Guidelines on management of cyclic vomiting syndrome in adults by the American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association

The increasing recognition of cyclic vomiting syndrome (CVS) in adults prompted the developmentoftheseevidence-basedguidelinesonthemanagementofCVSinadults, whichwassponsoredbytheAmericanNeurogastroenterologyandMotilitySociety (ANMS) and the Cyclic Vomiting Syndrome Association (CVSA). GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework was usedandaprofessionallibrarianperformedtheliteraturesearch.Theexpertcom-mitteeincludedthePresidentoftheCVSAwhobroughtapatientperspectiveinto the deliberations. The committee makes recommendations for the prophylaxis of CVS, treatment of acute attacks, diagnosis, and overall management of CVS. The committeestronglyrecommendsthatadultswithmoderate-to-severeCVSreceive a tricyclic antidepressant (TCA), such as amitriptyline, as a first-line prophylactic medication and receive topiramate or aprepitant as alternate prophylactic medications.Zonisamideorlevetiracetamandmitochondrialsupplements(CoenzymeQ10, L-carnitine,andriboflavin)areconditionallyrecommendedasalternateprophylactic medications,eitheraloneorconcurrentlywithotherprophylacticmedications.For acuteattacks,thecommitteeconditionallyrecommendsusingserotoninantagonists, such as ondansetron, and/or triptans, such as sumatriptan or aprepitant to abort symptoms. Emergency department treatment is best achieved with the use of an individualizedtreatmentprotocolandsharedwiththecareteam(exampleprovided).The committee recommended screening and treatment for comorbid conditions such asanxiety,depression,migraineheadache,autonomicdysfunction,sleepdisorders, and substance use with referral to appropriate allied health services as indicated.Techniqueslikemeditation,relaxation,andbiofeedbackmaybeofferedascomplementarytherapytoimproveoverallwell-beingandpatientcareoutcomes.K E Y W O R D Sabortivetreatment,cyclicvomiting,emergencydepartment,management,prophylaxis

## | introduc ti on
Cyclic vomiting syndrome (CVS) is a chronic functional gastrointestinal disorder that is being increasingly recognized in adults. [bib_ref] Cyclicvomitingsyndromein adults, Abelltl [/bib_ref] It is characterized by episodic nausea and vomiting and is associated with significant morbidity. Approximately one-third of adult patients become disabled. [bib_ref] Cyclicvomitingsyndrome(CVS): isthereadifferencebasedononsetofsymptoms-pediatricversus adult?, Kumarn [/bib_ref] There is considerable variation in recogni- The committee members, who were selected jointly by the CVSA and a council member of the ANMS clinical guidelines committee, included primarily gastroenterologists with clinical and research expertise, providers from other disciplines, such as psychology and neurology, methodologists with experience in evidence appraisal andguidelinedevelopment,andonepatientrepresentative,whowas alsoPresidentoftheCVSA.Thepanelchairwasagastroenterologist.

## Conflicts of interest of all participants were managed according to
ANMSpolicies.Atthetimeofappointment,amajorityoftheguidelinepanel,includingthechairandthevice-chair,hadnoconflictsof interest as defined and judged by ANMS policies. This manuscript was prepared by committee members and a patient advocate who served as part of the committee in order to incorporate patient valuesandpreferenceswhiledevelopingrecommendations,asperthe GRADE methodology. [bib_ref] TheAGAinstituteprocessfor developing clinical practice guidelines part one: grading the evidence, Sultans [/bib_ref] A librarian conducted the literature search and two GRADE experts reviewed and graded the literature. The reader is referred to the accompanying technical review for a more detailed understanding of the process and additional details about individualstudies.Thecommittee hadfourin-personmeetings and multiple conference calls during this process. Committee members except for the two GRADE experts voted on all recommendations and either "agreed" or "disagreed" and votes were tallied.
Recommendations for the diagnosis of CVS, suggested investigations,treatmentprotocolfortheemergencydepartment(ED),and algorithm for management are also provided. These recommendations are based on best practices and consensus of the committee members.
These were formulated based on review of the available literature and thecollectiveexperienceofthecommitteememberswhohavetaken care of more than 3000 patients with CVS in their practices.
With increasing attention paid to use of cannabis in CVS, Cannabinoid Hyperemesis Syndrome (CHS) has been proposed as a distinctentitybytheRomeFoundation. 7-10 CHS,theroleofcannabisinhyperemesis,andtheoverlapbetweenCHSandCVSaredescribed in a separate manuscript included with these CVS guidelines.

