Pain patterns in chronic pancreatitis and chronic primary pain.

BACKGROUND: Abdominal pain is the most distressing symptom of chronic pancreatitis (CP), and current treatments show limited benefit. Pain phenotypes may be more useful than diagnostic categories when planning treatments, and the presence or absence of constant pain in CP may be a useful prognostic indicator. AIMS: This cross-sectional study examined dimensions of pain in CP, compared pain in CP with chronic primary pain (CPP), and assessed whether constant pain in CP is associated with poorer outcomes. METHODS: Patients with CP (N = 91) and CPP (N = 127) completed the Comprehensive Pancreatitis Assessment Tool. Differences in clinical characteristics and pain dimensions were assessed between a) CP and CPP and b) CP patients with constant versus intermittent pain. Latent class regression analysis was performed (N = 192) to group participants based on pain dimensions and clinical characteristics. RESULTS: Compared to CPP, CP patients had higher quality of life (p < 0.001), lower pain severity (p < 0.001), and were more likely to use strong opioids (p < 0.001). Within CP, constant pain was associated with a stronger response to pain triggers (p < 0.05), greater pain spread (p < 0.01), greater pain severity, more features of central sensitization, greater pain catastrophising, and lower quality of life compared to intermittent pain (all p values ≤ 0.001). Latent class regression analysis identified three groups, that mapped onto the following patient groups 1) combined CPP and CP-constant, 2) majority CPP, and 3) majority CP-intermittent. CONCLUSIONS: Within CP, constant pain may represent a pain phenotype that corresponds with poorer outcomes. CP patients with constant pain show similarities to some patients with CPP, potentially indicating shared mechanisms.

Predictors of response to a low-FODMAP diet in patients with functional gastrointestinal disorders and lactose or fructose intolerance.

BACKGROUND: Diets low in fermentable sugars (low-FODMAP diets) are increasingly adopted by patients with functional gastrointestinal disorders (FGID), but outcome predictors are unclear. AIM: To identify factors predictive of an efficacious response to a low-FODMAP diet in FGID patients with fructose or lactose intolerance thereby gaining insights into underlying mechanisms. METHODS: Fructose and lactose breath tests were performed in FGID patients to determine intolerance (positive symptom score) and malabsorption (increased hydrogen or methane concentrations). Patients with fructose or lactose intolerance consumed a low-FODMAP diet and global adequate symptom relief was assessed after 6-8 weeks and correlated with pre-diet clinical symptoms and breath test results. RESULTS: A total of 81% of 584 patients completing the low-FODMAP diet achieved adequate relief, without significant differences between FGID subgroups or types of intolerance. Univariate analysis yielded predictive factors in fructose intolerance (chronic diarrhoea and pruritus, peak methane concentrations and fullness during breath tests) and lactose intolerance (peak hydrogen and methane concentrations and flatulence during breath tests). Using multivariate analysis, symptom relief was independently and positively predicted in fructose intolerance by chronic diarrhoea [odds ratio (95% confidence intervals): 2.62 (1.31-5.27), P = 0.007] and peak breath methane concentrations [1.53 (1.02-2.29), P = 0.042], and negatively predicted by chronic nausea [0.33 (0.16-0.67), P = 0.002]. No independent predictive factors emerged for lactose intolerance. CONCLUSIONS: Adequate global symptom relief was achieved with a low-FODMAP diet in a large majority of functional gastrointestinal disorders patients with fructose or lactose intolerance. Independent predictors of a satisfactory dietary outcome were only seen in fructose intolerant patients, and were indicative of changes in intestinal host or microbiome metabolism.

Prediction of postoperative opioid analgesia using clinical-experimental parameters and electroencephalography.

BACKGROUND: Opioids are often used for pain treatment, but the response is often insufficient and dependent on e.g. the pain condition, genetic factors and drug class. Thus, there is an urgent need to identify biomarkers to enable selection of the appropriate drug for the individual patient, a concept known as personalized medicine. Quantitative sensory testing (QST) and clinical parameters can provide some guidance for response, but better and more objective biomarkers are urgently warranted. Electroencephalography (EEG) may be suitable since it assesses the central nervous system where opioids mediate their effects. METHODS: Clinical parameters, QST and EEG (during rest and tonic pain) was recorded from patients the day prior to total hip replacement surgery. Postoperative pain treatment was performed using oxycodone and piritramide as patient-controlled analgesia. Patients were stratified into responders and non-responders based on pain ratings 24 h post-surgery. Parameters were analysed using conventional group-wise statistical methods. Furthermore, EEG was analysed by machine learning to predict individual response. RESULTS: Eighty-one patients were included, of which 51 responded to postoperative opioid treatment (30 non-responders). Conventional statistics showed that more severe pre-existing chronic pain was prevalent among non-responders to opioid treatment (p = 0.04). Preoperative EEG analysis was able to predict responders with an accuracy of 65% (p = 0.009), but only during tonic pain. CONCLUSIONS: Chronic pain grade before surgery is associated with the outcome of postoperative pain treatment. Furthermore, EEG shows potential as an objective biomarker and might be used to predict postoperative opioid analgesia. SIGNIFICANCE: The current clinical study demonstrates the viability of EEG as a biomarker and with results consistent with previous experimental results. The combined method of machine learning and electroencephalography offers promising results for future developments of personalized pain treatment.

