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Haloperidol, a Novel Treatment for Cannabinoid Hyperemesis Syndrome

Witsil, Joanne C. PharmD; Mycyk, Mark B. MD

doi: 10.1097/MJT.0000000000000157
Original Articles
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Cannabinoid hyperemesis syndrome (CHS) is typically unresponsive to conventional pharmacologic antiemetics, and patients often require excessive laboratory and radiographic testing and hospital admission. We report 4 cases of CHS that failed standard emergency department therapy but improved significantly after treatment with haloperidol. Although the exact mechanism for CHS remains unclear, dysregulation at cannabinoid type 1 seems to play a role. Recent animal data demonstrate complex interactions between dopamine and cannabinoid type 1 signaling, a potential mechanism for haloperidol success in patients with CHS. Our success with haloperidol in these 4 patients warrants further investigation of haloperidol as an emergency department treatment for CHS.

Departments of 1Emergency Medicine and

2Pharmacy, Cook County Hospital (Stroger), Chicago, IL.

Address for correspondence: Departments of Emergency Medicine and Pharmacy, Cook County Hospital (Stroger), 1900 West Polk Street, 10th Floor Emergency Medicine Administration, Chicago, IL 60612. E-mail: jwitsil@cookcountyhhs.org

The authors have no conflicts of interest to declare.

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INTRODUCTION

Cannabis is the most commonly used illegal drug in the United States.1,2 Recently, cannabis has received significant public attention because of its legalization in many states for medicinal uses.3 Also, recently, cannabis use has been linked to a hyperemesis syndrome in emergency departments (EDs) in the United States and throughout the world.2–8 Cannabinoid hyperemesis syndrome (CHS), first described in 2004 in Australia, is now a well-recognized cause of cyclic vomiting without other organic cause in patients with history of chronic cannabis use.2–10 The exact pathophysiology of CHS is unclear at this time and is frustrating to health care workers, because one of the medical reasons for legalizing cannabis is to use it as an antiemetic for some chronic medical problems.11

It has been reported that patients with CHS obtain symptomatic relief only from hot showers or hot baths, which results in an unusual pattern of compulsive bathing that can last for days.1,7,12–14 Many of these patients eventually end up in the hospital seeking relief. Unfortunately, most patients who seek ED treatment for CHS are hospitalized, as no other standard treatment has been shown to improve symptoms, decrease hospital admissions, or time in the hospital.6,9 Although most patients with CHS are young and otherwise healthy, CHS typically results in multiple ED visits and excessive resource utilization.2,6,13,14

Haloperidol is a drug that is well known to the emergency practitioner.15 Traditionally, its use in the ED is limited to treat agitation in patients with known psychosis or other behavioral problems. However, haloperidol has been used successfully in the past as an antiemetic in general surgery and by oncologists.16,17 Recent national drug shortages have limited the pharmacologic antiemetic options for patients in our ED, so haloperidol's pharmacologic success as an antiemetic in those other settings prompted our ED to include it as an alternative antiemetic.

Therefore, we sought to determine whether patients with CHS treated in the ED benefit from the use of haloperidol for their cyclical vomiting.

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METHODS

This study was a retrospective chart review that was conducted in large urban-based academic ED with annual visits greater than 130,000. The data were collected over a 3-month period (January 12, 2012, to January 03, 2013). All of the patient data, including the demographics and clinical data included in an electronic medical record, were abstracted into a de-identified study database. This retrospective study received approval from our institutional IRB.

Eligible subjects were identified by the documented chief complaint or the ED final diagnosis in the electronic medical record. Patients were included in this study only if they admitted to chronic long-term cannabis use, admitted compulsive bathing habits, had cyclical vomiting that failed other outpatient antiemetics, had multiple ED visits that failed to identify another cause, and had received haloperidol as treatment in our ED. Many previous authors have concluded that self-report of compulsive bathing is virtually diagnostic of CHS.12–14

Definitions and outcomes were determined a priori, and data abstraction was conducted according to the guidelines of Gilbert et al.18 One author abstracted all patient-reported and ED-documented data from an electronic hospital record into a de-identified study database, including age, gender, medical history, previous hospital evaluations, past medication use, social history, clinical examination and diagnostic results, ED medications given, and ED length of stay, and final disposition. A second author reviewed the clinical charts and the database to assess reliability of the data abstraction. A third independent clinician, not an author of this study, was retained to resolve any discrepancies. Only descriptive analysis was performed on the study data.

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RESULTS

There were a total of 4 cases that met inclusion criteria for this study. A brief description of each case follows and are presented in Table 1.

Table 1

Table 1

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Case 1

A 34-year-old man with previously diagnosed recurrent CHS arrived to the ED with vomiting for 4 days. He was previously admitted to our hospital 7 times and had multiple unremarkable diagnostic tests and several specialty consults. Other than habitual cannabis use, the patient had no other psychiatric disorder. According to the patient, only hot showers and abstinence helped his symptoms. In the past, pharmacological treatment included promethazine and ondansetron (OND), which were not successful. Initial ED treatment during this visit included OND 4 mg IV and IV fluids (IVF), but they did not improve his vomiting. He was then given haloperidol 5 mg IV, and within 1 hour, his symptoms resolved and was discharged home from the ED.

