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Objective: Polymorphisms of the IgG Fc-receptor, FcγRIIA and FcγRIIIB, genes have recently been related to disability in multiple sclerosis (MS) and Guillain-Barré syndrome. Methods: To investigate the role of FcγRIIA, FcγRIIIB as well as FcγRIIIA polymorphisms in a larger population of MS (155 patients, 102 females and 53 males) and 96 matched controls from the county of Hordaland. The results were compared with disease susceptibility and severity measured by EDSS. Results: The allele frequencies did not differ significantly between the MS patients and the controls. Patients homozygous for the FcγRIIIB NA1 allele had a significantly more benign course of MS than patients heterozygous or homozygous for the NA2 allele (p=0.009). Patients homozygous for the FcγRIIA H also had a more benign prognosis than those heterozygogous and homozygous for the R allele (p=0.052). There was also a trend toward a more benign prognosis in patients heterozygogous or homozygous for the FcγRIIIA F allele compared to those homozygous for the V allele (p=0.197). Conclusion: The most significant finding is the FcγRIIIB being a disease-modifying gene in MS. A more effective clearance of circulating immune complexes by FcγRIIIB NA1/NA1 leukocytes may be one of the mechanisms for the better clinical outcome. [ABSTRACT FROM AUTHOR]

Background: Causes of death other than COVID-19 seem to contribute significantly to the excess mortality observed during the 2020-2022 pandemic. In this study, we explore changes in non-COVID-19 causes of death in Norway during the COVID-19 pandemic from March 2020 to December 2022., Methods: We performed a population-based cross-sectional study on data from the Norwegian Cause of Death Registry. All recorded deaths from 1st January 2010 to 31st December 2022 were included. The main outcome measures were the number of deaths and age-standardised death rate (ASMR) per 100000 population from the major cause of death groups in 2020, 2021 and 2022. The predicted number of deaths and ASMRs were forecasted with a 95% prediction interval constructed from a general linear regression model based on the corresponding number of deaths and rates from the preceding ten prepandemic years (2010-2019). We also examined whether there were deviations from expected seasonality in the pandemic period based on prepandemic monthly data from 2010-2019. The cumulative number of deaths and ASMR were estimated based on monthly mortality data., Results: There was significant excess mortality (number of deaths) in 2021 and 2022 for all causes (3.7% and 14.5%), for cardiovascular diseases (14.3% and 22.0%), and for malignant tumours in 2022 (3.5%). In terms of ASMR, there was excess mortality in 2021 and 2022 for all causes (2.9% and 13.7%), and for cardiovascular diseases (16.0% and 25,8%). ASMR was higher than predicted in 2022 for malignant tumours (2.3%). There were fewer deaths than predicted from respiratory diseases (except COVID-19) in 2020 and 2021, and from dementia in 2021 and 2022. From March 2020 to December 2022, there were cumulatively 3754 (ASMR 83.8) more non-COVID-19 deaths than predicted, of which 3453 (ASMR: 79.6) were excess deaths from cardiovascular disease, 509 (ASMR 4.0) from malignant tumours. Mortality was lower than predicted for respiratory diseases (-1889 (ASMR: -44.3)), and dementia (-530 (ASMR -18.5))., Conclusions: There was considerable excess non-COVID-19 mortality in Norway from March 2020 until December 2022, mainly due to excess cardiovascular deaths. For respiratory diseases and dementia, mortality was lower than predicted., (© 2024. The Author(s).)

