International Journal of Risk & Safety in Medicine 26 (2014) 183–189 DOI 10.3233/JRS-140633 IOS Press
183
Zopiclone: Is there cause for concern in addiction services and general practice? Merlin Curreena,∗ and Jed Lidmilab a
Community Mental Health & Addiction Services, Northland District Health Board, Whangarei, New Zealand b Opioid Substitution Treatment Service, Northland District Health Board, Kaitaia, Whangarei, New Zealand Received 1 June 2014 Accepted 17 August 2014 Abstract. OBJECTIVE: To examine the research on the dependence and abuse potential of zopiclone and the concerns that may be raised for addiction treatment services and General Practice. The focus is on four main areas: Problems that may arise from recommended use; Driving; Issues relating to dependence, and Abuse or recreational misuse. METHOD: Internet-based searches were carried out using the key descriptors of zopiclone and driving, road traffic accidents, dependence, withdrawal, abuse, misuse and overdose. RESULTS: Problems arising from recommended use are rare and almost always confined to common side-effects. Drivingrelated studies indicate the potential for driving impairment for up to 12 hours following use and this has clear implications for both addiction services and general practice. The likelihood of dependence increases once recommended doses and time-frames are exceeded and vulnerable populations such as psychiatric patients and those with addiction problems are at risk. CONCLUSION: Somewhat contrary to impressions that Zopiclone has little or no abuse potential, there is evidence that this medication is prescribed at higher than recommended doses and for longer than recommended. It can also be obtained readily other than by prescription. The potential for deliberate abuse may now be regarded as established, albeit at low levels compared to the benzodiazepines and this requires a degree of vigilance by prescribers and care managers. Keywords: Zopiclone, abuse, dependence, overdose, driving, road traffic accidents
1. Introduction Zopiclone was first introduced to the market in 1986 by Rhone-Poulenc, which is now part of SanofiAventis, the principal world-wide manufacturer of the drug. Known also as Imovane and Zimovane, it is indicated for the short-term treatment of insomnia. Other, similar medications include eszopiclone, zaleplon and zolpidem and they are known colloquially as “Z-drugs.” Product information [1, 2] indicates that zopiclone should not be prescribed in quantities exceeding a one month supply, but that dependence ∗
Address for correspondence: Merlin Curreen, Community Mental Health & Addiction Services, Northland District Health Board, Private Bag 9742, Whangarei, New Zealand. Tel.: +64 9 430 4100; Fax: +64 9 438 0437; E-mail: merlin@ fourwinds.org.nz. 0924-6479/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
184
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
and withdrawal are rare, daytime anxiety tends to be reduced and the risk of rebound insomnia is very low. Its absorption time is approximately two hours, with a bioavailability of 70% and an elimination half-life of five hours, though this may be extended in the elderly. Whilst it has a different molecular structure to the benzodiazepines, it binds to the same receptors as the benzodiazepines. Its classification as a non-benzodiazepine appears to have led to the wide-spread impression of greatly reduced potential for dependency and misuse, although this perception has been the subject of some debate over the years. Even by 1993, some clinicians, noting reports of misuse in alcohol and drug service patients, had described it as a “benzodiazepine in disguise” [3]. There have been few fatalities involving zopiclone and it is rarely the sole cause of death. The lowest known fatal dose was 90 mg, taken in a successful suicide bid by a physically debilitated elderly man with lung cancer [4]. One study [5], noted that in 200 poisoning deaths in New Zealand, zopiclone was the sixth most commonly involved substance, however the authors of this study pointed out that hypnotics tend to be contributory in such deaths, rather than primary causal agents and zopiclone was still considered less toxic than alprazolam and chlormethiazole. A recent study [6], suggested that the prescription of any hypnotic significantly elevates the probability of premature death and that a number of the “Z-drugs” including zolpidem, eszopiclone, zaleplon, as well as temazepam, other benzodiazepines, barbiturates and sedating antihistamines are associated with elevation of incident cancer. This finding is, however, controversial. There are four areas of potential concern relating to zopiclone use by drug treatment agency clients and in General Practice. These are: 1. Problems arising from recommended use. Recommended use is one 7.5 mg tablet per night, for no longer than one month’s duration [1, 2]. 2. Effects on driving. 3. Problems relating to dependence. The term dependence relates to the primarily physiological process whereby an individual develops tolerance to a drug, becoming dependent on it to maintain normal function. Abstinence, or reduction produces discomfort or withdrawal reactions. 4. Problems relating to deliberate misuse. Misuse, or abuse is here taken to mean the use of a drug for purposes not consistent with legal or medical guidelines. Such purposes may include the attainment of states of euphoria, sedation, stimulation, or subjective feelings of well-being and may also encompass the amelioration or enhancement of the effects of other drugs. 2. Problems arising from recommended use One large study involving 20,513 subjects [7], considered patients who had complained of poor sleep, with symptoms of sleep onset latency of longer than one hour, more than two nocturnal awakenings, early morning awakening, sleep time of less than six hours and complaints of tiredness on awakening. After 21 consecutive days of treatment with zopiclone, improvements were rated by participants as excellent or good in more than 80%, fair in 11.6% and poor or bad in 4%. The incidence of adverse events was 9.2%, consisting of bitter taste 3.6%, dry mouth 1.6%, difficulty rising in the morning 1.3%, sleepiness 0.5%, nausea 0.5% and nightmares 0.5%. Other, smaller studies [8–11], have substantially confirmed these findings, adding that all sleep measures improved from the first night of treatment; that morning drowsiness was significantly less for Zopiclone than for benzodiazepines used for the same purpose; that day-time mood and somatic symptoms were insignificant and that there seemed to be clear advantages for ambulatory patients.
