Opioid Specific Effects on Central Processing of Sensation and Pain: A Randomized, Cross-Over, Placebo-Controlled Study.

Moderate to severe pain is often treated with opioids, but central mechanisms underlying opioid analgesia are poorly understood. Findings thus far have been contradictory and none could infer opioid specific effects. This placebo-controlled, randomized, 2-way cross-over, double-blinded study aimed to explore opioid specific effects on central processing of external stimuli. Twenty healthy male volunteers were included and 3 sets of assessments were done at each of the 2 visits: 1) baseline, 2) during continuous morphine or placebo intravenous infusion and 3) during simultaneous morphine + naloxone or placebo infusion. Opioid antagonist naloxone was introduced in order to investigate opioid specific effects by observing which morphine effects are reversed by this intervention. Quantitative sensory testing, spinal nociceptive withdrawal reflexes (NWR), spinal electroencephalography (EEG), cortical EEG responses to external stimuli and resting EEG were measured and analyzed. Longer lasting pain (cold-pressor test - hand in 2° water for 2 minutes, tetanic electrical), deeper structure pain (bone pressure) and strong nociceptive (NWR) stimulations were the most sensitive quantitative sensory testing measures of opioid analgesia. In line with this, the principal opioid specific central changes were seen in NWRs, EEG responses to NWRs and cold-pressor EEG. The magnitude of NWRs together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated. The decreases in EEG activity were correlated to subjective unpleasantness scores. Brain activity underlying slow cold-pressor EEG (1-4Hz) was decreased, whereas the brain activity underlying faster EEG (8-12Hz) was increased. These changes were strongly correlated to subjective pain relief. This study points to evidence of opioid specific effects on perception of external stimuli and the underlying central responses. The analgesic response to opioids is likely a synergy of opioids acting at both spinal and supra-spinal levels of the central nervous system. Due to the strong correlations with pain relief, the changes in EEG signals during cold-pressor test have the potential to serve as biomarkers of opioid analgesia. PERSPECTIVE: This exploratory study presents evidence of opioid specific effects on the pain system at peripheral and central levels. The findings give insights into which measures are the most sensitive for assessing opioid-specific effects.

Ambulatory assessment of colonic motility using the electromagnetic capsule tracking system: Effect of opioids.

BACKGROUND: Opioid treatment often causes debilitating constipation. However, it is not well described how opioids affect colonic motility and whether opioid-induced constipation is due to either a decrease of powerful peristaltic contractions or "uncoordinated" peristalsis. The present study aims to investigate the effect of oxycodone on parameters of colonic motility and to determine whether motility is normalized by the opioid antagonist naloxegol. METHODS: In two randomized, double-blind crossover trials, oxycodone or placebo was administered to 25 healthy males (Trial A), while another 24 healthy males were administered oxycodone with naloxegol or placebo (Trial B). Colonic motility was assessed by tracking the progression of an electromagnetic capsule throughout the large intestine. Segmental colonic transit times and capsule movements were calculated using displacement distance and velocity. KEY RESULTS: In Trial A, colonic transit time increased during oxycodone treatment compared with placebo (39 vs 18 hours, P < .01). Displacement during long fast antegrade movements was shorter during oxycodone treatment than with placebo (10 vs 20 cm, P = .03). In Trial B, colonic transit time was faster during oxycodone + naloxegol than during oxycodone + placebo (40 vs 55 hours, P = .049), mainly caused by an increase of the percentwise fraction of distance covered by fast movements in the left colon (P = .001). CONCLUSION & INFERENCES: Oxycodone treatment impaired colonic motility, manifested as increased transit time, specifically decreased long fast antegrade movements, and addition of naloxegol improved motility dynamics. In humans, the increased transit time during opioid treatment is caused by a decrease in long fast movements rather than uncoordinated peristalsis.

Effects of Naloxegol on Gastrointestinal Transit and Colonic Fecal Volume in Healthy Participants Receiving Oxycodone.

