Category Archives: Research

13Nov/17
Whole person to treat chronic pain

It’s not your mind, it’s not your body, it’s you!

Whole person to treat chronic pain

Its not your mind, it’s not your body, its you!

Mind and body — what do we mean?

In essence it is good news. Loud messages in the media about mind and body being connected (read article by Rachel Kelly here), thereby trying to update society’s thinking from dualism to what actually happens. To philosophers, neuroscientists, cognitive scientists though, this is familiar ground. Mind-body has been the subject of discussion and investigation for eons.

Today there is further reporting upon schizophrenia research, highlighting the limitations of a dualist perspective, which continues to predominate within our health system. The system and huge swathes of society persist in divvying up the so-called ‘mental’ and ‘physical’. We even have different buildings dedicated to each bit of us, and within those buildings, and rooms that divvy us up even more. We have a liver location, a heart hub, a bones bit, and other parts of the institution that focus on a mere piece of us. Where is the room that puts it all together and acknowledges a human being who thinks, feels, moves, and perceives in distinctly human ways? Let’s talk qualia, and here’s Dan Dennett talking about consciousness.

need states

There are reasons why this maybe convenient, however the separation is not how it works in reality. And try being an end user: ‘Hello, I’m the knee patient’. Within our language and thinking must be the start point of the whole, for it is the whole person who perceives a need via a variety of bodily sensations: thirst, hunger, pain, discomfort and anxiety as examples. What do I need to do here?

‘In the past, we’ve always thought of mind and the body being separate, but its just not like that’ said Oliver Howes, professor of molecular psychiatry. Too right! Its never been like that! He goes on to say that the mind and body ‘interact constantly and the immune system is no different’. I would propose a step further that there is no connection per se because they are one and the same: me and how I experience me and the world. If you are doing a maths puzzle for example, you could argue that this is a mental task. However, there is always the ‘you’ doing the puzzle and you are there, present and embodied. Your mind does not slip out and do the job and then slip back in.

The recent schizophrenia research findings suggest that treating the immune system could be a way forward. I think that society maybe surprised by this news in certain quarters, yet people will understand how this can work. I have great faith in society;s ability to learn, grow and evolve because that is what we have always done, naturally. There is much greater ‘attunement’ to the completeness of being human, although we still have a long way to go before the scientific and philosophical understanding is mainstream in society. Again, this is not news to people who have been studying and following the work of brain-body-person-immune interactions over the past 15 years. A notable example was Dantzer’s paper in 2008 on inflammation and the brain.

inflammation is a likely biological mechanism that links up many common problems: e.g./ pain, depression

It sounds simple to ‘treat the immune system’. Of course in reality this is not the case because our body systems work as a whole and interact in many, many ways. Modern society is very familiar and comfortable with the notion of taking medication to solve a problem. Indeed this is one case when a pharmacological agent is needed. However, this still fails to teach a person how to live or to live their best. This take understanding, practice, time and perseverance. In the rush-rush world we live in, people often want the quick fix that simply does not exist. Getting real means we pay attention to the data that now tells us that certain practices or skills each day are what we need to do to be well. This is non-negotiable. You make a choice.

I finish as I start — this is good news. It is another way in which society can see the changes in understanding afoot. Our thinking needs a drastic update, certainly in terms of chronic pain and chronic health. For years we have been led to believe that pills are the answer, yet they are not. They may have a role, but the main role is the person and the choices they make in how they ‘do life’. Their life-style if you like. We have so many known ways of building health, no matter where you start, no matter whether you have a condition or not, we can decide to live our best. And to do this needs recognition of the fact that we are whole. There is no mind-body separation, instead just ‘me’.


Pain Coach Programme to get the best of you, overcome pain and live well; t. 07518 445493
08Feb/16

CRPS Research

CRPSKeep up to date with some of the recent CRPS research papers. You can click on the title link for the full text version. My comments are posted ‘RS’ in italics.

Pain exposure physical therapy (PEPT) compared to conventional treatment in complex regional pain syndrome type 1: a randomised controlled trial

abstract

To compare the effectiveness of pain exposure physical therapy (PEPT) with conventional treatment in patients with complex regional pain syndrome type 1 (CRPS-1) in a randomised controlled trial with a blinded assessor.

The study was conducted at a level 1 trauma centre in the Netherlands.

56 adult patients with CRPS-1 participated. Three patients were lost to follow-up

Patients received either PEPT in a maximum of five treatment sessions, or conventional treatment following the Dutch multidisciplinary guideline.

Outcomes were assessed at baseline and at 3, 6 and 9 months after randomisation. The primary outcome measure was the Impairment level Sum Score—Restricted Version (ISS-RV), consisting of visual analogue scale for pain (VAS-pain), McGill Pain Questionnaire, active range of motion (AROM) and skin temperature. Secondary outcome measures included Pain Disability Index (PDI); muscle strength; Short Form 36 (SF-36); disability of arm, shoulder and hand; Lower Limb Tasks Questionnaire (LLTQ); 10 m walk test; timed up-and-go test (TUG) and EuroQol-5D.

The intention-to-treat analysis showed a clinically relevant decrease in ISS-RV (6.7 points for PEPT and 6.2 points for conventional treatment), but the between-group difference was not significant (0.96, 95% CI −1.56 to 3.48). Participants allocated to PEPT experienced a greater improvement in AROM (between-group difference 0.51, 95% CI 0.07 to 0.94; p=0.02). The per protocol analysis showed larger and significant between-group effects on ISS-RV, VAS-pain, AROM, PDI, SF-36, LLTQ and TUG.

We cannot conclude that PEPT is superior to conventional treatment for patients with CRPS-1. Further high-quality research on the effects of PEPT is warranted given the potential effects as indicated by the per protocol analysis.

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High-frequency repetitive sensory stimulation as intervention to improve sensory loss in patients with CRPS type 1

abstract

Achieving perceptual gains in healthy individuals or facilitating rehabilitation in patients is generally considered to require intense training to engage neuronal plasticity mechanisms. Recent work, however, suggested that beneficial outcome similar to training can be effectively acquired by a complementary approach in which the learning occurs in response to mere exposure to repetitive sensory stimulation (rSS). For example, high-frequency repetitive sensory stimulation (HF-rSS) enhances tactile performance and induces cortical reorganization in healthy subjects and patients after stroke. Patients with complex regional pain syndrome (CRPS) show impaired tactile performance associated with shrinkage of cortical maps. We here investigated the feasibility and efficacy of HF-rSS, and low-frequency rSS (LF-rSS) to enhance tactile performance and reduce pain intensity in 20 patients with CRPS type I. Intermittent high- or low-frequency electrical stimuli were applied for 45 min/day to all fingertips of the affected hand for 5 days. Main outcome measures were spatial two-point-discrimination thresholds and mechanical detection thresholds measured on the tip of the index finger bilaterally. Secondary endpoint was current pain intensity. All measures were assessed before and on day 5 after the last stimulation session. HF-rSS applied in 16 patients improved tactile discrimination on the affected hand significantly without changes contralaterally. Current pain intensity remained unchanged on average, but decreased in four patients by ≥30%. This limited pain relief might be due to the short stimulation period of 5 days only. In contrast, after LF-rSS, tactile discrimination was impaired in all four patients, while detection thresholds and pain were not affected. Our data suggest that HF-rSS could be used as a novel approach in CRPS treatment to improve sensory loss. Longer treatment periods might be required to induce consistent pain relief.

