A Methodology Study Of Brain Imaging Of Pain-Killers In Post-Traumatic Neuropathic Pain Patients

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00610155
• Collaborator: University of Oxford (Other)
• Enrollment: 18
• Locations: 2
• Arms: 3
• Duration (Months): 21.9
• Patients Per Site: 9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study is a methodology study designed to discover whether a brain imaging technology is a better way of compare the relative sensitivities of fMRI and subjective psychometric assessments of pain to multiple doses of pregabalin and tramadol SR in a cross-over clinical study design.

Condition or Disease	Intervention/Treatment	Phase
Pain	Drug: Placebo; Drug: Pregabalin; Drug: Tramadol SR	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Methodology Study To Assess The Feasibility Of Using Functional Magnetic Resonance Imaging (fRMI) To Quantify The Effects Of Analgesic Drugs In Post-Traumatic Neuropathic Pain Subjects
• Study Start Date: Sep 1, 2008
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: 1	Drug: Placebo; BID
Experimental: 2	Drug: Pregabalin; Dose 75 mg titrated to 150 mg, bid
Experimental: 3	Drug: Tramadol SR; Dose 50mg titrated to 200 mg, bid

Outcome Measures

Primary Outcome Measures

1. Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals Across the Whole Brain [Day 8, 22, 36]

   BOLD brain activation signals in whole brain was assessed using Contrast Parameter Estimates (COPE) images in response to dynamic mechanical allodynia of the affected side (DMAa), dynamic mechanical allodynia of the control side (DMAc), thermal pain (TH) and checkerboard visual stimuli (VIS).

2. Voxel-wise Blood Oxygen Level Dependent (BOLD) Using fMRI of Brain Activation Signals in Defined Brain Regions in Response to Dynamic Mechanical Allodynia of the Affected Side (DMAa) [Day 8, 22, 36]

   BOLD brain activation signals in pre-defined region of interest(ROI):anterior cingulate cortex(ACC);left,right anterior cortex([AIC_L ],[AIC_R]);left,right mid-insular cortex([MIC_L],[MIC_R]);left,right posterior insular cortex([PIC_L],[PIC_R]);left,right amygdala([Amyg_L],[Amyg_R]);primary,secondary somatosensory cortex([S1],[S2]);sensory part of thalamus(SensTHAL);midbrain reticular formation(MRF);nucleus cuneiformis(NucCun);periaqueductal gray(PAG). Prior to ROI analysis, a prelimanary anlysis was performed, wherein it was concluded that ROI analysis was to be carried out for DMAa, DMAc amd TH only. In voxel BOLD analysis,signal change is unit less measure but approximated to percent signal change by grand scaling(effects divided by 10000 to get percent signal change).

3. Voxel-wise Blood Oxygen Level Dependent (BOLD) Using fMRI of Brain Activation Signals in Defined Brain Regions in Response to Dynamic Mechanical Allodynia of the Control Side (DMAc) [Day 8, 22, 36]

   BOLD brain activation signals in pre-defined ROI. ROI were ACC; AIC_L; AIC_R; MIC_L; MIC_R; PIC_L; PIC_R; Amyg_L; Amyg_R; S1; S2; SensTHAL; MRF; NucCun; PAG. Prior to ROI analysis, a prelimanary anlysis was performed, wherein it was concluded that ROI analysis was to be carried out for DMAa, DMAc amd TH only. In voxel BOLD analysis, signal change is unit less measure but is approximated to percent signal change here by grand scaling (dividing effects by 10000 to get percent signal change).

4. Voxel-wise Blood Oxygen Level Dependent (BOLD) Using fMRI of Brain Activation Signals in Defined Brain Regions in Response to Thermal Stimulation (TH) [Day 8, 22, 36]

   BOLD brain activation signals in pre-defined ROI. ROI were ACC; AIC_L; AIC_R; MIC_L; MIC_R; PIC_L; PIC_R; Amyg_L; Amyg_R; S1; S2; SensTHAL; MRF; NucCun; PAG. Prior to ROI analysis, a prelimanary anlysis was performed, wherein it was concluded that ROI analysis was to be carried out for DMAa, DMAc amd TH only. In voxel BOLD analysis, signal change is unit less measure but is approximated to percent signal change here by grand scaling (dividing effects by 10000 to get percent signal change).

