Benzodiazepine misuse

Benzodiazepines
The core structure of benzodiazepines. "R" labels denote common locations of side chains, which give different benzodiazepines their unique properties.
Benzodiazepine List of benzodiazepines Benzodiazepine overdose Benzodiazepine dependence Benzodiazepine misuse Benzodiazepine withdrawal syndrome Effects of long-term benzodiazepine use
v t e

Benzodiazepine drug misuse
Classification and external resources
ICD-10	F13.1
eMedicine	article/290585

Benzodiazepine drug misuse, sometimes called benzodiazepine drug abuse (both terms are merely nominal, and cover all non-medical uses of the drugs), is defined as using benzodiazepines for recreational purposes i.e. to get "high" or continuing benzodiazepines long term against medical advice.^[1][2] The level of benzodiazepine misuse is as high as other common drugs of misuse. When used recreationally benzodiazepines are usually administered orally but sometimes they are taken intranasally or intravenously. Recreational use produces effects similar to alcohol intoxication.^[2][3] In tests in pentobarbital trained rhesus monkeys benzodiazepines produced effects similar to barbiturates.^[4] In a 1991 study, triazolam had the highest self-administration rate in cocaine trained baboons, among the five benzodiazepines examined: alprazolam, bromazepam, chlordiazepoxide, lorazepam, triazolam.^[5]

Studies have indicated that those benzodiazepines which are more rapidly absorbed and have a quick rate of elimination have the highest abuse potential. Self-injection rates of triazolam, temazepam and midazolam have been shown in several studies to be considerably higher when compared to other benzodiazepines.^[6][7][8]

A 1985 study found that triazolam and temazepam maintained higher rates of self-injection than a variety of other benzodiazepines.^[6]

A 1991 study indicated that diazepam, in particular, had a greater abuse liability among people who were drug abusers than did many of the other benzodiazepines. Some of the available data also suggested that lorazepam and alprazolam are more diazepam-like in having relatively high abuse liability, while oxazepam, halazepam, and possibly chlordiazepoxide, are relatively low in this regard.^[9]

A 1991–1993 British study found that the hypnotics flurazepam and temazepam were more toxic than average benzodiazepines in overdose.^[10]

A 1995 study found that temazepam is more rapidly absorbed and oxazepam is more slowly absorbed than most other benzodiazepines. The study showed that there are differences between temazepam, oxazepam, and other benzodiazepines in the degree of sedation they cause in overdose, and the observed differences are not due to confounding by age, sex, dose ingested, coingestion of alcohol, chronic benzodiazepine use, or history of drug or alcohol abuse. This provides a plausible explanation why temazepam and oxazepam have different fatal toxicity indices from other benzodiazepines. The sedation produced by benzodiazepines in therapeutic doses and overdose has a poor correlation with measured drug concentration but is increased with rapid absorption. Rapid absorption of temazepam has been linked to increased abuse liability.^[7]

Benzodiazepines have been abused both orally and intravenously. Different benzodiazepines have different abuse potential; the more rapid the increase in the plasma level following ingestion, the greater the intoxicating effect and the more open to abuse the drug becomes. The speed of onset of action of a particular benzodiazepine correlates well with the ‘popularity’ of that drug for abuse. The two most common reasons for preference were that a benzodiazepine was ‘strong’ and that it gave a good ‘high’.^[11]

According to Dr Chris Ford, former clinical director of Substance Misuse Management in General Practice, among drugs of abuse, benzodiazepines are often seen as the 'bad guys' by drug and alcohol workers. Illicit users of benzodiazepines have been found to take higher methadone doses, as well as showing more HIV/HCV risk-taking behaviour, greater poly-drug use, higher levels of psychopathology and social dysfunction. However, there is only limited research into the adverse effects of benzodiazepines in drug misusers and further research is needed to demonstrate whether this is the result of cause or effect.^[12]

Background

Benzodiazepines are a commonly abused class of drugs, although there is debate as to whether certain benzodiazepines have higher abuse potential than others.^[13] In animal and human studies the abuse potential of benzodiazepines is classed as moderate in comparison to other drugs of abuse.^[14] Benzodiazepines are commonly abused by poly drug users, especially heroin addicts, alcoholics or amphetamine addicts when "coming down".^[15] but sometimes are misused in isolation as the primary drug of misuse. They can be misused to achieve the high that benzodiazepines produce or more commonly they are used to either enhance the effects of other CNS depressant drugs, to stave off withdrawal effects of other drugs or combat the effects of stimulants. As many as 30–50% of alcoholics are also benzodiazepine misusers.^[16] Drug abusers often abuse high doses which makes serious benzodiazepine withdrawal symptoms such as psychosis or convulsions more likely to occur during withdrawal.