Objective: To explore the potential impact of the first wave of COVID-19 pandemic on all cause and cause-specific mortality in Norway., Design: Population-based register study., Setting: The Norwegian cause of Death Registry and the National Population Register of Norway., Participants: All recorded deaths in Norway from March to May from 2010 to 2020., Main Outcome Measures: Rate (per 100 000) of all-cause mortality and causes of death in the European Shortlist for Causes of Death from March to May 2020. The rates were age standardised and adjusted to a 100% register coverage and compared with a 95% prediction interval (PI) from linear regression based on corresponding rates for 2010-2019., Results: 113 710 deaths were included, of which 10 226 were from 2020. We did not observe any deviation from predicted total mortality. There were fewer than predicted deaths from chronic lower respiratory diseases excluding asthma (11.4, 95% PI 11.8 to 15.2) and from other non-ischaemic, non-rheumatic heart diseases (13.9, 95% PI 14.5 to 20.2). The death rates were higher than predicted for Alzheimer's disease (7.3, 95% PI 5.5 to 7.3) and diabetes mellitus (4.1, 95% PI 2.1 to 3.4)., Conclusions: There was no significant difference in the frequency of the major causes of death in the first wave of the 2020 COVID-19 pandemic in Norway compared with corresponding periods 2010-2019. There was an increase in diabetes mellitus and Alzheimer's deaths. Reduced mortality due to some heart and lung conditions may be linked to infection control measures., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Low dose naltrexone (LDN) is reported to have beneficial effects in several autoimmune diseases. The purpose of this study was to examine whether starting LDN was followed by changes in the dispensing of thyroid hormones to patients with hypothyroidism., Methods: We performed a quasi-experimental before-after study based on the Norwegian Prescription Database. Study participants were identified by using reimbursement codes for hypothyroidism. Cumulative dispensed Defined Daily Doses and the number of users of triiodothyronine (T3) and levothyroxine (LT4) 1 year before and after the first LDN prescription was compared in three groups based on LDN exposure., Results: We identified 898 patients that met the inclusion criteria. There was no association between starting LDN and the subsequent dispensing of thyroid hormones. If anything, there was a tendency towards increasing LT4 consumption with increasing LDN exposure., Conclusion: The results of this study do not support claims of efficacy of LDN in hypothyroidism.

In this controlled before-after study based on data from the Norwegian Prescription Database, we examine whether starting off-label use of Low Dose Naltrexone (LDN) is followed by changes in the consumption of psychotropic medicines including antiepileptics. Patients that collected LDN for the first time in 2013 (N = 11247) were included and stratified into three groups based on LDN exposure. We compared differences in means of cumulative number of defined daily doses (DDD) as well as changes in the number of users one year before and one year after starting LDN. There was a dose-response association between increasing LDN exposure and reductions in the number of users of antiepileptics, antipsychotics and antidepressants. There were significant difference-in-differences in DDDs between the groups with the lowest and highest LDN exposure of antipsychotics (1.4 DDD, 95% CI 0.4 to 2.3, p = 0.007), and in number of users of antiepileptics (3.1% points, 95% CI 1.6% to 4.6%, p < 0.001), antipsychotics (2.1% points, 95% CI 1.2% to 3%, p < 0.001), and antidepressants (2.8% points, 95% CI 1.1% to 4.4%, p = 0.001). The findings show an association between the initiation of persistent LDN use and reduced consumption of several psychotropic medicines and antiepileptics. Beneficial effects of LDN in the treatment of psychiatric diseases cannot be ruled out.

