Sedative Hypnotic Use and the Risk of Motor Vehicle Crash
Sedative Hypnotic Use and the Risk of Motor Vehicle Crash
This study suggests that filled prescriptions for 3 different types of sedative hypnotic agents were associated with increased risk of motor vehicle crash for new users of these medications. Sedative hypnotic exposure nearly doubled the risk of crash in new users. Of those evaluated, temazepam appears to be the sedative with the lowest risk of motor vehicle crashes. Translating these results to BAC equivalents suggests that the risk of motor vehicle crash in sedative hypnotic users is similar to that found in alcohol intoxication, exceeding the US legal limit to operate a motor vehicle.
When we examined the length of continuous exposure to sedative medications, there was a trend toward increased risk over time, with a peak between 1 and 4 months for zolpidem but at 4 to 8 months for trazodone and 8 to 12 months for temazepam. The risk of crash decreased over time for all 3 medications, yet there remained an increased risk of crash even after 1 year of prescription fills for both trazodone and zolpidem. The decreasing risk over the length of the study may result from tolerance to the sedative properties of the medications or, alternatively, it may reflect adjustment of driving behaviors on the basis of perception of risky behaviors.
The largest body of evidence regarding the risk of motor vehicle collisions and sedative hypnotics comes from Scandinavia and The Netherlands. However, only 1 study from that region has been able to compare commonly used hypnotic sleep medications. The largest studies, a registry-based cohort from Norway, evaluated almost 13 000 collisions among the 3.1 million residents in 2004 to 2005 and examined the association with exposure to several drug classes. The first study found a standardized incidence ratio (SIR) of crash for benzodiazepine hypnotics of 3.3 (95% CI = 2.1, 4.7). For comparison, the SIR for calcium receptor antagonists was 0.9 (95% CI = 0.5, 1.5). Gustavsen et al. followed this same national cohort from 2004 to 2006, and compared the risks associated with 2 z-hypnotics (zopiclone and zolpidem) and 2 benzodiazepines (flurnitrazepam and nitrazepam). That study found the highest risk of crash in users of flurnitrazepam with an SIR of 4.0 (95% CI = 2.4, 6.4), with zolpidem of lower risk at an SIR of 2.2 (95% CI = 1.4, 3.4). One recent additional study from Taiwan examined 5183 participants with a diagnosis code of a motor vehicle accident in a matched case–control methodology and found that 1 month of use of benzodiazepines, hypnotics, or z-hypnotics was associated with odds ratios for crash of 1.68 (95% CI = 1.50, 1.88), 1.80 (95% CI = 1.43, 2.26), and 1.63 (95% CI = 1.32, 2.01), respectively.
Other investigators have examined simulated driving behavior, which can be informative, but differs from real driving behavior. Eighteen healthy elderly participants were studied by Leufkens and Vermeeren comparing temazepam, zopiclone, and placebo treatment 10 to 11 hours before a standardized driving test. In this study, zopiclone was found to affect driving performance, but temazepam's effect was similar to placebo. Partinen et al. undertook a 3-arm, double-blind, placebo-controlled crossover study of zolpidem and temazepam, studying the effect of taking these drugs after midnight on driving simulator ability the following morning. This was a small study of female participants (n = 18) and the primary outcome of time to simulated crash did not differ between the groups. There was a statistically significant difference in lane position deviation: zolpidem produced greater deviations than either temazepam (0.135 meters of deviation; P = .05) or placebo (0.117 meters of deviation; P = .025). Therefore, although an association between the sedative hypnotics and motor vehicle crashes likely exists, previous research has not evaluated crash risk for different sedative medications. Furthermore, the largest cohort studies have not been replicated to examine the validity or generalizability of its results beyond the Norwegian population.
This study has a number of important limitations. As with all observational research, there is the possibility for confounding by indication. Medical conditions being treated by the drug exposures may be independently associated with crash and such confounding may bias our model estimates. Yet these conditions are not typically acute or rapid onset, thus allowing participants to contribute both exposed and unexposed time, which should mitigate this bias at the individual patient level. Trazodone is indicated for use to treat major depressive disorder but is used off-label for insomnia; thus, the underlying conditions for which study participants were undergoing treatment may have varied compared with the other sedatives.
