brain interaction that is characterized by recurrent episodes of severe nausea and vomiting interspersed by symptom-free periods (1). The pathogenesis of CVS is heterogeneous, believed to be related to genetic factors involving mitochondrial DNA, ion channels, and neurohumoral and neurogenic function (2). Chronic cannabis use in CVS can cause similar symptoms, which resolve with prolonged cessation of cannabis. This variant of CVS has been defined as cannabinoid hyperemesis syndrome (CHS) (1,3). We will discuss here the prevalence, symptoms, diagnostic workup, and treatment of CVS in adults and distinguishing CVS from CHS. The pathophysiology of CVS has been recently reviewed by Hasler et al (2) and is beyond the scope of this review.
EPIDEMIOLOGY
CVS presents in men and women across all races and of all ages, especially children and young adults, with some children growing out of it with age (3). The prevalence of CVS in adults is 10.8% based on the Rome III criteria and is 1.2% using Rome IV criteria, with United States having the highest prevalence of 2% (4–6). Among adults referred for unexplained nausea and vomiting, CVS is estimated to be the cause in 3%–14% (3). It can take a median of 15 emergency department (ED) visits and 5–6 years after symptom onset before a diagnosis of CVS is made (3).
Many patients with CVS use cannabis to treat symptoms (7). Currently, it is unknown whether CHS is a subset of CVS where cannabis triggers CVS attacks in susceptible individuals or whether it is a separate entity (8). The prevalence of CHS in adults is unclear, largely because of the lack of consistent diagnostic criteria in the past. Previous study using Rome IV criteria identified CHS in 0.1% of patients, which accounted for 9.6% of all patients with CVS and 23.3% of cannabis-consuming patients with CVS (5).
SYMPTOMS
CVS is characterized by an on-off stereotypical pattern of vomiting. There are 4 phases: prodrome, emetic, recovery, and interepisodic phase (Figure 1) (9).
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Figure 1.: Four phases of cyclic vomiting syndrome. Adapted from Kovacic et al (
9). A stereotypical CVS episode is characterized by a prodrome phase (minutes to hours), emetic phase (hours to days), and a recovery phase (hours to days). The episodes are separated by a relatively asymptomatic interepisodic phase (weeks to months). CVS, cyclic vomiting syndrome.
The prodrome phase can last minutes to hours and includes symptoms of nausea, diaphoresis, pallor, abdominal pain, fatigue, temperature changes, irritability, or sense of impending doom (3,9).
The emetic phase can last hours to days, usually less than 1 week. Episodes often begin in the early morning hours (1–8 am). It is characterized by intense repeated vomiting up to 6 times/hr, often associated with abdominal pain in up to 71% of adults, restlessness, diarrhea, intense thirst, and/or headaches, although rarely with visual disturbances as seen in migraine auras. Although taking prolonged hot showers or baths to help relieve nausea and vomiting is classically associated with CHS, it has been observed in 50% of patients with CVS who are not using cannabis (1,8,9). Severe, persistent nausea is often only relieved by shutting out all external stimuli and going to sleep (1,3,9).
The recovery phase ranges from hours to days. Nausea and vomiting gradually stop, and appetite returns with gradual reintroduction of oral intake. Patients then enter a symptom-free period without vomiting (1). During this interepisodic phase, which can last weeks to months, more than half of adult patients with CVS may still experience some nausea or dyspepsia (3).
Adult-onset CVS attacks usually last longer (5.9 vs 3.4 days) and occur more frequently (14.4 vs 9.6 episodes/yr) than attacks in children (3). In some adults, especially if left untreated, CVS attacks can gradually develop longer episodes and shorter asymptomatic intervals, progressing to a coalescent pattern of daily nausea and vomiting without intervening asymptomatic intervals (1,3).
The clinical presentation of CHS is similar to that of CVS. But, the distinguishing characteristic of CHS is that patients develop symptoms after chronic cannabis use and the vomiting episodes stop after sustained cessation of cannabis (8). CHS typically occurs in men with prolonged daily cannabis use (3–5 times daily) over at least 2 years, although these thresholds may be lower with increasing potency of cannabis (8,10).
