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Pharmacologic Treatment of Cannabinoid Hyperemesis Syndrome: A Systematic Review

2017; Wiley; Volume: 37; Issue: 6 Linguagem: Inglês

10.1002/phar.1931

1875-9114

John R. Richards, Brent K. Gordon, Aaron Danielson, Aimee Moulin,

Neuroscience and Neuropharmacology Research

Pharmacotherapy: The Journal of Human Pharmacology and Drug TherapyVolume 37, Issue 6 p. 725-734 Review of TherapeuticsFree Access Pharmacologic Treatment of Cannabinoid Hyperemesis Syndrome: A Systematic Review John R. Richards, Corresponding Author John R. Richards jrrichards@ucdavis.edu Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CaliforniaAddress for correspondence: John R. Richards, Department of Emergency Medicine, PSSB 2100, U.C. Davis Medical Center, 2315 Stockton Boulevard, Sacramento, CA 95817; e-mail: jrrichards@ucdavis.edu.Search for more papers by this authorBrent K. Gordon, Brent K. Gordon Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CaliforniaSearch for more papers by this authorAaron R. Danielson, Aaron R. Danielson Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CaliforniaSearch for more papers by this authorAimee K. Moulin, Aimee K. Moulin Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CaliforniaSearch for more papers by this author John R. Richards, Corresponding Author John R. Richards jrrichards@ucdavis.edu Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CaliforniaAddress for correspondence: John R. Richards, Department of Emergency Medicine, PSSB 2100, U.C. Davis Medical Center, 2315 Stockton Boulevard, Sacramento, CA 95817; e-mail: jrrichards@ucdavis.edu.Search for more papers by this authorBrent K. Gordon, Brent K. Gordon Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CaliforniaSearch for more papers by this authorAaron R. Danielson, Aaron R. Danielson Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CaliforniaSearch for more papers by this authorAimee K. Moulin, Aimee K. Moulin Department of Emergency Medicine, University of California Davis Medical Center, Sacramento, CaliforniaSearch for more papers by this author First published: 31 March 2017 https://doi.org/10.1002/phar.1931Citations: 62 Conflict of Interest Disclosures: The authors have no conflict of interest to report. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat 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. Cannabis is the most commonly used illicit drug throughout the world, with over 180 million users.1 From 2001 to 2013 in the United States, past-year cannabis use more than doubled from 4.1–9.5% of the adult population, and prevalence of cannabis use disorder rose from 1.5–2.9%.2 Among college students, daily cannabis use has more than tripled in the past 2 decades from 1.8% in 1994 to 5.9% in 2014.2 In 2013 an estimated 2.4 million persons 12 years or older had used cannabis for the first time within the past 12 months, or roughly 6600 new users each day.2 In 2011, a total of 456,000 emergency department visits were related to cannabis use, a 21% increase from 2009.3 According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), cannabis intoxication is defined by recent use of cannabis; clinically significant problematic behavioral or psychological changes (e.g., impaired motor coordination, euphoria, anxiety, sensation of slowed time, impaired judgment, social withdrawal) that developed during, or shortly after, cannabis use; at least two of the following signs developing within 2 hours of cannabis use: conjunctival injection, increased appetite, dry mouth, tachycardia; and symptoms not due to a general medical condition and not better accounted for by another mental disorder.4 As a result of the 2016 election, several states (California, Nevada, Maine, and Massachusetts) have legalized recreational cannabis, joining Washington, Oregon, Colorado, and Alaska. As the legalization and use of recreational and medical cannabis continues to rise, a variant of cyclic vomiting syndrome known as cannabinoid hyperemesis syndrome (CHS) has become increasingly recognized.5, 6 This is also reflected by the number of peer-reviewed articles on CHS that have increased significantly since 2004 (Figure 1). Figure 1Open in figure viewerPowerPoint Increasing Number of Cannabinoid Hyperemesis Syndrome Articles Screened Since 2004. CHS is not recognized as a unique clinical entity in either the DSM-5 or the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10).4, 