How should I manage a 70‑year‑old woman with Sjögren’s syndrome, hypertension, non‑alcoholic fatty liver disease and chronic insomnia who no longer responds to Ambien CR (zolpidem) extended‑release 12.5 mg at bedtime?

Management of Zolpidem-Refractory Insomnia in a 70-Year-Old Woman

Do not increase the zolpidem dose; instead, add low-dose trazodone 25–50 mg or doxepin 3–6 mg at bedtime and immediately initiate cognitive behavioral therapy for insomnia (CBT-I). 1

Why Dose Escalation Is Not the Answer

• Zolpidem extended-release 12.5 mg has only low-quality evidence for efficacy and provides minimal additional benefit over the immediate-release formulation for sleep maintenance. 1
• The FDA approves zolpidem only for short-term use (4–5 weeks), and tolerance develops with chronic nightly use, explaining why the medication "does not work anymore." 1, 2
• Elderly patients (≥65 years) should receive a maximum dose of 5 mg once daily regardless of sex due to increased sensitivity, fall risk (OR 4.28), and hip fracture risk (RR 1.92). 3, 2, 4
• Exceeding recommended doses in women and elderly patients markedly increases next-day impairment, falls, memory impairment, and complex sleep behaviors without proportional efficacy gains. 1

First-Line Add-On Strategy: Sedating Antidepressants

The American Academy of Sleep Medicine recommends sedating antidepressants as first-line add-on therapy when zolpidem alone is insufficient. 1

Specific Agent Selection

• For sleep maintenance insomnia (frequent awakenings or early-morning awakening): Use doxepin 3–6 mg at bedtime, which specifically targets sleep maintenance through histamine H1 receptor antagonism with minimal anticholinergic effects. 1

• For mixed sleep-onset and sleep-maintenance problems: Use trazodone 25–50 mg (start at 25 mg in elderly patients), which addresses both components with minimal anticholinergic burden. 1

• Avoid mirtazapine in this patient with fatty liver disease unless weight gain is desired or comorbid depression exists, as it may worsen metabolic parameters. 1

Why This Approach Works

• Adding agents with different mechanisms of action (serotonin antagonism, histamine antagonism) addresses specific sleep disturbance patterns that zolpidem's short half-life cannot manage. 1
• Zolpidem reduces sleep-onset latency by only 15–19 minutes and is ineffective for middle-of-the-night awakenings or early-morning awakening due to its 2.4-hour half-life. 1, 5

Mandatory Cognitive Behavioral Therapy Integration

The American College of Physicians recommends CBT-I as initial treatment for chronic insomnia and advises that it be added to any pharmacologic regimen. 1

• CBT-I improves sleep-onset latency, wake after sleep onset, and sleep efficiency with moderate-quality evidence. 1
• CBT-I provides durable benefits that persist after discontinuation of hypnotic medication, addressing the underlying behavioral perpetuating factors. 1

Alternative Strategy: Intermittent Dosing

If the patient prefers to continue zolpidem, switch to intermittent (as-needed) dosing 2–3 nights per week rather than nightly use. 1, 3

• Intermittent zolpidem 10 mg reduces sleep-onset latency by approximately 15 minutes and increases total sleep time by 48 minutes on nights taken, while reducing drug exposure and dependence risk. 1, 3
• This strategy addresses tolerance that develops with chronic nightly use. 1

Critical Safety Monitoring in This Elderly Patient

Complex Sleep Behaviors

• Screen for complex sleep behaviors (sleep-driving, sleep-walking, sleep-eating) at every visit and discontinue zolpidem immediately if any occur. The FDA has issued warnings that these behaviors can be life-threatening. 2, 4

Psychiatric Safety

• Assess for worsening depression, suicidal ideation, anxiety, hallucinations, and memory impairment at each follow-up. Zolpidem use is associated with increased risk of suicide attempts and completions (OR 2.08; 95% CI 1.83–2.63) independent of pre-existing psychiatric illness. 4

Fall Prevention

• Ensure the patient allows a full 7–8 hours of sleep opportunity after taking zolpidem to minimize next-day impairment. 6, 2
• The risk of daytime drowsiness is dramatically increased when zolpidem is taken less than 8 hours before awakening. 6

Evaluation for Underlying Sleep Disorders

Failure to improve insomnia after 7–10 days of appropriate treatment should trigger evaluation for primary sleep disorders (e.g., obstructive sleep apnea, restless legs syndrome) or psychiatric conditions (depression, anxiety). 1

• Sjögren's syndrome can cause sleep-disordered breathing due to upper airway dryness and inflammation, warranting consideration of polysomnography if symptoms persist. 1

What NOT to Do

• Do not increase zolpidem to 10 mg or switch to 12.5 mg extended-release in this 70-year-old woman, as elderly patients should receive a maximum of 5 mg regardless of formulation. 3, 2
• Do not combine zolpidem with other CNS depressants or alcohol due to additive effects on psychomotor performance and increased risk of CNS depression. 1, 2
• Do not prescribe benzodiazepines in this elderly patient due to risk of decreased cognitive performance, falls, and dependence. 1

Practical Implementation

1. Discontinue Ambien CR 12.5 mg (dose is too high for elderly patient). 3, 2
2. Start doxepin 3 mg at bedtime (for sleep maintenance) OR trazodone 25 mg at bedtime (for mixed sleep problems). 1
3. Consider intermittent zolpidem 5 mg (not 10 mg) on 2–3 nights per week if needed for sleep onset, taken only when able to stay in bed 7–8 hours. 1, 3, 2
4. Refer immediately to CBT-I (in-person or digital platform). 1
5. Reassess in 1–2 weeks for efficacy, adverse effects, and complex sleep behaviors. 1, 2