What is the role of olanzapine in treating refractory nausea and vomiting?

Olanzapine for Refractory Nausea and Vomiting

Olanzapine is an effective option for refractory nausea and vomiting, particularly in cancer-related settings, and should be considered when standard antiemetics fail. 1

Evidence from Guidelines

The MASCC/ESMO guidelines explicitly recognize olanzapine as a pharmacological intervention that "could be considered" for refractory nausea and vomiting, noting its activity at multiple dopaminergic, serotonergic, muscarinic, and histaminic receptor sites. 1 This multi-receptor blockade provides a mechanistic rationale for its efficacy when single-receptor antagonists fail.

The NCCN guidelines report that olanzapine was found effective for acute and delayed emesis in phase II trials, and specifically note its value for "delayed and refractory emesis and nausea." 1 However, these guidelines appropriately caution about use in elderly patients due to boxed warnings regarding death in patients with dementia-related psychosis, type II diabetes, and hyperglycemia. 1

The AGA clinical practice update on medically refractory gastroparesis does not specifically list olanzapine in their treatment table, but the Praxis Medical Insights summary notes that olanzapine is "especially helpful in palliative care settings for nausea management." 2

Dosing and Administration

The typical dose is 2.5-5 mg daily, with most patients responding to lower doses. 3

• A multicenter Japanese study found the average dose was 3.6 mg, with most patients receiving either 2.5 mg (n=61) or 5 mg (n=46). 3
• The phase II trial cited in NCCN guidelines used olanzapine in patients receiving highly emetogenic chemotherapy (cyclophosphamide, doxorubicin, cisplatin). 1
• Importantly, oral formulations may not be appropriate for patients with active vomiting or severe nausea, as ingestion itself could trigger emesis. 4

Efficacy in Specific Contexts

Chemotherapy-Induced Nausea and Vomiting (CINV)

Olanzapine demonstrates particularly strong efficacy for refractory CINV. 5

• A retrospective study showed symptom relief in 13 of 14 patients (93%) with CINV refractory to guideline-recommended prophylaxis. 5
• The Cochrane review (2018) found moderate-quality evidence that olanzapine probably doubles the likelihood of no nausea or vomiting during chemotherapy from 25% to 50% (RR 1.98,95% CI 1.59-2.47; NNTB=5) when added to standard therapy. 6
• Olanzapine probably reduces delayed nausea (RR 1.71,95% CI 1.40-2.09) and delayed vomiting (RR 1.28,95% CI 1.14-1.42). 6

Palliative Care Setting

In palliative care, olanzapine can control or reduce nausea and vomiting refractory to standard antiemetics. 4, 3

• The average treatment duration in palliative care patients was 18.7 days, with average duration from initial use until death of 39 days, suggesting use in patients with poor prognoses. 3
• No differences in duration of administration were found between 2.5 mg and 5 mg doses. 3

Safety Profile

The main concern is somnolence and fatigue, which occurs more frequently than with placebo. 6

• Olanzapine probably increases somnolence and fatigue (RR 2.33,95% CI 1.30-4.18; absolute risk increase 8.2%). 6
• It is uncertain if olanzapine increases serious adverse events (RR 2.46,95% CI 0.48-12.55; low-quality evidence). 6
• In elderly patients, use extreme caution due to increased mortality risk in dementia-related psychosis, and risks of type II diabetes and hyperglycemia. 1
• Short-term use (less than one week) has not been associated with weight gain or diabetes onset seen with chronic use. 7
• No treatment-related adverse events were reported in one retrospective study of 41 cancer patients. 5

Clinical Algorithm for Use

When to consider olanzapine:

1. First-line antiemetics have failed (5-HT3 antagonists, NK1 antagonists, dopamine antagonists, corticosteroids). 1
2. Delayed or breakthrough nausea/vomiting persists despite guideline-directed prophylaxis. 1, 5
3. Palliative care setting where multiple receptor blockade may address various etiologies. 2, 4

Dosing approach:

• Start with 2.5 mg daily, particularly in elderly or frail patients. 3
• May increase to 5 mg if inadequate response and tolerability is good. 3
• The Cochrane review found insufficient evidence to determine if 5 mg is as effective as 10 mg, but 5 mg may confer lower risk of somnolence. 6

Important Caveats

Olanzapine should not be first-line therapy—it is reserved for refractory cases after standard antiemetics have been tried. 1 The MASCC/ESMO guidelines emphasize that "antiemetics are most effective when used prophylactically" and that "it is preferable to use maximally effective antiemetics as first-line therapy." 1

All evidence pertains to oral administration only—findings cannot be extrapolated to injectable forms (IV, IM, or subcutaneous). 6

Monitor for sedation, which may be dose-limiting, particularly when combined with other sedating medications like opioids in palliative care. 6

Interestingly, one study found that 81.3% of patients continued olanzapine even after it was judged ineffective, suggesting possible placebo effects or benefits not captured by standard assessments. 5