Relations between short-term memory and the within-subject variability of experimental pain intensity reports: Results from healthy and Fibromyalgia patients.

While factors contributing to between-subjects differences in pain have been studied extensively, factors contributing to the within-subjects variability of pain reports are yet unexplored. The aim of this investigation was to assess possible associations between short-term memory and the within-subjects variability of pain reports in healthy and chronic pain patients. Healthy participants were recruited at the University of Haifa, Israel, and Fibromyalgia patients were recruited at a rheumatology department in a central hospital in Lisbon, Portugal. Following consent, both cohorts underwent the same procedures, including the digit-span test, assessing short-term memory, and the FAST procedure, assessing within-subject variability of pain intensity reports in response to experimental pain. One-hundred twenty-one healthy volunteers and 29 Fibromyalgia patients completed the study. While a significant correlation was found between the within-subjects variability and the total score of the short-term memory task (Spearman's r = 0.394, P = 0.046) in the Fibromyalgia group, a marginal correlation emerged in the healthy cohort (r = 0.174, P = 0.056). A possible interpretation of these results is that in the patients' group, at least some of the within-subjects variability of pain intensity reports might be due to error measurement derived by poorer short-term memory, rather than true fluctuations in perception.

Agreement between children's, nurses' and parents' pain intensity reports is stronger before than after analgesic consumption: Results from a post-operative study.

BACKGROUND: Included in their extensive duties caring for hospitalized children, nurses are the frontline for pain assessment and treatment. Research has found that when nurses' assessments are compared with independent reports by the children or their parents, there are often differences. However, no studies have considered the contribution of analgesic medication consumption to this difference. OBJECTIVES: The aim of this study, was to assess the concordance between the pain scores recorded independently by nurses, children, and their parents both before and 1 h after analgesic consumption. DESIGN/SETTING: The trial was registered at ClinicalTrials.gov (NCT04306679) and was conducted in a post-operative inpatient facility. Following surgery, at first request of analgesic, the clinical nurses recorded the child's pain, as part of routine clinical practice. Within 10 min, the child recorded their pain level in a pain diary. At the same time, the parents separately reported their assessment of their child's pain. This process was repeated again 1 h later, when the nurses, as part of the clinical routine, recorded the children's level of post-medication pain. PARTICIPANTS: Forty-seven children ages 8-17 hospitalized for elective surgery in the General Pediatric Surgery, Orthopedics, Ear-Nose-Throat (ENT), and Oral and Maxillofacial (OM) Departments, and their parents, were included in the current report. RESULTS: The mean pain scores reported by the children were significantly higher than those reported by the nurses, both before (5.77±2.51 vs. 3.90±3.12 [mean ±SD], p <0.001) and 1 h after (3.37±2.48 vs. 0.92±2.08, p <0.001) analgesic consumption. No significant differences were found either before or after analgesic consumption in the NPS reported by the child and parent. Agreement between the NPS scores reported by the child and nurses was good before (ICC = 0.754, p <0.001) and only moderate 1 h after (ICC = 0.504, p = 0.017) analgesic consumption. Similarly, agreement between the NPS scores reported by the child and parents was good before (ICC = 0.855, p <0.001) and only moderate 1 h after (ICC = 0.722, p <0.001) analgesic consumption. CONCLUSIONS: While self-report measures remain the gold standard for pediatric pain care, the results of this study suggest that after analgesic administration, agreement between children's and nurses' assessments, and between children's and parents' assessments of pain deteriorated. Our results further confirm that proxy assessments recorded by parents are closer to their children's assessments than are those of nurses and should consequently be preferred especially after analgesic consumption.

Temporal Summation Predicts De Novo Contralateral Pain After Cordotomy in Patients With Refractory Cancer Pain.

