Use of addictive anxiolytics and hypnotics in a national cohort of incident users in Norway

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1 Eur J Clin Pharmacol (2012) 68: DOI /s PHARMACOEPIDEMIOLOGY AND PRESCRIPTION Use of addictive anxiolytics and hypnotics in a national cohort of incident users in Norway Svein R. Kjosavik & Sabine Ruths & Steinar Hunskaar Received: 28 May 2011 / Accepted: 30 August 2011 / Published online: 18 September 2011 # Springer-Verlag 2011 Abstract Purpose To examine (1) incidence rates for treatment with addictive anxiolytics and hypnotics in Norway, (2) the proportions initiated by general practitioners (GPs), psychiatrists, and other physicians, and (3) the course of the treatment among incident users during a 3.5 year follow-up period. Method Data on all prescriptions of anxiolytics (ATC code N05B) and hypnotics (N05C) dispensed to the general population from 1 January 2004 to 31 August 2009 were extracted from the Norwegian Prescription Database and merged with data about GPs from the Norwegian Regular General Practitioner Scheme. Results One-year incidence rates per 1,000 inhabitants were 18.2 for anxiolytics, 24.5 for hypnotics, and 35.4 for anxiolytics and hypnotics combined. GPs and psychiatrists initiated the treatment to 75.4 and 2.4%, respectively. Only 30.8% received short-term treatment as recommended. Long-term use (11.8%) and heavy use (1.4%) were most common for treatments initiated by a GP, but the risk both of long-term and of heavy use was highest for patients initially treated by a psychiatrist. The amount redeemed during the first quarter was the strongest predictor of longterm use and of heavy use. However, even during the quarter with highest drug consumption, 81.5% of the patients received <1 DDD/day. S. R. Kjosavik (*) : S. Ruths : S. Hunskaar Research Group for General Practice, Department of Public Health and Primary Health Care, University of Bergen, P.O. Box 7804, 5020 Bergen, Norway svein.kjosavik@isf.uib.no S. R. Kjosavik : S. Ruths Research Unit for General Practice in Bergen, Uni Health, Bergen, Norway Conclusions This study indicates that physicians prescribing strategy towards initial users is crucial in order to prevent inappropriate drug use. There is a need to implement relevant guidelines and systems for structured clinical audits in general practice. Keywords Anxiolytics. Hypnotics. Incidence. Long-term use. General practitioners. Psychiatrists Introduction Anxiolytics and hypnotics are approved for the treatment of anxiety disorders, acute agitation and confusion, convulsions and muscular spasm, alcoholic withdrawal symptoms, and insomnia. Although proper use of these drugs effectively relieves symptoms, benzodiazepine (BZD) anxiolytics and hypnotics as well as z-hypnotics are considered addictive by the Norwegian Medicines Agency due to side effects such as development of tolerance, risk of misuse, and dependence [1, 2]. Other harmful side effects include hangover, rebound effect, increased risk of traffic and other accidents, as well as cognitive impairment, and risk of falls and fractures in older people [3 5]. Treatment guidelines recommend short-term use only, i.e., 2 4 weeks, provided that symptoms are severe, disabling, and causing extreme distress [6 10]. However, studies indicate that drug use for longer periods or in higher doses than recommended is prevalent and associated with patient characteristics such as old age, low level of education, social problems, multiple drug use, and high drug consumption during the first year of use [11 13]. The Norwegian Medicines Agency has assigned all prescription drugs to three classes. Ordinary prescription drugs are placed in class C, addictive drugs such as BZDs

2 312 Eur J Clin Pharmacol (2012) 68: and z-hypnotics in class B, and narcotics such as opioids and central stimulants in class A. Prescription groups A and B are for single use only. In order to increase awareness of the abuse potential and to achieve a stricter prescribing practice, the BZD hypnotic flunitrazepam was transferred from class B to A in January 2003 [14]. Physicians and dentists as well as veterinarians are authorized to prescribe anxiolytic and hypnotic drugs. The governmental reimbursement system does not include these drugs, except for terminal care of patients with malignant diseases or treatment of epilepsy. Compared to the other Nordic countries, Norway has a moderate sales level of anxiolytics and