Flunitrazepam

Flunitrazepam
Systematic (IUPAC) name
5-(2-fluorophenyl)-1-methyl-7-nitro-1H-benzo[e][1,4]diazepin-2(3H)-one
Clinical data
Pregnancy
category
  • AU: C
Legal status
Dependence
liability		 Very high
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability 64–77% (oral)
50% (suppository)
Metabolism Hepatic
Biological half-life 18–26 hours
Excretion Renal
Identifiers
CAS Number 1622-62-4 YesY
ATC code N05CD03
PubChem CID 3380
IUPHAR/BPS 4193
DrugBank DB01544 YesY
ChemSpider 3263 YesY
UNII 620X0222FQ YesY
KEGG D01230 YesY
ChEMBL CHEMBL13280 YesY
Chemical data
Formula C16H12FN3O3
Molar mass 313.3 g/mol
  (verify)

Flunitrazepam /ˌfluːnᵻˈtræzᵻpæm/, also known as Rohypnol among others,[1] is an intermediate acting benzodiazepine used as an hypnotic, sedative, anticonvulsant, anxiolytic, and skeletal muscle relaxant drug.[2] In general, the prescription of flunitrazepam as a hypnotic is intended to be for short-term treatment of chronic or severe insomniacs not responsive to other hypnotics, especially in inpatients. It is considered to be one of the most effective benzodiazepine hypnotics on a dose basis. Just as with other hypnotics, flunitrazepam should be strictly used only on a short-term basis or in those with chronic insomnia on an occasional basis.[3] It is also known and produced from common precursors to 1,4-benzophenones, in 1963.[4] Flunitrazepam has been referred to as a date rape drug even though its incidence is very rare in cases that have been reported.[5]

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).[6]

History

Flunitrazepam was developed by a team led by Leo Sternbach at Hoffmann La-Roche and produced from common precursors to 1,4-benzophenones, in 1963.[4] Flunitrazepam has been referred to as a date rape drug because of its high potency and ability to cause strong amnesia. However, Robertson's study (in the 1990s) indicated that Flunitrazepam was used in only around 1% of reported date rapes and 0.33% according to urine lab tests done (before 2001) by El Sohly.[5]

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.

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.[7]

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 better 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.[8] This may lead to somnolence.

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.[9]

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.[10]

Other

After discontinuation of flunitrazepam, a rebound effect may occur about 4 days after stopping flunitrazepam.[11] (See benzodiazepine withdrawal syndrome)

Flunitrazepam impairs cognitive functions. This may appear as 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:

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.[12] 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.[13]

Flunitrazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs, causes impairments in body balance and standing steadiness in individuals waking up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.[14]

Interactions

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

Overdose

Flunitrazepam is a drug that is frequently involved in drug intoxication, including overdose.[15][16] 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.

Presence in bodily fluids

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.[17][18][19]

Other uses

Hypnodorm 1 mg flunitrazepam tabs, Australia
Rohypnol

Recreational use

A 1989 journal on 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.[20]

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.[21]

Suicide

In studies in Sweden, flunitrazepam was the second-most-common drug used in suicides, being found in about 16% of cases.[22] 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 four 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.[23] [24]

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 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.

It is difficult to estimate just how many flunitrazepam-facilitated rapes have occurred. Very often, biological samples are taken from the alleged victim at a time when the effects of the drug would already have passed and only residual amounts would remain in the body fluids. These residual amounts would be difficult, and sometimes impossible, to detect using standard screening assays used in most countries. 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 alleged 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.[25]

An inability to remember events, including sexual encounters, is not conclusive evidence of having consumed a drugged drink: Psychotropic central nervous system (CNS) depressant drugs such as alcohol can cause 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 psychotropic substance used in the vast majority of cases of alleged drug-facilitated date-rape. A recent study conducted by doctors in the UK found that none of the subjects reporting spiked drinks had any traces of flunitrazepam or other medications popularly believed to be associated with drug-assisted rape, such as GHB. However, flunitrazepam was prohibited for prescription under the NHS in 1992 (The National Health Service (General Medical Services). Rohypnol (1 mg) is available under private prescription. The study results, however, suggest that binge drinking is more commonly a factor in alleged drug-assisted rapes than pharmaceutical drugs.[26]

Drug-facilitated robbery

In the United Kingdom, the use of flunitrazepam and other "date rape" drugs have 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,[27] making drug-assisted robbery a more commonly reported problem than drug-assisted rape.

Flunitrazepam is also known to induce anterograde amnesia making police interrogations more difficult.[28][29][30]

Pharmacology

Benzodiazepines, including flunitrazepam, bind to most glial cell membranes with high affinity in mouse astrocytes.[31] Flunitrazepam induces melanogenesis in B16/C3 mouse melanoma cell cultures via modulating high-affinity binding sites.[32] Benzodiazepines, including flunitrazepam have been shown to act on 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.[33]

Mechanism of action

The main pharmacological effects of flunitrazepam are the enhancement of GABA at the GABAA receptor.[34] Like other benzodiazepines, flunitrazepam's pharmacological effects include sedation, muscle relaxation, reduction in anxiety, and prevention of convulsions.

Intermediate-half-life benzodiazepines (such as loprazolam, lormetazepam, and temazepam) are also useful for patients with difficulty in maintaining sleep; these may be preferable to long-half-life benzodiazepines, which typically cause next-day sedation and impairments.

