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Pain is the primary symptom of chronic pancreatitis (CP), but methods for sensory testing and pain characterization have not previously been validated for clinical use. We present a clinically feasible method for the assessment and characterization of pain mechanisms in patients with CP based on quantitative sensory testing (QST). This was a cross-sectional, multicenter study of 122 control subjects without pancreatic disease and another 60 patients with painful CP. All subjects underwent standardized QST assessments including a cold pressor test, a conditioned pain modulation paradigm, repetitive pin-prick stimuli (temporal summation) and pressure stimulation of the upper abdominal (pancreatic) and control dermatomes. The effects of age and gender on QST assessment parameters were investigated and normative reference values based on quartile regression were derived and implemented in algorithms to categorize patients according to their patterns of central pain processing (normal vs. segmental sensitization vs. widespread sensitization). Absolute pressure thresholds were subject to clinically relevant gender effects (all p < 0.001), while the remainder of QST parameters were unaffected by age and gender. The algorithm with the best discriminatory capacity showed good separation between patients and controls (p < 0.001); 50% of patients had normal central pain processing, 23% had evidence of segmental sensitization and 27% had evidence of widespread sensitization. We show normative reference values for a clinically feasible method for assessment and characterization of pain mechanisms in patients with CP. Application of this method streamlines the evaluation of pancreatic pain and may be used to inform treatment. NCT03434392. [ABSTRACT FROM AUTHOR]

Poorly controlled pain is a global public health issue. The personal, familial and societal costs are immeasurable. Only a minority of European patients have access to a comprehensive specialist pain clinic. More commonly the responsibility for chronic pain management and initiating opioid therapy rests with the primary care physician and other non-specialist opioid prescribers. There is much confusing and conflicting information available to non-specialist prescribers regarding opioid therapy and a great deal of unjustified fear is generated. Opioid therapy should only be initiated by competent clinicians as part of a multi-faceted treatment programme in circumstances where more simple measures have failed. Throughout, all patients must be kept under close clinical surveillance. As with any other medical therapy, if the treatment fails to yield the desired results and/or the patient is additionally burdened by an unacceptable level of adverse effects, the overall management strategy must be reviewed and revised. No responsible clinician will wish to pursue a failed treatment strategy or persist with an ineffective and burdensome treatment. In a considered attempt to empower and inform non-specialist opioid prescribers, EFIC convened a European group of experts, drawn from a diverse range of basic science and relevant clinical disciplines, to prepare a position paper on appropriate opioid use in chronic pain. The expert panel reviewed the available literature and harnessed the experience of many years of clinical practice to produce these series of recommendations. Its success will be judged on the extent to which it contributes to an improved pain management experience for chronic pain patients across Europe.Significance: This position paper provides expert recommendations for primary care physicians and other non- specialist healthcare professionals in Europe, particularly those who do not have ready access to specialists in pain medicine, on the safe and appropriate use of opioid medications as part of a multi-faceted approach to pain management, in properly selected and supervised patients. [ABSTRACT FROM AUTHOR]

Background: Gastro-oesophageal reflux disease (GORD) is a major health problem that is frequently accompanied by debilitating oesophageal pain symptoms.Objectives: The first objective of the study was to examine the association between catastrophizing and oesophageal pain sensitivity. The second objective was to examine whether catastrophizing was associated with the magnitude of acid-induced oesophageal sensitization.Methods: Twenty-five healthy volunteers (median age: 24.0 years; range: 22-31) were recruited and were asked to complete the Pain Catastrophizing Scale (PCS). During two subsequent study visits, mechanical, thermal, and electrical pain sensitivity in the oesophagus was assessed before and after inducing oesophageal sensitization using a 30-min intraluminal oesophageal acid perfusion procedure.Results: Analyses were conducted based on data averaged across the two study visits. At baseline, catastrophizing was significantly associated with mechanical (r = -0.42, p < 0.05) and electrical (r = -0.60, p < 0.01) pain thresholds. After acid perfusion, catastrophizing was also significantly associated with mechanical (r = -0.58, p < 0.01) and electrical (r = -0.50, p < 0.05) pain thresholds. Catastrophizing was not significantly associated with thermal pain thresholds. Subsequent analyses revealed that catastrophizing was not significantly associated with the magnitude of acid-induced oesophageal sensitization.Conclusion: Taken together, findings from the present study suggest that catastrophic thinking exerts an influence on oesophageal pain sensitivity, but not necessarily on the magnitude of acid-induced oesophageal sensitization. WHAT DOES THIS STUDY ADD?: Catastrophizing is associated with heightened pain sensitivity in the oesophagus. This was substantiated by assessing responses to noxious stimulation of the oesophagus using an experimental paradigm mimicking features and symptoms experienced by patients with gastro-oesophageal reflux disease (GORD). [ABSTRACT FROM AUTHOR]

