Side Effects of Long-Term Montelukast Administration
The FDA issued a black box warning in 2020 for montelukast due to serious neuropsychiatric events, and these risks should be carefully weighed against benefits, particularly since montelukast is less effective than alternative therapies like inhaled corticosteroids for asthma and intranasal corticosteroids for allergic rhinitis. 1
Critical Neuropsychiatric Risks (Black Box Warning)
The most concerning side effects with long-term montelukast use are neuropsychiatric events, which prompted the FDA's strongest safety warning:
- Suicidal thoughts and actions are among the most serious risks associated with montelukast 1
- Depression is the most frequently reported adverse event in the global pharmacovigilance database (reporting odds ratio 6.93) 2
- Anxiety and sleep disturbances show consistent associations in large-scale observational studies, particularly in older adults 3
- Behavioral changes including aggression (especially in children with ROR 29.77), agitation, hostility, and irritability are well-documented 4, 2
- Sleep-related disorders including insomnia, nightmares, dream abnormalities, and sleepwalking occur frequently in both children and adults 4, 5
- Other neuropsychiatric manifestations include hallucinations, restlessness, and tremor 4
Age-Specific Considerations
- Children appear particularly susceptible to nightmares and aggression, with nightmares being one of the most frequently reported adverse events in pediatric populations 5, 2
- In a pediatric pulmonology series, 5.7% of children required treatment discontinuation due to adverse reactions, with insomnia (n=7) and hyperactivity (n=4) being most common 5
- Older adults may be particularly vulnerable to anxiety and sleeping disorders based on large observational studies 3
Common Non-Neuropsychiatric Side Effects
Beyond the black box warning events, several other adverse effects occur with long-term use:
- Headache is the most common side effect overall and was reported most frequently in the Dutch pharmacovigilance database (ROR 2.26) 1, 2
- Gastrointestinal effects including diarrhea, indigestion, nausea, vomiting, and abdominal pain are documented 4, 5
- Allergic reactions including facial/lip/tongue/throat swelling, hives, and itching can occur 4
- Increased bleeding tendency has been reported 4
- Musculoskeletal symptoms including joint pain, muscle aches, and muscle cramps 4
Rare but Serious Adverse Effects
- Hepatotoxicity: Hepatitis and elevated liver enzymes are less common but important adverse effects requiring monitoring 1
- Pancreatitis has been reported in clinical trials, though causality has not been definitively established 1
- Eosinophilic conditions: Systemic eosinophilia, sometimes with clinical features consistent with Churg-Strauss syndrome (allergic granulomatous angiitis), has been reported, particularly when oral corticosteroids are being tapered 4, 2
- Neurological symptoms: Pins and needles/numbness, seizures, and paresthesias in extremities (including two pediatric cases not previously described) have been documented 4, 5
Critical Risk-Benefit Context
The FDA explicitly states that montelukast's benefits may not outweigh the risks, especially when disease symptoms are mild and can be adequately treated with other medications. 1
- Montelukast is less effective than intranasal corticosteroids for allergic rhinitis and should not be considered first-line therapy 1
- For asthma, inhaled corticosteroids are generally more effective as first-line therapy for persistent asthma in children, with studies showing fluticasone provides better asthma control than montelukast 6
- The 2020 NAEPP guidelines note that cromolyn, nedocromil, leukotriene receptor antagonists including montelukast, and theophylline have "limited availability for use in the United States, and/or have an increased risk of adverse consequences" 7
Monitoring and Management Recommendations
Before Initiating Therapy
- Explicitly discuss neuropsychiatric risks with patients and families before starting montelukast, including the potential for suicidal thoughts and behavioral changes 1
- Do not prescribe for mild disease when safer alternatives like intranasal corticosteroids or inhaled corticosteroids are available and appropriate 1
During Treatment
- Monitor for unusual behavioral or mood changes, particularly in the first weeks of therapy 1
- Watch for signs of eosinophilic conditions: vasculitic rash, worsening pulmonary symptoms, cardiac complications, neuropathy, or severe sinusitis 4
- Do not continue therapy without reassessing risk-benefit if any neuropsychiatric symptoms emerge, even if mild 1
Timing of Adverse Events
- Neuropsychiatric symptoms can appear from the first days to months after starting treatment 5
- Symptoms typically disappear after stopping the medication 5
Important Clinical Pitfalls to Avoid
- Never use montelukast as monotherapy for acute asthma attacks or status asthmaticus—it is not indicated for reversal of bronchospasm 4
- Do not abruptly substitute montelukast for inhaled or oral corticosteroids; any dose reduction of steroids must be gradual under medical supervision 4
- Patients with aspirin sensitivity should continue avoiding aspirin and NSAIDs while taking montelukast, as it does not prevent aspirin-induced bronchoconstriction 4
- Do not prescribe additional doses for exercise-induced bronchoconstriction if the patient is already taking daily montelukast for chronic asthma 4
Long-Term Safety Profile from Clinical Trials
While controlled trials showed a tolerability profile similar to placebo, these studies preceded recognition of neuropsychiatric risks:
- In pooled analysis of 3,386 adults and 336 children, overall incidence of clinical and laboratory adverse events was similar to placebo 8
- No dose-related adverse effects were observed in adults treated with up to 200 mg daily (20 times the recommended dose) for 5 months 8
- However, post-marketing surveillance has revealed the neuropsychiatric adverse events that led to the black box warning 4, 3