Systematic review with meta‐analysis: conditioned pain modulation in patients with the irritable bowel syndrome

Albusoda, Ahmed; Ruffle, James K.; Friis, Kathrine A.; Gysan, Maximilian Robert; Drewes, Asbjørn Mohr; Aziz, Qasim; Farmer, Adam D.

doi:10.1111/apt.14965

Cited by 30 publications

(27 citation statements)

References 78 publications

(114 reference statements)

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“…CPM/DNIC likely reflect the net balance between descending inhibitory and facilitatory signalling; hence, the study of DNIC in rodents represents a useful translatable measure linking pre‐clinical and clinical investigations (Bannister & Dickenson, ). Inefficient CPM might provide insight into underlying pathophysiological mechanisms, and disturbances have been reported in neuropathic pain, irritable bowel syndrome, cluster headache and fibromyalgia (Albusoda et al., ; Kosek & Hansson, ; Perrotta et al., ; Yarnitsky, Granot, & Granovsky, ). This proposal has also garnered support of mechanism‐led treatment of neuropathic patients as CPM efficiency inversely correlates with pain relief from tapentadol and duloxetine (Niesters et al., ; Yarnitsky, Granot, Nahman‐Averbuch, Khamaisi, & Granovsky, ).…”

Section: Introductionmentioning

confidence: 99%

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats

Patel

Dickenson

2019

Eur J of Neuroscience

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Diffuse noxious inhibitory controls (DNIC) are a mechanism of endogenous descending pain modulation and are deficient in a large proportion of chronic pain patients. However, the pathways involved remain only partially determined with several cortical and brainstem structures implicated. This study examined the role of the dorsal reticular nucleus (DRt) and infralimbic (ILC) region of the medial prefrontal cortex in DNIC. In vivo electrophysiology was performed to record from dorsal horn lamina V/VI wide dynamic range neurones with left hind paw receptive fields in anaesthetised sham‐operated and L5/L6 spinal nerve‐ligated (SNL) rats. Evoked neuronal responses were quantified in the presence and absence of a conditioning stimulus (left ear clamp). In sham rats, DNIC were reproducibly recruited by a heterotopically applied conditioning stimulus, an effect that was absent in neuropathic rats. Intra‐DRt naloxone had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. In addition, intra‐DRt naloxone blocked DNIC in sham rats, but had no effect in SNL rats. Intra‐ILC lidocaine had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. However, differential effects were observed in relation to the expression of DNIC; intra‐ILC lidocaine blocked activation of DNIC in sham rats but restored DNIC in SNL rats. These data suggest that the ILC is not directly involved in mediating DNIC but can modulate its activation and that DRt involvement in DNIC requires opioidergic signalling.

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Section: Introductionmentioning

confidence: 99%

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats

Patel

Dickenson

2019

Eur J of Neuroscience

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“…The CNS has the ability to modulate the intensity and perception of afferent nociceptive signals, via endogenous pain inhibitory pathways (known as "conditioned pain modulation") or excitatory pathways (known as "central sensitization") both on the spinal and supraspinal level [165]. The latest meta-analysis of 12 studies on conditioned pain modulation in IBS populations showed diminished conditioned pain modulation in IBS in comparison to HC with odds ratio of 4.84 (95%CI, 2.18-10.71, p<.0001) [4]. However 88% of all the study participants were female, whereas previous meta-analysis performed on males reported less deficiency in conditioned pain modulation [140].…”

Section: Visceral Pain Pathwaysmentioning

confidence: 99%

“…Heterotopic stimulation, i.e. the phenomenon of diminished pain perception due to application of another painful stimulus, has been widely applicated in the studies of visceral pain modulation [4]. Graham et al presented that in IBS, pain modulation by heterotopic stimulation acti-vated brain areas connected to bottom-up control such as amygdala or hippocampus, whereas in HC it activated areas of top-down control such as ACC, INS, PAG and RVM [78].…”

Section: Visceral Pain Pathwaysmentioning

confidence: 99%

“…Graham et al presented that in IBS, pain modulation by heterotopic stimulation acti-vated brain areas connected to bottom-up control such as amygdala or hippocampus, whereas in HC it activated areas of top-down control such as ACC, INS, PAG and RVM [78]. Evidence of conditioned pain modulation and central sensitization in visceral pain entities, such as IBS, is accumulating [4,155,260].…”

Section: Visceral Pain Pathwaysmentioning

confidence: 99%

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Peripheral and Central Mechanisms in Irritable Bowel Syndrome : in search of links

