"Good" hypnotics are supposed to induce sleep quickly, have a great enough duration but low residual hypnotic effect, maintain sleep architecture, minimize tolerance, and dependence. Through many studies in the past, zolpidem was acknowledged to be a "better" sleeping pill compared to the benzodiazepine series that were being widely used at the time. In particular, it was expected that harmful occurrences, such as a fall due to the residual hypnotic effect of hypnotics, would occur much less among the elderly [38
]. However, in reality, several studies have claimed that there are not so many differences in terms of fracture or fall [19
], and the large-scale case-control study done by Wang et al. [27
], which used charge data, showed that the risk of fracture due to prescribing zolpidem to elder patients is as close to twice as high, and this is even higher than benzodiazepine series sleeping pills which is 1.5 times as high. Even in our study, it was found that the risk of fracture was more than 1.7 times higher when exposed to zolpidem, and the risk of fracture when exposed to benzodiazepine series, which are known to increase the risk of fracture, was rather insignificant.
Biologically, zolpidem is known to have less risk of a residual hypnotic effect the day after exposure than benzodiazepines [11
]. When the biological theory and epidemiological result are not matched, the research should examine with more a careful approach. For example, because benzodiazepines have a long half-life, and its hangover is much worse, leading to fewer activities the next day, thus, incidents like falls could have occurred less often. Also, there was a possibility that the risk of fracture increased for other reasons than the residual hypnotic effect of zolpidem. There have been consistent reports, although low in frequency, that claimed continuous somnambulism such as driving or sleepwalking with zolpidem [20
]. However, we were not able to confirm that in the present study because our data have no information about the subject's activity or cause of fracture. In addition, compared to zolpidem, benzodiazepines are used for purposes other than their sleep-inducing effect such as their sedative effect, and they are taken relatively consistently [24
]. In this consistent using case, because the number of patients exposed to both the hazard period and control period increases, it could have happened that the risk of fracture of benzodiazepines was not assessed appropriately [29
Elderly insomnia patients usually have comorbidities and take several medications. In addition, the event of fracture could be more greatly affected by the outside environment such as living habits more than pathological progress. Therefore, we should consider many confounding variables for our analysis. The strength of this study is that we controlled for the effects of these confounding variables to the maximum degree. Within the observation period of 141 days, the possibility of varying confounding factors, including lifestyle (e.g., drinking and smoking), obesity, cognitive function level, strength of grip, mobility, socioeconomic status, and residential environment among the elderly above 65 years old, was very low. In our study, patients matched themselves as the control group; therefore, these variables were possible to control through the design of this study. Furthermore, exposure to other drugs, which continuously changed the confounding variables, could be adjusted for by using prescription data.
For the elderly, the most powerful risk factor of fracture is age [34
]. In our study, the previous 5 months of each patient became the control group, and the age distribution of the patient group and control group is identical. Through this, we controlled for the effect that age has on fracture, but when we compared the risk different hypnotics have on patients, it was discovered that if the drugs (and their ingredients) prescribed were noticeably different by age then it could distort the results. In order to assess whether there were any changes according to age, we classified the subject patients into 5-year intervals, and we calculated the frequency of prescription of zolpidem and benzodiazepine series sleeping pills as well as the reaction risk level of fracture. As a result, from the patients (those people who were subjects of this research) who were 65 years old and above, we were unable to find the difference between the prescription and the reaction risk to be significant.
Out of the many adverse effects of hypnotics, fracture from falling is a serious harmful reaction, but due to its less frequent occurrence, it is not easy to prove a drug is a hazard. In this research, using large-scale administrative data, it was possible to secure a large enough number of subjects to statistically evaluate the risk of fracture due to exposure to zolpidem. However, since this study utilized only the fee data, the measurement of the result variable and exposure was done indirectly, and this study can be criticized for lacking the process to confirm the validity of these variable values.
Even if the patients were prescribed sleeping pills (according to the face-value of the prescription), we cannot confirm whether the patient actually took the pills. Even in other studies that required confirming exposure to the hypnotics using prescription data, there were many attempts to revise these differences, but those studies were unable to suggest any clear methods [9
]. In the present study, we judged that the method in which the risk of exposure in proportion to the prescription period was the most rational method; thus we hypothesized that there was exposure during the period where we multiplied 1.2 by the prescription period. Using this method, we tried to minimize the differences between prescription due to irregularity of zolpidem dosage and actual exposure in this research. However, in this circumstance, even when the patient did not take the sleeping pill, the result could speak as if the patient was exposed to the risk. There is a high possibility that this circumstance could occur during the control period in many cases, and as a result, there is also a possibility that the level of hazard could have appeared lower than the actuality.
By prescription data alone, even if fracture was caused by hangover, somnambulism, or other symptoms did not caused by hypnotics, fracture used as the result variable cannot distinguish among these. In this research, in order to eliminate fracture caused by reasons other than the hypnotics as much as possible, we decided to exclude cases where they were accompanied by traffic accidents or cases where stroke occurred within 6 months since the fracture occurred in the past, but there was still a possibility that it was a fracture not caused by a harmful reaction of hypnotics, and this cannot be overlooked.
Although we assumed that the life style factor, since it is considered not to change too much as time passes, could be controlled through matching, this is not an absolute truth. For example, even if a decrease in bone density caused by a chronic drinking habit may be controlled through matching, for a person whose drinking habit is in the form of intermittent and binge drinking, occurrence of fracture due to fall are not possible to control.
Clinical trials assesses the safety of a new drug before marketing are performed by selecting research subjects who are few in numbers, relatively young, who had few comorbidities and co-medications, and who have a low risk of fall and fracture. For these reasons, it is difficult to confirm the causality of serious harmful instances that occurs rarely or confirm the safety in the elderly population, which is a vulnerable group. The present study was significant because we analyzed serious harmful reactions (although they occurred relatively rarely) without conflicts (e.g., ethical issues) by using large-scale administrative data, from an older population, which is a difficult group to study as direct research subjects.
In conclusion, it was found that zolpidem, which was expected to have few cases of side effects such as fracture, among older subjects, increases the risk of fracture by 1.7 times, and there is a lack of evidence that can claim to have a lower risk of fracture compared to existing benzodiazepine series hypnotics. Therefore, when prescribing zolpidem as sleeping pills to older insomnia patients, it is necessary to be aware of this risk, and the patient should be warned and educated.