Date Published: August 7, 2018
Publisher: Public Library of Science
Author(s): Anna Sidorchuk, Kayoko Isomura, Yasmina Molero, Clara Hellner, Paul Lichtenstein, Zheng Chang, Johan Franck, Lorena Fernández de la Cruz, David Mataix-Cols, Lars Åke Persson
Abstract: BackgroundPharmacoepidemiological studies have long raised concerns on widespread use of benzodiazepines and benzodiazepine-related drugs (BZDs), in particular long-term use, among adults and the elderly. In contrast, evidence pertaining to the rates of BZD use at younger ages is still scarce, and the factors that influence BZD utilisation and shape the different prescribing patterns in youths remain largely unexplored. We examined the prevalence rates, relative changes in rates over time, and prescribing patterns for BZD dispensation in young people aged 0–24 years in Sweden during the period January 1, 2006–December 31, 2013, and explored demographic, clinical, pharmacological, and prescriber-related attributes of BZD prescribing in this group.Methods and findingsThrough the linkage of 3 nationwide Swedish health and administrative registers, we collected data on 17,500 children (0–11 years), 15,039 adolescents (12–17 years), and 85,200 young adults (18–24 years) with at least 1 dispensed prescription for a BZD during 2006–2013, out of 3,726,818 Swedish inhabitants aged 0–24 years. Age-specific annual prevalence rates of BZD dispensations were adjusted for population growth, and relative changes in rates were calculated between 2006 and 2013. We analysed how BZD dispensation varied by sex, psychiatric morbidity and epilepsy, concurrent dispensation of psychotropic medication, type of dispensed BZD, and type of healthcare provider prescribing the BZD. Prescribing patterns were established in relation to duration (3 months, >3 to ≤6 months, or >6 months), dosage (<0.5 defined daily dosage [DDD]/day, ≥0.5 to <1.5 DDD/day, or ≥1.5 DDD/day), and “user category” (“regular users” [≥0.5 to <1.5 DDD/day for ≥1 year], “heavy users” [≥1.5 DDD/day for ≥1 year], or otherwise “occasional users”). Multinomial regression models were fitted to test associations between BZD prescribing patterns and individual characteristics of study participants. Between 2006 and 2013, the prevalence rate of BZD dispensation among individuals aged 0–24 years increased by 22% from 0.81 per 100 inhabitants to 0.99 per 100 inhabitants. This increase was mainly driven by a rise in the rate among young adults (+20%), with more modest increases in children (+3%) and adolescents (+7%). Within each age category, overall dispensation of BZD anxiolytics and clonazepam decreased over time, while dispensation of BZD hypnotics/sedatives, including Z-drugs, showed an increase between 2006 and 2013. Out of 117,739 study participants with dispensed BZD prescriptions, 65% initiated BZD prescriptions outside of psychiatric services (92% of children, 60% of adolescents, 60% of young adults), and 76% were dispensed other psychotropic drugs concurrently with a BZD (46% of children, 80% of adolescents, 81% of young adults). Nearly 30% of the participants were prescribed a BZD for longer than 6 months (18% of children, 31% of adolescents, 31% of young adults). A high dose prescription (≥1.5 DDD/day) and heavy use were detected in 2.6% and 1.7% of the participants, respectively. After controlling for potential confounding by demographic and clinical characteristics, the characteristics age above 11 years at the first BZD dispensation, lifetime psychiatric diagnosis or epilepsy, and concurrent dispensation of other psychotropic drugs were found to be associated with higher odds of being prescribed a BZD for longer than 6 months, high dose prescription, and heavy use. Male sex was associated with a higher likelihood of high dose prescription and heavy use, but not with being prescribed a BZD on a long-term basis (> 6 months). The study limitations included lack of information on actual consumption of the dispensed BZDs and unavailability of data on the indications for BZD prescriptions.ConclusionsThe overall increase in prevalence rates of BZD dispensations during the study period and the unexpectedly high proportion of individuals who were prescribed a BZD on a long-term basis at a young age indicate a lack of congruence with international and national guidelines. These findings highlight the need for close monitoring of prescribing practices, particularly in non-psychiatric settings, in order to build an evidence base for safe and efficient BZD treatment in young persons.