RS: This is an interesting finding. Stimulation that brings about changes in the cortical maps is not a new notion, and indeed is part of normal learning. We stimulate with movement and/or touch under day to day circumstances, and in fact that is what we need to employ moment to moment at home to overcome CRPS and other painful conditions. Most people will not have access to equipment but are able to use simple touch, two point discrimination and movement, all of which form a vital part of the training and self-coaching programme. Pain is a lived experience and the programme must become part of life and hence be as simple as possible, which it can.

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Motor imagery and its effect on complex regional pain syndrome: an integrative review

abstract

The motor imagery (MI) has been proposed as a treatment in the complex regional pain syndrome type 1 (CRPS-1), since it seems to promote a brain reorganization effect on sensory-motor areas of pain perception. The aim of this paper is to investigate, through an integrative critical review, the influence of MI on the CRPS-1, correlating their evidence to clinical practice. Research in PEDro, Medline, Bireme and Google Scholar databases was conducted. Nine randomized controlled trials (level 2), 1 non-controlled clinical study (level 3), 1 case study (level 4), 1 systematic review (level 1), 2 review articles and 1 comment (level 5) were found. We can conclude that MI has shown effect in reducing pain and functionality that remains after 6 months of treatment. However, the difference between the MI strategies for CRPS-1 is unknown as well as the intensity of mental stress influences the painful response or effect of MI or other peripheral neuropathies.

RS: motor imagery does have an impact on our ability to move, and often rapidly so after a few repetitions. Using imagery and visualisation to assess mental representations, body sense and integrity alongside other simple tests gives an insight into the different hierarchical levels of contribution to the brain’s best guess about this moment for the individual. What we are experiencing now is our brain’s prediction (or best guess) when it has chosen from a number of hypotheses. Using imagery and visualisation, we can impact on the predictions as well as our own expecations that feed such predictions and our own conscious sense of what is to come. Pain is worse when we expect something to hurt, so what if we do not expect this and indeed anticipate something different, new and healthy?

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Fear and reward circuit alterations in padeiatric CRPS

abstract

In chronic pain, a number of brain regions involved in emotion (e.g., amygdala, hippocampus, nucleus accumbens, insula, anterior cingulate, and prefrontal cortex) show significant functional and morphometric changes. One phenotypic manifestation of these changes is pain-related fear (PRF). PRF is associated with profoundly altered behavioral adaptations to chronic pain. For example, patients with a neuropathic pain condition known as complex regional pain syndrome (CRPS) often avoid use of and may even neglect the affected body area(s), thus maintaining and likely enhancing PRF. These changes form part of an overall maladaptation to chronic pain. To examine fear-related brain circuit alterations in humans, 20 pediatric patients with CRPS and 20 sex- and age-matched healthy controls underwent functional magnetic resonance imaging (fMRI) in response to a well-established fearful faces paradigm. Despite no significant differences on self-reported emotional valence and arousal between the two groups, CRPS patients displayed a diminished response to fearful faces in regions associated with emotional processing compared to healthy controls. Additionally, increased PRF levels were associated with decreased activity in a number of brain regions including the right amygdala, insula, putamen, and caudate. Blunted activation in patients suggests that (a) individuals with chronic pain may have deficits in cognitive-affective brain circuits that may represent an underlying vulnerability or consequence to the chronic pain state; and (b) fear of pain may contribute and/or maintain these brain alterations. Our results shed new light on altered affective circuits in patients with chronic pain and identify PRF as a potentially important treatment target.

Pain Coach ProgrammeRS: we know that fear provokes on-going and more protection as we are perceiving a threat. Pain is also about perceived threat that is being predicted by our brain’s best guess about a particular situation or context base on what has happened before. This is one of the reasons why pain can be so specifically associated with a particular movement, a place or a thought. Many are puzzled by the changeable nature of pain and how it can exists one minute and not the next. Understanding pain allows people to realise that this is exactly the lived experience, especially in youngsters who can appear to be moving normally and then be in agony. Their brains have predicted a need for protection and hence they are in pain. The perceived threat passes and the new prediction is ‘no threat’ and hence no pain. This is how it works and unfortunately many people are not believed as a consequence and a really important reason why society needs to understand pain. Fear of pain being eradicated results in positive change and is a key step towards overcoming pain, starting with a working knowledge. I use UBER-M as a self-coaching tool that I give to individuals: U (understand pain; working knowledge), B (breathing & mindfulness), E (exercises – specific and general), R (re-charge energy to engage); M (movement for health and expression); the question to ask is this: ‘Are these thoughts and actions taking me towards my vision of a healthy me?’

Pain Coach Programme to overcome CRPS and chronic pain | t. 07518 445493

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29Oct/12

The brain changes

The nervous system is plastic meaning that it changes and moulds according to the stimuli presented. Norman Doidge wrote about the ‘brain that changes itself’ and we have seen over the past 10 years or so an increasing number of studies that show this in a range of conditions, some painful and others not. Our ability to change and adapt have been a vital characteristics for our survival and to learn new skills. The same principles apply when we think about rehabilitation and treatment of painful conditions. We need to tap into these properties and stimulate the brain and other body systems (e.g. immune system, neuroendocrine) so that we are creators of health manifesting physically through normal movement, function and optimal performance.

Here are some examples of studies that have shown brain changes using functional MRI. You will note the variety that includes rheumatoid arthritis, osteoarthritis, pain, chronic pelvic pain, schizophrenia and fibromyalgia. This has serious implications for treatment in that we need brain focused therapies as well as those that target the tissues and end-organs. This includes the absolute need to explain pain and symptoms from a neuroscience perspective.

Arthritis Rheum. 2012 Feb;64(2):371-9. doi: 10.1002/art.33326.

Structural changes of the brain in rheumatoid arthritis.

Wartolowska K, Hough MG, Jenkinson M, Andersson J, Wordsworth BP, Tracey I.

Abstract

OBJECTIVE: To investigate whether structural changes are present in the cortical and subcortical gray matter of the brains of patients with rheumatoid arthritis (RA).

METHODS: We used two surface-based style morphometry analysis programs and a voxel-based style analysis program to compare high-resolution structural magnetic resonance imaging data obtained for 31 RA patients and 25 age- and sex-matched healthy control subjects.

RESULTS: We observed an increase in gray matter content in the basal ganglia of RA patients, mainly in the nucleus accumbens and caudate nucleus. There were no differences in the cortical gray matter. Moreover, patients had a smaller intracranial volume.