BACKGROUND: Percutaneous cervical cordotomy (PCC), which selectively interrupts ascending nociceptive pathways in the spinal cord, can mitigate severe refractory cancer pain. It has an impressive success rate, with most patients emerging pain-free. Aside from the usual complications of neurosurgical procedures, the risks of PCC include development of contralateral pain, which is less understood. OBJECTIVE: To evaluate whether sensory and pain sensitivity, as measured by quantitative sensory testing (QST), are associated with PCC clinical outcomes. METHODS: Fourteen palliative care cancer patients with severe chronic refractory pain limited mainly to one side of the body underwent comprehensive quantitative sensory testing assessment pre-PPC and post-PCC. They were also queried about maximal pain during the 24 h precordotomy (0-10 numerical pain scale). RESULTS: All 14 patients reported reduced pain postcordotomy, with 7 reporting complete resolution. Four patients reported de novo contralateral pain. Reduced sensitivity in sensory and pain thresholds to heat and mechanical stimuli was recorded on the operated side (P = .028). Sensitivity to mechanical pressure increased on the unaffected side (P = .023), whereas other sensory thresholds were unchanged. The presurgical temporal summation values predicted postoperative contralateral pain (r = 0.582, P = .037). CONCLUSION: The development of contralateral pain in patients postcordotomy for cancer pain might be due to central sensitization. Temporal summation could serve as a potential screening tool to identify those who are most likely at risk to develop contralateral pain. Analysis of PCC affords a unique opportunity to investigate how a specific lesion to the nociceptive system affects pain processes.

Effects of Pain-Reporting Education Program on Children's Pain Reports-Results From a Randomized Controlled Post-operative Pediatric Pain Trial.

Objective: Accurate assessment of patients' pain is an essential part of adequate analgesic treatment. Although reporting pain is a complex task, limited-to-no instructions are provided to pediatric patients regarding this process. Our goal in this randomized parallel-group clinical trial (Clinicaltrial.gov study protocol number NCT04306679) was to evaluate if a training program designed to improve children's ability to understand and use pain scales in a post-surgical setting would affect their pain scores. Methods: Eligible children (aged 8-17), hospitalized for elective surgery and their parents were randomized into two groups. Pre-surgery the intervention group underwent a multi-media program aimed to teach and train how to report pain. The control group received standard pre-surgical instructions. Post-surgery, the children reported their pain on 4 pain scales. The primary outcome was the concordance between children's pain intensity scores reported on four pain scales, both in terms of within-child standard deviation and absolute difference. Results: Ninety-six children met inclusion criteria and completed the study. The trained subjects' pain reports had significantly (p = 0.002) lower within-subject standard deviation (0.41 ± 0.31) than the control group (0.67 ± 0.46). In line, regarding absolute difference, the concordance of children's pain reports was twice better in the trained group (mean difference of 0.43 ± 0.40) than in the control group (0.88 ± 0.70) (p < 0.001). Discussion: Our results suggests that children's ability to report pain is a skill that can be improved. Future studies should test the potential clinical impacts of educational interventions aimed to improve pain assessment in children and adults.

[SMALL FIBER POLYNEUROPATHY IN YOUNG PATIENTS].

INTRODUCTION: Small fiber polyneuropathy (SFPN) is associated with a variety of clinical conditions. Common to these conditions is the deviation from healthy physiological homeostatic balance, which hinders small fiber neurons viability, resulting in their damage. The most common cause for SFPN in the western world is diabetes, followed by a long list of other risk-factors, some are age-related. Accumulating evidence suggests that in young patients a leading cause (up-to 50% of cases) is autoimmune-related. A variety of symptoms can be seen in SFPN. Commonly, first to appear are sensory symptoms in the extremities. Autonomic symptoms can then join, or even be the presenting symptoms. This sensory-autonomic combination can have a dramatic mal-effect on the patient's quality of life. Diagnosis is based primarily on skin biopsy and/or Autonomic-Functional-Testing. Often, in cases where no etiology is identified, EMG is normal and the skin biopsy/autonomic testing is not performed, clinicians tend to incorrectly diagnose a non-organic situation. Correct and preferably early diagnosis is of essence since peripheral fibers can recover if the disease pathophysiological factor is removed, leading to less suffering and improved quality of life of patients.

Specific symptoms may discriminate between fibromyalgia patients with vs without objective test evidence of small-fiber polyneuropathy.

