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|Systematic (IUPAC) name|
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Flunitrazepam ( //) is marketed as a potent hypnotic, sedative, anticonvulsant, anxiolytic, amnestic, and skeletal muscle relaxant drug  most commonly known as Rohypnol. An intermediate acting benzodiazepine, flunitrazepam is prescribed for the treatment of severe insomnia, marketed by Roche.
In general, the prescription of flunitrazepam as a hypnotic is intended to be for short-term treatment of chronic or severe insomniacs not responsive to other hypnotics, especially in inpatients. It is considered to be one of the most effective benzodiazepine hypnotics on a dose basis. Just as with other hypnotics, flunitrazepam should be used only on a short-term basis or in those with chronic insomnia on an occasional basis.
Flunitrazepam is classed as a nitro-benzodiazepine. It is the fluorinated methylamino derivative of nitrazepam. Other nitro-benzodiazepines include nitrazepam — the parent compound — and clonazepam, the chlorinated derivative.
Though flunitrazepam is often cited as a date rape drug because of its high potency, strong effects and the ability to cause strong amnesia during its duration of action, investigations into its actual use as a date rape drug have contradicted popular belief. Test results indicated that flunitrazepam was used in only around 1% of reported date rapes, according to Robertson and 0.33% according to urine lab tests done by El Sohly.
Flunitrazepam was first synthesized in 1972 by Roche in Europe and was used in hospitals when deep sedation was needed. It first entered the commercial market in Europe in 1975 as Rohypnol produced by Roche, and in the 1980s it began to be available in other countries. It first appeared in the US in late 1983 - mid 1984. It originally came in doses of 1 mg and 2 mg, but due to its potency and potential for abuse, most European countries changed their drug laws and limited the dose to 1 mg—in many countries, the maximum dose per package was limited to 20 or 30 mg. In Germany there had been two changes in availability during a short period in the late 1990s; the first one restricting the dose to 20 mg per package, and for a short time only 10 tablets with 2 mg were available. Soon another change in the German Narcotic Act limited the dose for each tablet to 1 mg, while ampoules containing the 2 mg solution were not changed by Roche and have been handled as a controlled narcotic like morphine. In the countries where flunitrazepam is available for prescription as both 1 mg and 2 mg tablets, such as the Netherlands, generic alternatives are available for the 2 mg tablets. However, in Asia and South America there are original 2 mg tablets from Roche still available.
The newly designed 1 mg tablets introduced in the late 1990s by Roche for the European market are identical in all countries, only the packaging and packaging size differs since there are different laws in each country. The new tablets are green (containing a blue coloring) and are pressed harder during manufacturing—so that the tablets can only dissolve quickly in hot liquids, while turning the drink a blue color and leaving a green residue in the beverage—were introduced to prevent use as a rape drug and abuse on the drug scene. However there have been only few reported cases in Europe where flunitrazepam was used as a rape drug and in most countries flunitrazepam is still offered as a generic drug with white tablets that can be dissolved easily.
In the 2000s some European countries started to treat flunitrazepam as a strong narcotic, for example Poland in 2004. The most recent change was the change in the German drug law regarding flunitrazepam; since November 2011 the drug is only available with a special narcotic prescription. German Rohypnol tablets disappeared almost overnight from the black market. However it took only a few weeks before organized crime became the major supplier for the drug on the black market, as in the United States. The tablets come from western European countries where it is still available with a normal prescription. Some users living on the borders are driving to these countries and buy the drug on the black market, since there are no border controls within the European Union.
Benzodiazepines, including flunitrazepam, bind to most glial cell membranes with high affinity in mouse astrocytes. Flunitrazepam induces melanogenesis in B16/C3 mouse melanoma cell cultures via modulating high-affinity binding sites. Benzodiazepines, including flunitrazepam have been shown to act on benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive calcium uptake in rat brain cell components. This has been conjectured as a mechanism for high-dose effects against seizures in a study.
The main pharmacological effects of flunitrazepam are the enhancement of GABA at the GABAA receptor. Like other benzodiazepines, flunitrazepam's pharmacological effects include sedation, muscle relaxation, reduction in anxiety, and prevention of convulsions.
Intermediate-half-life benzodiazepines (such as loprazolam, lormetazepam, and temazepam) are also useful for patients with difficulty in maintaining sleep; these may be preferable to long-half-life benzodiazepines, which typically cause next-day sedation and impairments.
While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%.
Flunitrazepam has a long half-life of 18–26 hours and an active metabolite that has a half-life of 36–200 hours, which means that flunitrazepam's effects after nighttime administration persist throughout the next day. Residual "hangover" effects after nighttime administration of flunitrazepam, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely, and increase risks of falls and hip fractures.
Flunitrazepam is metabolized almost completely by cytochrome P450-3A4. Atorvastatin administration along with flunitrazepam results in a reduced elimination rate of this molecule. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations of flunitrazepam, which could result in overdose.
