An fMRI Study Of Brain Response In Patients With Fibromyalgia

A Double-Blind, Placebo-Controlled Cross-Over Study In Fibromyalgia Subjects To Examine Effects Of Pregabalin On Brain Response To Mechanical Pain As Assessed By Functional Magnetic Resonance Imaging, Proton Magnetic Resonance Spectroscopy And Subjective Ratings

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00760474

Enrollment

Registered

2008-09-26

Start date

2009-01-31

Completion date

2011-03-31

Last updated

2021-01-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fibromyalgia

Keywords

Fibromyalgia; fMRI; pain; pregabalin; Lyrica; imaging

Brief summary

The purpose of this study is to explore how pregabalin works in patients with fibromyalgia by evaluating brain imaging signals. To find out whether fMRI (functional magnetic resonance imaging) is an efficient way to show whether new pain medications are effective in treating fibromyalgia.

Detailed description

Methodology study

Interventions

DRUGPregabalin, then placebo

Placebo and pregabalin will be given orally twice daily in capsules at different times during the course of the study. The highest dose of pregabalin to be used in the study is 450 mg/day.

DRUGPlacebo, then pregabalin

Placebo and pregabalin will be given orally twice daily in capsules at different times during the course of the study. The highest dose of pregabalin to be used in the study is 450 mg/day.

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

OTHER

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

FEMALE

Age

18 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Women must have pain due to fibromyalgia * Fibromyalgia must have been diagnosed at least 6 months prior to be eligible for this study

Exclusion criteria

* Patients with severe depression or other serious illness, who are left-handed, or who are pregnant or nursing are not eligible for this study.

Design outcomes

Primary

Measure	Time frame	Description
Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	Single voxel spectra obtained from the anterior and posterior right insula at rest to compare ratios for Gln/Cr, Glu/Cr, and combined Glutamate + Glutamine (Glx/Cr) for pregabalin and placebo. Gln, Glu, Glx calculated as ratios to the internal standard creatine.
Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	BOLD fMRI imaging modality to assess brain activation signals across the whole brain in defined Region of Interest (ROI) brain regions in response to blunt pressure pain; acquired during resting state (no evoked pain) and during evoked pain (thumb pressure device with non-painful pressure, 2 kilograms \[kg\] pressure/equal stimulus conditions, and high pain pressure/up to 10 kg). Estimated as magnitude (percent change) of the betas representing brain signal activation associated with pressure induced pain. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Secondary

Measure	Time frame	Description
Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	Resting state brain activity assessed for correlation of brain seed region (pIns, anIns) to ROI connectivity at baseline (pre-dose) and post-dose (pre minus post) measured using z-score (mean of 0, standard deviation \[SD\] of 1); range approximately -3 to +3. Positive (+) z-scores reflect greater connectivity (+correlation between seed region and ROI). Negative (-) z-scores reflect -connectivity (anti-correlation between seed region and ROI). ROIs include PCC and IPL from within the default mode network (DMN). DMN is a constellation of regions in which connectivity is augmented in fibromyalgia.
Gracely Box Scales for Pain Intensity (GBSint) Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	Minimum and maximum pain intensity acquired during resting state (no evoked pain) and during evoked pain (thumb pressure device with non-painful pressure, 2 kg pressure/equal stimulus conditions, and high pain pressure/up to 10 kg) measured during fMRI and scored from 0 (no pain sensation) to 20 (extremely intense). Baseline and Post-dose data for Period 1 and Period 2 summarized as Least Squares Mean (LS Mean). Any observation with a studentized residual \>3 or \<-3 was considered an outlier.
Gracely Box Scales for Pain Unpleasantness (GBSunp) Including Outliers	Baseline/Pre-dose (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	Minimum and maximum pain unpleasantness acquired during resting state (no evoked pain) and during evoked pain (thumb pressure device with non-painful pressure, 2 kg pressure/equal stimulus conditions, and high pain pressure/up to 10 kg) measured during fMRI and scored from 0 (neutral) to 20 (very intolerable). Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.
Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 7 Day Average Pain Score Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	The daily pain diary consisted of the mBPI item regarding participant-rated average of pain over the past 24 hours. Scored on an 11-point numeric scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The 7 day average pain score was defined as the mean daily pain NRS value for the last 7 days prior to fMRI scanning visit. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.
Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 3 Day Average Pain Score Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	The daily pain diary consisted of the mBPI item regarding participant-rated average of pain over the past 24 hours. Scored on an 11-point numeric scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The 3 day average pain score was defined as the mean daily pain NRS value for the last 3 days prior to fMRI scanning visit. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.
Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	BOLD fMRI imaging modality to assess brain activation signals across the whole brain in defined ROI brain regions in response to checkerboard visual stimuli (flashing at 8 hertz \[Hz\]). Reported as percent change between the pre-dose (baseline) and post-dose values.
Short-Form McGill Pain Questionnaire (SF-MPQ): Overall Score Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	SF-MPQ was completed to assess pain over the past week and to assess present pain and consists of 15 pain descriptors: sensory dimension of pain experience (sum of items 1 to 11) and affective dimension (sum of items 12 to 15). Each descriptor was ranked by the participant on a 4-point intensity scale (0=none to 3=severe) and totaled in each subclass (sensory range 0 to 33; affective range 0 to 12). Total (overall) score was sum of items 1 to 15, range 0 to 45; higher scores indicated higher pain/impact. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.
Sphygmomanometry Evoked Allodynia in Relation to the Blood Pressure (BP) Value at Which Allodynia Was Evoked	Day 58	BP cuff evoked allodynia assessed based on participant response to the following question When I take your blood pressure, tell me if the cuff's pressure is painful. A standard BP cuff was inflated at approximately 10 millimeters of mercury (mm Hg) per second up to 180 mm Hg or to point when participant experienced pain; performed 3 times on each arm whether or not pain was reported. If no pain elicited at 180 mm Hg, it was recorded that no sphygmomanometry-evoked allodynia occurred. If pain was reported, value (in mm Hg) at which pain first occured was recorded for each of the assessments.
Pain at the Bilateral Epicondyle Tender Points Assessed Using American College of Rheumatology (ACR) Classification Criteria	Day 58	Participant rated severity of pain upon application of 4 kilograms (kg) pressure via dolorimeter at the bilateral epicondyle tender points (2 tender points, 2 centimeters distal to the epicondyles) described in the American College of Rheumatology (ACR) classification criteria and scored on a 0 (no pain) to 10 (worst possible pain) rating scale. Each arm was to be assessed for any pain (one point on each arm) with the application of pressure.
Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: Individual Daily Pain Score Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	The daily pain diary consisted of the mBPI item regarding participant-rated average of pain over the past 24 hours. Scored on an 11-point numeric scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The individual daily pain score was defined as the final score recorded in the last pain diary of the treatment period 24 hours prior to fMRI scanning visit. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.
Short-Form McGill Pain Questionnaire (SF-MPQ): Affective Total Score Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	SF-MPQ was completed to assess pain over the past week and to assess present pain and consists of 15 pain descriptors: sensory dimension of pain experience (sum of items 1 to 11) and affective dimension (sum of items 12 to 15). Each descriptor was ranked by participant on a 4-point intensity scale (0=none to 3=severe) and totaled in each subclass (sensory range 0 to 33; affective range 0 to 12); higher scores indicated higher pain/impact. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.
Short-Form McGill Pain Questionnaire (SF-MPQ): Sensory Total Score Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	SF-MPQ was completed to assess pain over the past week and to assess present pain and consists of 15 pain descriptors: sensory dimension of pain experience (sum of items 1 to 11) and affective dimension (sum of items 12 to 15). Each descriptor was ranked by participant on a 4-point intensity scale (0=none to 3=severe) and totaled in each subclass (sensory range 0 to 33; affective range 0 to 12); higher scores indicated higher pain/impact. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Other