7 As a specific diagnosis, CHS meets some criteria for “cannabis intoxication” as defined earlier and/or “cannabis use disorder,” characterized by at least 2 of the following 11 criteria: cannabis often taken in larger amounts or over a longer period than was intended; a persistent desire or unsuccessful efforts to cut down or control cannabis use; a great deal of time spent in activities necessary to obtain cannabis use cannabis, or recover from its effects; craving or a strong desire or urge to use cannabis; recurrent cannabis use resulting in a failure to fulfill major role obligations at work, school, or home; continued cannabis use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of cannabis; important social, occupational, or recreational activities given up or reduced because of cannabis use; recurrent cannabis use in situations where it is physically hazardous; continued cannabis use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by cannabis; tolerance, as defined by either a need for markedly increased cannabis to achieve intoxication or desired effect or markedly diminished effect with continued use of the same amount of the substance; and withdrawal, as manifested by either the characteristic withdrawal syndrome for cannabis or cannabis being taken to relieve or avoid withdrawal symptoms.4 First described in 2004,8 CHS 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. Complications from CHS may include acute renal failure, electrolyte derangement, and pneumomediastinum.9-11 Patients experiencing symptoms of CHS may visit the emergency department for intravenous antiemetics and rehydration. However, commonly used antiemetics are often ineffective for acute exacerbations, necessitating the use of multiple doses of different and unrelated pharmacologic agents until control of hyperemesis is achieved.12 At present, the only proven long-term treatment is cessation of cannabis use.13 The objective of this systematic review is to determine the most effective pharmacologic treatment for CHS. Methods All human trials, case series, or case reports of pharmacologic treatment of CHS were considered in the literature search. Data were abstracted systematically from an extensive query of Medline, PsycINFO, and the Cochrane Library from inception to February 2017. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed (Supplement 1).14 Non–English-language publications were included and translated when necessary. Our final search strategy included free-text words (TW) and controlled vocabulary terms using Medical Subject Headings for these topics, their synonyms, abbreviations, and alternate spellings: (“cannabis”[TW] or “cannabinoid”[TW] or “marijuana”[TW] or “tetrahydrocannabinol”[TW] or “THC”[TW] or “cannabidiol”[TW] or “cannabigerol”[TW]) and (“hyperemesis”[TW] or “emesis”[TW] or “vomiting”[TW] or “cyclic”[TW] or “nausea”[TW]). Additional searches of the Cochrane Central Register of Controlled Trials (CENTRAL), and the Database of Abstracts of Reviews of Effects (DARE) were made. References in each selected publication were also carefully hand-screened for any additional reports having relevance. In the development of specific treatment recommendations, all references are cited in their appropriate context. A gray literature search was also performed using OpenGrey, Google, and Google Scholar. All authors reviewed the articles independently, and articles without mention of specific pharmacologic treatment of CHS were excluded. A meaningful meta-analysis was not possible due to the wide variety of pharmacologic treatments, protocols, study durations, and limited number of relevant trials. Therefore, we analyzed the data qualitatively. Results The search resulted in 1262 articles with 63 of them eligible for inclusion and involving 205 human subjects (Figure 2). Articles were graded using the Oxford Centre for Evidence-Based Medicine (CEBM) levels of evidence.15 These levels are basically defined as 1 = properly powered and conducted randomized clinical trial, systematic review, or meta-analysis; 2 = well-designed controlled trial without randomization; prospective comparative cohort; 3 = case-control studies, retrospective cohort studies; 4 = case series with or without intervention, cross-sectional studies; and 5 = opinion of authorities, case reports. There were no high-quality (CEBM level 1) prospective randomized blinded studies. There