CONCLUSION: Our results suggest that RA is associated with changes in the subcortical gray matter rather than with cortical gray matter atrophy. Since the basal ganglia play an important role in motor control as well as in pain processing and in modulating behavior in response to aversive stimuli, we suggest that these changes may result from altered motor control or prolonged pain processing. The differences in brain volume may reflect either generalized atrophy or differences in brain development.

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Am J Psychiatry. 2002 Feb;159(2):244-50.

Volume changes in gray matter in patients with schizophrenia.

Hulshoff Pol HE, Schnack HG, Bertens MG, van Haren NE, van der Tweel I, Staal WG, Baaré WF, Kahn RS.

Abstract

OBJECTIVE: Schizophrenia is generally characterized by a progressive decline in functioning. Although structural brain abnormalities, particularly decrements in gray matter volume, are considered important to the pathology of schizophrenia, it is not resolved whether the brain abnormalities become more prominent over time.

METHOD: Magnetic resonance brain images from 159 patients with schizophrenia and 158 healthy comparison subjects between 16 and 70 years of age were compared. Using linear regression analysis, the authors analyzed the relationship between the volumes of the total brain, gray and white matter, cerebellum, and lateral and third ventricles with patient age.

RESULTS: Total brain (-2.2%), cerebral gray matter (-3.3%), prefrontal gray matter (-4.4%), and prefrontal white matter (-3.5%) volumes were smaller, and lateral (27%) and third (30%) ventricle and peripheral CSF (11%) volumes were larger in schizophrenia patients. A significant group-by-age interaction for gray matter volume was found, as shown by a steeper regression slope between age and gray matter volume in patients (-3.43 ml/year) than in healthy comparison subjects (-2.74 ml/year).

CONCLUSIONS: The smaller brains of the patients with schizophrenia can be explained by decreases in gray matter volume. Moreover, the finding that the smaller gray matter volume was more pronounced in older patients with schizophrenia may suggest progressive loss of cerebral gray matter in schizophrenia patients.

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Psychosom Med. 2009 Jun;71(5):566-73. Epub 2009 May 4.

Decreased gray matter volumes in the cingulo-frontal cortex and the amygdala in patients with fibromyalgia.

Burgmer M, Gaubitz M, Konrad C, Wrenger M, Hilgart S, Heuft G, Pfleiderer B.

Abstract

OBJECTIVE: Studies in fibromyalgia syndrome with functional neuroimaging support the hypothesis of central pain augmentation. To determine whether structural changes in areas of the pain system are additional preconditions for the central sensitization in fibromyalgia we performed voxel based morphometry in patients with fibromyalgia and healthy controls.

METHODS: We performed 3 Tesla magnetic resonance imaging of the brain in 14 patients with fibromyalgia and 14 healthy controls. Regional differences of the segmented and normalized gray matter volumes in brain areas of the pain system between both groups were determined. In those areas in which patients structurally differed from healthy controls, the correlation of disease-related factors with gray matter volumes was analyzed.

RESULTS: Patients presented a decrease in gray matter volume in the prefrontal cortex, the amygdala, and the anterior cingulate cortex (ACC). The duration of pain or functional pain disability did not correlate with gray matter volumes. A trend of inverse correlation of gray matter volume reduction in the ACC with the duration of pain medication intake has been detected.

CONCLUSIONS: Our results suggest that structural changes in the pain system are associated with fibromyalgia. As disease factors do not correlate with reduced gray matter volume in areas of the cingulo-frontal cortex and the amygdala in patients, one possible interpretation is that volume reductions might be a precondition for central sensitization in fibromyalgia.

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Brain. 2008 Dec;131(Pt 12):3222-31. Epub 2008 Sep 26.

Working memory performance is correlated with local brain morphology in the medial frontal and anterior cingulate cortex in fibromyalgia patients: structural correlates of pain-cognition interaction.

Luerding R, Weigand T, Bogdahn U, Schmidt-Wilcke T.

Abstract

Fibromyalgia (FM) is a disorder of unknown aetiology, characterized by chronic widespread pain, stiffness and sleep disturbances. In addition, patients frequently complain of memory and attention deficits. Accumulating evidence suggests that FM is associated with CNS dysfunction and with an altered brain morphology. However, few studies have specifically investigated neuropsychological issues in patients suffering from FM. We therefore sought to determine whether neuropsychological deficits found in FM patients may be correlated with changes in local brain morphology specifically in the frontal, temporal or cingulate cortices. Twenty FM patients underwent extensive testing for potential neuropsychological deficits, which demonstrated significantly reduced working memory and impaired non-verbal long-term memory (limited to free recall condition) in comparison with normative data from age- and education-matched control groups. Voxel-based morphometry (VBM) was used to evaluate for potential correlations between test results and local brain morphology. Performance on non-verbal working memory was positively correlated with grey matter values in the left dorsolateral prefrontal cortex, whereas performance on verbal working memory (digit backward) was positively correlated with grey matter values in the supplementary motor cortex. On the other hand, pain scores were negatively correlated with grey matter values in the medial frontal gyrus. White matter analyses revealed comparable correlations for verbal working memory and pain scores in the medial frontal and prefrontal cortex and in the anterior cingulate cortex. Our data suggest that, in addition to chronic pain, FM patients suffer from neurocognitive deficits that correlate with local brain morphology in the frontal lobe and anterior cingulate gyrus, which may be interpreted to indicate structural correlates of pain-cognition interaction.

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Pain. 2012 May;153(5):1006-14. Epub 2012 Mar 2.

Changes in regional gray matter volume in women with chronic pelvic pain: a voxel-based morphometry study.

As-Sanie S, Harris RE, Napadow V, Kim J, Neshewat G, Kairys A, Williams D, Clauw DJ, Schmidt-Wilcke T.

Abstract

Chronic pelvic pain (CPP) is a highly prevalent pain condition, estimated to affect 15%-20% of women in the United States. Endometriosis is often associated with CPP, however, other factors, such as preexisting or concomitant changes of the central pain system, might contribute to the development of chronic pain. We applied voxel-based morphometry to determine whether women with CPP with and without endometriosis display changes in brain morphology in regions known to be involved in pain processing. Four subgroups of women participated: 17 with endometriosis and CPP, 15 with endometriosis without CPP, 6 with CPP without endometriosis, and 23 healthy controls. All patients with endometriosis and/or CPP were surgically confirmed. Relative to controls, women with endometriosis-associated CPP displayed decreased gray matter volume in brain regions involved in pain perception, including the left thalamus, left cingulate gyrus, right putamen, and right insula. Women with CPP without endometriosis also showed decreases in gray matter volume in the left thalamus. Such decreases were not observed in patients with endometriosis who had no CPP. We conclude that CPP is associated with changes in regional gray matter volume within the central pain system. Although endometriosis may be an important risk factor for the development of CPP, acting as a cyclic source of peripheral nociceptive input, our data support the notion that changes in the central pain system also play an important role in the development of chronic pain, regardless of the presence of endometriosis.

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Arthritis Rheum. 2010 Oct;62(10):2930-40.

