A randomized placebo-controlled pilot study of the efficacy and safety of D-cycloserine in people with chronic back pain.

BACKGROUND: Few effective pharmacological treatment options exist for chronic back pain, the leading cause of disability in the US, and all are associated with significant adverse effects. OBJECTIVE: To determine the efficacy and safety of D-cycloserine, a partial agonist to the N-methyl-D-aspartate receptor, in the treatment of chronic low back pain. METHODS: A total of 41 participants with chronic back pain who met all inclusion and exclusion criteria were enrolled in a double-blind, placebo-controlled randomized pilot trial of D-cycloserine. Treatment was administered orally for six weeks at escalating daily doses of 100 mg, 200 mg, and 400 mg, each for two weeks. The primary outcome measure was back pain intensity using the Numeric Rating Scale (0-10). Secondary measures were back pain-related questionnaires: McGill Pain Questionnaire short form, painDETECT, PANAS, and BDI. The pre-specified analysis was a two-way repeated measures analysis of variance. RESULTS: A treatment difference was observed between groups treated with D-cycloserine and placebo at six weeks of 1.05 ± 3.1 units on the Numeric Rating Scale, with an effect size of 0.4 and p = 0.14. This trend of better chronic back pain relief with D-cycloserine was also observed in the secondary measures. No safety issues were seen. CONCLUSION: The difference in mean pain between the D-cycloserine and placebo groups did not reach statistical significance. However, a clinically meaningful effect size in the magnitude of pain relief was observed with a consistent pattern across multiple outcome measures with good safety, supporting further research into the effectiveness of D-cycloserine for chronic back pain

Spared nerve injury rats exhibit thermal hyperalgesia on an automated operant dynamic thermal escape Task

Well-established methods are available to measure thermal and mechanical sensitivity in awake behaving rats. However, they require experimenter manipulations and tend to emphasize reflexive behaviors. Here we introduce a new behavioral test, with which we examine thermal sensitivity of rats with neuropathic injury. We contrast thermal hyperalgesia between spared nerve injury and chronic constriction injury rats. This device is a fully automated thermal sensitivity assessment tool designed to emphasize integrated learned responses to thermal painful and non-painful stimuli that are applied dynamically to a surface on which the animal is standing. It documents escape behavior in awake, unrestrained animals to innocuous and noxious heating of the floor where the animal is located. Animals learn to minimize pain by escaping to the opposite non-heated side; escape latency is recorded. On this device, thermal stimulus-response curves showed > 6°C leftward shift in both groups of neuropathic rats. In contrast, when these animals were tested on hotplate the stimulus-response shift was < 2°C. Spared nerve injury rats showed even less evidence for thermal hyperalgesia when thermal sensitivity was tested by measuring paw withdrawal to infrared heating, plantar test. The implications of test dependent magnitude of thermal hyperalgesia are discussed from the viewpoint of the tests used, as well as the animal models studied. It is argued that the dynamic thermal operant task reveals the relevance of the neuropathic injury associated pain-like behavior in relation to the whole organism

Thalamically projecting cells of the lateral cervical nucleus in monkey

The number, location, and morphology of thalamically projecting lateral cervical nucleus (LCN) cells were determined in monkey using retrograde transport of wheatgerm agglutinin-conjugated horseradish peroxidase. These data were compared to the total population of LCN neurons as determined by Nissl stain. In 4 Macaca fascicularis and one Saimiri sciureus the average size of the thalamic projection from LCN was found to be 506 _+ 94 cells contralateral to the injections. Thalamically projecting LCN neurons were located between the lower medulla and the third cervical segment; approximately 90% of these cells were in the first two cervical segments. Morphologic analysis of thalamically projecting LCN cells showed that they were smaller in size, and more oblong in shape in caudal regions of the nucleus. In 3 macaques, the average total number of LCN cells was determined to be 1617 + 908 on one side, in Nissl material. In these Nissl-stained preparations LCN neurons were found as far caudal as the fourth cervical segment; 68% were located in the first two cervical segments. Hence, thalamically projecting LCN neurons in the monkey are located in the rostral portion of the nucleus and comprise about one-third of the total population. Comparison of these data with reports in the literature imply that, unlike the cat, the major projection from LCN in monkeys is to the mesencephalon rather than to the thalamus

A preliminary fMRI study of analgesic treatment in chronic back pain and knee osteoarthritis

The effects of an analgesic treatment (lidocaine patches) on brain activity in chronic low back pain (CBP) and in knee osteoarthritis (OA) were investigated using serial fMRI (contrasting fMRI between before and after two weeks of treatment). Prior to treatment brain activity was distinct between the two groups: CBP spontaneous pain was associated mainly with activity in medial prefrontal cortex, while OA painful mechanical knee stimulation was associated with bilateral activity in the thalamus, secondary somatosensory, insular, and cingulate cortices, and unilateral activity in the putamen and amygdala. After 5% lidocaine patches were applied to the painful body part for two weeks, CBP patients exhibited a significant decrease in clinical pain measures, while in OA clinical questionnaire based outcomes showed no treatment effect but stimulus evoked pain showed a borderline decrease. The lidocaine treatment resulted in significantly decreased brain activity in both patient groups with distinct brain regions responding in each group, and sub-regions within these areas were correlated with pain ratings specifically for each group (medial prefrontal cortex in CBP and thalamus in OA). We conclude that the two chronic pain conditions involve distinct brain regions, with OA pain engaging many brain regions commonly observed in acute pain. Moreover, lidocaine patch treatment modulates distinct brain circuitry in each condition, yet in OA we observe divergent results with fMRI and with questionnaire based instruments

