Flunitrazepam

Last updated

Flunitrazepam
Flunitrazepam structure.svg
Flunitrazepam-from-xtal-3D-balls.png
Clinical data
Pronunciation /ˌfluːnɪˈtræzɪpæm/
Trade names Rohypnol
Pregnancy
category
  • AU:C
Addiction
liability 		Moderate
Routes of
administration 		Oral
Drug class Benzodiazepine
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 64–77% (by mouth)
50% (suppository)
Metabolism Liver
Metabolites 7-aminoflunitrazepam, desmethylflunitrazepam and 3-hydroxydesmethylflunitrazepam
Elimination half-life 18–26 hours
Excretion Kidney
Identifiers
  • 5-(2-fluorophenyl)-1-methyl-7-nitro-1H-benzo[e][1,4]diazepin-2(3H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.015.089 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H12FN3O3
Molar mass 313.288 g·mol−1
3D model (JSmol)
Melting point 170–172 °C (338–342 °F)
  • CN1C(=O)CN=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
  • 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 Yes check.svgY
  • Key:PPTYJKAXVCCBDU-UHFFFAOYSA-N Yes check.svgY
   (verify)

Flunitrazepam, also known as Rohypnol among other names, [2] is a benzodiazepine used to treat severe insomnia and assist with anesthesia. [3] 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. [3]

Contents

It was patented in 1962 and came into medical use in 1974. [4] Flunitrazepam, nicknamed "roofies" or "floonies", is widely known for its use as a date rape drug. [5] [6]

Use

Rohypnol 1 mg tablets. Rohypnol.jpg
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. [3] [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]

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 among the elderly. [10] 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

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:

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

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 4–12 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] All benzodiazepines work by enhancing the effect of GABA receptors, which, when active, allow chloride ions to enter the neuron. [27] Negative ions such as chloride inhibit the ability of neurons to fire. It is this stimulation of GABA receptors which is responsible for the depressant effects of benzodiazepines. Flunitrazepam shows high affinity for the α-5 subunit of the GABA-A receptor, which causes some of its unique side effects, such as amnesia. [27]

While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%. [28]

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. [29]

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. [30]

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). [31]

Flunitrazepam has a melting point of around 170 degrees Celsius. [32]

History

Flunitrazepam was discovered at Roche as part of the benzodiazepine work led by Leo Sternbach; the patent application was filed in 1960 and it was first marketed in 1972. [33] [34]

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 Hypnodorm.jpg
Hypnodorm 1 mg flunitrazepam tablets, Australia
Rohypnol Rohypnol2.jpg
Rohypnol

Recreational use

A 1989 article in the European Journal of Clinical Pharmacology reports that benzodiazepines accounted for 52% of prescription forgeries in Sweden, suggesting that benzodiazepines were a major prescription drug class of abuse. Nitrazepam accounted for 13% of forged prescriptions, and accounted for 44% of forgeries specifically for benzodiazepines while flunitrazepam, diazepam, and oxazepam accounted for the majority of the rest of benzodiazepine forgeries. Prescription forgeries for other benzodiazepines marketed in Sweden (alprazolam, clonazepam, lorazepam, clobazam, and bromazepam) were negligible. When calculated in relation to utilization, the narcotic analgesics codeine, pentazocine, and ketobemidone were at the top of the list for the highest number of overall prescription forgeries, suggesting a higher abuse potential of these drugs. [35] In neighboring Finland, temazepam accounts for roughly 40–50% benzodiazepine prescription forgeries annually, while flunitrazepam accounts for approximately ~15% of benzodiazepine prescription forgeries. [36]

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. [37]

Suicide

In studies in Sweden, flunitrazepam was the second most common drug used in suicides, being found in about 16% of cases. [38] 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 occurred in significantly higher concentrations compared to natural deaths. Of the 159 deaths where any benzodiazepines were found, 4 deaths were caused by benzodiazepines alone (in the other 155 cases, benzodiazepines were combined with something else). One conclusion of the study was that flunitrazepam and nitrazepam might be more toxic than other benzodiazepines available in the Swedish market. [39] [40]

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. [41] [42] 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 it 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]