Thalamic atrophy associated with painful osteoarthritis of the hip is reversible after arthroplasty: a longitudinal voxel-based morphometric study.

Gwilym SE, Filippini N, Douaud G, Carr AJ, Tracey I.

Abstract

OBJECTIVE: Voxel-based morphometry (VBM) is a method of assessing brain gray matter volume that has previously been applied to various chronic pain conditions. From this previous work, it appears that chronic pain is associated with altered brain morphology. The present study was undertaken to assess these potential alterations in patients with painful hip osteoarthritis (OA).

METHODS: We studied 16 patients with unilateral right-sided hip pain, before and 9 months after hip arthroplasty. This enabled comparison of gray matter volume in patients with chronic musculoskeletal pain versus healthy controls, as well as identification of any changes in volume following alleviation of pain (after surgery). Assessment involved self-completion questionnaires to assess pain, function, and psychosocial variables, and magnetic resonance imaging scanning of the brain for VBM analysis.

RESULTS: Significant differences in brain gray matter volume between healthy controls and patients with painful hip arthritis were seen. Specifically, areas of the thalamus in patients with chronic OA pain exhibited decreased gray matter volume. Furthermore, when these preoperative changes were compared with the brain morphology of the patients 9 months after surgery, the areas of reduced thalamic gray matter volume were found to have “reversed” to levels seen in healthy controls.

CONCLUSION: Our findings confirm that gray matter volume decreases within the left thalamus in the presence of chronic pain and disability in patients with hip OA. The results also show that these thalamic volume changes reverse after hip arthroplasty and are associated with decreased pain and increased function. These findings have potential implications with regard to optimizing the timing of orthopedic interventions such as arthroplasty

29Oct/12

Pain: perception, expectation, meaning – it’s all important

I regularly scour the literature for the latest studies that look at pain mechanisms. Firstly I am fascinated by the science and philosophy of pain, both personally as it is so intrical to life and living, and because I need to understand the current thinking in pain to be effective as a clinician–one day I will post a picture of my study that is largely held together by books, journals and papers. Secondly, and related to the first reason, is because we simply must maintain a contemporary perspective and keep up to date with the rapidly developing knowledge base that crosses basic sciences, neuroscience, cognitive sciences and other fields that together can provide explnantion for the complex experience that is pain.

Ulrike Bingel has done some fascinating work and here are some of the abstracts with my brief comments following:

 

Neurogastroenterol Motil. 2012 Oct;24(10):935-e462. doi: 10.1111/j.1365-2982.2012.01968.x. Epub 2012 Jul 2.

Perceived treatment group affects behavioral and neural responses to visceral pain in a deceptive placebo study.

Kotsis V, Benson S, Bingel U, Forsting M, Schedlowski M, Gizewski ER, Elsenbruch S.

Abstract

To assess effects of perceived treatment (i.e. drug vs placebo) on behavioral and neural responses to rectal pain stimuli delivered in a deceptive placebo condition. Methods  This fMRI study analyzed the behavioral and neural responses during expectation-mediated placebo analgesia in a rectal pain model. In N = 36 healthy subjects, the blood oxygen level-dependent (BOLD) response during cued anticipation and painful stimulation was measured after participants were informed that they had a 50% chance of receiving either a potent analgesic drug or an inert substance (i.e., double-blind administration). In reality, all received placebo. We compared responses in subjects who retrospectively indicated that they received the drug and those who believed to have received placebo. Key Results  55.6% (N = 20) of subjects believed that they had received a placebo, whereas 36.1% (N = 13) believed that they had received a potent analgesic drug. Subjects who were uncertain (8.3%, N = 3) were excluded. Rectal pain-induced discomfort was significantly lower in the perceived drug treatment group (P < 0.05), along with significantly reduced activation of the insular, the posterior and anterior cingulate cortices during pain anticipation, and of the anterior cingulate cortex during pain (all P < 0.05 in regions-of-interest analyses).

Conclusions & Inferences

Perceived treatment constitutes an important aspect in placebo analgesia. A more refined understanding of individual treatment expectations and perceived treatment allocation has multiple implications for the design and interpretation of clinical trials and experimental studies on placebo and nocebo effects.

RS: The way in which we interact (therapist/doctor and patient) alongside the expectations that are brought along to the session need due consideration. This includes the language used to educate and explain pain and symptoms, the way in which it is delivered, the context and environment where the delivery takes place and preceeding events such as previous consultations and the journey to the appointment.

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Curr Biol. 2012 Jun 5;22(11):1019-22. doi: 10.1016/j.cub.2012.04.006. Epub 2012 May 17.

Attention modulates spinal cord responses to pain.

Sprenger C, Eippert F, Finsterbusch J, Bingel U, Rose M, Büchel C.

Abstract

Reduced pain perception while being distracted from pain is an everyday example of how cognitive processes can interfere with pain perception. Previous neuroimaging studies showed distraction-related modulations of pain-driven activations in various cortical and subcortical brain regions, but the precise neuronal mechanism underlying this phenomenon is unclear. Using high-resolution functional magnetic resonance imaging of the human cervical spinal cord in combination with thermal pain stimulation and a well-established working memory task, we demonstrate that this phenomenon relies on an inhibition of incoming pain signals in the spinal cord. Neuronal responses to painful stimulation in the dorsal horn of the corresponding spinal segment were significantly reduced under high working memory load compared to low working memory load. At the individual level, reductions of neuronal responses in the spinal cord predicted behavioral pain reductions. In a subsequent behavioral experiment, using the opioid antagonist naloxone in a double-blind crossover design with the same paradigm, we demonstrate a substantial contribution of endogenous opioids to this mechanism. Taken together, our results show that the reduced pain experience during mental distraction is related to a spinal process and involves opioid neurotransmission.

RS: Nervous system activity takes place on a spectrum. the peripheral nerves at one end, the spinal cord in the middle and the brain on top. Ascending and descending mechanisms are key players in the overall perception of pain which is why we can distract ourselves and feel less pain for example, or indeed by re-evaluating the meaning of our pain, we can use parts of our brain to facilitate the flow of messages down to the spinal cord to influence danger signals coming up from the tissues. In central sensitisation though, we can see facilitation of the flow of danger signals, this being one of the mechanism based features of chronic and persisting pain.

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J Neurosci. 2010 Dec 1;30(48):16324-31.

Anterior insula integrates information about salience into perceptual decisions about pain.

Wiech K, Lin CS, Brodersen KH, Bingel U, Ploner M, Tracey I.

