Flunitrazepam

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Flunitrazepam
197px
200px
Systematic (IUPAC) name
6-(2-fluorophenyl)- 2-methyl- 9-nitro- 2,5-diazabicyclo [5.4.0] undeca- 5,8,10,12- tetraen- 3-one
Clinical data
Pregnancy
category
  • AU: C
Routes of
administration		 Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability 50% (suppository)
64–77% (oral)
Metabolism Hepatic
Biological half-life 18–26 hours
Excretion Renal
Identifiers
CAS Number 1622-62-4
ATC code N05CD03 (WHO)
PubChem CID 3380
DrugBank DB01544
ChemSpider 3263
Chemical data
Formula C19H12FN3O3
Molar mass 313.3[[Script error: No such module "String".]]
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Flunitrazepam (pronounced /ˌfluːnɨˈtræzɨpæm/) is marketed as a strong hypnotic and powerful sedative, anticonvulsant, anxiolytic, amnestic, and skeletal muscle relaxant drug.[1] 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. 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).

The prescription of flunitrazepam as a hypnotic is generally intended to be for short-term treatment of chronic or severe insomniacs that are 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 only be used on a short-term basis or in those with chronic insomnia on an occasional basis.[2]

The drug is often cited as a date rape drug because of its high potency, strong effects and the ability to cause strong amnesia during its duration of action. However, after investigations into its apparent use as a date rape drug by Michael Robertson from the San Diego Medical Examiner's office and Dr. Mahmoud El Sohly of El Sohly Laboratories, the results pointed out that flunitrazepam was only used in around 1% of reported date rapes according to Robertson and 0.33% according to urine lab tests done by El Sohly.[3]

Flunitrazepam is classed as a nitro-benzodiazepine. It is the fluorinated methylamino derivative of nitrazepam. Other nitro-benzodiazepines include nitrazepam – the parent compound – and clonazepam, the chlorinated derivative.[4]

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.[5]

Medical uses

  • In the United States, the drug has not been approved by the Food and Drug Administration and is considered to be an illegal drug.[6][7][8]
  • In the United Kingdom, the drug is available only by private prescription.[9] 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 France, Rohypnol is prescribed by physicians, it is under the maximum list, being prescribed only when other drugs won't do, prescription non renewable (a new doctor visit every time), and only being available in 7 pill, theoretically one week, packaging.
  • In the Netherlands, flunitrazepam is a List 2 substance of the Opium Law and is available for prescription as 1 mg Rohypnol brand tablets by Roche, and as 1 mg and 2 mg generic tablets.
  • In Ireland, flunitrazepam is a Schedule 3 controlled substance with strict restrictions.[10]
  • In Singapore, flunitrazepam is a Class C controlled drug (Schedule II), 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.[11]
  • In Australia, prescription is restricted as a Schedule 8 medicine.[12][13] 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.[14] 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. It is a Class A substance under Norway's Narcotics Act. Only four hypnotics are prescribable in Norway: flunitrazepam, nitrazepam, zolpidem and zopiclone.[15]
  • In Sweden, the brand Rohypnol has been withdrawn from the domestic market. It is available as a generic and under the name Fluscand. It is listed as a List IV (Schedule IV) under the Narcotics Control Act (1968). Although it has for a long time been a first line drug for the treatment of insomnia, it has seen declines in prescriptions in recent years. Much more common are nitrazepam but above all zopiclone and zolpidem.
  • In Mexico, Rohypnol is approved for medical use,[8] however there have been many cases of trafficking of Rohypnol to the United States and other developed nations, most of it originating from Mexico.[16]
  • 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).
  • In Slovenia, it is regulated as a Group III (Schedule 3) controlled substance under The Production and Trade in Illicit DrugsAct. About 20 years ago Rohypnol was indicated for treatment of insomnia as well as used for preanesthetic medication was replaced mainly with Dormicum (midazolam), which has very similar properties.[17][18]

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 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.[19]

Adverse effects

Flunitrazepam is metabolized almost completely by cytochrome P450-3A4. Atorvastatin administration along with flunitrazepam results in a reduced elimination rate of this molecule. Grapefruit juice reduces intestinal 3A4 and results in less metabolism and higher plasma concentrations of flunitrazepam, which could result in overdose.

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.[20] 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.[21]

Hypotonia

See also: Hypotonia

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 hypotonia, also known as floppy infant syndrome.[22]

Other

After discontinuation of flunitrazepam a rebound effect may occur about 4 days after stopping flunitrazepam.[23] (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, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.[24] 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.[25]

Flunitrazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake 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.[26]

Pharmacology

Benzodiazepines, including flunitrazepam, bind to mouse glial cell membranes with high affinity.[27] Flunitrazepam induces melanogenesis in B16/C3 mouse melanoma cell cultures via modulating high affinity binding sites.[28] 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. [29]

Mechanism of action

The main pharmacological effects of flunitrazepam are the enhancement of GABA at the GABAA receptor.[30] Like other benzodiazepines, flunitrazepam's pharmacological effects include sedation, muscle relaxation, reduction in anxiety, and prevention of convulsions.

Pharmacokinetics

While 80% of flunitrazepam that is taken orally is absorbed, bioavailability in suppository form is closer to 50%.[31]

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.[32] 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 and hip fractures.[33]

Flunitrazepam is lipophilic and is metabolised hepatically via oxidative pathways. The enzyme CYP3A4 is the main enzyme in its phase 1 metabolism.[34]

Interactions

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

Overdose

See also: Benzodiazepine overdose

Flunitrazepam is a drug which is frequently involved in drug intoxication, including overdose.[35][36] 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 CNS depressants such as alcohol and opiates. Flunitrazepam overdose responds to the benzodiazepine receptor antagonist flumazenil, which thus can be used as a treatment.

