Stopping the Transition to Chronic Pain

The brain's limbic system plays a key role in chronic pain.

At NeuPSIG 2019, plenary speaker A. Vania Apkarian showed that it’s possible to identify and treat those who are at risk of developing chronic pain by targeting the brain’s limbic system. Image: A depiction of the limbic system. Credit: Joshua Abbas/123RF Stock Photo.

Editor’s Note: Seven early-career pain researchers took part in the Pain Research Forum (PRF) Correspondents program during the 7th International Congress on Neuropathic Pain (NeuPSIG 2019), which took place May 9-11, 2019, in London, UK. This unique science communications training program provides participants with knowledge and skills needed to communicate science effectively to a wide range of pain researchers and to patients and the broader public. Here, PRF Correspondent Danielle Perro, a DPhil candidate at the University of Oxford, UK, summarizes a plenary lecture at the meeting by A. Vania Apkarian, a pain researcher at Northwestern University in Chicago.

Acute pain is something that everyone has experienced—and that’s actually a good thing. This is because acute pain from spraining an ankle or touching a hot stove, for instance, serves as a protective mechanism, telling us to take care of ourselves and not overdo it until the injury heals. But acute pain is short-lived, typically lasting only for the duration of the injury that evoked it; as the injury gets better, the pain subsides.

Chronic pain, on the other hand, lasts long after the injury has healed. There is still no agreement within the scientific community about how long the pain should last in order to be deemed “chronic.” In addition, while pain researchers are making great progress towards understanding what happens in the nervous system during chronic pain, there is still an enormous amount to learn. And, for the roughly 20% of the worldwide population that experiences chronic pain, current treatments often don’t work or have serious negative side effects.

This was the backdrop that A. Vania Apkarian, a pain researcher at Northwestern University, Feinberg School of Medicine, Chicago, US, set forth during his plenary lecture at NeuPSIG 2019, a meeting of the International Association for the Study of Pain (IASP) Neuropathic Pain Special Interest Group. It set the stage for his discussion of research from his group, whose goal is to improve the challenging landscape of chronic pain by identifying pain biomarkers—objective measures that could indicate, for instance, who is most at risk of developing chronic pain—and to use those biomarkers to develop new treatment approaches.

The take-home message of his talk was that the brain’s limbic system—a network of brain structures that contribute to emotion and learning— plays a key role in the response to a painful event, and that changes in this system could potentially serve as a pain biomarker to identify who is at risk of developing chronic pain. And, he described recent clinical trial results showing it’s possible to prevent the transition to chronic pain by using drugs that target these alterations in the limbic system that occur during the setting of pain.

The road to chronic pain goes through the brain
Apkarian began by outlining four stages on the way to chronic pain. In the first stage, certain people have a predisposition to developing chronic pain. In those individuals, after an injury (the second stage) occurs, there is a transition period (stage three) after which pain is maintained (stage four). The end result is chronic pain that, unlike acute pain, no longer serves a useful purpose.

Apkarian explained that, traditionally, each of these stages of chronic pain was explained solely by nociceptive circuitry. Here, he was referring to the nervous system pathway in which neurons called nociceptors, which are found in the skin, muscle and internal organs, detect and relay information about potentially harmful stimuli—think of that hot stove, for instance—into the spinal cord.

However, Apkarian proposed that the development of chronic pain is better explained by looking to the brain, in particular its limbic system, which includes brain structures responsible for emotions, motivation, behavior and memory. Activity in this system, Apkarian believes, defines the predisposition and transition to chronic pain; when pain becomes chronic, the structure and function of limbic regions of the brain change. The limbic system is particularly important in controlling the emotions that we attach to pain and how those emotions affect what we learn from painful experiences.

Considering this, Apkarian’s group has recognized a need to examine the brain in order to identify pain biomarkers. His talk was especially focused on changes in brain activity in the limbic system that could be used as biomarkers to predict the transition to chronic pain.

