How Antidepressants Ease Pain from Nerve Injury

A new study identifies two different ways in which antidepressant medications can help improve neuropathic pain. Image: a depiction of the molecular structure of duloxetine, one of the antidepressants tested in the study. Credit: foxterrier2005/123RF Stock Photo.

People with pain from nerve injury, known as neuropathic pain, are often prescribed antidepressants for pain relief. These medications do improve pain in about half of patients who try them. But exactly how they do so has remained unclear.

Now, new research led by Michel Barrot from the French National Center for Scientific Research (CNRS) and the University of Strasbourg in France reports two distinct ways that duloxetine and amitriptyline, two different kinds of antidepressants, relieve neuropathic pain, at least in mice.

They find that, with short-term treatment, these drugs work in the central nervous system (brain and spinal cord). But, with long-term treatment, the antidepressants instead work in the peripheral nervous system (outside of the brain and spinal cord) and relieve pain by reducing inflammation.

Juan Antonio Micó, a researcher at the University of Cádiz in Spain who studies antidepressant effects on pain but did not contribute to the current work, says the new research provides a convincing explanation for how antidepressants improve pain, and that this knowledge should be helpful for both doctors and patients.

“You must bear in mind that when clinicians try to prescribe an antidepressant to a patient with chronic pain, they are often asked, ‘Why are you giving me a drug for depression? I’m not depressed. I don’t need this,’” he said. “This work shows that the effects are real and can be explained by these different mechanisms.”

The research was published November 14, 2018, in the Journal of Neuroscience.

A confusing picture
That antidepressants could ease neuropathic pain was first observed in the 1960s based on the use of tricyclic drugs—a class of antidepressants to which amitriptyline belongs—in psychiatric settings.

Studies since then confirmed that observation, and showed that newer antidepressants such as duloxetine also helped with pain. But Barrot said it was unclear exactly how these drugs functioned, at a cellular and molecular level in the nervous system, to alleviate pain.

“These studies showed us that the mechanism was separate from the action on depression itself—something was different—but we were not sure what was different,” Barrot said.

The researchers also wanted to understand if the time course of anti-depressant treatment played a role in how the drugs worked to improve pain.

“We wanted to approach this question in a way that we could really discriminate between long- and short-term effects so we could finally understand how these drugs work to relieve neuropathic pain,” Barrot said.

Short term vs. long term, central vs. peripheral
To do so, Barrot and colleagues first examined how duloxetine acted in the nervous system, when given for a short period of time or over the long term. The researchers used a mouse model of neuropathic pain in which injury to the sciatic nerve causes heightened pain sensitivity.

Previous studies suggested that noradrenaline—a chemical made by neurons—might be involved with duloxetine’s activity. So the researchers used a chemical toxin to get rid of nerve fibers in the spinal cord that make noradrenaline.

When they did so, they found that duloxetine no longer eased pain in the animals when they received the drug over short periods of time. But, chronic treatment with the drug was still effective.

They saw the opposite when they used a different toxin to eliminate nerve fibers that make noradrenaline outside of the central nervous system. In this case, they eliminated fibers that relay electrical signals from the body into the spinal cord (when these signals reach the brain, an experience of pain can develop). Here, short-term duloxetine still worked well for pain, but chronic duloxetine no longer helped.

Taken together, the results show that pain relief from short-term duloxetine requires noradrenaline in the central nervous system, while relief from long-term duloxetine also requires noradrenaline but in the peripheral nervous system.

The researchers also discovered that chronic duloxetine changed the activity of genes involved with immune system responses, particularly those involved with inflammation in the nervous system (known as neuro-inflammation).

Finally, the group was able to replicate the results in all of their experiments using amitriptyline, a different type of antidepressant.

What does it all mean for patients?
The researchers also compared blood plasma levels of duloxetine, in eight human patients with neuropathic pain who reported partial pain relief after chronic treatment with the antidepressant, to plasma levels seen in the mice.

They found comparable levels, which suggests that antidepressant drugs may be working in a similar fashion in people. Barrot hopes to do future work to identify patients with chronic neuropathic pain who are most likely to respond to antidepressant treatment.

“Right now, these drugs only work in one out of two neuropathic pain patients,” he said. “Clinically, we don’t yet know which patients will respond to antidepressants. But if biomarkers [objective, measureable indicators] of susceptibility to treatment could be identified, such as neuroinflammatory ones, that may help in treatment choice.”

Meanwhile, Micó said that the new findings should strengthen the conviction amongst doctors and patients that antidepressants are “a real analgesic” as well as a worthy alternative to opioid drugs.

“This can help clinicians understand that there are other options,” according to Micó. “This could also help reduce consumption of opioids in chronic pain patients and, as a consequence, reduce tolerance and dependence. That’s a good thing.”

Kayt Sukel is a freelance writer based outside Houston, Texas.

This story first appeared on the Pain Research Forum and has been adapted for RELIEF.