Cannabinoid Hyperemesis Syndrome: Are Antipsychotics the Answer?

CASE

25-year-old female presenting with worsening abdominal pain over the past one year. She describes it as a sharp, episodic and non-radiating 10/10 diffuse pain. It is associated with constant nausea and vomiting and relieved by frequent hot showers/tub baths. She has had minimal relief from daily Zofran.

PMH: Chronic, daily marijuana abuse for past 10+ years, currently in a recovery home for past week.

ROS: patient denies any fever, chills, diarrhea, constipation sob, cp, dysuria, vaginal discharge.

Physical exam: Remarkable for diffuse tenderness to palpation of abdomen.

Assessment and Plan: Given her history of chronic marijuana usage predating her clinical symptoms, cyclical nature of symptoms, and pathognomonic relief from frequent hot showers/baths, we suspect this patient has cannabinoid hyperemesis syndrome.

ED Course: She first received Zofran and Tylenol, which had no relief in symptoms. An EKG was done that showed a QTc within normal limits (Fig. 1). We then gave her Haloperidol with resolution of her symptoms within three hours.

Figure1: This was the patient's EKG, without any QTc prolongation. (Medications, such as Haloperidol and Ondansetron, can cause prolongation of the QT interval)

CHS can be differentiated from cyclical vomiting by the association of compulsive hot baths/showers, which typically provides relief for patients (1). The prevalence of cannabinoid hyperemesis syndrome and cyclical vomiting syndrome have been increasing, likely as a result of decriminalization and legalization of marijuana across the nation (2, 3). A recent study published in JAMA showed that monthly rates of ED visits related to CHS increased 13-fold (0.26 per 100,000 visits to 3.43 per 100,000), correlated with commercialization during COVID-19. (4) Typically, work up may be extensive and results are largely inconclusive, often resulting in hospitalizations and/or frequent visits to the ED.

Clinical Question: Are antipsychotics, superior to ondansetron in the acute management of suspected cannabinoid hyperemesis syndrome? What other treatments have been effective in the literature?

SUMMARY OF EVIDENCE

Antipsychotics: Haldol/Droperidol

In a retrospective review of electronic medical records from patients presenting with CHS to an Emergency Department, 76 patients who met cannabinoid hyperemesis syndrome criteria were studied. Among those who were treated with Droperidol 5mg IV (n=37), the median length of stay (6.7 vs. 13.9 hours, p = .014) was significantly lower than that of those not treated with droperidol. The frequency of administration of onandestron and metoclopramide was double in the group who received Droperidol in comparison to the group of patients who did not receive Droperidol. (5)

In a randomized, triple-blinded trial at 2 academic Emergency Departments in Canada, 30 patients were randomized to a low dose Haloperidol (0.05 mg/kg), higher dose Haloperidol (0.1 mg/kg), or Ondansetron 8 mg group. Nausea and abdominal pain were rated on the 10 cm VAS scale. Either dose of haloperidol was statistically more effective than ondansetron at improving nausea and abdominal pain at 120 minutes after administration (mean difference was 2.3 cm [95% confidence interval 0.6 to 4.0 cm]; P=.01). (6)

Capsaicin cream (7)

In a double-blind randomized placebo-controlled pilot trial, 30 patients (17 in Capsaicin arm and 13 in placebo arm) were studied. Topical 0.1% capsaicin or placebo cream was applied to the abdomen of participants. Utilizing the VAS (0-10cm scale), the severity of nausea at 30 minutes was 4.1 ± 2.3 cm in the capsaicin arm and 6.1 ± 3.3 cm in the placebo arm (difference = −2.0 cm, 95% confidence interval [CI] = 0.2 to −4.2 cm). The percent reduction in nausea at 60 minutes from baseline was 46.0% in the capsaicin arm and 24.9% in the placebo arm (difference = 21.1%, 95% CI = −5.6% to 47.9%).

Cessation of cannabis

Ultimately, cessation of cannabis appears to the be most effective treatment. In a systematic review of eight studies and 38 individual case reports, cumulative synthesis showed that 62 out of 64 (96.8%) patients had complete resolution of symptoms after cessation of cannabis use. Among 21 patients who did not stop smoking, all of them had ongoing symptoms. (8) Most patients have full resolution of symptoms anywhere from 7-10 days of abstinence (9).

