Clinical & PICO Question:

34 yo M with no significant medical history presents to the ED with intractable vomiting and nausea x3 hours. Patient reports vomiting occurs multiple times per hour and he has had similar episodes in the past. Admits daily marijuana use for 10 years.

For patients with cannabinoid hyperemesis is Haloperidol more effective than ondansetron for resolution of symptoms?

PICO Search Elements:

Identify the PICO elements – this should be a revision of whichever PICO you have already begun in a previous week

P	I	C	O
Adult	Haldol	Ondansetron	Resolution of symptoms
Vomiting	Haloperidol	Zofran	Efficacy
Intractible vomiting			Effectiveness
Cannabinoid hyperemesis			Resolution of vomiting
Cyclic vomiting syndrome

Search Strategy:

Outline the terms used, databases or other tools used, how many articles returned, and how you selected the final articles to base your CAT on.  This will likewise be a revision and refinement of what you have already done. A minimum of 3 search databases should be used.

PubMed:

• Cannabinoid hyperemesis, haloperidol, ondansetron – 48

Cochrane Library

• Cannabinoid hyperemesis, haloperidol – 3

Google Scholar

• Cannabinoid hyperemesis, haloperidol, ondansetron – 297
  • since 2020 – 93

• Narrowed search by focusing on systematic reviews and RCTs as these would provide the highest levels of evidence to answer my question. There were not a lot of systematic reviews about this subject but there were many case reports, and the systematic reviews available discussed the low quality of evidence due to inclusion of case reports. Focused on articles that compared only haloperidol and ondansetron. Focused on studies that evaluated treatment of vomiting and nausea caused by chronic cannabis use, ignored those that focused on symptoms from other causes. Studies were also considered that compared various treatments if haloperidol and ondansetron were 2 of the potential treatment options. Focused on articles that discussed treatment in adults, some included adolescents as well.

Articles Chosen At least 6 articles for Inclusion (please copy and paste the abstract with link):

Article 1:

Richards, J.R., Gordon, B.K., Danielson, A.R. and Moulin, A.K. (2017), Pharmacologic Treatment of Cannabinoid Hyperemesis Syndrome: A Systematic Review. Pharmacotherapy, 37: 725-734. https://doi.org/10.1002/phar.1931

Abstract:

Cannabinoid hyperemesis syndrome (CHS) has become more prevalent with increasing cannabis use. CHS is often resistant to standard antiemetics. The objective of this study is to review the current evidence for pharmacologic treatment of CHS. Medline, PsycINFO, DARE, OpenGrey, Google Scholar, and the Cochrane Library were searched from inception to February 2017. Articles were selected and reviewed independently. Evidence was graded using Oxford Center for Evidence-Based Medicine guidelines. The search resulted in 1262 articles with 63 of them eligible for inclusion (205 human subjects). There were 4 prospective level-2, 3 retrospective level-3 studies, 12 level-4 case series, and 44 level-5 case reports. Among level-2 studies (64 subjects), tricyclic antidepressants (TCAs) and lorazepam were discussed as effective long- and short-term treatments, respectively, in two studies. Ondansetron, promethazine, diphenhydramine, and opioids were also mentioned, but the authors did not comment on their efficacy. Among level-3 studies (43 subjects), one reported effective treatment with antiepileptics zonisamide and levetiracetam, but not TCAs. Another reported favorable response to morphine, ondansetron, and lorazepam but did not specify the actual number of patients receiving specific treatment. Among the level-4 case series (54 subjects), benzodiazepines, haloperidol, and capsaicin were reported as helpful. For level-5 case reports (44 subjects), benzodiazepines, metoclopramide, haloperidol, ondansetron, morphine, and capsaicin were reported as effective. Effective treatments mentioned only once included fentanyl, diazepam, promethazine, methadone, nabilone, levomepromazine, piritramide, and pantoprazole. Hot showers and baths were cited in all level-4 and -5 articles as universally effective. High-quality evidence for pharmacologic treatment of CHS is limited. Benzodiazepines, followed by haloperidol and capsaicin, were most frequently reported as effective for acute treatment, and TCAs for long-term treatment. As the prevalence of CHS increases, future prospective trials are greatly needed to evaluate and further define optimal pharmacologic treatment of patients with CHS.

https://accpjournals.onlinelibrary.wiley.com/doi/full/10.1002/phar.1931

Article 2:

Aaron J. Ruberto, Marco L.A. Sivilotti, Savannah Forrester, Andrew K. Hall, Frances M. Crawford, Andrew G. Day, Intravenous Haloperidol Versus Ondansetron for Cannabis Hyperemesis Syndrome (HaVOC): A Randomized, Controlled Trial, Annals of Emergency Medicine, Volume 77, Issue 6, 2021, Pages 613-619, ISSN 0196-0644, https://doi.org/10.1016/j.annemergmed.2020.08.021.