5. Voxel-wise Blood Oxygen Level Dependent (BOLD) Using fMRI of Brain Activation Signals in Defined Brain Regions in Response to Visual Stimulation (VIS) [Day 8, 22, 36]

   BOLD brain activation signals in pre-defined ROI in response to checkerboard visual stimuli (flashing at 2 Hz). ROI were ACC; AIC_L; AIC_R; MIC_L; MIC_R; PIC_L; PIC_R; Amyg_L; Amyg_R; S1; S2; SensTHAL; MRF; NucCun; PAG. Prior to ROI analysis, a prelimanary anlysis was performed, wherein it was concluded that ROI analysis was to be carried out for DMAa, DMAc amd TH only.

6. Arterial Spin Labelling (ASL) Using fMRI of Brain Activation Signals Across the Whole Brain and in Defined Brain Regions [Day 8, 22, 36]

   Continuous ASL sequence fMRI imaging modality assessing brain activation signals across the whole brain and in defined ROI to assess effects of evoked pain along with changes in regional cerebral blood flow (rCBF). ROI were ACC; AIC_L; AIC_R; MIC_L; MIC_R; PIC_L; PIC_R; Amyg_L; Amyg_R; S1; S2; SensTHAL; MRF; NucCun; PAG.

Secondary Outcome Measures

1. 36-Item Short-Form Health Survey (SF-36) [Day 8, 22, 36]

   SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning).

2. Beck Depression Inventory (BDI) [Day 8, 22, 36]

   BDI is a 21 item participant rated inventory evaluating depression symptoms, cognition, and physical symptoms of fatigue, weight loss, lack of interest in sex. Individual items are scored on a 4 point scale (0 to 3), with 0=none/absent and 3=most severe. Total score: 0 to 63; higher score indicate more depression.

3. State and Trait Anxiety Questionnaire [Day 8, 22, 36]

   Self-report scale completed by the participant. Separate scales measure state (20 items) and trait (20 items) anxiety. The participant report how they feel "right now at this moment" for state anxiety and how they "generally" feel for trait anxiety. The "state" items are scored as: 1 (not at all), 2 (somewhat true), 3 (moderately true), 4 (very much so). The "trait" items are scored as: 1 (almost never), 2 (sometimes), 3 (often), 4 (almost always). Scores range from 20-80 for each scale. Higher scores indicate more impaired participants.

4. Pain Catastrophising Scale (PCS) [Day 8, 22, 36]

   The PCS is a self-administered questionnaire with 13 items, each scored from 0 (not at all) to 4 (all the time) for extent to which participant catastrophizes postoperative pain. Total score is sum of scores for all questions (range: 0 to 52); Subscale scores: Rumination (sum of scores for 4 items; range: 0 to 16); Magnification (sum of scores for 3 items; range: 0 to 12); and Helplessness (sum of scores for 6 items; range: 0 to 24); higher scores indicate greater extent of pain catastrophizing.

5. Neuropathic Pain Symptom Inventory (NPSI) [Baseline (Day -7), Day 8, 22, 36]

   NPSI: participant rated questionnaire to evaluate different symptoms of neuropathic pain (dimensions: burning [superficial] spontaneous pain, pressing [deep] spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dyesthesia [P/D]). Includes 10 descriptors quantified on a 0 (no symptoms) to 10 (worst symptoms imaginable) and 2 temporal items assessing duration of spontaneous ongoing and paroxysmal pain. Questionnaire generates a score in each of the relevant dimensions and a total score of 0-100. Higher score indicate a greater intensity of pain.

