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Multidimensional clinical pain phenotypes after spinal cord injury

Practice Points

Eva Widerström-Noga* „„ Persistent pain is a common and refractory medical problem after spinal cord injury (SCI) that

significantly decreases quality of life. „„ Clinical neuropathic pain phenotypes after SCI can be based on assessments of pain symptoms, sensory

function/dysfunction and psychosocial factors related to persistent neuropathic pain. Therefore, the evaluation of these complex pain conditions requires multimodal pain evaluation protocols. „„ The characterization of clinical neuropathic pain phenotypes is important for the design of

interdisciplinary clinical interventions targeting persistent neuropathic pain, and for the exchange of research findings between basic and clinical science. „„ Neuropathic pain phenotypes after SCI may include: diagnosis and classification of neuropathic pain

based on pain symptoms, sensory function/dysfunction and clinical examinations; sensory profiles, including evoked pain and sensory function; psychosocial profiles influencing the perception of pain and the impact of pain on important life activities and satisfaction. „„ Clinical SCI research involving brain imaging supports relationships between the presence and severity

of neuropathic pain and changes in brain chemistry, suggesting glial proliferation or activation, neuronal dysfunction and structural reorganization.

SUMMARY

Persistent neuropathic pain after spinal cord injury (SCI) is a serious problem that significantly affects general health and wellbeing over and above what is caused by other medical consequences after SCI. The ideal approach to the management of the neuropathic pain conditions after SCI would be to identify the primary contributing mechanisms of pain in each person and tailor the treatment to these. However, despite significant basic and clinical research progress, this approach remains elusive. One strategy to further this effort is to define neuropathic pain phenotypes based on pain symptoms, sensory function/ dysfunction and psychosocial factors, and determine the relationship between these and treatment outcomes and biomarkers including brain imaging. This approach will facilitate the interaction between basic and clinical science and translational research, further the understanding of the mechanisms that contribute to the development and maintenance of neuropathic pain after SCI, and thus the development of effective mechanisms-based pain treatment strategies. *The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, LPLC (R-48) and Departments of Neurological Surgery & Rehabilitation Medicine, Miller School of Medicine, University of Miami, LPLC (R-48), 1095 NW, 14th Terrace Miami, FL 33136, USA; Tel.: +1 305 243 7125; Fax: +1 305 243 3921; [email protected]

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Review  Widerström-Noga Pain after spinal cord injury Persistent pain is a common medical consequence of a spinal cord injury (SCI) [1,2] . Pain after SCI is a serious problem since approximately 70% of people with SCI report persistent pain of various origins despite the availability of a multitude of clinical treatments including pharmacological and nonpharmacological interventions [3–5] . Only a few pharmacological agents have demonstrated a significant reduction of neuropathic pain in SCI clinical pain trials [6–10] , and no treatments are currently available that can completely relieve neuropathic pain in this population [11–13] . Persistent pain after SCI is associated with decreased general health and wellbeing, increased levels of depression and affective distress [14–18] , significant psychosocial impact [19–21] and a reduced quality of life [14,22–24] . Consequently, pain relief has been identified by individuals with SCI as a significant unmet need [19,25,26] . For that reason, there is a critical need to improve the management of SCI-related pain. After an SCI, it is common for a person to report several types of pain [1,27,28] . The pains experienced are classified into four distinct pain categories: ƒƒ Nociceptive pain due to nociceptor activation in muscles, visceral and other tissues; ƒƒ Neuropathic pain caused by trauma or disease

including the somatosensory system; ƒƒ Pain with unknown underlying pathology but

well-recognized pain condition (e.g., fibromyalgia); ƒƒ Unknown pain where in addition to unknown

underlying mechanisms, there is no known pain syndrome corresponding to the clinical characteristics [29] . Unknown pain cannot be assigned with any degree of certainty to the previously mentioned categories and does not include pain of mixed nociceptive and neuropathic origin. After SCI, the underlying pathophysiological mechanisms of nociceptive musculoskeletal pain are the same as in the general population, and include pain conditions such as shoulder pain due to overuse. Nociceptive pain is often caused by the physical impairments associated with the SCI. For example, musculoskeletal pain in the upper body may be caused by the overuse and repetitive movements that are necessary for transfer and propulsion of wheelchairs [24,30] .

