Systematic mechanism-orientated approach to chronic pancreatitis pain

Pain in chronic pancreatitis(CP) shows similarities with other visceral pain syndromes(i.e.,inflammatory bowel disease and esophagitis),which should thus be managed in a similar fashion.Typical causes of CP pain include increased intrapancreatic pressure,pancreatic inflammation and pancreatic/extrapancreatic complications.Unfortunately,CP pain continues to be a major clinical challenge.It is recognized that ongoing pain may induce altered central pain processing,e.g.,central sensitization or pro-nociceptive pain modulation.When this is present conventional pain treatment targeting the nociceptive focus,e.g.,opioid analgesia or surgical/endoscopic intervention,often fails even if technically successful.If central nervous system pain processing is altered,specific treatment targeting these changes should be instituted(e.g.,gabapentinoids,ketamine or tricyclic antidepressants).Suitable tools are now available to make altered central processing visible,including quantitative sensory testing,electroencephalograpy and(functional) magnetic resonance imaging.These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes.The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved.Future research should address the circumstances under which central nervous system pain processing changes in CP,and how this is influenced by ongoing nociceptive input and therapies.Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy,leading to improved treatment of chronic pain in CP and other visceral pain disorders.     

Patients with focal full-thickness cartilage lesions benefit less from ACL reconstruction at 2–5?years follow-up

Purpose

To investigate differences in patient-reported outcome after anterior cruciate ligament (ACL) reconstruction between patients with and without a concomitant full-thickness cartilage lesion.

Methods

30 primary ACL-reconstructed patients with an isolated concomitant full-thickness cartilage lesion and 59 matched controls without cartilage lesions were identified in the Norwegian National Knee Ligament Registry and included in the present study. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was used as the outcome measure. At a median follow-up of 2.1?years (range, 2–5?years) after ACL reconstruction, 80 (90%) of the patients completed the KOOS.

Results

Preoperatively, there were no differences in KOOS between the study group and the control group. At follow-up, patients with full-thickness cartilage lesions reported significantly decreased scores compared to patients without cartilage lesions in the KOOS subscales pain (mean difference, 8.1; 95% confidence interval [CI], 0.8–15.3), activities in daily living (mean difference, 5.8; 95% CI, 0.3–11.2), sport/recreation (mean difference, 19.8; 95% CI, 5.3–34.3) and quality of life (mean difference, 17.2; 95% CI, 4.2–30.1). Patients with full-thickness cartilage lesions reported significantly less improvement from preoperative to follow-up than patients without cartilage lesions for the KOOS subscales pain (mean difference, 11.6; 95% CI, 3.2–19.9), sport/recreation (mean difference, 20.6; 95% CI, 8.1–33.1) and quality of life (mean difference, 16.3; 95% CI, 3.8–28.7).

Conclusions

ACL-injured patients with full-thickness cartilage lesions reported worse outcomes and less improvement after ACL reconstruction than those without cartilage lesions at 2–5?years follow-up.

Level of evidence

Prognostic; prospective cohort study, Level I.     

Initial observations of endovascular aneurysm repair using Dyna-CT.

PURPOSE: To examine the feasibility of a new technology that provides images resembling computed tomographic (CT) slices on the operating table during elective endovascular abdominal aortic aneurysm (AAA) repair (EVAR). TECHNIQUE: Commercially available Dyna-CT equipment was used in conjunction with Voxar 3D software for image reconstruction. During the preliminary evaluation of 9 patients (7 men; median age 73 years, range 67-84) with non-ruptured AAA undergoing elective EVAR with the Zenith Trifab stent-graft under regional anesthesia, the equipment functioned sufficiently well to produce the planned image dataset in 8 of 9 patients. Rotation failed in 1 overweight individual due to a short distance between the patient's abdomen and the C-arm. In 7 of 8 patients, the radiologist was able to measure the diameter of the aneurysm, and it was possible to visualize the entire length of the treated aorta and the iliac arteries in all cases. The proximal aortic neck, including the stent-graft, was visualized in 7 cases. No endoleak or other complications was detected, which was confirmed on the pre-discharge CT scans. The time interval from the rotation of the C-arm until the appearance on the monitor of the first automatically generated 3D images was 7 minutes, which has subsequently been reduced to approximately 2 minutes. CONCLUSION: Our preliminary experience with Dyna-CT is promising, but further research is necessary to define the place of this imaging modality in EVAR.     