Abstract

The decision as to whether a sensation is perceived as painful does not only depend on sensory input but also on the significance of the stimulus. Here, we show that the degree to which an impending stimulus is interpreted as threatening biases perceptual decisions about pain and that this bias toward pain manifests before stimulus encounter. Using functional magnetic resonance imaging we investigated the neural mechanisms underlying the influence of an experimental manipulation of threat on the perception of laser stimuli as painful. In a near-threshold pain detection paradigm, physically identical stimuli were applied under the participants’ assumption that the stimulation is entirely safe (low threat) or potentially harmful (high threat). As hypothesized, significantly more stimuli were rated as painful in the high threat condition. This context-dependent classification of a stimulus as painful was predicted by the prestimulus signal level in the anterior insula, suggesting that this structure integrates information about the significance of a stimulus into the decision about pain. The anticipation of pain increased the prestimulus functional connectivity between the anterior insula and the midcingulate cortex (MCC), a region that was significantly more active during stimulation the more a participant was biased to rate the stimulation as painful under high threat. These findings provide evidence that the anterior insula and MCC as a “salience network” integrate information about the significance of an impending stimulation into perceptual decision-making in the context of pain.

RS: The anticipation and expectation of pain play a role in the end perception of pain, this study illustrating the connectivity within important brain regions known to be active in pain. Salience is key. The meaning that we give to the pain plays such a significant role in the threat level: how dangerous is this? Really? The brain has to answer this question biologically and on concluding that there is a problem, pain is an output in response. An amazing device that protects us and is vital for survival.

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Sci Transl Med. 2011 Feb 16;3(70):70ra14.

The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil.

Bingel U, Wanigasekera V, Wiech K, Ni Mhuircheartaigh R, Lee MC, Ploner M, Tracey I.

Abstract

Evidence from behavioral and self-reported data suggests that the patients’ beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual’s expectation of a drug’s effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients’ beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.

RS: Again this emphasises the point that we must address belief systems and expectations that patients bring along as an integral part of who they are as an individual. What we observe and what the patient experiences are key factors that require ‘marrying’ in order to target this interface with education, strategies, training and treatment. But, it has to make sense to the patient and fit with their belief system. In many cases this may require shifts in thinking to promote healthier behaviours and habits for moving forwards.

11Jul/12

Cervical Dystonia | What can we do?

I see a number of cases of cervical dystonia (spasmodic torticollis) that features awkward posturing and movement of the head and neck. This can be painful and have consequences for normal activities. We rely upon being able to orientate ourselves to our environment by controlling our head and gaze direction and then responding appropriately.

Primary dystonia has no neurological or metabolic cause whereas secondary dystonia is attributable to outside factors such as physical trauma, exposure to certain medications and other neurological or metabolic diseases.

Here is a fact sheet from the National Institute of Neurological Disorders & Stroke

Common treatment of cervical dystonia includes botulinum toxin injections and physiotherapy.

Modern physiotherapy for cervical dystonia at the Specialist Pain Physio Clinics

In addition to the manual techniques that are used to help ease tension and the soreness associated with spasm and tightness in the muscles, we use strategies that target the motor centres in the brain where the signals are coming from. In other words, as well as treating the symptoms, we are focusing upon the mechanisms and causes of the muscles going into spasm. The Graded Motor Imagery programme provides a way of aiming to retrain movement by targeting the adaptations that have occured in the motor system. Initially this programme was devised for complex regional pain syndrome, but since then the training has been found to help those with a range of painful problems with associated movement issues.

Typically a treatment programme includes themes that aim to develop a deep understanding of the problem(s), nourish and mobilise the body tissues, improve motor control, body sense and awareness, manage posture, increase exercise an activity tolerance and ultimately improve quality of life. We call the approach biobehavioural because it is a comprehensive way of tackling the issues and influencing factors that are unique to the individual, addressing the physical signs and symptoms as much as the underpinning beliefs and lifestyle factors that impact.

Call for appointments: 07518 445493

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Dr Marie-Helene Marion, a consultant neurologist specialising in the treatment of dystonia and movement disorders has a comprehensive blog here

Recent research papers

Behav Neurol. 2012 May 24.

Cervical dystonia: From pathophysiology to pharmacotherapy.

Patel S, Martino D.

Abstract

Background: Dystonia is a chronic disorder characterised by an aberration in the control of movement. Sustained co-contraction of opposing agonist and antagonist muscles can cause repetitive and twisting movements, or abnormal postures. Cervical dystonia (CD), often referred to as spasmodic torticollis, is a type of focal dystonia involving the muscles of the neck and sometimes the shoulders. Methods: This systematic review collates the available evidence regarding the safety and efficacy of a range of treatments for CD, focusing on their effectiveness as shown by double-blinded, randomised controlled trials. Results: Our review suggests that botulinum toxin type A (BTA), botulinum toxin type B (BTB) and trihexyphenidyl are safe and efficacious treatments for CD. Evidence shows that botulinum toxin therapies are more reliable for symptomatic relief and have fewer adverse effects than trihexyphenidyl. When comparing BTA to BTB, both are found to have similar clinical benefits, with BTA possibly having a longer duration of action and a marginally better side effect profile. BTB is also safe and probably just as efficacious a treatment in those patients who are unresponsive or have become resistant to BTA.

Discussion: The current evidence shows that the pharmacological management of CD relies on BTA and BTB, two agents with established efficacy and tolerability profiles.

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Lancet Neurol. 2002 Sep;1(5):316-25.

Classification and genetics of dystonia.

de Carvalho Aguiar PM, Ozelius LJ.

Abstract

Dystonia is a syndrome characterised by sustained muscle contractions, producing twisting, repetitive, and patterned movements, or abnormal postures. The dystonic syndromes include a large group of diseases that have been classified into various aetiological categories, such as primary, dystonia-plus, heredodegenerative, and secondary. The diverse clinical features of these disorders are reflected in the traditional clinical classification based on age at onset, distribution of symptoms, and site of onset. However, with an increased awareness of the molecular and environmental causes, the classification schemes have changed to reflect different genetic forms of dystonia. To date, at least 13 dystonic syndromes have been distinguished on a genetic basis and their loci are referred to as DYT1 to DYT13. This review focuses on the molecular and phenotypic features of the hereditary dystonias, with emphasis on recent advances.

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Mov Disord. 2002;17 Suppl 3:S49-62.

Pathophysiology of dystonia: a neuronal model.

Vitek JL.

Abstract

Dystonia has commonly been thought to represent a disorder of basal ganglia function. Although long considered a hyperkinetic movement disorder, the evidence to support such a classification was based on the presence of excessive involuntary movement, not on physiological data. Only recently, with the return of surgical procedures using microelectrode guidance for the treatment of dystonia, has electrophysiological data demonstrated an alteration in mean discharge rate, somatosensory responsiveness and the pattern of neuronal activity in the basal ganglia thalamocortical motor circuit. Previous models of dystonia suggested that reduced mean discharge rates in the globus pallidus internus (GPi) led to unopposed increases in activity in the thalamocortical circuit that precipitated the development of involuntary movement associated with dystonia. This model has subsequently been modified given the clear improvement in dystonic symptoms following lesions in the GPi, a procedure that is associated with a further reduction in pallidal output. The improvement in dystonia following pallidal lesions is difficult to reconcile with the “rate” hypothesis for hypokinetic and hyperkinetic movement disorders and has led to the development of alternative models that, in addition to rate, incorporate changes in pattern, somatosensory responsiveness and degree of synchronization of neuronal activity. Present models of dystonia, however, must not only take these changes into account but must reconcile these changes with the reported changes in cortical excitability reported with transcranial magnetic stimulation, the changes in metabolic activity in cortical and subcortical structures documented by positron emission tomography (PET), and the alterations in spinal and brainstem reflexes. A model incorporating these changes together with the reported changes in neuronal activity in the basal ganglia and thalamus is presented.