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Nociceptive pain conditions can also be visceral in nature and associated with factors such as myocardial infarction and bowel impaction. In addition to those neuropathic pain conditions that occur in the general population (e.g., diabetic neuropathic pain), neuropathic pain caused by the SCI presents at or below the level of injury [31,32] . While below-level neuropathic pain is a direct consequence of the SCI, at-level neuropathic pain may be caused by either spinal nerve root or spinal cord damage. SCI causes widespread changes in both sensory neurons and in various central pain pathways that in many cases result in persistent clinical neuropathic pain phenotypes. These phenotypes may depend on a combination of underlying mechanisms, and genetic, environmental and behavioral factors [33,34] . Mechanisms of persistent neuropathic pain after a SCI are complex with multiple combinations of contributing mechanisms [35–40] . Recently published preclinical research studies have shown that the development and maintenance of neuropathic pain after SCI is associated with a number of molecular and plastic changes in the CNS. These include upregulation of chemokines and chemokine receptors in the spinal cord [41] , changes in spinal cord BDNF and in TrkB tyrosine kinase signaling pathways [42] , brain plasticity induced by interaction among cannabinoid and vanilloid receptors, and chemokines [43] , changes in expression of calcium ion channels [44] , changes in membrane transporter proteins [45] , loss of GABA inhibitory interneurons in the superficial lamina of the dorsal horn [46] , inflammatory mediators [47] and activation of glial cells [37,48] . Clinical pain phenotypes The most rational approach to the management of persistent neuropathic pain conditions would be to identify the primary contributing mechanisms of pain in each person and tailor the treatment to these [33,34] . This is difficult and involves the identification of clinical pain phenotypes (i.e., subgroups or profiles based on clinical symptoms and/or sensory signs) and biomarkers that reflect specific spinal cord, thalamic and cortical pain mechanisms after SCI [35,36] . A biomarker has been defined by the Biomarkers Definitions Working Group as “A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a

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Multidimensional clinical pain phenotypes after spinal cord injury  therapeutic intervention” [49] .������������������ Thus, the identification of a biomarker can increase the mechanistic understanding of individual differences in pain and clinical trial responses. Some brain imaging has been used for this purpose and will be discussed later on in this review. Several different aspects of the pain condition can be used to characterize a specific clinical pain phenotype. Therefore, clinical assessment of pain after SCI should be comprehensive and include the assessments of pain symptoms (e.g., pain severity, pain quality, temporal pattern, pain aggravating and relieving factors), sensory function/dysfunction and psychosocial factors (e.g., pain interference, affective distress, social support, cognitive factors and coping). These clinical pain phenotypes can be linked to individual treatment responses and thus serve as a basis for responder analyses in clinical trials to facilitate the development of individualized clinical pain treatments. Clinical pain phenotypes may also be linked with various biomarkers including imaging findings, to facilitate translational research and the understanding of the specific mechanisms that contribute to the development and maintenance of pain, and thus to the development of mechanisms-based treatments [33] . The characterization of a clinical pain phenotype may include several aspects of the pain condition. The determination of whether pain is neuropathic or not is usually the first distinction made [50] , followed by a standardized classification of SCI-related pain [29] . In addition to a standardized classification of pain, further characterizations including both symptoms and specific sensory signs, and biomarkers can be made. This process is critical to the bridging between basic and clinical science because pain cannot be directly assessed in animal models. Thus, the development of measures and biomarkers that can be used across basic and clinical research to further an increased understanding of the underlying mechanisms contributing to the development and maintenance of chronic pain are vital. The different aspects of the clinical pain phenotypes will be discussed below. Neuropathic pain diagnosis The most important distinction of pain after SCI is made between nociceptive versus neuropathic pain since these pain types require different treatment strategies [51] . Unfortunately, there is currently no diagnostic method that can

