Pain Prevention and Treatment Through the Enhancement of the Anti-nociceptive Component of Pain Modulation Profiles

Study Overview
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Brief Summary
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To utilize the plasticity of the central pain pathways in order to (i) shift individuals with a pro-nociceptive pain modulation profile towards an anti-nociceptive one, and (ii) assess its relevance in minimizing pain-derived morbidity.

Detailed Description
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In the project proposed here our main aim is to shift pain modulation towards anti-nociception as a novel approach to pain prevention and treatment. Our first hypothesis is that individual's modulation profile, when not anti-nociceptive, can be pharmacologically shifted into being anti-nociceptive. We assert (the first hypothesis) that such shift can be optimized by coupling the drug's mode of action with the individual's pain modulation profile; based on limited available data, it is suggested that less efficient inhibitory pain modulation will be modified best by serotonin-norepinephrine reuptake inhibitors (SNRIs), whereas enhanced facilitatory modulation will be modified best by Ca++ channel ligands. Pain modulation will be assessed by psychophysical tools, and will include dynamic tests of pain modulation. The conditioned pain modulation (CPM) test protocol will be used for assessing pain inhibition, and the temporal summation (TS) test protocol will be used for assessment of pain facilitation. Our second hypothesis is that SNRIs will be most efficacious in shifting individuals into being antinociceptive if these individuals had lower activation of the anterior brain pain network in the CPM test paradigm. In turn, Ca++ channel ligands will be most efficacious for individuals showing enhanced activation of the posterior pain network sites in response to the TS test protocol. Our third hypothesis is that an anti-nociceptive pain modulation profile protects individuals from acquiring pain. The model we chose for this study is surgery for coronary artery bypass grafting (CABG). Individuals scheduled for surgery, who are pain free, will be assigned to 3 arms - (1) duloxetine (DUL) (SNRI), (2) pregabalin (PGB) (Ca++ channel ligand) and (3) placebo. Drugs will be taken for 48 hours prior to surgery in a double-blind non cross-over parallel design. Pain modulation will be assessed before treatment, 2-4 hours prior to surgery and at its end, 6 weeks before surgery. Post operative acute and chronic pain will be assessed up to 2 month after surgery.

Conditions
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Pain

Intervention / Treatment
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* Drug: Duloxetine
* Drug: Pregabalin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Otherwise healthy, age 18-75. Exclusion Criteria: Regular use of analgesia for any purpose, including SNRIs, gabapentins, COX inhibitors. Presence of diagnosed chronic pain disorders, psychiatric disorders, cognitive and /or neurological deficit. Inability to give informed consent, communicate and understand the purpose and instructions of this study. Pregnant or nursing women.

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Duloxetine<br>DUL 60mg x once a day x 2 days. This arm will also take 2 non-active placebo x once a day x 2 days | Drug: Duloxetine<br>* duloxetine 60mg<br>Drug: Placebo<br>* non active placebo<br>|
| Active Comparator: Pregabalin<br>PGB 150mg x twice a day x 2 days | Drug: Pregabalin<br>* pregabalin 150mg<br>|
| Placebo Comparator: Placebo<br>Non active placebo x twice a day x 2 days | Drug: Placebo<br>* non active placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The changes in pain response after administration of duloxetine and pregabalin | The changes in the excitatory and inhibitory pain modulation responses (assessed by temporal summation and conditioned pain modulation) will be examined before and after the administration of duloxetine and pregabalin in the set of pre and post coronary artery bypass grafting surgery. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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endogenous pain modulation, coronary artery bypass grafting, quantitative sensory testings, duloxetine, pregabalin, preemptive treatment