Central pain is characterized by spontaneous and/or evoked pain in an area with partial or complete sensory loss to one or more modalities. Decreased sensation to thermal or painful stimuli is present in most patients with central pain, whereas decreased sensation to other modalities is less common.^23,24,25,26 The location of pain and sensory abnormalities is within an area compatible with the CNS lesion (Fig. 28.2). Spontaneous pain may be ongoing, intermittent, or paroxysmal. Studies in different central pain conditions show that pain descriptors such as hot/burning, shooting, pricking, pins and needles, cold, sharp, squeezing, and aching are common.^{9,10,11,21,25,27,28,29,30,31,32,33,34,35} Evoked pain may be present as allodynia, which is pain due to a stimulus that does not normally provoke pain, and hyperalgesia, which is increased pain from a stimulus that normally provokes pain.^36,37 There may also be aftersensations, which is pain continuing after the stimulation has ceased. Cold allodynia and touch-evoked allodynia are particularly common in central pain.^{24,27,31,32,34,38} Hyperpathia is an abnormal—often explosive—painful reaction to a stimulus in an area with increased sensory threshold when the stimulus exceeds the threshold. Due to aftersensations, the distinction between spontaneous and evoked pain may be difficult. Spontaneous pain may also be generated by central sensitization mechanisms by which decreased thresholds and temporal summation cause ongoing pain from stimuli common in daily life (e.g., movement, breathing, ambient temperature).³⁹ Nonpainful abnormal sensations are also common.^11,31,35,40 These include paresthesia, which are evoked or spontaneous abnormal sensations that are not unpleasant, and dysesthesia, which are unpleasant abnormal sensations.³⁶ Such sensations are described in terms of tingling, numb, cold, pressing, or warm.

In the assessment of central pain, it is relevant to evaluate the intensity, impact, treatment, quality, and temporal aspects of pain as well as physical and emotional functioning and quality of life (Table 28.1).⁴¹ The pain intensity of average and worst pain may be evaluated using a numerical rating scale, a visual analog scale (VAS), or a verbal rating scale.^42,43,44 Different scales have been developed to assess the multidimensional aspects of pain. One such scale is the Multidimensional Pain Inventory (MPI), which assesses pain and the impact of pain on physical and emotional functioning.⁴⁵ It has been adapted for use in SCI (MPI-SCI).⁴⁶ Other scales may be used to assess mood, sleep, resilience, pain catastrophizing, disability, and satisfaction with life.⁴⁴

The quality of spontaneous and evoked pain may be assessed using open-ended questions or by providing the patients with a list of typical pain descriptors, for example, by using specific neuropathic pain scales such as the Neuropathic Pain Symptom Inventory (NPSI),⁴⁷ the NPQ,⁴ and the painDETECT questionnaire.⁷

A sensory examination is important to identify sensory loss and gain by assessing decreased or increased sensation in the affected area compared with an area not affected by the CNS lesion. Simple bedside tests include assessment of static and dynamic touch using a brush or cotton ball; assessment of pinprick sensation using a stick, pin, or monofilament; assessment of vibration sense with a 128-Hz tuning fork; and assessment of cold and warm sensation using thermo rollers or cold and warm metal or glass objects (see Table 28.1).^14,37 Allodynia and hyperalgesia can be quantified by using a numeric rating scale
for evoked pain intensity. Mapping of sensory abnormalities and pain is a crucial part of the diagnosis of central pain to ensure that the distribution is compatible with a CNS lesion (see Fig. 28.2). Detailed quantitative sensory testing can supplement bedside sensory examination, but it is time-consuming and mainly used for research purposes.¹⁴

Laboratory tests can be used to confirm the diagnosis of a CNS lesion and specific abnormalities of the pain pathways, including the use of CT and MRI scans. Trigeminal reflexes are used in the diagnosis of trigeminal pain, and contact heat- and laser-evoked potentials are useful for assessing the function of the spinothalamic tract.¹⁴

Different models of SCI, stroke, brain trauma, and MS are used in preclinical pain research.^{90,91,92,93,94,95,96} SCI models include hemisection, contusion, ischemic, electrolytic, and excitotoxic models.^97,98,99,100 The models mimic human CNS lesions reasonably well, but the assessment of pain and its translation into human central pain remains a challenge.¹⁰¹

