Flunitrazepam

[floo-ni-traz-uh-pam]

Flunitrazepam is a highly potent hypnotic drug with powerful sedative, anxiolytic, amnestic, and skeletal muscle relaxant properties. A short-intermediate acting benzodiazepine derivative, flunitrazepam is prescribed for the treatment of severe insomnia, marketed by Roche most commonly under the trade name Rohypnol -also marketed in some countries under the trade names Hipnosedon, Hypnodorm, Nilium, Vulbegal, Silece, Darkene, Ilman and Insom.

The prescription of flunitrazepam as a hypnotic is generally tended to be for short-term treatment of chronic, or severe insomnias that are not responsive to other hypnotics, especially in inpatients. It is considered to be one of the most potent benzodiazepine hypnotic on effect, rather than on dose basis; i.e., its hypnotic effect is considered to be one of the most strongly pronounced of all benzodiazepine hypnotics available. Use of flunitrazepam among recreational drug users is considerable and any possession of flunitrazepam without a valid prescription is illegal.

Just as with other hypnotics, flunitrazepam should only be used on a short term basis or in those with chronic insomnia on an occasional basis.

The drug is sometimes used as a date rape drug (commonly referred to in street slang as a "roofie").

Flunitrazepam is classed as a nitrobenzodiazepine. Other nitrobenzodiazepines include nitrazepam and clonazepam.

Pharmacokinetics

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

Benzodiazepines such as flunitrazepam are lipophilic and rapidly penetrate membranes.

Flunitrazepam has a long half-life of 18 - 26 hours and an active metabolite which has a half life of 36-200 hours, which means flunitrazepam effects after nighttime administration persist throughout the next day. Residual 'hangover' effects after nighttime administration of flunitrazepam such as sleepiness, impaired psychomotor and cognitive may persist into the next day which may impair the ability of users to drive safely and increase risks of falls and hip fractures.

Flunitrazepam is lipophilic and is metabolised hepatically via oxidative pathways. The enzyme CYP3A4 is the main enzyme in its phase 1 metabolism.

Pharmacology

Benzodiazepines, including flunitrazepam, bind to mouse glial cell membranes with high affinity. Flunitrazepam induces melanogenesis in rat melanoma cells via modulating high affinity binding sites. Benzodiazepines, including flunitrazepam have been shown to act via micromolar 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.

Desired effects

The main pharmacological effects of flunitrazepam are the enhancement of GABA at the GABA_A receptor. Like other benzodiazepines, flunitrazepam's pharmacological effects include sedation, muscle relaxation, reduction in anxiety, and prevention of convulsions.

Flunitrazepam's effects are approximately 7 to 10 times more potent than diazepam. 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.

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 floppy infant syndrome.

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.

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 poorer 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.

Overdose

Flunitrazepam is a drug which is very 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 alcohol, opiates or other CNS depressants.

This lethal effect of flunitrazepam overdose is commonly used in suicide, as seen in Abuse potential section.

Flunitrazepam overdose responds to the benzodiazepine receptor antagonist flumazenil, which thus can be used as a treatment.

Floppy infant syndrome

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 floppy infant syndrome.

Other

After discontinuation of flunitrazepam a rebound effect may occur about 4 days after stopping flunitrazepam. (See benzodiazepine withdrawal syndrome)

Flunitrazepam impairs cognitive functions. This may appear as a 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

Interactions

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

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, Flunitrazepam use is still present in modern culture; among other uses, it is used in some hospitals to sedate patients undergoing colonoscopy.
In the Netherlands, flunitrazepam is a List 2 substance of the Opium Law and is available for prescription as 1mg Rohypnol brand tablets by Roche, and as 1mg and 2mg generic tablets.
In Ireland, flunitrazepam is a Schedule 3 controlled substance with strict restrictions.
In Singapore, flunitrazepam is a Class C controlled drug, making it illegal to possess without a proper medical prescription.
In Japan, flunitrazepam is marketed by the Japanese pharmaceutical company Chugai under the tradename Rohypnol, and is indicated for the treatment of insomnia as well as used for preanesthetic medication.
In Greece, flunitrazepam is available as Hipnosedon in 1mg preparation and as Vulbegal and Nilium in 2mg preparations.
In Australia, prescription is restricted as a Schedule 8 medicine. 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 South Africa, Rohypnol is classified as a schedule 6 drug. 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, flunitrazepam is available as a prescription drug to treat insomnia under the brand name Flunipam 1 mg. Only four hypnotics are prescribable in Norway: flunitrazepam, nitrazepam, zolpidem and zopiclone.
In Sweden, the brand Rohypnol has been withdrawn from the domestic market. It is available as a generic and under the name Fluscand. Although it has for a long time been a first line drug for the treatment of insomnia, due to the stigma connected to it, flunitrazepam prescriptions are very hard to get nowadays. Much more common are nitrazepam but above all zopiclone, zolpidem, and zaleplon.
In Mexico, Rohypnol is approved for medical use, however there have been many cases of trafficking of Rohypnol to the United States and other developed nations, most of it originating from Mexico.
In Germany, flunitrazepam is available as the Roche-Brand Rohypnol 1 mg Film-Coated Tablets and several generic 1 mg tablets (e.g. Fluninoc, Flunitrazepam ratiopharm, Flunitrazepam neuraxpharm).

Abuse potential

Despite the fact that flunitrazepam is a Schedule IV controlled substance, it is not commercially available in the United States. Currently the DEA is recommending that Rohypnol be reclassified to Schedule I.

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.

It is difficult to estimate just how many flunitrazepam-facilitated rapes have occurred in the past. 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.

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 newspaper 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.

In a notable flunitrazepam related case, Selina Hakki was found guilty in December 2004 of using flunitrazepam to drug wealthy men and rob them of their clothes and accessories in the UK.

Recreational drug

Although 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 increase sedative effect in combination with 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

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.

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 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 and zolpidem and zopiclone 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 zolpidem and zopiclone.

Suicide

In studies in Sweden, flunitrazepam was the second most common drug used in suicides, being found in about 15% of cases. In a retrospective study of deaths, when benzodiazepines were implicated, the benzodiazepines flunitrazepam and nitrazepam were the most common benzodiazepines involved. In four of the cases benzodiazepines alone were the only cause of death. It was concluded that flunitrazepam and nitrazepam might be more toxic than other benzodiazepines.

Legal status

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

According to FDA Associate Director for Domestic and International Drug Control Nicholas Reuter:

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, and Pennsylvania. and 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 and on August 1st 2004 the manufacturer Roche removed Rohypnol from the market in Norway.

Alternatives

Intermediate half life benzodiazepines are also useful for patients with difficulty in maintaining sleep e.g. loprazolam, lormetazepam, temazepam and may be preferable to long half life benzodiazepines which typically cause next day sedation and impairments.

Street terms

Street names for Rohypnol include rophy, rufflels, roachies, roofies, ruffies, ruff up, rib, roach 2 (R2), roche, rope, ropies, circles, circes, forget it, forget-me-pill, Mexican Valium, and Run-Trip-And-Fall

History

Flunitrazepam was first synthesized in 1972 by Roche 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 U.S. in the early 1990s. It originally came in 1 mg and 2 mg doses, 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 only available as 1mg tablets. In the countries where flunitrazepam is available for prescription as both 1mg and 2mg tablets, such as the Netherlands, generic alternatives are available for the 2mg tablets.