Flunitrazepam is a drug that is frequently involved in drug intoxication, including overdose. Overdose of flunitrazepam may result in excessive sedation, impairment of balance and speech. This may progress in severe overdoses to respiratory depression or coma and possibly death. The risk of overdose is increased if flunitrazepam is taken in combination with CNS depressants such as alcohol and opiates. Flunitrazepam overdose responds to the benzodiazepine receptor antagonist flumazenil, which thus can be used as a treatment.
Flunitrazepam can be measured in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest, or assist in a medicolegal death investigation. Blood or plasma flunitrazepam concentrations are usually in a range of 5-20 μg/L in persons receiving the drug therapeutically as a nighttime hypnotic, 10-50 μg/L in those arrested for impaired driving and 100-1000 μg/L in victims of acute fatal overdosage. Urine is often the preferred specimen for routine drug abuse monitoring purposes. The presence of 7-aminoflunitrazepam, a pharmacologically-active metabolite and in vitro degradation product, is useful for confirmation of flunitrazepam ingestion. In postmortem specimens, the parent drug may have been entirely degraded over time to 7-aminoflunitrazepam.
Although flunitrazepam has become widely known in the USA for its use as a date-rape drug, it is used more frequently as a recreational drug. It is often used by high school and college students, rave party attendees, and heroin and cocaine users for recreational purposes, including:
Flunitrazepam is usually consumed orally, and is sometimes combined with alcohol (benzodiazepines and alcohol combined intensify each other's CNS depression to the point of being deadly). It is also occasionally insufflated (i.e., tablets are crushed into powder and snorted). In some European countries, there was an alcohol solution of flunitrazepam (Darkene), taken by injection, with very strong effects.
Benzodiazepines, including diazepam, nitrazepam, oxazepam, and flunitrazepam, account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines, suggesting that benzodiazepines are a major prescription drug class of abuse. Nitrazepam and flunitrazepam accounted for the vast majority of forged prescriptions.
Flunitrazepam and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other benzodiazepines (anxiolytic or hypnotic) and zolpidem and zopiclone (as well as similar hypnotic and anxiolytic drugs from the non-benzodiazepine families Cyclopyrrolones, Imidazopyridines, and Pyrazolopyrimidines) are also found in high numbers of suspected drugged drivers. Many drivers have blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and similar drugs.
Street names for Rohypnol include "rophy", "ruffles", "roachies", "roofies", "ruffies", "rufus," "rufalin," "ruff-up", "rib", "roach 2 (R2)", "roche", "rope", "ropies", "circles", "circes", "forget it", "forget-me-pill", "forget-me-now", "Mexican Valium", "Floories" and "Roofalin".
In studies in Sweden, flunitrazepam was the second-most-common drug used in suicides, being found in about 16% of cases. In a retrospective Swedish study of 1587 deaths, in 159 cases benzodiazepines were found. In suicides when benzodiazepines were implicated, the benzodiazepines flunitrazepam and nitrazepam were occurring in significantly higher concentrations, compared to natural deaths. In four of the 159 cases, where benzodiazepines were found, benzodiazepines alone were the only cause of death. It was concluded that flunitrazepam and nitrazepam might be more toxic than other benzodiazepines. 
Flunitrazepam is known to induce anterograde amnesia in sufficient doses; individuals are unable to remember certain events that they experienced while under the influence of the drug. This effect is particularly dangerous when flunitrazepam is used to aid in the commission of sexual assault; victims may be unable to clearly recall the assault, the assailant, or the events surrounding the assault.
It is difficult to estimate just how many flunitrazepam-facilitated rapes have occurred. Very often, biological samples are taken from the victim at a time when the effects of the drug have already passed and only residual amounts remain in the body fluids. These residual amounts are difficult, and sometimes impossible, to detect using standard screening assays used in most countries. If flunitrazepam exposure is to be detected at all, urine samples need to be collected within 72 hours and subjected to sensitive analytical tests. The problem is compounded by the onset of amnesia after ingestion of the drug, which causes the victim to be uncertain about the facts surrounding the rape. This uncertainty may lead to critical delays or even reluctance to report the rape and provide appropriate biological samples for testing. If a person suspects that he or she is the victim of a flunitrazepam-facilitated rape, he or she should get laboratory testing for flunitrazepam as soon as possible. In recent news, it has been discovered that scientists can now detect flunitrazepam and related compounds in urine at least up to 5 days after administration of a single dose of Rohypnol and up to a month in hair.
An inability to remember events, including sexual encounters, is not conclusive evidence of having consumed a drugged drink: Psychotropic CNS depressant drugs such as alcohol can cause blackouts, sleepiness, and a reduction in inhibitions. Only a timely screening for flunitrazepam can demonstrate its use. It has been shown that alcohol alone is the psychotropic substance used in the vast majority of cases of drug-facilitated date-rape. A recent study conducted by doctors in the UK found that none of the subjects reporting spiked drinks had any traces of flunitrazepam or other medications popularly believed to be associated with drug-assisted rape, such as GHB. However, flunitrazepam was prohibited for prescription under the NHS in 1992 (The National Health Service (General Medical Services). Rohypnol (1 mg) is available under private prescription. The study results, however, suggest that binge drinking is more commonly a factor in drug-assisted rapes than pharmaceutical drugs.
