Søren Schou Olesen

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.

Descending Inhibitory Pain Modulation Is Impaired in Patients With Chronic Pancreatitis

BACKGROUND & AIMS Pain is a prominent symptom in chronic pancreatitis (CP), but the underlying mechanisms are incompletely understood. We investigated the role of descending pain modulation from supraspinal structures as well as central nervous system sensitization in patients with pain from CP. METHODS Twenty-five patients with CP and 15 healthy volunteers were included. Descending pain modulation was investigated by diffuse noxious inhibitory control (a descending inhibitory response after conditioning stimulation). Central pain processing was investigated as the perceptual responses to multimodal (electrical, thermal, and mechanical) stimulations of the rectosigmoid and evoked brain potentials after electrical stimulation of the rectosigmoid. RESULTS Compared with healthy volunteers, the efficacy of diffuse noxious inhibitory control was reduced in patients with CP (13% +/- 21% vs 39% +/- 22%, respectively; F = 3.8; P = .01); central sensitization was indicated by remote hyperalgesia in the rectosigmoid to electrical stimulation (21 +/- 15 mA vs 27 +/- 15 mA; F = 6.2; P = .02) and heat stimulation (51 degrees C +/- 5 degrees C vs 53 degrees C +/- 4 degrees C; F = 5.9; P = .02). Compared with controls, patients with CP had increased latency of the early P1 peak to rectosigmoid stimulation (85 +/- 21 ms vs 108 +/- 28 ms, respectively; P = .02), possibly reflecting reorganization of central pain pathways. CONCLUSIONS Patients with CP have impairments in inhibitory pain modulation and evidence of central sensitization. Treatment of their pain therefore should focus not only on the pancreas, but also on descending pain modulation from supraspinal structures and central nervous system sensitization.

Acid hypersensitivity in patients with eosinophilic oesophagitis

Abstract Objective. Painful symptoms are prevalent in patients with eosinophilic oesophagitis but experimental data are sparse. The aim of this study was to compare the pain response to experimental oesophageal stimulation in 14 patients with eosinophilic oesophagitis and 15 healthy volunteers. Material and methods. A multimodal probe was placed in the oesophagus. The participants were subjected to mechanical, thermal and electrical pain stimuli followed by perfusion with 0.1 M HCl. Pain scores, referred pain areas and evoked brain potentials to electrical stimulation of the oesophagus were recorded. Results. Patients tolerated significantly less acid perfused in the oesophagus (median 123 versus 200 ml; P = 0.02) and felt the burning sensation evoked by the acid earlier (median 2.0 versus 5.0 min; P = 0.01). Eight patients had coexisting gastro-oesophageal reflux disease. Six patients had pure eosinophilic oesophagitis, and this group felt the acid earlier than those with concomitant reflux or the healthy volunteers (median 0.8 versus 2.0 and 5.0 min; P = 0.03). There were no differences between patients and controls in the responses to mechanical or thermal stimulation (P > 0.4). Furthermore, no differences were found for the proxies of central nervous system sensitization (response to electrical stimulations, referred pain areas or evoked brain potentials; P > 0.1). Conclusions. Patients with eosinophilic oesophagitis are hypersensitive to acid perfused in the oesophagus, and pathophysiologic findings are likely confined to the peripheral tissue. Reflux from physiological acid may play a role in the symptoms of eosinophilic oesophagitis.

Quantitative Sensory Testing Predicts Pregabalin Efficacy in Painful Chronic Pancreatitis

Background A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis. Methods Sixty-four patients with painful chronic pancreatitis received pregabalin (150–300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy. Results The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9–1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5–2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy. Conclusions The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient’s individual sensory profile and thus comprises a significant step towards personalized pain medicine.

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.

Effects of pregabalin on central sensitization in patients with chronic pancreatitis in a randomized, controlled trial.

