Chronic pain: Why it persists, even after the underlying cause has disappeared
Some types of pain—caused by an accident, a fall, or surgery—disappear as the body heals. Others do not. In a study published in the prestigious journal *Nature Communications* on March 12, our team shed some light on the mystery surrounding the origins of chronic pain. And paved the way for a potential treatment.
Jean Valmier, University of Montpellier and Cyril Rivat, National Institute of Health and Medical Research (Inserm)
Toa Heftiba/Unsplash
Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. There is not just one type of pain, but many. They can be distinguished based on various criteria, including their duration. Acute pain—which is short-lived—is thus contrasted with chronic pain, which has been present for 3 to 6 months.
Acute pain is a defense and protective mechanism for the individual, prompting behaviors aimed at addressing the cause of the pain in order to alleviate it. In this way, it promotes the survival of both the individual and the species.
Chronic pain, on the other hand, no longer serves as a warning signal. Worse still, it becomes a chronic condition in its own right. Just as acute pain has a protective effect for the individual, chronic pain leads to a harmful pathological condition when it persists over time. Chronic pain is very common: 20% of European adults suffer from it, according to a a study published in 2008 in the journal *Pain*. Since the incidence increases significantly with age, we can expect the number of patients to rise as the population ages.
Absenteeism, depression… a significant cost to society
Chronic pain has harmful physical, psychological, and social consequences. It leads to hospitalizations, absenteeism from work, and depression. The cost to society is considerable. It is estimated at $630 billion per year in the United States, more than the combined costs of cardiovascular disease and cancer.
Clinicians classify chronic pain into three categories. The first involves inflammatory pain, which is triggered by tissue damage and the subsequent inflammatory response to that damage.
The second category is neuropathic pain, resulting from damage to the nervous system. This can be caused by accidental trauma, surgery, diabetes, shingles, carpal tunnel syndrome, or cancer treatment. This category also includes so-called “phantom limb” pain, which is pain felt as real in a limb (hand, arm, foot, or leg) even though it has been amputated.
The third category encompasses dysfunctional pain resulting from an amplification of pain signals, even though there is neither inflammation nor nerve damage. Fibromyalgia is an example of this—even though this condition remains poorly defined at present.
In chronic neuropathic pain, the initial cause has often disappeared, yet the person continues to suffer. For instance, healing is complete after surgery, or the infection has cleared up, or cancer treatment has been completed. The pain persists and then becomes a chronic condition, just like Parkinson’s disease or diabetes.
When pain becomes an illness
This concept of a “painful disease” is relatively recent. It is only about fifteen years old, which is a short time in the history of medicine. The major problem posed by this disease is the lack of appropriate treatments. Indeed, certain substances, such as morphine, are very effective, but they cannot be used long-term due to severe side effects.
Others are medications originally designed to treat a different condition, such as antidepressants and antiepileptics. But they remain largely ineffective: fewer than 50% of patients achieve a significant and lasting reduction in their pain, according to a European study published in 2006.
One of the reasons for the lack of effective treatments is, without a doubt, a lack of understanding of the biological mechanisms underlying chronic pain. As a result, we do not treat the cause of the painful condition but only its symptoms.
4 million French people suffer from chronic neuropathic pain
Among persistent pain conditions, neuropathic pain is the most resistant to current treatments. Four million French people suffer from it every day. The pain is triggered by nerve damage (caused by trauma, for example) and becomes persistent even after the initial cause has disappeared. What do we know about this mechanism, known as “sensitization” or “chronicization”?
This sensitization is caused by certain peripheral sensory neurons, such as those that innervate the skin. They detect and transmit the sensation of pain. These neurons become hyperactive and function abnormally over the long term. They transmit abnormal signals to the brain and persistently alter the functioning of the entire nervous system.
These neurons, known as somatosensory neurons, are located in the dorsal root ganglia of the spinal cord, that is, along the spine. They detect pain at the site of the injury (for example, where the person was stabbed) and transmit this information to neurons in the spinal cord. These neurons, in turn, communicate with the neural circuits responsible for pain perception within the brain.
Sensory neurons in a state of hyperexcitation
What causes somatosensory neurons to become sensitized? It is now clear that their interaction with the blood-based immune system is crucial. During trauma, immune cells in the blood invade the site of the nerve injury. In this area, they secrete numerous molecules that facilitate tissue repair but also lead to “hyperexcitation” of sensory neurons.
Identifying these molecules and understanding how they act is a major challenge for researchers worldwide. Our team at the Institute of Neurosciences at the University of Montpellier is making progress in this area. In research published in Nature Communications, we show that immune cells secrete the cytokine “FL,” causing neuropathic pain to become chronic.
Injecting this molecule into healthy rodents indeed leads to the development of symptoms identical to those observed in humans. We observe hyperalgesia—that is, amplified pain sensations—and allodynia—that is, pain sensations in response to stimuli that are normally not painful. We have also established that FL binds to its FLT3 receptor located in the sensory neuron; and that this binding between FL and FLT3 triggers the cascade of events leading to chronic pain.
Next, we blocked the action of FLT3 by inactivating the FLT3 gene in various ways in mice with neuropathic pain. This inhibition of FLT3 eliminates pain in the animals, and does so in a lasting manner. Furthermore, it restores the molecular dysregulation of the somatosensory system induced by the painful condition.
In Search of a Future Drug
The mechanism, therefore, had been identified. The challenge now was to find a way to address the phenomenon. Currently, the only molecules that inhibit FLT3 activation are used to treat blood disorders, specifically acute myeloid leukemia. However, they cannot be administered long-term due to severe side effects.
The team of chemists led by Didier Rognan at the University of Strasbourg used computer simulations to screen three million possible configurations for a future active drug. The researchers identified an anti-FLT3 molecule, named BDT001, that targets the FL binding site. This molecule blocks the binding between FL and FLT3, thereby preventing the chain of events leading to neuropathic pain from occurring.
When administered to animal models, the compound BDT001 reduces neuropathic pain symptoms within three hours. The effect persists for 48 hours after a single dose.
Before it can become a fully-fledged drug, the BDT001 molecule must still go through several stages that will take at least five years. Its ability to prevent the chronicization of pain in humans still needs to be studied. This development is being led by the startup Biodol Therapeutics, based in Clapiers in the Hérault region. The company could thus develop the very first specific therapy for neuropathic pain and, ultimately, bring relief to many people.
This discovery is part of a series of new approaches, based on our understanding of pain disorders, that are expected to enable the treatment of neuropathic pain using new molecules—future medications. Other non-pharmacological treatments are also under development, some of which utilize electricity. This is particularly the case with the transcutaneous electrical stimulation, which targets the pain site using a low-voltage electrical current. The transcranial magnetic stimulation involves applying a magnetic field using magnets placed outside the skull. This technique painlessly modifies the electrical activity of the brain’s neurons. Finally, a wide range of complementary approaches are currently in use, such as acupuncture, sophrology, and hypnosis. The ultimate goal is to provide personalized care for each patient experiencing pain.
Jean Valmier, Professor of neuroscience, physician, researcher at Inserm, specialist in somesthesia, University of Montpellier and Cyril Rivat, Associate Professor of Neuroscience at the University of Montpellier, researcher, National Institute of Health and Medical Research (Inserm)
The original version This article was published on The Conversation.