Preventing the Inflammatory Response to Experimentally-induced Insomnia Symptoms

The main purpose of this study is to learn about the effects of sleep disruption (two days in a row where sleep is shortened and disrupted) on inflammation, mood (how you feel), and pain processing (your own experiences/perceptions of pain). In this research project, we are trying to figure out if we can change the effects of sleep disruption on inflammation, mood, and pain. Therefore, we will study whether taking a low-dose aspirin pill every day over 2 weeks can change how we respond to sleep disruption. For example, does the sensitivity to pain (e.g., how intense the feeling of pain is if we put our hand in very hot or very cold water) change with sleep disruption, and can low-dose aspirin influence this change. We are also interested in seeing how inflammation changes in relation to your own perceived experience of pain.

Study Overview

• Status: Completed
• Conditions: Insomnia
• Intervention / Treatment: Drug: Placebo; Drug: Aspirin

Detailed Description

Sleep that is deficient in quantity or quality leads to upregulation of inflammatory markers (Mullington et al., 2010). In particular, interleukin (IL)-6 and prostaglandin (PG) E2 are elevated in experimental models of sleep restriction or total sleep deprivation, as well as in insomnia. Inflammation is thought to be a key mechanism through which insufficient sleep increases the risk of developing or exacerbating various disorders, including cardiovascular and metabolic disorders (Mullington et al., 2009), as well as pain-related disorders (Haack et al., 2009c). With respect to pain, markers such as IL-6 and PGE2 are able to sensitize pain transmission neurons, thereby increasing their responsiveness to stimulation. In the context of insufficient sleep, both IL-6 and PGE2 have been shown to be associated with increased spontaneous pain (Haack et al., 2007;Haack et al., 2009a), suggesting their mediating role in pain amplification as a consequence of insufficient sleep.

These findings raise the question of whether pain amplification can be dampened by preventing the inflammatory increase in response to insufficient sleep.

The primary goal of this pilot project is to gather preliminary support for the hypothesis that deficient sleep leads to pain amplification through an inflammatory mechanism.

In addition to the primary goal of this proposal, the secondary goal is to gather preliminary data on the effects of aspirin on blood pressure regulation. Cardiovascular disease is the leading cause of death in the United States. A modest reduction of blood pressure (BP; i.e., 3 to 5 mmHg) in the population will produce a significant fall in serious cardiovascular events (Turnbull, 2003). It has been reported that low-dose aspirin may significantly reduce BP (i.e., 6 to 7 mmHg) when taken at bedtime (Hermida et al., 1994;Hermida et al., 1997;Hermida et al., 2003b;Hermida et al., 2003a;Hermida et al., 2005a;Hermida et al., 2005b). Aspirin, when taken at bedtime, may modulate 24h blood pressure by decreasing the nocturnal rise of renin-angiotensin-aldosterone system (RAAS) activity (Snoep et al., 2009) and attenuating the nocturnal drop in nitric oxide (NO) production (Hermida et al., 2005b). However, the underlying mechanisms are still unknown. Therefore, the second goal of this pilot project is to investigate the potential mechanisms contributing to BP reduction in response to aspirin taken at bedtime.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 31 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Women and men between the ages 18-35 years
• Body mass index (BMI) between 18.5 and 30.0 kg/m2
• For female participants: regular menstrual cycles, no significant discomfort during pre-menses/menses
• Daily sleep duration between 7.0-9.0 hours, verified by sleep log/actigraphy data for two weeks
• Habitual sleep period must begin within one hour of 2300h (to ensure normal entrainment)
• Blood chemistry in the normal range

Exclusion Criteria:

• Active infection/disease.
• History of psychiatric, neurological, pain-related, immune, gastrointestinal, or cardiovascular disease; significant allergy; Raynaud's syndrome.
• History of intolerance or allergy to non-steroidal anti-inflammatory drugs (NSAID)
• Esophageal reflux; gastric or duodenal ulcers; or asthma
• Pregnant/nursing.
• Respiratory disturbance index of >5 events/hour on polysomnographic sleep study, periodic leg movement index (PLMI) >15/hour; sleep efficiency <80% (findings indicative of a sleep disorder).
• Regular medication use other than oral contraceptives.
• Donation of blood or platelets 3 month prior to or in-between in-hospital visits.
• Substance abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Insomnia symptom induction/placebo; Daily intake of pill at bedtime over 2-week period prior to and during the 5-day in-hospital stay	Drug: Placebo; pill that looks like aspirin without the effects of aspirin
Experimental: Insomnia symptom induction/aspirin; Daily intake of pill at bedtime over 2-week period prior to and during the 5-day in-hospital stay	Drug: Aspirin; 81mg aspirin daily at bedtime over a 2 week period; Other Names: non-steroidal anti-inflammatory drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammation	interleukin 6	Measured in plasma and urine 3 times/day over the 5-day in-hospital stay (after 2 weeks of pill admin)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain sensitivity	Thermode will be attached to the skin and participant has to rate the intensity of the heat or cold sensation via visual analog scales	Measured once per day during in-hospital days 1-5 (after 2 weeks of pill admin)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain modulation	Participant has to immerse foot into cold or hot water and rate the intensity of heat pain or cold stimuli applied to the arm on visual analog scales	Measured once per day during in-hospital days 1-5

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): October 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: September 23, 2014
• First Submitted That Met QC Criteria: October 16, 2014
• First Posted (Estimate): October 20, 2014

Study Record Updates

• Last Update Posted (Actual): March 15, 2017
• Last Update Submitted That Met QC Criteria: March 13, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: sleep, insomnia, inflammation, pain; Insomnia symptom induction/placebo; Insomnia symptom induction/aspirin
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Sleep Initiation and Maintenance Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal
• Other Study ID Numbers: 2014P000269