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perfectly and consistently diagnose neuropathic pain after SCI [52] . This is recognized as a general problem in pain research as well as in clinical pain management. Therefore, the International Association for the Study of Pain (IASP) recently changed their pain terminology and definitions. The 2011 IASP taxonomy defines neuropathic pain as “pain caused by a lesion or disease of the somatosensory nervous system” [201] . Because of the difficulty in precisely diagnosing neuropathic pain, Treede and colleagues suggested a grading system of ‘definite’, ‘probable’ and ‘possible’ neuropathic pain [50] . According to these criteria, a ‘definite’ neuropathic pain diagnosis would require a pain distribution consistent with injury to the PNS or the CNS; a previous or current injury or disease affecting the PNS and/or CNS; abnormal sensory signs within the body area corresponding to the injured part of the CNS or PNS; and a diagnostic test confirming a lesion or disease in these structures. Despite these recommendations, the diagnosis of SCI-related neuropathic pain below the injury level is not always straight forward. This is especially true for incomplete injuries where sensory dysfunction may be similar in both nociceptive and neuropathic pain conditions [52] . In order to improve the neuropathic pain diagnosis after SCI, Finnerup and Baastrup added the following criteria to the IASP guidelines: onset of pain within 1 year following SCI; no primary relation to movement, inflammation or other local tissue damage; and the descriptive adjectives ‘hot-burning’, ‘tingling’, ‘pricking’, ‘pins-andneedles’, ‘sharp’, ‘shooting’, ‘squeezing’, ‘cold’, ‘electric’ or ‘shock-like’ quality of pain [37] . The International Spinal Cord Injury Basic Pain Dataset In order to accurately assess pain symptoms pertaining to a specific pain problem in a person with SCI who may experience several simultaneous pain types, he or she must be able to differentiate between these. Research has shown that approximately 75% of people with SCI and chronic pain can reliably differentiate between different types of pain with respect to location, intensity, quality and temporal pattern [53,54] . Consistent with this finding, each pain that an individual reports is evaluated separately in the International Spinal Cord Injury Basic Pain Dataset (ISCIBPD) [55] . The ISCIBPD contains clinically relevant information that can be collected by healthcare professionals with expertise

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Review  Widerström-Noga in SCI and across clinical settings. In addition to the pain classification made by a healthcare professional, the ISCIBPD also includes selfreported information regarding the number of pain problems, pain location, a pain-intensity rating and questions regarding the temporal pattern of pain (i.e., onset, presence and number of days with pain over the last 7 days, duration and variation in intensity) for each specific pain problem. Furthermore, the impact of pain on physical, social and emotional function, and sleep is evaluated. The ISCIBPD has been officially endorsed by major SCI and pain organizations (e.g., the International Spinal Cord Injury Society, the American Spinal Injury Association, the American Pain Society and the IASP) and is now part of the NIH Common Data Elements [202] . The psychometric properties of a self-report version of the ISCIBPD (without the pain classification included in the ISCIBPD [55]) were recently examined in 184 individuals with SCI and chronic pain [54] . The results from this study supported both the utility and validity of selfreported answers related to pain interference, pain intensity, pain location, frequency and duration of pain and time of day of worst pain. International spinal cord injury pain taxonomy Recently, a revised classification of chronic pain after SCI previously discussed was published by a consensus group consisting of SCI and pain experts [29] . This new international SCI pain taxonomy is consistent with current IASP pain definitions and represents a unification of previously published and commonly used SCI pain classifications [55–57] . The international SCI pain taxonomy classifies all neuropathic and nociceptive pain types that an individual with SCI may experience and also includes pains that are not caused by the SCI (e.g., diabetic neuropathy and pressure-sore pain). Importantly, the inter-rater reliability of this new taxonomy was recently shown to be adequate [58] . Pain symptom profiles Due to the fact that pain is a subjective phenomenon, both self-reported pain symptoms, and positive or negative sensory signs are important and commonly used to characterize a clinical pain phenotype. Distinct pain-symptom profiles that are stable over time have been identified in persons with SCI [2,59] and some of these symptom profiles are associated with specific

