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      Correlation of Pain Reduction with fMRI BOLD Response in Osteoarthritis Patients Treated with Paracetamol: Randomized, Double-Blind, Crossover Clinical Efficacy Study

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          Abstract

          Objective

          To assess the relationship between the analgesic efficacy of extended-release paracetamol (ER-APAP) and brain blood oxygen level–dependent (BOLD) signal activation in response to painful stimulation measured by functional magnetic resonance imaging (fMRI) in patients with osteoarthritis of the knee.

          Methods

          This placebo-controlled, double-blind, crossover, randomized trial (N = 25) comprised three treatment periods in which patients received four doses of an eight-hour ER-APAP caplet (2 x 665 mg), four doses of matched placebo, and no treatment. Pain intensity of the knee was measured before and after painful stimulation at the knee with osteoarthritis and before and after fMRI.

          Results

          ER-APAP significantly reduced prestimulation osteoarthritis knee joint pain compared with baseline ( P < 0.003) and placebo ( P < 0.004). ER-APAP and placebo significantly reduced knee joint pain after stimulation ( P = 0.014 and P = 0.032, respectively); however, pain reduction with ER-APAP was 35% greater than placebo. ER-APAP was associated with significant reductions in BOLD signal activation after stimulation compared with control in the sensory cortex ( P = 0.002) and supramarginal gyrus ( P = 0.003). Reduction in BOLD signal activation after stimulation for placebo was significantly greater than control in the subgenual prefrontal cortex ( P < 0.001), frontal cortex ( P < 0.001), insula ( P < 0.003), and sensory cortex ( P < 0.001).

          Conclusions

          ER-APAP had a significantly greater effect than placebo and no treatment in reducing knee pain, which was associated with reduced BOLD signal activations in pain pathways, including the sensory cortex and supramarginal gyrus. BOLD observations after placebo treatment may shed light on the role of the brain regions potentially involved in placebo response in clinical trials investigating pain therapies.

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          Most cited references28

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          Functional imaging of brain responses to pain. A review and meta-analysis (2000).

          Brain responses to pain, assessed through positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are reviewed. Functional activation of brain regions are thought to be reflected by increases in the regional cerebral blood flow (rCBF) in PET studies, and in the blood oxygen level dependent (BOLD) signal in fMRI. rCBF increases to noxious stimuli are almost constantly observed in second somatic (SII) and insular regions, and in the anterior cingulate cortex (ACC), and with slightly less consistency in the contralateral thalamus and the primary somatic area (SI). Activation of the lateral thalamus, SI, SII and insula are thought to be related to the sensory-discriminative aspects of pain processing. SI is activated in roughly half of the studies, and the probability of obtaining SI activation appears related to the total amount of body surface stimulated (spatial summation) and probably also by temporal summation and attention to the stimulus. In a number of studies, the thalamic response was bilateral, probably reflecting generalised arousal in reaction to pain. ACC does not seem to be involved in coding stimulus intensity or location but appears to participate in both the affective and attentional concomitants of pain sensation, as well as in response selection. ACC subdivisions activated by painful stimuli partially overlap those activated in orienting and target detection tasks, but are distinct from those activated in tests involving sustained attention (Stroop, etc.). In addition to ACC, increased blood flow in the posterior parietal and prefrontal cortices is thought to reflect attentional and memory networks activated by noxious stimulation. Less noted but frequent activation concerns motor-related areas such as the striatum, cerebellum and supplementary motor area, as well as regions involved in pain control such as the periaqueductal grey. In patients, chronic spontaneous pain is associated with decreased resting rCBF in contralateral thalamus, which may be reverted by analgesic procedures. Abnormal pain evoked by innocuous stimuli (allodynia) has been associated with amplification of the thalamic, insular and SII responses, concomitant to a paradoxical CBF decrease in ACC. It is argued that imaging studies of allodynia should be encouraged in order to understand central reorganisations leading to abnormal cortical pain processing. A number of brain areas activated by acute pain, particularly the thalamus and anterior cingulate, also show increases in rCBF during analgesic procedures. Taken together, these data suggest that hemodynamic responses to pain reflect simultaneously the sensory, cognitive and affective dimensions of pain, and that the same structure may both respond to pain and participate in pain control. The precise biochemical nature of these mechanisms remains to be investigated.
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            Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits.

            Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain-related brain activity between subjects who have had the condition for ∼2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub-acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large-scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain.
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              Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome

              Background Placebo treatment can significantly influence subjective symptoms. However, it is widely believed that response to placebo requires concealment or deception. We tested whether open-label placebo (non-deceptive and non-concealed administration) is superior to a no-treatment control with matched patient-provider interactions in the treatment of irritable bowel syndrome (IBS). Methods Two-group, randomized, controlled three week trial (August 2009-April 2010) conducted at a single academic center, involving 80 primarily female (70%) patients, mean age 47±18 with IBS diagnosed by Rome III criteria and with a score ≥150 on the IBS Symptom Severity Scale (IBS-SSS). Patients were randomized to either open-label placebo pills presented as “placebo pills made of an inert substance, like sugar pills, that have been shown in clinical studies to produce significant improvement in IBS symptoms through mind-body self-healing processes” or no-treatment controls with the same quality of interaction with providers. The primary outcome was IBS Global Improvement Scale (IBS-GIS). Secondary measures were IBS Symptom Severity Scale (IBS-SSS), IBS Adequate Relief (IBS-AR) and IBS Quality of Life (IBS-QoL). Findings Open-label placebo produced significantly higher mean (±SD) global improvement scores (IBS-GIS) at both 11-day midpoint (5.2±1.0 vs. 4.0±1.1, p<.001) and at 21-day endpoint (5.0±1.5 vs. 3.9±1.3, p = .002). Significant results were also observed at both time points for reduced symptom severity (IBS-SSS, p = .008 and p = .03) and adequate relief (IBS-AR, p = .02 and p = .03); and a trend favoring open-label placebo was observed for quality of life (IBS-QoL) at the 21-day endpoint (p = .08). Conclusion Placebos administered without deception may be an effective treatment for IBS. Further research is warranted in IBS, and perhaps other conditions, to elucidate whether physicians can benefit patients using placebos consistent with informed consent. Trial Registration ClinicalTrials.gov NCT01010191
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                Author and article information

                Journal
                Pain Med
                Pain Med
                painmedicine
                Pain Medicine: The Official Journal of the American Academy of Pain Medicine
                Oxford University Press
                1526-2375
                1526-4637
                February 2018
                29 August 2017
                29 August 2017
                : 19
                : 2
                : 355-367
                Affiliations
                GlaxoSmithKline Consumer Healthcare, Warren, New Jersey, USA
                Author notes
                Correspondence to: Yong Yue, MD, 1125 Bear Tavern Road, Titusville, NJ 08560, USA. Tel: 609-730-3277; E-mail: yjyue@ 123456yahoo.com .

                Funding sources: This study was sponsored by GlaxoSmithKline Consumer Healthcare (Warren, New Jersey, USA). Editorial assistance for the development of this manuscript was provided by Peloton Advantage LLC (Parsippany, NJ, USA) and was funded by GlaxoSmithKline Consumer Healthcare.

                Conflicts of interest: Y. Yue and A. Collaku were employees of GlaxoSmithKline Consumer Healthcare at the time of study. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

                Article
                pnx157
                10.1093/pm/pnx157
                5914370
                29025005
                a3376ec9-c5c7-4066-bf45-91e4a510962c
                © 2017 American Academy of Pain Medicine.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 13
                Categories
                MUSCULOSEKELTAL SECTION
                Original Research Article
                Editor's Choice

                Anesthesiology & Pain management
                functional magnetic resonance imaging (fmri),blood oxygen level–dependent (bold),brain activity,paracetamol,pain,osteoarthritis

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