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

Sequential Multiple Assignment Randomized Trial Comparing Commonly Prescribed and Over the Counter Medications for the Treatment of Insomnia in Adults

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).

Nearly 50% of primary care patients report symptoms of insomnia (e.g., problems initiating and/or maintaining sleep). Such sleep-related difficulties can presage new onset comorbid illness, as well as exacerbate, and be exacerbated by, existing comorbid illnesses. Accordingly, effectively treating insomnia in primary care patients is an untapped means towards the promotion of better public health.

Research Question:

While cognitive behavioral therapy for insomnia (CBT-I) is considered the first-line treatment, most patients (particularly those in primary care) do not have access to this form of therapy.

Instead, the majority of treated patients are using over-the-counter medications (OTCs), including melatonin and diphenhydramine (e.g., Benadryl), or are prescribed hypnotics (most commonly trazodone or zolpidem [e.g., Ambien]). Surprisingly, little is known about the absolute or relative effectiveness and safety of these commonly used medications, and of the often used medications, only Ambien is approved/recommended by the FDA and professional medical or sleep medicine societies. There are also limited data on which of these medical strategies has the best risk/benefit profile or is most acceptable to patients. The investigators' recent evaluation of FDA-approved medications for insomnia suggests doxepin, which is less commonly prescribed, has the most optimal risk/benefit profile. Multiple agencies have called for rigorous comparative effectiveness studies addressing these knowledge gaps, including the Agency for Healthcare Research and Quality (AHRQ), the National Institutes of Health (NIH), and the Patient-Centered Outcomes Research Institute (PCORI). Moreover, the investigators' feedback from stakeholders shows that the need for such data is not just a professional practice concern, but shared by primary care patients and clinicians. Thus, evidence-based guidance on the management of insomnia with OTC and prescriptive medications is urgently needed.

Protocol Synopsis:

The investigators propose to conduct a large-scale, double blinded, placebo-controlled sequential multiple assignment randomized trial (SMART) comparing the relative effectiveness and safety of over-the counter medications commonly used by patients to treat their insomnia (i.e., diphenhydramine and melatonin) and prescriptive medications that are either commonly prescribed by clinicians (i.e., zolpidem and trazodone) or less commonly used, but may have a more optimal risk/benefit profile (i.e., doxepin). All conditions will use a nightly dosing strategy and include sleep hygiene education. To better align with current practice, participants who tolerate an initial lower medication dose but do not exhibit a treatment response will increase to a higher dose after 2 weeks. Treatment responders at 1 month will be followed for up to 6 months to understand longer-term maintenance of treatment benefits. The SMART design will re-randomize treatment non-responders at 1 month to an alternative arm (with each successive treatment non-response), providing all participants the opportunity to secure a treatment response with one of the study medications. To maintain blinding, participants will be instructed to take each medication (including placebo) 30 minutes prior to bed and all medications will be manufactured by a central Pharmacy to appear identical. All participants will be further instructed to be in bed for a period of 7-9 hours to both promote safety and potentially increase medication effects on early morning awakening and total sleep time.

Inclusion Criteria

• Adults aged 18-80 years.
• Meet DSM-5 criteria for Insomnia Disorder.
• Score ≥15 on the Insomnia Severity Index (ISI).
• Sleep initiation and/or maintenance complaints: ≥30 minutes in duration, occurring ≥3 nights/week, with a duration of ≥3 months.
• Willingness to discontinue use of all sleep-related medications prior to enrollment.
• Completion of a 2-week washout period before starting any study medication.
• Willingness to provide clinician assent for participation.

Exclusion Criteria

Patients will be ineligible if they meet any of the following criteria: self-reported daytime napping (≥1 hour per day on ≥3 days per week); a history of suicidal attempts or current ideation, acute or chronic psychiatric or medical condition not controlled by therapy (according to their primary care physician), or current alcohol or drug misuse; or the diagnoses of (or high risk for) other sleep disorders, including circadian rhythm disorders (phase advance or phase delay syndromes), shift work related sleep disorder ("day sleepers" who work ~11pm to 7am) and those with rotating shiftwork schedules. To determine eligibility, all subjects will be screened using a multitier process including: an online screener; an intake interview; a review of the subjects EMR; and, finally, the receipt of the patient's PCP's assent. The following provides additional listing and details (AD) for the Exclusion Criteria:

General Considerations

• Age < 18 or > 80 years old
• Inadequate English language comprehension
• Minimal facility with smartphones, computers, i-Pads, or the internet.

Women's Health Given the potential for teratogenic effects with at least trazodone (FDA Class C), women intending to become pregnant, or who are pregnant, or who are breastfeeding will not be eligible for the study. Women will be asked to confirm the use of birth control using self-report and, if applicable, by providing evidence of contraceptive medication (e.g., prescription or pill pack). We will perform a urine pregnancy test at baseline for female participants who are of reproductive age to confirm eligibility. At study enrollment, participants will be told to alert the study team and stop taking study medications if they become pregnant. Participants will be asked to test for pregnancy in the event of a missed cycle.

Medical and Psychiatric Considerations

• Acute or unstable psychiatric conditions
• Unstable medical condition, significant medical disorder, or acute illness (as determined by their PCP), within one month prior to the study period.
• Significant liver or kidney problems
• Pheochromocytoma or porphyria (contraindicated for trazodone)
• Epilepsy or Seizure Disorder (contraindicated for trazodone)
• Glaucoma or urinary retention (contraindicated for doxepin)
• Increased ocular pressure (contraindicated for diphenhydramine)
• Diagnosis of alcohol or substance use disorder within 2 years prior to the screening visit
• Inability to refrain from drinking alcohol or substance use for at least 3 consecutive days

Sleep Disorders and Sleep Habits

• Any lifetime history of (diagnosis of) breathing disorders, including COPD and sleep apnea.
• Shift work related sleep disorder (work ~11pm to 7am and "day sleeper") and rotating shiftwork schedules
• Circadian rhythm disorders (phase advance or phase delay syndromes)
• Self-reported usual daytime napping ≥1 hour per day (3 or more days per week)

Medications and Concomitant meds

• Known hypersensitivity or contraindication to study drugs
• Known hypersensitivity or contraindication to drugs of the same class as the study treatments
• Known hypersensitivity or contraindication to any excipients of the study drug formulation
• Treatment with CNS active drugs prohibited by the protocol for five half-lives of the respective drug (or 2 weeks)

Lifestyle

• Heavy tobacco use (≥1 pack of cigarettes a day or inability to refrain from smoking during the night)
• Not able or willing to stop treatment with moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors