What is the role of ketotifen and Low Dose Naltrexone (LDN) in treating Mast Cell Activation Syndrome (MCAS)?

Ketotifen and Low Dose Naltrexone (LDN) for Mast Cell Activation Syndrome (MCAS)

Ketotifen can be used as a sedating H1-antihistamine for MCAS to treat dermatologic, gastrointestinal, and neuropsychiatric symptoms, while Low Dose Naltrexone (LDN) may help with SIBO remission in MCAS patients, though evidence for LDN is limited to case reports. 1, 2

First-Line Treatment Options for MCAS

• H1-antihistamines are a cornerstone of MCAS management, with ketotifen specifically mentioned in guidelines as a sedating H1-receptor antagonist that can be compounded as tablets in the US 1
• Ketotifen is approved in the US for allergic eye disease but is used off-label for MCAS to treat dermatologic, gastrointestinal, and neuropsychiatric symptoms 1
• First-generation H1-antihistamines like ketotifen have limitations due to their sedating effects, which can impair driving ability and potentially lead to cognitive decline, particularly in elderly patients 1
• The benefit of ketotifen beyond other antihistamines such as diphenhydramine remains unproven according to the AAAAI guidelines 1

Evidence for Ketotifen in MCAS

• Ketotifen has been used successfully in case reports of systemic mastocytosis, with one report showing substantial symptomatic improvement within 8 days of initiation 3
• A systematic review of H1-antihistamines for primary mast cell activation syndromes found limited evidence from small, historic trials using ketotifen, with most studies being at moderate to high risk of bias 4
• Ketotifen functions as a mast cell stabilizer, which may explain its potential benefits in MCAS beyond its antihistamine properties 5, 6
• A 2023 case report documented "immense improvement upon mast cell stabilization with ketotifen" in a 42-year-old female with MCAS and associated conditions 2

Low Dose Naltrexone (LDN) in MCAS

• LDN is not specifically mentioned in major MCAS treatment guidelines from the AAAAI or NCCN 1
• A recent case report (2023) documented remission of Small Intestinal Bacterial Overgrowth (SIBO) with LDN in a patient with MCAS, suggesting potential benefit in patients with overlapping conditions 2
• There is insufficient evidence from clinical trials to make strong recommendations about LDN use in MCAS 1

Comprehensive MCAS Management Approach

• First-line therapy typically includes H1 and H2 receptor antihistamines, with H1 antihistamines (like ketotifen) primarily targeting dermatologic manifestations, tachycardia, and abdominal discomfort 1
• Oral cromolyn sodium can be used alongside antihistamines, particularly for gastrointestinal symptoms such as bloating, diarrhea, and abdominal cramps 1, 7
• Leukotriene modifiers (montelukast, zafirlukast) or 5-lipoxygenase inhibitor (zileuton) may be added for respiratory or dermatologic symptoms 1
• Aspirin may help reduce flushing and hypotension in some patients, particularly those with elevated urinary prostaglandin metabolites, but should be introduced cautiously due to risk of triggering mast cell degranulation 1

Special Considerations and Cautions

• Sedating antihistamines like ketotifen may cause cognitive decline, especially in elderly populations 1
• Medication trials for MCAS should be conducted in a controlled setting with emergency equipment available 7
• Patients should be prescribed epinephrine autoinjectors if they have a history of systemic anaphylaxis or airway angioedema 1
• Careful trigger identification and avoidance is crucial for management alongside pharmacologic interventions 7

Monitoring and Follow-up

• Serum tryptase levels should be checked within 30-120 minutes of symptom onset during reactions to confirm mast cell activation 7
• Response to therapy should be assessed systematically, with consideration for alternative or additional treatments if symptoms persist 1
• Full allergic workup including skin testing and specific IgE detection should be conducted to identify potential IgE-mediated hypersensitivities 7