Abuse potential

See also: Benzodiazepine drug misuse
File:Hypnodorm.jpg
Hypnodorm 1mg Flunitrazepam tabs, Australia
File:Rohypnol2.jpg
Rohypnol

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

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 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 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.[37]

It must be noted that an inability to remember events, including sexual encounters, is not conclusive evidence of having consumed a drugged drink: psychotropic 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 drug-facilitated 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 drug assisted rape such as GHB. However, flunitrazepam is not prescribed in the UK and the study size was only based on 75 people which may in part account for the findings. The study results however, do suggest that binge drinking is much more commonly to blame for drug assisted rapes than pharmaceutical drugs.[38]

Drug-facilitated robbery

In the United Kingdom and the Philippines, 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,[39] 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.[40][41][42] In a notable flunitrazepam-related case, Selina Hakki was convicted in December 2004 and sentenced to five years in prison for of using rohypnol (flunitrazepam) to drug wealthy men and rob them of their clothes and accessories in the UK.[43]

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 sometimes combined with alcohol (benzodiazepines and alcohol combined intensify each others' CNS depression to the point of being deadly). 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.[44]

Flunitrazepam and other sedative hypnotic drugs are detected frequently in cases of people suspected of driving under the influence of drugs. Other benzodiazepines (anxiolytic or hypnotic) and zolpidem and zopiclone, (as well as similar hypnotic and anxiolytic drugs from the non-benzodiazepine families 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.[45]

Street names for Rohypnol include "rowies", "rophy", "ruffles", "roachies", "roofies", "ruffies", "ruff up", "rib", "roach 2 (R2)", "roche", "rope", "ropies", "circles", "circes", "forget it" ,"poppers", "forget-me-pill", "Mexican Valium" and more recently "rapies" as referred to in the movie The Hangover.[46][47]

Suicide

In studies in Sweden, flunitrazepam was the second most common drug used in suicides, being found in about 15% of cases.[48] 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.[49]

Detection of use

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 to 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.[50][51][52]

Legal status

Flunitrazepam is currently a Schedule III drug under the international Convention on Psychotropic Substances of 1971;[53] in the United States, it is on Schedule IV

According to FDA Associate Director for Domestic and International Drug Control Nicholas Reuter:[54]

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.

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 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 in Norway, and on August 1, 2004, the manufacturer Roche removed Rohypnol from the market there altogether.[55]

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.

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 1 mg tablets. 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.

See also

References

Footnotes

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External links

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  3. ↑ 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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  10. ↑ Irish Statute Book, Statutory Instruments, S.I. No. 342/1993 — Misuse of Drugs (Amendment) Regulations, 1993
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  16. ↑ DEA Briefs & Background, Drugs and Drug Abuse, State Factsheets, Texas
  17. ↑ Europa.eu
  18. ↑ Europa.eu
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  30. ↑ Oelschläger H.; Shader, Richard I.; Franke, Kate; MacLaughlin, Dean S.; Harmatz, Jerold S.; Allen, Marcia Divoll; Werner, Ann; Woo, Elaine (July 4, 1989). "[Chemical and pharmacologic aspects of benzodiazepines]". Schweiz Rundsch Med Prax. 78 (27-28): 766–72. doi:10.1002/jps.2600680119. PMID 2570451. 
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  32. ↑ Benzodiazepine Equivalents Table - A list of Equivalent Doses of Benzodiazepines
  33. ↑ Vermeeren A. (2004). "Residual effects of hypnotics: epidemiology and clinical implications". CNS Drugs. 18 (5): 297–328. doi:10.2165/00023210-200418050-00003. PMID 15089115. 
  34. ↑ CYP3A4 Is the Major CYP Isoform Mediating the in Vitro ...
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  36. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  37. ↑ Detection of "Date-Rape" Drugs in Hair and Urine, Final Report
  38. ↑ Hope, Jenny (February 16, 2007). "Drug rape myth exposed as study reveals binge drinking is to blame". Daily Mail. London. 
  39. ↑ Thompson, Tony (December 19, 2004). "'Rape drug' used to rob thousands". The Guardian. London. Retrieved May 2, 2010. 
  40. ↑ "Bankrånare stärkte sig med Rohypnol?". DrugNews. 
  41. ↑ "Mijailovic var påverkad av våldsdrog". Sydsvenskan. 
  42. ↑ "Mijailovic var påverkad av våldsdrog". Expressen. 
  43. ↑ News.BBC.co.uk
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  45. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  46. ↑ Rohypnol fact sheet at About.com Teen Advice
  47. ↑ Facts about Rohypnol and other date rape drugs - Facts on Rohypnol
  48. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  49. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  50. ↑ Jones AW, Holmgren A, Kugelberg FC. Concentrations of scheduled prescription drugs in blood of impaired drivers: considerations for interpreting the results. Ther. Drug Monit. 29: 248-260, 2007.
  51. ↑ Robertson MD, Drummer OH. Stability of nitrobenzodiazepines in postmortem blood. J. For. Sci. 43: 5-8, 1998.
  52. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 633-635.
  53. ↑ Annual Estimates Of Requirements Of Narcotic Drugs, Manufacture Of Synthetic Drugs, Opium Production And Cultivation Of The
  54. ↑ "Date Rape" Drugs
  55. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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