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Case 2

A 28-year-old man also with recurrent CHS and multiple ED visits and nondiagnostic workups came to the ED requesting admission to the hospital. This patient also had no other history of psychiatric disorder. The patient insisted no medical treatment ever improved his symptoms, including OND, metoclopramide (MET), or chlorpromazine. His initial ED treatment included haloperidol 5 mg IV, diphenhydramine 25 mg IV, and IVF. Within 1 hour, he improved, had no further episodes of vomiting, and was discharged from our ED 6 hours later.

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Case 3

A 48-year-old man presented to the ED with vomiting for 2 days. He had multiple unremarkable workups over the past year for cyclical vomiting in several other hospitals, but no one confirmed the diagnosis of CHS despite his admitted chronic cannabis use. He had no other psychiatric history. He also reported no medications ever helped him, included MET, promethazine, OND, and chlorpromazine. Initial ED treatment with OND 4 mg IV and IVF was unsuccessful. He was then given haloperidol 5 mg IV; within 1 hour, his vomiting resolved and was discharged home within 8 hours.

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Case 4

A 22-year-old man with recurrent CHS diagnosed 2 years ago arrived for treatment of cyclical vomiting and requesting admission because, according to him, MET and OND would not work. He had no psychiatric disorder. Initial ED treatment with OND 4 mg IV and IVF were unsuccessful. He was then given haloperidol 5 mg IV; within 2 hours, his vomiting resolved, and he was discharged home 6 hours later.

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DISCUSSION

Haloperidol was successful in treating our 4 patients with CHS. All of our cases obtained significant symptomatic relief and were discharged within 8 hours of receiving haloperidol. This was a significant response, since several of the subjects arrived to the ED thinking all ED antiemetic strategies would not work and that early hospital admission was warranted. None of these 4 patients needed a repeat dose of haloperidol.

Unfortunately, the mechanism by which chronic use of cannabinoids produces hyperemesis remains uncertain.6 It is believed that cannabinoids produce their effects by action on central cannabinoid type 1 (CB1) receptors and peripheral CB2 receptors.11 The CB1 receptors are responsible for the drug effects on memory, cognition, nausea, vomiting, and motor activities and thus are more likely to have a role in CHS. Activation of presynaptic CB1 receptors inhibits release of acetylcholine, γ-hydroxybutyric acid, norepinephrine, dopamine, L-glutamate, and 5-hydroxytryptamine. It is believed that chronic stimulation of these receptors may produce the paradoxical emetic response in certain individuals.11 CB2 receptors act primarily in immune tissue and are thought to be less likely to be responsible for hyperemesis in chronic users.1,11

Haloperidol is a well-known ED drug that is primarily used in the ED setting for sedation, behavioral agitation, and as an antipsychotic. However, haloperidol has a long history of use as an antiemetic, particularly in the anesthesia, general surgery, and oncology literature where it has been promoted as beneficial in postoperative nausea and vomiting.16,17 Haloperidol is a high-affinity antagonist at D2 DA receptors in the central nervous system. The drug's antipsychotic effects are thought to be derived from antagonism at D2 receptors in the mesolimbic and mesocortical pathways. There are also high concentrations of D2 receptors in the chemoreceptor trigger zone, which likely accounts for the drug's antiemetic properties.19 Furthermore, animal studies have suggested that complex interactions between dopamine and CB1 signaling mechanisms may exist.20,21 This may explain the use of haloperidol as an antiemetic for CHS.

Limitations of this retrospective case series need to be acknowledged. First, some patients eligible for inclusion in this study might have been missed during that study period because of how medical charts are coded. In addition to chief complaint and final diagnosis chart review, one of the study authors reviewed ED logs and inquired among caregivers daily to find all eligible cases, and a future study will include a more robust mechanism for identifying all consecutive patients. Second, because this was a retrospective study, the medications (including dose and route) given to patients before haloperidol was not controlled or blinded, and a future study will include a stepwise approach to treating these patients. However, it is important to note that all patients improved significantly only after haloperidol was administered. Third, substance abuse is often linked to psychiatric illness, and haloperidol's beneficial response in these cases could have resulted from that benefit. None of these 4 patients had a diagnosis of any psychiatric illness; some of them had previous formal psychiatric evaluation, but a future study should include formal comprehensive psychiatric evaluation to determine whether haloperidol truly has a pharmacologic benefit at the D2/CB1 receptors or if some of haloperidol's benefits are from treatment of underlying psychiatric illness.

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CONCLUSIONS

Haloperidol seems to be a promising treatment strategy for patients with CHS. Although this pilot study includes a small number of patients, all were successfully treated and then discharged after all other treatments failed. Ultimately, stopping use of cannabinoids is the only way to prevent recurrence, but efficient hospital-based symptom management with haloperidol could help to decrease time in the ED, costs, hospital admissions, and unnecessary testing. Further investigation of haloperidol as a treatment for CHS is warranted based on successful management of symptoms in our patients.

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ACKNOWLEDGMENTS

The authors are grateful to Jami Hickey, MD for her assistance with case identification and data collection for this project. The authors extend their heartfelt thanks to all members of the Cook County Hospital ED staff for cooperation on this study.

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Keywords:

cannabinoid hyperemesis syndrome; haloperidol; cyclical vomiting; emergency department; drug abuse

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