Beyond diagnosis: investigating hospital referral impact on biological treatment initiation, hospital admission, and surgery patterns in inflammatory bowel disease - a Danish population based study.

OBJECTIVES: Early biological treatment in patients with inflammatory bowel disease (IBD) is important in disease control. Previous studies have suggested that patients with IBD from Non-Academic Hospitals were less likely to receive biologics. The aims of this study were (1) to use the granular data in the clinical database, GASTROBIO, to study detailed differences in time from IBD diagnosis to first administration of biologics, hospital admission, and surgery in patients referred to Academic Hospitals versus to Non-Academic Hospitals, and (2) to explore differences in disease extent, behavior, and indication for biological treatment. MATERIAL AND METHODS: This was a retrospective cross-sectional descriptive population-based quality study of patients with IBD initiating biologics in the North Denmark Region between 2016 and 2018. Data from GASTROBIO were extracted, namely demographic data, time of diagnosis, biological treatments with indications, hospital admission, and surgery. RESULTS: Of the 146 patients included, 84 were from the Academic and 62 from the Non-Academic Hospitals. No significant differences in median time from diagnosis to (1) treatment, (2) hospital admission or (3) IBD surgery between the groups were observed. A higher percentage of patients with luminal Crohn's disease were treated with biologics at the Academic Hospital (78% and 66%). CONCLUSIONS: Based on the findings of this population-based study, we found no evidence that the referral area had a significant impact on the duration from diagnosis to the initiation of biological treatment, hospital admissions, or surgery. However, the data suggested that fewer patients with luminal Crohn's disease were referred to biologics from Non-Academic Hospitals.

Quantitative sensory testing, psychological factors, and quality of life as predictors of current and future pain in patients with knee osteoarthritis.

ABSTRACT: Substantial interindividual variability characterizes osteoarthritis (OA) pain. Previous findings identify quantitative sensory testing (QST), psychological factors, and health-related quality of life as contributors to OA pain and predictors of treatment outcomes. This exploratory study aimed to explain baseline OA pain intensity and predict OA pain after administration of a nonsteroidal anti-inflammatory drug in combination with paracetamol for 3 weeks. The Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score was used to estimate OA pain presentation. One hundred one patients were assessed at baseline and follow-up using QST (pressure pain thresholds and temporal summation of pain [TSP]), symptoms of depression and anxiety, pain catastrophizing scales (PCSs), and health-related quality of life. Linear regression with backward selection identified that PCS significantly explained 34.2% of the variability in baseline KOOS pain, with nonsignificant contributions from TSP. Pain catastrophizing score and TSP predicted 29.3% of follow-up KOOS pain, with nonsignificant contributions from symptoms of anxiety. When assessed separately, PCS was the strongest predictor (32.2% of baseline and 24.1% of follow-up pain), but QST, symptoms of anxiety and depression, PCS, and quality of life also explained some variability in baseline and follow-up knee OA pain. Further analyses revealed that only TSP and PCS were not mediated by any other included variables, highlighting their role as unique contributors to OA pain presentation. This study emphasizes the importance of embracing a multimodal approach to OA pain and highlights PCS and TSP as major contributors to the baseline OA pain experience and the OA pain experience after OA treatment.

Use of drugs with pharmacogenomics (PGx)-based dosing guidelines in a Danish cohort of persons with chronic kidney disease, both on dialysis and not on dialysis: Perspectives for prescribing optimization.

