Benzodiazepines are widely used in medicine to treat anxiety and insomnia. These are synthetic substances normally seen as pharmaceutically-manufactured tablets, capsules and occasionally as injectables. They act as depressants of the central nervous system (CNS). Chlordiazepoxide (Librium®) was the first to be synthesised in 1957 and introduced into medicine in 1961. Benzodiazepines are under international control.
The fully systematic (IUPAC) name for the nucleus of the benzodiazepine group (CAS 12794-10-4) is 2,3-diazabicyclo[5.4.0]undeca-3,5,7,9,11pentaene. The different drugs have varying substituents on this basic skeleton.
Diazepam (CAS 439-14-5) is one of the best known benzodiazepines (Valium®). According to IUPAC, the fully systematic name is 9-chloro-2-methyl-6-phenyl-2,5-diazabicyclo[5.4.0]undeca-5,8, 10,12-tetraen-3-one or 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one.
Molecular structure: Diazepam
Molecular formula: C16H13CIN2O
Molecular weight: 284.7
Tablets, capsules, injectables (e.g. diazepam, lorazepam, midazolam), suppositories.
Benzodiazepines are a group of CNS depressants which induce feelings of calm (anxiolysis), drowsiness and sleep. They act by facilitating the binding of the inhibitory neurotransmitter GABA at various GABA receptors throughout the CNS. Because they have a lower tendency to cause a potentially fatal CNS depression compared to earlier drugs such as barbiturates, benzodiazepines are widely used in medicine for the treatment of anxiety (anxiolytics) and insomnia (sedative/hypnotics), as well as other psychological conditions such as panic attacks and panic disorders. There is no clear division between anxiolytics and hypnotics, since most anxiolytics will induce sleep if taken at night and most hypnotics will sedate when taken during the day.
Different benzodiazepines vary in the rate in which they are metabolised to pharmacologically active forms and particularly in their half-lives (see Table 1): short-acting drugs have a half-life of less than 24 hours e.g. midazolam; intermediate-acting compounds such as nitrazepam have half-lives greater than 24 hours, whereas long-acting compounds such as diazepam have half-lives greater than 48 hours. Such half-lives vary between individuals, and the elderly tend to eliminate these drugs much more slowly. They are thus more at risk from the side-effects which include drowsiness, ataxia (staggering gait), mental confusion, impaired judgement and anterograde amnesia. There is a significantly increased risk of adverse events in the elderly such as falls, diminished cognitive function and driving impairment, although the latter is not confined to the elderly. The European prevalence studies show that, excluding alcohol, benzodiazepines are along with cannabis the psychoactive substances most prevalent in the driving population. Experimental studies show that these drugs impair driving ability and when alcohol is also used, the risk of being involved in or responsible for a road accident is significantly increased.
Benzodiazepine intoxication can be associated with behavioural disinhibition, potentially resulting in hostile or aggressive behaviour. The effect is perhaps most common when benzodiazepines are taken in combination with alcohol. The combined use of alcohol and benzodiazepines also increases the risk of a fatal overdose because both act as CNS depressants. A similar fatal interaction can occur when opiates are taken with benzodiazepines as part of a pattern of polydrug use. A significant number of problem drug users swallow, ‘snort’ or inject high doses of benzodiazepines to enhance the euphoriant effects of opiates or to minimise unpleasant effects of psychostimulants. The EMCDDA’s Annual report on the state of the drugs problem in Europe highlights the fact that concomitant use of benzodiazepines and opiates is a major risk factor in drug-related deaths. Apart from the increased risk of fatal overdoses, the usual injection-specific diseases such as tissue damage, gangrene and transmission of HIV and Hepatitis C also occur if the drugs are injected.
There is also the risk of cross-dependence developing to benzodiazepines. Medically, benzodiazepines should only be used for the short-term relief of anxiety or insomnia which is severe and disabling. This is because tolerance and dependence can occur just weeks after use has commenced. Withdrawal signs and symptoms can be classified as major or minor, like those of the alcohol syndrome. According to that classification, minor symptoms include anxiety, insomnia and nightmares. Major symptoms include perceptual disturbances, psychosis, hyperpyrexia and life-threatening convulsions.
