Colored Pain Drawing as a Clinical Tool in Differentiating Neuropathic Pain from Non-Neuropathic Pain.

OBJECTIVES: This is a prospective, blinded, case-control study of patients with chronic pain using body diagrams and colored markers to show the distribution and quality of pain and sensory symptoms (aching, burning, tingling, numbness, and sensitivity to touch) experienced in affected body parts. METHODS: Two pain physicians, blinded to patients' clinical diagnoses, independently reviewed and classified each colored pain drawing (CPD) for presence of neuropathic pain (NeuP) vs. non-neuropathic pain (NoP). A clinical diagnosis (gold standard) of NeuP was made in 151 of 213 (70.9%) enrolled patients. RESULTS: CPD assessment at "first glance" by both examiners resulted in correctly categorizing 137 (64.3% by examiner 1) and 156 (73.2% by examiner 2) CPDs. Next, classification of CPDs by both physicians, using predefined criteria of spatial distribution and quality of pain-sensory symptoms, improved concordance to 212 of 213 CPDs (Kappa = 0.99). The diagnostic ability to correctly identify NeuP and NoP by both examiners increased to 171 (80.2%) CPDs, with 80.1% sensitivity and 80.6% specificity (Kappa = 0.56 [95% confidence interval: 0.44-0.68]). The severity scores for pain and sensory symptoms (burning, tingling, numbness, and sensitivity to touch) on the Neuropathic Pain Questionnaire were significantly elevated in NeuP vs. NoP (P < 0.001). CONCLUSIONS: This study demonstrates good performance characteristics of CPDs in identifying patients with NeuP through the use of a simple and easy-to-apply classification scheme. We suggest use of CPDs as a bedside screening tool and as a method for phenotypic profiling of patients by the quality and distribution of pain and sensory symptoms.

Are Pain Ratings Irrelevant?

Pain intensity ratings have been the basis of pain diagnosis and a fundamental tool in pain research, but are not always used. Frequent comments by physicians that pain ratings, sometimes called pain scores, are not useful in clinical practice and comments by basic scientists that pain ratings may measure the wrong thing, have been in significant part supported by a short survey conducted among members of American Pain Society (APS). Though limited by small number of respondents, the findings of this survey and additional comments by members of APS raise critical questions about why pain ratings do not serve the clinical communities. These findings send an urgent call to the pain community to reassess the status of currently used pain ratings and to find solutions to this fundamental issue.

Sensory small fiber function differentially assessed with diode laser (DL) quantitative sensory testing (QST) in painful neuropathy (PN).

Sensory function of small peripheral nerve fiber was assessed by means of quantitative sensory testing (QST) during which sensory stimulation was provided using diode laser (DL) in patients suffering from painful neuropathy (PN) and compared with symptom-free healthy controls (HC). Based on previous research work using DL stimulation, parameters that demonstrated safe and specific activation of A-delta, which were distinct from stimulation parameters for the activation of C-fibers, were utilized in this study. Results of this study demonstrated that this differential activation pointed to the impaired function of A-delta fibers while C-fiber function was unaffected. Stimulation of HC reproduced previously published results, and stimulation during this study was safe also without any dermal effect in patients with PN and in HC. Parameters used in this study were demonstrated in previous preclinical rodent study identical differential effect on activation of A-delta and C-fibers, and as such, DL is an ideal tool for translational pain research where specific activation of A-delta or C-fibers, or both, is required.

Review of neuropathic pain screening and assessment tools.

Chronic pain due to injury to or diseases of the nervous system, known as neuropathic pain (NP), is a common debilitating medication condition for which there are currently several symptomatically effective therapies. Therefore, early identification of NP in the primary and specialty care setting will avoid unnecessary delays in amelioration of symptoms. Given that it is associated with unique symptoms and physical exam signs, several assessment tools have been developed to aid medical practitioners in the identification of patients with NP. The majority of these tools have been developed to differentiate NP from nonNP and to quantify the severity of symptoms that define NP, and some have been used to aid in assessment of response to interventions. This focused review will describe the primary NP assessment tools that are currently available, and discuss their suitability for screening patients and for research applications. Wider use of NP assessment tools will facilitate the development of new therapies, further clarify the epidemiology of this condition, and improve the treatment of NP.

Turning on the alarm: the neural mechanisms of the transition from innocuous to painful sensation.

