Addressing Neuropathic Pain

By general concept, pain is a useful adaptive mechanism that protects us, not a nightmare. Sometimes, however, the mechanism does not work properly. Forty percent of people with spinal cord injury will develop neuropathic pain, a multi-symptom pain, which may be perceived as a burning, persistent or unpleasant sensation, localized to areas of the body where motor control or sensation has been lost.

It may be moderate or severe and interfere with activities of daily living and physical functioning, including, in addition:

  • Sleep disturbances.
  • Anxiety symptoms.
  • Depression.

These symptoms can impact, over time, on the perception of psychological well-being and quality of life.

Although many advances have been made in the understanding of the neurophysiological mechanisms involved in the onset of this pain, as well as in the development of new pharmacological treatments, its proper management continues to be a common problem for many health professionals.

Several pharmacological treatments are available, but their total eradication is rarely achieved, so the main goal of treatment is to modify its intensity to a more tolerable level. In addition, numerous studies have published that available medications only provide 50% pain relief 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 injury. The scientific literature on pain has for years investigated the problems associated with the reorganization of the nervous system after injury. An important part of these studies has focused on the contribution of mechanisms at the level of the spinal cord. However, if we review the publications related to therapies aimed at relieving pain, using local anesthetics or surgical interventions targeting the spinal cord and periphery, the results are inconsistent and relatively poor. These difficulties have suggested that there may also be mechanisms at the cerebral level that play a relevant role in this pain.

Causes of pain

Neuropathic pain is due to an injury to the nervous system due to a malfunction of the nervous system and is a dynamic process that cannot be easily explained by a single theory. In the last decade, numerous studies have described that, after 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 damage to a segment. The initial neuronal damage is only the beginning of a cascade of physiological and biochemical changes generated by ischemic or traumatic damage to the cord, which is reproduced at all levels of the nervous system and amplified as the neural pathway increases in size until it reaches the brain.

The brain is the most important organ of the central nervous system. Sensory stimuli corresponding to touch, pressure, pain or temperature that are registered on the surface of the body or inside the organism have to travel a long way to be perceived: the specific receptors that detect the stimuli (under the skin and distributed throughout 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 there are about 4 million receptors for pain sensation and 500,000 for pressure on the surface of the body. All signals from the sensory receptors throughout the body reach a specific area of the cerebral cortex, where they are processed and become conscious. For example, the touch signals from the entire skin surface of the left side of the body are represented in the right cerebral hemisphere, in a vertical ribbon of cortical tissue called the postcentral gyrus. This is a faithful representation of the entire surface of the body, almost as if there were a small person standing on the surface of the brain. This map is called homunculus. In reality, there are several maps at brain level but, for the sake of simplicity, we can assume that there is only one map called primary somatosensory cortex.

When, after a complete spinal cord injury or amputation, the brain stops receiving signals from sensory receptors, for example, from the legs or an arm, as illustrated in Figure 2, we say that the corresponding territory of the hand or legs in the sensory cortex is deafferentiated. As a consequence, the receptor fields of other adjacent body regions begin to invade the territory that has been left empty, which corresponded to the absent hand or legs affected by the lesion. In other words, the brain does not usually remain as it was before the injury, with unoccupied areas; it reorganizes itself to continue providing its functions. This capacity of the brain to change is called plasticity. It is a spontaneous characteristic 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.

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This capacity to reorganize at the neurological level has been demonstrated in numerous studies using neuroimaging techniques. In humans, cortical reorganization has been related to the presence of phantom sensations after amputation or spinal cord injury. We also have studies that have shown that neuropathic pain, following 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 papers illustrate the concept that cortical reorganization in response to injury is not always beneficial, providing the risk of changing inappropriately and perpetuating deficits. This reinforces the idea that strategies aimed at reversing this reorganization process may have therapeutic potential in addressing central neuropathic pain. This also points to the importance of acting at the cerebral level even if the origin 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 spinal cord injury. In the research work we carried out in our center, we demonstrated that this type of techniques can influence and reverse the abnormal reorganization that occurs after a spinal cord injury and improve the painful 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/she could see his/her body reflected from the waist up, while we projected the image of moving legs that perfectly matched the lower part of the reflected image. With this set-up, what the brain actually sees is the projection of healthy legs moving, recreating a visual illusion of the affected legs 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, the mental representation of the body as if the person could again feel that he/she is performing the tasks he/she did before the injury. Seeing oneself immersed in this type of stimulus creates a mental image, it leads the brain to experience the same changes as if it were performing it. We have to 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 doing what is imagined. So, just as acting or perceiving changes the brain, so thinking or imagining changes it. It is a way of rehabilitation, of reinforcing neuronal connections. The idea of applying it was not specifically to recover motor function, since this is not possible in these injuries, but to treat pain.

The following points should be highlighted about this technique: it is a non-invasive and painless technique; it does not present serious side effects; the analgesic effects of tDCS are cumulative, that is, the repetition of several tDCS sessions on consecutive days generates a greater effect on pain than a single application; and the modulatory effects of tDCS can be of long duration. However, this effect is not permanent and high variability in the duration of pain relief has been observed among individuals. To maintain long-term treatment benefits on chronic pain, tDCS treatment should be repeated. However, some patients benefit from the technique over a long period of time, as the pain intensity after the sessions may not return to the pre-treatment level. Finally, repeated application of the tDCS stimulation treatment does not result in “desensitization” (the effect observed with certain types of analgesic medication, such as opioids, where the analgesic effect may decrease with repeated use), indicating the potential of tDCS for repeated long-term use.

The results of our study showed that if we applied both techniques, visual illusion and tDCS, in combination, pain intensity was significantly reduced, pain interference with activities of daily living was significantly reduced, and their effects were maintained for about three to four weeks. And we detected no significant side effects, demonstrating the safety of both techniques.

In the end, these two combined neuromodulatory strategies are useful alternatives for targeting plasticity for therapeutic purposes. Non-invasive stimulation would increase cortical excitability, which translates into a state more prone to change, while the visual illusion would guide this reorganization favoring a more adaptive central sensory representation. These results have currently 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.