Flunitrazepam

Done by: Neda’a Al-Muallem

Introduction

• Flunitrazepam (formerly marketed under the trade name Rohypnol )

• is a powerful hypnotic drug which is a benzodiazepine derivative. It has powerful hypnotic, sedative, anxiolytic, and skeletal muscle relaxant properties. The drug is sometimes abused as a date rape drug.

History

• Flunitrazepam was first synthesized in the early 1970s by Roche and was used in hospitals when deep sedation was needed. It first entered the commercial market in Europe in 1975, and in the 1980s it began to be available in other countries. It first appeared in the U.S. in the early 1990s.

• It originally came in 1 mg, 2 mg, and 5 mg doses, but due to its potency and potential for abuse the higher doses were soon taken off the market and it is now only available in 1 mg.

Pharmacology

• flunitrazepam's pharmacological effects include sedation, muscle relaxation, reduction in anxiety, and prevention of convulsions .

• However, flunitrazepam's effects are approximately 7 to 10 times more potent than diazepam.

Cont.

• The effects of flunitrazepam appear approximately 15 to 20 minutes after oral administration, and last for approximately four to six hours. Some residual effects can persist up to 12 hours or more after administration.

Medical uses • In the United States, the drug has not been approved by the

Food and Drug Administration for medical use, and is considered to be an illegal drug.

• In the United Kingdom, the drug is available only by private prescription. Though Rohypnol was discontinued in 1986, Rohypnol use is still present in modern culture; among other uses, it is used in some hospitals to sedate patients undergoing colonoscopy.

• In Australia, prescription is restricted. It is used primarily for the treatment of severe insomnia that has not responded to other treatments.

• In South Africa, Rohypnol is classified as a schedule 6 drug in. 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• In Norway, Rohypnol has been withdrawn from market because of its reputation, but the drug is still available under the brand-name Flunipam.

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 not be able to clearly recall the assault, the assailant, or the events surrounding the assault.

• 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.

• It must be noted that an inability to remember events, including sexual encounters, is not conclusive evidence of having consumed a drugged drink: Drunkenness itself causes 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 substance used in the vast majority of cases of 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 rape such as GHB. The study claims that binge drinking was to blame.

Drug-facilitated robbery • In the United Kingdom, the use of flunitrazepam

and other "date rape" drugs has been connected to stealing from sedated victims. One expert quoted in a British tabloid estimated that up to 2,000 individuals are robbed each year after being spiked with powerful sedatives, 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.

Recreational drug • flunitrazepam has become widely known in USA for

its use as a date-rape drug, it is used more frequently as a recreational drug. It is 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 (Kurt Cobain overdosed on a mixture of flunitrazepam and champagne several weeks before his death)

• To boost the high produced by heroin, 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

• To improve sex drive and appetite.

Cont.

• Flunitrazepam is usually consumed orally, and is often combined with alcohol. 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.

Side effects • Flunitrazepam is considered to be one of the most

addictive of the benzodiazepines, along with clonazepam, midazolam, alprazolam, and particularily, temazepam, nitrazepam, and nimetazepam. Its use causes several notable side effects, including:

• Drowsiness • Loss of motor control

– Dizziness – Lack of coordination

• Slurred speech • Amnesia • Confusion • Gastrointestinal disturbances, lasting 12 or more

hours. • Respiratory depression in higher doses

Cont.

• Long-term use of flunitrazepam can result in psychological and physical dependence and the appearance of withdrawal symptoms when the drug is discontinued.

• Flunitrazepam impairs cognitive and psychomotor functions, affecting reaction time and driving skill. The use of this drug in combination with alcohol potentiates these side effects, and can lead to toxicity.

HPLC analysis • A new analytical methodology was developed for

simultaneous high-performance liquid chromatographic quantitation of nitrazepam, estazolam, flunitrazepam, and triazolam in plasma. After addition of the internal standard nor-prazepam, biological samples and calibration standards were extracted at basic pH into diethyl ether-methylene chloride (2:1, v/v). The reconstituted extract was separated on a reversed-phase Nova Pak C18 column with acidic buffer (6mM)-acetonitrile-methanol (64:23:13, v/v) as mobile phase. The detection was performed at 242 nm. Within-run and day-to-day precision values were about 2-8%.

• The method is thus sensitive and reproducible for use in clinical and experimental toxicokinetic studies.

Gas chromatographic analysis• A rapid method for the determination of flunitrazepam

and desmethylflunitrazepam in human serum in the range 10-300 ng/ml is described. Both drugs are isolated from biological material by means of a single extraction, part of the organic phase is evaporated to dryness and the residue is dissolved in a small volume of benzene. Without further purification, the substance is determined gas chromatographically with an electron-capture detector configuration of 63Ni-type. The method permits the quantitative determination of at least 25-300 ng/ml with an overall recovery of flunitrazepam of 99.7 +/- 4.9% and of desmethylflunitrazepam of 98.6 +/- 7.8% from serum. All calculations were carried out by a data system that was programmed for this purpose. The limit of detection for flunitrazepam is of the order of 1 ng/ml in serum.

• The method is sufficiently sensitive and specific for therapy control purposes. The time needed for an analysis is less than 1 h.

Hair Analysis using GC–MS-

NCI • The method involved decontamination of hair

samples with dichloromethane, incubation in Sorenson buffer (pH 7.6) in the presence of diazepam-d5 used as internal standard, direct liquid–liquid extraction with diethylether–chloroform (80:20, v/v), derivatization with heptafluorobutyric anhydride and analysis by gas chromatography coupled to mass spectrometry in the negative chemical ionization mode of detection. Flunitrazepam and its major metabolite, 7-amino-flunitrazepam, were both detected. The concentrations determined in the proximal hair segment were 89.5 and 24.0 pg/mg for flunitrazepam and 7-amino-flunitrazepam, respectively.

PRECAUTIONS 1. Benzodiazepines should not be used alone to treat

depression or anxiety associated with depression. Suicide may be precipitated in such patients.

2. The should not be used for phobic or obsessional states.

3. They should not be used for the treatment of chronic psychosis.

4. In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

5. Disinhibiting effects may be manifested in various ways. Suicide may be precipitated in patients who are depressed, and aggressive behaviour towards self and others may be precipitated.Extreme caution should therefore be used in prescribing benzodiazepines in patients with personality disorders.

Cont.

6. The lowest dose which can control the symptoms should be used. It should not be continued beyond four weeks.

7. Long-term chronic use is not recommended.

8. Treatment should always be tapered off gradually.

9. Patients who have taken benzodiazepines for a long time may require a longer period during which doses are reduced.

10. When a benzodiazepine is used as a hypnotic, treatment should, if possible, be intermittent.