Alternative Medications for Chronic Insomnia in an 89‑Year‑Old After Trazodone and Mirtazapine Failure
Switch to low‑dose doxepin 3 mg at bedtime as the preferred next‑line agent, because it specifically targets sleep‑maintenance insomnia with minimal anticholinergic burden and no abuse potential, and it is the safest option for older adults who have failed sedating antidepressants. 1
Why Low‑Dose Doxepin Is the Best Choice
The American Academy of Sleep Medicine recommends low‑dose doxepin (3–6 mg) as a second‑line agent for sleep‑maintenance insomnia, with moderate‑quality evidence showing a 22–23 minute reduction in wake after sleep onset, improvements in sleep efficiency, total sleep time, and sleep quality, with no significant difference in adverse events versus placebo. 1
At hypnotic doses of 3–6 mg, doxepin exhibits minimal anticholinergic activity, making it especially suitable for older adults transitioning off anticholinergic antihistamines or other sedating agents. 1
Doxepin has no abuse potential and carries no risk of dependence or withdrawal, which is critical in an 89‑year‑old patient who may require long‑term therapy. 1
Start doxepin 3 mg at bedtime; if insufficient after 1–2 weeks, increase to 6 mg while preserving the favorable safety profile and providing additional efficacy. 1
Why Trazodone and Mirtazapine Failed
The American Academy of Sleep Medicine issues a weak recommendation against using trazodone for insomnia because it yields only a minimal, clinically insignificant improvement (≈10 min shorter sleep latency, ≈22 min longer total sleep time, ≈8 min less wake after sleep onset), and subjective sleep quality does not improve compared with placebo. 1
In older adults, adverse events occur in ≈75 % of participants on trazodone versus ≈65 % on placebo, with headache in ≈30 % and somnolence in ≈23 %, and the guideline task force concluded that potential harms outweigh any modest benefits. 1
Mirtazapine at 30 mg is above the optimal sedating dose range (7.5–15 mg), because paradoxically, lower doses are more sedating through histamine H₁‑receptor antagonism, while higher doses activate noradrenergic pathways that can reduce sedation and cause next‑day hangover effects. 1, 2
A recent randomized controlled trial in older adults (MIRAGE study) showed that mirtazapine 7.5 mg significantly reduced insomnia severity (mean ISI change −6.5 vs −2.9 for placebo, p=0.003), but 6 participants in the mirtazapine group discontinued due to adverse events, indicating that even at lower doses, tolerability remains a concern in this age group. 2
Alternative Second‑Line Options (If Doxepin Fails or Is Contraindicated)
For Persistent Sleep‑Maintenance Problems
Suvorexant 10 mg (orexin‑receptor antagonist) reduces wake after sleep onset by ≈16–28 minutes via a mechanism distinct from benzodiazepine‑type agents, and carries a lower risk of cognitive and psychomotor impairment than benzodiazepine‑type agents. 1, 3
Suvorexant is FDA‑approved for insomnia in older adults at a starting dose of 10 mg (maximum 15 mg), with polysomnographic data showing sustained efficacy at 1 and 3 months without tolerance development. 3
The American Academy of Sleep Medicine suggests suvorexant for sleep‑maintenance insomnia, though the recommendation is classified as WEAK due to low overall quality of evidence and imprecision. 1
For Combined Sleep‑Onset and Maintenance Problems
Eszopiclone 1 mg at bedtime (maximum 2 mg for adults ≥65 years) improves both sleep onset and maintenance, increasing total sleep time by 28–57 min and yielding moderate‑to‑large improvements in subjective sleep quality. 1
Elderly adults (≥65 years) must initiate eszopiclone at 1 mg and not exceed 2 mg because of increased sensitivity and fall risk. 1
FDA labeling limits eszopiclone use to ≤4 weeks for acute insomnia; evidence beyond 4 weeks is limited, although 6‑month trials exist. 1
For Sleep‑Onset Insomnia Only
