What is the best treatment for a patient with a fight-or-flight state during sleep who is non-responsive to Cognitive Behavioral Therapy for Insomnia (CBT-I)?

Treatment for Fight-or-Flight State During Sleep in CBT-I Non-Responsive Patients

For patients with hyperarousal during sleep who have failed CBT-I, pharmacotherapy should be initiated with either low-dose doxepin (3-6 mg) for sleep maintenance issues or a nonbenzodiazepine benzodiazepine receptor agonist (eszopiclone, zolpidem) for short-term use, while simultaneously addressing potential underlying psychiatric or medical conditions that may be perpetuating the hyperarousal state. 1

Initial Assessment Before Pharmacotherapy

Before initiating medication, several critical evaluations are necessary:

• Rule out primary psychiatric or medical disorders - The failure of insomnia to remit after 7-10 days of any treatment may indicate an underlying psychiatric or physical disorder requiring evaluation, as sleep disturbances may be the presenting manifestation of these conditions 2
• Assess for comorbid conditions - Depression, PTSD, anxiety disorders, or medical conditions can manifest as hyperarousal during sleep and require targeted treatment 3, 4
• Evaluate for other sleep disorders - Consider polysomnography if sleep apnea, periodic limb movements, or other primary sleep disorders are suspected as contributors to the arousal state 5

Pharmacological Treatment Algorithm

First-Line Pharmacotherapy Options

For sleep maintenance problems (middle-of-night or early morning awakenings):

• Low-dose doxepin (3-6 mg) is the preferred first choice, as it improved Insomnia Severity Index scores at week 4 in older adults and demonstrated improvements in subjective sleep latency, total sleep time, and sleep quality with no statistically significant differences in adverse event rates compared to placebo 1
• This dose has no black box warning for suicide risk, though the risk for suicidal ideation cannot be excluded 1

For sleep onset problems:

• Nonbenzodiazepine BZRAs (eszopiclone, zolpidem, zaleplon) improved sleep efficiency, sleep onset latency, sleep quality, total sleep time, and wake after sleep onset compared to placebo 1
• Eszopiclone has a relatively longer half-life and is more likely to improve sleep maintenance, though it may produce residual sedation in a minority of patients 1
• Zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks and on sleep efficiency for weeks 2 and 4 in chronic insomnia patients 6
• Ramelteon may be appropriate for patients who prefer non-DEA-scheduled drugs or those with substance use disorder history, particularly for sleep initiation difficulty 1

Critical Safety Considerations

• Use the lowest effective dose for the shortest duration - The FDA has issued safety warnings about serious injuries caused by sleep behaviors (sleepwalking, sleep driving) with nonbenzodiazepine BZRAs 1, 2
• Avoid in high-risk situations - Patients should be counseled that taking sedative-hypnotics while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness 2
• Monitor for complex behaviors - Discontinuation should be strongly considered for patients who report "sleep-driving" episodes or other complex behaviors performed while not fully awake 2
• Screen for contraindications - Avoid benzodiazepines and trazodone due to unfavorable risk-benefit profiles 1

Alternative Behavioral Interventions for CBT-I Non-Responders

If the patient is willing to attempt additional behavioral approaches before or alongside pharmacotherapy:

• Single-component behavioral therapies can be considered when full CBT-I has failed, including sleep restriction therapy alone, stimulus control alone, or relaxation therapy alone, all of which received conditional recommendations from the American Academy of Sleep Medicine 1
• Brief Behavioral Therapy for Insomnia (BBT-I) emphasizes behavioral components (sleep restriction, stimulus control) over cognitive restructuring and may be effective in 1-4 sessions 1, 7
• Relaxation training specifically targets somatic arousal through progressive muscle relaxation, which may directly address the fight-or-flight physiology 1, 8

Addressing Underlying Hyperarousal

The "fight-or-flight state" suggests autonomic hyperarousal that may require specific attention:

• Evaluate for anxiety disorders or PTSD - CBT-I demonstrated large effect sizes (1.5) for insomnia reduction in PTSD patients and medium effect sizes (1.3) for PTSD symptom reduction 3
• Consider psychiatric comorbidity treatment - Treating underlying psychiatric conditions alongside insomnia may be necessary, as CBT-I showed medium to large effects on comorbid psychiatric symptoms 4
• Relaxation-focused interventions - Progressive muscle relaxation training involves methodical tensing and relaxing different muscle groups to lower somatic arousal states that interfere with sleep 1

Common Pitfalls to Avoid

• Do not use antihistamines (diphenhydramine), melatonin, or herbal supplements - These lack efficacy data and carry safety concerns according to the American Academy of Sleep Medicine 5, 8
• Avoid triazolam - It has been associated with rebound anxiety and is not considered a first-line hypnotic 1
• Do not use benzodiazepines - They have an unfavorable risk-benefit profile compared to alternatives 1
• Avoid long-term pharmacotherapy without behavioral intervention - Evidence is insufficient for long-term use beyond 4-5 weeks, and combining with behavioral strategies is essential 1, 8

Monitoring and Follow-Up

• Reassess after 7-10 days - If insomnia does not improve, this indicates the need to evaluate for primary psychiatric or medical illness 2
• Use shared decision-making - Discuss benefits, harms, and costs of short-term medication use with patients 1
• Consider combination therapy - Pharmacotherapy may be used as a temporary adjunct during behavioral therapy attempts 8
• Regular follow-up - Monitor until insomnia stabilizes, then every 6 months 5