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Professor C Heather Ashton, DM, FRCP
First published in
Drugs and Dependence,
Harwood Academic Publishers (2002)
London & New York
The Ashton Manual · Professor Ashton's Main Page
Benzodiazepine abuse is a growing problem and carries serious risks to health and society.
Benzodiazepines are commonly used by polydrug abusers, alcoholics and sometimes as primary recreational drugs.
People who abuse benzodiazepines often take very large doses orally, by injection or by snorting.
Benzodiazepine use leads to dependence and a withdrawal syndrome which may include convulsions and psychosis.
Further research is needed on the optimal short-term and long-term management of benzodiazepine abuse.
The primary source of illicit benzodiazepines is from doctors' prescriptions.
Benzodiazepines are consumed by two main populations with different characteristics: (1) low-dose prescribed benzodiazepine users and (2) high-dose, non-prescribed benzodiazepine abusers. This paper is concerned with the second group and also with a smaller intermediate group of high-dose prescribed users, some of whom become involved in illicit use. While the prevalence of prescribed dose benzodiazepine use is declining, that of illicit use has been rising steeply since the 1980s and now presents a major health problem.
Who abuses benzodiazepines?
Benzodiazepines are taken for recreational purposes by increasing numbers of drug abusers (Drug and Therapeutics Bulletin 1997). The true prevalence is not known but benzodiazepines commonly form part of a polysubstance abuse pattern; for example, at the Liverpool Drug Dependency Unit, 44 per cent of a random sample of 100 injecting drug users entering treatment were also using benzodiazepines (Shaw et al. 1994). Benzodiazepines have been taken by opiate, amphetamine and cocaine users worldwide for about 20 years and are now creeping into the teenage 'rave' scene amongst users of MDMA (Ecstasy) and LSD (Strang et al. 1993). Various intoxicating drug- benzodiazepine combinations such as 'Tem-Tems' (buprenorphine and temazepam) and temazepam and lager are popular, particularly in the north of England and Scotland. Indeed. benzodiazepines are the single most misused category of drug in Scotland (Robertson and Ronald 1992). A contemporary youth craze in Glasgow is to ride the buses all day 'high' and 'wobbling' on oral temazepam, fortified by high-strength lager and/or cannabis (Parrott 1995).
To begin with, as with alcohol, smoking and cannabis, some of these youths become involved in recreational benzodiazepine use at 13 and 14 years of age (Wilkinson 1997; Pedersen and Lavik 1991). The age range of benzodiazepine abusers surveyed in various British addiction clinics was 19-31 and the male-to-female ratio was between 2.8 : 1 and 2.1 : 1 (Strang et al. 1994; Ruben and Morrison 1992).
Second, benzodiazepine abuse is also common in alcoholics. Around 30-50 per cent of alcoholics attending for detoxification also use non-prescribed benzodiazepines (Borg et al. 1993). Third, some people (again an unknown number) use benzodiazepines as their primary recreational drug, typically bingeing intermittently on high doses (Strang et al. 1993).
It has been claimed that benzodiazepine abuse is 'of little or no consequence' in the vast population of prescribed benzodiazepine users (Woods et al. 1988). However, a proportion of prescribed users do escalate dosage, take the drugs for hedonic effects and enter into the illicit drug scene (see Case 1). It is important to remember that substance misuse can occur across a wide spectrum of ages and not to allow prejudice to hinder older people's diagnosis and treatment (Greenwood 2000).
Case 1. 'The one that got away': escalation from prescribed to street use of temazepam
Peter is the youngest of nine siblings. His mother is alcoholic; his father is unknown. He was taken into care at the age of 2 and brought up in a series of children's homes. He was said to be a quiet and sensitive child who was always terrified of violence. When he was about 13, following an incident with one of the teachers at a boarding school, Peter 'discovered' he was gay.
In his 20s, Peter was involved, as a passenger on a motor cycle, in a road traffic accident. He sustained serious injuries including fractures of his arm and collar bone and compound fractures in his leg. He spent several months in an orthopaedic ward and suffered complications including infection, non-healing of the leg fractures, bone-grafting, insertion of pins and plates, etc.
