Substance Use & Misuse, Early Online:1–8, 2014 C 2014 Informa Healthcare USA, Inc. Copyright ISSN: 1082-6084 print / 1532-2491 online DOI: 10.3109/10826084.2014.980955
ORIGINAL ARTICLE
Correlates of Dependence and Beliefs About the Use of Hypnotics Among Zolpidem and Zopiclone Users Cheng-Fang Yen1 , Chia-Nan Yen2 , Chih-Hung Ko1,3 , Tzung-Jeng Hwang4 , Cheng-Sheng Chen1 , Tzu-Ting Chen5 , Po-Wen Su6 , Shao-Tsu Chen7 and Jin-Jia Lin8,9 Subst Use Misuse Downloaded from informahealthcare.com by University of Otago on 12/25/14 For personal use only.
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Department of Psychiatry, Kaohsiung Medical University Hospital, and School of Medicine and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2 Department of Psychiatry, Tainan Hospital, Ministry of Health and Welfare, Executive Yuan, Tainan, Taiwan; 3 Department of Psychiatry, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 4 Department of Psychiatry, National Taiwan University Hospital, and College of Medicine and Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan; 5 Department of Psychiatry, Yun-Lin Branch, National Taiwan University Hospital, Yunlin, Taiwan; 6 Department of Psychiatry, Puzi Hospital, Ministry of Health and Welfare, Executive Yuan, Chiayi, Taiwan; 7 School of Medicine, Buddhist Tzu Chi University, and Department of Psychiatry, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; 8 Department of Psychiatry, Chi-Mei Medical Center, and Chi-Mei Hospital, Liuying Campus, Taiwan; 9 Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taiwan were differences in the level of dependence and belief about hypnotic use between zolpidem and zopiclone users. The correlates of dependence and belief identified in this study can serve as the basis for prevention and intervention programs.
Background: Zolpidem and zopiclone are the two most commonly prescribed Z-drugs approved to treat insomnia. Objectives: To examine the demographic and clinical correlates of dependence and beliefs about hypnotic use among long-term zolpidem and zopiclone users in psychiatric treatment for insomnia. Methods: A total of 392 psychiatric outpatients who received zolpidem or zopiclone treatment for at least 3 months for insomnia were studied. Participants’ severity of hypnotic dependence and beliefs about the use of hypnotics to treat sleep problems were assessed. The correlation of dependence and beliefs about zolpidem and zopiclone treatment with demographic characteristics, hypnotic-using behaviors, co-use of addictive substances, and depressive symptoms were analyzed using multiple regression analysis models. Results: Zolpidem users reported more severe dependence and a lower level of necessity regarding the use of hypnotics than zopiclone users did. High equivalent doses of hypnotics and long duration of use were significantly associated with severe dependence and a low level of necessity. Severe depressive symptoms were signiciantly associated with severe dependence, a low level of necessity, and a low level of concern. Educational level was also associated with the levels of concern and necessity. Conclusions/Importance: There
Keywords
Belief, Z-drugs, dependence, zolpidem, zopiclone
INTRODUCTION
Z-drugs are hypnotic compounds that have been developed to induce sleep quickly, while minimizing residual day-after effects (Sanger, 2004). Z-drugs are structurally different from benzodiazepines (BZDs), but act on the same binding sites as gamma-aminobutyric acid type A (GABA-A) receptors do (Sanger, 2004). Although Zdrugs appear to offer efficacy and safety advantages over classic BZDs (Darcourt, Pringuey, Salli`ere, & Lavoisy, 1999), they can still induce clinically significant adverse events, such as memory and psychomotor performance impairments (Zammit, 2009). Abuse liability is a major concern in the use of Z-drugs (Victorri-Vigneau, Dailly, Veyrac, & Jolliet, 2007). Z-drugs have been reported to present a low risk of developing dependence (Hajak, Muller, Wittchen, Pittrow, & Kirch, 2003; Soyka, Bottlender, & M¨oller, 2000). However, recent research has indicated that despite chemical differences between
Dr. C-F Yen and Dr. C-N Yen contributed equally to this study. Address correspondence to Shao-Tsu Chen, Buddhist Tzu Chi General Hospital 970, Hualien, Taiwan; E-mail: [email protected] and Jin-Jia Lin, Department of Psychiatry, Chimei Medical Center, Tainan 702, Taiwan; E-mail: [email protected]
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CHENG-FANG YEN ET AL.