DIAGNOSTIC WORKUP
Both CVS and CHS are diagnosed based on conducting a medical history, physical examination, diagnostic testing, and using symptom-based criteria, which also require an absence of organic pathology causing symptoms (Figure 2, Tables 1 and 2) (3,8). The CVS Guidelines Committee has also proposed a revised set of criteria for CHS with specifications on duration/frequency of cannabis use and duration of cannabis cessation to optimize the diagnostic accuracy of CHS (Table 2) (8).
Figure 2.: Rome IV diagnostic algorithm for chronic or recurrent nausea and/or vomiting (
18). For a patient with chronic or recurrent nausea and/or vomiting, a history and physical examination, blood work, upper endoscopy, and imaging studies are needed to exclude other diseases and make the diagnosis of CVS. Permission granted by the Rome Foundation. CVS, cyclic vomiting syndrome.
Rome IV diagnostic criteria for cyclic vomiting syndrome (
3)
Diagnostic criteria for cannabinoid hyperemesis syndrome
Routine biochemical testing (complete blood count, serum electrolytes and glucose, liver panel, lipase, thyroid function, and urinalysis) and esophagogastroduodenosopy should be performed. Imaging studies such as a right upper-quadrant ultrasound to exclude biliary pathologies and a small bowel follow-through or computed tomography/magnetic resonance enterography can be considered to exclude obstructive pathologies. Urine drug testing can be considered to evaluate for illicit drug use or if CHS is suspected but cannabis use is denied (3,8). Diagnostic testing should also be performed during the interepisodic phase to avoid confounding variables such as dehydration or opioid use. If these tests are unrevealing, one can consider a gastric emptying study, although results are variable with patients with CVS often exhibiting rapid or normal gastric emptying times. It may be more useful in patients who have interepisodic symptoms. Patients with localizing neurological symptoms should undergo brain imaging and see a neurologist. Evaluation for more rare conditions such as Addison disease or acute intermittent porphyria can be considered if there are supporting symptoms (8). In select cases, antroduodenal manometry to evaluate for enteric neuropathy or myopathy or pH testing to evaluate for vomiting as an atypical presentation of gastroesophageal reflux disease can be considered (3).
TREATMENT
Treatment of CVS requires assessment of potential triggers, comorbid conditions, and disease severity. The main goals of treatment are to reduce episode frequency and severity and improve quality of life. This review focuses on the outpatient management of CVS.
Lifestyle modifications, including good sleep hygiene, avoiding fasting or dehydration, stress management, and identifying and avoiding potential triggers, should be encouraged. One series reported that education and lifestyle modifications alone reduced episode frequency in 70% of patients (4). Common triggers for CVS attacks include physiologic stressors (stress or excessive excitement, sleep deprivation, fasting, infections, and motion sickness) and foods. Certain foods (e.g., cow's milk, cheese, soy, egg white, chocolate, monosodium glutamate, and red wine) are possible triggers (11,12). It is reasonable to avoid potential food triggers for a period lasting at least 3 typical cycles to see if symptoms improve. CVS may also be triggered by menses (i.e., catamenial CVS) or pregnancy. Catamenial CVS can be treated with hormonal contraceptives containing low-dose estrogen or progesterone alone (13).
CVS is frequently associated with other comorbid conditions such as psychiatric disorders, autonomic dysfunction, migraines, sleep disorders, or substance use. These conditions should be screened for so they can be appropriately managed. Psychiatric conditions such as anxiety and depression can be present in up to 40% of CVS adults (1). Mood disturbance can trigger CVS episodes and CVS symptoms can also worsen mood disturbance, resulting in a vicious cycle. Mind-body interventions such as meditation or cognitive behavioral therapy may also be helpful (1). Autonomic dysfunction such as postural orthostatic tachycardia syndrome has been reported in CVS, and treatment of the underlying autonomic dysfunction may reduce CVS symptoms. Among CVS adults, 13%–70% have a history of migraines, and 57% have a family history of migraines. It is unclear whether independently treating migraines improve CVS symptoms, although some of the prophylactic and abortive medications are effective for both (1). Substance use is also more frequent in patients with CVS than in general population, with 39%–81% using cannabis, 19% using alcohol, 36% using tobacco, and 17% using narcotics for pain. Concurrent substance use or abuse may further contribute to symptoms and complicate treatment, so screening and appropriate treatment should be pursued (1).
