British Journal of Addiction (1992) 87, 1373-1375
EDITORIAL
Intravenous and other novel abuses of benzodiazepines: the opening of Pandora's box? Intravenous abuse of benzodiazepines became a major problem in the UK during the late 1980s, when drug users began to inject the contents of temazepam capsules. Reports came from the North West of England and Scotland in particular but there were no published reports from other countries of this phenomenon. Our early clinical impressions are that this new form of drug taking behaviour has not been widely taken up by nationals of other countries who are part of the UK drug scene. However in view of the considerable movement of drug users between the UK and certain other European countries (perhaps most notably Ireland, Holland and Italy), it will be imponant to look for evidence on the timing and extent of dissemination of this new drug taking behaviour through the European community as state boundaries are steadily diminished (see Farrell & Strang, 1992). Intravenous abuse of benzodiazepines was first reported in 1984. There was a small outbreak of intravenous injection of flurazepam (Dalmane) by heroin addicts in Manchester, who reported that the intensity and duration of the heroin effect was thereby extended (Strang, 1984). In the same year there were reports from New Zealand and from Israel of single cases of the intravenous abuse of ampoule preparations of benzodiazepines (Kaminer & Modia, 1984). By 1986, Perera et al. (1987) reported that about a third of drug addicts at a combination of treatment agencies in Sheffield had previously been injecting benzodiazepines along with other drug use. However it was in the last few years of the 1980s that extensive intravenous abuse of benzodiazepines was seen—particularly in Scotland (Sakol et al., 1989; Hammersley et al., 1990) and North-West England (Seivewright, Donmall & Daly, 1992; Ruben & Morrison, 1992) as well as in London (Farrell & Strang, 1988). Temazepam became the benzodiazepine of choice for intravenous abuse—almost exclusively in the
form of the soft temazepam capsules which contained a clear liquid that was easily injectable and which were known among drug users as "soft eggs". Because of the scale of the problem consideration turned to whether temazepam should be withdrawn or should be the subject of greater controls, and the manufacturers undertook to alter the formulation of the capsules to a hard gel (like candlewax) in the hope that this would prevent further intravenous abuse (Drake & Ballard, 1988; Launchbury et ai, 1989) while one other manufacturer chose to convert it to tablet form. However, in the year or two following this re-formulation, there has been evidence of the considerable entrepreneurial nature of the injecting drug user, with reports of warming the new hard capsules in an oven or microwave until the gel contents are sufficiently soft to inject through a wide bore needle. It is likely that this is now associated with more severe physical complications (Griffiths & Rothwell, 1990; Grahame-Smith, 1991). Thus Ruben & Morrison (1992) report on the findings from a study of 23 temazepam injectors in Liverpool, and find that all their clients had at some time injected the old soft capsules, while 70% of them had injected the new hard capsules. Although 30% had injected the tablets, most reported that they would prefer to swallow the tablets; and only two of the subjects had ever injected the temazepam elixir. A larger-scale study by Seivewright et al. (1992), employing information from the North Western Regional Drug Misuse Database on all illicit drug users taking benzodiazepines during a 2-year period, confirmed the prominence of temazepam in the injected abuse of benzodiazepines but also detected some injecting of diazepam and nitrazepam. Also, prior to the banning of triazolam (Halcion) this benzodiazepine was being extensively injected by drug users in Glasgow (Green et al, 1992). Whilst we are unaware of any report in the literature, we have also encountered the intravenous abuse of the
1373
1374
Editorial
rapid onset short acting benzodiazepines midazolam and lorazepam by physicians who have access to this drug in ampoule form. Why should drug users bother to inject benzodiazepines, especially when both the old and new capsule formulations of temazepam require wide bore needles which are both unpleasant and damaging? Is it that the intravenous injection of temazepam is itself associated with sufficient hedonic tone to account for its extensive intravenous abuse? Or is it that the injecting of the benzodiazepine is more directly associated with the concurrent use of another drug such as heroin? In one unpublished survey of the consumer appeal of different potentially injectable drugs, the majority of subjects disliked injecting