Flunitrazepam

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Flunitrazepam
Flunitrazepam structure.svg
Flunitrazepam-from-xtal-3D-balls.png
Clinical data
Pronunciation/ˌfluːnɪˈtræzɪpæm/
Trade namesRohypnol
Pregnancy
category
  • AU: C
Routes of
administration		By mouth
Drug classBenzodiazepine
ATC code
Legal status
Legal status
  • AU: S8 (Controlled drug)
  • CA: Schedule I
  • DE: Anlage III (Special prescription form required)
  • UK: Class C
  • US: Schedule IV
  • UN: Psychotropic Schedule III
Pharmacokinetic data
Bioavailability64–77% (by mouth)
50% (suppository)
MetabolismLiver
Metabolites7-aminoflunitrazepam, desmethylflunitrazepam and 3-hydroxydesmethylflunitrazepam
Elimination half-life18–26 hours
ExcretionKidney
Identifiers
IUPAC name
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.015.089 Edit this at Wikidata
Chemical and physical data
FormulaC16H12FN3O3
Molar mass313.288 g·mol−1
3D model (JSmol)
SMILES
InChI
  

Flunitrazepam, also known as Rohypnol among other names,[1] is a benzodiazepine used to treat severe insomnia and assist with anesthesia.[2] As with other hypnotics, flunitrazepam has been advised to be prescribed only for short-term use or by those with chronic insomnia on an occasional basis.[2] It is said to be 10 times more potent than diazepam.[3]

It was patented in 1962 and came into medical use in 1974.[4] Flunitrazepam, nicknamed "roofies," has been referred to as a date rape drug.[5][6]

Use[]

Rohypnol 1 mg tablets.

In countries where this drug is used, it is used for treatment of severe cases of sleeping problems, and in some countries as a preanesthetic agent.[2][7] These were also the uses for which it was originally studied.[8]

It has also been administered as a concurrent dose for patients that are taking ketamine. Rohypnol lowers the side effects of the anesthetic (ketamine), resulting in less confusion in awakening states, less negative influence on pulse rate, and fewer fluctuations in blood pressure.[9]

It has also been shown to have therapeutic use in polysubstance use when combined with anesthetics, opioids, ethanol, cocaine, and methamphetamine.[10]

Adverse effects[]

Adverse effects of flunitrazepam include dependency, 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 late pregnancy, it might cause hypotonia of the fetus.

Dependence[]

Flunitrazepam, as with other benzodiazepines, can lead to drug dependence.[11] Discontinuation may result in benzodiazepine withdrawal syndrome, characterised by seizures, psychosis, insomnia, and anxiety. Rebound insomnia, worse than baseline insomnia, typically occurs after discontinuation of flunitrazepam even from short-term single nightly dose therapy.[12]

Paradoxical effects[]

Flunitrazepam may cause a paradoxical reaction in some individuals, 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.[13]

Hypotonia[]

See also: Hypotonia

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 baby syndrome.[14]

Other[]

Flunitrazepam impairs cognitive functions. This may appear as lack of concentration, confusion and anterograde amnesia—the inability to create memories while under the influence. It can be described as a hangover-like effect which can persist to the next day.[15] It also impairs psychomotor functions similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs; falls and hip fractures were frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.[16]

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.[17]

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.[18][19]

Interactions[]

The use of flunitrazepam in combination with alcoholic beverages synergizes the adverse effects, and can lead to toxicity and death.[20]

Overdose[]

See also: Benzodiazepine overdose

Flunitrazepam is a drug that is frequently involved in drug intoxication, including overdose.[21][22] Overdose of flunitrazepam may result in excessive sedation, or impairment of balance or 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 ethanol (alcohol) and opioids. Flunitrazepam overdose responds to the GABAA receptor antagonist flumazenil, which thus can be used as a treatment.

Detection[]

As of 2016, blood tests can identify flunitrazepam at concentrations of as low as 4 nanograms per millilitre; the elimination half life of the drug is 11–25 hours. For urine samples, metabolites can be identified for 60 hours to 28 days, depending on the dose and analytical method used. Hair and saliva can also be analyzed; hair is useful when a long time has transpired since ingestion, and saliva for workplace drug tests.[23]

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 substance use 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.[24][25][26] Other metabolites include desmethylflunitrazepam and 3-hydroxydesmethylflunitrazepam.