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
185
Some cautions were expressed regarding rebound insomnia and adverse reactions such as sedation, unpleasant taste and clumsiness. Some patients found that deterioration of sleep quality after cessation of zopiclone was not evident for a few days, but then led to extended sleep problems. Several amnestic episodes were reported in a 54 year old male subject [12], however this was after two years of continuous use and a dose increase to 15 mg. Vietnam war veterans treated with zopiclone over a six month period showed no improvements in their sleep difficulties and continued to respond poorly after a further six months [13]. It can then, be reasonably concluded that for recommended doses and time-frames, zopiclone causes minimal difficulty and that (subject to caveats discussed below) significant problems only begin to manifest when doses are increased over extended periods of time. Even so, problems seem to be markedly lower than those experienced with benzodiazepines used for the same purposes. 3. Driving Potential difficulties relating to driving are of particular relevance to addiction services, as many clients drive to attend appointments, or to receive medications. Likewise, patients of General Practice residing in rural areas where public transport is sparse, or non-existent, will make use of private vehicles as a matter of course. All the driving-related studies discovered [14–18], stated warnings of varying degree about driving vehicles post-zopiclone ingestion. Blood test analysis of drivers in road traffic accidents and from routine roadside testing [14, 15] indicated a significant increase of the likelihood of accidents for users of anxiolytic benzodiazepines and zopiclone [14] and higher blood concentrations than would be expected after the intake of therapeutic doses [15]. A high proportion of subjects also tested positive for illegal drugs, prescription medications with abuse potential, or alcohol, indicating a tendency for poly-drug use by many drivers. Driving test simulations [16–18], found that increased collision rates were associated with Zopiclone use and that vulnerability to impaired driving was apparent during the morning after ingestion, though this had passed by the afternoon. One study [16] found that EEG recordings of subjects who had taken zopiclone showed typical benzodiazepine-like patterns. The foregoing indicates that zopiclone has the potential to significantly impair driving abilities during the morning following normal usage. There are also indications of higher than recommended use of zopiclone, together with other psychoactive substances. This has implications for countries where there is poor access to public transport and high use of personal motor vehicles. 4. Issues relating to dependence Accounts of dependence in the literature are sporadic, consisting mostly of single case presentations, or with small numbers of subjects. Opinion relating to the dependence potential of zopiclone tends to be divided. A common finding [19–23], has been that people initially begin taking zopiclone as prescribed for sleep problems, then escalate doses over time, either in search of greater efficacy, or to reduce anxiety, or in conjunction with substance abuse problems and psychiatric difficulties. Sometimes doses reached extreme levels and on cessation, or withdrawal, subjects experienced insomnia, strong craving, anxiety, tachycardia, tremor and, occasionally seizures [22–25]. “Doctor shopping” to obtain more supplies, and
186
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
the widespread purchase of excessive amounts have been reported [24, 25], sometimes up to 180 daily doses at a time. Some subjects have reported that zopiclone is easily purchased off the streets and that it is readily prescribed by doctors [19, 20]. Three comprehensive reviews [25–27], have, however, found very low problem rates over substantial periods of time since the introduction of zopiclone to the market. One [26], concluded that in the UK, 90% of patients remain on the standard dose of 7.5 mg and that efficacy tends to be maintained over time. The other two reviewers [25, 27], whilst acknowledging a certain abuse potential for zopiclone, particularly for those with psychiatric disorders, found only 22 reported cases of misuse. Some doses were extremely high, however the authors, pointing out that there were 664,897,000 tablets dispensed in Europe and Japan from June 2001 to June 2002, considered that the problem rate was insignificant. It is apparent that physical dependence on zopiclone does occur, particularly with long-term use and with higher doses, but considering the numbers of prescriptions and individual doses, the problem rate has been considered to be insignificant. There are indications, however that long-term use, at higher than recommended doses, is fairly commonplace and that this may indicate hidden problems. 5. Problems stemming from deliberate misuse Again, accounts of deliberate or ‘recreational’ abuse are sporadic throughout the literature and opinion as to seriousness tends to be divided. Several of the single-case presentations in this category [28–32] relate to people who have escalated doses over time in order to achieve states of psychological well-being, intoxication and sedation. Typical of these cases was that of a 59 year old woman [29], who increased her intake to 150 mg per day. The dose increase was associated with subjective feelings of euphoria and fitness, but also with fatigue and forgetfulness. On withdrawal, she suffered from restlessness, psychomotor agitation, abdominal pains and hypertension. Seizures on withdrawal have been reported and patients with alcohol problems and psychiatric disorders appear to be vulnerable [28, 30, 31]. One report [30], presented the cases of three teenagers in South Wales, who had been prescribed zopiclone, or purchased it on the streets. Two used it to intensify, or prolong the effects of alcohol, whilst the third was crushing the tablets for intravenous injection. None of the three displayed evidence of dependency. Reports from drug treatment agencies in Ireland and the UK, present mixed findings [33–35]. One survey of 297 admissions to three addiction treatment sites in the UK [33], found that zopiclone and zolpidem had low abuse liability, being on a par with antihistamines and the sedating anti-depressants and substantially less than the benzodiazepines. Others, however found that between 23% and 42% of programme clients had persistently misused zopiclone, for up to 10 years, at doses ranging from 15 to 300 mg [34, 35]. Whilst some used it to attain various degrees of tranquilization, others found that it potentiated the experience of heroin and stated that its popularity was growing. Some used it when heroin was not available, or when its quality was poor and to ‘come down’ from stimulant abuse [33–35]. Some subjects mixed zopiclone with crack cocaine and alcohol [35]. Effects reported were sedation and euphoria, but also memory and emotional problems, craving and aggression. Other clients reported that they liked zopiclone because it did not cause amnesia, one person claiming a preference over the benzodiazepines, stating that she would return to zopiclone use as soon as she was free to do so [36]. It is evident that some subjects have obtained large quantities of zopiclone, either by ‘doctor shopping’ or by obtaining extra supplies for the streets, or from family and friends. Intravenous use was rare [31, 36], some subjects claiming that they were not aware that it could be injected.