Z-drugs and BZDs, the dependence and abuse potential of Z-drugs is similar to that of BZDs (Victorri-Vigneau et al., 2007). It is well-recognized that dependence on hypnotics develops not only at high doses, but also with long-term therapeutic doses (Wolf & Griffiths, 1991). Further evaluation is necessary to evaluate the safety of the long-term use of Z-drugs in managing insomnia (Terzano, Rossi, Palomba, Smerieri, & Parrino, 2003). Identifying the factors characterizing dependence on Zdrugs can serve as a basis for prevention, early detection, and intervention programs; determining the correlates of users’ beliefs about the use of Z-drugs is also crucial. The beliefs toward receiving medication treatment will influence patients’ medical adherence. Research has found that the beliefs about prescribed medication will influence patients’ adherence to treatment for chronic physical illnesses such as hypertension, asthma treatment, and medical adherence (Petrie et al., 1996; Phatak and Thomas, 2006; Horne and Weinman, 1999). Compared with the prescribed medication for chronic physical illnesses, few studies have examined the beliefs about hypnotics. Owing to the concern about the risk to be addictive to hypnotics, individuals may hesitate to receive prescribed hypnotics for their insomnia (Rosenbaum, 2005). A quantitative study using in-depth interview found that the individuals feel indecisive to receive BZDs treatment for the first time; they may think it necessary to receive BZDs treatment, whereas they worry about the risk to be dependent to BZDs (Anthierens et al., 2007). Some people may amplify their discomforts to persuade themselves into taking BZDs, whereas some people may reduce the dosage of BZDs by themselves to resolve their worry (Anthierens et al., 2007). It is reasonable to hypothesize that expecting positive outcomes from Z-drug use, and not expecting negative outcomes, increases the risk of dependence. People exhibiting factors associated with favorable beliefs about Z-drugs can be targeted by dependence prevention programs. Zolpidem and zopiclone were the first two Z-drugs approved to treat insomnia, and are currently the two most commonly prescribed hypnotics in Taiwan (Su et al., 2002). Zolpidem is an agonist on the BZD binding site of GABA-A receptors, and has a selective and high binding affinity for the alpha-1 subunit of the receptor (Holm & Goa, 2000). Zopiclone is less selective for the alpha1-subunit compared with zolpidem, and more closely resembles a BZD in its GABA-A receptor-binding profile (Sanger, 2004). The World Health Organization (WHO), in line with its consideration that the frequency of zolpidem abuse and dependence was similar to that of benzodiazepine, transferred zolpidem, but not zopiclone, to the list of Schedule IV drugs of the 1971 Convention in 2002. However, few studies have compared the tendencies toward dependence among zolpidem and zopiclone users in the long-term management of insomnia. One review study demonstrated that zolpidem and zopiclone were similar in their levels of drug self-administration in experimental animals, recreational abuse, and nonmedical use based on drug abuse epidemiology data, and withdrawal symptoms in animals and humans, but zopiclone had higher levels
of liking/reinforcement among humans than those of zolpidem (Griffiths & Johnson, 2005). By contrast, in a pharmacoepidemiological study, Victorri-Vigneau and colleagues identified a subgroup of problematic users of zolpidem, but not zopiclone (Victorri-Vigneau et al., 2013), and discovered that “pharmacy shopping” behavior among zolpidem users was more widespread than among zopiclone users (Victorri-Vigneau et al., 2013). Moreover, medication possession ratios, calculated as the number of days of supply divided by the number of days between the first and final dispensing, were higher among zolpidem users than among zopiclone users (Victorri-Vigneau et al., 2013). A previous review study indicated that zolpidem and zopiclone users had similar relative incidences of reported dependence (Hajak et al., 2003), but a more recent review study found that dependence on zolpidem has been more frequently reported than dependence on zopiclone (Victorri-Vigneau et al., 2013). Based on our research, no head-to-head study has compared the reported levels of dependence between long-term zolpidem and zopiclone users; thus, differences in dependence liability remain unclear. Moreover, no head-to-head study has compared beliefs about the use of hypnotics between long-term zolpidem and zopiclone users. A previous study comparing the efficacy of zolpidem and zopiclone in a 2-week period revealed that users’ ratings of treatment efficacy were similar; however, a greater number of zopiclone than zolpidem users had rebound insomnia (Tsutsui & Zolpidem Study Group, 2001). Zopiclone was found to be less selective than zolpidem for the alpha-1-subunit of the GABA-A receptor (Sanger, 2004). Based on these results, we hypothesized that beliefs about the necessity of taking hypnotics were similar between zolpidem and zopiclone users, and that zopiclone users were more concerned about potential adverse consequences of hypnotics than zolpidem users. Long-term use and high daily dosages of hypnotics have been associated with tolerance and dependence on both BZDs (Andersen & Frydenberg, 2011; Manthey et al., 2012) and zolpidem (Liappas et al., 2003; Vlaini´c, Jembrek, Vlaini´c, Strac, & Periˇci´c, 2012). Having a history of drug and alcohol dependence can also increase the risks of both zolpidem (Hajak et al., 2003) and BZD dependence (Manthey et al., 2012). Research has also demonstrated that people with chronic pain have a higher risk of developing problematic hypnotic use (Griffiths & Weerts, 1997). It is thus reasonable to hypothesize that the use of pain-relievers is associated with hypnotic dependence. The results of previous studies on the demographic correlates of hypnotic dependence have been mixed. One post-marketing surveillance report shows similar rates of zolpidem abuse among men and women in all age groups (Hajak et al., 2003). However, research on BZD has demonstrated that female sex (Andersen & Frydenberg, 2011) and old age (Manthey et al., 2012) are significantly associated with BZD dependence. Previous studies have also shown that high educational levels (Andersen & Frydenberg, 2011) and severe mood symptoms (Manthey et al., 2012) are considerably associated with BZD dependence. Most of these studies, however, have
