Sleep Disturbance + Study Drug for Sleep Disorders

(Sleep-MOR Trial)

Overseen By Nicholas G Wolf, BA

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Johns Hopkins University

Must not be taking: Antidepressants, Neuroleptics, Opioids, others

Disqualifiers: Chronic pain, Sleep disorder, Bipolar, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests how different types of sleep problems affect the brain's response to a pain-relief drug and its potential for abuse. Healthy subjects will have their sleep patterns manipulated and then undergo brain scans and pain tests. The goal is to see if poor sleep makes pain drugs less effective or more likely to be abused.

Will I have to stop taking my current medications?

The trial requires that participants have not used certain medications like antidepressants, neuroleptics, sedative hypnotics, and opioids in the last three months. If you are currently taking these, you would need to stop before joining the trial.

What data supports the effectiveness of the study drug for sleep disorders?

The meta-analysis on trazodone, a medication often used for insomnia, shows it can be effective in improving sleep compared to a placebo, suggesting that similar medications might help with sleep disturbances. ^{1 2 3 4 5}

What safety data exists for the study drug used in sleep disorders?

The safety data for sleep medications shows that melatonin receptor agonists have the lowest rate of adverse events, while non-benzodiazepine benzodiazepine receptor agonists have the highest. Zolpidem, a short-acting hypnotic, was studied in Switzerland, where 7.2% to 8.9% of patients reported mild side effects like drowsiness and headaches, but no serious adverse events were found. ^{6 7 8 9 10}

How does the study drug for sleep disorders differ from other treatments?

The study drug for sleep disorders is unique because it involves a within-subject test of a blinded study medication, which means that the same participants receive both the active drug and a placebo at different times without knowing which is which. This approach allows for a direct comparison of the drug's effects on the same individuals, potentially providing more accurate results than traditional methods where different groups receive either the drug or a placebo. ^{1 2 6 11 12}

Research Team

Eric C Strain, MD

Principal Investigator

Johns Hopkins University

Naresh Punjabi, MD

Principal Investigator

Johns Hopkins University

Claudia Campbell, PhD

Principal Investigator

Johns Hopkins University

Patrick H Finan, PhD

Principal Investigator

Johns Hopkins University

Jeannie Leoutsakos, PhD

Principal Investigator

Johns Hopkins University

Michael T Smith, PhD

Principal Investigator

Johns Hopkins University

Hiroto Kuwabara, MD

Principal Investigator

Johns Hopkins University

Alexandra Kearson, BA

Principal Investigator

Johns Hopkins University

Eligibility Criteria

This trial is for healthy adults aged 18-48 who sleep well (6.5 to 8.5 hours a night with good quality), don't smoke or use nicotine, and consume little caffeine. They must have had some exposure to opioids in the past but can't be overweight, have sleep disorders, metal implants unsafe for MRI, significant neurological diseases, recent serious medical issues or substance abuse history.

Inclusion Criteria

You drink two cups of coffee or less per day.

You sleep between 6.5 and 8.5 hours per night and have a sleep efficiency of at least 85%.

You have taken opioids for pain in the past.

Exclusion Criteria

My BMI is over 35.

I am currently experiencing severe pain.

You feel uncomfortable in small, enclosed spaces.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

2 visits (in-person)

Treatment

Participants undergo sleep manipulation and study drug administration to assess receptor function, analgesia, and abuse liability

4 days

1 visit (inpatient stay)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

Treatment Details

Interventions

• Within-Subject test of blinded study medication (Other)

Trial Overview The study tests how different types of sleep disturbances affect the brain's response to various drugs including stimulants, benzodiazepines, opioids, cannabinoids and pain relievers compared to placebo. It looks at drug effects on pain relief and potential for misuse under normal sleep conditions versus disrupted sleep.

Participant Groups

Group I: Sleep Fragmentation Experimental Treatment 2 Interventions

The Sleep fragmentation condition will be conducted on two consecutive nights. Subjects are provided an 8-hour sleep opportunity during which their sleep will be disturbed by microarousals that simulate sleep apnea.

Group II: Sleep Continuity Disruption Experimental Treatment 2 Interventions

The Sleep Continuity Disruption condition will be conducted on two consecutive nights. An 8-hour sleep opportunity period will be disturbed by several forced awakenings at random intervals during which no sleep is permitted.

Group III: Undisturbed Sleep Active Control 2 Interventions

An 8-hour period of undisturbed sleep is permitted on each night.

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

A study involving 238 women who started prescription sleep medications found no significant improvement in self-reported sleep disturbances after 1 or 2 years compared to 447 women who did not use these medications.

Both groups reported similar levels of difficulty initiating sleep, waking frequently, and early morning awakening, suggesting that long-term use of sleep medications may not be effective in reducing sleep disturbances.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prescription medications for sleep disturbances among midlife women during 2 years of follow-up: a SWAN retrospective cohort study. Solomon, DH., Ruppert, K., Habel, LA., et al.[2021]

In a review of seven randomized placebo-controlled trials involving 429 patients, trazodone was found to significantly improve perceived sleep quality compared to placebo, although it did not enhance sleep efficiency or other objective sleep measures.

Trazodone effectively reduced the number of awakenings during the night, indicating its potential for improving sleep maintenance, while demonstrating good tolerability in short-term use for treating insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trazodone for the treatment of insomnia: a meta-analysis of randomized placebo-controlled trials. Yi, XY., Ni, SF., Ghadami, MR., et al.[2022]

In a comparison of sleep disorder medication patterns, the study found that 11.7% of the French population used psychotropic medications, significantly higher than the 5.5% in Quebec, indicating a notable difference in medication consumption between the two regions.