In recent years, low dose naltrexone (LDN) has been used as an off-label therapy for several chronic diseases. Results from small laboratory and clinical studies indicate some beneficial effects of LDN in autoimmune diseases, but clinical research on LDN in rheumatic disease is limited. Using a pharmacoepidemiological approach, we wanted to test the hypothesis that starting LDN leads to reduced dispensing of medicines used in the treatment of rheumatic disease. We performed a controlled before-after study based on the Norwegian Prescription Database (NorPD) to compare prescriptions to patients one year before and one year after starting LDN in 2013. The identified patients (n = 360) were stratified into three groups based on LDN exposure. Outcomes were differences in dispensing of medicines used in rheumatic disease. In persistent LDN users, there was a 13% relative reduction in cumulative defined daily doses (DDD) of all medicines examined corresponding to -73.3 DDD per patient (95% CI -120,2 to -26.4, p = 0.003), and 23% reduction of analgesics (-21.6 DDD (95% CI -35.5 to -7.6, p<0.009)). There was no significant DDD change in patients with lower LDN exposure. Persistent LDN users had significantly reduced DDDs of NSAID and opioids, and a lower proportion of users of DMARDs (-6.7 percentage points, 95% CI -12.3 to-1.0, p = 0.028), TNF-α antagonists and opioids. There was a decrease in the number of NSAID users among patients with the least LDN exposure. Important limitations are that prescription data are proxies for clinical effects and that a control group unexposed to LDN is lacking. The results support the hypothesis that persistent use of LDN reduces the need for medication used in the treatment of rheumatic and seropositive arthritis. Randomised clinical trials on LDN in rheumatic disease are warranted., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: Low-dose naltrexone [LDN] is a controversial off-label treatment used by many Crohn's disease [CD] and ulcerative colitis [UC] patients. A small number of preliminary studies indicate that LDN might be beneficial in CD, but evidence is too scarce to demonstrate efficacy. We sought to examine whether initiation of LDN therapy by patients with inflammatory bowel disease [IBD] was followed by changes in dispensing of relevant medication., Methods: We performed a quasi-experimental before-and-after study following a sudden increase in LDN use in the Norwegian population in 2013. IBD patients were identified from among all the patients who had at least one LDN prescription recorded in the Norwegian Prescription Database [NorPD] in 2013. Drug dispensing 2 years before and after the first LDN prescription was compared., Results: We identified 582 IBD patients who had received LDN. Of the 256 patients who became persistent LDN users, there were reductions in the number of users for [i] all examined drugs [-12%], [ii] intestinal anti-inflammatory agents [-17%], [iii] other immunosuppressants [-29%], [iv] intestinal corticosteroids [-32%] and [v] aminosalicylates [-17%]. In subgroups of identified CD and UC patients, there were significant reductions in the number of users of intestinal corticosteroids [CD: -44%, UC: -53%] and systemic corticosteroids [UC: -24%]. No significant differences in cumulative defined daily doses were observed., Conclusions: Our findings imply that the initiation of LDN in IBD is followed by reduced dispensing of several drugs considered essential in the treatment of CD and UC.

Background: There are several examples of inadequate staffing at local emergency medical communication centres (LEMCs) resulting in limited availability and long waits on the telephone. There are no guidelines for population size or the staffing of a LEMC. In the following, we present models of catchment areas and staffing., Material and Method: Traffic intensity on Saturdays and Sundays was based on data on figures for patient contacts at seven LEMCs in 2014 and 2015. We defined the minimum optimal population base as at least 50 % probability of ≥ 10 contacts in the course of a night duty. The Erlang-C formula was used to estimate service level and hence staffing requirements on the basis of population and response-time requirements. We have surveyed the combined staffing requirements of all the LEMCs in Norway., Result: The minimum optimal population base was 29 134. In 2016, 48 of 103 LEMCs were smaller than this. In order to be able to satisfy the response-time requirements in the Norwegian Emergency Medicine Regulations, 112 LEMC night operators and 158 day operators would be necessary for the whole of Norway. A reduction of the response-time requirement from 120 to ten seconds would require 9.8 % more operators at night and 17 % more operators during the day., Interpretation: The models we have presented provide a basis for planning the population base and staffing of LEMCs. Significantly stricter response-time requirements will result in limited need for more personnel.

Low dose naltrexone (LDN) has become a popular off-label therapy for multiple sclerosis (MS). A few small, randomized studies indicate that LDN may have beneficial effects in MS and other autoimmune diseases. If proven efficacious, it would be a cheap and safe alternative to the expensive treatments currently recommended for MS. We investigated whether a sudden increase in LDN use in Norway in 2013 was followed by changes in dispensing of other medications used to treat MS. We performed a quasi-experimental before-and-after study based on population data from the Norwegian Prescription Database (NorPD). We included all patients that collected at least one LDN prescription in 2013, and had collected at least two medications with a reimbursement code for MS, or collected a medication with MS as the only indication in 2009 or 2010. Outcomes were differences in cumulative dispensed doses and incidence of users of disease modifying MS therapies, and medications used to treat MS symptoms two years before and two years after dispensing the initial LDN prescription. The eligible 341 patients collected 20 921 prescriptions in the observation period. Apart from changes in line with general trends in MS therapy in Norway, there was no difference in neither dispensed cumulative doses or number of prevalent users of MS specific medication. Initiation of LDN was not followed by reductions of other medications used to treat symptoms associated with MS.

