Effects of NMDA-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy in Young and Elderly Patients
The immediate postoperative period is associated with spontaneous pain and hyperalgesia,
i.e., increased pain response (both intensity and duration) to normally painful stimuli
following tissue injury or damage.
The development and maintenance of secondary hyperalgesia depend on complex plastic changes
in spinal cord dorsal horn cells after peripheral injury or damage. Afferent impulses
signaling the damage are carried to the dorsal horn by slowly conducting, unmyelinated
C-fibres. C-fibres release glutamate which acts at three receptor types: metabotropic,
kainate/AMPA and NMDA. NMDA receptor activation, through a complex cascade of intracellular
events, results in dorsal horn neuron hyperexcitability or central sensitization. These
cells have increased spontaneous activity, decreased threshold, increased response to
afferent input, prolonged afterdischarge to repeated stimulation, and an expansion of
receptive fields. Central sensitization is expressed behaviorally as secondary hyperalgesia
and contributes to prolonged postoperative pain. It also may trigger pathological
reorganization of neural circuitry leading to the development of chronic postsurgical pain.
Through these processes, tissue injury may have profound effects on the CNS that long
outlast the injury.
In animal models of pain, NMDA agonists induce central sensitization and hyperalgesia
whereas antagonists decrease or prevent hyperalgesia. In humans, NMDA-receptor antagonism
decreases secondary hyperalgesia subsequent to experimentally-induced pain.
Perioperative administration of NMDA antagonists, that is, before, during and after surgery,
may be the ideal intervention to block the initiation and maintenance of central
sensitization. Several studies have found that this intervention reduces postoperative
hyperalgesia, pain, and analgesic use; however, others have not found these effects. This is
not surprising given the variability across studies in factors such as surgical procedure,
extent and nature of tissue damage, duration of surgery, pharmacokinetics of the agent(s)
tested, and intraoperative and postoperative analgesia. Nonetheless, the weight of the
evidence suggests that preventing or minimizing central sensitization reduces pain and
Co-administration of NMDA antagonists and opioids has been advocated as an effective
approach. The combination of morphine and amantadine should reduce postoperative pain by
inducing analgesia through actions on opioid-mediated receptor systems and by reducing
hyperalgesia via NMDA receptor-mediated events . The combination also should produce fewer
opioid-related adverse effects due to the anticipated opioid-sparing effect. The present
proposal describes the first direct comparison of perioperative NMDA receptor blockade
coupled with intra- and post-operative opioid administration in young and elderly patients.
In order to minimize the influence of other perioperative factors on the outcome variables,
all patients will undergo the same surgical procedure and anesthetic protocol. Furthermore,
factors that cannot readily be standardized (e.g., surgical duration, mood) will be measured
and controlled for statistically. This increases the internal validity of the proposed study
and our ability to detect age and drug effects.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Educational/Counseling/Training
To investigate the effects of perioperative NMDA receptor blockade on postoperative hyperalgesia, pain and analgesic consumption in young and elderly men
Lucia Gagliese, PhD
University Health Network, Toronto
Canada: Health Canada