ORIGINAL ARTICLE
Sedative-Hypnotics Are Widely Abused by Drivers Apprehended for Driving Under the Influence of Drugs Pirkko Kriikku, MSc,*† Hannes Hurme, MB,*‡ Lars Wilhelm, PhD,§ Janne Rintatalo, MSc,¶ Jukka Hurme, Lic Med,* Jan Kramer, MD,§k and Ilkka Ojanperä, PhD†
Background: Sedative-hypnotics are commonly encountered in
Key Words: driving, DUID, sedative-hypnotics, sleeping medication, drug abuse
drivers apprehended for driving under the influence of drugs (DUID). Previous research has mainly concentrated on the residual effects of the drugs.
(Ther Drug Monit 2015;37:339–346)
Methods: In this study, the extent of sleep medication use and abuse among drivers apprehended on suspicion of DUID was assessed. Additionally, the prevalence and concentrations of the drugs, concomitant use of other drugs of abuse, and the age and sex of the drivers positive for the most commonly prescribed sedativehypnotics (temazepam, midazolam, nitrazepam, zopiclone, and zolpidem) in DUID cases in Finland in 2009 to 2011 were examined. Results: Sedative-hypnotics were found in 3155 samples of the 13,248 that were analyzed. Temazepam was present in over half of the cases (57.9%), along with other benzodiazepines such as midazolam (13.1%) and nitrazepam (7.0%) and the nonbenzodiazepine hypnotics zopiclone (12.2%) and zolpidem (9.8%). The mean age of the drivers using the studied sedative-hypnotics was 33.5 years. Many of the drivers were polydrug users; concomitant stimulant use was found in nearly half of the cases. Cannabis and alcohol were also very common co-findings. In nearly 20% of the cases, the driver had taken more than 1 of the studied sedativehypnotics; only 2.5% had no findings other than a single sedativehypnotic in their blood. The drug use pattern of those positive for zopiclone and zolpidem was somewhat different from that of users of benzodiazepine sedative-hypnotics; their age was higher and the concomitant use of illegal stimulants was markedly less prevalent than among the users of temazepam, midazolam, and nitrazepam. Conclusions: There were very few cases in our study population where the positive sedative-hypnotic finding could have been due to appropriate medical use. The extremely prevalent concomitant use of other psychoactive drugs and the high median serum concentrations of the studied sedative-hypnotics suggest their widespread abuse among apprehended drivers. Received for publication February 3, 2014; accepted August 21, 2014. From the *Vita Laboratory, Vita Health Care Services Ltd, Helsinki; †Department of Forensic Medicine, Hjelt Institute, University of Helsinki; ‡Medical School, University of Eastern Finland, Kuopio; §LADR GmbH MVZ Dr. Kramer & Colleagues, Geesthacht, Germany; ¶National Bureau of Investigation Forensic Laboratory, Vantaa, Finland; and kMedical Department I, University of Lübeck, Germany. P. Kriikku and H. Hurme have contributed equally. The authors declare no conflict of interest. Correspondence: Pirkko Kriikku, MSc, Department of Forensic Medicine, Hjelt Institute, University of Helsinki, PO Box 40, Helsinki FI-00014, Finland (e-mail: pirkko.kriikku@helsinki.fi). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Ther Drug Monit Volume 37, Number 3, June 2015
INTRODUCTION Insomnia is an enormous public health problem in the modern world in all age groups and in all classes of society. It has been clearly shown that insomnia has major negative effects on the individual’s daily functioning. Impaired work performance, lower physical and social functioning, and an overall lower quality of life have been reported to result from insomnia.1 Insomnia is a risk for major depressive disorder and increases the probability of relapse.2 Insomnia can be either problems in initiating sleep or in staying asleep, or both. Sleeping problems can be further divided into transient (,2 weeks), short-term (2–12 weeks), or chronic (.3 months).3 Approximately one third of the Finnish adult population suffers from transient insomnia, while the prevalence of chronic insomnia is about 10%.4 The problem is more prominent in the elderly and in women.2,5 In Finland, the zero-tolerance law prohibits drivers from operating a motor-driven vehicle with scheduled medicinal substances in their blood, unless there is a valid prescription for the particular drug. Furthermore, the blood concentration of a prescribed drug needs to be within a reasonable therapeutic range, and the driver should not show signs of impairment while driving under the influence of the drug.6 Benzodiazepines have been the substances most frequently found in Finnish driving under the influence of drugs (DUID) cases in the last 4 years (police statistics from 2009 to 2012). The drug use pattern among apprehended drivers is similar in all Nordic countries.7–10 Benzodiazepines cause psychomotor impairment that is associated with driving difficulties, such as decreased alertness, decision-making capacity, and slower reaction times.11 With prolonged administration, users develop tolerance to some of the effects of benzodiazepines and are less troubled by tiredness and dizziness; however, even in experienced users, significant driving impairment remains.12 In several studies, benzodiazepines have been shown to markedly increase the risk of being involved in road accidents.11,13–16 Use of the newer non-benzodiazepine hypnotics, zopiclone, and zolpidem has also been connected with increased risk of road traffic accidents.16,17
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When selecting which sedative-hypnotic drug and dose to prescribe, physicians have to balance clinical efficacy versus adverse effects on psychomotor performance. Most psychoactive drugs do have severe effects on driving performance, and these effects are most prominent in the first 2 weeks of the treatment.18 With benzodiazepines, the risk of traffic accidents in the first weeks of treatment equals the risk associated with a blood alcohol concentration of 1.0 g/L.18 The International Council on Alcohol, Drugs and Traffic Safety has published a list of medicinal drugs classified into 3 categories according to their impairing properties.19 Most hypnotics fall into category 3, which means that they are likely to produce severe impairment comparable with that of a blood alcohol content of .0.5 g/L.19 However, as is true for most psychoactive drugs, despite potential impairing effects, particularly early in the course of treatment, the overall impact of sedative-hypnotics on psychomotor performance could be favorable if the original health problem, in this case fatigue due to lack of sleep, has been resolved. The psychomotor performance of the insomniac is likely to improve because of the increased sleep achieved with the help of the prescribed sedative-hypnotic. The net effect on driving performance will be the result of the balance between the benefits of improved sleep and direct impairment by the sedative-hypnotic. The data on residual effects of sleep medication on driving performance were thoroughly reviewed a few years ago.20 That review concluded that all benzodiazepines and also the newer, non-benzodiazepine, hypnotics (the so-called “Z-drugs”) impair driving performance. The magnitude of the effect is dose-dependent, and its course of time is related to the half-life of the drug.20 The aim of this study was to investigate the prevalence and blood concentrations of some widely prescribed shortacting hypnotics in DUID cases in Finland. The drugs monitored in this study (temazepam, midazolam, nitrazepam, zolpidem, and zopiclone) were selected because, according to the Finnish Medicines Agency, these drugs are the 5 most popular prescription drugs for the treatment of insomnia in Finland.21 A great number of other drugs are frequently used for the same indication, but as we did not have access to information about the possible medical indication for the use of a particular drug, this study was restricted to the short-acting hypnotics that are primarily prescribed to treat insomnia and excluded substances (eg, oxazepam or doxepin) that are frequently prescribed for other indications. The following drugs were monitored in the study: • Temazepam is the 3-hydroxylated metabolite of diazepam, but it is also marketed as an independent medicinal product. In a previous study, 18 women with nonorganic insomnia were administered a single after-midnight dose of temazepam (20 mg), and no significant changes in their psychomotor performance was monitored when compared with placebo the next morning, 5.5 hours after taking the drug.22 • Nitrazepam is a nitrogen-substituted benzodiazepine that has been used for the treatment of insomnia for decades.23 In earlier studies of a group of 11 female insomniacs, bedtime oral administration of 10 mg nitrazepam had an adverse effect on the ability to keep a steady lateral position, measured 10 and 14 hours of administration, on
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a 100-km highway course, the effect being greatest in the 14-hour study point.24 The authors suggested the effect to be equivalent with a blood alcohol concentration of 0.5‰. • Midazolam is an imidazobenzodiazepine that is used, besides insomnia, as a preoperative anxiolytic and anesthetic inducing agent. It has been in medical use since 1982.25 To our knowledge, no research has been performed on the effects of residual midazolam on driving. • Zolpidem is an imidazopyridine derivative used as a hypnotic agent since 1986 in European countries and since 1993 in the United States.26 Zolpidem is not a structural analog of the benzodiazepines but exhibits similar effects in relation to the treatment of insomnia. Zolpidem is believed to possess a selectivity for the gamma-aminobutyric (GABA) component of the benzodiazepine receptor that is responsible for its sedative effects, which makes it more targeted for the treatment of insomnia than the more traditional hypnotics.27,28 Earlier research on residual effects of zolpidem have shown that there is little or no effect on driving ability after at least 5-hour sleep.22,29 • Zopiclone is currently the most prescribed hypnotic in Finland.21 It belongs to the group of cyclopyrrolones and has been available as a prescription drug since 1982. Zopiclone has been shown to be at least as effective as the benzodiazepines in the treatment of insomnia.30 In an earlier study, the effects of zopiclone on driving performance were suggested to equal those of blood alcohol concentration of 1.0 g/L when the blood concentration of zopiclone was above 0.130 mg/L.31 Typical doses, elimination half-lives, and plasma concentrations associated with therapeutic drug use of the selected hypnotics are presented in Table 1. For most of these drugs, a smaller dose (in most cases half of the normal dose) is recommended for the elderly. Along with the levels of the drugs, we looked at the differences in age and sex distribution of different hypnotics and in the concomitant use of other drugs.