ZOLPIDEM AND ZOPICLON
examined correlates of BZD dependence, rather than correlates of dependence and beliefs about the use of Z-drugs. People with psychiatric illness have been found to have high risks of developing zolpidem dependence (Hajak et al., 2003). Therefore, this study examined the demographic and clinical correlates of dependence and beliefs about hypnotic use among long-term zolpidem and zopiclone users in psychiatric treatment for insomnia. METHODS
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Participants
Patients from the psychiatric outpatient clinics of six general hospitals in Taiwan, who had received zolpidem (including zolpidem extended-release) or zopiclone treatment for at least 3 months for insomnia, were consecutively invited to receive interviews between July 2011 and November 2012. The period of 3 months of hypnotic use was determined on the basis of the fact that hypnotics may lose their sedation efficacy after several months of regular use (McLeod, Hung, Tamblyn, & Gayton, 1997). The six general hospitals were located in Northern Taiwan, Tao-Chu-Miao, Central Taiwan, Chia-Nan, Kao-Ping, and Eastern Taiwan. Those who used other hypnotics besides zolpidem and zopiclone concomitantly, or who were unable to complete the study because of prominent psychotic symptoms or cognitive deficits, were excluded. A total of 392 patients participated in this study and were interviewed on the basis of the research questionnaire. The protocol was approved by the Institutional Review Boards of all six hospitals.
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hypnotics to improve their sleep, and a higher level of concern about the potential adverse consequences of taking prescribed hypnotics (Horne, Weinman, & Hankins, 1999). Chinese version of Drug Use Disorders Identification Test (DUDIT-E). Three questions from the Chinese version of the DUDITE were used to survey the participants’ use of alcohol, pain-relievers, and cigarettes in the past month (Berman, Palmstierna, K¨allm´en, & Bergman, 2007; Lee & Berman, 2009). The participants who had used alcohol, painrelievers, or cigarettes in the past 1 month were classified as having co-used alcohol, pain-relievers, and cigarettes, respectively. Mandarin Chinese version of the Center for Epidemiological Studies-Depression Scale (CES-D). The severity of depressive symptoms in the past week was determined using the 20-item CES-D (Chien & Cheng, 1985; Radloff, 1977). The CES-D is a self-administered 4-point evaluation scale assessing the frequency of depressive symptoms, and scores range from 0 (none or extremely few) to 3 (always). High CES-D scores indicate severe depressive symptoms. This study collected data on participant demographic characteristics, including age, gender, and educational level. The dose of prescribed zolpidem and zopiclone and total duration of zolpidem and zopiclone treatment were recorded. The dosage data were transformed into dosages equivalent to 1 mg of lorazepam (Ashton, 2002). Procedure and Statistical Analysis
Measures
Chinese Version of the Severity of Dependence Scale (SDS[Ch] ). The 5-item SDS[Ch] was used to evaluate the severity of the participants’ zolpidem or zopiclone dependence in the past month (Chen et al., 2008; Gossop et al., 1995). The five items were: “Do you think your use of hypnotics was out of control?” “Did the prospect of missing a fix or dose make you anxious or worried?” “Did you worry about your use of hypnotics?” “Did you wish you could stop using hypnotics?” and “How difficult was it to stop or go without hypnotics?” The SDS is a valid, brief, self-reporting questionnaire used to assess hypnotic and sedative dependence (de las Cuevas, Sanz, de la Fuente, Padilla, & Berenguer, 2000). The psychometrics of the SDS[Ch] for patients using hypnotics in Taiwan have been examined (Tsai et al., 2012). Total SDS scores range from 0 to 15, and a higher score indicates a greater degree of dependence. Beliefs About Medicines Questionnaire (BMQ). The 10-item BMQ was applied to evaluate the participants’ beliefs about the use of zolpidem or zopiclone to treat sleep problems. The BMQ comprises two five-item subscales, and a higher total score indicates that the participants perceived a higher level of necessity of prescribed
Research psychiatrists performed interviews using the research questionnaires. Data analysis was performed using SPSS 17.0 statistical software (SPSS Inc., Chicago, IL, USA). The levels of zolpidem and zopiclone dependence on the SDS[Ch] and the belief toward zolpidem or zopiclone treatment (including necessity and concern about the potential adverse consequences) were calculated by mean and standard deviation (SD). The correlation of dependence and beliefs about zolpidem and zopicolne treatment with demographic characteristics, hypnotic-using behaviors, co-use of addictive substances, and depressive symptoms were analyzed using multiple regression analysis models. The correlations between dependence and beliefs and between necessity and concern were also examined using multiple regression analysis to control for the effects of other factors. Because of three regression models examined in this study, a p value of .016 (.05/3) indicated statistical significance. RESULTS
The severity of dependence, levels of beliefs about the use of hypnotics, demographic characteristics, variety of hypnotics, equivalent dose and duration of hypnotics use, co-use of other addictive substances, and severity of depressive symptoms among the participants are shown in
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CHENG-FANG YEN ET AL.
