Jens Brøndum Frøkjær

Opioid-induced Bowel Dysfunction: Pathophysiology and Management

Opioids are the most commonly prescribed medications to treat severe pain in the Western world. It has been estimated that up to 90% of American patients presenting to specialized pain centres are treated with opioids. Along with their analgesic properties, opioids have the potential to produce substantial side effects, such as nausea, cognitive impairment, addiction and urinary retention. In the gut, opioids exert their action on the enteric nervous system, where they bind to the myenteric and submucosal plexuses, causing dysmotility, decreased fluid secretion and sphincter dysfunction, which all leads to opioid-induced bowel dysfunction (OIBD). In the clinic, this is reported as nausea, vomiting, gastro-oesophageal reflux-related symptoms, constipation, etc.One of the most severe symptoms is constipation, which can be assessed using different scales for subjective assessment. Objective methods such as radiography and colonic transit time can also be used, together with manometry and evaluation of anorectal function to explore the pathophysiology.Dose-limiting adverse symptoms of OIBD can lead to insufficient pain treatment. Even though several treatment strategies are available, the side effects are still a major challenge. Traditional laxatives are normally prescribed but they are often insufficient to alleviate symptoms, especially those from the upper gastrointestinal tract. Newer prokinetics, such as prucalopride and lubiprostone, may be more effective in alleviating OIBD. Another treatment approach is co-administration of opioid antagonists, which either cannot cross the blood-brain barrier or selectively target opioid receptors in the gastrointestinal tract. However, although these new agents have proved to be more efficacious than placebo, clinical trials still need to prove their superiority to standard co-prescribed laxative regimes.

A new technique for evaluating sphincter function in visceral organs: application of the functional lumen imaging probe (FLIP) for the evaluation of the oesophago–gastric junction

No quantitative method has been implemented routinely in clinical practice to assess the oesophago-gastric junction (OGJ). Using impedance planimetry a functional lumen imaging probe (FLIP) was constructed to measure eight cross-sectional areas (CSA) at 4 mm intervals inside a saline-filled bag. To validate the FLIP technique for profiling the OGJ, polymethylmethacrylate (Perspex) cylinders with different CSAs were measured ten times by the FLIP to assess reproducibility and accuracy. A geometric sphincter phantom was constructed and its geometry was measured with a 360 degrees radial ultrasound (US) mini-probe pulled through it at a rate of 1 mm s(-1). The measurements were compared with FLIP measurements. Safety and technique reproducibility were tested on a volunteer. Reproducibility and accuracy between the ten samples were good. The probe performed well with and without a balloon mounted on it except for the smallest CSA (38.5 mm(2)) where there was a difference of 22% from the actual value at one CSA measurement point. The FLIP imaged the phantom geometry as well as the radial scanning US mini-probe. Pilot studies on a volunteer showed that the probe could be placed in the OGJ and the balloon distensions revealed the geometry of the sphincter at various levels of distension. The technique may be useful in accessing the role of the OGJ in diseases such as gastroesophageal reflux disease (GORD) and achalasia and their treatments with surgical and endoscopic therapies.

Effects of Gabapentin on Experimental Somatic Pain and Temporal Summation

Background and Objectives: Gabapentin is used for treatment of neuropathic pain, but its effect on different somatic pain modalities and integrative mechanisms are not completely understood. The aim of this double-blind, placebo-controlled experimental pain study, conducted on 20 healthy volunteers, was to examine the effect of a single dose of 1200 mg gabapentin on multi-modal experimental cutaneous and muscle pain models. Methods: The following pain models were applied: (1) pain thresholds to single and repeated cutaneous and intramuscular electrical stimulation (temporal summation to 5 stimuli delivered at 2 Hz); (2) stimulus-response function relating pain intensity scores (visual analog scale, VAS) to increasing current intensities for electrical skin and muscle stimuli (single and repeated, determined at baseline); and (3) the pain intensity (VAS) and pain areas after intramuscular injection of hypertonic saline. Pain assessments were performed prior to, and at 4, 6, and 8 hours after medication. Results: When responses were averaged across the post-dose times, gabapentin: (1) significantly increased the temporal summation pain threshold in skin compared with placebo (P = .03); (2) significantly reduced the area under the pain intensity curve to hypertonic saline injections in the muscle (P = .02); and (3) significantly reduced the area of pain evoked by hypertonic saline (P = .03). Conclusions: Gabapentin reduces temporal summation of skin stimuli at pain threshold intensities; this may have potential as a biomarker for drugs with efficacy on neurogenic pain. The data also suggest that tonic muscle pain is responsive to gabapentin treatment and suggest further clinical studies.

Reduced cortical thickness of brain areas involved in pain processing in patients with chronic pancreatitis.