In a 2001 study, the benzodiazepines midazolam and temazepam were the two most common benzodiazepines utilized for date rape. [43]

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, [44] 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. [45]

Icelandic Flunitrazepam Iceland Flunitrazepam Mylan 1mg.png
Icelandic Flunitrazepam

Names

Flunitrazepam is marketed under many brand names in the countries where it is legal. [2] 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. [58]

Related Research Articles

<span class="mw-page-title-main">Benzodiazepine</span> Class of depressant drugs

Benzodiazepines, colloquially called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures. The first benzodiazepine, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955 and was made available in 1960 by Hoffmann–La Roche, who soon followed with diazepam (Valium) in 1963. By 1977, benzodiazepines were the most prescribed medications globally; the introduction of selective serotonin reuptake inhibitors (SSRIs), among other factors, decreased rates of prescription, but they remain frequently used worldwide.

<span class="mw-page-title-main">Diazepam</span> Benzodiazepine sedative

Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to cause memory loss during certain medical procedures. It can be taken orally, as a suppository inserted into the rectum, intramuscularly, intravenously or used as a nasal spray. When injected intravenously, effects begin in one to five minutes and last up to an hour. Orally, effects begin after 15 to 60 minutes.

<span class="mw-page-title-main">Temazepam</span> Insomnia medication

Temazepam, sold under the brand name Restoril among others, is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hypnotic effects begin in less than 30 minutes and can last for up to eight hours. Prescriptions for hypnotics such as temazepam have seen a dramatic decrease since 2010, while anxiolytics such as alprazolam, clonazepam, and lorazepam have increased or remained stable. Temazepam and similar hypnotics, such as triazolam (Halcion) are generally reserved for severe and debilitating insomnia. They have largely been replaced by z-drugs and atypical antidepressants as first line treatment for insomnia.

<span class="mw-page-title-main">Sedative</span> Drug that reduces excitement without inducing sleep

A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but the majority of them affect the neurotransmitter gamma-aminobutyric acid (GABA). In spite of the fact that each sedative acts in its own way, most produce relaxing effects by increasing GABA activity.

<span class="mw-page-title-main">Zolpidem</span> Hypnotic medication

Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and behavioral changes, such as sleep hygiene, have been tried. It decreases the time to sleep onset by about fifteen minutes and at larger doses helps people stay asleep longer. It is taken by mouth and is available in conventional tablets, sublingual tablets, or oral spray.

<span class="mw-page-title-main">Triazolam</span> Triazolobenzodiazepine class medication

Triazolam, sold under the brand name Halcion among others, is a central nervous system (CNS) depressant tranquilizer of the triazolobenzodiazepine (TBZD) class, which are benzodiazepine (BZD) derivatives. It possesses pharmacological properties similar to those of other benzodiazepines, but it is generally only used as a sedative to treat severe insomnia. In addition to the hypnotic properties, triazolam's amnesic, anxiolytic, sedative, anticonvulsant, and muscle relaxant properties are pronounced as well.

<span class="mw-page-title-main">Zopiclone</span> Hypnotic medication

Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone. However, zopiclone increases the normal transmission of the neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system, via modulating GABAA receptors similarly to the way benzodiazepine drugs do.

<span class="mw-page-title-main">Nitrazepam</span> Benzodiazepine sedative

Nitrazepam, sold under the brand name Mogadon among others, is a hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia. It also has sedative (calming) properties, as well as amnestic, anticonvulsant, and skeletal muscle relaxant effects.

<span class="mw-page-title-main">Flurazepam</span> Hypnotic medication

Flurazepam is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days. Flurazepam was patented in 1968 and came into medical use the same year. Flurazepam, developed by Roche Pharmaceuticals, was one of the first benzodiazepine hypnotic medications to be marketed.

<span class="mw-page-title-main">Eszopiclone</span> Hypnotic medication

Eszopiclone, sold under the brand name Lunesta among others, is a medication used in the treatment of insomnia. Evidence supports slight to moderate benefit up to six months. It is taken by mouth.

