Haloperidol Versus Ondansetron for Cannabis Hyperemesis Syndrome (HaVOC) (HaVOC)

Haloperidol Versus Ondansetron for Cannabis Hyperemesis Syndrome (HaVOC): A Randomized Controlled Trial

Cannabis Hyperemesis Syndrome (CHS) has become a well-documented syndrome since 2004 and is expected to increase in prevalence with continuing liberalization of marijuana and recognition of the disease. Regardless of whether the association with heavy cannabis use is recognized, there is well-documented resistance to traditional anti-emetic treatment. Given promising reports of the use of intravenous haloperidol, a randomized controlled trial comparing it to the commonly administered anti-emetic ondansetron will contribute to the management of CHS

Study Overview

• Status: Completed
• Conditions: Cannabis Use Disorder
• Intervention / Treatment: Drug: Ondansetron 8mg; Drug: Haloperidol 0.05mg/kg; Drug: Haloperidol 0.1mg/kg

Detailed Description

This is a double-blinded, randomized, cross-over clinical trial that will enroll approximately 80 subjects from at least four different research sites. Patients who have been diagnosed with CHS and enrolled in our study will act as their own controls upon their return to the ED for a subsequent bout of CHS for up to 3 visits per subject. Each patient will be allocated in a 1:1:1 fashion into one of three treatment groups: high- or low-dose haloperidol, or ondansetron, with a minimum 7-day washout period between treatments. As CHS tends to be a recurrent syndrome (presumably given the continued use of cannabis despite recommendations to taper and abstain), it is expected that most subjects will return at least once again, and a substantial subset of the study population will complete all three treatment visits during the trial.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston General Hospital
    • Kingston, Ontario, Canada, K7L 3N6
      • Queen's University
    • Kingston, Ontario, Canada, K7L 2V7
      • Hotel Dieu Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age > 18 years
2. Self-report of ≥3 episodes of emesis occurring in a cyclic pattern for greater than 1 month in the preceding 2 years
3. Current episode >2 hours of emesis
4. At least one episode of emesis/forceful retching witnessed (including products of emesis at bedside) or heard by an independent observer (healthcare provider or family/friend) in the emergency department
5. Self-reported frequent (near daily to daily x at least 6 months) use of cannabis by inhalation.
6. Working diagnosis of cannabis hyperemesis syndrome in the opinion of the treating emergency physician

Exclusion Criteria:

1. Chronic, daily use of opioid equivalent to ≥10mg morphine/day
2. Inability to comprehend study consent or instructions
3. Unreliable follow-up/unlikely to return for cross-over
4. Administration of an intravenous antiemetic, anticholinergic or antipsychotic (other than up to 100mg dimenhydrinate) in the previous 24 hours
5. Allergy or intolerance to haloperidol or ondansetron
6. Pregnancy
7. Any other medical or psychiatric condition that in the opinion of the enrolling physician would interfere with participation in the trial
8. Current active participation in an investigational drug trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ondansetron 8mg; 8mg Ondansetron prepared in a 100mL normal saline mini-bag	Drug: Ondansetron 8mg; Ondansetron 8 MG prepared in a 100 mL normal saline min-bag; Other Names: Zofran
Experimental: Haloperidol 0.05mg/kg; 0.05mg/kg of Haloperidol prepared in a 100mL normal saline mini-bag	Drug: Haloperidol 0.05mg/kg; Haloperidol 0.05 mg/kg prepared in a 100 mL normal saline min-bag; Other Names: Haldol
Experimental: Haloperidol 0.1mg/kg; 0.1mg/kg of Haloperidol prepared in a 100mL normal saline mini-bag	Drug: Haloperidol 0.1mg/kg; Haloperidol 0.1 mg/kg prepared in a 100 mL normal saline min-bag; Other Names: Haldol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain and nausea	Difference between arithmetic mean of Pain Score and Nausea Score (each on a 10-cm VAS) at 2 hours versus at baseline	2 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in pain	Changes in abdominal pain score at 1, 2, 24 and 48 hours vs. baseline	1, 2, 24 and 48 hours
Change in nausea	Changes in nausea score at 1, 2, 24 and 48 hours vs. baseline	1, 2, 24 and 48 hours
Treatment success	Treatment success = both abdominal pain and nausea score < 2 at 2, 24 and 48 hours	2, 24 and 48 hours
Oral intake	Cumulative oral intake from t=0 to 2 hours (in mL)	2 hours
Emesis volume	Cumulative emesis from t=0 to 2 hours (in mL)	2 hours
Urine output	Cumulative urine output (in mL)	2 hours
Discharge ready at 2 hours	Deemed discharge-ready at 2 hours in the opinion of the treating physician	2 hours
Rescue anti-emetics in ED	Given rescue anti-emetics prior to discharge	at discharge from Emergency Department or 12 hours whichever comes first
Time to discharge from ED	Time interval to discharge-ready from t=0 (min)	at discharge from Emergency Department or 12 hours whichever comes first
Subject preferred arm	Subject preference of high- vs low-dose haloperidol, and of haloperidol vs ondansetron (-10, 10)	2 hours
Return to ED	Unscheduled return visits to ED within 7 days (count)	7 days
ED consult	Consulted to admitting service	From time of study intervention until admitting service consulted or subject discharged from Emergency Department, whichever comes first, assessed up to 48 hours
Prolonged ED Length of stay	Outcome 10 "Time to Discharge from ED" > 12 hours (binary yes/no)	at discharge from Emergency Department or 12 hours whichever comes first

Collaborators and Investigators

• Sponsor: Dr. Marco L.A. Sivilotti
• Investigators: Principal Investigator: Marco LA Sivilotti, MD, MSc, Dept. of Emergency Medicine, Queen's University

Publications and helpful links

General Publications

• Ruberto AJ, Sivilotti MLA, Forrester S, Hall AK, Crawford FM, Day AG. Intravenous Haloperidol Versus Ondansetron for Cannabis Hyperemesis Syndrome (HaVOC): A Randomized, Controlled Trial. Ann Emerg Med. 2021 Jun;77(6):613-619. doi: 10.1016/j.annemergmed.2020.08.021. Epub 2020 Nov 5.

Study record dates

Study Major Dates

• Study Start (Actual): May 21, 2017
• Primary Completion (Actual): June 30, 2019
• Study Completion (Actual): July 7, 2019

Study Registration Dates

• First Submitted: January 23, 2017
• First Submitted That Met QC Criteria: February 14, 2017
• First Posted (Actual): February 17, 2017

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: cannabis; haloperidol; ondansetron; hyperemesis; cyclic vomiting syndrome
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Signs and Symptoms, Digestive; Pregnancy Complications; Morning Sickness; Vomiting; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Marijuana Abuse; Hyperemesis Gravidarum; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Dopamine Antagonists; Serotonin 5-HT3 Receptor Antagonists; Antipruritics; Anti-Dyskinesia Agents; Haloperidol; Haloperidol decanoate; Ondansetron
• Other Study ID Numbers: EMED-251-17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No