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Spontaneous rating 2.4.1 pain



  • Spontaneous rating 2.4.1 pain
  • Towards a theory of chronic pain
  • 1. Introduction
  • Spontaneous pain was assessed every 4 hours during the waking Ratings (5 per day) were aggregated across the daytime. subsequent pain ratings in chronic pain patients and healthy volunteers. Keywords: Pain . same participant. Both chronic pain patients experiencing spontaneous pain and healthy volunteers exposed to . Pain model. For chronic pain. vectors: (a) when ratings of spontaneous pain were high in .. the role of supraspinal circuitry. in chronic pain. Ascending pathways.

    Spontaneous rating 2.4.1 pain

    We also introduce data emphasizing that distinct chronic pain conditions impact on the cortex in unique patterns. Fourth, animal studies regarding nociceptive transmission, recent evidence for supraspinal reorganization during pain, the necessity of descending modulation for maintenance of neuropathic behavior, and the impact of cortical manipulations on neuropathic pain is also reviewed.

    We further expound on the notion that chronic pain can be reformulated within the context of learning and memory, and demonstrate the relevance of the idea in the design of novel pharmacotherapies.

    Lastly, we integrate the human and animal data into a unified working model outlining the mechanism by which acute pain transitions into a chronic state. It incorporates knowledge of underlying brain structures and their reorganization, and also includes specific variations as a function of pain persistence and injury type, thereby providing mechanistic descriptions of several unique chronic pain conditions within a single model.

    Chronic pain is a controversial topic, and doubts have been raised regarding its diagnosis and treatment as a clinical condition e. During the past twenty years or so, however, tremendous advances have been made in our understanding of the peripheral and central processes involved in chronic pain conditions.

    The present chapter is an attempt to develop from these recent studies ideas that may lead toward a theory of chronic pain capable of accounting for its various clinical manifestations.

    We examine current definitions and clinical subtypes of chronic pain, assess data from human and animal studies, and expound upon the correspondence or lack thereof between proposed models. We conclude by presenting a speculative theory of chronic pain rooted in the neural mechanisms underlying this phenomenon that is consistent with both the human and animal research. The standard definition of chronic pain endorsed by the International Association for the Study of Pain states that it is pain that persists past the healing phase following an injury Merskey and Bogduk, Determining the end of the healing phase is difficult, however, and instead the common clinical definition is a fixed time of persistent pain following its initial onset.

    For chronic back pain the usual time is 6 months, whereas in post-herpetic neuralgia 3 months of persisting pain is the more common time point at which the condition is dubbed chronic. These are purely functional and relatively arbitrary time posts that have little relation to underlying mechanisms. The details of these plastic changes are beyond the current review, and will therefore only be summarized in relation to their relevance to clinical chronic pain.

    These models, especially the variety of peripheral nerve injuries that give rise to neuropathic pain behavior, indicate that subtle differences in the type of injury giving rise to pain behavior stabilize at different time delays from the initial injury. For example, the Seltzer partial sciatic nerve injury model Seltzer et al. In contrast, in the spared nerve injury model Decosterd and Woolf, where the tibial and peroneal branches of the sciatic nerve are cut, stable and peak thermal hyperalgesia and mechanical allodynia are only observed at about two weeks after the initial injury.

    While the difference between these two neuropathic pain models may seem trivial, the point is that the ensuing pain behaviors require very different time delays to reach their full expression. To our knowledge there are no studies as to the mechanisms underlying these time delays. If one assumes that the peak pain is an indication for the longer lasting stable pain behavior that we equate to chronic pain, then the delay to reaching this behavior is clinically relevant.

    The processes underlying this delay, therefore, would be largely unrelated to the duration of the healing phase because the extent of injury and its related healing are very similar in both cases. These animal behavioral results cast doubt even regarding the validity of the standard definition for chronic pain. Moreover, they point to the notion that the definition of chronicity cannot be independent of the type of chronic pain in question and thus should be functionally determined for each type separately, as well as be based on the peripheral and central mechanisms undergoing reorganization in each condition.

    There is a long list of chronic clinical pain conditions. These are generally labeled by their site of injury e. Clinical manifestations are often a combination of multiple pain conditions; even in a single condition several diverse tissue types are observed to contribute.

    Perhaps the most notorious example is chronic back pain, where it is very difficult to ascertain the type of tissue injured, and with the extent of joint degeneration, muscle, and nerve injuries varying broadly across patients the relative involvement of each remains obscure and undeterminable. Clinical scientists continue to argue over the validity of diverse chronic pain conditions, such as CRPS and fibromyalgia, or whether they are not the creation of the patient in complicity with consenting physicians.

    This frustration seems to emanate mainly from an inability to localize peripheral parameters that can define the condition coupled with the lack of efficacious treatments. Physicians dealing with complicated chronic pain patients complain that regardless what they do the patients continue to complain and continue to report suffering from pain.

    However, this grim picture is beginning to change. The animal models developed over the last 20 years or so along with our ability to peer into the brains of chronic pain patients are rapidly changing our notions regarding chronic pain. This review will use the example of chronic back pain to illustrate the new advances in understanding the mechanisms of chronic pain. The significance of this choice is evidenced by the impact of this particular condition on society. Moreover, this is the condition that we have studied for over ten years from the viewpoint of central nervous system mechanisms.

    In the USA, chronic and acute back pain is the most common cause of activity limitation in people younger than 45 years and the second most frequent reason for visits to physicians Hart et al. Data from other Western countries are similar. Estimates from the UK show low back pain as the largest single cause of absence from work, accounting for An article by Deyo Deyo, states that:.

    And yet the prevalence of back pain is perhaps matched in degree only by the lingering mystery accompanying it. Defining low back pain is difficult. In general, acute low back pain refers to 0—7 days of pain pain free at onset , subacute low back pain is classified as pain between 7 days and 3 months of duration, and chronic low back pain is defined as pain lasting for more than 3 months Frank, Furthermore, back pain can arise due to either mechanical or non-mechanical causes, the latter being associated with other underlying diseases.

    For instances in which such other processes are not identified, back pain is assumed to occur on a mechanical basis, even when an exact underlying anatomic abnormality cannot be clearly detected. Many people with mechanical back pain also show a neuropathic presentation traditionally classified as radiculopathy manifest by tingling, burning, or numbness Audette et al.

    Though commonly associated with acute disc herniation these neuropathic symptoms are also now commonly being identified in people with chronic low back pain. Animal models for chronic pain have become a fundamental tool with which underlying mechanisms can be systematically studied.

