Sleep Apnea, Obstructive
Conditions
Brief summary
We would like to test the effect of opioid medication on pain sensitivity in subjects who have been diagnosed with a sleep disorder called Obstructive Sleep Apnea (OSA) compared to other subjects without OSA. Patients with OSA may have an altered sensitivity to the sedative, analgesic, and respiratory depressant effects of opioids.
Detailed description
The purpose of the study is to test the hypothesis that patients who suffer from moderate-to-severe OSA have increased pain thresholds and are more sensitive to the analgesic effects of opioids compared to patients with normal sleep-related breathing physiology. We will evaluate the effect of remifentanil, a short acting mu-opioid receptor agonist, on pain using an experimental heat and cold-induced pain tests, and compare it between volunteers with and without a polysomnography (PSG)-based diagnosis of obstructive sleep apnea.
Interventions
DRUGRemifentanil
Remifentanil was administered as a computer-controlled infusion, targeting two different effect site concentrations, 1 and 2 mcg/mL, in randomized order.
PROCEDURECold pain threshold and tolerance
Ice water was used to assess cold-related pain threshold and tolerance, defined as the time that the volunteers could keep their hands in the water before they started feeling pain or this feeling becomes unbearable, for threshold and tolerance, respectively.
DEVICEHeat pain threshold and tolerance
TSAII Neuroanalyzer (Medoc Advanced Medical Systems, Durham, NC), was used to assess the heat-related pain and tolerance of the volunteers defined as the respective temperatures where they started feeling as painful or unbearable.
PROCEDUREPolysomnography
All volunteers underwent a polysomnography study at home or at Stanford Sleep Center, approximately one week before their experimental pain assessment in the laboratory
Sponsors
Stanford University
Study design
Observational model
COHORT
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male 2 .18 - 55 years of age 3. Body mass index (BMI) lower or equal to 30 kg/m2 4. Absence of severe systemic disease that results in functional limitations (i.e. poorly controlled hypertension, angina pectoris, prior myocardial infarction, pulmonary disease that limits activity) 5.Subjects must be able to comprehend spoken and written English
Exclusion criteria
1. Major psychiatric, neurological, or neuromuscular disorder 2. Known diabetes mellitus or thyroid disease 3. Allergy to study medication (remifentanil) 4. History of addiction 5. Alcohol consumption which exceeds 2 drinks per day and /or drug abuse. 6. Chronic or acute use of opioids, or other medications affecting the CNS.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Experimental Cold-induced Pain - IGFBP-1 | 2 to 3 weeks | The effect of insulin growth factor binding protein-1 (IGFBP-1), a serum hypoxia marker, on the change of cold-induced pain thresholds under remifentanil was estimated using a mixed linear regression model. The results were expressed by the estimated beta (95% CI), indicating how much the change in the cold pain threshold (expressed in seconds) under remifentanil, was altered per unit of change in the IGFBP-1. For example, for every 1-pg/mL increase in the serum level of IGFBP-1, cold pain threshold will additionally increase by 0.0025 seconds for every 1-mcg/mL increase in the plasma level of remifentanil. |
| Experimental Heat-induced Pain - IGFBP-1 | 2 to 3 weeks | The effect of arterial oxyhemoglobin desaturation during sleep (chronic intermittent hypoxia expressed by insulin growth factor binding protein-1 (IGFBP-1), a serum hypoxia marker, on the change of heat-induced pain thresholds under remifentanil was estimated using a mixed linear regression model. The results were expressed by the estimated betas (95% CI), indicating how much the change in the heat pain threshold (expressed in C') under remifentanil, was altered per unit of change in the IGFBP-1. For example, for every 1-pg/mL increase in serum level of IGFBP-1, the heat pain threshold will additionally decrease by 0.0001 'C for every 1-mcg/mL increase in the plasma level of remifentanil. |
| Experimental Cold-induced Pain - SaO2 | 2 to 3 weeks | The effect of arterial oxyhemoglobin desaturation during sleep (chronic intermittent hypoxia expressed by nadir SaO2 during polysomnography) on the change of cold-induced pain thresholds under remifentanil was estimated using a mixed linear regression model. The results were expressed by the estimated betas (95% CI), indicating how much the change in the cold pain threshold (expressed in seconds) under remifentanil, was altered per unit of change in the SaO2. For example, for every 1-%-absolute decrease in the nadir SaO2, the cold pain threshold will additionally increase by 0.9694 seconds for every 1-mcg/mL increase in the plasma level of remifentanil. |
| Experimental Heat-induced Pain - SaO2 | 2 to 3 weeks | The effect of arterial oxyhemoglobin desaturation during sleep (chronic intermittent hypoxia expressed by nadir SaO2 during polysomnography), on the change of heat-induced pain thresholds under remifentanil was estimated using a mixed linear regression model. The results were expressed by the estimated betas (95% CI), indicating how much the change in the heat pain threshold (expressed in C') under remifentanil, was altered per unit of change in the SaO2. For example, for every 1-%-absolute decrease in the nadir SaO2, the heat pain threshold will additionally increase by 0.0172 'C for every 1-mcg/mL increase in the plasma level of remifentanil. |
Countries
United States
Participant flow
Recruitment details
From January 2008 till March 2010, we invited male volunteers (18-55 years old) with a history of habitual snoring and/or a formal diagnosis of OSA to participate in a study evaluating sleep and experimental pain processing at the Human Pain Laboratory in the Department of Anesthesiology at Stanford University.
Pre-assignment details
We screened 167 male volunteers; 56 consented to participate to the study.