Central sensitization in patients with non-cardiac chest pain: A clinical experimental study

Objective. Patients with non-cardiac chest pain (NNCP) suffer from unexplained and often intractable pain which can pose a major clinical problem. The aim of this study was to investigate nociceptive processing in NNCP patients and their response to experimentally acid-induced oesophageal hyperalgesia using a multimodal stimulation protocol. Material and methods. Ten highly selected patients with NCCP (mean age 43?years, 1?M) were compared with an age- and gender-matched group of 20 healthy subjects. After preconditioning, the distal oesophagus was painfully distended with a balloon using “impedance planimetry”. This method assesses the luminal cross-sectional area of the oesophagus based on the electrical impedance of the fluid inside the balloon. The baseline distensions were done before and after pharmacological relaxation of the smooth muscle with 20?mg butylscopolamine. After baseline distensions, a series of up to 10 mechanical stimuli was performed (temporal summation). The stimulations were repeated after sensitization of the oesophagus induced by acid perfusion. The sensory intensities were assessed during the stimulations and the referred pain area was mapped. Results. At baseline distensions, no differences were seen between patients and controls before and after relaxation of the smooth muscles. The patients tolerated fewer repeated distensions than controls (4.8±0.5 versus 9.1±0.9; p=0.04) and had an increased size of the referred pain areas to the mechanical stimulations (32.9±6.2 versus 64.9±18.3?cm²; p=0.01). After sensitization with acid, the patients developed hyperalgesia (p<0.001), whereas no significant changes were seen in controls. Conclusions. NCCP patients showed facilitated central pain mechanisms (temporal summation and visceral hyperalgesia after sensitization). This could be used in the diagnosis and understanding of the symptoms in these patients.     

Somatosensory changes in the referred pain area before and after cholecystectomy in patients with uncomplicated gallstone disease

Objective. It is estimated that 25–40% of patients have continuing symptoms after cholecystectomy and that 5–10% have pain. The pain may be related to central neuroplastic changes of sensory pathways induced by the gallstone disease. Such neuronal hyperexcitability can be reflected in the somatic referred pain area sharing central pathways with the gallbladder. The aim of this study was to examine somatosensory changes in the referred pain area evoked by painful gallstone attacks before and after cholecystectomy in patients with uncomplicated gallstone disease. Material and methods. Thirty-seven patients with uncomplicated gallstone disease were included in the study. The sensations and pain thresholds to pinprick, pinching, pressure, thermal and electrical stimulation were studied before and 4–12 weeks after surgery in the area where the pain was referred to during the previous gallstone attacks. An area on the contralateral side of the abdomen served as the control. Results. Somatosensory hyperalgesia in the referred pain area was observed in 84% of the patients before surgery. After elective cholecystectomy, none of the patients had pain complaints, and the sensibility in the referred area was normalized. Conclusions. Uncomplicated gallstone disease leads to significant hyperalgesia in the somatic referred pain area. At the time of the postoperative investigation none of the patients suffered from pain, which was reflected in the normal sensory findings in the previous referred pain area.     

Pharmacological pain management in chronic pancreatitis

Intense abdominal pain is a prominent feature of chronic pancreatitis and its treatment remains a major clinical challenge.Basic studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain disorders.An important ultimate outcome of such aberrant pain processing is that once the disease has advanced and the pathophysiological processes are firmly established,the generation of pain can become self-perpetuating and independent of the initial peripheral nociceptive drive.Consequently,the management of pain by traditional methods based on nociceptive deafferentation(e.g.,surgery and visceral nerve blockade)becomes difficult and often ineffective.This novel and improved understanding of pain aetiology requires a paradigm shift in pain management of chronic pancreatitis.Modern mechanism based pain treatments taking into account altered pain processing are likely to increasingly replace invasive therapies targeting the nociceptive source,which should be reserved for special and carefully selected cases.In this review,we offer an overview of the current available pharmacological options for pain management in chronic pancreatitis.In addition,future options for pain management are discussed with special emphasis on personalized pain medicine and multidisciplinarity.     

Altered Brain Microstructure Assessed by Diffusion Tensor Imaging in Patients With Diabetes and Gastrointestinal Symptoms

OBJECTIVE

In patients with long-standing diabetes mellitus (DM), there is increasing evidence for abnormal processing of gastrointestinal sensations in the central nervous system. Using magnetic resonance diffusion tensor imaging, we characterized brain microstructure in areas involved in visceral sensory processing and correlated these findings to clinical parameters.

RESEARCH DESIGN AND METHODS

Twenty-six patients with DM and gastrointestinal symptoms and 23 healthy control subjects were studied in a 3T scanner. The apparent diffusion coefficient (i.e., diffusivity of water) and fractional anisotropy (FA) (i.e., organization of fibers) were assessed in the “sensory matrix” (cingulate cortex, insula, prefrontal and secondary sensory cortex, amygdala, and corona radiata) and in corpus callosum.

