When Cyclic Vomiting Has You Spinning Your Wheels

Cyclic vomiting and cannabinoid hyperemesis syndromes repeatedly bring patients through the doors of the ED. Here’s your clinical refresher. 

The symptoms patients experience during an acute cyclic vomiting syndrome (CVS) or cannabinoid hyperemesis syndrome (CHS) episode can be difficult to manage, as the nausea is often resistant to typical anti-emetics like ondansetron and promethazine. There has been much discussion and sharing of glowing anecdotes about the use of dopamine-antagonists such as haloperidol for CVS and CHS. This led us to investigate the evidence for their use, and whether there are any other hidden gems in the literature that can help us care for patients who present with these syndromes. What we found is that, unfortunately, the level of evidence is poor, but there is support in the literature for use of haloperidol in both syndromes. Sumatriptan may also be a useful abortive therapy for CVS flares, particularly when given early after symptom onset. The medications suggested by the literature that does exist are outlined below.

Presentation and Pathophysiology
CVS and the rarer CHS are clinically very similar. The criteria for CVS diagnosis include:

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1. Episodes of nausea and vomiting lasting less than a week.
2. Periods of good health essentially symptom-free in between the flares.
3. Three or more episodes in a year and at least two episodes in the last 6 months, more than a week apart.

Definitive diagnosis cannot be made until other organic causes have been ruled out, and at least six months after symptom onset [^1,2]. Symptoms from both CVS and CHS are relieved by hot showers in 60% of patients, so this cannot necessarily be used to differentiate them [3]. The important difference is that CVS is idiopathic, while CHS is triggered by regular heavy cannabis use and is completely relieved by cessation of cannabis exposure, typically returning after repeat exposure [^3,4].

CVS has significant overlap in symptoms, and likely pathophysiology, with migraine headaches. Symptoms in CVS include vomiting in 100% of cases, abdominal pain in 3-81%, and headaches in 38-59%. Other symptoms may include fatigue, anorexia, and photophobia. Episodes of vomiting can be triggered by infection, psychosocial stress, diet, and menstruation [1].

The exact biochemical mechanisms involved in the syndromes are not clear and are likely multifactorial. CVS is one of the episodic syndromes that can be associated with migraines, along with the abdominal migraine syndrome. A family history of migraines is present in the majority of patients with CVS. CVS likely has a complex neuronal and neurotransmitter underpinning, but has also been postulated to involve the gut microbiome, autonomic reactivity, gastric motility, mitochondrial disorders, and the HPA axis, which means it could be all of the above, and the greatest contributing factors may vary by patient [^1,5].

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Epidemiology
CVS has an incidence of 3.5/100,0005 and typically manifests first in childhood. The prevalence among school-aged children may be as high as 2%, with average symptom onset at around five-years-old [^5,1]. It is a diagnosis of exclusion, and at each healthcare encounter, other possible organic causes such as bowel obstruction, appendicitis, cholecystitis, gastroenteritis, and other potential pathologies should be considered before symptoms are attributed to CVS.

CVS Treatment
Unfortunately, there have not been any RCTs comparing treatments for acute management of CVS. However, there is evidence from case series and expert consensus that a number of non-opioid-based treatment that can be effective.

Treatment is divided into preventative, abortive, and supportive.

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1. Preventative treatment in adults and patients over five-years-old may include tricyclic antidepressants, such as amitriptyline. Other agents such as beta-blockers and anticonvulsants such as phenobarbital, as well as dietary supplements with L-carnitine and Coenzyme Q 10 have also been used with some effect [6].
2. Abortive treatment may be achievable by treating during the early prodrome of the flare for children 12 years and older and adults with sumatriptan and ondansetron.
3. Supportive treatment should focus on IV fluids, anti-emetics, such as ondansetron, metoclopramide, or promethazine, sedatives such as diphenhydramine or lorazepam, antipsychotics like haloperidol, which also have antiemetic effects, and analgesics such as ketorolac. A proton pump inhibitor or H2-blocker may also help relieve GI symptoms [^1,5,7].