hypnotics [15], with prevalence rates of 6.2 and 7.9% in 2005 for anxiolytics and hypnotics, respectively [16]. However, systematic knowledge is sparse regarding incident use of anxiolytics and hypnotics, which prescribers initiate treatment with these drugs, and to what extent they comply with recommendations. The purpose of this study was to examine (1) incidence rates for treatment with addictive anxiolytics and hypnotics in Norway, (2) the proportions initiated by GPs, psychiatrists, and other physicians, (3) and the course of the treatment among incident users during a 3.5 year period of follow-up. Materials and methods Data sources This study is based on merged data from two sources: the Norwegian Prescription Database (NorPD) maintained at the Norwegian Institute of Public Health, and the Regular General Practitioner Database at the Norwegian Social Science Data Services. NorPD is a national health register containing information on all prescription drugs dispensed at all Norwegian pharmacies to community-dwelling individuals from 1 January The register covers medications fully paid for by patients, as well as those reimbursed by the government. Detailed information on dispensed drugs and basic demographic information on patients and prescribers are stored in the database, but information is lacking on medications issued to institutionalized patients in nursing homes and hospitals [17]. The following variables were used in the present study: patients and prescribers unique personal identifying code, age, and gender; patients death month and year; prescribers profession and approved clinical specialty; dispensed items generic name, Anatomical Therapeutical Chemical (ATC) code, strength, number of packages, and defined daily dose (DDD) [18]. A national regular GP scheme was implemented in Norway in 2001, giving all inhabitants the right to choose a GP as their regular doctor [19]. The reform aimed at improving the quality and availability of health services for patients with chronic conditions. More than 99% of the population is contracted to a GP, and both patients and GPs are mainly satisfied with the reform [20, 21]. The Regular GP Database contains monthly updated information on individual GP patient populations, derived from the Norwegian Labour and Welfare Service [22]. In this study we used the Regular GP Database to distinguish doctors working in general practice from those employed elsewhere in the health care system. The variables extracted from the Regular GP Database include GPs unique prescriber code and their patient population by age and gender, at the end of February, May, August, and November during the period from January 2004 until August Data from both sources were merged by Statistics Norway, using patients and prescribers unique encrypted identifying code, enabling us to analyze the data at the individual level while personal anonymity was ensured. Material Information on all prescriptions of anxiolytics (ATC subgroup N05B) and hypnotics (N05C) redeemed in Norway from 1 January 2004 until 31 August 2009 was extracted from NorPD. In this study, only anxiolytics and hypnotics classified by the Norwegian Medicines Agency as class A or B drugs and prescribed as oral formulations were included, and hereafter referred to as anxiolytics and hypnotics (Table 1). Consequently, the following drugs were excluded: hydroxyzine, buspirone, and scopolamine (class C drugs); midazolam (only parenteral formulation); barbital (used by fewer than five patients); lorazepam, clobazam, meprobamate, triazolam, and zaleplon (drugs not approved by the Norwegian Medicines Agency in 2005); and clonazepam (only approved as an anticonvulsive drug in Norway, ATC code N03AE01). Drugs prescribed by dentists or veterinarians were also excluded. The year 2004 was defined as baseline. The whole year of 2005 was defined as the inclusion period, and the period from 1 January 2006 until 31 August 2009 was defined as follow-up period. Included in the study cohort were all patients who redeemed one or more prescriptions of addictive anxiolytics or hypnotics during 2005, provided that they did not receive any of these drugs during 2004 (Table 1). Methods For each included patient, the day of the first redeemed prescription of anxiolytics or hypnotics was set as the index day. All further prescriptions of these drugs released during the next 1,274 days (14 quarters defined as 91 consecutive days) were included in the analyses.