AIM: The objective of this registry study is to assess the utilization of pharmacogenomic (PGx) drugs among patients with chronic kidney disease (CKD). METHODS: This study was a retrospective study of patients affiliated with the Department of Nephrology, Aalborg University Hospital, Denmark in 2021. Patients diagnosed with CKD were divided into CKD without dialysis and CKD with dialysis. PGx prescription drugs were retrieved from the Patient Administration System. Actionable dosing guidelines (AG) for specific drug-gene pairs for CYP2D6, CYP2C9, CYP2C19 and SLCO1B1 were retrieved from the PharmGKB homepage. RESULTS: Out of 1241 individuals, 25.5% were on dialysis. The median number of medications for each patient was 9 within the non-dialysis group and 16 within the dialysis group. Thirty-one distinct PGx drugs were prescribed. Altogether, 76.0% (943 individuals) were prescribed at least one PGx drug and the prevalence of prescriptions of PGx drugs was higher in the dialysis group compared to the non-dialysis group. The most frequently prescribed drugs with AG were metoprolol, pantoprazole, atorvastatin, simvastatin and warfarin. CONCLUSION: This study demonstrated that a substantial proportion of patients with CKD are exposed to drugs or drug combinations for which there exists AG related to PGx of CYP2D6, CYP2C19, CYP2C9 and SLCO1B1.

Review: application of the Safety Attitudes Questionnaire (SAQ) in primary care - a systematic synthesis on validity, descriptive and comparative results, and variance across organisational units.

Patient safety research has focused mostly on the hospital and acute care setting whereas assessments of patient safety climate in primary health care settings are warranted. Valid questionnaires as e.g., the Safety Attitudes Questionnaire (SAQ) may capture staff perceptions of patient safety climate but until now, an overview of the use of SAQ in primary care has not been systematically presented. Thus, the aim of this systematic review is to present an overview of SAQ used in primary care.Methods The electronic databases: PubMed, Embase, Cinahl, PsycInfo and Web of Science were used to find studies that used any version of SAQ in primary care. Studies were excluded if only abstract or poster was available, as the information in abstract and posters was deemed insufficient. Commentaries and nonempirical studies (e.g., study protocols) were excluded. Only English manuscripts were included.Results A total of 43 studies were included and 40 of them fell into four categories: 1) validation analysis, 2) descriptive analysis, 3) variance assessment and 4) intervention evaluation and were included in further analyses. Some studies fell into more than one of the four categories. Seventeen studies aimed to validate different versions of SAQ in a variety of settings and providers. Twenty-five studies from fourteen different countries reported descriptive findings of different versions of SAQ in a variety of settings. Most studies were conducted in primary health care centres, out-of-hours clinics, nursing homes and general practice focusing on greatly varying populations. One study was conducted in home care. Three studies investigated variance of SAQ scores. Only five studies used SAQ to assess the effects of interventions/events. These studies evaluated the effect of electronic medical record implementation, a comprehensive Unit-based Safety Program or COVID-19.Conclusion The synthesis demonstrated that SAQ is valid for use in primary care, but it is important to adapt and validate the questionnaire to the specific setting and participants under investigation. Moreover, differences in SAQ factor scores were related to a variety of descriptive factors, that should be considered in future studies More studies, especially variance and intervention studies, are warranted in primary care.Trial registration This systematic review was not registered in any register.

Deprescribing in primary care without deterioration of health-related outcomes: A real-life, quality improvement project.

Medication reviews focusing on deprescribing can reduce potentially inappropriate medication; however, evidence regarding effects on health-related outcomes is sparse. In a real-life quality improvement project using a newly developed chronic care model, we investigated how a general practitioner-led medication review intervention focusing on deprescribing affected health-related outcomes. We performed a before-after intervention study including care home residents and community-dwelling patients affiliated with a large Danish general practice. The primary outcomes were changes in self-reported health status, general condition and functional level from baseline to 3-4 months follow-up. Of the 105 included patients, 87 completed the follow-up. From baseline to follow-up, 255 medication changes were made, of which 83% were deprescribing. Mean self-reported health status increased (0.55 [95% CI: 0.22 to 0.87]); the proportion with general condition rated as 'average or above' was stable (0.06 [95% CI: -0.02 to 0.14]); and the proportion with functional level 'without any disability' was stable (-0.05 [95% CI: -0.09 to 0.001]). In conclusion, this general practitioner-led medication review intervention was associated with deprescribing and increased self-reported health status without the deterioration of general condition or functional level in real-life primary care patients. The results should be interpreted carefully given the small sample size and lack of control group.

