The NMDA-receptor antagonist CPP abolishes neurogenic ‘wind-up pain’ after intrathecal administration in humans

Abstract

Involvement of the NMDA receptor system in the transmission of nociceptive information, including the development of central sensitization and a wind-up phenomenon, has increased interest in NMDA-receptor antagonists as antinociceptive drugs. This case report describes the use of an NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) in a carefully selected patient with severe and intractable neurogenic pain in her left leg. The pain syndrome had components of a continuous deep pain, an allodynia, and a wind-up-like component, including afterdischarge and spread of painful sensations outside the territory of the injured nerve. After intrathecal (i.t.) administration of 200 nmol of CPP the continuous deep pain component and allodynia were unchanged, but the following 'wind-up' phenomenon with afterdischarge and spread of the pain sensation in the left half of the body was completely abolished. Another 500 nmol of CPP administered over 2 h did not improve pain relief. Pain thresholds for heat and cold stimulation, measured with a Marstock thermostimulator, did not change. There was no effect on blood pressure, heart rate, sensitivity, reflexes, coordination or motor performance. Psychotomimetic ketamine-like side effects developed 4 h after the last injection of CPP and were probably due to rostral spread of CPP. These early experiences with i.t. administration of NMDA-receptor antagonists to humans indicate that the NMDA-receptor system plays an important role in neurogenic pain and that antagonizing this system may be a useful way to obtain better pain control although psychotomimetic side effects due to rostral spread may be a problem.

Targeting the NMDA Receptor Subunit NR2B for the Treatment of Neuropathic Pain

“…Among clinically assessed NMDA antagonists, however, the narrow separation between effectiveness and liabilities such as sedation, memory impairments, motor incoordination, and psychotomimetic effects has severely hampered their utility for the treatment of neuropathic pain. For example, intrathecal administration of CPP, a competitive NMDA antagonist, prevented radiation of the pain outside the territory of the injured nerve in a patient suffering from surgery-induced nerve injury, 74 but psychotomimetic adverse effects of the drug resulted in the termination of the study.…”

Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity

“…However, NMDA antagonists have significant side effects. In adult humans they trigger psychosis, [1][2][3][4][5][6][7][8][9][10] and in adult rats they produce neurotoxicity. [11][12][13][14][15][16][17][18][19][20][21] Developing methods for controlling or preventing these adverse reactions is an important goal, as it may permit the therapeutic potential of these agents to be realized.…”

Effects of a partial agonist and a full antagonist acting at the glycine site of the NMDA receptor on inflammation‐induced mechanical hyperalgesia in rats

“…In man, both ketamine (Stannard & Porter, 1993;Backonja et al, 1994;Park et al, 1994;Arendt-Neilson et al, 1995;Cherry et al, 1995;Persson et al, 1995) and the competitive glutamate recognition site antagonist, CPP (Kristensen et al, 1992) have been shown to have analgesic properties in a variety of experimental and clinical pain states. However, even in studies in which the drug is given intrathecally, psychotomimetic effects are seen with these agents (White et al, 1982;Kristensen et al, 1992;Backonja et al, 1994;Park et al, 1994). In order to exploit the therapeutic potential of this class of compounds it is therefore important to develop NMDA antagonists with reduced side-effect liability.…”