## | tre atment of c ycli c vomiting syndrome
TreatmentofCVSshouldbebasedonabiopsychosocialcaremodel, integrating lifestyle modification, prophylactic and/or abortive medications, and evidenced-based psychotherapy to address psychiatric comorbidity. Ongoing care by a dedicated team will likely improve overall healthcare outcomes. Given the lack of validated outcomes to assess the severity of CVS, the committee arbitrar-

## | prophyl ac ti c med i c ati on s in c vs
3.1 | Recommendation 1. We strongly recommend that adults with moderate-to-severe CVS receive tricyclic antidepressants (TCAs), especially amitriptyline, as a first-line prophylactic medication Themeaneffectivedoseinadultsis75-100mgdailyor1-1.5mg/ kg body weight. [bib_ref] Cyclicvomitingsyndrome(CVS): isthereadifferencebasedononsetofsymptoms-pediatricversus adult?, Kumarn [/bib_ref] [bib_ref] Efficacyoftricyclicantidepressanttherapyinadults with cyclic vomiting syndrome: a two-year follow-up study, Hejazi [/bib_ref] [bib_ref] NorthAmericanSocietyfor Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement on the diagnosis and..., Libu [/bib_ref] Amitriptyline is best titrated in 10-25 mg increments as this improves tolerability by allowing adaptation to and preventingdiscontinuationfromsideeffects,particularlydaytimesedation. This improves the ultimate efficacy of the medication. Most of the panelists used 10 mg but some used 25 mg. As always, this needs to be individualized based upon the patient response. The in-cidenceofsideeffectswithATvariesfrom9%to25%althoughthis did not result in discontinuation of the drug in most studies. [bib_ref] Treatmentof cyclicvomitingsyndromewithco-enzymeQ10andamitriptyline,a retrospective study, Bolesrg [/bib_ref] Westronglyrecommendthatadultswithmoderate-to-severeCVSreceivetricyclicantidepressants(TCAs)suchasamitriptyline,asa first-lineprophylacticmedication(verylow-qualityevidence)

## 2.
Weconditionallyrecommendthatadultswithmoderate-to-severeCVSreceivetopiramateasanalternateprophylacticmedication (verylow-qualityevidence)

## 3.
Weconditionallyrecommendthatadultswithmoderate-to-severeCVSreceiveaprepitantasanalternateprophylacticmedication (verylow-qualityevidence)

## 4.
Weconditionallyrecommendthatadultswithmoderate-to-severeCVSreceivezonisamideorlevetiracetamasanalternateprophylacticmedication(verylow-qualityevidence)

## 5.
WeconditionallyrecommendusingCo-Q10,andriboflavinasprophylactictherapyinthetreatmentofCVS.Mitochondrialsupplementsmaybeusedconcurrentlyinadditiontootherprophylacticagents(verylow-qualityevidence)

## 6.
WeconditionallyrecommendusingtriptanslikesumatriptantoabortsymptomsofaCVSepisode.(moderate-qualityevidence)

## 7.
We conditionally recommend using serotonin antagonists such as ondansetron to abort symptoms of a CVS episode (consensus statement)

## 8.
WeconditionallyrecommendaprepitanttoabortsymptomsofaCVSepisode(verylow-qualityevidence)

## 9.
Wesuggestscreeningandtreatmentforcomorbidconditionssuchasanxiety,depression,migraineheadache,sleepdisorders,autonomicdysfunction,andsubstanceuse.Wesuggestreferraltoappropriatealliedhealthservices(psychologist,psychiatrist,neurologist,sleep,orsubstanceusespecialist)asindicated(consensusstatement)