6. Daily Pain Score [Day -35 through Day 36]

   Daily Pain Score: Day 1 pain intensity over past 24 hours recorded on waking every morning using 0-10 numeric rating scale (NRS): 0 (no pain) to 10 (worst possible pain). The daily pain scores for an average of the last 7 days and an average of last 3 days were calculated.

7. Present Pain Intensity Score (PPIS) [Day 8, 22, 36]

   Participants answered: "Please rate your pain from 0-10 that best describes the intensity of pain right now". PPIS assessed on 0-10 numeric rating scale (NRS), 0 (no pain) to 10 (worst possible pain).

8. Doleur Neuropathic 4 (DN4) Score [Day -35]

   DN4 questionnaire provides a simple diagnosis of Neuropathic pain (NeP) by asking for yes/no answers to 4 questions (10 sub questions in total). Each question was scored on a scale of 0 (No) and 1 (Yes). Total score was calculated as sum of the 10 individual questions. Total score range 0-10, higher score indicated more neuropathic pain.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of neuropathic pain associated with brush allodynia in specific dermatomes.

• Brush allodynia score of ≥4 and calculated average pain score of ≥3 on an 11-point numerical rating scale by the completion of down-titration of existing medications.

• Right-handed

Exclusion Criteria:

• Subjects with trigeminal neuralgia, central pain (due to cerebrovascular lesions, multiple sclerosis and/or traumatic spinal cord injuries including spinal surgery).

• Phantom limb pain, painful diabetic neuropathy.

• Subjects with any other co-existing pain which he/she or a qualified pain physician cannot differentiate from NeP of peripheral origin.

• Subjects with diabetes mellitus and with an HbA1C value of >10% upon measurement at screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Portsmouth	Hampshire	United Kingdom	PO3 6AD
2	Pfizer Investigational Site	Solihull	West Midlands	United Kingdom	B91 2JL

Sponsors and Collaborators

• Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• University of Oxford

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
• ClinicalTrials.gov Identifier: NCT00610155
• Other Study ID Numbers: A0081173
• First Posted: Feb 7, 2008
• Last Update Posted: Jan 22, 2021
• Last Verified: Sep 1, 2013

• Additional relevant MeSH terms: Neuralgia; Pregabalin; Tramadol

Study Results

Participant Flow

Arm/Group Title	Pregabalin Then Tramadol Then Placebo	Tramadol Then Placebo Then Pregabalin	Placebo Then Pregabalin Then Tramadol	Pregabalin Then Placebo Then Tramadol	Placebo Then Tramadol Then Pregabalin	Tramadol Then Pregabalin Then Placebo
Arm/Group Description	Pregabalin (PGB) capsule titrated to 150 milligram (mg) orally twice daily for 7 days in first intervention period; followed by tramadol (TMD) sustained release (SR) capsule titrated to 200 mg orally twice daily for 7 days in second intervention period; then matching placebo (PBO) capsule orally for 7 days in third intervention period. A placebo wash-out period of 7 days was maintained between each period.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in first intervention period; followed by matching placebo capsule orally for 7 days in second intervention period; then pregabalin capsule titrated to 150 mg orally twice daily for 7 days in third intervention period. A placebo wash-out period of 7 days was maintained between each period.	Matching placebo capsule orally for 7 days in first intervention period; followed by pregabalin capsule titrated to 150 mg orally twice daily for 7 days in second intervention period; then tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in third intervention period. A placebo wash-out period of 7 days was maintained between each period.	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in first intervention period; followed by matching placebo capsule orally for 7 days in second intervention period; then tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in third intervention period. A placebo wash-out period of 7 days was maintained between each period.	Matching placebo capsule orally for 7 days in first intervention period; followed by tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in second intervention period; then pregabalin capsule titrated to 150 mg orally twice daily for 7 days in third intervention period. A placebo wash-out period of 7 days was maintained between each period.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in first intervention period; followed by pregabalin capsule titrated to 150 mg orally twice daily for 7 days in second intervention period; then matching placebo capsule orally for 7 days in third intervention period. A placebo wash-out period of 7 days was maintained between each period.
Period Title: Period 1
STARTED	4	3	4	3	3	1
COMPLETED	4	3	3	3	3	1
NOT COMPLETED	0	0	1	0	0	0
Period Title: Period 1
STARTED	4	3	3	3	3	1
COMPLETED	4	3	3	3	3	1
NOT COMPLETED	0	0	0	0	0	0
Period Title: Period 1
STARTED	4	3	3	3	3	1
COMPLETED	4	3	3	3	3	1
NOT COMPLETED	0	0	0	0	0	0
Period Title: Period 1
STARTED	4	3	3	3	3	1
COMPLETED	4	3	3	3	3	1
NOT COMPLETED	0	0	0	0	0	0
Period Title: Period 1
STARTED	4	3	3	3	3	1
COMPLETED	3	3	3	3	3	1
NOT COMPLETED	1	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes all participants enrolled in the study.
Overall Participants	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.7 (9.7)
Sex: Female, Male (Count of Participants)
Female	12 66.7%
Male	6 33.3%

