Effects of oral morphine on experimentally evoked itch and pain: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: Pain and itch share similar neuronal networks; hence, it is difficult to explain why opioids can relieve pain but provoke itching. The present human volunteer study aimed to investigate the similarities and differences in responses to experimentally provoked pain and itching to explore the underlying fundamental mechanisms. METHODS: Twenty-four healthy volunteers were enrolled in this single-center, randomized, double-blind, placebo-controlled, parallel-group trial. Three volar forearms and two mandibular areas were marked, and participants randomly received morphine (20 mg) or identical placebo tablets. Heat, cold, and pressure pain thresholds, and vasomotor responses were assessed at baseline and after oral morphine administration. Itch provocations were induced by intradermal application of 1 % histamine or a topical cowhage (non-histaminergic itch) to a marked area of the skin. The participants were subsequently asked to rate their itching and pain intensities. The assessments were repeated for all marked areas. RESULTS: Morphine caused analgesia, as assessed by the significant modulation of cold and pressure pain thresholds (p<0.05). There were no significant differences in histaminergic or non-histaminergic itch or pain intensity between the morphine and placebo groups. Superficial blood perfusion (vasomotor response) following histamine provocation was significantly increased by morphine (p<0.05) in both areas. No correlation was found between the provoked itch intensity and analgesic efficacy in any area or group. CONCLUSIONS: Oral administration of morphine caused analgesia without modulating itch intensities but increased neurogenic inflammation in response to histamine, suggesting that different opioid mechanisms in histaminergic and non-histaminergic neurons evoke neurogenic inflammation.

The effect of duloxetine on mechanistic pain profiles, cognitive factors and clinical pain in patients with painful knee osteoarthritis-A randomized, double-blind, placebo-controlled, crossover study.

BACKGROUND: Duloxetine is indicated in the management of pain in osteoarthritis. Evidence suggests that duloxetine modulates central pain mechanisms and cognitive factors, and these factors are assumed contributing to the analgesic effect. This proof-of-mechanism, randomized, placebo-controlled, crossover, double-blinded trial evaluated the effect of duloxetine on quantitative sensory testing (QST), cognitive factors and clinical pain in patients with osteoarthritis and to predict the analgesic effect. METHODS: Twenty-five patients completed this cross-over study with either 18-week duloxetine (maximum 60 mg/daily) followed by placebo or vice-versa. Pressure pain thresholds, temporal summation of pain and conditioned pain modulation were assessed using cuff algometry. The Hospital Anxiety and Depression Scale and the Pain Catastrophizing Scale evaluated cognitive factors. Clinical pain was assessed using Brief Pain Inventory and Western Ontario and McMaster Universities Osteoarthritis Index. Linear regression models were used to predict the analgesic effect of duloxetine. RESULTS: Depending on the clinical pain outcome, 40%-68% of patients were classified as responders to duloxetine. Linear regression models predicted the analgesic effect (predictive value of 45%-75% depending on clinical pain outcome parameter) using a combination of pretreatment QST parameters, cognitive factors and clinical pain. No significant changes were found for QST, cognitive factors or clinical pain on a group level when comparing duloxetine to placebo. CONCLUSION: A combination of pretreatment QST, cognitive factors and clinical pain was able to predict the analgesic response of duloxetine. However, in this relatively small study, duloxetine did not selectively modulate QST, cognitive factors or clinical pain intensity when compared with placebo. SIGNIFICANCE: Duloxetine is proposed as a treatment for chronic pain. Pre-clinical trials suggest that duloxetine provides analgesia through modulation of descending pain inhibitory pathways or through improvements in cognitive factors. The current study demonstrates that pretreatment mechanistic pain profiling, cognitive factors and clinical pain can predict the analgesic effect of duloxetine and that only a subset of patients might benefit from duloxetine treatment.

A mechanism-based proof of concept study on the effects of duloxetine in patients with painful knee osteoarthritis.

BACKGROUND: The global burden of osteoarthritis (OA) is steadily increasing due to demographic and lifestyle changes. The nervous system can undergo peripheral and central neuroplastic changes (sensitization) in patients with OA impacting the options to manage the pain adequately. As a result of sensitization, patients with OA show lower pressure pain thresholds (PPTs), facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM). As traditional analgesics (acetaminophen and non-steroidal anti-inflammatory drugs) are not recommended for long-term use in OA, more fundamental knowledge related to other possible management regimes are needed. Duloxetine is a serotonin-noradrenalin reuptake inhibitor, and analgesic effects are documented in patients with OA although the underlying fundamental mechanisms remain unclear. The descending pain inhibitory control system is believed to be dependent on serotonin and noradrenalin. We hypothesized that the analgesic effect of duloxetine could act through these pathways and consequently indirectly reduce pain and sensitization. The aim of this mechanistic study is to investigate if PPTs, TSP, CPM, and clinical pain parameters are modulated by duloxetine. METHODS: This proof of concept study is a randomized, placebo-controlled, double-blinded, crossover trial, which compares PPTs, TSP, and CPM before and after 18 weeks of duloxetine and placebo in forty patients with knee OA. The intervention periods include a titration period (2 weeks), treatment period (60 mg daily for 14 weeks), and a discontinuation period (2 weeks). Intervention periods are separated by 2 weeks. DISCUSSION: Duloxetine is recommended for the treatment of chronic pain, but the underlying mechanisms of the analgesic effects are currently unknown. This study will investigate if duloxetine can modify central pain mechanisms and thereby provide insights into the underlying mechanisms of the analgesic effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT04224584 . Registered on January 6, 2020. EudraCT 2019-003437-42 . Registered on October 22, 2019. The North Denmark Region Committee on Health Research Ethics N-20190055. Registered on October 31, 2019.