Measure	Time frame	Description
Hospital Anxiety and Depression Scale (HADS): Depression Total Score Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	A participant rated questionnaire with 2 subscales. HADS-A assessed state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D assessed state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items with range 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score 0 to 21 for each subscale; higher score indicated greater severity of anxiety and depression symptoms. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.
Pain Catastrophizing Scale (PCS) Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	PCS is a participant rated 13-item instrument to measure the presence and severity of catastrophizing. Scored 0 (not at all) to 4 (all the time) to statements such as When I'm in pain…I worry all the time about whether the pain will end. All 13 statements start with When I'm in pain…. Total score ranged from 0 to 52; higher scores reflected greater impairment. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.
Hospital Anxiety and Depression Scale (HADS): Anxiety Total Score Including Outliers	Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)	A participant rated questionnaire with 2 subscales. HADS-A assessed state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D assessed state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items with range 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score 0 to 21 for each subscale; higher score indicated greater severity of anxiety and depression symptoms. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Countries

United States

Participant flow

Pre-assignment details

Participants who met entrance criteria received placebo for 1 week (Day 1 to 8) then were randomized in a 1:1 ratio to blinded treatment sequence.

Participants by arm

Arm	Count
Entire Study Population Participants who met entrance criteria received placebo for 1 week (Day 1 to 8) then were randomized in a 1:1 ratio to blinded treatment sequence to receive either: Pregabalin, then placebo: Pregabalin 75 mg PO BID Period 1/Day 9 to 11; 150 mg BID Day 12 to 16; 200 mg BID Day 17 to 19; 225 mg BID Day 20 to 22 followed by taper Day 23 to 29 and an 8-day placebo washout period. Then, placebo matching study treatment in a similar pattern was administered beginning Period 2/Day 38 and included dose escalation through Day 51 followed by placebo taper Day 52 to 58. Or placebo, then Pregabalin: Placebo matching study treatment was administered in a similar fashion to Pregabalin treatment beginning Period 1/Day 9 and included dose escalation, taper and an 8-day placebo washout period. Then, Pregabalin 75 mg BID Period 2/Day 38 to 40; 150 mg BID Day 41 to 45; 200 mg BID Day 46 to 48; 225 mg BID Day 49 to 51 followed by placebo taper Day 52 to 58.	25
Total	25

Arm

Count

Entire Study Population

Participants who met entrance criteria received placebo for 1 week (Day 1 to 8) then were randomized in a 1:1 ratio to blinded treatment sequence to receive either: Pregabalin, then placebo: Pregabalin 75 mg PO BID Period 1/Day 9 to 11; 150 mg BID Day 12 to 16; 200 mg BID Day 17 to 19; 225 mg BID Day 20 to 22 followed by taper Day 23 to 29 and an 8-day placebo washout period. Then, placebo matching study treatment in a similar pattern was administered beginning Period 2/Day 38 and included dose escalation through Day 51 followed by placebo taper Day 52 to 58. Or placebo, then Pregabalin: Placebo matching study treatment was administered in a similar fashion to Pregabalin treatment beginning Period 1/Day 9 and included dose escalation, taper and an 8-day placebo washout period. Then, Pregabalin 75 mg BID Period 2/Day 38 to 40; 150 mg BID Day 41 to 45; 200 mg BID Day 46 to 48; 225 mg BID Day 49 to 51 followed by placebo taper Day 52 to 58.