MATERIALS AND METHODS In Finland, drivers apprehended on suspicion of DUID are taken to the nearest municipal health center and a specimen of venous blood is taken for toxicological analysis. All the cases between January 1, 2009, and December 31, 2011, positive for 1 or more of the selected sedative-hypnotics were included in the study. In the background material delivered to
TABLE 1. Typical Doses for the Treatment of Insomnia, Drug Half-Lives, and the Concentration Ranges in Plasma Associated With Therapeutic Drug Use32–34 Dose (mg) Temazepam Midazolam Zopiclone Zolpidem Nitrazepam
10–20 7.5–15 5–7.5 5–12.5 5–10
Half-Life (h)
Typical Concentration Range (mg/L)
3–13 1–4 3.5–6.5 1.4–4.5 17–48
0.100–1.000 0.010–0.100 0.010–0.050 0.080–0.150 0.020–0.070
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Ther Drug Monit Volume 37, Number 3, June 2015
the laboratory with the samples, no information on the identity of the suspect was available, and thus it was not necessary to de-identify the samples before the study. Moreover, there was no information available about the doses the suspects had taken of the studied drugs. Therefore, the study was conducted based exclusively on analytical and demographic data. The original intent for the study was to also include zaleplon and triazolam, but there were no zaleplon-positive cases and only 1 triazolam-positive case in the study period. Temazepam cases were excluded if they were considered to be metabolites of diazepam based on concentration ratios of the substances, as described elsewhere.35
Chemicals and Reagents Reference materials for temazepam, midazolam, zopiclone, zolpidem, nitrazepam, and the internal standards (ISTD), diazepam-d5 and temazepam-d5, were purchased from LGC Standards (Wesel, Germany). HPLC-grade methanol, acetonitrile, ammonia 32% pro analysi, and acetic acid pro analysi were obtained from Baker (Griesheim, Germany), formic acid 98%–100% from Merck (Darmstadt, Germany), and water from LGC. Solid-phase extraction was performed using Bond Elut Plexa-3 ML cartridges with 30 mg sorbent from Agilent (Böblingen, Germany). Buffer solution for the LC–MS/MS system was prepared in-house by mixing 15 mL of 0.01 mol/L PBS-buffer (KH2PO4: 2.0 g/L, Na2HPO4 · 2H2O: 14.4 g/L, KCl: 2.0 g/L, NaCl: 80 g/L in 1 L water) with 1 mL of sodium acetate buffer (232 g sodium acetate and 124 mL acetic acid was mixed with deionized water for 1 L of solution with pH 4.8). Chromatographic separation was performed on a Luna phenyl-hexyl 3 mm 50 · 3 mm column from Phenomenex (Aschaffenburg, Germany).
Sample Preparation and LC–MS/MS Conditions All samples in the study period were subjected to a broad screening of various psychoactive drugs. The identification and analysis of the selected sedative-hypnotics in serum samples was performed by an LC–MS/MS method that has been described in detail elsewhere.36 The LC–MS/MS system consisted of a Shimadzu LC 20A LC-system and a triple quadrupole mass spectrometer (API 4000; AB SCIEX) with Turbo Ion Spray. Eluent flow from the LC was led to the turbo ion spray source without splitting. Ion spray voltage was set at 5.5 kV at a turbo ion spray heater temperature 6008C. The nebulizer gas was 60 psi and turbo heater gas 70 psi. The AB Sciex control software was set at 35 for the curtain gas and the collision gas at 12. Collision energy, declustering potential, and collision exit potential were optimized for each compound. Two intense fragments were used for the monitoring the analytes and 1 for the ISTD. Detailed LC–MS/MS conditions are listed in Table 2. Validation of the method was performed according to Peters et al for limit of detection (LOD), lower limit of quantification (LLOQ), linear range (LR), matrix effect, extraction recovery, within- and between-run percent of Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Sedative-Hypnotics in DUID Cases
TABLE 2. MS/MS Conditions Compound Temazepam 1 Temazepam 2 Midazolam 1 Midazolam 2 Zopiclone 1 Zopiclone 2 Zolpidem 1 Zolpidem 2 Nitrazepam 1 Nitrazepam 2 Temazepam-d5 Diazepam-d5
Q1–Q3 (m/z)*
DP (V)
CXP (V)
CE (eV)
301 . 255 301 . 283 326 . 291 326 . 249 389 . 245 389 . 217 308 . 235 308 . 263 282 . 236 282 . 180 306 . 260 290 . 262
81 81 111 111 36 36 101 101 60 60 56 101
33 21 41 51 27 50 51 37 35 53 31 33
26 14 22 6 20 10 12 16 18 16 16 6
ISTD Temazepam-d5 Diazepam-d5 Diazepam-d5 Diazepam-d5 Diazepam-d5
*Monitored ion transitions. CE, collision energy; CXP, collision exit potential; DP, declustering potential; ISTD, internal standard.
relative standard deviation, stability, and selectivity.37,38 Calculations for the LOD were performed according to the German standard specification DIN 32645.39 Selectivity was established by analyzing unexposed specimens and potential interfering drugs. Carry over was evaluated by injecting blank samples after a specimen spiked with all analytes at the upper limit of the LR. No analyte peaks were detectable in the blanks. The LR was studied over a concentration range up to 2000 mg/L for temazepam, 1000 mg/L for midazolam, and 200 mg/L for zopiclone, zolpidem, and nitrazepam. Process stability was studied under the conditions of the LC–MS/MS analysis by analyzing serum samples spiked with all analytes over a period of 60 hours. All analytes were tested in 2 concentrations: close to the lower and higher limits of the typical concentration range associated with therapeutic drug use. The test solutions were stored in autosampler vials and kept in a refrigerator between runs. All analytes were stable for the studied period. Long-term stability of the analytes has been studied before.40 LOD, LLOQ, retention times, and other validation data are listed in Table 3. The identification of MDPV was based on 2 multiple reaction monitoring transitions for each analyte and the retention time.
Statistical Analysis All statistical analyses were performed using IBM SPSS software (version 21.0). Comparisons between different groups were performed using the Student t test or Mann– Whitney U test.
RESULTS In Finland, the number of DUID cases in which a blood sample is taken has been approximately 4000–4500 per year the last few years. All the toxicological analyses in DUID cases in Finland are performed in 1 central laboratory. Between January 1, 2009, and December 31, 2011, blood samples from 13,248 DUID cases were analyzed for drugs. All these samples were also analyzed for the short-acting
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TABLE 3. Validation Data RSD (%)* Compound
LOD (mg/L)
LLOQ (mg/L)
Rt (min)
ME (%)
RC (%)
Within
Between
Temazepam Midazolam Zopiclone Zolpidem Nitrazepam
0.0025 0.0018 0.0030 0.0030 0.0014
0.0041 0.0058 0.0032 0.0048 0.0041
2.7 2.4 1.6 2.0 2.5
29.9 23.6 17.7 7.1 5.2
58.7 68.1 73.8 77.5 63.8
2.9 4.2 5.8 3.9 4.8
9.0 10.6 14.8 11.6 12.2
*RSD measured at the lower part of the concentration range associated with therapeutic drug use. RC, extraction recovery; Rt, retention time; RSD, relative standard deviation.