Both studies revealed that the majority of sleep-promoting medications were prescribed for long durations (over a year) and that general practitioners were responsible for about 80% of these prescriptions, highlighting a common trend in prescribing practices despite the differences in overall consumption rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Psychotropic medication and insomnia complaints in two epidemiological studies. Ohayon, MM., Caulet, M.[2022]

In a meta-analysis of 34 studies involving 1392 subjects, pharmacological placebos significantly improved subjective sleep onset latency and total sleep time compared to untreated groups, indicating that even inactive treatments can influence sleep outcomes.

No significant sleep changes were observed in psychological placebo groups, suggesting that the type of placebo may affect the magnitude of sleep improvements, and further research is needed to clarify these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of sleep changes in control groups of insomnia treatment trials. Bélanger, L., Vallières, A., Ivers, H., et al.[2007]

Cognitive-behavioral therapy for insomnia (CBT-I) helps correct the common issue of individuals underreporting their sleep, as shown in a study of 60 adults with insomnia, where self-reported sleep improved after treatment.

Although there were no significant changes in objective sleep measurements from polysomnography (PSG), a decrease in stage N1 sleep was linked to better self-reported sleep quality, suggesting that CBT-I may enhance the accuracy of sleep estimation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The discrepancy between subjective and objective measures of sleep in older adults receiving CBT for comorbid insomnia. Lund, HG., Rybarczyk, BD., Perrin, PB., et al.[2022]

Melatonin receptor agonists have the lowest rate of adverse events (43.1 per 1000), while non-benzodiazepine benzodiazepine receptor agonists have the highest (255.0 per 1000), indicating a significant difference in safety profiles among insomnia medications.

Benzodiazepines showed the highest efficacy in improving sleep outcomes with an effect size of 1.94, while melatonin receptor agonists had the lowest efficacy (0.109), suggesting that histamine antagonists may offer the best risk-benefit ratio for treating insomnia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative short-term safety and efficacy of hypnotics: A quantitative risk-benefit analysis. Cheung, JMY., Scott, H., Muench, A., et al.[2023]

In a review of 24 studies involving 2417 older adults with insomnia, sedative hypnotics showed statistically significant improvements in sleep quality, total sleep time, and reduced nighttime awakenings, but the overall effect size was small.

However, the use of sedatives was associated with a significantly higher risk of adverse events, including cognitive impairment and daytime fatigue, raising concerns about their safety in older adults, especially those at risk for falls.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. Glass, J., Lanctôt, KL., Herrmann, N., et al.[2022]

In a study of 987 Japanese adults with chronic insomnia, ramelteon 8 mg significantly reduced the time it took for patients to fall asleep (sleep latency) after just one week of treatment, compared to a placebo.

Ramelteon also improved total sleep time and sleep quality, and was well tolerated with no evidence of rebound insomnia after stopping the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of subjective efficacy and safety of ramelteon in Japanese subjects with chronic insomnia. Uchiyama, M., Hamamura, M., Kuwano, T., et al.[2022]

In a study of 4221 participants aged 45 to 75, the intake of drugs labeled as sleep disturbing showed little to no association with self-reported nocturnal sleep disturbances, suggesting that the information from drug labels may not apply well to the general population.

The analysis indicated that the prevalence ratios for sleep disturbances did not significantly increase with the number of sleep disturbing drugs taken, raising questions about the reliability of clinical trial data in predicting real-world effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Do patients with intake of drugs labelled as sleep disturbing really sleep worse? A population based assessment from the Heinz Nixdorf Recall Study. Lehnich, AT., Kowall, B., Kuß, O., et al.[2021]

In two multicenter safety studies involving nearly 4,000 patients treated with zolpidem for insomnia, only 8.9% and 7.2% reported adverse events, indicating a relatively low incidence of side effects.

The most common adverse effects were related to the central nervous system, such as somnolence and confusion, but no new serious adverse events were identified, supporting the established safety profile of zolpidem.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety profile of zolpidem: two studies of 3805 patients by Swiss practitioners]. Ganzoni, E., Gugger, M.[2018]

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 of 405 sleep studies, it was found that using multiple psychotropic medications (like antidepressants combined with anticonvulsants or antipsychotics) does not significantly harm sleep architecture, suggesting these combinations may be safe for sleep health.

Antidepressants alone were linked to longer REM latency and a higher prevalence of periodic limb movement disorder, but the addition of anticonvulsants or antipsychotics may help protect against these sleep-related issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effects of psychotropic medications on sleep architecture: a retrospective review of diagnostic polysomnography sleep parameters. Ghossoub, E., Geagea, L., Kobeissy, F., et al.[2022]

References

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

Prescription medications for sleep disturbances among midlife women during 2 years of follow-up: a SWAN retrospective cohort study. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Trazodone for the treatment of insomnia: a meta-analysis of randomized placebo-controlled trials. [2022]

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

Psychotropic medication and insomnia complaints in two epidemiological studies. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Meta-analysis of sleep changes in control groups of insomnia treatment trials. [2007]

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

The discrepancy between subjective and objective measures of sleep in older adults receiving CBT for comorbid insomnia. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Comparative short-term safety and efficacy of hypnotics: A quantitative risk-benefit analysis. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Evaluation of subjective efficacy and safety of ramelteon in Japanese subjects with chronic insomnia. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Do patients with intake of drugs labelled as sleep disturbing really sleep worse? A population based assessment from the Heinz Nixdorf Recall Study. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

[Safety profile of zolpidem: two studies of 3805 patients by Swiss practitioners]. [2018]

11. 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]

12. Germany pubmed.ncbi.nlm.nih.gov

Comparative effects of psychotropic medications on sleep architecture: a retrospective review of diagnostic polysomnography sleep parameters. [2022]