According to the United Nations World Drug Report, cannabis was the most used drug in the world in 2017, accounting for 183 million users.¹ Legalization of cannabis has been increasing since 2012. In May 2019, the Illinois General Assembly passed HB-1438, Cannabis Regulation & Tax Act, which legalized recreational cannabis for use and sale. As of January 1, 2020, Illinois residents aged 21 years and older can legally purchase and possess up to 30 grams of plant material, edibles totaling no more than 500 mg of tetrahydrocannabinol, and 5 grams of cannabis concentrate products.² With legalization, pharmacists should be aware of the signs, symptoms, and management of Cannabinoid Hyperemesis Syndrome (CHS).

 

CHS is characterized by recurrent, paroxysmal episodes of nausea, vomiting, and abdominal discomfort in chronic cannabis users.³ Patients present to Emergency Departments seeking treatment for intractable vomiting. There are three phases of CHS which include prodrome, hyperemesis, and recovery. During the prodrome phase, patients may experience early morning nausea, fear of vomiting, and abdominal discomfort. The hyperemesis phase can last up to 24 hours where patients have nausea, vomiting, and abdominal pain. Diagnostic criteria for CHS includes weekly use of cannabis, long-term cannabis use (>1 year), severe cyclic nausea and vomiting (SCNV), relief of symptoms with hot showers, abdominal pain, age <50 years, weight loss of >5 kg, and morning predominance of symptoms.^5,6 CHS should be included in the differential diagnosis for patients presenting with gastrointestinal symptoms of unknown origin and in those with social history notable for chronic cannabis use who report resolution of symptoms with hot showers. Obtaining an in-depth social history for patients with CHS can potentially avoid additional imaging and diagnostic testing from being performed while in the ED.

The complex pathophysiology of SCNV involves the chemoreceptor trigger zone of the medulla oblongata, also known as the area postrema.⁶  This structure is found outside of the blood-brain barrier and is sensitive to blood and cerebrospinal fluid-born chemicals.⁶ Emesis begins with increased salivation, deep respirations, closure of the glottis, and relaxation of the pyloric sphincter. From there, retroperistalsis begins from the small intestine to the stomach and contraction of the abdominal muscles, resulting in emesis.⁷ The pathophysiology of CHS involves the endocannabinoid system. Endogenous cannabinoids bind to G protein-coupled cannabinoid receptors CB1. These receptors are found in the central nervous system and gastrointestinal (GI) tract and contribute to emesis. They modulate gastric secretion, motility, inflammation, and sensation.⁶ Activation of these receptors by endogenous cannabinoids inhibit the hypothalamic-pituitary-adrenal axis and central nervous system response to stressful stimuli.⁸ Early use of cannabis may lead to anti-nausea effects, but repeated use of cannabis can lead to desensitization of these receptors resulting in vomiting. 

Several medications are often trialed in the Emergency Department for the management of CHS. Dopamine antagonists (metoclopramide, promethazine, haloperidol, droperidol, prochlorperazine) inhibit dopamine in the chemoreceptor trigger zone and have prokinetic effects on motor function of the GI tract. Serotonin antagonists (ondansetron) work on enterochromaffin cells in the GI tract, which release serotonin in response to noxious substances, to inhibit afferent sensory neurons. Benzodiazepines may also have a role in CHS due to their inhibition of medullary and vestibular nuclei associated with SCNV. These are considered standard therapies trialed for CHS but are often observed to be ineffective in clinical practice.

Other therapies have been reported for CHS and are largely driven by case reports and small case series. Capsaicin, a chemical found in chili peppers, binds to transient receptor potential vanilloid-1 (TRPV1) receptors which are found near CB1 receptors in the GI tract and medullary vomiting center. These receptors are activated by low pH and high temperature and regulate the release of substance P. Hot showers are theorized to work due to dose-dependent hypothermic effect of cannabinoids binding to CB1 receptors of the hypothalamus. Another theory is that hot showers cause cutaneous vasodilation which alters core temperature, splanchnic circulation leading to decreased abdominal discomfort.⁴ 

Despite only low methodological quality of evidence, some institutions are trialing capsaicin cream as an anti-emetic.¹⁰ Capsaicin cream is marketed for temporary relief of pain due to arthritis and strains/sprains. It is available over-the-counter in concentrations of 0.025% to 0.1%. It is reasonable to recommend capsaicin 0.075% cream to be applied to the abdomen and upper arms 3-4 times a day. Capsaicin does not have comparative efficacy data to support its use as a first-line agent. An advantage to capsaicin is its ease of administration as a cream since other anti-emetics, in the oral dosage forms, are contraindicated in active vomiting. If patients are discharged on the medication, there are several critical counseling points to ensure patient safety. Common side effects include local skin reactions at the application site and sneezing due to inhalation of dried cream. Patients should avoid application to the eyes, genitourinary regions, sensitive skin, and mucous membranes. To avoid exposure to hands and fingers, patients should wash hands after application and consider wearing gloves or using finger cots during application. Patients should also be advised to avoid application of heat or occluding the application site.¹⁸ Most importantly, patients should be advised abstinence from cannabis is the most effective treatment for CHS.

A systematic review including three case reports^11,12,13 and two case series^14,15 found capsaicin to be effective in 18 patients. Two retrospective cohort studies did not find capsaicin to demonstrate a significant benefit on ED length of stay. In one of the retrospective cohort studies, capsaicin administration was associated with a non-significant prolonged time to ED discharge (51.1 minutes longer; 95% CI: -17.6 to 119.9) and non-significantly reduced rate of hospital admission (33.3% vs 61.9%; P=0.055).¹⁶ In the other retrospective cohort study, ED length of stay was non-significantly reduced in CHS patient visits during which capsaicin was administered compared with those in which it was not (179 vs 201 minutes, P=0.33).¹⁷ Most patients experienced clinical resolution of CHS after 1 dose. Time to resolution of symptoms may have ranged from within 30 minutes up to 11 hours after use.^11-15 

With states passing laws allowing the sale of cannabis for recreational use, health care providers can expect to see an increase in use and possibly an increase in CHS. When standard anti-emetic agents fail to treat CHS, patients may try topical capsaicin. Although weak literature exists, pharmacists should be cognizant of its place in therapy and should be able to recommend safe dosing and administration. ■

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2. Illinois General Assembly. Cannabis Regulation & Tax Act Springfield, IL. 2019. http://www.ilga.gov/legislation/ilcs/ilcs5.asp?ActID=3992&ChapterID=35 (accessed 2020 Jun 23).
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