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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Pain

Intervention / Treatment
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* Drug: Placebo
* Drug: Pregabalin
* Drug: Tramadol SR


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1<br> | Drug: Placebo<br>* BID<br>|
| Experimental: 2<br> | Drug: Pregabalin<br>* Dose 75 mg titrated to 150 mg, bid<br>|
| Experimental: 3<br> | Drug: Tramadol SR<br>* Dose 50mg titrated to 200 mg, bid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Voxel-wise Blood Oxygen Level Dependent (BOLD) Using Functional Magnetic Resonance Imaging (fMRI) of Brain Activation Signals Across the Whole Brain | 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). | Day 8, 22, 36 | 
| 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) | 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). | Day 8, 22, 36 | 
| 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) | 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). | Day 8, 22, 36 | 
| Voxel-wise Blood Oxygen Level Dependent (BOLD) Using fMRI of Brain Activation Signals in Defined Brain Regions in Response to Thermal Stimulation (TH) | 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). | Day 8, 22, 36 | 
| Voxel-wise Blood Oxygen Level Dependent (BOLD) Using fMRI of Brain Activation Signals in Defined Brain Regions in Response to Visual Stimulation (VIS) | 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. | Day 8, 22, 36 | 
| Arterial Spin Labelling (ASL) Using fMRI of Brain Activation Signals Across the Whole Brain and in Defined Brain Regions | 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. | Day 8, 22, 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 36-Item Short-Form Health Survey (SF-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). | Day 8, 22, 36 | 
| Beck Depression Inventory (BDI) | 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. | Day 8, 22, 36 | 
| State and Trait Anxiety Questionnaire | 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. | Day 8, 22, 36 | 
| Pain Catastrophising Scale (PCS) | 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. | Day 8, 22, 36 | 
| Neuropathic Pain Symptom Inventory (NPSI) | 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. | Baseline (Day -7), Day 8, 22, 36 | 
| Daily Pain Score | 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. | Day -35 through Day 36 | 
| Present Pain Intensity Score (PPIS) | 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). | Day 8, 22, 36 | 
| Doleur Neuropathic 4 (DN4) Score | 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. | Day -35 |