All patients with CVS need abortive therapies (Table 3) administered as soon as possible during the prodrome phase. Abortive therapy includes triptans, 5-HT3 antagonists, phenothiazines, antihistamines, and NK1 antagonist. Sumatriptan has shown high efficacy rates in all patients with CVS, with higher efficacy in patients with a personal or family history of migraines. Ondansetron is a 5-HT3 antagonist that, although not specifically studied in CVS, is efficacious in reducing nausea and vomiting and is recommended as an abortive agent. Phenothiazines and antihistamines can also be used for its antiemetic and sedative effects. For more severe symptoms, especially if anxiety is prominent, benzodiazepines can be considered as abortive therapy, although the data in CVS are limited. Oral aprepitant, an NK1 antagonist, can be second-line therapy in patients with refractory symptoms. Abortive therapies can be combined if needed, and oral preparation is least preferred because of poor tolerance during an episode and unpredictable absorption (1,9).
Table 3.: Abortive treatment options for cyclic vomiting syndrome
For patients with CVS with mild symptoms (<4 episodes/yr, ≤2 days per episode, quick recovery, and no ED visit or hospitalizations), prophylaxis is not necessary, although coenzyme Q10 can be considered, given evidence of efficacy in a small study with children and low risk of side effects. For patients with moderate to severe symptoms (≥4 episodes/yr, >2 days per episode, long recovery, ED visits, or hospitalizations), prophylaxis is recommended (Table 4) (1). Low-dose tricyclic antidepressant (TCA), especially amitriptyline, is recommended as a first-line prophylactic medication. Studies in children and adults treated with a TCA demonstrated that 70% reported complete or partial symptom improvement. If amitriptyline cannot be tolerated because of side effects, a TCA with less anticholinergic effects, e.g., desipramine, can be used. If a TCA is not effective or tolerated, topiramate may be used as an alternative. Aprepitant can be used prophylactically if patients are refractory or intolerant to TCA or topiramate (1). Antiepileptic drugs such as zonisamide or levetiracetam are third-line prophylactic therapies (1). Mitochondrial supplements are mostly studied in children, but given their low risk profile, they can be used as adjunctive prophylaxis (1,14). Beta-blockers and cyproheptadine are also studied in children but can be considered for adult use (1,15–17). Generally, treatment studies for CVS are small or uncontrolled.
Table 4.: Prophylactic treatment options for cyclic vomiting syndrome
Although the first-line treatment for CHS is sustained cessation of cannabis, some patients may not be able to adhere to this (8). If a patient has suspected CHS, the same abortive and prophylactic treatments that are used for CVS can be used (8).
SUMMARY
CVS is underrecognized and can severely impact quality of life. Management includes diagnostic testing and use of symptom-based criteria, a combination of lifestyle modifications, treatment of comorbid conditions, and timely use of abortive therapies. For moderate to severe symptoms, prophylactic treatment should be used. Although patients with CVS may use cannabis to reduce symptoms, CHS is currently considered a separate entity in which sustained cannabis discontinuation resolves CVS-like symptoms.
CONFLICTS OF INTEREST
Guarantor of the article: Lin Chang, MD.
Specific author contributions: L.L.: drafted and revised the manuscript. L.C.: reviewed and revised the manuscript. Both authors approved the final draft submitted.
Financial support: None to report.
Potential competing interests: L.L.: has nothing to disclose. Lin Chang is a member of the Rome Foundation Board of Directors and Rome IV Editorial Board and was a member of the Rome IV Functional Bowel Disorders committee. She has served on advisory boards or consultant for Ardelyx, Arena, Ironwood, Immunic, Mauna Kea Technologies, and Trellus. She has research grants with AnX Robotica, Arena, and Ironwood and stock options with ModifyHealth and Trellus.
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