New Medications for the Treatment of Insomnia

THE OREGON STATE DRUG REVIEW

AN EVIDENCE BASED DRUG THERAPY RESOURCE http://pharmacy.oregonstate.edu/drug-policy/newsletter

Insomnia is defined as the subjective perception of difficulty with

sleep which occurs despite adequate opportunity for sleep and

causes functional impairment during the day.

1,2

It is estimated

that about 5-10% of people experience chronic insomnia.

This

newsletter will summarize the evidence for insomnia treatments

and describe new policy changes for Oregon Medicaid.

Treatment Factors to Consider

Insomnia is often classified as short-term (typically <3 months in

duration with an identifiable stressor), long-term (i.e., chronic;

(occurring ≥3 times per week for >3 months) or other (if criteria

for short- and long-term criteria are not met). Insomnia is more

common in elderly, females, individuals who are divorced or

separated, those with shift work, and patients with lower

socioeconomic status.

Insomnia symptoms have been

associated with reduced health-related quality of life and

cognitive decline in patients over 65 years of age.

Insomnia can

also worsen outcomes for patients with comorbid conditions

including cardiovascular disease, post-traumatic stress disorder,

and depression.

Because insomnia may be associated with a

wide variety of medical and psychological conditions,

identification and treatment of contributing factors and comorbid

conditions (such as medical conditions, substance misuse, and

psychiatric conditions) is important for management of insomnia.

Treatments for Insomnia

Cognitive Behavioral Therapy (CBT) is recommended as first-line

therapy for chronic insomnia by the American Academy of Sleep

Medicine (AASM),

the European Sleep Research Society,

and

the Department of Veteran Affairs/Department of Defense

(VA/DoD)

based on high-quality evidence. Other treatments

(including medications) may have benefit if CBT is ineffective or

inaccessible.

Cognitive Behavioral Therapy

Evidence supports efficacy of both brief CBT interventions and

longer therapy.

Not all "talk therapy" is CBT. CBT is structured

and goal-driven to reduce symptoms and improve functional

status. It often involves homework for the patient.

CBT-I (CBT for insomnia) is typically offered over multiple

sessions. Cognitive components of CBT-I attempt to address

maladaptive thoughts, beliefs, and expectations about sleep.

Behavioral components address sleep habits and can include

sleep restriction therapy, stimulus control, relaxation therapy, and

sleep hygiene education.

For example, sleep restriction therapy

involves establishing a sleep schedule that restricts the time

spent in bed. The schedule is initially set based on the patient’s

average total sleep time and is gradually modified to allow

longer a sleep time when sleep efficiency improves. CBT-I

has been shown to improve insomnia severity and sleep

efficiency.

There is also evidence that CBT-I can improve

sleep quality, sleep latency (the time it takes to fall asleep),

and time spent awake after initial sleep onset in adults with

insomnia.

Brief behavioral interventions, focusing on the

behavioral componenets included in CBT-I, have also

demonstrated efficacy for treatment of insomnia.

Access to nonpharmacological treatments such as CBT may

be a significant barrier for many patients. Currently, there are

not enough qualified providers to meet the need for services

in Oregon, and it may be especially difficult for patients to find

providers with specialized training in both CBT and sleep

medicine. Additionally, patients may have to travel significant

distances to get care, or be unable to commit to the time

required for CBT (e.g., scheduling time off work for visits).

Telehealth services may help expand treatment options,

particularly for people in rural areas, but the evidence

supporting this provider-directed telemedicine or self-directed

internet programs is limited. In a 2019 systematic review of

therapy for insomnia, the VA/DoD found insufficient evidence

to recommend for or against internet-based CBT-I as an

alternative to face-to-face CBT-I.

There is some evidence

that internet-based CBT-I is more effective than no treatment,

but the magnitude of benefit is unclear.

Evidence was limited

by inconsistency, imprecision and indirectness.

Since the

coronavirus pandemic, telehealth services have become

more common, especially for behavioral health conditions.

2023 systematic review evaluated telehealth services during

the COVID-19 pandemic.

A wide range of populations,

outcomes, and conditions were identified comparing tehealth

to in-person care which limits ability to make any general

statements about differences in treatment delivery. Overall,

authors concluded that telehealth may be comparable to in-

person care when evaluating outcomes related to follow-up

visits and patient-reported clinical outcomes.

They identified

mixed results for healthcare utilization outcomes, and

highlighted the need to develop best practices around

telehealth delivery for various conditions, patient populations,

and treatment settings.

If patients are unable to access CBT-I, a variety of other

options may provide benefit for insomnia symptoms, though

the evidence supporting these therapies in treatment of

insomnia is limited. These options can include lifestyle

changes, relaxation techniques, sleep hygiene, self-directed

Updates for Insomnia: Evidence and Oregon Medicaid Policy

Sarah Servid, Pharm.D., Oregon State University Drug Use Research and Management Group

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DRUG USE RESEARCH & MANAGEMENT

Managing Editor: Kathy Sentena

[email protected]

psychoeducation, other types of psychotherapy, and medicine.