Total

Withdrawals & dropouts

Period	Reason	FG000	FG001
Period 1 (P1)	Discontinued then re-entered	1	1
Period 2 (P2)	Adverse Event	0	1
Period 2 (P2)	Lost to Follow-up	1	0
Placebo Washout Period	Other	0	1

Baseline characteristics

Characteristic	Entire Study Population
Age, Continuous	38.6 years STANDARD_DEVIATION 12
Sex/Gender, Customized	25 participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	18 / 24	13 / 25
serious Total, serious adverse events	1 / 24	1 / 25

Outcome results

Primary

Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)

Single voxel spectra obtained from the anterior and posterior right insula at rest to compare ratios for Gln/Cr, Glu/Cr, and combined Glutamate + Glutamine (Glx/Cr) for pregabalin and placebo. Gln, Glu, Glx calculated as ratios to the internal standard creatine.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: Full Analysis Set (FAS) all participants who received a minimum fixed dose of 300 mg/day of study treatment. N=number of participants with analyzable data at observation.

Arm	Measure	Group	Value (MEAN)	Dispersion
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glu/Cr ratio posterior insula - pre-dose	1.1751 ratio	Standard Deviation 0.119537
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glu/Cr ratio posterior insula - post-dose	1.1046 ratio	Standard Deviation 0.1418
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Gln/Cr ratio posterior insula - pre-dose	0.5311 ratio	Standard Deviation 0.117359
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Gln/Cr ratio posterior insula - post-dose	0.4857 ratio	Standard Deviation 0.14534
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glx/Cr ratio posterior insula - pre-dose	1.70624 ratio	Standard Deviation 0.177312
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glx/Cr ratio posterior insula - post-dose	1.5903 ratio	Standard Deviation 0.19461
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glu/Cr ratio anterior insula - pre-dose	1.22731 ratio	Standard Deviation 0.154333
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glu/Cr ratio anterior insula - post-dose	1.2393 ratio	Standard Deviation 0.2229
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Gln/Cr ratio anterior insula - pre-dose	0.53144 ratio	Standard Deviation 0.115606
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Gln/Cr ratio anterior insula - post-dose	0.5290 ratio	Standard Deviation 0.19367
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glx/Cr ratio anterior insula - pre-dose	1.75888 ratio	Standard Deviation 0.164256
Pregabalin	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glx/Cr ratio anterior insula - post-dose	1.7684 ratio	Standard Deviation 0.30019
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glx/Cr ratio anterior insula - pre-dose	1.71671 ratio	Standard Deviation 0.203157
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glu/Cr ratio posterior insula - pre-dose	1.13253 ratio	Standard Deviation 0.123897
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glu/Cr ratio anterior insula - pre-dose	1.23788 ratio	Standard Deviation 0.183282
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glu/Cr ratio posterior insula - post-dose	1.17129 ratio	Standard Deviation 0.151535
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Gln/Cr ratio anterior insula - post-dose	0.47541 ratio	Standard Deviation 0.100247
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Gln/Cr ratio posterior insula - pre-dose	0.52635 ratio	Standard Deviation 0.143649
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glu/Cr ratio anterior insula - post-dose	1.18524 ratio	Standard Deviation 0.164847
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Gln/Cr ratio posterior insula - post-dose	0.51553 ratio	Standard Deviation 0.147882
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glx/Cr ratio anterior insula - post-dose	1.66124 ratio	Standard Deviation 0.166421
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glx/Cr ratio posterior insula - pre-dose	1.65894 ratio	Standard Deviation 0.215505
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Gln/Cr ratio anterior insula - pre-dose	0.47882 ratio	Standard Deviation 0.143684
Placebo	Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)	Glx/Cr ratio posterior insula - post-dose	1.68747 ratio	Standard Deviation 0.227398

Comparison: Glu/Cr posterior insulap-value: 0.083t-test, 2 sided

Comparison: Glu/Cr posterior insulap-value: 0.436t-test, 2 sided

Comparison: Gln/Cr posterior insulap-value: 0.306t-test, 2 sided

Comparison: Gln/Cr posterior insulap-value: 0.809t-test, 2 sided

Comparison: Glx/Cr posterior insulap-value: 0.016t-test, 2 sided

Comparison: Glx/Cr posterior insulap-value: 0.708t-test, 2 sided

Comparison: Glu/Cr anterior insulap-value: 0.809t-test, 2 sided

Comparison: Glu/Cr anterior insulap-value: 0.154t-test, 2 sided

Comparison: Gln/Cr anterior insulap-value: 0.96t-test, 2 sided

Comparison: Gln/Cr anterior insulap-value: 0.937t-test, 2 sided

Comparison: Glx/Cr anterior insulap-value: 0.897t-test, 2 sided

Comparison: Glx/Cr anterior insulap-value: 0.309t-test, 2 sided

Primary

Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers

BOLD fMRI imaging modality to assess brain activation signals across the whole brain in defined Region of Interest (ROI) brain regions in response to blunt pressure pain; acquired during resting state (no evoked pain) and during evoked pain (thumb pressure device with non-painful pressure, 2 kilograms \[kg\] pressure/equal stimulus conditions, and high pain pressure/up to 10 kg). Estimated as magnitude (percent change) of the betas representing brain signal activation associated with pressure induced pain. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS. Change from baseline for Period 1 and Period 2 summarized as Least Squares Mean (LS Mean). Abbreviation: Dorso Lateral Prefrontal Cortex (DLPFC).