Second, our ascertainment of exposure in the retrospective analysis was based on prescription dispensing records at GH and may not represent actual ingestion of medications in the period preceding a crash.
Third, we are unable to ascertain the actual driving status of the study participants; thus, we do not know if systematic differences exist between the exposed and nonexposed participants with regard to actual driving behaviors, experience, and total miles driven, though we restricted study participation to those individuals who were licensed to drive during the study period.
Fourth, we were unable to evaluate alcohol or illicit drug use as potential confounders. We only had access to alcohol status for participants who crashed and these data were incomplete (22% unknown or missing). Concomitant use of alcohol with sedatives is discouraged because of synergistic effects and could be an important area for future research.
Fifth, the relative sedative effects of the 3 chemicals we studied are not well understood and cannot be proportionately adjusted for. Finally, we evaluated people aged 21 to 79 years from a single large health plan in Washington State, which could affect generalizability beyond GH.
The 3 sedative hypnotics included in our study appear to be associated with increased risk of motor vehicle crash, with the risk depending on the sedative being used and the length of continuous exposure. The potential for residual confounding by underlying sleep disorders cannot be ignored. Future research is needed to investigate various sleep disorders and risk of crash to identify whether the medications or the sleep disorders are the causal factor in this association.
Additional important areas for future research include the latency of medication ingestion in relation to crashes, sedative dose, tolerance to these medications, concurrent consumption of other substances, and the link between sedatives and fatal crashes, as well as further investigation into the factors that influence crash risk related to the length of prescription exposure. Identifying high-risk prescriptions may improve public health by educating the prescribers and users of these medications about the particular types of exposures that could increase an individual's likelihood of crashing.
Depending on an individual's need to drive regularly combined with a medical indication for sedative use, the choice of a particular sedative may affect the risk of crashing. Prescribers, pharmacists, and patients should discuss this potential risk and consider the implications of this analysis when selecting a sedative hypnotic medication. Physicians may also wish to consider nonsedating approaches to encouraging healthy sleep. In the interest of the public safety on the roads and highways in the United States, individuals who have been prescribed sedative hypnotic medications should be counseled about driving risk and alternative transportation strategies addressed when under the influence of these medications. Future research should evaluate whether this association extends to crash-associated mortality.
Discussion
This study suggests that filled prescriptions for 3 different types of sedative hypnotic agents were associated with increased risk of motor vehicle crash for new users of these medications. Sedative hypnotic exposure nearly doubled the risk of crash in new users. Of those evaluated, temazepam appears to be the sedative with the lowest risk of motor vehicle crashes. Translating these results to BAC equivalents suggests that the risk of motor vehicle crash in sedative hypnotic users is similar to that found in alcohol intoxication, exceeding the US legal limit to operate a motor vehicle.
When we examined the length of continuous exposure to sedative medications, there was a trend toward increased risk over time, with a peak between 1 and 4 months for zolpidem but at 4 to 8 months for trazodone and 8 to 12 months for temazepam. The risk of crash decreased over time for all 3 medications, yet there remained an increased risk of crash even after 1 year of prescription fills for both trazodone and zolpidem. The decreasing risk over the length of the study may result from tolerance to the sedative properties of the medications or, alternatively, it may reflect adjustment of driving behaviors on the basis of perception of risky behaviors.
The largest body of evidence regarding the risk of motor vehicle collisions and sedative hypnotics comes from Scandinavia and The Netherlands. However, only 1 study from that region has been able to compare commonly used hypnotic sleep medications. The largest studies, a registry-based cohort from Norway, evaluated almost 13 000 collisions among the 3.1 million residents in 2004 to 2005 and examined the association with exposure to several drug classes. The first study found a standardized incidence ratio (SIR) of crash for benzodiazepine hypnotics of 3.3 (95% CI = 2.1, 4.7). For comparison, the SIR for calcium receptor antagonists was 0.9 (95% CI = 0.5, 1.5). Gustavsen et al. followed this same national cohort from 2004 to 2006, and compared the risks associated with 2 z-hypnotics (zopiclone and zolpidem) and 2 benzodiazepines (flurnitrazepam and nitrazepam). That study found the highest risk of crash in users of flurnitrazepam with an SIR of 4.0 (95% CI = 2.4, 6.4), with zolpidem of lower risk at an SIR of 2.2 (95% CI = 1.4, 3.4). One recent additional study from Taiwan examined 5183 participants with a diagnosis code of a motor vehicle accident in a matched case–control methodology and found that 1 month of use of benzodiazepines, hypnotics, or z-hypnotics was associated with odds ratios for crash of 1.68 (95% CI = 1.50, 1.88), 1.80 (95% CI = 1.43, 2.26), and 1.63 (95% CI = 1.32, 2.01), respectively.
