Flunitrazepam

Flunitrazepam

Systematic (IUPAC) name
6-(2-fluorophenyl)-2-methyl-9-nitro-2,5-diazabicyclo[5.4.0]undeca-5,8,10,12-tetraen-3-one
Clinical data
Pregnancy cat.	C(AU)
Legal status	Controlled (S8) (AU) CD No Reg POM (UK) Schedule IV (US) III (International)
Routes	Oral
Pharmacokinetic data
Bioavailability	50% (suppository) 64–77% (oral)
Metabolism	Hepatic
Half-life	18–26 hours
Excretion	Renal
Identifiers
CAS number	1622-62-4 Y
ATC code	N05CD03
PubChem	CID 3380
DrugBank	DB01544
ChemSpider	3263 Y
UNII	620X0222FQ Y
KEGG	D01230 Y
ChEMBL	CHEMBL13280 Y
Chemical data
Formula	C16H12FN3O3
Mol. mass	313.3
SMILES	eMolecules & PubChem
InChI InChI=1S/C16H12FN3O3/c1-19-14-7-6-10(20(22)23)8-12(14)16(18-9-15(19)21)11-4-2-3-5-13(11)17/h2-8H,9H2,1H3 Y Key:PPTYJKAXVCCBDU-UHFFFAOYSA-N Y
Y(what is this?)  (verify)

Flunitrazepam ( /ˌfluːnɨˈtræzɨpæm/) is marketed as a potent hypnotic, sedative, anticonvulsant, anxiolytic, amnestic, and skeletal muscle relaxant drug ^[1] 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.^[2]

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.^[3]

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.^[4]

History

Flunitrazepam was first synthesized in 1960 by Roche^[5] 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 the early 1990s. It originally came in doses of 1 mg and 2 mg, but, due to its potency and potential for abuse, the higher doses of Rohypnol were soon taken off the market by its producer, Roche, and it is now available only as 1 mg tablets. 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.

Pharmacology

Benzodiazepines, including flunitrazepam, bind to most glial cell membranes with high affinity in mouse astrocytes.^[6] Flunitrazepam induces melanogenesis in B16/C3 mouse melanoma cell cultures via modulating high-affinity binding sites.^[7] 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.^[8]

Mechanism of action

The main pharmacological effects of flunitrazepam are the enhancement of GABA at the GABA_A receptor.^[9] 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.

Pharmacokinetics

While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%.^[10]

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.^[11] 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.^[12]

Flunitrazepam is lipophilic and is metabolised hepatically via oxidative pathways. The enzyme CYP3A4 is the main enzyme in its phase 1 metabolism in human liver microsomes.^[13]

Interactions

The use of flunitrazepam in combination with alcohol synergizes the adverse effects, and can lead to toxicity and death.

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.^{[citation needed]}

Overdose

See also: Benzodiazepine overdose

Flunitrazepam is a drug that is frequently involved in drug intoxication, including overdose.^[14][15] 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.

Presence in bodily fluids

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.^[16][17][18]

Other uses

Hypnodorm 1mg Flunitrazepam tabs, Australia

Rohypnol

Recreational use

See also: Benzodiazepine drug misuse

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 (who call a dose of flunitrazepam a "roofie") for recreational purposes, including:

• To produce profound intoxication
• To increase sedative effect in combination with heroin (or any other opiate) and/or get desired effects from a smaller dose, or ease the anxiety and/or sleeplessness of withdrawal
• To counteract the side-effects of stimulants (e.g., insomnia, paranoia, jitteriness)
• To "soften" the so-called "crash," which follows heavy usage of stimulants, such as cocaine or methamphetamine

Flunitrazepam is usually consumed orally, and is sometimes combined with alcohol (benzodiazepines and alcohol combined intensify each others' 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.^[19]

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.^[20]

Street names for Rohypnol include "rophy", "ruffles", "roachies", "roofies", "ruffies", "ruff-up", "rib", "rips", "roach 2 (R2)", "roche", "rope", "ropies", "circles", "circes", "forget it", "forget-me-now", "Mexican Valium".^[21][22]

Suicide

In studies in Sweden, flunitrazepam was the second-most-common drug used in suicides, being found in about 15% of cases.^[23] 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.^[24]

Drug-facilitated sexual assault

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 available in the United States. 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.^[25]

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 U.K. 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 is not prescribed in the UK and the study size was based on only 75 people, which may in part account for the findings. The study results, however, do suggest that binge drinking is much more commonly to blame for drug-assisted rapes than pharmaceutical drugs.^[26]

Drug-facilitated robbery

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,^[27] making drug-assisted robbery a more common problem than drug-assisted rape.

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.^[28][29][30] In a notable flunitrazepam-related case, Selina Hakki was convicted in December 2004 and sentenced to five years in prison for using rohypnol (flunitrazepam) to drug wealthy men and rob them of their clothes and accessories in the UK.^[31]

Adverse effects

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.

Dependence

Flunitrazepam as with other benzodiazepine drugs can lead to physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome.

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.^[32]

Sleep depth

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.^[33] This may lead to somnolence.

