Fibromyalgia
Conditions
Keywords
Fibromyalgia Chronic Pain
Brief summary
The aim of this study is to evaluate the impact of electro-acupuncture in pain processing on patients with fibromyalgia (FM). The investigators hypothesize that electro-acupuncture is effective for FM because it functions as a desensitization therapy, which when applied repeatedly over multiple treatment sessions, gradually habituates the nervous system to continuing pain and sensory signaling.
Detailed description
This study design has two components: 1) a cross sectional assessment of brain chemistry, connectivity and response to pain in healthy controls and age- and sex-matched fibromyalgia patients, and 2) a longitudinal assessment of the same outcomes in fibromyalgia patients randomized to either electro-acupuncture (EA) or laser acupuncture. The investigators will evaluate 80 fibromyalgia patients who will receive acupuncture treatment twice a week for 4 weeks, for a total of 8 treatments. Baseline data from these patients will be compared to results from 40 pain-free controls. Participants will undergo experimental pain assessments as well as brain neuroimaging. Note added after completion of study data gathering: Within the registration in ClinicalTrials.gov and the informed consent, one arm was referred to as non-traditional acupuncture. In fact, this was a control arm, receiving mock laser acupuncture (Vita Laser 650, Lhasa OMS). They received 2 treatments per week for 4 weeks. As consented, they were told, with IRB permission, that they were receiving non-traditional laser acupuncture. This deception was essential to maintaining scientific integrity of the masking. The laser acupuncture device (Vita Laser 650, Lhasa OMS) was positioned over all of the same acupoints used in electro-acupuncture (EA), but was turned off during treatment sessions. There was no palpation prior to positioning these devices, and there was no physical contact between device and skin.
Interventions
DEVICENeedle acupuncture (Traditional Acupuncture)
This group will receive needle acupuncture at 3 pairs of sites. The needles will be stimulated with low intensity, low frequency electric current using a constant-current electro-acupuncture device (AS Super 4 digital needle stimulator).
DEVICELaser acupuncture (Non-traditional Acupuncture)
For non-traditional acupuncture, a laser acupuncture device (Vita Laser 650, Lhasa OMS) will be positioned over all of the same acupoints used in EA. There will be no palpation prior to positioning these devices, and there will be no physical contact between device and skin.
Sponsors
National Center for Complementary and Integrative Health (NCCIH)
Massachusetts General Hospital
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
for Fibromyalgia Participants * Have self-reported FM symptoms for at least one year and also meet the Wolfe et al 2011 criteria for Fibromyalgia. * Continued presence of pain more than 50% of days. * Pain greater than a certain threshold on the Visual Analog Scale (VAS) for pain; 7-day recall; \[Note: The VAS is widely used in clinical pain research and as such we chose to use it for inclusion criteria and for clinical pain assessment below. Within our group numerical ratings scales 0-100 are more commonly used in quantitative sensory assessment, and as such we chose to use NRS scales for evoked pain assessments below.\] * Willing to limit the introduction of any new medications or treatment modalities for control of FM symptoms during the study. * Able to travel to the study site to receive acupuncture treatments up to two times weekly. * Over 18 and under 65 years of age. * Right-handed. * Female. * Capable of giving written informed consent. Inclusion Criteria for Healthy Control Participants * Over 18 and under 65 years of age. * Female. * Right-handed. * Do not have fibromyalgia or an associated pain disorder, including: migraine, temporomandibular joint disorder (TMJ), chronic pelvic pain (CPP), or chronic fatigue syndrome (CFS). * Pain less than a certain threshold on the Visual Analog Scale (VAS) for pain; 7-day recall * Willing to complete all study procedures. * Capable of giving written informed consent.
