Small molecule alleviates pain more effectively than gabapentin, minus the side effects

A small molecule alleviates four different types of acute and chronic pain in rodents, so far with none of the side effects associated with widely prescribed non-opioid painkiller gabapentin.

In an article published Nov. 13 in Proceedings of the National Academy of Sciences, researchers from New York University described how they discovered their compound, dubbed CBD3063, and tested it in models of injury- and chemotherapy-induced neuropathy, trigeminal nerve pain and inflammatory pain. They hope to eventually take it to the clinic.

“The compound can be given [via] multiple routes, it works in different species—mice and rats—and in males and females,” senior author Rajesh Khanna, Ph.D., who is also working on a gene therapy for chronic pain, told Fierce Biotech Research in an interview. “No toxicity has been seen, and it works across an array of pain conditions. That’s really the crux of this paper.”

CBD3063, gabapentin and pregabalin all ultimately exert their effects through their interactions with a calcium channel called Cav2.2 on pain-sensing neurons, but they do so via different mechanisms. Where gabapentin acts on the outside of the channel, CBD3063 alters it from the inside by stopping a protein called CRMP2 from binding to it. Decoupling the two keeps calcium from entering the channel, which ultimately leads to less neurotransmitter release—and pain reduction.

Khanna’s lab first discovered the peptide that would become the basis for CBD3063 back in 2011. Since then, the team has worked on formulating it into a small molecule, figuring out that they could take the number of necessary amino acids down from 15 to just two and pairing those with a protein taken from the HIV virus to help it get into cells. As part of the new study, they worked with the University of Pittsburgh to run a large screen of 27 million existing drug compounds to see whether any had the same composition.

The results led them to CBD3063. After a barrage of cell studies to show that the compound did indeed inhibit CRMP2 and was highly selective for Cav2.2—an important consideration, as drugs for arrhythmias and hypertension target similar channels—the researchers tested it in double-blinded experiments on a mouse model of nerve injury, assessing it head-to-head with gabapentin. They found that mice who received the compound were less debilitated by pain than untreated mice. On top of that, CBD3063 worked at a fraction of gabapentin’s effective dose. 

“We were getting the same amount of relief [with 1 to 10 milligrams per kilogram of CBD3063] that the clinically available compound gabapentin was producing at 30 milligrams per kilogram,” Khanna said. “That’s very important, because now we are comparing it to a clinical benchmark.”

The researchers then conducted experiments on rodents that had nerve damage caused by treatment with paclitaxel, a chemotherapy drug. After giving four doses of paclitaxel over eight days, the researchers waited for the animals to develop nerve damage and an aversion to cold, another common symptom experienced by people who undergo chemotherapy. When the animals developed symptoms two or three weeks later, the team gave them single doses of CBD3063.

“We saw a beautiful reversal of both nerve pain and cold aversion,” Khanna said.

Next, the researchers looked at how well the drug could control orofacial pain. Until this set of experiments, the scientists had been giving the drug through the animals’ abdomens via what’s known as intraperitoneal delivery. This time, they tried giving it intranasally, thinking that a nasal spray formulation would be ideal for this kind of scenario.

“It also bypasses the blood-brain barrier, and it goes right into the regions it needs to,” Khanna said. Once again, the drug worked: It relieved pain consistent with the expected half-life of the compound in such a formulation, he said, which is a little more than three hours.

His team then moved to their final models. An assessment of whether CBD3063 could relieve chronic pain from inflammatory conditions like arthritis showed that single injections of the drug into mice with paw inflammation relieved their pain for at least four hours afterward. And an experiment on rats with a chronic nerve injury showed that they didn’t develop tolerance to the drug even with multiple injections over a two-week period.

But the researchers weren’t done yet: They wanted to be sure that CBD3063 didn’t block out unrelated types of pain or replicate gabapentin’s side effects, which include memory loss, mood changes, lethargy and more. Experiments on uninjured mice showed that the drug had no effect on types of pain that were unrelated to the type of neuropathy it was designed to treat. Meanwhile, gabapentin seemed to make mice less responsive to important acute pain signals.

As for side effects, the scientists found that abdominal injections of CBD3063 had no impact on rodents’ memory or cognition—unlike gabapentin, which dramatically diminished their ability to recognize objects. Their compound also had no effects on the animals’ cardiovascular function, which case studies suggest may be impacted by gabapentin.

“This demonstrates that CBD3063 preserves that adaptive role of pain without causing any kind of neurological side effects,” Khanna said. “That’s really the benefit.”

There’s still a long road to the clinic. The researchers will need to do many more experiments to understand the drug’s long-term effects as well as whether tolerance eventually arises. And while CBD3063 has never been used for pain relief, it is not technically a new compound. Thus, Khanna’s team will need to substantially transform and optimize it before they can patent it, then will need to partner with a pharmaceutical company to take it into development, he said.

“I don’t want to provide any false hope, because the path to humans is three to five years away at the very least,” Khanna said. “In order to get there, there’s a huge journey ahead.”