Background: Opioids are used for the treatment of pain. However, 30-50% of patients have insufficient effect to the opioid initially selected by the physician, and there is an urgent need for biomarkers to select responders to the most appropriate drug. Since opioids mediate their effect in the central nervous system, this study aimed to investigate if electroencephalography (EEG) during rest or pain before treatment could predict the analgesic response.Methods: EEG from 62 channels was recorded in volunteers during rest and tonic pain (cold pressor test). Morphine (30 mg) or placebo was then administered, and the pain test repeated 60 min after. Washout period between drugs was 7 days. Based on pain ratings, subjects were stratified into responders and non-responders. Spectral analysis was performed on the EEG. Conventional statistics on group basis were used and, furthermore, the most discriminative EEG features were subjected to support vector machine classification to predict the response for the individual subjects.Results: Conventional statistics on the frequency bands revealed no differences between responders and non-responders. On the individual basis, no differences between groups were found using resting EEG. However, EEG during cold pain was able to classify responders with an accuracy of 72% (p = 0.01) and the result was reproducible using baseline data from both study days.Conclusions: Machine learning based on EEG before treatment enabled separation between responders and non-responders. This study represents the first step towards the prediction of opioid analgesia based on EEG features prior to drug administration, and advocates for the use of machine learning in future studies. [ABSTRACT FROM AUTHOR]

Background: The underlying pain mechanisms of chronic pancreatitis (CP) are incompletely understood, but recent research points to involvement of pathological central nervous system processing involving pain‐relevant brain areas. We investigated the organization and connectivity of brain networks involved in nociceptive processing in patients with painful CP. Methods: Contact heat‐evoked potentials (CHEPs) were recorded in 15 patients with CP and in 15 healthy volunteers. The upper abdominal area (sharing spinal innervation with the pancreatic gland) was used as a proxy of ‘pancreatic stimulation’, while stimulation of a heterologous region remote to the pancreas (right forearm) was used as a control. Subjective pain scores were assessed by visual analogue scale. The brain source organization and connectivity of CHEPs components were analysed. Results: After pancreatic area stimulation, brain source analysis revealed abnormalities in the cingulate/operculo‐insular network. A posterior shift of the operculo‐insular source (p = 0.004) and an anterior shift of the cingulate source (p < 0.001) were seen in CP patients, along with a decreased strength of the cingulate source (p = 0.01). The operculo‐insular shift was positively correlated with the severity of patient clinical pain score (r = 0.61; p = 0.03). No differences in CHEPs characteristics or source localizations were seen following stimulation of the right forearm. Conclusions: CP patients showed abnormal cerebral processing after stimulation of the upper abdominal area. These changes correlated to the severity of pain the patient was experiencing. Since the upper abdominal area shares spinal innervation with the pancreatic gland, these findings likely reflect maladaptive neuroplastic changes, which are characteristic of CP. [ABSTRACT FROM AUTHOR]