Outcome Measures

1. Primary Outcome

Title	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals Across the Whole Brain
Description	BOLD brain activation signals in whole brain was assessed using Contrast Parameter Estimates (COPE) images in response to dynamic mechanical allodynia of the affected side (DMAa), dynamic mechanical allodynia of the control side (DMAc), thermal pain (TH) and checkerboard visual stimuli (VIS).
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

Data not available to report, as BOLD brain activation signals in whole brain were obtained as specific Contrast Parameter Estimates (COPE) images only, as per planned analysis.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	0	0	0

2. Primary Outcome

Title	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using fMRI of Brain Activation Signals in Defined Brain Regions in Response to Dynamic Mechanical Allodynia of the Affected Side (DMAa)
Description	BOLD brain activation signals in pre-defined region of interest(ROI):anterior cingulate cortex(ACC);left,right anterior cortex([AIC_L ],[AIC_R]);left,right mid-insular cortex([MIC_L],[MIC_R]);left,right posterior insular cortex([PIC_L],[PIC_R]);left,right amygdala([Amyg_L],[Amyg_R]);primary,secondary somatosensory cortex([S1],[S2]);sensory part of thalamus(SensTHAL);midbrain reticular formation(MRF);nucleus cuneiformis(NucCun);periaqueductal gray(PAG). Prior to ROI analysis, a prelimanary anlysis was performed, wherein it was concluded that ROI analysis was to be carried out for DMAa, DMAc amd TH only. In voxel BOLD analysis,signal change is unit less measure but approximated to percent signal change by grand scaling(effects divided by 10000 to get percent signal change).
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

BOLD analysis set included all participants who completed all the 3 treatment periods of the study.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	16	16	16
ACC	-17.3 (9.7)	18.6 (9.7)	7.4 (9.7)
AIC_L	8.1 (8.8)	23.3 (8.8)	30.8 (8.8)
AIC_R	11.1 (10.0)	21.9 (10.0)	17.1 (10.0)
MIC_L	3.8 (8.4)	23.4 (8.4)	30.0 (8.4)
MIC_R	8.6 (8.4)	13.4 (8.4)	18.3 (8.4)
PIC_L	-6.8 (5.2)	-5.8 (5.2)	-0.3 (5.2)
PIC_R	-13.6 (8.5)	2.9 (8.5)	6.5 (8.5)
Amyg_L	-5.7 (10.2)	5.5 (10.2)	8.5 (10.2)
Amyg_R	-1.4 (8.5)	20.3 (8.5)	21.7 (8.5)
S1	-28.5 (20.5)	-4.1 (20.5)	-2.9 (20.5)
S2	2.5 (10.8)	-3.2 (10.8)	10.8 (10.8)
SensTHAL	8.0 (5.4)	16.5 (5.4)	9.6 (5.4)
MRF	7.0 (5.0)	6.4 (5.0)	11.7 (5.0)
NucCun	1.1 (5.5)	-0.9 (5.5)	12.9 (5.5)
PAG	-3.8 (7.9)	-15.3 (7.9)	2.5 (7.9)

