In 1979, the International Association for the Study of Pain redefined pain as “an unpleasant sensory and emotional experience, associated with actual or potential damage or described in terms of such damage.” This definition not only emphasizes that pain involves thoughts and feelings, but also that pain is real whether or not the biological “causes” are known. The definition reflects the comprehension that pain is a subjective experience involving all sensory modalities.

As physicians, we have been trained to perceive “pain” as a disorder with a certain mechanism or try to unravel the mechanism involved. However, this may not be always possible or really happening in our daily practice, especially for chronic pain. Sitting in a pain clinic, you probably will someday meet some patients with generalized complaints and find it difficult to give a precise diagnosis or explanation for why he or she is suffering. Then, this may be the time for you to consider the diagnosis of “chronic medically unexplained symptoms of pain,” as mentioned by Li et al¹ in this issue of Acta Anaesthesiologica Taiwanica. Chronic medically unexplained symptoms of pain may include syndromes such as fibromyalgia, chronic fatigue syndrome, and somatic symptoms in mood disorders.² Patients with these medically unexplained symptoms of pain may also suffer from depression and anxiety disorders, with repeated treatment-seeking behaviors and psychological distress. In psychiatry, “somatoform disorders” have been used to define a group of patients with medically unexplained symptoms.

In their review article, Li et al¹ tender the repetitive transcranial magnetic stimulation (rTMS) as an alternative treatment for chronic refractory pain and discuss its therapeutic validity. TMS is a noninvasive method to trigger depolarization or hyperpolarization in the neurons of the brain. TMS uses electromagnetic stimulation to induce weak electric currents via a rapidly changing magnetic field. It can cause activity in specific or general parts of the brain with minimal discomfort. In neurosurgery, navigated TMS has been used for mapping the motor cortex in patients with brain tumors.³ rTMS has been tested as a treatment tool for various neurological and psychiatric disorders including migraines, strokes, Parkinson's disease, depression, and auditory hallucinations. Recently, TMS was even proposed to be used as a measure for brain health.⁴

As we know, the somatic pain pathway may start from periphery, travel via the spinal cord, and terminate in the cortex, for example, the spino–thalamo–cortical pathway (not to mention the descending facilitatory and inhibitory pathways). Up to now, the main neuromodulatory methods using neurostimulation principles include peripheral nerve stimulation, spinal cord stimulation, deep brain stimulation, motor cortex stimulation, and rTMS. Just like stimulation to the spinal cord, rTMS is used to modulate the brain pain pathway in a noninvasive manner. It has been hypothesized that rTMS could influence cortical and subcortical neurons, thereby reducing pain transmission ascending from spinothalamic tracts.⁵ Another working mechanism is that it may drive top–down opioidergic analgesia, which is naloxone-reversible.⁶ Twenty minutes of high-frequency (20 Hz) rTMS has been reported to increase pain thresholds in the contralateral hand of healthy volunteers.⁷

In the past decades, neuroimage studies have shown that there are morphological or biochemical changes in the brain for various pain statuses.8, 9 These noninvasive neuroimage studies, together with animal studies, also revealed functional and structural brain plasticity induced by noxious stimuli or peripheral nerve injury.10, 11 Now we know that noxious stimuli or peripheral nerve injuries could produce electrophysiological or biochemical changes in the supraspinal site.12, 13 These important pain-related areas or pain matrix in the brain include prefrontal cortex anterior cingulate cortex, amygdala, and periaqueductal gray.14, 15, 16 A growing body of evidence indicates that peripheral nerve injury triggers structural changes in the cortical neuromatrix, including the primary somatosensory cortex and the medial prefrontal cortex.¹⁷ In animal studies, Kim and Nabekura¹⁸ have demonstrated that sciatic nerve ligation induces rapid remodeling of cortical neuronal circuits.

rTMS on the right dorsolateral prefrontal cortex or motor cortex has been reported to possess antidepressive and pain-modulating effects in patients with fibromyalgia and neuropathic pain, complex regional pain syndrome type I, all of which belong to the category of chronic pain.¹ In preclinical studies, rTMS could attenuate spinal cord injury-induced astroglial and microglial activation in rats.¹⁹ Even though rTMS shows some promising therapeutic effects for certain disorders, considerable work is still needed to reveal its action mechanism, the most optimal parameters, and evaluate its potential side effects.⁷