From acute to long-term alterations in pain processing and modulation after spinal cord injury: mechanisms related to chronification of central neuropathic pain.

ABSTRACT: A severe and debilitating consequence of a spinal cord injury (SCI) is central neuropathic pain (CNP). Our aim was to investigate the processes leading to CNP emergence and chronification by analyzing causal relationship over time between spinothalamic function, pain excitability, and pain inhibition after SCI. This longitudinal follow-up study included 53 patients with acute SCI and 20 healthy controls. Spinothalamic, pain excitability, and intrasegmental and extrasegmental pain inhibition indices were repeatedly evaluated at 1.5, 3, and 6 months post-SCI. Between- and within-group analyses were conducted among those patients who eventually developed CNP and those who did not. Healthy controls were evaluated twice for repeatability analysis. Patients who developed CNP, compared with those who did not, exhibited increased thermal thresholds (P < 0.05), reduced pain adaptation (P < 0.01), and conditioned pain modulation (P < 0.05), early post-injury, and the CNP group's manifestations remained worse throughout the follow-up. By contrast, allodynia frequency was initially similar across SCI groups, but gradually increased in the subacute phase onward only among the CNP group (P < 0.001), along with CNP emergence. Early worse spinothalamic and pain inhibition preceded CNP and predicted its occurrence, and early worse pain inhibition mediated the link between spinothalamic function and CNP. Crossover associations were observed between early and late pain inhibition and excitability. Inefficient intrasegmental and extrasegmental inhibition, possibly resulting from spinothalamic deafferentation, seems to ignite CNP chronification. Pain excitability probably contributes to CNP maintenance, possibly via further exhaustion of the inhibitory control. Preemptive treatment promoting antinociception early post-SCI may mitigate or prevent CNP.

Different clinical phenotypes of persistent post-traumatic headache exhibit distinct sensory profiles.

INTRODUCTION: Persistent post-traumatic headache remains a poorly understood clinical entity. Although there are currently no accepted therapies for persistent post-traumatic headache, its clinical symptoms, which primarily resemble those of migraine or tension-type headache, often serve to guide treatment. However, evidence-based justification for this treatment approach remains lacking given the paucity of knowledge regarding the characteristics of these two major persistent post-traumatic headache phenotypes and their etiology. METHODS: We compared clinical features and quantitative sensory testing profiles between two distinct cohorts of persistent post-traumatic headache subjects that exhibited symptoms resembling either migraine (n = 15) or tension-type headache (n = 13), as well as to headache-free subjects that had suffered traumatic brain injury (n = 19), and to healthy controls (n = 10). We aimed to determine whether the two persistent post-traumatic headache subgroups could be discriminated based on additional clinical features, distinct quantitative sensory testing profiles, or the interaction of pain severity with the level of post-traumatic stress disorder. RESULTS: Persistent post-traumatic headache subjects with migraine-like symptoms reported that bright light and focused attention aggravated their pain, while stress and nervousness were reported to aggravate the headache in subjects with tension-type headache-like symptoms. Quietness was better in alleviating migraine-like persistent post-traumatic headache, while anti-inflammatory medications provided better relief in tension-type headache-like persistent post-traumatic headache. The two persistent post-traumatic headache subgroups exhibited distinct quantitative sensory testing profiles with subjects exhibiting tension-type headache-like persistent post-traumatic headache displaying a more pronounced cephalic and extracephalic thermal hypoalgesia that was accompanied by cephalic mechanical hyperalgesia. While both persistent post-traumatic headache subgroups had high levels of post-traumatic stress disorder, there was a positive correlation with pain severity in subjects with tension-type headache-like symptoms, but a negative correlation in subjects with migraine-like symptoms. CONCLUSIONS: Distinct persistent post-traumatic headache symptoms and quantitative sensory testing profiles may be linked to different etiologies, potentially involving various levels of neuropathic and inflammatory pain, and if confirmed in a larger cohort, could be used to further characterize and differentiate between persistent post-traumatic headache subgroups in studies aimed to improve treatment.

Biomarkers for predicting central neuropathic pain occurrence and severity after spinal cord injury: results of a long-term longitudinal study.

Central neuropathic pain (CNP) after spinal cord injury (SCI) is debilitating and immensely impacts the individual. Central neuropathic pain is relatively resistant to treatment administered after it develops, perhaps owing to irreversible pathological processes. Although preemptive treatment may overcome this shortcoming, its administration necessitates screening patients with clinically relevant biomarkers that could predict CNP early post-SCI. The aim was to search for such biomarkers by measuring pronociceptive and for the first time, antinociceptive indices early post-SCI. Participants were 47 patients with acute SCI and 20 healthy controls. Pain adaptation, conditioned pain modulation (CPM), pain temporal summation, wind-up pain, and allodynia were measured above, at, and below the injury level, at 1.5 months after SCI. Healthy control were tested at corresponding regions. Spinal cord injury patients were monitored for CNP emergence and characteristics at 3 to 4, 6 to 7, and 24 months post-SCI. Central neuropathic pain prevalence was 57.4%. Central neuropathic pain severity, quality, and aggravating factors but not location somewhat changed over 24 months. Spinal cord injury patients who eventually developed CNP exhibited early, reduced at-level pain adaptation and CPM magnitudes than those who did not. The best predictor for CNP emergence at 3 to 4 and 7 to 8 months was at-level pain adaptation with odds ratios of 3.17 and 2.83, respectively (∼77% probability) and a cutoff value with 90% sensitivity. Allodynia and at-level CPM predicted CNP severity at 3 to 4 and 24 months, respectively. Reduced pain inhibition capacity precedes, and may lead to CNP. At-level pain adaptation is an early CNP biomarker with which individuals at risk can be identified to initiate preemptive treatment.