BACKGROUND & AIMS Patients with painful chronic pancreatitis (CP) might have abnormal brain function. We assessed cortical thickness in brain areas involved in visceral pain processing. METHODS We analyzed brain morphologies of 19 patients with painful CP and compared them with 15 healthy individuals (controls) by using a 3T magnetic resonance scanner. By using an automated method with surface-based cortical segmentation, we assessed cortical thickness of the primary (SI) and secondary (SII) somatosensory cortex; prefrontal cortex (PFC); frontal cortex (FC); anterior (ACC), mid (MCC), and posterior (PCC) cingulate cortex; and insula. The occipital middle sulcus was used as a control area. The pain score was determined on the basis of the average daily amount of pain during 1 week. RESULTS Compared with controls, patients with CP had reduced overall cortical thickness (P = .0012), without effects of modification for diabetes, alcoholic etiologies, or opioid treatment (all P values >.05). In patients with CP, the cortical thickness was decreased in SII (P = .002, compared with controls), PFC (P = .046), FC (P = .0003), MCC (P = .001), and insula (P = .002). There were no differences in cortical thickness between CP patients and controls in the control area (P = .20), SI (P = .06), ACC (P = .95), or PCC (P = .42). Cortical thickness in the affected areas correlated with pain score (r = 0.47, P = .003). CONCLUSIONS In patients with CP, brain areas involved in pain processing have reduced cortical thickness. As a result of long-term, ongoing pain input to the neuromatrix, cortical thickness might serve as a measure for overall pain system dysfunction, as observed in other diseases characterized by chronic pain.

Pain-associated adaptive cortical reorganisation in chronic pancreatitis.

Background/Aims: In various chronic pain conditions cortical reorganisation seems to play a role in the symptomatology. The aims of this study were to investigate cortical reorganisation in patients with pain caused by chronic pancreatitis (CP) and to correlate putative cortical reorganisation to clinical pain scores. Methods: 24 patients suffering from CP and 14 healthy volunteers were included. Patients’ daily experience of pain was recorded in a pain diary. The sigmoid was stimulated electrically with simultaneous recording of evoked brain potentials (EPs). The brain source localisations reflecting direct neuronal activity were fitted by a five-dipole model projected to magnetic resonance imaging of the individual brains. Results: Patients showed prolonged latencies of the EPs confined to the frontal region of the brain (p < 0.01). The corresponding brain sources were located in the bilateral insula, cingulate gyrus and bilateral secondary somatosensory area. The insular dipoles were localised more posterior in the patients than in healthy subjects (p < 0.01). The shift in insular dipole localisation was negatively correlated with the patients’ clinical pain scores (p < 0.05). Conclusions: The findings indicate that sustained pain in CP leads to functional reorganisation of the insular cortex. We suggest its physiological correlate to be an adaptive response to chronic pain.

An experimental study of viscero-visceral hyperalgesia using an ultrasound-based multimodal sensory testing approach

Abstract Widespread visceral hypersensitivity and the overlap of symptom complexes observed in functional gastrointestinal disorders may be related to central sensitization and neuroplastic changes. A multimodal and multi‐segmental model was developed to evaluate viscero‐visceral hyperalgesia induced by experimental esophageal sensitization in healthy volunteers. Twelve healthy subjects were studied using a double‐blinded, placebo‐controlled design. The sensitivity to mechanical and heat stimulations was assessed in the proximal esophagus, duodenum and rectum before and after perfusion of the distal esophagus with acid or saline. A special‐designed probe was used allowing cross‐sectional ultrasound imaging during mechanical and heat stimulation of the esophagus and duodenum. Another probe was used for mechanical stimulation of the rectum. The referred somatic pain areas to gut pain stimulations were also assessed. Following acid perfusion 11 of 12 volunteers showed increased sensitivity to one or more stimulation modalities. An overall increased sensitivity to mechanical stretch in the three gut segments was seen (P=0.0001). Posthoc analysis showed that this was mainly due to increased sensitivity in the rectum (P<0.001). No changes were seen to thermal stimulations (all P‐values>0.4). The somatic referred pain area to duodenal stimulations increased (P=0.04), while it was unaffected to esophageal and rectal stimulations (P>0.3). The present method demonstrated a new approach to assess multimodal sensitivity to experimental sensitization of the esophagus and related viscero‐visceral hyperalgesia. Central mechanisms can explain the remote hyperalgesia to mechanical visceral stimulation and the increase in referred pain areas. The present method may be used to explore pathophysiology and pharmacological interventions in patients with visceral hypersensitivity.

Multimodal sensory testing of the rectum and rectosigmoid: development and reproducibility of a new method

Abstract  Evaluation of rectal and rectosigmoid sensation is important in basic, clinical and pharmacological studies. New methods to evoke and assess multimodal (electrical, thermal and mechanical) experimental pain of the upper gut activate distinct pathways and mimics clinical pain. The aims of the current study were to characterize the sensory response and reproducibility to multimodal stimulation of rectum and the rectosigmoid. A multimodal rectal probe was developed. Mucosal electrostimulation was delivered at the recto‐sigmoid junction. In Rectum, impedance planimetry was used for measurement of cross‐sectional area (CSA) during distension. Circulation of water within the bag at either 4 or 60 °C was applied for thermal stimulation. The method was tested in 12 healthy volunteers (six men mean age 32 years) on two subsequent days. Mechanical and sensory responses and referred pain areas were assessed. Stimulation with electrical, thermal and mechanical modalities resulted in different sensory perceptions. The relationship between stimulus intensity and sensory response was linear for all modalities. Sensory response to different modalities did not differ between investigation days (all P‐values > 0.1). Approximately 75% of subjects felt referred pain in distinct skin locations. Between‐days reproducibility was good for all modalities [intra‐class correlation (ICC) ≥0.6]. At sensory threshold, CSA showed best reproducibility (ICC ≥ 0.9). At pain detection threshold stretch ratio, CSA and electrostimulation showed best reproducibility (ICC = 1.0; 0.9; 0.9). The present model was easily implemented, robust and showed good reproducibility. It can be used to study pathophysiology or pharmacological interventions in healthy controls and in patients with diseases involving the distal hindgut.