3. Primary Outcome

Title	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using fMRI of Brain Activation Signals in Defined Brain Regions in Response to Dynamic Mechanical Allodynia of the Control Side (DMAc)
Description	BOLD brain activation signals in pre-defined ROI. ROI were ACC; AIC_L; AIC_R; MIC_L; MIC_R; PIC_L; PIC_R; Amyg_L; Amyg_R; S1; S2; SensTHAL; MRF; NucCun; PAG. Prior to ROI analysis, a prelimanary anlysis was performed, wherein it was concluded that ROI analysis was to be carried out for DMAa, DMAc amd TH only. In voxel BOLD analysis, signal change is unit less measure but is approximated to percent signal change here by grand scaling (dividing effects by 10000 to get percent signal change).
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

BOLD analysis set included all participants who completed all the 3 treatment periods of the study.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	16	16	16
ACC	-22.3 (12.0)	-3.7 (12.0)	0.2 (12.0)
AIC_L	-13.5 (8.0)	18.2 (8.0)	20.2 (8.0)
AIC_R	-10.6 (7.4)	10.3 (7.4)	20.2 (7.4)
MIC_L	-7.6 (8.4)	9.7 (8.4)	9.0 (8.4)
MIC_R	-9.2 (6.2)	2.8 (6.2)	0.7 (6.2)
PIC_L	-14.9 (6.9)	-8.1 (6.9)	0.8 (6.9)
PIC_R	-17.2 (9.4)	2.4 (9.4)	6.3 (9.4)
Amyg_L	-14.3 (7.3)	1.5 (7.3)	-3.4 (7.3)
Amyg_R	-10.3 (9.7)	2.0 (9.7)	-3.8 (9.7)
S1	-31.6 (16.2)	-4.5 (16.2)	14.6 (16.2)
S2	-0.4 (8.3)	9.6 (8.3)	13.5 (8.3)
SensTHAL	3.9 (5.3)	-2.8 (5.3)	6.7 (5.3)
MRF	1.5 (4.6)	-6.6 (4.6)	-1.7 (4.6)
NucCun	1.0 (4.9)	-8.2 (4.9)	-1.8 (4.9)
PAG	1.6 (7.8)	-12.0 (7.8)	-5.0 (7.8)

4. Primary Outcome

Title	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using fMRI of Brain Activation Signals in Defined Brain Regions in Response to Thermal Stimulation (TH)
Description	BOLD brain activation signals in pre-defined ROI. ROI were ACC; AIC_L; AIC_R; MIC_L; MIC_R; PIC_L; PIC_R; Amyg_L; Amyg_R; S1; S2; SensTHAL; MRF; NucCun; PAG. Prior to ROI analysis, a prelimanary anlysis was performed, wherein it was concluded that ROI analysis was to be carried out for DMAa, DMAc amd TH only. In voxel BOLD analysis, signal change is unit less measure but is approximated to percent signal change here by grand scaling (dividing effects by 10000 to get percent signal change).
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

BOLD analysis set included all participants who completed all the 3 treatment periods of the study.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	16	16	16
ACC	102.2 (25.9)	92.5 (25.8)	83.3 (25.8)
AIC_L	92.1 (21.9)	103.4 (21.8)	118.7 (21.8)
AIC_R	121.7 (20.7)	104.6 (20.6)	104.0 (20.6)
MIC_L	93.4 (19.6)	105.2 (19.5)	100.4 (19.5)
MIC_R	106.6 (17.3)	71.1 (17.3)	92.0 (17.3)
PIC_L	31.2 (16.0)	44.6 (15.9)	34.2 (15.9)
PIC_R	75.3 (20.1)	95.5 (20.0)	91.8 (20.0)
Amyg_L	29.7 (16.5)	24.9 (16.5)	36.4 (16.5)
Amyg_R	77.5 (22.5)	57.2 (22.5)	67.0 (22.5)
S1	-49.0 (30.2)	37.7 (30.1)	27.7 (30.1)
S2	73.6 (21.2)	94.6 (21.2)	74.5 (21.2)
SensTHAL	19.4 (12.1)	0.8 (12.1)	10.4 (12.1)
MRF	34.3 (14.7)	25.5 (14.6)	37.7 (14.6)
NucCun	38.7 (11.5)	27.7 (11.5)	40.5 (11.5)
PAG	63.3 (15.9)	53.6 (15.8)	44.6 (15.8)