BACKGROUND/AIMS: Opioids cause gastrointestinal (GI) dysmotility, decrease gut secretion, and affect gut sphincters. Symptoms of opioid-induced bowel dysfunction may be alleviated by peripherally acting opioid antagonists like naloxegol, but detailed knowledge on GI effects of this drug is lacking. We hypothesized that naloxegol, compared to placebo, would reduce GI transit time and colonic fecal volume in opioid-treated healthy participants. METHODS: We conducted a randomized, double-blinded, single-center, 2-way cross-over study in 24 healthy males, randomized to a 6 day treatment period of oxycodone (15 mg twice a day) co-administered with either naloxegol (25 mg once a day) or matching placebo. Participants swallowed an electromagnetic capsule which determined GI transit times. Colonic fecal volume was quantified with magnetic resonance imaging both pre-treatment and post-treatment. RESULTS: Naloxegol reduced total GI transit time by 21% (56 hours vs 71 hours, P = 0.02) and colonic transit time by 23% (45 hours vs 59 hours, P < 0.01), compared to placebo. However, no difference in colonic fecal volume was found (818 mL vs 884 mL, P = 0.20). CONCLUSION: Short-term administration of naloxegol in healthy participants reverses the retardation of total GI and colonic transit induced by oxycodone. This supports the use of naloxegol in the treatment of GI side effects to opioid treatment, and add knowledge to the current understanding of mechanisms behind peripherally-acting opioid antagonists.

Patient and Disease Characteristics Associate With Sensory Testing Results in Chronic Pancreatitis.

BACKGROUND: Abdominal pain is the most common symptom in chronic pancreatitis (CP) and has an extensive impact on patients' lives. Quantitative sensory testing (QST) provides information on sensitivity to pain and mechanisms that can help quantify pain and guide treatment. The aims of this study were (1) to explore sensitivity to pain in patients with CP using QST and (2) to associate patient and disease characteristics with QST results. METHODS: Ninety-one patients with painful CP and 28 healthy control participants completed a QST paradigm using static tests (muscle pressure stimulation and electrical skin stimulations) to unravel segmental and widespread hyperalgesia as a consequence of visceral pain. A dynamic conditioned pain modulation (CPM) paradigm was used as a proxy of pain modulation from the brainstem to inhibit incoming nociceptive barrage, and questionnaires were used to gather information on pain experience and quality of life. RESULTS: Patients had impaired CPM compared with controls (18.0±29.3% vs. 30.9±29.3%, P=0.04) and were hypersensitive to pressure stimulation, specifically in the pancreatic (Th10) dermatome (P<0.001). The capacity of CPM was associated with clinical pain intensity (P=0.01) and (in the univariate analysis only) the use of opioids was associated with hyperalgesia to pressure stimulation (P<0.05). CONCLUSIONS: Sensitivity to pain in CP patients can be characterized by a simple bedside QST. Severe clinical pain in CP was associated with reduced CPM function and should be targeted in management.

MRI analysis of fecal volume and dryness: Validation study using an experimental oxycodone-induced constipation model.

BACKGROUND: Opioids are known to affect gastrointestinal motility, but their effect on fluid absorption and secretion is poorly understood in humans. PURPOSE: To investigate the effect of oxycodone on colonic fecal volume and stool dryness by using a novel MRI-based technique. STUDY TYPE: Prospective, randomized, double-blinded, crossover study. SUBJECTS: Twenty-five healthy male volunteers (median age: 24 years [range: 21-56]; mean body mass index [BMI]: 23.9 kg/m2 [range: 22.9-25.0]) without known gastrointestinal disease. FIELD STRENGTH/SEQUENCE: T2 -weighted and two-point Dixon MRI scans of the abdomen at 1.5 T. ASSESSMENT: Subjects were treated for 5 days with prolonged-release oxycodone or a placebo. Imaging was performed on the first and last study day in each period. Images of the colon were analyzed with semiautomatic k-means-based segmentation software. Regional colonic fecal volumes were quantified excluding gas volume and colon wall. Two-point Dixon and T2 -weighted MRI signal intensity were assessed as a proxy of colonic stool dryness. Data were obtained in a previously reported study. STATISTICAL TESTS: Intraclass correlation coefficients were used to test the reliability of measurements between days, while repeated measures mixed models were applied to test treatment effects. RESULTS: After oxycodone treatment, total colonic fecal volume was significantly increased compared with placebo (mean change 100 mL vs. -13 mL; P = 0.001), with the largest increase (24%) observed in the ascending colon/cecum (P = 0.001). Dixon signal increased (less water in colon content) after oxycodone treatment compared with placebo (mean 0.09 vs. -0.02; P < 0.001). T2 -weighted signal decreased (less water in colon content) after oxycodone treatment compared with placebo (mean -0.03 vs. 0.03; P = 0.002). DATA CONCLUSION: The 5-day oxycodone treatment increased colonic fecal volume and increased stool dryness compared with placebo. This imaging-based method for noninvasive analysis of colon content has the potential to characterize gastrointestinal symptoms in general, such as in constipation. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:733-745.

