Pain medicine training resources: Module 1

Abstract
Individual differences in pain sensitivity have long remained a perplexing and challenging clinical problem. How can one individual have a sensory experience that is vastly different than that of another, even when they have received similar sensory input? Developing an understanding of such differences and the mechanisms that support them has progressed substantially as psychophysical findings are integrated with measures of brain activation provided by functional brain imaging techniques. Continued delineation of these mechanisms will contribute substantially to the development of combined psychophysical/psychological models that can be used to optimize pain treatment on an individual-by-individual basis.

Abstract
Objective: This review summarizes the scientific literature relating to the use of quantitative sensory testing (QST) for mechanism-based pain management.

Design: A literature search was undertaken using PubMed and search terms including quantitative sensory testing, pain, chronic pain, response to treatment, outcome measure.

Settings and patients: Studies including QST in healthy individuals and those with painful disorders were reviewed.

Measures: Publications reported on QST methodological issues including associations among measures and reliability. We also included publications on the use of QST measures in case-control studies, their associations with biopsychosocial mechanisms, QST measures predicting clinical pain, as well as predicting and reflecting treatment responses.

Results: Although evidence suggests that QST may be useful in a mechanism-based classification of pain, there are gaps in our current understanding that need to be addressed including making QST more applicable in clinical settings. There is a need for developing shorter QST protocols that are clinically predictive of various pain subtypes and treatment responses without requiring expensive equipment. Future studies are needed, examining the clinical predictive value of QST including sensitivity and specificity for pain classification or outcome prediction. These findings could enable third-party payers' reimbursement, which would facilitate clinical implementation of QST.

Conclusions: With some developments, QST could become a cost-effective and clinically useful component of pain assessment and diagnosis, which can further our progress toward the goal of mechanism-based personalized pain management.

Abstract
Background: New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis.

Methods: Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method.

Findings: 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.

Interpretation: Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies.

Funding: NeuPSIG of the International Association for the Study of Pain.

Abstract
Allodynia (pain due to a stimulus that does not usually provoke pain) and hyperalgesia (increased pain from a stimulus that usually provokes pain) are prominent symptoms in patients with neuropathic pain. Both are seen in various peripheral neuropathies and central pain disorders, and affect 15-50% of patients with neuropathic pain. Allodynia and hyperalgesia are classified according to the sensory modality (touch, pressure, pinprick, cold, and heat) that is used to elicit the sensation. Peripheral sensitisation and maladaptive central changes contribute to the generation and maintenance of these reactions, with separate mechanisms in different subtypes of allodynia and hyperalgesia. Pain intensity and relief are important measures in clinical pain studies, but might be insufficient to capture the complexity of the pain experience. Better understanding of allodynia and hyperalgesia might provide clues to the underlying pathophysiology of neuropathic pain and, as such, they represent new or additional endpoints in pain trials.

Abstract
Chronic pain is maintained in part by central sensitization, a phenomenon of synaptic plasticity, and increased neuronal responsiveness in central pain pathways after painful insults. Accumulating evidence suggests that central sensitization is also driven by neuroinflammation in the peripheral and central nervous system. A characteristic feature of neuroinflammation is the activation of glial cells, such as microglia and astrocytes, in the spinal cord and brain, leading to the release of proinflammatory cytokines and chemokines. Recent studies suggest that central cytokines and chemokines are powerful neuromodulators and play a sufficient role in inducing hyperalgesia and allodynia after central nervous system administration. Sustained increase of cytokines and chemokines in the central nervous system also promotes chronic widespread pain that affects multiple body sites. Thus, neuroinflammation drives widespread chronic pain via central sensitization. We also discuss sex-dependent glial/immune signaling in chronic pain and new therapeutic approaches that control neuroinflammation for the resolution of chronic pain.

Abstract
One popular description of current society is that it is a depressed society and medical evidence about depression's prevalence may well make such an estimation plausible. However, such normative-critical assessments surrounding depression have to date usually operated with a one-sided understanding of depression. This understanding widely neglects the various ways depression manifests as well as its comorbidities. This becomes evident at the latest when considering one of depression's most prominent and well-known comorbidities: chronic pain. Against this background, we aim in this article to substantiate our leading claim that the phenomenal interconnection between depression and chronic pain must be acknowledged in the global diagnosis of a depressive society. Thus, we argue here for a complementation of the dominant interpretation of a depressed society. This would support the overcoming of oversimplified images and estimations about depression in current society and further, help to recognize chronic pain properly on the larger scale of assessments that address society as a whole.

