Pain, Touch
Conditions
Keywords
NALOXONE, fMRI, Functional Magnetic Resonance Imaging (fMRI)
Brief summary
Background: Medicines called opioids are used to treat pain. The body also produces opioids. These are called endorphins. Researchers want to learn more about how these natural opioids work. This might lead to new therapies for conditions like depression, anxiety, and chronic pain. Objective: To determine how opioids affect how pleasant or unpleasant it feels when the skin is touched, compressed, or heated. Eligibility: Healthy right-handed adults ages 18-50. Design: Participants will be screened under another protocol. Participants will have 2 study visits with the same procedures, at least 1 day apart. Each visit will last 3-4 hours. Participants will wear shorts or change into scrubs so researchers can test on their legs. Participants will answer questions and have urine tests. Participants will have a brain magnetic resonance imaging (MRI) scan. The scanner is a metal cylinder in a strong magnetic field. Participants will lie on a table that slides in and out of the cylinder. A device called a coil will be placed over the head. During MRI, participants will have sensory testing. They will get several types of touch to the calf of the leg. These include gentle brushing of the skin, gentle compression of the calf with an inflation sleeve, and heat stimuli. Participants will have an intravenous line placed each day. They will get naloxone 1 day and saline the other day. Participants will not be told which they get. Naloxone is a drug that blocks opioid receptors. The MRI and sensory testing will then be repeated. After each stimuli block, participants will rate the sensations as well as their mood and calmness/anxiety.
Detailed description
Objective: Our recent pilot study found evidence suggesting that blocking endogenous opioid release increases the pleasantness associated with having the skin stroked. Deep pressure touch (observed in hugs and massage) also typically conveys a sense of pleasantness. This increased pleasantness contrasts with evidence that blocking endogenous opioid release increases pain. The current study will examine the role of endogenous opioids in the pleasantness of light skin stroking and deep pressure touch, and contrast it with their role in the unpleasantness of a painful heat stimulus. Further, it will examine the neural basis of observed perceptual changes, using fMRI. This study constitutes the first study of the K99 phase of a K99/R00 grant application recently submitted to National Center for Complementary and Integrative Health (NCCIH) by Dr. Laura Case. Study Population: 30 healthy participants will be enrolled in the study. Design: Participants will receive intravenous saline or intravenous naloxone on separate days to investigate the effect of mu-opioid antagonism on the intensity and pleasantness of superficial and deep affective touch and the intensity and unpleasantness of cutaneous heat pain. Using a double-blind cross-over design, functional Magnetic Resonance Imaging (fMRI) will be conducted during sensory testing before and after the infusion of each drug to examine the neural mediation of opioid effects on touch perception. Ratings of mood, anxiety, pain intensity, pleasantness/unpleasantness, wanting and liking will also be collected throughout the study session. Outcome measures: We will compare subjective ratings (mood, calmness, anxiety, pleasantness, wanting, liking, pain intensity and unpleasantness) during naloxone and saline to: 1) Determine whether naloxone increases the pleasantness and/or intensity of affective touch (light brush and deep compression); 2) Determine whether naloxone increases the unpleasantness and/or intensity of cutaneous heat pain; 3) Determine the role of mood or anxiety changes in mediating the effect of endogenous opioids on these perceptual measures; 3) Determine changes in the brain activation related to these effects.
Interventions
OTHERPlacebo
saline
DRUGNaloxone
We will be using naloxone at normal clinical doses as the study drug. Naloxone is an opiate antagonist and has been used since the 1960 s to reverse the effects of opiate overdoses.
Sponsors
National Center for Complementary and Integrative Health (NCCIH)
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
-INCLUSION CRITERIA: All subjects must be: * Between 18 and 50 years old. * Right-handed (on Edinburgh Handedness Inventory). * Fluent in English. * Able to provide written informed consent.