Background: The primary care out-of-hours (OOH) services in Norway are characterized by high contact rates by telephone. The telephone contacts are handled by local emergency medical communication centres (LEMCs), mainly staffed by registered nurses. When assessment by a medical doctor is not required, the nurse often handles the contact solely by nurse telephone counselling. Little is known about this group of contacts. Thus, the aim of this study was to investigate characteristics of encounters with the OOH services that are handled solely by nurse telephone counselling., Methods: Nurses recorded ICPC-2 reason for encounter (RFE) codes and patient characteristics of all patients who contacted six primary care OOH services in Norway during 2014. Descriptive statistics and frequency analyses were applied., Results: Of all telephone contacts (n = 61,441), 23% were handled solely by nurse counselling. Fever was the RFE most frequently handled (7.3% of all nurse advice), followed by abdominal pain, cough, ear pain and general symptoms. Among the youngest patients, 32% of the total telephone contacts were resolved by nurse advice compared with 17% in the oldest age group. At night, 31% of the total telephone contacts were resolved solely by nurse advice compared with 21% during the day shift and 23% in the evening. The share of nurse advice was higher on weekdays compared to weekends (mean share 25% versus 20% respectively)., Conclusion: This study shows that nurses make a significant contribution to patient management in the Norwegian OOH services. The findings indicate which conditions nurses should be able to handle by telephone, which has implications for training and routines in the LEMCs. There is the potential for more nurse involvement in several of the RFEs with a currently low share of nurse counselling.

Background: Frequencies of reasons for encounter (RFEs) in emergency primary care out-of-hours (OOH) services are relevant for planning of capacities as well as to target the training of staff at casualty clinics. We aimed to present frequencies of RFEs in the different organ systems, and to identify the most frequent RFEs at different urgency levels., Methods: We analyzed data on RFEs in Norwegian OOH services. International Classification of Primary Care (ICPC-2) RFE codes were recorded in all contacts to eight representative OOH casualty clinics in 2014 and 2015 covering 20 municipalities with a total population of 260 196. Frequencies of each ICPC-2 chapters and groups of ICPC-2 codes were calculated at different urgency levels., Results: Musculoskeletal, respiratory, skin, digestive and general and unspecified issues were the most frequent RFE groups. Fever was the most frequent single ICPC-2 RFE code, but was less common among the most urgent cases. Abdominal pain was the most common RFE in patients with yellow urgency level (urgent), and chest pain dominated the potentially red (potentially life threatening) cases. There was less variation in the use of ICPC-2 with increasing urgency level., Conclusions: This study identifies important differences in RFEs between urgency levels in the Norwegian OOH services. The findings provide new insight into the function of the primary health care emergency services in the Norwegian health care system, and should have implications for staffing, training and equipment in the OOH services.

Purpose: Low-dose naltrexone (LDN) is used in a wide range of conditions, including chronic pain and fibromyalgia. Because of the opioid antagonism of naltrexone, LDN users are probably often warned against concomitant use with opioids. In this study, based on data from the Norwegian prescription database, we examine changes in opioid consumption after starting LDN therapy., Methods: We included all Norwegian patients (N = 3775) with at least one recorded LDN prescription in 2013 and at least one dispensed opioid prescription during the 365 days preceding the first LDN prescription. We allocated the patients into three subgroups depending on the number of collected LDN prescriptions and recorded the number of defined daily doses (DDDs) on collected prescriptions on opioids, nonsteroidal anti-inflammatory drugs and other analgesics and antipyretics from the same patients., Results: Among the patients collecting ≥4 LDN prescriptions, annual average opioid consumption was reduced by 41 DDDs per person (46%) compared with that of the previous year. The reduction was 12 DDDs per person (15%) among users collecting two to three prescriptions and no change among those collecting only one LDN prescription. We observed no increase in the number of DDDs in nonsteroidal anti-inflammatory drugs or other analgesics and antipyretics corresponding to the decrease in opioid use., Conclusions: Possibly, LDN users avoided opioids because of warnings on concomitant use or the patients continuing on LDN were less opioid dependent than those terminating LDN. Therapeutic effects of LDN contributing to lower opioid consumption cannot be ruled out. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd., (© 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.)