5. Primary Outcome

Title	Voxel-wise Blood Oxygen Level Dependent (BOLD) Using fMRI of Brain Activation Signals in Defined Brain Regions in Response to Visual Stimulation (VIS)
Description	BOLD brain activation signals in pre-defined ROI in response to checkerboard visual stimuli (flashing at 2 Hz). ROI were ACC; AIC_L; AIC_R; MIC_L; MIC_R; PIC_L; PIC_R; Amyg_L; Amyg_R; S1; S2; SensTHAL; MRF; NucCun; PAG. Prior to ROI analysis, a prelimanary anlysis was performed, wherein it was concluded that ROI analysis was to be carried out for DMAa, DMAc amd TH only.
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

For VIS, based on preliminary analysis results, it was not considered significant to collect data according to Investigator's opinion.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	0	0	0

6. Primary Outcome

Title	Arterial Spin Labelling (ASL) Using fMRI of Brain Activation Signals Across the Whole Brain and in Defined Brain Regions
Description	Continuous ASL sequence fMRI imaging modality assessing brain activation signals across the whole brain and in defined ROI to assess effects of evoked pain along with changes in regional cerebral blood flow (rCBF). ROI were ACC; AIC_L; AIC_R; MIC_L; MIC_R; PIC_L; PIC_R; Amyg_L; Amyg_R; S1; S2; SensTHAL; MRF; NucCun; PAG.
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

Data was not analyzed since these methods were not technically robust enough to make any clear conclusions.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	0	0	0

7. Secondary Outcome

Title	36-Item Short-Form Health Survey (SF-36)
Description	SF-36 is a standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, mental health. The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning).
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was plotted against treatment for each participant as per planned analysis but not statistically summarized for analysis.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	0	0	0

8. Secondary Outcome

Title	Beck Depression Inventory (BDI)
Description	BDI is a 21 item participant rated inventory evaluating depression symptoms, cognition, and physical symptoms of fatigue, weight loss, lack of interest in sex. Individual items are scored on a 4 point scale (0 to 3), with 0=none/absent and 3=most severe. Total score: 0 to 63; higher score indicate more depression.
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was plotted against treatment for each participant as per planned analysis but not statistically summarized for analysis.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	0	0	0

9. Secondary Outcome

Title	State and Trait Anxiety Questionnaire
Description	Self-report scale completed by the participant. Separate scales measure state (20 items) and trait (20 items) anxiety. The participant report how they feel "right now at this moment" for state anxiety and how they "generally" feel for trait anxiety. The "state" items are scored as: 1 (not at all), 2 (somewhat true), 3 (moderately true), 4 (very much so). The "trait" items are scored as: 1 (almost never), 2 (sometimes), 3 (often), 4 (almost always). Scores range from 20-80 for each scale. Higher scores indicate more impaired participants.
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was plotted against treatment for each participant as per planned analysis but not statistically summarized for analysis.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	0	0	0

10. Secondary Outcome

Title	Pain Catastrophising Scale (PCS)
Description	The PCS is a self-administered questionnaire with 13 items, each scored from 0 (not at all) to 4 (all the time) for extent to which participant catastrophizes postoperative pain. Total score is sum of scores for all questions (range: 0 to 52); Subscale scores: Rumination (sum of scores for 4 items; range: 0 to 16); Magnification (sum of scores for 3 items; range: 0 to 12); and Helplessness (sum of scores for 6 items; range: 0 to 24); higher scores indicate greater extent of pain catastrophizing.
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was plotted against treatment for each participant as per planned analysis but not statistically summarized for analysis.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	0	0	0

