Acute Treatment of Adolescent Cannabinoid Hyperemesis Syndrome with Haloperidol, Lorazepam, and/or Capsaicin: A Single Institution Case Series

Abstract

Cannabinoid Hyperemesis Syndrome (CHS), an under-recognized and seemingly paradoxical condition, arises in some adolescents and adults who chronically use cannabis. It presents acutely with intractable nausea, vomiting, and abdominal pain but standard antiemetic therapy leads to improvement for only a minority of patients. Randomized controlled trial evidence in adults indicates superiority of haloperidol over ondansetron in alleviating the acute symptoms of CHS, but safe and effective treatment for adolescents with the disorder is currently unknown. The successful use of topical capsaicin has also been reported. We report a case series of six adolescent patients with CHS who presented to Johns Hopkins All Children’s Hospital and were treated with haloperidol, lorazepam, and/or capsaicin. Four patients given 5mg intravenous haloperidol and 2mg intravenous lorazepam and one patient treated with 5mg intravenous haloperidol and peri-umbilical topical capsaicin (0.025%) experienced full acute symptomatic relief. One patient, treated only with topical capsaicin, reported improvement of symptoms with some persistent nausea. Haloperidol/lorazepam, haloperidol/capsaicin and topical capsaicin alone appear safe and effective in adolescents, but larger studies are required to confirm our findings.

Introduction

Cannabinoid Hyperemesis Syndrome (CHS) is an increasingly recognized condition in some chronic users of cannabis who develop recurrent vomiting resembling Cyclical Vomiting Syndrome (CVS). Pragmatic diagnostic criteria for CHS in adolescents have previously been published(1) and are shown in Box 1. The diagnosis requires the presence of a patient-endorsed history of long-term cannabis use and cyclic nausea and vomiting, with or without supporting features. It should be made after the exclusion of all other possible causes. The only known long-term effective treatment for CHS is continued abstinence from cannabis use(2, 3).

Box 1. Pragmatic diagnostic criteria for pediatric and adolescent cannabinoid hyperemesis(1).

Major Criteria

Regular cannabis use for three months or more

Onset or worsening of episodic nausea and vomiting resembling CVS after the start of regular cannabis use

Absence of other underlying medical conditions which could explain the symptoms, after all appropriate negative investigations

Supporting Criteria

Symptomatic relief with hot showers or baths

Weight loss

Change in bowel habit

Abdominal pain

The effect of delta-9-tetrahydrocannabinol (THC) on the body is largely driven by its action on the cannabinoid receptors CB-1 and CB-2(4), but the specific pro-emetic mechanisms resulting in CHS remain unknown. Standard antiemetic therapy has failed to demonstrate a significant improvement in the acute symptoms of CHS for the majority of both adolescent and adult patients(1, 5). This has necessitated the exploration of alternative therapies for the management of these acute symptoms,(6, 7) including the use of haloperidol, which has been found effective for intractable chemotherapy-related(8) and post-operative nausea and vomiting(9). Reports of these therapies have previously been limited to short case reports on the effectiveness of a one-time dose of haloperidol, lorazepam, or topical capsaicin(10); but, a recent randomized controlled trial in 33 adult patients demonstrated the superiority of haloperidol over ondansetron(11). Of seven patients who received a higher dose of haloperidol (0.1mg/kg) in the study, three experienced extra-pyramidal (EPS) adverse events (1 moderate akathisia, 2 acute dystonia). The safety and efficacy of the acute treatment of adolescent CHS has not yet been ascertained, with only single- or two-patient case reports available to guide healthcare providers(3, 12). To the authors’ knowledge, there are no published case reports of patients under 18 years of age who received haloperidol for the acute treatment of CHS(3).

We therefore report a series of six unique patients with CHS presenting to Johns Hopkins All Children’s Hospital, St Petersburg, Florida, USA between April 1, 2020 and July 31, 2020. The efficacy of haloperidol, lorazepam, and topical capsaicin are examined as potential alternative therapies for the relief of the acute symptoms of CHS.