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Amygdala	-0.040 percent change	Standard Error 0.0502
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_BA23_base	0.005 percent change	Standard Error 0.0267
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Orbito Front	0.033 percent change	Standard Error 0.1
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Inferior Parietal Lobule (IPL)_base	-0.042 percent change	Standard Error 0.0301
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	BA40	-0.047 percent change	Standard Error 0.0436
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Insula_base	-0.010 percent change	Standard Error 0.0595
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Periaqueductal gray (PAG)	0.014 percent change	Standard Error 0.0351
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Mid Insula	0.015 percent change	Standard Error 0.0423
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Cerebellum	-0.056 percent change	Standard Error 0.0317
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Mid Front_DLPFC	-0.011 percent change	Standard Error 0.0432
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Posterior Insula (pIns)	0.001 percent change	Standard Error 0.0294
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Mid Temporal Pole	-0.048 percent change	Standard Error 0.025
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Brodman Area (BA) 22	-0.050 percent change	Standard Error 0.0709
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Orbito Front	-0.046 percent change	Standard Error 0.0709
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Posterior Cingulate	-0.132 percent change	Standard Error 0.0414
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_PAG	0.034 percent change	Standard Error 0.0349
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_DLPFC	-0.002 percent change	Standard Error 0.0255
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Posterior Insula	0.063 percent change	Standard Error 0.0345
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Precuneus	-0.057 percent change	Standard Error 0.0281
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Posterior Insula	0.050 percent change	Standard Error 0.0434
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Left (L)_Anterior Insula (anIns)	0.073 percent change	Standard Error 0.0378
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Posterior Cingulate	-0.175 percent change	Standard Error 0.0476
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Putamen	0.081 percent change	Standard Error 0.0347
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Precuneus	-0.070 percent change	Standard Error 0.0332
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Mid Insula	-0.011 percent change	Standard Error 0.0672
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Precuneus_base	-0.040 percent change	Standard Error 0.0273
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Secondary Somatosensory Area (S2)	-0.016 percent change	Standard Error 0.0746
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Superior Temporal	-0.039 percent change	Standard Error 0.0645
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Right (R)_DLPFC	-0.004 percent change	Standard Error 0.0467
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Premotor	-0.022 percent change	Standard Error 0.0415
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Anterior Cingulate	0.008 percent change	Standard Error 0.0454
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Putamen	0.088 percent change	Standard Error 0.0395
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Anterior Insula	0.080 percent change	Standard Error 0.0378
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Primary Somatosensory Area (S1)	-0.048 percent change	Standard Error 0.0419
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Mid Temporal Pole	-0.024 percent change	Standard Error 0.0307
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Thalamus	0.010 percent change	Standard Error 0.0245
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Precuneus	-0.066 percent change	Standard Error 0.0301
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Amygdala	-0.077 percent change	Standard Error 0.0572
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Precuneus	-0.078 percent change	Standard Error 0.0301
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Thalamus	0.018 percent change	Standard Error 0.0245
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Anterior Cingulate	-0.024 percent change	Standard Error 0.0454
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Brodman Area (BA) 22	0.029 percent change	Standard Error 0.0709
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	BA40	0.026 percent change	Standard Error 0.0436
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Left (L)_Anterior Insula (anIns)	0.044 percent change	Standard Error 0.0378
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Amygdala	0.041 percent change	Standard Error 0.0502
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Cerebellum	0.021 percent change	Standard Error 0.0317
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_DLPFC	0.023 percent change	Standard Error 0.0255
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Mid Insula	0.100 percent change	Standard Error 0.0672
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Mid Temporal Pole	-0.044 percent change	Standard Error 0.0307
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Orbito Front	-0.136 percent change	Standard Error 0.1
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Periaqueductal gray (PAG)	0.016 percent change	Standard Error 0.0351
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Posterior Insula (pIns)	0.002 percent change	Standard Error 0.0294
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Posterior Cingulate	-0.083 percent change	Standard Error 0.0414
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Precuneus	-0.084 percent change	Standard Error 0.0281
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Putamen	0.037 percent change	Standard Error 0.0347
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Right (R)_DLPFC	0.101 percent change	Standard Error 0.0467
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Anterior Insula	0.002 percent change	Standard Error 0.0378
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Amygdala	0.076 percent change	Standard Error 0.0572
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_BA23_base	-0.017 percent change	Standard Error 0.0267
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Inferior Parietal Lobule (IPL)_base	-0.015 percent change	Standard Error 0.0301
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Insula_base	0.034 percent change	Standard Error 0.0595
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Mid Insula	0.028 percent change	Standard Error 0.0423
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Mid Front_DLPFC	0.083 percent change	Standard Error 0.0432
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Mid Temporal Pole	-0.036 percent change	Standard Error 0.025
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Orbito Front	-0.056 percent change	Standard Error 0.0709
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_PAG	0.011 percent change	Standard Error 0.0349
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Posterior Insula	-0.024 percent change	Standard Error 0.0345
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Posterior Insula	-0.002 percent change	Standard Error 0.0434
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Posterior Cingulate	-0.093 percent change	Standard Error 0.0476
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Precuneus	-0.070 percent change	Standard Error 0.0332
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Precuneus_base	-0.038 percent change	Standard Error 0.0273
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	Superior Temporal	0.026 percent change	Standard Error 0.0645
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Premotor	-0.022 percent change	Standard Error 0.0415
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Putamen	0.032 percent change	Standard Error 0.0395
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	R_Primary Somatosensory Area (S1)	0.037 percent change	Standard Error 0.0419
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers	L_Secondary Somatosensory Area (S2)	0.111 percent change	Standard Error 0.0746

Comparison: R\_Mid Temporal Polep-value: 0.775295% CI: [-0.0991, 0.0754]Mixed Models Analysis

Comparison: Anterior Cingulatep-value: 0.634795% CI: [-0.1081, 0.1714]Mixed Models Analysis

Comparison: BA22p-value: 0.518195% CI: [-0.3356, 0.1771]Mixed Models Analysis

Comparison: BA40p-value: 0.298795% CI: [-0.2161, 0.0714]Mixed Models Analysis

Comparison: L\_anInsp-value: 0.515195% CI: [-0.064, 0.1219]Mixed Models Analysis

Comparison: L\_Amygdalap-value: 0.236995% CI: [-0.2228, 0.0599]Mixed Models Analysis

Comparison: L\_Cerebellump-value: 0.075895% CI: [-0.1642, 0.0092]Mixed Models Analysis

Comparison: L\_DLPFCp-value: 0.460995% CI: [-0.0947, 0.0452]Mixed Models Analysis