Background: Offset analgesia (OA) is a pain ‐ inhibiting mechanism, defined as a disproportionately large decrease in pain perception in response to a discrete decrease in noxious stimulus intensity. Hence, the aims were (1) to investigate whether psychophysics and electroencephalography (EEG) can be assessed simultaneously during OA and (2) to assess whether OA is reproducible within the same day as well as between different days. Methods: Two separate studies investigated OA: Study I (13 healthy volunteers; seven men; 25.5 ± 0.65 years) aimed at determining the feasibility of recording psychophysics and EEG simultaneously during OA. Study II (18 healthy volunteers; 12 men; 34 ± 3.15 years) assessed reproducibility of OA in terms of psychophysics and EEG. Subjects were presented to a 30 ‐ s OA heat stimulus paradigm on the volar forearm and psychophysics, and EEG recordings were obtained throughout the procedure. Reproducibility was assessed within the same day and between different days, using intraclass correlation coefficients (ICCs). Additionally, the reproducible psychophysical parameters were correlated to relevant EEG frequency bands. Results: Simultaneous recording of psychophysics and EEG affects the frequency distribution in terms of alpha suppression. Reproducibility was proven for the psychophysics and EEG frequency bands both within the same day (all ICCs > 0.62) and between different days (all ICCs > 0.66, except for the delta band). Correlations between psychophysics and EEG were found in the theta (4–8 Hz), alpha (8–12 Hz) and gamma (32–80 Hz) bands (all p < 0.01). Conclusion: OA is a robust and reproducible model for experimental pain research, making it suitable for future research. [ABSTRACT FROM AUTHOR]

The role of quantitative sensory testing (QST) in prediction of analgesic effect in humans is scarcely investigated. This updated review assesses the effectiveness in predicting analgesic effects in healthy volunteers, surgical patients and patients with chronic pain. A systematic review of English written, peer-reviewed articles was conducted using PubMed and Embase (1980-2013). Additional studies were identified by chain searching. Search terms included 'quantitative sensory testing', 'sensory testing' and 'analgesics'. Studies on the relationship between QST and response to analgesic treatment in human adults were included. Appraisal of the methodological quality of the included studies was based on evaluative criteria for prognostic studies. Fourteen studies (including 720 individuals) met the inclusion criteria. Significant correlations were observed between responses to analgesics and several QST parameters including (1) heat pain threshold in experimental human pain, (2) electrical and heat pain thresholds, pressure pain tolerance and suprathreshold heat pain in surgical patients, and (3) electrical and heat pain threshold and conditioned pain modulation in patients with chronic pain. Heterogeneity among studies was observed especially with regard to application of QST and type and use of analgesics. Although promising, the current evidence is not sufficiently robust to recommend the use of any specific QST parameter in predicting analgesic response. Future studies should focus on a range of different experimental pain modalities rather than a single static pain stimulation paradigm. [ABSTRACT FROM AUTHOR]

Background & Aims Long-term diabetes mellitus ( DM) has been associated with neuronal changes in the enteric, peripheral and/or central nervous system. Moreover, abnormal visceral sensation and gastrointestinal ( GI) symptoms are seen in up to 75% of patients. To explore the role of diabetic autonomic neuropathy ( DAN) in patients with long-standing DM, we investigated psychophysical responses and neuronal activity recorded as evoked brain potentials and dipolar source modelling. Methods Fifteen healthy volunteers and 14 type-1 DM patients with DAN were assessed with a symptom score index characterizing upper GI abnormalities. Multichannel (62) electroencephalography was recorded during painful electrical stimulation of the lower oesophagus. Brain activity to painful stimulations was modelled using Brain Electrical Source Analysis ( besa). Results Diabetic patients had higher stimulus intensities to evoke painful sensation ( p ≤ 0.001), longer latencies of N2 and P2 components (both p ≤ 0.001), and lower amplitudes of P1-N2 and N2-P2 complexes ( p ≤ 0.001; p = 0.02). Inverse modelling of brain sources showed deeper bilateral insular dipolar source localization ( p = 0.002). Symptom score index was negatively correlated with the depth of insular activity ( p = 0.004) and positively correlated with insular dipole strength ( p = 0.03). Conclusion DM patients show peripheral and central neuroplastic changes. Moreover, the role of abnormal insular processing may explain the appearance and persistence of GI symptoms related to DAN. This enhanced understanding of DAN may have future clinical and therapeutical implications. [ABSTRACT FROM AUTHOR]