were 4 higher quality prospective (level 2) studies, 3 retrospective (level 3) studies, 12 case series (level 4), and 44 case reports (level 5). Figure 2Open in figure viewerPowerPoint Selection Process for Study Inclusion. A level-2 study involving 64 patients8 examined the association of chronic cannabis abuse and cyclic vomiting in 9 patients treated specifically with benzodiazepines but did not report on the efficacy. Another study16 prospectively examined tricyclic antidepressant (TCA) treatment of 132 patients with cyclic vomiting syndrome. There were 34 chronic cannabis users, of whom 25 (74%) responded favorably to amitriptyline, nortriptyline, or doxepin. During this study, several patients ceased using cannabis that in itself may have resolved their hyperemesis. It is also unclear if TCA treatment directly ameliorated hyperemesis or enabled subjects to mitigate their cannabis use and/or facilitate cessation. One group investigated 31 patients with cyclic vomiting treated with amitriptyline, 13 of whom were chronic cannabis users.17 Amitriptyline was effective as long-term therapy. At 3 months, 93% had decreased symptoms, and 26% achieved full remission. At 12 months there was a statistically significant mean improvement of 69% and 78% for nausea and vomiting, respectively. Of the cannabis subgroup, two were able to cease cannabis completely, and seven reported improvement in symptoms despite ongoing use, which is a lower rate of success than the overall study group. Based on this discrepancy, the authors stated that the relationship between cyclic vomiting syndrome and cannabis use is inconclusive. Lorazepam was mentioned as the most effective acute therapy in the emergency department, but actual numbers treated were not specified.17 Another prospective study18 reported the relative serum levels of endocannabinoids, salivary cortisol, and α-amylase, which are markers for stress in patients with cyclic vomiting. Subgroup analysis revealed cannabis users had significantly higher cortisol and α-amylase than nonusers. Both groups were noted to respond to treatment with ondansetron, promethazine, diphenhydramine, lorazepam, and hydromorphone, but further details were not given.18 In a level-3 study involving 43 regular cannabis users, the authors19 reported that 3 regular cannabis users among a cohort of 20 patients with cyclic vomiting experienced effective treatment with the antiepileptics zonisamide and levetiracetam, but not with TCAs. A study of 28 patients, of whom 4 were cannabis users,20 reported favorable response to morphine, ondansetron, and lorazepam; however, the actual number of patients receiving specific treatment was unspecified. In a multicenter review of emergency department visits in Europe following cannabis use,21 the use of benzodiazepines, olanzapine, chlorprothixene, and hydroxyzine for hyperemesis termination was mentioned, but actual patient response rates are not given. A total of 12 level-4 case series involved 54 patients.9, 22-32 For these case series, the following CHS pharmacologic treatments were reported as helpful: benzodiazepines (six), topical capsaicin (five), haloperidol (five), and olanzapine (one).24, 27-32 The 44 level-5 case reports involved 44 patients.10, 11, 33-74 For these case reports, the following CHS pharmacologic treatments were reported as effective: benzodiazepines (five), metoclopramide (four), haloperidol (four), ondansetron (two), morphine (two), and topical capsaicin (two).11, 34, 37, 38, 45, 46, 48, 50, 51, 53, 58, 60, 64, 69, 72, 73 Other effective treatments mentioned only once included fentanyl, promethazine, methadone, nabilone, levomepromazine, piritramide, and pantoprazole.37, 38, 43, 56, 66 Of note, hot showers and bathing were mentioned either by the authors or patients in all level-4 and -5 articles as universally effective at ameliorating CHS. Table 1 summarizes the eligible articles. Table 1. Summary of Evidence for Pharmacologic Treatment of Cannabinoid Hyperemesis Syndrome Type of study/trial Treatment Level of evidence No. of subjects Summary Prospective, longitudinal8 Benzodiazepines (unspecified) 2 9 Study authors did not report success of specific treatments Prospective, longitudinal16 Tricyclic antidepressants (Amitriptyline, nortriptyline, doxepin) 2 34 25 of 34 chronic marijuana users had successful response Prospective, longitudinal17 Lorazepam, ondansetron, amitriptyline, phenothiazines (unspecified) 