Table 1: List of benzodiazepines under international control
|Name||Duration of action||Major trade name||CAS No|
Flunitrazepam (Rohypnol®) is the benzodiazepine most commonly linked by media reports to drug-facilitated sexual assaults, more commonly referred to as ‘date rape’. However, forensic toxicology shows that only a very small number of such assaults actually involve the use of flunitrazepam. A number of studies, cited in the EMCDDA Technical data sheet on Sexual assaults facilitated by drugs or alcohol (EMCDDA 2008), suggest that alcohol and other benzodiazepines are an underestimated problem in such cases. Other work has identified covert use of benzodiazepines to facilitate theft. Forensic analysis cannot unequivocally distinguish between the deliberately covert ‘spiking’ of drinks, and voluntary or prescribed use of benzodiazepines, however some forms of hair analysis can distinguish regular long-term use from a single ingestion.
The synthesis of benzodiazepines is performed by the pharmaceutical and chemical industry, often using patented methods. While the vast bulk of benzodiazepines are manufactured pharmaceutically, information on Internet websites describes a series of routes to producing diazepam using 5-chloro-N-methyl-isatoicanhydride and 2-amino-5-chlorobenzophenone as precursors.
Benzodiazepines are usually swallowed as tablets but can be injected for both medical and non-medical purposes and there are some reports of intranasal (snorting) misuse.
Numerous synonyms and proprietary names exist for the 35 benzodiazepines under international control. When originally introduced, they were misleadingly referred to as ‘minor’ tranquillisers to distinguish them from ‘major’ tranquillisers used as anti-psychotics.
Users’ terms include: benzos, blues/blueys, tranx, roche’s, mother's little helpers, duck eggs (temazepam), roofies (Rohypnol®), V’s, and many others.
Most benzodiazepines including diazepam give an orange colour with a mixture of formaldehyde and concentrated sulphuric acid when heated at 100° C for 1 minute (this is a variant of the Marquis test, where heat is applied). Flunitrazepam gives a pink colour. Benzodiazepines also give a reddish-purple or pink colour in the Zimmerman test. The mass spectrum for diazepam shows a major ion at m/z = 256 and others at 283, 284, 285, 257, 255, 258 and 286. The major ions for temazepam (molecular weight 300.7) are at 271, 273, 300 and 272, whereas those for flunitrazepam (molecular weight 313.28) are at 285, 312, 313 and 286. Using gas chromatography–mass spectrometry the limit of detection for diazepam in blood is 0.2–20 µg/L. With high performance liquid chromatography–mass spectrometry the limit in serum or urine is 2 µg/L.
Typical therapeutic concentrations are 0.1–1.0 mg/L, while toxic effects occur at levels of more than 1.5 mg/L. Fatalities (rare where only one drug is involved) may occur at levels in excess of 5 mg/L.
Thirty-three benzodiazepines were included in Schedule IV of the 1971 United Nations Convention on Psychotropic Substances in 1984 (Table 1). Midazolam (1990) and brotizolam (1995) were subsequently added to the Schedule. In 1995, flunitrazepam (CAS 1622-62-4) was transferred from Schedule IV to Schedule III because the International Narcotics Control Board (INCB) stated that it was one of the most misused benzodiazepines and because of its frequent diversion into the illicit market.
Phenazepam (fenazepam) (CAS 51753-57-2), which is used in medical practice in some countries outside of the European Union, is not scheduled in the 1971 United Nations Convention on Psychotropic Substances.
The INCB reported that in 2006, total global licit production of benzodiazepines amounted to at least 180 metric tonnes, 56 tonnes of which was diazepam. Italy (32 %), India (19 %), China (11 %) and Germany (10 %) were the leading manufacturers between 1997 and 2006.
The INCB statistics for 2009 show that Europe has the highest average consumption of both for sedative-hypnotics and for anxiolytics, expressed as defined daily doses for statistical purposes (S-DDD) per 1 000 inhabitants per day.