RESULTS

Patients had decreased FA values compared with control subjects in 1) all areas (P = 0.025); 2) anterior (P < 0.001), mid- (P = 0.001), and posterior (P < 0.001) cingulate cortex; 3) prefrontal cortex gray matter (P < 0.001); 4) corona radiata (P < 0.001); 5) secondary sensory cortex (P = 0.008); and 6) anterior white matter (P = 0.045), anterior gray matter (P = 0.002), and posterior gray matter (P = 0.002) insula. No difference was found in corpus callosum (P > 0.05). The microstructural changes in some areas correlated with clinical parameters such as bloating (anterior insula), mental well-being (anterior insula, prefrontal cortex, and mid-cingulated and corona radiata), autonomic function based on electrocardiographic results (posterior insula and anterior cingulate), and presence of gastroparesis (anterior insula).

CONCLUSIONS

The findings of this explorative study indicate that microstructural changes of brain areas involved in visceral sensory processing are associated with autonomic dysfunction and therefore may be involved in the pathogenesis of gastrointestinal symptoms in DM patients.Diabetes mellitus (DM) is a common disease with a worldwide increase in prevalence (1). DM is associated with the risk of severe complications of which especially neuronal dysfunction manifested as peripheral and autonomic neuropathies has great clinical impact (2,3). Evidence of widespread DM-induced nerve damage at peripheral, spinal, and brain levels has been observed (3), but most studies have primarily focused on peripheral neuropathy. The use of magnetic resonance imaging (MRI) with analysis of brain volumetry, spinal cross-section area measurements, spectroscopy, diffusion tensor imaging (DTI), perfusion, and functional MRI has revealed central nervous system changes (3–9).Gastrointestinal symptoms, such as nausea, vomiting, bloating, postprandial fullness, early satiety, and abdominal pain, are also frequent in DM patients (2,10,11). These symptoms are typically difficult to manage and have a negative impact on health-related quality of life (12). The pathogenesis is complex in nature, multifactorial, and not well understood (2). DM autonomic neuropathy likely plays a central role in the development and progression of the gastrointestinal dysfunction and discomfort (2,13). However, abnormal gut motor dysfunction, glycemic control, and psychological factors, among other factors, are also of relevance for symptom generation in DM (2,14). Neurophysiological changes have been observed in these patients with increased latency and reduced amplitude of esophageal electrically evoked brain potentials and altered sensory brain processing correlating to the gastrointestinal symptoms (15,16). This indicates changes in peripheral nerves as well as changes in the central nervous system with reorganization and neuroplasticity in structures involved in processing of visceral sensations. However, a better understanding of the brains’ processing of afferent information from the gastrointestinal tract is highly needed to explore the mechanisms behind gastrointestinal symptoms in patients with DM.Previously, we studied the microstructural changes in painful chronic pancreatitis patients using DTI and found abnormal microstructure in areas involved in visceral sensory processing indicating structural reorganization of the sensory neuromatrix (17). DTI allows measurement of the apparent diffusion coefficient (ADC) (i.e., mean diffusivity of water) and fractional anisotropy (FA) (i.e., organization of fibers) of selected brain areas. Even though DTI has been done in DM patients showing altered microstructure in several regions (4–8), DTI-based measurements of areas involved in visceral sensory processing have, to the best of our knowledge, never been conducted.We hypothesized that patients with long-standing DM and gastrointestinal symptoms have microstructural changes, specifically in brain areas involved in visceral sensory processing, which (as part of a neuropathic-like process) associate with clinical data. Hence, the aims of the study were 1) to assess the brain microstructure described by DTI in brain areas involved in the visceral sensory processing in healthy control subjects and in patients with long-standing DM and gastrointestinal symptoms and 2) to correlate the findings with the clinical parameters in patients.     

Diabetic Autonomic Neuropathy Affects Symptom Generation and Brain-Gut Axis

OBJECTIVE

Long-term diabetes leads to severe peripheral, autonomous, and central neuropathy in combination with clinical gastrointestinal symptoms. The brain-gut axis thus expresses a neurophysiological profile, and heart rate variability (HRV) can be correlated with clinical gastrointestinal symptoms.

RESEARCH DESIGN AND METHODS

Fifteen healthy volunteers and 15 diabetic patients (12 with type 1 diabetes) with severe gastrointestinal symptoms and clinical suspicion of autonomic neuropathy were included. Psychophysics and evoked brain potentials were assessed after painful rectosigmoid electrostimulations, and brain activity was modeled by brain electrical source analysis. Self-reported gastrointestinal symptoms (per the Patient Assessment of Upper Gastrointestinal Disorder Severity Symptom Index) and quality of life (SF-36 Short Form Survey) were collected.

