What treatment options are available for a patient with Central Nervous System (CNS) hyperarousal, who has undergone Cognitive Behavioral Therapy for Insomnia (CBT-I) without response, and requires a non-sedating intervention to manage their condition?

Treatment for CNS Hyperarousal After CBT-I Failure

For a patient with persistent CNS hyperarousal despite adequate CBT-I, low-dose pregabalin (75-150 mg at bedtime) or low-dose doxepin (3-6 mg) should be considered as these specifically target hyperarousal mechanisms rather than providing sedation. 1, 2

Understanding the Clinical Problem

Your patient's presentation—adequate sleep architecture but persistent sympathetic activation—represents a specific subtype of insomnia characterized by psychophysiological hyperarousal that persists despite behavioral intervention. 3, 4 This is distinct from typical insomnia where sleep itself is disrupted.

• Hyperarousal manifests as elevated cognitive and somatic activation during sleep periods, preventing restorative sleep quality even when sleep duration appears adequate. 3, 4
• CBT-I resistance may indicate trait arousal predisposition, where baseline hyperarousal levels moderate treatment response—patients with higher trait arousal benefit less from standard CBT-I. 4
• This represents a failure of the arousal regulation systems rather than circadian or homeostatic sleep drive dysfunction. 5, 6

Pharmacological Approach for Hyperarousal

First-Line: Pregabalin (Off-Label)

Pregabalin 75-150 mg at bedtime directly reduces CNS hyperarousal through alpha-2-delta calcium channel modulation without causing traditional sedation. 7

• Start at 75 mg and titrate to 150 mg based on response over 1 week. 7
• This targets the underlying arousal mechanism rather than forcing sleep through GABAergic sedation. 7
• Side effects are dose-dependent (dizziness 23%, drowsiness 15%, peripheral edema 10%) and manageable with dose reduction. 7
• Renal dosing adjustment required—98% renal excretion necessitates dose reduction in renal impairment. 7

Alternative First-Line: Low-Dose Doxepin

Doxepin 3-6 mg targets histamine H1 receptors to reduce arousal without the anticholinergic burden of higher doses. 1, 2

• This dose range specifically reduces wake after sleep onset by 22-23 minutes through antihistaminergic effects. 1, 2
• Unlike traditional sedating antidepressants, low-dose doxepin has no black box warning for suicide risk at hypnotic doses, though this risk cannot be entirely excluded. 1
• Preferred when comorbid depression/anxiety exists, as it may address both conditions. 1, 2

Second-Line: Ramelteon

Ramelteon 8 mg works through melatonin receptor agonism to normalize circadian arousal patterns without sedation. 1, 2

• This modulates the circadian component of arousal rather than forcing sleep through receptor antagonism. 2
• Particularly useful when hyperarousal has a circadian dysregulation component. 2
• No abuse potential or withdrawal risk, making it suitable for long-term use. 2

What NOT to Use

Avoid Traditional Sedative-Hypnotics

Benzodiazepine receptor agonists (zolpidem, eszopiclone, zaleplon) and benzodiazepines should be avoided as they provide sedation without addressing underlying hyperarousal. 1, 2

• These agents force sleep through GABAergic mechanisms but don't reduce sympathetic tone or arousal. 2
• Risk of tolerance, dependence, cognitive impairment, and complex sleep behaviors (sleep-driving, sleep-walking). 1, 2
• They may actually worsen recovery quality by suppressing slow-wave sleep architecture. 1

Avoid Over-the-Counter Antihistamines

Diphenhydramine and similar agents lack efficacy data and carry significant safety concerns, particularly anticholinergic effects and daytime sedation. 1, 2, 8

• These provide sedation without addressing arousal mechanisms. 2
• Increased risk of delirium, especially in older adults. 2

Trazodone Not Recommended

Trazodone is specifically not recommended for insomnia treatment by the American Academy of Sleep Medicine despite widespread off-label use. 2

• Lacks robust efficacy data for insomnia. 2
• Provides sedation without targeting hyperarousal pathways. 2

Augmenting CBT-I Rather Than Replacing It

Pharmacotherapy must supplement, not replace, behavioral interventions even when CBT-I has been "unsuccessful." 1

• Re-evaluate CBT-I implementation: Was sleep restriction adequately titrated? Was stimulus control strictly followed? 8
• Consider trait arousal-specific modifications: Patients with high baseline arousal may need more intensive cognitive restructuring targeting arousal-related beliefs. 4
• Add mindfulness-based components to standard CBT-I, as these specifically target hyperarousal reduction. 4

Treatment Algorithm

1. Verify CBT-I adequacy: Ensure all components (sleep restriction, stimulus control, cognitive therapy) were properly implemented for 6-8 weeks. 8

2. Rule out occult comorbidities: Reassess for sleep apnea, restless legs syndrome, circadian disorders, or psychiatric conditions driving hyperarousal. 1, 2

3. Initiate pregabalin 75 mg at bedtime OR doxepin 3 mg at bedtime based on:

   • Choose pregabalin if no renal impairment and patient prefers non-antidepressant option. 7
   • Choose doxepin if comorbid depression/anxiety present. 1, 2

4. Titrate after 1 week: Increase pregabalin to 150 mg or doxepin to 6 mg if inadequate response. 1, 2, 7

5. Reassess at 4 weeks: Evaluate arousal reduction, sleep quality improvement, and daytime functioning. 1

6. If inadequate response: Consider switching to ramelteon 8 mg OR combining low-dose doxepin with ramelteon. 1, 2

7. Long-term management: Attempt medication taper after 3-6 months of stability while maintaining behavioral interventions. 1, 2

Critical Monitoring Parameters

• Sleep diary data throughout treatment to track sleep efficiency, wake after sleep onset, and subjective sleep quality. 1, 9
• Daytime arousal symptoms: Monitor for reduction in fight-or-flight symptoms during waking hours. 3
• Side effects: Particularly dizziness and cognitive effects with pregabalin; anticholinergic effects with doxepin. 1, 7
• Reassess every 2-4 weeks initially, then every 6 months given high relapse rates. 1, 9

Common Pitfalls

• Using sedative-hypnotics for hyperarousal: This treats the symptom (poor sleep) rather than the mechanism (elevated arousal). 2, 6
• Abandoning behavioral interventions: Medication alone has inferior long-term outcomes compared to combined treatment. 1
• Inadequate dose titration: Both pregabalin and doxepin require adequate dosing—starting doses may be insufficient. 1, 7
• Failing to address trait arousal: Patients with high baseline arousal need augmented CBT-I with arousal-specific cognitive interventions. 4
• Polypharmacy with multiple sedatives: Combining sedative medications significantly increases risks without addressing underlying hyperarousal. 2, 9