Benzodiazepine abuse increases risk taking behaviours such as unprotected sex and sharing of needles amongst intravenous abusers of benzodiazepines. Abuse is also associated with blackouts, memory loss, aggression, violence, and chaotic behaviour associated with paranoia. There is little support for long-term maintenance of benzodiazepine abusers and thus a withdrawal regime is indicated when benzodiazepine abuse becomes a dependence or addiction. The main source of illicit benzodiazepines are diverted benzodiazepines obtained originally on prescription; other sources include thefts from pharmacies and pharmaceutical warehouses. Benzodiazepine abuse is steadily increasing and is now a major public health problem. Benzodiazepine abuse is mostly limited to individuals who abuse other drugs, i.e. poly-drug abusers. Most prescribed users do not abuse their medication, however, some high dose prescribed users do become involved with the illicit drug scene. Abuse of benzodiazepines occurs in a wide age range of people and includes teenagers and the old. The abuse potential or drug-liking effects appears to be dose related, with low doses of benzodiazepines having limited drug liking effects but higher doses increasing the abuse potential/drug-liking properties.^[17]

Health related complications

Complications of benzodiazepine abuse include drug-related deaths due to overdose especially in combination with other depressant drugs such as opioids. Other complications include: blackouts and memory loss, paranoia, violence and criminal behaviour, risk-taking sexual behaviour, foetal and neonatal risks if taken in pregnancy, dependence, withdrawal seizures and psychosis. Injection of the drug carries risk of: thrombophlebitis, deep vein thrombosis, deep and superficial abscesses, pulmonary microembolism, rhabdomyolysis, tissue necrosis, gangrene requiring amputation, hepatitis B and C, as well as blood borne infections such as HIV infection (caused by sharing injecting equipment).^[16] Long-term use of benzodiazepines can worsen pre-existing depression and anxiety and may potentially also cause dementia with impairments in recent and remote memory functions.^[18]

Use is widespread among amphetamine users, with those that use amphetamines and benzodiazepines having greater levels of mental health problems and social deterioration. Benzodiazepine injectors are almost four times more likely to inject using a shared needle than non-benzodiazepine-using injectors. It has been concluded in various studies that benzodiazepine use causes greater levels of risk and psycho-social dysfunction among drug misusers.^[19] Poly-drug users who also use benzodiazepines appear to engage in more risk taking behavior. Those who use stimulant and depressant drugs are more likely to report adverse reactions from stimulant use, more likely to be injecting stimulants and more likely to have been treated for a drug problem than those using stimulant but not depressant drugs.^[20]

Rates of misuse

Little attention has focused on the degree that benzodiazepines are abused as a primary drug of choice, but they are frequently abused alongside other drugs of abuse, especially alcohol, stimulants and opiates.^[21] The benzodiazepine most commonly abused can vary from country to country and depends on factors including local popularity as well as which benzodiazepines are available. Nitrazepam for example is commonly abused in Nepal and the United Kingdom,^[22][23] whereas in the United States of America where nitrazepam is not available on prescription other benzodiazepines are more commonly abused.^[9] In the United Kingdom and Australia there have been epidemics of temazepam abuse. Particular problems with abuse of temazepam are often related to gel capsules being melted and injected and drug-related deaths.^[24][25][26] Injecting most benzodiazepines is dangerous because of their relative insolubility in water (with the exception of midazolam), leading to potentially serious adverse health consequences for users.^[27][28]

Benzodiazepines are a commonly misused class of drug. A study in Sweden found that benzodiazepines are the most common drug class of forged prescriptions in Sweden.^[29] Concentrations of benzodiazepines detected in impaired motor vehicle drivers often exceeding therapeutic doses have been reported in Sweden and in Northern Ireland.^[30][31] One of the hallmarks of problematic benzodiazepine drug misuse is escalation of dose. Most licit prescribed users of benzodiazepines do not escalate their dose of benzodiazepines.^[32]

A 2004 US government study of nationwide ED visits conducted by SAMHSA found that sedative-hypnotics in the USA are the most frequently misused pharmaceutical drug with 35% of drug-related visits to the Emergency Department involving sedative hypnotics. Benzodiazepines accounted for the majority of these. Benzodiazepines are more commonly misused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. Males and females misuse benzodiazepines equally. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drug with 26% of attempted suicides involving benzodiazepines. Alprazolam is the most commonly misused benzodiazepine, followed by clonazepam, lorazepam and diazepam as the 4th in the USA.^[33]

