Shifting pain modulation towards anti-nociceptivity: Mechanism-specific pharmacological prevention of post sternotomy pain

Postoperative pain and the development of chronic pain is a serious
complication of surgical interventions. While the treatment of acute
postoperative pain is well organized in current medical practice, the
development of chronic pain still has a relatively large incidence. The latter
depends on many factors including the type of surgery (a high incidence of
postoperative chronic pain is observed following thoracotomies, sternotomies
for coronary bypass surgery, mastectomies and inguinal hernia repairs) and
specific patient-related factors. These patient-related factors include the
state of the endogenous analgesia system, a modulatory and highly plastic
system that is involved in modulation of afferent nociceptive input to central
sites using top-down inhibitory and facilitatory pathways that inhibit or
facilitate pain perception. The preoperative balance between anti- and
pronociception may play a crucial role in the development of postoperative
chronic pain. For example, it has been shown previously that the ability to
engage endogenous inhibitory pathways (as tested by the experimental paradigm
of Conditioned Pain Modulation) was associated with a lower risk of development
of chronic post-thoractomy pain (odd ratio 0.52). These data suggest that
improvement of preoperative nociceptive profile of the patient or pain
modulatory profile (PMP), for example by pharmacological intervention to
enhance endogenous inhibition or to inhibit facilitation, may reduce the risk
of postoperative pain. Routinely there is no preemptive analgesic medication
for patient undergoing thoracotomies at LUMC.

In this research project we explore anti-nociception as a state of pain
modulation. Our main objectives in utilizing the plasticity of the central pain
pathways are to:
(i) Shift individuals from a pro-nociceptive pain modulation profile to an
anti-nociceptive profile;
(ii) Explore how this affects their chances of developing chronic pain; and
(iii) Explore whether a pharmacologically induced shift towards an
anti-nociceptive state is efficient in the prevention of chronic postoperative
pain.

Randomized, placebo controlled, interventional

Maximal 3 weeks before elective surgery patients will be assessed for pain
modulation using psychophysical and neurophysiological tests (as defined below;
day 1). They will then be impartially randomized to one of three treatment
arms: Duloxetine (DLX), Pregabalin (PGB) or placebo (PLC). A second similar
assessment session will be held within 2 days before surgery (day 13/14 -
20/21). The last study intake will be on the day of surgery (day 14-21). After
surgery, we will record acute pain intensity (in rest and during coughing) and
analgesic consumption during the first 3-5 days hours (day 15-20). A two-weekly
phone call for chronic post-operative pain and analgesic use will be pursued
for 3 months (day 105). One year after surgery there will be a last assessment
of pain (via telephone) and the study will end.

1. Medication: Lightheadedness/dizziness which will dissipate with a few days;
2. Pain testing: no serious burden is expected.