Acute and Chronic Pain Management
Background and Goal of Study: The role of NMDAR in chronic pain states has been well documented in the scientific literature. NMDAR antagonists have shown efficacy in preclinical models as well as in patients with neuropathic pain (NP). Large-scale clinical use of NMDAR antagonists is limited due to side effects of currently available compounds of this class (ketamine: K). A new compound Traxoprodil (Trx) has been described as a potent, selective NR2B subunit of NMDAR antagonist. This study aims to investigate the therapeutic value of Traxoprodil in a rat model of NP (Spared Nerve Injury - SNI model) as compared to Ketamine.
Materials and Methods: The SNI model in 9 wk female Sprague-Dawley rats gives a robust, prolonged neuropathic pain state (>90 days) with allodynia and hyperalgesia. Drugs were titrated to a dose that gave analgesia with tolerable side effects (K: i.v. 3 mg/kg/hour and Trx: 10 mg/kg/hour for 3 hours, 5 consecutive days). Response to tactile allodynia and mechanical hyperalgesia was assessed. Functional assessment was performed with a gait analysis system. Side effects were scored and registered.
Results and Discussion: Both NMDAR antagonists alleviated tactile allodynia in rats with neuropathic pain. Ketamine relieved tactile allodynia for 39±18 post operative days (POD), Traxoprodil for 40±5 POD (fig 1a). Gait analysis showed improvement of function after treatment with NMDAR antagonists. Amount of time spent on injured paw (stand) was improved (36±9% for K, 41±8% for Trx versus 32±10% for placebo). Weight distribution (maximum intensity) also improved (62±11% for K, 78±13% for Trx and 47±16% for placebo, Fig 1b). While K treatment was accompanied by important side effects (locomotor hyperactivity, overflow incontinence), there was no evidence of any side effects during Trx treatment.
Conclusion(s): NMDAR antagonists prove to be effective therapeutic drugs against mechanical allodynia, in this rat model of neuropathic pain. The central finding in our preliminary study demonstrates the potential of NMDAR antagonists to improve functional recovery, with more time spent on the injured paw and a more even distribution of the body weight. Trx exhibited a superior therapeutic index for efficacy versus side effects.