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
187
Lam [37, 38], made a retrospective study of zopiclone abusers in a Hong Kong substance abuse clinic, that provides services to a population of about a million. Of a group of 104, 41 had a primary dependence on zopiclone, 46 a secondary dependence and 17 a past dependence. The proportion of abusers had increased in the previous four years, comprising up to 30% of new clinic cases. Because this clinic provides services to a large population base, it was thought likely that the sample represented only the most severe cases. Since then, rates of client presentation with zopiclone misuse and dependence have continued to increase, now being problematic for 40% of new presentations (Ming Lam, personal communication.)
6. Discussion It is evident that if prescribing guidelines relating to doses and time-frames are followed, problems with zopiclone are minimal and confined almost entirely to common side-effects such as bitter taste, dry mouth, itching, headaches and the like [7, 8–11]. In our clinical practice we have noted, however that prescribing guidelines are exceeded with frequency and it is common to find patients on higher doses, for extended periods of time. This is hardly surprising. The enormous worldwide popularity of hypnotics such as zopiclone, bespeaks very substantial and persistent community problems with sleep. In New Zealand, (pop. 4.4 million approx.) there were 540,000 prescriptions for zopiclone during the year June 2010 to June 2011, comprising 20.2 million individual doses, (Pharmac NZ, personal communication). When medical service patients find a medication that works for them, at least initially, they will quite naturally seek to continue taking it. Yet the above does not mean an absence of concern. All of the studies relating to driving [14–18], indicated that there was an increased likelihood of accidents, or other potentially dangerous road events for up to 11 hours post zopiclone ingestion. These studies highlight the fact that there has been very little by way of functional cognitive analysis of the effects of zopiclone, as there has been for the benzodiazepines. This is an area in which further research is needed. Driving, then, is an area of concern both for addiction services and for General Practice, for reasons already stated above. Many patients, or service clients will claim that they have no choice but to drive, so professional staff may need to be clearer and more specific in warnings about driving at appropriate times after ingestion of doses, particularly if they become aware that recommended doses are being exceeded. It is also apparent that once dose levels increase and continue over longer time-periods, the likelihood of both dependence and misuse increases, particularly in vulnerable populations such as psychiatric patients and those with addiction problems [28–32]. Several authors have pointed out that given the very large numbers of prescriptions and individual doses, that this problem is very small and statistically insignificant [25, 27]. Small numbers and statistical insignificance, however do not equate to the absence of a problem at practice level, particularly for those affected. There seem to be gaps here in the research, firstly as to how many patients are nowadays prescribed at higher doses for longer than recommended and secondly, regarding the clinical effectiveness of zopiclone over longer time-frames. Service providers need to maintain an awareness of the possibilities of dependence and to have clinical pathways to address this when necessary. Similarly, the abuse potential of zopiclone can now be regarded as quite well established, with some evidence that its popularity is increasing [37–38]. Abuse does, however seem to be at low levels, does not approach the prevalence of problems encountered with the benzodiazepines and it seems to be seldom injected. There are, however consistent anecdotal reports from case-managers and nurses in addiction and mental health services, of misuse of zopiclone by clients and there is a need for alertness as to the
188
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
potential for abuse, as well as for pathways and staff training to deal with this. There is also a need for vigilance in General Practice regarding those who escalate doses over time and who may “doctor shop” for extra supplies. Again, there is a need for on-going research in this particular area as many services appear to have a low level of awareness of the likelihood of zopiclone abuse, or that the nature of misuse seems to be evolving over time Acknowledgments The authors would like to acknowledge Margaret Hart of Whangarei Hospital Library, for her expertise in sourcing references. Conflict of interest Neither author has any conflict of interest. References [1] Sanofi-Aventis. Imovane (Zopiclone). Product Monograph. (2011). Available at: http://products.sanofi.ca/en/imovane.pdf [2] Medsafe Editorial Team. Dependence with Zopiclone. Medsafe, New Zealand. 1998. Available at: http://www. medsafe.govt.nz/PUarticles/3.htm [3] Luty S, Sellman D. Imovane – a benzodiazepine in disguise. N.Z. Medical Journal. 1993;106:959. [4] Meatherall, RC, Zopiclone fatality in a hospitalized patient. J Forensic Sci. 1997; 42(2):340-43. [5] Reath DM, Fountain J, McDowell R, Tilyard M. Comparison of the fatal toxicity index of zopiclone with benzodiazepines. J Toxicol Clin Toxicol. 