<span class="mw-page-title-main">Oxazepam</span> Benzodiazepine medication

Oxazepam is a short-to-intermediate-acting benzodiazepine. Oxazepam is used for the treatment of anxiety and insomnia and in the control of symptoms of alcohol withdrawal syndrome.

<span class="mw-page-title-main">Clorazepate</span> Benzodiazepine medication

Clorazepate, sold under the brand name Tranxene among others, is a benzodiazepine medication. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. Clorazepate is an unusually long-lasting benzodiazepine and serves as a prodrug for the equally long-lasting desmethyldiazepam, which is rapidly produced as an active metabolite. Desmethyldiazepam is responsible for most of the therapeutic effects of clorazepate.

<span class="mw-page-title-main">Nimetazepam</span> Benzodiazepine medication

Nimetazepam is an intermediate-acting hypnotic drug which is a benzodiazepine derivative. It was first synthesized by a team at Hoffmann-La Roche in 1964. It possesses powerful hypnotic, anxiolytic, sedative, and skeletal muscle relaxant properties. Nimetazepam is also a particularly potent anticonvulsant. It is marketed in 5 mg tablets known as Erimin, which is the brand name manufactured and marketed by the large Japanese corporation Sumitomo. Japan is the sole manufacturer of nimetazepam in the world. Outside of Japan, Erimin is available in much of East and Southeast Asia and was widely prescribed for the short-term treatment of severe insomnia in patients who have difficulty falling asleep or maintaining sleep. Sumitomo has ceased manufacturing Erimin since November 2015. It is still available as a generic drug or as Lavol.

<span class="mw-page-title-main">Etizolam</span> Chemical compound

Etizolam is a thienodiazepine derivative which is a benzodiazepine analog. The etizolam molecule differs from a benzodiazepine in that the benzene ring has been replaced by a thiophene ring and triazole ring has been fused, making the drug a thienotriazolodiazepine.

<span class="mw-page-title-main">Brotizolam</span> Benzodiazepine

Brotizolam is a sedative-hypnotic thienotriazolodiazepine drug which is a benzodiazepine analog. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties, and is considered to be similar in effect to other short-acting hypnotic benzodiazepines such as triazolam or midazolam. It is used in the short-term treatment of severe insomnia. Brotizolam is a highly potent and short-acting hypnotic, with a typical dose ranging from 0.125 to 0.25 milligrams, which is rapidly eliminated with an average half-life of 4.4 hours.

<span class="mw-page-title-main">Chlordiazepoxide</span> Benzodiazepine class sedative and hypnotic medication

Chlordiazepoxide, trade name Librium among others, is a sedative and hypnotic medication of the benzodiazepine class; it is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol and other drugs.

<span class="mw-page-title-main">Fosazepam</span> Benzodiazepam

Fosazepam is a drug which is a benzodiazepine derivative; it is a water soluble derivative of diazepam. It has sedative and anxiolytic effects, and is a derivative of diazepam which has been substituted with a dimethylphosphoryl group to improve solubility in water.

<span class="mw-page-title-main">Benzodiazepine overdose</span> Medical condition

Benzodiazepine overdose describes the ingestion of one of the drugs in the benzodiazepine class in quantities greater than are recommended or generally practiced. The most common symptoms of overdose include central nervous system (CNS) depression, impaired balance, ataxia, and slurred speech. Severe symptoms include coma and respiratory depression. Supportive care is the mainstay of treatment of benzodiazepine overdose. There is an antidote, flumazenil, but its use is controversial.

<span class="mw-page-title-main">Barbiturate</span> Class of depressant drugs derived from barbituric acid

Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential among other possible adverse effects. They have been used recreationally for their anti-anxiety and sedative effects, and are thus controlled in most countries due to the risks associated with such use.

<span class="mw-page-title-main">Benzodiazepine use disorder</span> Medical condition

Benzodiazepine use disorder (BUD), also called misuse or abuse, is the use of benzodiazepines without a prescription and/or for recreational purposes, which poses risks of dependence, withdrawal and other long-term effects. Benzodiazepines are one of the more common prescription drugs used recreationally. When used recreationally benzodiazepines are usually administered orally but sometimes they are taken intranasally or intravenously. Recreational use produces effects similar to alcohol intoxication.

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