    Since then new models are continually being proposed that are becoming more sophisticated in their ability to more closely model real clinical conditions. Animal models for cancer pain Mantyh, , for spinal cord injury pain Yezierski, , and for migraine Yamamura et al. At minimum, these animal models confirm that chronic pain states are biological entities and not just the imagination of patients.

    Moreover, they allow for a mechanistic study of pathophysiology, and this has been a fantastic boon to understanding the peripheral and spinal cord mechanisms underlying various types of chronic pain. Where these models fall short, however, is in many clinical conditions where the actual correspondence between the purported model and the clinical manifestation remains to be directly tested.

    As a result we are often unsure if these models are providing specific mechanistic information or general hints as to the possible list of mechanisms that may underlie the true clinical condition. In chronic back pain, for example, do models of peripheral nerve injury provide insights into symptoms of back pain?

    What about skin or muscle inflammation? Another shortcoming is their inability to dispel suspicion regarding more complex conditions, such as CRPS and fibromyalgia, for which we do not even know how to begin building animal models. Thus in many respects the initial excitement that these models provided regarding the opportunity for designing new therapies for clinical pain conditions has already waned. It is now almost 20 years since the Bennett CCI model, and despite over a hundred peripheral and central molecular targets having been generated from these models and large sums of research dollars invested by pharmaceutical companies we have yet to identify any new therapy based on an animal model for neuropathic pain.

    The reasons behind this failure may be complex and multifactorial. Nonetheless, it underscores the necessity of translational studies where information generated in animal models are tested in humans and vice versa, allowing mechanistic notions to guide human research and hints from human studies tested thoroughly in animal models.

    Recent studies in this population have highlighted the importance of early mobilization and the early use of effective analgesic agents Hagen et al. Of this group, a high percentage will fail treatment and are often referred to pain clinics and centers, where multi-disciplinary techniques utilizing non-pharmacologic, pharmacologic and anesthesiologic interventions are variably beneficial. Most chronic low back pain patients, however, continue to have significant degrees of pain, are significantly limited in their functional capacity, and become emotionally altered by their chronic pain condition.

    A broad range of management options have been advocated including oral, topical and injectable medications, devices, surgical approaches, physical therapy, educational and psychological interventions, and others. Yet remarkably there remain a lack of well-designed and appropriately conducted clinical trials to evaluate the efficacy of these treatments Schnitzer et al.

    Furthermore, while the few short-term only weeks in length placebo-controlled trials conducted to date have found some support for the use of non-steroidal anti-inflammatory drugs NSAIDs and antidepressants in treating lower back pain, their results are usually not significant enough to reach the level of clinical effectiveness. A systematic review of antidepressants treatment for chronic back pain also concluded that they produce only a moderate symptom reduction Staiger et al.

    Others have side effects that outweigh their usefulness in relieving pain. The World Health Organization Advisory Panel likewise concluded that there is no single treatment superior to others for relieving chronic back pain Ehrlich, The lack of long-term and failure of short-term clinical trails on chronic low back pain is worsened by the fact that few if any studies have evaluated patients with a neuropathic component to their pain.

    Indeed, in many studies evidence of neuropathy is an exclusion criterion. Nevertheless, a significant number of individuals display a neuropathic component to their chronic back pain.

    This is of significant clinical importance considering that neuropathy has traditionally been unresponsive to treatment with NSAIDs, anti-depressants, and other pharmacologic agents.

    Nevertheless, disc space narrowing appears to be more strongly associated with back pain than other radiographic features Pye et al.

    Moreover, the histological composition of herniated disc material seems to correlate with clinical symptoms such as reported pain correlation coefficient 0.

    Another cause of pain and radicular symptoms seems to be due to pressure on the nerve tissue from ligamentum flavum and facet joints Okuda et al. A similar Danish study also showed a genetic influence, albeit with more modest results Hartvigsen et al. Other experiments have identified a number of candidate genes that underlie disc degeneration and pain, see Manek and MacGregor, , suggesting that genetic factors may also have an important role.

    As peripheral physical factors have failed to show a relationship with back pain, a long list of psychosocial and demographic factors have been studied. Cumulatively, however, these factors provide poor predictions regarding chronic pain. Depression is ranked as one of the strongest predictors for low back pain.

    This association is observed by multiple studies. The results indicate that depression and low back pain are interrelated correlation coefficient of about 0. Similar results have been reported earlier Reid et al. In order to investigate the predictive power of baseline depression on the transition from acute to chronic pain 3 months post-acute back pain , a recent prospective model evaluating the direct and indirect effects of cumulative trauma exposure, acute pain severity and disability, baseline depressive symptomology, and pain beliefs on chronic pain severity and disability Young et al.

    Acute pain intensity did not directly predict pain three months later and baseline pain beliefs failed to predict chronic pain. Despite these relatively weak relationships to chronic pain, the authors argued that their findings support the growing literature contending that progression to chronic pain is more dependent on psychosocial and occupational factors than on medical characteristics of the spinal condition.

    The prognostic value of factors influencing the course of low back pain and return to work in occupational health care was studied in a cohort of workers on sick leave between 3 and 6 weeks due to low back pain Heymans et al. The authors investigated the possible associations between a broad set of prognostic indicators related to characteristics of worker, job, low back pain, and psychosocial issues upon return to work lasting for a follow-up period of 12 months.

    The explained variation of the models was also calculated. Median time to return to work was 75 days. An earlier study examining workers with acute back pain found that of the recruited claimants Their model demonstrated that severe leg pain, obesity, high scores on a disability index and health questionnaire, and physical requirements of the workplace to which subjects would return were all significant, independent risk factors for chronicity Fransen et al.

    Smoking is also reported to increase risk for low back pain Feldman et al. In general, a long series of studies now describe psychosocial and psychological factors in predicting functional and social disability, where the interrelationship between ratings of catastrophizing, pain-related fear of re- injury, depression, disability, and pain severity are studied and modeled in combination with demographics in various chronic pain conditions.

    Yet while these factors may be associated with pain in certain individuals, attempts to create models of chronic back pain based upon them have been unproductive. For example, one model - the fear-avoidance model Vlaeyen and Linton, - suggests that fear of pain and related pain behaviors can be relieved by exposing individuals to movements and tasks they have avoided due to fear of re- injury, predicting that such exposure should then result in reducing the intensity of chronic pain.

    To test this, a recent randomized controlled trial investigation Woods and Asmundson, assessed effectiveness of exposure relative to other conditions in 45 chronic low back pain patients.

    Although the exposed patients improved on a long list of measures related to fear, the primary outcome measure regarding their disability showed no improvement. Further, if psychological and social factors had strong power in predicting chronic back pain, then quality of life and health care utilization, which have been shown to be dependent upon such factors Keeley et al. Yet even when back pain is caused by a major physical trauma Harris et al.