A new measurement of oesophago-gastric junction competence

Knowledge of the competence of the oesophago‐gastric junction (OGJ) is fundamental to the understanding of gastro‐oesophageal reflux disease (GORD), a disorder with a high incidence among the general population. A catheter with a bag 9.5 cms long mounted towards the distal end was swallowed by three volunteers. Using manometry readings and the point of respiratory inversion as a guide the probe was placed in the OGJ. The bag was distended with saline at a fixed rate volume before and after the administration of butylscopolamine to block cholinergic‐mediated contractile smooth muscle activity. Using impedance planimetry three cross‐sectional areas (CSA) measurements were made between three pairs of electrodes with 4 mm between each electrode on the catheter placed inside the ballon. Using the law of Laplace, CSA and pressure data could be calculated to give wall tension. Tension rose in all volunteers as the radius increased and it was higher towards the proximal end of the OGJ indicating that this measurement can be used to show the distensibility of the OGJ at different degrees of opening. This technique could be useful in identifying changes in the competence of the lower oesophageal sphincter in some patients with GORD.

Magnetic resonance imaging of the small bowel in Crohn's disease

Objective There may be advantages in using magnetic resonance imaging (MRI) in small-bowel disease. The aims of this study were to optimize the MRI examination technique and to evaluate the capabilities of MRI compared with those of conventional enteroclysis (CE). Material and methods MRI and CE were performed in 36 patients suspected of Crohns disease. Based on 26 pilot studies optimal oral administration of plum juice and bulk fibre laxative was found. T2-weighted and gadolinium enhanced T1-weighted images were obtained using a breath-holding technique and butylscopolamine. Virtual endoscopy was performed. Conventional enteroclysis entailed duodenal intubation and administration of barium and air. Two radiologists evaluated the examinations independently. Finally, each patient scored the degree of discomfort, and preference for either MRI or CE was found. Results The MRI technique ensured sufficient distension of the small bowel and small-bowel changes were found in 12 patients. In 3 patients this was not seen on conventional enteroclysis, which did not reveal any pathology that was not already seen on MRI. Pathological abdominal changes were found in 70% more patients during MRI than during conventional enteroclysis (p<0.001). Endoscopic examination corresponded with the MRI findings. The examination quality decreased with increasing age (p = 0.002) and the interobserver agreement of the pathological changes was high (p<0.001). Virtual endoscopy resulted in excellent demonstration of the mucosal surface. The examination discomfort scores obtained during the MRI were lower than those during conventional enteroclysis (p<0.001). Conclusions MRI using the current technique is preferable to conventional enteroclysis because of superior demonstration of the entire small-bowel pathology, low level of patient discomfort and absence of radiation exposure.

Central pain mechanisms following combined acid and capsaicin perfusion of the human oesophagus

Visceral afferents originating from different gut‐segments converge at the spinal level. We hypothesized that chemically‐induced hyperalgesia in the oesophagus could provoke widespread visceral hypersensitivity and also influence descending modulatory pain pathways. Fifteen healthy volunteers were studied at baseline, 30, 60 and 90 min after randomized perfusion of the distal oesophagus with either saline or 180 ml 0.1 M HCl + 2 mg capsaicin. Electro‐stimulation of the oesophagus, 8 cm proximal to the perfusion site, rectosigmoid electrical stimulation and rectal mechanical and heat stimulations were used. Evoked brain potentials were recorded after electrical stimulations before and after oesophageal perfusion. After the perfusion, rectal hyperalgesia to heat (P < 0.01, 37%) and mechanical (P = 0.01, 11%) stimulations were demonstrated. In contrast, hypoalgesia to electro‐stimulation was observed in both the oesophagus (P < 0.03, 23%) and the sigmoid colon (P < 0.001, 18%). Referred pain areas to electro‐stimulation in oesophagus were reduced by 13% after perfusion (P = 0.01). Evoked brain potentials to rectosigmoid stimulations showed decreased latencies and amplitudes of P1, N1 and P2 (P < 0.05), whereas oesophagus‐evoked brain potentials were unaffected after perfusion. In conclusion, modality‐specific hyperalgesia was demonstrated in the lower gut following chemical sensitization of the oesophagus, reflecting widespread central hyperexcitability. Conversely, hypoalgesia to electrical stimulation, decreases in referred pain and latencies of evoked brain potentials was seen. This outcome may reflect a counterbalancing activation of descending inhibitory pathways. As these findings are also seen in the clinical setting, the model may be usable for future basic and pharmacological studies.