Exclusion criteria
Overall
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pleasantness of Skin Brushing From Before to After Infusion | One day, within a 2 hour session | Measurement of brushing pleasantness using a visual analogue scale. Sensory hedonics (unpleasantness vs. pleasantness) was assessed on a scale ranging from extremely unpleasant (-100) to neutral (0), to extremely pleasant (100). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Pleasantness of Deep Skin Pressure From Before to After Infusion | One day, within a 2 hour session | Measurement of pressure pleasantness/unpleasantness using a visual analogue scale. Sensory hedonics (unpleasantness vs. pleasantness) was assessed on a scale ranging from extremely unpleasant (-100) to neutral (0), to extremely pleasant (100). |
| Change in Unpleasantness of Cutaneous Heat Pain From Before to After Infusion | One day, within a 2 hour session | Measurement of heat pleasantness/unpleasantness using a visual analogue scale. Sensory hedonics (unpleasantness vs. pleasantness) was assessed on a scale ranging from extremely unpleasant (-100) to neutral (0), to extremely pleasant (100). |
| Changes in Intensity of Skin Brushing From Before to After Infusion | One day, within a 2 hour session | Measurement of brushing intensity using a visual analogue scale. Intensity was assessed on a scale ranging from no sensation (-100) to pain threshold (0), to intolerable pain (100). |
| Changes in Intensity of Deep Skin Pressure From Before to After Infusion | One day, within a 2 hour session | Measurement of pressure intensity using a visual analogue scale. Intensity was assessed on a scale ranging from no sensation (-100) to pain threshold (0), to intolerable pain (100). |
| Changes in Intensity of Cutaneous Heat Pain From Before to After Infusion | One day, within a 2 hour session | Measurement of heat intensity using a visual analogue scale. Intensity was assessed on a scale ranging from no sensation (-100) to pain threshold (0), to intolerable pain (100). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Anxiety During Deep Skin Pressure From Before to After Infusion | One day, within a 2 hour session | Anxiety during pressure was assessed using a visual analog scale ranging from extreme anxiety (-100) to neutral (0) to extreme calm (100). |
| Activation in Somatosensory Cortex (S2) Brain Area of Interest (ROI) During Brushing | One day, within a 2 hour session | Functional MRI Blood-oxygen-level-dependent (BOLD) activation in secondary somatosensory cortex (S2) during brushing. BOLD signal is typically expressed as arbitrary units (AU's) measured from 0 to 100% change. 0 being no change and 100% maximum change |
| Changes in Anxiety During Cutaneous Heat From Before to After Infusion | One day, within a 2-hour session | Anxiety during heat was assessed using a visual analog scale ranging from extreme anxiety (-100) to neutral (0) to extreme calm (100). |
| Activation in Somatosensory Cortex (S2) Brain Area of Interest (ROI) During Pressure | One day, within a 2 hour session | Functional MRI Blood-oxygen-level-dependent (BOLD) activation in secondary somatosensory cortex (S2) during pressure. BOLD signal is typically expressed as arbitrary units (AU's) measured from 0 to 100% change. 0 being no change and 100% maximum change |
| Changes in Mood During Skin Brushing From Before to After Infusion | One day, within a 2 hour session | Mood during brushing was assessed using a visual analogue scale ranging from extremely bad mood (-100) to neutral mood (0), to extremely good mood (100). |
| Changes in Mood During Skin Pressure From Before to After Infusion | One day, within a 2 hour session | Mood during skin pressure was assessed using a visual analogue scale ranging from extremely bad mood (-100) to neutral mood (0), to extremely good mood (100). |
| Changes in Mood During Cutaneous Heat From Before to After Infusion | One day, within a 2 hour session | Mood during heat was assessed using a visual analogue scale ranging from extremely bad mood (-100) to neutral mood (0), to extremely good mood (100). |
| Changes in Anxiety During Skin Brushing From Before to After Infusion | One day, within a 2 hour session | Anxiety during brushing was assessed using a visual analog scale ranging from extreme anxiety (-100) to neutral (0) to extreme calm (100). |
Countries
United States
Participant flow
Pre-assignment details
29 subject consented; one subject consented but did not start either arm of the study
Participants by arm
| Arm | Count |
|---|---|
| Naloxone, Then Placebo Day one - During MRI session participant underwent sensory stimulus testing followed by bolus and infusion doses of naloxone (0.05 mg/kg bodyweight). When infusion levels reached stability, sensory testing was performed again.
Day two - During MRI session participant underwent sensory stimulus testing followed by bolus and infusion doses of normal saline. When infusion levels reached stability, sensory testing was performed again. | 15 |
| Placebo, Then Naloxone Day one - During MRI session participant underwent sensory stimulus testing followed by bolus and infusion doses of normal saline. When infusion levels reached stability, sensory testing was performed again.