In the case of anxiolytics, the figure for European consumption was around 37 S-DDD in 2001–03. which rose to around 46 S-DDD in 2005–06, and then dropped to around 42 S-DDD in 2007–09.
For sedatives it was approximately 24 S-DDD in 2005–07 up which fell to 22 S-DDD in 2006–08.
In 2007, global consumption of anxiolytics was around 22 billion S-DDD, which first rose to around 25 billion S-DDD and then dropped to around 21 billion S-DDD in 2009.
There is a lack of self-reported prevalence data on the use of benzodiazepines in the general population. Monitoring is limited by the very broad range of benzodiazepine products available in Europe and the lack of clear definitions for the general population to report their levels of use.
Among 15- to 16-year-old school students, lifetime prevalence of the use of ‘tranquillisers or sedatives without a doctor’s prescription’ ranged from 2 % to 15 % in the 24 EU Member States and Norway with ESPAD surveys in 2011, with six countries reporting prevalence levels of 10 % or more (Hibell et al, 2012).
Ashton, H. (2002), ‘Benzodiazepine abuse’, in Caan, W. and De Belleroche, J. (editors), Drink, drugs and dependence: from science to clinical practice, Routledge, London.
Bramness, J., Skurtveit, S. and Morland, J. (2002), 'Clinical impairment of benzodiazepines–relation between benzodiazepine concentrations and impairment in apprehended drivers', Drug and Alcohol Dependence, Volume 68, No 2, pp. 131–41.
EMCDDA (2008), 'Sexual assaults facilitated by drugs or alcohol', EMCDDA Technical Data Sheet (http://www.emcdda.europa.eu/html.cfm/index50537EN.html).
Glass, J., Lanctôt, K. L, Herrmann, N., Sproule, B. A., Busto, U.E. (2005), 'Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits', British Medical Journal, Volume 331, No 7526, pp. 1169-1173.
Hibell, B., Andersson, B., Bjarnasson, T. et al. (2004), The ESPAD report 2003: alcohol and other drug use among students in 35 European countries, the Swedish Council for Information on Alcohol and Other Drugs (CAN) and Council of Europe Pompidou Group.
Hindmarch, J., Beaumont, G., Brandon, S. and Leonard, B.E. (editors) (1990), Benzodiazepines: current concepts — biological, clinical and social perspectives, John Wiley & Sons, Chichester.
International Narcotics Control Board (2007), Psychotropic Substances, Statistics for 2006: Assessments of Annual Medical and Scientific Requirements for Substances in Schedules II, III and IV of the Convention on Psychotropic Substances of 1971, United Nations Publications, New York.
International Programme on Chemical Safety, ‘Benzodiazepines’, Poisons Information Monographs, World Health Organization, Geneva
King, L.A. and McDermott, S. (2004), ‘Drugs of abuse’, in Moffat, A.C., Osselton, M.D. and Widdop, B. (editors), Clarke’s Analysis of Drugs and Poisons, 3rd edition, Volume 1, pp. 37–52, Pharmaceutical Press, London.
Moffat, A.C., Osselton, M.D. and Widdop, B. (editors) (2004), Clarke’s Analysis of Drugs and Poisons, 3rd edition, Volume 2, Pharmaceutical Press, London.
Royal College of Psychiatrists (1997), Benzodiazepines: risks, benefits or dependence. A re-evaluation, Council Report CR59, London.
Sadock, B.J. and Sadock, V.A. (editors) (2004), Kaplan and Sadock's Comprehensive Textbook of Psychiatry, 8th edition, Lippincott Williams and Wilkins, Philadelphia.
United Nations (2006), Multilingual Dictionary of Narcotic Drugs and Psychotropic Substances under International Control, United Nations, New York.
United Nations (1997), Recommended Methods for the Detection and Assay of Barbiturates and Benzodiazepines in Biological specimens, Manual for Use by National Laboratories, United Nations, New York.
United Nations (1988), Recommended Methods for Testing Benzodiazepines under International Control, Manual for Use by National Narcotics Laboratories, United Nations, New York.