Relative abuse liability among different benzodiazepines

Numerous studies have consistently concluded that triazolam (Halcion) and temazepam (Restoril, Normison) have a higher potential for abuse and addiction compared other benzodiazepines. Most, if not all, of research studies on abuse were based on self-administration rates. Studies have been conducted on non-human primates and humans with similar results.^[6] Drug self-administration procedures in laboratory animals permit assessment of the relative efficacy with which different drugs maintain self-administration. The validity of this approach to providing information relevant to human drug abuse is supported by the high correspondence between those drugs that are self-administered and abused by humans,^[34] or that produce profiles suggesting abuse liability in human experiments.^[35] Past research into the relative abuse liability of different opioids, amphetamines, barbiturates, as well as that of cocaine and tobacco, using the same procedures have been consistently deemed effective, accurate and reliable based on peer-reviewed, journalistic work.

Self-administration of a variety of benzodiazepines has been studied in lab rats and non-human primates.^[36] Triazolam self-administration has not been studied in rodents, but five such studies have been conducted in non-human primates, three of which involved in the intravenous (IV) route.

Intravenous self-administration

The first study used procedures to examine self-injection of diazepam, triazolam, pentobarbital (Nembutal), and chlorpromazine in baboons. Intravenous injections of a given drug was dependent upon completion of 160 lever presses (a 160-response, fixed-ratio schedule). A three hour timeout followed each injection, permitting a maximum of eight injections per day. Before testing each dose of a drug, self-injection performance was established with cocaine; subsequently, a test dose was substituted with cocaine for a period of either twelve or fifteen days. For triazolam, the dose levels in milligrams per kilogram body mass for each injection and number of animals studied at each dose level (indicated in parentheses) were: 0.0001 (2), 0.001 (2), 0.0032 (3), 0.01 (4), 0.032 (2), 0.1 (2), and 0.32 (2). Chlorpromazine failed to maintain self-injection performance above vehicular control levels. Diazepam was associated with relatively low levels of self-injection (3.1 injections/day, maximum), which exceeded vehicular control levels in two of three animals tested. Triazolam maintained levels of self-injection (5.6 injections/day, maximum), which were substantially higher than vehicular control levels, although clearly below cocaine's vehicular control levels in all animals tested. Finally, pentobarbital was associated with dose-dependent increases in self-injection performance, with maximal levels (7.7 injections/day) maintained in the range of cocaine.

The second intravenous study was conducted by Romer,^[37] using standard procedures,^[38] to evaluate the self-administration of four benzodiazepines in three or four male rhesus monkeys. Access to triazolam (0.001, 0.0032 mg/kg), temazepam (0.01, 0.032 mg/kg), flurazepam (0.18, 0.56 mg/kg), chlordiazepoxide (0.32 mg/kg), and saline was provided 23 hr/day under a lever-pressing schedule (probably fixed-ratio 1) with a 10 second timeout following each injection. The lowest dose of each drug was selected as a proportion of a dose which produced CNS-depressant effects in naive monkeys. Drug doses were studied for at least 4 weeks. During the first week of drug availability, there was a 15-rain period each day, during which each lever press produced both a drug injection and a food pellet. Subsequently, the food condition was eliminated and lever presses only produced drug injections. The results showed that triazolam and temazepam maintained more consistent and greater numbers of injections than any of the other drug conditions. For instance, during the first week when the drug alone was available, triazolam maintained an average of 112 and 123 injections/23 hr at 0.001 and 0.0032 mg/kg respectively, compared to a saline control and all the other drug conditions, which ranged between 12-63 injections/23 hr. The rank ordering of the mean number of injections/23 hr on the fourth week of drug alone availability was: 146 (0.001 triazolam), 118 (0.0032 triazolam), 103 (0.032 temazepam), 33 (0.18 flurazepam), 25 (0.56 flurazepam), 13 (0.32 chlordiazepoxide). The results indicate that triazolam and temazepam maintained significantly higher self-injection rates in male rhesus monkeys when compared to flurazepam and chlordiazepoxide.