temazepam whilst only one fifth of the subjects who injected actually rated it as a likeable activity (Farrell, Herrod & Strang, personal communication). Perera et al. (1987) had previously reported that a few of their subjects took benzodiazepine in order to boost the opiate "high", and this same reported boost had been described with oral diazepam (Kleber & Gold, 1978; Stitzer« ai, 1981) and with intravenous fiurazepam (Strang, 1984). But studies of such interactions remain equivocal with some investigators finding no evidence of an interaction (Preston et al., 1986). In a study of HIV risk related behaviour, misuse of temazepam was associated with higher risk taking (Klee et al, 1990). A possible explanation for this is that the more chaotic users were misusing temazepam but it is also quite possible that high serum levels of benzodiazepines result in amnesia and disinhibition with resultant risky behaviour. Finally it may be appropriate to consider the response of the pharmaceutical industry to this emerging problem with a major product in the pharmaceutical market. The response in 1989 was to re-formulate the soft capsules of temazepam into hard capsules with thick gel contents. The failure to withdraw stocks of the old 'soft eggs' led to the continued availability of the more injectable form for at least 12-18 months, which confused interpretation of the continued reports of intravenous abuse of temazepam. However the hard capsules are now also being injected—at least by some drug injectors. How are we to assess the success of the reformulation by the manufacturers? At first glance, the reformulation has been associated with an increased likelihood of harm amongst those who continued to inject the drug. However, when considered from a control perspective or a public health perspective, it may be that the intervention could be neutral or
even result in lower levels of overall harm to the community, even if there is increased harm accrued by the smaller number of injectors who continue to use the hard capsules. The consumer difference reported by Ruben and Morrison (1992) about the temazepam tablet needs further evaluation as there is variation in the relative injectability of different formulations. An objective opinion will only be formed once adequate data are available on the overall extent of injecting of the temazepam before and after the reformulation, and the associated morbidities. Sadly, in view of the lack of systematic collection of data in the UK, the opportunities for informed debate are few. A concluding caveat may be required. Has the full range of possible routes of administration yet been explored by the black market entrepreneur? Most recently there have been reports of the snorting of benzodiazepines (Sheehan et al., 1991). Is this a preferable channel to injecting or might this result in even greater levels of benzodiazepine abuse? The intravenous abuse of benzodiazepines has been taken up with great speed, suggesting that this unwelcome development was a discovery waiting to be made. Now that the wider abuse potential of benzodiazepines has been identified, we may find that it is now too late to wish that Pandora's box had not been opened.
JOHN STRANG
Getty Senior Lecturer and Deputy Director, Addiction Research Unit, National Addiction Centre, The Maudsley Hospital, Institute of Psychiatry, London SE5 8AF
NICHOLAS SEIVEWRIGHT
Senior Lecturer in Drug Dependence, University of Manchester Department of Psychiatry, Rawnsley Building, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL
MICHAEL FARRELL
Senior Registrar in Psychiatry, The Maudsley, London SE5 8AZ
Editorial References DRAKE, J, & BALLARD, R, (1988) Misuse of temazepam: manufacturer's response, British Medical Journal, 297, p, 1402, FARRELL, M , & STRANG, J, (1988) Misuse of temazepam, British Medical Journal, 297, p, 1402, FARRELL, M , & STRANG, J, (1992) Medicine in Europe: alcohol and drugs, British Medical Journal, 304, pp, 489-491, GRAHAME-SMITH, D , (1991) Misuse of temazepam, British Medical Journal, 302, p, 1210,
1375
PERERA, K . M , H , , TULLEY, M , & JENNER, F , A, (1987)
The use of benzodiazepines among drug addicts, British Journal of Addiction, 82, pp, 511-515, PRESTON, K , L . , GRIFFITHS, R, R,, CONE, E, J,, DARWIN,
W, D, & GORODETZKY, C, W, (1986) Diazepam and methadone blood levels following concurrent administration of diazepam and methandone. Drug and Alcohol Dependence, 18, pp, 195-202, RUBEN, S. & MORRISON, C. (1992) Temazepam misuse in a group of injecting drug users, British Journal of Addiction, 87, pp. 1387-1392,
GREEN, S,, GOLDBERG, D , , FRISCHER, M , & MCKHGANEY,
SAKOL, M , S,, STARK, C , & SYKES, R, (1989) Buprenor-
N, (1992) Triazolam as a substance of abuse among injecting drug users, British Journal of Addiction, 87, pp, 941-942.