Exclusion criteria
for Fibromyalgia Participants: * Acupuncture within last 6-months. * Presence of a known coagulation abnormality, thrombocytopenia, or bleeding diathesis that may preclude the safe use of acupuncture. * Presence of a concurrent autoimmune or inflammatory disease such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc., or any other chronic pain condition with pain greater than fibromyalgia pain. * Peripheral neuropathy of know cause that interferes with activities of daily living. * History of vascular surgery in lower limbs or current lower limb vascular dysfunction. * History of head injury with substantial loss of consciousness. * Routine daily use of narcotic analgesics, marijuana or have a history of substance abuse in the past 24 months as determine by subject self-report. * Stimulant medications, such as those used to treat ADD/ADHD (e.g., amphetamine/ dextroamphetamine \[Adderall®\], methylphenidate, dextroamphetamine), or the fatigue associated with sleep apnea or shift work (e.g., modafinil), are excluded. * Concurrent participation in other therapeutic trials. * Pregnant or nursing. * Severe psychiatric illnesses (current schizophrenia, major depression with suicidal ideation, substance abuse within two years). * Contraindications to fcMRI, fMRI, or 1H-MRS methods. These may include but are not limited to: surgical clips, surgical staples, metal implants, and certain metallic dental material. \[Note: a more formal description of contraindications for MRI is present in our DSM Plan\]. * Use of over the counter pain medications (NSAIDs, etc.) on the day of MRI scan. * Use of as needed narcotic pain medication 48 hours prior to MRI scan. * Current, habitual, or previous use within the last 12 months of artificial nails, nail enhancements, or nail extensions that cover any portion of either thumbnail. Exceptions, including brief and/or occasional use, may be permissible at the discretion of the principle investigator. * Any impairment, activity or situation that in the judgment of the Study Coordinator or Principal Investigator that would prevent satisfactory completion of the study protocol. * Contraindications to the Electrostimulator device: Participants with electrical implants (i.e. pacemakers, defibrillators), cardiac rhythmic disorders, seizure disorders, any skin disorder in the vicinity of the electrode or an malignant diseases in the region of application. (Fibromyalgia participants only)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Neurocircuitry Underlying Chronic Pain (Percent of Time of a Somato-sensory Cortex Coactivation Pattern) | At baseline | Characterize the altered somatosensory-related neurocircuitry underlying chronic pain in FM, as shown by the difference in brain connectivity between healthy controls and FM patients as measured by FMRI (occurrence rate of co-activation pattern). For each arm, the coactivation pattern was assessed at rest and during a pressure pain stimulation. This is measured by the percent of scan time that an individual's brain displayed a particular coactivation pattern related to the somatosensory system. |
| Change in Brain Connectivity With Acupuncture Treatment | Baseline and 4 weeks | Brain connectivity will be assessed at baseline and following either electro-acupuncture or mock laser acupuncture. Primary somatosensory cortex to insula connectivity. (Z-stat) A positive Z score reflects positive correlation in FMRI signal between different between brain areas. A negative Z score represents anti-correlation between in FMRI signal between brain regions. These scores reflect either positive connectivity or inhibitory connectivity. A mean of 0 represents no correlation or connectivity between regions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Brain Neurochemistry of Combined Glutamate and Glutamine (Glx) Within the Anterior Insular Cortex With Acupuncture Treatment | Baseline and 4 weeks | Brain neurochemistry assessed at baseline and following either electro-acupuncture or mock laser acupuncture using proton magnetic resonance spectroscopy (1H-MRS) measures of combined glutamate and glutamine (Glx). |
| Change in Brain Neurochemistry of Gama-aminobutyric Acid (GABA) Within the Anterior Insular Cortex With Acupuncture Treatment | Baseline and 4 weeks | Brain neurochemistry assessed at baseline and following either electro-acupuncture or mock laser acupuncture using proton magnetic resonance spectroscopy (1H-MRS) measures gama-aminobutyric acid (GABA). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Predicting Response to Acupuncture Using Brain Neurochemistry | Baseline | Baseline neuroimaging outcomes of neurochemistry are used to predict subsequent response to electro-acupuncture and laser acupuncture. |
| Predicting Response to Acupuncture Using Brain Connectivity | Baseline | Baseline neuroimaging outcomes of connectivity are used to predict subsequent response to electroacupuncture and laser acupuncture. |
Countries
United States
Participant flow
Pre-assignment details
15 FM Participants were consented and eligible for the study but withdrew prior to being randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Controls Healthy pain free controls were recruited for comparison with fibromyalgia patients. | 26 |
| Non-Traditional (Mock) Acupuncture 39 fibromyalgia patients were randomized to non-traditional laser acupuncture (Vita Laser 650, Lhasa OMS).
