Neuroimaging revolutionizes therapeutic approaches to chronic pain

An understanding of how the brain changes in chronic pain or responds to pharmacological or other therapeutic interventions has been significantly changed as a result of developments in neuroimaging of the CNS. These developments have occurred in 3 domains : (1) Anatomical Imaging which has demonstrated changes in brain volume in chronic pain; (2) Functional Imaging (fMRI) that has demonstrated an altered state in the brain in chronic pain conditions including back pain, neuropathic pain, and complex regional pain syndromes. In addition the response of the brain to drugs has provided new insights into how these may modify normal and abnormal circuits (phMRI or pharmacological MRI); (3) Chemical Imaging (Magnetic Resonance Spectroscopy or MRS) has helped our understanding of measures of chemical changes in chronic pain. Taken together these three domains have already changed the way in which we think of pain – it should now be considered an altered brain state in which there may be altered functional connections or systems and a state that has components of degenerative aspects of the CNS

The Application of Functional Magnetic Resonance Imaging in Neuropathic Pain

In the past, neuropathic pain has been lacking in ideal imaging research methods, which not only limits our research on the pathogenesis of neuropathic pain but also seriously affects the prognosis of treatments. With the rapid development of fMRI technology, more and more scholars have begun to use fMRI technology in the study of neuropathic pain in recent years. This provides a new idea for revealing the underlining mechanisms of neuropathic pain and improving the clinical treatment concepts. In this chapter, we summarized the recent studies of fMRI in neuropathic pain so that readers can better understand the research status and future research directions

Enhanced c-Fos expression in the central amygdala correlates with increased thigmotaxis in rats with peripheral nerve injury

Pain is associated with affective, cognitive and sensory dysfunction. Animal models can be used to observe ethologically relevant behaviours such as thigmotaxis, giving insight into how ongoing sensory abnormalities influence natural rodent behaviours. The amygdala is a complex group of nuclei implicated in the integration and generation of emotional behavioural responses, including those associated with pain, and a region known as the central amygdala is particularly associated with generation of behavioural responses, due to its links to the descending pain modulation pathways; as such, study of amygdalar c-Fos immunoreactivity can help identify the neuronal circuits involved.This study investigated changes in both nociceptive evoked responses and open field behaviour following spinal nerve transection (SNT) in male Wistar rats, and attempted to correlate these with changes in central amygdala c-Fos immunoreactivity.Fourteen days after SNT, mechanical hypersensitivity was present in the hind paw ipsilateral to site of injury. Thigmotactic behaviour was significantly increased in both SNT and sham surgery animals, with c-Fos immunoreactivity in the central amygdala significantly greater in SNT animals compared to both sham and naive groups. Activation was greatest in the capsular and lateral subnuclei of the central amygdala, and in the caudal-most regions. There was a strong correlation between thigmotactic behaviour and central amygdala activation following SNT surgery not seen in sham animals suggesting a role for the amygdala in behavioural responses to peripheral nerve injury.This study provides evidence to support the role of the amygdala in thigmotactic open field behaviour following SNT. WHAT DOES THIS STUDY ADD?: Thigmotaxis and amygdala activation are positively correlated in rats following spinal nerve transection. Behavioural changes seen in sham animals did not correlate with amygdala activation, suggesting amygdala activation is related to nociceptive input. Evoked measures, such as hindpaw withdrawal, are not correlated with either thigmotaxis or amygdala activation, emphasizing the importance of complex behaviours when studying pain

Multimodal Investigation of Peripheral and Central Nervous System Pain Mechanisms in Burning Mouth Syndrome (BMS) Using Magnetic Resonance Imaging and Psychometry (MRIBMS)

