Melatonin treatment has consistent but transient beneficial effects on sleep measures and pain in patients with severe chronic pain: the DREAM-CP randomised controlled trial.

BACKGROUND: Sleep disturbance is a major issue for patients with chronic pain. Melatonin has been shown to improve symptoms of fibromyalgia, but its efficacy in other chronic non-malignant pain conditions is not fully known. Hence, we determined the effect of melatonin in patients with severe noncancer chronic pain. METHODS: This was a randomised double-blinded crossover trial of modified-release melatonin as Circadin™ compared with placebo. Sixty male and female subjects with chronic severe pain were randomised to receive either 2 mg of Circadin™ or placebo before sleep for 6 weeks, followed by a >4 week washout, then crossing over to the other treatment. Sleep disturbance, quality, and latency were measured using three different validated sleep assessment tools. The primary outcome measure was self-reported sleep disturbance after 6 weeks of treatment. Adverse events were also recorded. RESULTS: Sleep disturbance after 6 weeks was not significantly altered by melatonin treatment, but differences between melatonin and placebo treatment periods after 3 weeks were seen: sleep disturbance (P=0.014), latency (P=0.04), overall sleep quality (P=0.004), and effect of pain on sleep (P=0.032). Pain intensity scores improved during both treatment periods (both P<0.001). There were no differences in adverse events between treatment periods. CONCLUSIONS: Circadin™ treatment did not improve sleep disturbance in patients with severe chronic pain compared with placebo at 6 weeks, but there were consistent improvements in aspects of sleep in the shorter term. Given its favourable safety profile, it could be beneficial for some patients with chronic pain. CLINICAL TRIAL REGISTRATION: ISRCTN12861060.

Enfortumab vedotin and pembrolizumab as monotherapies and combination treatment in locally advanced or metastatic urothelial carcinoma: A narrative review.

Background: Bladder cancer is the 10th most common cancer globally. The majority of bladder cancers are urothelial carcinomas (UCs), which, if locally advanced or metastatic, carry poor long-term prognosis. Cancer cells can evade the immune system by expressing the programmed cell death ligand 1 protein (PD-L1). Programmed cell death ligand 1 protein binds to programmed cell death protein 1 (PD-1) on T cells, inhibiting their antitumor action. Bladder tumor cells also overexpress nectin-4, a cell adhesion polypeptide that contributes to metastasis, worsening prognosis. Current platinum-based chemotherapy treatments are suboptimal. This review aimed to assess novel treatments for locally advanced or metastatic UC that specifically target PD-L1 or nectin-4, namely, the PD-1 inhibitor pembrolizumab and the anti-nectin-4 antibody-drug conjugate enfortumab vedotin (EV). Materials and methods: Relevant English-language peer-reviewed articles and conference abstracts from the last 5 years were identified through MEDLINE and EMBASE database searches. A narrative review was performed, with key results outlined below. Results: Pembrolizumab was demonstrated to be superior to chemotherapy as a second-line treatment for platinum-unresponsive participants in the KEYNOTE-045 trial, resulting in its Food and Drug Administration (FDA) approval. Enfortumab vedotin therapy resulted in superior outcomes compared with chemotherapy in the EV-301 trial, resulting in FDA approval for its use for patients with locally advanced or metastatic UC who had previously undergone treatment with platinum-based chemotherapy and PD-1/PD-L1 inhibitors. Positive preliminary results for pembrolizumab and EV combination therapy have led to FDA approval in patients with locally advanced or metastatic UC who are not eligible for platinum chemotherapy. Conclusions: Pembrolizumab and EV represent novel treatment options for patients with locally advanced or metastatic UC with documented superior outcomes and tolerability as compared with standard chemotherapy.

Supraneural versus Infraneural Approach to transforaMinal Epidural StEroid injection for unilateral lumbosacral radicular pain (SIAMESE): a study protocol for a randomised non-inferiority trial.

