Introduction
Central pain (CP) is a term used to describe pain associated with an insult to the central nervous system (CNS). It is formally defined by the International Association for the Study of Pain (IASP) Taxonomy Taskforce as “pain caused by a lesion or disease of the central somatosensory system.” Clinically, it can be observed as neuropathic pain evolving or persisting in patients with neurologic complications as a result of an injury to the brain or spinal cord. There is a wide spectrum of CP-associated CNS injuries that exist resulting from vascular, infectious, demyelinating, neoplastic, or traumatic etiologies. The most commonly studied conditions associated with CP are spinal cord injury (SCI) and stroke. Although these conditions are different entities, research suggests an overlap in the pathophysiologic mechanisms, as well as similarities in their clinical characteristics. Therefore, initial treatment modalities for CP have been similar in both populations. CP has a number of clinical implications due to its medical complexity and potential to result in significant disability in those affected.
History and Terminology
The concept of “central arising pains” first appeared in published literature in the early 19th century by German neurologist Dr. L. Edinger. Up until then, there have only been observational case reports describing pain arising from brain or cord origin. , This gave rise to a number of case studies describing pain, or “hyperesthesia” following damage in specific CNS locations (cortex, subcortex, internal capsule, thalamus, and brainstem) found through autopsy investigations. Furthermore, in the early 20th century, Dejerine and Roussy concluded that damage to the thalamus resulted in pain in association with other symptoms, and thus earning its name “thalamic syndrome.” Later, Head and Holmes published a seminal review identifying and quantifying sensory disturbances in CP, mainly as it related to thalamic injury. Holmes also observed similar pains associated with spinal cord lesions in WWI solders. Although it was becoming increasingly known that CPs could arise from extrathalamic regions, the anatomical origin of CP remained a mystery. Later, a pivotal review by Cassinari and Pagni in the 1960s suggested that CP occurs as a result from lesion in the spinothalamic tract.
Even with such discoveries, the terms “thalamic syndrome” and “central pain syndrome” remained interchangeable. With the rise of neuroimaging (CT scans and MRI) and functional neurophysiologic testing, evidence supported that neurological insults at any point within the CNS, from the spinal cord and up to the sensory cortex, could manifest with CP. As a result, the term CP syndrome has been increasingly adapted to reflect this shift in thought.
Clinical Characteristics
CP is often categorized as a type of neuropathic pain, presenting similarly to other types of neuropathies. Some common descriptors include burning, pins and needles, tingling, shooting, stabbing, electrical, squeezing, cramping, extreme cold, and itching, which can occur alone or in various combinations.
Pain intensity can vary between individuals, ranging from mild discomfort to agonizing pain. Studies have demonstrated that the degree of neurological deficit, nature of pain components, and comorbid mood disturbances may play a role in the severity of pain. The degree of sensory deficits, specifically of pinprick and thermal sensations, has been shown to be correlated with pain severity. In a study of 157 patients with CP, deficits in pinprick and thermal sensations were more pronounced in areas of greatest pain, whereas tactile sensation, vibration, and two-point discrimination was uninfluenced in areas of pain.
In addition, CP may present with different qualities of neuropathic pain and it is not uncommon for several qualities to present in the same person. , The characteristics of CP can be classified as steady, intermittent, or evoked pain components (see Fig. 3.1 ). Intermittent pain tends to be spontaneous and more severe compared with steady pain. Evoked pain is often induced and can result in hyperesthesia (increased sensitivity to normal stimuli), allodynia (pain as a result of nonpainful stimuli), or hyperalgesia (increased pain as a result of normally painful stimuli). Often, patients experience a combination of intense, intermittent pain superimposed on dull, constant pain. , In general, the more components of pain present, the more intense the perceived pain. The severity of pain is usually higher in individuals with an incomplete sensory deficit compared with those with complete sensory deficits as they exhibit intense evoked pain in areas with mildly impaired sensory loss.
Regardless of the characteristics and intensity, pain can become functionally limiting and have a negative impact on quality of life. , Functional impairment and pain was found to coexist with depression and sleeping difficulties 1 year after stroke. , Therefore, it is important to consider mood and sleep dysfunction when evaluating or treating CP, as difficulties with either may change the perception of pain intensity.
Diagnosis
The diagnosis and classification of CP has been an ongoing discussion between researchers as well as clinicians. As a type of neuropathic pain, the presence of characteristic neuropathy often prompts investigation.