One of the most obvious challenges for all preclinical models of pain is the difficulty in assessing the correlate of ongoing pain. Except for a very few studies that have used conditioned place preference paradigms¹⁰² or overgrooming,¹⁰³ most preclinical studies of central pain exclusively use evoked responses to mechanical, cold, or warm stimuli. This may be valid because evoked pain is common and predicts the development of central pain,^31,38,104 but evoked pain-related responses do not always correlate with ongoing pain, and ongoing central pain may exist without evoked pain. A particular challenge in assessing pain-like behavior in models of CNS injury is the frequent coexistence of spasticity making the use of simple withdrawal reflexes unreliable as a pain-like behavioral outcome.^{101,105,106,107,108} Because withdrawal reflexes are spinally mediated, persist after complete spinal transection, and may be increased as part of the spastic syndrome, methods that depend on brainstem or cortical processing (e.g., operant escape or place escape/avoidance paradigms) are needed.¹⁰⁹

Experimental animal models and studies in humans have provided insights into the pathophysiology of central pain, which involves plasticity in various areas and pathways of the CNS. Sensitization of the CNS plays a major role in central pain and involves neuronal hyperexcitability resulting in an increased response to synaptic inputs, decreased threshold, expansion of receptive fields, and access of low-threshold Aβ mechanoreceptors to pain pathways.^110,111 The clinical consequences are allodynia, hyperalgesia, and aftersensations. Central sensitization may also include spontaneous discharges.¹¹² Spontaneous discharges in damaged pain pathways or deafferented rostral neurons may be responsible for spontaneous ongoing or intermittent pain.¹¹³ Seemingly, spontaneous pain may also be a result of decreased thresholds in nociceptor excitation and temporal summation of stimulus-evoked pain occurring at physiologic levels from stimuli caused by daily activity such as breathing, movement, and ambient temperature.³⁹ Recent studies have found that sensory hypersensitivity (mechanical and cold allodynia, hyperalgesia, and temporal summation of pain) precedes and predicts later development of central pain (CPSP and below-level SCI pain), supporting a role of neuronal hyperexcitability also for ongoing pain.^31,38,104

The functional changes underlying central sensitization involve a range of anatomical, neurochemical, excitotoxic, and inflammatory mechanisms.^114,115,116 Changes in ion channels (sodium, calcium, potassium, acid-sensing) and phosphorylation of glutamate receptors may occur at various levels of the CNS,^{117,118,119,120,121} and altered opioid receptor binding has also been demonstrated in patients with central pain.^122,123 Changes in the functions of microglia and astrocytes and release of inflammatory mediators also contribute to chronic pain following CNS injury.^{90,119,124,125} Loss of inhibition, either through the altered balance of descending inhibitory and facilitatory pathways, loss of interneurons containing glycine or γ-aminobutyric acid (GABA), or via decreased GABAergic inhibitory function through downregulation of the potassium chloride exporter, may be additional mechanisms underlying central sensitization.^126,127

Lesions of the STT and STT-thalamocortical pathways play an important but not well-understood role in the mechanisms of central pain. Impairment of pain and temperature sensation and STT injury are hallmarks of central pain,^48,128,129 but abnormal STT function is not a sufficient condition as STT lesions are also frequent in pain-free subjects. Approximately 50% of patients with a lesion of the STT after SCI or operculo-insular strokes develop central pain,¹³⁰ and the question is why STT lesions cause pain in some but not all individuals. Although central pain can occur in patients with complete lesions of the STT,¹³¹ it is suggested that central pain is caused by sensitization of partially preserved residual STT neurons in some patients.^{125,132,133,134} This is consistent with studies showing that microsimulation in the ventral caudal (Vc) sensory nucleus of the thalamus, which receives dense STT terminations, evokes pain in patients with central pain.^135,136 It is likely that the role of lesioned versus preserved ascending pathways in central pain depends on the pain phenotype. Patients with evoked pain are more likely to have preserved large- and small-fiber function than patients with spontaneous pain only, as shown in studies using quantitative sensory testing, somatosensory, and laser-evoked potentials and functional MRI (fMRI).^{26,137,138,139}