Ingebjørg Gustavsen

Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam

BACKGROUND Despite the high prescription rate of benzodiazepine-like hypnotics (z-hypnotics), there is limited information on the road traffic accident risk associated with the use of these drugs. We wanted to investigate whether filling a prescription for zopiclone or zolpidem was associated with increased risk of road traffic accidents at a national population level. Nitrazepam and flunitrazepam were used as comparator drugs. METHOD All Norwegians 18-69 years (3.1 million) were followed-up from January 2004 until the end of September 2006. Information on prescriptions, road traffic accidents and emigration/death was obtained from three Norwegian population-based registries. The first week after the hypnotics had been dispensed was considered to be the exposure period. Standardized incidence ratios (SIRs) were calculated by comparing the incidence of accidents in the exposed person-time to the incidence of accidents in the unexposed person-time. RESULTS During exposure, 129 accidents were registered for zopiclone, 21 for zolpidem, 27 for nitrazepam and 18 for flunitrazepam. The SIRs were (SIR for all ages and both sexes combined; 95% CI): z-hypnotics (zopiclone+zolpidem) 2.3; 2.0-2.7, nitrazepam 2.7; 1.8-3.9 and flunitrazepam 4.0; 2.4-6.4. The highest SIRs were found among the youngest users for all hypnotics. CONCLUSIONS This study found that users of hypnotics had a clearly increased risk of road traffic accidents. The SIR for flunitrazepam was particularly high.

Impairment related to blood drug concentrations of zopiclone and zolpidem compared to alcohol in apprehended drivers

BACKGROUND About 3-7% of the adult population receives prescribed hypnotics. The benzodiazepine-like hypnotics, zopiclone and zolpidem, are the most commonly prescribed and may cause traffic-relevant impairment similar to that found for benzodiazepines. We investigated the relationship between blood zopiclone and zolpidem concentrations and driving impairment, as assessed by the clinical test for impairment. We compared these groups of drivers to a group suspected of alcohol-related impairment. METHODS Blood samples from suspected impaired drivers during 2000-2007, screened for approximately 25 possible impairing drugs with only one single drug detected, were studied in relation to the assessment of impairment. The 79 zopiclone positive drivers, the 43 zolpidem positive drivers, and the 3480 alcohol positive drivers were divided into groups depending on blood drug concentrations. RESULTS/DISCUSSION The proportion of drivers judged as impaired tended to increase the higher the blood zopiclone concentrations. Such a positive relationship was not found for zolpidem. For alcohol the proportion of impaired drivers was significantly related to blood alcohol concentrations (BACs). There were few drivers with low zopiclone or zolpidem concentrations included, which may have obscured any positive significant relationship. The percentage of impaired drivers among drivers with blood zopiclone concentrations above 130 microg/l roughly corresponded to the percentage of impaired drivers among drivers with BACs higher than 0.1%.

Individual psychomotor impairment in relation to zopiclone and ethanol concentrations in blood – a randomized controlled double‐blinded trial

AIMS To investigate individual traffic-relevant impairment related to measured blood zopiclone and ethanol concentrations. Also, we aimed to study possible development of acute tolerance. DESIGN A randomized controlled four-way cross-over double-blind trial. Study drugs were zopiclone 5 or 10 mg, 50 g ethanol or placebo. SETTING Laboratory study with computerized tests: Connors Continuous Performance test, Choice Reaction Time and Stockings of Cambridge. Altogether, the tests consisted of 15 test components, representing three levels of behaviour (automotive, control, executive planning), relevant to traffic safety. PARTICIPANTS Sixteen healthy male volunteers. MEASUREMENTS Each study day, 10 blood samples were collected from each volunteer. Fifteen psychomotor test components were registered at baseline and a further three times after intake. Impairment was defined as any individual deterioration in performance compared to individual baseline performance. FINDINGS Blood drug concentrations up to 74 µg/l zopiclone and 0.100% ethanol were measured. We found a clear positive concentration-effect relationship for zopiclone and ethanol for both automotive and control behaviours, and a modest relationship for executive planning behaviour. Significant impairment started to be observed at concentrations above 16 µg/l zopiclone (automotive and control behaviour) and above 0.026% ethanol (automotive behaviour). Acute tolerance was found for both drugs. CONCLUSIONS The hypnotic, zopiclone, can impair psychomotor performance at blood concentrations as low as 16 µg/l.

Psychomotor Performance After Intake of Zopiclone Compared With Intake of Ethanol: A Randomized, Controlled, Double-Blinded Trial

The sleep medicine zopiclone (eszopiclone) is commonly used in most Western countries. The focus on legislation for possible traffic-impairing nonalcohol drugs have caused a need for comparing traffic relevant behavior after intake of commonly used psychoactive drugs to blood alcohol concentrations (BACs). We aimed to compare psychomotor effects at 3 levels of behavior at different blood zopiclone concentrations to effects seen at different BACs. We performed a randomized double-blinded trial on 16 healthy volunteers who received either 10 or 5 mg zopiclone, 50 g ethanol or placebo in a crossover design. The volunteers performed computerized tests at baseline, 1, 3.5, and 6.5 hours after intake, accompanied by blood sampling. Impairment was found at all 3 behavior levels. For zopiclone, impairment was most pronounced at behavior level 1 (automotive behavior); a mean blood zopiclone concentration at 39 &mgr;g/L achieved 1 hour after intake of 10 mg zopiclone was accompanied by more impairment than BAC 0.074 %. At behavior levels 2 (control behavior) and 3 (executive planning), the psychomotor impairment accompanying approximately 39 &mgr;g/L zopiclone seemed comparable to a BAC of approximately 0.074%. No test components were impaired at 6.5 hours after intake.

