Sanchoy Sarkar

Contribution of central sensitisation to the development of noncardiac chest pain

BACKGROUND Non-cardiac chest pain mimics angina pectoris but generally originates from the oesophagus. Visceral hypersensitivity may contribute, but its neurophysiological basis is unclear. We investigated whether central sensitisation, an activity-dependent amplification of sensory transfer in the central nervous system, underlies visceral pain hypersensitivity and non-cardiac chest pain. METHODS We studied 19 healthy volunteers and seven patients with non-cardiac chest pain. Acid was infused into the lower oesophagus. Sensory responses to electrical stimulation were monitored within the acid-exposed lower oesophagus, the non-exposed upper oesophagus, and the cutaneous area of pain referral, before and after the infusion. FINDINGS In healthy volunteers, acid infusion into the lower oesophagus lowered the pain threshold in the upper oesophagus (mean decrease 18.2% [95% CI 10.4 to 26.0]; p=0.01) and on the chest wall (24.5% [10.2 to 38.7]; p=0.01). Patients with non-cardiac chest pain had a lower resting oesophageal pain threshold than healthy controls (45 [30 to 58] vs 64 [49 to 81] mA; p=0.04). In response to acid infusion, their pain threshold in the upper oesophagus fell further and for longer (mean fall in area under threshold/time curve 26.7 [11.0 to 42.3] vs 5.8 [2.8 to 8.8] units; p=0.04). INTERPRETATION The finding of secondary viscerovisceral and viscerosomatic pain hypersensitivity suggests that central sensitisation may contribute to visceral pain disorders. The prolonged visceral pain hypersensitivity in patients with non-cardiac chest pain suggests a central enhancement of sensory transfer. New therapeutic opportunities are therefore possible.

Patients with chest pain and occult gastroesophageal reflux demonstrate visceral pain hypersensitivity which may be partially responsive to acid suppression.

OBJECTIVES:Mechanisms of chest pain in gastroesophageal reflux disease (GERD) are poorly understood. The recent demonstration in healthy subjects that lower esophageal acid exposure induces pain hypersensitivity within the nonacid-exposed upper esophagus (secondary allodynia) raises the possibility that an increase in spinal neuronal excitability (i.e., central sensitization) contributes to chest pain in GERD. The aim of this study was to determine whether in patients with unexplained chest pain, acid reflux contributes to esophageal pain hypersensitivity.METHODS:In 14 patients with chest pain and GERD and 8 healthy volunteers, electrical pain thresholds (PT) were recorded from the upper esophagus before, and then repeatedly for 90 min after either hydrochloric acid (0.15 M) or saline (0.15 M) infusion into the lower esophagus. Six patients underwent a repeat study after 6 wk of high-dose proton pump inhibitor (PPI) therapy.RESULTS:GERD patients had lower resting upper esophageal PT than in healthy subjects (40.8 ± 9 mA and 70.4 ± 11 mA, respectively; P = 0.018). Acid infusion reduced PT in the non-acid-exposed upper esophagus in healthy subjects, but not in the patients (area under curve [AUC] − 304 ± 333 and 786 ± 464; P = 0.03, respectively). Following PPI therapy, resting PT increased (34.65 ± 13.4 to 40.5 ± 12.5 mA; P = 0.03), and a reduction in PT now occurred in acid infusion (AUC − 369 ± 321; P = 0.03).CONCLUSIONS:Patients with unexplained chest pain and occult GERD have esophageal pain hypersensitivity that is PPI responsive. The increase in resting PT and secondary allodynia only following PPI therapy suggests that pain hypersensitivity in these GERD patients may partially be the result of central sensitization.

Development of esophageal hypersensitivity following experimental duodenal acidification.

OBJECTIVE:As visceral afferents from different regions of the gastrointestinal tract converge at the level of the spinal cord, we hypothesized that sensitization of one gut organ would induce visceral hypersensitivity in another gut organ, remote to the sensitizing stimulus.METHODS:Protocol 1: Eight healthy male volunteers, age 30 ± 8.2 yr, underwent three studies on different days. Esophageal pain thresholds (PT) were recorded at 10-min intervals prior to and for 2 h following a 30-min duodenal infusion of either 0.15 M hydrochloric acid (HCl), saline, or no infusion. Five subjects repeated the study to demonstrate reproducibility. Protocol 2: Esophageal evoked potentials (EEP) were studied in six subjects on two occasions prior to and 1 h after a 30-min duodenal infusion of 0.15 M HCl or saline.RESULTS:Protocol 1: After acid infusion, there were reproducible reductions in esophageal PT (ICC = 0.88), which were maximal at 110 min (15.05 ± 2.25 mA) (p < 0.002). Following saline infusion there was an increase in esophageal PT (ICC = 0.71), which was similar to the no-infusion condition (6.21 ± 1.54 mA vs 8.5 + 7.6 mA; p > 0.05). Protocol 2: Esophageal sensation scores increased (p= 0.02) after acid, but not after saline infusion (p= 0.1). A comparison of the latencies of EEP components prior to and following acid and saline infusion revealed a reduction in the N1 (p= 0.02) and P2 components (p= 0.04).CONCLUSION:This study provides the first objective evidence that duodenal acidification can induce esophageal hypersensitivity associated with changes in sensitivity of the central visceral pain pathway. As the esophagus was remote from the sensitizing stimulus, central sensitization of spinal dorsal horn neurons is likely to have contributed to these changes.

