Understanding central sensitization for advances in management of carpal tunnel syndrome

Spreading pain symptoms in carpal tunnel syndrome

The most common symptoms usually experienced by patients with CTS include pain and/or paresthesia in areas innervated by the median nerve, i.e. the thumb, index, and/or middle fingers. Symptoms can be worse during activities involving the hand/wrist but also at night. It seems that paresthesia, but not pain, is the symptom most commonly associated with neurophysiological damage of the median nerve⁵.

It is commonly seen in clinical practice that patients with CTS exhibit symptoms not only in those areas innervated by the median nerve but also in extra-median nerve areas. This was confirmed by Zanette et al., who observed that 35% of patients with CTS exhibit a glove distribution of their symptoms, whereas 5% exhibit an ulnar distribution⁶. The same authors also reported that 45% of CTS sufferers also report pain in proximal areas of the upper extremity including the elbow or the shoulder⁷. A more recent study, using new electronic software for analyzing pain extent, found that 88% of women with CTS showed extra-median pain symptoms⁸. The presence of spreading symptoms is a clinical manifestation of neuropathic but also nociceptive pain involving sensitization mechanisms and plasticity⁹. This hypothesis is confirmed by the fact that extra-median symptoms are not associated with electrical nerve conduction data, suggesting an association between neuropathic and nociceptive pain with expansion of receptive fields of central neurons in CTS¹⁰.

Peripheral and central sensory changes in carpal tunnel syndrome

‘Sensitization’ is a term describing the changes in nociceptive neurons. It is mainly grouped into peripheral/central sensitization, and it is present in several musculoskeletal and neuropathic chronic pain conditions^11,12. ‘Peripheral sensitization’ refers to increased responsiveness and reduced threshold of peripheral nociceptors; it is usually associated with the release of endogenous algogenic substances and neurogenic inflammation. ‘Central sensitization’ is defined by the International Association for the Study of Pain (IASP) as an increased responsiveness of the nociceptive neurons in the central nervous system to their normal or subthreshold afferent input, which may include increased responsiveness due to dysfunction of endogenous pain control systems¹³. The relationship between peripheral and central sensitization is well established. It is accepted that the presence of long-lasting and prolonged nociceptive peripheral inputs induces plastic changes in the central nervous system; therefore, central sensitization seems to be a dynamic process that is dependent on peripheral nociception^11,12. In some patients, once central sensitization has been established, minimal peripheral nociception can be required to maintain this process and non-nociceptive inputs might also contribute to the subsequent pain and mechanical allodynia observed in this situation. Nevertheless, central sensitization is mainly driven by peripheral impulses. In such a scenario, in people with CTS, the entrapment of the median nerve at the carpal tunnel represents the peripheral input towards the central nervous system. Gracely et al. proposed this model for neuropathic pain in 1992 where peripheral nociception from an entrapped nerve could lead to neuroplastic changes in the central nervous system¹⁴. In CTS, the neurogenic inflammation of the median nerve induced by its entrapment can act as a peripheral driver for the gradual sensitization of nociceptive pathways. In fact, Truini et al. found that affectation of both nociceptive and non-nociceptive fibers contributed to the different symptoms experienced in CTS¹⁵.

The peripheral component of entrapment neuropathies such as CTS is supported by current literature¹⁶ and will not be further discussed in this text. In the last decade, different studies have investigated the presence of central sensitization by assessing widespread sensory disorders throughout quantitative sensory testing in CTS. Fernández-de-las-Peñas et al. found that women with strictly unilateral CTS symptoms exhibit widespread pressure pain sensitivity over the radial, ulnar, and median nerves, the cervical spine, and the tibialis anterior muscle, suggesting widespread hypersensitivity to pressure pain¹⁷. Widespread pressure hypersensitivity is a manifestation of the sensitization of central pathways; however, pressure pain hypersensitivity has also been found to be heterogeneously distributed in the symptomatic hand, supporting the relevant role of the peripheral input¹⁸. Similar results were also found by Zanette et al., who observed that CTS patients with extra-median symptoms exhibited generalized pressure hyperalgesia and enhanced wind-up¹⁹. Interestingly, widespread pressure pain hyperalgesia was not associated with the electrodiagnostic findings, since women with minimal, moderate, or severe CTS exhibit similar widespread sensory changes²⁰. These results support the notion that widespread hyperalgesia to pressure pain can be a common manifestation of CTS from the beginning of symptom onset. In line with this hypothesis, Tampin, Vollert, and Schmid found that individuals with a peripheral neuropathy such as CTS exhibit similar sensory changes to those with a proximal (cervical) radiculopathy, although pain profiles were different²¹. Nevertheless, Schmid et al. did not observe widespread pressure hyperalgesia in patients with CTS without concomitant neck pain symptoms, suggesting that groups of patients with CTS could exist and that the observed widespread sensory changes can be more related to the presence of extra-median/proximal symptoms²². The hypothesis of different subgroups of patients with CTS has been supported by a study identifying a subgroup of women with CTS with higher bilateral widespread pressure hyperalgesia based on the presence of a cluster of symptoms²³. Therefore, it is possible that CTS can be peripherally mediated in some patients but more centrally mediated in others.

The presence of central sensitization in CTS is also supported by imaging studies.

Tecchio et al. found that patients with CTS with symptoms of glove distribution exhibited an enlargement in cortical representation and neuroplastic changes in the somatosensory cortex compared to those individuals with just median nerve distribution symptoms²⁴. Different studies have also shown larger contralateral sensorimotor cortical representation²⁵ and smaller cortical source separation²⁶ of the second/third digits in patients with CTS as compared to controls. All of these studies hypothesized that long-lasting paresthesia/pain symptoms (peripheral drive) can promote blurring of median nerve-innervated digit representations through neural mechanisms (central drive)^25,26. There is also current evidence showing the presence of reduced endogenous inhibition and increased pain facilitation in patients with CTS²⁷. In conclusion, long-lasting peripheral nociceptive stimuli originating in the median nerve could lead to neuroplastic changes in the central nervous system at both spinal cord and brainstem levels.

Motor output changes in carpal tunnel syndrome

It is interesting to consider that sensitization mechanisms and sensory loss also have output manifestations. Motor control disturbances may be a perpetuating factor for pain since pain-related fear or avoidance behaviors can also promote negative attitudes. In addition, altered motor control patterns could reflect the reorganization of motor control strategies in the central nervous system, as sensory neuroplastic changes in the somatosensory cortex result in decreased fine motor control²⁸. The presence of bilateral deficits in fine motor control and pinch grip force in women with strictly unilateral CTS supports this hypothesis²⁹. Additionally, these bilateral deficits in fine motor control and pinch grip force were not associated with either median nerve damage or the presence of unilateral or bilateral symptoms³⁰. Data suggest that motor output disorders are present from the onset of symptoms and could be related to neuroplastic changes in the cortex. Nevertheless, it is probable that peripheral and central mechanisms can be involved at the same time in the motor control disturbances observed in CTS.