11Feb/12

Manual therapy, pain and the immune system

As a physiotherapist I frequently use my hands to treat the joints and tissues. It comes with the territory, everyone expects hands-on therapy and it does helps to reduce tension and pain. Most likely, the pain relief from joint mobilisation is due to descending mechanisms that include those that are powered by serotonin and noradrenaline (see here). This is very useful to know as it tells us about the effects of passively moving joints and importantly permits wise selection of techniques to target the pain mechanisms. Building on the knowledge base, two very recent studies have identified some extremely interesting results.

Firstly, Martins et al. (2011) found that ankle joint mobilisation reduced pain in a neuropathic pain model in rats along with seeing the regeneration of nerve tissue and inhibition of glial cell activation (a blog will be coming soon that discusses the immune system in pain states) in the dorsal horn of the spinal cord. Secondly, Crane et al. (2012) looked at how massage helps reduce the pain of exercise-induced muscle damage in young males. Taking muscle biopsies they found that massaged subjects demonstrated attenuation of proinflammatory cytokines, key players in sensitisation. It was also noted that massage had no effect upon metabolites such as lactate – see below.

More research into the mechanisms that underpin the effects of hands-on therapy is needed despite the advancements in our understanding. The ability to focus treatment upon this understanding can only develop our effectiveness in treating pain. I am very optimistic about the movement forwards in pain and basic science, and how this can be applied  in our thinking with individual patients. The language is changing with the words ‘treatment’ being used rather than ‘management’, the latter of which can imply that one has reached their limit of improvement. This is exciting and more importantly, realistic when one considers therapies such as the graded motor imagery. We do not have treatments that work for all pains but we do have brains and body systems that are flexible, dynamic and can change if given the opportunity, the right stimulation within the right context on the background of good understanding. It is our duty to keep this rolling onwards and thinking hard about how to best use the findings such as those highlighted in this blog.

Pain. 2011 Nov;152(11):2653-61. Epub 2011 Sep 8.

Ankle joint mobilization reduces axonotmesis-induced neuropathic pain and glial activation in the spinal cord and enhances nerve regeneration in rats.

Martins DF, Mazzardo-Martins L, Gadotti VM, Nascimento FP, Lima DA, Speckhann B, Favretto GA, Bobinski F, Cargnin-Ferreira E, Bressan E, Dutra RC, Calixto JB, Santos AR.

Source

Laboratório de Neurobiologia da Dor e Inflamação, Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis, SC, Brazil.

Abstract

An important issue in physical rehabilitation is how to protect from or to reduce the effects of peripheral nerve injury. In the present study, we examined whether ankle joint mobilization (AJM) would reduce neuropathic pain and enhance motor functional recovery after nerve injury. In the axonotmesis model, AJM during 15 sessions every other day was conducted in rats. Mechanical and thermal hyperalgesia and motor performance deficit were measured for 5 weeks. After 5 weeks, we performed morphological analysis and quantified the immunoreactivity for CD11b/c and glial fibrillary acidic protein (GFAP), markers of glial activation, in the lumbar spinal cord. Mechanical and thermal hyperalgesia and motor performance deficit were found in the Crush+Anesthesia (Anes) group (P<0.001), which was significantly decreased after AJM (P<0.001). In the morphological analysis, the Crush+Anes group presented reduced myelin sheath thickness (P<0.05), but the AJM group presented enhanced myelin sheath thickness (P<0.05). Peripheral nerve injury increased the immunoreactivity for CD11b/c and GFAP in the spinal cord (P<0.05), and AJM markedly reduced CD11b/c and GFAP immunoreactivity (P<0.01). These results show that AJM in rats produces an antihyperalgesic effect and peripheral nerve regeneration through the inhibition of glial activation in the dorsal horn of the spinal cord. These findings suggest new approaches for physical rehabilitation to protect from or reduce the effects of nerve injury.

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Sci Transl Med. 2012 Feb 1;4(119):119ra13.

Massage therapy attenuates inflammatory signaling after exercise-induced muscle damage.

Crane JD, Ogborn DI, Cupido C, Melov S, Hubbard A, Bourgeois JM, Tarnopolsky MA.

Source

Department of Kinesiology, McMaster University, Hamilton, Ontario L8S 4L8, Canada.

Abstract

Massage therapy is commonly used during physical rehabilitation of skeletal muscle to ameliorate pain and promote recovery from injury. Although there is evidence that massage may relieve pain in injured muscle, how massage affects cellular function remains unknown. To assess the effects of massage, we administered either massage therapy or no treatment to separate quadriceps of 11 young male participants after exercise-induced muscle damage. Muscle biopsies were acquired from the quadriceps (vastus lateralis) at baseline, immediately after 10 min of massage treatment, and after a 2.5-hour period of recovery. We found that massage activated the mechanotransduction signaling pathways focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1/2 (ERK1/2), potentiated mitochondrial biogenesis signaling [nuclear peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)], and mitigated the rise in nuclear factor κB (NFκB) (p65) nuclear accumulation caused by exercise-induced muscle trauma. Moreover, despite having no effect on muscle metabolites (glycogen, lactate), massage attenuated the production of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and reduced heat shock protein 27 (HSP27) phosphorylation, thereby mitigating cellular stress resulting from myofiber injury. In summary, when administered to skeletal muscle that has been acutely damaged through exercise, massage therapy appears to be clinically beneficial by reducing inflammation and promoting mitochondrial biogenesis.

21Jan/12

Central sensitisation is more common than you may think

Clifford Woolf recently said this about central sensitisation:

Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.

And Latremolier

Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy as well as to reduced inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury. The net effect of central sensitization is to recruit previously subthreshold synaptic inputs to nociceptive neurons, generating an increased or augmented action potential output: a state of facilitation, potentiation, augmentation, or amplification. Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and exemplifies the fundamental contribution of the central nervous system to the generation of pain hypersensitivity. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of noxious peripheral stimuli. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations. PERSPECTIVE: In this article, we review the major triggers that initiate and maintain central sensitization in healthy individuals in response to nociceptor input and in patients with inflammatory and neuropathic pain, emphasizing the fundamental contribution and multiple mechanisms of synaptic plasticity caused by changes in the density, nature, and properties of ionotropic and metabotropic glutamate receptors.

In essence we are talking about changes within the central nervous system that underpin the widespread, unpredictable and varied nature of persisting pain.