Sleep hygiene involves education on healthy lifestyle practices to

improve sleep.

The American Acadamy of Sleep Medicine and

VA/DoD recommend that all patients with insomnia follow

principles of good sleep hygiene in combination with other

treatments since there is insufficient evidence that these

therapies are effective alone.

1,5

Sleep hygiene education is

typically incorporated into CBT-I. Common practices include:

- Modify sleep environment so that it is conducive to sleep (e.g.,

cool temperatures, separating sleep and work environments).

- Keep a regular sleep schedule 7 nights a week; avoid naps

during the day.

- Avoid going to bed until drowsy, do not watching the clock,

get out of bed if not asleep within 15-20 minutes, and return

to bed only when drowsy.

- Avoid substances that interfere with sleep (such as caffeine,

nicotine, alcohol) before bedtime.

- Avoid electronic devices before bedtime. Light from screens

can promote wakefulness and make it more difficult to sleep.

- Exercise regularly (at least 6 hours before sleep).

Sedative Drugs

Efficacy

When compared to CBT-I, medications were less effective for

treating long-term insomnia symptoms (e.g., greater then 4

weeks) based on low-quality evidence.

Most studies have only

evaluated short-term use of insomnia drugs, and there is a lack

of clear long-term safety data. A 2019 systematic literature review

from the VA/DoD found insufficient evidence that use of

diphenhydramine, ramelteon, suvorexant, or antipsychotics

improve insomnia symptoms. Additionally, they suggest against

use of melatonin, antipsychotics, trazodone, dihphenhydramine,

or benzodiazepines because risks of therapy likely outweigh any

potential benefits. If drugs are offered for insomnia, they suggest

the use of low-dose (3 or 6 mg) doxepin or non-benzodiazepine

receptor agonists such as zolpidem, zaleplon or eszopiclone.

There is a lack of clear efficacy or safety data for most sedatives

beyond 2 to 4 weeks.

Table 1. VA/DoD recommendations for insomnia drug therapy

Suggested for

Short-term Use

Insufficient Evidence

For or Against

Not Recommended

doxepin (3 or 6 mg)

ramelteon

antipsychotics

eszopiclone

suvorexant

benzodiazepines

zaleplon

chamomile*

zolpidem

dihphenhydramine*

kava*

melatonin*

trazodone

valerian*

*Available in over-the-counter (OTC) formulations

There was low-quality evidence that melatonin was no different

from placebo in adults with insomnia, and many clinical studies

evaluating diphenhydramine did not differentiate from

placebo.

Tolerance to sedating effects of diphenhydramine

have also been observed even after 3 to 4 days of continuous

use, limiting efficacy for insomnia.

Similarly, trazodone,

benzodiazepines, and antipsychotics are associated with

serious long-term adverse effects and their efficacy for

treatment of insomnia symptoms is limited. A systematic

review found moderate-quality evidence that trazadone

improved subjective sleep quality, but low-quality evidence of

no improvement in other efficacy outcomes (such as total

sleep time or sleep latency).

Quetiapine, though commonly

prescribed at low doses, has not been studied for insomnia,

and evidence is limited to a few case studies and case series.

Therefore, quetiapine is not recommended because unknown

benefits in insomnia do not outweigh risk for known adverse

effects (such as dyskinesias, metabolic changes,

anticholinergic and ophthalmic effects).

Safety

Drug-drug and drug-disease interactions are common with

sedatives. Before initiating therapy, providers should evaluate

sleep history and assess for contraindications. Because some

sedatives are available as over-the-counter (OTC) drugs,

routine assessment for drug interactions and patient

education regarding adverse effects is important. Over-the-

counter formulations undergo less regulation by the FDA and

may have varying levels of active ingredient or additional

ingredients. One study evaluating content of 31 melatonin

products identified that the amount of melatonin ranged from

-83% to 465% of the labelled content and varied across lots,

manufacturers, and product types.

Varying levels of

serotonin were identified in 8 (26%) of the products.

Common adverse effects associated with all sedative

medications include dizziness, daytime drowsiness, and

somnolence. Risk for daytime impairment may be higher in

women or elderly who metabolize and eliminate sedative

medications more slowly from the body.

The Food and Drug

Administration (FDA) warns that high levels of a sedative in

the bloodstream can result in impairment even if patients feel

fully awake.

Other notable safety concerns include anticholinergic adverse

effects (including confusion, palpitations, dry mouth, and

cognitive impairment) associated with antihistamines like

doxepin and diphenhydramine. FDA labeling for all

prescription sedative drugs (i.e., benzodiazepines, non-

benzodiazepine receptor agonists, melatonin receptor

agonists and orexin receptor antagonists) includes risk for

rare but serious adverse effects like worsening depression

and suicidal ideation, abnormal behavior changes (e.g.,

agitation, amnesia, hallucinations), and complex sleep

behaviors (e.g., sleep driving). Additionally, parasomnias

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DRUG USE RESEARCH & MANAGEMENT

Managing Editor: Kathy Sentena

[email protected]

(such as sleep paralysis) have been reported with suvorexant

and daridorexant. All sedating drugs may increase risk of

respiratory depression in patients with pulmonary conditions such

as sleep apnea or obesity-related hypoventilation.