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sensory abnormalities. For example, burning, electric and stinging pain was associated with exacerbation of pain due to mechanical stimuli, such as light touch and muscle spasms, whereas aching and throbbing pain was associated with pain exacerbation due to cold weather and visceral stimuli such as constipation [60] . There are also important relationships between clinical pain symptoms and psychosocial factors. For example, clinical pain characteristics that are common in neuropathic pain conditions such as more intense pain, evoked pain, electric and constant pain have been associated with greater psychosocial impact [59,61] , perceived as particularly disturbing [53] and predictive of using p­rescription medication [4] . The neuropathic pain symptom inventory (NPSI) is an instrument specifically designed to evaluate the severity of different neuropathic pain symptoms (burning, pressure, squeezing, electric shocks, stabbing, tingling and pins and needles), and pain evoked by brushing, pressure and cold [62] . The NPSI discriminates and quantifies five different dimensions of neuropathic pain that are sensitive to change: ƒƒ Evoked pain includes three items related to pain evoked by brushing, pressure or the cold ƒƒ Pressing (deep) pain includes sensations of

pressure or squeezing ƒƒ Paroxysmal pain includes electric shock and

stabbing ƒƒ Paresthesia/dysesthesia includes tingling and

pins and needles ƒƒ Burning (superficial) pain includes a single

item rating burning pain The psychometric properties of the NPSI, including sensitivity to change, suggest that it may be useful both for the characterization of clinical neuropathic pain phenotypes and for the evaluation of treatment outcomes. The psychometric properties for NPSI has not yet been evaluated for the SCI neuropathic pain population but research both in the SCI population [63,64] and in other neuropathic pain populations [62] suggest that it may be a useful instrument for characterizing pain phenotypes after SCI. Quantitative sensory testing In order for a method to be useful for characterizing specific pain phenotypes and link these to treatment outcomes or underlying mechanisms, it should be both valid and reliable. The

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Multidimensional clinical pain phenotypes after spinal cord injury  German network on neuropathic pain recently examined the test–retest reliability and the interobserver reliability of quantitative sensory testing (QST) in a heterogeneous group of 60 individuals recruited from four centers [65] . The participants experienced pain and sensory abnormalities and had lesions or diseases of the somatosensory system. QST was performed in the most painful area and in a less affected or unaffected control area, by two examiners on two consecutive days. Test–retest reliability and interobserver reliability, exhibited excellent reliability for thermal detection and pain thresholds, vibration detection threshold, mechanical detection threshold, mechanical pain threshold for pinprick stimuli, mechanical pain sensitivity for pinprick stimuli and dynamic mechanical allodynia for stroking light touch, and pressure pain threshold, tested in the most painful area (coefficients ranging between 0.80 and 0.93). The authors concluded that when QST is used by trained examiners it is a reliable diagnostic method that is useful for assessing sensory disturbances in persons with lesions or diseases of the somatosensory system. Evidence supporting the reliability of QST measures over a 2–4-week period has also been provided for the SCI neuropathic pain population [63] . In this study, QST was used to assess several different test sites in each subject. For study participants with SCI and neuropathic pain, sensory thresholds were assessed in areas with and without neuropathic pain above, at and below the neurological level of injury. Pain-free controls were tested in standardized sites corresponding to the distribution of SCI participants’ pain. The QST data across test sites and subjects were standardized, consistent with the data procedures recommended by the German network on neuropathic pain [66] . The results from the study by Felix and Widerström-Noga demonstrated excellent test–retest reliability for the light touch, vibration, cool and warm modalities, with intra-class correlation coefficients ranging from 0.84 to 0.95 [63] . The QST modalities cold pain and hot pain thresholds, however, exhibited lower reliability (intra-class correlation coefficient = 0.50). Similarly, Defrin and colleagues compared thermal perception and pain thresholds at two separate occasions (with a minimum of 1 week apart) and found no significant differences between two tests [67] . Thus, the test–retest reliability of QST in persons with SCI and chronic neuropathic pain