2003; 41(7):975-80. [6] Kripke DF, Langer RD, Kline LE. Hypnotics’ association with mortality or cancer: A matched cohort study. BMJ Open. 2012; 2 e000850 doi:10.1136/bmjopen-2012-000850. [7] Allain H, Delahaye Ch, Le Coz F, Blin P, Decombe R, Martinet JP. Postmarketing surveillance of zopiclone in insomnia: Analysis of 20,513 cases. Sleep. 1991;14(5):408-13. [8] Hajak G, Clarenbach P, Fischer W, Rodenbeck A, Bandelow, Broocks A Ruther E. Rebound insomnia after hypnotic withdrawal in insomniac outpatients. Eur Arch Psychiatry Clin Neurosci. 1998;248(3):148-56. [9] Anderson AA. Zopiclone and Nitrazepam: A multicenter placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice. Sleep. 1987;10 (Suppl 1):54-62. [10] van der Kleijn E. Effects of zopiclone and temazepam on sleep, behaviour and mood during the day. Eur J Clin Pharmacol. 1989;36(3):247-51. [11] Begg E, Robson R, Frampton C, Campbell J. A comparison of efficacy and tolerance of the short acting sedative midazolam and zopiclone. N.Z. Medical Journal. 1992;105:428-9. [12] Fava GA. Amnestic syndrome induced by zopiclone. Eur J Clin Pharmacol. 1996;36:509. [13] Alderman CP,Gilbert AL, A qualitative investigation of long-term zopiclone use and sleep quality among Vietnam war veterans with PTSD. Ann Pharmacother. 2009;43: 1575-82. [14] Barbone F, McMahon AD, Davey PG, Morris AD, Reid IC, McDevitt DG, MacDonald TM. Association of road-traffic accidents with benzodiazepine use. The Lancet. 1998;352:1331-6. [15] Bramness J, Skurtveit S, Mørland J. Detection of zopiclone in many drivers – a sign of misuse of abuse. Tidsskr Nor Laegeforen. 1999;119(19):2820-2821. [16] Staner L, Ertle S, Boeijinga P, Rinaudo G, Arnal MA, Muzet A. Luthringer R. Next-day residual effects of hypnotics in DSM-lV primary insomnia: A driving simulator study with simultaneous electroencephalogram monitoring. Psychopharmacology (Berl). 2005;181(4):790-8. [17] Leufkens TR, Vermeeren A. Highway driving in the elderly the morning after bedtime use of hypnotics; a comparison between temazepam 20mg, zopiclone 7.5mg, and placebo. J Clin Psychopharmacol. 2009;29(5):432-8.
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
189
[18] Verster JC, Veldhuijzen DS, Patat A, Olivier B, Volkerts ER. Hypnotics and driving safety: Meta-analyses of randomized controlled trials applying the on-the-Road Driving Test. Current Drug Safety. 2006;1:63-71. [19] Sikdar S, Ruben SM. Zopiclone abuse among polydrug abusers. Addiction. 1996;91(2):285-91. [20] Sikdar S. Physical Dependence on Zopiclone. BMJ. 1998; 317(1751):146. [21] Ayonrinde O, Sampson E. Risk of dependence may be greater in those with dependent personalities. BMJ. 1998;317(7151):146. [22] Jones IR, Sullivan G. Physical Dependence on Zopiclone: Case reports. BMJ. 1998; 316:117. [23] Flynn A, Cox D. Dependence on Zopiclone. Addiction. 2006;101:898-900. [24] Hoffmann F, Pfannkuche M, Glaeske G. High use of zolpidem and zopiclone: A cross sectional study using claims data. Der Nervenzarzt. 2008;79(1):67-72. [25] Lader M. Zopiclone: Is there any dependence and abuse potential? J Neurol. 1997; 244(Suppl 1):18-22. [26] Hakak G. A comparative assessment of the risks and benefits of zopiclone: A review of 15 years clinical experience. Drug Safety. 1999;21(6):457-69. [27] Hajak G, Muller WE, Wittchen HU, Pittrow D, Kirch W. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: A review of case reports and epidemiological data. Addiction. 2003;98:1371-1378. [28] Aranko K, Henriksson M, Hublin C, Seppalainen A M. Misuse of zopiclone and convulsions during withdrawal. Pharmacopsychiatry. 1991;24(4):138-40. [29] Kahlert I, Brune M. A case of primary zopiclone dependence. Dtch Med Wochenschr. 2001;126(22):653-4. [30] Sullivan G, McBride AJ, Clee WB. Zopiclone abuse in South Wales: Three case reports. Human Psychopharmacology. 1995;10:351-2. [31] Rooney S, O’Connor J. Zopiclone, a current drug of abuse. Addiction. 1998; 93(6):925. [32] Jaffe JH, Bloor R, Crome I, Carr M, Alam F, Simmons A, Meyer RE. A postmarketing study of relative abuse liability of hypnotic sedative drugs. Addiction. (2004); 99(2):165-73. [33] Bannon N, Rooney S, Maguire R, Moran C, Dowling M, O’Connor J. Zopiclone misuse on a methadone maintenance programme. Irish Psychiatrist. 2005;6(5):201-6. [34] Bannon N, Rooney S, O’Conno, J. Zopiclone misuse: An update from Dublin. Drug and Alcohol Review. 2007;26:83-5. [35] Newcombe R. Assessment of the consumption and consequences of zopiclone (zimovane) among drugtakers in a North-East town. Lifeline Publications and Research. 2009. Available at: http://www.lifelineprojectdev. co.uk/uploads/docs/zopiclone-report-sep09.pdf [36] Morinan A. Keaney F. Long-term misuse of zopiclone in an alcohol dependent woman with a history of anorexia nervosa: A case study. Journal of Medical Case Reports. 2010;4:403 [37] Lam M. Retrospective study on characteristics of 104 zopiclone abusers in a substance abuse clinic in Hong Kong. Paper presented at the International Conference on Tackling Drug Abuse, Hong Kong, 2006. Available at: http://www.nd.gov.hk/en/conference proceedings/Drugs proBK Part5Drugs ProBK LamMing.pdf [38] Lam M. Liability of abuse and dependence of zopiclone. Chinese Journal of Drug Dependence. 2007;16(3):226-9.