Bednarska

2019

Linköping University Medical Dissertations

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Irritable bowel syndrome (IBS) is a chronic visceral pain disorder with female predominance, characterized by recurrent abdominal pain and disturbed bowel habits in the absence of an identifiable organic cause. This prevalent and debilitating disease, which accounts for a substantial economic and individual burden, lacks exact diagnostic tools and effective treatment, since its pathophysiology remains uncertain. The bidirectional and multilayered brain-gut axis is a well-established disease model, however, the interactions between central and peripheral mechanisms along the brain-gut axis remain incompletely understood. One of the welldescribed triggering factors, yet accounting for only a fraction of IBS prevalence, is bacterial gastroenteritis that affects mucosal barrier function. Altered gut microbiota composition as well as disturbed intestinal mucosal barrier function and its neuroimmune regulation have been reported in IBS, however, the impact of live bacteria, neither commensal nor pathogenic, on intestinal barrier has not been studied yet. Furthermore, abnormal central processing of visceral sensations and psychological factors such as maladaptive coping have previously been suggested as centrally-mediated pathophysiological mechanisms of importance in IBS. Brain imaging studies have demonstrated an imbalance in descending pain modulatory networks and alterations in brain regions associated with interoceptive awareness and pain processing and modulation, particularly in anterior insula (aINS), although biochemical changes putatively underlying these central alterations remain poorly understood. Most importantly, however, possible associations between these documented changes on central and peripheral levels, which may as complex interactions contribute to disease onset and chronification of symptoms, are widely unknown. VMpo ventromedial thalamic nucleus posterior portion VPAC vasoactive intestinal polypeptide receptor VSI Visceral Sensitivity Index Recurrent abdominal pain or discomfort** at least 3 days per month in the last 3 months associated with 2 or more of the following: 1. Improvement with defecation 2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool *Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis. **Discomfort means an uncomfortable sensation not described as pain. In pathophysiology research and clinical trials, a pain/discomfort frequency of at least 2 days a week during screening evaluation for subject eligibility.

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“…Intestinal and generalized somatic hypersensitivity and sensitization might be related to inflammatory and cognitive causes, among others. Indeed, endogenous pain modulation by the central nervous system (CNS) is abnormal in IBS and functional dyspepsia (FD), providing a plausible explanation for modified extra-GI sensory, autonomic, and GI neuronal function in FGID ( 15 – 20 ). To further examine the relationships between GI and extra-GI symptoms in FGID and underlying sensory function, sugar breath tests were used, which have been shown to evoke GI and extra-GI symptoms in patients with FGID ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

Extragastrointestinal Symptoms and Sensory Responses During Breath Tests Distinguish Patients With Functional Gastrointestinal Disorders

Wilder‐Smith¹,

Drewes

Materna³

et al. 2020

Clinical and Translational Gastroenterology

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INTRODUCTION: Patients with functional gastrointestinal disorders (FGIDs) are classified based on their gastrointestinal (GI) symptoms, without considering their frequent extra-GI symptoms. This study defined subgroups of patients using both GI and extra-GI symptoms and examined underlying mechanisms with fructose and lactose breath tests. METHODS: Latent class analysis defined distinct clusters of patients with FGID based on their long-term GI and extra-GI symptoms. Sensory and breath gas responses after fructose and lactose ingestion were compared across symptom clusters to investigate differences in sensory function and fermentation by intestinal microbiota. RESULTS: Six symptom clusters were identified in 2,083 patients with FGID. Clusters were characterized mainly by GI fermentation-type (cluster 1), allergy-like (cluster 2), intense pain-accentuated GI symptoms (cluster 3), central nervous system (cluster 4), musculoskeletal (cluster 5), and generalized extra-GI (cluster 6) symptoms. In the 68% of patients with complete breath tests, the areas under the curve of GI and central nervous system symptoms after fructose and lactose ingestion differed across the clusters ( P < 0.001). The clusters with extensive long-term extra-GI symptoms had greater symptoms after the sugars and were predominantly women, with family or childhood allergy histories. Importantly, the areas under the curves of hydrogen and methane breath concentrations were similar ( P > 0.05) across all symptom clusters. Rome III criteria did not distinguish between the symptom clusters. DISCUSSION: Patients with FGID fall into clusters defined extensively by extra-GI symptoms. Greater extra-GI symptoms are associated with evidence of generalized sensory hypersensitivity to sugar ingestion, unrelated to intestinal gas production. Possible underlying mechanisms include metabolites originating from the intestinal microbiota and somatization.

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Systematic review with meta‐analysis: conditioned pain modulation in patients with the irritable bowel syndrome

Abstract: Conditioned pain modulation is significantly diminished in patients with IBS vs healthy controls. These data suggest that abnormal descending pathways may play an important pathophysiological role in IBS, which could represent an investigation and a therapeutic target in IBS.

Cited by 30 publications

References 78 publications

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats

Peripheral and Central Mechanisms in Irritable Bowel Syndrome : in search of links

Extragastrointestinal Symptoms and Sensory Responses During Breath Tests Distinguish Patients With Functional Gastrointestinal Disorders

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