Z-drugs and driving

By: Dr Francisco Javier Resa López
General Practitioner. Public Health and Preventive Medicine Working Group – SEMERGEN.

Today, traffic accidents related to the use of prescription drugs are one of the main public health problems in developed countries. Driving requires the appropriate use of the sensory, cognitive and motor functions that allow people to adapt to the different situations that might occur on the highway. These functions are affected to a greater or lesser extent by the use of various substances with a psychotropic effect on the central nervous system, thus leading to an increase in the risks associated with driving. Amongst these, due to their high and ever-increasing consumption, sedative-hypnotics are one of the therapeutic groups with the biggest impact in this respect, as shown by the vast amount of scientific evidence available^(1-5).

Insomnia is a common disorder and often a chronic one, which increases with age – especially after age 40 – whose prevalence in Europe ranges between 4% and 37%, depending on the criteria and classification systems used. Approximately half of people with sleep problems consult their doctor and although it is recommended that pharmacological treatment is restricted to the most severe cases of insomnia, i.e. those that have a severely limiting effect on the patient’s regular activities, and only for a few weeks, the truth is that it is extremely common for the consultation to end with the doctor prescribing a hypnotic which, in the vast majority of cases, is taken for much longer than the recommended treatment period^(6-8).

In Spain, it is estimated that around 5% of the population take hypnotics several times a week, a figure which does not differ greatly in our neighboring countries. Given that according to data from the National Institute of Statistics for 2012 there are more than 26.3 million drivers, this gives you an idea of the scale of this problem. In the period between July 2012 and June 2013, some 4.8 million patient consultations on sleep disorders were dealt with in Spain, at which some form of medication was prescribed to the patient in 85% of cases. Around 25% of these prescriptions were for non-benzodiazepines – known as Z-drugs – mainly Zolpidem, a percentage very similar to that of the paradigmatic Lormetazepam (27.3%) and exceeding that of Lorazepam (20.0%), the two main benzodiazepines used for this purpose in Spain⁽⁹⁾.

Although in absolute terms the use of hypnotic drugs is lower than the use of anxiolytics, their use in the last few years has increased much more in our neighboring countries, to a large extent to the detriment of Z-drugs, especially Zolpidem and Zopiclone. In Spain, the data based on prescriptions made out by National Health System doctors – not including the Mutual Insurance systems of public sector workers – indicate that the use of Zolpidem increased by at least 85.07% between 2000 and 2011, going from 4.05 to 7.50 DDD/1000 hab/day, lower than Lormetazepam, at 18.26 DDD/1000 hab/day, which showed an increase of 103.26%⁽¹⁰⁾. However, if we analyze the data on the sales volume in pharmacies, which also includes private prescriptions and those of Mutual Insurance systems, we find that between July 2012 and June 2013, orders for dispensing Zolpidem accounted for 21.4% of the total hypnotic drugs, exceeding 3.5 million units, plus a further 500,000 units of Zopiclone⁽⁹⁾, the only two drugs of this kind currently available in Spain, as Eszopiclone, the only derivative authorized by the FDA for long-term use, is not yet marketed in this country and Zaleplon, although still authorized for use, was withdrawn in 2007.

Despite Good Clinical Practice recommendations, the true situation is reflected in a British study that showed how 91.6% of patients who take this kind of non-benzodiazepine analogs do so regularly, in 66.5% of cases every day, and that only 3.5% of cases adhere to the maximum prescribed duration of four weeks for Zolpidem and Zopiclone and two weeks for Zaleplon, while 77.3% of patients continued treatment for more than one year, GPs being responsible for 86.5% of prescriptions. Only 11.4% of the patients treated were aged under 45 and 44.8% of patients were over 65. It is also noteworthy that almost one of every three patients in the study had not been warned by their doctor of the risk of side effects and, when questioned about their perception of the risk of being involved in a traffic accident because of their treatment, only 1.4% of patients openly acknowledged their awareness of this risk, while 51.4% refused to accept that any such risk existed⁽⁸⁾.

With regard to Spain, like other countries in our region^(8-11), the use of these drugs increases considerably with age and the presence of a concomitant somatic or psychiatric disorder, so that much of their consumption is concentrated in elderly people⁽⁹⁾. By way of example, in Catalonia alone it is estimated that there are currently more than 40,000 chronic users of Zolpidem, of whom around 53% are over 70.

The significant increase in the use of these drugs is undoubtedly partly due to the fact that because of their more selective effect on the benzodiazepine receptor ω-1 at a cerebral level – representing the minimum impact on the phases of sleep, specifically the REM phase, thus respecting the physiological sleep pattern in healthy people and improving it in insomniacs^(1-6-7) – and also due to their relatively short average lifespan – around 1.5-3.2 hours for Zolpidem and 3.5-6.5 hours for Zopiclone⁽⁴⁾ – they have always been regarded by doctors as safer and more effective, especially for older patients^(8-12).