Other investigators have examined simulated driving behavior, which can be informative, but differs from real driving behavior. Eighteen healthy elderly participants were studied by Leufkens and Vermeeren comparing temazepam, zopiclone, and placebo treatment 10 to 11 hours before a standardized driving test. In this study, zopiclone was found to affect driving performance, but temazepam's effect was similar to placebo. Partinen et al. undertook a 3-arm, double-blind, placebo-controlled crossover study of zolpidem and temazepam, studying the effect of taking these drugs after midnight on driving simulator ability the following morning. This was a small study of female participants (n = 18) and the primary outcome of time to simulated crash did not differ between the groups. There was a statistically significant difference in lane position deviation: zolpidem produced greater deviations than either temazepam (0.135 meters of deviation; P = .05) or placebo (0.117 meters of deviation; P = .025). Therefore, although an association between the sedative hypnotics and motor vehicle crashes likely exists, previous research has not evaluated crash risk for different sedative medications. Furthermore, the largest cohort studies have not been replicated to examine the validity or generalizability of its results beyond the Norwegian population.
Limitations
This study has a number of important limitations. As with all observational research, there is the possibility for confounding by indication. Medical conditions being treated by the drug exposures may be independently associated with crash and such confounding may bias our model estimates. Yet these conditions are not typically acute or rapid onset, thus allowing participants to contribute both exposed and unexposed time, which should mitigate this bias at the individual patient level. Trazodone is indicated for use to treat major depressive disorder but is used off-label for insomnia; thus, the underlying conditions for which study participants were undergoing treatment may have varied compared with the other sedatives.
Second, our ascertainment of exposure in the retrospective analysis was based on prescription dispensing records at GH and may not represent actual ingestion of medications in the period preceding a crash.
Third, we are unable to ascertain the actual driving status of the study participants; thus, we do not know if systematic differences exist between the exposed and nonexposed participants with regard to actual driving behaviors, experience, and total miles driven, though we restricted study participation to those individuals who were licensed to drive during the study period.
Fourth, we were unable to evaluate alcohol or illicit drug use as potential confounders. We only had access to alcohol status for participants who crashed and these data were incomplete (22% unknown or missing). Concomitant use of alcohol with sedatives is discouraged because of synergistic effects and could be an important area for future research.
Fifth, the relative sedative effects of the 3 chemicals we studied are not well understood and cannot be proportionately adjusted for. Finally, we evaluated people aged 21 to 79 years from a single large health plan in Washington State, which could affect generalizability beyond GH.
Conclusions
The 3 sedative hypnotics included in our study appear to be associated with increased risk of motor vehicle crash, with the risk depending on the sedative being used and the length of continuous exposure. The potential for residual confounding by underlying sleep disorders cannot be ignored. Future research is needed to investigate various sleep disorders and risk of crash to identify whether the medications or the sleep disorders are the causal factor in this association.
Additional important areas for future research include the latency of medication ingestion in relation to crashes, sedative dose, tolerance to these medications, concurrent consumption of other substances, and the link between sedatives and fatal crashes, as well as further investigation into the factors that influence crash risk related to the length of prescription exposure. Identifying high-risk prescriptions may improve public health by educating the prescribers and users of these medications about the particular types of exposures that could increase an individual's likelihood of crashing.
Depending on an individual's need to drive regularly combined with a medical indication for sedative use, the choice of a particular sedative may affect the risk of crashing. Prescribers, pharmacists, and patients should discuss this potential risk and consider the implications of this analysis when selecting a sedative hypnotic medication. Physicians may also wish to consider nonsedating approaches to encouraging healthy sleep. In the interest of the public safety on the roads and highways in the United States, individuals who have been prescribed sedative hypnotic medications should be counseled about driving risk and alternative transportation strategies addressed when under the influence of these medications. Future research should evaluate whether this association extends to crash-associated mortality.
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