Comparison: L\_Mid Insulap-value: 0.381395% CI: [-0.3745, 0.1524]Mixed Models Analysis

Comparison: L\_Mid Temporal Polep-value: 0.7295% CI: [-0.0964, 0.1361]Mixed Models Analysis

Comparison: L\_Orbito Frontp-value: 0.209995% CI: [-0.1065, 0.4434]Mixed Models Analysis

Comparison: PAGp-value: 0.955195% CI: [-0.1047, 0.0992]Mixed Models Analysis

Comparison: Posterior Insulap-value: 0.99495% CI: [-0.0855, 0.0848]Mixed Models Analysis

Comparison: L\_Posterior Cingulatep-value: 0.429195% CI: [-0.1792, 0.0806]Mixed Models Analysis

Comparison: L\_Precuneusp-value: 0.46795% CI: [-0.0496, 0.1028]Mixed Models Analysis

Comparison: L\_Putamenp-value: 0.444395% CI: [-0.0752, 0.1624]Mixed Models Analysis

Comparison: L\_S2p-value: 0.282395% CI: [-0.3704, 0.1165]Mixed Models Analysis

Comparison: R\_DLPFCp-value: 0.136995% CI: [-0.2481, 0.0378]Mixed Models Analysis

Comparison: R\_anInsp-value: 0.237695% CI: [-0.0573, 0.2127]Mixed Models Analysis

Comparison: R\_Amygdalap-value: 0.096895% CI: [-0.3365, 0.0313]Mixed Models Analysis

Comparison: R\_BA23\_basep-value: 0.57295% CI: [-0.061, 0.1062]Mixed Models Analysis

Comparison: R\_IPL\_basep-value: 0.582295% CI: [-0.1303, 0.0761]Mixed Models Analysis

Comparison: R\_Insula\_basep-value: 0.685195% CI: [-0.2697, 0.1824]Mixed Models Analysis

Comparison: R\_Mid Insulap-value: 0.865695% CI: [-0.1699, 0.1446]Mixed Models Analysis

Comparison: R\_Mid Front\_DLPFCp-value: 0.156295% CI: [-0.2296, 0.0407]Mixed Models Analysis

Comparison: R\_Orbito Frontp-value: 0.918295% CI: [-0.1912, 0.2109]Mixed Models Analysis

Comparison: L\_PAGp-value: 0.654495% CI: [-0.0829, 0.1278]Mixed Models Analysis

Comparison: R\_pInsp-value: 0.081395% CI: [-0.0123, 0.1863]Mixed Models Analysis

Comparison: R\_pInsp-value: 0.460595% CI: [-0.0956, 0.2004]Mixed Models Analysis

Comparison: R\_Posterior Cingulatep-value: 0.313695% CI: [-0.2484, 0.0856]Mixed Models Analysis

Comparison: R\_Precuneusp-value: 0.992995% CI: [-0.0885, 0.0893]Mixed Models Analysis

Comparison: R\_Precuneus\_basep-value: 0.94995% CI: [-0.0815, 0.0767]Mixed Models Analysis

Comparison: Superior Temporalp-value: 0.566895% CI: [-0.3019, 0.1722]Mixed Models Analysis

Comparison: R\_Premotorp-value: 0.995895% CI: [-0.1398, 0.1391]Mixed Models Analysis

Comparison: R\_Putamenp-value: 0.337995% CI: [-0.0659, 0.1795]Mixed Models Analysis

Comparison: R\_S1p-value: 0.218695% CI: [-0.2262, 0.0565]Mixed Models Analysis

Comparison: R\_Thalamusp-value: 0.819195% CI: [-0.0843, 0.0678]Mixed Models Analysis

Comparison: Precuneusp-value: 0.764795% CI: [-0.0698, 0.093]Mixed Models Analysis

Secondary

Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 3 Day Average Pain Score Including Outliers

The daily pain diary consisted of the mBPI item regarding participant-rated average of pain over the past 24 hours. Scored on an 11-point numeric scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The 3 day average pain score was defined as the mean daily pain NRS value for the last 3 days prior to fMRI scanning visit. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 3 Day Average Pain Score Including Outliers	4.3467 scores on a scale	Standard Error 0.4436
Placebo	Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 3 Day Average Pain Score Including Outliers	4.7745 scores on a scale	Standard Error 0.4436

Secondary

Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 7 Day Average Pain Score Including Outliers

The daily pain diary consisted of the mBPI item regarding participant-rated average of pain over the past 24 hours. Scored on an 11-point numeric scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The 7 day average pain score was defined as the mean daily pain NRS value for the last 7 days prior to fMRI scanning visit. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 7 Day Average Pain Score Including Outliers	4.1014 scores on a scale	Standard Error 0.4104
Placebo	Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 7 Day Average Pain Score Including Outliers	4.7038 scores on a scale	Standard Error 0.4104

Secondary

Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: Individual Daily Pain Score Including Outliers

The daily pain diary consisted of the mBPI item regarding participant-rated average of pain over the past 24 hours. Scored on an 11-point numeric scale ranging from 0 (no pain) to 10 (pain as bad as you can imagine). The individual daily pain score was defined as the final score recorded in the last pain diary of the treatment period 24 hours prior to fMRI scanning visit. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: Individual Daily Pain Score Including Outliers	4.3110 scores on a scale	Standard Error 0.4787
Placebo	Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: Individual Daily Pain Score Including Outliers	5.0527 scores on a scale	Standard Error 0.4787

