Metabolic Profile of Flunitrazepam: Clinical and Forensic Toxicological Aspects.

BACKGROUND: Flunitrazepam (FNZ) is a potent hypnotic, sedative, and amnestic drug used to treat insomnia and as a pre-anesthetic agent. The illicit practice in drug-facilitated sexual assault led to important clinical and forensic concerns. OBJECTIVE: In this work the metabolism of FNZ, and pharmacological- and toxicological-related effects, were fully reviewed. METHODS: FNZ and related known metabolizing enzymes and metabolites were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. RESULTS: Major metabolic pathways include N-demethylation, 3-hydroxylation, nitro-reduction, and further N-acetylation of the amino group, yielding N-desmethylflunitrazepam, 3-hydroxy-flunitrazepam, 7-aminoflunitrazepam, and 7-acetamidoflunitrazepam, respectively. A combination of these reactions may lead to the formation of 7-amino-N-desmethylflunitrazepam, 7-acetamido-N-desmethylflunitrazepam, 3- hydroxy-7-aminoflunitrazepam, 3-hydroxy-7-acetamidoflunitrazepam, 3-hydroxy-N-desmethylflunitrazepam and glucuronide conjugates. Genotypic variations in enzymes, interactions with other drugs or stability of FNZ during storage can result in large interindividual variability in the toxicological results. CONCLUSION: It is aimed that knowing the metabolism of FNZ may lead to the development of new analytical strategies for early detection, since this drug is typically present in very low concentrations in blood and urine when used to facilitate sexual assault.

Use of GABAergic sedatives after subarachnoid hemorrhage is associated with worse outcome-preliminary findings.

STUDY OBJECTIVE: Recent experimental evidence identified GABAergic sedation as a possible cause for deprived neuroregeneration and poor outcome after acute brain injury. Patients with aneurysmal subarachnoid hemorrhage are often sedated, and GABAergic sedation, such as midazolam and propofol, is commonly used. DESIGN: Retrospective cohort study based on a prospectively established database. SETTING: Single-center neurointensive care unit. PATIENTS: Twenty-nine patients after subarachnoid hemorrhage. INTERVENTION: Noninterventional study. MEASUREMENTS: The relationship between mean GABAergic sedative dose during the acute phase and outcome after 6 months according to the Glasgow Outcome Scale, and initial Glasgow Coma Scale was investigated. MAIN RESULTS: Use of GABAergic sedatives was negatively correlated with Glasgow Outcome Scale (r2=0.267; P=.008). Administration of sedatives was independent of the initial Glasgow Coma Scale. GABAergic sedatives flunitrazepam, midazolam, and propofol were used differently during the first 10 days after ictus. CONCLUSION: Administration of GABAergic sedation was associated with an unfavorable outcome after 6 months. To avoid bias (mainly through the indication to use sedation), additional experimental and comparative clinical investigation of, for example, non-GABAergic sedation, and clinical protocols of no sedation is necessary.

Good clinical outcome after accidental intra-arterial injection of flunitrazepam tablets in 16 drug abusers with critical limb ischaemia.

OBJECTIVES: Inadvertent intra-arterial injection of flunitrazepam tablets intended for intravenous use by drug abusers has devastating effects. We report here on the clinical outcome of 16 drug abusers developing critical limb ischaemia after flunitrazepam injection. METHODS: Treatment combined immediate analgesia and anticoagulation, long-lasting local thrombolysis and vasodilatation, antibiotic prophylaxis, and physical mobilization. The immediate bolus injection of 5,000 IU heparin was followed by a continuous heparin infusion up to the target partial thromboplastin time. Under arteriographic control local intra-arterial infusion with alternating 4-h cycles of 5 mg recombinant tissue plasminogen activator followed by 5 µg prostaglandinE1 (PGE1) was performed for 24-48 hours. Subsequently, 60 µg PGE1 was applied once daily. RESULTS: Drug abusers, having been injected with 4-30 mg flunitrazepam, were treated 3-72 hours after the accident, with six of them not being treated until after 24 hours. All showed a high tissue ischaemia score. At the time of being discharged from hospital 13 patients had a normal extremity. In one patient, first receiving treatment 72 hours after injection, minor amputation of fingers was necessary. The life of the patient who injected 30 mg flunitrazepam in the leg was saved after hip disarticulation. One patient developed neurological dysfunction in the affected toes. CONCLUSIONS: Intensive treatment after inadvertent intra-arterial drug injection normalized the affected extremity in most drug abusers, even after the late onset of therapy.