RECOMMENDATIONS

Our recommendations are based on limited data, including small-sample trials and retrospective reviews.... Below is our guideline for “trial-and-error” symptomatic treatment for pain and nausea/vomiting associated with CHS in the acute setting.

1. In the setting of suspected cannabinoid hyperemesis syndrome, the team should consider therapeutic interventions include Haloperidol/Droperidol, which has shown to be superior to Zofran. The patient’s symptoms should be reassessed in 2 hours.

2. Note than an EKG should be done to ensure that the QT interval is of normal length before giving medications that have the potential to prolong the QT. If pain is mild/moderate, more conservative treatment with capsaicin cream and heat packs can be recommended.

3. In regards to management in the outpatient setting, we recommend education on the importance of cannabis cessation.

REFERENCES

(1) Venkatesan, T., Levinthal, D. J., Li, B., Tarbell, S. E., Adams, K. A., Issenman, R. M., Sarosiek, I., Jaradeh, S. S., Sharaf, R. N., Sultan, S., Stave, C. D., Monte, A. A., & Hasler, W. L. (2019). Role of chronic cannabis use: Cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, 31 Suppl 2(Suppl 2), e13606. https://doi.org/10.1111/nmo.13606

(2) Kim HS, Anderson JD, Saghafi O, Heard KJ, Monte AA. Cyclic vomiting presentations following marijuana liberalization in Colorado. Acad Emerg Med 2015;22:694–9.

(3) Bhandari S, Jha P, Lisdahl KM, Hillard CJ, Venkatesan T. Recent trends in cyclic vomiting syndrome-associated hospitalisations with liberalisation of cannabis use in the state of Colorado. Intern Med J 2019;49:649–55.

(4) Myran DT, Roberts R, Pugliese M, Taljaard M, Tanuseputro P, Pacula RL. Changes in Emergency Department Visits for Cannabis Hyperemesis Syndrome Following Recreational Cannabis Legalization and Subsequent Commercialization in Ontario, Canada. JAMA Netw Open. 2022;5(9):e2231937. doi:10.1001/jamanetworkopen.2022.31937

(5) Lee, C., Greene, S. L., & Wong, A. (2019). The utility of droperidol in the treatment of cannabinoid hyperemesis syndrome. Clinical toxicology (Philadelphia, Pa.), 57(9), 773–777. https://doi.org/10.1080/15563650.2018.1564324

(6) Ruberto, A. J., Sivilotti, M., Forrester, S., Hall, A. K., Crawford, F. M., & Day, A. G. (2021). Intravenous Haloperidol Versus Ondansetron for Cannabis Hyperemesis Syndrome (HaVOC): A Randomized, Controlled Trial. Annals of emergency medicine, 77(6), 613–619. https://doi.org/10.1016/j.annemergmed.2020.08.021

(7) Dean, D. J., Sabagha, N., Rose, K., Weiss, A., France, J., Asmar, T., Rammal, J. A., Beyer, M., Bussa, R., Ross, J., Chaudhry, K., Smoot, T., Wilson, K., & Miller, J. (2020). A Pilot Trial of Topical Capsaicin Cream for Treatment of Cannabinoid Hyperemesis Syndrome. Academic emergency medicine:official journal of the Society for Academic Emergency Medicine, 27(11), 1166–1172. https://doi.org/10.1111/acem.14062

(8) Lapoint, J., Meyer, S., Yu, C. K., Koenig, K. L., Lev, R., Thihalolipavan, S., Staats, K., & Kahn, C. A. (2018). Cannabinoid Hyperemesis Syndrome: Public Health Implications and a Novel Model Treatment Guideline. The western journal of emergency medicine, 19(2), 380–386. https://doi.org/10.5811/westjem.2017.11.36368

(9) Sorensen CJ, DeSanto K, Borgelt L, et al. Cannabinoid hyperemesis syndrome: diagnosis, pathophysiology, and treatment- a systematic review. J Med Toxicol. 2017; 13(1):71-87.