What's the next step for a patient with insomnia, taking Adderall (amphetamine) IR 20mg, who has tried Seroquel (quetiapine), Lunesta (eszopiclone), Trazodone, and Tempazepam (temazepam) without success?

Treatment-Resistant Insomnia: Next Steps After Multiple Failed Agents

For this patient who has failed temazepam, eszopiclone (Lunesta), trazodone, and quetiapine while on Adderall IR 20mg, the strongest recommendation is to initiate suvorexant 10-20mg as the next pharmacological agent, while simultaneously implementing cognitive behavioral therapy for insomnia (CBT-I). 1, 2

Why Suvorexant is the Optimal Next Choice

Suvorexant represents a mechanistically distinct approach from all previously failed medications, working through orexin receptor antagonism rather than GABA modulation (temazepam, eszopiclone), serotonin/histamine effects (trazodone, quetiapine), or dopamine pathways (Adderall). 1

• The American Academy of Sleep Medicine specifically recommends suvorexant for treatment-resistant insomnia due to its unique mechanism of blocking wakefulness-promoting orexin neuropeptides. 1
• Suvorexant has demonstrated efficacy over 12 months of continuous use without significant withdrawal effects, addressing concerns about long-term management. 1
• It has a favorable side effect profile in patients already on psychiatric medications like Adderall. 1
• Suvorexant is specifically indicated for sleep maintenance insomnia, reducing wake after sleep onset by 16-28 minutes compared to placebo. 2

Alternative Second-Line Options

If suvorexant is unavailable or contraindicated, consider these alternatives in order:

Doxepin 3-6mg

• Low-dose doxepin works through selective H1 receptor antagonism, avoiding GABA-related tolerance issues that may have contributed to temazepam failure. 2
• The American Academy of Sleep Medicine recommends doxepin specifically for sleep maintenance insomnia, reducing wake after sleep onset by 22-23 minutes. 2
• Moderate-quality evidence shows doxepin improves sleep efficiency and total sleep time in adults. 3
• This represents a mechanistically different approach than the higher-dose trazodone previously tried. 3, 2

Eszopiclone 2-3mg (if Lunesta trial was inadequate)

• If the previous Lunesta trial was brief, subtherapeutic in dose, or poorly tolerated due to timing issues, a retrial may be warranted. 1
• Eszopiclone is effective for both sleep onset and maintenance insomnia with demonstrated long-term efficacy. 1, 4

Critical: Implement CBT-I Simultaneously

Pharmacotherapy alone is insufficient for treatment-resistant insomnia. The American College of Physicians states that CBT-I provides better overall value than pharmacologic treatment, with superior long-term efficacy and fewer harms. 2

• CBT-I should be started immediately alongside any new pharmacotherapy, not sequentially. 2
• Components include stimulus control, sleep restriction therapy, relaxation techniques, and sleep hygiene education. 2
• CBT-I facilitates medication tapering and discontinuation when conditions allow. 3

Medications to Explicitly Avoid

Do not add or retry the following:

• Additional benzodiazepines (beyond the failed temazepam) due to cumulative GABA-ergic effects, cognitive impairment, tolerance, dependence, and fall risk. 1, 2
• Trazodone at any dose - The American Academy of Sleep Medicine specifically does not recommend trazodone for insomnia despite widespread off-label use. 4, 2
• Quetiapine or other antipsychotics - Already failed and carry serious metabolic and movement disorder risks. 3
• Over-the-counter antihistamines (diphenhydramine, doxylamine) - Explicitly not recommended due to lack of efficacy and safety data for chronic insomnia. 3, 1, 2
• Ramelteon - While recommended for sleep onset insomnia, this patient has likely already failed endogenous melatonin pathways given the complexity of their case. 1

Addressing the Adderall Component

Verify that Adderall IR 20mg is truly "not close to bedtime":

• Amphetamine IR has a half-life of 10-13 hours; even afternoon dosing can interfere with sleep initiation. [@General Medicine Knowledge@]
• Consider switching to morning-only dosing or evaluating whether the stimulant is still necessary. [@General Medicine Knowledge@]
• The insomnia may be partially iatrogenic from the Adderall, making pharmacological management more challenging. [@General Medicine Knowledge@]

Treatment Algorithm

1. Initiate suvorexant 10mg at bedtime (can increase to 20mg after 1-2 weeks if inadequate response). 1, 2
2. Simultaneously refer for CBT-I or begin implementing components if formal therapy unavailable. 2
3. Reassess every 2-3 weeks for effectiveness, side effects, and need for dose adjustment. 3, 2
4. If inadequate response after 4 weeks, switch to doxepin 3-6mg rather than adding another agent. 2
5. Monitor for sleep-related behaviors (sleep-walking, sleep-driving), next-day impairment, and worsening depression. 2

Monitoring and Safety Considerations

• The FDA approves pharmacologic therapy for short-term use (4-5 weeks), though chronic use may be necessary for severe refractory insomnia. 3, 2
• Follow patients every few weeks initially to assess effectiveness, side effects, and ongoing medication need. 1
• Use the lowest effective maintenance dose and attempt tapering when conditions allow. 3
• Long-term hypnotic use should be accompanied by consistent follow-up and periodic reassessment. 3

Common Pitfalls to Avoid

• Do not add another sedating agent to existing failed medications without discontinuing previous agents - this increases fall risk and cognitive impairment without improving efficacy. 1, 2
• Do not rely solely on pharmacotherapy - medication without CBT-I has inferior long-term outcomes. 2
• Do not prescribe long-term without periodic reassessment and tapering attempts. 3, 2
• Do not ignore the potential contribution of Adderall to the insomnia presentation. [@General Medicine Knowledge@]