Pharmacokinetics

While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%.[35]

Flunitrazepam has a long half-life of 18–26 hours, which means that flunitrazepam's effects after nighttime administration persist throughout the next day.[36] Residual "hangover" effects after nighttime administration of flunitrazepam, such as sleepiness and impaired psychomotor and cognitive functions, may persist into the next day. This may impair the ability of users to drive safely, and increase risks of falls. This is of particular concern in the elderly where falls are often associated with hip fractures and other injuries.[37]

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.[38]

History

Flunitrazepam was first synthesized in 1972 by Roche in Europe 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 US in late 1983 – mid 1984. It originally came in doses of 1 mg and 2 mg, but due to its potency and potential for abuse, most European countries changed their drug laws and limited the dose to 1 mg—in many countries, the maximum dose per package was limited to 20 or 30 mg. In Germany there had been two changes in availability during a short period in the late 1990s; the first one restricting the dose to 20 mg per package, and for a short time only 10 tablets with 2 mg were available. Soon another change in the German Narcotic Act limited the dose for each tablet to 1 mg, while ampoules containing the 2 mg solution were not changed by Roche and have been handled as a controlled narcotic like morphine. In the countries where flunitrazepam is available for prescription as both 1 mg and 2 mg tablets, such as the Netherlands, generic alternatives are available for the 2 mg tablets. However, in Asia and South America there are original 2 mg tablets from Roche still available.

The newly designed 1 mg tablets introduced in the late 1990s by Roche for the European market are identical in all countries, only the packaging and packaging size differs since there are different laws in each country. The new tablets, which are green (containing a blue coloring) and are pressed harder during manufacturing (so that the tablets can only dissolve quickly in hot liquids, while turning the drink a blue color and leaving a green residue in the beverage) were introduced to prevent use as a rape drug and abuse on the drug scene. However, there have been only few reported cases in Europe where flunitrazepam was used as a rape drug and in most countries flunitrazepam is still offered as a generic drug with white tablets that can be dissolved easily.

In the 2000s Patrick S. Coined the term of pillow candies. some European countries started to treat flunitrazepam as a strong narcotic, for example Poland in 2004. The most recent change was the change in the German drug law regarding flunitrazepam; since November 2011 the drug is only available with a special narcotic prescription. German Rohypnol tablets disappeared almost overnight from the black market. However it took only a few weeks before organized crime became the major supplier for the drug on the black market, as in the United States. Pillow Candies come from western European countries where it is still available with a normal prescription. Some users living on the borders are driving to these countries and buying the drug on the black market, since there are no border controls within the European Union.

Regional use

Flunitrazepam is marketed by Roche most commonly under the trade name Rohypnol. It is also marketed in some countries under the trade names Flunitrazepam, Hipnosedon, Hypnodorm, Flunipam, Nilium, Vulbegal, Silece, Darkene, Ilman, Insom, Inervon and Fluscand. In street slang, the pharmaceutical is commonly referred to as a roofie (USA) or a roh'ie (Australia).

Flunitrazepam is currently a Schedule III drug under the international Convention on Psychotropic Substances of 1971;[50] in the United States, it is on Schedule IV.

According to FDA Associate Director for Domestic and International Drug Control Nicholas Reuter:[51]

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, Pennsylvania, and Virginia.

21 U.S.C. § 841 and 21 U.S.C. § 952 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 substituted amphetamines and opioid analgesics. All other benzodiazepines (except alprazolam) 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 in Norway, and, on August 1, 2004, the manufacturer Roche removed Rohypnol from the market there altogether.[52]

The Dutch, British and French use a system called the System of Objectified Judgement Analysis for assessing whether drugs should be included in drug formularies based on clinical efficacy, adverse effects, pharmacokinetic properties, toxicity and drug interactions. A Dutch analysis using the system found that flunitrazepam is unsuitable to be included in drug prescribing formularies.[53]

Brand names

Narcozep, Rohypnol, Rohipnol, Roipnol, Flunipam, "rufies" or "roofies".

References

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  2. ↑ Mandrioli R, Mercolini L, Raggi MA (October 2008). "Benzodiazepine metabolism: an analytical perspective". Current Drug Metabolism 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614.
  3. ↑ Rickels, K. (1986). "The clinical use of hypnotics: indications for use and the need for a variety of hypnotics". Acta Psychiatrica Scandinavica Suppl. 74 (S332): 132–41. doi:10.1111/j.1600-0447.1986.tb08990.x. PMID 2883820.
  4. 1 2 US Patent US 3203990 2-amino-2'-halo-5-nitro benzophenones
  5. 1 2 ElSohly, Mahmoud A.; Lee, Luen F.; Holzhauer, Lynn B.; Salamone, Salvatore J. (2001). "Analysis of urine samples in cases of alleged sexual assault case history". Benzodiazepines and GHB: 127–144.
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  36. ↑ A list of Equivalent Doses of Benzodiazepines
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  48. ↑ DEA Resources, For Law Enforcement Officers, Intelligence Reports, Rohypnol
  49. ↑ Rohypnol Fast Facts
  50. ↑ Annual Estimates Of Requirements Of Narcotic Drugs, Manufacture Of Synthetic Drugs, Opium Production And Cultivation
  51. ↑ "Date Rape" Drugs
  52. ↑ Bramness JG; Skurtveit S; Furu K; Engeland A; Sakshaug S; Rønning M. (February 23, 2006). "[Changes in the sale and use of flunitrazepam in Norway after 1999]". Tidsskr nor Laegeforen 126 (5): 589–90. PMID 16505866.
  53. ↑ Janknegt R, van der Kuy A, Declerck G, Idzikowski C; Van Der Kuy; Declerck; Idzikowski (August 1996). "Hypnotics. Drug selection by means of the System of Objectified Judgement Analysis (SOJA) method". PharmacoEconomics 10 (2): 152–63. doi:10.2165/00019053-199610020-00007. PMID 10163418.

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