phine and temazepam abuse by drug takers in Glasgow—an increase, British Journal of Addiction, 84, pp. 439-441,
GRIFFITHS, S, J, & ROTHWELL, J, G, (1990) Misuse
SEIVEWRIGHT, N , , DONMALL, M , & DALY, C , (1992)
of temazepam, Pharmaceutical Journal, 9th June, p, 675, HAMMERSLEY, R, H , , LAVHLLE, T , L , & FORSYTH, A, J, M,
(1990) Buprenorphine and temazepam abuse, Briris/i Journal of Addiction, 85, pp, 301-303, KAMINER, Y, & MODIA, I, (1984) Parenteral abuse of diazepam: a case report. Drug and Alcohol Dependence, 14, pp, 63-65, KLEBER, H . D , & GOLD, M , S, (1978) Use of psychotropic
drugs in treatment of methadone maintained narcotic addicts. Annals of the New York Academy of Science, 311, pp. 81-98, KLEE, H . , FAUGIER, J,, HAYES, C , BOULTON, T , &
MORRIS, J, (1990) AIDS-related risk behaviour, polydrug use and temazepam, British Journal of Addiction, 85, pp. 1125-1132, LAUNCHBURY, A, P , , MORTON, F , S. S. & LACY, J. E,
(1989) The development of temazepam gelthix. Manufacturing Chemist, 60, pp. 38-40,
Benzodiazepines in the illicit drugs scene—the UK picture and some treatment dilemmas, in: MCDERMOTT, P, & O'HARE, P , (Eds) Reducing Drug Related Harm: Recent Developments in Theory and Practice (London, Whurr Publishers) (in press), SHEEHAN, M , F , , SHEEHAN, D . V,, TORRES, A,, KOPPOLA,
A. & FRANCIS, E. (1991) Snorting benzodiazepines, American Journal of Drug and Alcohol Abuse, 17, pp. 457-468, STITZER, M . L , , GRIFFITHS, R. R,, MCLELLAN, A, T,, GRABOWSKI, J, & HAWTHORNE, J. W, (1981) Dia-
zepam use among methadone maintenance patients: patterns and dosages. Drug and Alcohol Dependence, 8, pp, 189-199, STRANG, J, (1984) Intravenous benzodiazepine abuse, British Medical Journal, 289, p, 964.
EDITORIAL
Intravenous and other novel abuses of benzodiazepines: the opening of Pandora's box? Intravenous abuse of benzodiazepines became a major problem in the UK during the late 1980s, when drug users began to inject the contents of temazepam capsules. Reports came from the North West of England and Scotland in particular but there were no published reports from other countries of this phenomenon. Our early clinical impressions are that this new form of drug taking behaviour has not been widely taken up by nationals of other countries who are part of the UK drug scene. However in view of the considerable movement of drug users between the UK and certain other European countries (perhaps most notably Ireland, Holland and Italy), it will be imponant to look for evidence on the timing and extent of dissemination of this new drug taking behaviour through the European community as state boundaries are steadily diminished (see Farrell & Strang, 1992). Intravenous abuse of benzodiazepines was first reported in 1984. There was a small outbreak of intravenous injection of flurazepam (Dalmane) by heroin addicts in Manchester, who reported that the intensity and duration of the heroin effect was thereby extended (Strang, 1984). In the same year there were reports from New Zealand and from Israel of single cases of the intravenous abuse of ampoule preparations of benzodiazepines (Kaminer & Modia, 1984). By 1986, Perera et al. (1987) reported that about a third of drug addicts at a combination of treatment agencies in Sheffield had previously been injecting benzodiazepines along with other drug use. However it was in the last few years of the 1980s that extensive intravenous abuse of benzodiazepines was seen—particularly in Scotland (Sakol et al., 1989; Hammersley et al., 1990) and North-West England (Seivewright, Donmall & Daly, 1992; Ruben & Morrison, 1992) as well as in London (Farrell & Strang, 1988). Temazepam became the benzodiazepine of choice for intravenous abuse—almost exclusively in the
form of the soft temazepam capsules which contained a clear liquid that was easily injectable and which were known among drug users as "soft eggs". Because of the scale of the problem consideration turned to whether temazepam should be withdrawn or should be the subject of greater controls, and the manufacturers undertook to alter the formulation of the capsules to a hard gel (like candlewax) in the hope that this would prevent further intravenous abuse (Drake & Ballard, 1988; Launchbury et ai, 1989) while one other manufacturer chose to convert it to tablet form. However, in the year or two following this re-formulation, there has been evidence of the considerable entrepreneurial nature of the injecting drug user, with reports of warming the new hard capsules in an oven or microwave until the gel contents are sufficiently soft to inject through a wide bore needle. It is likely that this is now associated with more severe physical complications (Griffiths & Rothwell, 1990; Grahame-Smith, 1991). Thus Ruben & Morrison (1992) report on the findings from a study of 23 temazepam injectors in Liverpool, and