Copyright of International Journal of Risk & Safety in Medicine is the property of IOS Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
183
Zopiclone: Is there cause for concern in addiction services and general practice? Merlin Curreena,∗ and Jed Lidmilab a
Community Mental Health & Addiction Services, Northland District Health Board, Whangarei, New Zealand b Opioid Substitution Treatment Service, Northland District Health Board, Kaitaia, Whangarei, New Zealand Received 1 June 2014 Accepted 17 August 2014 Abstract. OBJECTIVE: To examine the research on the dependence and abuse potential of zopiclone and the concerns that may be raised for addiction treatment services and General Practice. The focus is on four main areas: Problems that may arise from recommended use; Driving; Issues relating to dependence, and Abuse or recreational misuse. METHOD: Internet-based searches were carried out using the key descriptors of zopiclone and driving, road traffic accidents, dependence, withdrawal, abuse, misuse and overdose. RESULTS: Problems arising from recommended use are rare and almost always confined to common side-effects. Drivingrelated studies indicate the potential for driving impairment for up to 12 hours following use and this has clear implications for both addiction services and general practice. The likelihood of dependence increases once recommended doses and time-frames are exceeded and vulnerable populations such as psychiatric patients and those with addiction problems are at risk. CONCLUSION: Somewhat contrary to impressions that Zopiclone has little or no abuse potential, there is evidence that this medication is prescribed at higher than recommended doses and for longer than recommended. It can also be obtained readily other than by prescription. The potential for deliberate abuse may now be regarded as established, albeit at low levels compared to the benzodiazepines and this requires a degree of vigilance by prescribers and care managers. Keywords: Zopiclone, abuse, dependence, overdose, driving, road traffic accidents
1. Introduction Zopiclone was first introduced to the market in 1986 by Rhone-Poulenc, which is now part of SanofiAventis, the principal world-wide manufacturer of the drug. Known also as Imovane and Zimovane, it is indicated for the short-term treatment of insomnia. Other, similar medications include eszopiclone, zaleplon and zolpidem and they are known colloquially as “Z-drugs.” Product information [1, 2] indicates that zopiclone should not be prescribed in quantities exceeding a one month supply, but that dependence ∗
Address for correspondence: Merlin Curreen, Community Mental Health & Addiction Services, Northland District Health Board, Private Bag 9742, Whangarei, New Zealand. Tel.: +64 9 430 4100; Fax: +64 9 438 0437; E-mail: merlin@ fourwinds.org.nz. 0924-6479/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
184
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
and withdrawal are rare, daytime anxiety tends to be reduced and the risk of rebound insomnia is very low. Its absorption time is approximately two hours, with a bioavailability of 70% and an elimination half-life of five hours, though this may be extended in the elderly. Whilst it has a different molecular structure to the benzodiazepines, it binds to the same receptors as the benzodiazepines. Its classification as a non-benzodiazepine appears to have led to the wide-spread impression of greatly reduced potential for dependency and misuse, although this perception has been the subject of some debate over the years. Even by 1993, some clinicians, noting reports of misuse in alcohol and drug service patients, had described it as a “benzodiazepine in disguise” [3]. There have been few fatalities involving zopiclone and it is rarely the sole cause of death. The lowest known fatal dose was 90 mg, taken in a successful suicide bid by a physically debilitated elderly man with lung cancer [4]. One study [5], noted that in 200 poisoning deaths in New Zealand, zopiclone was the sixth most commonly involved substance, however the authors of this study pointed out that hypnotics tend to be contributory in such deaths, rather than primary causal agents and zopiclone was still considered less toxic than alprazolam and chlormethiazole. A recent study [6], suggested that the prescription of any hypnotic significantly elevates the probability of premature death and that a number of the “Z-drugs” including zolpidem, eszopiclone, zaleplon, as well as temazepam, other benzodiazepines, barbiturates and sedating antihistamines are associated with elevation of incident cancer. This finding is, however, controversial. There are four areas of potential concern relating to zopiclone use by drug treatment agency clients and in General Practice. These are: 1. Problems arising from recommended use. Recommended use is one 7.5 mg tablet per night, for no longer than one month’s duration [1, 2]. 2. Effects on driving. 3. Problems relating to dependence. The term dependence relates to the primarily physiological process whereby an individual develops tolerance to a drug, becoming dependent on it to maintain normal function. Abstinence, or reduction produces discomfort or withdrawal reactions. 4. Problems relating to deliberate misuse. Misuse, or abuse is here taken to mean the use of a drug for purposes not consistent with legal or medical guidelines. Such purposes may include the attainment of states of euphoria, sedation, stimulation, or subjective feelings of well-being and may also encompass the amelioration or enhancement of the effects of other drugs. 2. Problems arising from recommended use One large study involving 20,513 subjects [7], considered patients who had complained of poor sleep, with symptoms of sleep onset latency of longer than one hour, more than two nocturnal awakenings, early morning awakening, sleep time of less than six hours and complaints of tiredness on awakening. After 21 consecutive days of treatment with zopiclone, improvements were rated by participants as excellent or good in more than 80%, fair in 11.6% and poor or bad in 4%. The incidence of adverse events was 9.2%, consisting of bitter taste 3.6%, dry mouth 1.6%, difficulty rising in the morning 1.3%, sleepiness 0.5%, nausea 0.5% and nightmares 0.5%. Other, smaller studies [8–11], have substantially confirmed these findings, adding that all sleep measures improved from the first night of treatment; that morning drowsiness was significantly less for Zopiclone than for benzodiazepines used for the same purpose; that day-time mood and somatic symptoms were insignificant and that there seemed to be clear advantages for ambulatory patients.
