Drug dependency may develop during long-term benzodiazepine use, indicated, for example, by dose escalation. The first benzodiazepine chosen may affect the risk of dose escalation.
To detect possible differences in benzodiazepine use between new users of diazepam and oxazepam over time.
This 5-year prescription database study included 19 747 new benzodiazepine users, inhabitants of Norway, aged 30-60 years, with first redemption for diazepam or oxazepam.
Individuals starting on diazepam versus oxazepam were analysed by logistic regression with sex, age, other drug redemptions, prescriber's specialty, household income, education level, type of work, and vocational rehabilitation support as background variables. Time to reach a daily average intake of =1 defined daily doses (DDD) over a 3-month period was analysed using a Cox proportional hazard regression model.
New users of oxazepam had a higher risk for dose escalation compared with new users of diazepam. This was true even when accounting for differences in sociodemographic status and previous drug use (hazard ratio [HR] 1.33, 95% confidence interval = 1.17 to 1.51).
Most doctors prescribed, according to recommendations, oxazepam to individuals they may have regarded as prone to and at risk of dependency. However, these individuals were at higher risk for dose escalation even when accounting for differences in sociodemographic status and previous drug use. Differences between the two user groups could be explained by different preferences for starting drug, DDD for oxazepam being possibly too low, and some unaccounted differences in illness.
To identify risk factors for becoming an excessive user over time.
Prescription database study over five years.
Norwegians between 30 and 60 years with a first dispensation of a benzodiazepine during 2006, encompassing 23 227 individuals. A Cox hazard regression model was defined, initially stratifying on gender, age, county, previous relevant drug dispensations, household income, education level, and vocational rehabilitation support.
The time from the first redemption until excessive use was defined as using more than two DDDs per day on average within a three-month period.
Women's risk was lower than men's for excessive use (HR = 0.42, CI 0.35-0.51). Initial oxazepam, alprazolam, or nitrazepam/flunitrazepam use indicated higher risk compared with diazepam (HR = 1.51, CI 1.24-1.85, HR = 2.75, CI 1.54-4.91, HR = 1.67, CI 1.29-2.16). Previous antidepressants or lithium, antipsychotics or opioids, anti-alcohol and smoke cessation treatment indicated a higher risk compared with no such use (HR = 1.4, CI 1.16-1.69, HR = 1.92, CI 1.54-2.4, and HR = 2.88, CI 2-4.15). Higher education and average or high household income were associated with a low risk compared with low education and income (HR = 0.68, CI 0.57-0.81, HR = 0.58, CI 0.46-0.73, and HR = 0.37, CI 0.26-0.54). Working in the private or public sector was associated with a low risk compared with no registered work (HR = 0.53, CI 0.4-0.71 and HR = 0.57, CI 0.45-0.74).
The prevalence of excessive use over a five-year observation period was 2.34%. Risk factors were indications of psychiatric illness, first benzodiazepine choice, low income, and education. Excessive users were also characterized by a more severe disease, indicated by having prescription fulfilments by a psychiatrist and by switching benzodiazepines. Key points Guidelines state that benzodiazepines should be used for a short time and excessive use indicates drug dependency. Of all new benzodiazepine users 2.34% became excessive users, defined as consuming above two defined daily doses (DDDs) per day on average over three months, within a five-year period. Previous use of other psychotropic drugs, opioids and anti-alcohol and smoke cessation drugs, first benzodiazepine prescribed, low household income, and low education were risk factors for excessive use. Excessive users were characterized by switching benzodiazepines and having prescription fulfilments by a psychiatrist suggesting a more severe disease.
Cites: J Am Podiatr Med Assoc. 2003 Jan-Feb;93(1):42-5012533556
In Norway, total sales of benzodiazepines and Z drugs (zopiclone and zolpidem) have increased since the mid-1990s. On the basis of data from the Norwegian Prescription Database, we have studied the choice of medications and patterns of use in various gender and age groups.
Numbers for redemptions of benzodiazepines and Z drugs in Norwegian pharmacies for the years 2004-2011 were collected from the Prescription Registry. Population figures were collected from Statistics Norway. Consumption was calculated by the number of DDDs (defined daily doses).
Among those who were supplied with benzodiazepines or Z drugs, recipients of more than 2 DDDs per day (heavy users) accounted for a small group. We registered an extensive use of Z drugs among older women, many of whom were prescribed an amount corresponding to a regular daily use of 1-2 DDDs. The total prescription of alprazolam and nitrazepam/flunitrazepam was minor, but high dosages were not uncommon among those who were prescribed these drugs. Only a small proportion of the patients who were prescribed clonazepam received a reimbursable prescription. The prescribing of a number of benzodiazepines and Z drugs at the same time remains not uncommon.
Prescribing of Z drugs to the elderly, and to women in particular, may indicate that many people in this group are regular users of sedative hypnotics, which is contrary to the guidelines. A considerable proportion of the prescriptions for clonazepam are outside of the approved indications. Among the users of the drugs studied, only a small fraction were heavy users, but since the use is widespread, this represents a considerable number of individuals.
Comment In: Tidsskr Nor Laegeforen. 2013 Oct 29;133(20):211824172611
The antipsychotic agent quetiapine was introduced in Norway in 2003. We have assessed changes in dispensed prescriptions, including dosing, of quetiapine in Norway from 2004 to 2015.