TABLE 1. Dependence, beliefs regarding use of hypnotics, demographic characteristics, variety of hypnotics, equivalent dose and duration of hypnotics use, co-use of other addictive substances, and depressive symptoms among zolpidem or zopiclone users (N = 392)
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Mean (SD) Severity of dependence on the SDS[Ch] Beliefs regarding hypnotic use on the BMQ Level of necessity Level of concern Age (years) Gender Female Male Educational level (years) Varity of hypnotics Zolpidem Zopiclone Equivalent dose of hypnotics (mg/day) Duration of hypnotic use (months) Co-use of other addictive substances Alcohol Pain-relievers Smoking Severity of depressive symptoms
n (%)
5.6 (3.3)
10.7 (3.8) 16.3 (4.4) 48.0 (13.9) 242 (61.7) 150 (38.3) 11.7 (4.6) 317 (80.9) 75 (19.1) 0.5 (0.4) 65.2 (63.6) 82 (20.9) 131 (33.4) 121 (30.9) 21.5 (14.8)
BMQ: Beliefs about Medicines Questionnaire; SD: standard deviation; SDS[Ch] : Chinese version of the Severity of Dependence Scale.
Table 1. Of the 392 participants, 242 (61.7%) were female and 150 (38.3%) were male; the mean age was 48.0 years (standard deviation, 13.9 years), and 317 (80.9%) and 75 (19.1%) were zolpidem and zopiclone users, respectively. Multiple regression analysis was used to examine the correlates of dependence and beliefs about zolpidem or zopiclone use, and the results are shown in Table 2. Zolpidem users reported more severe dependence (5.8 vs. 5.1, p = .001) and a lower level of necessity regard-
ing the use of hypnotics (10.5 vs. 11.7, p = .007) than zopiclone users did. Although not reaching the level of significnace, zolpidem users tended to report a higher level of concern about the potential adverse consequences of hypnotics than zopiclone users did (16.7 vs. 14.5, p = .022). High equivalent doses of hypnotics and long duration of use were significantly associated with severe dependence (p = .001 and .008, respectively) and a low level of necessity (p = .001 and .003, respectively). Severe depressive symptoms were signiciantly associated with severe dependence (p < .001), a low level of necessity (p < .001), and a low level of concern (p < .001). The participants with high educational levels had significantly higher levels of necessity (p = .004) and lower levels of concern (p = .004). The older participants tended to have a higher level of concern (p = .023). The co-use of alcohol, painrelievers, and cigarettes was not considerably associated with dependence or beliefs about hypnotic use. After controlling for the effects of other factors, dependence was negatively correlated with necessity (Beta = −.217, t = −4.139, p < .001) and concern (Beta = −.307, t = − 6.047, p < .001) and beliefs in multiple regression analysis models. There was no significant correlation between concern and beliefs (Beta = −.035, t = −.669, p = .504).
DISCUSSION
Zolpidem users have reported more severe dependence on hypnotics than zopiclone users have. This result contrasts with the results of a previous review study, in which the authors found that levels of drug self-administration in experimental animals, levels of nonmedical use, and withdrawal symptoms in animals and human beings between zolpidem and zopiclone were similar, and that zopiclone had higher levels of liking/reinforcement among human beings than those of zolpidem (Griffiths & Johnson, 2005). However, the studies reviewed were
TABLE 2. Correlates of dependence and belief toward zolpidem or zopiclone use: Multiple regression analysis Beliefs toward hypnotic use Dependence
Age Gender Educational level Varity of hypnotics Equivalent dosage of hypnotics Duration of hypnotic use Alcohol Pain-relievers Smoking Depressive symptoms Adjusted R2 F p
Necessity
Concern
Beta
t
P
Beta
t
p
Beta
t
p
−.063 −.015 −.100 −.154 .177 .123 .060 .060 .011 .375
−1.050 −.321 −1.909 −3.365 3.314 2.684 1.284 1.308 .212 7.860 .252 14.131
ORIGINAL ARTICLE
Correlates of Dependence and Beliefs About the Use of Hypnotics Among Zolpidem and Zopiclone Users Cheng-Fang Yen1 , Chia-Nan Yen2 , Chih-Hung Ko1,3 , Tzung-Jeng Hwang4 , Cheng-Sheng Chen1 , Tzu-Ting Chen5 , Po-Wen Su6 , Shao-Tsu Chen7 and Jin-Jia Lin8,9 Subst Use Misuse Downloaded from informahealthcare.com by University of Otago on 12/25/14 For personal use only.