Secondary

Gracely Box Scales for Pain Intensity (GBSint) Including Outliers

Minimum and maximum pain intensity acquired during resting state (no evoked pain) and during evoked pain (thumb pressure device with non-painful pressure, 2 kg pressure/equal stimulus conditions, and high pain pressure/up to 10 kg) measured during fMRI and scored from 0 (no pain sensation) to 20 (extremely intense). Baseline and Post-dose data for Period 1 and Period 2 summarized as Least Squares Mean (LS Mean). Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Gracely Box Scales for Pain Intensity (GBSint) Including Outliers	Minimum pain intensity	4.1184 scores on a scale	Standard Error 0.6535
Pregabalin	Gracely Box Scales for Pain Intensity (GBSint) Including Outliers	Maximum pain intensity	14.5701 scores on a scale	Standard Error 0.6953
Placebo	Gracely Box Scales for Pain Intensity (GBSint) Including Outliers	Minimum pain intensity	3.4725 scores on a scale	Standard Error 0.6535
Placebo	Gracely Box Scales for Pain Intensity (GBSint) Including Outliers	Maximum pain intensity	15.6117 scores on a scale	Standard Error 0.6953

Secondary

Gracely Box Scales for Pain Unpleasantness (GBSunp) Including Outliers

Minimum and maximum pain unpleasantness acquired during resting state (no evoked pain) and during evoked pain (thumb pressure device with non-painful pressure, 2 kg pressure/equal stimulus conditions, and high pain pressure/up to 10 kg) measured during fMRI and scored from 0 (neutral) to 20 (very intolerable). Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Time frame: Baseline/Pre-dose (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS

Arm	Measure	Group	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Gracely Box Scales for Pain Unpleasantness (GBSunp) Including Outliers	Minimum pain unpleasantness	3.3924 scores on a scale	Standard Error 0.5803
Pregabalin	Gracely Box Scales for Pain Unpleasantness (GBSunp) Including Outliers	Maximum pain unpleasantness	10.1576 scores on a scale	Standard Error 0.8294
Placebo	Gracely Box Scales for Pain Unpleasantness (GBSunp) Including Outliers	Maximum pain unpleasantness	11.2742 scores on a scale	Standard Error 0.8294
Placebo	Gracely Box Scales for Pain Unpleasantness (GBSunp) Including Outliers	Minimum pain unpleasantness	3.4258 scores on a scale	Standard Error 0.5803

Secondary

Pain at the Bilateral Epicondyle Tender Points Assessed Using American College of Rheumatology (ACR) Classification Criteria

Participant rated severity of pain upon application of 4 kilograms (kg) pressure via dolorimeter at the bilateral epicondyle tender points (2 tender points, 2 centimeters distal to the epicondyles) described in the American College of Rheumatology (ACR) classification criteria and scored on a 0 (no pain) to 10 (worst possible pain) rating scale. Each arm was to be assessed for any pain (one point on each arm) with the application of pressure.

Time frame: Day 58

Population: FAS; N=number of participants with analyzable data at observation.

Arm	Measure	Group	Value (MEAN)	Dispersion
Pregabalin	Pain at the Bilateral Epicondyle Tender Points Assessed Using American College of Rheumatology (ACR) Classification Criteria	Pain Severity Left Epicondyle	6.25 scores on a scale	Standard Deviation 2.84
Pregabalin	Pain at the Bilateral Epicondyle Tender Points Assessed Using American College of Rheumatology (ACR) Classification Criteria	Pain Severity Right Epicondyle	5.72 scores on a scale	Standard Deviation 2.671

Secondary

Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions

Resting state brain activity assessed for correlation of brain seed region (pIns, anIns) to ROI connectivity at baseline (pre-dose) and post-dose (pre minus post) measured using z-score (mean of 0, standard deviation \[SD\] of 1); range approximately -3 to +3. Positive (+) z-scores reflect greater connectivity (+correlation between seed region and ROI). Negative (-) z-scores reflect -connectivity (anti-correlation between seed region and ROI). ROIs include PCC and IPL from within the default mode network (DMN). DMN is a constellation of regions in which connectivity is augmented in fibromyalgia.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: Participants in FAS with quality resting state data (data able to be corrected for motion \[head and cardiorespiratory artifacts\]).

