Medications for PTSD-Related Insomnia

(NAP Trial)

Recruiting at 24 trial locations

Overseen By Robert Swift, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: VA Office of Research and Development

Must not be taking: Sleep medications

Disqualifiers: Bipolar, Schizophrenia, TBI, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

774 Participants Needed

Trial Summary

What is the purpose of this trial?

Many Veterans with posttraumatic stress disorder (PTSD) have trouble sleeping or have frequent nightmares. So far, no medication has been approved for treatment of insomnia in PTSD. The purpose of this research study is to find out if taking medications called trazodone or eszopiclone can help decrease symptoms of insomnia in patients with PTSD. PTSD is a form of intense anxiety which sometimes results from severe trauma. Symptoms may include nightmares, flashbacks, troublesome memories, difficulty sleeping, poor concentration, irritability, anger, and emotional withdrawal. Insomnia is a disorder that can make it hard to fall sleep, stay asleep or cause a person to wake up too early and not be able to fall back to sleep.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications listed in Appendix A. If you're taking one of these medications to help with sleep, you can participate if you stop taking it for a period of time (called a washout period) under your doctor's care.

What data supports the effectiveness of the drugs Eszopiclone, Lunesta, Gabapentin, Neurontin, and Trazodone for treating PTSD-related insomnia?

Research suggests that gabapentin may help improve sleep difficulties and reduce nightmares in PTSD patients, with 77% of patients showing moderate or greater improvement in sleep duration. Additionally, trazodone is often prescribed to veterans with PTSD who report severe insomnia, indicating its potential effectiveness for this condition. ^{1 2 3 4 5}

Is gabapentin safe for treating PTSD-related insomnia?

Gabapentin has been used to help with sleep issues in PTSD patients, and most people in a study reported better sleep. The most common side effects were feeling sleepy and mild dizziness. ^{2 3 4 6 7}

How is the drug combination of Eszopiclone, Gabapentin, and Trazodone unique for treating PTSD-related insomnia?

This drug combination is unique because it targets PTSD-related insomnia using three different mechanisms of action, with Gabapentin showing promise in improving sleep duration and reducing nightmares, and Eszopiclone being a non-benzodiazepine that aids sleep. This approach is novel as there are currently no validated pharmacotherapies specifically for PTSD-related insomnia. ^{3 4 6 8 9}

Research Team

John H. Krystal, MD

Principal Investigator

VA Connecticut Healthcare System West Haven Campus, West Haven, CT

Eligibility Criteria

This trial is for veterans aged 18-75 with PTSD-related insomnia, who have a significant level of sleep disturbance and PTSD symptoms. Participants must be able to give informed consent, adhere to lifestyle guidelines, and allow phone interview recordings. They should not have severe medical conditions or substance dependence, nor be involved in other clinical studies.

Inclusion Criteria

Total CAPS-5 score 23

Primary DSM-5 diagnosis of PTSD, assessed by structured interview using the CAPS-5

Allow digital recording of phone interviews

Exclusion Criteria

A comorbid current or lifetime diagnosis of certain psychiatric disorders

I have not had thoughts of harming myself or others in the last 3 months.

I have untreated thyroid issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive trazodone hydrochloride, eszopiclone, or placebo for insomnia symptoms in PTSD, with dose titration over the initial 3 weeks and continued treatment until week 12

12 weeks

Interim Analysis

Mid-point interim analysis to evaluate treatment efficacy and potentially drop arms meeting futility criteria

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Eszopiclone
• Gabapentin
• Placebo
• Trazodone

Trial Overview The study tests if trazodone, eszopiclone, or gabapentin can improve sleep for those with PTSD-related insomnia. It's a comparison against a placebo over approximately 17 weeks. Patients are randomly assigned to one of the medications or placebo without knowing which they receive.

Participant Groups

Group I: Trazodone Active Control 1 Intervention

Participants who are assigned to take trazodone, an active study medication.

Group II: Eszopiclone Active Control 1 Intervention

Participants who are assigned to take eszopiclone, an active study medication.

Group III: Placebo Placebo Group 1 Intervention

Participants who are assigned to take a placebo, a non-active study medication.

Eszopiclone is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Lunesta for:

• Insomnia

Approved in Canada as Lunesta for:

• Insomnia

Approved in European Union as Lunesta for:

• Insomnia

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Findings from Research

Veterans with PTSD show low rates of insomnia diagnoses (3.5-5.6%) but high rates of sedative-hypnotic prescriptions (44.2-49.0%), indicating a potential under-diagnosis of insomnia.

Younger Veterans and those without breathing-related sleep disorders are more likely to be diagnosed with insomnia, while those with greater service connection and substance use disorders are more likely to be prescribed sedative-hypnotics, highlighting the need for policy changes to prioritize behavioral treatments over medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Characterization of Insomnia among Veterans with PTSD: Identifying Risk Factors for Diagnosis and Treatment with Sedative-Hypnotics. Bramoweth, AD., Luther, J., Hanusa, BH., et al.[2023]

In a 12-week study involving 10 Vietnam combat veterans with chronic PTSD, nefazodone treatment significantly reduced PTSD and depressive symptoms, indicating its efficacy as a therapeutic option.