Abstract:
Study objective

Little is known about the cause or optimal treatment of hyperemesis in habitual cannabis users. Anecdotal evidence supports the use of haloperidol over traditional antiemetics for this newly recognized disorder. We compare haloperidol with ondansetron for cannabis hyperemesis syndrome.

Methods

We randomized cannabis users with active emesis to either haloperidol (with a nested randomization to either 0.05 or 0.1 mg/kg) or ondansetron 8 mg intravenously in a triple-blind fashion. The primary outcome was the reduction from baseline in abdominal pain and nausea (each measured on a 10-cm visual analog scale) at 2 hours after treatment. Although the trial allowed for crossover, the primary analysis used only the first treatment period because few subjects crossed over.

Results

We enrolled 33 subjects, of whom 30 (16 men, aged 29 years [SD 11 years] using 1.5 g/day [SD 0.9 g/day] since age 19 years [SD 2 years]) received at least 1 treatment (haloperidol 13, ondansetron 17). Haloperidol at either dose was superior to ondansetron (difference 2.3 cm [95% confidence interval 0.6 to 4.0 cm]; P=.01), with similar improvements in both pain and nausea, as well as less use of rescue antiemetics (31% versus 59%; difference –28% [95% confidence interval –61% to 13%]) and shorter time to emergency department (ED) departure (3.1 hours [SD 1.7] versus 5.6 hours [SD 4.5]; difference 2.5 hours [95% confidence interval 0.1 to 5.0 hours]; P=.03). There were 2 return visits for acute dystonia, both in the higher-dose haloperidol group.

Conclusion

In this clinical trial, haloperidol was superior to ondansetron for the acute treatment of cannabis-associated hyperemesis. The efficacy of haloperidol over ondansetron provides insight into the pathophysiology of this now common diagnosis in many EDs.

https://www.sciencedirect.com/science/article/abs/pii/S0196064420306661

Article 3:

Witsil, Joanne C. PharmD1,2,*; Mycyk, Mark B. MD1,2 Haloperidol, a Novel Treatment for Cannabinoid Hyperemesis Syndrome, American Journal of Therapeutics: January/February 2017 – Volume 24 – Issue 1 – p e64-e67 doi: 10.1097/MJT.0000000000000157

Abstract:
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.

https://journals.lww.com/americantherapeutics/fulltext/2017/01000/haloperidol,_a_novel_treatment_for_cannabinoid.10.aspx

Article 4:

Inayat F, Virk HU, Ullah W, Hussain Q. Is haloperidol the wonder drug for cannabinoid hyperemesis syndrome?. BMJ Case Rep. 2017;2017:bcr2016218239. Published 2017 Jan 4. doi:10.1136/bcr-2016-218239

Abstract:

Cannabinoid hyperemesis syndrome (CHS) is a rare clinical syndrome characterised by nausea, cyclic vomiting and severe abdominal pain in association with chronic cannabis use. It is often under-recognised or misdiagnosed, resulting in the unnecessary workup and frequent hospitalisations. Long-term treatment of CHS is abstinence from cannabis, but acute symptomatic management has been a struggle for many clinicians. The present report highlights the use of haloperidol as an agent that successfully and safely treats the unrelenting symptoms of CHS.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256592/

Article 5:

Khattar N, Routsolias JC. Emergency Department Treatment of Cannabinoid Hyperemesis Syndrome: A Review. Am J Ther. 2018 May/Jun;25(3):e357-e361. doi: 10.1097/MJT.0000000000000655. PMID: 28953512.

Abstract

Background: Cannabinoid hyperemesis syndrome (CHS) is a syndrome of cyclic vomiting associated with chronic cannabis use. As cannabis consumption steadily increases each year, CHS is becoming a commonplace and costly occurrence in hospitals nationwide. Currently, there are no best treatment strategies agreed upon universally.

Areas of uncertainty: Thus far, most data about CHS have come from case reports and case series. Consequently, the pathophysiology of the syndrome is unclear, and its occurrence in some cannabis users, but not others, is not understood.

Data sources: A literature search was conducted through PubMed, Embase, and Google Scholar from inception until 2017. Publications only in English describing the epidemiology, pathophysiology, diagnostic criteria, and treatments of CHS were incorporated after thorough evaluation. National government surveys were also referred to for current information about the CHS patient population.

Results: CHS should be considered in the differential diagnosis of any patient presenting with persistent nausea and vomiting. In particular, the diagnosis is suggested if the patient demonstrates regular and chronic cannabis use, intractable nausea and vomiting, cyclical vomiting, relief of symptoms with hot baths, and resolution of symptoms after cannabis cessation. There are currently many possible explanations regarding the mechanisms behind CHS. A variety of treatment options have also been examined, including hot water baths, haloperidol, capsaicin, and benzodiazepines.

Conclusions: CHS is becoming an increasingly prevalent and complicated problem for health care providers and patients. Further research must be done to address the diagnostic and therapeutic challenges of this syndrome.

https://pubmed.ncbi.nlm.nih.gov/28953512/

Article 6:

Sorensen CJ, DeSanto K, Borgelt L, Phillips KT, Monte AA. Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment-a Systematic Review. J Med Toxicol. 2017;13(1):71-87. doi:10.1007/s13181-016-0595-z

Abstract

Cannabinoid hyperemesis syndrome (CHS) is a syndrome of cyclic vomiting associated with cannabis use. Our objective is to summarize the available evidence on CHS diagnosis, pathophysiology, and treatment. We performed a systematic review using MEDLINE, Ovid MEDLINE, Embase, Web of Science, and the Cochrane Library from January 2000 through September 24, 2015. Articles eligible for inclusion were evaluated using the Grading and Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Data were abstracted from the articles and case reports and were combined in a cumulative synthesis. The frequency of identified diagnostic characteristics was calculated from the cumulative synthesis and evidence for pathophysiologic hypothesis as well as treatment options were evaluated using the GRADE criteria. The systematic search returned 2178 articles. After duplicates were removed, 1253 abstracts were reviewed and 183 were included. Fourteen diagnostic characteristics were identified, and the frequency of major characteristics was as follows: history of regular cannabis for any duration of time (100%), cyclic nausea and vomiting (100%), resolution of symptoms after stopping cannabis (96.8%), compulsive hot baths with symptom relief (92.3%), male predominance (72.9%), abdominal pain (85.1%), and at least weekly cannabis use (97.4%). The pathophysiology of CHS remains unclear with a dearth of research dedicated to investigating its underlying mechanism. Supportive care with intravenous fluids, dopamine antagonists, topical capsaicin cream, and avoidance of narcotic medications has shown some benefit in the acute setting. Cannabis cessation appears to be the best treatment. CHS is a cyclic vomiting syndrome, preceded by daily to weekly cannabis use, usually accompanied by symptom improvement with hot bathing, and resolution with cessation of cannabis. The pathophysiology underlying CHS is unclear. Cannabis cessation appears to be the best treatment

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330965/

For the DRAFT & Final CAT (Rotations 8 & 9) – YOU WILL INCLUDE THE PARTS ABOVE AND COMPLETE THE REMAINING PARTS BELOW:

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
Richards (2017)	Systematic Review	Searched Medline, PsycINFO, and the Cochrane Library from inception to February 2017 and identified 63 studies with a total of 205 patients with cannabinoid hyperemesis treated with a variety of medications including benzodiazepines, tricyclic antidepressants, ondansetron, promethazine, diphenhydramine, opioids, antiepileptics, haloperidol, capsaicin	Cannabis use. Resolution of symptoms. Efficacy of medications including benzodiazepines, tricyclic antidepressants, ondansetron, promethazine, diphenhydramine, opioids, antiepileptics, haloperidol, capsaicin	Benzodiazepines, specifically lorazepam, were most frequently studied medication followed by haloperidol and capsaicin. Benzopiazepines, metoclopramide, haloperidol, ondansetron, morphine, and capsaicin were all found to be effective for short term management. 5 studies found haloperidol effective, 1 study showed effectiveness of haloperidol after failure of other treatments, no studies found haloperidol ineffective. 2 studies found ondansetron effective, 32 showed ondansetron was either ineffective or less effective than other treatments such as haloperidol or hot showers	Limited by incomplete reporting and small sample size. There were no large scale RCT included allowing bias from included studies to potentially impact the review.   Limited by lack of high quality studies focusing on pharmacological treatment of cannabinoid hyperemesis.
Ruberto (2021)	RCT	Triple blind RCT at 2 EDs in Canada with 33 patients, 13 treated with haloperidol 0.05 or 0.1 mg/kg, 17 with ondansetron 8 mg	Primary outcome: change in abdominal pain and nausea within 2 hours after treatment. Secondary outcome: change in abd pain or nausea >2 hours, discharge, use of rescue antiemetics, length of stay >12 hours, unscheduled return visits within 7 days, adverse effects	Either dose of haloperidol had significantly greater reduction in abd pain and nausea within 2 hours compared to ondansetron. Haloperidol had 54% chance of treatment success (ondansetron 29%), reduced use of rescued antiemetics, and shorter time to discharge. Similar outcomes were observed between the 2 doses of haloperidol however more adverse events were seen with higher dose. Extension of trial was halted due to strong effectiveness in favor of haloperidol.	Limited by not meeting the enrollment target, half of potentially eligible patients refused consent. Also limited by some patients receiving treatment before being evaluated in the ED
Witsil (2017)	Retrospective cohort	Single ED with 4 eligible patients with cannabinoid hyperemesis over a 3 month period	Long term cannabis use, compulsive hot bathing, cyclical vomiting refractory to antiemetics, ED length of stay	First patient initially treated with ondansetron with no improvement in symptoms,  Haloperidol 5 mg IV was then given and symptoms resolved within 1 hour. Second patient previously treated with ondansetron, metoclopramide, or chlorpromazine with no improvement, after haloperidol 5 mg IV and Benadryl symptoms resolved within 1 hour and discharged within 6 hours. Third patient previously treated with metoclopramide, promethazine, ondansetron, and chlorpromazine with no improvement, after haloperidol 5 mg IV improved within 1 hour and discharged within 8 hours. Fourth patient failed metoclopramide and ondansetron, after haloperidol 5 mg IV improved within 2 hours and discharged within 6 hours. No patients needed repeat dose of haloperidol.	Number of patients limited by available data for retrospective study, some patients may have been missed due to how they were diagnosed or coded. Because it was retrospective the medications were not blinded.
Inayat (2017)	Case report	27 year old male in an Emergency Department	Symptoms (nausea, vomiting, abdominal pain), marijuana use, hot shower, resolution of symptoms with cannabis cessation, resolution of symptoms with treatment including IV hydration, ondansetron, lorazepam, and haloperidol, tolerating PO intake, recurrence of symptoms	No relief was found after 2 days of administration of ondansetron, IV hydration, and lorazepam. 1 mg IV haloperidol was then given and the patient had significant clinical improvement and no adverse effects. Subsequently given 2, 2 mg doses of haloperidol and the compulsive hot bathing and GI symptoms subsided.  1 day after use of haloperidol the patient was able to tolerate PO intake. No recurrence of symptoms at 1 month follow up	Limited by being a case report of a single patient.
Khattar (2017)	Systematic review	Searched PubMed, Embase, and Google Scholar to identify 29 case reports, review articles, and clinical trials about cannabinoid hyperemesis syndrome	History of cannabis use, compulsive hot water bathing, treatment used, symptom resolution	Only definitive treatment is abstinence from marijuana. Antiemetics such as ondansetron, promethazine, prochlorperazine, and metoclopramide were commonly used but were not found to be effective in relief of nausea and vomiting. Multiple case reports found Haloperidol to have significant antiemetic effect in patients with cannabinoid hyperemesis. Haloperidol led to resolution of nausea, vomiting, abdominal pain that was refractory to standard therapies including IV fluids, ondansetron, lorazepam. Haloperidol led to resolution of symptoms within 2 hours and discharge within 8 hours. Hot showers or baths were found to be effective in symptom management however some case reports involved patients coming to ER with scald burns requiring treatment. 2 case reports used topical capsaicin with some success.	Limited by available studies, many were case reports that did not use the same treatments or study the same outcomes
Sorensen (2016)	Systematic review	Searched MEDLINE, Ovid MEDLINE, Embase, Web of Science, and Cochrane Library to identify 170 articles published between January 2000 and September 24, 2015 with a total of 211 patients	Age at diagnosis, age of onset of cannabis use, age of symptoms onset, duration of cannabis use prior to onset, presence of cyclic vomiting/abdominal pain, relief with compulsive hot bath/shower, relief with abstinence, relief with other treatments	Only definitive treatment identified was abstinence of cannabis.   Compulsive hot baths/showers lead to relief of symptoms in 92.3% of cases (170 patients).   1 of the included studies found complete resolution of symptoms 1 hour after administration of haloperidol 5 mg   Very limited evidence supported the use of dopamine antagonists for symptomatic care, some limited evidence supported use of capsaicin cream.	Limited by heterogeneity across studies used and incomplete reporting. Limited search to English language articles, excluding potentially relevant articles in foreign languages.   Low quality of evidence in selected articles prevented meta-analysis   Search did not yield any RCTs evaluating treatment   Limited research into other treatments at the time of this review

Conclusion(s):

Briefly summarize the conclusions of each article, then provide an overarching conclusion.

• Richards- Systematic review evaluated multiple medications for cannabinoid hyperemesis, 2 of which were ondansetron and haloperidol. Benzodiazepines, specifically lorazepam, were most frequently studied medication followed by haloperidol and capsaicin. Benzopiazepines, metoclopramide, haloperidol, ondansetron, morphine, and capsaicin were all found to be effective for short term management. 5 studies found haloperidol effective, 1 study showed effectiveness of haloperidol after failure of other treatments, no studies found haloperidol ineffective. 2 studies found ondansetron effective, 32 showed ondansetron was either ineffective or less effective than other treatments such as haloperidol or hot showers. Concluded that more higher quality studies are required focusing on acute pharmacologic treatment of cannabinoid hyperemesis
• Ruberto – Triple blind RCT concluded that haloperidol 0.05 mg/kg IV onetime dose is superior for nausea, vomiting, and abdominal pain caused by cannabinoid hyperemesis and ondansetron 4 mg should no longer be used as first line agent. Study compared haloperidol at 2 different doses (0.05 or 0.1 mg/kg) and ondansetron 8 mg. Either dose of haloperidol caused significantly greater reduction in nausea and abdominal pain within 2 hours compared to ondansetron. Haloperidol also had higher treatment success (54% vs 29%), reduced use of rescue antiemetics, shorter time to discharge. Similar outcomes were seen between 2 doses of haloperidol however more adverse events were seen with higher dose of haloperidol. Extension of trial was halted due to strong effectiveness in favor of haloperidol
• Witsil – Retrospective cohort concluded that haloperidol is a promising treatment for cannabinoid hyperemesis and warrants further investigation. The sample size was small with only 4 patients meeting eligibility criteria. All 4 patients were previously treated with ondansetron with no improvement. All 4 patients improved after haloperidol 5 mg IV, 3 within 1 hour of administration and 1 within 2 hours. Haloperidol lead to significant symptom relief and all were discharged within 8 hours. No patients required repeat dose of haloperidol.
• Inayat – Case report following 1 patient with cannabinoid hyperemesis and multiple episodes in the past. Initially treated with ondansetron, IV hydration, and lorazepam with no relief. Patient was then given haloperidol 1 mg with significant improvement in symptoms and no adverse events, they were then given 2 subsequent doses of haloperidol 2 mg with resolution of symptoms and was able to tolerate PO intake. No recurrence at 1 month follow up. Concluded that clinical trials are required to further understand the therapeutic role of haloperidol and to form guidelines for treatment of cannabinoid hyperemesis.
• Khattar – Systematic review found that the only definitive treatment is abstinence from marijuana. Antiemetics such as ondansetron, promethazine, prochlorperazine, and metoclopramide were commonly used but were not found to be effective in relief of nausea and vomiting. Multiple case reports found Haloperidol to have significant antiemetic effect in patients with cannabinoid hyperemesis. Haloperidol led to resolution of nausea, vomiting, abdominal pain that was refractory to standard therapies including ondansetron. Haloperidol led to resolution of symptoms within 2 hours and discharge within 8 hours. Hot showers or baths were found to be effective in symptom management however some case reports involved patients coming to ER with scald burns requiring treatment. Concluded that more research needs to be done aimed at developing empiric treatment regiment by comparing different types of treatment.
• Sorensen – Systematic review concluded that abstinence of cannabis was the only treatment that lead to complete resolution of symptoms. Compulsive hot baths and showers provided temporary relief in 92.3% of cases. 1 of the included studies used haloperidol 5 mg with complete resolution of symptoms within 1 hour however the quality of the evidence was found to be very low. There was also limited evidence to support other treatments such as capsaicin cream.