2 13 Lorazepam most effective acutely, amitriptyline long term Prospective, longitudinal18 Ondansetron, promethazine, diphenhydramine, benzodiazepines, opioids (unspecified) 2 8 Study authors did not report success of specific treatments Retrospective19 Zonisamide, levetiracetam, tricyclic antidepressants (unspecified) 3 3 Improvement with antiepileptics, tricyclic antidepressants prone to failure Retrospective20 Morphine, ondansetron, lorazepam, acetaminophen, fluoxetine, codeine, Buscopan, coenzyme Q, propranolol, carbamazepine 3 4 Morphine, ondansetron, lorazepam most helpful Retrospective21 Benzodiazepines (unspecified), olanzapine, chlorprothixene, hydroxyzine 3 36 Study authors did not report success of specific treatments Case series22 Ondansetron, promethazine, metoclopramide, lorazepam, esomeprazole, morphine sulfate, erythromycin 4 2 Multiple drugs given, but hot shower most effective Case series23 Ondansetron, promethazine, proton pump inhibitors (unspecified), metoclopramide, Dilaudid 4 8 Poor response to antiemetics in general Case series24 Alprazolam, lorazepam, ondansetron, prochlorperazine 4 4 Alprazolam improved symptoms for one patient; other antiemetics unhelpful Case series25 Opioids (unspecified) 4 2 Symptoms did not improve with opioids Case series26 Morphine 4 7 Study authors did not report success or failure of morphine Case series27 Haloperidol, ondansetron, diphenhydramine, chlorpromazine, metoclopramide 4 4 Haloperidol successful after other antiemetics failed Case series28 Capsaicin 4 5 Successful treatment with 0.075% capsaicin cream Case series29 Lorazepam 4 6 Lorazepam prescribed for outpatient treatment with favorable outcome in three cases Case series30 Diazepam, clonazepam, metoclopramide, nabilone 4 2 Self-treatment with benzodiazepines minimally relieved symptoms, not metoclopramide Case series9 Metoclopramide, ondansetron, alprazolam 4 6 Author did not report success of specific treatments Case series31 Metoclopramide, ondansetron, diazepam, olanzapine, haloperidol 4 6 Temporary improvement with haloperidol and olanzapine; other medications unclear Case series32 Alprazolam 4 2 Successful outpatient treatment with alprazolam Case report10 Metoclopramide, prochlorperazine, benzodiazepines (unspecified), haloperidol 5 1 Medications ineffective Case report33 Metoclopramide, domperidone, cisapride, amitriptyline, ondansetron 5 1 Author did not report success of specific treatments Case report34 Metoclopramide, diazepam 5 1 Medications effective Case report35 Promethazine, alprazolam 5 1 Authors did not report success of promethazine Case report36 Metoclopramide, granisetron, prochlorperazine 5 1 Medications ineffective Case report37 Metoclopramide, morphine, pantoprazole 5 1 Combination treatment effective Case report38 Ondansetron, droperidol, diphenhydramine, promethazine, chlorpromazine, lorazepam 5 1 Promethazine and lorazepam most effective Case report39 Morphine, ondansetron 5 1 Author did not report success of specific treatments Case report40 Ondansetron 5 1 Authors did not report success of ondansetron Case report41 Pantoprazole, “analgesics, antiemetics” 5 1 Medications ineffective Case report42 Metoclopramide, antihistamines, granisetron, tropisetron, scopolamine 5 1 Medications ineffective Case report43 Pantoprazole, metoclopramide, ondansetron, dexamethasone, levomepromazine, piritramide 5 1 Levomepromazine, piritramide effective, other medications were not Case report44 Vitamin B6, metoclopramide, chlorazine, dexamethasone, ondansetron 5 1 Medications ineffective Case report45 Metoclopramide, haloperidol 5 1 Medications effective Case report46 Morphine, ondansetron, lorazepam 5 1 Medications ineffective with exception of lorazepam Case report47 Ondansetron 5 1 Authors did not report success of ondansetron Case report48 Ondansetron 5 1 Ondansetron effective Case report49 Ondansetron, prochlorperazine 5 1 Medications ineffective Case report50 Ondansetron 5 1 Ondansetron “of limited benefit” Case report11 Metoclopramide 5 1 Minimal relief with metoclopramide Case report51 Morphine, ondansetron, haloperidol 5 1 Haloperidol successful after other medications failed Case report52 Morphine, “antiemetics” 5 1 Medications ineffective Case report53 Morphine, methadone, benzodiazepines (unspecified) 5 1 Morphine then methadone taper resulted in symptom resolution Case report54 Amitriptyline, paroxetine, sertraline, tegaserod 5 1 Medications