Comparison of subjective and objective measures of constipation - Employing a new method for categorizing gastrointestinal symptoms.

INTRODUCTION: Correlations between subjective and objective measures of constipation have seldom been demonstrated. This could be due to multiple confounding factors in clinical studies and the broad span of symptoms represented in questionnaires used to assess constipation. We developed a new method for categorizing gastrointestinal (GI) symptoms into relevant symptom groups, and used this in a controlled experimental study aimed to investigate whether GI transit times and colonic volumes were correlated to self-reported GI symptoms. METHODS: Twenty-five healthy male participants were enrolled in a randomized, double-blinded, placebo-controlled, five-day crossover study with the treatments oxycodone and placebo. Objective measures of GI transit times and colonic volumes were obtained by the means of the 3D-Transit System and magnetic resonance colonography, whereas subjective GI symptoms were measures via three validated questionnaires. The symptoms were then categorized into five groups; "abdominal symptoms", "defecation difficulties", "incomplete bowel evacuation", "reduced bowel movement frequency", and "stool symptoms". Spearman's rank order correlation was used to determine correlations between the five groups of symptoms and the objective measures. RESULTS: No correlations between the GI symptoms and transit times or colonic volumes were found (all P > 0.05). DISCUSSION: GI transit times and colonic volumes were not correlated to self-reported GI symptoms even in a controlled experimental study and when symptoms were categorized into relevant symptom groups. Thus, both subjective and objective measures must be considered relevant when assessing constipation in clinical and research settings, ensuring that both physiological aspects as well as the severity and impact of symptoms experienced by patients can be assessed.

The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction.

BACKGROUND AND AIMS: Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co-administration of the peripherally acting µ-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo. METHODS: In a double-blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale. RESULTS: During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (-45.9 vs -38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01). CONCLUSIONS: In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process.

Prediction of opioid dose in cancer pain patients using genetic profiling: not yet an option with support vector machine learning.

OBJECTIVE: Use of opioids for pain management has increased over the past decade; however, inadequate analgesic response is common. Genetic variability may be related to opioid efficacy, but due to the many possible combinations and variables, statistical computations may be difficult. This study investigated whether data processing with support vector machine learning could predict required opioid dose in cancer pain patients, using genetic profiling. Eighteen single nucleotide polymorphisms (SNPs) within the µ and δ opioid receptor genes and the catechol-O-methyltransferase gene were selected for analysis. RESULTS: Data from 1237 cancer pain patients were included in the analysis. Support vector machine learning did not find any associations between the assessed SNPs and opioid dose in cancer pain patients, and hence, did not provide additional information regarding prediction of required opioid dose using genetic profiling.

Prolonged-Release Oxycodone/Naloxone Improves Anal Sphincter Relaxation Compared to Oxycodone Plus Macrogol 3350.

BACKGROUND: Opioid analgesics inhibit anal sphincter function and contribute to opioid-induced bowel dysfunction (OIBD). However, it is unknown whether the inhibition can be reduced by opioid antagonism with prolonged-release (PR) naloxone and how this compares to laxative treatment. AIMS: To compare the effects of combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350 on anal sphincter function and gastrointestinal symptoms. METHODS: A randomized, double-blind, crossover trial was conducted in 20 healthy men. Participants were treated for 5 days with combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350. Resting anal pressure, anal canal distensibility, and relaxation of the internal sphincter to rectal distension were evaluated before treatment (baseline) and on day 5. The Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire, stool frequency, and stool consistency were assessed daily. RESULTS: Both PR oxycodone/naloxone and PR oxycodone plus macrogol treatment decreased sphincter relaxation compared to baseline (- 27.5%; P < 0.001 and - 14.7%; P = 0.01). However, sphincter relaxation was increased after PR naloxone/oxycodone treatment compared to macrogol (difference = + 17.6%; P < 0.001). Resting anal pressure and anal canal distensibility did not differ between treatments. PAC-SYM abdominal symptoms score was lower during PR naloxone compared to macrogol (0.2 vs. 3.2; P = 0.002). The number of bowel movements was lower during PR naloxone versus macrogol (4.2 vs. 5.4; P = 0.035). CONCLUSION: Relaxation of the internal anal sphincter was significantly better after PR oxycodone/naloxone treatment compared to PR oxycodone plus macrogol 3350. These findings highlight that OIBD may require specific therapy against the complex, pan-intestinal effects of opioids.