The third intravenous study^[39] compared the self-administration of pentobarbital and three benzodiazepines in female rhesus monkeys. The drug was available during daily 4-hr sessions under a (fixed-ratio 1) of lever-pressing, with a 20-second injection duration. High rates of self-injection were initially established with cocaine (0.2 mg/kg), and so the test drug was substituted with cocaine. After 7 days at an initial dose of the test drug, the dose was increased, and the dosage remained available for the next 7 days. This double-dose portion of each tested drug was selected as a proportion of a dose which produced observable CNS depression. Each of the four test drugs was tested in four monkeys with drug order counterbalanced across animals. The rank ordering of the mean number of injections per session for the last 3 days was 105.9, 103.3 (pentobarbital 0.1 and 0.2 mg/kg, respectively), 33.3, 32.2 (triazolam 0.001 and 0.0016 mg/kg, respectively), 25.7, 28.7 (temazepam 0.05 and 0.1 mg/kg, respectively), 15.4 and 13.4 (diazepam 0.12 and 0.25 mg/kg, respectively). Although absolute differences between compounds were sometimes small, the same rank ordering was also apparent with this data on a per-subject basis (i.e., within all four monkeys mean injections for the last 3 days maintained by the four drugs were: pentobarbital > triazolam > temazepam > diazepam). Except for one monkey with diazepam, the mean injections for the last 3 days with all four compounds exceeded that for a saline control period obtained when the animals were drug naive. The results of this study indicate that triazolam and temazepam produced comparable self-injection rates that were considerably higher than diazepam self-injection rates. Diazepam only barely exceeded the saline control injection rates, having one of the monkeys even prefer the saline control over the diazepam.

The results of these five triazolam self-administration studies with baboons and rhesus monkeys are consistent with the results of previous research in non-human primates, showing that: (1) benzodiazepines are more efficacious as reinforcers than some drugs, including chlorpromazine, imipramine, haloperidol or perphenazine, and (2) benzodiazepines are less efficacious as reinforcers than a range of other drugs, including pentobarbital, amobarbital, secobarbital, and cocaine. It is possible that the absorption rate, especially the elimination rate, is a determinant of self-injection rates. The finding that triazolam and temazepam maintain significantly higher levels of self-injection than a variety of other benzodiazepines which are more slowly eliminated or have active metabolites which are more slowly eliminated in humans is consistent with another study wherein midazolam produced the highest levels of self-injection compared to clonazepam, clorazepate, diazepam, flurazepam, and medazepam.^[8] Further corroborating these studies, a 1995 study found that temazepam is more rapidly absorbed, and oxazepam less rapidly absorbed, than most other benzodiazepines.^[7] Drugs, in this case, benzodiazepines with a more rapid absorption rate have been proven to be more liable to abuse, dependence and user-subjective "liking".^[11]

Other Research and Studies

Another study, conducted in 1988, compared the abuse liability of alprazolam, temazepam, lorazepam, diazepam, methaqualone, and placebo. Subjective effects of two benzodiazepines—alprazolam and lorazepam—were compared with three drugs of known abuse potential—diazepam, temazepam, and methaqualone—and placebo. This double-blind, crossover trial tested 30 casual recreational sedative users in a semi-naturalistic setting. Methaqualone was more euphoriant and less sedating than the benzodiazepines. Among the benzodiazepines, temazepam was more euphoriant and more sedating than the rest of the benzodiazepines. Diazepam, alprazolam and lorazepam were more euphoriant than placebo. On other measures of abuse liability, the benzodiazepine, temazepam rated the highest. Diazepam ranked slightly above lorazepam and alprazolam, while the latter two did not differ from each other.

In 2004-2005 Griffiths conducted a large study comparing the abuse liability of 19 different hypnotic compounds: pentobarbital, methaqualone, diazepam, flunitrazepam, lorazepam, GHB, temazepam, zaleplon, eszopiclone, triazolam, zopiclone, flurazepam, zolpidem, oxazepam, estazolam, diphenhydramine, quazepam, trazodone, and ramelteon. Relative abuse liability is defined as an interaction between the relative reinforcing effects (i.e., the capacity to maintain drug self-administration behavior, thereby increasing the likelihood of recreational problematic use) and the relative toxicity (i.e., adverse effects having the capacity to harm the individual and/or society). An algorithm is provided that differentiates relative likelihood of abuse and relative toxicity of the 19 hypnotics. Factors in the analysis include preclinical and clinical assessments of reinforcing effects, preclinical and clinical assessments of withdrawal, actual abuse, acute sedation and memory impairment, and overdose lethality. The analysis shows that both the likelihood of abuse and the toxicity range from high to none across these compounds. The primary clinical implication of the range of differences in abuse liability is that concern about recreational abuse, inappropriate long-term use, or adverse effects should not deter physicians from prescribing hypnotics when clinically indicated. Based upon the factors which were considered in the study, the 19 hypnotics ranked as follows: methaqualone, pentobarbital, GHB, triazolam, temazepam, flunitrazepam, diazepam, lorazepam, flurazepam, estazolam, zaleplon, oxazepam, quazepam, zolpidem, zopiclone, eszopiclone, diphenhydramine, trazodone, and finally, ramelteon.^[40]