Abstract
Objective: The study aimed to seek a unifying biological basis for the phenomena encompassed in fibromyalgia syndrome (chronic widespread pain and associated morbidities).

Setting: While much progress has been made in the last decade in understanding chronic widespread pain, its pathogenesis remains stubbornly obscure and its treatment difficult. Two themes are gaining currency in the field: that chronic widespread pain is the result of central sensitization of nociception, and that chronic pain is somehow related to activation of a global stress response.

Design: In this article we merge these two ideas within the perspective of evolutionary biology to generate a hypothesis about the critical molecular pathway involved in chronic stress response activation, namely substance P and its preferred receptor, neurokinin-1 (NK-1R), which has many empirically testable implications.

Conclusion: Drawing on diverse findings in neurobiology, immunology, physiology, and comparative biology, we suggest that the form of central sensitization that leads to the profound phenomenological features of chronic widespread pain is part of a whole-organism stress response, which is evolutionarily conserved, following a general pattern found in the simplest living systems.

Abstract
Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.

Abstract
Context: Higher education has invested in defining the role of generic skills in developing effective, adaptable graduates fit for a changing workplace. Research confirms that the development of generic skills that underpin effectiveness and adaptability in graduates is highly context-dependent and is shaped by the discipline within which these skills are conceptualised, valued and taught. This places the responsibility for generic skills enhancement clearly within the remit of global medical education.

Implications: Many factors will influence the skill set with which students begin their medical training and experience at entry needs to be taken into account. Learning and teaching environments enhance effective skill development through active learning, teaching for understanding, feedback, and teacher-student and student-student interaction. Medical curricula need to provide students with opportunities to practise and develop their generic skills in a range of discipline-specific contexts. Curricular design should include explicit and integrated generic skills objectives against which students' progress can be monitored. Assessment and feedback serve as valuable reinforcements of the professed importance of generic skills to both learner and teacher, and will encourage students to self-evaluate and take responsibility for their own skill development. The continual need for students to modify their practice in response to changes in their environment and the requirements of their roles will help students to develop the ability to transfer these skills at transition points in their training and future careers.

Conclusions: If they are to take their place in an ever-changing profession, medical students need to be competent in the skills that underpin lifelong learning. Only then will the doctors of the future be well placed to adapt to changes in knowledge, update their practice in line with the changing evidence base, and continue to contribute effectively as societal needs change.

Abstract
Peripheral nerve injuries and diseases often lead to pain persisting beyond the resolution of damage, indicating an active disease-promoting process, which may result in chronic pain. This is regarded as a maladaptive mechanism resulting from neuroinflammation that originally serves to promote regeneration and healing. Knowledge on these physiological and pathophysiological processes has accumulated over the last few decades and has started to yield potential therapeutic targets. Key players are macrophages, T-lymphocytes, cytokines, and chemokines. In the spinal cord and brain, microglia and astrocytes are involved. Recently, data have been emerging on the regulation of these players. MicroRNAs and other noncoding RNAs have been discussed as potential master switches that may link nerve injury, pain, and inflammation. Clinical disorders most intensely studied in the context of neuroinflammation and pain are the complex regional pain syndrome, polyneuropathies, postherpetic neuralgia, and the fibromyalgia syndrome, in which recently a neuropathic component has been described. Research from several groups has shown an important role of both proinflammatory and anti-inflammatory cytokines in neuropathic and other chronic pain states in humans. There is ample evidence of an analgesic action of anti-inflammatory cytokines in animal models. The interplay of anti-inflammatory cytokines and the nociceptive system provides possibilities and challenges concerning treatment strategies based on this concept.

Abstract
The importance of lifelong learning in medicine is well recognised. This article explores how junior doctors can develop learning strategies for use throughout their working life

Abstract
After nerve injury maladaptive changes can occur in injured sensory neurons and along the entire nociceptive pathway within the CNS, which may lead to spontaneous pain or pain hypersensitivity. The resulting neuropathic pain syndromes present as a complex combination of negative and positive symptoms, which vary enormously from individual to individual. This variation depends on a diversity of underlying pathophysiological changes resulting from the convergence of etiological, genotypic, and environmental factors. The pain phenotype can serve therefore, as a window on underlying pathophysiological neural mechanisms and as a guide for developing personalized pain medicine.

Abstract
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.