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
185
Some cautions were expressed regarding rebound insomnia and adverse reactions such as sedation, unpleasant taste and clumsiness. Some patients found that deterioration of sleep quality after cessation of zopiclone was not evident for a few days, but then led to extended sleep problems. Several amnestic episodes were reported in a 54 year old male subject [12], however this was after two years of continuous use and a dose increase to 15 mg. Vietnam war veterans treated with zopiclone over a six month period showed no improvements in their sleep difficulties and continued to respond poorly after a further six months [13]. It can then, be reasonably concluded that for recommended doses and time-frames, zopiclone causes minimal difficulty and that (subject to caveats discussed below) significant problems only begin to manifest when doses are increased over extended periods of time. Even so, problems seem to be markedly lower than those experienced with benzodiazepines used for the same purposes. 3. Driving Potential difficulties relating to driving are of particular relevance to addiction services, as many clients drive to attend appointments, or to receive medications. Likewise, patients of General Practice residing in rural areas where public transport is sparse, or non-existent, will make use of private vehicles as a matter of course. All the driving-related studies discovered [14–18], stated warnings of varying degree about driving vehicles post-zopiclone ingestion. Blood test analysis of drivers in road traffic accidents and from routine roadside testing [14, 15] indicated a significant increase of the likelihood of accidents for users of anxiolytic benzodiazepines and zopiclone [14] and higher blood concentrations than would be expected after the intake of therapeutic doses [15]. A high proportion of subjects also tested positive for illegal drugs, prescription medications with abuse potential, or alcohol, indicating a tendency for poly-drug use by many drivers. Driving test simulations [16–18], found that increased collision rates were associated with Zopiclone use and that vulnerability to impaired driving was apparent during the morning after ingestion, though this had passed by the afternoon. One study [16] found that EEG recordings of subjects who had taken zopiclone showed typical benzodiazepine-like patterns. The foregoing indicates that zopiclone has the potential to significantly impair driving abilities during the morning following normal usage. There are also indications of higher than recommended use of zopiclone, together with other psychoactive substances. This has implications for countries where there is poor access to public transport and high use of personal motor vehicles. 4. Issues relating to dependence Accounts of dependence in the literature are sporadic, consisting mostly of single case presentations, or with small numbers of subjects. Opinion relating to the dependence potential of zopiclone tends to be divided. A common finding [19–23], has been that people initially begin taking zopiclone as prescribed for sleep problems, then escalate doses over time, either in search of greater efficacy, or to reduce anxiety, or in conjunction with substance abuse problems and psychiatric difficulties. Sometimes doses reached extreme levels and on cessation, or withdrawal, subjects experienced insomnia, strong craving, anxiety, tachycardia, tremor and, occasionally seizures [22–25]. “Doctor shopping” to obtain more supplies, and
186
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
the widespread purchase of excessive amounts have been reported [24, 25], sometimes up to 180 daily doses at a time. Some subjects have reported that zopiclone is easily purchased off the streets and that it is readily prescribed by doctors [19, 20]. Three comprehensive reviews [25–27], have, however, found very low problem rates over substantial periods of time since the introduction of zopiclone to the market. One [26], concluded that in the UK, 90% of patients remain on the standard dose of 7.5 mg and that efficacy tends to be maintained over time. The other two reviewers [25, 27], whilst acknowledging a certain abuse potential for zopiclone, particularly for those with psychiatric disorders, found only 22 reported cases of misuse. Some doses were extremely high, however the authors, pointing out that there were 664,897,000 tablets dispensed in Europe and Japan from June 2001 to June 2002, considered that the problem rate was insignificant. It is apparent that physical dependence on zopiclone does occur, particularly with long-term use and with higher doses, but considering the numbers of prescriptions and individual doses, the problem rate has been considered to be insignificant. There are indications, however that long-term use, at higher than recommended doses, is fairly commonplace and that this may indicate hidden problems. 5. Problems stemming from deliberate misuse Again, accounts of deliberate or ‘recreational’ abuse are sporadic throughout the literature and opinion as to seriousness tends to be divided. Several of the single-case presentations in this category [28–32] relate to people who have escalated doses over time in order to achieve states of psychological well-being, intoxication and sedation. Typical of these cases was that of a 59 year old woman [29], who increased her intake to 150 mg per day. The dose increase was associated with subjective feelings of euphoria and fitness, but also with fatigue and forgetfulness. On withdrawal, she suffered from restlessness, psychomotor agitation, abdominal pains and hypertension. Seizures on withdrawal have been reported and patients with alcohol problems and psychiatric disorders appear to be vulnerable [28, 30, 31]. One report [30], presented the cases of three teenagers in South Wales, who had been prescribed zopiclone, or purchased it on the streets. Two used it to intensify, or prolong the effects of alcohol, whilst the third was crushing the tablets for intravenous injection. None of the three displayed evidence of dependency. Reports from drug treatment agencies in Ireland and the UK, present mixed findings [33–35]. One survey of 297 admissions to three addiction treatment sites in the UK [33], found that zopiclone and zolpidem had low abuse liability, being on a par with antihistamines and the sedating anti-depressants and substantially less than the benzodiazepines. Others, however found that between 23% and 42% of programme clients had persistently misused zopiclone, for up to 10 years, at doses ranging from 15 to 300 mg [34, 35]. Whilst some used it to attain various degrees of tranquilization, others found that it potentiated the experience of heroin and stated that its popularity was growing. Some used it when heroin was not available, or when its quality was poor and to ‘come down’ from stimulant abuse [33–35]. Some subjects mixed zopiclone with crack cocaine and alcohol [35]. Effects reported were sedation and euphoria, but also memory and emotional problems, craving and aggression. Other clients reported that they liked zopiclone because it did not cause amnesia, one person claiming a preference over the benzodiazepines, stating that she would return to zopiclone use as soon as she was free to do so [36]. It is evident that some subjects have obtained large quantities of zopiclone, either by ‘doctor shopping’ or by obtaining extra supplies for the streets, or from family and friends. Intravenous use was rare [31, 36], some subjects claiming that they were not aware that it could be injected.