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appears to be adequate although the psychometric properties should be re-examined in a larger sample to confirm these results. An important goal related to the usefulness of QST measures is to clarify to what extent QST measures and combinations of these are generalizable between different disease or injury types. Generalizable pain phenotypes may suggest commonality also in underlying mechanisms of neuropathic pain. Substantial progress in the general area of neuropathic pain has been made by the German network on neuropathic pain in that this group has applied a standardized protocol for the assessment and analysis of QST data from large numbers of patients (n = 1236) with the clinical diagnosis of neuropathic pain [68] . Although general sensory abnormalities were found in all the different neurological syndromes, there were important differences with respect to how frequently these were present. The most common sensory profile or phenotype experienced by 27.5% of persons with central pain conditions included mixed thermal/mechanical sensory loss without hyperalgesia. This was also the most common sensory profile in persons with polyneuropathy (26.2%), but less common in postherpetic neuralgia (13.9%), peripheral nerve injuries (11.7%), complex regional pain syndromes (3.5%) and trigeminal neuralgia (7.6%). These findings suggest that sensory assessment is a useful tool that can provide generalizable clinical pain phenotypes important for the development of mechanisms‑based treatment interventions. Another important issue relating to the utility of QST in characterizing a neuropathic pain phenotype is the validity, or the relationship between sensory measures and the presence and severity of neuropathic pain. Several studies have investigated the relationship between the presence of neuropathic pain and sensory function after SCI. Many of these studies have focused on the role of deficits in major sensory pathways (i.e., the spinothalamic tract [STT] and the dorsal column medial lemniscus pathway). While injury of the STT appears to be necessary for the development and maintenance of neuropathic pain after SCI, it is unclear whether damage to the dorsal column medial lemniscus pathway is required [69–75] . The relationship between QST measures and severity of neuropathic pain after SCI was examined in 17 patients with SCI and neuropathic pain in a multiple regression analysis [63] .

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Review  Widerström-Noga The severity of neuropathic pain symptoms was assessed with the NPSI and the total score entered as the dependent variable. The independent variables included a composite thermal pain threshold (average cold and hot pain threshold z-scores) in an area with neuropathic pain, together with level and completeness of injury. The analysis showed that increased severity of neuropathic pain symptoms was significantly associated with increased thermal pain z-scores (i.e., greater sensitivity to pain). Consistent with these findings, Wasner and colleagues evoked heat pain within painful areas after the induction of peripheral sensitization in persons with SCI and neuropathic pain [76] . Based on their results, they suggested that neuropathic pain after SCI was associated with spontaneous activity in residual thermosensitive STT neurons caused by inflammatory processes within the injured STT. Another important aspect related to the usefulness of sensory assessments is their predictive ability. For example, Hari and collegues showed that a greater recovery of spinothalamic function (determined with pinprick) within the first year after SCI was associated with the development of neuropathic pain [77] . In addition, they found a significant correlation between pain intensity ratings 5  years after injury and the extent of functional recovery. Similarly, Zelig and collegues performed longitudinal QST assessments up to 6 months after injury or until central neuropathic pain developed in 30 persons with SCI and in 27 normative controls [78] . The results of this study suggested that the best predictor for the development of neuropathic pain was dynamic mechanical allodynia below the level of injury. Therefore, these investigators concluded that neuronal hyperexcitability preceded the development of pain and that this clinical sign may be used early after SCI to determine the risk for the development of neuropathic pain. These clinical studies concur with basic SCI research studies suggesting that some types of neuropathic pain may be caused by hyperactivity in residual STT neurons partly due to complex molecular processes including upregulation of intracellular signaling proteins that influence the phosphorylation of kinases, transcription factors and/or changes in m­embrane excitability of receptors [38,79,80] . In conclusion, QST holds great promise to be particularly useful for the identification of specific clinical neuropathic pain phenotypes

