Pain is said to be the cause of nearly two-thirds of medical appointments, and is thus the subject of numerous studies, both fundamental and clinical in nature. This particularly active research is vital in order to have a more accurate understanding of the mechanisms at play in pain, and thus to develop new treatments.
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According to the official definition of the International Association for the Study of Pain (IASP), "pain is an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of such damage".
Since pain is therefore primarily based on the patient's perception, it is difficult to quantify and qualify. Furthermore, it is not automatically associated with injury, a characteristic which makes its exploration even more complex.
From hand to brain, the pain signaling pathway
The pain signaling pathway in the body can nonetheless be described, using the example of acute pain caused by inadvertently placing a hand on a hot oven ring: the burning sensation stimulates nerve endings, located on the skin in this case, but also found in other types of tissue (muscles, joints, organs, etc.). This information will then spread along the nociceptive nerves reaching the spinal cord, then the brain.
It is only on reaching the brain that the signal is identified as pain and we experience the pain sensation. However, even before this pain signal is deciphered, the hand recoils from the heat source due to a reflex arc located in the spinal cord. This is also where the first pain modulation systems come into play. These involve the GABA neurotransmitter or endorphins, and reduce the perceived pain. Unfortunately, under certain conditions, other endogenous systems may conversely exacerbate the pain signal.
Acute pain therefore acts as an alarm which enables the body to react and protect itself from a mechanical, chemical or thermal stimulus. However, when pain is chronic, this alarm mechanism is no longer justified: pain then becomes a disorder in its own right.
Congenital insensitivity to pain (CIP)
Very rare, congenital insensitivity to pain (CIP) is characterized by the absence, or very substantial reduction in the pain sensation, from birth. In most cases, this genetic disorder causes damage to the nerve fibers transmitting the pain signal. Analysis of the few cases of patients suffering from this disorder has allowed researchers to improve their understanding of normal pain, by elucidating the mechanisms for the absence of pain.
Inflammatory, neuropathic or mixed pain?
Two pain categories are usually distinguished, acute and chronic, according to their duration. Acute pain is intense, but often short-lived. This is the type of pain we experience when we cut our finger, for example. Pain is said to be chronic (or pathological), when the painful sensation lasts more than three months and becomes recurrent. This category includes certain types of muscular pain, migraines or even pain associated with nerve damage.
Different forms of pain may, moreover, be distinguished according to the physiological mechanisms brought into play:
- inflammatory pain, which covers all pain associated with inflammatory phenomena (this usually involves joint pain),
- neuropathic pain, associated with peripheral and central nervous system damage (spinal cord or sciatic nerve damage, etc.),
- mixed pain, which include both an inflammatory component and a neuropathic component, such as lumbago-sciatica. This pain is often encountered in cancer or after surgery.
In certain cases, such as fibromyalgia, irritable bowel syndrome, no damage (inflammatory or neurological) can be identified: the mechanisms for this type of pain are still unclear. The term dysfunctional pain has been proposed to describe this type of pain, which could be related to dysfunction of the endogenous pain modulation systems.
Pain and its context
Pain is subjective: its perception can be extremely different from one individual to another, but also in a given individual, depending on their environment. These variations are explained by the close relationship between pain and the psychosocial context. Brain imaging has shown that the brain centers responsible for pain perception are closely related to the emotion centers. This relationship has also been evidenced by studies showing that an individual who is distracted will perceive pain to a lesser extent than an individual who is focused on the painful event.
Nearly 30% of the population suffer from chronic pain
According to a vast French study conducted among 30,155 individuals representative of the general population, chronic pain affects approximately 30% of adults. This incidence increases with age. In two-thirds of cases, pain intensity is moderate to severe. It affects women to a greater extent, and less privileged socioprofessional categories. Neuropathic pain affects nearly 7% of the French population, peaking between the age of 50 and 64 years. This type of pain mainly affects individuals with manual occupations, living in a rural setting.