Drug absorption from oral formulations in patients with short bowel syndrome: a comprehensive update of the literature.

INTRODUCTION: Drug absorption is often altered and typically diminished in patients with short bowel syndrome (SBS). It is important to understand the patient's gastrointestinal anatomy, the absorptive capacity of the remaining bowel, and the physicochemical and pharmacokinetic properties of the drug to optimize oral pharmacotherapy. AREAS COVERED: The primary focus was to provide an updated understanding of the absorption of various drugs in patients with short bowel syndrome. Forty-seven studies covering 13 different drug classes were included in the review and study details, patient characteristics, drug characteristics and pharmacokinetic findings were summarized for each drug class. EXPERT OPINION: Improving and simplifying drug treatment in patients with SBS have high priority, but the patients are multi diseased so knowledge regarding absorption of drugs as e.g. antithrombotic agents, immunosuppressants is urgently needed. Therefore, it is crucial to advance our understanding of the fundamental factors involved in drug absorption, spanning from drug design to pathophysiology. With the growing knowledge in drug design and gastrointestinal pathophysiology, we anticipate the development of computer models that can accurately predict optimal absorption in the future.

Positive Predictive Value of Non-Traumatic Bleeding Diagnoses in the Danish National Patient Register.

Purpose: The majority of bleeding diagnoses in the Danish National Patient Registry have not been validated despite extensive use in epidemiological research. Therefore, we examined the positive predictive value (PPV) of non-traumatic bleeding diagnoses in the Danish National Patient Registry. Study Design: Population-based validation study. Patients and Methods: Based on a manual review of electronic medical records, we estimated the PPV of diagnostic coding (International Classification of Diseases, Tenth Revision (ICD-10)) for non-traumatic bleeding for all patients ≥65 years of age with any hospital contact in the North Denmark Region during March-December 2019 as registered in the Danish National Patient Registry. We calculated PPVs and associated 95% confidence intervals (CI) for non-traumatic bleeding diagnoses overall and stratified according to primary or secondary diagnosis, and according to major anatomical sites. Results: A total of 907 electronic medical records were available for review. The population mean age was 79.33 years (standard deviation (SD)=7.73) and 57.6% were males. Primary bleeding diagnoses accounted for 766 of the records and 141 were secondary bleeding diagnoses. The overall PPV for bleeding diagnoses was 94.0% (95% CI: 92.3-95.4). The PPV was 98.7% (95% CI: 97.6-99.3) for the primary diagnoses and 68.8% (95% CI: 60.7-75.9) for the secondary diagnoses. When stratified according to subgroups of major anatomical sites, the PPVs ranged between 94.1% and 100% for the primary diagnoses, and between 53.8% and 100% for secondary diagnoses. Conclusion: The overall validity of non-traumatic bleeding diagnoses in the Danish National Patient Registry is high and considered acceptable for epidemiological research. However, PPVs were substantially higher for primary than for secondary diagnosis.

Safe Medication in Nursing Home Residents Through the Development and Evaluation of an Intervention (SAME): Protocol for a Fully Integrated Mixed Methods Study With a Cocreative Approach.

