Flunitrazepam, sold under the brand name Rohypnol among others, 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]
Flunitrazepam was patented in 1962 and came into medical use in 1974.[4] Nicknamed "roofies" or "floonies", it is widely known for its use as a date rape drug.[5][6]
Use
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] These were also the uses for which it was originally studied.[7]
It has also been administered as a concurrent dose for patients that are taking ketamine. Flunitrazepam 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.[8]
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.[9] When used in late pregnancy, it might cause hypotonia of the fetus.
Dependence
Flunitrazepam, as with other benzodiazepines, can lead to drug dependence. 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.[10]
Paradoxical effects
Interactions
The use of flunitrazepam in combination with alcoholic beverages synergizes the adverse effects, and can lead to toxicity and death.[18]
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 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.
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.[21][22][23] 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.[18] All benzodiazepines work by enhancing the effect of GABA receptors, which, when active, allow chloride ions to enter the neuron.[24] 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.[24]
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.[13]
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).[28]
Flunitrazepam has a melting point of around 170 degrees Celsius.[29]
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.[30] [31]
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.[32] 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.[32]
Society and culture
Recreational and illegal uses
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.[33] In neighboring Finland, temazepam accounts for roughly 40–50% benzodiazepine prescription forgeries annually, while flunitrazepam accounts for approximately ~15% of benzodiazepine prescription forgeries.[34]
External links
References
- Anvisa. RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial Diário Oficial da União, 2023-03-31, retrieved 2023-08-16^
- Principles of addiction medicine Wolters Kluwer/Lippincott Williams & Wilkins, 2009^
- Prescribing of Benzodiazepines Alprazolam and Flunitrazepam