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based on neurological function/dysfunction and thus further both the understanding of the mechanisms that contribute to the development and maintenance of neuropathic pain after SCI, and facilitate the translation of basic research findings to clinical applications. Psychosocial phenotypes Multiaxial psychometric instruments, assessing multiple aspects of the pain experience and associated psychosocial factors, can be used to subgroup or classify persons with chronic pain [81,82] . Using an SCI version of the multidimensional pain inventory [16] , Widerström-Noga and colleagues identified three different psychosocial subgroups associated with SCI-related chronic pain [83] . Two of the three subgroups, dysfunctional (with higher levels of pain severity, life interference, affective distress and lower levels of life control and activities) and adaptive copers (with lower levels of pain severity, life interference, and affective distress, and greater levels of life control and activities) were similar to subgroups observed in heterogeneous chronic pain populations [82] . A third subgroup unique to SCI, the interpersonally supported, reported high levels of perceived positive support from significant others in response to pain in combination with intimate-interpersonal support and lower degree of pain interference and affective distress, despite moderately high pain severity [83] . The inter-relationship between these subgroups and pain characteristics show that the dysfunctional subgroup exhibits more neuropathic pain symptoms [61] , evoked pain [84] , frequent exacerbation of pain [60] , electric quality and continuous pain, than the other subgroups [61] . A recent review by Jensen and colleagues in disabled populations including SCI suggested that catastrophizing cognitions, task persistence, guarding, and resting coping responses, and perceived social support and solicitous responding, were particularly predictive of pain and dysfunction and therefore should be evaluated in c­linical studies [85] . Clinical pain phenotypes based on important pain-related psychosocial variables associated with neuropathic pain and SCI might be useful in the design of treatment strategies in m­u ltidisciplinary pain management settings and linked with biomarkers to further the understanding of the factors that contribute to the development and maintenance of n­europathic pain after SCI.

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Multidimensional clinical pain phenotypes after spinal cord injury  Supraspinal research findings related to neuropathic pain Of importance to a mechanism-based understanding of chronic pain after SCI are alterations in the functional state of the CNS and the extent to which these alterations translate into clinical pain phenotypes. One method that has been used for this purpose is magnetic resonance spectroscopy (MRS), which is a noninvasive method of assessing brain chemistry. The advantage of MRS for utility in clinical research is the stability of the signals analyzed [86] . Therefore, when changes are detected, they are presumed to reflect long-term plasticity. MRS can measure the distribution and concentration of naturally occurring molecules such as N-acetylaspartate (NAA), one of the most common amino acids of the brain. NAA is localized primarily in neurons [87] and is presumed to be a neuronal marker [88] . Another metabolite of interest is myo-inositol (Ins), which is thought to be a glial marker possibly indicating gliosis or glial activation [88] . In a study by Pattany et al., MRS was used to assess thalamic metabolite concentrations in a group of people with SCI and chronic neuropathic pain [89] . The concentrations of NAA were significantly lower in those with SCI compared with able-bodied pain-free controls and the severity of pain was significantly correlated with lower NAA and higher Ins concentrations. The low levels of NAA were hypothesized to be related to decreased function of inhibitory neurons in the thalamic region, whereas higher concentrations of Ins were hypothesized to reflect gliosis. Consistent with these findings, thalamic levels of NAA were lower in persons with diabetic neuropathic pain compared with pain-free individuals with diabetes [90] . These authors suggested that the reduction of thalamic NAA may be responsible for amplification of the pain signal in those with diabetes. Basic research suggests that glial activation or proliferation in the CNS is ��������������������� an important mechanism underlying neuropathic pain after SCI [91,92] . Consequently, increased brain concentra���������� tions (including the thalamus, prefrontal cortex and the anterior cingulate cortex) of Ins have been found in persons with neuropathic pain after SCI [89,93] . The hypothesis that there may be increased numbers of glia in the brains of persons with chronic neuropathic pain is supported by human studies showing both functional reorganization and loss of gray matter in supraspinal structures such as the somatosensory cortex and