Data on the sales of antipsychotics and antidepressants were drawn from the Norwegian Prescription Database. A total of 47,474 outpatients filled 195,622 prescriptions of quetiapine. Reimbursement codes, use of antipsychotics or antidepressants 12 months prior to the first prescription of quetiapine and estimated mean volume used measured as defined daily doses (DDDs) per day were used as proxies for diagnoses. We conducted a regression analysis with DDD per day as a function of possible explanatory variables.
The number of users filling at least two prescriptions of quetiapine per year increased from 584 in 2004 to 8506 in 2015 and the mean dose declined from 1.58 DDD per day (SD 8.00) to 0.48 DDD per day (SD 2.27). The latter is much lower than recommended for treatment of psychoses. In 2015, 60.1% of the 8506 quetiapine users did not seek reimbursement for the treatment of a major psychiatric disorder and only 2.6% of the patients were prescribed 1 DDD or more per day and reimbursed in accordance with the drug's primary indication, psychosis. A reported diagnosis of psychosis was not associated with higher quetiapine doses.
In 2015, the pattern of quetiapine dispensing in Norway most likely reflects predominant off-label use. This is unsettling considering poorly documented effects in non-psychotic disorders, profound side effects, significant toxicity and growing concern regarding abuse.
Legislative limits for driving under the influence of 20 non-alcohol drugs were introduced in Norway in February 2012. Per se limits corresponding to blood alcohol concentrations (BAC) of 0.2g/kg were established for 20 psychoactive drugs, and limits for graded sanctions corresponding to BACs of 0.5 and 1.2g/kg were determined for 13 of these drugs. This new legislation made it possible for the courts to make sentences based on the analytical results, similar to the situation for alcohol. To ensure that the reported concentration is as least as high as the true concentration, with a 99% safety level, safety margins had to be calculated for each of the substances. Diazepam, tetrahydrocannabinol (THC) and alcohol were used as model substances to establish a new model for estimating the safety margins. The model was compared with a previous used model established several years ago, by a similar yet much simpler model, and they were found to be in agreement. The measurement uncertainties depend on the standard batch used, the work list and the measurements' replicate. A Bayesian modelling approach was used to determine the parameters in the model, using a dataset of 4700 diazepam positive specimens and 5400 THC positive specimens. Different safety margins were considered for low and high concentration levels of diazepam (=2µM (0.6mg/L) and >2µM) and THC (=0.01µM (0.003mg/L) and >0.01µM). The safety margins were for diazepam 19.5% (=2µM) and 34% (>2µM), for THC 19.5% (=0.01µM) and 24.9% (>0.01µM). Concentration dependent safety margins for BAC were based on a dataset of 29500 alcohol positive specimens, and were in the range 10.4% (0.1g/kg) to 4.0% (4.0g/kg) at a 99% safety level. A simplified approach was used to establish safety margins for the compounds amphetamine, MDMA, methamphetamine, alprazolam, phenazepam, flunitrazepam, clonazepam, nitrazepam, oxazepam, buprenorphine, GHB, methadone, ketamine, cocaine, morphine, zolpidem and zopiclone. The safety margins for these drugs were in the range 34-41%.
The World Health Organization recommends the defined daily dose (DDD) as the standard unit of measurement for antibiotic use, but this is not applicable in children. We aimed to assess paediatric antibiotic use in a Norwegian tertiary care hospital using a novel weight-adjusted method.
We obtained antibiotic purchase data from the hospital pharmacy and administrative data for all admissions from 2002 to 2009 to the paediatric wards at Oslo University Hospital, Rikshospitalet. Recommended daily doses per 100 kg days (RDDs/kg days) were calculated based on national guidelines for paediatric antibiotic use, length of stay and estimated weight for sex and age using national growth references.
Total antibiotic use increased significantly from 51.8 to 65.5 RDDs/100 kg days. We found statistically significant annual increases in the consumption of carbapenems (18.0%), third-generation cephalosporins (6.0%) and imidazole derivatives (6.6%) and a considerable difference between total antibiotic use measured in RDDs/100 kg days and DDDs/100 bed days for neonates.
Weight-adjusted antibiotic use provided a more meaningful description of the quantities of antibiotics consumed than DDDs/100 bed days, particularly for neonates. Total antibiotic use, use of meropenem, third-generation cephalosporins and imidazole derivatives increased significantly despite low prevalence of antibiotic-resistant pathogens.
Association between previous antibiotic use and emergence of antibiotic resistance has been reported for several microorganisms. The relationship has been extensively studied, and although the causes of antibiotic resistance are multi-factorial, clear evidence of antibiotic use as a major risk factor exists. Most studies are carried out in countries with high consumption of antibiotics and corresponding high levels of antibiotic resistance, and currently, little is known whether and at what level the associations are detectable in a low antibiotic consumption environment. We conduct an ecological, retrospective study aimed at determining the impact of antibiotic consumption on antibiotic-resistant Pseudomonas aeruginosa in three hospitals in Norway, a country with low levels of antibiotic use. We construct a sophisticated statistical model to capture such low signals. To reduce noise, we conduct our study at hospital ward level. We propose a random effect Poisson or binomial regression model, with a reparametrisation that allows us to reduce the number of parameters. Inference is likelihood based. Through scenario simulation, we study the potential effects of reduced or increased antibiotic use. Results clearly indicate that the effects of consumption on resistance are present under conditions with relatively low use of antibiotic agents. This strengthens the recommendation on prudent use of antibiotics, even when consumption is relatively low.