Flunitrazepam

Flunitrazepam, also known as Rohypnol among other names,[1] is a benzodiazepine used in some countries to treat severe insomnia and assist with anesthesia.[2] As with other hypnotics, flunitrazepam has been advised to be prescribed only on a short-term basis or by those with chronic insomnia on an occasional basis.[2] It is a Schedule IV controlled substance in the United States of America.[3]

Flunitrazepam
Clinical data
Pronunciation/ˌfluːnɪˈtræzɪpæm/
Trade namesRohypnol
Pregnancy
category
  • AU: C
    Routes of
    administration    		By mouth (tablets)
    ATC code
    Legal status
    Legal status
    • AU: S8 (Controlled)
    • CA: Schedule I
    • DE: Anlage III (Special prescription form required)
    • UK: Class C
    • US: Schedule IV

    Sweden schedule II

    • UN: Psychotropic Schedule III
    Pharmacokinetic data
    Bioavailability64–77% (by mouth)
    50% (suppository)
    MetabolismLiver
    Elimination half-life18–26 hours
    ExcretionKidney
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.015.089
    Chemical and physical data
    FormulaC16H12FN3O3
    Molar mass313.3 g/mol g·mol−1
    3D model (JSmol)
      (verify)

    It was patented in 1962 and came into medical use in 1974.[4] Flunitrazepam has been referred to as a date rape drug,[5][6] though the percentage of reported rape cases in which it is involved is small.[7]

    Use
    Rohypnol 1 mg tablets.

    In countries where this drug is used, it is used for treatment of sleeping problems, and in some countries to begin anesthesia.[2][8] These were also the uses for which it was originally studied.[9]

    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 benzodiazepines can lead to drug dependence and benzodiazepine withdrawal syndrome.[10] Discontinuation may result in the appearance of withdrawal symptoms. Abrupt withdrawal may lead to a 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.[11]

    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.[12]

    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.[13]

    Other

    Flunitrazepam impairs cognitive functions. This may appear as lack of concentration, confusion and anterograde amnesia. It can be described as a hangover-like effect which can persist to the next day.[14] 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.[15]

    Other adverse effects include:

    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.[16]

    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.[17][18]

    Interactions

    The use of flunitrazepam in combination with alcoholic beverages synergizes the adverse effects, and can lead to toxicity and death.[7]

    Overdose
    See also: Benzodiazepine overdose

    Flunitrazepam is a drug that is frequently involved in drug intoxication, including overdose.[19][20] 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 benzodiazepine 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 ng/ml; the elimination half life of the drug is 11–25 hours. For urine samples, metabolites can be identified 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.[21]

    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.[22][23][24] Other metabolites include desmethylflunitrazepam and 3-hydroxydesmethylflunitrazepam.

    Pharmacology

    The main pharmacological effects of flunitrazepam are the enhancement of GABA at various GABA receptors.[7]

    While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%.[25]

    Flunitrazepam has a long half-life of 18–26 hours, which means that flunitrazepam's effects after nighttime administration persist throughout the next day.[14]

    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.[26]

    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).[27]

    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.[28][29]

    Due to abuse 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.[21] It was never marketed in the US, and by 2016 had been withdrawn from the markets in Spain, France, Germany, and the UK.[21]

    Society and culture

    Recreational and illegal uses
    Hypnodorm 1 mg flunitrazepam tabs, 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.[30]

    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 abuse potential for benzodiazepines and similar drugs.[31]

    Suicide

    In studies in Sweden, flunitrazepam was the second most common drug used in suicides, being found in about 16% of cases.[32] 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 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.[33][34]

    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.[35][36] 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.[21]

    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.[7]

    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,[37] 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.[38]

    • 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][39]
    • In France, as of 2016 flunitrazepam was not marketed.[21]
    • 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).[40]
    • In Ireland, flunitrazepam is a Schedule 3 controlled substance with strict restrictions.[41]
    • In Japan, flunitrazepam is marketed by Japanese pharmaceutical company Chugai under the tradename Rohypnol and is indicated for the treatment of insomnia as well as used for preanesthetic medication.[8]
    • In Mexico, Rohypnol is approved for medical use.
    • 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.[42]
    • In South Africa, Rohypnol is classified as a schedule 6 drug.[43] 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, flunitrazepam is available from Mylan.[44] It is listed as a List II (Schedule II) under the Narcotics Control Act (1968).
    • In the United Kingdom, flunitrazepam is not licensed for medical use[18][21] and is a controlled drug under Schedule 3 and Class C[45]
    • 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.[21][46] 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.[10]

    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".[10]

    References
    1. Drugs.com International brands for Flunitrazepam Page accessed April 13, 2016
    2. "Prescribing of Benzodiazepines Alprazolam and Flunitrazepam" (PDF). Pharmaceutical Services Branch. New South Wales Health. November 2013.
    3. United States Drug Enforcement Administration. https://www.dea.gov/factsheets/rohypnol Archived: https://web.archive.org/web/20190721033343/https://www.dea.gov/factsheets/rohypnol Retrieved July 20, 2019 22:34 CST
    4. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 53X. ISBN 9783527607495.
    5. Schwartz, R. H.; Milteer, R.; LeBeau, M. A. (June 2000). "Drug-facilitated sexual assault ('date rape')". Southern Medical Journal. 93 (6): 558–561. doi:10.1097/00007611-200093060-00002. ISSN 0038-4348. PMID 10881768.
    6. Gautam, Lata; Sharratt, Sarah D.; Cole, Michael D. (February 19, 2014). "Drug Facilitated Sexual Assault: Detection and Stability of Benzodiazepines in Spiked Drinks Using Gas Chromatography-Mass Spectrometry". PLoS ONE. 9 (2): e89031. doi:10.1371/journal.pone.0089031. ISSN 1932-6203. PMC 3929633. PMID 24586489.
    7. European Monitoring Centre for Drugs and Drug Addiction Benzodiazepines drug profile. Page last updated January 8, 2015
    8. "Kusuri-no-Shiori Drug Information Sheet". RAD-AR Council, Japan. October 2015. Retrieved June 13, 2016.
    9. Mattila, MA; Larni, HM (November 1980). "Flunitrazepam: a review of its pharmacological properties and therapeutic use". Drugs. 20 (5): 353–74. doi:10.2165/00003495-198020050-00002. PMID 6108205.
    10. Center for Substance Abuse Research at the University of Maryland Flunitrazepam (Rohypnol) Last Updated on Tuesday, October 29, 2013
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    43. "Drug Wars – About Drugs". October 11, 2006.
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    46. DEA [Lists of Scheduling Actions Controlled Substances Regulated Chemicals May 2016]
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