find that all their clients had at some time injected the old soft capsules, while 70% of them had injected the new hard capsules. Although 30% had injected the tablets, most reported that they would prefer to swallow the tablets; and only two of the subjects had ever injected the temazepam elixir. A larger-scale study by Seivewright et al. (1992), employing information from the North Western Regional Drug Misuse Database on all illicit drug users taking benzodiazepines during a 2-year period, confirmed the prominence of temazepam in the injected abuse of benzodiazepines but also detected some injecting of diazepam and nitrazepam. Also, prior to the banning of triazolam (Halcion) this benzodiazepine was being extensively injected by drug users in Glasgow (Green et al, 1992). Whilst we are unaware of any report in the literature, we have also encountered the intravenous abuse of the
1373
1374
Editorial
rapid onset short acting benzodiazepines midazolam and lorazepam by physicians who have access to this drug in ampoule form. Why should drug users bother to inject benzodiazepines, especially when both the old and new capsule formulations of temazepam require wide bore needles which are both unpleasant and damaging? Is it that the intravenous injection of temazepam is itself associated with sufficient hedonic tone to account for its extensive intravenous abuse? Or is it that the injecting of the benzodiazepine is more directly associated with the concurrent use of another drug such as heroin? In one unpublished survey of the consumer appeal of different potentially injectable drugs, the majority of subjects disliked injecting temazepam whilst only one fifth of the subjects who injected actually rated it as a likeable activity (Farrell, Herrod & Strang, personal communication). Perera et al. (1987) had previously reported that a few of their subjects took benzodiazepine in order to boost the opiate "high", and this same reported boost had been described with oral diazepam (Kleber & Gold, 1978; Stitzer« ai, 1981) and with intravenous fiurazepam (Strang, 1984). But studies of such interactions remain equivocal with some investigators finding no evidence of an interaction (Preston et al., 1986). In a study of HIV risk related behaviour, misuse of temazepam was associated with higher risk taking (Klee et al, 1990). A possible explanation for this is that the more chaotic users were misusing temazepam but it is also quite possible that high serum levels of benzodiazepines result in amnesia and disinhibition with resultant risky behaviour. Finally it may be appropriate to consider the response of the pharmaceutical industry to this emerging problem with a major product in the pharmaceutical market. The response in 1989 was to re-formulate the soft capsules of temazepam into hard capsules with thick gel contents. The failure to withdraw stocks of the old 'soft eggs' led to the continued availability of the more injectable form for at least 12-18 months, which confused interpretation of the continued reports of intravenous abuse of temazepam. However the hard capsules are now also being injected—at least by some drug injectors. How are we to assess the success of the reformulation by the manufacturers? At first glance, the reformulation has been associated with an increased likelihood of harm amongst those who continued to inject the drug. However, when considered from a control perspective or a public health perspective, it may be that the intervention could be neutral or
even result in lower levels of overall harm to the community, even if there is increased harm accrued by the smaller number of injectors who continue to use the hard capsules. The consumer difference reported by Ruben and Morrison (1992) about the temazepam tablet needs further evaluation as there is variation in the relative injectability of different formulations. An objective opinion will only be formed once adequate data are available on the overall extent of injecting of the temazepam before and after the reformulation, and the associated morbidities. Sadly, in view of the lack of systematic collection of data in the UK, the opportunities for informed debate are few. A concluding caveat may be required. Has the full range of possible routes of administration yet been explored by the black market entrepreneur? Most recently there have been reports of the snorting of benzodiazepines (Sheehan et al., 1991). Is this a preferable channel to injecting or might this result in even greater levels of benzodiazepine abuse? The intravenous abuse of benzodiazepines has been taken up with great speed, suggesting that this unwelcome development was a discovery waiting to be made. Now that the wider abuse potential of benzodiazepines has been identified, we may find that it is now too late to wish that Pandora's box had not been opened.