Thus despite the lack of scientific evidence in support of the existence of differences with regard to either short-action benzodiazepines or the level of symptomatic control, or in terms of the side effect profile⁽⁸⁾, it is generally accepted that compared to benzodiazepines, Z-drugs cause a lower feeling of morning drowsiness and do not have a particularly significant effect on memory or cognitive ability, and are also not expected to have a negative effect on driving ability the following day. To be specific, it is believed that Zolpidem offers a safer therapeutic alternative, compared to benzodiazepines or Zopiclone, provided that patients strictly observe the recommendations for use and avoid driving until eight hours have elapsed since taking the drug⁽¹³⁾.

However, the use of these drugs is in no way risk-free. Apart from the fact that there is insufficient data on the side effects of chronic use, we not only have compelling evidence that the incidence and nature of side effects in general is not very different from those observed in the use of benzodiazepines –around 42-43%-⁽⁸⁾ but also that the data obtained from numerous controlled experiments indicate that the same outcome occurs with respect to impaired driving ability. It has been shown that a single standard dose of Zopiclone -7.5 mg taken last thing at night- can impair driving ability in a similar way to a blood alcohol level of 0.3 g/l14 and it is known that its negative effects on driving can continue for up to 10 hours⁽¹⁾, although it is possible that these figures are considerably lower in chronic users⁽¹⁵⁾. Meanwhile, four hours after a dose of 10-20 mg of Zolpidem, impaired driving ability is similar to that caused by a blood alcohol level of 0.5 and 0.8 mg/l, respectively⁽¹⁶⁾ although some of the cognitive and psychomotor impairments caused may also last for up to eight hours⁽¹⁾.

In placebo-controlled studies, both Zolpidem and Zopiclone, in the above-mentioned doses, can affect driving ability in an equivalent and significant way, evaluated based on an analysis of specific parameters such as SDLP (standard deviation of lateral position), speed and the number of lane exits, in real driving tests at a constant speed, having previously specifically checked, in both cases, any significant impairment in the subjective alertness factor⁽¹⁷⁾. Similarly, they have been associated with statistically significant differences from placebos in the number, scale and duration of attention lapses –defined as deviations to the moving trajectory of more than 1 meter wide for four or more seconds, in a standardized prolonged driving test at a constant speed⁽¹⁸⁾.

Consequently, patients treated with these drugs have more than double the risk of experiencing a traffic accident⁽³⁾. In a large pharmaco-epidemiological study conducted in Norway⁽⁵⁾, drivers aged between 18 and 69 presented double the risk of having a traffic accident in the week after starting Zopiclone or Zolpidem – a rate of 5-9 accidents per 1,000 people per year, RR=2.3 – compared to those who had not taken the drugs – a rate of two accidents per 1,000 people per year – with no significant differences being observed in terms of the risk of having an accident while being treated with a benzodiazepine with intermediate action such as Nitrazepam – in this case, RR=2.7.

Similar results were found in another study⁽²⁾ on 5,200 drivers involved in vehicle accidents as opposed to a control group of 31,000 who had not experienced one, which observed an increase in the risk of accident among those being treated with Zolpidem or Zaleplon – RR=1.42 for one month of treatment – which did not differ greatly from that found in the case of people treated with benzodiazepines for the same period of time – RR=1.56.

Although these effects should be given special consideration in the case of elderly patients, who are also those most likely to present sleep disorders, given that age is associated with pharmacokinetic and pharmacodynamic changes that would lead to an increase in the half-life and oral availability and duration of the pharmacological effect of the drug, increasing patients’ vulnerability to their effects, there is evidence that these changes might progressively develop at earlier ages, around 50-55, especially in women⁽¹⁹⁾, due to their lower relative liver function capacity. In this respect, a recent study⁽¹⁷⁾ highlighted the fact that in people aged over 55, the residual effects of Zolpidem can be similar to those of Zopiclone after a single nightly dose following the doctor’s recommendations – 10 mg and 7.5 mg respectively, taken before going to bed. Indeed, in 68.7% of the cases studied, significant concentrations of Zolpidem in blood were observed not only first thing in the morning, after eight hours’ sleep, but also, though to a lesser extent, up to 14 hours after taking the drug.

Consequently, apart from giving some serious thought to the suitability of our clinical practice in line with current recommendations, doctors in general and GPs in particular, given our important role in tackling sleep disorders, must consider the possibility that in certain older or elderly drivers, especially women, there may be significant concentrations after treatment with these kinds of drugs, including Zolpidem, even when they follow the prescribed dosages correctly. In this respect, the recent recommendations of the US FDA point to the advisability of reducing the standard dose of Zolpidem to 5 mg, and not just for the over-65s or for patients with liver disorders, reserving higher doses exclusively for people who do not present the proper clinical response and are able to tolerate the medication well.

There also seems to be a clear need for all patients receiving treatment with these drugs to be properly informed as to the side effects they may cause, both in general terms and specifically in relation to the driving of vehicles, as well as the vital importance of adhering exactly to the prescription recommendations.

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