3 Eur J Clin Pharmacol (2012) 68: Table 1 Addictive anxiolytics and hypnotics included in the study, with Anatomical Therapeutic Chemical (ATC) codes and defined daily dose (DDD), and the distribution of redeemed initial prescriptions Drug ATC Code DDD Prescriptions Number Percentage Anxiolytics 62, Diazepam N05BA01 10 mg 34, Oxazepam N05BA04 50 mg 27, Alprazolam N05BA12 1 mg Hypnotics 92, Zopiclone N05CF mg 75, Zolpidem N05CF02 10 mg 10, Nitrazepam N05CD02 5 mg 4, Flunitrazepam N05CD03 1 mg Clometiazole N05CM02 1,500 mg In order to categorize patients drug use according to volume and length, the total volume (DDD) of anxiolytics and hypnotics released during the 1,274 days from index day were summarized per patient. In addition, the number of quarters with at least one prescription released, and the drug volume (DDD) per quarter were calculated per patient. We defined three groups based on the following criteria: short-term users only redeemed prescriptions during the first quarter and received a total volume of 30 DDD; longterm users redeemed prescriptions in 3 quarters in a row and received >180 DDD in total during the three quarter period; heavy users received an average of 3 DDD/day during the quarter with highest redeemed drug volume. These definitions of long-term and heavy use are meant for regression analysis, not for clinical purposes. Further, patients were divided into two groups according to the amount of drug received at index day (i.e., <50DDD or 50DDD) and into five groups according to the total volume of anxiolytics and hypnotics redeemed during the first quarter (i.e., 20 DDD, >20 and 30 DDD, >30 and 75 DDD, >75 and 120 DDD, and >120 DDD). NorPD includes information about prescribers specialties, but no information about their actual working place. The Regular GP Database comprises all physicians working as GPs, but no information about specialty. Based on the merged data, we assigned the prescribers to four groups. All physicians registered in the Regular GP Database were defined as GPs, including specialists in family medicine (73%), physicians without specialty (25%), and other specialists working as GPs (2%). Since the working place for physicians not registered in the Regular GP Database was unavailable, we defined all specialists in psychiatry and physicians approved as specialists in psychiatry during the study period as psychiatrists. Prescribers neither working as GPs nor defined as psychiatrists were labeled other specialists if they were approved for any specialty before or during the study period. All others were labeled without specialty. Physicians without specialty are mainly residents in various clinical departments and fully authorized to prescribe drugs. In order to categorize the physician s prescribing practice of addictive anxiolytics and hypnotics, the total dispensed volume of these drugs to the general population in Norway in 2005 was calculated for each physician. Subsequently, all prescribers were divided into six groups according to issued volume: 10,000 DDD; >10,000 and 18,000 DDD; >18,000 and 27,000 DDD; >27,000 and 38,000 DDD; >38,000 and 52,000 DDD; and >52,000. Each of these groups prescribed similar shares of the total dispensed volume. In addition, GPs were split into five groups according to their mean enlisted population in 2005: <1,000, 1,000 1,199, 1,200 1,399, 1,400 1,599, 1,600. The denominators used for calculations of annual rates were according to the figures from Statistics Norway as regards the mean population of men and women in different age groups and in total. According to these figures the total Norwegian population in 2005 comprised 4,623,291 persons [23]. Statistical analysis The research database comprised 945,702 prescriptions of addictive anxiolytics and hypnotics. Prescriptions (n=996) from unidentified prescribers (n=16) were included in all analyses except regression analysis (numerators marked in tables). Data were analyzed by means of descriptive statistical methods. The follow-up analysis (Fig. 1) shows the share of the included patients who redeemed at least one prescription for each specific quarter. The calculation was performed by dividing all patients redeeming at least one prescription in the quarter by the number of included patients still alive in that quarter, assigned to the prescriber group that initiated the treatment.