    In summary, there is a long list of risk factors but no dominant physical or psychosocial parameter that can substantially explain chronic pain. This clinical data e. Importantly, the emerging evidence for a genetic component also implies that certain brain-derived parameters described below may be part of a predisposition for chronic pain rather than its consequence.

    The primary objective of research in our lab over the last ten years or so has been to develop brain markers discriminating chronic pain patients from healthy subjects.

    We published the first study showing that brain chemistry is abnormal in chronic back pain patients as compared to matched healthy controls, using magnetic resonance spectroscopy Grachev et al.

    Our study revealed correlations between brain regional chemistry and clinical parameters of pain duration, intensity, and McGill Questionnaire dimensions. We found that the relative concentrations of chemicals in the cingulate cortex and thalamus reflected pain duration in opposite directions. Moreover, chemical concentrations were found to positively correlate with sensory, affective, and intensity ratings of chronic back pain. In the study we reported: Yet, the topic remains in its infancy.

    It is likely that the method would provide clinically important information regarding various chronic pain conditions, especially as it is becoming an important biomarker in neurodegenerative conditions.

    For example metabolic changes are observed in presymptomatic mutation carriers years before onset of Alzheimer disease Godbolt et al. An alternative approach is the use of positron emission tomography PET to examine binding changes for various ligands in chronic pain.

    With this approach a recent study identified mu-opiate binding decreases in fibromyalgia, with the decrease being related to the pain characteristics in a number of brain regions Harris et al.

    Dopamine release in the basal ganglia is also disrupted in fibromyalgia patients Wood et al. We reported that, in contrast to age, sex, and education matched healthy controls, chronic back pain and CRPS patients are significantly impaired on an emotional decision-making task Apkarian et al.

    The latter implies that the brain mechanisms underlying the two types of chronic pain may be distinct and thus also distinctly modulate emotional states. A long list of cognitive abnormalities has been described in chronic pain patients. The most noteworthy are attentional and memory deficits Dick and Rashiq, ; Sjogren et al. However, little effort has been placed in differentiating such deficits based on chronic pain type, and only the results we describe on emotional decision-making has been related to the brain see below.

    We concluded the brain chemistry study by stating: This result has now been replicated in chronic back pain and other types of chronic pain conditions Kuchinad et al.

    Notably we were again able to show that these morphological changes are correlated with the clinical parameters of the condition.

    Neocortical gray matter volume, after correcting for intracranial volume, age and sex, was significantly less in chronic back pain patients than in matched controls. Moreover, this parameter showed dependence on pain duration, with similar slopes for patients with and without neuropathic radicular back pain, but only significantly for the neuropathic back pain group.

    When the same data was analyzed to directly compare regional gray matter differences between CBP patients and controls, two brain areas showed the most robust difference: Moreover, to differentiate the relationship between regional gray matter and pain characteristics, we derived an index of change in DLPFC gray matter, corrected for age and gender confounds, and regressed it with pain characteristics.

    Furthermore, when CBP subgroups were analyzed separately, we discovered distinct relationships. Thus, regional gray matter changes are strongly related to pain characteristics, and this pattern is different for neuropathic compared with non-neuropathic types.

    This dissociation is consistent with extensive clinical data showing that neuropathic pain conditions are more debilitating and have a stronger negative affect Dworkin, , and we suggested that this difference is directly attributable to the larger decrease in gray matter density in the DLPFC of neuropathic CBP patients.

    We recently revealed that the spontaneous pain of chronic pain patients fluctuates in the scale of seconds to minutes, that these fluctuations are distinct for various chronic pain conditions, and that normal healthy subjects are unable to mimic them Foss et al. Participants were instructed to continuously rate their subjective assessment of the intensity of pain.

    We observed that the fluctuations of spontaneous pain do not possess stable mean or variance, implying that these time series can be better characterized by fractal analysis. To this end, we applied time and frequency domain techniques to characterize variability of pain ratings with a single parameter: We demonstrated that D is distinct between types of chronic pain, and from ratings of thermal stimulation and of imagined pain; and that there is a correspondence between D for pain ratings and D for brain activity in chronic back pain patients using fMRI.

    Back pain patients mainly show anti-persistence; meaning that on the average more intense pain is followed by weaker pain. By contrast, PHN patients show both anti-persistent and persistent time series. We concluded the study by stating: This study remains the only one where spontaneous pain fluctuations at such time scales have been characterized. Using non-invasive brain imaging fMRI in combination with online ratings of fluctuations of spontaneous pain we identified the brain activity idiosyncratic to chronic back pain Baliki et al.

    Our data was analyzed using two different vectors: The brain activity obtained, after subtracting a visual rating task that corrects for the cognitive, evaluative and motor confounds, differed greatly for the two conditions.

    During epochs when pain was high, activation of the medial prefrontal cortex mPFC was most robust, with less activity seen in the amygdala and the ventral striatum. For periods when pain was rapidly increasing, however, the insula, anterior cingulate cortex ACC , multiple cortical parietal regions, and the cerebellum became activated. In the same study, using the same procedures continuous ratings of perceived pain and subtraction of a visual control , we identified brain activity in back pain patients and healthy controls for an acute thermal stimulus applied to the back.

    The results showed no difference between patients and healthy controls for brain regions activated during acute thermal pain stimulation of the back. This activity pattern closely matched brain activity observed in earlier studies regarding acute pain in healthy subjects Apkarian et al. Moreover, in both groups mPFC activity was strongly correlated with pain intensity at the time of scan.

    In contrast, when levels of anxiety or depression were examined, none of the brain regions identified showed any relationship to these parameters. These results indicate that spontaneous CBP engages the emotional-mentalizing region of the brain into a state of continued negative emotions suffering regarding the self, punctuated by occasional nociceptive inputs that perpetuate the state.

    The sustained prefrontal activity is most likely related to the maladaptive psychological and behavioral cost associated with chronic pain. In the discussion of this paper we pose the question: What is chronic back pain? The answer we offered is particularly relevant to the present review:.

    It is associated with a specific pattern of brain chemical changes [see 2. Therefore, they must be considered an integral part of the clinical state of CBP. A recent review of advances regarding mechanisms of back pain that heavily relies on our findings concludes:. They display a number of biomechanical abnormalities, however treatment directed at normalising lumbar biomechanics has little effect and there is no relationship between changes in outcome and changes in spinal mechanics.

    Finally, these patients demonstrate some psychological problems but psychologically based treatments offer only partial solution to the problem. A possible explanation for these findings is that they are epiphenomena, features that are incidental to a problem of neurological reorganisation and degeneration.