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Department of Psychiatry, Kaohsiung Medical University Hospital, and School of Medicine and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 2 Department of Psychiatry, Tainan Hospital, Ministry of Health and Welfare, Executive Yuan, Tainan, Taiwan; 3 Department of Psychiatry, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; 4 Department of Psychiatry, National Taiwan University Hospital, and College of Medicine and Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan; 5 Department of Psychiatry, Yun-Lin Branch, National Taiwan University Hospital, Yunlin, Taiwan; 6 Department of Psychiatry, Puzi Hospital, Ministry of Health and Welfare, Executive Yuan, Chiayi, Taiwan; 7 School of Medicine, Buddhist Tzu Chi University, and Department of Psychiatry, Buddhist Tzu Chi General Hospital, Hualien, Taiwan; 8 Department of Psychiatry, Chi-Mei Medical Center, and Chi-Mei Hospital, Liuying Campus, Taiwan; 9 Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taiwan were differences in the level of dependence and belief about hypnotic use between zolpidem and zopiclone users. The correlates of dependence and belief identified in this study can serve as the basis for prevention and intervention programs.
Background: Zolpidem and zopiclone are the two most commonly prescribed Z-drugs approved to treat insomnia. Objectives: To examine the demographic and clinical correlates of dependence and beliefs about hypnotic use among long-term zolpidem and zopiclone users in psychiatric treatment for insomnia. Methods: A total of 392 psychiatric outpatients who received zolpidem or zopiclone treatment for at least 3 months for insomnia were studied. Participants’ severity of hypnotic dependence and beliefs about the use of hypnotics to treat sleep problems were assessed. The correlation of dependence and beliefs about zolpidem and zopiclone treatment with demographic characteristics, hypnotic-using behaviors, co-use of addictive substances, and depressive symptoms were analyzed using multiple regression analysis models. Results: Zolpidem users reported more severe dependence and a lower level of necessity regarding the use of hypnotics than zopiclone users did. High equivalent doses of hypnotics and long duration of use were significantly associated with severe dependence and a low level of necessity. Severe depressive symptoms were signiciantly associated with severe dependence, a low level of necessity, and a low level of concern. Educational level was also associated with the levels of concern and necessity. Conclusions/Importance: There
Keywords
Belief, Z-drugs, dependence, zolpidem, zopiclone
INTRODUCTION
Z-drugs are hypnotic compounds that have been developed to induce sleep quickly, while minimizing residual day-after effects (Sanger, 2004). Z-drugs are structurally different from benzodiazepines (BZDs), but act on the same binding sites as gamma-aminobutyric acid type A (GABA-A) receptors do (Sanger, 2004). Although Zdrugs appear to offer efficacy and safety advantages over classic BZDs (Darcourt, Pringuey, Salli`ere, & Lavoisy, 1999), they can still induce clinically significant adverse events, such as memory and psychomotor performance impairments (Zammit, 2009). Abuse liability is a major concern in the use of Z-drugs (Victorri-Vigneau, Dailly, Veyrac, & Jolliet, 2007). Z-drugs have been reported to present a low risk of developing dependence (Hajak, Muller, Wittchen, Pittrow, & Kirch, 2003; Soyka, Bottlender, & M¨oller, 2000). However, recent research has indicated that despite chemical differences between
Dr. C-F Yen and Dr. C-N Yen contributed equally to this study. Address correspondence to Shao-Tsu Chen, Buddhist Tzu Chi General Hospital 970, Hualien, Taiwan; E-mail: [email protected] and Jin-Jia Lin, Department of Psychiatry, Chimei Medical Center, Tainan 702, Taiwan; E-mail: [email protected]
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CHENG-FANG YEN ET AL.