INTRODUCTION: Multiple studies now confirm that ∼40% of patients with fibromyalgia syndrome meet diagnostic criteria for small-fiber polyneuropathy (SFPN) and have objective pathologic or physiologic evidence of SFPN, whereas 60% do not. Given possibilities that tens or hundreds of millions globally could have SFPN, developing screening tools becomes important. OBJECTIVES: This analysis explored whether specific symptoms might help distinguish these fibromyalgia endophenotypes. METHODS: With institutional review board approval, all adults tested for SFPN by distal-leg skin biopsy or autonomic function testing at Massachusetts General Hospital in 2014 to 2015 were queried about symptoms. Inclusion required a physician's fibromyalgia syndrome diagnosis plus meeting the American College of Rheumatology 2010 Fibromyalgia Criteria. The primary outcome was the validated Small-fiber Symptom Survey, which captures severity of all known SFPN-associated symptoms. The Composite Autonomic Symptom Score-31, Short-Form Health Survey-36, and Short-Form McGill Pain Questionnaires provided secondary outcomes. RESULTS: Among the 39 participants, 14 had test-confirmed SFPN (SFPN+) and 25 did not (SFPN-). Their pain severity did not differ. Paresthesias ("tingling") were different (worse) in the SFPN+ group (3.14 ± 0.9 vs 2.28 ± 1.1; P = 0.16). Their component subscore for dysautonomia symptoms was also worse (10.42 ± 4.0 vs 7.16 ± 4.0; P = 0.019). Receiver operating characteristic analyses revealed that each item had fair diagnostic utility in predicting SFPN, with areas under the curve of 0.729. No secondary questionnaires discriminated significantly. CONCLUSION: Among patients with fibromyalgia, most symptoms overlap between those with or without confirmed SFPN. Symptoms of dysautonomia and paresthesias may help predict underlying SFPN. The reason to screen for SFPN is because-unlike fibromyalgia-its medical causes can sometimes be identified and definitively treated or cured.

Initial Development and Validation of a Patient-Reported Symptom Survey for Small-Fiber Polyneuropathy.

Small-fiber polyneuropathy (SFPN) affects unmyelinated and thinly myelinated peripheral axons. Several questionnaires have been developed to assess polyneuropathy from diabetes or chemotherapy, but none for SFPN from other or unknown causes. A comprehensive survey could help clinicians diagnose and assess treatment responses, define prevalence natural history and cures, and identify research subjects. Thus, we developed the 1-page Small-Fiber Symptom Survey, using input from patients and 21 medical/scientific experts. Participants comprised consenting consecutive patients evaluated for SFPN at the Massachusetts General Hospital plus normal control subjects. Participants SFPN status was stratified on the basis of the results of their objective diagnostic tests (distal leg skin biopsy and autonomic function testing). We measured internal consistency, test retest reliability, convergent validity, and performed a receiver operating curve analysis. The 179 participants averaged 46.6 ± 15.6 years old; they were 73.2% female and 92.2% Caucasian. Eighty-five had confirmed SFPN, mostly idiopathic. Principal component analysis revealed 5 symptom clusters. The questionnaire had good internal consistency (Cronbach α = .893), excellent test retest reliability (r = .927, P < .001) and good to fair convergent validity. Participants with confirmed SFPN had more severe symptoms than others (P = .009). The Small-Fiber Symptom Survey has satisfactory psychometric properties, indicating potential future utility for surveying patient-reported symptoms of SFPN regardless of its cause. PERSPECTIVE: This article reports the initial development and early psychometric validation of a new patient-reported outcome measure intended to capture the wide range of multisystem symptoms of SFPN. When further developed, it could potentially help clinicians diagnose and monitor patients, and help advance research.

Impaired Pain Modulation in Fibromyalgia Patients in Response to Social Distress Manipulation.