Background: Lumbosacral radicular pain is commonly treated by transforaminal steroid epidural injection. There are two methods: the supraneural and the infraneural approaches. The supraneural approach can result in rare but catastrophic consequences from injury to the radiculomedullary artery. The infraneural technique avoids the artery; both approaches show efficacy and are used locally. Methods: This is a protocol for a randomised, single-blinded, non-inferiority trial of infraneural vs supraneural transforaminal epidural injection for lumbosacral radicular pain at a tertiary referral pain management clinic. Adult patients (n=92) with moderate-to-severe lumbosacral radicular pain of >3 months duration, scheduled for transforaminal epidural steroid injection, will be randomised to epidural by either the infraneural or supraneural approach. Only the treating physicians will know which route is used. The primary outcome measure is the differential impact on pain intensity score at 3 months. Secondary outcome measures will include disability and function scores, sleep and activity measures, and adverse events. Participants will be followed up for 12 months. Conclusions: This study will determine whether the techniques are comparable and, if so, will enable recommendations for the use of an approach without risk of artery damage and catastrophic injury. Clinical trial registration: ISRCTN 36195887.

The effect of Preoperative threshold inspiratory muscle training in adults undergoing cardiac surgery on postoperative hospital stay: a systematic review.

BACKGROUND: Systematic reviews have reported benefits of preoperative inspiratory muscle training in adults undergoing cardiac surgery, however there have been inconsistencies with the devices used. Threshold devices generate a constant inspiratory load independent of respiratory rate. OBJECTIVE: To assess the effect of preoperative inspiratory muscle training using threshold devices in adults undergoing cardiac surgery. METHODS: A literature search was conducted across five electronic databases. Seven randomized controlled trials met the inclusion criteria and were critically appraised. The primary outcome was length of hospital stay. Secondary outcomes included postoperative pulmonary complications, quality of life and mortality. RESULTS: Seven eligible randomized controlled trials were identified with a total of 642 participants. One study was a post hoc analysis of one of the included studies. Three out of five studies reported a decrease in length of postoperative hospital stay (p < 0.05). A significant reduction in postoperative pulmonary complications was reported by three studies (p < 0.05). There were concerns with bias across all papers. CONCLUSIONS: Preoperative threshold inspiratory muscle training has potential to reduce postoperative length of hospital stay and pulmonary complications after cardiac surgery. The evidence on quality of life and mortality is inconclusive. The overall evidence for these conclusions may be influenced by bias.

An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression.

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection.

Maternal mortality, safe abortion, and the anaesthetist.

Reproductive health is an active area of practice and research for anaesthetists, intensivists, and pain medicine specialists. The purpose of the British Journal of Anaesthesia is to promote the health, welfare, and safety of all persons by disseminating knowledge to further our understanding of anaesthetic principles and improve practice and skills. This includes supporting safe abortion care as an integral part of safe reproductive health.

Dose assessment of melatonin in sepsis (DAMSEL2) study: Pharmacokinetics of two doses of oral melatonin in patients with sepsis.

Sepsis is defined as a dysregulated host response to infection, and high-dose melatonin has been proposed as a treatment due to its antioxidant and anti-inflammatory properties. However, there are no data describing the pharmacokinetics of high-dose oral melatonin in critically ill patients. We undertook an open-label trial to determine the tolerance of melatonin administration in these patients and pharmacokinetic analysis, to inform a planned randomised controlled trial. Two cohorts of critically ill patients with sepsis due to community-acquired pneumonia received either 20 or 50 mg oral melatonin liquid as a single dose. Blood samples and clinical measures were analysed over the next 24 h. Melatonin was well tolerated and there were no adverse events. Pharmacokinetic modelling showed that a semiphysiological model, which incorporates saturable first-pass hepatic extraction, was a good fit for our data. Maximum levels of melatonin were extremely high in patients receiving the 50 mg dose and levels of the major metabolite were much lower than expected and not different from those seen after 20 mg, suggesting saturation at the higher dose. We conclude that 20 mg seems a suitable dose of liquid melatonin in patients with sepsis.

Extent of sleep problems and relationship with severity of chronic pain using three validated sleep assessment tools.