In hospital, he experienced 'dreadful panic attacks and fears'. He received no psychological treatment or counselling of any kind but was prescribed temazepam and dihydrocodeine. At first, the dosage of temazepam was 20mg nocte for sleep, but was increased to 60mg in hospital. After discharge, he continued to receive temazepam from his general practitioner because of panics and insomnia and the dosage was increased over a period of years until he was taking 80mg temazepam each night and 40-80mg during the day. He felt he had to take the temazepam, otherwise he got panicky and frightened, suffered pains in the stomach and was unable to sleep. After taking temazepam, he stated that he felt 'all nice and calm for a time, but then the panics and fear return'.
At the age of 30, Peter was removed from his GP's practice when it was discovered that he had altered a prescription for temazepam. He was taken on by another GP but later attended a series of GPs, obtaining ever larger prescriptions of temazepam and dihydrocodeine from each, often presenting with stories that his last prescription had been lost or stolen. He also attempted to obtain supplies of temazepam from the hospital pharmacy, the orthopaedic clinic and the casualty department, sometimes wearing a white tunic and name badge, giving the impression he was a nurse.
When he could no longer satisfy his need from prescriptions, Peter took to obtaining temazepam on the street, taking large and irregular doses by mouth. His behaviour became chaotic and he was twice sent to prison for credit card frauds. In prison, he was terrified and made bizarre claims about his health: that he was on renal dialysis. that he was HIV-positive, that he expected to have his leg amputated through disease. He was able to obtain temazepam in prison from other prisoners.
After discharge, and now aged 34, Peter agreed to enter a detoxification centre and apparently made a real effort to stop the temazepam. Initially, he made good progress. The temazepam was replaced with decreasing doses of diazepam and following his admission he continued for some months to attend the centre weekly as an outpatient. Withdrawal symptoms consisted of increasing anxiety, panics and stomach pains. He took no other drugs, as confirmed by weekly urine tests, and very little alcohol. He had never injected any drugs. Unfortunately, when down to only 4mg diazepam daily, he 'broke his contract' and obtained some temazepam on the street. This resulted in immediate discharge from the detoxification centre and no further medical supervision.
When last heard of, Peter, aged 35, was again buying temazepam illicitly and was involved in a court case for obtaining money on false pretences.
Initially prescribed benzodiazepines, if not carefully supervised, can lead to escalation of dosage and entry into the illicit drug scene in vulnerable individuals.
Strict contract methods are not always appropriate for benzodiazepine-dependent patients. If Peter had been given another chance by the drug clinic (having come so far in his treatment), he might have been able to break his dependence.
The possibility of a maintenance dose of diazepam, rather than complete withdrawal, could perhaps have been considered in this case.
Why abuse benzodiazepines?
The most common reason given by polydrug abusers for taking benzodiazepines is that they enhance and often prolong the 'high' obtained from other drugs including heroin, other opioids, cocaine and amphetamines. Benzodiazepines are mainly taken along with the primary drug, but sometimes used alone as an alternative or in times of shortage. Second, benzodiazepines alleviate withdrawal effects, including anxiety and insomnia, when supplies of other drugs are limited. Users of stimulants including cocaine, amphetamines and Ecstasy also take benzodiazepines as 'downers' to overcome the effects of their 'uppers' and to combat hangover effects. In alcoholics, benzodiazepines are used partly to alleviate the anxiety associated with chronic alcohol use, but also because the mixture of alcohol and benzodiazepines produces a hedonic effect. Finally, benzodiazepines, when taken alone in high doses and particularly when injected, can themselves provide a 'kick'.
Although benzodiazepines in therapeutic doses have been claimed to have little abuse potential compared with other drugs of abuse (Warburton 1988), their abuse liability may vary along the dose-response curve, becoming greater at doses above the therapeutic range (Strang el al. 1993). Diazepam, alprazolam, lorazepam and triazolam have all been shown in clinical laboratory studies to possess abuse liability. Alprazolam 1mg was comparable with 10mg d-amphetamine in scores for 'elation' and 'abuse potential' in experienced but non-dependent users. 'High' ratings for oxazepam and chlordiazepoxide were lower than for other benzodiazepines (Zawertailo et al. 1995; Griffiths and Wolf 1990). The non-benzodiazepine hypnotic zolpidem produced 'drug liking' scores similar to triazolam (Evans et al. 1990); this drug and the similar non-benzodiazepine hypnotic zopiclone may also have abuse potential.