Treatment Dosing
For adults presenting with acute CVS symptoms in which other organic causes are ruled out, a range of supportive and abortive treatments can be used. The recommendations are based primarily on case series and expert opinion with no RCTs to date. The treatment options can include items from each category in the table below.

If the patient is on other QT-prolonging agents or if you are combining anti-psychotics along with the anti-emetics, both of which can cause QT prolongation, it is prudent to obtain an EKG first. Once patients have tried some of the above medications, they may learn what works best for them other than the oft-requested hydromorphone and promethazine.

CHS has a simple cure: Avoidance of cannabis. For the acute management of CHS symptoms, the treatment can be very similar to the above management of CVS with the exception of sumatriptan, which is not routinely recommended. The nausea and vomiting may respond well to IV fluids, anti-emetics, benzodiazepines, and anti-psychotics such as haloperidol. The other, rather unusual, medication that can be used in CHS is capsaicin cream applied to the chest or abdomen, which has some evidence for symptomatic improvement [^4,8,9].

Prevention
If patients are having frequent attacks of CVS, then preventative therapy with amitryptiline could be considered. The starting dose is 25-50mg PO (0.25-0.5mg/kg/day in children) QHS. However, the dose will need to be titrated up, so the patient will require follow-up with an outpatient physician. In addition, patients can be trialed on L-carnitine (50-100mg/kg/day divided TID to max 1g TID) and CoezymeQ10 (10mg/kg/day divided TID to max 100mg TID), both of which may reduce the frequency and severity of symptoms, though data is not high quality [6]. In addition, these supplements are not FDA-regulated, so the quality and efficacy of commercially available products may vary. You can also instruct patients to keep a symptom diary to try to figure out triggers such as sleep deprivation, dehydration, or stress, which could help them avoid flares in the future.

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REFERENCES

1. Desilets D. Cyclic vomiting syndrome – UpToDate. https://www.uptodate.com/contents/cyclic-vomiting-syndrome?source=search_result&search=cyclic vomiting syndrome&selectedTitle=1~20. Published 2017. Accessed July 11, 2017.
2. Bhandari S, Venkatesan T. Clinical Characteristics, Comorbidities and Hospital Outcomes in Hospitalizations with Cyclic Vomiting Syndrome: A Nationwide Analysis. Dig Dis Sci. January 2017. doi:10.1007/s10620-016-4432-7.
3. Blumentrath CG, Dohrmann B, Ewald N. Cannabinoid hyperemesis and the cyclic vomiting syndrome in adults: recognition, diagnosis, acute and long-term treatment. Ger Med Sci. 2017;15:Doc06. doi:10.3205/000247.
4. Sorensen CJ, DeSanto K, Borgelt L, Phillips KT, Monte AA. Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment—a Systematic Review. J Med Toxicol. 2017;13(1):71-87. doi:10.1007/s13181-016-0595-z.
5. Irwin S, Barmherzig R, Gelfand A. Recurrent Gastrointestinal Disturbance: Abdominal Migraine and Cyclic Vomiting Syndrome. Curr Neurol Neurosci Rep. 2017;17(3):21. doi:10.1007/s11910-017-0731-4.
6. Bhandari S, Venkatesan T. Novel Treatments for Cyclic Vomiting Syndrome: Beyond Ondansetron and Amitriptyline. Curr Treat Options Gastroenterol. 2016;14(4):495-506. doi:10.1007/s11938-016-0114-y.
7. Hermus IPM, Willems SJB, Bogman ACCF, Janssen PKC, Brabers L, Schieveld JNM. Cyclic Vomiting Syndrome: An Update Illustrated by a Case Report. Prim care companion CNS Disord. 2016;18(3). doi:10.4088/PCC.15br01912.
8. Richards JR, Gordon BK, Danielson AR, Moulin AK. Pharmacologic Treatment of Cannabinoid Hyperemesis Syndrome: A Systematic Review. Pharmacother J Hum Pharmacol Drug Ther. 2017;37(6):725-734. doi:10.1002/phar.1931.
9. Dezieck L, Hafez Z, Conicella A, et al. Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series. Clin Toxicol. May 2017:1-6. doi:10.1080/15563650.2017.1324166.