Chronic pain: why it persists even when the cause has disappeared
Some pains, caused by an accident, a fall or surgery, disappear with recovery. Others don't. In a study published in the prestigious journal Nature Communications on March 12, our team has lifted some of the mystery surrounding the origin of chronic pain. And opened the way to a possible treatment.
Jean Valmier, University of Montpellier and Cyril Rivat, French National Institute for 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 one kind of pain, but many. They can be distinguished according to various criteria, including their duration. Acute pain - of short duration - 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 to see it diminish. In this way, it promotes the survival of the individual and the species.
Chronic pain, on the other hand, is no longer a warning sign. Worse still, they become chronic illnesses in their own right. Just as pain has a protective effect on the individual when it is acute, so it leads to a deleterious pathological state when it settles in over time. Chronic pain is very common: 20% of European adults suffer from it, according to an study published in 2008 in Pain magazine. As the frequency increases 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 hospitalization, absenteeism from work and depression. The cost to society is considerable. It is estimated at 630 billion dollars a year in the United States, more than the combined costs of cardiovascular disease and cancer.
Clinicians classify chronic pain into three categories. The first is inflammatory pain, triggered by tissue aggression, and the inflammatory response secondary to this aggression.
The second category is neuropathic pain, caused by damage to the nervous system. This can be caused by accidental trauma, surgery, diabetes, shingles, carpal tunnel syndrome or cancer treatment. Also included in this category is "phantom limb" pain, which is felt as real in a limb (hand, arm, foot or leg) even though it has been amputated.
The third category is dysfunctional pain, where pain signals are amplified even though there is no inflammation or nerve damage. Fibromyalgia is a case in point - even if the disease remains poorly defined at present.
In chronic neuropathic pain, the initial cause has often disappeared, yet the person continues to suffer. For example, healing is complete after an operation, or an infection has been cured, or anti-cancer treatment has been completed. The pain persists and becomes a chronic illness, like Parkinson's disease or diabetes.
When pain becomes a disease
This concept of a "painful disease" is relatively recent. It is only about fifteen years old, which is not very long in medical terms. The major problem with this disease is the absence of suitable treatments. Some substances, such as morphine, are highly effective, but it is impossible to use them on a long-term basis, as the side effects are too severe.
Others, such as antidepressants and anti-epileptics, were originally designed to treat another disease. But these are not very effective: according to a European study published in 2006, less than 50% of patients achieve a significant and lasting reduction in their pain.
One of the reasons for the lack of effective therapies is undoubtedly a lack of understanding of the biological mechanisms underlying chronic pain. As a result, we do not treat the cause of the painful disease, but only its symptoms.
4 million French suffer from chronic neuropathic pain
Among persistent pain types, neuropathic pain is the most resistant to current treatments. Four million French people suffer from it every day. Pain is triggered by nerve damage (during trauma, for example) and becomes persistent once the initial cause has disappeared. What do we know about this mechanism, known as "sensitization" or "chronicization"?
This sensitization is due to certain peripheral sensory neurons, such as those innervating the skin. They detect and convey the sensation of pain. These neurons become hyperactive and function in a persistently aberrant way. They transmit abnormal signals to the brain, persistently modifying the functioning of the entire nervous system.
These so-called somato-sensory neurons are located in the dorsal root ganglia of the spinal cord, i.e. along the spinal column. They detect pain at the site of injury (for example, where the person has been stabbed) and transmit this information to neurons in the spinal cord. These in turn communicate with the neural circuits of pain perception within the brain.
Hyperexcited sensory neurons
What causes sensitization of somato-sensory neurons? It is now clear that their interaction with the blood immune defense system is crucial. During trauma, immune cells in the blood invade the site of nerve damage. In this area, they secrete numerous molecules which not only repair the tissue, but also "hyperexcite" sensory neurons.
Identifying these molecules and how they act is a major challenge for researchers worldwide. 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 chronic neuropathic pain.
Injecting this molecule into healthy rodents leads to the development of symptoms identical to those observed in humans. These include hyperalgesia, i.e. amplified pain sensations, and allodynia, i.e. painful sensations to stimuli that are not normally painful. We 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 at the origin of chronicization.
Next, we blocked the action of FLT3 by invalidating the FLT3 gene in different ways, in mice with neuropathic pain. This FLT3 blockade removes pain in the animal, and does so in a lasting way. It also restores the molecular disturbances in the somato-sensory system induced by the pain disease.
In search of a future drug
The mechanism had been identified. All that remained was to find a way of acting on the phenomenon. At present, the only molecules inhibiting FLT3 activation are used in acute myeloid leukemia, a blood disease. However, they cannot be administered on a long-term basis, as their side-effects are too severe.
A team of chemists led by Didier Rognan at the University of Strasbourg has computer-assisted screened three million possible configurations for a future active drug. The researchers identified an anti-FLT3 molecule, named BDT001, targeting the FL binding site. This molecule blocks the binding between FL and FLT3, thus preventing the events leading to neuropathic pain from occurring in sequence.
When administered to animal models, BDT001 reduced neuropathic pain symptoms within three hours. The effect persisted for 48 hours after a single administration.
Before becoming a real drug, the BDT001 molecule will have to go through several stages which will take at least 5 years. Its "anti-chronicizing" effect on pain in humans remains to be studied. This development is being undertaken 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 part of a series of new avenues, based on an understanding of the painful disease, which should make it possible to treat neuropathic pain with new molecules - future drugs. Other non-drug treatments are also being developed, some of them using electricity. These include transcutaneous electrical stimulationwhich acts on the site of pain thanks to a weak electric current. The transcranial magnetic stimulation involves applying a magnetic field using magnets placed outside the skull. This technique painlessly alters the electrical activity of the brain's neurons. Finally, a large number of complementary approaches are currently used, such as acupuncture, sophrology and hypnosis. The ultimate aim is to provide personalized care for every pain patient.
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, French National Institute for Health and Medical Research (Inserm)
Visit original version of this article was published on The Conversation.