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Three Part Question

In [patients presenting to the emergency department with nausea and vomiting due to cannabinoid hyperemesis syndrome (CHS)], is [haloperidol] [effective at treating the symptoms of CHS]?

Clinical Scenario

A 25 year old male presents to the emergency department in the late evening with symptoms of persistent nausea, vomiting and abdominal pain. He denies any diarrhea, fever, anorexia, sick contacts, or travel history. He reports daily use of 1-2g of THC/marijuana for the last 2 years, having started smoking in his early teens. He has had previous similar episodes in the last year lasting a few hours at a time. He typically takes 2-3 hot showers a day to improve his general symptoms of mild nausea and abdominal pain on a regular basis. He had a previous presentation and admission to hospital for two days with similar symptoms resolved with fluids and anti-emetics. This time, the symptoms have been persisting now for two days with no improvement. Clinically, he appears diaphoretic, and uncomfortable in pain. Vital signs are within normal limits. He appears clinically dehydrated with generalized abdominal tenderness but no acute peritonitis. History, physical exam, and investigations have ruled out emergent non-functional causes for his abdominal pain and vomiting. The clinical presentation is felt to be in keeping with cannabinoid hyperemesis syndrome (CHS). He received fluids, anti-emetics and pain control, all of which did not resolve his symptoms. You have heard that a single dose of haloperidol can improve symptoms of hyperemesis cannabinoid syndrome in the emergency department and avoid admission to hospital.

Search Strategy

[{cannabis.mp. or exp CANNABIS/} OR {cannabinoid.mp. or exp CANNABINOIDS/} OR {marijuana.mp. or exp Cannabis/} OR {drug abuse.mp. or exp Substance-Related Disorders/}] AND [{ exp Vomiting/or cyclic vomiting.mp. or exp Syndrome/} OR { exp Vomiting/or exp Nausea/or cannabinoid hyperemesis syndrome.mp. or exp Syndrome/} OR {abdominal pain.mp. or exp Abdominal Pain/} AND [{ haloperidol.mp. or exp HALOPERIDOL/} OR {antipsychotic.mp. or exp Antipsychotic Agents/} OR {antiemetics.mp. or exp ANTIEMETICS/}] and [{ exp PATIENT DISCHARGE/ or discharge.mp.} OR {hospitalization.mp. or exp HOSPITALIZATION/} OR {treatment.mp. or exp Therapeutics/}]
Medline 1946 to present using the OVID interface.
Search up to March 5, 2018
235 articles in total (n=235, see Box 1)

Two authors (J.D. and N.W.) independently screened all titles for eligibility based on our predefined research question. Discordances were resolved through discussion. The abstracts of eligible titles were then screened and full texts analysed for those meeting the inclusion criteria based on the research question. There were no language restrictions.

The authors also hand searched the references of systematic reviews and meta-analyses for additional original articles. All original articles were either already included on the Medline search or were original case reports and series. Therefore, no new articles were added to this review (n=0).

Additional searches for current or previous RCTs at clinicaltrials.gov were also undertaken. One study was relevant (n=1).

Search Outcome

Two hundred and thirty five (235) papers were found using the above-described search strategy. Twenty four (24) papers in total out of 235 were selected after title reviewing by two independent authors (J.D. and N.W.).


Of the twenty four (24) articles, seven (7) articles were excluded after abstract review as they were not relevant to the research question. 4 of the 7 articles were also excluded after abstract reviewing because they were both not relevant to the clinical question and were case reports.

Seventeen (17) articles were included for full text review. Of the seventeen papers, sixteen (16) were excluded after review. Fourteen (14) of the 16 were individual case reports or case series looking at treatment of cannabis hyperemesis syndrome with haloperidol in the emergency department. One (1) study was a retrospective chart review looking at the rate of presumed CHS in the emergency department, and percentage of these patients that received anti-emetics, opioids, intravenous fluids, had bloodwork done, underwent imaging, were admitted to hospital and referred to gastroenterology service. However, it did not report on the efficacy of the aforementioned pharmacological treatments and specifically it did not include use of haloperidol therefore not contributing to this review (Hernandez et al., 2017). One (1) study was a systematic review that was repeated again by the same primary author in 2018 including a few more additional case reports and was therefore excluded from this review (Richards et al., 2017).

One (1) article was therefore retained for final analysis (Figure 1).