Brain Morphological Signatures for Chronic Pain

Chronic pain can be understood not only as an altered functional state, but also as a consequence of neuronal plasticity. Here we use in vivo structural MRI to compare global, local, and architectural changes in gray matter properties in patients suffering from chronic back pain (CBP), complex regional pain syndrome (CRPS) and knee osteoarthritis (OA), relative to healthy controls. We find that different chronic pain types exhibit unique anatomical ‘brain signatures’. Only the CBP group showed altered whole-brain gray matter volume, while regional gray matter density was distinct for each group. Voxel-wise comparison of gray matter density showed that the impact on the extent of chronicity of pain was localized to a common set of regions across all conditions. When gray matter density was examined for large regions approximating Brodmann areas, it exhibited unique large-scale distributed networks for each group. We derived a barcode, summarized by a single index of within-subject co-variation of gray matter density, which enabled classification of individual brains to their conditions with high accuracy. This index also enabled calculating time constants and asymptotic amplitudes for an exponential increase in brain re-organization with pain chronicity, and showed that brain reorganization with pain chronicity was 6 times slower and twice as large in CBP in comparison to CRPS. The results show an exuberance of brain anatomical reorganization peculiar to each condition and as such reflecting the unique maladaptive physiology of different types of chronic pain

Inflammatory and neuropathic pain animals exhibit distinct responses to innocuous thermal and motoric challenges

Most current methods for assessing pain in animals are based on reflexive measures and require constant interaction between the observer and the animal. Here we explore two new fully automated methods to quantify the impact of pain on the overall behavior of the organism. Both methods take advantage of the animals' natural preference for a dark environment. We used a box divided into two compartments: dark and bright. In the motoric operant task, "AngleTrack", one end of the box was raised so that the animals had to climb uphill to go from the light to the dark compartment. In the thermal operant task, "ThermalTrack", the floor of the dark compartment was heated to a given temperature, while the light compartment remained at 25°C. Rats were individually placed in the light box and their crossing between chambers monitored automatically for 30 minutes. The angle of the box, or the temperature of the dark compartment, was altered to challenge the animals' natural preference. We test the hypothesis that different models of pain (inflammatory or neuropathic) can be differentiated based on performance on these devices. Three groups of rats were tested at five different challenge levels on both tasks: 1) normal, 2) neuropathic injury pain (Spared Nerve Injury), and 3) inflammatory pain (intraplantar injection of Carrageenan). We monitored the position of the animals as well as their rate of switching between compartments. We find significant differences between the three groups and between the challenge levels both in their average position with respect to time, and in their switching rates. This suggests that the angle-track and thermal-track may be useful in assessing automatically the global impact of different types of pain on behavior

Human brain mechanisms of pain perception and regulation in health and disease

Context The perception of pain due to an acute injury or in clinical pain states undergoes substantial processing at supraspinal levels. Supraspinal, brain mechanisms are increasingly recognized as playing a major role in the representation and modulation of pain experience. These neural mechanisms may then contribute to interindividual variations and disabilities associated with chronic pain conditions. Objective To systematically review the literature regarding how activity in diverse brain regions creates and modulates the experience of acute and chronic pain states, emphasizing the contribution of various imaging techniques to emerging concepts. Data Sources MEDLINE and PRE‐MEDLINE searches were performed to identify all English‐language articles that examine human brain activity during pain, using hemodynamic (PET, fMRI), neuroelectrical (EEG, MEG) and neurochemical methods (MRS, receptor binding and neurotransmitter modulation), from January 1, 1988 to March 1, 2003. Additional studies were identified through bibliographies. Study Selection Studies were selected based on consensus across all four authors. The criteria included well‐designed experimental procedures, as well as landmark studies that have significantly advanced the field. Data Synthesis Sixty‐eight hemodynamic studies of experimental pain in normal subjects, 30 in clinical pain conditions, and 30 using neuroelectrical methods met selection criteria and were used in a meta‐analysis. Another 24 articles were identified where brain neurochemistry of pain was examined. Technical issues that may explain differences between studies across laboratories are expounded. The evidence for and the respective incidences of brain areas constituting the brain network for acute pain are presented. The main components of this network are: primary and secondary somatosensory, insular, anterior cingulate, and prefrontal cortices (S1, S2, IC, ACC, PFC) and thalamus (Th). Evidence for somatotopic organization, based on 10 studies, and psychological modulation, based on 20 studies, is discussed, as well as the temporal sequence of the afferent volley to the cortex, based on neuroelectrical studies. A meta‐analysis highlights important methodological differences in identifying the brain network underlying acute pain perception. It also shows that the brain network for acute pain perception in normal subjects is at least partially distinct from that seen in chronic clinical pain conditions and that chronic pain engages brain regions critical for cognitive/emotional assessments, implying that this component of pain may be a distinctive feature between chronic and acute pain. The neurochemical studies highlight the role of opiate and catecholamine transmitters and receptors in pain states, and in the modulation of pain with environmental and genetic influences. Conclusions The nociceptive system is now recognized as a sensory system in its own right, from primary afferents to multiple brain areas. Pain experience is strongly modulated by interactions of ascending and descending pathways. Understanding these modulatory mechanisms in health and in disease is critical for developing fully effective therapies for the treatment of clinical pain conditions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90300/1/j.ejpain.2004.11.001.pd