Neuropathic pain scales such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale , Neuropathic Pain Questionnaire , and the Douleur Neuropathique 4 (DN4) were developed to aid in identifying the presence of neuropathic pain; however, these scales are limited in identifying CP. The Neuropathic Pain System Inventory (NPSI), which further characterizes neuropathic pain into subtypes, provides some insight into identifying CP; however, the NPSI is limited in sensitivity and specificity. In general, these scales are not recommended to be used as diagnostic tools, but rather in conjunction with history and examination and review of ancillary testing if available.
The grading system for neuropathic pain is a tool used to identify, with a level of certainty, that neuropathic pain is present. This was developed based on the definition outlined by the IASP “neuropathic pain caused by a lesion or disease of the somatosensory nervous system.” The criteria require history and the distribution of pain to be consistent with sensory changes on physical exam and congruent with location of lesion confirmed on imaging. ,
There are a number of limitations to consider when diagnosing CP. First, the presence of neuropathic pain does not delineate whether or not the lesion is localized to the central or peripheral nervous system (i.e.,“burning” sensation can be found in both diabetic neuropathy and central post stroke pain [CPSP]). Second, CP may overlap with other pain entities, which can confound the diagnosis (i.e., a patient with CPSP may have concomitant lumbar radiculopathy affecting the same extremity). Further, there is high variability of clinical presentation that exists in patients with CP.
CP is often a multifactorial diagnosis, sharing overlapping features with other chronic pain conditions, further complicating evaluation and management. This is commonly demonstrated in neurologically impaired patients with limited mobility, who are at risk for musculoskeletal complications as a result of their impairments. A cross-sectional study by de Oliveira et al. investigated the presence of myofascial pain (MP) in stroke patients diagnosed with CP syndrome. It was found that the presence of MP cannot be excluded after stroke and may be present as a comorbid condition. Failure to consider other causes of pain could result in ineffective treatment.
As a result of the difficulty in evaluating and treating CP, the American Pain Society Pain Taxonomy (AAPT) provided evidence-based, multidimensional diagnostic criteria based on the classification of CP associated with SCI, stroke, and multiple sclerosis. The proposed criteria includes 5 dimensions: 1) core diagnostic criteria, 2) common features, 3) common medical and psychiatric comorbidities, 4) neurobiological, psychosocial, functional consequences, and 5) putative neurobiological mechanisms, risk factors, and protective factors.
Central Post Stroke Pain
Definition and Epidemiology
Chronic pain is a long-term complication of stroke. Data suggest that one-fifth to half of patients experience some pain following a stroke. , Pain can be further characterized as stroke-related pain and nonstroke-related pain where the latter tends to be explained by premorbid conditions such as arthritis or polyneuropathy. Stroke-related pain is categorized into subtypes that classically occur as a consequence of stroke. This includes CP, spasticity, complex regional pain syndrome, nociceptive/myofascial (i.e., shoulder) pain, and headaches.
Central post stroke pain (CPSP) describes pain or sensory abnormalities following a stroke that corresponds to the area of cerebrovascular insult. For example, an infarct in the left hemisphere of the brain resulting in right-sided hemiplegia may potentially result in pain in the hemiplegic limbs. The prevalence of CPSP has been highly variable in studies over the past two decades, ranging from 3% to 35%. , , This can be partially explained by differences in study design and specific definition of post stroke pain. In addition, CPSP is often underrecognized by clinicians, due to the lack of a specific pain scale or inquiry, and has been underreported by patients, which can add to the inconsistency in prevalence studies. Risk factors for developing CPSP include young age, premorbid depression, tobacco use, and significant sensory and motor impairments. , Its development is also strongly associated with the severity of stroke-related deficits, depression, and other pain conditions. Screening and recognition of CPSP should include examination of functional and cognitive impairments as well as emotional well-being.
Onset and Description
The onset of CPSP occurs around 3–6 months; however, there has been reports of a latency period of up to 18 months. The onset of pain has been suggested to be correlated with improvement in sensory and motor deficits. It can be sudden or gradual and may precede neurological recovery. , , As mentioned earlier in the chapter, pain can be continuous, intermittent, and/or evoked. Continuous pain is most common to be present and is often dull in nature. Intermittent and evoked pain tends to be more severe. ,
The heterogenous nature of reported symptoms can lead to challenges in recognizing CPSP. For this reason, more efforts have been made in identifying characteristics and patterns suggestive of CP as opposed to other pain syndromes. Although pain descriptors, such as burning, tingling, or shooting, are not necessarily exclusive to CP, a distinguishing feature to consider is the area of pain distribution. If pain corresponds with the area of the central lesion, one can attribute these symptoms to be of central origin.