They received 2 treatments per week for 4 weeks. As consented, they were told, with IRB permission, that they were receiving laser acupuncture. This deception was essential to maintaining scientific integrity of the masking.
Laser acupuncture (Non-traditional Acupuncture): For non-traditional acupuncture, a laser acupuncture device (Vita Laser 650, Lhasa OMS) was positioned over all of the same acupoints used in electro-acupuncture (EA), but was turned off during treatment sessions. There was no palpation prior to positioning these devices, and there was no physical contact between device and skin. | 38 |
| Traditional Acupuncture 40 fibromyalgia patients were randomized to receive electro-acupuncture (AS Super 4 digital needle stimulator, Harmony Medical Co). They received 2 treatments per week for 4 weeks.
Needle acupuncture (Traditional Acupuncture): This group received needle acupuncture at 3 pairs of sites. The needles were stimulated with low intensity, low frequency electric current using a constant-current electro-acupuncture device (AS Super 4 digital needle stimulator). | 38 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Eligibility to Baseline Data Collection | Withdrawal by Subject | 1 | 0 | 0 |
| Intervention | Withdrawal by Subject | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Controls | Non-Traditional (Mock) Acupuncture | Traditional Acupuncture |
|---|---|---|---|---|
| Age, Continuous | 43 years STANDARD_DEVIATION 12.203111 | 43.5 years STANDARD_DEVIATION 14.542881 | 41.5 years STANDARD_DEVIATION 9.865814 | 44.5 years STANDARD_DEVIATION 12.40337 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 7 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 0 Participants | 4 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 85 Participants | 19 Participants | 31 Participants | 35 Participants |
| Region of Enrollment United States | 102 Participants | 26 Participants | 38 Participants | 38 Participants |
| Sex: Female, Male Female | 102 Participants | 26 Participants | 38 Participants | 38 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 39 | 0 / 40 |
| other Total, other adverse events | 0 / 27 | 9 / 39 | 22 / 40 |
| serious Total, serious adverse events | 0 / 27 | 0 / 39 | 0 / 40 |
Outcome results
Primary
Brain Neurocircuitry Underlying Chronic Pain (Percent of Time of a Somato-sensory Cortex Coactivation Pattern)
Characterize the altered somatosensory-related neurocircuitry underlying chronic pain in FM, as shown by the difference in brain connectivity between healthy controls and FM patients as measured by FMRI (occurrence rate of co-activation pattern). For each arm, the coactivation pattern was assessed at rest and during a pressure pain stimulation. This is measured by the percent of scan time that an individual's brain displayed a particular coactivation pattern related to the somatosensory system.
Time frame: At baseline
Population: Because this is at baseline (pre-treatment) all fibromyalgia patients are combined in a single analysis group. Some individuals' data was unable to be analyzed because of typical collection challenges (e.g. participant movement). Three participants were lost to follow-up. Four fibromyalgia patients were excluded due to: pain from shingles (N=1), starting Adderall treatment (N=1), inadequate treatments (N=1), and doubling pregabalin dosage (N=1), taking place during the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Controls | Brain Neurocircuitry Underlying Chronic Pain (Percent of Time of a Somato-sensory Cortex Coactivation Pattern) | Sensorimotor co-activation pattern at rest | 0.1281 percentage of scan time | Standard Deviation 0.05229 |
| Healthy Controls | Brain Neurocircuitry Underlying Chronic Pain (Percent of Time of a Somato-sensory Cortex Coactivation Pattern) | Salience network co-activation pattern at rest | 0.1213 percentage of scan time | Standard Deviation 0.05289 |
| Healthy Controls | Brain Neurocircuitry Underlying Chronic Pain (Percent of Time of a Somato-sensory Cortex Coactivation Pattern) | Sensorimotor co-activation pattern at pressure pain | 0.1328 percentage of scan time | Standard Deviation 0.05213 |
