Pain
Conditions
Brief summary
The aim of this study is to use a brain stimulation tool called transcranial direct current stimulation (tDCS) to investigate the analgesic (reducing sensitivity to pain) effects of lidocaine cream and the hyperalgesic (increasing sensitivity to pain) effects of capsaicin cream using a neutral cream as a control. tDCS stimulation has been shown to temporarily influence the way the stimulated part of the brain functions. With this method, the involvement of specific parts of the brain can be investigated in the working of the brain as a whole.
Interventions
DEVICEtranscranial direct current stimulation (tDCS)
tCDS safely applies a weak electrical current to your scalp using two sponge electrodes that look like flat circular pads. The pads will be held in place on your head with a neoprene cap. The pads will be attached to a generator that will send a weak stimulus to your scalp. This current influences the way that your brain cells work. When the stimulus starts, you might feel a tingling sensation underneath the electrode pads. That sensation is not painful and goes away in seconds.
OTHERLidocaine cream
Lidocaine cream will be applied on the arm to reduce pain sensitivity (analgesia).
OTHERCapsaicin cream
Capsaicin cream will be applied on the arm to increase pain sensitivity (hyperalgesia).
OTHERControl cream
A neutral cream will be applied on the arm as a control.
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Right handed healthy male and female adults aged 21-50 * No contraindications to fMRI scanning * At least a 10th grade English-reading level; English can be a second language provided that the patients feel they understand all the questions used in the assessment measures.
Exclusion criteria
* Current or past history of major medical, neurological, or psychiatric illness * Claustrophobia * History of head trauma * Instability of responses to experimental pain * Non-fluent speaker of English * Presence of any contraindications to fMRI scanning. For example: cardiac pacemaker, metal implants, fear of closed spaces, pregnancy * History of alcohol/substance abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparison of Functional Connectivity Changes of the DLPFC Before and After tDCS Stimulation | up to 2 weeks | We investigated the effects of cathodal (inhibition) and anodal (enhancement) tDCS on rDLPFC functional connectivity (FC) with the supplementary motor area (SMA) and anterior insula. Higher Fisher Z-scores represent greater resting-state functional connectivity. |
| fMRI Resting States Functional Connectivity Changes During Pain Stimulation | up to 2 weeks | We measured changes in blood oxygen level-dependent (BOLD) activity in the brain during pain stimulation. In the outcome measure data table, placebo contrast indicates lidocaine - neutral and nocebo contrast indicates capsaicin - neutral. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS | up to 2 weeks | The Gracely Sensory Scale allows participants to rate the intensity of heat pain stimuli on a scale from 0 to 20, with 0 indicating no pain sensation and 20 indicating extremely intense pain. The outcome measure data table shows mean pain ratings for the lidocaine, capsaicin, and neutral creams after enhancement, inhibition, or sham tDCS stimulation. |
Countries
United States
Participant flow
Pre-assignment details
18 subjects were dropped prior to randomization. Reasons for this included inconsistent or non-differentiable pain ratings to heat stimuli, pain thresholds that were too high or low, inability to finish subsequent sessions, too much discomfort with noxious stimuli, no SSN/hairstyle incompatible with tDCS, participated in a previous pain study.
Participants by arm
| Arm | Count |
|---|---|
| tDCS Enhancement In this group, the transcranial direct current stimulation (tDCS) stimulates the areas of the brain being examined in this study to increase their activity.
transcranial direct current stimulation (tDCS): tCDS safely applies a weak electrical current to your scalp using two sponge electrodes that look like flat circular pads. The pads will be held in place on your head with a neoprene cap. The pads will be attached to a generator that will send a weak stimulus to your scalp. This current influences the way that your brain cells work. When the stimulus starts, you might feel a tingling sensation underneath the electrode pads. That sensation is not painful and goes away in seconds.
Lidocaine cream: Lidocaine cream will be applied on the arm to reduce pain sensitivity (analgesia).
Capsaicin cream: Capsaicin cream will be applied on the arm to increase pain sensitivity (hyperalgesia).
Control cream: A neutral cream will be applied on the arm as a control. | 27 |
| tDCS Inhibition In this group, the transcranial direct current stimulation (tDCS) inhibits the areas of the brain being examined in this study to decrease their activity.
transcranial direct current stimulation (tDCS): tCDS safely applies a weak electrical current to your scalp using two sponge electrodes that look like flat circular pads. The pads will be held in place on your head with a neoprene cap. The pads will be attached to a generator that will send a weak stimulus to your scalp. This current influences the way that your brain cells work. When the stimulus starts, you might feel a tingling sensation underneath the electrode pads. That sensation is not painful and goes away in seconds.
Lidocaine cream: Lidocaine cream will be applied on the arm to reduce pain sensitivity (analgesia).