ineffective Case report55 Ondansetron, omeprazole 5 1 Authors did not report success of specific treatments Case report56 Dimenhydrinate, ondansetron, metoclopramide, nabilone 5 1 Medications ineffective with exception of nabilone Case report57 Ondansetron 5 1 Ondansetron ineffective Case report58 Ondansetron, hydromorphone, metoclopramide, promethazine, lorazepam 5 1 Medications ineffective with exception of lorazepam Case report59 Ondansetron 5 1 Ondansetron ineffective Case report60 Capsaicin, ondansetron 5 1 Ondansetron ineffective; successful treatment with 0.025% capsaicin cream Case report61 Metoclopramide 5 1 Authors did not report success of metoclopramide Case report62 Metoclopramide 5 1 Author did not report success of metoclopramide Case report63 Pantoprazole, ondansetron, dimenhydrinate, metoclopramide 5 1 Medications ineffective Case report64 Lorazepam, “antiemetic therapy” 5 1 Lorazepam improved symptoms, not antiemetic therapy Case report65 Ondansetron 5 1 Authors did not report success of ondansetron Case report66 Corticosteroids, prucalopride, clonidine, fentanyl, “usual antiemetics” 5 1 Medications ineffective with exception of fentanyl patches Case report67 Morphine, ondansetron 5 1 Medications ineffective Case report68 Ondansetron, promethazine 5 1 Medications ineffective Case report69 Haloperidol, ondansetron, promethazine, prochlorperazine, metoclopramide, lorazepam, and omeprazole 5 1 Haloperidol successful after patient reported failure of other treatments Case report70 Diazepam, haloperidol, ondansetron 5 1 Authors did not report success of specific treatments Case report71 Promethazine, ondansetron, tramadol, chlordiazepoxide/clidinium, amitriptyline 5 1 Authors did not report success of specific treatments Case report72 Capsaicin, metoclopramide, granisetron 5 1 Metoclopramide and granisetron ineffective, successful treatment with 0.075% capsaicin cream Case report73 Ondansetron, lorazepam, haloperidol 5 1 Ondansetron and lorazepam ineffective; successful treatment with haloperidol Case report74 Lorazepam, ondansetron 5 1 Hyperemesis was refractory to lorazepam and ondansetron Total 205 Discussion Our systematic review revealed a lack of high-quality studies focusing on acute pharmacologic treatment of CHS, and the failure of many case studies and reports to clearly detail the efficacy of their chosen treatments. Benzodiazepines (most commonly lorazepam) were mentioned most frequently, followed by haloperidol and capsaicin for acute treatment of CHS among cannabis users. For long-term treatment, TCAs were utilized most frequently for mitigation of cyclic vomiting in patients who were also cannabis users. Given the complexity of the endocannabinoid system and hypothalamic-pituitary-adrenal (HPA) axis regulation of nausea and emesis, it is not surprising that no one consistently effective class of antiemetics was cited for the treatment of CHS.12 Endogenous cannabinoids bind to the G protein–coupled cannabinoid receptors CB1 and CB2. The CB1 receptors are located in the central nervous system (CNS) and nerves throughout the gastrointestinal (GI) tract and modulate gastroprotection, gastric secretion, motility, inflammation, sensation, as well as oral salivation.75 CB2 receptors are localized in lymphoid tissues in the periphery and associated with immune system regulation.12 It is believed the antiemetic properties of cannabinoids are mediated by CB1 activation in the hypothalamus and the pro-emetic properties from CB1 activation in the GI tract.11 Activation of the CB1 receptor by endogenous cannabinoids suppresses activation of the HPA axis and sympathetic nervous system to stress.18 It is paradoxical that cannabis has well-known antiemetic properties, yet chronic cannabis use may lead to CHS. The active compound in cannabis, ∆9-tetrahydrocannabinol (THC), binds to CB1 and CB2 receptors.12 Chronic THC exposure leads to its accumulation in adipose cells. Prolonged supranormal levels of THC desensitize and downregulate CB1 receptors, thus increasing the stress response that may in turn induce CHS.11 Cannabidiol, a cannabinoid molecule in marijuana, is antiemetic in low doses but pro-emetic at higher doses.76 Similar to THC, buildup of cannabidiol in chronic cannabis users may also be a factor in CHS. Patients with CHS may also have genetic variation in their hepatic drug-transforming enzymes, leading to excessive levels of pro-emetic cannabis metabolites.23 