When I am listening to a patient, observing their movements and performing a ‘multi-system’ examination, I am in part looking for the pain mechanisms at play, including central sensitisation. Several of my questions are: ‘what is going on here to create this experience for the person in front of me?’, ‘why are the nervous and other systems responding in such a way?’ and ‘what is influencing the behaviour of those systems?’. I really need to know what it is that is prolonging this protection and is it really worthwhile for the individual.

Suspecting that there is a component of central sensitisation at play in many cases of chronic pain that I see, it is pleasing to see a group looking at this closely and finding evidence to support this thinking:

J Bone Joint Surg Br. 2011 Apr;93(4):498-502.

Evidence that central sensitisation is present in patients with shoulder impingement syndrome and influences the outcome after surgery.

Gwilym SE, Oag HC, Tracey I, Carr AJ.

Source

Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX3 7LD, UK. [email protected]

Abstract

Impingement syndrome in the shoulder has generally been considered to be a clinical condition of mechanical origin. However, anomalies exist between the pathology in the subacromial space and the degree of pain experienced. These may be explained by variations in the processing of nociceptive inputs between different patients. We investigated the evidence for augmented pain transmission (central sensitisation) in patients with impingement, and the relationship between pre-operative central sensitisation and the outcomes following arthroscopic subacromial decompression. We recruited 17 patients with unilateral impingement of the shoulder and 17 age- and gender-matched controls, all of whom underwent quantitative sensory testing to detect thresholds for mechanical stimuli, distinctions between sharp and blunt punctate stimuli, and heat pain. Additionally Oxford shoulder scores to assess pain and function, and PainDETECT questionnaires to identify ‘neuropathic’ and referred symptoms were completed. Patients completed these questionnaires pre-operatively and three months post-operatively. A significant proportion of patients awaiting subacromial decompression had referred pain radiating down the arm and had significant hyperalgesia to punctate stimulus of the skin compared with controls (unpaired t-test, p < 0.0001). These are felt to represent peripheral manifestations of augmented central pain processing (central sensitisation). The presence of either hyperalgesia or referred pain pre-operatively resulted in a significantly worse outcome from decompression three months after surgery (unpaired t-test, p = 0.04 and p = 0.005, respectively). These observations confirm the presence of central sensitisation in a proportion of patients with shoulder pain associated with impingement. Also, if patients had relatively high levels of central sensitisation pre-operatively, as indicated by higher levels of punctate hyperalgesia and/or referred pain, the outcome three months after subacromial decompression was significantly worse.

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Arthritis Rheum. 2009 Sep 15;61(9):1226-34.

Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients.

Gwilym SE, Keltner JR, Warnaby CE, Carr AJ, Chizh B, Chessell I, Tracey I.

Source

University of Oxford, Oxford, UK. [email protected]

Abstract

OBJECTIVE:

The groin pain experienced by patients with hip osteoarthritis (OA) is often accompanied by areas of referred pain and changes in skin sensitivity. We aimed to identify the supraspinal influences that underlie these clinical manifestations that we consider indicative of possible central sensitization.

METHODS:

Twenty patients with hip OA awaiting joint replacement and displaying signs of referred pain were recruited into the study, together with age-matched controls. All subjects completed pain psychology questionnaires and underwent quantitative sensory testing (QST) in their area of referred pain. Twelve of 20 patients and their age- and sex-matched controls underwent functional magnetic resonance imaging (MRI) while the areas of referred pain were stimulated using cold stimuli (12 degrees C) and punctate stimuli (256 mN). The remaining 8 of 20 patients underwent punctate stimulation only.

RESULTS:

Patients were found to have significantly lower threshold perception to punctate stimuli and were hyperalgesic to the noxious punctate stimulus in their areas of referred pain. Functional brain imaging illustrated significantly greater activation in the brainstem of OA patients in response to punctate stimulation of their referred pain areas compared with healthy controls, and the magnitude of this activation positively correlated with the extent of neuropathic-like elements to the patient’s pain, as indicated by the PainDETECT score.

DISCUSSION:

Using psychophysical (QST) and brain imaging methods (functional MRI), we have identified increased activity with the periaqueductal grey matter associated with stimulation of the skin in referred pain areas of patients with hip OA. This offers a central target for analgesia aimed at improving the treatment of this largely peripheral disease.

18Jan/12

Contemporary understanding of factors in joint pain

Recent research has identified biological reasons for joint pain in arthritis:

  • Interleukin-6, a pro-inflammatory cytokine released both locally at the joint and in the spinal cord, consequently plays a role in the widespread nature of the pain via its role in central sensitisation.
  • Sprouting of sensory and sympathetic fibres at the joint may well have a role in sensitisation
  • Angiogenesis, the growth of new blood vessels, at the joint, perhaps having a role in inflammation

Some of this may sound familiar. IL-6 is known to play a role in the spinal cord following nerve injury, sprouting of the sympathetic fibres at the DRG and in tendinopathy, and angiogenesis also seen in tendinopathy. All are clearly responses by the body and are involved in pain–remembering that pain is a brain experience 100% of the time of course.

Spinal interleukin-6 is an amplifier of arthritic pain (Vazquez et al. 2011)

Objective.

Significant joint pain is usually widespread beyond the afflicted joint which results from the sensitization of nociceptive neurons in the central nervous system (central sensitization). In the present study we explored (a) whether the proinflammatory cytokine interleukin-6 (IL-6) in the joint induces central sensitization, (b) whether joint inflammation causes IL-6 release in the spinal cord, and (c) whether spinal IL-6 contributes to central sensitization.

Methods.

In anesthetized rats electrophysiological recordings were made from spinal cord neurons with sensory input from the knee joint. Neuronal responses to mechanical stimulation of the knee and the leg were monitored. IL-6 and its soluble receptor sIL-6R were applied to the knee joint or the spinal cord. Spinal release of IL-6 was measured by ELISA. Sgp130 which neutralizes IL-6/sIL-6R was spinally applied during development of joint inflammation or during established inflammation.

Results.

A single injection of IL-6/sIL-6R into the knee joint as well as spinal application of IL-6/sIL-6R significantly increased the responses of spinal neurons to mechanical stimulation of the knee and ankle joint, i.e. induced central sensitization. Spinally applied sgp130 attenuated this IL-6 effect. Development of knee inflammation caused spinal release of IL-6. Spinal application of spg130 attenuated the development of inflammation-evoked central sensitization but did not reverse it.

Conclusions.

Not only IL-6 in the joint is involved in the generation of joint pain but also IL-6 which is released in the spinal cord. Spinal IL-6 contributes to central sensitization and thus promotes the widespread hyperalgesia in the course of joint disease.

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Neuroplasticity of sensory and sympathetic nerve fibers in the painful arthritic joint (Ghilardi et al. 2011)

Objective.

Many forms of arthritis are accompanied by significant chronic joint pain. Here we studied whether there is significant sprouting of sensory and sympathetic nerve fibers in the painful arthritic knee joint and whether nerve growth factor (NGF) drives this pathological reorganization.

Methods.