Ramelteon 8 mg (melatonin‑receptor agonist) has no abuse potential, is not DEA‑scheduled, and does not cause withdrawal, making it appropriate for patients with a history of substance use or concern about dependence. 1
Ramelteon does not impair next‑day cognitive or motor performance, unlike benzodiazepines and Z‑drugs (zolpidem, eszopiclone), which commonly cause morning grogginess and cognitive impairment. 1
Mandatory Concurrent Behavioral Therapy
The American Academy of Sleep Medicine and the American College of Physicians issue a strong recommendation that all adults with chronic insomnia receive Cognitive Behavioral Therapy for Insomnia (CBT‑I) as the initial intervention, either alone or combined with pharmacotherapy, because it provides superior long‑term efficacy and maintains benefits after medication discontinuation. 1
Core CBT‑I components include stimulus control (use the bed only for sleep, leave the bed if unable to fall asleep within ≈20 minutes), sleep restriction (limit time in bed to approximate actual sleep time plus a short buffer), relaxation techniques, and cognitive restructuring of maladaptive sleep beliefs. 1
CBT‑I can be delivered via individual sessions, group programs, telephone, web‑based platforms, or self‑help books, making it feasible even in settings with limited resources. 1
Agents to Explicitly Avoid in This Patient
Over‑the‑counter antihistamines (diphenhydramine, doxylamine) are not recommended due to lack of efficacy data, strong anticholinergic effects (confusion, urinary retention, falls, daytime sedation, delirium), and tolerance development within 3–4 days. 1
Traditional benzodiazepines (lorazepam, temazepam, clonazepam) have long half‑lives leading to drug accumulation, prolonged daytime sedation, higher fall and cognitive‑impairment risk, and are linked to dementia and fractures in older adults. 1
Antipsychotics (quetiapine, olanzapine) have weak evidence for insomnia benefit and significant risks such as weight gain, metabolic dysregulation, extrapyramidal symptoms, and increased mortality in elderly patients with dementia. 1
Melatonin supplements produce only ≈9 min reduction in sleep latency; evidence of efficacy is insufficient. 1
Safety Monitoring and Duration Considerations
Reassess after 1–2 weeks to evaluate sleep‑onset latency, total sleep time, nocturnal awakenings, and daytime functioning; adjust dose or switch agents if response is inadequate. 1
Monitor for complex sleep behaviors (e.g., sleep‑driving, sleep‑walking, sleep‑eating) at every visit; discontinue the medication immediately if such behaviors are identified. 1
All hypnotics carry risks of daytime impairment, driving impairment, falls, fractures, and cognitive decline, particularly in older adults; therefore, prescribe the lowest effective dose for the shortest necessary duration. 1
If insomnia persists beyond 7–10 days despite appropriate therapy, evaluate for comorbid sleep disorders (e.g., sleep apnea, restless‑legs syndrome, periodic limb movement disorder, circadian‑rhythm disorders). 1
Common Pitfalls to Avoid
Do not add a second hypnotic (e.g., benzodiazepine or Z‑drug) to mirtazapine or trazodone; this creates dangerous polypharmacy with additive CNS depression, respiratory risk, falls, and cognitive impairment. Instead, either switch agents or optimize the current regimen. 1
Do not assume trazodone or mirtazapine are safer than FDA‑approved hypnotics; guideline evidence does not support a superior safety profile, and the American Academy of Sleep Medicine recommends against trazodone for primary insomnia. 1
Do not initiate or escalate pharmacotherapy without concurrent CBT‑I, as behavioral therapy provides more durable benefits than medication alone and is mandated as first‑line treatment by guideline societies. 1
Do not use adult dosing in older adults; age‑adjusted dosing (e.g., doxepin ≤6 mg, eszopiclone ≤2 mg, suvorexant ≤15 mg) is essential to reduce fall risk and cognitive impairment. 1