RESULTS

Diabetic patients had autonomous neuropathy, evidenced by decreased electrocardiographic R-R interval (P = 0.03) and lower HRV (P = 0.008). Patients were less sensitive to painful stimulation (P = 0.007), had prolonged latencies of evoked potentials (P ≤ 0.001), and showed diminished amplitude of the N2–P2 component in evoked potentials (P = 0.01). There was a caudoanterior shift of the insular brain source (P = 0.01) and an anterior shift of the cingulate generator (P = 0.01). Insular source location was associated with HRV assessments (all P < 0.02), and the shift (expressed in mm) correlated negatively with physical health (P < 0.001) and positively with nausea (P = 0.03) and postprandial fullness (P = 0.03). Cingulate source shift was correlated negatively with physical health (P = 0.005) and positively with postprandial fullness (P ≤ 0.001).

CONCLUSIONS

This study provides evidence for interaction between autonomic neuropathy and peripheral nervous degeneration, as well as changes in dipole sources in diabetic patients with gastrointestinal symptoms. The findings may lead to improved treatment modalities targeting pharmacological neuroprotection or neuromodulation.Diabetes is one of the leading causes of severe peripheral, autonomous, and central neuropathy. Diabetic peripheral neuropathy classically manifests as progressive symmetric thick-fiber (Aβ) and thin-fiber (Aδ) neuropathy affecting axons of the distal lower extremities. Patients may also suffer from diabetic autonomic neuropathy (DAN). According to the Toronto criteria, DAN is a disorder of the autonomic nervous system (ANS) in the setting of diabetes or metabolic derangements (1). DAN may affect cardiovascular, gastrointestinal, and urogenital systems and sudomotor function. Autonomic abnormalities can be classified as structural or functional disorders, and they may be subclinical, diagnosable only by tests, or clinical, with symptoms or signs (2).As many as 50% of diabetic patients with long duration of the disease have severe gastrointestinal symptoms, including postprandial fullness, nausea, vomiting, bloating, early satiety, and abdominal pain. These symptoms likely represent clinical DAN, leading to significant reduction in quality of life and presenting a severe socioeconomic burden (3).The underlying pathogenesis of DAN is multifactorial and comprises gastrointestinal motility dysfunction, metabolic insults to internal nerve fibers, neurovascular insufficiency, alterations in gastrointestinal hormone secretion, and abnormal interoception (combined perception of afferent neural trafficking from the internal organs). Clinical management of diabetic patients is therefore challenging, calling for a better understanding of the brain-gut axis. Introduction of such peptides as glucagon-like peptide 1 (GLP-1) agonists has contributed to understanding of this complex interaction. When released postprandially in the small intestine GLP-1 acts as a hormone or a signal to sensory vagal afferents. In the central nervous system, it primarily affects stimulation of glucose-dependent insulin secretion (4) and inhibition of glucagon secretion (5). When GLP-1 is released in brain hypothalamic nuclei from nerve endings originating from, for example, the solitary tract, however, it functions as a neuropeptide (6), affecting vagal activity and hence homeostatic regulation of the gut.Psychophysical studies of the brain-gut axis in type 1 diabetes have focused on the upper gastrointestinal tract. Increased pain detection thresholds (hyposensitivity) to esophageal electrical stimulation were shown in patients with motor dysfunction and gastrointestinal discomfort (7), and interestingly hyposensitivity was accompanied by increased size of convergent somatic pain referrals in patients with evident DAN and gastrointestinal symptoms (8). Authors suggest that the latter finding involves central pain processing, indicating a central “neuropathy-like” component contributing to symptom generation. The mechanism in diabetes differs from classical neuropathy, however, in which hyperalgesia and allodynia (and not hyposensitivity) typically are present.Neurophysiologically, laser evoked potentials (EPs) have been used to characterize patients with somatic neuropathic pain, with the reduced amplitudes reflecting Aδ-fiber reduction (9). Further, EPs have been used to explore the esophageal sensory afferents in type 1 diabetic patients, revealing similar findings: prolonged latencies and reduced amplitudes relative to healthy volunteers (10). Moreover, our group have shown central alterations in diabetic patients and reorganization of the cingulate-operculum network (11).In light of previous findings, we wanted to study the brain-gut axis in diabetic patients. We hypothesized that the neurophysiological profile differed between diabetic patients and healthy volunteers, including 1) psychophysical response; 2) heart rate variability (HRV); 3) EP latency, amplitude, and topography; and 4) electrical brain activity according to dipolar source location. Furthermore, to characterize the consequence of altered interoception, we investigated the interactions of HRV, dipolar source location, gastrointestinal symptoms, and self-reported quality of life.