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the thalamus [94–96] . The studies conducted in persons with SCIs show that increased cortical reorganization is significantly associated with increased severity of neuropathic pain [95,97] . In an interesting functional MRI study by Gustin et al., subjects with complete thoracic SCI and below-level neuropathic pain were asked to imagine foot movements [97] . This procedure caused pain in non-painful areas and significant increases in pain ratings within painful areas. In addition to increases in activation of the primary motor cortex and the cerebellar cortex, the extent of activation in the perigenual anterior cingulate cortex and right dorsolateral prefrontal cortex was significantly correlated with increases in pain intensity. Similarly, a study in chronic back pain patients using MRS imaging of the dorsolateral part of the prefrontal cortex showed very strong relationships with clinical pain pheno­t ypes based upon symptoms and psycho­ social factors [98] . For example, the combination of sharp pain, stabbing pain, pain duration and trait anxiety predicted the concentration of the dorsolateral part of the prefrontal cortex NAA in persons with low back pain. Diffusion tensor imaging allows in vivo assessment of white matter nervous spinal cord and brain structures. Fractional anisotropy is one of the most commonly used measures of deviation from isotropy [99] and reflects the degree of alignment in cellular structures within fiber tracts, as well as their structural integrity. Mean diffusivity (MD) is a measure of the average molecular motion independent of any tissue directionality and is affected by cellular size and integrity [99,100] . A reduction in MD suggests more restrictive tissue barriers, such as neuronal sprouting and cellular proliferation. By contrast, an increase in MD suggests decreased tissue barriers associated with edema, demyelination, cell death and axonal loss [101,102] . The relationship between persistent neuropathic pain following SCI and changes in regional brain anatomy and connectivity has been studied using diffusion tensor imaging [103] . This study included 12 people with SCIrelated neuropathic pain, and their MD values suggested significant changes in regional brain anatomy compared with pain-free controls. The anatomical changes were located in nucleus accumbens and orbitofrontal, dorsolateral prefrontal and posterior parietal cortices. Another clinical study in SCI showed that increased cortical reorganization was significantly associated

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Review  Widerström-Noga with the decreased extent of aligned structures as indicated by decreased fractional anisotropy values [97] . Similarly, a study including 27 subjects with neuropathic pain and syringomyelia found no significant differences in diffusion tensor imaging measures between individuals with pain and ten people with syringomyelia Clinical pain phenotypes based on: Pain type – Nociceptive pain (musculoskeletal, visceral and other) – Neuropathic pain (at-level, below-level and other) – Other pain – Unknown pain Pain symptoms E.g., pain severity, pain quality, temporal pattern, pain aggravating and relieving factors

Biomarkers E.g., imaging of spinal cord and brain (fMRI, MRS and DTI) and others

Sensory function/dysfunction E.g., quantitative sensory testing of functional status of the spinothalamic tract and the dorsal column medial lemniscus pathway, and evoked pain (allodynia and hyperalgesia) Psychosocial factors E.g., pain interference, affective distress, social support, cognitive factors and coping

Clinical trials – Multimodal outcome evaluation including clinical pain phenotypes and biomarkers – Responder analyses for the prediction of treatment outcome and increased mechanistic understanding

– Exchange of clinical and basic research findings – Elucidate mechanisms contributing to the development of neuropathic pain after SCI

Future mechanism-based treatments

Figure 1. Clinical spinal cord injury neuropathic pain research. A simple and hypothetical framework for clinical SCI neuropathic pain research with the overall goal of developing treatments that are tailored to underlying mechanisms of neuropathic pain after SCI. DTI: Diffusion tensor imaging; fMRI: Functional MRI; MRS: Magnetic resonance spectroscopy; SCI: Spinal cord injury.