    We do not, however, completely discount the contribution of peripheral injury related signals that may be critical in the final neurological outcome. In fact we continue to search for approaches that may provide information regarding spinal cord processes that we can relate to brain abnormalities.

    There seems to be a tight relationship between impairments in emotional decision-making and activity in brain regions involved in the perception of ongoing chronic back pain, suggesting that the two may be causally related.

    As the extent of impairment on emotional decision making in chronic back pain is directly related on the magnitude of pain suffering by the patient at the time the task is performed, and as the extent of mPFC activity is also tightly correlated to the magnitude of pain perceived by these patients, one can conclude that these events are in fact inter-related.

    There is also a tight relationship between brain regional atrophy and brain chemistry abnormalities. As the primary chemical observed to decrease in DLPFC was N-acetyl-aspartate and as this chemical is mainly found within the soma of neurons, one is tempted to conclude that there is in fact a neuronal density decrease in the DLPFC that is more severe in patients that have had the condition for longer times.

    The latter suggests that the neuronal loss is a continuous ongoing process that is at least partially irreversible. Nevertheless, these implications need to be directly tested. The question regarding the extent to which brain atrophy may be reversed with successful and aggressive therapy is one that requires urgent determination. It should also be noted that genetic predispositions cannot be excluded regarding both abnormal brain chemistry and decreased regional gray matter density.

    In fact, the published results regarding the relationship between whole neocortical gray matter volume and its decrease with pain duration indicates that if one extrapolates the data to time zero i. The observation that spontaneous pain in chronic pain fluctuates over the scale of seconds to minutes is novel and potentially provides a simple objective tool for determining the presence and magnitude of chronic pain in the clinic.

    Considering that normal healthy subjects are unable to mimic these fluctuations, and report fluctuations in response to applied thermal painful stimuli that do not even remotely resemble those of chronic pain patients, this method would be particularly useful in identifying chronic pain patients.

    Furthermore, given that distinct chronic clinical pain conditions seem to result in distinct patterns of fluctuations, it could also serve to clinically discriminate between patient groups. Since fluctuations likely reflect the integration of pain signaling mechanisms with pain coping mechanisms, the presence of distinct fluctuation patterns suggests that the underlying mechanisms for various clinical chronic pain conditions must also be distinct.

    This point was recently directly tested by us and is further elaborated below. Given that distinct chronic pain conditions show unique fluctuations of spontaneous pain, fluctuation patterns provide a unique signature with which one can interrogate the brain regarding related neuronal activity. By utilizing this approach our fMRI study indicated that when spontaneous chronic back pain was increasing, it activated brain regions closely resembling those found to be active during acute pain.

    By contrast, during time periods when spontaneous pain was sustained at a high level, the mPFC was the only primary area activated. Thus it appears that in these patients an initial nociceptive signal invades several brain pain regions, and then goes on to be sustained in the mPFC. Given the decreased levels of NAA and gray matter density in the DLPFC of these patients, together the results evidence a tight interplay between brain activity, neuronal death, and cognitive abnormalities in chronic back pain.

    The causal interrelationship between these factors remains to be demonstrated, and the temporal evolution of these changes in relation to the initial injury and relative to each other needs to be studied. Still, it is remarkable that inter-relationships between brain derived activity, atrophy, chemistry, and cognitive parameters can all be found by examination of only a single clinical chronic pain condition. Moreover, such studies provide a new means of mapping clinical parameters to brain parameters.

    The brain biomarkers discussed above, for example, all show tight relationships albeit to different extents with certain clinical characteristics, particularly back pain intensity and duration. They do not, however, relate to patient increases in anxiety or depression, suggesting that these psychosocial factors are not directly related to the chronic pain condition and are instead represented by separate brain mechanisms.

    In sum, investigating chronic pain in terms of its underlying neural mechanisms not only sheds insight on how brain-derived biomarkers relate to one another, but also provides a means for mapping clinical parameters in the brain and reevaluating prior speculations of their role in the condition. An additional thesis of this review is that different chronic pain conditions involve distinct brain activity. We argue that at least two parameters control the diversity of these patterns: Acute pain appears to activate a fairly constant set of brain regions, as demonstrated in a meta-analysis Apkarian et al.

    In contrast with acute pain, figure 1 shows that distinct chronic pain conditions such as CBP, post-herpetic neuralgia PHN , osteoarthritis of the knee OA , and pelvic pain PP all show different patterns of brain activity when ratings of either evoked pain or fluctuating spontaneous pain are contrasted with visual control task.

    There is now growing data regarding brain activity in various clinical pain conditions. However, direct comparison of reported brain activations are complicated by the difficulty of comparing results from diverse labs, distinct paradigms, and a variety of unique manipulations performed. Nevertheless, despite these complications a meta-analysis confirms that overall brain activity patterns in chronic pain patients generally diverge from that seen in acute pain, particularly with respect to the emerging prominence of prefrontal cortex activations Apkarian et al.

    The data shown in figure 1 are more reliably comparable in that all the results were generated within our lab using the same fMRI magnet, the same data analysis techniques, and the same general experimental approach, all of which provides more confidence that observed differences are less likely to be due to non-interesting confounds. In all cases presented the activations are taken from a contrast between the pain state and a visual rating control task, which has allowed us to ascertain brain activity for spontaneous pain in three distinct clinical conditions.

    Consistent with the discussion above, where distinct temporal properties of spontaneous pain were seen for CBP versus PHN, brain activity related to spontaneous pain appears to also be distinct between these two groups, see Geha et al.

    The PHN patients studied all also suffered from touch-evoked pain tactile allodynia , and were further tested while they rated pain evoked by stroking the allodynic skin in contrast to visual rating Geha et al.

    We also conducted a study on knee OA examining pain evoked by mechanical stimulation of the painful joint. While we were unable to separate spontaneous pain from evoked pain in these patients, the brain activity elicited by mechanical stimulation of the painful joint in knee OA is in itself distinct from acute pain and other chronic painful conditions. Lastly, while our studies with chronic pelvic pain patients are still in the initial stages, preliminary data suggests that this spontaneous visceral type of pain can also be uniquely differentiated from other types of pain in the brain.

    Group average brain activity for pain in 6 different chronic pain populations or conditions. In all cases activity for continuous rating of pain contrasted with rating equivalent visual bar magnitudes is shown. Figure 2 reveals in some of the same groups and conditions as in figure 1 that the brain regions correlating with pain ratings are more circumscribed and again distinct for each condition and group. In healthy subjects, pain ratings during the application of thermal painful stimuli are encoded in the insula, anterior cingulate, DLPFC, thalamus and basal ganglia.

