**2. Importance of developing neuromodulation for pain relief**

Chronic pain is a global health problem with both a high economic cost in addition to its substantial detrimental impact on quality of life [3]. Remarkably lifetime prevalence of chronic pain has been put as high as 50% of the global population [4, 5]. Chronic pain is the most common co-morbidity for a disease, with pain as the most frequent reason for seeking healthcare. Recently chronic pain has been recognized by the World Health Organization as a disease and included in the international classification of diseases (ICD-11) [6]. However, treatment interventions are lacking; pharmacological interventions providing inadequate pain relief with the mismanagement of opioids well documented as both increasing mortality and exacerbating pain. For neuromodulation to be an effective alternative for analgesia, an understanding of the mechanisms leading to pain conditions and the networks that enhance pain or inhibit pain is essential. For therapeutic benefit, neurostimulation techniques should modulate the nervous system in a non-destructive way with reversible effects that can be applied long term and have specificity to a targeted network. Further the intervention should be controlled dependent on individual patient requirements [7]. Recently a number of new non-invasive techniques have emerged; weak electric currents applied transcranially to cortical or sub-cortical site are proposed as interventions for a number of diseases that are associated with pathological alterations in neuronal excitability [8, 9], including chronic pain. Further the recent development of transcutaneous vagal nerve stimulation also offers therapeutic potential for some pain patients. Although these novel non-invasive interventions offer

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nervous systems.

*From Mechanisms to Analgesia: Towards the Use of Non-Invasive Neuromodulation for Pain…*

promise, there remain areas of uncertainty with regards to how to optimize stimulation protocols and standardize their efficacy across individuals.

The sensation of acute pain originates from stimulation of nociceptors. Nociceptive input has different modalities; thermal, chemical or mechanical; that are all capable of causing pain. Receptor types and ion channels will differ dependent on the stimulus and intensity, but with free nerve endings transmitting the noxious information to Aδ and C afferents. The TRP channels for transduction of noxious temperature sensation are well characterized [10, 11], with less known about mechanical pain [12]. Myelinated, high velocity (20 m/s) Aδ fibers and un-myelinated, low velocity (2 m/s) and C fibers transmit nociceptive information from the periphery to the dorsal horn. Both Aδ and C afferent fibers terminate in the dorsal horn of the spinal cord, where afferent input is organized in the rexed laminae; finer diameter fibers terminate more laterally, and larger fibers more medially. Large diameter Aβ fibers conveying innocuous touch can modulate nociception transmission as formulated by the gate-control theory of pain. This theory represented a ground breaking advance in the understanding of the peripheral and spinal processing of nociceptive inputs that led to the development of therapeutic neuromodulation interventions [13]. There is transmission from the spinal cord via multiple ascending pathways; spinothalamic, spinoreticular, spinomesencephalic, and spinocervical pathways [14]. The thalamus is an important site of nociceptive transmission to different brain regions known to be involved in pain processing and interpretation. Additionally significant modulation of afferent input occurs at the thalamus that has led to the region being one of the first supraspinal areas targeted in neuromodulation interventions. The multiple cortical and sub-cortical regions of the brain that are involved in pain processing and modulation have become known as the pain neuromatrix [15], or the pain connectome [16]. Particularly critical to the modulation of pain is the descending pain pathways providing endogenous inhibitory

Chronic pain typically is defined as pain that lasts 3-6 months, with the pain experienced no longer associated with a tissue injury. Chronic pain can result from defects in different sites of the pain processing pathways [17] and is often associated with both peripheral and central sensitization [18]. The pain processing network is known to be complex and distributed. In the brain, painful stimuli is known to lead to activation in diverse brain regions; including the frontal lobe, anterior cingulate cortex (ACC), primary motor cortex (M1), primary sensory cortex (S1), secondary sensory cortex (S2), insular; hypothalamus; nucleus cuneiformis; periaqueductal grey; rostral ventromedial medulla; as observed via fMRI studies [19]. The development of chronic pain is thought not just to involve neural changes but also alterations in glia [20]. These glial changes are thought to partly underlie alterations in pain transmission and the formation of chronic pain circuitry. Imaging studies show that chronic pain leads to structural and functional changes in multiple brain regions [21]. Chronic pain has also been reported to be associated with dysregulation of both the sympathetic and parasympathetic nervous systems [22]. Therefore, the potential targets for non-invasive neuromodulation for pain relief are diverse and could be within the central or peripheral

**3. The anatomical substrates for pain: potential targets for** 

*DOI: http://dx.doi.org/10.5772/intechopen.93277*

**neuromodulation**

control of nociceptive input.

*From Mechanisms to Analgesia: Towards the Use of Non-Invasive Neuromodulation for Pain… DOI: http://dx.doi.org/10.5772/intechopen.93277*

promise, there remain areas of uncertainty with regards to how to optimize stimulation protocols and standardize their efficacy across individuals.