The types of pain reported mainly affect the back, neck, shoulders, limbs, head and abdomen. Pain is often associated with depression, anxiety, sleep disorders, and deterioration in quality of life. Owing to this impact and the resulting burden on the healthcare system, pain has a high socioeconomic cost.
Migraine, a typical case of pain
Nearly 11 million individuals in France suffer from migraines, approximately 15% of women and 7% of men. This disorder causes recurrent attacks, which are often intolerable, lasting from a few hours to several days. Researchers have evidenced a number of risk factors, mainly genetic, and have a better insight into the mechanisms involved. Although the trigger factors for these attacks are still unclear, effective medications have now been discovered: triptans.
Inflammatory pain is now effectively managed using reference analgesics: paracetamol, aspirin, or even morphine and its derivatives for the most persistent refractory pain. These medications, effective on acute pain, have significant side effects (gastric and renal disorders, morphine tolerance and dependence, etc.), when used long term.
Neuropathic pain, usually related to nervous system damage, responds very poorly to the above analgesics, except for certain opioids. However, these cannot be used for chronic pain due to their long-term side effects. Therefore, the main treatments currently used are antidepressants, together with antiepileptic drugs. These two types of medications have fewer undesirable effects. However, their efficacy is only moderate, observed in only around 50% of patients. It is therefore essential to identify other treatment avenues.
Acupuncture, relaxation, sophrology or even hypnosis: numerous non-medicinal approaches now play an important role in pain treatment centers. In certain patients, these methods are sometimes able to reduce medication use.
Electrical spinal cord stimulation has, moreover, been used for several years in patients suffering from radiculopathy, particularly chronic lumbago-sciatica. This technique involves implanting electrodes along the dura mater, a membrane which surrounds the spinal cord. These are connected to a stimulator, implanted under the patient's skin on the abdomen. The system is controlled by an external device, which allows the patient to trigger stimulation when pain increases. This stimulation blurs the pain signal and reduces its intensity.
Measurement of pain
Although pain is subjective being based on personal perception, a number of tools are available to characterize and evaluate pain. Pain scales and questionnaires are used to describe the symptoms, measure intensity and impact on quality of life. For adults, the most widely used scale is the numerical rating scale, graduated from 0 for "no pain", to 10 for "worst pain imaginable". For children, physicians often use a scale depicting facial expressions. For neuropathic pain, two scales - developed in France but applied internationally - are used to diagnose this type of pain (DN4) and evaluate pain intensity (NPSI), respectively. These tools help medical teams to adapt treatment.
Challenges facing research
Research into pain is highly active. In France, the Inserm Pain Research Network brings together approximately thirty teams based on both fundamental and clinical research themes.
A better understanding
Major progress in understanding pain has been achieved in recent years, particularly concerning the mechanisms at play in chronic pain.
Hence, pain has been shown to be not solely neuronal: glial cells in the central nervous system and certain immune cells are also involved in the onset of pain, particularly neuropathic pain. If certain glial functions are impaired, these cells secrete substances (gliotransmitters) which stimulate sensory neurons and exacerbate pain.
The discovery of the central and peripheral sensitization phenomenon has, moreover, shed more light on the fact that hypersensitivity to pain develops further to surgery or nerve damage, which can sometimes persist for long periods. This partly explains why the perception of subsequent painful events may be exacerbated in certain patients.
Brain imaging techniques, particularly functional MRI (fMRI), have undeniably been a major milestone in pain research. Thanks to these techniques, pain can now be identified, visualized, and, indeed, quantified in the brain. The close relationship between pain and emotion in particular can now be translated into images.
Expanding the armamentarium
Other teams are attempting to broaden the armamentarium:
In Clermont-Ferrand, the team led by Alain Eschalier (Inserm Unit 1107) analyzed the action mechanisms of existing treatments, to identify new mechanisms and new targets. The objective: to develop more potent and/or better tolerated analgesics. These researchers notably evidenced the action of paracetamol, first over-activating TRPV1 receptors, then inhibiting central Cav3.2 calcium channels. Blocking these channels is said to be of interest in potentiating the analgesic effect of the medicinal product. The team also studied morphine: these studies showed that its analgesic effect and undesirable effects (nausea, vomiting, risk of dependence, etc.) are separate and follow different biological pathways. By exclusively activating the pathway associated with the analgesic effect (involving a TREK-1 channel), researchers are attempting to develop an analgesic as potent as morphine, but devoid of its undesirable effects.