Background We investigated whether patients with painful chronic pancreatitis ( CP) present abnormalities in the cerebral response to experimental pain stimuli. Methods Contact heat-evoked potentials ( CHEPS) were recorded in 15 patients with CP and in 15 healthy volunteers during repetitive stimulation of the upper abdominal region (pancreatic 'viscerotome') and the right forearm (heterologous area). Three sequences of painful stimuli were applied at each site. Subjective pain scores were assessed by a visual analogue scale. Habituation was calculated as the relative change in CHEPS amplitudes between the first and the third stimulation sequence. Results As expected pain scores decreased in healthy volunteers during successive stimulations at both sites (i.e., habituation), while in the CP group, they remained unchanged. The cerebral response consisted of an early-latency, low-amplitude response (N1, contralateral temporal region) followed by a late, high-amplitude, negative-positive complex ( N2/ P2, vertex). During successive stimulation of the pancreatic area, N2/ P2 amplitude increased 25% in CP patients, while they decreased 20% in healthy volunteers ( p = 0.006). After stimulation of the forearm, N2/ P2 amplitudes increased 3% in CP patients compared to a decrease of 20% in healthy volunteers ( p = 0.06). Conclusions Taken together, CP patients had an abnormal cerebral response to repetitive thermal stimuli. This was most prominent after stimulation of the upper abdominal area. As this area share spinal innervation with the pancreatic gland, these findings likely mirror distinctive abnormalities in cerebral pain processing. [ABSTRACT FROM AUTHOR]

Introduction Application of electrical stimulation through conventional surface electrodes activates both non-nociceptive and nociceptive fibres. To encompass this problem, electrical stimulation through small area pin electrode was introduced where subjective description of stimulation quality indicated preferential activation of nociceptors. The present study aimed to show that brain areas involved in nociceptive processing are activated by stimulation through cutaneous pin electrode ( CPE) to a larger extent than conventional surface electrodes. Methods Evoked potentials ( EPs) were induced by electrical stimulation through conventional surface and CPE electrodes. The EPs were recorded from 62 scalp electrodes in 12 healthy volunteers where stimulation intensity was 10 times the sensory threshold. Dipolar models of brain sources were built by using the brain electrical source analysis. Results The solution for the conventional large area surface electrode was a four-dipole model including contralateral primary somatosensory cortex, bilateral secondary somatosensory cortex ( SII) and mid-cingulate sources. The solution for CPE was a five-dipole model and very similar to that previously described to explain the topography of laser EPs. The solution included bilateral SII, bilateral insula and mid-cingulate sources. Since laser stimuli mainly activate nociceptive fibres, the strong similarity suggests that mainly nociceptive inputs are involved in generation of CPE-evoked responses. Conclusion The current study gives evidence that CPE activates the nociceptive brain areas to a greater extent than conventional surface electrode. Therefore, CPE should preferentially be utilized in future studies where electrical stimuli are used to study nociception. [ABSTRACT FROM AUTHOR]

Electrical low-frequency stimulation ( LFS) inhibits pain perception and nociceptive processing as shown by psychophysical and electrophysiological means (long-term depression, LTD). Information regarding central mechanisms involved in LTD induction and maintenance are still missing. This study hypothesizes that electrical LFS induces changes in activation pattern of pain-related brain areas. Thirty-two electrophysiological and psychophysical experiments were performed in 16 healthy volunteers. Painful electrical test stimulation (0.125 Hz, 60 pulses) and conditioning LFS (1 Hz, 1200 pulses) were applied by a concentric electrode to the right hand. Test stimulation series were performed before ( Pre) and after LFS ( Post) or no stimulation period ( Control). Volunteers rated pain perception according to a verbal rating scale (0-100). Somatosensory evoked cortical potentials were recorded with 64-channel electroencephalography. Individual dipole source modeling using CURRY software ( Compumedics, Hamburg, Germany) yielded information about dipole location and strength. The strongest decrease in LFS-induced pain perception was shown after LFS ( p < 0.01). Topographic distribution of cortical potentials revealed reproducible negative ( N1, N2) and positive ( P2) components. Dipole magnitude analysis showed a significant difference between Post LFS and Post Control for P2 ( p < 0.01). P2 dipole location analysis yielded a significant posterior ( p < 0.05) shift following LTD induction. Thus, data reveal central changes of pain processing after LTD induction. These experiments may help judging the potency of LTD as model for electrostimulation in future analgesic therapy. [ABSTRACT FROM AUTHOR]