Day two - During MRI session participant underwent sensory stimulus testing followed by bolus and infusion doses of naloxone (0.05 mg/kg bodyweight). When infusion levels reached stability, sensory testing was performed again. | 13 |
| Total | 28 |
Baseline characteristics
| Characteristic | Naloxone, Then Placebo | Placebo, Then Naloxone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 13 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 11 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Female | 9 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 0 / 24 | 0 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
Change in Pleasantness of Skin Brushing From Before to After Infusion
Measurement of brushing pleasantness using a visual analogue scale. Sensory hedonics (unpleasantness vs. pleasantness) was assessed on a scale ranging from extremely unpleasant (-100) to neutral (0), to extremely pleasant (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Change in Pleasantness of Skin Brushing From Before to After Infusion | -9.6875 Units on a scale | Standard Deviation 21.6314 |
| Placebo | Change in Pleasantness of Skin Brushing From Before to After Infusion | -4.9583 Units on a scale | Standard Deviation 22.3983 |
Secondary
Change in Unpleasantness of Cutaneous Heat Pain From Before to After Infusion
Measurement of heat pleasantness/unpleasantness using a visual analogue scale. Sensory hedonics (unpleasantness vs. pleasantness) was assessed on a scale ranging from extremely unpleasant (-100) to neutral (0), to extremely pleasant (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Change in Unpleasantness of Cutaneous Heat Pain From Before to After Infusion | -5.75 Units on a scale | Standard Deviation 27.2969 |
| Placebo | Change in Unpleasantness of Cutaneous Heat Pain From Before to After Infusion | -3.4783 Units on a scale | Standard Deviation 26.2728 |
Secondary
Changes in Intensity of Cutaneous Heat Pain From Before to After Infusion
Measurement of heat intensity using a visual analogue scale. Intensity was assessed on a scale ranging from no sensation (-100) to pain threshold (0), to intolerable pain (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Changes in Intensity of Cutaneous Heat Pain From Before to After Infusion | 4.4583 Units on a scale | Standard Deviation 22.197 |
| Placebo | Changes in Intensity of Cutaneous Heat Pain From Before to After Infusion | -1.3043 Units on a scale | Standard Deviation 24.6092 |
Secondary
Changes in Intensity of Deep Skin Pressure From Before to After Infusion
Measurement of pressure intensity using a visual analogue scale. Intensity was assessed on a scale ranging from no sensation (-100) to pain threshold (0), to intolerable pain (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Changes in Intensity of Deep Skin Pressure From Before to After Infusion | -3.8333 Units on a scale | Standard Deviation 21.2671 |
| Placebo | Changes in Intensity of Deep Skin Pressure From Before to After Infusion | -4 Units on a scale | Standard Deviation 20.4762 |
Secondary
Changes in Intensity of Skin Brushing From Before to After Infusion
Measurement of brushing intensity using a visual analogue scale. Intensity was assessed on a scale ranging from no sensation (-100) to pain threshold (0), to intolerable pain (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Changes in Intensity of Skin Brushing From Before to After Infusion | -4.5833 Units on a scale | Standard Deviation 12.7511 |
| Placebo | Changes in Intensity of Skin Brushing From Before to After Infusion | 4.7917 Units on a scale | Standard Deviation 23.3065 |
Secondary
Changes in Pleasantness of Deep Skin Pressure From Before to After Infusion
Measurement of pressure pleasantness/unpleasantness using a visual analogue scale. Sensory hedonics (unpleasantness vs. pleasantness) was assessed on a scale ranging from extremely unpleasant (-100) to neutral (0), to extremely pleasant (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Changes in Pleasantness of Deep Skin Pressure From Before to After Infusion | -2.25 Units on a scale | Standard Deviation 22.3527 |
| Placebo | Changes in Pleasantness of Deep Skin Pressure From Before to After Infusion | -1.375 Units on a scale | Standard Deviation 15.4196 |
Other Pre-specified
Activation in Somatosensory Cortex (S2) Brain Area of Interest (ROI) During Brushing
Functional MRI Blood-oxygen-level-dependent (BOLD) activation in secondary somatosensory cortex (S2) during brushing. BOLD signal is typically expressed as arbitrary units (AU's) measured from 0 to 100% change. 0 being no change and 100% maximum change
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Activation in Somatosensory Cortex (S2) Brain Area of Interest (ROI) During Brushing | 0.0475 Arbitrary units | Standard Deviation 32.5047 |
| Placebo | Activation in Somatosensory Cortex (S2) Brain Area of Interest (ROI) During Brushing | 9.6547 Arbitrary units | Standard Deviation 31.2841 |
Other Pre-specified
Activation in Somatosensory Cortex (S2) Brain Area of Interest (ROI) During Pressure
Functional MRI Blood-oxygen-level-dependent (BOLD) activation in secondary somatosensory cortex (S2) during pressure. BOLD signal is typically expressed as arbitrary units (AU's) measured from 0 to 100% change. 0 being no change and 100% maximum change
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Activation in Somatosensory Cortex (S2) Brain Area of Interest (ROI) During Pressure | -3.1585 Arbitrary units | Standard Deviation 42.3639 |
| Placebo | Activation in Somatosensory Cortex (S2) Brain Area of Interest (ROI) During Pressure | 17.4139 Arbitrary units | Standard Deviation 32.507 |
Other Pre-specified
Changes in Anxiety During Cutaneous Heat From Before to After Infusion
Anxiety during heat was assessed using a visual analog scale ranging from extreme anxiety (-100) to neutral (0) to extreme calm (100).