Nefazodone also improved both subjective and objective sleep quality, leading to longer total sleep time and better sleep maintenance, which is crucial for veterans suffering from sleep disturbances related to PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of nefazodone on subjective and objective sleep quality in posttraumatic stress disorder. Neylan, TC., Lenoci, M., Maglione, ML., et al.[2019]

In a retrospective review of 30 PTSD patients treated with gabapentin, 77% experienced moderate or greater improvement in sleep duration and a reduction in nightmares, suggesting gabapentin may effectively address sleep disturbances associated with PTSD.

While gabapentin was generally well-tolerated, with sedation and mild dizziness as common side effects, further controlled studies are necessary to confirm its efficacy in treating insomnia and other PTSD symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gabapentin in PTSD: a retrospective, clinical series of adjunctive therapy. Hamner, MB., Brodrick, PS., Labbate, LA.[2019]

The NAP Study is a large-scale clinical trial involving 1224 veterans with PTSD, comparing the efficacy of three insomnia medications (trazodone, eszopiclone, and gabapentin) against a placebo over 12 weeks, aiming to find effective treatments for PTSD-related insomnia.

The study features an adaptive design that allows for real-time adjustments based on interim results, potentially enhancing the statistical power of the remaining treatment comparisons and guiding future research on biomarkers for treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of the National Adaptive Trial for PTSD-related Insomnia (NAP Study), VA Cooperative Study Program (CSP) #2016. Krystal, JH., Chow, B., Vessicchio, J., et al.[2022]

In a study analyzing veterans with PTSD, it was found that the severity of insomnia and nightmares significantly influenced the prescription of sleep medications, with trazodone prescribed for insomnia and prazosin for nightmares.

Over time, there was a shift in prescribing patterns, with veterans more likely to receive trazodone and prazosin, and less likely to be prescribed benzodiazepines, indicating a move towards potentially safer sleep medication options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Symptom Presentation and Prescription of Sleep Medications for Veterans With Posttraumatic Stress Disorder. Greenbaum, MA., Neylan, TC., Rosen, CS.[2018]

In a 12-week study involving 25 participants with PTSD and insomnia, both eszopiclone (ESZ) and placebo showed significant improvements in PTSD symptoms, but there were no significant differences between the two treatments.

While ESZ did not demonstrate a specific advantage over placebo in improving sleep or PTSD symptoms, there was a notable correlation between sleep improvement and overall PTSD symptom reduction in the ESZ group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Double-blind randomized controlled study of the efficacy, safety and tolerability of eszopiclone vs placebo for the treatment of patients with post-traumatic stress disorder and insomnia. Dowd, SM., Zalta, AK., Burgess, HJ., et al.[2021]

In a 12-week open-label trial with 10 combat-related PTSD patients, nefazodone was well tolerated and led to significant improvements in most PTSD symptoms, sleep quality, and anger management, with all patients rated as much improved by the end of the study.

The treatment showed moderate to large effect sizes for symptom improvement, although self-reported depression did not show significant change, indicating nefazodone's potential effectiveness in managing PTSD symptoms, particularly sleep disturbances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open trial of nefazodone for combat-related posttraumatic stress disorder. Hertzberg, MA., Feldman, ME., Beckham, JC., et al.[2019]

This review highlights that sleep disorders like insomnia and nightmares are prevalent in PTSD and significantly affect quality of life, yet the pharmacological treatment options remain under-researched.

Promising results have been found for medications such as the atypical antipsychotic olanzapine and the alpha1-adrenoceptor antagonist prazosin, but more randomized controlled trials with larger participant groups are needed to confirm their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for disordered sleep in post-traumatic stress disorder: a systematic review. van Liempt, S., Vermetten, E., Geuze, E., et al.[2022]

Prazosin and Image Rehearsal Therapy (IRT) are both highly recommended (Level A) for treating PTSD-associated nightmares and nightmare disorder, respectively, indicating strong evidence for their efficacy.

Venlafaxine is not recommended for PTSD-associated nightmares, while clonidine may be considered, highlighting the importance of selecting appropriate treatments based on available evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Best practice guide for the treatment of nightmare disorder in adults. Aurora, RN., Zak, RS., Auerbach, SH., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Clinical Characterization of Insomnia among Veterans with PTSD: Identifying Risk Factors for Diagnosis and Treatment with Sedative-Hypnotics. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

The effect of nefazodone on subjective and objective sleep quality in posttraumatic stress disorder. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Gabapentin in PTSD: a retrospective, clinical series of adjunctive therapy. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

Design of the National Adaptive Trial for PTSD-related Insomnia (NAP Study), VA Cooperative Study Program (CSP) #2016. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Symptom Presentation and Prescription of Sleep Medications for Veterans With Posttraumatic Stress Disorder. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Double-blind randomized controlled study of the efficacy, safety and tolerability of eszopiclone vs placebo for the treatment of patients with post-traumatic stress disorder and insomnia. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Open trial of nefazodone for combat-related posttraumatic stress disorder. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Pharmacotherapy for disordered sleep in post-traumatic stress disorder: a systematic review. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Best practice guide for the treatment of nightmare disorder in adults. [2022]