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Effects of NMDA-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy in Young and Elderly Patients

Phase 1/Phase 2
18 Years
80 Years
Open (Enrolling)
Hyperalgesia, Pain, Prostate Cancer

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Trial Information

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
analgesic requirements.

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.

Inclusion Criteria:

1. Able to read and write English;

2. Age 18-59 or >= 60 years;

3. American Society of Anesthesiologists Class 1 to 3;

4. Scheduled for elective radical prostatectomy;

5. Body weight between 50-110 kg, body mass index (BMI) <= 30.

Exclusion Criteria:

1. Significant central nervous system (CNS), respiratory, cardiac, hepatic, renal or
endocrine dysfunction and/or any significant sequelae;

2. Contraindications, allergies to, and/or past adverse reactions to opioid analgesics,
amantadine or nonsteroidal anti-inflammatory drugs (NSAIDS);

3. Current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM
IV) Axis I disorder or cognitive dysfunction or history of this within the last year;

4. History of epilepsy or other seizures;

5. History of chronic pain of at least 6 months duration;

6. History of long term opioid use for chronic pain of at least 6 months duration;

7. History of long term use of amantadine or other antiparkinsonian drug;

8. Ingestion of antitussive medication (dextromethorphan) within the 48 hours before

9. History of alcohol or drug dependency/abuse of at least 6 months duration

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Educational/Counseling/Training

Outcome Measure:

To investigate the effects of perioperative NMDA receptor blockade on postoperative hyperalgesia, pain and analgesic consumption in young and elderly men

Principal Investigator

Lucia Gagliese, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University Health Network, Toronto


Canada: Health Canada

Study ID:




Start Date:

January 2004

Completion Date:

December 2006

Related Keywords:

  • Hyperalgesia
  • Pain
  • Prostate Cancer
  • Hyperalgesia
  • Quantitative Sensory Testing
  • Pain
  • Opioid use
  • Elderly
  • Hyperalgesia
  • Prostatic Neoplasms