11. Secondary Outcome

Title	Neuropathic Pain Symptom Inventory (NPSI)
Description	NPSI: participant rated questionnaire to evaluate different symptoms of neuropathic pain (dimensions: burning [superficial] spontaneous pain, pressing [deep] spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dyesthesia [P/D]). Includes 10 descriptors quantified on a 0 (no symptoms) to 10 (worst symptoms imaginable) and 2 temporal items assessing duration of spontaneous ongoing and paroxysmal pain. Questionnaire generates a score in each of the relevant dimensions and a total score of 0-100. Higher score indicate a greater intensity of pain.
Time Frame	Baseline (Day -7), Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was plotted against treatment for each participant as per planned analysis but not statistically summarized for analysis.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	0	0	0

12. Secondary Outcome

Title	Daily Pain Score
Description	Daily Pain Score: Day 1 pain intensity over past 24 hours recorded on waking every morning using 0-10 numeric rating scale (NRS): 0 (no pain) to 10 (worst possible pain). The daily pain scores for an average of the last 7 days and an average of last 3 days were calculated.
Time Frame	Day -35 through Day 36

Outcome Measure Data

Analysis Population Description

FAS included all the participants who were enrolled in the study. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	18	17	18
Last 7 days	5.57 (0.371)	5.28 (0.370)	6.40 (0.370)
Last 3 days	5.46 (0.466)	5.10 (0.454)	6.33 (0.454)

13. Secondary Outcome

Title	Present Pain Intensity Score (PPIS)
Description	Participants answered: "Please rate your pain from 0-10 that best describes the intensity of pain right now". PPIS assessed on 0-10 numeric rating scale (NRS), 0 (no pain) to 10 (worst possible pain).
Time Frame	Day 8, 22, 36

Outcome Measure Data

Analysis Population Description

FAS included all the participants who were enrolled in the study. 'N' (number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	17	17	17
Least Squares Mean (Standard Error) [units on a scale]	5.54 (0.552)	4.13 (0.551)	5.83 (0.551)

14. Secondary Outcome

Title	Doleur Neuropathic 4 (DN4) Score
Description	DN4 questionnaire provides a simple diagnosis of Neuropathic pain (NeP) by asking for yes/no answers to 4 questions (10 sub questions in total). Each question was scored on a scale of 0 (No) and 1 (Yes). Total score was calculated as sum of the 10 individual questions. Total score range 0-10, higher score indicated more neuropathic pain.
Time Frame	Day -35

Outcome Measure Data

Analysis Population Description

Data for this outcome measure was plotted against treatment for each participant as per planned analysis but not statistically summarized for analysis.

Arm/Group Title	Pregabalin	Tramadol	Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.	Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.	Matching placebo capsule orally for 7 days in either of the intervention periods.
Measure Participants	0	0	0