At the Molecular and Cell Pharmacology Institute (Sophia-Antipolis), another team is inspired by natural molecules: By screening toxins secreted by plants or animals, researchers have discovered two toxins in Mamba snake venom capable of strongly inhibiting the receptors involved in the pain sensation (ASICs receptors). These molecules are said to be as potent as morphine, but devoid of its undesirable effects. They refer to these toxins as mambalgins and are currently working on synthesizing derivatives which are as effective and non-toxic.
Other teams are working on endogenous morphines: enkephalins. These molecules, naturally secreted by the body in the event of pain, have an analgesic effect. Researchers have shown that, by inhibiting their degradation, pain was reduced. Their strategy is thus based on the administration of mixed enkephalinase inhibitors (DENKIs), responsible for degrading enkephalins. A medicinal product able to be orally administered, based on this approach, is currently in development, for the treatment of chronic neuropathic pain associated with diabetes. A start-up (Pharmaleads) is currently conducting a phase II clinical trial in France, the United Kingdom and Bulgaria, to evaluate its efficacy and safety.
Botulism toxin has also begun to establish its role in the range of agents used to fight peripheral pain. In addition to its muscle-relaxant effect, a number of studies have shown that it relieves pain by acting on sensory nerve fibers. Subcutaneous injection, into properly identified painful sites, procures effective pain relief in certain patients. Moreover, researchers have shown that repeated injections of the toxin allow the analgesic effect to persist for six months, without any noteworthy undesirable effects. Researchers are now attempting to identify patients who respond to this treatment.
Aiming for tailored management
Numerous studies aim to tailor pain treatment, by identifying patients who respond well to a given treatment, whether for existing medications or those in development. Biological, genetic and clinical markers for response are being investigated with this aim in mind: these will make it possible to avoid not only needlessly treating certain patients with an agent which is ineffective in their case, but also to examine sub-groups of patients responding to a new therapeutic approach. To date, the (predominantly clinical) markers identified are, for instance, used to determine whether a patient suffering from neuropathic pain should benefit from antidepressant or antiepileptic treatment. These markers are taken from the results of psychophysical tests which enable a highly in-depth evaluation of symptoms, in order to differentiate between patient sub-types a priori presenting a specific type of pain. Along these lines, the European DOLORisk project aims to identify the risk factors and decisive factors for neuropathic pain, so as to identify the most vulnerable patients and develop new tailored treatments.
Other teams are working on the development of non-medicinal strategies, notably transcranial magnetic stimulation, used for severe pain resistant to treatment. This technique is being developed as an alternative to central electrical stimulation, which can be effective, but requires electrodes to be implanted in the brain. Magnetic stimulation is non-invasive and devoid of undesirable effects: a coil placed on the patient's scalp emits a targeted magnetic field, which is able to modify nerve transmissions in pain control areas. The idea is thus to improve the function of this control.
This technique has been in routine use at Assistance Publique-Hôpitaux de Paris (AP-HP) since 2014. Researchers from Hôpital Ambroise-Paré (Boulogne-Billancourt) and Hôpital Henri-Mondor (Créteil) showed that this approach is able to achieve a durable analgesic effect over six months, in female patients suffering from fibromyalgia. The protocol used comprised an induction phase based on ten sessions over two weeks, followed by a maintenance phase of one session per month. This relieves pain in approximately two-thirds of eligible patients. Transcranial magnetic stimulation is also the subject of a vast clinical study, TRANSNEP, in the treatment of neuropathic pain. The objective of this study is to compare the effect of stimulation of two areas of the brain, the prefrontal cortex and motor cortex. Four university hospitals are taking part: Boulogne-Billancourt, Créteil, Nantes and Saint-Étienne. The initial results are expected by the end of 2017.