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BackgroundThe clinically used methods of pain diagnosis do not allow for objective and robust measurement, and physicians must rely on the patient’s report on the pain sensation. Verbal scales, visual analog scales (VAS) or numeric rating scales (NRS) count among the most common tools, which are restricted to patients with normal mental abilities. There also exist instruments for pain assessment in people with verbal and / or cognitive impairments and instruments for pain assessment in people who are sedated and automated ventilated. However, all these diagnostic methods either have limited reliability and validity or are very time-consuming. In contrast, biopotentials can be automatically analyzed with machine learning algorithms to provide a surrogate measure of pain intensity.MethodsIn this context, we created a database of biopotentials to advance an automated pain recognition system, determine its theoretical testing quality, and optimize its performance. Eighty-five participants were subjected to painful heat stimuli (baseline, pain threshold, two intermediate thresholds, and pain tolerance threshold) under controlled conditions and the signals of electromyography, skin conductance level, and electrocardiography were collected. A total of 159 features were extracted from the mathematical groupings of amplitude, frequency, stationarity, entropy, linearity, variability, and similarity.ResultsWe achieved classification rates of 90.94% for baseline vs. pain tolerance threshold and 79.29% for baseline vs. pain threshold. The most selected pain features stemmed from the amplitude and similarity group and were derived from facial electromyography.ConclusionThe machine learning measurement of pain in patients could provide valuable information for a clinical team and thus support the treatment assessment.

Objectives:Small-fiber polyneuropathy (SFPN) has various underlying causes, including associations with systemic autoimmune conditions. We have proposed a new cause; small-fiber-targeting autoimmune diseases akin to Guillain-Barré and chronic inflammatory demyelinating polyneuropathy (CIDP). There are no treatment studies yet for this ‘apparently autoimmune SFPN’ (aaSFPN), but intravenous immunoglobulin (IVIg), first-line for Guillain-Barré and CIDP, is prescribed off-label for aaSFPN despite very high cost. This project aimed to conduct the first systematic evaluation of IVIg’s effectiveness for aaSFPN.Methods:With IRB approval, we extracted all available paper and electronic medical records of qualifying patients. Inclusion required having objectively confirmed SFPN, autoimmune attribution and other potential causes excluded. IVIg needed to have been dosed at ⩾1 g/kg/4 weeks for ⩾3 months. We chose two primary outcomes – changes in composite autonomic function testing (AFT) reports of SFPN and in ratings of pain severity – to capture objective as well as patient-prioritized outcomes.Results:Among all 55 eligible patients, SFPN had been confirmed by 3/3 nerve biopsies, 62% of skin biopsies, and 89% of composite AFT. Evidence of autoimmunity included 27% of patients having systemic autoimmune disorders, 20% having prior organ-specific autoimmune illnesses and 80% having ⩾1/5 abnormal blood-test markers associated with autoimmunity. A total of 73% had apparent small-fiber-restricted autoimmunity. IVIg treatment duration averaged 28 ± 25 months. The proportion of AFTs interpreted as indicating SFPN dropped from 89% at baseline to 55% (p ⩽ 0.001). Sweat production normalized (p = 0.039) and the other four domains all trended toward improvement. Among patients with pre-treatment pain ⩾3/10, severity averaging 6.3 ± 1.7 dropped to 5.2 ± 2.1 (p = 0.007). Overall, 74% of patients rated themselves ‘improved’ and their neurologists labeled 77% as ‘IVIg responders’; 16% entered remissions that were sustained after IVIg withdrawal. All adverse events were expected; most were typical infusion reactions. The two moderate complications (3.6%) were vein thromboses not requiring discontinuation. The one severe event (1.8%), hemolytic anemia, remitted after IVIg discontinuation.Conclusion:These results provide Class IV, real-world, proof-of-concept evidence suggesting that IVIg is safe and effective for rigorously selected SFPN patients with apparent autoimmune causality. They provide rationale for prospective trials, inform trial design and indirectly support the discovery of small-fiber-targeting autoimmune/inflammatory illnesses.

Background The recently developed composite autonomic symptom score-31 (COMPASS-31) is a questionnaire for assessing symptoms of dysautonomia. It was distilled from the well established autonomic symptom profile questionnaire. COMPASS-31 has not yet been externally validated. To do so, we assessed its psychometric properties and its convergent validity in patients with or without objective diagnosis of small fiber polyneuropathy (SFPN). Methods The internal validity and reliability of COMPASS-31 were assessed in participants with or without SFPN spanning the full autonomic symptoms severity. Convergent validity was assessed by comparing results of the COMPASS-31 and the gold standard autonomic function testing (AFT) which measures cardiovagal, adrenergic, and sudomotor functions. Additionally, relationships between COMPASS-31 and the Short Form McGill pain questionnaire, Short Form Health Survey and a 0-10 numeric pain scale were assessed. COMPASS-31 and all other questionnaires results were compared between patients with or without evidence of SFPN, objectively confirmed by distal-leg PGP9.5-immunolabeled skin biopsy. Results Among 66 participants (28 SFPN+, 38 SFPN-), COMPASS-31 total scores had excellent internal validity (Cronbach's α =0.919), test-retest reliability (rs=0.886; p<0.001), and good convergent validity (rs=0.474; p<0.001). COMPASS-31 scores differed between subjects with or without SFPN (Z=−3.296, p<0.001), and demonstrated fair diagnostic accuracy. Area under the receiver operating characteristic curve was 0.749 (P =0.01, 95% confidence interval 0.627-0.871). Conclusions COMPASS-31 has good psychometric properties in the population of patients being evaluated for SFPN and thus it might be useful as an initial screening tool for the more expensive SFPN objective tests.