Both γ-aminobutyric acid (GABA) and its receptors reside in the CNS as well as in the GI tract, where GABA modulates motility, mucosal homeostasis, and release of histamine, acetylcholine, serotonin, and prostaglandins.77 Benzodiazepines have GABA receptor agonist-like properties with antiemetic effects through anxiolysis, sedation, and inhibition of medullary and vestibular nuclei.77 In our review, benzodiazepines such as lorazepam and alprazolam were touted as successful treatment for CHS in several articles.17, 20, 24, 29, 30, 32, 38, 46, 58, 64 Dopamine receptors D2 and D3 in the medulla are also involved in the pathophysiology of emesis, and antagonists such as metoclopramide, prochlorperazine, and promethazine are commonly used antiemetics.12 However, data suggest that metoclopramide is not an effective treatment for cyclic vomiting syndrome.77 A total of 13 metoclopramide treatment failures were noted for CHS based on our review.10, 23, 27, 30, 36, 42, 13, 44, 56, 58, 63, 69, 72 The butyrophenone haloperidol was reported as effective in several case series and reports that may reflect its unique pharmacology relative to the other more common antiemetics.27, 31, 51, 69, 73 Haloperidol is primarily an antipsychotic but has been used off-label as an effective general antiemetic.78 Serotonin, or 5-hydroxytryptamine (5-HT), is a major neuroendocrine transmitter in the regulation of emesis.77 Histamine activates neurons in the medulla implicated with nausea, emesis, and motion sickness.77 Although the combined role of serotonin and histamine in CHS and cyclic vomiting syndrome is unknown, tricyclic antidepressants were shown to be effective for long-term treatment of both CHS and cyclic vomiting syndrome.16, 17 This may be secondary to the inhibition of serotonin reuptake from TCA blockade of the serotonin transporter and TCA antihistamine effects.77 Interestingly, the 5-HT3 antagonists, such as ondansetron, were used infrequently and/or not mentioned as successful treatment for CHS in the articles screened in our review. In all level-4 and -5 articles, hot showers and bathing were reported to be universally effective at mitigating or abating CHS. Several theories have been suggested to explain this mechanism. One theory is the dose-dependent hypothermic effect of THC on the CB1 receptors of the hypothalamus, the thermoregulatory center of the brain.22 A “cutaneous steal” syndrome is another putative mechanism, in which cutaneous vasodilation from hot water alters core temperature and splanchnic circulation, thus lessening abdominal discomfort.12, 64 Another possibility is that the dysphoria and anxiety associated with CHS may be subjectively relieved with hot showering or bathing. Capsaicin, or 8-methyl-N-vanillyl-6-nonenamide, is a chemical found in chili peppers that produces a sensation of heat on contact with skin. Available as a topical cream, capsaicin binds to transient receptor potential vanilloid-1 (TRPV1) receptors found widely throughout the body, often in proximity to CB-1 receptors and thus suggesting a functional interaction.79, 80 Such areas include the medullary vomiting center and GI tract. The TRPV1 receptors are also activated by low pH and high temperature, and they may regulate release of substance P, an important mediator of nausea and emesis, from sensory nerves.81 As such, TRPV1 receptors may play a teleological role in the efficacy of hot showers/baths for symptomatic relief of CHS. Seven patients with acute CHS successfully treated with topical capsaicin were reported.28, 60, 72 Our systematic review has potential limitations. There are no large-scale randomized multicenter double-blind studies regarding the pharmacologic treatment of CHS. Therefore, any bias associated with the design or conduct of the included studies could have influenced the results of our systematic review. The overall number of patients is small. Because publication bias is a concern, we used a search strategy with a low inclusion threshold of all published and unpublished reports. For this reason, we also included case series and case reports to be as comprehensive as possible. Conclusion High-quality evidence for pharmacologic treatment of CHS is extremely limited. Benzodiazepines are most frequently reported as effective for acute treatment of CHS, followed by haloperidol and capsaicin. Because the prevalence of CHS is likely to increase, future prospective trials are greatly need