Chronic pain (cancer and nonmalignant) remains a significant medical problem. Its treatment, in particular chronic neuropathic pain, is an especially challenging task. The development of drugs and drug delivery systems for the treatment of chronic neuropathic pain is an important endeavor. One group of drugs with potential use for neuropathic pain is the N-methyi-Daspartate (NMDA) receptor antagonists. Drugs from this class have also been shown to enhance the analgesic effect of morphine and to inhibit development of tolerance to this opioid. Ketamine, a clinically available nonselective NMDA receptor antagonist, has been used parenterally for pain. Despite its analgesic potency, side effects (psychotomimetic, motor, sedation) have limited its use. These effects are prominent following parenteral administration being associated with peak plasma levels. Transdermal application, a delivery approach minimizing peak plasma levels, would be expected to provide a better profile of analgesia to side effects. The ideal candidate for a successful transdermal delivery system is a potent drug with a low clearance rate. The rapid clearance rate of ketamine makes it an undesirable candidate for transdermal delivery. However, ketamine is metabolized to norketamine. Norketamine is an NMDA receptor antagonist and has analgesic activity. Its clearance rate is significantly less than that of ketamine. Therefore, it represents a better candidate for a transdermal delivery system. Prior to consideration for use in a transdermal system the analgesic properties of norketamine in a preclinical model of neuropathic pain needs to be evaluated. Locomotor activity will also be studied to verify that analgesia is not due to depression in motor function or sedation. The purpose of this proposal is to characterize the analgesic properties of norketamine as an initial feasibility study to provide a basis for its future use as an analgesic in a transdermal system. The enantiomers of norketamine will also be studied. Analgesic potency and side effect differences have been seen with the enantiomers of ketamine and are likely to occur with norketamine.
The specific aims are to: 1) characterize the analgesic properties of S-, R- and RS- norketamine in response to thermal and mechanical stimuli in a rat model of neuropathic pain and 2) characterize the effect of S-, R- and RS- norketamine on activity level in intact rats. Findings from this Phase I study are important to the long-term goal (Phase II studies) of developing a clinically useful transdermal analgesic drug (norketamine enantiomer) suitable for the management of chronic neuropathic pain.