hypnotics studied in this article. One or several of the studied substances was found in 3155 samples (23.8% of all DUID cases in this period). All positive findings with a serum concentration above the LLOQ were included in the study. The median serum concentrations and the concentration ranges of the 5 studied substances are illustrated in Figure 1. The mean (median/highest) concentrations of the drugs were: temazepam 0.611 (0.250/12.000) mg/L, midazolam 0.080 (0.033/1.700) mg/L, zopiclone 0.014 (0.040/4.000) mg/L, zolpidem 0.318 (0.190/4.600) mg/L, and nitrazepam 0.074 (0.032/0.600) mg/L. The prevalence of the drugs in our material, and the proportion that can be attributed to appropriate medical use, is shown in Figure 2. The cases of appropriate medical use were identified by finding the low morning levels typical for prescribed sedative-hypnotics. Of the drivers positive for the studied hypnotic drugs, 84.8% were male. The mean (range) age of the drivers was 33.5 (14–88) years. The age distribution in males and females is illustrated in Figure 3. In this study, the women using sleep medication were somewhat older than men (mean age, 35.9 versus 33.1 years). The difference was statistically significant (P , 0.001). The mean age of drivers using zopiclone or zolpidem was significantly higher than the mean age of all users of the
FIGURE 1. Serum concentrations of the studied sedativehypnotic drugs. The boxes represent the interquartile ranges, the bars in the middle of the boxes represent the median values, and the whiskers represent the highest and lowest nonextreme values. For clarity, the outliers (extreme high values, eg, temazepam 12 mg/L) are not shown in the whiskers but are listed in Table 2.
hypnotics selected for this study (zopiclone: 40.3 years/zolpidem: 37.6 years versus 33.5 years; P , 0.001 for both). The mean age of drivers using temazepam, midazolam, and nitrazepam was slightly lower than the mean age of all users of sedativehypnotics (temazepam: 32.3 years/midazolam: 31.6 years/nitrazepam: 31.1 years versus 33.5 years; P , 0.05 for each). More than 1 of the studied sedative-hypnotics was present in 16.9% (N = 533) of the cases. The vast majority of the multiple-sedative cases included temazepam (N = 522). It was most commonly found together with midazolam (N = 185), zopiclone (N = 115), and nitrazepam (N = 109). There were 28 cases with 3 of the studied sedative-hypnotics present. In only 85 cases (2.7%), the sedative-hypnotic was the only psychoactive substance detected. Zopiclone and zolpidem were much more often found with no other drugs present than the sedative-hypnotic benzodiazepines. Nitrazepam was never the only sedative-hypnotic present. The mean concentration of zopiclone was significantly higher in those cases in which it was the only drug of any type present; the same was true of zolpidem. In contrast, the concentrations of the other sedative-hypnotics studied were lower in those cases where they were the only drug of any type present (Table 4). In those cases in which temazepam or midazolam was the only drug of any type found, the concentration was mostly within or below the lower third of the concentration range associated with therapeutic use of the drug (83.3% of temazepam alone cases and 60.0% of midazolam alone cases). In those cases in which zopiclone or zolpidem was the only drug of any type found, the concentration was usually above the concentration range associated with therapeutic drug use (81.8% of zopiclone alone cases and 88.9% of zolpidem alone cases). Of all the drivers who tested positive for 1 or more of the studied sedative-hypnotics, 25.3% (N = 798) had a blood alcohol concentration above the cutoff value (0.10 g/kg). The mean (median/highest) blood alcohol concentration was 1.30 (1.14/3.71) g/kg. Opioids were present in 33.3% (N = 1051) cases, with buprenorphine the most common opioid found (N = 621). Tetrahydrocannabinol and/or the inactive carboxy-metabolite were present in 35.8% (N = 1130) of the cases. The mean (median/highest) serum concentration of tetrahydrocannabinol was 0.0034 (0.020/0.0640) mg/L. Of the drivers using temazepam, midazolam, or nitrazepam, more than 50% had also taken stimulants, in most cases amphetamine. In zopiclone and zolpidem cases, the proportion of stimulant users was 21.3% and 24.4%, respectively. The
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Sedative-Hypnotics in DUID Cases
FIGURE 2. Prevalence of the studied sedativehypnotics. The darker areas represent the proportions of cases containing the indicated sedative-hypnotic at concentrations below the lower limit of the concentration range associated with therapeutic use of the drug. Numbers above the bars indicate the absolute numbers of cases positive for the indicated drug in the study material.
concomitant use of stimulants is presented in Table 4. Overall, stimulants were present in 47.2% of the sedative-hypnotic– positive cases (N = 149). Amphetamine was the by far the most popular stimulant (N = 1479). The new so-called designer drugs, such as 3,4-methylenedioxypyrovalerone (MDPV), desoxypipradrol (2-DPMP), PMMA, methylone, fluoroamphetamines, 4-methylamphetamine, or synthetic cannabinoids, were present in 71 cases; in 8 cases, a designer stimulant (MDPV or 2-DPMP) was the only stimulant found. The median concentration of the sedative-hypnotics in cases with concomitant stimulant use was markedly lower than the median concentration in all cases for each sedative-hypnotic. These differences were statistically significant except for nitrazepam (Table 4). The serum concentration of the sedative-hypnotic was below the concentration range associated with therapeutic use of the drug in 26.6% (N = 838) and above in 27.2% (N = 859) of all the positive cases.
DISCUSSION Sedative-hypnotics are used for treating different kinds of sleeping disorders. Many studies indicate that they are also widely abused, often together with other drugs of abuse.41–43 Sleep medicines are frequently found in the serum of
apprehended drivers. In our study period, nearly a quarter of the apprehended drivers was positive for at least 1 of the studied sedative-hypnotics. By far, the most common substance was temazepam, which alone accounted for over half of the positive sedative-hypnotic findings in the study period. The number of temazepam positive cases in our study was nearly 5 times the number of positive zopiclone cases, although zopiclone is the most commonly prescribed sleeping medication in Finland defined as daily defined doses (DDD) per 1000 inhabitants. For zopiclone, DDD in Finland was 20.37 in 2013, whereas temazepam held the second place with a DDD of 10.86.21 Because of the fast elimination of most sedativehypnotics (Table 1), ideally and when used appropriately, there should be little or no drug detectable in the blood the morning after the use of these drugs.27,44 This is not always the case, which has been demonstrated for zopiclone and zolpidem in aged individuals.45 When stopped by the police, a driver using prescribed sleep medication correctly should only have traces of the drug left in his system or at least the serum concentration should by no means exceed the concentration range associated with therapeutic drug use but rather be below it.44 Furthermore, in appropriate medical treatment of insomnia, no more than 1 sedative-hypnotic drug should be present simultaneously. Of the drugs studied in this article,
FIGURE 3. Age distribution of males and females in DUID cases positive for 1 or more sedative-hypnotics. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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TABLE 4. Serum Concentrations of the Studied Sedative-Hypnotics in All Cases, Cases With a Single Sedative-Hypnotic Only, and Cases With Concomitant Use of Stimulants All Cases Number of Cases Temazepam Midazolam Zopiclone Zolpidem Nitrazepam
1827 414 384 309 221
Mean/Median (mg/L) 0.661/0.250 0.080/0.033 0.137/0.040 0.318/0.190 0.074/0.032
Sedative-Hypnotic-Only Cases Percentage (%) 0.3 2.4 8.6 11.7 —
Sedative-Hypnotic Plus Stimulant
Mean/Median (mg/L) 0.156/0.060 0.042/0.025 0.323/0.160 0.455/0.365 —
P
Percentage (%)
,0.05 .0.05 ,0.001 ,0.001 —
51.9 58.7 20.8 23.9 62.0
Mean/Median (mg/L) 0.450/0.184 0.062/0.025 0.047/0.021 0.112/0.026 0.067/0.027
P ,0.001 ,0.02 0.001 ,0.001 .0.05
P values versus all cases are calculated for the differences in concentrations using the Mann–Whitney U test.