Long-term Use of Z-Hypnotics and Co-Medication with Benzodiazepines and Opioids.

Benzodiazepine‐like drugs (z‐hypnotics) are the most commonly used drugs for treatment of insomnia in Norway. Z‐hypnotics are recommended for short‐term treatment not exceeding 4 weeks. We aimed to study the use of z‐hypnotics in the adult population in Norway with focus on recurrent use in new users, treatment intensity and co‐medication with benzodiazepines and opioids in long‐term users. Data were obtained from the Norwegian Prescription Database. New users in 2009 were followed through 2013. Recurrent z‐hypnotic use was defined as new fillings at least once in each of the four 365‐day follow‐up periods. Age groups of 18–39, 40–64 and 65+ years were analysed separately for men and women. In 2013, 354,571 (8.9%) of the population filled at least one prescription of z‐hypnotics and the prevalence was relatively stable over time. Among the 92,911 new users of z‐hypnotics in 2009, 13,996 (16.8%) received z‐hypnotics all four 365‐day periods of follow‐up. In these long‐term recurrent users, the treatment intensity was high already the second year, with mean annual amounts of 199 and 169 DDDs per patient in men and women, respectively. The interquartile differences were greatest in the youngest age group. 27.9% of the long‐term recurrent users of z‐hypnotics used benzodiazepines the fourth year and 33.9% used opioids. The proportions with co‐medication increased with level of z‐hypnotic treatment intensity. Overall, many z‐hypnotic users had medicines dispensed for longer periods than recommended, and co‐medications with drugs that may reinforce the central depressing and intoxicating effects were common.

Can a simple clinical test detect impairment of zopiclone and alcohol? – A randomized controlled trial

PURPOSE The risk of traffic accident involvement is increased among patients prescribed the z-hypnotic drug zopiclone. Clinical test observations able to indicate drug impairment are therefore essential. This study compared the findings of a simplified clinical test of impairment (SCTI) with those of a battery of computerized psychomotor tests of impairment (CPTI). METHODS 16 healthy young male volunteers attended a research unit on four different study days, receiving in randomized order either placebo, zopiclone 5mg, zopiclone 10mg, or alcohol 50g. The SCTI was performed twice and the CPTI was performed three times on each study day, with blood samples being collected for drug analysis. RESULTS The SCTI (and the CPTI) was able to demonstrate impairment at 1.5h, but no major impairment was found at 7h with the SCTI, after intake of both zopiclone and ethanol. The CPTI detected a significantly higher proportion of impaired observations than the SCTI, both for zopiclone and for ethanol, at all concentration levels. The sensitivity of the clinical tests in detecting blood drug concentrations often associated with impairment, due to zopiclone (above 23ng/ml) and alcohol (above 0.5g/l), was low, revealing 27 per cent and 18 per cent, respectively. The specificity, however, was higher, both for zopiclone (88 per cent) and for alcohol (96 per cent). DISCUSSION The SCTI may be a useful tool, especially during roadside investigation, when the police are in doubt as to whether the apprehended driver is impaired or not. A subject, who has consumed zopiclone or alcohol, tested with the SCTI, with one or more subtests diverging from a habitual result, is likely to have a blood zopiclone concentration above 23ng/ml or a BAC above 0.5g/l. A negative result, however, is less helpful.

Fatal Adverse Event with Dabigatran in Elderly Patient with Reduced Kidney Function

An elderly man with decreased kidney function was admitted to hospital with gastrointestinal bleeding. After remaining stable for 2 days in hospital, he became haemodynamically unstable and an adverse effect of dabigatran was suspected, but efforts to treat the patient failed and the following morning he passed away. In conjunction with the autopsy, blood samples from his hospital stay were analysed for dabigatran, revealing the highest concentration (6400 ng/mL) apparently reported to date. Supra‐therapeutic dosing was, however, never suspected. Dabigatran is largely excreted through the kidneys. A possible cause of the high dabigatran concentrations could be a rapid decrease in kidney function that seemingly occurred over a period of 2 months, sometime between his initiation of treatment (eGFR 51–55 mL/min/1.73 m2) and subsequent hospital admission (eGFR 31 mL/min/1.73 m2). The increasing dabigatran concentrations in the patient was, however, not apparent to the prescribing doctor, as therapeutic drug monitoring of dabigatran is not recommended in current guidelines and no such analyses were performed. There may be a need to evaluate blood concentrations of dabigatran, in the light of the reported differences in interindividual concentrations, along with the increased risks of thromboembolic events with lower concentrations and major bleeding events with higher concentrations. Functional assays to assess concentrations of dabigatran in blood have been developed and are available in some hospitals to be used in suspected overdoses or before emergency surgeries. Methods to determine concentrations of dabigatran specifically have also been developed and can additionally be used for therapeutic drug monitoring in an outpatient setting, especially in high‐risk individuals.