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without pain [104] . However, within the neuropathic-pain group, highly significant relationships were found between fractional anisotropy of the spinal cord and average pain intensity (r = -0.64; p = 0.02). This relationship was particularly strong in individuals with spontaneous pain only (r = -0.93; p = 0.008). Collectively, these studies support a relationship between the presence and severity of neuropathic pain and structural changes in the brain and spinal cord. Conclusion & future perspective This review emphasizes the heterogeneity of pain after SCI and that several clinical neuropathic pain phenotypes that are dependent on partly different contributing mechanisms are likely. Basic research has made significant progress both in the understanding of the mechanisms that contribute to neuropathic pain syndromes and how to target these. Despite this progress and a significant increase in both pharmacological and nonpharmacological treatment options, persistent neuropathic pain continues to be a common and very difficult condition that frequently leads to substantially reduced quality of life after SCI. There are significant gaps between basic and clinical research and the clinical management of neuropathic pain after SCI. This gap can potentially be bridged by concentrated translational research efforts including defining reliable and valid clinical pain phenotypes and biomarkers, and determining the relationships between these and their underlying mechanisms. Below is an outline including the hypothetical relationships between clinical pain phenotypes, biomarkers and their use in clinical trials, and how this working hypothesis may facilitate progress towards future mechanismsbased treatments for those with SCI and neuropathic pain. Figure 1 illustrates a simple and hypothetical framework for the clinical SCI neuropathic pain research with the overall goal of developing treatments that are tailored to the underlying and maintaining mechanisms of neuropathic pain after SCI. Clinical pain phenotypes can be used to characterize persons and their SCI-related pains in various ways. As mentioned previously, these clinical phenotypes can be based on pain type, pain symptoms, sensory function and dysfunction, and psychosocial factors. Moreover, any clinical pain phenotype needs to be reliable, for example, have adequate test-retest stability, inter-rater

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Multidimensional clinical pain phenotypes after spinal cord injury  reliability and validity. Characterizing clinical pain phenotypes are not only important for clinical research and clinical practice but also for the interaction between clinical and basic research with regards to outcomes and animal models. The use of biomarkers, for example, brain and spinal cord imaging or other biomarkers can be expected to expand substantially in the future. Biomarkers have significant importance for translational research since these can link human and animal studies mechanistically. The utility of various biomarkers needs to be determined both in clinical and basic research. This would include determining the relationships between biomarkers, and clinical pain phenotypes and clinical pain trial outcomes. For basic research studies, similar relationships could be established between biomarkers and behavioral and nociceptive outcomes, and response to interventions. Utilizing similar biomarkers and outcomes in clinical and basic research would facilitate the develop�������� ment of mechanisms-based therapies. Clinical trials should be designed to include multimodal measures for the characterization of clinical pain phenotypes and biomarkers to facilitate research translation and to develop predictors of treatment outcome via responder analyses, with the goal of elucidating the mechanisms contributing to chronic neuropathic pain after SCI ��������������������������������������� and thus future mechanisms-based treatments. As an example, a recent clinical trial in SCI used transcranial stimulation and visual illusion to treat neuropathic pain and utilized a multimodal outcome assessment battery including the NPSI [64] . The combination of both treatments significantly reduced the severity of

Papers of special note have been highlighted as: of interest n

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Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ. A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain 103(3), 249–257 (2003). Cruz-Almeida Y, Martinez-Arizala A, Widerström-Noga EG. Chronicity of pain associated with spinal cord injury: a longitudinal analysis. J. Rehabil. Res. Dev. 42(5), 585–594 (2005). Warms CA, Turner JA, Marshall HM, Cardenas DD. Treatments for chronic pain associated with spinal cord injuries: many are

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all subtypes of neuropathic pain as assessed by NPSI (i.e., continuous pain, paroxysmal pain, mechanical allodynia and dysesthesia). By contrast, patients receiving transcranial stimulation experienced a significant decrease in only continuous and paroxysmal pain, and patients in the visual illusion group only improved in their continuous pain and dysesthesia ratings. The differential pain-relieving effects by different treatments on specific clinical pain phenotypes, may suggest a relationship between these and different mechanistic origins. At present, we lack important knowledge regarding how to implement mechanisms-based treatments in persons with SCI who suffer from neuropathic pain. This fact emphasizes the need for an approach to this problem that includes: ƒƒ The identification of reliable and translatable pain phenotypes and biomarkers; ƒƒ Clinical trials with multimodal outcome var-

iables and biomarkers that can facilitate the exchange of research findings between basic and clinical science; ƒƒ The investigation of the relationships between

clinical pain phenotypes, underlying mechanisms and treatment responses. Financial & competing interests disclosure The manuscript preparation was supported by Miami Project to Cure Paralysis. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the m­anuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. tried, few are helpful. Clin. J. Pain 18(3), 154–163 (2002).

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