the proportion of zolpidem-positive cases in which the drug concentration was under the concentration range associated with therapeutic drug use was greater than the equivalent proportion for the other sedative-hypnotics studied. This could be explained by the very short elimination half-life of the drug, or it could suggest that zolpidem is less abused and thus not taken at inappropriate times and quantities as often as the other substances studied. Almost 20% of the drivers who tested positive for 1 of the studied sedative-hypnotic drugs also had 1 or more of the others in their blood. As it would not be good practice for a physician to prescribe a patient more than 1 sedativehypnotic to be used simultaneously, it can be concluded that drivers positive for more than 1 of the studied substances are probably abusing at least 1 of them. Polydrug use is extremely prevalent among recreational drug users and also among drivers suspected of DUID.46,47 In our study, only 2.7% of the drivers did not have any other psychoactive substances, besides 1 of the sedative-hypnotics, in their blood. Surprisingly, users of either of the studied Z-drugs, zopiclone or zolpidem, who had only the Z-drug, in their system had a higher median concentration of the Z-drug than those who tested positive for several different drugs of abuse. This phenomenon is hard to explain, as the lack of multiple drugs suggests prescribed use whereas high concentration points towards abuse. In previous studies, unauthorized use of sedatives has been divided into 2 categories: recreational abuse by polydrug users and unauthorized chronic use by patients.48 The individuals suffering from severe prolonged insomnia and who have been treated with sedative-hypnotics for a long period may have created a functional tolerance for the subjectively recognizable impairing effects of the drug. To still achieve the hypnotic effect of the drug, the insomniac may gradually increase the dosage while not noticing their unfitness to drive. Benzodiazepines, for example, have been shown to impair driving even in experienced users in a dose-dependent manner.12 Moreover, there is very little research on the risks associated with long-term sedative use.48 Although previous studies have shown that the long-term use of sedativehypnotic drugs is common,49–51 the above-mentioned reasons together with the known abuse potential of the sedativehypnotic drugs strongly discourage chronic use. The studied sedative-hypnotic drugs were very often found together with stimulants. Nearly half of all studied
sedative-hypnotic cases showed concomitant use of amphetamine, methamphetamine, ecstasy, or MDPV, which are the most prevalent stimulants among the apprehended drivers in Finland. Abusive stimulant use is generally known to produce insomnia, which is why the presence of sedative-hypnotics in the blood of stimulant users is not very surprising. Those driving under the influence of both a sedative-hypnotic drug and a stimulant drug had a lower serum concentration of the sedative-hypnotic than in the overall study population. This is in good accordance with our previous observations that in stimulant users, the serum sedative concentrations are not as high as in those using sedatives only.36 Cannabis was found in more than 30% of the drivers positive for the studied substances. Moreover, 30% had taken opioids. Alcohol was very often found together with sedativehypnotic drugs, many times in alarming concentrations. Zopiclone and zolpidem were markedly less frequently found together with stimulants than the benzodiazepine-type hypnotics. Also, the users of zopiclone and zolpidem were older than all the sedative-hypnotic users in the study material. These findings may indicate that these drugs are at least somewhat less abused than the other substances studied in this article. Most previous research on sleeping medication and driving has focused on the residual effects of sedativehypnotics on the driving ability after appropriate prescribed use of sleep medication. In this study, we sought to examine the extent of abuse of sedative-hypnotics by looking at the drug use patterns and profile of the drivers using sleeping medication. Although patients are instructed in the Medication Guide and should be advised by physicians to remain inactive and to avoid complicated tasks such as driving for at least 7–8 hours after the administration of the sedative-hypnotic drug, people tend to first try and fall asleep without the drug and only take the drug when they finally admit that they have failed the attempt.22 This leads to sleep medication being administered close to midnight or later. This kind of use of sedative-hypnotics must be considered misuse and should be strongly discouraged by physicians and pharmacists. However, even such inappropriate use of sleep medication would be expected to lead to serum concentrations that are, at most, in the lower part of or below the concentration range associated with therapeutic use of the drug in a blood sample taken
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Ther Drug Monit Volume 37, Number 3, June 2015
the following morning. However, in our study material, more than 15% of the drivers positive for 1 or more of the studied sedative-hypnotics had a serum concentration that was above the upper limit of the concentration range associated with therapeutic drug use, which clearly suggests abuse of the drug. Some of the concentrations were more than 10 times the upper limit of the typical concentration range. In addition to causing dangerous impairment of driving ability, such concentrations are potentially lethal, especially in combination with other central nervous sedatives, which markedly enhance toxicity.52,53 Our results further support previous studies, which have shown that the use of benzodiazepine or benzodiazepine-like hypnotics should be avoided with patients with tendency for drug abuse.54,55
Sedative-Hypnotics in DUID Cases
1. Drake CL, Roehrs T, Roth T. Insomnia causes, consequences, and therapeutics: an overview. Depress Anxiety. 2003;18:163–176. 2. Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment: prevalence and correlates. Arch Gen Psychiatry. 1985;42:225–232. 3. Finnish national recommendations for the treatment of insomnia [in Finnish]. Available at: http://www.kaypahoito.fi/web/kh/suositukset/ naytaartikkeli/tunnus/hoi50067. Accessed March 25, 2013. 4. Hublin C. Unettomuus [in Finnish]. Duodecim. 2010;126:563–565. 5. Partinen M, Hublin C. Epidemiology of sleep disorders. In: Kryger M, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. New York, NY: Saunders; 2000:558–579. 6. The Criminal Code of Finland, Chapter 23 (Rikoslaki 39/1889). Available in English at: http://www.finlex.fi/en/laki/kaannokset/1889/ en18890039.pdf. Accessed September 22, 2014. 7. Christophersen A, Ceder G, Kristinsson J, et al. Drugged driving in the Nordic countries: a comparative study between five countries. Forensic Sci Int. 1999;106:173–190. 8. Holmgren A, Holmgren P, Kugelberg FC, et al. Predominance of illicit drugs and poly-drug use among drug-impaired drivers in Sweden. Traffic Inj Prev. 2007;8:361–367. 9. Wiese Simonsen K, Steentoft A, Bernhoft IM, et al. Psychoactive substances in seriously injured drivers in Denmark. Forensic Sci Int. 2013; 224:44–50. 10. Jones AW, Holmgren A. What non-alcohol drugs are used by drinking drivers in Sweden? Toxicological results from ten years of forensic blood samples. J Safety Res. 2012;43:151–156. 11. van Laar MW, Volkerts ER, van Laar M. Driving and benzodiazepine use. CNS Drugs. 1998;10:383–396. 12. Bramness JG, Skurtveit S, Mørland J. Clinical impairment of benzodiazepines—relation between benzodiazepine concentrations and impairment in apprehended drivers. Drug Alcohol Depend. 2002;68:131–141.
13. Engeland A, Skurtveit S, Mørland J. Risk of road traffic accidents associated with the prescription of drugs: a registry-based cohort study. Ann Epidemiol. 2007;17:597–602. 14. Movig K, Mathijssen M, Nagel P, et al. Psychoactive substance use and the risk of motor vehicle accidents. Accid Anal Prev. 2004;36:631–636. 15. Smink BE, Egberts AC, Lusthof KJ, et al. The relationship between benzodiazepine use and traffic accidents. CNS Drugs. 2010;24:639–653. 16. Orriols L, Philip P, Moore N, et al. Benzodiazepine-like hypnotics and the associated risk of road traffic accidents. Clin Pharmacol Ther. 2011; 89:595–601. 17. Gustavsen I, Bramness JG, Skurtveit S, et al. Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam. Sleep Med. 2008;9:818–822. 18. de Gier JJ, Alvarez FJ, Mercier-Guyon C, et al. Prescribing and dispensing guidelines for medicinal drugs affecting driving performance. In: Verster JC, Pandi-Perumal SR, Ramaekers JG, et al, eds. Drugs, Driving and Traffic Safety. Basel, Switzerland: Birkäuser Verlag; 2009:121–134. 19. Medicinal drugs affecting driving performance. Available at: http://www. icadts.nl/reports/medicinaldrugs2.pdf. Accessed March 25, 2013. 20. Verster JC, Veldhuijzen DS, Volkerts ER. Residual effects of sleep medication on driving ability. Sleep Med Rev. 2004;8:309–325. 21. Report on drug consumption in Finland in 2013 by the Finnish Medicines Agency [in Finnish]. Available at: http://raportit.nam.fi/raportit/kulutus/ ev_laakekulutus.htm. Accessed June 3, 2014. 22. Partinen M, Hirvonen K, Hublin C, et al. Effects of after-midnight intake of zolpidem and temazepam on driving ability in women with nonorganic insomnia. Sleep Med. 2003;4:553. 23. Andersen T, Lingjaerde O. Nitrazepam (mogadon) as a sleep-inducing agent. Br J Psychiatry. 1969;115:1393–1397. 24. O’Hanlon JF, Volkerts E. Hypnotics and actual driving performance. Acta Psychiatr Scand Suppl. 1986;74:95–104. 25. Monti JM, Debellis J, Gratadoux E, et al. Sleep laboratory study of the effects of midazolam in insomniac patients. Eur J Clin Pharmacol. 1982; 21:479–484. 26. Lichtenwalner M, Tully R. A fatality involving zolpidem. J Anal Toxicol. 1997;21:567–569. 27. De Haas SL, Schoemaker RC, Van Gerven JMA, et al. Pharmacokinetics, pharmacodynamics and the pharmacokinetic/pharmacodynamic relationship of zolpidem in healthy subjects. J Psychopharmacol. 2010;24:1619– 1629. 28. Sanger DJ. The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS Drugs. 2004;18:9–15. 29. Verster JC, Volkerts ER, Schreuder A, et al. Residual effects of middleof-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance. J Clin Psychopharmacol. 2002;22:576–583. 30. Buscemi N, Vandermeer B, Friesen C, et al. The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-analysis of RCTs. J Gen Intern Med. 2007;22:1335–1350. 31. Gustavsen I, Al-Sammurraie M, Mørland J, et al. Impairment related to blood drug concentrations of zopiclone and zolpidem compared to alcohol in apprehended drivers. Accid Anal Prev. 2009;41:462–466. 32. Baselt RC. Drug Effects on Psychomotor Performance. Foster City, CA: Biomedical Publications; 2001. 33. Summaries of product characteristics (SPC) for human medicinal products: Tenox (temazepam) 2013, Dormicum (midazolam) 2013, Imovane (zopiclon) 2014, Stella (zolpidem) 2014, Insomin (nitrazepam) 2008. The Internet pages of the Finnish Medicines Agency. Available at: http:// www.fimea.fi/medicines/fimeaweb. Accessed July 21, 2014. 34. Hiemke C, Baumann P, Bergemann N, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44:195–235. 35. Häkkinen M, Launiainen T, Vuori E, et al. Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning. Eur J Clin Pharmacol. 2012;68:301–309. 36. Kriikku P, Wilhelm L, Rintatalo J, et al. Phenazepam abuse in Finland: findings from apprehended drivers, post-mortem cases and police confiscations. Forensic Sci Int. 2012;220:111–117. 37. Peters FT, Drummer OH, Musshoff F. Validation of new methods. Forensic Sci Int. 2007;165:216–224. 38. Peters F, Hartung M, Herbold M, et al. Anhang B zur Richtlinie der GTFCh zur Qualitätssicherung bei forensisch-toxikologischen Untersu-
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CONCLUSIONS Our results indicate that the majority of the positive sedative-hypnotic findings in DUID cases results from abuse of the drugs, in most cases used as a part of a combination of drugs of abuse. Drivers who use medically appropriate sleep medication are practically absent from the police statistics of apprehended drivers. In a significant proportion of cases, the concentration of the sedative-hypnotic was within or above the concentration range associated with therapeutic drug use and would likely cause impairment of driving ability.