Dynamic spectral indices of the electroencephalogram provide new insights into tonic pain.

OBJECTIVE: This study aimed to investigate reliability of electroencephalography (EEG) during rest and tonic pain. Furthermore, changes in EEG between the two states as well as dynamics and relation to pain ratings were investigated. METHODS: On two separate days EEG was recorded in 39 subjects during rest and tonic pain (cold pressor test: left hand held in 2°C water for 2 min.) while pain intensity was rated continuously. Dynamic spectral analysis was performed on the EEG. Between-day reliability of spectral indices was assessed and correlations to pain ratings were investigated. RESULTS: EEG reliability was high during both states. The relative spectral indices increased in delta (1-4 Hz; P=0.0002), beta3 (18-32 Hz; P<0.0001) and gamma (32-70 Hz; P<0.0001) bands during tonic pain, and decreased in theta (4-8 Hz; P<0.0001), alpha1 (8-10 Hz; P<0.0001), alpha2 (10-12 Hz; P<0.0001) bands. Theta, beta3 and gamma bands correlated significantly to the area-under-curve of pain ratings, but only theta was dynamic and correlated to the pain ratings (R=0.88, P<0.0001). CONCLUSIONS: EEG assessed during tonic pain is a valid experimental pain model both in terms of reliability between days and in connection between cortical activity and pain perception. SIGNIFICANCE: EEG during tonic pain is more pain-specific and should be used in future basic and pharmacological studies.

Functional reorganization of brain networks in patients with painful chronic pancreatitis.

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.

Central response to painful electrical esophageal stimulation in well-defined patients suffering from functional chest pain.

BACKGROUND: Functional chest pain (FCP) of presumed esophageal origin is considered a common cause for chest pain in which central nervous system hyperexcitability is thought to play an important role. We aimed to compare cerebral responses with painful esophageal stimuli between FCP patients and healthy subjects (HS). METHODS: Thirteen patients with FCP (seven females, mean age 50.4 ± 7.5 years) and 15 HS (eight females, mean age 49.1 ± 12.9 years) were enrolled. Inclusion criteria consisted of typical chest pain, normal coronary angiogram, and normal upper gastrointestinal evaluation. Electrical stimulations evoking the pain threshold were applied in the distal esophagus, while cortical evoked potentials were recorded from the scalp. Pain scores, resting electroencephalogram (EEG), evoked potential characteristics and brain electrical sources to pain stimulation were compared between groups. KEY RESULTS: No differences were seen between patients and HS regarding (i) pain thresholds (patients: 20.1 ± 7.4 mA vs HS: 22.4 ± 8.3 mA, all P > 0.05), (ii) resting-EEG (P > 0.05), (iii) evoked brain potential latencies (N2: patients 181.7 ± 25.7 mS vs HS 182.2 ± 25.8 mS, all P > 0.05) and amplitudes (N2P2: patients 8.2 ± 7.2 µV vs HS: 10.1 ± 3.4 µV, all P > 0.05), (iv) topography (P > 0.05), and (v) brain source location (P > 0.05). CONCLUSIONS & INFERENCES: No differences in activation of brain areas to painful esophageal stimulation were seen in this group of well characterized patients with FCP compared with sex- and age-matched HS. The mechanism of pain in FCP and whether it originates in the esophagus remains unsolved.

Cerebral excitability is abnormal in patients with painful chronic pancreatitis.

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.

Assessment of rectal afferent neuronal function and brain activity in patients with constipation and rectal hyposensitivity.