    Allodynia pain ratings in PHN patients, on the other hand, appear to be represented in the insula, S2 and basal ganglia. We attribute these differences to the type of peripheral injury neuropathic, inflammatory or both , to the duration that each group of patients have had the condition, as well as to the type of stimulus used thermal, allodynia, knee OA.

    The memory traces of pain both prior to injury as well as those accumulated since injury — which would continue to be stored as long as the pain persists and as such the duration of chronic pain would impart a specific brain anatomical and physiological reorganization signature -may also be critical in the transition from acute to chronic pain and in the persistence of chronic pain see below.

    While resolving the relationships between all these parameters will require many years of study, the identification of distinct activity patterns and their links to pain intensity provides an important initial step in connecting clinical characteristics with brain parameters in various chronic pain conditions.

    Brain regions modulated by rating perceived pain for some of the conditions shown in Figure 1. Abbreviations are the same as in Figure 1. In a recent study we used this manipulation to examine the relationship between brain activity and both spontaneous and touch-evoked pain in PHN patients Geha et al.

    The general concept is simple. If Lidocaine treatment modulates pain, then subjects scanned before and after the treatment should show a modulation of brain regions related to their subjective reports of changes in pain. Clinically this procedure has been shown to result in an initial decrease in pain that is reported maximum at 6 hours after application of the patch, even though patients report further benefits with continued use.

    Therefore, these studies were also designed to test whether fMRI can be used to differentiate short-term from long-term effects at the level of brain activity.

    The general logic was that the specific therapy has the advantage that it acts locally by modulating Na channel excitability. Thus, it cannot confound the effects of subjective perceptual changes by direct action of the drug on the brain. Moreover, just as studies have begun to identify those brain regions activated for spontaneous versus evoked pain, this therapeutic manipulation afforded the opportunity to make further discriminations between regions that respond to treatment acutely versus those modulated in the longer run.

    For spontaneous pain of PHN Geha et al. In addition, the brain regions responding to the therapy in the short tem were in fact distinct from those responding in the longer term. Seventeen distinct brain regions were identified activated for spontaneous pain. Only twelve of these regions, however, were modulated by the lidocaine therapy.

    Of those, only two regions decreased in activity in the short term left thalamus and ACC. Another two decreased in activity in the longer term left vental striatum and left amygdala. These four areas, therefore, were the most specific responses to the therapy and distinguished between acute effects of the therapy from the longer-term effects.

    The mechanisms underlying this brain response shift between short and long-term therapy remains unclear. It may underlie differential sensitivity of peripheral fibers as well as differential reorganization of central circuitry.

    More importantly the effects suggest functional segregation of brain circuitry where the short term effects appear to be mediated more by the spinothalamic tract while the longer effects more through pathways outside of the spinothalamic tract, especially those with projections from non-peptidergic IB4 neurons terminating in spinal cord lamina II Braz et al. In contrast with spontaneous pain, touch evoked pain dynamical mechanical allodynia was not modulated by lidocaine therapy Geha et al.

    Therefore therapy effects could not be distinguished between brain regions. Across the three scan sessions, however, bilateral ventral striatum and left medial temporal gyrus including amygdala and extended amygdala were the regions best correlated to the change in allodynia pain. These same regions were also the ones that best coded the change in spontaneous pain with lidocaine therapy, although there was minimal overlap in the subdivisions of the ventral striatum and medial temporal gyrus for coding the two types of pain.

    In an earlier study we showed that brain responses to an analgesic can be studied in individual subjects Baliki et al. Studying a psoriatic arthritis patient we found that decreases in activity in S2 and anterior insula were tightly correlated with the change in pain perception following ingesting the drug.

    Statistical power in this case was obtained by performing repeated fMRI scans. Repeat scan fMRI study in an experimental sensitization paradigm in healthy subjects has also been studied for gabapentin Iannetti et al. In this case the main outcome was a reduction in deactivations during sensitization. While these studies show that fMRI can be used to study analgesics, they are limited to drugs that show minimal central, especially cortical, effects.

    It is not clear how drugs that bind to receptors in the cortex would be studied with fMRI, as a long list of pitfalls may distort such studies. In the context of understanding functional specialization of brain activity in chronic pain, the use of analgesics and their relationship to regional brain modulation provides a powerful tool for further parcellating the functional specialization of various brain activities. Such an approach has been used recently, for example, to differentiate brain activations in acute pain in relation to modulation with opiate analgesia using PET studies Zubieta et al.

    However, whether fMRI may eventually be used for identifying new therapeutic drugs remains to be demonstrated, for a discussion on these issues see Borsook et al. In PHN we now have evidence that brain activity during a visual attentional task is modulated by the intensity of ongoing pain at the time of performing the task Geha et al.

    The finding provides insight into the adjustments the brain in chronic pain undergoes to compensate for the condition. For instance, the result shows that even in a simple, clearly non-emotional task, activity in mPFC is increased, while motor and posterior parietal cortical activity is decreased, in proportion to the intensity of the chronic PHN pain. The actual parameters that control this compensation remain to be identified. The observation is has two important implications.

    First, it indicates the pitfall of studying brain activity in chronic pain patients in general by indicating that any task that such subjects perform is distorted by the ongoing presence of the chronic pain. Therefore, observed brain activity differences in contrasts between healthy subjects and chronic pain patients on a given task may be due to this distortion rather than actual differences in neuronal processing. This would explain the inconsistent results of a long list of studies performed using acute painful stimuli to understand distinctions in pain processing for various clinical pain conditions, see Apkarian et al.

    Second, it suggests that while the effects of chronic pain can in fact be demonstrated and studied by using simple everyday non-painful tasks, comparisons based on simple subtractions leading to contrast maps may be misleading.

    On the other hand, brain activity comparisons between chronic pain patients and normal controls for peripheral stimuli can be more meaningful and result in important new information if brain activity is compared after equating pain perception magnitudes, rather than just comparing stimulus evoked activity differences.

    This approach has been adopted to compare brain activity in chronic back pain and fibromyalgia to mechanical painful stimuli, and in both patient groups brain activity seems exaggerated relative to healthy subjects, after equating pain perception Giesecke et al. Characterization of this state is fundamental in neuroimaging studies, because it defines the baseline or control against which other task-related conditions can be compared.

    The notion of a specific network of brain regions active in rest-states RSN came from the observation of a consistent pattern of deactivations seen across many goal-oriented tasks Shulman et al. This view attributes signal decreases during cognitive tasks in PET studies in the RSNs present at baseline and attenuated during specific goal-oriented tasks Raichle et al. In other words, what was activated in resting state is inferred by identifying what is being deactivated during a task.