BACKGROUND: Medication safety is increasingly challenging patient safety in growing aging populations. Developing positive patient safety cultures is acknowledged as a primary goal to improve patient safety, but evidence on the interventions to do so is inconclusive. Nursing home residents are often cognitively and physically impaired and are therefore highly reliant on frontline health care providers. Thus, interventions to improve medication safety of nursing home residents through patient safety culture among providers are needed. Using cocreative partnerships, integrating knowledge of residents and their relatives, and ensuring managerial support could be beneficial. OBJECTIVE: The primary aim of the Safe Medication of Nursing Home Residents Through Development and Evaluation of an Intervention (SAME) study is to improve medication safety for nursing home residents through developing an intervention by gaining experiential knowledge of patient safety culture in cocreative partnerships, integrating knowledge of residents and their relatives, and ensuring managerial support. METHODS: The fully integrated mixed method study will be conducted using an integrated knowledge translation approach. Patient safety culture within nursing homes will first be explored through qualitative focus groups (stage 1) including nursing home residents, their relatives, and frontline health care providers. This will inform the development of an intervention in a multidisciplinary panel (stage 2) including cocreators representing the medication management process across the health care system. Evaluation of the intervention will be done in a randomized controlled trial set at nursing homes (stage 3). The primary outcome will be changes in the mean scale score of an adapted version of the Danish "Safety Attitudes Questionnaire" (SAQ-DK) for use in nursing homes. Patient safety-related outcomes will be collected through Danish health registers to assess safety issues and effects, including medication, contacts to health care, diagnoses, and mortality. Finally, a mixed methods analysis on patient safety culture in nursing homes will be done (stage 4), integrating qualitative data (stage 1) and quantitative data (stage 3) to comprehensively understand patient safety culture as a key to medication safety. RESULTS: The SAME study is ongoing. Focus groups were carried out from April 2021 to September 2021 and the workshop in September 2021. Baseline SAQ-DK data were collected in January 2022 with expected follow-up in January 2023. Final data analysis is expected in spring 2024. CONCLUSIONS: The SAME study will help not only to generate evidence on interventions to improve medication safety of nursing home residents through patient safety culture but also to give insight into possible impacts of using cocreativity to guide the development. Thus, findings will address multiple gaps in evidence to guide future patient safety improvement efforts within primary care settings of political and scientific scope. TRIAL REGISTRATION: ClinicalTrials.gov NCT04990986; https://clinicaltrials.gov/ct2/show/NCT04990986. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/43538.

Clinical characteristics of hospitalized patients with paracetamol poisoning before and after restrictions of over-the-counter sale of paracetamol.

INTRODUCTION: Paracetamol poisoning is a frequent cause of hospitalization in Denmark. On 30 September 2013, the Danish authorities restricted packages available without a prescription in pharmacy outlets to contain a maximum of 10 g of paracetamol. We aimed to investigate the effects of this regulation. METHODS: This was a cross-sectional study of two groups of patients admitted consecutively to a Danish University Hospital due to poisoning with paracetamol in 365 days in 2012-13 before 30 September 2013, and a corresponding 365-day period in 2017-18. Data were extracted from patient records. RESULTS: In 2012-2013 and 2017-18, 156 and 92 admissions in 127 and 78 unique patients, respectively, were identified. Ingestion of more than 20 g paracetamol occurred in a significantly higher proportion of cases in 2012-13 compared to 2017-18 (29% vs 13%, P < 0.01). In accordance, there were no cases of international normalized ratio >1.5 or alanine aminotransferase activity >1000 U/L in the post-legislation period, and seven and five cases in the pre-legislation period, respectively. Females accounted for 80% and 78% of patients in the two periods, respectively, and were considerably younger than males (median [interquartile range]: 22 [17-40] vs. 47 [30-56], P < 0.01 in 2012-13, and 23 [18-46] vs. 43 [27-49] years, P = 0.02 in 2017-18). Furthermore, in 2012-13, intentional poisonings occurred in a higher proportion of females than males 2012-13 (97% vs 85%, P < 0.01). CONCLUSIONS: The present study demonstrated a lower number of paracetamol poisonings, a decreased proportion of poisonings involving ingestion of more than 20 g of paracetamol, and a lower occurrence of hepatotoxicity after the regulation. However, circumstances other than pack size restrictions, such as increased public awareness of the danger of paracetamol poisonings, may affect these associations. Furthermore, the study showed that females and males constitute two distinct groups in terms of age and intentional poisoning.

Less prevalent use of biologics for inflammatory bowel disease in patients from Non-Academic hospitals - a Danish register-based study of a region with 580,000 citizens.

