New therapeutic broach in neuropathic pain

As a rule, pain is a useful adaptive mechanism, a gift that protects us, not a nightmare. But sometimes the mechanism fails. 40% of people with spinal cord injury will develop neuropathic pain, a pain that presents a variety of symptoms and can be perceived as a burning sensation, persistent or lancinating, very unpleasant, often located in areas of the body where the motor control or sensitivity.

Neuropathic pain can be moderate or intense and interfere with activities of daily living and physical functioning, including sleep disturbances, anxiety and / or depression symptoms. These symptoms may affect, over time, the perception of psychological well-being and quality of life.

Although there has been progress in understanding the neurophysiological mechanisms involved in the onset of this pain, and in the development of new pharmacological treatments, its proper management continues to be a common problem for health services. There are a number of pharmacological treatments available, but pain control is difficult to achieve and rarely is complete eradication, with the main goal of treatment being to modify its intensity to a more tolerable level. Several studies have reported that the available medications alone provide relief in 50% of the pain to one-third of people with spinal cord injury and neuropathic pain.

The difficulty in managing this type of pain may be related, in part, to a lack of knowledge about how the nervous system reacts after an injury. The scientific literature on pain has investigated for years on the problems associated with the reorganization of the nervous system after an injury. An important part of these studies has focused on the contribution of mechanisms at the level of the spinal cord. However, reviewing publications related to pain-relieving therapies, using local anesthetics or surgical interventions for the spinal cord and periphery, the results are inconsistent and relatively poor. These difficulties have suggested that there may also be mechanisms at the brain level that play a relevant role in neuropathic pain.

Causes

Neuropathic pain is mainly due to an injury to the nervous system, to a malfunction of the nervous system and is a dynamic process that can not be explained by a single theory or single mechanism. In the last decade, numerous studies describe that after the spinal cord injury, important plastic changes occur not only at the level of the spinal cord itself, but also at the brain level, as the nervous system attempts to reorganize its functional circuits after the damage of a segment. The initial neuronal damage is only the beginning of a cascade of physiological and biochemical changes generated by ischemic or traumatic damage in the marrow, which reproduces at all levels of the nervous system and is amplified as the neural pathway increases size (see Figure 1) to the brain.

The brain is the most important organ of the central nervous system. Sensory stimuli corresponding to the touch, pressure, pain or temperature that are recorded on the surface of the body or inside the body have to go a long way to be perceived: the specific receptors that detect the stimuli (under the skin and distributed all over the body) generate nerve impulses that are transmitted through nerve fibers to the spinal cord and along specific pathways to the brain, where the sensations become conscious. It is estimated that, on the body surface, there are about 4 million receptors for the sensation of pain and 500,000 for the pressure. All signals from the sensory receptors of the whole body reach a specific area of ​​the cerebral cortex, where they are processed and become conscious. For example, the touch signals of the entire skin surface of the left side of the body are represented in the right cerebral hemisphere in a vertical cortical tissue called the postcentral gyrus. It is a faithful representation of the entire surface of the body, almost as if there were a small person placed on the surface of the brain. This map is called the homunculus (figure 2). In fact, there are several maps at the brain level but, to simplify, we can assume that there is only one map called the primary somatosensory cortex.

When, after a complete spinal cord injury or an amputation, the brain ceases to receive signals from the sensory receptors, eg from the legs or an arm, as shown in Figure 2, we say that the corresponding territory of the hand or legs in the sensory cortex is deferred. As a consequence, the receptor fields of other adjacent body regions begin to invade the territory that has been empty, which corresponded to the absent hand or legs affected by the injury. That is, the brain does not usually stay the same as before the injury, with unoccupied areas; reorganized to continue to perform its functions. This ability to change the brain is called plasticity. It is a spontaneous feature of the brain and supports the idea that plasticity is not an occasional state of the nervous system, but the normal state of the nervous system throughout life.

This ability to reorganize at the neurological level has been demonstrated, using neuroimaging techniques, in numerous works. In humans, cortical reorganization has been linked to the presence of phantom sensations after amputation or spinal cord injury. We also have papers that have demonstrated that neuropathic pain, after spinal cord injury or amputation, is related to changes in cortical somatosensory reorganization and that the magnitude of this reorganization corresponds to the presence and intensity of pain.

