Is Inapsine (clonazepam) an appropriate treatment for cannabinoid hyperemesis syndrome?

Inapsine (Droperidol) for Cannabinoid Hyperemesis Syndrome

Inapsine (droperidol) is a highly effective second-line agent for acute cannabinoid hyperemesis syndrome, with evidence showing it can reduce emergency department length of stay by nearly 50% compared to standard antiemetics. 1, 2

First-Line vs. Second-Line Treatment Hierarchy

Benzodiazepines—specifically lorazepam (0.5–2 mg IV or PO every 4–6 hours)—are the most effective first-line agents for acute CHS-related nausea and vomiting. 1, 2, 3 Multiple prospective studies and case series demonstrate superior efficacy compared to conventional antiemetics, providing both antiemetic effects through sedation and anxiolytic properties that address the stress-mediated component of CHS. 2, 4

Droperidol (Inapsine) and haloperidol serve as second-line antipsychotic agents when benzodiazepines are insufficient or contraindicated. 1, 2, 5 These butyrophenones have demonstrated the ability to halve hospital length of stay (6.7 hours vs. 13.9 hours; p=0.014). 2, 5

Mechanism of Action in CHS

The endocannabinoid system's dysregulation in CHS involves CB1 receptors densely distributed in the dorsal vagal complex, leading to loss of negative feedback on the hypothalamic-pituitary-adrenal axis and increased vagal nerve discharges that trigger vomiting. 1, 5 Droperidol's dopamine D2 receptor antagonism in the chemoreceptor trigger zone, combined with its powerful sedating effects, addresses both the neurochemical and stress-mediated components of CHS. 6

Practical Acute Management Algorithm

Step 1: Rule Out Life-Threatening Conditions

• Exclude acute abdomen, bowel obstruction, mesenteric ischemia, pancreatitis, and myocardial infarction before attributing symptoms solely to CHS. 2, 5, 3

Step 2: First-Line Pharmacotherapy

• Administer lorazepam 0.5–2 mg IV/PO every 4–6 hours as the initial agent. 1, 2, 3

Step 3: Second-Line Agents (if inadequate response)

• Add haloperidol or droperidol for superior efficacy in reducing hospital stay. 1, 2, 5
• Alternative antipsychotics include promethazine (12.5–25 mg every 4–6 hours) or prochlorperazine (5–10 mg every 6–8 hours), though these are less effective than haloperidol. 2

Step 4: Adjunctive Therapy

• Apply topical capsaicin 0.1% cream to the abdomen to activate TRPV1 receptors, which provides consistent symptom relief. 1, 2, 5, 3

Critical Medications to Avoid

Never use opioids in CHS patients—they exacerbate nausea, carry high addiction risk, and do not address the underlying pathophysiology. 1, 2, 5, 3 This is a common pitfall that worsens outcomes. 2, 7

Ondansetron and other 5-HT3 antagonists have limited efficacy in CHS and often fail to provide adequate symptom control. 1, 3, 8 While they may be tried, they should not be relied upon as primary therapy. 3

Definitive Long-Term Management

Complete and sustained cannabis cessation is the only curative treatment for CHS, requiring at least 6 months of continuous abstinence (or duration equal to three typical vomiting cycles). 1, 2, 3 Partial reduction or switching to edible forms does not lead to symptom improvement. 2

Initiate amitriptyline as preventive pharmacotherapy: start at 25 mg at bedtime, increase by 25 mg weekly, targeting a maintenance dose of 75–100 mg at bedtime. 1, 2, 3 Tricyclic antidepressants are the mainstay of long-term prophylaxis. 1, 3

Diagnostic Confirmation

Suspect CHS when all three criteria are met: 1, 2

• Cannabis exposure: ≥1 year of regular use (>4 times/week) before symptom onset
• Clinical pattern: Stereotypical episodic vomiting occurring ≥3 times annually with acute onset
• Definitive confirmation: Complete symptom resolution after ≥6 months of continuous cannabis abstinence

Hot water bathing behavior is present in 44–71% of CHS cases but also occurs in 44% of cyclic vomiting syndrome patients, limiting its diagnostic specificity. 1, 2, 5

Common Pitfalls

Avoid extensive diagnostic testing once CHS is suspected—this leads to unnecessary procedures and diagnostic delays averaging several years. 2, 5 Focus on making an early diagnosis to facilitate appropriate treatment. 1

Do not accept patient denial of the cannabis-symptom link—many patients attribute vomiting to food, alcohol, or stress, which impedes appropriate counseling. 2

Refer all CHS patients to addiction medicine specialists or substance use counselors, as relapse rates exceed 40% and ongoing support is essential. 2, 3 Co-management with psychiatry is advisable given high prevalence of anxiety and depression comorbidities. 1, 3