This study shows that zopiclone contributed to 17% of all intoxication suicides autopsied in Sweden between 2012 and 2020. The 8% of monointoxications found in this study indicates that zopiclone is a substance with the potential of being lethal on its own. Although zopiclone fatalities are common in intoxication deaths in Sweden, they decreased at the end of the study period.

The declining number of zopiclone intoxications is in line with Swedish data on intoxication deaths in general [31]. The present study also found that the sales (measured in dispensed DDD) of zopiclone decreased between 2016 and 2020 in Sweden. A potential explanation for the reduction of zopiclone fatalities could be that medical professionals are more restrictive in prescribing the drug; there is evidence suggesting that limiting the access to lethal means is effective in the prevention of suicide [32, 33].

Among all intoxication fatalities in Sweden, men constituted 65% of the deaths, which is in line with results from a Swedish publication on 6894 intoxication fatalities between 1998 and 2007 [34]. Interestingly, our study found that women and men were equally represented in fatal intoxications with zopiclone. Previous research has found women to be predisposed to insomnia [35]; in Sweden, women are prescribed more zopiclone, and drugs in general, compared with men, which could partially explain this finding [4]. We found that the proportion of suicides in intoxications with zopiclone (62%) was larger compared with the proportion in all intoxication fatalities (29%). The majority of suicides with zopiclone (56%) and suicides through intoxication in general (55%) found in this study were committed by women. The large portion of suicides in zopiclone fatalities and the overrepresentation of women in this group could potentially explain the equal representation of sexes in zopiclone deaths.

A speculative explanation for the large proportion of suicides in zopiclone deaths could be the correlation between sleep disturbances and depression. Insomnia is a common issue among individuals suffering from depressive symptoms [36], and sleep disturbances are important risk factors for suicide, even when adjusted for mental disorders [37]. This study found that 48% of zopiclone fatalities also had findings of antidepressant drugs, and therefore, it is likely that a prominent proportion of the individuals had been diagnosed with depression. Since zopiclone is prescribed to patients with sleep disturbances, it could be speculated that the patient group suffers an increased risk for suicide, which could potentially explain the findings of this study. A randomized controlled trial found a greater incidence of depression among patients receiving treatment with hypnotic drugs compared with placebo [38]. It could be speculated that the treatment with zopiclone potentially increased depressive symptoms among the patients.

As mentioned, women were overrepresented in suicides both among all intoxications (55%) and in intoxications with zopiclone (56%). This result contrasts previous research on completed suicides, where men commit almost twice as many compared with women [33]. Evidence suggests that women tend to choose less violent methods of suicide [17, 39, 40], and intoxication with drugs is the most common suicide method for women in Sweden [31]. Women are considerably overrepresented in suicide attempts, which are more frequent than completed suicides [33]. When attempting suicide, intoxication with drugs is a common method, which could partially explain the large finding of women among intoxication suicides seen in this study. When specifically investigating intoxication suicides, there are previous studies finding women to be equally represented and overrepresented [16,17,18, 31, 34, 41], supporting the results of this study.

Individuals dying in zopiclone fatalities were older compared with all fatal intoxications in Sweden; the median age was 55 and 44 years, respectively (Table 1). This study found that women dying in the case of zopiclone intoxications was associated with older age, which has been seen in previous research of intoxication deaths [17, 31, 34]. Therefore, it could be speculated that the large representation of women among the zopiclone fatalities could explain the higher median age seen in this study.

Among individuals aged > 65 years, 76% of deaths were suicides, and in total they constituted about one-third of all suicides with zopiclone. The large representation of the elderly in suicides is in line with previous research [33, 40], and a Swedish study found that intoxication with drugs constituted about 40% of female and 16% of male suicides in the elderly population [16]. According to data published by the Swedish National Board of Health and Welfare, the largest group of patients receiving a prescription for zopiclone were > 84 years of age. In 2020, women constituted 65% of the patients aged > 64 years and prescribed zopiclone [4]. It could be speculated that the large prescription to the elderly and elderly women is a contributing factor to their representation in zopiclone suicides.

In this study, 8% of the fatalities with zopiclone were monointoxications. Early clinical trials failed to show major morbidity or mortality in connection with zopiclone [1, 3, 7,8,9,10], and details regarding its toxicity have remained unclear. The present findings indicate that the use of zopiclone alone can have fatal consequences, especially among the elderly. Some previous studies on intoxication deaths have found fatalities with zopiclone as the sole toxicological finding, supporting the thesis that zopiclone can be lethal on its own [42, 43]. Acute toxicity from lone use of both Z-drugs and benzodiazepines has been shown to be common among intoxications presented at emergency departments throughout Europe [15].

The elderly (aged > 65 years) constituted 65% of all monointoxications and 80% of monointoxications, with no additional findings in this study. Among the monointoxications, 86% of deaths were suicides, and an explanation for the overrepresentation of the elderly could be that they apply more lethal means in their attempts to commit suicide [40], and therefore might have ingested higher dosages. Another theory could be that the frailty as well as comorbidities and polypharmacy of the elderly made them more susceptible to the toxicity of zopiclone.