JOHN STRANG
Getty Senior Lecturer and Deputy Director, Addiction Research Unit, National Addiction Centre, The Maudsley Hospital, Institute of Psychiatry, London SE5 8AF
NICHOLAS SEIVEWRIGHT
Senior Lecturer in Drug Dependence, University of Manchester Department of Psychiatry, Rawnsley Building, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL
MICHAEL FARRELL
Senior Registrar in Psychiatry, The Maudsley, London SE5 8AZ
Editorial References DRAKE, J, & BALLARD, R, (1988) Misuse of temazepam: manufacturer's response, British Medical Journal, 297, p, 1402, FARRELL, M , & STRANG, J, (1988) Misuse of temazepam, British Medical Journal, 297, p, 1402, FARRELL, M , & STRANG, J, (1992) Medicine in Europe: alcohol and drugs, British Medical Journal, 304, pp, 489-491, GRAHAME-SMITH, D , (1991) Misuse of temazepam, British Medical Journal, 302, p, 1210,
1375
PERERA, K . M , H , , TULLEY, M , & JENNER, F , A, (1987)
The use of benzodiazepines among drug addicts, British Journal of Addiction, 82, pp, 511-515, PRESTON, K , L . , GRIFFITHS, R, R,, CONE, E, J,, DARWIN,
W, D, & GORODETZKY, C, W, (1986) Diazepam and methadone blood levels following concurrent administration of diazepam and methandone. Drug and Alcohol Dependence, 18, pp, 195-202, RUBEN, S. & MORRISON, C. (1992) Temazepam misuse in a group of injecting drug users, British Journal of Addiction, 87, pp. 1387-1392,
GREEN, S,, GOLDBERG, D , , FRISCHER, M , & MCKHGANEY,
SAKOL, M , S,, STARK, C , & SYKES, R, (1989) Buprenor-
N, (1992) Triazolam as a substance of abuse among injecting drug users, British Journal of Addiction, 87, pp, 941-942.
phine and temazepam abuse by drug takers in Glasgow—an increase, British Journal of Addiction, 84, pp. 439-441,
GRIFFITHS, S, J, & ROTHWELL, J, G, (1990) Misuse
SEIVEWRIGHT, N , , DONMALL, M , & DALY, C , (1992)
of temazepam, Pharmaceutical Journal, 9th June, p, 675, HAMMERSLEY, R, H , , LAVHLLE, T , L , & FORSYTH, A, J, M,
(1990) Buprenorphine and temazepam abuse, Briris/i Journal of Addiction, 85, pp, 301-303, KAMINER, Y, & MODIA, I, (1984) Parenteral abuse of diazepam: a case report. Drug and Alcohol Dependence, 14, pp, 63-65, KLEBER, H . D , & GOLD, M , S, (1978) Use of psychotropic
drugs in treatment of methadone maintained narcotic addicts. Annals of the New York Academy of Science, 311, pp. 81-98, KLEE, H . , FAUGIER, J,, HAYES, C , BOULTON, T , &
MORRIS, J, (1990) AIDS-related risk behaviour, polydrug use and temazepam, British Journal of Addiction, 85, pp. 1125-1132, LAUNCHBURY, A, P , , MORTON, F , S. S. & LACY, J. E,
(1989) The development of temazepam gelthix. Manufacturing Chemist, 60, pp. 38-40,
Benzodiazepines in the illicit drugs scene—the UK picture and some treatment dilemmas, in: MCDERMOTT, P, & O'HARE, P , (Eds) Reducing Drug Related Harm: Recent Developments in Theory and Practice (London, Whurr Publishers) (in press), SHEEHAN, M , F , , SHEEHAN, D . V,, TORRES, A,, KOPPOLA,
A. & FRANCIS, E. (1991) Snorting benzodiazepines, American Journal of Drug and Alcohol Abuse, 17, pp. 457-468, STITZER, M . L , , GRIFFITHS, R. R,, MCLELLAN, A, T,, GRABOWSKI, J, & HAWTHORNE, J. W, (1981) Dia-
zepam use among methadone maintenance patients: patterns and dosages. Drug and Alcohol Dependence, 8, pp, 189-199, STRANG, J, (1984) Intravenous benzodiazepine abuse, British Medical Journal, 289, p, 964.