Purpose: Following a TV documentary in 2013, there was a tremendous increase in low dose naltrexone (LDN) use in a wide range of unapproved indications in Norway. We aim to describe the extent of this sudden and unprecedented increase in LDN prescribing, to characterize patients and LDN prescribers, and to estimate LDN dose sizes., Methods: LDN prescriptions recorded in the Norwegian Prescription Database (NorPD) in 2013 and 2014, and sales data not recorded in NorPD from the only Norwegian LDN manufacturer were included in the study., Results: According to NorPD, 15 297 patients (0.3% of population) collected at least one LDN prescription. The actual number of users was higher as at least 23% of total sales were not recorded in NorPD. After an initial wave, there was a steady stream of new and persistent users throughout the study period. Median patient age was 52 years, and 74% of patients were female. Median daily dose was 3.7 mg. Twenty percent of all doctors and 71% of general medicine practitioners registered in Norway in 2014 prescribed LDN at least once., Conclusions: The TV documentary on LDN in Norway was followed by a large increase in LDN prescribing, and the proportion of LDN users went from an insignificant number to 0.3% of the population. There was a high willingness to use and prescribe off label despite limited evidence. Observed median LDN dose, and age and gender distribution were as expected in typical LDN using patients. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd., (© 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.)

Background: Geographical factors have an impact on the utilisation of out-of-hours services. In this study we have investigated the travel distance to out-of-hours casualty clinics in Norwegian municipalities in 2011 and the number of municipalities covered by the proposed recommendations for secondary on-call arrangements due to long distances., Material and Method: We estimated the average maximum travel times and distances in Norwegian municipalities using a postcode-based method. Separate analyses were performed for municipalities with a single, permanently located casualty clinic. Altogether 417 out of 430 municipalities were included. We present the median value of the maximum travel times and distances for the included municipalities., Results: The median maximum average travel distance for the municipalities was 19 km. The median maximum average travel time was 22 minutes. In 40 of the municipalities (10 %) the median maximum average travel time exceeded 60 minutes, and in 97 municipalities (23 %) the median maximum average travel time exceeded 40 minutes. The population of these groups comprised 2 % and 5 % of the country's total population respectively. For municipalities with permanent emergency facilities(N = 316), the median average flight time 16 minutes and median average distance 13 km.., Interpretation: In many municipalities, the inhabitants have a long average journey to out-of-hours emergency health services, but seen as a whole, the inhabitants of these municipalities account for a very small proportion of the Norwegian population. The results indicate that the proposed recommendations for secondary on-call duty based on long distances apply to only a small number of inhabitants. The recommendations should therefore be adjusted and reformulated to become more relevant.

Background: It has been documented from a number of out-of-hours primary health care services that the utilisation of the services declines with increasing travel distances. In this study we have investigated the correlation between travel distances and the use of out-of-hours medical services for all Norwegian municipalities that provide such services at a single permanent casualty clinic round the clock. In addition, we have sought to reveal any differences in consultation rates between municipalities that maintain single-municipality or inter-municipal out-of-hours services, as well as between municipalities in which the casualty clinics are co-located with a hospital or located separately., Material and Method: Information on the types of out-of-hours services existing in 2011 was retrieved from the Norwegian Emergency Primary Health Care Registry, and 315 municipalities with single permanent casualty clinic premises were included. Rates for various types of utilisation of these clinics were calculated on the basis of statistics generated from reimbursement claims., Results: The number of medical consultations and house calls per inhabitant fell by 48 % and 55 % respectively when average travel distance increased from 0 to 50 kilometres. The use of telephone/letter contact was not significantly associated with distances. Single-municipality casualty clinics located outside hospitals had the highest consultation rate for out-of-hours medical services when adjusted for distance., Interpretation: This supports previous findings to the fact that distance is a crucial factor for the utilisation of out-of-hours medical services. Establishing inter-municipal casualty clinics and co-locating them with hospitals may contribute to a lower rate of use of out-of-hours medical services.