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
187
Lam [37, 38], made a retrospective study of zopiclone abusers in a Hong Kong substance abuse clinic, that provides services to a population of about a million. Of a group of 104, 41 had a primary dependence on zopiclone, 46 a secondary dependence and 17 a past dependence. The proportion of abusers had increased in the previous four years, comprising up to 30% of new clinic cases. Because this clinic provides services to a large population base, it was thought likely that the sample represented only the most severe cases. Since then, rates of client presentation with zopiclone misuse and dependence have continued to increase, now being problematic for 40% of new presentations (Ming Lam, personal communication.)
6. Discussion It is evident that if prescribing guidelines relating to doses and time-frames are followed, problems with zopiclone are minimal and confined almost entirely to common side-effects such as bitter taste, dry mouth, itching, headaches and the like [7, 8–11]. In our clinical practice we have noted, however that prescribing guidelines are exceeded with frequency and it is common to find patients on higher doses, for extended periods of time. This is hardly surprising. The enormous worldwide popularity of hypnotics such as zopiclone, bespeaks very substantial and persistent community problems with sleep. In New Zealand, (pop. 4.4 million approx.) there were 540,000 prescriptions for zopiclone during the year June 2010 to June 2011, comprising 20.2 million individual doses, (Pharmac NZ, personal communication). When medical service patients find a medication that works for them, at least initially, they will quite naturally seek to continue taking it. Yet the above does not mean an absence of concern. All of the studies relating to driving [14–18], indicated that there was an increased likelihood of accidents, or other potentially dangerous road events for up to 11 hours post zopiclone ingestion. These studies highlight the fact that there has been very little by way of functional cognitive analysis of the effects of zopiclone, as there has been for the benzodiazepines. This is an area in which further research is needed. Driving, then, is an area of concern both for addiction services and for General Practice, for reasons already stated above. Many patients, or service clients will claim that they have no choice but to drive, so professional staff may need to be clearer and more specific in warnings about driving at appropriate times after ingestion of doses, particularly if they become aware that recommended doses are being exceeded. It is also apparent that once dose levels increase and continue over longer time-periods, the likelihood of both dependence and misuse increases, particularly in vulnerable populations such as psychiatric patients and those with addiction problems [28–32]. Several authors have pointed out that given the very large numbers of prescriptions and individual doses, that this problem is very small and statistically insignificant [25, 27]. Small numbers and statistical insignificance, however do not equate to the absence of a problem at practice level, particularly for those affected. There seem to be gaps here in the research, firstly as to how many patients are nowadays prescribed at higher doses for longer than recommended and secondly, regarding the clinical effectiveness of zopiclone over longer time-frames. Service providers need to maintain an awareness of the possibilities of dependence and to have clinical pathways to address this when necessary. Similarly, the abuse potential of zopiclone can now be regarded as quite well established, with some evidence that its popularity is increasing [37–38]. Abuse does, however seem to be at low levels, does not approach the prevalence of problems encountered with the benzodiazepines and it seems to be seldom injected. There are, however consistent anecdotal reports from case-managers and nurses in addiction and mental health services, of misuse of zopiclone by clients and there is a need for alertness as to the
188
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
potential for abuse, as well as for pathways and staff training to deal with this. There is also a need for vigilance in General Practice regarding those who escalate doses over time and who may “doctor shop” for extra supplies. Again, there is a need for on-going research in this particular area as many services appear to have a low level of awareness of the likelihood of zopiclone abuse, or that the nature of misuse seems to be evolving over time Acknowledgments The authors would like to acknowledge Margaret Hart of Whangarei Hospital Library, for her expertise in sourcing references. Conflict of interest Neither author has any conflict of interest. References [1] Sanofi-Aventis. Imovane (Zopiclone). Product Monograph. (2011). Available at: http://products.sanofi.ca/en/imovane.pdf [2] Medsafe Editorial Team. Dependence with Zopiclone. Medsafe, New Zealand. 1998. Available at: http://www. medsafe.govt.nz/PUarticles/3.htm [3] Luty S, Sellman D. Imovane – a benzodiazepine in disguise. N.Z. Medical Journal. 1993;106:959. [4] Meatherall, RC, Zopiclone fatality in a hospitalized patient. J Forensic Sci. 1997; 42(2):340-43. [5] Reath DM, Fountain J, McDowell R, Tilyard M. Comparison of the fatal toxicity index of zopiclone with benzodiazepines. J Toxicol Clin Toxicol. 