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Sympatico–vagal balance is essential for regulating cardiac electrophysiology and plays an important role in arrhythmogenic conditions. Various noninvasive methods, including electrocardiography (ECG), have been used for clinical assessment of the sympatico–vagal balance. This study aimed to use a custom-designed wearable device to record ECG and ECG-based cardiac function biomarkers to assess sympatico–vagal balance during tonic pain in healthy controls. Nineteen healthy volunteers were included for the ECG measurements using the custom-designed amplifier based on the Texas Instruments ADS1299. The ECG-based biomarkers of the sympatico–vagal balance, (including heart rate variability, deceleration capacity of the heart rate, and periodic repolarization dynamic), were calculated and compared between resting and pain conditions (tonic pain). The custom-designed device provided technically satisfactory ECG recordings. During exposure to tonic pain, the periodic repolarization dynamics increased significantly (p = 0.02), indicating enhancement of sympathetic nervous activity. This study showed that custom-designed wearable devices can potentially be useful in healthcare as a new telemetry technology. The ECG-based novel biomarkers, including periodic repolarization dynamic and deceleration capacity of heart rate, can be used to identify the cold pressor-induced activation of sympathetic and parasympathetic systems, making it useful for future studies on pain-evoked biomarkers. [ABSTRACT FROM AUTHOR]

Background: The effective management of pain in chronic pancreatitis (CP) remains a therapeutic challenge. Analgesic drugs, such as opioids, and the underlying pathology can impair gut function. The autonomic nervous system influences hormone secretion and gut motility. In healthy volunteers, electrical (using noninvasive transcutaneous vagal nerve stimulation [t-VNS]) and physiological (using deep slow breathing [DSB]) modulation of parasympathetic tone results in pain attenuation and enhanced gut motility. Thus, the aims were to investigate whether t-VNS and DSB could enhance the parasympathetic tone, decrease pain sensitivity and improve gut motility in CP. Patients and methods: A total of 20 patients (12 males, mean age=61 years, range: 50-78 years) with CP were randomized to short-term (60 minutes) t-VNS and DSB, or their placebo equivalent, in a crossover design. Cardiometrically derived parameters of autonomic tone, quantitative sensory testing of bone and muscle pain pressure, conditioned pain modulation (CPM) and assessments of gastroduodenal motility with ultrasound were performed. Results: In comparison to sham, t-VNS and DSB increased cardiac vagal tone (CVT) (P<0.001). However, no changes in pain pressure thresholds for bone (P=0.95) or muscle (P=0.45) were seen. There was diminished CPM (P=0.04), and no changes in gastroduodenal motility were observed (P=0.3). Conclusion: This explorative study demonstrated that t-VNS and DSB increased CVT in patients with CP. However, this short-lasting increase did not affect pain sensitivity to musculoskeletal pain or gastroduodenal motility. The chronic pain in CP patients is complex, and future trials optimizing neuromodulation for pain relief and improved motility are needed. [ABSTRACT FROM AUTHOR]

Background: Pain control in chronic pancreatitis is a major challenge; the mechanisms behind analgesic treatment are poorly understood. This study aims to investigate the differences in pain sensitivity and modulation in chronic pancreatitis patients, based on their clinical response (responders vs nonresponders) to placebo or pregabalin treatment. Methods: This study was part of a randomized, double-blind, placebo-controlled trial evaluating the analgesic effects of pregabalin and placebo in chronic pancreatitis. Post hoc, patients were assigned to one of four groups, ie, responders and nonresponders to pregabalin (n=16; n=15) or placebo (n=12; n=17) treatment. Responders were defined as patients with .30% pain reduction after 3 weeks of treatment. We measured change in pain sensitivity before and after the treatment using electric pain detection thresholds (ePDT) in dermatomes C5 (generalized effects) and Ventral T10 (segmental effects). Descending endogenous pain modulation was quantified via conditioned pain modulation (CPM) paradigm. Results: Sixty patients were analyzed in a per-protocol analysis. ePDT change in C5 was significant vs baseline and greater in pregabalin (1.3 mA) vs placebo responders (-0.1 mA; P=0.015). This was not so for ePDT in Ventral T10. CPM increased more in pregabalin (9%) vs placebo responders (-17%; P,0.001). CPM changed significantly vs baseline only for pregabalin responders (P=0.006). Conclusion: This hypothesis-generating study provides the first evidence that pain relief with pregabalin is associated with anti-hyperalgesic effects and increased endogenous inhibitory modulation. No such effects were observed in patients experiencing pain relief with the placebo treatment. The mechanisms underlying analgesic response to placebo vs drug treatments are different and, together with their interactions, deserve further study. [ABSTRACT FROM AUTHOR]

Background: A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis. Methods: Sixty-four patients with painful chronic pancreatitis received pregabalin (150–300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy. Results: The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9–1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5–2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy. Conclusions: The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient’s individual sensory profile and thus comprises a significant step towards personalized pain medicine. [ABSTRACT FROM AUTHOR]