INTRODUCTION: Biologic therapy is widely used for inflammatory bowel disease (IBD) and may decrease surgery rates. However, it remains uncertain if there is unwarranted geographic variation in access to biologic therapy. The aim of the study was to explore if all patients had equal access to biologic therapy in the North Denmark Region. METHODS: A cross-sectional register-based study of use of biologics, hospital contacts and surgery among all IBD patients having a hospital contact in the geographically well-defined North Denmark Region during 2016-2018. ICD-10 diagnosis codes, hospital contacts and procedure codes were retrieved from the region's hospital registry. The population is served by an Academic Hospital and two Non-Academic Hospitals constituting three referral areas (according to postal codes). RESULTS: In total, 2371 patients with ulcerative colitis (UC) and 1383 patients with Crohn's disease (CD) had a hospital contact in the region during 2016-2018. Compared to patients from the Academic Hospital, patients from the Non-Academic Hospitals experienced a lower incidence of biologic therapy for UC IRR 0.786 (0.621: 0.994), as well as for CD IRR 0.912 (0.781: 1.065). The incidence of bowel related hospital contacts were higher in patients from Non-Academic hospitals for both UC IRR 1.318 (1.207: 1.438) and CD IRR 1.165 (0.915: 1.483). CONCLUSIONS: Patients with IBD living in a referral area to a Non-Academic Hospital in the North Denmark Region are less likely to receive biologics. This was associated with an increased prevalence of IBD related surgical procedures.

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.

Acute drug poisonings leading to hospitalization.

Knowledge about current trends and epidemiology in poisonings is important to maintain quality in diagnostics, treatment and prevention. We performed a cross-sectional study of all cases (n = 261) admitted with drug poisoning to Aalborg University Hospital during 1 year in 2017-2018. Median age was 30 (22-49) years, and 58% were female. Fifty percent were suicide attempts. In most cases, involved drugs were identified by history taking; blood analysis barely revealed any additional paracetamol and salicylicate poisonings. Drugs prescribed to the patient or available over the counter were involved in nearly two thirds of cases. Weak analgesics dominated by paracetamol (n = 91, 35%) was the most frequently involved group of drugs followed by opioids and benzodiazepines. Gender differences were observed with respect to involvement of weak analgesics and central stimulants. A higher prevalence of unidentified involved drugs was observed in 26 cases (10%) in which the length of admission exceeded 2 days and/or intensive care was needed. No deaths, cardiac arrhythmias or physical complications occurred. Thus, current handling of the acute poisoning seems effective in most cases. However, a more tailored use of blood analyses including a toxicological screen in selected cases may represent an opportunity for improvement.

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.

Pain medication use for musculoskeletal pain among children and adolescents: a systematic review.

OBJECTIVES: Musculoskeletal pain is common among children and adolescents. Despite the lack of evidence regarding harms and benefits, musculoskeletal pain is often managed with pain medication. The aim of this systematic review is to assess the prevalence of pain medication use for musculoskeletal pain among children and adolescents and the factors and side effects associated with use. CONTENT: Three databases (EMBASE, CINAHL and PsychINFO) were systematically searched to identify studies designed to examine the prevalence, frequency or factors associated with the use of pain medication for musculoskeletal pain in children and adolescents (aged 6-19 years). The included studies were assessed for study quality and data were extracted. SUMMARY: The search initially provided 20,135 studies. After screening titles, abstracts and full-texts, 20 studies were included. In school settings, 8-42% of children used pain medication for musculoskeletal pain, and 67-75% of children in sports clubs and from pain clinics used pain medication. The most consistent factors associated with the use of pain medications were pain characteristics and psychological factors (e.g. being bullied, low-self-esteem), while mixed evidence was found for increasing age and female gender. Only two studies reported on the duration of use and only one study on adverse effects related to the use of pain medication. OUTLOOK: We found that 8-42% of adolescents from school-based samples use pain medication for MSK pain, while the prevalence among adolescents from sports clubs and pain clinics is higher (67-75%). Pain characteristics (pain duration, severity, intensity, disability levels and the presence of ≥2 pain conditions or multisite pain) and psychological factors were associated with a higher use of pain medication, while for higher age and female gender the evidence of association was mixed. Future studies should systematically collect information on the type, duration of use of pain medication and side effects to confirm the findings of this review.