Capsaicin cream: Capsaicin cream will be applied on the arm to increase pain sensitivity (hyperalgesia).
Control cream: A neutral cream will be applied on the arm as a control. | 27 |
| Sham tDCS Sham transcranial direct current stimulation (tDCS) does not provide real stimulation though you will not know this until your debriefing at the end of the study. Sham will be used to determine if results of this study are due to tDCS or other reasons.
transcranial direct current stimulation (tDCS): tCDS safely applies a weak electrical current to your scalp using two sponge electrodes that look like flat circular pads. The pads will be held in place on your head with a neoprene cap. The pads will be attached to a generator that will send a weak stimulus to your scalp. This current influences the way that your brain cells work. When the stimulus starts, you might feel a tingling sensation underneath the electrode pads. That sensation is not painful and goes away in seconds.
Lidocaine cream: Lidocaine cream will be applied on the arm to reduce pain sensitivity (analgesia).
Capsaicin cream: Capsaicin cream will be applied on the arm to increase pain sensitivity (hyperalgesia). | 27 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Dental metal affected MRI scan quality | 1 | 0 | 0 |
| Overall Study | Nausea during MRI scan | 0 | 1 | 0 |
| Overall Study | Subject unable to attend final session | 0 | 1 | 0 |
| Overall Study | Technical issues during final MRI scan | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Sham tDCS | tDCS Inhibition | tDCS Enhancement |
|---|---|---|---|---|
| Age, Continuous | 27.39 years | 27.89 years | 26.87 years | 27.42 years |
| Baseline pain ratings for high pain stimuli | 14.53 units on a scale STANDARD_DEVIATION 2.38 | 14.52 units on a scale STANDARD_DEVIATION 2.2 | 14.56 units on a scale STANDARD_DEVIATION 2.33 | 14.52 units on a scale STANDARD_DEVIATION 2.67 |
| Baseline pain ratings for low pain stimuli | 5.22 units on a scale STANDARD_DEVIATION 2.36 | 5.08 units on a scale STANDARD_DEVIATION 2.14 | 4.54 units on a scale STANDARD_DEVIATION 2.04 | 6.05 units on a scale STANDARD_DEVIATION 2.67 |
| Baseline pain ratings for moderate pain stimuli | 9.04 units on a scale STANDARD_DEVIATION 2.28 | 8.97 units on a scale STANDARD_DEVIATION 2.34 | 8.84 units on a scale STANDARD_DEVIATION 2.54 | 9.31 units on a scale STANDARD_DEVIATION 1.97 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 3 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 64 Participants | 23 Participants | 21 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 6 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 5 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 52 Participants | 15 Participants | 19 Participants | 18 Participants |
| Region of Enrollment United States | 81 Participants | 27 Participants | 27 Participants | 27 Participants |
| Sex: Female, Male Female | 37 Participants | 13 Participants | 11 Participants | 13 Participants |
| Sex: Female, Male Male | 44 Participants | 14 Participants | 16 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 30 | 0 / 27 |
| other Total, other adverse events | 2 / 28 | 1 / 30 | 0 / 27 |
| serious Total, serious adverse events | 0 / 28 | 0 / 30 | 0 / 27 |
Outcome results
Primary
Comparison of Functional Connectivity Changes of the DLPFC Before and After tDCS Stimulation
We investigated the effects of cathodal (inhibition) and anodal (enhancement) tDCS on rDLPFC functional connectivity (FC) with the supplementary motor area (SMA) and anterior insula. Higher Fisher Z-scores represent greater resting-state functional connectivity.
Time frame: up to 2 weeks
Population: Participants who completed all study sessions
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| tDCS Enhancement | Comparison of Functional Connectivity Changes of the DLPFC Before and After tDCS Stimulation | rDLPFC-SMA Functional Connectivity (post-pre) | -0.11 Fisher Z value | Standard Deviation 0.22 |
| tDCS Enhancement | Comparison of Functional Connectivity Changes of the DLPFC Before and After tDCS Stimulation | rDLPFC-Insula Functional Connectivity (post-pre) | -0.13 Fisher Z value | Standard Deviation 0.23 |
| tDCS Inhibition | Comparison of Functional Connectivity Changes of the DLPFC Before and After tDCS Stimulation | rDLPFC-SMA Functional Connectivity (post-pre) | -0.09 Fisher Z value | Standard Deviation 0.16 |
| tDCS Inhibition | Comparison of Functional Connectivity Changes of the DLPFC Before and After tDCS Stimulation | rDLPFC-Insula Functional Connectivity (post-pre) | -0.13 Fisher Z value | Standard Deviation 0.2 |
| Sham tDCS | Comparison of Functional Connectivity Changes of the DLPFC Before and After tDCS Stimulation | rDLPFC-SMA Functional Connectivity (post-pre) | 0.08 Fisher Z value | Standard Deviation 0.2 |
| Sham tDCS | Comparison of Functional Connectivity Changes of the DLPFC Before and After tDCS Stimulation | rDLPFC-Insula Functional Connectivity (post-pre) | 0.07 Fisher Z value | Standard Deviation 0.18 |
Primary
fMRI Resting States Functional Connectivity Changes During Pain Stimulation
We measured changes in blood oxygen level-dependent (BOLD) activity in the brain during pain stimulation. In the outcome measure data table, placebo contrast indicates lidocaine - neutral and nocebo contrast indicates capsaicin - neutral.