Which benzodiazepines are abused?
Nearly all the available benzodiazepines have been abused (Table 1). In general, those which enter the brain rapidly (e.g. diazepam) are preferred to those which are absorbed more slowly (e.g. oxazepam) (Griffiths et al. 1984). However, preferred drugs vary between countries and over time depending on their availability and reputation in the illicit drug world. In the UK, temazepam has superseded diazepam, nitrazepam and flurazepam as the most commonly abused benzodiazepine, in line with the increase in temazepam prescriptions and possibly (until recently) because of the availability of easily injectable forms of temazepam from capsules, 'jellies', 'eggs' (Stark et al. 1987). In the US, flunitrazepam tablets ('roaches') have become popular, partly because of diversion of supplies across the Mexican border (Roche Pharmaceuticals report 1996). Potent benzodiazepines such as triazolam (no longer available in the UK), alprazolam (widely prescribed in the US) and lorazepam have also achieved popularity among benzodiazepine abusers.
Table 1. Some benzodiazepines used recreationally (UK, Europe and USA)
Generic name Brand name (UK) Potency
Alprazolam Xanax 0.5 Bromazepam Lexotan 5 Chlordiazepoxide Librium 25 Diazepam Valium 10 Flunitrazepam Rohypnol 1 Flurazepam Dalmane 15-30 Ketazolam1 Anxon 15-30 Lorazepam Ativan 1 Medazepam1 Nobrium 10 Nitrazepam Mogadon 10 Oxazepam Serenid 20 Prazepam1 Centrax 15 Temazepam Normison, Euhypnos 20 Triazolam1 Halcion 0.5 (Zopiclone)2 Zimovane) (15) (Zolpidem)2 (Stilnoct) (20)
- No longer in British National Formulary.
- Non-benzodiazepine hypnotics with similar actions to benzodiazepines;
may have abuse liability.
Routes of administration and dosage
Benzodiazepines can be taken by mouth, inhaled as snuff or injected. The commonest practice is oral ingestion but, recently, novel forms of administration have been used. Intranasal 'snorting' of powdered flunitrazepam is described (McNamee 1994) and this method can be used for other benzodiazepines and accompanying drugs such as buprenorphine (Strang 1991). However, the main alternative to the oral route is intravenous injection, reported first for flurazepam (Strang 1984) and now increasingly practised in the UK. Diazepam and other benzodiazepines have been injected but at present temazepam is mainly involved. Strang et al. (1994) conducted a questionnaire survey of subjects attending drug clinics in seven British cities. Of 208 subjects returning the questionnaire, 186 had used benzodiazepines and 103 had injected them intravenously. Temazepam was the most commonly used and had been injected from preparations of capsules, tablets and syrup. Other injected benzodiazepines were diazepam, lorazepam, triazolam, nitrazepam and chlordiazepoxide. Attempts to discourage temazepam injections by substituting liquid with gel-filled capsules and by introducing tablets and elixir appear to be unsuccessful since the gel can be warmed to a liquid consistency, the tablets can be dissolved in warm water (Carnwath 1993) and the elixir diluted to provide injectable solutions.
Doses used by recreational benzodiazepine users are usually far in excess of those recommended for therapeutic purposes. Oral and intravenous doses of 100-150mg temazepam and diazepam are common (Robertson and Ronald 1992) while some youths may take up to fifty tablets of temazepam (500-1,000mg) for hedonic effects (Parrott 1995). A patient described by Cole and Chiarello (1990) had been taking 10mg alprazolam several times a day for its euphoriant actions. In twenty-three intravenous temazepam abusers, the mean daily dose injected was 610mg; the maximum was 3,600mg (Ruben and Morrison 1992). Farrell and Strang (1988) reported a polydrug user who had been injecting the contents of 30-90 temazepam (20mg) capsules daily. Subjects become remarkably tolerant to the sedative/hypnotic effects of benzodiazepines and the latter patient had no major alterations in consciousness (see also Case 2).
Case 2. Inappropriate benzodiazepine prescribing after alcohol detoxification
Despite her name, Joy was an unloved child. Her mother told her: 'The biggest mistake you made in life was being born.' She was physically abused by her stepfather and raped by a gang of youths when she was 16. She ran away from home and worked for some years in hotels. By the age of 21, she had a serious alcohol problem. She was rarely sober, suffered from blackouts and blood tests showed early liver damage.