Objective: Chronic pain can impact on sleep, but the extent and nature of sleep problems in patients with chronic pain are incompletely clear. Several validated tools are available for sleep assessment but they each capture different aspects. We aimed to describe the extent of sleep issues in patients with chronic non-malignant pain using three different validated sleep assessment tools and to determine the relationship of sleep issues with pain severity recorded using the Brief Pain Inventory (BPI), a commonly used self-assessment tool in pain clinics. The BPI has a single question on the interference of pain on sleep and we also compared this with the validated sleep tools. Design: Prospective, cross-sectional study. Setting: Pain management clinic at a large teaching hospital in the United Kingdom. Subjects: Adult patients (with chronic non-malignant pain of at least 3 months' duration) attending clinic during a 2-month period. Methods: Participants completed the Pittsburgh Sleep Quality Index (PSQI), the Pain and Sleep Questionnaire-3 (PSQ-3) and the Verran Snyder-Halpern (VSH) sleep scale, plus the BPI. Duration and type of pain, current medications and demographic data were recorded. Results: We recruited 51 patients and 82% had poor sleep quality as shown by PSQIscores above five. PSQI (p = 0.0002), PSQ-3 (p = 0.0032), VSH sleep efficiency (p = 0.012), sleep disturbance (p = 0.0014) and waking after sleep onset (p = 0.0005) scores were associated with worse BPI pain scores. BPI sleep interference scores concurred broadly with the validated sleep tools. Median [range] sleep duration was 5.5 [3.0-10.0] hours and was also related to pain score (p = 0.0032). Conclusion: Chronic pain has a marked impact on sleep regardless of the assessment tool used. The sleep interference question in the BPI could be used routinely for initial identification of sleep problems in patients with chronic pain.

Melatonin and Related Compounds: Antioxidant and Anti-Inflammatory Actions.

Melatonin, an indoleamine derived from tryptophan and produced in the pineal gland and other tissues [...].

Sensory mapping of lumbar facet joint pain: a feasibility study.

OBJECTIVE: To evaluate the feasibility of sensory mapping of lumbar facet joint pain in patients scheduled to undergo radiofrequency (RF) denervation. DESIGN: Prospective cohort study. SETTING: University teaching hospital. SUBJECTS: A total of 15 participants listed for RF denervation of lumbar facet joint. METHOD: After written informed consent, participants were recruited to the study. Participants completed a pain diagram prior to their procedure. After successful image-guided placement of RF cannulas, the sensory detection threshold using 50 Hz stimulation was obtained, followed by application of suprathreshold stimulation. Participants mapped their stimulated area in comparison to their pre-procedure pain diagram. RESULTS: All 15 participants had previously undergone diagnostic blocks. All participants were able to report either pain or paraesthesia during suprathreshold stimulation. In total, 14 out of 15 participants reported complete coverage of their usual painful area with suprathreshold stimulation of nerves scheduled for RF denervation. In one of the participants, an area of upper lumbar pain was not covered during suprathreshold stimulation. Nearly two-thirds of the participants (n = 9), reported either pain or paraesthesia, outside their normal painful area during suprathreshold stimulation. A total of 71 nerves were scheduled for RF denervation. Sensory electrical stimulation was successfully achieved in 68 out of 71 nerves (96%). The average sensory detection threshold was found to be 0.3 V while the suprathreshold stimulation was 0.6 V. CONCLUSION: Lumbar facet joint pain can be mapped using suprathreshold sensory stimulation, which has the potential to introduce objectivity during RF denervation.

Can soluble urokinase plasminogen receptor predict outcomes after cardiac surgery?

