Double Blind, Randomized, Placebo Controlled Clinical Trial to Evaluate the Efficacy of Repetitive Transcranial Magnetic Stimulation in Patients Victims of Landmines With Phantom Limb Pain

Background In 2007 Colombia was one of the five countries in the world with the highest number of anti-personnel landmine victims [1]. These are small devices designed to injure or kill people and animals by exploding when a minimum pressure is exerted on them (approximately 6 Force-Kg) [2]. Between 1999 and 2008 there were 6696 reported incidents with these artifacts in Colombia, partly due to an intensified civil war conflict in this period of time, however, it is estimated that the number of affected subjects might be higher due to underreporting [1]. This problem has had an enormous impact on Public Health in Colombia, aggravated by the fact that victims, often children or young adults, frequently suffer significant degrees of physical and psychological disabilities, leading to an increase in the number of healthy life years (DALYs) lost in our population, together with important secondary economic impacts [1-5]. Anderson et al [3] estimated that the quality of life is affected in 25 to 87% of families with a relative victim of a landmine.

Among the multiple physical and psychological disabilities and sequels derived from landmines [6-8], one of the most important consequences is the chronic neuropathic pain secondary to amputation. Ketz conducted a retrospective study among 30 soldiers wounded in combat, finding a prevalence of 77% of Phantom Limb Pain (PLP) after traumatic amputation [9]. The factors associated with development of neuropathic pain in these patients include central and peripheral phenomena [10-12]. The direct damage to the involved tissue produces inflammation, and in some cases infection which induces the release of several molecules, such as hydrogen, potassium and arachidonic acid, which in turn, activate and sensitize pain receptors, leading to exaggerated responses to any minimal painful stimuli [11]. Another proposed mechanism for the development of PLP is the fact that damaged peripheral nerve tissues grows into so-called "neuromas" [13, 14]. These have shown to express a greater density of sodium channels in their cell membranes, increasing the activity of peripheral nociceptors [15]. This increased activity leads to changes in the synaptic structure of neurons located in the dorsal horn of the spinal cord, increasing their excitability as well as reducing the frequency and intensity of their inhibitory processes [11, 16]. Besides spinal and peripheral changes, encephalic alterations have also been found [17-24]. Melzack introduced the neuromatrix theory, which suggested that pain is a multidimensional experience, which involves a large neural network that enables the integration and simultaneous processing of information from multiple peripheral receptors with the processed information permanently in these neural circuits, emphasizing the importance of central structures in all aspects of pain [25]. In addition, Merzenich et al [26] conducted a study in adult monkeys, finding that after amputation of a limb, the primary somatosensory cortex seems to rearrange itself in the cortical areas representing the amputated limb.

The high prevalence of PLP after amputation has led to major efforts in order to lessen the pain in affected patients. However, results using conventional medical treatment, including opiates, N-methyl-D-aspartate (NMDA) receptor antagonists and surgery, are poor, with an general efficacy rate of about 30%, not statistically better than placebo [20, 27-33]. Recently, it has been proposed that repetitive Transcranial Magnetic Stimulation (rTMS) can be an effective alternative in the treatment of neuropathic pain [34].

The rTMS is a non-invasive stimulation technique of the human brain that generates a small magnetic field of high intensity through a brief electrical current generated by a magnetic coil placed over the head of the individual [35, 36]. The electric currents induced in the cerebral cortex run in a parallel plane to the plane of the stimulation, in such a way that this stimulation affects mainly those brain elements of the cerebral cortex activating the pyramidal cells transinaptically (37). The use of high frequency rTMS (> 1Hz) raises the blood flow in the stimulated area, inducing an increased brain activity. On the other hand, low-frequency stimulation (<1 Hz) reduces brain activity [38, 39]. In addition to vascular changes, the rTMS may induce modifications in several hormonal axes and even in the production of neurotransmitters, such as dopamine serotonin, arginine, NMDA, taurine and aspartate [40-43]. Additionally it was found that rTMS may regulate the expression of some genes including c-fos and c-jun, which are vital structural components of the activator protein 1, a special transcription factor that helps to regulate cellular processes including differentiation, proliferation and apoptosis. The rTMS also helps to modulate some peptide biosynthetic pathways, such as brain-derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP), important molecules for neuronal plasticity processes [42-44]. Using functional Magnetic Resonance Imaging (fMRI), Li et al [45], observed that stimulation with 1Hz rTMS on the left dorsolateral prefrontal cortex induced an immediate increase in the local blood flow, followed by perfusion of the bilateral middle prefrontal cortex, right orbital frontal cortex, left hippocampus, middorsal nucleus of the thalamus, bilateral putamen, pulvinar and insula. These previous observations suggest that in addition to producing local changes in the stimulated cerebral cortex, rTMS might also influence the activity of other cortical and sub-cortical regions through different brain circuits and connections [46, 47].

Reported side effects of rTMS are minor events, mainly related with cephalagia, changes in the stimulation threshold of hearing, tinnitus, local erythema, syncopal episodes and in some cases mild and transient cognitive disorders related to the area stimulated [48-51]. The most important complication described has been possible induction of seizures (<0.1%); however these seizures have not been associated with sequels or with development of epilepsy [52-54]. There are some medical and non-medical contraindications to its use, such as, the presence of metal endo-cranial, cardiac pacemakers or hearing, as well as cardiac arrhythmias, intracranial hypertension, use of medications that lower the seizures threshold and personal or family history of epilepsy [55].