How do you treat insomnia with medications if CBTi doesn’t help?

Part 2 of “When the sheep are gone, how do you treat insomnia?”

In a prior PsychSnap, we met Ms. Rose, a 65 year old woman with diabetes who is the primary caregiver for her adult son. She has been struggling with sleep maintenance, waking up multiple times in the middle of the night and taking 30-90 minutes to fall back asleep each time. At your last visit together, you recommended the first line treatment for insomnia disorder, CBTi, and Ms. Rose started using the free app Insomnia Coach. Despite using the app consistently, she continues to struggle with sleep maintenance. She is unable to access in-person CBTi. She asks if there is a medication to help her insomnia. 

Treatment of Insomnia Disorder with Medications

Medications for insomnia disorder are summarized in the table below. The most well-known medications for sleep are the benzodiazepines and non-benzodiazepines (ie z-drugs). These medications are the most effective medications in helping people fall asleep, but also cause problems with drowsiness, dizziness, and falls in the elderly. Medications with longer half-lives (temazepam, eszopiclone) or that are released over time (zolpidem CR) can also help people stay asleep. 

There are also insomnia medications that work to block wakefulness instead of promoting sleep. Doxepin and lemborexant are the most useful medications in their respective classes at this time. Their safety profile is very different from that of the benzos and non-benzos, particularly in the elderly. Because doxepin does not promote sleep (ie causing sedation), it can be used with caregivers who may need to wake up in the middle of the night. It doesn’t prevent them from waking up, but it does help them fall back to sleep faster. 

Ramelteon, a melatonin receptor agonist, is effective for sleep onset insomnia only and is well-tolerated.   

This table is not a comprehensive list of available medications for insomnia, but rather a list of the most clinically useful ones that are also FDA-approved.  

In a meta-analysis of insomnia pharmacologic treatments in those >60 years of age, Chiu et al. evaluated objective and subjective measures of sleep continuity and adverse event ratios to evaluate relative efficacy: zaleplon was ranked best for reducing sleep latency (time to fall asleep initially), temazepam for reducing wake after sleep onset time (# of minutes awake after initially falling asleep), and eszopiclone and doxepin for extending total sleep time. While suvorexant was included in the meta-analysis, lemborexant was not. Compared with placebo, adverse events odds ratios were highest for triazolam and lowest for zaleplon and doxepin.

Somewhat similarly, in a 2022 Lancet meta-analysis, lemborexant and eszopiclone were found to have the best efficacy, acceptability, and tolerability profile. Eszopiclone was associated with more dizziness and nausea than placebo and lemborexant with more headaches. While benzodiazepines were effective in the acute treatment of insomnia, their tolerability and safety profiles were unfavorable, and there is no long term trial data on efficacy and safety.

Non-FDA Approved Medications

There are also many non-FDA approved and over the counter agents used to treat insomnia. While melatonin is often offered and encouraged, it has at most a very modest effect on sleep onset only. The primary mechanism of action of melatonin is alteration of the biologic clock; therefore, the primary indication for melatonin is for circadian rhythm disorders, defined as a mismatch between actual sleep time and socially acceptable or desired sleep times (i.e. delayed or advanced sleep-wake phase disorders, jet lag, shift work).

While antidepressant medications (such as amitriptyline, trazodone or mirtazapine) are commonly used off-label to treat insomnia, doxepin is the only antidepressant that is FDA approved for insomnia treatment. A 2018 Cochrane review evaluated 3 studies that demonstrated improved subjective sleep outcomes for trazodone over placebo and 1 study with improved objective measures of sleep; however, the adverse event profile could not be evaluated, and the studies were deemed to be at high risk for bias. 

Diphenhydramine is available over the counter (and may be preferentially covered by insurance) for insomnia. However, diphenhydramine is much less selective for the H1 receptor than doxepin, causing unwanted anticholinergic side effects and next-morning drowsiness due to its long duration of action. The American Academy of Sleep Medicine found limited evidence of benefit for diphenhydramine (Sateia 2017). 

Finally, while herbal supplements like valerian and chamomile are readily available, a 2015 meta-analysis found no statistically significant difference between any herbal medicine and placebo, or any herbal medicine and active control, in their review.

Ultimately, the American Academy of Sleep Medicine does not recommend using trazodone, melatonin, diphenhydramine, or valerian over no treatment for insomnia in their clinical practice guidelines (Sateia 2017). 

Treatment Approach

If prescribing a medication for insomnia for younger patients, there are multiple approaches, based on the medication’s onset of action, duration, and risk of daytime sedation. I recommend prescribing the lowest effective dose, with a follow up within a few weeks to assess treatment response. You can use the Insomnia Sleep Index to measure treatment response.

For Ms. Rose, I recommend prescribing doxepin 3mg at bedtime for problems with sleep maintenance. To cut down on cost, try prescribing generic liquid doxepin (as opposed to Silenor, the branded pill form). Unfortunately, the lowest dose generic doxepin pill is a 10mg capsule that cannot be broken. Because Ms. Rose is 65 years old and works as a caregiver who may be needed at night, benzos and non-benzos for sleep are relatively contraindicated. It would be helpful if she can keep a sleep log until our next appointment, either on paper or in the Insomnia Coach App. When we see each other again in 2-3 weeks, we can review the data from her sleep log and discuss when she is taking the medication, when she is falling asleep, is she achieving the desired effect of sleep maintenance, and how she is feeling during the daytime. 

Key Points

  1. For younger people with insomnia, there are multiple drugs that are available and FDA-approved; choose one based on the patient’s concerns around falling and/or staying asleep and the medication’s onset of action, duration, and risk of daytime sedation.
  2. For older people with insomnia, consider doxepin for issues with sleep maintenance and ramelteon for issues with sleep onset. Doxepin’s mechanism of action inhibits wakefulness, but does not promote sedation, making it effective and safe for caregivers and older people. Lemborexant can help with sleep onset and sleep maintenance and has fewer side effects than benzos or non-benzos.
  3. The American Academy of Sleep Medicine does not recommend over the counter herbal supplements, melatonin, or antihistamines, or prescribed antidepressants (except for doxepin) for the treatment of insomnia. 

References 

Chiu HY, Lee HC, Liu JW, et al. Comparative efficacy and safety of hypnotics for insomnia in older adults: a systematic review and network meta-analysis. Sleep. 2021;44(5):zsaa260. doi:10.1093/sleep/zsaa260

De Crescenzo F, D’Alò GL, Ostinelli EG, et al. Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis. The Lancet. 2022;400(10347):170-184. doi:10.1016/S0140-6736(22)00878-9

Everitt H, Baldwin DS, Stuart B, et al. Antidepressants for insomnia in adults. Cochrane Common Mental Disorders Group, ed. Cochrane Database of Systematic Reviews. 2018;2018(5). doi:10.1002/14651858.CD010753.pub2

​​Leach MJ, Page AT. Herbal medicine for insomnia: A systematic review and meta-analysis. Sleep Medicine Reviews. 2015;24:1-12. doi:10.1016/j.smrv.2014.12.003

Perlis ML, Posner D, Riemann D, Bastien CH, Teel J, Thase M. Insomnia. The Lancet. 2022;400(10357):1047-1060. doi:10.1016/S0140-6736(22)00879-0

Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. Journal of Clinical Sleep Medicine. 2017;13(02):307-349. doi:10.5664/jcsm.6470

Sutton EL. Insomnia. Ann Intern Med. 2021;174(3):ITC33-ITC48. doi:10.7326/AITC202103160

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