BACKGROUND: Blunted rectal sensation (rectal hyposensitivity: RH) is present in almost one-quarter of patients with chronic constipation. The mechanisms of its development are not fully understood, but in a proportion, afferent dysfunction is likely. To determine if, in patients with RH, alteration of rectal sensory pathways exists, rectal evoked potentials (EPs) and inverse modeling of cortical dipoles were examined. METHODS: Rectal EPs (64 channels) were recorded in 13 patients with constipation and RH (elevated thresholds to balloon distension) and 11 healthy controls, in response to electrical stimulation of the rectum at 10 cm from the anal verge using a bipolar stimulating electrode. Stimuli were delivered at pain threshold. Evoked potential peak latencies and amplitudes were analyzed, and inverse modeling was performed on traces obtained to determine the location of cortical generators. KEY RESULTS: Pain threshold was higher in patients than controls [median 59 (range 23-80) mA vs 24 (10-55) mA; P = 0.007]. Median latency to the first negative peak was 142 (±24) ms in subjects compared with 116 (±15) ms in controls (P = 0.004). There was no difference in topographic analysis of EPs or location of cortical activity demonstrated by inverse modeling between groups. CONCLUSIONS & INFERENCES: This study is the first showing objective evidence of alteration in the rectal afferent pathway of individuals with RH and constipation. Prolonged latencies suggest a primary defect in sensory neuronal function, while cerebral processing of visceral sensory information appears normal.

Randomised clinical trial: pregabalin attenuates experimental visceral pain through sub-cortical mechanisms in patients with painful chronic pancreatitis.

BACKGROUND: Pregabalin has a broad spectrum of analgesic and antihyperalgesic activity in both basic and clinical studies. However, its mechanisms and sites of action have yet to be determined in humans. AIMS: To assess the antinociceptive effect of pregabalin on experimental gut pain in patients with visceral hyperalgesia due to chronic pancreatitis and to reveal putative changes in corresponding central pain processing as assessed by evoked brain potentials. METHODS: Thirty-one patients were randomly assigned to receive increasing doses of pregabalin or placebo for three consecutive weeks. Perceptual thresholds to electrical stimulation of the sigmoid with recording of corresponding evoked brain potentials were obtained at baseline and study end. The brain source localisations reflecting direct neuronal activity were fitted by a five-dipole model projected to magnetic resonance imaging of the individuals' brains. RESULTS: As compared to placebo, pregabalin significantly increased the pain threshold to electrical gut stimulation from baseline (P=0.02). No differences in evoked brain potential characteristics were seen, neither after pregabalin nor placebo treatment (all P>0.05). In agreement with this, brain source locations remained stable during study treatment (all P>0.05). CONCLUSION: Pregabalin was superior to placebo for attenuation of experimental visceral pain in chronic pancreatitis patients. We suggest its antinociceptive effects to be mediated primarily through sub-cortical mechanisms.

Gastrointestinal sensations and pain: a review on basic, experimental and clinical findings.

Painful sensations from the gastrointestinal (GI) tract are common symptoms in the clinic but the etiology is often not fully understood and underlying diseases can be difficult to diagnose and treat successfully. In clinical practice, GI pain is often diffuse and pain referral to somatic structures can be the presenting symptom. In addition, concomitant symptoms from the autonomic and enteric nervous system can be present and affect the pain experience. To examine patients suffering from GI pain, basic knowledge about the GI pain system is essential and assists to explain the often complex and diverse symptoms. Information about anatomical and physiological characteristics of the GI pain system come from basic, experimental and clinical research, which have also gained insight into pain mechanisms underlying chronic GI pain. Evidence for sensitisation at the peripheral and central level of the nervous system seems to be of importance. These findings have major implication for the evaluation and treatment of patients suffering from GI pain.

An endoscopic method for thermal and chemical stimulation of the human oesophagus.

Previous methods for visceral thermal stimulation have lacked control of the temperature rate and visual inspection of the organ. The aims of this study was to develop a method for linear control of heat stimulation in the human oesophagus combined with endoscopy, to assess the reproducibility of this method and to investigate sensitivity to thermal stimulation of the distal oesophagus before and after acid perfusion. A probe with a 2.8 mm endoscope inside was constructed permitting heat and chemical stimulation. Three different temperature ramps were applied in the distal oesophagus in 12 healthy subjects by recirculation of heated water in a bag. Endoscopy of the oesophageal mucosa was performed prior to experimental stimulation. The temperature, the time of stimulation and the area under the temperature curve (AUC) were measured at the pain detection threshold. Thermal stimulation was repeated after perfusion of the oesophagus with acid. The method was tested on two subsequent days to assess reproducibility. All subjects had a normal endoscopic examination. Day-to-day reproducibility was good for the three temperature ramps (intra-class correlations >0.6). The subjects tolerated less heat stimulation, a decrease in AUC (P = 0.0003), a decrease in time to pain detection threshold (P = 0.005) and decreased temperature at pain detection threshold (P = 0.0001) after acid perfusion. The slow ramp was the most sensitive, showing a decrease in AUC of 29%. The present method was easily implemented and showed good reproducibility. It can potentially be used in basic experiments, drug and clinical studies as it provides a controllable thermal stimulus.