Background The International Classification of Orofacial Pain (ICOP) has defined burning mouth syndrome (BMS-ICOP) as an intraoral burning or dysaesthetic sensation that reoccurs daily for more than two hours per day and more than three months without evidence of causative lesions upon clinical examination and investigation. The burning mouth symptoms can be caused by primary and secondary BMS. Primary BMS is idiopathic BMS or true BMS, while secondary BMS, also known as burning mouth disorder (BMD), is attributed to local factors or systemic conditions. The prevalence of BMS in women was significantly higher than in men and mainly occurred at the post-menopausal age between 50 and 80 years. This intense, continuous, spontaneous pain severely affects the patient’s oral function, health, and psychology, with high reported rates of anxiety and depression. The pathophysiology of primary BMS as defined by ICOP (BMS-ICOP) remains uncertain, and with no standardised treatment protocol, treatment outcomes are further complicated. Over the years, there have been reports of altered cerebral activities in various levels of the neuraxis in patients with BMS-ICOP, which implies that BMS pain has a central nervous system component. AimThis thesis aimed to characterise patients’ cerebral responses associated with chronic trigeminal pain following administration of two topical peripheral-acting analgesics, clonazepam mouthwash (CMW) and dental local anaesthetic (LA), and the difference between treatment responders and non-responders. Attenuating or escalating pain in response to peripheral medications will allow in-depth phenotyping of patients with BMS-ICOP and facilitate tailored medicine. This thesis also studied and described the characteristics of patients with BMS-ICOP and the psychological impact of BMS-ICOP.MethodsThis prospective, open-label study was conducted at King’s College Dental Institute and Clinical Research Facilities, King’s College London. In the first visit, 26 participants diagnosed with BMS-ICOP were clinically screened and psychologically assessed using psychometric questionnaires. Functional magnetic resonance imaging (fMRI) and pulsed-continuous arterial spin labelling (pCASL) imaging techniques were employed to provide quantitative measurements of the resting-state functional connectivity (FC) and regional cerebral blood flow (rCBF), respectively, that related to changes in the brain activity. Participants underwent a series of fMRI and pCASL scans and rated their pain intensity using the numerical rating scale (NRS, 0-10) and visual analogue scale (VAS, 0-100) before and after the administration of CMW and LA. A subgroup of 15 BMS-ICOP patients with burning pain across the tongue was selected from the initial 26 BMS-ICOP patients to receive LA intervention. In addition to it, patients’ grey matter volume (GMV) was quantified using voxel-based morphometry (VBM) analysis. Here, we performed seed-based FC and pCASL analysis of the regions of interest (ROIs), including the left hippocampus, ventromedial prefrontal cortex (vmPFC), left amygdala, thalamus, right anterior insula (RAI), and periaqueductal grey matter (PAG); given reports of perturbed functioning changes in this region in chronic pain. Treatment responders were defined as reporting 50% or greater pain reduction from baseline following analgesic administration. ResultsOverall, the cohort of patients had daily recurring and continuously hot burning pain, with a mean NRS intensity rating of 5.15, progressively worsening during the day.Although experiencing a high pain level, most patients had a low tendency to catastrophise the threat value of pain or pain-related thoughts and did not exhibit depression, anxiety, or somatic symptom disorders. When comparing the pain and control sites, more than 90% of patients showed no chairside qualitative sensory deficit to touch and two-point discrimination. Meanwhile, 42% and 20% of patients had pin-prick and thermal sensitivity changes, respectively. This similarity was also reflected in the quantitative mechanical detection threshold assessment, where there were no significant changes between the control and pain sites (p = 0.695, SE =0.06). We also did not observe any statistically significant correlation between behaviour changes and cerebral responses to pain (pre-intervention), such as anxiety (r=0.09, p=0.677, 95% CI= -0.31-0.46) and depression (r= -0.21, 95% CI= -0.55 – 0.2, p=0.314). ClonazepamRinsing with 2mg CMW for 10 minutes significantly reduced pain intensity across the participants. An acute 2mg dose was selected to provide an immediate state of pain relief effect, keeping in mind that the suggested maximum daily prescribed clonazepam dose for pain relief is 4mg/day. Patients experienced a mean pain intensity NRS score reduction of 2.67 (p<0.001), and 15 patients responded to treatment. The study found a correlation between patients’ brain GMV and resting-state FC and pain intensity before and after rinsing with CMW. These changes were seen in the brain regions responsible for pain-related cognitive and affective processing and descending pain modulation. We also demonstrated the effect of CMW, which caused a decrease in the FC in the L hippocampus and RAI ROIs. There were alterations in the FC (∆FC) following treatment that were associated with changes in pain levels, as seen in the L hippocampus and vmPFC ROIs. In attempting to predict treatment response towards clonazepam, we tested the baseline FC with changes in pain ratings, and we did not observe any significant correlation. In addition, patients with a minimum of 50% pain reduction following CMW had a lower baseline FC than non-responders in all six ROIs. Conversely, an increased FC was noted in responders between L hippocampus-brainstem/ cerebellum and vmPFC-primary motor/somatosensory cortices. Similarly, there was a reduction in post-mouthwash rCBF compared to pre-mouthwash rCBF. No significant changes were reported upon analysis of the baseline rCBF and changes in the rCBF (∆rCBF) along with pain intensity.Dental local anaesthesiaFollowing bilateral inferior alveolar nerve block, patients achieved greater pain intensity relief than CMW with a reduction of 3.73 NRS units (p<0.001, SD=1.91), with 13 patients responding to it, but two patients did not. At baseline, we also observed the FC presence between brain regions involved in cognitive and affective (emotion) pain processing and modulation, and these connectivities were associated with pain ratings and area size. Participants with a greater reduction in their pain intensity NRS (∆NRS) and VAS (∆VAS) scores after LA had weak baseline FC strength between L hippocampus-temporal lobe (p=0.024) and PAG–L amygdala (p=0.032), respectively. However, no significant association was found between the ∆FC with pain ratings and pain area size. Contrary to CMW’s pCASL analysis, no correlation was observed between LA group patients’ baseline rCBF and pain ratings and area size. However, further exploratory pCASL analysis (uncorrected initial threshold of p=0.005) showed a reduction in rCBF after LA administration in the cognitive (dorsolateral prefrontal cortex), primary motor cortex, and primary somatosensory cortex brain regions. When comparing the studies, differences in cerebral responses to pain are likely related to the context of expectancy effect and the differential in afferent nociceptive ascending trigeminothalamic inputs to the brain and descending pain inhibition modulation system.ConclusionOur cohort of patients with BMS-ICOP had a remarkable ability to engage in valued daily activities by having high pain acceptance behaviour and a low tendency to magnify the value of pain. Administration of topical peripheral analgesics during the ongoing experience of chronic pain modulated the brain’s resting state activities, such as FC and rCBF. Alterations in FC and rCBF between brain regions involved in chronic pain modulation may reflect ongoing BMS-ICOP pain symptomatology, possibly due to impaired central and/or peripheral nervous system function. Understanding the peripheral and central processes involved in BMS-ICOP pain and how analgesics alter them may provide preliminary insights into the mechanism of action of potential topical analgesics, which may be a valuable parameter in predicting treatment response and is fundamental to advancing pain medicine

