Zopiclone and traffic safety : Introducing legalized blood zopiclone concentration limits - is it evidence based?
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AbstractZopiclone is one of the most commonly prescribed sleep medications in the world. Driving in the morning, after regular nighttime zopiclone consumption, is, by many, considered to be safe traffic wise, due to the fast zopiclone elimination. Still, it is well known that the effects of zopiclone are comparable to that of benzodiazepines’, and certain negative effects due to zopiclone intake, with respect to traffic safety, are therefore to be expected. This thesis aimed to investigate if zopiclone was suitable for implementing legal limits, by the use of blood zopiclone concentrations, in a manner similar to what is being conducted for ethanol in most countries. With the previous being plausible, an increased traffic accident risk was expected to be found related to the use of zopiclone, in addition to a positive concentration-effect relationship between blood zopiclone concentrations and traffic-related impairment, comparable to that of what has been found for ethanol.
We performed a coupling between the Norwegian Accident Registry (NRAR) and the Norwegian Prescription Database (NorPD), and found an increased traffic accident risk related to zopiclone exposure. There may, however, have been confounding factors present leading to a stronger relationship than what is actually true. Still, a significant traffic accident risk was found related to zopiclone exposure, in a case-crossover calculation, indicating a true drug effect.
An observational study design was used to investigate the relationship between high blood zopiclone concentrations and impairment, in a population of apprehended suspected drugged drivers, as assessed by the Norwegian by-the-road clinical test for impairment (CTI). A high share of impairment was found, increasing the higher the blood zopiclone concentrations. Similar results were found for ethanol.
Finally, a randomized controlled trial (RCT) was performed on 16 healthy volunteers. They were each given two different doses of zopiclone (5 and 10 mg), ethanol (50 g) and placebo, in a crossover design. The study found a positive concentration-effect relationship for zopiclone, as well as for ethanol. In addition, acute tolerance was found for zopiclone, as well as for ethanol. The relationship between blood zopiclone concentrations and blood alcohol concentrations (BACs) is found to be positive; however, there was some variation in response to the different impairment tests.
In total, the presented studies indicate that blood zopiclone concentrations may be as suited for legal limits as BACs.
List of papers
|Paper I Gustavsen I, Bramness JG, Skurtveit S, Engeland A, Neutel I, Mørland J. Road Traffic Accident Risk Related to Prescription of the Hypnotics: Zopiclone, Zolpidem, Flunitrazepam and Nitrazepam. Sleep Med 2008; 9 (8) 818-822. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.sleep.2007.11.011|
|Paper II Gustavsen I, Al-Sammurraie M, Mørland J, Bramness JG. Impairment Related to Blood Drug Concentrations of Zopiclone and Zolpidem Compared with Alcohol in Apprehended Drivers. Accid Anal Prev 2009; 41 (3) 462-466. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.aap.2009.01.011|
|Paper III Gustavsen I, Hjelmeland K, Bernard JP, Mørland J. Psychomotor Performance after Intake of Zopiclone compared with Intake of Ethanol– A randomized Controlled Double-Blinded Trial. J Clin psychopharmacol 2011; 31(4): 481-488. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1097/JCP.0b013e3182214be6|
|Paper IV Gustavsen I, Hjelmeland K, Bernard JP, Mørland J. Individual Psychomotor Impairment in Relation to Zopiclone and Ethanol Concentrations in Blood– A Randomized Controlled Double-Blinded Trial. Addiction 2012; 107(5):925-932. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1111/j.1360-0443.2011.03693.x|