4 314 Eur J Clin Pharmacol (2012) 68: Fig. 1 The share of incident users in 2005 who redeemed at least one prescription in each subsequent quarter after the initial prescription, assigned to the prescriber group that initiated the treatment. (Quarter 1 included all, i.e., 100%) Logistic regression analysis was performed to examine the predictive value of patient and physician characteristics and initially prescribed drugs on the risk of patients becoming long-term users or heavy users during the follow-up period. First, an unadjusted logistic regression analysis was performed for the different drugs prescribed initially, and the risk of long-term or heavy use. Second, an adjusted regression analysis based on the block procedure was conducted for all actual variables included concomitantly in the model. Reference values for each variable are shown in the tables. Effect estimates are presented as odds ratios (ORs) with 95% confidence intervals (CIs). STATA software version 9.2 (Stata, College Station, TX, USA) was used. Ethics and approvals The Regional Committee for Medical and Health Research Ethics, the Norwegian Directorate for Health and Social Affairs, and the Norwegian Data Inspectorate approved the study. Results The study population of incident users of addictive anxiolytic and hypnotic drugs comprised 151,079 patients with a mean age of 53.3 years [women 53.8 (SD 18.8) and men 52.6 (SD 19.3)], and 60.6% were women. Altogether 12,122 (8.0%) included patients died during the study period. They had a mean age of 73.6 years [women 75.1 (SD 14.6) and men 69.4 (SD 14.7)], and 46.3% were women. None of the initial prescriptions were covered by the reimbursement system. During follow-up 4,284 (0.45%) of all prescriptions were reimbursed concerning 1,282 (0.85%) of the patients 1,118 for terminal cancer, 154 for epilepsy, and 10 for unknown diagnosis. Of initial users, 38.7% received anxiolytics only, 58.4% hypnotics only, and 2.9% both anxiolytics and hypnotics. Initial prescriptions of anxiolytics comprised long-acting benzodiazepines (55.8%) and short-acting benzodiazepines (44.2%), while initially prescribed hypnotics were mainly z-hypnotics (93.4%) (Table 1). One-year incidence rates per 1,000 inhabitants were 18.2 for anxiolytics, 24.5 for hypnotics, and 35.4 for anxiolytics and hypnotics combined. For both drug groups, incidence rates increased with patients age. For all age groups, incidence rates were higher for women than men, except those aged 80 years and older receiving hypnotics. The differences between the genders were significant for all age groups (P < ), except for the youngest users of anxiolytics (Table 2). For new users 20 years and older, GPs initiated the treatment with anxiolytics for 72.0% and hypnotics for 79.8%. Of patients younger than 20 years, 37.5 and 64.9% received their first prescriptions of anxiolytics and hypnotics from a GP, and 5.0 and 9.8% from a psychiatrist. Psychiatrists share of initial prescriptions declined rapidly with patients age, accounting for 1.3% for patients aged 60 and older (Table 2). Long-term use and heavy use The prospective part of the study revealed that, according to our definitions, 30.8% of the study population received short-term, 11.8% long-term, and 1.4% heavy treatment (Table 3). Altogether 81.5% of the initial users redeemed less than 1 DDD/day on average during the quarter they received most. Short-term users redeemed anxiolytics only or hypnotics only in 97.9% of cases, while long-term and heavy users received drugs from both groups in 54.1 and 77.1% of the cases, respectively (Table 3). Of the cohort, 54,543 (36.1%) redeemed prescriptions in the first quarter only, while 3,350 (2.2%) redeemed drugs in each and every quarter throughout the follow-up period. For each specific quarter on average 21.8% of the included patients redeemed at least one prescription. Figure 1 shows the share of the incident users still alive, who received at least one prescription in each specific quarter, assigned to the prescriber group that initiated the treatment. As compared to patients initially treated by a GP, a larger share of patients initially treated by a psychiatrist, and a smaller share of those initially treated by other prescribers received drugs in quarters 2 8. Predictors of long-term use and of heavy use Using diazepam as reference drug, unadjusted logistic regression analysis revealed that initial prescriptions of