• Cannabinoid hyperemesis is a syndrome of cyclic vomiting associated with chronic use of cannabis. The only definitive treatment known at this time is abstinence from marijuana use. Ondansetron, an antiemetic, and haloperidol, an antipsychotic, are 2 potential treatment options. Ondansetron was rarely effective in resolution of symptoms. Haloperidol led to significant improvement in vomiting, nausea, and abdominal pain. Patients treated with haloperidol also required fewer rescue medications, shorter time to ED discharge, fewer return visits to ED. One of the studies found the results to be so significant that they conclude that ondansetron should no longer be used as the first-line agent to abort emesis. When different doses of haloperidol were studied (0.05 or 0.1 mg/kg), the lower dose was found to be as effective as the higher dose and the higher dose was associated with more adverse effects. While 0.05 mg/kg haloperidol is a promising treatment for cessation of emesis and decreased time in ED, stopping use of cannabis is the only way to prevent recurrence. More investigation is needed with larger sample sizes in order to more clearly identify the effectiveness and safety of haloperidol.

Clinical Bottom Line:

Please include an assessment of the following:

• Weight of the evidence – summarize the weaknesses/strengths of the articles and explain how they factored into your clinical bottom line (this may recap what you discussed in the criteria for choosing the articles)
  • Ruberto not only compared haloperidol and ondansetron but also compared 2 different doses of haloperidol. Haloperidol at either dose was found to be significant more effective than ondansetron. The author’s concluded that haloperidol 0.05 mg/kg IV onetime dose is superior for nausea, vomiting, and abdominal pain caused by cannabinoid hyperemesis and the evidence was strong enough that they also suggest that ondansetron 4 mg should no longer be used as first line agent. While this article is an RCT and not a systematic review I still weighed it most heavily as it is the only article that specifically compared the 2 treatment options. Extension of the trial was halted due to the effectiveness of haloperidol. The small sample size is the greatest limitation of the article and it was attributed to patients being treated with standing order of ondansetron for vomiting before evaluation in the ED.
  • Richards was weighed next as it was a systematic review comparing multiple treatment options for cannabinoid hyperemesis, 2 of which were haloperidol and ondansetron. 63 studies were included, 5 of which found haloperidol effective, 1 study showed effectiveness of haloperidol after failure of other treatments, no studies found haloperidol ineffective. . 2 studies found ondansetron effective, 32 showed ondansetron was either ineffective or less effective than other treatments such as haloperidol or hot showers. This systematic review was limited by the small sample size (205) and lack of high quality studies with no large scale RCTs included.
  • Witsil was a retrospective cohort with small sample size (only 4 eligible patients). It was weighed next because all 4 patients failed treatment with ondansetron before being treated with haloperidol however because it was retrospective the medications were not blinded.. Ondansetron had no improvement in symptoms, haloperidol lead to significant symptom relief in all 4 patients. 3 patients had resolution of symptoms within 1 hour of haloperidol 5 mg, 1 patient within 2 hours. None of the patients required repeat dose of haloperidol. The findings in these 4 patients show that haloperidol is a promising treatment option and warrants further investigation.
  • Khattar was a smaller systematic review with only 29 articles. Many of the included studies were case reports that did not use the same treatments or study the same outcomes. Multiple case reports found Haloperidol to have significant antiemetic effect in patients with cannabinoid hyperemesis. Haloperidol led to resolution of nausea, vomiting, abdominal pain that was refractory to standard therapies including IV fluids, ondansetron, lorazepam. Antiemetics such as ondansetron, promethazine, prochlorperazine, and metoclopramide were commonly used but were not found to be effective in relief of nausea and vomiting. Hot showers or baths were found to be effective in symptom management however some case reports involved patients coming to ER with scald burns requiring treatment. The only definitive treatment identified was abstinence from marijuana.
  • Inayat: there were many case reports to choose from regarding treatment of cannabinoid hyperemesis, I chose this one because the patient was successfully treated with haloperidol after not responding to ondansetron. The patient also had episodes of intractable vomiting multiple times in the past that only improved with hot baths. This evidence of this article is weak because it is a case report of a single patient. 
  • Sorensen article weighed lower, even though it is a systematic review, because of it being the earliest publication. While it was published in 2016 and is only 5 years old, many of the other publications and case studies about cannabinoid hyperemesis were published after 2017. Also, the authors concluded that the level of evidence of the included articles was low. Cannabinoid hyperemesis is a relatively new diagnosis and the treatment options are quickly evolving, this article being from 2016 greatly limits its usefulness. At the time of this article’s publication there was limited research into treatments and symptom management for cannabinoid hyperemesis, the review includes 1 study that used haloperidol and only briefly addressed the use of antiemetics including ondansetron.