Participants by arm
| Arm | Count |
|---|---|
| Male Volunteers at Risk for Sleep Apnea After approval from the Institutional Review Board and informed consent, we assessed cold and heat pain thresholds in volunteers after overnight polysomnography (PSG). We measured insulin growth factor binding protein-1 (IGFBP-1) a hypoxia-related serum marker. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 mg/ml), an mu-opioid agonist. Linear mixed effects regression model was employed to evaluate the association of the lowest oxyhemoglobin saturation (SaO2) during sleep and IGFBP-1 with the changes in pain thresholds after remifentanil administration. | 53 |
| Total | 53 |
Baseline characteristics
| Characteristic | Male Volunteers at Risk for Sleep Apnea |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants |
| Age, Continuous | 36 years STANDARD_DEVIATION 11 |
| Region of Enrollment United States | 53 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 53 |
| serious Total, serious adverse events | 0 / 53 |
Outcome results
Primary
Experimental Cold-induced Pain - IGFBP-1
The effect of insulin growth factor binding protein-1 (IGFBP-1), a serum hypoxia marker, on the change of cold-induced pain thresholds under remifentanil was estimated using a mixed linear regression model. The results were expressed by the estimated beta (95% CI), indicating how much the change in the cold pain threshold (expressed in seconds) under remifentanil, was altered per unit of change in the IGFBP-1. For example, for every 1-pg/mL increase in the serum level of IGFBP-1, cold pain threshold will additionally increase by 0.0025 seconds for every 1-mcg/mL increase in the plasma level of remifentanil.
Time frame: 2 to 3 weeks
Population: Volunteers with evaluable data were included in the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| at Risk for Sleep Apnea | Experimental Cold-induced Pain - IGFBP-1 | 0.0025 [sec/(mcg/mL)] /pg/mL |
Comparison: Beta for IGFBP-1: for every 1-pg/mL increase in its serum level the cold pain threshold will additionally increase by 0.0025 seconds for every 1-mcg/mL increase in the plasma level of remifentanil.p-value: <0.0595% CI: [0.0009, 0.0041]Regression, Linear
Comparison: Beta for SaO2: for every 1-%-absolute decrease in the nadir SaO2 the cold pain threshold will additionally increase by 0.9694 seconds for every 1-mcg/mL increase in the plasma level of remifentanil.p-value: 0.0595% CI: [-1.9127, -0.0261]Regression, Linear
Primary
Experimental Cold-induced Pain - SaO2
The effect of arterial oxyhemoglobin desaturation during sleep (chronic intermittent hypoxia expressed by nadir SaO2 during polysomnography) on the change of cold-induced pain thresholds under remifentanil was estimated using a mixed linear regression model. The results were expressed by the estimated betas (95% CI), indicating how much the change in the cold pain threshold (expressed in seconds) under remifentanil, was altered per unit of change in the SaO2. For example, for every 1-%-absolute decrease in the nadir SaO2, the cold pain threshold will additionally increase by 0.9694 seconds for every 1-mcg/mL increase in the plasma level of remifentanil.
Time frame: 2 to 3 weeks
Population: Volunteers with evaluable data were included in the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| at Risk for Sleep Apnea | Experimental Cold-induced Pain - SaO2 | -0.9694 [sec/(mcg/mL)] /% |
Primary
Experimental Heat-induced Pain - IGFBP-1
The effect of arterial oxyhemoglobin desaturation during sleep (chronic intermittent hypoxia expressed by insulin growth factor binding protein-1 (IGFBP-1), a serum hypoxia marker, on the change of heat-induced pain thresholds under remifentanil was estimated using a mixed linear regression model. The results were expressed by the estimated betas (95% CI), indicating how much the change in the heat pain threshold (expressed in C') under remifentanil, was altered per unit of change in the IGFBP-1. For example, for every 1-pg/mL increase in serum level of IGFBP-1, the heat pain threshold will additionally decrease by 0.0001 'C for every 1-mcg/mL increase in the plasma level of remifentanil.
Time frame: 2 to 3 weeks
Population: Volunteers with evaluable data were included in the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| at Risk for Sleep Apnea | Experimental Heat-induced Pain - IGFBP-1 | -0.0001 ['C/(mcg/mL)] /pg/mL |
Comparison: Beta for IGFBP-1: for every 1-pg/mL increase in its serum level, the heat pain threshold will additionally decrease by 0.0001 'C for every 1-mcg/mL increase in the plasma level of remifentanil.p-value: <0.0595% CI: [-0.0001, -0.0001]Regression, Linear
Comparison: Beta for SaO2: for every 1-%-absolute decrease in the nadir SaO2, the heat pain threshold will additionally increase by 0.0172 'C for every 1-mcg/mL increase in the plasma level of remifentanil.p-value: <0.0595% CI: [-0.018, 0.0556]Regression, Linear
Primary
Experimental Heat-induced Pain - SaO2
The effect of arterial oxyhemoglobin desaturation during sleep (chronic intermittent hypoxia expressed by nadir SaO2 during polysomnography), on the change of heat-induced pain thresholds under remifentanil was estimated using a mixed linear regression model. The results were expressed by the estimated betas (95% CI), indicating how much the change in the heat pain threshold (expressed in C') under remifentanil, was altered per unit of change in the SaO2. For example, for every 1-%-absolute decrease in the nadir SaO2, the heat pain threshold will additionally increase by 0.0172 'C for every 1-mcg/mL increase in the plasma level of remifentanil.
Time frame: 2 to 3 weeks
Population: Volunteers with evaluable data were included in the analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| at Risk for Sleep Apnea | Experimental Heat-induced Pain - SaO2 | -0.0172 ['C/(mcg/mL)] /% |