Diagnostic Criteria
The diagnostic criteria for CPSP set forth by the AAPT was created on the basis of neuropathic pain. There are six diagnostic criteria (see Fig. 3.2 ). The first requirement is a diagnostic test confirming recent or remote stroke. Second, pain must be present immediately after stroke or up to 1 year following the event, must be present for at least 3 months duration and distributed in the area affected by stroke. Third, there must be neuropathic features present such as allodynia or decreased sensation to stimuli. Lastly, there must be no other plausible diagnosis to explain the pain.
Brain Localization
Classically, thalamic lesions have been shown to have the greatest association with pain after stroke, first described by Dejerine-Roussy as “thalamic pain syndrome.” However, subsequent studies have challenged this theory by demonstrating that only a minority of patients with post stroke pain was of thalamic origin. It appears that a lesion anywhere along the neuroaxis responsible for transmitting and regulating pain correlates with the development of CPSP. Three areas have been relevant in the discussion of CPSP which include the spinothalamic tract, the medullary tract, and areas of the cerebral cortex.
The spinothalamic tract is located at the anterolateral spinal cord, travels rostral, and synapses at the ventroposterior thalamus. This tract is generally responsible for both pain and temperature transmission. The medullary tract involves the trigeminothalamic pathway, which regulates similar nociception (i.e., pain and temperature) within the face. The medullary tract is implicated in brainstem strokes such as Lateral Medullary “Wallenberg” Syndrome, where about 25% of patients report ipsilateral facial pain. Generally, infarcts within the cerebral cortex are rarely associated with the development of CPSP; however, lesions in cerebral structures involved in regulating and processing pain, such as the posterior insular cortex and medial operculum, have been shown to contribute to the development of CP. These structures contribute to the pain due to their role as a receiving area for the spinothalamic tract and having close connections to the limbic and sensory cortices.
Interestingly, right hemispheric infarcts are more likely to develop CPSP. This is suspected to be due to the right hemisphere playing a larger role in pain processing. , Other areas of the brain which are associated with the development of CPSP include the thalamus and brainstem generally seen in the setting of lacunar infarcts (small vessel strokes).
Pathophysiology
The exact pathophysiology of CPSP is unknown; however, there are a few theories that have been proposed on the basis of neuronal and biochemical pathways which include central disinhibition and sensitization.
Studies by Head and Holmes in the early 1900s suggested the theory of central disinhibition observed with injury to the lateral thalamus. Pain was thought to be as a result of injury to the inhibitory, GABAnergic, pathways which communicate with the ventral-posterior lateral nuclei and medial thalamus, thus disinhibiting them from regulating pain control. This theory, later confirmed by SPECT studies, remains widely accepted as a mechanism of CPSP. ,
Later, it was found that lesions along the spinothalamic-cortical pathway (responsible for pain and temperature sensation) can result in disinhibition and subsequent hyperactivity in the thalamus which lead to painful symptoms. This is further evident by multiple studies which have demonstrated impaired pinprick pain as well as temperature (especially cold) disturbances in the development of CP. , Moreover, disinhibition requires the integrity of the sensory tract to be somewhat maintained in order to explain the hyperactive component of this mechanism. Studies have shown that pain was more common in patients with partial lesions of the spinothalamic tract compared with complete involvement, further supporting this theory.
Central sensitization is a sequela of chronic pain and is not to be confused with CP syndrome. Central sensitization is thought to occur from loss of inhibition or increased neuronal activity leading to overexcitability and hypersensitivity. It remains one of the mechanisms thought to drive chronic pain states. Its implication in CPSP is suggested by studies in post stroke cohorts, which concludes that CP occurs as a result of spontaneous discharges from thalamic and cortical areas causing further neuronal hyperexcitability and central sensitization. Central sensitization can be evaluated clinically by identifying hypersensitive areas and measuring thresholds in response to various stimuli.
Hyperexcitability on a cellular level can be explained by firing patterns of neurons, specifically in the thalamus. A review by Kumar et al. suggested two firing patterns: 1) bursting during hyperpolarization and 2) single-spike depolarization, both of which are modulated by neurotransmitters. Regulation of firing patterns is determined by serotonergic, noradrenergic, and cholinergic input and plays a role in pain processing. For instance, serotonin and noradrenaline was shown to increase GABAnergic transmission, which explains the benefit of using antidepressants in the treatment of CPSP (to be discussed later in the chapter). Biochemical pathways involving opioid receptors have also been investigated suggesting that decreased opioid receptor binding is a consequence of post stroke pain, though clinical implications with opioids are limited and often discouraged in this population.