ACKNOWLEDGMENTS The authors thank Niall Doherty, Stefan Jenckel, Markku Pekkola, and Sanna Taskinen for their assistance. REFERENCES
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chungen: anforderungen an die Validierung von Analysenmethoden [in German]. Toxichem Krimtech. 2009;76:185–208. DIN 32645, Chemische Analytik-Nachweis-, Erfassungs-und Bestimmungsgrenze, in: Chemical analysis-Decision limit, detection limit and determination limit under repeatability conditions-Terms, methods, evaluation. Berlin, Germany: Beuth Verlag; 1994. Kratzsch C, Tenberken O, Peters FT, et al. Screening, library‐assisted identification and validated quantification of 23 benzodiazepines, flumazenil, zaleplone, zolpidem and zopiclone in plasma by liquid chromatography/mass spectrometry with atmospheric pressure chemical ionization. J Mass Spectrom. 2004;39:856–872. Sikdar S, Ruben SM. Zopiclone abuse among polydrug users. Addiction. 1996;91:285–286. Ruben SM, Morrison CL. Temazepam misuse in a group of injecting drug users. Br J Addict. 1992;87:1387–1392. Fraser AD. Use and abuse of the benzodiazepines. Ther Drug Monit. 1998;20:481–489. Jones AW, Holmgren A. Concentrations of zolpidem and zopiclone in venous blood samples from impaired drivers compared with femoral blood from forensic autopsies. Forensic Sci Int. 2012;222:118–123. Bocca ML, Marie S, Lelong-Boulouard V, et al. Zolpidem and zopiclone impair similarly monotonous driving performance after a single nighttime intake in aged subjects. Psychopharmacology (Berl). 2011;214:699–706. Karjalainen KK, Lintonen TP, Impinen AO, et al. Poly-drug findings in drugged driving cases during 1977–2007. J Subst Use. 2010;15:143–156.
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47. Blencowe T, Raaska K, Lillsunde P. Benzodiazepines and sedative– hypnotics in blood of drivers under the influence and their association with other common illegal drug use and national sales figures. Ther Drug Monit. 2011;33:64–71. 48. Griffiths RR, Weerts EM. Benzodiazepine self-administration in humans and laboratory animals—implications for problems of long-term use and abuse. Psychopharmacology (Berl). 1997;134:1–37. 49. Blennow G, Romelsjo A, Leifman H, et al. Sedatives and hypnotics in Stockholm: social factors and kinds of use. Am J Public Health. 1994;84: 242–246. 50. Kripke DF. Chronic hypnotic use: deadly risks, doubtful benefit: review article. Sleep Med Rev. 2000;4:5–20. 51. Tiihonen M, Nordlund S, Nousiainen S, et al. Apteekkifarmaseuttien käsitykset unettomuuden hoidosta ja unilääkkeiden käytöstä Suomessa [in Finnish]. Dosis. 2013;29:75–83. 52. Koski A, Ojanperä I, Vuori E. Alcohol and benzodiazepines in fatal poisonings. Alcohol Clin Exp Res. 2002;26:956–959. 53. Jones AW, Kugelberg FC, Holmgren A, et al. Drug poisoning deaths in Sweden show a predominance of ethanol in mono-intoxications, adverse drug–alcohol interactions and poly-drug use. Forensic Sci Int. 2011;206:43–51. 54. O’Brien CP. Benzodiazepine use, abuse, and dependence. J Clin Psychiatry. 2005;66:28–33. 55. Hajak G, Müller W, Wittchen H, et al. Abuse and dependence potential for the non‐benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction. 2003;98:1371–1378.
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Sedative-Hypnotics Are Widely Abused by Drivers Apprehended for Driving Under the Influence of Drugs Pirkko Kriikku, MSc,*† Hannes Hurme, MB,*‡ Lars Wilhelm, PhD,§ Janne Rintatalo, MSc,¶ Jukka Hurme, Lic Med,* Jan Kramer, MD,§k and Ilkka Ojanperä, PhD†
Background: Sedative-hypnotics are commonly encountered in
Key Words: driving, DUID, sedative-hypnotics, sleeping medication, drug abuse
drivers apprehended for driving under the influence of drugs (DUID). Previous research has mainly concentrated on the residual effects of the drugs.
(Ther Drug Monit 2015;37:339–346)
Methods: In this study, the extent of sleep medication use and abuse among drivers apprehended on suspicion of DUID was assessed. Additionally, the prevalence and concentrations of the drugs, concomitant use of other drugs of abuse, and the age and sex of the drivers positive for the most commonly prescribed sedativehypnotics (temazepam, midazolam, nitrazepam, zopiclone, and zolpidem) in DUID cases in Finland in 2009 to 2011 were examined. Results: Sedative-hypnotics were found in 3155 samples of the 13,248 that were analyzed. Temazepam was present in over half of the cases (57.9%), along with other benzodiazepines such as midazolam (13.1%) and nitrazepam (7.0%) and the nonbenzodiazepine hypnotics zopiclone (12.2%) and zolpidem (9.8%). The mean age of the drivers using the studied sedative-hypnotics was 33.5 years. Many of the drivers were polydrug users; concomitant stimulant use was found in nearly half of the cases. Cannabis and alcohol were also very common co-findings. In nearly 20% of the cases, the driver had taken more than 1 of the studied sedativehypnotics; only 2.5% had no findings other than a single sedativehypnotic in their blood. The drug use pattern of those positive for zopiclone and zolpidem was somewhat different from that of users of benzodiazepine sedative-hypnotics; their age was higher and the concomitant use of illegal stimulants was markedly less prevalent than among the users of temazepam, midazolam, and nitrazepam. Conclusions: There were very few cases in our study population where the positive sedative-hypnotic finding could have been due to appropriate medical use. The extremely prevalent concomitant use of other psychoactive drugs and the high median serum concentrations of the studied sedative-hypnotics suggest their widespread abuse among apprehended drivers. Received for publication February 3, 2014; accepted August 21, 2014. From the *Vita Laboratory, Vita Health Care Services Ltd, Helsinki; †Department of Forensic Medicine, Hjelt Institute, University of Helsinki; ‡Medical School, University of Eastern Finland, Kuopio; §LADR GmbH MVZ Dr. Kramer & Colleagues, Geesthacht, Germany; ¶National Bureau of Investigation Forensic Laboratory, Vantaa, Finland; and kMedical Department I, University of Lübeck, Germany. P. Kriikku and H. Hurme have contributed equally. The authors declare no conflict of interest. Correspondence: Pirkko Kriikku, MSc, Department of Forensic Medicine, Hjelt Institute, University of Helsinki, PO Box 40, Helsinki FI-00014, Finland (e-mail: pirkko.kriikku@helsinki.fi). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Ther Drug Monit Volume 37, Number 3, June 2015
INTRODUCTION Insomnia is an enormous public health problem in the modern world in all age groups and in all classes of society. It has been clearly shown that insomnia has major negative effects on the individual’s daily functioning. Impaired work performance, lower physical and social functioning, and an overall lower quality of life have been reported to result from insomnia.1 Insomnia is a risk for major depressive disorder and increases the probability of relapse.2 Insomnia can be either problems in initiating sleep or in staying asleep, or both. Sleeping problems can be further divided into transient (,2 weeks), short-term (2–12 weeks), or chronic (.3 months).3 Approximately one third of the Finnish adult population suffers from transient insomnia, while the prevalence of chronic insomnia is about 10%.4 The problem is more prominent in the elderly and in women.2,5 In Finland, the zero-tolerance law prohibits drivers from operating a motor-driven vehicle with scheduled medicinal substances in their blood, unless there is a valid prescription for the particular drug. Furthermore, the blood concentration of a prescribed drug needs to be within a reasonable therapeutic range, and the driver should not show signs of impairment while driving under the influence of the drug.6 Benzodiazepines have been the substances most frequently found in Finnish driving under the influence of drugs (DUID) cases in the last 4 years (police statistics from 2009 to 2012). The drug use pattern among apprehended drivers is similar in all Nordic countries.7–10 Benzodiazepines cause psychomotor impairment that is associated with driving difficulties, such as decreased alertness, decision-making capacity, and slower reaction times.11 With prolonged administration, users develop tolerance to some of the effects of benzodiazepines and are less troubled by tiredness and dizziness; however, even in experienced users, significant driving impairment remains.12 In several studies, benzodiazepines have been shown to markedly increase the risk of being involved in road accidents.11,13–16 Use of the newer non-benzodiazepine hypnotics, zopiclone, and zolpidem has also been connected with increased risk of road traffic accidents.16,17