The experience of pain occurs when the level of a stimulus is sufficient to elicit a marked affective response, putatively to warn the organism of potential danger and motivate appropriate behavioral responses. Understanding the biological mechanisms of the transition from innocuous to painful levels of sensation is essential to understanding pain perception as well as clinical conditions characterized by abnormal relationships between stimulation and pain response. Thus, the primary objective of this study was to characterize the neural response associated with this transition and the correspondence between that response and subjective reports of pain. Towards this goal, this study examined BOLD response profiles across a range of temperatures spanning the pain threshold. 14 healthy adults underwent functional magnetic resonance imaging (fMRI) while a range of thermal stimuli (44-49°C) were applied. BOLD responses showed a sigmoidal profile along the range of temperatures in a network of brain regions including insula and mid-cingulate, as well as a number of regions associated with motor responses including ventral lateral nuclei of the thalamus, globus pallidus and premotor cortex. A sigmoid function fit to the BOLD responses in these regions explained up to 85% of the variance in individual pain ratings, and yielded an estimate of the temperature of steepest transition from non-painful to painful heat that was nearly identical to that generated by subjective ratings. These results demonstrate a precise characterization of the relationship between objective levels of stimulation, resulting neural activation, and subjective experience of pain and provide direct evidence for a neural mechanism supporting the nonlinear transition from innocuous to painful levels along the sensory continuum.

Neuropathic pain therapy: from bench to bedside.

Neuropathic pain is a result of complex interactions between peripheral and central mechanisms with multiple potential therapeutic targets. However, the complexity of these mechanisms and relative youth of translational pain research, which is in its infancy, have prevented translation of successful basic bench research to human therapy. Most of the clinically available neuropathic pain treatments are borrowed from other therapeutic areas, such as antidepressants and antiepileptics, or involve application of older therapy, such as opioids. Exceptions are ziconotide, tapentadol, and the high-concentration capsaicin patch. Similar to all other analgesic agents, these provide only partial pain relief in subsets of patients. The standard of care for patients with chronic neuropathic pain is multimodal and multidisciplinary. For most patients to achieve and maintain satisfactory pain relief a combination of therapeutic agents is necessary, providing the empiric basis for rational polypharmacy, which has become a standard approach as well.

Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients.

This study replicates and extends prior reports of abnormal cytokine levels in chronic pain patients and has correlated the alterations with pain severity. In addition, there appeared to be a need to directly assess cerebrospinal fluid (CSF) because previous findings on cytokine concentrations in peripheral circulation have been inconsistent. CSF and blood specimens were obtained from 14 patients with distal painful non-diabetic polyneuropathy (DPPN) or post-traumatic neuralgia (PTN). Elevated receptor levels for Tumor Necrosis Factor (sTNFr) were the most distinctive abnormality along with low interleukin-10 (IL-10). sTNFr in CSF and blood, and IL-1ss in CSF, were positively associated with pain intensity, whereas IL-10 in both compartments was inversely correlated with pain symptoms. An imbalance of pro- and anti-inflammatory cytokines appears to be a clinically relevant feature, which may contribute to the maintenance of chronic pain.

Development and validation of Arabic version of the Neuropathic Pain Questionnaire-Short Form.

INTRODUCTION: The Neuropathic Pain Questionnaire-Short Form (NPQ-SF) is the shortest diagnostic tool for the assessment of neuropathic pain, designed with the goal to differentiate between neuropathic and nonneuropathic pain. The aim of this study was to translate, culturally adapt, and validate the NPQ-SF questionnaire in Arabic. METHODS: A systematic translation process was used to translate the original English NPQ-SF into Arabic. After the pilot study, the Arabic version was validated among patients with chronic pain in two tertiary care centers. Reliability of the translated version was examined using internal consistency, test-retest reliability, and intraclass correlation coefficient (ICC). We examined the validity of the Arabic NPQ-SF via construct validity, concurrent validity (associations with the numeric pain scale, Brief Pain Inventory, and Self-completed Leeds Assessment of Neuropathic Symptoms and Signs [S-LANSS]), face validity, and diagnostic validity. To investigate the responsiveness, the translated NPQ-SF questionnaire was administered twice among the same group of patients. RESULTS: A total of 142 subjects (68 men, 74 women) were included in the study. Cronbach's α were 0.45 (95% CI: 0.29, 0.61) and 0.48 (95% CI: 0.33, 0.63), and the ICC was 0.78 (95% CI: 0.72, 0.85). The NPQ-SF was moderately to strongly associated with the S-LANSS questionnaire. Results showed our Arabic NPQ-SF to have good diagnostic accuracy, with area under the curve of 0.76 (95% CI: 0.67, 0.84). Results from the receiver operating characteristic analysis identified a cut-off score of ≥0.52 as the best score to distinguish between patients with or without neuropathic pain, which was higher than the recommended cut-off score (≥0) in the original study. With both sensitivity and specificity of 71%. Most patients found the NPQ-SF questionnaire to be clear and easy to understand. CONCLUSION: Our translated version of NPQ-SF is reliable and valid for use, thus providing physicians a new tool with which to evaluate and diagnose neuropathic pain among Arabic-speaking patients.

Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus.

Quantitative sensory testing (QST) is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients. Although QST shares similarities with the quantitative assessment of hearing or vision, which is extensively used in clinical practice and research, it has not gained a large acceptance among clinicians for many reasons, and in significant part because of the lack of information about standards for performing QST, its potential utility, and interpretation of results. A consensus meeting was convened by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) to formulate recommendations for conducting QST in clinical practice and research. Research studies have confirmed the utility of QST for the assessment and monitoring of somatosensory deficits, particularly in diabetic and small fiber neuropathies; the assessment of evoked pains (mechanical and thermal allodynia or hyperalgesia); and the diagnosis of sensory neuropathies. Promising applications include the assessment of evoked pains in large-scale clinical trials and the study of conditioned pain modulation. In clinical practice, we recommend the use QST for screening for small and large fiber neuropathies; monitoring of somatosensory deficits; and monitoring of evoked pains, allodynia, and hyperalgesia. QST is not recommended as a stand-alone test for the diagnosis of neuropathic pain. For the conduct of QST in healthy subjects and in patients, we recommend use of predefined standardized stimuli and instructions, validated algorithms of testing, and reference values corrected for anatomical site, age, and gender. Interpretation of results should always take into account the clinical context, and patients with language and cognitive difficulties, anxiety, or litigation should not be considered eligible for QST. When appropriate standards, as discussed here, are applied, QST can provide important and unique information about the functional status of somatosensory system, which would be complementary to already existing clinical methods.

Combination drug therapy for chronic pain: a call for more clinical studies.

UNLABELLED: Chronic pain is a debilitating clinical condition associated with a variety of disease entities including diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. For many general practitioners and specialists, managing chronic pain has become a daunting challenge. As a modality of multidisciplinary chronic pain management, medications are often prescribed in combinations, an approach referred to as combination drug therapy (CDT). However, many medications for pain therapy, including antidepressants and opioid analgesics, have significant side effects that can compound when used in combination and impact the effectiveness of CDT. To date, clinical practice of CDT for chronic pain has been based largely on clinical experiences. In this article, we will focus on (1) the scientific basis and rationales for CDT, (2) current clinical data on CDT, and (3) the need for more clinical studies to establish a framework for the use of CDT. PERSPECTIVE: More preclinical, clinical, and translational studies are needed to improve the efficacy of combination drug therapy that is an integral part of a comprehensive approach to the management of chronic pain.

Quantitative sensory testing in measurement of neuropathic pain phenomena and other sensory abnormalities.

Neuropathic pain disorders are usually characterized by spontaneous ongoing or intermittent symptoms, stimulus-evoked positive sensory phenomena, and negative sensory phenomena. Spontaneous individual subject specific phenomena are identified in the neurologic history and are quantifiable by means of self-reported neuropathic pain symptoms tools such as scales, inventories, and questionnaires. Negative and positive sensory phenomena are assessed by the neurologic bedside examination and quantitative sensory testing (QST), which refers to psychophysical tests of sensory perception during the administration of stimuli with predetermined physical properties and following specific protocols. QST is able to capture and quantify stimulus-evoked negative and positive sensory phenomena, and as such should become standard if not a critical tool in neuropathic pain research and practice. Although the advent of anatomic and functional imaging modalities is revolutionizing our understanding of the mechanisms of neuropathic pain, only by anchoring such test results to individual subjects' own perceptions via QST can they provide meaningful information about neuropathic pain, which is based on perceptual experience. To yield useful results, QST requires a cooperative subject and carefully standardized methods, including standardization of the stimulus parameters as well as the testing environment, instructions, and evaluation methods. This manuscript provides a concise review of fundamental concepts necessary for understanding the role of QST in the process of eliciting information about sensory abnormalities associated with neuropathic pain and the place of that information in analysis of pain mechanisms. Together with the companion manuscript, this review provides definitions that should help further the use of QST as a diagnostic tool as well.

Pathogenesis of pain in peripheral diabetic neuropathy.

Recent advances in understanding the pain associated with diabetic neuropathy are likely to provide significant mechanistic insights and offer better therapies. In clinical research, new tools for measuring neuropathic pain and validation of histologic and other biomarkers will provide the foundation for research advances, and new clinical trial designs will allow better discrimination of beneficial treatments and may reveal underlying pathogenic mechanisms. Ongoing refinement of relevant animal models and assays to more accurately reflect the clinical condition will improve evaluation of novel pharmacologic approaches while dissecting peripheral versus central effects of diabetes on pain pathways will provide a more complete picture of the pathophysiologic mechanisms. Such multidisciplinary work may soon allow physicians to offer improved therapeutic options to patients suffering this distressing condition.