## 10.
Wesuggestthattechniquessuchasmeditation,relaxationandbiofeedbackbeofferedascomplementarytherapyinCVS.These measuresaregenerallydevoidofsideeffectsandmayimproveoverallwell-beingandpatientcareoutcomes(consensusstatement)
Recommendationsarelabeledaseither"strong"or"conditional"accordingtotheGRADEapproach.Cliniciansmayinterpret"strong"recommendations to mean that most individuals should receive the intervention. Clinicians may interpret "conditional" recommendations to mean that different choiceswillbeappropriateforindividualpatients,andcliniciansmusthelpeachpatientarriveatamanagementdecisionconsistentwiththepatient's valuesandpreferences.ConsensusstatementswerenotbasedontheGRADEapproachandwererecommendationsmadebythecommitteebased onindirectevidenceand/ortheircollectiveexperienceinmanagingadultandpediatricCVSpatients. episodes,andonly6%didnotrespond. [bib_ref] Anewapproachtotheprophylaxisofcyclicvomiting: topiramate, Sezerob [/bib_ref] In a retrospective study of18adultstreatedwithprophylactictopiramate,72%had50% reduction in frequency/severity of CVS episodes. Some patients on topiramate were also receiving AT and mitochondrial supplements in this study. [bib_ref] Cyclicvomitingsyndrome(CVS): isthereadifferencebasedononsetofsymptoms-pediatricversus adult?, Kumarn [/bib_ref] We recommend starting topiramate at 25 mg daily and titrating

## | recommendation 3. we conditionally recommend that adults with moderate-tosevere cvs receive aprepitant as an alternate prophylactic medication

## | recommendation 4. we conditionally recommend that adults with moderate-to-severe cvs receive zonisamide or levetiracetam as an alternate prophylactic medication
Grade: Conditional recommendation, very low-quality evidence. Vote:

## 100% agreement
Zonisamide is an oral sulfonamide anti-epileptic (AED) with direct influence on sodium and calcium channel function as well as modulation of GABAergic receptors. [bib_ref] Clinicalpharmacologyandmechanismofactionofzonisamide, Bitonv [/bib_ref] In one non-placebo-controlled study of 11 children with CVS, the efficacy of sumatriptan treatment was high in those with a family history of migraine compared to cases without a family history of migraine. [bib_ref] Sumatriptan as a treatment for cyclic vomiting syndrome: a clinical trial, Hikita [/bib_ref] However,thosewithoutafamilyhistoryofmigrainestill responded to sumatriptan in 50% of their attacks. In this study, sumatriptan was administered by SC injection in nine and via nasal route inthreepatients.Althoughthenumberofpatientswassmall,theadministration of sumatriptan reduced vomiting in nine patients (82%) and the nasal route seemed less effective. Three other case reports describe the efficacy of injectable sumatriptan in aborting episodes of CVS. [bib_ref] Injectable sumatriptan for cyclic vomiting syndrome in adults: a case series, Calhoun [/bib_ref] The committee believes that sumatriptan is effective in the acutetreatmentofCVSalthoughrandomizedplacebo-controlledstud-iesinvestigatingtheefficacyofsumatriptaninCVSattacksarelacking.
We recommend administration of triptans during the prodrome

## | recommendation 7. we conditionally recommend using serotonin antagonists such as ondansetron to abort symptoms of a cvs episode
Vote: 100% agreement

## | recommendation 8. we conditionally recommend aprepitant to abort symptoms of a cvs episode
Grade: Conditional recommendation, very low-quality evidence. Vote:

## >80% agreement
There is a single open-label trial of oral aprepitant used as abortive treatment of CVS in children and adolescents who were refractory to conventional treatment. [bib_ref] Efficacy of the neurokinin-1receptorantagonistaprepitantinchildrenwithcyclicalvomit-ing syndrome, Cristofori [/bib_ref] All children >20 kg were given the standard regimen used in chemotherapy-induced nauseaand vomiting (CINV)of125mginitially during theprodrome, Widespread drug usage has been found in CVS with 39%-81% usingcannabis,19%alcohol,36%tobacco,and17%reliantonnarcotics for pain management. [bib_ref] Cyclic vomiting syndrome and functional vomiting in adults: association with cannabinoid use..., Choung [/bib_ref] [bib_ref] AnInternetsurveyofmarijuana and hot shower use in adults with cyclic vomiting syndrome (CVS), Venkatesant [/bib_ref] Although none of these studies containedaspecificcomparisongroup,mostofthesefiguresappear tobehigherthanthosefoundinthegeneralpopulation.Co-occurring substance use or abuse can interact with medications for the managementofCVSandcomplicatetreatment,andthus,standard screening for such disorders and appropriate treatment is indicated.