Current evidence for a modulation of low back pain by human genetic variants

The manifestation of chronic back pain depends on structural, psychosocial, occupational and genetic influences. Heritability estimates for back pain range from 30% to 45%. Genetic influences are caused by genes affecting intervertebral disc degeneration or the immune response and genes involved in pain perception, signalling and psychological processing. This inter-individual variability which is partly due to genetic differences would require an individualized pain management to prevent the transition from acute to chronic back pain or improve the outcome. The genetic profile may help to define patients at high risk for chronic pain. We summarize genetic factors that (i) impact on intervertebral disc stability, namely Collagen IX, COL9A3, COL11A1, COL11A2, COL1A1, aggrecan (AGAN), cartilage intermediate layer protein, vitamin D receptor, metalloproteinsase-3 (MMP3), MMP9, and thrombospondin-2, (ii) modify inflammation, namely interleukin-1 (IL-1) locus genes and IL-6 and (iii) and pain signalling namely guanine triphosphate (GTP) cyclohydrolase 1, catechol-O-methyltransferase, μ opioid receptor (OPMR1), melanocortin 1 receptor (MC1R), transient receptor potential channel A1 and fatty acid amide hydrolase and analgesic drug metabolism (cytochrome P450 [CYP]2D6, CYP2C9)

Emotional and motivational pain processing : current state of knowledge and perspectives in translational research

Pain elicits fear and anxiety and promotes escape, avoidance, and adaptive behaviors that are essential for survival. When pain persists, motivational priority and attention shift to pain-related information. Such a shift often results in impaired functionality, leading to maladaptive pain-related fear and anxiety and escape and avoidance behaviors. Neuroimaging studies in chronic pain patients have established that brain activity, especially in cortical and mesolimbic regions, is different from activity observed during acute pain in control subjects. In this review, we discuss the psychophysiological and neuronal factors that may be associated with the transition to chronic pain. We review information from human studies on neural circuits involved in emotional and motivational pain processing and how these circuits are altered in chronic pain conditions. We then highlight findings from animal research that can increase our understanding of the molecular and cellular mechanisms underlying emotional-motivational pain processing in the brain. Finally, we discuss how translational approaches incorporating results from both human and animal investigations may aid in accelerating the discovery of therapies

From acute to chronic pain: tapentadol in the progressive stages of this disease entity

OBJECTIVE: Chronic pain is now recognized as a neural disease, which results from a maladaptive functional and structural transformation process occurring over time. In its chronic phase, pain is not just a symptom but also a disease entity. Therefore, pain must be properly addressed, as many patients still report unsatisfactory pain control despite on-going treatment. The selection of the therapy - taking into account the pathophysiological mechanisms of pain - and the right timing can result in a successful analgesic outcome. This review will present the functional and structural modifications leading to chronification of pain, focusing on the role of tapentadol in this setting. MATERIALS AND METHODS: For inclusion in this review, research studies were retrieved via a keyword-based query of multiple databases (MEDLINE, Embase, Cochrane). The search was last updated in November 2016; no limitations were applied. RESULTS: Functional and structural abnormalities of the nervous system associated with pain chronification have been reported in several conditions, including osteoarthritis, chronic back pain, chronic pelvic pain and fibromyalgia. Correct identification and treatment of pain in recurrent/progressive stage is crucial to prevent chronification and related changes in neural structures. Among analgesic drugs, tapentadol, with its dual mechanism of action (opioid agonist and noradrenaline reuptake blocker), has recently resulted active in pain control at both central and spinal level. CONCLUSIONS: Tapentadol represents a suitable candidate for patients at early progressive stage of pain who have developed neuroplasticity with modification of pain pathways. The availability of different doses of tapentadol may help clinicians to tailor treatment based on the individual need of each patient, with the aim to enhance therapeutic appropriateness in the treatment of musculoskeletal and neuropathic pain

The Role of the Locus Coeruleus in Pain and Associated Stress-Related Disorders

The locus coeruleus (LC)-noradrenergic system is the main source of noradrenaline in the central nervous system and is involved intensively in modulating pain and stress-related disorders (e.g., major depressive disorder and anxiety) and in their comorbidity. However, the mechanisms involving the LC that underlie these effects have not been fully elucidated, in part owing to the technical difficulties inherent in exploring such a tiny nucleus. However, novel research tools are now available that have helped redefine the LC system, moving away from the traditional view of LC as a homogeneous structure that exerts a uniform influence on neural activity. Indeed, innovative techniques such as DREADDs (designer receptors exclusively activated by designer drugs) and optogenetics have demonstrated the functional heterogeneity of LC, and novel magnetic resonance imaging applications combined with pupillometry have opened the way to evaluate LC activity in vivo. This review aims to bring together the data available on the efferent activity of the LC-noradrenergic system in relation to pain and its comorbidity with anxiodepressive disorders. Acute pain triggers a robust LC stress response, producing spinal cord–mediated endogenous analgesia while promoting aversion, vigilance, and threat detection through its ascending efferents. However, this protective biological system fails in chronic pain, and LC activity produces pain facilitation, anxiety, increased aversive memory, and behavioral despair, acting at the medulla, prefrontal cortex, and amygdala levels. Thus, the activation/deactivation of specific LC projections contributes to different behavioral outcomes in the shift from acute to chronic pain