Increased psychological distress among individuals with spinal cord injury is associated with central neuropathic pain rather than the injury characteristics.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: Central neuropathic pain (CNP) is common after spinal cord injury (SCI). The psychological impact of CNP is not clear. Previous studies reported depression and pain catastrophizing among patients with SCI and CNP; however, the lack of control groups prevented discerning whether these were attributed to CNP or to the SCI itself. The aim was to examine the psychological distress among individuals with SCI with and without CNP and controls to evaluate its impact and possible source. SETTING: Outpatient clinic of a large rehabilitation center. METHODS: Individuals with SCI and CNP (n = 27) and without CNP (n = 23), and able-bodied controls (n = 20) participated. Data collection included sociodemographics, SCI characteristics, and level of post-traumatic stress disorder (PTSD), anxiety, stress, depression, and pain catastrophizing. The sensory, affective, and cognitive dimensions of CNP were analyzed. RESULTS: Individuals with SCI and CNP exhibited elevated levels of PTSD, anxiety, stress, depression, and pain catastrophizing compared to the two control groups, which presented similar levels. The psychological variables among the CNP group correlated positively only with the affective dimension of CNP. Neither CNP nor the psychological variables correlated with SCI characteristics. CONCLUSIONS: Irrespective of CNP intensity, the affective dimension (suffering) is associated with increased psychological distress. Perhaps individual differences in the response to SCI and/or individual traits rather than the mere exposure to SCI may have a role in the emergence of CNP and psychological distress/mood dysfunction. Rehabilitation programs should prioritize stress management and prevention among individuals with SCI and CNP.

Differential pain modulation properties in central neuropathic pain after spinal cord injury.

It seems that central neuropathic pain (CNP) is associated with altered abilities to modulate pain; whereas dysfunction in descending pain inhibition is associated with the extent of chronic pain distribution, enhanced pain excitation is associated with the intensity of chronic pain. We investigated the hypothesis that CNP is associated with decreased descending pain inhibition along with increased neuronal excitability and that both traits are associated with spinothalamic tract (STT) damage. Chronic spinal cord injury subjects with CNP (n = 27) and without CNP (n = 23) and healthy controls (n = 20) underwent the measurement of pain adaptation, conditioned pain modulation (CPM), tonic suprathreshold pain (TSP), and spatial summation of pain above injury level. Central neuropathic pain subjects also underwent at and below-lesion STT evaluation and completed the questionnaires. Central neuropathic pain subjects showed decreased CPM and increased enhancement of TSP compared with controls. Among CNP subjects, the dysfunction of CPM and pain adaptation correlated positively with the number of painful body regions. The magnitude of TSP and spatial summation of pain correlated positively with CNP intensity. STT scores correlated with CNP intensity and with TSP, so that the more affected the STT below injury level, the greater the CNP and TSP magnitude. It seems that CNP is associated with altered abilities to modulate pain, whereas dysfunction in descending pain inhibition is associated with the extent of chronic pain distribution and enhanced pain excitation is associated with the intensity of chronic pain. Thus, top-down processes may determine the spread of CNP, whereas bottom-up processes may determine CNP intensity. It also seems that the mechanisms of CNP may involve STT-induced hyperexcitability. Future, longitudinal studies may investigate the timeline of this scenario.

Quantitative somatosensory testing of subjects with chronic post-traumatic headache: implications on its mechanisms.

BACKGROUND: Chronic headache is one of the most prominent symptoms among subjects with traumatic head injury (THI). Despite the relatively high prevalence of chronic post-traumatic headache (CPTHA) and its enormous effect on the already poor quality of life of subjects with THI, its mechanisms has not been studied in depth. OBJECTIVE: To conducted quantitative somatosensory testing in THI subjects with and without chronic post-traumatic headache (CPTHA) in order to shed light on the yet, unknown pathophysiology of CPTHA. METHODS: THI subjects with and without CPTHA and healthy controls underwent thermal and mechanical threshold measurements in painful and pain-free regions in the head and in their hands (a remote pain-free region) and filled out and the post-traumatic stress disorder (PTSD) inventory. In addition, the THI and CPTHA filled out the Mc'Gill pain questionnaire (MPQ). RESULTS: THI subjects with CPTHA had significantly higher thermal thresholds in both the head and hand indicating central damage to the pain and temperature system and in addition, a significantly lower pressure-pain threshold in the head as well as more severe PTSD symptomatology than the pain-free THI subjects and healthy controls. CONCLUSIONS: The sensory profile of subjects with CPTHA suggests that CPTHA may be a form of central pain. The cranial mechanical hyperalgesia may originate from peripheral tissue damage accompanying the THI. Psychological factors may contribute to the development, and maintenance of CPTHA in susceptible individuals.