• Magnitude of any effects
  • All 6 articles came to similar conclusions about the effectiveness of haloperidol for cannabinoid hyperemesis. None of the articles found haloperidol to be ineffective, however ondansetron was rarely found to be effective. When haloperidol and ondansetron were compared, haloperidol was found to be significantly more effective than ondansetron in symptom relief. In one RCT, haloperidol had 54% treatment success compared to 29% for ondansetron. 59% of patients that took ondansetron required rescue antiemetics and 41% required benzodiazepines compared to only 31% and 8% for haloperidol. Haloperidol also lead to discharge 2.5 hours earlier compared to ondansetron. The quality of the evidence is not strong and more large scale studies are required to establish diagnostic and treatment guidelines for cannabinoid hyperemesis

• Clinical significance (not just statistical significance)
  • All 6 articles provide evidence showing that haloperidol is effective for resolution of symptoms in patients with cannabinoid hyperemesis. While abstinence from marijuana was the only definitive treatment identified, haloperidol was found to be effective for resolving symptoms. Ruberto et al found strong enough evidence to suggest that ondansetron no longer be used as first line agent. Haloperidol lead to resolution of symptoms within 1-2 hours of administration and also lead to faster discharge from ED. The mean difference between ondansetron and haloperidol groups was 2.3 cm in favor of haloperidol, haloperidol had 54% treatment success compared to 29% for ondansetron. 59% of patients that took ondansetron required rescue antiemetics and 41% required benzodiazepines compared to only 31% and 8% for haloperidol. Haloperidol use also lead to shorter time to discharge at 3.1 hours compared to 5.6 hours for ondansetron. Haloperidol was found to be so effective that extension of the trial was halted. The evidence across the studies consistently showed that ondansetron was less effective than other treatment options. There was some evidence showing the effectiveness of topical capsaicin for symptom relief and temporary relief was also found with hot showers/baths however some patients went to the emergency department with scald burns secondary to compulsive hot showers. The reviews that included topical capsaicin creams obtained their evidence from a limited number of case reports. The evidence for topical capsaicin cream was promising but limited, one case report that was cited in multiple reviews followed 5 patients who experienced near complete resolution of symptoms after it was applied to the abdomen. Compulsive hot baths/showers was seen as both part of the diagnosis and part of the treatment. In one study, 92.3% of patients presented with cyclic vomiting that improved with hot baths/showers. It was described as a learned behavior pattern of cannabinoid hyperemesis. The mechanism is unclear however many authors suggest that hot baths/showers works in a similar way as topical capsaicin and favored the use of the topical due to decreased risk of scald and burns. Cannabinoid hyperemesis is a relatively new diagnosis and the research is very limited, none of the studies had large sample sizes and more research is required in order to more clearly define treatment guidelines.

• Any other considerations important in weighing this evidence to guide practice  – If the evidence you retrieved was not enough to conclude an answer to the question, discuss what aspects still need to be explored and what the next studies will have to answer/provide (e.g. larger number, higher level of evidence, answer which sub-group benefits, etc)
  • The results consistently show that haloperidol is more effective than ondansetron however the only definitive treatment identified across the articles was abstinence. Many clinicians prefer to use ondansetron, IV fluids, and/or lorazepam as first line for intractable vomiting and the authors of all articles concluded that more research needs to be done with large sample sizes to compare the treatment options and develop diagnostic criteria and treatment guidelines. There is also a focus toward patient education and marijuana cessation, which at this time is the only definitive treatment for cannabinoid hyperemesis. Topical capsaicin cream was shown to be effective in multiple reviews, however the evidence is very limited from case reports and the authors also acknowledge that topical capsaicin cream is not commonly stocked in hospitals and EDs. While topical capsaicin is a promising option, the evidence is limited and more large scale studies are required. Cost of the medications is another important aspect to consider when deciding which medication to use first line. While Ondansetron may be cheaper per dose compared to Haloperidol, the need for repeat doses of ondansetron, other rescue medications, and longer ED stay could potentially offset this savings. Further economic analysis is required in order to determine which medication is more cost effective.