SBIR-STTR Award

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.

Thesaurus Terms:
NMDA receptor, analgesia, chronic pain, drug design /synthesis /production, inhibitor /antagonist, ketamine, transdermal drug delivery clearance rate, neuropathology, skin absorption, stereoisomer gas chromatography mass spectrometry, laboratory rat

Chronic pain is a significant medical problem. Its treatment, in particular chronic neuropathic pain, remains an area of unmet therapeutic need. An important potential group of drugs for the treatment of neuropathic pain are compounds which act as antagonists at the N-methyl-D-aspartate (NMDA) receptor. Drugs from this class have also been shown to enhance the analgesic effect of morphine and to inhibit tolerance development to this opioid. Despite their great promise as analgesics, the clinical usefulness of the only available NMDA receptor antagonist, ketamine, has been limited due to its psychotomimetic, sedative and motor side effects. This has prompted an effort towards identifying other NMDA receptor antagonists which retain analgesic properties but with a more acceptable side effect profile. Phase I STTR funding for this project has demonstrated that the novel NMDA receptor antagonist, norketamine (NK) and its enantomers [R(+) and S(-)-NK] have analgesic properties in a rodent model of neuropathic pain. The majority of side effects are with the R(+)-enantiomer. Thus, we have established the feasibility that norketamine, specifically S(-)-NK, has the potential for development as a novel agent for the treatment of neuropathic pain. The ultimate objective in the proposed Phase II STTR funding is to develop an NMDA receptor antagonist with fewer and more tolerable side effects for the treatment of chronic pain. The specific aims of the Phase II STTR proposal are to: 1) further characterize the pharmacologic profile of S(-j-NK, in comparison to R(+)- NK, in established rat models of pain and behavior; 2) perform non-cGMP bulk synthesis of S(-)-NK for preclinical studies; 3) evaluate the oral bioavailability, assess the metabolic profile, and determine the optimal oral dose of S(-)-NK in the rat; 4) provide a bulk manufacturing process for the API, formulate an oral capsule dosage form of S(-)-NK and obtain cGMP S(-)-NK and cGMP placebo for use in the Phase I clinical trial; 5) evaluate toxicological properties of S(-)-NK including neurotoxicity; 6) conduct a Phase I clinical trial to assess the safety of S(-) NK. In summary, Phase I STTR findings have established the feasibility that S(- )-NK is a viable candidate for further development as a drug for neuropathic pain. The Phase II STTR proposal will build upon Phase I STTR findings to further characterize the pharmacology and toxicology of S(-)-NK, to obtain an Investigational New Drug application, with the overall goal of proceeding to a Phase I clinical trial in humans. The development of a clinically useful drug for chronic neuropathic pain will have potential broad application for the treatment of pain including cancer, AID'S, neuropathy, diabetic neuropathy, complex regional pain syndrome and radiculopathy