Arm	Measure	Group	Value (MEAN)	Dispersion
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_L IPL 3a post-dose	-0.3792 z-score	Standard Deviation 2.18759
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_PCC post-dose	2.1504 z-score	Standard Deviation 1.87564
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_Right (R) IPL 3b pre-dose	0.8310 z-score	Standard Deviation 2.01819
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_primary motor region (M1) pre-dose	3.1486 z-score	Standard Deviation 3.14585
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_Left (L) IPL 3a pre-dose	0.2025 z-score	Standard Deviation 1.92233
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_M1 post-dose	3.2605 z-score	Standard Deviation 2.80878
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_R IPL 3b post-dose	0.9766 z-score	Standard Deviation 2.52679
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_L IPL 3b pre-dose	0.6552 z-score	Standard Deviation 1.82208
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_L IPL post-dose	2.6493 z-score	Standard Deviation 2.0404
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_cuneus pre-dose	2.1363 z-score	Standard Deviation 1.97131
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_R IPL pre-dose	2.6956 z-score	Standard Deviation 2.61359
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_cerebellum post-dose	0.0213 z-score	Standard Deviation 2.24014
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_R IPL post-dose	1.2863 z-score	Standard Deviation 1.31165
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_cuneus post-dose	3.0410 z-score	Standard Deviation 1.84499
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_S2 pre-dose	1.6592 z-score	Standard Deviation 1.6916
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_L IPL 3b post-dose	1.5614 z-score	Standard Deviation 1.58417
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_S2 post-dose	3.1466 z-score	Standard Deviation 2.1368
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_L IPL pre-dose	2.1404 z-score	Standard Deviation 2.21726
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_cuneus pre-dose	2.5103 z-score	Standard Deviation 2.48669
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_Posterior cingulate (PCC) pre-dose	1.1647 z-score	Standard Deviation 1.71738
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_cuneus post-dose	1.8042 z-score	Standard Deviation 2.08443
Pregabalin	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_cerebellum pre-dose	0.3984 z-score	Standard Deviation 1.73
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_cuneus post-dose	1.1899 z-score	Standard Deviation 1.67701
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_cerebellum pre-dose	1.4439 z-score	Standard Deviation 1.46341
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_cerebellum post-dose	1.0704 z-score	Standard Deviation 2.66882
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_Left (L) IPL 3a pre-dose	-0.9296 z-score	Standard Deviation 1.50499
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_L IPL 3a post-dose	-1.2977 z-score	Standard Deviation 1.37551
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_L IPL 3b pre-dose	1.7390 z-score	Standard Deviation 2.00764
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_L IPL 3b post-dose	0.9930 z-score	Standard Deviation 2.5093
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_Right (R) IPL 3b pre-dose	0.7420 z-score	Standard Deviation 1.57551
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_R IPL 3b post-dose	0.9081 z-score	Standard Deviation 2.1844
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_cuneus pre-dose	1.8543 z-score	Standard Deviation 1.85494
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_cuneus post-dose	2.3324 z-score	Standard Deviation 1.84622
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_Posterior cingulate (PCC) pre-dose	1.5405 z-score	Standard Deviation 1.70926
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_PCC post-dose	1.2409 z-score	Standard Deviation 2.2989
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_primary motor region (M1) pre-dose	1.3267 z-score	Standard Deviation 1.94564
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	pIns_M1 post-dose	1.3771 z-score	Standard Deviation 2.0162
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_L IPL pre-dose	1.9982 z-score	Standard Deviation 2.4079
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_L IPL post-dose	2.6797 z-score	Standard Deviation 2.50765
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_R IPL pre-dose	1.7848 z-score	Standard Deviation 2.27345
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_R IPL post-dose	2.6194 z-score	Standard Deviation 2.37251
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_S2 pre-dose	1.6799 z-score	Standard Deviation 1.64784
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_S2 post-dose	2.4225 z-score	Standard Deviation 2.68238
Placebo	Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions	anIns_cuneus pre-dose	1.7550 z-score	Standard Deviation 1.65232

Secondary

Short-Form McGill Pain Questionnaire (SF-MPQ): Affective Total Score Including Outliers

SF-MPQ was completed to assess pain over the past week and to assess present pain and consists of 15 pain descriptors: sensory dimension of pain experience (sum of items 1 to 11) and affective dimension (sum of items 12 to 15). Each descriptor was ranked by participant on a 4-point intensity scale (0=none to 3=severe) and totaled in each subclass (sensory range 0 to 33; affective range 0 to 12); higher scores indicated higher pain/impact. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Short-Form McGill Pain Questionnaire (SF-MPQ): Affective Total Score Including Outliers	1.4100 scores on a scale	Standard Error 0.3095
Placebo	Short-Form McGill Pain Questionnaire (SF-MPQ): Affective Total Score Including Outliers	1.8173 scores on a scale	Standard Error 0.3095

Secondary

Short-Form McGill Pain Questionnaire (SF-MPQ): Overall Score Including Outliers

SF-MPQ was completed to assess pain over the past week and to assess present pain and consists of 15 pain descriptors: sensory dimension of pain experience (sum of items 1 to 11) and affective dimension (sum of items 12 to 15). Each descriptor was ranked by the participant on a 4-point intensity scale (0=none to 3=severe) and totaled in each subclass (sensory range 0 to 33; affective range 0 to 12). Total (overall) score was sum of items 1 to 15, range 0 to 45; higher scores indicated higher pain/impact. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Short-Form McGill Pain Questionnaire (SF-MPQ): Overall Score Including Outliers	10.0862 scores on a scale	Standard Error 1.2657
Placebo	Short-Form McGill Pain Questionnaire (SF-MPQ): Overall Score Including Outliers	11.2774 scores on a scale	Standard Error 1.2657

Secondary

Short-Form McGill Pain Questionnaire (SF-MPQ): Sensory Total Score Including Outliers

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Short-Form McGill Pain Questionnaire (SF-MPQ): Sensory Total Score Including Outliers	8.6641 scores on a scale	Standard Error 1.0759
Placebo	Short-Form McGill Pain Questionnaire (SF-MPQ): Sensory Total Score Including Outliers	9.4722 scores on a scale	Standard Error 1.0759

Secondary

Sphygmomanometry Evoked Allodynia in Relation to the Blood Pressure (BP) Value at Which Allodynia Was Evoked

BP cuff evoked allodynia assessed based on participant response to the following question When I take your blood pressure, tell me if the cuff's pressure is painful. A standard BP cuff was inflated at approximately 10 millimeters of mercury (mm Hg) per second up to 180 mm Hg or to point when participant experienced pain; performed 3 times on each arm whether or not pain was reported. If no pain elicited at 180 mm Hg, it was recorded that no sphygmomanometry-evoked allodynia occurred. If pain was reported, value (in mm Hg) at which pain first occured was recorded for each of the assessments.

Time frame: Day 58

Population: FAS; N=number of participants with analyzable data at observation.

Arm	Measure	Group	Value (MEAN)	Dispersion
Pregabalin	Sphygmomanometry Evoked Allodynia in Relation to the Blood Pressure (BP) Value at Which Allodynia Was Evoked	Mean Left Arm BP Cuff Pressure	107.92 mm Hg	Standard Deviation 19.837
Pregabalin	Sphygmomanometry Evoked Allodynia in Relation to the Blood Pressure (BP) Value at Which Allodynia Was Evoked	Mean Right Arm BP Cuff Pressure	129.31 mm Hg	Standard Deviation 19.917

Secondary

Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli

BOLD fMRI imaging modality to assess brain activation signals across the whole brain in defined ROI brain regions in response to checkerboard visual stimuli (flashing at 8 hertz \[Hz\]). Reported as percent change between the pre-dose (baseline) and post-dose values.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS.