Z-drugs and BZDs, the dependence and abuse potential of Z-drugs is similar to that of BZDs (Victorri-Vigneau et al., 2007). It is well-recognized that dependence on hypnotics develops not only at high doses, but also with long-term therapeutic doses (Wolf & Griffiths, 1991). Further evaluation is necessary to evaluate the safety of the long-term use of Z-drugs in managing insomnia (Terzano, Rossi, Palomba, Smerieri, & Parrino, 2003). Identifying the factors characterizing dependence on Zdrugs can serve as a basis for prevention, early detection, and intervention programs; determining the correlates of users’ beliefs about the use of Z-drugs is also crucial. The beliefs toward receiving medication treatment will influence patients’ medical adherence. Research has found that the beliefs about prescribed medication will influence patients’ adherence to treatment for chronic physical illnesses such as hypertension, asthma treatment, and medical adherence (Petrie et al., 1996; Phatak and Thomas, 2006; Horne and Weinman, 1999). Compared with the prescribed medication for chronic physical illnesses, few studies have examined the beliefs about hypnotics. Owing to the concern about the risk to be addictive to hypnotics, individuals may hesitate to receive prescribed hypnotics for their insomnia (Rosenbaum, 2005). A quantitative study using in-depth interview found that the individuals feel indecisive to receive BZDs treatment for the first time; they may think it necessary to receive BZDs treatment, whereas they worry about the risk to be dependent to BZDs (Anthierens et al., 2007). Some people may amplify their discomforts to persuade themselves into taking BZDs, whereas some people may reduce the dosage of BZDs by themselves to resolve their worry (Anthierens et al., 2007). It is reasonable to hypothesize that expecting positive outcomes from Z-drug use, and not expecting negative outcomes, increases the risk of dependence. People exhibiting factors associated with favorable beliefs about Z-drugs can be targeted by dependence prevention programs. Zolpidem and zopiclone were the first two Z-drugs approved to treat insomnia, and are currently the two most commonly prescribed hypnotics in Taiwan (Su et al., 2002). Zolpidem is an agonist on the BZD binding site of GABA-A receptors, and has a selective and high binding affinity for the alpha-1 subunit of the receptor (Holm & Goa, 2000). Zopiclone is less selective for the alpha1-subunit compared with zolpidem, and more closely resembles a BZD in its GABA-A receptor-binding profile (Sanger, 2004). The World Health Organization (WHO), in line with its consideration that the frequency of zolpidem abuse and dependence was similar to that of benzodiazepine, transferred zolpidem, but not zopiclone, to the list of Schedule IV drugs of the 1971 Convention in 2002. However, few studies have compared the tendencies toward dependence among zolpidem and zopiclone users in the long-term management of insomnia. One review study demonstrated that zolpidem and zopiclone were similar in their levels of drug self-administration in experimental animals, recreational abuse, and nonmedical use based on drug abuse epidemiology data, and withdrawal symptoms in animals and humans, but zopiclone had higher levels
of liking/reinforcement among humans than those of zolpidem (Griffiths & Johnson, 2005). By contrast, in a pharmacoepidemiological study, Victorri-Vigneau and colleagues identified a subgroup of problematic users of zolpidem, but not zopiclone (Victorri-Vigneau et al., 2013), and discovered that “pharmacy shopping” behavior among zolpidem users was more widespread than among zopiclone users (Victorri-Vigneau et al., 2013). Moreover, medication possession ratios, calculated as the number of days of supply divided by the number of days between the first and final dispensing, were higher among zolpidem users than among zopiclone users (Victorri-Vigneau et al., 2013). A previous review study indicated that zolpidem and zopiclone users had similar relative incidences of reported dependence (Hajak et al., 2003), but a more recent review study found that dependence on zolpidem has been more frequently reported than dependence on zopiclone (Victorri-Vigneau et al., 2013). Based on our research, no head-to-head study has compared the reported levels of dependence between long-term zolpidem and zopiclone users; thus, differences in dependence liability remain unclear. Moreover, no head-to-head study has compared beliefs about the use of hypnotics between long-term zolpidem and zopiclone users. A previous study comparing the efficacy of zolpidem and zopiclone in a 2-week period revealed that users’ ratings of treatment efficacy were similar; however, a greater number of zopiclone than zolpidem users had rebound insomnia (Tsutsui & Zolpidem Study Group, 2001). Zopiclone was found to be less selective than zolpidem for the alpha-1-subunit of the GABA-A receptor (Sanger, 2004). Based on these results, we hypothesized that beliefs about the necessity of taking hypnotics were similar between zolpidem and zopiclone users, and that zopiclone users were more concerned about potential adverse consequences of hypnotics than zolpidem users. Long-term use and high daily dosages of hypnotics have been associated with tolerance and dependence on both BZDs (Andersen & Frydenberg, 2011; Manthey et al., 2012) and zolpidem (Liappas et al., 2003; Vlaini´c, Jembrek, Vlaini´c, Strac, & Periˇci´c, 2012). Having a history of drug and alcohol dependence can also increase the risks of both zolpidem (Hajak et al., 2003) and BZD dependence (Manthey et al., 2012). Research has also demonstrated that people with chronic pain have a higher risk of developing problematic hypnotic use (Griffiths & Weerts, 1997). It is thus reasonable to hypothesize that the use of pain-relievers is associated with hypnotic dependence. The results of previous studies on the demographic correlates of hypnotic dependence have been mixed. One post-marketing surveillance report shows similar rates of zolpidem abuse among men and women in all age groups (Hajak et al., 2003). However, research on BZD has demonstrated that female sex (Andersen & Frydenberg, 2011) and old age (Manthey et al., 2012) are significantly associated with BZD dependence. Previous studies have also shown that high educational levels (Andersen & Frydenberg, 2011) and severe mood symptoms (Manthey et al., 2012) are considerably associated with BZD dependence. Most of these studies, however, have
ZOLPIDEM AND ZOPICLON
examined correlates of BZD dependence, rather than correlates of dependence and beliefs about the use of Z-drugs. People with psychiatric illness have been found to have high risks of developing zolpidem dependence (Hajak et al., 2003). Therefore, this study examined the demographic and clinical correlates of dependence and beliefs about hypnotic use among long-term zolpidem and zopiclone users in psychiatric treatment for insomnia. METHODS
Subst Use Misuse Downloaded from informahealthcare.com by University of Otago on 12/25/14 For personal use only.
