A SMART Approach to Evaluating the Benefits of Common Prescription and OTC Medications for Insomnia

Summary

The purpose of this study is to assess the relative effectiveness, safety, and durability of the most commonly used prescription (zolpidem, trazodone) and over-the-counter (OTC) (melatonin, diphenhydramine) medications for insomnia, as well as a less commonly used prescription that may have a better risk/benefit profile (doxepin).

Conditions

• Insomnia
• Insomnia Disorder
• Chronic Insomnia
• Chronic Insomnia Disorder

Interventions

DRUG

Diphenhydramine, 25 mg

Diphenhydramine 25 mg, once nightly 30 minutes prior to bed. Note: Given the strong recommendation against the use of diphenhydramine in older adults (i.e., the Beers Criteria), participants ≥64 years of age will not be randomized to the diphenhydramine arm.

DRUG

Diphenhydramine, 50 mg

Diphenhydramine, 50 mg, once nightly 30 minutes prior to bed. Note: Given the strong recommendation against the use of diphenhydramine in older adults (i.e., the Beers Criteria), participants ≥64 years of age will not be randomized to the diphenhydramine arm.

DRUG

Doxepin, 3 mg

Doxepin, 3 mg, once nightly 30 minutes prior to bed

DRUG

Doxepin, 6 mg

Doxepin, 6 mg, once nightly 30 minutes prior to bed

DRUG

Trazodone, 50 mg

Trazodone, 50 mg, once nightly 30 minutes prior to bed

DRUG

Trazodone, 100 mg

Trazodone, 100 mg, once nightly 30 minutes prior to bed

DRUG

Placebo

Placebo, once nightly 30 minutes prior to bed

DRUG

Zolpidem, 5 mg

Zolpidem, 5 mg, once nightly 30 minutes prior to bed

DRUG

Zolpidem, 10 mg

Zolpidem, 10 mg, once nightly 30 minutes prior to bed

OTHER

Sleep Hygiene Education

Standard behavioral and environmental recommendations aimed at promoting healthy sleep

DIETARY_SUPPLEMENT

Melatonin IR, 3 mg

Immediate release formulation of melatonin, once nightly 30 minutes prior to bed

DIETARY_SUPPLEMENT

Melatonin IR, 5 mg

Immediate release formulation of melatonin, once nightly 30 minutes prior to bed

Sponsors & Collaborators

• Patient-Centered Outcomes Research Institute

  collaborator OTHER

• University of Pennsylvania

  lead OTHER

Principal Investigators

• Michael L Perlis, PhD · University of Pennsylvania

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

SEQUENTIAL

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-05-31

Primary Completion

2032-01-01

Completion

2032-01-01

FDA Drug

Yes

Countries

• United States

Study Locations