These works illustrate the concept that cortical reorganization in response to injury is not always beneficial, providing the risk of inadequate change and perpetuating deficits. This reinforces the idea that strategies aimed at reversing this reorganization process may have therapeutic potential in the management of central neuropathic pain. This also points to the importance of acting at the brain level although the source of the pain is at the spinal level.

For this reason, we decided to evaluate the analgesic effects of neuromodulatory therapies in patients with neuropathic pain associated with a spinal cord injury. In the research carried out in our center, we demonstrate that this type of techniques can influence and reverse the anomalous reorganization that occurs after a spinal cord injury and improve the pain symptomatology. We studied, on the one hand, the effect of a visual illusion strategy that consisted of placing the person in front of a mirror, in which he could see his body reflected from the waist up, while projecting the image of moving legs that they fit perfectly at the bottom of the reflected image. With this assembly in reality, what the brain sees is the projection of healthy legs moving, recreating a visual illusion of the legs affected in motion, which would be restoring in the person an integrated and coherent body image in the brain.

It is a visual trick that modifies, reshapes, mental representation of the body as if the person could again feel that he performs the tasks he did before the injury. Being immersed in this type of stimulus creates a mental image, leads the brain to experience the same changes as if it were doing it. We must consider that thinking is as important a brain activity as acting on the world or receiving stimuli from the world. We know that imagining activates the same brain circuits as when you do what you imagine. Then, just as acting or perceiving changes the brain, so too, thinking or imagining changes it. It is a way of rehabilitation, of reinforcing neural connections. The idea of ​​applying it was not specifically to recover the motor function, because in these injuries it is not possible, but to treat the pain.

In this same work, we also tried to evaluate the effectiveness of the non-invasive stimulation techniques in the motor cortex, namely transcranial direct current stimulation (tDCS). The tDCS is a non-invasive, painless method that applies a slight electric current to the scalp (through two electrodes covered by sponges) penetrating the skull to the brain. The exact mechanism of tDCS is not clear, but research has shown that it modifies the level of excitability in a group of brain areas related to pain processing. One reason for the modulation of cortical excitability is based on the evidence that patients with neuropathic pain develop changes in the somatosensory and motor cortex excitability and that normalization of these changes is associated with pain relief.

TDCS has been used in a variety of pain syndromes, including neuropathic pain after spinal cord injury, fibromyalgia, central pain after stroke, trigeminal neuralgia and other types of facial pain, and complex regional pain syndrome.

The main benefit of treatment is pain relief. However, some patients also report secondary benefits such as improved sleep, mood, daily activities, and decreased consumption of pain medication. Our experience indicates that about 66-70% of patients respond to tDCS, ie experience pain relief and / or secondary benefits after receiving treatment. The study and use of this experimental treatment is being developed in several countries highlighting its use in the United States and Germany, where it is currently used as a therapeutic option.

It is necessary to emphasize of this technique the following points: it is a technique noninvasive and not painful; no serious side effects; the analgesic effects of tDCS are cumulative, ie repetition of several sessions of tDCS on consecutive days generates a greater effect on pain than a single application; and the modulatory effects of tDCS may be long-lasting. However, this effect is not permanent and has been observed among individuals a high variability in the duration of pain relief. To maintain the benefits of long-term treatment over chronic pain, tDCS treatment should be repeated. However, some patients benefit from the technique over a long period of time, since the intensity of pain after the sessions may not return to the pre-treatment level. Finally, applying tDCS stimulation treatment several times does not result in "desensitization" (the effect observed in certain types of analgesic medication such as opiates, where the analgesic effect can be decreased with repeated use) , indicating the potential of tDCS for its repeated long-term use.

The results of our work showed that if we applied both techniques, visual illusion and tDCS, the intensity of the pain, the interference of pain in the activities of daily life were significantly reduced and their effects were maintained for about three or four weeks. And we did not detect significant side effects, demonstrating the safety of both techniques.

Our conclusion has been that these two neuromodulatory strategies, applied in combination, are useful alternatives to orient the plasticity with a therapeutic purpose. Noninvasive stimulation would increase cortical excitability, which translates into a more proclivity to change, whereas visual illusion would guide this reorganization favoring a more adaptive central sensory representation. These results have encouraged us to continue investigating the therapeutic potential of both techniques in different groups of patients, with the expectation that they may benefit from them in the near future.