Time frame: One day, within a 2-hour session
Population: All participants who completed both the treatment and placebo phases of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Changes in Anxiety During Cutaneous Heat From Before to After Infusion | 4.0833 Units on a scale | Standard Deviation 22.2583 |
| Placebo | Changes in Anxiety During Cutaneous Heat From Before to After Infusion | -12.0435 Units on a scale | Standard Deviation 19.3654 |
Other Pre-specified
Changes in Anxiety During Deep Skin Pressure From Before to After Infusion
Anxiety during pressure was assessed using a visual analog scale ranging from extreme anxiety (-100) to neutral (0) to extreme calm (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Changes in Anxiety During Deep Skin Pressure From Before to After Infusion | 0.0417 Units on a scale | Standard Deviation 28.3568 |
| Placebo | Changes in Anxiety During Deep Skin Pressure From Before to After Infusion | -5.9167 Units on a scale | Standard Deviation 12.7392 |
Other Pre-specified
Changes in Anxiety During Skin Brushing From Before to After Infusion
Anxiety during brushing was assessed using a visual analog scale ranging from extreme anxiety (-100) to neutral (0) to extreme calm (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Changes in Anxiety During Skin Brushing From Before to After Infusion | -2.7917 Units on a scale | Standard Deviation 21.8197 |
| Placebo | Changes in Anxiety During Skin Brushing From Before to After Infusion | -8.5 Units on a scale | Standard Deviation 22.4304 |
Other Pre-specified
Changes in Mood During Cutaneous Heat From Before to After Infusion
Mood during heat was assessed using a visual analogue scale ranging from extremely bad mood (-100) to neutral mood (0), to extremely good mood (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Changes in Mood During Cutaneous Heat From Before to After Infusion | 0.3333 Units on a scale | Standard Deviation 21.0717 |
| Placebo | Changes in Mood During Cutaneous Heat From Before to After Infusion | -5.3478 Units on a scale | Standard Deviation 20.7476 |
Other Pre-specified
Changes in Mood During Skin Brushing From Before to After Infusion
Mood during brushing was assessed using a visual analogue scale ranging from extremely bad mood (-100) to neutral mood (0), to extremely good mood (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Changes in Mood During Skin Brushing From Before to After Infusion | -2.375 Units on a scale | Standard Deviation 19.0652 |
| Placebo | Changes in Mood During Skin Brushing From Before to After Infusion | 1.16667 Units on a scale | Standard Deviation 17.5537 |
Other Pre-specified
Changes in Mood During Skin Pressure From Before to After Infusion
Mood during skin pressure was assessed using a visual analogue scale ranging from extremely bad mood (-100) to neutral mood (0), to extremely good mood (100).
Time frame: One day, within a 2 hour session
Population: All participants who completed both the treatment and placebo phases of the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Naloxone | Changes in Mood During Skin Pressure From Before to After Infusion | 3.2083 Units on a scale | Standard Deviation 20.8287 |
| Placebo | Changes in Mood During Skin Pressure From Before to After Infusion | -1.7917 Units on a scale | Standard Deviation 28.6657 |