Spinal Cord Injury Central Pain
Definition and Epidemiology
CP in patients with SCI refers to neuropathic pain as a result of damage to the CNS, specifically the spinal cord and not the nerve roots. This pain is often classified as at-level neuropathic pain or below-level neuropathic pain according to the International Spinal Cord Injury Pain classification. A significant number of patients with SCI experience pain with the prevalence estimated to be around 45% for both at-level and below-level neuropathic pain. Pain interferes with rehabilitations, daily activities, and significantly affects the quality of life in individuals with SCI.
Spine Localization
In SCI, at-level CP is thought be the result of damage to the substance of the spinal cord. At-level CP is defined as neuropathic pain perceived in a segmental pattern within the dermatome or up to three dermatomes below the neurological level. Thus, this type of pain is often referred to as “segmental” or “transitional zone pain.” This is not to be confused with at-level peripheral neuropathic pain in the setting of SCI which can be secondary damage to the nerve roots at the level of injury. Pain is described as either spontaneous or stimulus evoked. Evoked pain typically has additional characteristics of allodynia, hyperalgesia, wind-up pain (abnormal temporal summation of pain), and aftersensations (persistent pain after painful stimulation has ceased). Pain generally follows the dermatome of the neurological level of injury and can be present on one or both sides of the body.
Similar to at-level CP, below-level SCI neuropathic pain is considered to be a CP syndrome caused by spinal cord trauma. It has been previously referred to as “deafferentation central pain.” Below-level neuropathic pain is defined as neuropathic pain that is perceived more than three dermatomes below the neurological level. It often has similar clinical characteristics as at-level CP with both spontaneous and stimulus-evoked neuropathic pain. However, unlike at-level CP, below-level CP is often described as being asymmetric, patch, and not characteristically dermatome. It may be perceived as coming from a particular body party (i.e., rectal, bladder, genitals).
Pathophysiology
The mechanisms of at- and below-level neuropathic pain are poorly understood and likely multifactorial in nature. It is often associated with neurochemical and excitotoxic changes. There is evidence of postinflammatory cytokines and excitatory amino acids (glutamate) briefly released in and around the site of SCI. , This is thought to contribute to pathologic changes in the spinal cord leading to increased sensitivity due to loss of normal neuronal input, removal of inhibitory influences, increased efficacy of alternative synapses and deafferentation, hyperexcitability of spinal and/or thalamic neurons, and further alterations in cellular activity of neurochemical and excitatory amino acids due to changes in ion channels and transport activity.
There are also anatomical changes at the level of injury resulting in structural changes in the gray/white matter and subsequent structural reorganization. These changes alter the balance between spinal pathways (i.e., spinothalamic tract-dorsal column, spinothalamic-spinoreticulothalamic tract), which may contribute to development of CP.
In addition to dysfunction of neurons, recent evidence indicates that alterations in the neuroimmune system also contribute to chronic pain, specifically to the microglia. Microglia are thought to be principally phagocytes that are mobilized after injury, infection, disease, and seizures. When activated, glial cells produce proinflammatory cytokines, excitatory amino acids, and nitric acid which mediate pain following neural injury and produce neuronal hyperexcitability in the dorsal horn. Dysfunction of the microglia is associated with neuropathic pain-related behaviors (i.e., allodynia and hyperalgesia) and is hypothesized to be responsible for the development of chronic CP. ,
Treatment
Pharmacologic
There has been a variety of treatment options shown to be effective in managing CP disorders; however, supporting data are limited to only a few studies. Pharmacologic agents shown to be effective in treating CP include antidepressants, anticonvulsants, steroids, and opioid analgesia.
Neuropathic pain medications
Anticonvulsants and antidepressants are commonly prescribed as first-line therapy for CP disorders. Pregabalin and gabapentin are anticonvulsants agents that have been a well-accepted choice for the treatment of neuropathic pain due to their relative affordability and tolerability. , , , , While similar medications, pregabalin has been more frequently tested in CP disorders. Although the data on pain control have been marginal, large studies have demonstrated the efficacy of pregabalin for improved sleep and anxiety in patients with post stroke CP.
Tricyclic antidepressants are also considered first-line agents for CP disorders. These medications are thought to produce analgesia through blocking reuptake of serotonin and norepinephrine transmitters. In a small (n = 15) double blinded-placebo controlled trial, amitriptyline was shown to produce significant reduction of pain and well tolerated in CPSP syndrome. Still, this agent is known to have anticholinergic side effects as well as risk for developing cardiac arrhythmia.
Second-line neuropathic medications include serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs), which have been effective in treating various neuropathic pain states. However, there are limited studies about its efficacy in CP syndrome. , , Other neuropathic agents, including carbamazepine and lamotrigine, have been studied in CP and are generally used as second-line agents due to higher incidence of side effects , (see Table 3.1 ).
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