Partial Text: Widespread use of benzodiazepines and benzodiazepine-related drugs (BZDs) has long raised public health concerns, owing to the risks of developing tolerance, dependence, withdrawal syndromes, and severe adverse effects, particularly among long-term users [1–3]. A recently published perspective piece makes parallels between the contemporary epidemic of overprescribing of opioids and that of BZDs, with the former phenomenon being well acknowledged by clinicians and policymakers, while for the latter one a lesser effort is being made to address today’s prescribing practices . Current knowledge on BZD prescribing, incidence and prevalence rates, and patterns of use mainly rely on data on adults and the elderly, for whom BZDs are often prescribed for managing anxiety symptoms and insomnia [1,3]. International and national guidelines recommend using BZDs for no longer than 2–4 weeks since the risk–benefit ratio beyond that period is debatable [5–8]. Evidence pertaining to the corresponding issues in individuals at younger ages is limited, not least due to BZDs not being recommended as a pharmacological option for treatment of any psychiatric disorders in persons below 18 years of age [9–11]. Indeed, the only firmly established indications of BZDs in this age group are the control of different types of seizures and the treatment of status epilepticus [12–15]. Studies on BZD prescribing in children and adolescents consistently report low annual prevalence rates (0.3%–0.5% in North America  and 0.2%–0.9% in Europe [17–20]), while the results of time-trend analyses appear to vary between countries. Over the last 2 decades, BZD prescription rates have increased in children and adolescents in various Western countries [16,21,22], while remaining stable or decreasing in others [17,18,21]. Depending on how each study defines the age boundaries for the category of young adults, BZD prescription rates are reported to range between 1% and 5%, and to mainly increase over time [21,23,24]. Noteworthy is that recent European data on new BZD users show a low and decreasing incidence in the age group below 18 years . This, in light of stable or increasing prevalence rates, points towards a risk for chronic BZD use in this population.
This total population register-based study is among the first to systematically evaluate BZD dispensation and its attributes among children, adolescents, and young adults at a nationwide level. There were 5 principal findings. First, the study indicated a 22% increase in the prevalence rate of BZD dispensation between 2006 (0.81 per 100 inhabitants) and 2013 (0.99 per 100 inhabitants) in the population aged 0–24 years. This increase was mainly driven by a steady rise in the rate among young adults, with more modest increases in children and adolescents. Second, in all age categories of those with dispensed BZD prescriptions, a high proportion of polypharmacy was observed, with almost half of children and over 80% of adolescents and young adults having been dispensed other psychotropic drugs concomitantly with a BZD. Third, off-label BZD prescription was common. This was particularly notable in adolescents, among whom a substantial proportion were dispensed zopiclone and zolpidem—drugs that are not approved for ages below 18 years, according to international and Swedish pharmaceutical guidelines [5,50]—with a marked increase in dispensations of both drugs between 2006 and 2013 in this age group. Fourth, although the type of healthcare provider that initiated BZD prescriptions varied between the age categories, the prescribers were mainly outside of specialised psychiatric services; approximately 65% of all prescriptions originated either in primary care or non-psychiatric specialist services. Fifth, the most alarming results came from the analyses of prescribing patterns, with an unexpectedly high proportion of individuals across all ages being prescribed a BZD on a long-term basis—nearly every fifth child and every third adolescent and young adult among those who received a BZD in 2006–2013 were prescribed such medication for longer than 6 months. An elevated likelihood of long-term prescribing was associated with age above 11 years at first BZD dispensation, lifetime diagnosis of any psychiatric disorder or epilepsy, and concomitant dispensation of other psychotropic medication. Sensitivity analyses provided additional evidence of long-term prescribing being a common phenomenon, as the proportion of adolescents and young adults who were prescribed a BZD for longer than 6 months remained large even when individuals with lifetime diagnosis of epilepsy were excluded. Among children, although the proportion of those prescribed a BZD on a long-term basis dropped by 80% after excluding those with lifetime diagnosis of epilepsy, BZD prescribing for longer than 6 months remained present in nearly 4% of study participants in this age group.