Columbia scientists working to combat injury-related depression, substance abuse and suicide due to unremitting, persistent pain may have discovered a new way of treating that pain: a powerful analgesic dubbed N60 that leads to neither tolerance nor addiction.
Pain is a perception in the brain triggered by signals sent along nerves in the peripheral nervous system. It is a sensation that serves as a defense mechanism for the organism but how it works is only beginning to be understood. Scientists now know, though, that there are several pathways by which the brain perceives different types of pain.
The research team, led by Dr. Richard Ambron, Professor of Pathology & Cell Biology at Columbia University Medical Center, began to develop N60 after his colleague, Dr. Ying-Ju Sung, Assistant Professor of Clinical Pathology, discovered the pathway that neurons use to inform the brain of an injury. Left uncontrolled, this pathway persistently alters the electrical properties of the neuron, ultimately causing chronic pain. The Columbia team found that a specific protein in the pathway, called PKG, acts like a switch. As long as the switch is on, the pathway is activated and the brain continues to receive signals that are perceived as pain, even after an injury has healed.
Sung and Ambron quickly realized that PKG would be an excellent target for drug development. Since PKG is specific for biochemical signaling involved with chronic pain, shutting off PKG will not prevent a patient from feeling fresh injuries. It also operates in the peripheral nervous system, rather than the central nervous system. This means that a drug that blocks PKG does not have to cross the blood-brain barrier, a formidable challenge in drug development.
"The only drugs that work consistently on chronic pain are opiates and anti-depressants," said Ambron. "A significant problem with opiates is that extended use often leads to addiction."
"Everyone is looking for a solution that is not addictive," Sung added. "There's increasing concern, from clinicians, patients, and regulatory agencies, with drugs that act on the central nervous system where addiction can develop."
Once they understood the function of PKG, the team began to work with medicinal chemists in Dr. Donald Landry's group, also at Columbia, to design a compound that would block PKG from sending signals to the brain. After considerable effort, they discovered N60, which laboratory tests have shown to be a powerful and very selective PKG blocker.
"We found in PKG a well-defined target that has been implicated in several types of pain that are particularly refractory to treatment," Ambron said. "Now, we have an excellent inhibitor of the target which imparts no evident toxic or behavioral side effects and which also alleviates chronic pain in animal models of nerve injury and inflammation. N60 is non-addictive and non-sedative, and a single dose attenuates pain for at least 24 hours."
Ambron and Sung believe N60 may have particularly meaningful impact for military personnel, who are at particularly high risk of suffering from chronic pain due to combat-related physical injuries and emotional stress. Recent pilot studies show analgesic effects in an animal model of neuroma, an abnormal growth in nerves. Neuromas can be extremely painful and result from injury to nerves, such as that caused by limb loss from trauma, amputations, or from other surgeries. Additionally, a growing body of research is finding direct biochemical connections between chronic pain and Post-Traumatic Stress Disorder (PTSD), anxiety, depression, and suicide.
Funding to-date has allowed the Columbia team to manufacture pharmaceutical (GMP)-grade compound, ready for studies which will evaluate the safety of the drug.
"We've got the drug, we're confident in its efficacy, and we are actively looking for investors and experienced partners to help us put this through clinical testing," explains Jerry Kokoshka, a representative from Columbia Technology Ventures, the university office that oversees commercialization of novel technologies. "Anyone who has ever experienced the suffering of chronic pain, personally or through a family member or friend, knows the intense frustration and emotional burden of this problem.
"We believe a compound like N60 has significant potential to transform the way chronic pain is treated ," Ambron said. "If it works the way we think it can, we may be able to alleviate chronic pain in some of its most intractable forms without the risk of addiction, a problem that conveys a whole set of economic and social issues for our country and society at-large."
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