Chronic pain: why it persists, even when the cause has disappeared
Some pain, caused by an accident, a fall, or surgery, disappears as the body heals. Other pain does not. In a study published in the prestigious journal Nature Communications on March 12, our team shed some light on the mystery surrounding the origin of chronic pain. And paved the way for a possible 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 according to various criteria, including their duration. Acute pain—short-lasting—is thus opposed to chronic pain, which has been present for 3 to 6 months.
Acute pain is a defense and protection mechanism for the individual, generating behaviors whose purpose is to act on the cause of the pain in order to reduce it. Thus, it promotes the survival of the individual and the species.
Chronic pain, on the other hand, no longer serves as a warning signal. Worse still, it becomes a chronic disease in itself. While 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 study published in 2008 in the journal PainAs the frequency increases significantly with age, we can predict an increase in the number of patients as the population ages.
Absenteeism, depression... a considerable cost to society
Chronic pain has harmful physical, psychological, and social consequences. It leads to hospitalizations, absenteeism from work, and depression. Its 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 category is inflammatory pain, which is triggered by tissue damage and the inflammatory response to that damage.
The second category is neuropathic pain, which is caused by 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 "phantom limb" pain, which is pain that feels real in a limb (hand, arm, foot, or leg) that has been amputated.
The third category includes dysfunctional pain, which is caused by an amplification of pain signals, even though there is no inflammation or nerve damage. Fibromyalgia is one example, although this condition remains poorly defined.
In chronic neuropathic pain, the initial cause has often disappeared, yet the person continues to suffer. For example, healing may be complete after surgery, the infection may be cured, or cancer treatment may be finished. The pain persists and 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 not long in medical terms. The main problem with this disease is the lack of suitable treatments. Certain substances such as morphine are very effective, but cannot be used long-term due to their significant side effects.
Others are drugs originally designed to treat other diseases, such as antidepressants and anti-epileptics. However, they remain ineffective: less than 50% of patients achieve a significant and lasting reduction in pain, according to a European study published in 2006.
One of the reasons for the lack of effective treatment is undoubtedly the lack of understanding of the biological mechanisms underlying chronic pain. As a result, the cause of the painful disease is not treated, 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 (during trauma, for example) and becomes persistent 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 a long period of time. 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, i.e., 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 of 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 immune defense system in the blood is crucial. When trauma occurs, immune cells in the blood invade the site of the nerve injury. In this area, they secrete numerous molecules that repair the tissue but also cause "hyperexcitation" of the sensory neurons.
Identifying these molecules and how they work is a major challenge for researchers around the world. Our team at the Institute of Neuroscience at the University of Montpellier is making progress in this area. In work 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 leads to the development of symptoms identical to those observed in humans. We observe hyperalgesia, i.e., amplified pain sensations, and allodynia, i.e., pain sensations in response to stimuli that are not normally 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 that leads to chronicity.
We then blocked the action of FLT3 by invalidating the FLT3 gene in various ways in mice with neuropathic pain. This blocking of FLT3 eliminated the animals' pain on a lasting basis. It also restored the molecular imbalances in the somatosensory system caused by the painful condition.
In search of a future drug
The mechanism had therefore been identified. The next step was to find a way to act on the phenomenon. Currently, the only molecules that inhibit FLT3 activation are used in blood diseases, such as acute myeloid leukemia. However, they cannot be administered over the long term due to serious side effects.
The team of chemists led by Didier Rognan at the University of Strasbourg used computer modeling to sift through 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 events that lead to neuropathic pain from occurring.
When administered to animal models, the molecule BDT001 reduces neuropathic pain symptoms within three hours. The effect persists for 48 hours after a single administration.
Before becoming a fully-fledged drug, the BDT001 molecule will still have to go through several stages that will take at least five years. Its effect on preventing pain from becoming chronic in humans still needs to be studied. This development is being carried out by the start-up Biodol Therapeutics, based in Clapiers in the Hérault region of France. The company could thus develop the very first specific therapy for neuropathic pain and, ultimately, bring relief to many people.
This discovery is one of a number of new avenues, based on an understanding of painful conditions, which should enable neuropathic pain to be treated using new molecules—future drugs. Other non-drug treatments are also being developed, some of which use electricity. This is particularly the case with transcutaneous electrical stimulation, which acts on the site of pain using a low-voltage electrical current. The transcranial magnetic stimulation consists of applying a magnetic field using magnets placed outside the skull. This technique painlessly modifies the electrical activity of neurons in the brain. Finally, a number of complementary approaches are currently used, such as acupuncture, sophrology, and hypnosis. The ultimate goal is to provide personalized care for each patient suffering from pain.
Jean ValmierProfessor of neuroscience, physician, researcher at Inserm, specialist in somesthesia, University of Montpellier and Cyril RivatAssociate Professor of Neuroscience at the University of Montpellier, researcher, National Institute of Health and Medical Research (Inserm)
The original version of this article was published on The Conversation.