Is it safe to combine mirtazapine with Unisom (doxylamine)?

Combining Mirtazapine with Unisom (Doxylamine): Safety Considerations

Combining mirtazapine with Unisom (doxylamine) carries significant risk for additive CNS depression and anticholinergic effects and should generally be avoided, particularly in older adults. Both agents have potent sedating and anticholinergic properties that can compound when used together, increasing the risk of excessive daytime sedation, cognitive impairment, falls, and other adverse effects 1.

Why This Combination Is Problematic

Additive Sedative Effects

• Both mirtazapine and doxylamine (the active ingredient in Unisom) are potent histamine H1 receptor antagonists, which is the primary mechanism responsible for their sedating effects 2, 3.
• Clinical guidelines explicitly warn about the "additive effect on psychomotor performance with concomitant CNS depressants," which includes combining multiple sedating agents 1.
• The combined sedation can lead to impaired motor coordination, increased fall risk, and next-day cognitive impairment that extends beyond the intended sleep period 1.

Anticholinergic Burden

• Doxylamine, as an antihistamine, possesses significant anticholinergic properties that can cause dry mouth, constipation, urinary retention, confusion, and cognitive impairment 1.
• While mirtazapine has relatively low affinity for muscarinic cholinergic receptors compared to tricyclic antidepressants, it still contributes some anticholinergic effects 2, 4.
• The cumulative anticholinergic burden from combining these agents increases the risk of delirium, particularly in vulnerable populations 1.

Guideline Recommendations on Sleep Medications

Mirtazapine for Insomnia

• Mirtazapine is considered a third-line option for insomnia treatment, recommended only after trials of short-intermediate acting benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon) and ramelteon have been attempted 1, 5.
• When used for insomnia, mirtazapine should be prescribed at doses of 7.5-30 mg at bedtime 1, 5.
• Lower doses (7.5-15 mg) are typically more sedating due to greater histaminergic effects, while higher doses engage more noradrenergic activity that can be less sedating 5.

Over-the-Counter Antihistamines (Including Doxylamine)

• OTC antihistamine sleep aids are explicitly not recommended for chronic insomnia treatment due to relative lack of efficacy and safety data 1.
• Guidelines note that "evidence for their efficacy and safety is very limited" and highlight concerns about "serious side effects arising from their concurrent anticholinergic properties" 1.
• The American Academy of Sleep Medicine consensus states that antihistamines should not be used for chronic insomnia management 1.

Clinical Algorithm for Managing This Situation

If a Patient Is Currently Taking Both:

1. Assess for adverse effects immediately: excessive sedation, confusion, falls, urinary retention, constipation, dry mouth 1.
2. Discontinue the doxylamine (Unisom) as it is the less evidence-based agent and contributes more anticholinergic burden 1.
3. Optimize mirtazapine dosing for sleep if insomnia persists, typically starting at 7.5-15 mg at bedtime 1, 5.
4. Consider cognitive-behavioral therapy for insomnia (CBT-I) as first-line non-pharmacological treatment, which should be implemented even when using pharmacotherapy 1.

If Insomnia Persists on Mirtazapine Alone:

• Do not add doxylamine; instead, consider evidence-based alternatives 1:
  • First, ensure adequate trial of CBT-I 1
  • Consider switching to or adding a short-intermediate acting benzodiazepine receptor agonist (zolpidem 5 mg, eszopiclone, zaleplon) 1
  • Consider ramelteon as an alternative mechanism 1
  • Evaluate and treat underlying causes: pain, depression, anxiety, sleep apnea, medication side effects 1

Special Considerations for Older Adults:

• The risk-benefit ratio is particularly unfavorable in elderly patients due to increased sensitivity to anticholinergic and sedative effects 1.
• Mirtazapine dosing should start at the lower end (7.5 mg) in older adults 1, 5.
• Antihistamines like doxylamine should be especially avoided in this population 1.

Common Pitfalls to Avoid

• Do not assume OTC sleep aids are safer than prescription options – the evidence suggests otherwise, particularly for chronic use 1.
• Do not combine sedating agents without clear clinical justification and close monitoring for additive effects 1.
• Do not neglect non-pharmacological interventions – CBT-I should be the foundation of insomnia treatment 1.
• Do not continue ineffective treatments – if mirtazapine alone is insufficient after an adequate trial (4-8 weeks), reassess the approach rather than adding more sedating agents 1.

Bottom Line

The combination of mirtazapine and doxylamine (Unisom) should be avoided. If a patient requires pharmacological treatment for insomnia beyond mirtazapine alone, evidence-based alternatives include short-acting benzodiazepine receptor agonists or ramelteon, combined with cognitive-behavioral therapy for insomnia 1, 5. The antihistamine component of Unisom adds risk without established benefit for chronic insomnia management 1.