Why do antidepressants help with nerve pain relief?

Tricyclic antidepressants have long been known to have more than one purpose: among other things, they can alleviate pain – particularly nerve pain.

Recent research has finally established why these tricyclic antidepressants (TCAs) can help with nerve pain. The discovery could lead to the rapid development of pain relief medications that don’t include the side effects of TCAs.

Nerve pain comes from a variety of sources – including cancer, diabetes, trauma, multiple sclerosis, and infections. These treatments could address a range of different types of nerve pain.

It turns out the drugs inhibit a key protein in our nerves, called an N-type calcium channel. These N-type calcium channels are shaped like tiny gates, allowing positively charged calcium ions, or Ca²⁺, through them. This helps with the transmission of pain signals in the body.

Researchers have long been keen to find things that “close” the gate of these calcium channels because that’s likely to have analgesic effects.

Adjunct Professor Peter Duggan, a researcher with the CSIRO and senior collaborator on the project, says that he and his colleagues initially stumbled across TCAs from a very different direction: they were investigating the toxins of venomous marine cone snails.

“A few of the components in that toxin are actually painkillers and they block these calcium ion channels very, very effectively,” says Duggan.

The cone snail toxin has the potential to be very dangerous to people, as well as needing to be administered in an impractical way, so the researchers started looking at similar compounds that might have some of the same properties.

“What we’ve been doing is designing and making small molecules that mimic the activity of those kinds of toxins,” says Duggan.

“One class that we looked at gradually trended towards the same structure as the tricyclic antidepressants.”

Once they realised that TCA-like molecules could block these calcium channels, the researchers set out to look at TCAs specifically.

Duggan’s collaborators at the University of Queensland set up a lab-based experiment with 11 TCAs and two drugs that are chemically very similar to TCAs.

These 13 drugs were administered to in vitro neuroblastoma cells.

“They’re (neuroblastoma) a type of brain cancer cell that naturally expresses the channel we’re interested in,” explains Duggan.

Analysis of the cells by UQ, CSIRO and Monash University researchers showed that the drugs could all limit the amount of calcium that got transmitted through the cells. This means that these TCAs must alleviate pain by inhibiting the N-type calcium channel.

A paper describing the work is published in RSC Medicinal Chemistry.

Duggan says that there may be other mechanisms by which TCAs kill pain as well, and they definitely have other biochemical effects in the body. But it’s unlikely that the calcium channel-blocking is helpful in treating depression.

TCAs are a very old and well-established form of antidepressant, and for treating depression, they’ve largely been replaced by newer drugs with fewer side effects.

“They’re what we call ‘dirty drugs’,” explains Dr Michael Vagg, dean of the Faculty of Pain Medicine at the Australian and New Zealand College of Anaesthetists, and an associate professor at Deakin University.

“They have effects on lots of transmitter systems and receptors in the body. They don’t have just the one straightforward action; they have multiple actions.”

This means that TCAs typically have several side effects, including drowsiness, blurred vision and constipation.

But because the researchers now have a specific understanding of how they alleviate pain, they can develop new drugs that don’t have these side effects.

“The more we understand about how TCAs are causing the painkilling effect, the actual intimate mechanism of how they’re doing it, then there’s more chance of us being able to develop compounds that target that type of activity and not have other side effects or the other antidepressant effects,” says Duggan.

Vagg is optimistic that better drugs are on the way. He cites the recent proliferation of new migraine treatments, which arrived less than a decade after researchers found a similar key mechanism in the brain, as his reasoning for this.

He emphasises that it’s not yet a done deal – any new drug based on this research would still need to make it through the development pipeline and clinical trials.

“I think because the tricyclic drugs are already widely used, and already seem to have – for most people – an acceptable level of safety, I suspect that means that development will go smoother rather than rougher,” says Vagg.

This is good news for the roughly one in 20 Australians who suffer from nerve pain.

“Nerve pain is highly disabling and ruins lives. The best current treatments only work to a useful degree on every third or fourth person who receives them,” says Vagg.

“We have not had any really effective new treatments for nerve pain for a long time and this work opens up the possibility of designing a new class of drugs with improved safety and effectiveness.”