Treating Insomnia in Older Adults: Doxepin Highlights

The American Geriatrics Society recently published their Alternative Treatments to Selected Medications in reference to the most recent update to the AGS Beers Criteria in 2023.  This guidance is helpful because while the 2023 AGS Beers Criteria warned about which medications were "potentially inappropriate" in older adults, they left clinicians guessing by not offering suggestions as to which medications should alternatively be used.

 

Treating Insomnia in Older Adults: What's NOT Recommended 

One category where the alternative treatment guidance is particularly helpful is in the area of insomnia, where the 2023 AGS Beers Criteria make STRONG recommendations to AVOID a number of classes of medications and the recommendations are supported by either Moderate or High quality evidence.  As a reminder, an "Avoid" recommendation does not mean that the drug is contraindicated, rather that it should not be used except in unusual circumstances (such as when the safer option did not achieve its goal).  Specific classes relevant to treating insomnia that should be avoided in the older adult include:

• Benzodiazepines
• "Z-drugs" (e.g., zolpidem, zaleplon, eszopiclone)
• First-generation antihistamines
• Tricyclic antidepressants
• Barbiturates

Warning not to use these classes left clinicians to choose from an assorted list of medications with questionable efficacy/safety profiles such as trazodone, mirtazapine, or melatonin.  The Alternative Treatments to Selected Medications specifies these three medications unfortunately have insufficient evidence to be recommended with the qualifier that melatonin can be offered to patients requesting a natural remedy.

 

Treating Insomnia in Older Adults: What IS Recommended 

The Alternative Treatments to Selected Medications identifies how to approach treating insomnia.  First, underlying conditions adversely affecting sleep should be assessed and addressed.  Second, cognitive behavioral therapy for insomnia (CBT-I) should be attempted and the AGS provide a number of resources and links in Table 3.  If CBT-I is unsuccessful, a shared-decision can be made whether or not to try short-term pharmacologic treatment.  Options with relative safety in the older adult that also have evidence for effectiveness in treating insomnia include:

• Low-dose doxepin
• Ramelteon 
• Dual orexin receptor antagonists (e.g., suvorexant, lemborexant, daridorexant)

 

Doxepin Reviewed

Clinicians might not be as familiar with doxepin as they are with the more popular (but less desirable) options, so some details are highlighted here.

• First, how studies assess effects on sleep:
• There are many subjective and objective ways to assess if a medication for insomnia is efficacious.  Two common endpoints in studies are WASO (wake after sleep onset or wake-time after sleep onset) and TST (total sleep time). WASO measures how much time is spent awake during the night after sleep is initially achieved, whereas TST is total time spent sleeping from when sleep begins until the final awakening.  Other outcomes are sleep efficiency and sleep onset latency.
• Here are a few of the better quality studies that have been done with doxepin compared to placebo for insomnia:
• Krystal et al. published a randomized, double-blind, placebo-controlled trial of placebo versus doxepin 1 mg or 3 mg in participants at least 65 years old.
• At multiple time points (including night 1 and after week 12), doxepin significantly improved WASO (by about 35 minutes) and TST (by about 40 minutes).
• If this does not seem like a particularly drastic improvement, for some comparison, the Clinical Practice Guideline on the treatment of chronic insomnia in adults from the American Academy of Sleep Medicine summarize the effects of zolpidem (the classic choice) of improving WASO by about 25 minutes and TST by about 30 minutes.
• The side effect profile in the Krystal et al study was similar to placebo with more patients in the placebo group experiencing adverse effects, overall. 
• Roth et al. published a randomized, double-blind, placebo-controlled crossover study of placebo versus doxepin 1,3, or 6 mg in elderly adults.
• After a single dose, multiple sleep parameters including WASO and TST were improved compared to placebo.
• Adverse effects were similar to placebo.
• Lankford et al. also published a randomized, double-blind, placebo-controlled trial of placebo versus doxepin 6 mg over four weeks in elderly adults.
• At multiple time points, the doxepin group had improvements in several sleep metrics including WASO and TST.
• Adverse effects were similar to placebo and there were no reports of anticholinergic adverse events. 
• A systematic review and network meta-analysis concluded that low-dose doxepin was the optimal pharmacotherapy choice for improving TST and sleep efficiency in older adults due to its efficacy and safety profile.

 

How to use doxepin

• One might have noticed the use of "low-dose" above, or in the linked studies, with regard to doxepin dosing.  This is a detail not to be overlooked because doxepin was originally approved as an antidepressant in 1969 and can be used in doses up to 300 mg per day.  As a tricyclic antidepressant, patients at these doses were likely to experience the classic anticholinergic toxidrome which older adults are particularly susceptible to.  In contrast, the "low-dose" is for the more recently approved Silenor®, approved in 2010, which makes doxepin the only tricyclic antidepressant approved for treating insomnia.  At 100th of the antidepressant dose, the medication seems to be largely devoid of any anticholinergic side effects.
• Dosing details are as follows:
• 3 mg orally daily initially in the elderly (up to 6 mg daily)
• Administer within 30 minutes of bedtime
• Do NOT give:
• Within 3 hours of a meal (this would increase the AUC and delay peak effects - so it will not onset as quickly and could lead to next day sedation side effects)
• In patients with untreated narrow angle glaucoma  
• In patients with severe urinary retention
• In patients also treated with monoamine oxidase inhibitors (MAOIs) within 2 weeks 
•  Here is the full prescribing information

 

Place in Guidelines 

• If there is concern about the place in clinical practice guidelines for doxepin, it has been recommended as an option for many years in the following places: 
• The U.S. Department of Veterans Affairs and Department of Defense include doxepin (of course low-dose 3 or 6 mg) as treatment for chronic insomnia in patients unable or unable to perform CBT-I.
•  The American Academy of Sleep Medicine includes low-dose doxepin as an option for chronic insomnia.
• The American College of Physicians identify doxepin as a treatment option for chronic insomnia, including in older adults. 

image by Dimitar Atanasov (no changes made)