Description of the voided urinary microbiota in asymptomatic prepubertal children - A pilot study.

BACKGROUND: Recently, it has been established that the urine of a healthy adult bladder contains a microbiota and that urinary dysbiosis may be involved in the development of urinary tract diseases. The urinary microbiota and its relation to bladder health and disease in children is yet to be established. The objective of the present study was to investigate the voided urinary microbiota in asymptomatic prepubertal children. STUDY DESIGN: Thirty asymptomatic children (15 boys and 15 girls) participated in the study. Bacterial DNA in "clean-catch" midstream urine (CC MSU) samples was analysed using Illumina MiSeq sequencing of the V4 region of the bacterial 16 S rRNA gene. All children had normal bladder function as ensured by uroflowmetry, ultrasonic post-void residual, and frequency-volume charts. Bladder-related parameters and gender comparisons were analysed statistically by parametric and non-parametric tests. Alpha diversity, beta diversity, and a Venn diagram were used to analyse sequencing data. RESULTS: All CC MSU samples contained bacterial DNA. The voided urinary microbiota differed significantly between girls and boys in terms of operational taxonomic unit (OTU) richness, Shannon diversity index, and relative abundances of bacterial genera, but not for evenness. The urine of girls was dominated by Prevotella (18.2%), Porphyromonas (12.9%), Ezakiella (8.1%), Prevotella 6 (7.4%), and Dialister (7.0%). Porphyromonas (22.4%) was the most abundant genus in boys, followed by Ezakiella (12.0%), Campylobacter (11.6%), Prevotella (8.6%), and Dialister (3.7%). Girls had 10 unique core OTUs, whereas boys had no unique core OTUs. Porphyromonas appeared as a shared core OTU between genders. DISCUSSION: Contrary to previous findings, this study found significant differences in the voided urinary bacterial composition among asymptomatic prepubertal children. Moreover, the bacterial composition diverged from that found among healthy adults by other research groups. Among adults, the gender specific urinary microbiota has been hypothesised to be caused by anatomical differences in the reproductive organs and differences in sex hormone levels. This could also be evident for asymptomatic prepubertal children as sex hormone levels are different even at the prepubertal stage. The limitations of the study encompass small sample size and urine collection by CC MSU with risk of contamination from surrounding areas. CONCLUSIONS: This study documents that CC MSU samples of asymptomatic prepubertal children are not sterile. The composition of the voided urinary microbiota seems gender specific and unequal to that of healthy adults. The role of the urinary microbiota in paediatric urological disorders should be considered in future studies.

Pre- and postmenopausal women have different core urinary microbiota.

Recent studies suggest that alterations in the female urinary microbiota is associated to development of bladder disease. However, the normal microbiota composition and variation in healthy women are poorly described. Moreover, the effects of hormonal changes on microbiota during menopause is not well understood. The aim of our study was to investigate the urinary microbiota in healthy pre- and postmenopausal women without urinary tract symptoms. Microbiota composition in catheterized urine samples was mapped using 16S rRNA gene sequencing. In total, 41 premenopausal and 42 postmenopausal women were initially included. Samples with first PCR amplification concentration below level of the negative control were excluded, resulting in 34 premenopausal and 20 postmenopausal women included in data analysis. Urine from postmenopausal women showed significantly higher alpha diversity compared to premenopausal women. Lactobacillus was the most abundant bacteria in both groups, however the relative abundance of Lactobacillus accounted for 77.8% in premenopausal versus 42.0% in postmenopausal women. In conclusion, urine from premenopausal mostly presented with Lactobacillus dominated urotypes, whereas urine from postmenopausal women presented a more diverse urinary microbiota with higher abundance of the genera Gardnerella and Prevotella. The clinical and pathophysiological implications of this difference remain to be elucidated.

Voided Urinary Microbiota Is Stable Over Time but Impacted by Post Void Storage.

Background: New sensitive techniques have revealed a thriving bacterial community in the human urinary tract, challenging the perception that urine in healthy humans is sterile. While the functional role of this urinary microbiota is unknown, dysbiosis has been linked to urgency urinary incontinence and risk of urinary tract infections. When comparing studies, it is crucial to account for possible confounders introduced due to methodological differences. Here we investigated whether collection and storage conditions had any impact on the urinary microbial composition. Results: For comparison of different storage conditions, midstream urine was collected from five healthy adult female donors and analyzed by 16S rRNA gene sequencing. Samples stored at -80 and -20°C, but not 4°C, were found to be comparable to freshly handled voided urine. Using the same methods, the daily or day-to-day variation in urinary microbiota was investigated in 19 healthy donors, including four women, five men, five girls, and five boys. Apart from two male adult donors, none of the tested conditions gave rise to significant differences in alpha and beta diversities between individuals. Conclusion: The composition of voided urinary microbiota was found to be effectively maintained by freezing, but not storage at 4°C. In addition, we did not observe any intrapersonal daily or day-to-day variations in microbiota composition in women, girls or boys. Together our study supports present methodologies that can be used in future studies investigating the urinary microbiota.