5 Eur J Clin Pharmacol (2012) 68: Table 2 One-year incidence rate per 1,000 inhabitants for use of addictive anxiolytics and hypnotics in Norway in 2005 by patients age and gender, and the distribution of the prescribers of the initial prescriptions (%) Incidence rates (unique patients) Distribution of the initial prescriber (unique patients) Anxiolytics Age group (years) Patients (80,573) Women (49,758) Men (30,815) GPs (59,395) Psychiatrists (2,248) Other specialists (8,609) Without specialty (10,321) < Overall rate Hypnotics Age group (years) Patients (106,970) Women (64,548) Men (42,422) GPs (80,015) Psychiatrists (2,798) Other specialists (10,396) Without specialty (13,761) < Overall rate Anxiolytics and hypnotics combined Age group (years) Patients (151,079) Women (91,635) Men (59,444) GPs (113,925) Psychiatrists (3,653) Other specialists (15,299) < Overall rate GP General practitioner Differences between genders were significant for all age groups (P<0.0001) except for the youngest group receiving anxiolytics Without specialty (18,202) alprazolam, flunitrazepam, and nitrazepam were strong predictors of long-term use while alprazolam and flunitrazepam also were highly associated with heavy use (Table 4). When adjusting for other variables, associations with initial drugs were weakened, and the total drug volume redeemed during the first quarter emerged to be the strongest predictor both of long-term and of heavy use (Table 5). The odds ratio for long-term use was 22.6 (CI ) for patients redeeming >120 DDD during the first quarter, compared with the reference group redeeming >20 and 30 DDD. The corresponding figure for heavy use was OR 37.3 (CI ). Even the drug volume received the first day had a substantial influence on the risk, with OR 2.27 (CI ) for long-term use and OR 4.48 (CI ) for heavy use for patients redeeming 50 DDD, compared with patients redeeming <50 DDD (not shown in table). The risk of long-term use also increased with patients age, and when treatment was initiated by a psychiatrist, a young doctor, or a physician with a large overall drug prescribing volume. Heavy use was predicted by relatively younger patient age, male gender, and when treatment was initiated by a heavy prescriber or a psychiatrist. In a separate logistic regression analysis, only the patients initially treated by a GP were included. The total number of patients on the GPs list was included as an additional variable. The analysis revealed a decreased risk both of long-term use and of heavy use with increased number of patients on the GPs list. The risk of long-term

6 316 Eur J Clin Pharmacol (2012) 68: Table 3 The mean volume of addictive anxiolytics and hypnotics per day per patient in the quarter with largest redeemed volume, in defined daily doses (DDD), and distribution of drugs received by users assigned to short-term, long-term, and heavy use use had an OR of 0.74 (CI ) and of heavy use an OR of 0.63 (CI ) if the GP had 1,600 enlisted patients, compared to physicians with <1,000 patients (not shown in table). Discussion Total Women Men All users (n=151,079) Mean DDD/day (%) < > Short-term users (n=46,591) Share of all users (%) Gender distribution (%) Drugs received Anxiolytics only Hypnotics only Both drug groups Long-term users (n=17,752) Share of all users (%) Gender distribution (%) Drug received Anxiolytics only Hypnotics only Both drug groups Heavy users (n=2,112) Share of all users (%) Gender distribution (%) Drug received Anxiolytics only Hypnotics only Both drug groups Short-term users Patients receiving prescriptions in the first quarter only and 30 DDD in total, long-term users patients receiving prescriptions in 3 quarters in a row and >180 DDD in total during the three quarter period with highest redeemed volume, heavy users patients receiving 3 DDD per day on average during the quarter with highest redeemed volume This study reveals overall incidence rates per 1,000 inhabitants of 18.2 for anxiolytics and 24.5 for hypnotics classified as addictive in Norway in Corresponding Norwegian figures for antipsychotics and antidepressants in 2008 were 3.4 and 8.6, respectively [24]. These findings confirm that anxiolytics and hypnotics are still more commonly introduced to new users than other psychotropic drugs. Z-hypnotics emerged as preferred sleeping medications, complying with guidelines, while long-acting anxiolytics accounted for more than half of initial anxiolytics. Our study confirms that the actual treatment length for anxiolytics and hypnotics deviates from recommendations, as short-term treatment was provided for only 30.8% of the cohort. Long-term treatment and even heavy use may be appropriate for some patients, especially in palliative care, but such indications can hardly explain our findings as