Adverse Events

Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. But, distinct events are presented. An event may be categorized as serious in 1 subject; as nonserious in another subject or 1 subject may have experienced both serious, nonserious events in study.'At risk population'=who received study treatments in different interventions;PGB=17,TMD=17,PBO=18.
Arm/Group Title	Pregabalin		Tramadol		Placebo
Arm/Group Description	Pregabalin capsule titrated to 150 mg orally twice daily for 7 days in either of the intervention periods.		Tramadol SR capsule titrated to 200 mg orally twice daily for 7 days in either of the intervention periods.		Matching placebo capsule orally for 7 days in either of the intervention periods.
All Cause Mortality
	Pregabalin		Tramadol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Pregabalin		Tramadol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Pregabalin		Tramadol		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/17 (82.4%)		14/17 (82.4%)		11/18 (61.1%)
Ear and labyrinth disorders
Vertigo	1/17 (5.9%)		1/17 (5.9%)		0/18 (0%)
Eye disorders
Vision blurred	1/17 (5.9%)		0/17 (0%)		0/18 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/17 (0%)		0/17 (0%)		1/18 (5.6%)
Abdominal distension	0/17 (0%)		0/17 (0%)		1/18 (5.6%)
Abdominal pain	0/17 (0%)		2/17 (11.8%)		0/18 (0%)
Abdominal pain upper	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Constipation	0/17 (0%)		4/17 (23.5%)		0/18 (0%)
Diarrhoea	1/17 (5.9%)		2/17 (11.8%)		0/18 (0%)
Dry mouth	3/17 (17.6%)		0/17 (0%)		1/18 (5.6%)
Gastrooesophageal reflux disease	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Nausea	1/17 (5.9%)		8/17 (47.1%)		1/18 (5.6%)
Tooth loss	0/17 (0%)		0/17 (0%)		1/18 (5.6%)
Toothache	1/17 (5.9%)		1/17 (5.9%)		0/18 (0%)
Vomiting	0/17 (0%)		4/17 (23.5%)		0/18 (0%)
General disorders
Adverse drug reaction	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Fatigue	3/17 (17.6%)		6/17 (35.3%)		1/18 (5.6%)
Feeling hot	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Feeling of body temperature change	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Malaise	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Thirst	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Infections and infestations
Nasopharyngitis	3/17 (17.6%)		0/17 (0%)		1/18 (5.6%)
Tooth abscess	1/17 (5.9%)		0/17 (0%)		1/18 (5.6%)
Injury, poisoning and procedural complications
Limb injury	0/17 (0%)		0/17 (0%)		1/18 (5.6%)
Metabolism and nutrition disorders
Decreased appetite	0/17 (0%)		3/17 (17.6%)		0/18 (0%)
Increased appetite	1/17 (5.9%)		0/17 (0%)		0/18 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/17 (5.9%)		1/17 (5.9%)		1/18 (5.6%)
Back pain	0/17 (0%)		0/17 (0%)		1/18 (5.6%)
Mobility decreased	2/17 (11.8%)		0/17 (0%)		0/18 (0%)
Neck pain	1/17 (5.9%)		0/17 (0%)		1/18 (5.6%)
Nervous system disorders
Balance disorder	1/17 (5.9%)		1/17 (5.9%)		1/18 (5.6%)
Clumsiness	1/17 (5.9%)		0/17 (0%)		0/18 (0%)
Disturbance in attention	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Dizziness	7/17 (41.2%)		8/17 (47.1%)		2/18 (11.1%)
Dysarthria	1/17 (5.9%)		0/17 (0%)		0/18 (0%)
Headache	2/17 (11.8%)		2/17 (11.8%)		1/18 (5.6%)
Lethargy	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Somnolence	2/17 (11.8%)		4/17 (23.5%)		1/18 (5.6%)
Psychiatric disorders
Confusional state	1/17 (5.9%)		0/17 (0%)		1/18 (5.6%)
Insomnia	0/17 (0%)		2/17 (11.8%)		1/18 (5.6%)
Libido decreased	1/17 (5.9%)		0/17 (0%)		1/18 (5.6%)
Loss of libido	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Mood swings	1/17 (5.9%)		0/17 (0%)		1/18 (5.6%)
Renal and urinary disorders
Dysuria	0/17 (0%)		1/17 (5.9%)		0/18 (0%)
Reproductive system and breast disorders
Erectile dysfunction	1/17 (5.9%)		0/17 (0%)		1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Nasal polyps	1/17 (5.9%)		1/17 (5.9%)		1/18 (5.6%)
Oropharyngeal pain	1/17 (5.9%)		0/17 (0%)		0/18 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/17 (0%)		2/17 (11.8%)		0/18 (0%)
Pruritus	0/17 (0%)		5/17 (29.4%)		0/18 (0%)
Surgical and medical procedures
Tooth extraction	0/17 (0%)		1/17 (5.9%)		0/18 (0%)

Limitations/Caveats

Results for primary outcome, BOLD activation signals(whole brain) was not available to reported, as DMAa, DMAc, TH and VIS were captured as COPE images only, which could not be included in basic results format.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.