OBJECTIVES: Fibromyalgia (FM), a chronic pain condition, is associated with abnormalities in pain modulation. A growing body of evidence has shown that social distress modulates pain sensitivity. The current study aimed to assess the effects of social distress manipulation on pain in FM patients compared with positive (rheumatoid arthritis, RA) and negative (pain-free) controls. MATERIALS AND METHODS: FM, RA patients and pain-free controls (PFC) were recruited. Demographic, medical, and psychological data were collected. Each participant was exposed to 3 study conditions in a random order: the inclusion (positive social effects) and exclusion (negative social effects) conditions of Cyberball, a game that manipulates social distress, and a control condition. Pain sensitivity in response to nociceptive electrical and thermal (cold) stimuli was assessed before and during each study condition. RESULTS: In response to electrical stimuli, pain decreased in both the inclusion and exclusion conditions in PFC and RA groups, whereas inclusion conditions significantly increased pain in the FM group. Social manipulation (inclusion or exclusion) did not affect pain sensitivity as measured in response to thermal stimulation. DISCUSSION: These results are in line with previous studies demonstrating altered pain inhibition in FM patients, and suggest that unlike PFC or other non-"stress-related" chronic pain conditions, being socially included may increase pain perception in FM patients. Possible underlying mechanisms and clinical relevance are discussed.

Diagnostic value of blood tests for occult causes of initially idiopathic small-fiber polyneuropathy.

Small-fiber polyneuropathy (SFPN) causes non-specific symptoms including chronic pain, cardiovascular, gastrointestinal, and sweating complaints. Diagnosis is made from history and exam in patients with known risk factors such as diabetes, but objective test confirmation is recommended for patients without known risks. If tests confirm SFPN, and it is "initially idiopathic" (iiSFPN), screening for occult causes is indicated. This study's aim was to evaluate the 21 widely available, recommended blood tests to identify the most cost-effective ones and to learn about occult causes of iiSFPN. Records were reviewed from all 213 patients with SFPN confirmed by distal-leg skin biopsy, nerve biopsy, or autonomic-function testing in our academic center during 2013. We determined the prevalence of each abnormal blood-test result (ABTR) in the iiSFPN cohort, compared this to population averages, and measured the costs of screening subjects to obtain one ABTR. Participants were 70 % female and aged 43.0 ± 18.6 years. High erythrocyte sedimentation rate (ESR) and antinuclear antibody (ANA; ≥1:160 titer) were most common, each present in 28 % of subjects. The ABTR ≥3 × more prevalent in iiSFPN than in the total population were high ESR, high ANA, low C3, and Sjögren's and celiac autoantibodies. Together, these suggest the possibility of a specific association between iiSFPN and dysimmunity. ABTR identifying diabetes, prediabetes, and hypertriglyceridemia were less common in iiSFPN than in the population and thus were not associated with iiSFPN here. The six most cost-effective iiSFPN-associated blood tests-ESR, ANA, C3, autoantibodies for Sjögren's and celiac, plus thyroid-stimulating hormone-had estimated cost of $99.57/person and 45.6 % probability of obtaining one abnormal result. Angiotensin-converting enzyme was elevated in 45 %, but no patients had sarcoidosis, so this test was futile here.

Non-invasive Transcranial Magnetic Stimulation (TMS) of the Motor Cortex for Neuropathic Pain-At the Tipping Point?

The term "neuropathic pain" (NP) refers to chronic pain caused by illnesses or injuries that damage peripheral or central pain-sensing neural pathways to cause them to fire inappropriately and signal pain without cause. Neuropathic pain is common, complicating diabetes, shingles, HIV, and cancer. Medications are often ineffective or cause various adverse effects, so better approaches are needed. Half a century ago, electrical stimulation of specific brain regions (neuromodulation) was demonstrated to relieve refractory NP without distant effects, but the need for surgical electrode implantation limited use of deep brain stimulation. Next, electrodes applied to the dura outside the brain's surface to stimulate the motor cortex were shown to relieve NP less invasively. Now, electromagnetic induction permits cortical neurons to be stimulated entirely non-invasively using transcranial magnetic stimulation (TMS). Repeated sessions of many TMS pulses (rTMS) can trigger neuronal plasticity to produce long-lasting therapeutic benefit. Repeated TMS already has US and European regulatory approval for treating refractory depression, and multiple small studies report efficacy for neuropathic pain. Recent improvements include "frameless stereotactic" neuronavigation systems, in which patients' head MRIs allow TMS to be applied to precise underlying cortical targets, minimizing variability between sessions and patients, which may enhance efficacy. Transcranial magnetic stimulation appears poised for the larger trials necessary for regulatory approval of a NP indication. Since few clinicians are familiar with TMS, we review its theoretical basis and historical development, summarize the neuropathic pain trial results, and identify issues to resolve before large-scale clinical trials.