Eventually, aged 24, Joy entered a clinic for alcohol detoxification. followed by prolonged psychotherapy and counselling. She was successful in stopping drinking, but, because of severe anxiety, insomnia and social phobia, the benzodiazepines initially prescribed during alcohol detoxification were continued by the psychiatrist and the dosage increased. When referred to a tranquilliser withdrawal clinic 2 years later, Joy was taking prescribed doses of 240mg oxazepam and 240mg diazepam daily - amounting to forty-eight tablets each day. In spite of this dosage, she was able to ride a bicycle and attend a writing course, but still suffered from anxiety and insomnia and seemed to exist in a permanent daze.
Nevertheless, she was keen to withdraw from benzodiazepines as they were dominating her life. Her course over the next 3 years was stormy. She made repeated suicide gestures with overdoses and with self-injury. She became depressed and the slightest attempts at dosage reduction were followed by panic attacks and threats of suicide. After four planned 2-week admissions to hospital for moderate dosage reduction, she eventually became drug-free. Withdrawal symptoms, which were severe, included depersonalisation, tremor, muscle pain and stiffness, palpitations, blurred vision, nightmares and increased aggression. She received the SSRI sertraline during the last 6 months of withdrawal but this was later tapered off and stopped. A psychiatric assessment performed by a different psychiatrist at that time suggested borderline personality disorder.
One year after withdrawal, Joy, now aged 30, is no longer depressed, sleeps well and has lost much of her anxiety although she still suffers from social phobia for which she is receiving cognitive therapy. Neuropsychological testing revealed some frontal lobe dysfunction which was attributed to the heavy alcohol/benzodiazepine use, but Joy is now actively seeking employment.
Prescriptions for benzodiazepines during alcohol detoxification can lead to benzodiazepine dependence.
Chronic use of benzodiazepines can lead to a remarkable degree of tolerance to their hypnotic, anxiolytic and ataxic effects.
Patients who have taken large doses of benzodiazepines for several years can be withdrawn if sufficiently motivated and carefully handled, and their psychological state may improve.
Patients dependent on large prescribed doses of benzodiazepines do not necessarily progress to illicit use.
To treat someone with multiple problems successfully, it can be valuable to take a 'long' view. How would you take account of Joy's early experience of family turmoil, her past use of alcohol, her vulnerability to depression and especially her previous experience of frightening symptoms during drug withdrawal (Moos et al. 2002)?
Sources of benzodiazepines
Benzodiazepines are widely available on the Street and are cheap (about £1 a tablet in Newcastle-upon-Tyne at present). A major source is from general practitioners' prescriptions. Some users attend several practitioners using false names and temporary patient status; others obtain supplies from friends or patients (often elderly people) who exaggerate their needs to their doctors and sell off the excess (Ruben and Morrison 1992). Some children obtain them from prescriptions for their parents (Pedersen and Lavik 1991). Benzodiazepines are also obtained by theft from health centres or retail chemists, and large amounts have been stolen from pharmaceutical warehouses. In 1996, 29,000 temazepam tablets were known to be stolen from such a warehouse in Newcastle-upon-Tyne and 30,000 diazepam tablets from a similar source in Cumbria (Newcastle police information).
Health risks and social consequences
Some hazards associated with high-dose benzodiazepine abuse are shown in Table 2. These risks have probably been underestimated. Benzodiazepines are generally believed to be safe in overdose, but deaths following self-poisoning do occur, even when the drugs are taken alone, and a fatal outcome from overdose is more likely with flurazepam and temazepam than with other benzodiazepines (Serfaty and Masterton 1993). Benzodiazepines also add to the respiratory depression caused by other drugs: the combination of temazepam with injected opioids (e.g. buprenorphine) is said to cause approximately 100 deaths a year in Glasgow alone (Parrott 1995).
Benzodiazepine use increases the risk of road traffic accidents, especially when driving under the influence of higher doses (Bandolier 1998).