the proportion of reimbursed prescriptions for patients with cancer or epilepsy was less than 1%. The risk of long-term use and heavy use was strongly associated with the drug volume redeemed during the first quarter, in line with a study from the Netherlands [25]. Our study demonstrates that even the drug volume received on index day had significant impact on the risk of long-term use and heavy use. Of initially prescribed drugs, alprazolam was associated with a particularly high risk of subsequent heavy use. Compared to other BZDs, alprazolam is more often prescribed for younger men, and drug withdrawal seems to be more difficult. The Norwegian Medicine Agency has stated that a majority of fabricated prescriptions detected in Norwegian pharmacies were for alprazolam [26]. Studies based on prevalence rates have shown that the risk of long-term use increased with patients age [11, 13]. Our study confirms this trend for incident users too, but the risk of heavy use was highest among male adults aged and declined with higher age. Probably, younger users include more patients with mental problems who use anxiolytics or hypnotics prescribed by psychiatrists, while older patients tend to have chronic illnesses and get treatment that may be prescribed by GPs or other specialists treating their chronic illnesses. The responsibility and key role of GPs in the Norwegian health care system has been clarified by the introduction of the Regular GP Scheme. Referral from a GP is mandatory for service in secondary care, and the majority of patients are treated in primary health care only. Patients whose treatment was initiated by a psychiatrist were at highest risk both of long-term use and of heavy use. However, GPs initiated treatment with anxiolytics and hypnotics for the vast majority of new users, and consequently, most long-term users and heavy users received their first prescription from a GP. Physicians prescribing profile had a significant impact on patients risk of long-term use, and even more of heavy use, i.e., frequent prescribers initiated long-term use and heavy use more often than other physicians.

7 Eur J Clin Pharmacol (2012) 68: Table 4 The crude association between the included drugs redeemed at index day, and long-term use or heavy use, calculated as odds ratio (OR) with 95% confidence interval (CI) a Patients who died during the study period and prescriptions lacking information on any variable were excluded from the analysis Drugs redeemed the index day (n=139,740 a ) Long-term use Heavy use Drug Number Percentage OR CI OR CI Diazepam 31, Reference 1 Reference Oxazepam 24, Alprazolam Nitrazepam 4, Flunitrazepam Zopiclone 67, Zolpidem 10, Clometiazole Statistics χ 2 (7) = 1, χ 2 (7) = p<0.0001, R 2 = p<0.0001, R 2 = Our findings underscore the need for increased compliance with treatment recommendations. The most appropriate strategy to decrease problematic use of anxiolytics and hypnotics is a preventive approach with limited amounts of drug prescribed for short-term use. As a signal to emphasize the importance of this recommendation, the health authorities should consider restrictions with regard to prescribing large drug packages. The exceptions are palliative care and epilepsy where long-term treatment often is necessary and covered by the reimbursement system in Norway. We were not able to identify any other studies revealing incidence rates for anxiolytics or hypnotics, except one study based on the same prescription database as this study that examined prescribing of hypnotics to the general Norwegian population between 18 and 69 years old. That study revealed similar incidence figures as our study, when comparing corresponding age groups [27]. To our knowledge, this is the first population-based study assessing the initiation of treatment with anxiolytics and hypnotics by different prescriber groups. A telephone survey in France, Italy, Germany, and UK conducted in revealed that, of the total consumption, GPs prescribed 69.8% of anxiolytics and 81.5% of hypnotics, while psychiatrists issued 6.1 and 5.7%, respectively [28]. A study of BZD treatment in psychiatric specialist practice in Italy [29] showed that 30% of patients registered in the local Psychiatric Case Register in the South Verona catchment area used BZD in Long-term treatment was observed in most cases and treatment discontinuation was unusual, especially in the elderly and in those using BZDs for more than 1 year. Other studies have shown that specialists in internal medicine and psychiatry issued highquantity prescriptions to a greater extent than other physicians, and