Background: The most dominant feature in chronic pancreatitis is intense abdominal pain. Changes in spinal and/or supraspinal central nervous system pain processing due to visceral nociceptive input play an important role in this pain. How altered pain processing is related to disease stage still needs study. Methodology/Principal Findings: Sixty chronic pancreatitis patients were compared to 15 healthy controls. Two subgroups of pancreatitis patients were defined based on the M-ANNHEIM severity index of chronic pancreatitis; i.e. moderate and severe. Pain detection and tolerance thresholds for pressure and electric stimuli were measured in six selected dermatomes (C5, T4, T10, L1, L4 and T10BACK). In addition, the conditioned pain modulation response to cold pressor task was determined. These measures were compared between the healthy controls and chronic pancreatitis patients. Severe pancreatitis patients showed lower pain thresholds than moderate pancreatitis patients or healthy volunteers. Healthy controls showed a significantly larger conditioned pain modulation response compared to all chronic pancreatitis patients taken together. Conclusions/Significance: The present study confirms that chronic pancreatitis patients show signs of altered central processing of nociception compared to healthy controls. The study further suggests that these changes, i.e. central sensitization, may be influenced by disease stage. These findings underline the need to take altered central pain processing into account when managing the pain of chronic pancreatitis. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Pregabalin is an anticonvulsive agent prescribed as a secondary analgesic for patients when standard pain treatment is insufficient. • The analgesic effect resides in the central nervous system. • The central analgesic effect can be evaluated by electroencephalography. WHAT THIS STUDY ADDS • The analgesic effect of pregabalin is reflected as a slowing of brain oscillations. • The slowing of brain oscillations for each individual patient is correlated with subjective pain scores. • The developed methodology may be used as a mechanistic approach to monitor the analgesic effect of pregabalin in pharmacological studies. AIM To identify electroencephalographic (EEG) biomarkers for the analgesic effect of pregabalin in patients with chronic visceral pain. METHODS This was a double-blind, placebo-controlled study in 31 patients suffering from visceral pain due to chronic pancreatitis. Patients received increasing doses of pregabalin (75 mg-300 mg twice a day) or matching placebo during 3 weeks of treatment. Pain scores were documented in a diary based on a visual analogue scale. In addition, brief pain inventory-short form (BPI) and quality of life questionnaires were collected prior to and after the study period. Multi-channel resting EEG was recorded before treatment onset and at the end of the study. Changes in EEG spectral indices were extracted, and individual changes were classified by a support vector machine (SVM) to discriminate the pregabalin and placebo responses. Changes in individual spectral indices and pain scores were correlated. RESULTS Pregabalin increased normalized intensity in low spectral indices, most prominent in the theta band (3.5-7.5 Hz), difference of −3.18, 95% CI −3.57, −2.80; P= 0.03. No changes in spectral indices were seen for placebo. The maximum difference between pregabalin and placebo treated patients was seen in the parietal region, with a classification accuracy of 85.7% ( P= 0.009). Individual changes in EEG indices were correlated with changes in pain diary ( P= 0.04) and BPI pain composite scores ( P= 0.02). CONCLUSIONS Changes in spectral indices caused by slowing of brain oscillations were identified as a biomarker for the central analgesic effect of pregabalin. The developed methodology may provide perspectives to assess individual responses to treatment in personalized medicine. [ABSTRACT FROM AUTHOR]

Background: Pain is the primary symptom of chronic pancreatitis (CP) and remains a considerable therapeutic challenge. In patients with obstruction of the pancreatic duct, including stones and strictures, endoscopic treatment with or without preceding extracorporeal shock wave lithotripsy (ESWL) has been used for pancreatic duct decompression. The rationale for these procedures is based on the assumption that obstruction of the pancreatic duct leads to ductal hypertension and pain. However, clinical pain symptoms correlate poorly with pancreatic duct morphology, and the evidence for pancreatic duct decompression as an effective treatment for pain is based on case series and comparison between different procedures. No randomized, prospective, sham-controlled trials are currently available. The SCHOKE (Extracorporeal Shock Wave Lithotripsy and Endotherapy for Pain in Chronic Pancreatitis) trial is a randomized, sham-controlled trial designed to determine if pancreatic duct decompression is an effective treatment for pain in patients with CP.Methods: The SCHOKE trial is a randomized, single-blind, parallel-group, sham-controlled trial designed to evaluate the effect of combined ESWL and endoscopic treatment for pain in patients with CP. In total, 106 adult patients with painful CP and pancreatic duct obstruction will be randomized to combined ESWL and subsequent endoscopic treatment or corresponding sham procedures. The primary outcome is pain relief during the 3-month postrandomization period as documented in a pain diary. Secondary outcomes include quality of life and functional scores, patient global impression of change, change in use of analgesics, frequency of hospitalization, and complications. Standard follow-up is at 3 and 6 months after randomization. In an experimental substudy, quantitative sensory testing obtained before and after intervention will be used to obtain information on central pain processing and to develop models for prediction of treatment outcome.Discussion: The SCHOKE trial investigates if pancreatic duct decompression, obtained by combined ESWL and endoscopic treatment, is effective for pain treatment in patients with CP.Trial Registration: ClinicalTrials.gov, NCT03966781. Registered on May 25, 2019. Protocol date and version identifier: March 1, 2020; version 3.0.Sponsor: Rupjyoti Talukdar, Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, Telangana, India. [ABSTRACT FROM AUTHOR]