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.

Oral absorption of oxycodone in patients with short bowel syndrome.

BACKGROUND: Short bowel syndrome is a disorder with several complications such as malnutrition and failure of drug therapy. Treatment with opioids is needed in many patients, and oral medication is preferred. However, optimal dosing is a difficult task as current guidelines are based on an intact gastrointestinal tract. Hence, the aim of this explorative case study was to assess the pharmacokinetics of orally administered oxycodone in patients with short bowel syndrome. METHODS: Six patients with short bowel syndrome were administered 10 mg oral solution oxycodone after an overnight fast. Oxycodone plasma concentrations were determined over a 6-hour period. Pharmacokinetic profiles were visually inspected. Pharmacokinetic parameters: maximum plasma concentration, time of maximum concentration and area under the curve were calculated. Data were also compared to mean values obtained in healthy participants. RESULTS: A clinically relevant concentration of oxycodone was found in all patients, although with large inter-individual variation. The absorption fraction tended to correlate positively with total intestinal length. Additionally, preservation of some or the entire colon seemed further to increase the absorption fraction. Time of maximum concentration varied from 30 min to approximately 90 min. CONCLUSIONS: Oxycodone is absorbed in a clinically relevant extent in patients with short bowel syndrome, but bioavailability varies greatly between patients, which shall be taken into consideration. Absorption is related to functional small intestinal length, but preservation of colon is also beneficial. Still, optimal therapeutic dosing must be individualized, and other factors such as those related to malnutrition and motility shall also be taken into consideration.

Emergency drug kits at the Danish hospital pharmacies: varying management and challenges.

OBJECTIVES: Access to emergency drug kits (EDK) during medical emergencies can be life-saving; however, recent doubts about the quality of the kits have been expressed. Procurements of pharmaceuticals to the five regional authorities in Denmark are serviced by Amgros, a public sector organisation owned by the regions and established to create economies of scale and achieve administrative savings by centralisation. This means that Amgros calls for tenders for the supply of pharmaceuticals to the hospital pharmacies. The Hospital Pharmacy in the North Denmark Region does not currently have an effective method to manage Amgros procurements in relation to EDKs. Thus, the objectives were to explore how quality in the management and packing of EDKs is assured and maintained at different hospital pharmacies in Denmark and how this is affected by Amgros procurements. METHODS: The hospital pharmacies in Denmark were enrolled in a cross-sectional study. Information about the management and challenges of the EDKs was inquired by means of a questionnaire. Responses were analysed by simple statistics. RESULTS: All eight hospital pharmacies in Denmark completed the questionnaire, and the distribution between single-use and reusable packaging was nearly equal. The hospital pharmacies comply with a variation of regulations of which good distribution practice is the most common. Six hospital pharmacies experience challenges with drug replacements in the EDKs and only one hospital pharmacy complies completely with the Amgros procurement. The majority of the hospital pharmacies use parameters such as price of the new drug and potential expense for new packaging in their decision of whether to comply with the Amgros procurement. CONCLUSION: The management of the EDKs varies greatly among the hospital pharmacies in Denmark, and national requirements are therefore encouraged to ensure the quality. The challenges experienced with drug replacements reflect that complying with the Amgros procurement can be troublesome.

Analyzing and Benchmarking Global Consumption Statistics for Opioid Analgesics 2015: Inequality Continues to Increase.