## | tre atment of comorb id conditions

## | recommendation 9. we suggest screening
The role of cannabis in CVS and CHS is discussed in detail in a separate paper in this supplement.

## | recommendation 10. we suggest that techniques such as meditation, relaxation and biofeedback be offered as complementary therapy in cvs. these measures are generally devoid of side effects and may improve overall well-being and patient care outcomes

## Vote: 100% agreement
Cyclic vomiting syndrome is a functional GI disorder that is thought to be due to altered brain-gut interaction. [bib_ref] Cyclicvomitingsyndrome:abrain-gutdisorder, Libu [/bib_ref] The recommendations provided are summarized in and aredrawnfromasystematicGRADEevaluationoftheliterature(1-6 and 8) and expert committee consensus . We provide theserecommendationswithanappreciationofthelimited,andlowquality evidence provided from the literature aiming to bridge the gapbetweenwhatweknowandhowwecanbesthelppatientsat the present time.

## | consensus statement on diagnosis and management of cvs
The following section addresses the diagnosis, appropriate inves-

## | diagnosis
Cyclic vomiting syndrome has typical clinical features, and the hallmarkofCVSisthepresenceofintermittentepisodesofsevere nausea and vomiting interspersed with symptom-free intervals.
However,patientsmayexperienceinter-episodicnauseaordyspepsia and may not be completely asymptomatic in between typical episodes. This feature of adult CVS was recognized for the first time in theupdatedRomeIVcriteriaforCVS(Table2).Atthepresenttime, theexpertcommitteeendorsestheRomeIVdiagnosticcriteriafor CVS but also acknowledges that the sensitivity and specificity of these criteria have not been subjected to rigorous study. The use of chronic cannabis in CVS has led to a putative new diagnosis of CHS and is discussed in a separate article in this special supplement.
TherearefourphasesofCVS:prodromalphase,vomitingphase, recovery,andasymptomaticorinter-episodicphase. [bib_ref] Cyclic VomitingSyndromein41adults:theillness,thepatients,andproblems of management, Fleisher [/bib_ref] During the prodrome,patientshaveintensenausea,somewithsymptomsofpanic.
Autonomic symptoms such as diarrhea, cold and hot flashes, and profuse sweating may also be present. This is followed by the acute emetic phase where patients will have severe vomiting and retching.
Thevomitingcanoftenberelentlessvaryingfrom1to6times/hour, and the retching often persists even after the stomach has been com- proposed data collection sheet for use in clinic to capture the salient features while entertaining a diagnosis of CVS is shown in . ful history focusing on symptoms at the onset of the disorder is important to make an accurate diagnosis, as most patients endorse a discernable cyclic pattern that was part of the initial presentation.

## | investigations
The Rome IV criteria for the diagnosis of CVS require that there is "noorganicpathology"toexplainthesymptoms.Hence,itisreason- Personal or family history of migraine headaches Criteria must be fulfilled for the last 6 months with symptom onset at least 3 months before diagnosis
Ongoing care with a team to provide support is crucial to achieve good outcomes.

## | treatment of cvs in the emergency department
The present review evaluates the evidence for effectiveness of different drugs used in the acute care setting. The review demonstrates the paucity of Grade I evidence for the effectiveness of any one drug. It is possible that some of these drugs are more effective when used sequentially or in combination. [bib_ref] Cyclicvomitingsyndromein adults, Abelltl [/bib_ref] [bib_ref] Cyclic VomitingSyndromein41adults:theillness,thepatients,andproblems of management, Fleisher [/bib_ref] [bib_ref] Review article: cyclic vomiting syndromeinadults-rediscoveringandredefininganoldentity, Hejazi [/bib_ref] 

## | con clus ions
Cyclic vomiting syndrome is a condition that challenges both patients and healthcare providers alike due to the considerable morbidity and misery associated with it and the lack of a clear understand- Allauthorscriticallyreviewedthemanuscript.

## R e fe r e n c e s