Motivations for drug misuse

Benzodiazepines reduce the tolerance to reward delay in rats.^[41] Humans are motivated to misuse benzodiazepines to achieve a sedative-hypnotic high which often produces effects including feeling energetic, relaxed, drunken, talkative and euphoric. In India up to 50–60% of heroin addicts use benzodiazepines and 20% of injecting substance misusers also inject benzodiazepines.^[42] Benzodiazepines can be used to counter effects of other drugs e.g. to "come down" from stimulants or enhance the effects of other CNS depressant drugs e.g. alcohol, or heroin in rats.^[43][44][45] Compulsive benzodiazepine use is believed to be due to adaptational changes in the GABA_A receptor and possibly also its effects on the opioid system. The abuse potential of sedative-hypnotics are governed mainly by their effects on the alpha1 containing GABA_A receptors.^[46]

Risk factors for misuse

Individuals with a substance abuse history are at an increased risk of misusing benzodiazepines.^[47]

Several (primary research) studies, even into the last decade, claimed, that individuals with a history of familial abuse of alcohol or who are siblings or children of alcoholics appeared to respond differently to benzodiazepines than so called genetically healthy persons, with males experiencing increased euphoric effects and females having exaggerated responses to the adverse effects of benzodiazepines.^{[48][49][50][51]}

Whilst all benzodiazepines have abuse potential, certain characteristics increase the potential of particular benzodiazepines for abuse. These characteristics are chiefly practical ones—most especially, availability (often based on popular perception of 'dangerous' versus 'non-dangerous' drugs) through prescribing physicians or illicit distributors. Pharmacological and pharmacokinetic factors are also crucial in determining abuse potentials. A short elimination half-life, high potency and a rapid onset of action are characteristics which increase the abuse potential of benzodiazepines.^[52] The following table provides the elimination half-life, relevant potency to other benzodiazepines, speed of onset of action and duration of behavioural effects.^[53][54]

Drug Name	Common Brand Names*	Onset of action	Duration of action (h)**	Elimination Half-Life (h) [active metabolite]	Approximate Equivalent Dose***
Alprazolam	Xanax, Xanor, Tafil, Alprox, Niravam	Intermediate	3–5	6–12 hours	0.5 mg
Chlordiazepoxide	Librium, Tropium, Risolid, Klopoxid	Intermediate	???	5–30 hours [36–200 hours]	25 mg
Clonazepam	Klonopin, Klonapin, Rivotril, Iktorivil	Intermediate	10–12	18–50 hours	0.5 mg
Clorazepate	Tranxene	Intermediate	???	[36–100 hours]	15 mg
Diazepam	Valium, Apzepam, Stesolid, Vival, Apozepam, Hexalid, Valaxona	Fast	4–6	20–100 hours [36–200]	10 mg
Estazolam	ProSom	Slow	6–8	10–24 h	1–2 mg
Flunitrazepam	Rohypnol, Fluscand, Flunipam, Ronal	Fast	6–8	18–26 hours [36–200 hours]	1 mg
Flurazepam	Dalmadorm, Dalmane	Fast	7–10	[40–250 hours]	15–30 mg
Lorazepam	Ativan, Temesta, Lorabenz	Intermediate	4–6	10–20 hours	1 mg
Midazolam	Dormicum, Versed, Hypnovel	Fast	0.5–1	3 hours (1.8–6 hours)	5 mg
Oxazepam	Seresta, Serax, Serenid, Serepax, Sobril, Oxascand, Alopam, Oxabenz, Oxapax	Slow	4–6	4–15 hours	30 mg
Prazepam	Lysanxia, Centrax	Slow	???	36–200 hours	20 mg
Quazepam	Doral	Slow	6	39–120 hours	20 mg
Temazepam	Restoril, Normison, Euhypnos, Tenox	Fast	5–6	8–22 hours	20 mg
Triazolam	Halcion, Rilamir	Fast	0.5–1	2 hours	0.25 mg

*Not all trade names are listed. Click on drug name to see a more comprehensive list.
**The duration of apparent action is usually considerably less than the half-life. With most benzodiazepines, noticeable effects usually wear off within a few hours. Nevertheless, as long as the drug is present it will exert subtle effects within the body. These effects may become apparent during continued use or may appear as withdrawal symptoms when dosage is reduced or the drug is stopped.^{[citation needed]}
***Equivalent doses are based on clinical experience but may vary between individuals.^{[55][citation needed]}