The postmortem concentrations of zopiclone found in this study were in line with the results of previous research [42, 43]. A Swedish study on data between 1992 and 2006 found the median concentration of zopiclone in intoxications caused by one substance (0.80 µg/g) to be similar to the concentrations of the monointoxications in this study [42]. The same study also investigated the concentrations of zopiclone in fatal intoxications caused by multiple substances. They found the median concentration to be 0.70 µg/g, and the upper 90th percentile was 1.90 µg/g, which is slightly higher compared with the corresponding concentrations in the present study comprising all manners of deaths (median 0.47 µg/g and upper 90th percentile 1.6 µg/g).

The majority of zopiclone fatalities were caused by more than one substance. This phenomenon is seen when studying fatal intoxications in general where most deaths are caused by the synergic effects of multiple substances [12, 34, 41, 43]. Ethanol was the most common substance found, which is in line with previous data [13, 18, 41, 43]. For suicides and fatalities with an undetermined manner of death, the most common additional findings were hypnotics. Hypnotic and sedative drugs have previously been shown to be common toxicological findings in intoxication fatalities [16,17,18, 21, 43]. Our study found that 70% of all accidental zopiclone intoxications also had findings of opioids in the toxicological analysis. Previous studies have found opioids to be common findings among accidental intoxications [21, 23, 44].

This study found the FTI to be 0.79 for zopiclone, and 0.06 for monointoxications, which corresponds with the findings of previous publications [29, 42, 45, 46] and can be considered quite low. Ojanperä et al. [29] reasoned that substances with an FTI > 1 had “an especially high toxicity” in relation to sales. Our interpretation of this result is that, although it is a common substance used in fatal intoxications, the number of zopiclone fatalities are somewhat low in relation to sales. Jönsson et al. [42] found other sedatives/hypnotics, such as propiomazine (FTI 1.49), flunitrazepam (FTI 1.43), and hydroxyzine (FTI 2.02), with higher FTI’s compared with zopiclone. A publication by Geulayov et al. [47] utilized FTI to compare relative toxicity of substances in fatal self-poisonings and found zopiclone/zolpidem to be nine times more toxic compared with diazepam (odds ratio 9.14, 95% CI 5.01–16.65).

An interesting result of this study was that 87% of the fatalities had a prescription for zopiclone, indicating that most individuals received the substance from the Swedish healthcare system. The proportion of prescribed users remained relatively unchanged throughout the years, even when the sales of zopiclone started to decrease by the end of the study period. To our knowledge, the prevalence of prescribed use of zopiclone in fatal zopiclone intoxications has not been reported previously. However, Haukka et al. [48] investigated zolpidem (another Z-drug) within this context and found that 88% were prescribed users, a result similar to the findings of this study. In comparison with previous publications investigating other substances, such as tramadol or oxycodone, the proportion of prescribed users was lower compared with the 87% seen in this study [48, 49]. Tjäderborn et al. [14] also found that the prevalence of prescribed zopiclone (70%) and zaleplon (79%) use among impaired drivers was higher compared with other substances, supporting the results of this study.

The high proportion of prescribed zopiclone use potentially indicates that a more restrictive prescribing rate could serve as a preventive measure for intoxication deaths, especially when caring for patients with an increased suicide risk. However, sleep disturbances are known risk factors for suicide [37], and it could be speculated that treatment with sedatives is an important factor for suicide prevention. Prescribing potentially harmful substances to patients with an increased risk for suicide is a balancing act for medical professionals. Through identifying individuals with an increased risk for misuse as well as examining the potential harm of zopiclone, medical professionals can make more informed assessments when prescribing the substance.

A major strength of this study is the national standardization of forensic autopsies in Sweden. All autopsies are performed by one governmental institution, and the toxicological analysis is performed at one central laboratory.

Another strength is that each death was reviewed individually to conclude whether zopiclone contributed to the lethality of the poisoning or not. When uncertainties appeared, the autopsy reports were scrutinized. This method enabled an understanding of the role of zopiclone in fatal intoxications and prevented inclusion of incidental zopiclone findings.

One limitation of this study is the risk for circular reasoning when utilizing postmortem concentrations of substances to investigate the cause of death in potential intoxications. A high concentration of a substance could potentially make the forensic pathologist more inclined to assume that the death was caused by an intoxication and vice versa.

Another limitation of this study is the instability of zopiclone in vitro. If a sample is stored in suboptimal conditions, zopiclone can be degraded, resulting in lower concentrations or even undetectable levels [50]. A lower concentration of zopiclone could potentially make the forensic pathologist less inclined to consider zopiclone as a contributor to the lethality of the intoxication, which could have resulted in an underestimation of zopiclone intoxications.

This study only included cases with detection of zopiclone in femoral blood. This is a limitation since fatalities without access to femoral blood were excluded, which could have resulted in an underestimation of cases. However, femoral blood is the site least susceptible for postmortem changes and therefore optimal for studying concentrations of xenobiotics after death [51,52,53].

A prescription for zopiclone was defined as valid if it was dispensed within 1 year before the date of death in our study. A sensitivity analysis was carried out prolonging and shortening the time interval between the day for the last dispense and the death date, none of which had a relevant impact on the results in this study. When shortening the time interval to 6 months, the proportion of prescribed users of zopiclone was 84%; when prolonging the period to 1 year and 6 months, 88% of zopiclone fatalities were prescribed users.