Perceptual wind‐up in the human oesophagus is enhanced by central sensitisation

Background: Oesophageal acid infusion induces enhanced pain hypersensitivity in non-acid exposed upper oesophagus (secondary hyperalgesia) in patients with non-cardiac chest pain, thus suggesting central sensitisation contributes to visceral pain hypersensitivity in functional gut disorders (FGD). Perceptual wind-up (increased pain perception to constant intensity sensory stimuli at frequencies ⩾0.3 Hz) is used as a proxy for central sensitisation to investigate pain syndromes where pain hypersensitivity is important (for example, fibromyalgia). Aims: Wind-up in central sensitisation induced human visceral pain hypersensitivity has not been explored. We hypothesised that if wind-up is a proxy for central sensitisation induced human visceral pain hypersensitivity, then oesophageal wind-up should be enhanced by secondary hyperalgesia. Methods: In eight healthy volunteers (seven males; mean age 32 years), perception at pain threshold to a train of 20 electrical stimuli applied to the hand and upper oesophagus (UO) at either 0.1 Hz (control) or 2 Hz was determined before and one hour after a 30 minute lower oesophageal acid infusion. Results: Wind-up occurred only with the 2 Hz train in the UO and hand (both p = 0.01). Following acid infusion, pain threshold decreased (17 (4)%; p = 0.01) in the UO, suggesting the presence of secondary hyperalgesia. Wind-up to the 2 Hz train increased in the UO (wind-up ratio 1.4 (0.1) to 1.6 (0.1); p = 0.03) but not in the hand (wind-up ratio 1.3 (0.1) and 1.3 (0.1); p = 0.3) Conclusion: Enhanced wind-up after secondary oesophageal hyperalgesia suggests that visceral pain hypersensitivity induced by central sensitisation results from increased central neuronal excitability. Wind-up may offer new opportunities to investigate the contribution of central neuronal changes to symptoms in FGD.

Prostaglandin PGE2 is an important mediators of central sensitization in the human viscera: The EP-1prostinoid receptor antagonist ZD 6416 is a novel therapy in visceral hypersensitivity

acid clearance was evaluated by measuring the duration of time for pH to return to 4.0 after infusion of 15 ml 0.1 N HCI. GER was recorded by pH probe placed 5 cm above the LES. Heartburn symptoms were evaluated by a 0-10 cm visual analogue scale. RESULTS: Chocolate significantly increased reflux events and acid exposure time when compared to 3% NaCl. Granisetron significantly reduced reflux events and tended to reduce acid exposure time. Furthermore, chocolate reduced LES pressure, which was reversed by granisetron. In addition, after chocolate the heartburn symptoms were increased compared to 3% NaCI, which was reduced by granisetron. CONCLUSIONS: We demonstrated that chocolate induces GER symptoms by reducing LES pressure and increasing reflux events and acid exposure duration in GERD patients. These events could be antagonized by granisetron. These results suggest that 5HT3 antagonist may be a novel treatment of GERD.

Comparison of cortical potentials evoked by mechanical and electrical stimulation of the human oesophagus

BACKGROUND: The pathways mediating Cortical Evoked Potentials (CEP) obtained by mechanical (MS) and electrical (ES) stimulation of the oesophagus remain controversial. Whilst CEP have been recorded with either stimuli, the longer latency of CEP to MS has led to the suggestion that these responses are mediated via unmyelinated C-fibres whereas the shorter latency CEP to ES are mediated via myelinated A-6 fibres. However, a direct comparison of the CEP characteristics in the same subject have not been reported. Aim: To compare oesnphageal CEP obtained by MS and ES. Methods: CEP were recorded from the vertex (Cz) in 6 male subjects (age 25-31) using surface electrodes connected to a signal averager via an amplifier. Stimulation was applied 5cm above the LOS. Electrical Stimulation: Was performed using a bipolar ring electrode connected to a stimulator. Stimulation Intensity (SI) was 75% of the subjects maximum tolerated intensity. A grand average of 200 stimuli were recorded. Mechanical Stimulation: Was performed using a 2cm silicone balloon connected to a pump. SI was set at a level which produced a strong, non-painful sensation. A grand average of 200 stimuli were recorded. The rise time to maximum balloon inflation was constant (165ms). Peak latencies were measured from the onset of inflation. Results: Reproducible, triphasic CEP were evoked in all subjects by ES and MS of the oesopha ~us. Values given as group mean _+ SD.