    The mPFC, precuneus, and hippocampus are commonly observed in RSNs, which seem to be particularly sensitive to cognitive states in self-referential tasks Simpson, Jr.

    Thus, RSNs are proposed to be involved in attending to environmental stimuli, both internally and externally generated Raichle et al. We recently demonstrated the impact of chronic pain on resting state brain activity Baliki et al. In a group of CBP patients and healthy subjects, participants tracked the variability of a bar presented on a screen.

    Performance of this task was the same between the two groups, as was the brain activity positively engaged in the task. However, deactivations in CBP patients were less. As the deactivations in this task involve the mPFC and precuneus, and given that in CBP the mPFC is continuously overactive due to the presence of spontaneous pain, we propose that the decreased deactivation is a direct consequence of the chronic pain.

    There is a growing literature regarding the role of deactivation in brain function in general Greicius et al. Abnormal deactivations therefore imply that the RSN itself may be abnormal.

    When distinct brain regional activity were used as seeds, as well as the conjunction between all networks identified with six seeds, in CBP and in controls, we observed that these networks were not comparable between the two groups and that some elements had shrunk in space while others had enlarged. These results demonstrate that the impact of back pain on the brain can be studied with this simple task and that specific patterns of RSN activity may be related to the temporal evolution of chronic pain.

    A similar approach was recently used to study RSN changes during acute pain in healthy subjects for a cognitive task Seminowicz and Davis, The study shows that the RSN changed in a pattern opposite to our observation in CBP, namely, the positive RSN component was enhanced while the negative component remained unchanged or further enhanced.

    The latter at least demonstrates yet again that studying the brain in acute pain may in fact provide the wrong clues, as to the impact of chronic pain on the brain. There has been a historic divide between scientists identifying themselves as localizationists and those who considered the brain to be a connected network, where the dynamics of the connected network characterize brain states.

    This is now changing, and it is now more widely accepted that both localization and integration are present in the central nervous system at almost every level examined. This view is particularly supported by functional brain imaging research, which can examine regional brain activity and integrate such activity into networks whose properties may be studied using a long list of recently developed tools.

    We have used a similar approach to examine the topological properties of the connectivity of the functional brain when network connectivity for all gray matter voxels together is examined for a variety of tasks Eguiluz et al. These results indicate that the healthy brain can be regarded as a network with fast signal processing, able to synchronize and manifests well-defined properties that make it resistant to failure.

    The resting brain state and its properties in fact are more recent extensions in the topic and perhaps some of the most exciting new developments in our understanding of the functional human brain as a dynamical network. The earlier sections of this review have been dedicated more to the issue of which brain regions are specifically engaged in various types of chronic pain.

    Taken more generally, our position is that subjective states can only really be understood in the context of the dynamics of the brain when it is viewed as a connected network. Demonstrating abnormal resting state network in CBP is the most concrete step towards this effort. We have also recently shown that the perception of tactile allodynia pain in PHN can be understood as a temporal evolution of distinct brain states, as characterized by network connectivity Geha et al.

    While tactile allodynia activity in the putamen was seen as best correlated to perception, this activity preceded perception of allodynia by a few seconds and lagged behind the touch stimulus that gave rise to the pain perception. We reasoned therefore that studying brain connectivity in relation to this signal should indicate brain connectivity properties relative to perception of allodynia. This approach revealed two highly distinct maps.

    When the signal was delayed to better match the stimulus, large parts of the parietal cortex were anti-correlated, while the brainstem, cerebellar, and inferior temporal areas were positively correlated with the delayed seed signal. Alternatively, when the signal was advanced to better match with perception, thalamus and large parts of parietal cortex were positively correlated, while medial prefrontal cortex was anti-correlated with the delayed seed signal.

    As correlations are transitive, and given that putamen activity was correlated to perceived magnitude of allodynia, the networks identified were also correlated to the magnitude of allodynia. Therefore, the observed spatial-temporal change in brain connectivity reflects transmission of allodynia-related information within the brain.

    This demonstration poses many novel questions that need to be investigated in the future. Therefore, we expected only a partial normalization of secondary heat hyperalgesia in the forearm and not necessarily an overall reduction of clinical pain. Informed consent was obtained from all subjects and the study protocol conformed to the ethical guidelines of the Declaration of Helsinki. The University of Florida Institutional Review Board approved the procedures and protocol for this study.

    Prior to testing, all subjects underwent a clinical examination and were excluded from the study if they had abnormal findings unrelated to FM. Use of analgesics, including non-steroidal anti-inflammatory drugs NSAID and acetaminophen, was not allowed during the study.

    All subjects were asked to discontinue analgesics for the duration of five drug half-lives before testing, except narcotics which had to be stopped at least two weeks prior to study entry. Special care was taken to exclude participants from the study who previously had adverse events to lidocaine injections.

    The study drug was always administered by the study physician R. A parallel group, randomized, double-blind, placebo-controlled study design was used to evaluate the effects of a single lidocaine injection on primary and secondary hyperalgesia of NC and FM subjects Figure 1. The injections site of the study drug was the TrapM of a randomly selected shoulder corresponding with a tender point TP according to the American College of Rheumatology FM Criteria [ 55 ].

    The NC and FM participants were placed on the examination table in the supine position. All participants were tested in the same order depicted in Figure 1. Although the shoulder used for TrapM TP stimulation was selected using a counter-balanced design, each individual received all test and stimulation procedures to the selected shoulder pressure pain threshold [PPT] testing and tonic muscle stimulation and ipsilateral forearm heat testing.

    Shoulder injections were given into the same TrapM TP used for stimulation and testing. Flow diagram of study procedures. PPTs were tested at the shoulder primary hyperalgesia and 10 sec thermal ramps were applied to the forearms secondary hyperalgesia before and after the injections. The left side of this figure shows the pressure device used for tonic mechanical TrapM stimulation. Pressurized air was applied to the muscle stimulator resulting in expansion of a telescoping prong diameter 1cm for up to 4 cm.

    A calibrated force transducer mounted to the tip of the prong provided real-time information on an electronic display. This information was used to continuously adjust tonic pressure stimuli to the TrapM TP. Testing of the TP contralateral to the injection site was also done as a condition check. Subsequently all subjects rated individually adjusted 10 sec heat ramp stimuli applied to the forearm ipsilateral to the side subsequently used for TrapM TP stimulation.

    Testing was done in counterbalanced fashion to avoid order effects. While resting comfortably, all subjects had individually adjusted tonic pressure stimulation applied to a randomly selected TrapM TP to normalize shoulder pain at the TrapM across FM and NC subjects 4.