Background Clinical evidence has revealed the antipruritic effect of botulinum toxin type A (BoNT/A). BoNT/A is believed to be effective against itch as it inhibits the release of acetylcholine as well as some other substances that may be involved in itch. Objectives To investigate the effect of subcutaneous administration of BoNT/A on experimentally histamine-induced itch in human skin. Methods In this double-blind, placebo-controlled study, 14 healthy men (mean ± SD age 26·3 ± 2·6 years) received BoNT/A (Botox®; Allergan, Irvine, CA, U.S.A.; 5 U) and isotonic saline on the volar surface of either forearm. Histamine prick tests were performed four times at the treatment sites (before treatment, and days 1, 3 and 7 after treatment). The itch intensity (as rated on a 0–10 visual analogue scale), itch area, neurogenic inflammation (visible flare area), blood flow (laser Doppler) and cutaneous temperature (thermographic images) were measured over the course of the trials. Results BoNT/A reduced the histamine-induced itch intensity ( F1,39 = 30·2, P < 0·001) and itch area ( F1,39 = 8·8, P = 0·011) compared with saline at all time points after treatment. The duration of itch was also shorter for BoNT/A-treated areas ( F1,39 = 19·4, P < 0·001), with a peak effect at day 7. The flare area was smaller in the BoNT/A-treated arm compared with the saline-treated arm at all time points after treatment ( F1,39 = 15·4, P = 0·002). Findings from blood flow ( F1,26 = 177·3, P < 0·001) and temperature measurements ( F1,26 = 27·6, P < 0·001) clearly showed the suppressive effect of BoNT/A on vasomotor reactions, with the maximal effect on days 3 and 7. Conclusions BoNT/A reduced the itch intensity, blood flow and neurogenic inflammation in response to the histamine prick test in human skin. The findings could be applicable in the treatment of some pruritic conditions that can be difficult to treat with conventional treatments. [ABSTRACT FROM AUTHOR]

Background: The relation between mechanical distension of the gut and the sensory response is poorly understood. The current experimental study aimed to examine the sensory response in the human oesophagus during on-line recording of the luminal pressure, cross-sectional area (CSA) and sensory rating using different distension rates before and during relaxation of the smooth muscle. Methods: An impedance planimetric probe for bag distension of the oesophagus was used in 13 healthy subjects aged 43 ± 15 years. Ramp distensions were done with an electromechanical pump using infusion rates of 10, 25 and 50 ml/min, with and without relaxation of the smooth muscle with butylscopolamine. The sensory intensity was measured using a 0-10 visual analogue scale (VAS), with 5 as the pain threshold. The pump was reversed at 8 on the scale, corresponding to medium pain intensity, and the pressure, volume, tension and CSA were evaluated. Finally, three isovolumetric experiments where the CSA was held constant for 2 min at initial VAS ratings of 3, 5 and 7 were performed. Results: A total of 104 distension profiles were investigated. The volume at maximal pain intensity (VAS = 8) increased as a function of the distension rate (P < 0.001), whereas the pressure, tension and CSA were not affected. When the smooth muscle was relaxed, there was a 29% fall in pressure at maximal pain intensity (P = 0.004), a 27% fall in tension (P = 0.003), whereas CSA did not change (P = 0.3). When the pressure was recorded as a function of the sensory intensity, there was an exponential increase after the pain threshold was reached, whereas the stimulus-response functions for tension, volume and CSA were nearly linear. In the isovolumetric experiments the ratings during the three sensory intensities were the same in the individual subjects, but the between-individual pain response was variable, probably reflecting individual differences in adaptation/central integration. Conclusions: The... [ABSTRACT FROM AUTHOR]