OBJECTIVES: Soluble urokinase plasminogen activator receptor (suPAR) is a biomarker that has been implicated in several cardiac pathologies and has been shown to be elevated in critically ill populations. We measured plasma suPAR in a cohort of cardiac surgical patients to evaluate its ability to predict prolonged intensive care unit (ICU) and hospital length of stay and development of complications following surgery. We compared suPAR against EuroSCORE II and C-reactive protein (CRP). METHODS: Ninety patients undergoing cardiac surgery were recruited with samples taken preoperatively and on postoperative days 1, 2 and 3. suPAR was measured using enzyme-linked immunosorbent assay. Area under the receiver operator curve (AUROC) was used to test predictive capability of suPAR. Comparison was made with EuroSCORE II and CRP. RESULTS: suPAR increased over time (P < 0.001) with higher levels in patients requiring prolonged ICU and hospital stay, and prolonged ventilation (P < 0.05). suPAR was predictive for prolonged ICU and hospital stay, and prolonged ventilation at all time points (AUROC 0.66-0.74). Interestingly, this association was also observed preoperatively, with preoperative suPAR predicting prolonged ICU (AUROC 0.66), and hospital stay (AUROC 0.67) and prolonged ventilation (AUROC 0.74). The predictive value of preoperative suPAR compared favourably to EuroSCORE II and CRP. CONCLUSIONS: suPAR increases following cardiac surgery and levels are higher in those who require prolonged ICU stay, prolonged hospital stay and prolonged ventilation. Preoperative suPAR compares favourably to EuroSCORE II and CRP in the prediction of these outcomes. suPAR could be a useful biomarker in predicting outcome following cardiac surgery, helping inform clinical decision-making. CLINICAL REGISTRATION: West of Scotland Research Ethics Committee Reference: 12/WS/0179 (AM01).

Melatonin Is a Feasible, Safe, and Acceptable Intervention in Doctors and Nurses Working Nightshifts: The MIDNIGHT Trial.

Nightshift working is associated with sleep deprivation, fatigue and attention/concentration deficits which, in healthcare workers, may impact on patient safety. Clinical staff in the UK routinely work several 12 h nightshifts in a row at about 1-3 month intervals. We investigated the feasibility and acceptability of a crossover trial of melatonin administration in clinical staff working nightshifts with an exploration of effects on sleep measures and attention/concentration tasks. This was a pilot, double-blinded, randomized, placebo-controlled crossover feasibility trial in doctors and nurses working 3 consecutive nightshifts at a tertiary referral hospital in the UK. Twenty five male and female subjects were randomized to receive either 6mg Circadin™ slow release melatonin or placebo before sleep after each consecutive nightshift, followed by a washout period, before crossing over to the other experimental arm. We used actigraphy for objective assessment of sleep parameters. The trial design was feasible and acceptable to participants with negligible side effects, but elevated melatonin levels were prolonged during the active arm (P=0.016). Double digit addition testing, a concentration/attention task, improved with melatonin treatment (P<0.0001). Lapses of vigilance or judgement while doctors or nurses are working nightshifts could impact on patient safety and melatonin may be a useful intervention. This study supports the conclusion that a larger definitive trial of this design is both feasible and safe. Clinical Trial Registration: identifier ISRCTN15529655. https://www.isrctn.com/.

Reply to Comment on "Differential Effects of MitoVitE, α-Tocopherol and Trolox on Oxidative Stress, Mitochondrial Function and Inflammatory Signalling Pathways in Endothelial Cells Cultured under Conditions Mimicking Sepsis. Antioxidants 2020, 9(3), 195".

We thank Drs Hegarty and Byrne for their interest in our paper and appreciate the opportunity to respond to their insightful comments [...].

Differential Effects of MitoVitE, α-Tocopherol and Trolox on Oxidative Stress, Mitochondrial Function and Inflammatory Signalling Pathways in Endothelial Cells Cultured under Conditions Mimicking Sepsis.