Background: It is common practice to warn against intake of alcohol (ethanol) when taking metronidazole because of the risk of an effect similar to disulfiram (Antabuse). In this article we investigate whether such a warning has any real basis. KNOWLEDGE BASE: The article is based on a review of relevant literature retrieved through a search in PubMed. A search was also made in the WHO's database on adverse effects., Results: No in-vitro studies, animal models, reports of adverse effects or clinical studies provide any convincing evidence of a disulfiram-like interaction between ethanol and metronidazole., Interpretation: The warning against simultaneous use of alcohol and metronidazole appear to be based on laboratory experiments and individual case histories in which the reported reactions are equally likely to have been caused by ethanol alone or by adverse effects of metronidazole. Recent research does not confirm a clinically relevant interaction between ethanol and metronidazole.

We describe a method that uses crowdsourced postcode coordinates and Google maps to estimate average distance and travel time for inhabitants of a municipality to a casualty clinic in Norway. The new method was compared with methods based on population centroids, median distance and town hall location, and we used it to examine how distance affects the utilisation of out-of-hours primary care services. At short distances our method showed good correlation with mean travel time and distance. The utilisation of out-of-hours services correlated with postcode based distances similar to previous research. The results show that our method is a reliable and useful tool for estimating average travel distances and travel times.

Background: Long travel distances limit the utilisation of health services. We wanted to examine the relationship between the utilisation of a Norwegian out-of-hours service and the distance from the municipality population centroid to the associated casualty clinic., Methods: All first contacts from ten municipalities in Arendal out-of-hours district were registered from 2007 through 2011. The main outcomes were contact and consultation rates for each municipality for each year. The associations between main outcomes and distance from the population centroid of the participating municipalities to the casualty clinic and were examined by linear regression. Demographic and socioeconomic factors were included in multivariate linear regression. Secondary endpoints include association between distance and rates of different first actions taken and priority grades assessed by triage nurses. Age and gender specific subgroup analyses were performed., Results: 141 342 contacts were included in the analyses. Increasing distance was associated with marked lower rates of all contact types except telephone consultations by doctor. Moving 43 kilometres away from the casualty clinic led to a 50 per cent drop in the rate of face-to-face consultations with a doctor. Availability of primary care doctors and education level contributed to a limited extent to the variance in consultation rate. The rates of all priority grades decreased significantly with increasing distance. The rate of acute events was reduced by 22 per cent when moving 50 kilometres away. The proportion of patients above 66 years increased with increasing distance, while the proportion of 13- to 19 year olds decreased. The proportion of female patients decreased with increasing distance., Conclusions: The results confirm that increasing distance is associated with lower utilisation of out-of-hours services, even for the most acute cases. Extremely long distances might compromise patient safety. This must be taken into consideration when organising future out-of-hours districts.

Reactions to drug withdrawal may lead to unnecessary reintroduction and inappropriate prescribing. This problem is often encountered after long-term therapy with drugs acting on the cardiovascular and central nervous systems. The adverse effects include rebound effects, withdrawal syndrome, termination of drug-drug interaction, increased risk of disease and recurrence of disease. Lack of scientific evidence limits development of guidelines on how to terminate drug therapy. Slow and gradual tapering schedules for substances with long half-lives is usually recommended to avoid withdrawal syndrome and rebound effects. However, the most important measure is to avoid prescribing drugs that are difficult to withdraw. Appropriate information and involvement of the patient are also important.