    The application of pressure was only interrupted during the injection of the study drug. Otherwise tonic pressure was carefully maintained at the predetermined level throughout the experiment. The total duration of tonic TrapM TP stimulation was approximately 30 min for each subject. Shoulder pain ratings were obtained at the beginning, after 5 min, and at the end of tonic TrapM stimulation. After 5 min of tonic pressure stimulation, 10 sec sensitivity adjusted heat ramp pain ratings were obtained for the second time at the ipsilateral forearm see 2.

    After suprathreshold heat pain testing at the forearm, tonic mechanical stimulation of the TrapM was interrupted for 1 min for repeat PPT testing. Slow injection of the study medication was undertaken to prevent lidocaine related side effects that could jeopardize allocation concealment.

    The study drug was always prepared by a study nurse who otherwise did not participate in the experiments. A 5 min pause after the injection was used to allow the medications to reach maximal effectiveness.

    For this purpose the subjects were brought into the seated position and the study drug was slowly injected over 1 min by the study physician R. The subjects were frequently asked to report any injection related sensation.

    If such sensations occurred the injection was interrupted and only resumed after resolution of all injection related symptoms. After the injection, a 5 min waiting period was observed by all subjects to allow the study drug to take full effect. During this time the subjects remained seated and vital signs were monitored. Afterwards they were again brought into the supine position and tonic shoulder stimulation resumed at the previously stimulated TrapM TP site.

    Special care was taken not to inject study medication into the skin because cutaneous anesthesia could have resulted in removing the blind from subjects and investigators. At the end of the trial the participants were asked to estimate whether they had been injected with lidocaine, placebo, or were unable to tell whether they had been injected with either.

    A 15 cm mechanical visual analogue scale 0 — 10 was used for ratings of experimental pain during mechanical and heat stimulation [ 29 ]. The same mechanical visual analogue scale 0 — 10 was also used for ratings of somatic pain of all study participants before and after the experimental protocol [ 30 ].

    Although the NC subjects were required to be pain free at enrollment their somatic pain ratings were obtained before and after the testing session to capture possible new onset pains like back pain, headaches, etc.

    Tonic pressure stimulation was applied to the TrapM halfway between the neck and acromion using a proprietary muscle stimulator with a telescoping plastic prong see Figure 1.

    The round telescoping prong diameter: The pressure stimulation site was selected in a counterbalanced fashion. The TrapM TP was marked with a marker pen for stimulation and injection. Constant mechanical pressure was applied to the TrapM total time: These brief intervals were considered useful to prevent tissue damage by the prong as well as to limit the duration of uninterrupted experimental pain.

    The intensity of mechanical stimuli was carefully maintained for each individual at a pre-determined pressure level see 2. This was particularly important after muscle injections, since analgesia or hyperalgesia were likely to affect the stimulus dependent pain ratings.

    This manipulation provided a measure of mechanical pain sensitivity for each subject. To identify individual stimulus intensities associated with such moderate pressure pain ratings 4. If necessary, the pressure was raised or lowered during subsequent trials until subjects achieved target pressure pain ratings of 4.

    This pressure intensity was subsequently used for the tonic pressure stimulation at the TrapM TP. For heat pain testing the preheated probe was brought into firm contact with the skin of the volar forearm. Experimental pain was elicited by 10 sec sensitivity adjusted heat pulses to the volar surface of the forearm ispilateral to the stimulation and injection site see 2.

    Three adjusted 10 sec heat pulses were applied to three different areas of the forearm separated by 10 cm, in counterbalanced order. At the end of each 10 sec heat stimulus the participants were immediately asked to rate the intensity of their experimental pain sensations using the VAS. Thus, to measure heat pain sensitivity, we determined the unique temperature for each subject during preliminary experiments that resulted in final heat pain ratings of 4.

    Stimulus intensities resulting in such pain ratings 4. To identify individual stimulus intensities associated with moderate heat pain ratings 4. The temperature slowly increased from baseline to target temperature by 0. After it reached target temperature it was maintained for 2 sec. If necessary, peak temperatures were raised or lowered during subsequent trials until subjects achieved maximal heat pain ratings of 4.

    This temperature was subsequently used for all heat pain experiments. Thus, similar to pressure pain stimuli, these heat pain trials provided a standard condition which was designed to be very similar within and between subject groups. All subjects were trained to attend to and rate mechanical pain stimuli applied to the TrapM. The test sites were located at the trapezius muscle TP and identical to those chosen for the muscle injection.

    The mechanical force transmitted to the muscle was tested with a calibrated mechanical pressure algometer Somedic AB, Horby, Sweden. The rubber tip of the algometer was 1 cm in diameter.

    The subjects were instructed to push a hand-held button when the sensation changed from pressure to pain at the examination site. PPT testing was stopped at that moment and the results were automatically recorded. Nine paired TPs as defined by the ACR Criteria [ 55 ] and two control points at the center of the right forearm and the right thumbnail were assessed by a trained investigator using a Wagner Dolorimeter Force Measurement, Greenwich, CT.

    The rubber tip of the Dolorimeter was 1 cm in diameter. The subjects were instructed to report when the sensation at the examination site changed from pressure to pain.

    Statistical analyses were conducted using SPSS All group results were averaged SD. A priori hypotheses were evaluated by simple contrasts two-tailed. We recruited 22 middle-aged healthy pain-free female subjects [mean age SD: NC and FM participants had 5. All participants were right handed except two females and included 41 Caucasian Non-Hispanics, four African-American and four Hispanic subjects. The healthy subjects reported no somatic pain before and after the muscle injections.

    To achieve maximum heat pain ratings of 4. All participants underwent prolonged sensitivity adjusted tonic pressure stimulation at the TrapM and 10 sec sensitivity adjusted heat stimulation at the forearm Average tonic pressure used to achieve shoulder pain ratings of 4. To achieve similar intensity levels of heat pain ratings at the forearm, stimulus temperatures of In order to achieve tonic pressure pain ratings of 4.

    All study participants received either lidocaine or placebo injections into the same TrapM area where tonic mechanical stimuli were applied throughout the experiments. Tonic muscle stimulation was only briefly interrupted for the injection and for measuring PPT at the shoulder Figure 1.

    Afterwards tonic pressure was resumed at the same predetermined intensity as before. PPT [mean SD ] were measured with an electronic algometer at baseline, before, and after shoulder injections with lidocaine or placebo.

    However, no significant PPT changes occurred at the opposite shoulder over time in any of the four groups with either lidocaine or saline injections. The natural history of tonic TrapM pain was determined over the first 30 sec of shoulder stimulation, followed by tonic pain ratings before and after muscle injections Figure 4.