Sepsis is a life-threatening response to infection associated with inflammation, oxidative stress and mitochondrial dysfunction. We investigated differential effects of three forms of vitamin E, which accumulate in different cellular compartments, on oxidative stress, mitochondrial function, mRNA and protein expression profiles associated with the human Toll-like receptor (TLR) -2 and -4 pathways. Human endothelial cells were exposed to lipopolysaccharide (LPS)/peptidoglycan G (PepG) to mimic sepsis, MitoVitE, α-tocopherol, or Trolox. Oxidative stress, mitochondrial function, mitochondrial membrane potential and metabolic activity were measured. NFκB-P65, total and phosphorylated inhibitor of NFκB alpha (NFκBIA), and STAT-3 in nuclear extracts, interleukin (IL)-6 and IL-8 production in culture supernatants and cellular mRNA expression of 32 genes involved in Toll-like receptor-2 and -4 pathways were measured. Exposure to LPS/PepG caused increased total radical production (p = 0.022), decreased glutathione ratio (p = 0.016), reduced membrane potential and metabolic activity (both p < 0.0001), increased nuclear NFκB-P65 expression (p = 0.016) and increased IL-6/8 secretion (both p < 0.0001). MitoVitE, α- tocopherol and Trolox were similar in reducing oxidative stress, NFκB activation and interleukin secretion. MitoVitE had widespread downregulatory effects on gene expression. Despite differences in site of actions, all forms of vitamin E were protective under conditions mimicking sepsis. These results challenge the concept that protection inside mitochondria provides better protection.

Phase II double-blind randomised controlled trial of exogenous administration of melatonin in chronic pain (DREAM-CP): a study protocol.

INTRODUCTION: Chronic pain is prevalent, and approximately half of patients with chronic pain experience sleep disturbance. Exogenous melatonin is licensed to treat primary insomnia and there is some evidence for analgesic effects of melatonin.The aim of this study is to investigate the effects of oral melatonin (as Circadin) 2 mg at night in adults with severe non-malignant pain of at least 3 months' duration. METHODS AND ANALYSIS: We will conduct a randomised double-blind placebo-controlled cross-over study. The primary outcome is sleep disturbance. Secondary outcomes are pain intensity, actigraphy, fatigue, reaction time testing, serum melatonin and endogenous opioid peptide levels along with patient views about study participation.We aim to recruit 60 patients with severe chronic pain (average pain intensity ≥7 on the Brief Pain Inventory (BPI)) from a tertiary referral pain clinic in Northeast Scotland. Participants will be randomised to receive melatonin (as modified release Circadin) 2 mg daily for 6 weeks or placebo, followed by a 4-week washout period, then 6 weeks treatment with the treatment they did not receive. Participants will complete the Verran Snyder-Halpern Sleep Scale, Pittsburgh Sleep Quality Index, Pain and Sleep Questionnaire 3-item index, BPI and psychomotor vigilance reaction time testing at 6 points over 20 weeks. Actigraphy watches will be used to provide objective measures of sleep duration and latency and other sleep measures and will prompt patients to report contemporaneous pain and fatigue scores daily.Cross-over analyses will include tests for effects of treatment, period, treatment-period interaction (carryover effect) and sequence. Within-patient effects and longitudinal data will be analysed using mixed linear models, accounting for potential confounders. ETHICS AND DISSEMINATION: Approved by Office for Research Ethics Committees Northern Ireland, reference 19/NI/0007. Results will be published in peer-reviewed journals and will be presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN12861060.

Maternal Serum Melatonin Increases During Pregnancy and Falls Immediately After Delivery Implicating the Placenta as a Major Source of Melatonin.

Melatonin is a neuroendocrine hormone which regulates circadian rhythm and is also an antioxidant. The role of melatonin in pregnancy is emerging. The enzymes needed for endogenous synthesis of melatonin have been identified in the placenta, although the contribution to circulating maternal melatonin in normal pregnancy is unclear. This work aimed to determine serum levels of melatonin and its major metabolite 6-hydroxymelatonin sulfate (6-OHMS) in normal pregnant women during each trimester of pregnancy, and immediately after delivery. Blood samples were obtained from a cohort of healthy pregnant women during each trimester of pregnancy (n = 26), from women scheduled for elective Cesarean section (CS) before and after delivery (n = 15), along with placental samples, and from healthy non-pregnant women as controls (n = 30). Melatonin and its major metabolite, 6-OHMS, were measured using enzyme immunoassay. Levels of serum melatonin were significantly higher during pregnancy than in non-pregnant women (P = 0.025) and increased throughout pregnancy (P < 0.0001). In women undergoing CS, serum melatonin decreased markedly 24 h after delivery (P = 0.0013). Similar results were seen for serum levels of 6-OHMS, and placental tissue 6-OHMS levels correlated with week of gestation at delivery (p = 0.018). In summary, maternal melatonin production is higher in pregnant than in non-pregnant women, increases significantly during pregnancy with highest levels in the third trimester, and decreases abruptly after delivery. These results suggest that the placenta is a major source of melatonin and supports a physiological role for melatonin in pregnancy.

Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat.

Chemotherapy-induced neuropathic pain is a debilitating and common side effect of cancer treatment. Mitochondrial dysfunction associated with oxidative stress in peripheral nerves has been implicated in the underlying mechanism. We investigated the potential of melatonin, a potent antioxidant that preferentially acts within mitochondria, to reduce mitochondrial damage and neuropathic pain resulting from the chemotherapeutic drug paclitaxel. In vitro, paclitaxel caused a 50% reduction in mitochondrial membrane potential and metabolic rate, independent of concentration (20-100 µmol/L). Mitochondrial volume was increased dose-dependently by paclitaxel (200% increase at 100 µmol/L). These effects were prevented by co-treatment with 1 µmol/L melatonin. Paclitaxel cytotoxicity against cancer cells was not affected by co-exposure to 1 µmol/L melatonin of either the breast cancer cell line MCF-7 or the ovarian carcinoma cell line A2780. In a rat model of paclitaxel-induced painful peripheral neuropathy, pretreatment with oral melatonin (5/10/50 mg/kg), given as a daily bolus dose, was protective, dose-dependently limiting development of mechanical hypersensitivity (19/43/47% difference from paclitaxel control, respectively). Melatonin (10 mg/kg/day) was similarly effective when administered continuously in drinking water (39% difference). Melatonin also reduced paclitaxel-induced elevated 8-isoprostane F2 α levels in peripheral nerves (by 22% in sciatic; 41% in saphenous) and limited paclitaxel-induced reduction in C-fibre activity-dependent slowing (by 64%). Notably, melatonin limited the development of mechanical hypersensitivity in both male and female animals (by 50/41%, respectively), and an additive effect was found when melatonin was given with the current treatment, duloxetine (75/62% difference, respectively). Melatonin is therefore a potential treatment to limit the development of painful neuropathy resulting from chemotherapy treatment.

Brief isoflurane anaesthesia affects differential gene expression, gene ontology and gene networks in rat brain.

Much is still unknown about the mechanisms of effects of even brief anaesthesia on the brain and previous studies have simply compared differential expression profiles with and without anaesthesia. We hypothesised that network analysis, in addition to the traditional differential gene expression and ontology analysis, would enable identification of the effects of anaesthesia on interactions between genes. Rats (n=10 per group) were randomised to anaesthesia with isoflurane in oxygen or oxygen only for 15min, and 6h later brains were removed. Differential gene expression and gene ontology analysis of microarray data was performed. Standard clustering techniques and principal component analysis with Bayesian rules were used along with social network analysis methods, to quantitatively model and describe the gene networks. Anaesthesia had marked effects on genes in the brain with differential regulation of 416 probe sets by at least 2 fold. Gene ontology analysis showed 23 genes were functionally related to the anaesthesia and of these, 12 were involved with neurotransmitter release, transport and secretion. Gene network analysis revealed much greater connectivity in genes from brains from anaesthetised rats compared to controls. Other importance measures were also altered after anaesthesia; median [range] closeness centrality (shortest path) was lower in anaesthetized animals (0.07 [0-0.30]) than controls (0.39 [0.30-0.53], p<0.0001) and betweenness centrality was higher (53.85 [32.56-70.00]% compared to 5.93 [0-30.65]%, p<0.0001). Simply studying the actions of individual components does not fully describe dynamic and complex systems. Network analysis allows insight into the interactions between genes after anaesthesia and suggests future targets for investigation.