Paradoxical effects

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.^[34]

Hypotonia

See also: Hypotonia

Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes and, therefore, rapidly crosses 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.^[35]

Other

After discontinuation of flunitrazepam, a rebound effect may occur about 4 days after stopping flunitrazepam.^[36] (See benzodiazepine withdrawal 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:

• Slurred speech
• Gastrointestinal disturbances, lasting 12 or more hours/Vomiting
• Respiratory depression in higher doses

Special precautions

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.^[37] 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.^[38]

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.^[39]

Regional use

• In Australia, prescription is restricted as a Schedule 8 medicine.^[40][41] It is used primarily for the treatment of severe insomnia that has not responded to other treatments. In some states, it is also manufactured in generic form by Alphapharm under the name Hypnodorm. As a Schedule 8 medicine, it is illegal to have this drug in possession without an authority prescription from a registered doctor.
• In France, Rohypnol is prescribed by physicians, it is under the maximum list, being prescribed only when other drugs will not do, prescription nonrenewable (a new doctor visit every time), and being available only in 7-pill, in theory one-week, packaging.
• In Germany, flunitrazepam is available for prescription as the Roche-Brand Rohypnol 1 mg Film-Coated Tablets and several generic 1 mg tablets (e.g., Fluninoc, Flunitrazepam ratiopharm, Flunitrazepam neuraxpharm).
• In Ireland, flunitrazepam is a Schedule 3 controlled substance with strict restrictions.^[42]
• In Japan, flunitrazepam is marketed by Japanese pharmaceutical company Chugai under the tradename Rohypnol, by Japanese pharmaceutical company Eisai under the name of Silece and by some manufacturers as generic drugs. Flunitrazepam is indicated for the treatment of insomnia as well as used for preanesthetic medication.^[43][44][45]
• In Mexico, Rohypnol is approved for medical use.
• In the Netherlands, flunitrazepam is a List 2 substance of the Opium Law and is available for prescription as 1 mg Rohypnol brand tablets by Roche, and as 1 mg and 2 mg generic tablets.
• In Norway, flunitrazepam is available as a prescription drug to treat insomnia under the brand name Flunipam 1 mg. It is a Class A substance under Norway's Narcotics Act. Only four hypnotics are prescribable in Norway: flunitrazepam, nitrazepam, zolpidem and zopiclone.^[46]
• In Singapore, flunitrazepam is a Class C controlled drug (Schedule II), making it illegal to possess without a proper medical prescription.
• In Slovenia, it is regulated as a Group III (Schedule 3) controlled substance under The Production and Trade in Illicit DrugsAct. About 20 years ago, Rohypnol was indicated for treatment of insomnia as well as used for preanesthetic medication, replaced mainly with Dormicum (midazolam), which has very similar properties.
• In South Africa, Rohypnol is classified as a schedule 6 drug.^[47] It is available by prescription only, and restricted to 1 mg doses. Travelers from South Africa to the United States are limited to a 30-day supply. The drug must be declared to US Customs upon arrival. If a valid prescription cannot be produced, the drug may be subject to Customs search and seizure, and the traveler may face criminal charges or deportation.
• In Sweden, the brand Rohypnol has been withdrawn from the domestic market. It is available as a generic and under the name Fluscand. It is listed as a List IV (Schedule IV) under the Narcotics Control Act (1968). Although it has for a long time been a first-line drug for the treatment of insomnia, it has seen declines in prescriptions in recent years. Much more common are nitrazepam, but above all zopiclone and zolpidem.
• In the United Kingdom, the drug is available only by private prescription.^[48] Though Rohypnol was discontinued in 1986, Flunitrazepam use is still present in modern culture; among other uses, it is used in some hospitals to sedate patients undergoing colonoscopy.
• In the United States, the drug has not been approved by the Food and Drug Administration and is considered to be an illegal drug.^[49][50]

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).

Flunitrazepam is currently a Schedule III drug under the international Convention on Psychotropic Substances of 1971;^[51] in the United States, it is on Schedule IV

According to FDA Associate Director for Domestic and International Drug Control Nicholas Reuter:^[52]

Flunitrazepam was "temporarily controlled in Schedule IV pursuant to a treaty obligation under the 1971 Convention on Psychotropic Substances. At the time flunitrazepam was placed temporarily in Schedule IV . . . there was no evidence of abuse or trafficking of the drug in the United States."

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.

21 U.S.C. § 841 and 21 U.S.C. § 952 provide for stiff prison terms for the possession of flunitrazepam; penalties for use or distribution include life in prison, should death or serious injury occur.

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.^[53]

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.^[54]

See also

• Benzodiazepines
• Date rape drugs
• Gamma-Hydroxybutyric acid (GHB)
• Long-term effects of benzodiazepines
• Nimetazepam
• Nitrazepam
• Scopolomine
• Temazepam
• Twilight sleep

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External links

• Inchem.org - Retrieved 2007-2-27
• Drugs Factfile on Rohypnol all you need to know
• Molecule of the Month
• Statement on "Date Rape" Drugs by Nicholas Reuter, M.P.H., Mar. 11, 1999.
• Club Drugs - Fact Sheet by Drug Policy Information Clearing House, United States.