A painful arthritic knee joint was produced by injection of complete Freund’s adjuvant (CFA) into the knee joint of young adult mice. CFA-injected mice were then treated systemically with vehicle or anti-NGF antibody. Pain behaviors were assessed and at 28 days following the initial CFA injection, the knee joints were processed for immunohistochemistry using antibodies raised against calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kDa (NF200; sensory nerve fibers), growth associated protein-43 (GAP43; sprouted nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), CD31 (endothelial cells) or CD68 (monocytes/macrophages).

Results.

In CFA-injected mice, but not vehicle-injected mice, there was a significant increase in the density of CD68+ macrophages, CD31+ blood vessels, CGRP+, NF200+, GAP43+, and TH+ nerve fibers in the synovium as well as joint pain-related behaviors. Administration of anti-NGF reduced these pain-related behaviors and the ectopic sprouting of nerve fibers, but had no significant effect on the increase in density of CD31+ blood vessels or CD68+ macrophages.

Conclusions.

Ectopic sprouting of sensory and sympathetic nerve fibers occurs in the painful arthritic joint and may be involved in the generation and maintenance of arthritic pain.

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Contributions of angiogenesis to inflammation, joint damage, and pain in a rat model of osteoarthritis (Ashraf et al. 2011)

Objective

To determine the contributions of angiogenesis to inflammation, joint damage, and pain behavior in a rat meniscal transection model of osteoarthritis (OA).

Methods

OA was induced in male Lewis rats (n = 8 per group) by meniscal transection. Animals were orally dosed with dexamethasone (0.1 mg/kg/day), indomethacin (2 mg/kg/day), or the specific angiogenesis inhibitor PPI-2458 (5 mg/kg every other day). Controls consisted of naive and vehicle-treated rats. Synovial inflammation was measured as the macrophage fractional area (expressed as the percentage), thickness of the synovial lining, and joint swelling. Synovial angiogenesis was measured using the endothelial cell proliferation index and vascular density. Channels positive for vessels at the osteochondral junction were assessed (osteochondral angiogenesis). Medial tibial plateaus were assessed for chondropathy, osteophytosis, and channels crossing the osteochondral junction. Pain behavior was measured as weight-bearing asymmetry.

Results

Dexamethasone and indomethacin each reduced pain behavior, synovial inflammation, and synovial angiogenesis 35 days after meniscal transection. Dexamethasone reduced, but indomethacin had no significant effect on, the total joint damage score. PPI-2458 treatment reduced synovial and osteochondral angiogenesis, synovial inflammation, joint damage, and pain behavior.

Conclusion

Our findings indicate that synovial inflammation and joint damage are closely associated with pain behavior in the meniscal transection model of OA. Inhibition of angiogenesis may reduce pain behavior both by reducing synovitis and by preventing structural change. Targeting angiogenesis could therefore prove useful in reducing pain and structural damage in OA.

19Apr/11

Complex Regional Pain Syndrome (CRPS/RSD)

Complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy (RSD), is undoubtedly a nasty condition in many cases. It can be hugely disruptive in the desire to lead a normal and fulfilling life due the experience of sheer pain and the difficulty in doing day to day activities.

I hear a huge range of stories of how the problem began and how it has been treated. Sometimes there is a significant injury, but often it is the type of event that one would associate with recovery such as an ankle sprain, a knocked elbow or a fracture. Unfortunately in a number of cases this simply does not happen. The injury is sustained, the area usually hurts as you would expect but then it continues to hurt and gets worse. There are associated signs and symptoms such as colour change, temperature change, altered sensation (pins and needles, numbness), an altered sense of position, a feeling of ‘largeness’, ‘thickened’ skin, huge sensitivity to light touch (allodynia), changes in skin, hair and nails. Fortunately we understand much more about the underlying mechanisms and can explain what and why this is happening, giving the problem a meaning which is so important in a condition that is troubling and causing great suffering.

CRPS in the foot and leg causes great difficulty in walking and standing in many cases. If the tissues are stiffened and the control of movement is poor, the ability to walk normally can be severely limited. Add the pain to this scenario and it becomes incredibly disabling at times as the sufferer simply cannot undertake normal activities. In CRPS in the upper limb it is writing, computer use, dressing, holding tools and self-care that are challenged.

Similar to any painful state, determining the pain mechanism(s) is important in deciding where to focus the treatment. Often there can be co-existing mechanisms such as inflammatory pain and neuropathic pain underpinned by different processes and manifesting in different ways. Neuropathic pain is often sharp, lancing, shooting and accompanied by a loss of sensation in the same area that can be confounding until you understand how it works. Inflammatory pain can be provoked by movement and touch with the mechanism being excited sensory nerves (nociceptors) as a result of the release of inflammatory molecules. Nerves themselves can release such chemicals into the tissues (neurogenic inflammation) and thereby keep the process going. There are many other aspects to the pain and the drivers and influences.

As well as elucidating the pain mechanisms, identifying the influences is also very important. This can include stress, fatigue, emotional state, past experience, culture, beliefs in addition to lifestyle factors and general health. Personally I look for risk factors for chronicity with all new assessments so that these can be fealty with swiftly. When a condition has been in existence for a longer period, adapting this to understand behaviours, choices and other factors that could be prolonging the problem is important.

Modern treatment of pain including CRPS should be within a biopsychosocial framework. That means looking at the biological mechanisms, psychology and social factors that are all part of the pain experience and mould the individual perception. In many cases the sufferer needs input from physiotherapy, pain medicine and psychology. Initially educating the patient to develop understanding, reduce fear of the pain and movement and enable effective coping and self-care is key. Desensitising the body with a range of techniques that blend the physical with the cognitive through the application of various stimuli is useful. This could be a paint brush or cotton wool for example. Tactile discrimination and two point discrimination are normal sensory functions that can be altered and according to recent studies are likely to need training. The graded motor imagery programme is part of the treatment, targeting brain changes that can occur. The three stages are laterality, imagined movement and mirror therapy. This is a newer intervention and is demonstrating good results in CRPS and with other nasty pains. The self-care aspects are fundamental. Teaching the patient to manage their activities and to develop consistency through their day is key. Sometimes activities are overdone and there is a trade off. For example standing at a party, but you really want to go and afterwards you know it will hurt but accept that this will be the case. Good flare-up management skills can play a huge role during these times. A further group of interventions I call perceptual exercises. Due to the plastic changes in the sensory and motor cortices, the sense of self, body and movement can feel different in many ways. Working with this through the use of imagery, mindfulness, awareness and other strategies can really help to get back in touch with the body alongside the other techniques. Finally, motor control exercise to normalise movement is very important but to be done at the right time in the right way.

The context of the treatment can affect the success of the strategy. Timing, environment, understanding and belief must all be considered when designing a programme. Newer ideas and research about neuroimmune responses to exercise, movement and thoughts suggest that we need to be mindful of these factors. This is the modern way of looking at the individual, their pain and circumstances to offer practical and effective strategies in improving outcomes and quality of life.

Subsequent blogs will look at the other symptoms, why and how they manifest and the effects of stress upon the body.