2003; 41(7):975-80. [6] Kripke DF, Langer RD, Kline LE. Hypnotics’ association with mortality or cancer: A matched cohort study. BMJ Open. 2012; 2 e000850 doi:10.1136/bmjopen-2012-000850. [7] Allain H, Delahaye Ch, Le Coz F, Blin P, Decombe R, Martinet JP. Postmarketing surveillance of zopiclone in insomnia: Analysis of 20,513 cases. Sleep. 1991;14(5):408-13. [8] Hajak G, Clarenbach P, Fischer W, Rodenbeck A, Bandelow, Broocks A Ruther E. Rebound insomnia after hypnotic withdrawal in insomniac outpatients. Eur Arch Psychiatry Clin Neurosci. 1998;248(3):148-56. [9] Anderson AA. Zopiclone and Nitrazepam: A multicenter placebo controlled comparative study of efficacy and tolerance in insomniac patients in general practice. Sleep. 1987;10 (Suppl 1):54-62. [10] van der Kleijn E. Effects of zopiclone and temazepam on sleep, behaviour and mood during the day. Eur J Clin Pharmacol. 1989;36(3):247-51. [11] Begg E, Robson R, Frampton C, Campbell J. A comparison of efficacy and tolerance of the short acting sedative midazolam and zopiclone. N.Z. Medical Journal. 1992;105:428-9. [12] Fava GA. Amnestic syndrome induced by zopiclone. Eur J Clin Pharmacol. 1996;36:509. [13] Alderman CP,Gilbert AL, A qualitative investigation of long-term zopiclone use and sleep quality among Vietnam war veterans with PTSD. Ann Pharmacother. 2009;43: 1575-82. [14] Barbone F, McMahon AD, Davey PG, Morris AD, Reid IC, McDevitt DG, MacDonald TM. Association of road-traffic accidents with benzodiazepine use. The Lancet. 1998;352:1331-6. [15] Bramness J, Skurtveit S, Mørland J. Detection of zopiclone in many drivers – a sign of misuse of abuse. Tidsskr Nor Laegeforen. 1999;119(19):2820-2821. [16] Staner L, Ertle S, Boeijinga P, Rinaudo G, Arnal MA, Muzet A. Luthringer R. Next-day residual effects of hypnotics in DSM-lV primary insomnia: A driving simulator study with simultaneous electroencephalogram monitoring. Psychopharmacology (Berl). 2005;181(4):790-8. [17] Leufkens TR, Vermeeren A. Highway driving in the elderly the morning after bedtime use of hypnotics; a comparison between temazepam 20mg, zopiclone 7.5mg, and placebo. J Clin Psychopharmacol. 2009;29(5):432-8.
M. Curreen and J. Lidmila / Zopiclone: Is there cause for concern in addiction services and general practice?
189
[18] Verster JC, Veldhuijzen DS, Patat A, Olivier B, Volkerts ER. Hypnotics and driving safety: Meta-analyses of randomized controlled trials applying the on-the-Road Driving Test. Current Drug Safety. 2006;1:63-71. [19] Sikdar S, Ruben SM. Zopiclone abuse among polydrug abusers. Addiction. 1996;91(2):285-91. [20] Sikdar S. Physical Dependence on Zopiclone. BMJ. 1998; 317(1751):146. [21] Ayonrinde O, Sampson E. Risk of dependence may be greater in those with dependent personalities. BMJ. 1998;317(7151):146. [22] Jones IR, Sullivan G. Physical Dependence on Zopiclone: Case reports. BMJ. 1998; 316:117. [23] Flynn A, Cox D. Dependence on Zopiclone. Addiction. 2006;101:898-900. [24] Hoffmann F, Pfannkuche M, Glaeske G. High use of zolpidem and zopiclone: A cross sectional study using claims data. Der Nervenzarzt. 2008;79(1):67-72. [25] Lader M. Zopiclone: Is there any dependence and abuse potential? J Neurol. 1997; 244(Suppl 1):18-22. [26] Hakak G. A comparative assessment of the risks and benefits of zopiclone: A review of 15 years clinical experience. Drug Safety. 1999;21(6):457-69. [27] Hajak G, Muller WE, Wittchen HU, Pittrow D, Kirch W. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: A review of case reports and epidemiological data. Addiction. 2003;98:1371-1378. [28] Aranko K, Henriksson M, Hublin C, Seppalainen A M. Misuse of zopiclone and convulsions during withdrawal. Pharmacopsychiatry. 1991;24(4):138-40. [29] Kahlert I, Brune M. A case of primary zopiclone dependence. Dtch Med Wochenschr. 2001;126(22):653-4. [30] Sullivan G, McBride AJ, Clee WB. Zopiclone abuse in South Wales: Three case reports. Human Psychopharmacology. 1995;10:351-2. [31] Rooney S, O’Connor J. Zopiclone, a current drug of abuse. Addiction. 1998; 93(6):925. [32] Jaffe JH, Bloor R, Crome I, Carr M, Alam F, Simmons A, Meyer RE. A postmarketing study of relative abuse liability of hypnotic sedative drugs. Addiction. (2004); 99(2):165-73. [33] Bannon N, Rooney S, Maguire R, Moran C, Dowling M, O’Connor J. Zopiclone misuse on a methadone maintenance programme. Irish Psychiatrist. 2005;6(5):201-6. [34] Bannon N, Rooney S, O’Conno, J. Zopiclone misuse: An update from Dublin. Drug and Alcohol Review. 2007;26:83-5. [35] Newcombe R. Assessment of the consumption and consequences of zopiclone (zimovane) among drugtakers in a North-East town. Lifeline Publications and Research. 2009. Available at: http://www.lifelineprojectdev. co.uk/uploads/docs/zopiclone-report-sep09.pdf [36] Morinan A. Keaney F. Long-term misuse of zopiclone in an alcohol dependent woman with a history of anorexia nervosa: A case study. Journal of Medical Case Reports. 2010;4:403 [37] Lam M. Retrospective study on characteristics of 104 zopiclone abusers in a substance abuse clinic in Hong Kong. Paper presented at the International Conference on Tackling Drug Abuse, Hong Kong, 2006. Available at: http://www.nd.gov.hk/en/conference proceedings/Drugs proBK Part5Drugs ProBK LamMing.pdf [38] Lam M. Liability of abuse and dependence of zopiclone. Chinese Journal of Drug Dependence. 2007;16(3):226-9.
Copyright of International Journal of Risk & Safety in Medicine is the property of IOS Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