Drug dependence and withdrawal effects

Sedative hypnotics such as alcohol, benzodiazepines and the barbiturates are notorious for the severe physical dependence that they are capable of inducing which can result in severe withdrawal effects.^{[56][citation needed]} This severe neuroadaptation is even more profound in high dose drug users and misusers. A high degree of tolerance often occurs in chronic benzodiazepine abusers due to the typically high doses they consume which can lead to a severe benzodiazepine dependence. The benzodiazepine withdrawal syndrome seen in chronic high dose benzodiazepine abusers is similar to that seen in therapeutic low dose users but of a more severe nature. Extreme antisocial behaviours in obtaining continued supplies and severe drug-seeking behaviour when withdrawing occurs. The severity of the benzodiazepine withdrawal syndrome has been described by one benzodiazepine drug misuser who stated that^[16]

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.

Those who use benzodiazepines intermittently are less likely to develop a dependence and withdrawal symptoms upon dose reduction or cessation of benzodiazepines than those who use benzodiazepines on a daily basis.^[16]

Misuse of benzodiazepines is widespread amongst drug misusers; however, many of these people will not require withdrawal management as their use is often restricted to binges or occasional misuse. Benzodiazepine dependence when it occurs requires withdrawal treatment. There is little evidence of benefit from long-term substitution therapy of benzodiazepines, and conversely, there is growing evidence of the harm of long-term use of benzodiazepines, especially higher doses. Therefore gradual reduction is recommended, titrated against withdrawal symptoms.^[57] For withdrawal purposes, stabilisation with a long acting agent such as diazepam is recommended before commencing withdrawal. Chlordiazepoxide (librium), a long-acting benzodiazepine, is gaining attention as an alternative to diazepam in substance abusers dependent on benzodiazepines due to its decreased abuse potential.^[21] In individuals dependent on benzodiazepines who have been using benzodiazepines long-term, taper regimes of 6–12 months have been recommended and found to be more successful. More rapid detoxifications e.g. of a month are not recommended as they lead to more severe withdrawal symptoms.^[58]

Tolerance leads to a reduction in GABA receptors and function; when benzodiazepines are reduced or stopped this leads to an unmasking of these compensatory changes in the nervous system with the appearance of physical and mental withdrawal effects such as anxiety, insomnia, autonomic hyperactivity and possibly seizures.^[52]

Some common withdrawal symptoms which can occur when stopping the use of benzodiazepines include:^[16]

All sedative-hypnotics, e.g. alcohol, barbiturates, benzodiazepines and the nonbenzodiazepine Z-drugs have a similar mechanism of action, working on the GABA_A receptor complex and are cross tolerant with each other and also have abuse potential. Use of prescription sedative-hypnotics e.g. the non-benzodiazepine Z-drugs often leads to a relapse back into substance misuse with one author stating this occurs in over a quarter of those who have achieved abstinence.^[58]

Drug-related crime

Problem benzodiazepine use can be associated with various deviant behaviors, including drug-related crime. In a survey of police detainees carried out by the Australian Government, both legal and illegal users of benzodiazepines were found to be more likely to have lived on the streets, less likely to have been in full-time work and more likely to have used heroin or methamphetamines in the past 30 days from the date of taking part in the survey. Benzodiazepine users were also more likely to be receiving illegal incomes and more likely to have been arrested or imprisoned in the previous year. Benzodiazepines were sometimes reported to be used alone, but most often formed part of a poly drug-using problem. Female users were more likely than men to be using heroin, whereas male users were more likely to report amphetamine use. Benzodiazepine users were more likely than non-users to claim government financial benefits and benzodiazepine users who were also poly-drug users were the most likely to be claiming government financial benefits. Those who reported using benzodiazepines alone were found to be in the mid range when compared to other drug using patterns in terms of property crimes and criminal breaches. Of the detainees reporting benzodiazepine use, one in five reported injection use, mostly of illicit temazepam, with some who reported injecting prescribed benzodiazepines. Injection was a concern in this survey due to increased health risks. The main problems highlighted in this survey were concerns of dependence, the potential for overdose of benzodiazepines in combination with opiates and the health problems associated with injection of benzodiazepines.^[59]

Benzodiazepines are also sometimes used for drug facilitated sexual assaults and robbery, however, alcohol remains the most common drug involved in drug facilitated assaults. The muscle relaxant, disinhibiting and amnesia producing effects of benzodiazepines are the pharmacological properties which make these drugs effective in drug-facilitated crimes.^[60][61] Serial killer Jeffrey Dahmer admitted to using triazolam (Halcion), and occasionally temazepam (Restoril), in order to sedate his victims prior to murdering them.^[62]