Learning from animals about the nucleus accumbens, dopamine and pain
Researchers like Apkarian who do human studies also do experiments in animals, especially in rodents. This is because using mice and rats allows pain investigators to more easily study what happens in the nervous system, at the cellular and molecular level, during chronic pain.

Rodents are good model organisms for the study of pain because they have brain structures similar to those in people. This includes the nucleus accumbens (NAc), a key structure in the limbic system, and the medial prefrontal cortex (mPFC), a region towards the front of the brain that receives information from the NAc.

In a human brain imaging study, Apkarian and his colleagues showed that functional connectivity (the tendency of certain brain areas to activate together) between the NAc and mPFC predicted, with 80% accuracy, whether patients with subacute (lasting for weeks) back pain would go on to develop chronic back pain.

To learn more about the role of the NAc in pain becoming chronic, Apkarian’s team then turned to a nerve injury model of pain in rodents. Here, a nerve is experimentally injured, causing the animals to show features such as tactile allodynia—when a normally innocuous light touch becomes painful—just as people with nerve injury do.

The researchers have found that limbic regions of the brain in rats and mice with nerve injury show changes in the activity and shape of neurons in a particular region of the NAc. The investigators also saw that levels of dopamine, a brain chemical that regulates reward behavior, was lower in nerve-injured mice, compared to mice without nerve injury.

Given those findings, Apkarian tested whether, by increasing levels of dopamine in the NAc by administering a drug called L-dopa, which is a precursor to dopamine, along with using naproxen (a type of pain reliever called a non-steroidal anti-inflammatory drug, or NSAID), could ease pain in the animals with nerve injury. Apkarian and his group indeed found that treatment with L-dopa in combination with naproxen improved the nerve-injured animals’ tactile allodynia. In contrast, only using L-dopa, or only giving the animals naproxen, had little effect.

Interestingly, other researchers have found sex differences in dopamine levels in the ventral striatum (a brain structure that includes the NAc). In particular, in 2006, a study in healthy adults found that men made more dopamine in the ventral striatum under certain experimental conditions than women did.

From animals to a human clinical trial
Based on these earlier findings in animals, Apkarian and his colleagues recently designed a clinical trial in people to answer two questions. First, could treatment that increases levels of dopamine, in combination with an NSAID, prevent the transition from sub-acute back pain to chronic back pain? Second, would the effects of this treatment approach be different in men vs. women?

For this human study, the researchers recruited 125 people with subacute back pain and used brain imaging to determine which patients were at highest risk to transition to chronic pain—a brain biomarker approach.

Then, for those identified as high-risk patients, the researchers gave some of those individuals medication that increases levels of dopamine (called Sinemet), along with naproxen. Others received a placebo plus naproxen, over the course of 12 weeks. Those at low risk did not receive treatment and were simply observed throughout the study. Participants rated how intense their pain was, three times per day, over the course of six months.

The researchers saw that, compared to those who received no treatment, those who received treatment reported less pain. This was true for those who received the medication that increases dopamine plus naproxen, and for those who received a placebo plus naproxen.

Interestingly, as predicted, the researchers observed differences when looking specifically at what happened in men vs. women rather than at the entire study group. In this instance, women reported full pain relief from both treatments (Sinemet plus naproxen), whereas men did not. In men, naproxen alone was better in blocking the transition to chronic pain.

Results from the trial have been made available on ClinicalTrials.gov.

While larger studies that replicate these initial findings are needed, the results support Apkarian’s view that what’s happening in the brain’s limbic system could serve as a biomarker for who is at risk of transitioning to chronic pain. They also bulwark the hypothesis that this system is amenable to treatment—that the likelihood of transitioning to chronic pain can be lowered with therapies that change activity in limbic regions of the brain. This will improve the emotional response to pain and what we learn from the pain experience.

Danielle Perro is a DPhil candidate at the University of Oxford, UK.