Methods

The study’s protocol was determined as no more than minimal risk to patients and, therefore, was judged as exempt research by the Johns Hopkins All Children’s Hospital Institutional Review Board (IRB00260351). Patients were included in the series if they had a cannabinoid hyperemesis-related ICD-10 code and presented between April 1, 2020 and July 31, 2020. Six unique patients were identified over this four-month period. Johns Hopkins All Children’s Hospital is a 257-bed tertiary academic facility with an on-site outpatient surgical day center.

Relevant data extraction from the electronic medical record was completed using institutional software, Cerner PowerChart [Cerner Corporation, Kansas City, MO, USA]. The collected information included patient demographics, presenting symptoms, diagnostic tests, substance-use history, treatment, and outcome measures. We report our findings using the EQUATOR Network’s CARE Guidelines(13).

Results

Demographics of the six patients are summarized in Table 1. The median age was 18 years (range 16–19 years) and patients were mostly female, all were non-Hispanic, and 50 percent were Caucasian/White. Cannabis use was reported by all patients, but no patient had a detailed documented substance history.

Table 1.

Demographics

Gender
Female	5
Male	1
Median Age at the Start of the Encounter (Range in Years)	18 years (16–19)
Non-Hispanic Ethnicity	6 (100%)
Race
Caucasian/White	3 (50%)
Black	2 (33%)
Not documented	1 (17%)

The symptoms reported at presentation are summarized in Table 2. All six patients had nausea, vomiting, cyclical emesis, and abdominal pain with no recognizable diurnal pattern. All had experienced at least one period of similar symptoms in the past. The quality of abdominal pain reported was not consistent between patients: it was located in the epigastric region in three of the six cases, but this, again, showed no clear inter-patient pattern. Most of the patients experienced altered bowel habits, with diarrhea reported by three of the six patients at the time of presentation. Only two patients were questioned about compulsive bathing behavior, a supporting diagnostic feature of CHS; both endorsed the use of hot showers or baths to ease symptoms. Three patients had documentation of near-daily use of an unspecified amount of cannabis, and three had no documented quantitative history of cannabis use, other than reporting long-term use. Detailed substance use histories were not available in the electronic medical record for any patient in the case series. Four of the six patients were referred for substance-abuse counseling with a social worker, three of whom attended. The remaining two patients had no documented evidence of referral or follow-up.

Table 2.

Presenting symptoms of CHS patients

Nausea	6 (100%)
Emesis	6 (100%)
Cyclical Nature	6 (100%)
Abdominal Pain	6 (100%)
Location of Abdominal Pain
Epigastric	3 (50%)
Generalized	1 (17%)
Lower quadrant(s)	2 (33%)
Description of Abdominal Pain
Sharp	2 (33%)
Crampy	2 (33%)
Not documented	2 (33%)
Bowel Habits
Diarrhea	3 (50%)
Constipation	1 (17%)
Normal	2 (33%)
Time of Day of Symptoms
Morning	1 (17%)
Throughout day	5 (83%)
Relief with Hot Showers
Yes	2 (33%)
Not documented	4 (67%)
Previous Similar Episodes	6 (100%)
Number of Previous Episodes
Median (Range)	4 (2 – 7)
Duration of Similar Episodes
1–7 days	5 (83%)
>7 days	1 (17%)

A variety of diagnostic tests were performed to rule out underlying medical conditions with symptomatic overlap. This included imaging tests with associated radiation exposure in three of the six patients. All six patients underwent comprehensive urine drug screening that confirmed the presence of THC in every case.

All patients were initially given intravenous (IV) fluids to manage dehydration and electrolyte imbalance caused by recurrent vomiting. Four patients were treated with a one-time dose of 5mg IV haloperidol and 2mg IV lorazepam. All four of these patients experienced complete resolution of acute symptoms without side effects. One patient was treated with 5mg IV haloperidol and an application of 0.025% periumbilical topical capsaicin cream. This patient also reported full symptomatic resolution. One patient was treated with only a single application of 0.025% peri-umbilical topical capsaicin and reported partial improvement with reduced but persistent nausea. This patient was also successfully treated for constipation with a polyethylene glycol electrolyte solution, but this did not lead to improvement in their nausea and vomiting.

