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.

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.

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.