| Healthy Controls | Brain Neurocircuitry Underlying Chronic Pain (Percent of Time of a Somato-sensory Cortex Coactivation Pattern) | Salience network co-activation pattern at pressure pain | 0.1121 percentage of scan time | Standard Deviation 0.05065 |
| Fibromyalgia Patients | Brain Neurocircuitry Underlying Chronic Pain (Percent of Time of a Somato-sensory Cortex Coactivation Pattern) | Salience network co-activation pattern at pressure pain | 0.1054 percentage of scan time | Standard Deviation 0.04662 |
| Fibromyalgia Patients | Brain Neurocircuitry Underlying Chronic Pain (Percent of Time of a Somato-sensory Cortex Coactivation Pattern) | Sensorimotor co-activation pattern at rest | 0.1190 percentage of scan time | Standard Deviation 0.03835 |
| Fibromyalgia Patients | Brain Neurocircuitry Underlying Chronic Pain (Percent of Time of a Somato-sensory Cortex Coactivation Pattern) | Sensorimotor co-activation pattern at pressure pain | 0.1362 percentage of scan time | Standard Deviation 0.03972 |
| Fibromyalgia Patients | Brain Neurocircuitry Underlying Chronic Pain (Percent of Time of a Somato-sensory Cortex Coactivation Pattern) | Salience network co-activation pattern at rest | 0.1345 percentage of scan time | Standard Deviation 0.0456 |
Comparison: Salience co-activation pattern at rest vs. with pressure pain.p-value: 0.333t-test, 2 sided
Comparison: This statistical analysis covers the sensorimotor co-activation pattern at rest vs. with pressure pain for Healthy controlsp-value: 0.6474t-test, 2 sided
Comparison: Salience co-activation pattern at rest vs. with pressure painp-value: <0.0001t-test, 2 sided
Comparison: This statistical analysis covers the sensorimotor co-activation pattern at rest vs. with pressure pain for Fibromyalgia patientsp-value: 0.0004t-test, 2 sided
Primary
Change in Brain Connectivity With Acupuncture Treatment
Brain connectivity will be assessed at baseline and following either electro-acupuncture or mock laser acupuncture. Primary somatosensory cortex to insula connectivity. (Z-stat) A positive Z score reflects positive correlation in FMRI signal between different between brain areas. A negative Z score represents anti-correlation between in FMRI signal between brain regions. These scores reflect either positive connectivity or inhibitory connectivity. A mean of 0 represents no correlation or connectivity between regions.
Time frame: Baseline and 4 weeks
Population: Of the 38 participants in each arm who completed the intervention, three participants from the traditional acupuncture arm and one from the mock laser acupuncture arm were excluded from analysis for reasons complicating treatment interpretation, (e.g. addition of a new pain symptom or addition of an external study treatment.) Three participants from the Traditional Acupuncture arm were excluded due to poor data quality at either the pre- or post-treatment scanning visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Controls | Change in Brain Connectivity With Acupuncture Treatment | Baseline | 0.5492 Z - stat | Standard Deviation 1.799 |
| Healthy Controls | Change in Brain Connectivity With Acupuncture Treatment | Post-treatment (4 weeks) | -0.08589 Z - stat | Standard Deviation 1.182 |
| Fibromyalgia Patients | Change in Brain Connectivity With Acupuncture Treatment | Baseline | -0.3013 Z - stat | Standard Deviation 1.178 |
| Fibromyalgia Patients | Change in Brain Connectivity With Acupuncture Treatment | Post-treatment (4 weeks) | 1.125 Z - stat | Standard Deviation 1.379 |
Comparison: This is a comparison of Mock Laser Acupuncture pre-and post 4 weeks of treatment.p-value: 0.0653t-test, 2 sided
Comparison: This is a P value for the change in Traditional Acupuncture, pre and post 4 weeks of treatment.p-value: <0.0001t-test, 2 sided
Secondary
Change in Brain Neurochemistry of Combined Glutamate and Glutamine (Glx) Within the Anterior Insular Cortex With Acupuncture Treatment
Brain neurochemistry assessed at baseline and following either electro-acupuncture or mock laser acupuncture using proton magnetic resonance spectroscopy (1H-MRS) measures of combined glutamate and glutamine (Glx).