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When selecting which sedative-hypnotic drug and dose to prescribe, physicians have to balance clinical efficacy versus adverse effects on psychomotor performance. Most psychoactive drugs do have severe effects on driving performance, and these effects are most prominent in the first 2 weeks of the treatment.18 With benzodiazepines, the risk of traffic accidents in the first weeks of treatment equals the risk associated with a blood alcohol concentration of 1.0 g/L.18 The International Council on Alcohol, Drugs and Traffic Safety has published a list of medicinal drugs classified into 3 categories according to their impairing properties.19 Most hypnotics fall into category 3, which means that they are likely to produce severe impairment comparable with that of a blood alcohol content of .0.5 g/L.19 However, as is true for most psychoactive drugs, despite potential impairing effects, particularly early in the course of treatment, the overall impact of sedative-hypnotics on psychomotor performance could be favorable if the original health problem, in this case fatigue due to lack of sleep, has been resolved. The psychomotor performance of the insomniac is likely to improve because of the increased sleep achieved with the help of the prescribed sedative-hypnotic. The net effect on driving performance will be the result of the balance between the benefits of improved sleep and direct impairment by the sedative-hypnotic. The data on residual effects of sleep medication on driving performance were thoroughly reviewed a few years ago.20 That review concluded that all benzodiazepines and also the newer, non-benzodiazepine, hypnotics (the so-called “Z-drugs”) impair driving performance. The magnitude of the effect is dose-dependent, and its course of time is related to the half-life of the drug.20 The aim of this study was to investigate the prevalence and blood concentrations of some widely prescribed shortacting hypnotics in DUID cases in Finland. The drugs monitored in this study (temazepam, midazolam, nitrazepam, zolpidem, and zopiclone) were selected because, according to the Finnish Medicines Agency, these drugs are the 5 most popular prescription drugs for the treatment of insomnia in Finland.21 A great number of other drugs are frequently used for the same indication, but as we did not have access to information about the possible medical indication for the use of a particular drug, this study was restricted to the short-acting hypnotics that are primarily prescribed to treat insomnia and excluded substances (eg, oxazepam or doxepin) that are frequently prescribed for other indications. The following drugs were monitored in the study: • Temazepam is the 3-hydroxylated metabolite of diazepam, but it is also marketed as an independent medicinal product. In a previous study, 18 women with nonorganic insomnia were administered a single after-midnight dose of temazepam (20 mg), and no significant changes in their psychomotor performance was monitored when compared with placebo the next morning, 5.5 hours after taking the drug.22 • Nitrazepam is a nitrogen-substituted benzodiazepine that has been used for the treatment of insomnia for decades.23 In earlier studies of a group of 11 female insomniacs, bedtime oral administration of 10 mg nitrazepam had an adverse effect on the ability to keep a steady lateral position, measured 10 and 14 hours of administration, on
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a 100-km highway course, the effect being greatest in the 14-hour study point.24 The authors suggested the effect to be equivalent with a blood alcohol concentration of 0.5‰. • Midazolam is an imidazobenzodiazepine that is used, besides insomnia, as a preoperative anxiolytic and anesthetic inducing agent. It has been in medical use since 1982.25 To our knowledge, no research has been performed on the effects of residual midazolam on driving. • Zolpidem is an imidazopyridine derivative used as a hypnotic agent since 1986 in European countries and since 1993 in the United States.26 Zolpidem is not a structural analog of the benzodiazepines but exhibits similar effects in relation to the treatment of insomnia. Zolpidem is believed to possess a selectivity for the gamma-aminobutyric (GABA) component of the benzodiazepine receptor that is responsible for its sedative effects, which makes it more targeted for the treatment of insomnia than the more traditional hypnotics.27,28 Earlier research on residual effects of zolpidem have shown that there is little or no effect on driving ability after at least 5-hour sleep.22,29 • Zopiclone is currently the most prescribed hypnotic in Finland.21 It belongs to the group of cyclopyrrolones and has been available as a prescription drug since 1982. Zopiclone has been shown to be at least as effective as the benzodiazepines in the treatment of insomnia.30 In an earlier study, the effects of zopiclone on driving performance were suggested to equal those of blood alcohol concentration of 1.0 g/L when the blood concentration of zopiclone was above 0.130 mg/L.31 Typical doses, elimination half-lives, and plasma concentrations associated with therapeutic drug use of the selected hypnotics are presented in Table 1. For most of these drugs, a smaller dose (in most cases half of the normal dose) is recommended for the elderly. Along with the levels of the drugs, we looked at the differences in age and sex distribution of different hypnotics and in the concomitant use of other drugs.
MATERIALS AND METHODS In Finland, drivers apprehended on suspicion of DUID are taken to the nearest municipal health center and a specimen of venous blood is taken for toxicological analysis. All the cases between January 1, 2009, and December 31, 2011, positive for 1 or more of the selected sedative-hypnotics were included in the study. In the background material delivered to
TABLE 1. Typical Doses for the Treatment of Insomnia, Drug Half-Lives, and the Concentration Ranges in Plasma Associated With Therapeutic Drug Use32–34 Dose (mg) Temazepam Midazolam Zopiclone Zolpidem Nitrazepam
10–20 7.5–15 5–7.5 5–12.5 5–10
Half-Life (h)
Typical Concentration Range (mg/L)
3–13 1–4 3.5–6.5 1.4–4.5 17–48
0.100–1.000 0.010–0.100 0.010–0.050 0.080–0.150 0.020–0.070
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Ther Drug Monit Volume 37, Number 3, June 2015
the laboratory with the samples, no information on the identity of the suspect was available, and thus it was not necessary to de-identify the samples before the study. Moreover, there was no information available about the doses the suspects had taken of the studied drugs. Therefore, the study was conducted based exclusively on analytical and demographic data. The original intent for the study was to also include zaleplon and triazolam, but there were no zaleplon-positive cases and only 1 triazolam-positive case in the study period. Temazepam cases were excluded if they were considered to be metabolites of diazepam based on concentration ratios of the substances, as described elsewhere.35
Chemicals and Reagents Reference materials for temazepam, midazolam, zopiclone, zolpidem, nitrazepam, and the internal standards (ISTD), diazepam-d5 and temazepam-d5, were purchased from LGC Standards (Wesel, Germany). HPLC-grade methanol, acetonitrile, ammonia 32% pro analysi, and acetic acid pro analysi were obtained from Baker (Griesheim, Germany), formic acid 98%–100% from Merck (Darmstadt, Germany), and water from LGC. Solid-phase extraction was performed using Bond Elut Plexa-3 ML cartridges with 30 mg sorbent from Agilent (Böblingen, Germany). Buffer solution for the LC–MS/MS system was prepared in-house by mixing 15 mL of 0.01 mol/L PBS-buffer (KH2PO4: 2.0 g/L, Na2HPO4 · 2H2O: 14.4 g/L, KCl: 2.0 g/L, NaCl: 80 g/L in 1 L water) with 1 mL of sodium acetate buffer (232 g sodium acetate and 124 mL acetic acid was mixed with deionized water for 1 L of solution with pH 4.8). Chromatographic separation was performed on a Luna phenyl-hexyl 3 mm 50 · 3 mm column from Phenomenex (Aschaffenburg, Germany).