Mental disturbances caused by benzodiazepines include blackouts and memory loss, aggression, violence and chaotic behaviour associated with paranoia. Over a third of intravenous temazepam users surveyed by Ruben and Morrison (1992) used the drug 'to give confidence to engage in criminal activity' and there is a high incidence of illicit benzodiazepine use in remand prisoners (Mason et al. 1997). The loss of judgement and amnesia caused by benzodiazepines may also be associated with high-risk sexual behaviour including casual sexual contacts and unprotected sexual activity which appears to be a particular feature of temazepam abusers (Klee et al. 1990). Cognitive impairment, including deficits in learning and memory and in sustained attention, has been shown in many studies of long-term benzodiazepine users, even at therapeutic dose levels, and may persist after benzodiazepine withdrawal (Golombok et al. 1988; Tata et al. 1994; Gorenstein et al. 1995). Risks of maternal use during pregnancy include foetal developmental abnormalities (Laegreid et al. 1992), 'floppy infant syndrome' (Stirrat 1976) and a neonatal benzodiazepine withdrawal syndrome (Levy and Spino 1993).
Regular use of benzodiazepines, especially in high doses, readily leads to physical dependence, evidenced by withdrawal symptoms on sudden cessation (see below).
Many of the risks for injecting benzodiazepine users are common to self-injectors of all types of drugs (Table 2). It has been claimed that the use of temazepam is especially associated with the practice of sharing injecting equipment, thus increasing the risk of HIV infection and hepatitis (Klee et al. 1990). In addition, benzodiazepines, particularly temazepam (whether obtained from capsules, tablets or elixir), are extremely irritating and likely to cause tissue damage. When arm veins become occluded due to local irritation, users may proceed to injecting in the groin, where inadvertent intra-arterial injection has led to amputation. The severity of the addiction which can develop to temazepam is illustrated by the case of a temazepam injector who needed his leg amputated but was later admitted for a second amputation since he had continued injecting into his remaining leg (Parrott 1995). A second subject, following a leg amputation, injected temazepam gel into his eye, resulting in bilateral blindness (Figure 1).
Table 2. Health and social hazards of benzodiazepine abuse
of IV use
Fatalities due to overdose (particularly in combination with opioids) Thrombophlebitis Blackouts and memory loss Deep and superficial abscesses Paranoia Deep vein thrombosis Violence and criminal behaviour Pulmonary microembolism Risk-taking sexual behaviour Rhabdomyolysis, tissue necrosis Foetal and neonatal risks if taken in pregnancy Gangrene, requiring amputation (usually due to inadvertent intra-arterial injection) Dependence Hepatitis B and C Withdrawal seizures HIV infection
Click for larger image
Figure 1. A complication of temazepam injection. A man aged 40 who misused drugs and had had a leg amputated after ischaemic damage from intra-arterial injections presented with blindness of recent onset. He was blind in both eyes. The left eye was ophthalmoplegic, with corneal clouding and no pupillary reflexes. This was the result of his injecting gel temazepam into the inner canthus. This substance is known to cause vascular occlusion (with permission from Thompson et al. 1993).
Dependence and withdrawal symptoms
Dependence and a withdrawal syndrome has been well described in chronic benzodiazepine users over a range of therapeutic and supratherapeutic doses. There is less information on dependence and withdrawal in benzodiazepine abusers, who sometimes use the drugs intermittently or in binges and who often use other drugs. However, in a careful study, Seivewright and Dougal (1993) recorded symptoms in thirty-three polydrug users who for various reasons had abruptly stopped their benzodiazepines but not their other drugs. The results, shown in Table 3, clearly showed that the high dose abusers experienced a profile of withdrawal symptoms similar to, though more severe than that described in low-dose users (Tyrer et al. 1990). The severity of symptoms was significantly related to the size of previous dosage in the abusers. It was notable in this study that the abusers had only stopped their benzodiazepines for 2-3 days, probably before withdrawal symptoms had reached their peak. Even so, four of the subjects reported epileptic fits and there were sixteen reports of hallucinations and/or paranoid ideation. These severe symptoms may be especially common in high-dose abusers and have been reported in other studies (Stark et al. 1987; Busto and Sellers 1991; Scott 1990). Seivewright and Dougal (1993) noted that benzodiazepine abusers reported extreme antisocial behaviours in obtaining continued supplies, avoiding disruption of supplies and in drug-seeking behaviour when withdrawing. The severity and specificity of the benzodiazepine withdrawal syndrome was typified by one patient's remark: 'I'd rather withdraw off heroin any day. If I was withdrawing from benzos you could offer me a gram of heroin or just 20mg of diazepam and I'd take the diazepam every time - I've never been so frightened in my life' (Seivewright and Dougal 1993: 20).