Time frame: Baseline and 4 weeks
Population: Sixteen of the thirty-nine Non-Traditional Acupuncture treatment participants were excluded either for missing data or poor data quality while twenty-one of the forty Traditional Acupuncture treatment participants were excluded for missing data or poor data quality.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Controls | Change in Brain Neurochemistry of Combined Glutamate and Glutamine (Glx) Within the Anterior Insular Cortex With Acupuncture Treatment | Glx at baseline | 11.91 AIU (arbitrary institutional units) | Standard Deviation 1.005 |
| Healthy Controls | Change in Brain Neurochemistry of Combined Glutamate and Glutamine (Glx) Within the Anterior Insular Cortex With Acupuncture Treatment | Glx at 4 weeks | 11.82 AIU (arbitrary institutional units) | Standard Deviation 1.042 |
| Fibromyalgia Patients | Change in Brain Neurochemistry of Combined Glutamate and Glutamine (Glx) Within the Anterior Insular Cortex With Acupuncture Treatment | Glx at baseline | 12.11 AIU (arbitrary institutional units) | Standard Deviation 1.94 |
| Fibromyalgia Patients | Change in Brain Neurochemistry of Combined Glutamate and Glutamine (Glx) Within the Anterior Insular Cortex With Acupuncture Treatment | Glx at 4 weeks | 11.88 AIU (arbitrary institutional units) | Standard Deviation 1.572 |
Comparison: Glx statistical comparisonp-value: 0.7399t-test, 2 sided
Comparison: Glx statistical comparisonp-value: 0.6226t-test, 2 sided
Secondary
Change in Brain Neurochemistry of Gama-aminobutyric Acid (GABA) Within the Anterior Insular Cortex With Acupuncture Treatment
Brain neurochemistry assessed at baseline and following either electro-acupuncture or mock laser acupuncture using proton magnetic resonance spectroscopy (1H-MRS) measures gama-aminobutyric acid (GABA).
Time frame: Baseline and 4 weeks
Population: Fourteen of the thirty-nine Non-Traditional Acupuncture treatment participants were excluded either for missing data or poor data quality while twenty-two of the forty Traditional Acupuncture treatment participants were excluded for missing data or poor data quality.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Controls | Change in Brain Neurochemistry of Gama-aminobutyric Acid (GABA) Within the Anterior Insular Cortex With Acupuncture Treatment | GABA at baseline | 3.250 AIU (arbitrary institutional units) | Standard Deviation 0.9074 |
| Healthy Controls | Change in Brain Neurochemistry of Gama-aminobutyric Acid (GABA) Within the Anterior Insular Cortex With Acupuncture Treatment | GABA at 4 weeks | 3.135 AIU (arbitrary institutional units) | Standard Deviation 0.665 |
| Fibromyalgia Patients | Change in Brain Neurochemistry of Gama-aminobutyric Acid (GABA) Within the Anterior Insular Cortex With Acupuncture Treatment | GABA at baseline | 3.264 AIU (arbitrary institutional units) | Standard Deviation 0.484 |
| Fibromyalgia Patients | Change in Brain Neurochemistry of Gama-aminobutyric Acid (GABA) Within the Anterior Insular Cortex With Acupuncture Treatment | GABA at 4 weeks | 3.210 AIU (arbitrary institutional units) | Standard Deviation 0.8271 |
Comparison: GABA statistical comparisonp-value: 0.6344t-test, 2 sided
Comparison: GABA statistical comparisonp-value: 0.7985t-test, 2 sided
Other Pre-specified
Predicting Response to Acupuncture Using Brain Connectivity
Baseline neuroimaging outcomes of connectivity are used to predict subsequent response to electroacupuncture and laser acupuncture.
Time frame: Baseline
Other Pre-specified
Predicting Response to Acupuncture Using Brain Neurochemistry
Baseline neuroimaging outcomes of neurochemistry are used to predict subsequent response to electro-acupuncture and laser acupuncture.
Time frame: Baseline