Time frame: up to 2 weeks
Population: Participants who completed all study sessions and whose task fMRI data had no issues.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| tDCS Enhancement | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity change in mPFC/ACC: placebo contrast | 0.14 Arbitrary unit | Standard Deviation 0.47 |
| tDCS Enhancement | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity change in mPFC/ACC: nocebo contrast | 0.26 Arbitrary unit | Standard Deviation 0.8 |
| tDCS Enhancement | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity in the left insula: placebo contrast | 0.11 Arbitrary unit | Standard Deviation 0.35 |
| tDCS Enhancement | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity in the left insula: nocebo contrast | 0.08 Arbitrary unit | Standard Deviation 0.36 |
| tDCS Inhibition | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity in the left insula: nocebo contrast | 0.16 Arbitrary unit | Standard Deviation 0.35 |
| tDCS Inhibition | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity change in mPFC/ACC: placebo contrast | 0.50 Arbitrary unit | Standard Deviation 0.57 |
| tDCS Inhibition | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity in the left insula: placebo contrast | 0.21 Arbitrary unit | Standard Deviation 0.81 |
| tDCS Inhibition | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity change in mPFC/ACC: nocebo contrast | 0.27 Arbitrary unit | Standard Deviation 0.81 |
| Sham tDCS | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity in the left insula: nocebo contrast | 0.30 Arbitrary unit | Standard Deviation 0.39 |
| Sham tDCS | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity change in mPFC/ACC: nocebo contrast | 0.25 Arbitrary unit | Standard Deviation 1.15 |
| Sham tDCS | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity in the left insula: placebo contrast | 0.18 Arbitrary unit | Standard Deviation 0.64 |
| Sham tDCS | fMRI Resting States Functional Connectivity Changes During Pain Stimulation | BOLD activity change in mPFC/ACC: placebo contrast | -0.17 Arbitrary unit | Standard Deviation 0.68 |
Secondary
Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS
The Gracely Sensory Scale allows participants to rate the intensity of heat pain stimuli on a scale from 0 to 20, with 0 indicating no pain sensation and 20 indicating extremely intense pain. The outcome measure data table shows mean pain ratings for the lidocaine, capsaicin, and neutral creams after enhancement, inhibition, or sham tDCS stimulation.
Time frame: up to 2 weeks
Population: Participants who completed all study sessions
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| tDCS Enhancement | Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS | Pain rating on placebo cream | 7.29 units on a scale | Standard Deviation 2.74 |
| tDCS Enhancement | Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS | Pain rating on nocebo cream | 8.54 units on a scale | Standard Deviation 3.54 |
| tDCS Enhancement | Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS | Pain rating on neutral cream | 8.10 units on a scale | Standard Deviation 2.65 |
| tDCS Inhibition | Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS | Pain rating on placebo cream | 6.41 units on a scale | Standard Deviation 2.86 |
| tDCS Inhibition | Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS | Pain rating on nocebo cream | 8.80 units on a scale | Standard Deviation 2.6 |
| tDCS Inhibition | Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS | Pain rating on neutral cream | 7.96 units on a scale | Standard Deviation 2.9 |
| Sham tDCS | Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS | Pain rating on nocebo cream | 9.01 units on a scale | Standard Deviation 2.75 |
| Sham tDCS | Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS | Pain rating on neutral cream | 7.88 units on a scale | Standard Deviation 2.56 |
| Sham tDCS | Gracely Sensory Scale Pain Rating Changes in Response to Lidocaine and Capsaicin Creams and tDCS | Pain rating on placebo cream | 7.38 units on a scale | Standard Deviation 2.84 |
Comparison: To assess the modulation effects of tDCS on placebo, we first performed an analysis of covariance (ANCOVA) with placebo as the dependent variable and group (i.e., anodal, cathodal, and sham tDCS) as the fixed factor.p-value: 0.03ANCOVA
Comparison: To assess the modulation effects of tDCS on nocebo, we first performed an analysis of covariance (ANCOVA) with nocebo as the dependent variable and group (i.e., anodal, cathodal, and sham tDCS) as the fixed factor.p-value: 0.04ANCOVA