Risk of

overdose may be increased when sedatives (particularly

benzodiazepines) are combined with opioids, alcohol or other

medications. Adverse effects of sedatives may exacerbate

symptoms in people who have cognitive disorders, are elderly, or

are already at risk of falls.

Evidence from observational studies

indicates long-term sedative use increases risk of fractures and

dementia.

5,10,11

The risk of fracture may depend on the length of

time people used the drugs, with new users of these drugs at

greatest risk of hip fracture.

10,11

All sedative-hypnotics can be associated with physical

dependence, but dependence is typically most pronounced with

benzodiazepines. When discontinuing treatment, a taper plan is

usually recommended to minimize withdrawal symptoms and

facilitate discontinuation after routine, long-term use. The Oregon

Health Authority Mental Health Clinical Advisory Group (MHCAG)

has published guidance and best practices on how to approach

a benzodiazepine taper.

Taper schedules should be

individualized based on patient circumstances, diagnoses, dose,

and length of benzodiazepine use. Many patients may benefit in

switching, or cross-tapering, to a longer-acting benzodiazepine

like diazepam before reducing their total benzodiazepine dose.

Oregon Medicaid Policy Updates

Melatonin coverage in children

In October 2021, the Oregon fee-for-service (FFS) Open Card

coverage policy was expanded to cover melatonin in children.

This policy change was made based on a review of available low-

quality evidence which demonstrated that melatonin may

improve sleep latency and sleep duration in children, but

evidence is insufficient to draw conclusions on improvements in

nighttime awakenings or functional outcomes, or on increased

frequency of some adverse events (e.g., dizziness, daytime

drowsiness, and bed-wetting).

Doses studied ranged from 2 to

12 mg.

The American Acadamy of Sleep medicine suggests

that doses of 3 to 5 mg may be effective in children.

Children

with autism or other neurodevelopmental disorders had the

largest improvement in sleep outcomes with melatonin nightly.

However, evidence was generally limited to short-term studies

(<6 months), and the long-term safety of melatonin use is less

clear.

15,16

Because of the unknown long-term safety concerns

related to use of a hormone in children, non-pharmacologic

behavioral therapy remains a first-line treatment option, and

melatonin is usually recommended at the lowest effective dose

with frequent re-assessment to evaluate change in symptoms.

Melatonin is not currently covered for adults enrolled in FFS

Medicaid due to the limited evidence of benefit in this population.

Cognitive behavioral therapy (CBT) coverage

Beginning in January 2024, the Health Evidence Review

Commission (HERC) adopted a new guideline which

addresses treatments for insomnia. This new policy provides

coverage of CBT for insomnia. Historically, both medical and

pharmacological treatments for insomnia have been

unfunded and had very limited coverage. Beginning January

1, 2024, providers can bill the Oregon Health Plan for CBT

visits related to insomnia.

Coverage of provider-directed telemedicine varies based on

the insurance carrier. When referring patients for internet-

based programs, providers might consider directing patients

toward the evidence-based app developed by the VA/DoD for

management of insomnia.

Limits for sedatives

As part of coverage changes for insomnia starting January

2024, HERC has also recommended additional limits for

sedative-hypnotic use for insomnia. Consistent with current

guidelines, use of sedative-hypnotics for insomnia is

recommended for short-term therapy only. Coverage is

limited to one month per year with additional therapy requiring

documentation that treatment benefits outweigh risks. The

specific duration of treatment was recommended due to

concerns with long-term risks of sedative hypnotics and

increasing risk of dependence with longer-term use.

Conclusion

CBT-I is recommended as first-line treatment for chronic

insomnia symptoms. Drugs are only recommended for short-

term treatment of insomnia due to their limited evidence of

benefit and serious long-term adverse effects. Oregon

Medicaid recently updated their coverage for CBT-I. Initial

treatment of sedative-hypnotics for insomnia is limited to one

month.

Resources

Peer reviewed by: Cydreese Aebi, PhD, RPh, BCPP,

Clinical Pharmacy Coordinator, Oregon State Hospital,

Salem, Oregon

References

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 MHCAG: general recommendations for CBT

 MHCAG: How to approach a benzodiazepine taper

 Prior Authorization Criteria for FFS Medicaid patients

 CBT-I Coach, a mobile app from the VA/DOD for

insomnia

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Oregon DUR Board Newsletter Produced by OSU COLLEGE of PHARMACY

DRUG USE RESEARCH & MANAGEMENT

Managing Editor: Kathy Sentena

[email protected]

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