Drug regulation and enforcement

Europe

Temazepam abuse and seizures have been falling in the UK probably due to its reclassification as Schedule 3 controlled drug with tighter prescribing restrictions and the resultant reduction in availability.^[63] A total of 2.75 million temazepam capsules were seized in the Netherlands by authorities between 1996 and 1999.^[64] In Northern Ireland statistics of individuals attending drug addiction treatment centers found that benzodiazepines were the 2nd most commonly reported main problem drugs (31 percent of attendees). Cannabis was the top with 35 percent of individuals reporting it as their main problem drug. The statistics showed that treatment for benzodiazepines as the main problematic drug had more than doubled from the previous year and was a growing problem in Northern Ireland.^[65]

Oceania

Benzodiazepines are common drugs of abuse in Australia and New Zealand, particularly among those who may also be using other illicit drugs. The intravenous use of temazepam poses the greatest threat to those who misuse benzodiazepines. Simultaneous consumption of temazepam with heroin is a potential risk factor of overdose. An Australian study of non-fatal heroin overdoses, noted that 26% of heroin users had consumed temazepam at the time of their overdose. This is consistent with a NSW investigation of coronial files from 1992. Temazepam was found in 26% of heroin-related deaths. Temazepam, including tablet formulations, are used intravenously. In an Australian study of 210 heroin users who used temazepam, 48% had injected it. Although abuse of benzodiazepines has decreased over the past few years, temazepam continues to be a major drug of abuse in Australia. In certain states like Victoria and Queensland, temazepam accounts for most benzodiazepine sought by forgery of prescriptions and through pharmacy burglary. Darke, Ross & Hall found that different benzodiazepines have different abuse potential. The more rapid the increase in the plasma level following ingestion, the greater the intoxicating effect and the more open to abuse the drug becomes. The speed of onset of action of a particular benzodiazepine correlates well with the ‘popularity’ of that drug for abuse. The two most common reasons for preference for a benzodiazepine were that it was the ‘strongest’ and that it gave a good ‘high’.^[11]

North America

Abuse of benzodiazepine drugs is a serious problem in North America. The most frequently abused of the benzodiazepines in both the United States and Canada are alprazolam, clonazepam, lorazepam and diazepam.^[66]

East and Southeast Asia

Abuse of benzodiazepines is a serious problem throughout East and Southeast Asia.

The Central Narcotics Bureau of Singapore seized 94,200 nimetazepam tablets in 2003. This is the largest nimetazepam seizure recorded since nimetazepam became a controlled drug under the Misuse of Drugs Act in 1992. In Singapore nimetazepam is a Class C controlled drug.^[67]

In Hong Kong abuse of prescription medicinal preparations continued in 2006 and seizures of midazolam (120,611 tablets), nimetazepam/nitrazepam (17,457 tablets), triazolam (1,071 tablets), diazepam (48,923 tablets) and chlordiazepoxide (5,853 tablets) were made. Heroin addicts used such tablets (crushed and mixed with heroin) to prolong the effect of the narcotic and ease withdrawal symptoms.^[68]

Legal status

In the United States, benzodiazepines are Schedule IV drugs under the Federal Controlled Substances Act, even when not on the market (for example, nitrazepam and bromazepam). Flunitrazepam is subject to more stringent regulations in certain states and temazepam prescriptions require specially coded pads in certain states.

In Canada, possession of benzodiazepines is legal for personal use. All benzodiazepines are categorized as Schedule IV substances under the Controlled Drugs and Substances Act.^[69]

In the United Kingdom, the benzodiazepines are schedule 4 controlled drugs, except for flunitrazepam, temazepam and midazolam, which are schedule 3 controlled drugs and carry stronger penalties for possession and trafficking.^[70][71]

In the Netherlands, since October 1993, benzodiazepines, including formulations containing less than 20 mg of temazepam, are all placed on List 2 of the Opium Law. A prescription is needed for possession of all benzodiazepines. Temazepam formulations containing 20 mg or greater of the drug are placed on List 1, thus requiring prescriptions to be written in the List 1 format.^[72]

In East Asia and Southeast Asia, temazepam and nimetazepam are often heavily controlled and restricted. In certain countries, triazolam, flunitrazepam, flutoprazepam and midazolam are also restricted or controlled to certain degrees. In Hong Kong, all benzodiazepines are regulated under Schedule 1 of Hong Kong's Chapter 134 Dangerous Drugs Ordinance.^[73] Previously only brotizolam, flunitrazepam and triazolam were classed as dangerous drugs.^[74]

