It is impossible not to be aware of the crisis that the “opioid epidemic” has created in the treatment of chronic pain. While there is no question as to their efficacy, the clinical use of opioids is severely limited due to the rapid development of tolerance and the production of respiratory depression, the major cause of opioid-induced lethality. Research programs are underway nationwide to discover and develop new non-opioid drugs that are effective analgesics without the tolerance and abuse liability ascribed to the opioids. Chronic pain is especially difficult to treat due to its complex nature with a variety of different etiologies. For example, chronic pain may be produced by injury, surgery, the inflammation produced by arthritis or by certain drugs such as cancer chemotherapeutics. For these reasons, management and control of chronic pain continues to be a serious gap in medical practice with multiple alternative medicines that either lack critical efficacy and/or produce unacceptable side-effects.

Data from both preclinical and clinical studies are consistent with the idea that GABAergic neurotransmission is an important regulatory mechanism for the control of pain. Gabapentin (Neurontin^®) and pregabalin (Lyrica^®) two commonly used drugs for the treatment of chronic pain are believed to produce their analgesic effects by enhancing GABAergic neurotransmission. However, although they have received FDA approval, the clinical results have not been overwhelming. The most common side effects produced by gabapentin were sedation, dizziness and problems walking. It is uncertain whether greater efficacy is not observed because of poor intrinsic pharmacological efficacy or insufficient dosages due to dose limiting side effects.

An alternate approach to enhancing GABAergic neurotransmission, is the use of GABAkines. This approach has been under-utilized because of the general lack of efficacy of the 1,4-benzodiazepine GABA modulators. However, a strong case for the potential value of subtype selective GABAkines for the treatment of pain can be made. First, GABA_A receptor regulated pathways are integral to pain processing with α2/3 containing GABA_A receptor subtypes present on nerve pathways modulating pain sensation and perception. Second, we believe that the analgesic properties of benzodiazepines may be masked by concurrent activation of other receptor subtypes that mediate the side effects. Diazepam has been reported to produce maximal analgesia if the side effects are attenuated by GABA_A subtype genetic manipulation. Third, predecessor compounds made by Dr. Cook that selectively amplify α2/3- GABA_A receptor signaling are effective in pain models in rodents at doses lower than those producing motor side effects.

In a number of laboratory procedures, KRM-II-81has been shown to selectively bind to α2/3- GABA_A receptors and enhance GAGAergic neurotransmission. In rodents, KRM-II-81 facilitated GABA_A neurotransmission in the dorsal root ganglion, a primary sensory relay in the pain pathway. In addition, oral administration of KRM-II-81 to rats attenuated formalin-induced pain behaviors and the chronic pain engendered by chronic spinal nerve ligation. KRM-II-81 was also active against acute pain provocation (e.g., acid-induced pain) and inflammatory pain. More recently, KRM-II-81 was shown to be effective against chronic pain induced by a chemotherapeutic agent. Sub-chronic dosing for 22 days with KRM-II-81 and the structural analog, MP-III-80, demonstrated enduring analgesic efficacy without the development of tolerance. In contrast, tolerance developed to the analgesic effects of gabapentin. Also, KRM-II-81 does not substitute for the benzodiazepine, midazolam, in a drug discrimination assay, suggesting a reduced abuse liability. Furthermore, KRM-II-81 did not produce the respiratory depression observed with alprazolam, a major problem with benzodiazepines leading to emergency room visits and overdose.

We believe that the ability to attenuate both acute and chronic pain combined with a greatly reduced side effect profile, a lack of tolerance and a reduced abuse potential makes KRM-II-81a promising clinical lead and a potential advance in pain therapeutics. Results from preliminary chemistry, metabolism and pharmacokinetic studies support its further development.