In the United Kingdom, the use of flunitrazepam and other "date rape" drugs have been connected to stealing from sedated victims. One expert quoted in a British newspaper estimated that up to 2,000 individuals are robbed each year after being spiked with powerful sedatives, making drug-assisted robbery a more commonly reported problem than drug-assisted rape. In a notable flunitrazepam-related case, Selina Hakki was convicted in December 2004 and sentenced to five years in prison for using flunitrazepam to drug wealthy men and rob them of their clothes and accessories in the UK.
Criminals sometimes use flunitrazepam before committing robbery, as it has a calming and anti-emotive effect. This allows the criminal to perform the robbery without becoming anxious. Flunitrazepam is also known to induce anterograde amnesia making police interrogations more difficult.
Adverse effects of flunitrazepam include dependence, both physical and psychological; reduced sleep quality resulting in somnolence; and overdose, resulting in excessive sedation, impairment of balance and speech, respiratory depression or coma, and possibly death. Because of the latter, flunitrazepam is commonly used in suicide. When used in pregnancy, it might cause hypotonia.
Discontinuation may result in the appearance of withdrawal symptoms when the drug is discontinued. Abrupt withdrawal may lead to a severe benzodiazepine withdrawal syndrome characterised by seizures, psychosis, severe insomnia, and severe anxiety. Rebound insomnia, worse than baseline insomnia, typically occur after discontinuation of flunitrazepam even after short-term single nightly dose therapy.
Flunitrazepam produces a decrease in delta wave activity. The effect of benzodiazepine drugs on delta waves, however, may not be mediated via benzodiazepine receptors. Delta activity is an indicator of depth of sleep within non-REM sleep; increased levels of delta sleep reflects better quality of sleep. Thus, flunitrazepam and other benzodiazepines cause a deterioration in sleep quality. Cyproheptadine may be superior to benzodiazepines in the treatment of insomnia as it enhances sleep quality based on EEG studies. This may lead to somnolence.
Flunitrazepam may cause a paradoxical reaction in some individuals causing symptoms including anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behavior, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour.
Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes and, therefore, rapidly cross over into the placenta with significant uptake of the drug. Use of benzodiazepines including flunitrazepam in late pregnancy, especially high doses, may result in hypotonia, also known as floppy infant syndrome.
Flunitrazepam impairs cognitive functions. This may appear as lack of concentration, confusion and anterograde amnesia. It can be described as a hangover-like effect, with impairment of mental arithmetic abilities.
Impaired psychomotor functions is another adverse effect, affecting reaction time and driving skill. This may also be expressed as impaired coordination, impaired balance and dizziness.
Other adverse effects include:
Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, in alcohol- or drug-dependent individuals, and in individuals with comorbid psychiatric disorders. Impairment of driving skills with a resultant increased risk of road traffic accidents is probably the most important adverse effect. This side-effect is not unique to flunitrazepam but also occurs with other hypnotic drugs. Flunitrazepam seems to have a particularly high risk of road traffic accidents compared to other hypnotic drugs. Extreme caution should be exercised by drivers after taking flunitrazepam.
Flunitrazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs, causes impairments in body balance and standing steadiness in individuals waking up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.
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Flunitrazepam is marketed by Roche most commonly under the trade name Rohypnol. It is also marketed in some countries under the trade names Flunitrazepam, Hipnosedon, Hypnodorm, Flunipam, Nilium, Vulbegal, Silece, Darkene, Ilman, Insom, Inervon and Fluscand. In street slang, the pharmaceutical is commonly referred to as a roofie (USA) or a roh'ie (Australia).
According to FDA Associate Director for Domestic and International Drug Control Nicholas Reuter:
Rohypnol is currently under consideration to be rescheduled to Schedule I, and is already considered such in the States of Florida, Idaho, Minnesota, New Hampshire, New Mexico, North Dakota, Oklahoma, Pennsylvania, and Virginia.
In Australia, flunitrazepam is a schedule 8 drug, along with amphetamines and narcotic analgesics. All other benzodiazepines (except Temazepam) are schedule 4 drugs. Unauthorized possession of certain quantities of the drug is punishable by criminal sanctions in New South Wales under Schedule 1 of the Drug Misuse and Trafficking Act 1985.
On January 1, 2003, flunitrazepam was moved up one level in the schedule of controlled drugs in Norway, and, on August 1, 2004, the manufacturer Roche removed Rohypnol from the market there altogether.
The Dutch, British and French use a system called the System of Objectified Judgement Analysis for assessing whether drugs should be included in drug formularies based on clinical efficacy, adverse effects, pharmacokinetic properties, toxicity and drug interactions. A Dutch analysis using the system found that flunitrazepam is unsuitable to be included in drug prescribing formularies.
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