Participants
Patients from the psychiatric outpatient clinics of six general hospitals in Taiwan, who had received zolpidem (including zolpidem extended-release) or zopiclone treatment for at least 3 months for insomnia, were consecutively invited to receive interviews between July 2011 and November 2012. The period of 3 months of hypnotic use was determined on the basis of the fact that hypnotics may lose their sedation efficacy after several months of regular use (McLeod, Hung, Tamblyn, & Gayton, 1997). The six general hospitals were located in Northern Taiwan, Tao-Chu-Miao, Central Taiwan, Chia-Nan, Kao-Ping, and Eastern Taiwan. Those who used other hypnotics besides zolpidem and zopiclone concomitantly, or who were unable to complete the study because of prominent psychotic symptoms or cognitive deficits, were excluded. A total of 392 patients participated in this study and were interviewed on the basis of the research questionnaire. The protocol was approved by the Institutional Review Boards of all six hospitals.
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hypnotics to improve their sleep, and a higher level of concern about the potential adverse consequences of taking prescribed hypnotics (Horne, Weinman, & Hankins, 1999). Chinese version of Drug Use Disorders Identification Test (DUDIT-E). Three questions from the Chinese version of the DUDITE were used to survey the participants’ use of alcohol, pain-relievers, and cigarettes in the past month (Berman, Palmstierna, K¨allm´en, & Bergman, 2007; Lee & Berman, 2009). The participants who had used alcohol, painrelievers, or cigarettes in the past 1 month were classified as having co-used alcohol, pain-relievers, and cigarettes, respectively. Mandarin Chinese version of the Center for Epidemiological Studies-Depression Scale (CES-D). The severity of depressive symptoms in the past week was determined using the 20-item CES-D (Chien & Cheng, 1985; Radloff, 1977). The CES-D is a self-administered 4-point evaluation scale assessing the frequency of depressive symptoms, and scores range from 0 (none or extremely few) to 3 (always). High CES-D scores indicate severe depressive symptoms. This study collected data on participant demographic characteristics, including age, gender, and educational level. The dose of prescribed zolpidem and zopiclone and total duration of zolpidem and zopiclone treatment were recorded. The dosage data were transformed into dosages equivalent to 1 mg of lorazepam (Ashton, 2002). Procedure and Statistical Analysis
Measures
Chinese Version of the Severity of Dependence Scale (SDS[Ch] ). The 5-item SDS[Ch] was used to evaluate the severity of the participants’ zolpidem or zopiclone dependence in the past month (Chen et al., 2008; Gossop et al., 1995). The five items were: “Do you think your use of hypnotics was out of control?” “Did the prospect of missing a fix or dose make you anxious or worried?” “Did you worry about your use of hypnotics?” “Did you wish you could stop using hypnotics?” and “How difficult was it to stop or go without hypnotics?” The SDS is a valid, brief, self-reporting questionnaire used to assess hypnotic and sedative dependence (de las Cuevas, Sanz, de la Fuente, Padilla, & Berenguer, 2000). The psychometrics of the SDS[Ch] for patients using hypnotics in Taiwan have been examined (Tsai et al., 2012). Total SDS scores range from 0 to 15, and a higher score indicates a greater degree of dependence. Beliefs About Medicines Questionnaire (BMQ). The 10-item BMQ was applied to evaluate the participants’ beliefs about the use of zolpidem or zopiclone to treat sleep problems. The BMQ comprises two five-item subscales, and a higher total score indicates that the participants perceived a higher level of necessity of prescribed
Research psychiatrists performed interviews using the research questionnaires. Data analysis was performed using SPSS 17.0 statistical software (SPSS Inc., Chicago, IL, USA). The levels of zolpidem and zopiclone dependence on the SDS[Ch] and the belief toward zolpidem or zopiclone treatment (including necessity and concern about the potential adverse consequences) were calculated by mean and standard deviation (SD). The correlation of dependence and beliefs about zolpidem and zopicolne treatment with demographic characteristics, hypnotic-using behaviors, co-use of addictive substances, and depressive symptoms were analyzed using multiple regression analysis models. The correlations between dependence and beliefs and between necessity and concern were also examined using multiple regression analysis to control for the effects of other factors. Because of three regression models examined in this study, a p value of .016 (.05/3) indicated statistical significance. RESULTS
The severity of dependence, levels of beliefs about the use of hypnotics, demographic characteristics, variety of hypnotics, equivalent dose and duration of hypnotics use, co-use of other addictive substances, and severity of depressive symptoms among the participants are shown in
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CHENG-FANG YEN ET AL.