How do morphological alterations caused by chronic pain distribute across the brain? A meta-analytic co-alteration study

It was recently suggested that in brain disorders neuronal alterations does not occur randomly, but tend to form patterns that resemble those of cerebral connectivity. Following this hypothesis, we studied the network formed by co-altered brain regions in patients with chronic pain. We used a meta-analytical network approach in order to: i) find out whether the neuronal alterations distribute randomly across the brain; ii) find out (in the case of a non-random pattern of distribution) whether a disease-specific pattern of brain co-alterations can be identified and characterized in terms of altered areas (nodes) and propagation links between them (edges); iii) verify whether the co-alteration pattern overlaps with the pattern of functional connectivity; iv) describe the topological properties of the co-alteration network and identify the highly connected nodes that are supposed to have a pre-eminent role in the diffusion timing of neuronal alterations across the brain. Our results indicate that: i) gray matter (GM) alterations do not occur randomly; ii) a symptom-related pattern of structural co-alterations can be identified for chronic pain; iii) this co-alteration pattern resembles the pattern of brain functional connectivity; iv) within the co-alteration network a set of highly connected nodes can be identified.This study provides further support to the hypothesis that neuronal alterations may spread according to the logic of a network-like diffusion suggesting that this type of distribution may also apply to chronic pain. Keywords: Chronic pain, Neuronal alterations, Pathoconnectomics, Co-alteration network, Network analysis, Voxel-based morphometr

Altered resting state neuromotor connectivity in men with chronic prostatitis/chronic pelvic pain syndrome: A MAPP: Research Network Neuroimaging Study.

Brain network activity associated with altered motor control in individuals with chronic pain is not well understood. Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a debilitating condition in which previous studies have revealed altered resting pelvic floor muscle activity in men with CP/CPPS compared to healthy controls. We hypothesized that the brain networks controlling pelvic floor muscles would also show altered resting state function in men with CP/CPPS. Here we describe the results of the first test of this hypothesis focusing on the motor cortical regions, termed pelvic-motor, that can directly activate pelvic floor muscles. A group of men with CP/CPPS (N = 28), as well as group of age-matched healthy male controls (N = 27), had resting state functional magnetic resonance imaging scans as part of the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network study. Brain maps of the functional connectivity of pelvic-motor were compared between groups. A significant group difference was observed in the functional connectivity between pelvic-motor and the right posterior insula. The effect size of this group difference was among the largest effect sizes in functional connectivity between all pairs of 165 anatomically-defined subregions of the brain. Interestingly, many of the atlas region pairs with large effect sizes also involved other subregions of the insular cortices. We conclude that functional connectivity between motor cortex and the posterior insula may be among the most important markers of altered brain function in men with CP/CPPS, and may represent changes in the integration of viscerosensory and motor processing

Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain,”The

Living with unrelenting pain (chronic pain) is maladaptive and is thought to be associated with physiological and psychological modifications, yet there is a lack of knowledge regarding brain elements involved in such conditions. Here, we identify brain regions involved in spontaneous pain of chronic back pain (CBP) in two separate groups of patients (n ϭ 13 and n ϭ 11), and contrast brain activity between spontaneous pain and thermal pain (CBP and healthy subjects, n ϭ 11 each). Continuous ratings of fluctuations of spontaneous pain during functional magnetic resonance imaging were separated into two components: high sustained pain and increasing pain. Sustained high pain of CBP resulted in increased activity in the medial prefrontal cortex (mPFC; including rostral anterior cingulate). This mPFC activity was strongly related to intensity of CBP, and the region is known to be involved in negative emotions, response conflict, and detection of unfavorable outcomes, especially in relation to the self. In contrast, the increasing phase of CBP transiently activated brain regions commonly observed for acute pain, best exemplified by the insula, which tightly reflected duration of CBP. When spontaneous pain of CBP was contrasted to thermal stimulation, we observe a double-dissociation between mPFC and insula with the former correlating only to intensity of spontaneous pain and the latter correlating only to pain intensity for thermal stimulation. These findings suggest that subjective spontaneous pain of CBP involves specific spatiotemporal neuronal mechanisms, distinct from those observed for acute experimental pain, implicating a salient role for emotional brain concerning the self