Anti tumor necrosis factor - alpha adalimumab for complex regional pain syndrome type 1 (CRPS-I): a case series.

BACKGROUND AND AIMS: Evidence suggests tumor necrosis factor-alpha (TNF-α) mediates, at least in part, symptoms and signs in complex regional pain syndrome (CRPS). Here, we present a case series of patients with CRPS type 1, in whom the response to the anti-TNF-α adalimumab was assessed. METHODS: Ten patients with CRPS type 1 were recruited. Assessments were performed before treatment, at 1 week, and 1, 3, and 6 months following 3 biweekly subcutaneous injections (40 mg/0.8 mL) adalimumab (Humira(®) ) and included the followings: Pain intensity using a 0-10 cm visual analog scale; the Short Form of the McGill Pain Questionnaire; the Beck Depression Inventory; the SF-36 questionnaire and mechanical and thermal thresholds (Von frey hair and Thermal Sensory Analyzer, respectively). In addition to the description of individual patient responses, both intention to treat (ITT) and per-protocol (PP) analyses were performed for the entire group. RESULTS: Three subgroups of patients were identified (3 patients in each): "nonresponders", "partial responders", and "robust responders" in whom improvement in almost all parameters was noted. Both the ITT and PP analyses demonstrated only a trend toward improvement in mechanical pain thresholds following treatment (ITT χ² = 13.83, P = 0.008; PP χ² = 10.29, P = 0.036). CONCLUSION: These results suggest adalimumab, and possibly other anti-TNF-α, can be potentially useful in some (although not in all) patients with CRPS type 1. These preliminary results along with the growing body of evidence which points to the involvement of TNF-α in the pathogenesis of CRPS justify further studies in this area.

Is opioid-induced hyperalgesia reversible? A study on active and former opioid addicts and drug naïve controls.

OBJECTIVE: Hyperalgesia has been observed in active opioid addicts (OAs). The aim of this study was to explore whether opioid-induced hyperalgesia (OIH) is a reversible phenomenon. DESIGN: Observational study. PARTICIPANTS: The study included the following three groups of male subjects: 1) active addicts on heroin or methadone (OAs, n = 50); 2) former opioid addicts with at least 5 months of abstinence from drug use (FOAs, n = 43); and 3) drug naïve controls (C, n = 50). INTERVENTIONS: All subjects were exposed to the cold pressor test (1°C). MAIN OUTCOME MEASURES: Cold pain threshold (latency to pain onset, seconds) and cold pain tolerance (latency to pain intolerability, seconds). RESULTS: Mean ± standard deviation (SD) pain thresholds were 10.8 ± 7.7, 6.9 ± 3.9, and 6.8 ± 3.5 seconds for the OAs, FOAs, and C groups, respectively (analysis of variance [ANOVA], p = 0.002, 95% CI = 7.5-9.2). Mean ± SD pain tolerance levels were 30 ± 36.2, 64 ± 58.1, and 56.4 ± 51.4 seconds for the OAs, FOAs, and C groups, respectively (ANOVA, p < 0.001, 95% CI = 43-60.4). Post hoc analyses revealed significant changes between the OAs and the other two groups for both variables. CONCLUSIONS: It is suggested that altered pain perception in OAs is a reversible phenomenon that may require a long period of abstinence to reset, rather than being an individual long-term stable trait.

Associations between polymorphisms in dopamine neurotransmitter pathway genes and pain response in healthy humans.

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.