TABLE 1. Dependence, beliefs regarding use of hypnotics, demographic characteristics, variety of hypnotics, equivalent dose and duration of hypnotics use, co-use of other addictive substances, and depressive symptoms among zolpidem or zopiclone users (N = 392)
Subst Use Misuse Downloaded from informahealthcare.com by University of Otago on 12/25/14 For personal use only.
Mean (SD) Severity of dependence on the SDS[Ch] Beliefs regarding hypnotic use on the BMQ Level of necessity Level of concern Age (years) Gender Female Male Educational level (years) Varity of hypnotics Zolpidem Zopiclone Equivalent dose of hypnotics (mg/day) Duration of hypnotic use (months) Co-use of other addictive substances Alcohol Pain-relievers Smoking Severity of depressive symptoms
n (%)
5.6 (3.3)
10.7 (3.8) 16.3 (4.4) 48.0 (13.9) 242 (61.7) 150 (38.3) 11.7 (4.6) 317 (80.9) 75 (19.1) 0.5 (0.4) 65.2 (63.6) 82 (20.9) 131 (33.4) 121 (30.9) 21.5 (14.8)
BMQ: Beliefs about Medicines Questionnaire; SD: standard deviation; SDS[Ch] : Chinese version of the Severity of Dependence Scale.
Table 1. Of the 392 participants, 242 (61.7%) were female and 150 (38.3%) were male; the mean age was 48.0 years (standard deviation, 13.9 years), and 317 (80.9%) and 75 (19.1%) were zolpidem and zopiclone users, respectively. Multiple regression analysis was used to examine the correlates of dependence and beliefs about zolpidem or zopiclone use, and the results are shown in Table 2. Zolpidem users reported more severe dependence (5.8 vs. 5.1, p = .001) and a lower level of necessity regard-
ing the use of hypnotics (10.5 vs. 11.7, p = .007) than zopiclone users did. Although not reaching the level of significnace, zolpidem users tended to report a higher level of concern about the potential adverse consequences of hypnotics than zopiclone users did (16.7 vs. 14.5, p = .022). High equivalent doses of hypnotics and long duration of use were significantly associated with severe dependence (p = .001 and .008, respectively) and a low level of necessity (p = .001 and .003, respectively). Severe depressive symptoms were signiciantly associated with severe dependence (p < .001), a low level of necessity (p < .001), and a low level of concern (p < .001). The participants with high educational levels had significantly higher levels of necessity (p = .004) and lower levels of concern (p = .004). The older participants tended to have a higher level of concern (p = .023). The co-use of alcohol, painrelievers, and cigarettes was not considerably associated with dependence or beliefs about hypnotic use. After controlling for the effects of other factors, dependence was negatively correlated with necessity (Beta = −.217, t = −4.139, p < .001) and concern (Beta = −.307, t = − 6.047, p < .001) and beliefs in multiple regression analysis models. There was no significant correlation between concern and beliefs (Beta = −.035, t = −.669, p = .504).
DISCUSSION
Zolpidem users have reported more severe dependence on hypnotics than zopiclone users have. This result contrasts with the results of a previous review study, in which the authors found that levels of drug self-administration in experimental animals, levels of nonmedical use, and withdrawal symptoms in animals and human beings between zolpidem and zopiclone were similar, and that zopiclone had higher levels of liking/reinforcement among human beings than those of zolpidem (Griffiths & Johnson, 2005). However, the studies reviewed were
TABLE 2. Correlates of dependence and belief toward zolpidem or zopiclone use: Multiple regression analysis Beliefs toward hypnotic use Dependence
Age Gender Educational level Varity of hypnotics Equivalent dosage of hypnotics Duration of hypnotic use Alcohol Pain-relievers Smoking Depressive symptoms Adjusted R2 F p
Necessity
Concern
Beta
t
P
Beta
t
p
Beta
t
p
−.063 −.015 −.100 −.154 .177 .123 .060 .060 .011 .375
−1.050 −.321 −1.909 −3.365 3.314 2.684 1.284 1.308 .212 7.860 .252 14.131
![[Benzodiazepine hypnotics, zolpidem and zopiclone on private prescriptions: use between 1993 and 2012].](/assets/img/hold.png)