Sample Preparation and LC–MS/MS Conditions All samples in the study period were subjected to a broad screening of various psychoactive drugs. The identification and analysis of the selected sedative-hypnotics in serum samples was performed by an LC–MS/MS method that has been described in detail elsewhere.36 The LC–MS/MS system consisted of a Shimadzu LC 20A LC-system and a triple quadrupole mass spectrometer (API 4000; AB SCIEX) with Turbo Ion Spray. Eluent flow from the LC was led to the turbo ion spray source without splitting. Ion spray voltage was set at 5.5 kV at a turbo ion spray heater temperature 6008C. The nebulizer gas was 60 psi and turbo heater gas 70 psi. The AB Sciex control software was set at 35 for the curtain gas and the collision gas at 12. Collision energy, declustering potential, and collision exit potential were optimized for each compound. Two intense fragments were used for the monitoring the analytes and 1 for the ISTD. Detailed LC–MS/MS conditions are listed in Table 2. Validation of the method was performed according to Peters et al for limit of detection (LOD), lower limit of quantification (LLOQ), linear range (LR), matrix effect, extraction recovery, within- and between-run percent of Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
Sedative-Hypnotics in DUID Cases
TABLE 2. MS/MS Conditions Compound Temazepam 1 Temazepam 2 Midazolam 1 Midazolam 2 Zopiclone 1 Zopiclone 2 Zolpidem 1 Zolpidem 2 Nitrazepam 1 Nitrazepam 2 Temazepam-d5 Diazepam-d5
Q1–Q3 (m/z)*
DP (V)
CXP (V)
CE (eV)
301 . 255 301 . 283 326 . 291 326 . 249 389 . 245 389 . 217 308 . 235 308 . 263 282 . 236 282 . 180 306 . 260 290 . 262
81 81 111 111 36 36 101 101 60 60 56 101
33 21 41 51 27 50 51 37 35 53 31 33
26 14 22 6 20 10 12 16 18 16 16 6
ISTD Temazepam-d5 Diazepam-d5 Diazepam-d5 Diazepam-d5 Diazepam-d5
*Monitored ion transitions. CE, collision energy; CXP, collision exit potential; DP, declustering potential; ISTD, internal standard.
relative standard deviation, stability, and selectivity.37,38 Calculations for the LOD were performed according to the German standard specification DIN 32645.39 Selectivity was established by analyzing unexposed specimens and potential interfering drugs. Carry over was evaluated by injecting blank samples after a specimen spiked with all analytes at the upper limit of the LR. No analyte peaks were detectable in the blanks. The LR was studied over a concentration range up to 2000 mg/L for temazepam, 1000 mg/L for midazolam, and 200 mg/L for zopiclone, zolpidem, and nitrazepam. Process stability was studied under the conditions of the LC–MS/MS analysis by analyzing serum samples spiked with all analytes over a period of 60 hours. All analytes were tested in 2 concentrations: close to the lower and higher limits of the typical concentration range associated with therapeutic drug use. The test solutions were stored in autosampler vials and kept in a refrigerator between runs. All analytes were stable for the studied period. Long-term stability of the analytes has been studied before.40 LOD, LLOQ, retention times, and other validation data are listed in Table 3. The identification of MDPV was based on 2 multiple reaction monitoring transitions for each analyte and the retention time.
Statistical Analysis All statistical analyses were performed using IBM SPSS software (version 21.0). Comparisons between different groups were performed using the Student t test or Mann– Whitney U test.
RESULTS In Finland, the number of DUID cases in which a blood sample is taken has been approximately 4000–4500 per year the last few years. All the toxicological analyses in DUID cases in Finland are performed in 1 central laboratory. Between January 1, 2009, and December 31, 2011, blood samples from 13,248 DUID cases were analyzed for drugs. All these samples were also analyzed for the short-acting
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TABLE 3. Validation Data RSD (%)* Compound
LOD (mg/L)
LLOQ (mg/L)
Rt (min)
ME (%)
RC (%)
Within
Between
Temazepam Midazolam Zopiclone Zolpidem Nitrazepam
0.0025 0.0018 0.0030 0.0030 0.0014
0.0041 0.0058 0.0032 0.0048 0.0041
2.7 2.4 1.6 2.0 2.5
29.9 23.6 17.7 7.1 5.2
58.7 68.1 73.8 77.5 63.8
2.9 4.2 5.8 3.9 4.8
9.0 10.6 14.8 11.6 12.2
*RSD measured at the lower part of the concentration range associated with therapeutic drug use. RC, extraction recovery; Rt, retention time; RSD, relative standard deviation.
hypnotics studied in this article. One or several of the studied substances was found in 3155 samples (23.8% of all DUID cases in this period). All positive findings with a serum concentration above the LLOQ were included in the study. The median serum concentrations and the concentration ranges of the 5 studied substances are illustrated in Figure 1. The mean (median/highest) concentrations of the drugs were: temazepam 0.611 (0.250/12.000) mg/L, midazolam 0.080 (0.033/1.700) mg/L, zopiclone 0.014 (0.040/4.000) mg/L, zolpidem 0.318 (0.190/4.600) mg/L, and nitrazepam 0.074 (0.032/0.600) mg/L. The prevalence of the drugs in our material, and the proportion that can be attributed to appropriate medical use, is shown in Figure 2. The cases of appropriate medical use were identified by finding the low morning levels typical for prescribed sedative-hypnotics. Of the drivers positive for the studied hypnotic drugs, 84.8% were male. The mean (range) age of the drivers was 33.5 (14–88) years. The age distribution in males and females is illustrated in Figure 3. In this study, the women using sleep medication were somewhat older than men (mean age, 35.9 versus 33.1 years). The difference was statistically significant (P , 0.001). The mean age of drivers using zopiclone or zolpidem was significantly higher than the mean age of all users of the
FIGURE 1. Serum concentrations of the studied sedativehypnotic drugs. The boxes represent the interquartile ranges, the bars in the middle of the boxes represent the median values, and the whiskers represent the highest and lowest nonextreme values. For clarity, the outliers (extreme high values, eg, temazepam 12 mg/L) are not shown in the whiskers but are listed in Table 2.
hypnotics selected for this study (zopiclone: 40.3 years/zolpidem: 37.6 years versus 33.5 years; P , 0.001 for both). The mean age of drivers using temazepam, midazolam, and nitrazepam was slightly lower than the mean age of all users of sedativehypnotics (temazepam: 32.3 years/midazolam: 31.6 years/nitrazepam: 31.1 years versus 33.5 years; P , 0.05 for each). More than 1 of the studied sedative-hypnotics was present in 16.9% (N = 533) of the cases. The vast majority of the multiple-sedative cases included temazepam (N = 522). It was most commonly found together with midazolam (N = 185), zopiclone (N = 115), and nitrazepam (N = 109). There were 28 cases with 3 of the studied sedative-hypnotics present. In only 85 cases (2.7%), the sedative-hypnotic was the only psychoactive substance detected. Zopiclone and zolpidem were much more often found with no other drugs present than the sedative-hypnotic benzodiazepines. Nitrazepam was never the only sedative-hypnotic present. The mean concentration of zopiclone was significantly higher in those cases in which it was the only drug of any type present; the same was true of zolpidem. In contrast, the concentrations of the other sedative-hypnotics studied were lower in those cases where they were the only drug of any type present (Table 4). In those cases in which temazepam or midazolam was the only drug of any type found, the concentration was mostly within or below the lower third of the concentration range associated with therapeutic use of the drug (83.3% of temazepam alone cases and 60.0% of midazolam alone cases). In those cases in which zopiclone or zolpidem was the only drug of any type found, the concentration was usually above the concentration range associated with therapeutic drug use (81.8% of zopiclone alone cases and 88.9% of zolpidem alone cases). Of all the drivers who tested positive for 1 or more of the studied sedative-hypnotics, 25.3% (N = 798) had a blood alcohol concentration above the cutoff value (0.10 g/kg). The mean (median/highest) blood alcohol concentration was 1.30 (1.14/3.71) g/kg. Opioids were present in 33.3% (N = 1051) cases, with buprenorphine the most common opioid found (N = 621). Tetrahydrocannabinol and/or the inactive carboxy-metabolite were present in 35.8% (N = 1130) of the cases. The mean (median/highest) serum concentration of tetrahydrocannabinol was 0.0034 (0.020/0.0640) mg/L. Of the drivers using temazepam, midazolam, or nitrazepam, more than 50% had also taken stimulants, in most cases amphetamine. In zopiclone and zolpidem cases, the proportion of stimulant users was 21.3% and 24.4%, respectively. The
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Sedative-Hypnotics in DUID Cases
FIGURE 2. Prevalence of the studied sedativehypnotics. The darker areas represent the proportions of cases containing the indicated sedative-hypnotic at concentrations below the lower limit of the concentration range associated with therapeutic use of the drug. Numbers above the bars indicate the absolute numbers of cases positive for the indicated drug in the study material.
concomitant use of stimulants is presented in Table 4. Overall, stimulants were present in 47.2% of the sedative-hypnotic– positive cases (N = 149). Amphetamine was the by far the most popular stimulant (N = 1479). The new so-called designer drugs, such as 3,4-methylenedioxypyrovalerone (MDPV), desoxypipradrol (2-DPMP), PMMA, methylone, fluoroamphetamines, 4-methylamphetamine, or synthetic cannabinoids, were present in 71 cases; in 8 cases, a designer stimulant (MDPV or 2-DPMP) was the only stimulant found. The median concentration of the sedative-hypnotics in cases with concomitant stimulant use was markedly lower than the median concentration in all cases for each sedative-hypnotic. These differences were statistically significant except for nitrazepam (Table 4). The serum concentration of the sedative-hypnotic was below the concentration range associated with therapeutic use of the drug in 26.6% (N = 838) and above in 27.2% (N = 859) of all the positive cases.