The results are summarized in Table 1.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Richards JR 2018 California	All studies including patients presenting with CHS symptoms in the emergency department treated with anti-emetics, anti-psychotics, anti-histamine, serotonin antagonists, benzodiazepines, corticosteroids, opioids and dopamine antagonists	Systematic review – Most studies were level IV and V (case series and reports) with few level III (case control studies)*	Improvement of CHS symptoms	Standard anti-emetics are frequently ineffective at treating the symptoms of CHS Alternative agents, used mainly off-label, might be more effective than anti-emetics at treating symptoms of CHS, but there is no current evidence. Haloperidol was reported in case reports only.	No controlled studies, mainly case reports and series and a couple of prospective ones. There is a lack of high quality studies focusing on acute pharmacologic treatment of CHS Individual case reports commented on acute symptoms improvement but unclear if complete resolution was achieved. Unclear if patients were successfully discharged from the ED following treatment Many individual case reports did not report whether the treatment was successful or not

Comment(s)

Cannabis is the most commonly used drug in the world, with over 183 million users reported in 2017, and with numbers only increasing across the world (United Nations Office on Drugs and Crime, 2018). Cannabis hyperemesis syndrome (CHS), first described in 2004, is characterized by recurrent paroxysmal episodes of nausea and vomiting in chronic cannabis users that are mitigated by frequent hot bathing or showering and interspersed with symptom-free periods (Allen et al., 2004). With new legislation rules on legalization of cannabis, the numbers of users are expected to continue to rise in the upcoming years with ED visits and hospital admissions for CHS and other cannabis related disorders likely to rise in parallel. Various pharmacological treatments for the symptoms of CHS have been previously reported with minimal effect (Richards et al., 2018). Off label use of haloperidol as an anti-emetic in CHS has been reported on multiple case reports and case series (Richards et al., 2018). However, despite the increasing prevalence of CHS, this review identifies the lack of high-quality research when it comes to pharmacological treatment of CHS, especially with haloperidol. There was only one study that addressed the research question at hand. A systematic review looking at pharmacological treatment of CHS concluded that traditional anti-emetics are often unsuccessful at treating the symptoms of CHS with newer agents, such as off label use of haloperidol, showing promise. Their conclusion was however mainly based on case reports and case series of using haloperidol with a clear lack of controlled studies. Furthermore, when looking at individual case reports and case series, very few were monotherapy with just haloperidol and most included use of multiple other treatments like anti-emetics, fluids and pain medications prior to using haloperidol (Richards et al., 2018 and hand searched references within the review). Haloperidol was reported as the second most commonly used pharmacological treatment for CHS after benzodiazepines (Richards et al., 2018). This however was again based only on observational analysis of current case series and reports with no randomized controlled trials looking at haloperidol specifically (Richards et al., 2017). To date, no controlled studies exist to report on the use of haloperidol. Currently, a randomized controlled trial in Canada is comparing haloperidol to ondansetron. The study may shed light into the effectiveness of haloperidol in treating CHS symptoms in the emergency department.

Clinical Bottom Line

High-quality evidence for pharmacologic treatment of CHS is extremely limited, with most of the data coming from case reports and series with few prospective studies. Of date, multiple agents have been used to attempt treatment of symptoms of CHS with common ones being anti-emetics, benzodiazepines, anti-psychotics, anti-dopaminergic agents and capsaicin cream. Off label use of antipsychotics, specifically haloperidol, may be effective at treating symptoms of CHS (Richards et al., 2018). However, to date, no controlled studies exist to report on the use of haloperidol. Because the prevalence of CHS is likely to increase, future prospective trials are greatly needed to evaluate and further define optimal pharmacologic treatment of CHS patients.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. Richards, J. R, Gordon, B. K., Danielson, A. R., and Moulin, A.K. Pharmacologic Treatment of Cannabinoid Hyperemesis Syndrome: A Systematic Review Pharmacotherapy:The Journal of Human Pharmacology & Drug Therapy. 37(6):725-734, 2017 Jun
2. Allen, J. H., de Moore, G. M., Heddle, R., and Twartz, J. C. Cannabinoid hyperemesis: cyclical hyperemesis in association with chronic cannabis use.
3. Hernandez, J.M., Paty, J., and Price, I.M. Cannabinoid hyperemesis syndrome presentation to the emergency department: A two-year multicentre retrospective chart review in a major urban area CJEM Canadian Journal of Emergency Medical Care 1-6, 2017 Aug 24.
4. Richard, J.R. Cannabinoid Hyperemesis Syndrome: Pathophysiology and Treatment in the Emergency Department Journal of Emergency Medicine. 2018 Jan 05.
5. United Nations Office on Drugs and Crime (UNODC). World Drug Report 2017 United Nations Accessed March 5, 2018.