    As planned, the initial pain ratings of sensitivity adjusted tonic muscle stimuli Tonic-start were similar across groups and close to 4. After the TrapM injections the tonic pressure pain ratings of both NC groups diminished further as did the mean tonic pain ratings of both FM groups Figure 4. The statistical analysis shown below was performed to assess: Effects of muscle injections on sensitivity adjusted pressure pain ratings at the TrapM.

    Whereas one likely explanation for this reduction of pressure pain in NC is habituation, this did not seem to occur in FM participants [ 36 ]. Their pressure pain ratings only declined after the muscle injections, although these effects were not different for lidocaine or placebo.

    Heat pain ratings were obtained before and after shoulder injections with either lidocaine or placebo into the TrapM TP see Figure 5. As planned the mean pain ratings of 10 sec heat pulses at the forearm were similar for all groups at baseline see Table 2.

    Subsequently, no significant change in heat pain ratings was observed during tonic TrapM pressure and injection conditions in any group of subjects, except FM participants who were injected with lidocaine. Heat pain ratings of NC and FM subjects at the forearm. For this experiment, 10 sec heat stimuli to the forearm were individually adjusted to achieve maximal pain ratings of 4.

    At the end of the experiments the study participants were asked to estimate whether they received active study drug or placebo. A single lidocaine injection into a TrapM TP of FM subjects resulted in decreased mechanical hyperalgesia at the shoulder as well as reduction of distal secondary heat hyperalgesia at the forearm.

    Heat hyperalgesia was present in FM participants because they required significantly lower stimulus intensities than NC subjects to achieve moderate heat pain ratings of 4. Whereas lidocaine injections resulted in selective reductions of heat pain ratings of FM subjects which most likely reflects anti-hyperalgesic mechanisms, they had no analgesic effects on NC subjects.

    Similarly, the anti-hyperalgesic effects in FM participants were unlikely related to systemic lidocaine absorption because only a very small dose 50 mg was injected into one muscle. Thus, these results show for the first time that reductions of impulse input from painful muscle tissue at least partially normalize distal heat hyperalgesia in FM patients, similar to local anesthetic blockade in other chronic pain syndromes, such as CRPS and IBS.

    Tests using multiple local anesthetic injections into painful muscle areas may be required to determine significant effects of local anesthetic blockade on overall clinical pain. If tonic impulse input from muscles and other deep tissues is at least partly responsible for induction and maintenance of widespread FM pain, it is important to consider potential primary afferent mechanisms.

    The present study provides evidence that TrapM impulse input at least partly maintains secondary heat hyperalgesia of FM subjects at distant sites like the forearm.

    This finding argues against widespread sensitization of cutaneous nociceptors as an alternative FM mechanism. It is also supported by sensory testing of FM patients which showed abnormalities of cutaneous C-fiber pain specifically related to central abnormalities of temporal summation not sensitization of heat nociceptors [ 38 ]. Although our results support a role for impulse input from muscles in maintaining secondary heat hyperalgesia, no direct evidence for such input is presently available.

    However, several deep tissue abnormalities, including ragged red fibers and decreased microcirculation of muscles [ 4 — 6 ; 10 ; 11 ; 19 ; 27 ], provide indirect evidence for such mechanisms in FM, which may result in sensitization of intramuscular nociceptors, specifically ASIC 3 [ 35 ]. This type of sensitization may also depend on up-regulation of N-methyl-D-aspartate receptors and substance-P in deep tissues, as has been previously demonstrated in FM [ 5 ; 20 ].

    The importance of peripheral impulse activity in dynamically maintaining central sensitization has been proposed for other chronic pain syndromes, like CRPS and IBS. Thus, understanding the peripheral mechanisms of one chronic pain condition, such as FM, may provide additional insights into the pathophysiology of IBS.

    Not surprisingly, the normalization of heat hyperalgesia in our FM study was limited by the small dose injected into a single site. This limitation and the large variability in baseline clinical pain likely accounted for the observed lack of effects on overall clinical pain.

    Likewise, overall FM pain may be based on impulse input from multiple sites and therefore one might not expect effects on clinical pain after a single injection [ 49 ]. Overall, this study was not designed to develop or evaluate a treatment for FM, but rather test a highly specific mechanistic hypothesis about the contribution of muscle impulse input to secondary FM hyperalgesia.

    Nevertheless, it is possible that multiple injections into painful muscle areas would effectively reduce ongoing FM pain. The feasibility of local anesthetics treatments was indirectly supported by observed pain reductions in CRPS and IBS patients [ 31 ; 52 ; 53 ]. If local anesthetic effects on overall clinical pain are indeed similar across these conditions, then one might predict long lasting effects in FM, similar to those observed for CRPS and IBS.

    Considerable evidence from studies of local anesthetics on normal and abnormal ion channels showed that injured nerves or nerve terminals were blocked for a much longer time than predicted by the pharmacokinetics of local anesthetics [ 9 ; 34 ].

    The effects of local injection into a single TP may have implications for understanding the mechanisms of widespread FM pain, because it is well known that small areas of local pain can have enhancing effects on overall pain sensitivity. This effect, however, depends on several factors including the duration of pain.

    Towards a theory of chronic pain

    a list of descriptors reflecting spontaneous ongoing or paroxysmal pain, evoked pain (i.e. the Neuropathic Pain Scale was developed for the assess- . Assessment of the psychometric properties of the NPSI. Test–retest reliability. function and the perception of (1) spontaneous pain; (2) spontaneous pain ratings, more severe sensory neu- . Heat pain thresholds. Furthermore, they marked the areas of spontaneous pain on a body chart . past 24 h: ± (1–9); the highest pain intensity the past 24 h: ± (4–10).

    1. Introduction



    a list of descriptors reflecting spontaneous ongoing or paroxysmal pain, evoked pain (i.e. the Neuropathic Pain Scale was developed for the assess- . Assessment of the psychometric properties of the NPSI. Test–retest reliability.


    function and the perception of (1) spontaneous pain; (2) spontaneous pain ratings, more severe sensory neu- . Heat pain thresholds.


    Furthermore, they marked the areas of spontaneous pain on a body chart . past 24 h: ± (1–9); the highest pain intensity the past 24 h: ± (4–10).


    We observed that the fluctuations of spontaneous pain do not possess stable Our data was analyzed using two different vectors: a) when ratings of spontaneous pain were high in contrast to .. Ascending pathways.


    Shoulder pain ratings were obtained at the beginning, after 5 min, Adjustment of Tonic Pressure to Each Individual's Pain Sensitivity.

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