Pharmacology[]

The main pharmacological effects of flunitrazepam are the enhancement of GABA, an inhibitory neurotransmitter, at various GABA receptors.[20]

While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%.[27]

Flunitrazepam has a long half-life of 18–26 hours, which means that flunitrazepam's effects after nighttime administration persist throughout the next day.[15] This is due to the production of active metabolites. These metabolites further increase the duration of drug action compared to benzodiazepines that produce nonactive metabolites.[28]

Flunitrazepam is lipophilic and is metabolised by the liver via oxidative pathways. The enzyme CYP3A4 is the main enzyme in its phase 1 metabolism in human liver microsomes.[29]

Chemistry[]

Flunitrazepam is classed as a nitro-benzodiazepine. It is the fluorinated N-methyl derivative of nitrazepam. Other nitro-benzodiazepines include nitrazepam (the parent compound), nimetazepam (methylamino derivative) and clonazepam (2ʹ-chlorinated derivative).[30]

History[]

Flunitrazepam was discovered at Roche as part of the benzodiazepine work led by Leo Sternbach; the patent application was filed in 1962 and it was first marketed in 1974.[31][32]

Due to use of the drug for date rape and recreation, in 1998 Roche modified the formulation to give lower doses, make it less soluble, and add a blue dye for easier detection in drinks.[23] It was never marketed in the United States, and by 2016 had been withdrawn from the markets in Spain, France, Norway, Germany, and the United Kingdom.[23]

Society and culture[]

Recreational and illegal uses[]

Hypnodorm 1 mg flunitrazepam tablets, Australia
Rohypnol

Recreational use[]

A 1989 article in the European Journal of Clinical Pharmacology reports that benzodiazepines accounted for 52% of prescription forgeries, suggesting that benzodiazepines was a major prescription drug class of abuse. Nitrazepam accounted for 13% of forged prescriptions.[33]

Flunitrazepam and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other benzodiazepines and nonbenzodiazepines (anxiolytic or hypnotic) such as zolpidem and zopiclone (as well as 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 potential for addiction for benzodiazepines and similar drugs.[34]

Suicide[]

In studies in Sweden, flunitrazepam was the second most common drug used in suicides, being found in about 16% of cases.[35] In a retrospective Swedish study of 1,587 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 4 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.[36][37]

Drug-facilitated sexual assault[]

Main article: 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, which complicates investigations.[38][39] This effect could be particularly dangerous if 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.[23]

While use of flunitrazepam in sexual assault has been prominent in the media, as of 2015 appears to be fairly rare, and use of alcohol and other benzodiazepine drugs in date rape appears to be a larger but underreported problem.[20]

Drug-facilitated robbery[]

In the United Kingdom, the use of flunitrazepam and other "date rape" drugs have also been connected to stealing from sedated victims. An activist quoted by a British newspaper estimated that up to 2,000 individuals are robbed each year after being spiked with powerful sedatives,[40] making drug-assisted robbery a more commonly reported problem than drug-assisted rape.

Regional use[]

Flunitrazepam is a Schedule III drug under the international Convention on Psychotropic Substances of 1971.[41]

  • In Australia, as of 2013 the drug was authorized for prescribing for severe cases of insomnia but was restricted as a Schedule 8 medicine.[2][42]
  • In France, as of 2016 flunitrazepam was not marketed.[23]
  • In Germany, as of 2016 flunitrazepam is an Anlage III Betäubungsmittel (controlled substance which is allowed to be marketed and prescribed by physicians under specific provisions) and is available on a special narcotic drug prescription as the Rohypnol 1 mg film-coated tablets and several generic preparations (November 2016).[43]
  • In Ireland, flunitrazepam is a Schedule 3 controlled substance with strict restrictions.[44]
  • In Japan, flunitrazepam is marketed by Japanese pharmaceutical company Chugai under the trade name Rohypnol and is indicated for the treatment of insomnia as well as used for preanesthetic medication.[7]
  • In Mexico, Rohypnol is legally available[45] and approved for medical use.[citation needed]
  • In Norway, on January 1, 2003, flunitrazepam was moved up one level in the schedule of controlled drugs and, on August 1, 2004, the manufacturer Roche removed Rohypnol from the market there altogether.[46]
  • In South Africa, Rohypnol is classified as a Schedule 6 drug.[47] It is available by prescription only, and restricted to 1 mg doses.
Icelandic Flunitrazepam
  • In Iceland, Flunitrazepam is a controlled substance available from Mylan. It is prescribed for severe insomnia and is sometimes used before surgery to induce a calm, relaxed state of mind for the patient.[48]
  • In Sweden, flunitrazepam was previously available from Mylan,[49] but has been removed from the market in January 2020.[50] It is listed as a List II (Schedule II) under the Narcotics Control Act (1968).[citation needed]
  • In the United Kingdom, flunitrazepam is not licensed for medical use[19][23] and is a controlled drug under Schedule 3 and Class C.[51]
  • In the United States, the drug has not been approved by the Food and Drug Administration and is considered to be an illegal drug; as of 2016 it is Schedule IV.[23][52] 21 U.S.C. § 841 and 21 U.S.C. § 952 provide for punishment for the importation and distribution of up to 20 years in prison and a fine; possession is punishable by three years and a fine.[11] Travelers travelling into 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.

Names[]

Flunitrazepam is marketed under many brand names in the countries where it is legal.[1] It also has many street names, including "roofie" and "ruffie".[11] It is also known as Circles, Forget Me Pill, La Rocha, Lunch Money Drug, Mexican Valium, Pingus, R2, and Roach 2.[53]

References[]

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