patients receiving prescriptions by other prescribers than GPs had a higher risk of long-term use [11, 30 32]. A Norwegian interview study of GPs regarding BZD prescribing revealed consensus about proper practice among low, medium, and high prescribers, but high prescribers had more difficulty refusing demands from patients [33]. However, several limitations should be taken into consideration. Dispensed prescriptions served as proxy for drugs consumed by the patients, as well as for drugs prescribed by the physicians. Although psychotropic drugprescribing patterns to a certain extent may reflect the efforts made by different healthcare providers towards their patients, mental health care comprises many other aspects than pharmacotherapy. Lack of diagnostic information in NorPD hampered investigation of patients morbidity and indications for drug use. Differences in prescribing patterns between the different prescriber groups found in this study may thus be confounded by indication. In addition, patients in hospitals and nursing homes are not included. Information was lacking about prescribers working field in areas other than general practice. Residents in psychiatry, who may be expected to have prescribing patterns similar to specialists in psychiatry, could consequently not be distinguished from residents in other departments. The incidence rate may be overestimated due to a baseline period of only 1 year. Patients may have used anxiolytics or hypnotics earlier, but not during baseline. If the treatment was reactivated during our inclusion period, the patients were incorrectly recognized as new users. In addition, no information was available about patients who bought drugs legally abroad or illegally on the black market. Neither do we know the occurrence of false prescriptions. Conclusion Physicians prescribing strategy towards incident users seems to be crucial. This study revealed that only one out of three new users of addictive anxiolytics and hypnotics

8 318 Eur J Clin Pharmacol (2012) 68: Table 5 The association between selected variables and long-term use or heavy use, calculated as odds ratio (OR) with 95% confidence interval (CI) a Long-term users Patients receiving prescriptions in 3 quarters in a row and >180 DDD in total during the three quarter period with highest redeemed volume, heavy users patients receiving 3 DDD per day on average during the quarter with highest redeemed volume a The logistic regression was performed as a block analysis, with all the variables included concomitantly in the model. The effects for each variable are thereby adjusted by the effects of the others b Patients who died during the study period and prescriptions lacking information on any variable were excluded from the analysis c Physicians total prescribed volume of addictive anxiolytics and hypnotics to all their patients in 2005 in DDD Long-term use (n=15,731) Heavy use (n=1,979) Variable Percentage OR CI OR CI All users (n=139,740 b ) Women Reference 1 Reference Men Patients age group (years) < Reference 1 Reference Drug volume in first quarter (DDD) >20 to Reference 1 Reference >30 to >75 to > Drugs redeemed at index day Diazepam Reference 1 Reference Oxazepam Alprazolam Nitrazepam Flunitrazepam Zopiclone Zolpidem Clometiazole Prescriber of initial prescription GPs Reference 1 Reference Psychiatrists Other specialists Without specialty All prescribing physicians (n=12,633) Women Reference 1 Reference Men Physicians age group (years) < Reference 1 Reference Total prescribed volume (DDD) c 10, >10,000 to 18, Reference 1 Reference >18,000 to 27, >27,000 to 38, >38,000 to 52, >52, Statistics χ 2 (29) = 19, χ 2 (29) = 5, p<0.0001, R 2 = p<0.0001, R 2 =0.2732

9 Eur J Clin Pharmacol (2012) 68: received short-term treatment as recommended. There is an obvious need for implementation of relevant guidelines and systems for structured clinical audit, especially in general practice. Future research in this area should include clinical information to assess the quality of treatment provided to individual patients. Acknowledgments We thank the Fund for Research in General Practice, the Norwegian Medical Association, and the Norwegian Directorate of Health for grants supporting this study. The authors thank professor Stein Atle Lie at Uni Research, Bergen, for his statistical advice. Declaration of interest References None declared. 1. The Norwegian Institute of Public Health (2010) Addictive drugs Hajak G, Muller WE, Wittchen HU, Pittrow D, Kirch W (2003) Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. 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