Although evidence shows that several dopamine neurotransmission pathway genes are associated with specific clinical pain syndromes, such as fibromyalgia, chronic headache, and postoperative pain, the exact role of dopamine in pain processing is not fully understood. The aim of this study was to explore the relationship between functional polymorphisms in dopaminergic candidate genes and sensitivity to pain in healthy subjects. Healthy subjects (n=192; 105 F, 87 M) were exposed to experimental tonic cold pain (1 degrees C) and phasic heat pain (47 degrees C) stimuli. DNA samples were obtained from both participants and their parents. The relationships between pain response (intensity in response to heat and cold; threshold and tolerance in response to cold only) and the functional Variable Number of Tandem Repeat (VNTR) polymorphisms of three dopamine-related genes were investigated using a Transmission Disequilibrium Test (TDT). Specifically, 30-bp repeat in the promoter region of the monoamine oxidase-A gene (MAO-A), 40-bp repeat in the 3'-untranslated region of the dopamine transporter gene (DAT-1), and 48-bp repeat in the exon 3 of the dopamine receptor 4 gene (DRD4) were examined. Significant associations between cold pain tolerance and DAT-1 (p=0.008) and MAO-A (p=0.024) polymorphisms were found. Specifically, tolerance was shorter for carriers of allele 10 and the rarer allele 11, as compared to homozygous for allele 9, and for carriers of allele 4 as compared to homozygous for allele 3, respectively. These results, together with the known function of the investigated candidate gene polymorphisms, suggest that low dopaminergic activity can be associated with high pain sensitivity and vice versa.

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Objective:To present standardized diagnostic criteria for idiopathic distal sensory polyneuropathy (iDSP) and its subtypes: idiopathic mixed fiber sensory neuropathy (iMFN), idiopathic small fiber sensory neuropathy (iSFN), and idiopathic large fiber sensory neuropathy (iLFN) for use in research.Methods:The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) public-private partnership with the Food and Drug Administration convened a meeting to develop consensus diagnostic criteria for iMFN, iSFN, and iLFN. After background presentations, a collaborative, iterative approach was used to develop expert consensus for new criteria.Results:An iDSP diagnosis requires at least one small fiber (SF) or large fiber (LF) symptom, at least one SF or LF sign, abnormalities in sensory nerve conduction studies (NCS) or distal intra-epidermal nerve fiber density (IENFD), and exclusion of known etiologies. An iMFN diagnosis requires that at least one of the above clinical features is SF and one clinical feature is LF. Diagnostic criteria for iSFN require at least one SF symptom and at least one SF sign with abnormal IENFD, normal sensory NCS, and the absence of LF symptoms and signs. Diagnostic criteria for iLFN require at least one LF symptom and at least one LF sign with normal IENFD, abnormal NCS, and absence of SF symptoms and signs.Conclusions:Adoption of these standardized diagnostic criteria will advance research and clinical trials and spur development of novel therapies for iDSPs..

Recognizing that electrically stimulating the motor cortex could relieve chronic pain sparked development of noninvasive technologies. In transcranial magnetic stimulation (TMS), electromagnetic coils held against the scalp influence underlying cortical firing. Multiday repetitive transcranial magnetic stimulation (rTMS) can induce long-lasting, potentially therapeutic brain plasticity. Nearby ferromagnetic or electronic implants are contraindications. Adverse effects are minimal, primarily headaches. Single provoked seizures are very rare. Transcranial magnetic stimulation devices are marketed for depression and migraine in the United States and for various indications elsewhere. Although multiple studies report that high-frequency rTMS of the motor cortex reduces neuropathic pain, their quality has been insufficient to support Food and Drug Administration application. Harvard's Radcliffe Institute therefore sponsored a workshop to solicit advice from experts in TMS, pain research, and clinical trials. They recommended that researchers standardize and document all TMS parameters and improve strategies for sham and double blinding. Subjects should have common well-characterized pain conditions amenable to motor cortex rTMS and studies should be adequately powered. They recommended standardized assessment tools (eg, NIH's PROMIS) plus validated condition-specific instruments and consensus-recommended metrics (eg, IMMPACT). Outcomes should include pain intensity and qualities, patient and clinician impression of change, and proportions achieving 30% and 50% pain relief. Secondary outcomes could include function, mood, sleep, and/or quality of life. Minimum required elements include sample sources, sizes, and demographics, recruitment methods, inclusion and exclusion criteria, baseline and posttreatment means and SD, adverse effects, safety concerns, discontinuations, and medication-usage records. Outcomes should be monitored for at least 3 months after initiation with prespecified statistical analyses. Multigroup collaborations or registry studies may be needed for pivotal trials.