Discussion

We report a series of six adolescent patients presenting with acute symptoms of CHS who were treated with a combination of haloperidol, lorazepam, and topical capsaicin. Patients’ symptom profiles were similar to those previously reported for CHS(1, 5). Five patients treated with haloperidol and either lorazepam or topical capsaicin reported full resolution of their symptoms following treatment. One patient who received only topical capsaicin reported significant improvement.

Previous observational studies of the treatment of acute CHS in both adults and adolescents have found limited symptomatic improvement associated with standard antiemetic therapy, including ondansetron and metoclopramide(1, 3, 5, 14). In this study, all patients reported significant improvement of symptoms. This suggests a clinically significant improvement in symptomatic relief compared to standard antiemetic treatment. However, further randomized controlled studies are needed to confirm this observed effect in adolescents. We note that all patients treated with haloperidol showed improvement. Although we cannot infer from our data if the use of haloperidol as a sole agent would be as effective, data from the HaVOC study in adults with CHS(11) suggests that this conclusion may be logical.

The pathophysiology of CHS is yet to be fully elicited(15) but the mechanism of action of haloperidol and capsaicin in the treatment of the acute symptoms of CHS is at least partially understood. Haloperidol antagonizes dopaminergic D2 receptors in the chemoreceptor trigger zone, and capsaicin activates the TRPV-1 (Transient receptor potential vanilloid-1) receptor that is co-expressed in the nucleus tractus solitarius, where the emetic influence of cannabinoids is thought to occur(15). Lorazepam has GABA-ergic ( γ-aminobutyric acid) actions which inhibit medullary and vestibular nuclei and its effectiveness in cyclical vomiting disorder suggests a therapeutic role in CHS(16).

These treatments may be useful for the control of the acute symptoms of CHS, but the only known definitive method for long-term relief is sustained cessation of cannabis; therefore, clinicians must both treat the acute symptoms of CHS and support patients to permanently cease use of cannabis through referral to specialist substance-use counseling(5, 17). Follow-up information for the patients in this case series was not available.

CHS is demonstrably associated with cannabis use disorder in patients who meet DSM-IV criteria (18); however, under-recognition of CHS in pediatric patients persists. Detailed documentation of drug use history was unavailable in all patients in this case series, presenting a challenge for determining specific patterns of cannabis use leading to the onset of CHS. Physicians must be diligent in their efforts to ascertain a detailed substance use history from their patients in order to provide a prompt, accurate diagnosis and appropriate treatment(19). We recognize that this can be challenging when many adolescent patients are reluctant to provide details to healthcare providers, particularly in the presence of family members or guardians(17, 20). Physicians must take steps to create an environment that facilitates accurate reporting (e.g., using established interviewing tools, such as the HEEADSSS assessment(21), and requesting that adults involved with the patient’s care leave the room while these questions are being asked). A complete substance use history provides the information that is necessary to avoid mistaken exclusion of CHS from a differential diagnosis list. It may also allow a patient to avoid exposure to unnecessary and ultimately negative clinical testing, including invasive tests and those involving radiation.

All three treatment combinations in this case series demonstrated efficacy in the treatment of the acute presentation of adolescent CHS. Topical capsaicin is associated with the lowest risk of serious adverse effects, but also with only partial improvement in symptoms. Lorazepam is generally safe in age-appropriate dosing but carries a risk of addiction with repeated use. Haloperidol is likely the most effective agent, but also carries the rare but serious risks of EPS symptoms and neuroleptic malignant syndrome (NMS). No patient in this case series developed EPS symptoms or NMS. Physicians must balance the risk of adverse effects against benefit on an individual patient level, while recognizing the need to support patients towards long-term cessation of cannabis use. Larger studies are needed in children and adolescents to confirm our findings and ensure that adolescents receive appropriate care for this debilitating condition.