DISCUSSION Sedative-hypnotics are used for treating different kinds of sleeping disorders. Many studies indicate that they are also widely abused, often together with other drugs of abuse.41–43 Sleep medicines are frequently found in the serum of
apprehended drivers. In our study period, nearly a quarter of the apprehended drivers was positive for at least 1 of the studied sedative-hypnotics. By far, the most common substance was temazepam, which alone accounted for over half of the positive sedative-hypnotic findings in the study period. The number of temazepam positive cases in our study was nearly 5 times the number of positive zopiclone cases, although zopiclone is the most commonly prescribed sleeping medication in Finland defined as daily defined doses (DDD) per 1000 inhabitants. For zopiclone, DDD in Finland was 20.37 in 2013, whereas temazepam held the second place with a DDD of 10.86.21 Because of the fast elimination of most sedativehypnotics (Table 1), ideally and when used appropriately, there should be little or no drug detectable in the blood the morning after the use of these drugs.27,44 This is not always the case, which has been demonstrated for zopiclone and zolpidem in aged individuals.45 When stopped by the police, a driver using prescribed sleep medication correctly should only have traces of the drug left in his system or at least the serum concentration should by no means exceed the concentration range associated with therapeutic drug use but rather be below it.44 Furthermore, in appropriate medical treatment of insomnia, no more than 1 sedative-hypnotic drug should be present simultaneously. Of the drugs studied in this article,
FIGURE 3. Age distribution of males and females in DUID cases positive for 1 or more sedative-hypnotics. Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
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TABLE 4. Serum Concentrations of the Studied Sedative-Hypnotics in All Cases, Cases With a Single Sedative-Hypnotic Only, and Cases With Concomitant Use of Stimulants All Cases Number of Cases Temazepam Midazolam Zopiclone Zolpidem Nitrazepam
1827 414 384 309 221
Mean/Median (mg/L) 0.661/0.250 0.080/0.033 0.137/0.040 0.318/0.190 0.074/0.032
Sedative-Hypnotic-Only Cases Percentage (%) 0.3 2.4 8.6 11.7 —
Sedative-Hypnotic Plus Stimulant
Mean/Median (mg/L) 0.156/0.060 0.042/0.025 0.323/0.160 0.455/0.365 —
P
Percentage (%)
,0.05 .0.05 ,0.001 ,0.001 —
51.9 58.7 20.8 23.9 62.0
Mean/Median (mg/L) 0.450/0.184 0.062/0.025 0.047/0.021 0.112/0.026 0.067/0.027
P ,0.001 ,0.02 0.001 ,0.001 .0.05
P values versus all cases are calculated for the differences in concentrations using the Mann–Whitney U test.
the proportion of zolpidem-positive cases in which the drug concentration was under the concentration range associated with therapeutic drug use was greater than the equivalent proportion for the other sedative-hypnotics studied. This could be explained by the very short elimination half-life of the drug, or it could suggest that zolpidem is less abused and thus not taken at inappropriate times and quantities as often as the other substances studied. Almost 20% of the drivers who tested positive for 1 of the studied sedative-hypnotic drugs also had 1 or more of the others in their blood. As it would not be good practice for a physician to prescribe a patient more than 1 sedativehypnotic to be used simultaneously, it can be concluded that drivers positive for more than 1 of the studied substances are probably abusing at least 1 of them. Polydrug use is extremely prevalent among recreational drug users and also among drivers suspected of DUID.46,47 In our study, only 2.7% of the drivers did not have any other psychoactive substances, besides 1 of the sedative-hypnotics, in their blood. Surprisingly, users of either of the studied Z-drugs, zopiclone or zolpidem, who had only the Z-drug, in their system had a higher median concentration of the Z-drug than those who tested positive for several different drugs of abuse. This phenomenon is hard to explain, as the lack of multiple drugs suggests prescribed use whereas high concentration points towards abuse. In previous studies, unauthorized use of sedatives has been divided into 2 categories: recreational abuse by polydrug users and unauthorized chronic use by patients.48 The individuals suffering from severe prolonged insomnia and who have been treated with sedative-hypnotics for a long period may have created a functional tolerance for the subjectively recognizable impairing effects of the drug. To still achieve the hypnotic effect of the drug, the insomniac may gradually increase the dosage while not noticing their unfitness to drive. Benzodiazepines, for example, have been shown to impair driving even in experienced users in a dose-dependent manner.12 Moreover, there is very little research on the risks associated with long-term sedative use.48 Although previous studies have shown that the long-term use of sedativehypnotic drugs is common,49–51 the above-mentioned reasons together with the known abuse potential of the sedativehypnotic drugs strongly discourage chronic use. The studied sedative-hypnotic drugs were very often found together with stimulants. Nearly half of all studied
sedative-hypnotic cases showed concomitant use of amphetamine, methamphetamine, ecstasy, or MDPV, which are the most prevalent stimulants among the apprehended drivers in Finland. Abusive stimulant use is generally known to produce insomnia, which is why the presence of sedative-hypnotics in the blood of stimulant users is not very surprising. Those driving under the influence of both a sedative-hypnotic drug and a stimulant drug had a lower serum concentration of the sedative-hypnotic than in the overall study population. This is in good accordance with our previous observations that in stimulant users, the serum sedative concentrations are not as high as in those using sedatives only.36 Cannabis was found in more than 30% of the drivers positive for the studied substances. Moreover, 30% had taken opioids. Alcohol was very often found together with sedativehypnotic drugs, many times in alarming concentrations. Zopiclone and zolpidem were markedly less frequently found together with stimulants than the benzodiazepine-type hypnotics. Also, the users of zopiclone and zolpidem were older than all the sedative-hypnotic users in the study material. These findings may indicate that these drugs are at least somewhat less abused than the other substances studied in this article. Most previous research on sleeping medication and driving has focused on the residual effects of sedativehypnotics on the driving ability after appropriate prescribed use of sleep medication. In this study, we sought to examine the extent of abuse of sedative-hypnotics by looking at the drug use patterns and profile of the drivers using sleeping medication. Although patients are instructed in the Medication Guide and should be advised by physicians to remain inactive and to avoid complicated tasks such as driving for at least 7–8 hours after the administration of the sedative-hypnotic drug, people tend to first try and fall asleep without the drug and only take the drug when they finally admit that they have failed the attempt.22 This leads to sleep medication being administered close to midnight or later. This kind of use of sedative-hypnotics must be considered misuse and should be strongly discouraged by physicians and pharmacists. However, even such inappropriate use of sleep medication would be expected to lead to serum concentrations that are, at most, in the lower part of or below the concentration range associated with therapeutic use of the drug in a blood sample taken
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Ther Drug Monit Volume 37, Number 3, June 2015
the following morning. However, in our study material, more than 15% of the drivers positive for 1 or more of the studied sedative-hypnotics had a serum concentration that was above the upper limit of the concentration range associated with therapeutic drug use, which clearly suggests abuse of the drug. Some of the concentrations were more than 10 times the upper limit of the typical concentration range. In addition to causing dangerous impairment of driving ability, such concentrations are potentially lethal, especially in combination with other central nervous sedatives, which markedly enhance toxicity.52,53 Our results further support previous studies, which have shown that the use of benzodiazepine or benzodiazepine-like hypnotics should be avoided with patients with tendency for drug abuse.54,55
Sedative-Hypnotics in DUID Cases
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CONCLUSIONS Our results indicate that the majority of the positive sedative-hypnotic findings in DUID cases results from abuse of the drugs, in most cases used as a part of a combination of drugs of abuse. Drivers who use medically appropriate sleep medication are practically absent from the police statistics of apprehended drivers. In a significant proportion of cases, the concentration of the sedative-hypnotic was within or above the concentration range associated with therapeutic drug use and would likely cause impairment of driving ability.
ACKNOWLEDGMENTS The authors thank Niall Doherty, Stefan Jenckel, Markku Pekkola, and Sanna Taskinen for their assistance. REFERENCES
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