Arm	Measure	Group	Value (MEAN)	Dispersion
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	R inferior parietal lobule, Brodman area 40	0.27 percent change in BOLD signal	Standard Deviation 0.21
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Right primary somatosensory cortex	0.14 percent change in BOLD signal	Standard Deviation 0.14
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Left (L) mid insula cortex	0.23 percent change in BOLD signal	Standard Deviation 0.2
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Left primary somatosensory cortex	0.21 percent change in BOLD signal	Standard Deviation 0.18
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	L inferior parietal lobule, Brodman area 40	0.28 percent change in BOLD signal	Standard Deviation 0.27
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Left supplementary motor area	0.02 percent change in BOLD signal	Standard Deviation 0.32
Pregabalin	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Right (R) anterior mid insula cortex	0.32 percent change in BOLD signal	Standard Deviation 0.19
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Left supplementary motor area	0.30 percent change in BOLD signal	Standard Deviation 0.34
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Right (R) anterior mid insula cortex	-0.05 percent change in BOLD signal	Standard Deviation 0.25
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Left (L) mid insula cortex	0.00 percent change in BOLD signal	Standard Deviation 0.21
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	R inferior parietal lobule, Brodman area 40	0.05 percent change in BOLD signal	Standard Deviation 0.23
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	L inferior parietal lobule, Brodman area 40	0.02 percent change in BOLD signal	Standard Deviation 0.25
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Right primary somatosensory cortex	-0.01 percent change in BOLD signal	Standard Deviation 0.22
Placebo	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli	Left primary somatosensory cortex	0.06 percent change in BOLD signal	Standard Deviation 0.25

Other Pre-specified

Hospital Anxiety and Depression Scale (HADS): Anxiety Total Score Including Outliers

A participant rated questionnaire with 2 subscales. HADS-A assessed state of generalized anxiety (anxious mood, restlessness, anxious thoughts, panic attacks); HADS-D assessed state of lost interest and diminished pleasure response (lowering of hedonic tone). Each subscale comprised of 7 items with range 0 (no presence of anxiety or depression) to 3 (severe feeling of anxiety or depression). Total score 0 to 21 for each subscale; higher score indicated greater severity of anxiety and depression symptoms. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Hospital Anxiety and Depression Scale (HADS): Anxiety Total Score Including Outliers	4.3896 scores on a scale	Standard Error 0.6132
Placebo	Hospital Anxiety and Depression Scale (HADS): Anxiety Total Score Including Outliers	5.1558 scores on a scale	Standard Error 0.6132

Other Pre-specified

Hospital Anxiety and Depression Scale (HADS): Depression Total Score Including Outliers

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Hospital Anxiety and Depression Scale (HADS): Depression Total Score Including Outliers	3.1750 scores on a scale	Standard Error 0.4147
Placebo	Hospital Anxiety and Depression Scale (HADS): Depression Total Score Including Outliers	3.8705 scores on a scale	Standard Error 0.4147

Other Pre-specified

Pain Catastrophizing Scale (PCS) Including Outliers

PCS is a participant rated 13-item instrument to measure the presence and severity of catastrophizing. Scored 0 (not at all) to 4 (all the time) to statements such as When I'm in pain…I worry all the time about whether the pain will end. All 13 statements start with When I'm in pain…. Total score ranged from 0 to 52; higher scores reflected greater impairment. Baseline and Post-dose data for Period 1 and Period 2 summarized as LS Mean. Any observation with a studentized residual \>3 or \<-3 was considered an outlier.

Time frame: Baseline (Day 8, Day 37), Post-dose (Period 1/Day 22, Period 2/Day 51)

Population: FAS

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
Pregabalin	Pain Catastrophizing Scale (PCS) Including Outliers	11.4050 scores on a scale	Standard Error 1.0192
Placebo	Pain Catastrophizing Scale (PCS) Including Outliers	12.0041 scores on a scale	Standard Error 1.0192

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026

An fMRI Study Of Brain Response In Patients With Fibromyalgia

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Other

Countries

Participant flow

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Glutamine/Creatine (Gln/Cr) and Glutamate/Creatine (Glu/Cr) Ratios Measured by Proton Magnetic Resonance Spectroscopy (1H-MRS)

Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to Blunt Pressure Pain: Percent Change in BOLD Activations Including Outliers

Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 3 Day Average Pain Score Including Outliers

Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: 7 Day Average Pain Score Including Outliers

Daily Pain Diary Numeric Rating Scale (NRS) Item From the Modified Brief Pain Inventory (mBPI) for Assessment of Clinical Pain: Individual Daily Pain Score Including Outliers

Gracely Box Scales for Pain Intensity (GBSint) Including Outliers

Gracely Box Scales for Pain Unpleasantness (GBSunp) Including Outliers

Pain at the Bilateral Epicondyle Tender Points Assessed Using American College of Rheumatology (ACR) Classification Criteria

Resting State Brain Activity (Connectivity Analysis) Assessed by Temporal Correlations in Low Frequency fMRI BOLD Signals Across Pain Processing Regions

Short-Form McGill Pain Questionnaire (SF-MPQ): Affective Total Score Including Outliers

Short-Form McGill Pain Questionnaire (SF-MPQ): Overall Score Including Outliers

Short-Form McGill Pain Questionnaire (SF-MPQ): Sensory Total Score Including Outliers

Sphygmomanometry Evoked Allodynia in Relation to the Blood Pressure (BP) Value at Which Allodynia Was Evoked

Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals in Response to a Control Visual (Checkerboard) Stimuli

Hospital Anxiety and Depression Scale (HADS): Anxiety Total Score Including Outliers

Hospital Anxiety and Depression Scale (HADS): Depression Total Score Including Outliers

Pain Catastrophizing Scale (PCS) Including Outliers