Background Intense abdominal pain is the dominant feature of chronic pancreatitis. During the disease changes in central pain processing, e.g. central sensitization manifest as spreading hyperalgesia, can result from ongoing nociceptive input. The aim of the present study is to evaluate the effect of pregabalin on pain processing in chronic pancreatitis as assessed by quantitative sensory testing (QST). Methods This randomized, double-blind, placebo-controlled trial evaluated effects of pregabalin on pain processing. QST was used to quantify pain processing by measuring thresholds to painful electrical and pressure stimulation in six body dermatomes. Descending endogenous pain modulation was quantified using the conditioned pain modulation (CPM) paradigm to elicit a DNIC (diffuse noxious inhibitory controls) response. The main effect parameter was the change in the sum of all body pain threshold values after three weeks of study treatment versus baseline values between both treatment groups. Results 64 patients were analyzed. No differences in change in sum of pain thresholds were present for pregabalin vs. placebo after three weeks of treatment. For individual dermatomes, change vs. baseline pain thresholds was significantly greater in pregabalin vs. placebo patients for electric pain detection threshold in C5 (P = 0.005), electric pain tolerance threshold in C5 (P = 0.04) and L1 (P = 0.05), and pressure pain tolerance threshold in T4 (P = 0.004). No differences were observed between pregabalin and placebo regarding conditioned pain modulation. Conclusion Our study provides first evidence that pregabalin has moderate inhibitory effects on central sensitization manifest as spreading hyperalgesia in chronic pancreatitis patients. These findings suggest that QST can be of clinical use for monitoring pain treatments in the context of chronic pain. Trial Registration ClinicalTrials.gov NCT00755573

The analgesic effect of pregabalin in patients with chronic pain is reflected by changes in pharmaco-EEG spectral indices

AIM To identify electroencephalographic (EEG) biomarkers for the analgesic effect of pregabalin in patients with chronic visceral pain. METHODS This was a double-blind, placebo-controlled study in 31 patients suffering from visceral pain due to chronic pancreatitis. Patients received increasing doses of pregabalin (75mg-300mg twice a day) or matching placebo during 3 weeks of treatment. Pain scores were documented in a diary based on a visual analogue scale. In addition, brief pain inventory-short form (BPI) and quality of life questionnaires were collected prior to and after the study period. Multi-channel resting EEG was recorded before treatment onset and at the end of the study. Changes in EEG spectral indices were extracted, and individual changes were classified by a support vector machine (SVM) to discriminate the pregabalin and placebo responses. Changes in individual spectral indices and pain scores were correlated. RESULTS Pregabalin increased normalized intensity in low spectral indices, most prominent in the theta band (3.5-7.5Hz), difference of -3.18, 95% CI -3.57, -2.80; P= 0.03. No changes in spectral indices were seen for placebo. The maximum difference between pregabalin and placebo treated patients was seen in the parietal region, with a classification accuracy of 85.7% (P= 0.009). Individual changes in EEG indices were correlated with changes in pain diary (P= 0.04) and BPI pain composite scores (P= 0.02). CONCLUSIONS Changes in spectral indices caused by slowing of brain oscillations were identified as a biomarker for the central analgesic effect of pregabalin. The developed methodology may provide perspectives to assess individual responses to treatment in personalized medicine.

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

Aliment Pharmacol Ther 2011; 34: 878–887

Slowed EEG rhythmicity in patients with chronic pancreatitis: evidence of abnormal cerebral pain processing?

Background and aim Intractable pain usually dominates the clinical presentation of chronic pancreatitis (CP). Slowing of electroencephalogram (EEG) rhythmicity has been associated with abnormal cortical pain processing in other chronic pain disorders. The aim of this study was to investigate the spectral distribution of EEG rhythmicity in patients with CP. Patients and methods Thirty-one patients with painful CP (mean age 52 years, 19 male) and 15 healthy volunteers (mean age 49, nine male) were included. A multichannel EEG was recorded from 62 surface electrodes. Amplitude strengths of the resting EEG were retrieved based on wavelet frequency analysis and summarized in frequency bands with corresponding topographic mapping. Results Patients with CP had slowed EEG rhythmicity compared with healthy volunteers. This was evident as increased activity in the lower frequency bands &dgr; (1–3.5 Hz) (P=0.05), &thgr; (3.5–7.5 Hz) (P<0.001) and &agr; (7.5–13.5 Hz) (P<0.001). Due to normalization a reciprocal relationship was observed for the high frequency band &bgr; (13.5–32 Hz). In a sub-analysis, &dgr; band activity was modified by diabetes, opioid treatment and alcohol aetiology of CP. However, no effect modification was seen for the &thgr; or &agr; bands. Differences in &thgr; activity were located over centro-frontal brain regions, whereas differences in &dgr;, &agr; and &bgr; band activity were located in frontal regions. Conclusion Slowed EEG rhythmicity was evident in patients with CP. This possibly mirrors abnormal central pain processing and may serve as a clinically useful biomarker of abnormal central pain processing.