Many countries around the world have a very low per capita consumption of opioid analgesics, which is probably related to absence or inadequate management of moderate and severe pain for large parts of their populations. We conducted a longitudinal observational study with opioid analgesic consumption data for all countries from 2000-2015, to assess 2015 per capita consumption data for strong opioid analgesics and to investigate the hypothesis that inequality decreased over the years 2000-2015. We based our study on the official statistics kept by the International Narcotics Control Board, built on data submitted by governments annually. Adequate consumption was defined as the average 2015 opioid analgesic consumption of the 20 most-developed countries, or above. In addition, we defined categories of moderate, low, very low and extremely low consumption, each category differing 0.5 on a logarithmic scale. Consumption was expressed as the AOC Index. The direction of inequality in consumption between different countries' development levels through the years 2000-2015 was assessed using a mixed effects model. We found that the average consumption of the 20 most-developed countries was 256 ± 208 mg per capita (range 5.9-778) in 2015. In all, 119 countries did not have a moderate or adequate consumption of opioid analgesics. Inequality of adequacy of consumption between low- and highly-developed countries increased from 2000 to 2015. The world needs 1867 tonnes ME for treating pain with opioids analgesics at an adequate level (actual use: 365 tonnes or 19.5% of the global need). We concluded that in 2015, almost 6.5 billion people lived in countries where opioid analgesic consumption was low, very low, or extremely low.

Pain inhibitory mechanisms and response to weak analgesics in patients with knee osteoarthritis.

BACKGROUND: Conditioned pain modulation (CPM) and offset analgesia are different features of descending pain inhibition. This study investigated CPM, offset analgesia and clinical pain measures in patients with knee osteoarthritis (KOA) before and after treatment with the combination of a non-steroidal anti-inflammatory drug (NSAIDs) plus acetaminophen. METHODS: Forty-two patients with KOA received Ibuprofen 1.2 g/daily and acetaminophen 3.0 g/daily for three weeks. Before administration, CPM magnitude was assessed as the difference between cuff pain detection (cPDT) with and without a conditioning stimulus (evoked by tourniquet pain). Offset analgesia was assessed as the pain intensities evoked by a constant 46°C for 30-s stimulus compared to an offset analgesia paradigm of 46°C for 5-s, 47°C for 5-s and 46°C for 20-s. The worst pain within the last 24-hr and pain during activity were assessed before and after treatment. RESULTS: Clinical pain significantly decreased after treatment (p < 0.001) and less efficient CPM before treatment was associated with weaker analgesic effect (R = 0.354, p = 0.043). No significant modulation of CPM or offset analgesia was found for the treatment. CONCLUSION: This study found that less efficient CPM is associated with reduced analgesic effect of NSAIDs plus acetaminophen in patients with KOA whereas the treatment did not modulate CPM nor offset analgesia magnitude. SIGNIFICANCE: This study demonstrated that conditioned pain modulation is correlated with the response to a standard pharmaceutical interventions treating osteoarthritis pain. Furthermore, we demonstrated that a decrease in clinical pain intensity is not associated with a normalization of conditioned pain modulation or offset analgesia, which questions if restoring these descending pain inhibitory mechanisms are pain intensity driven.

Pathophysiology and management of diabetic gastroenteropathy.

Polyneuropathy is a common complication to diabetes. Neuropathies within the enteric nervous system are associated with gastroenteropathy and marked symptoms that severely reduce quality of life. Symptoms are pleomorphic but include nausea, vomiting, dysphagia, dyspepsia, pain, bloating, diarrhoea, constipation and faecal incontinence. The aims of this review are fourfold. First, to provide a summary of the pathophysiology underlying diabetic gastroenteropathy. Secondly to give an overview of the diagnostic methods. Thirdly, to provide clinicians with a focussed overview of current and future methods for pharmacological and nonpharmacological treatment modalities. Pharmacological management is categorised according to symptoms arising from the upper or lower gut as well as sensory dysfunctions. Dietary management is central to improvement of symptoms and is discussed in detail, and neuromodulatory treatment modalities and other emerging management strategies for diabetic gastroenteropathy are discussed. Finally, we propose a diagnostic/investigation algorithm that can be used to support multidisciplinary management.