Internationally, benzodiazepines are categorized as Schedule IV controlled drugs, apart from flunitrazepam which is a Schedule III drug under the Convention on Psychotropic Substances.^[75]

See also

• Drug abuse
• Benzodiazepine overdose
• Long term effects of benzodiazepines

References

v t e Benzodiazepine derivatives 1,4-Benzodiazepines Bromazepam Camazepam Carburazepam Chlordiazepoxide Cinazepam Cinolazepam Clonazepam Clorazepate Cyprazepam Delorazepam Demoxepam Devazepide * Diazepam Diclazepam Doxefazepam Elfazepam Ethyl carfluzepate Ethyl dirazepate Ethyl loflazepate Flubromazepam Fletazepam Fludiazepam Flunitrazepam Flurazepam Flutemazepam Flutoprazepam Fosazepam Gidazepam Halazepam Iclazepam Ketazolam Lorazepam Lormetazepam Lufuradom * Meclonazepam Medazepam Menitrazepam Metaclazepam Motrazepam Nimetazepam Nitrazepam Nitrazepate Nordazepam Nortetrazepam Oxazepam Phenazepam Pinazepam Pivoxazepam Prazepam Proflazepam Quazepam QH-II-66 Reclazepam RO4491533 * Ro5-2904 Ro5-4864 * Sulazepam Temazepam Tetrazepam Tifluadom * Tolufazepam Tuclazepam Uldazepam 1,5-Benzodiazepines Arfendazam Clobazam CP-1414S Lofendazam Triflubazam 2,3-Benzodiazepines * Girisopam GYKI-52466 GYKI-52895 Nerisopam Talampanel Tofisopam Triazolobenzodiazepines Adinazolam Alprazolam Estazolam Flubromazolam Pyrazolam Triazolam Imidazobenzodiazepines Bretazenil Climazolam FG-8205 Flumazenil Imidazenil Iomazenil (123I) L-655,708 Loprazolam Midazolam PWZ-029 Remimazolam Ro15-4513 Ro48-6791 Ro48-8684 Ro4938581 Sarmazenil SH-053-R-CH3-2′F Oxazolobenzodiazepines Cloxazolam Flutazolam Haloxazolam Mexazolam Oxazolam Thienodiazepines Bentazepam Brotizolam Ciclotizolam Clotiazepam Etizolam JQ1 * Olanzapine * Pyridodiazepines Lopirazepam Zapizolam Pyrazolodiazepines Razobazam * Ripazepam Zolazepam Zomebazam Zometapine * Pyrrolodiazepines Premazepam Tetrahydroisoquinobenzodiazepines Clazolam Benzodiazepine prodrugs Avizafone Rilmazafone * atypical activity profile (not GABAA receptor ligands)

v t e Psychoactive substance-related disorder (F10–F19, 291–292; 303–305) General SID Substance intoxication / Drug overdose Withdrawal Substance-induced psychosis SUD Substance abuse Physical dependence / Substance dependence Alcohol SID Diseases Neurological disorders Alcoholic hallucinosis Alcohol withdrawal Fetal alcohol spectrum disorder (FASD) Fetal alcohol syndrome (FAS) Korsakoff's syndrome Wernicke–Korsakoff syndrome Wernicke's encephalopathy Digestive system Alcohol flush reaction Alcoholic hepatitis Alcoholic liver disease Nervous system Alcohol dementia Alcoholic hallucinosis Hangover Cardiovascular system Alcoholic cardiomyopathy SUD Alcoholism Alcohol dependence Alcohol abuse Opioids SID Opioid overdose SUD Opioid dependence Caffeine SID Effect of caffeine on memory Caffeine-induced sleep disorder SUD Caffeine addiction Cannabis SID Effects of cannabis Long-term effects of cannabis SUD Cannabis dependence Sedative / hypnotic benzodiazepine: SID Benzodiazepine overdose Benzodiazepine withdrawal SUD Benzodiazepine misuse Benzodiazepine dependence barbiturate: SID Barbiturate overdose SUD Barbiturate dependence Cocaine SID Cocaine intoxication SUD Cocaine dependence Stimulants SID Stimulant psychosis SUD Amphetamine dependence Hallucinogen SID Hallucinogen persisting perception disorder Tobacco SID Nicotine poisoning Nicotine withdrawal Volatile solvent Inhalant abuse: Toluene toxicity Multiple Poly drug use M: PSO/PSI mepr dsrd (o, p, m, p, a, d, s), sysi/epon, spvo proc (eval/thrp), drug (N5A/5B/5C/6A/6B/6D)