Table 3. Symptoms reported during abrupt benzodiazepine
withdrawal in thirty-three high-dose
benzodiazepine and polydrug abusers
Apparent movement of still objects
Pins and needles
The incidence of withdrawal symptoms in benzodiazepine abusers is not known and deserves further study. Clinical observations suggest that some polydrug users, like some prescribed dose patients, can withdraw benzodiazepines without difficulty, especially polydrug users maintained on methadone. Regular daily benzodiazepine users are more likely than intermittent users to develop symptoms (Williams et al. 1996). The duration of withdrawal symptoms is also not clear; acute symptoms in the first few weeks may merge into prolonged anxiety and insomnia which may continue for weeks or months (Smith and Landry 1990).
Management of benzodiazepine withdrawal
Withdrawal methods for long-term prescribed therapeutic dose benzodiazepine users are well established and consist mainly of slow dosage tapering over weeks or months in an outpatient setting, combined with psychological support (Lader and Morton 1991: Ashton 1994). These methods are not entirely appropriate for high-dose benzodiazepine abusers. First, benzodiazepine abuse is often part of polydrug abuse and attention also has to be given to the primary drug. Second, a long period of outpatient dosage tapering is unlikely to be adhered to since additional benzodiazepines may be obtained illicitly. On the other hand, as described above, benzodiazepine abusers commonly use high doses and may he at particular risk of severe withdrawal symptoms including epileptic fits if the drugs are stopped abruptly. Therefore, a moderately rapid, controlled schedule of detoxification in an inpatient unit is preferable.
Several methods have been described. The most common technique is substitution of a slowly eliminated benzodiazepine (usually diazepam) for the abused drug (commonly, a shorter acting drug such as temazepam) followed by dosage tapering over 2 or more weeks (Harrison et al. 1984; Scott 1990; Williams et al. 1996). Some workers (Ries et al. 1989) have advocated the use of carbamazepine as an anticonvulsant in benzodiazepine withdrawal, though its ability to prevent other withdrawal symptoms is doubtful (Ashton 1994). A third method of detoxification recommended in some centres, particularly in the US, is phenobarbitone substitution (Smith and Landry 1990).
Longer term outpatient management of benzodiazepine abusers is problematic. Some centres have found benzodiazepines to be helpful in reducing overall illicit drug use and injecting (Greenwood 1996), and, occasionally, benzodiazepine use may be adaptive, allowing the opiate abusers to manage on a smaller dose of methadone (Strang et al. 1993). However, the overwhelming advice is that it is generally inadvisable to prescribe benzodiazepines as maintenance treatment for drug misusers (Smith and Landry 1990; Department of Health 1991, 1999; Seivewright and Dougal 1992; Seivewright et al. 1993) or alcoholics (see Case 2). A possible approach for opiate addicted patients who use benzodiazepines to increase the euphoriant effects of methadone is to alter the methadone treatment so that individuals feel less need for benzodiazepines (Seivewright et al. 1993). Alternatively, avoidance of benzodiazepines can form part of a contract for receiving a higher dose of methadone or other rewards (Stitzer et al. 1982). Nevertheless, it is clear that many benzodiazepine abusers, like prescribed users, suffer from anxiety, insomnia and depression. It may be that a flexible, individually tailored approach to benzodiazepine and other psychotropic drug prescribing, as well as psychological methods where practical, carried out in specialist centres, would bring the best results.
Unfortunately, in the present climate the rate of relapse after short-term benzodiazepine detoxification may be as high as it is with opiate detoxification (i.e. over 90 per cent after 1 year: Seivewright et al. 1993), and further experience is needed to establish the optimal long-term management. Meanwhile, efforts to reduce inappropriate prescribing of benzodiazepines both in general practice (Buetow et al. 1996) and in hospital (Zisselman et al. 1996) may help to decrease the quantity of benzodiazepines at present spilling into the illicit drug market.
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