[Neuroleptic malignant syndrome after cardiac surgery].

A 64-year-old man without any psychiatric disease, including Parkinson's disease underwent aortic valve replacement and mitral valve replacement for rheumatic valvular disease. One day after the cardiac surgery, he developed hyperthermina, muscle rigidity, coma and delirium, and his serum creatine kinase (CK) level was elevated. In spite of his negative brain computed tomography(CT), his consciousness remained unclear. He had received diazepam, flunitrazepam and buprenorphine after the cardiac surgery because of his hyper-reactivity. Although these drugs were not typical antipsychotics' causing neuroleptic malignant syndrome (NMS), NMS was strongly suspected because of his clinical appearance. Dantrolene was administered in a dose of 60 mg per day and he recovered consciousness and his CK level began to decrease. We reported a case of neuroleptic malignant syndrome after cardiac surgery.

Chemical submission to commit robbery: a series of involuntary intoxications with flunitrazepam in Asian travellers in Brussels.

Between January 17, 2003 and August 29, 2003, the Emergency Department admitted a patient who had been surreptitiously intoxicated and robbed of his valuables every Friday. The first cases were considered anecdotal, but criminal activity was rapidly suspected. The cohort includes 16 male Asian patients aged 28-50 years. All the victims had just arrived in Brussels through one of the main rail station of the town and were admitted via the emergency ambulance service from different locations in the centre of Brussels around the CHU Saint-Pierre Hospital. Haemodynamic parameters upon admission were within normal limits. The Glasgow Coma Scale was equal or higher than 9/15 in 14 of the 16 victims. Toxicology screening obtained in 12 patients revealed the presence of flunitrazepam, which was further quantified at levels ranging from 21 to 75 µg/l. One of the Japanese patients, who returned to Belgium afterwards for professional reasons, was approached by the police and accepted to press charges. This allowed the police to investigate and send undercover agents to the railway station on Friday afternoons and evenings. They found a person who was offering welcome cookies to Asian travellers. He arrived from Amsterdam and returned once his crime was committed. Flunitrazepam is well known as a rape drug. We report a series of victims in whom flunitrazepam was used to facilitate robbery.

Incidence and risk factors of postoperative delirium in patients with esophageal cancer.

BACKGROUND: Postoperative delirium is a common complication after major surgery and is characterized by acute confusion with fluctuating consciousness. The aim of this study was to investigate the incidence and risk factors of postoperative delirium in patients with esophageal cancer. METHODS: We conducted a retrospective cohort analysis of 306 consecutive patients who had undergone an esophagectomy at Keio University Hospital from January 1998 to December 2009. All data were assessed by psychiatrists, and delirium was diagnosed according to criteria of the Diagnostic and Statistical Manual Disorder, fourth edition. Univariate and multivariate analyses were performed. RESULTS: Postoperative delirium developed in 153 (50.0 %) of 306 patients. One hundred fourteen (37.3 %) of the 306 patients required psychoactive medication for symptoms associated with delirium. Univariate analyses showed that older age, male gender, additional flunitrazepam for sedation in intensive care unit (ICU) after surgery, longer periods of time under mechanical ventilation after surgery, longer ICU stays, occurrence of postoperative complications, and longer hospital stays were significantly associated with postoperative delirium. Multivariate analysis revealed that development of delirium was linked to older age, additional flunitrazepam in ICU, and occurrence of postoperative complication. CONCLUSIONS: The development of postoperative delirium in patients with esophageal cancer is a problem that cannot be ignored. Our results suggest that the risk of developing delirium is associated with older age, use of flunitrazepam in ICU, and postoperative complications.

Structure-based development of bacterial nitroreductase against nitrobenzodiazepine-induced hypnosis.

Nitrobenzodiazepine (NBDZ) is an addictive drug of the abused substances that causes severe neurological effects and even death. Bacterial type I nitroreductase NfsB (EC 1.5.1.34) has been reported to catalyze NBDZ into inactive metabolite 7-amino-benzodiazepine (7ABDZ) with promising activity, so as to become an attractive candidate for treatment of NBDZ overdose and addiction. Here, we investigate the nitroreduction of an NBDZ, flunitrazepam (FZ), by various mutants of NfsB designed from the solved crystal structure and characterize their in vitro and in vivo potency. Conformational changes occurred in the active site of N71S/F124W in contrast to the wild-type, including the flipping on the aromatic rings of W124 and F70 as well as the extension on the hydrogen bond network between flavin mononucleotide (FMN) and S71, which allow the significant enlargement in the active site pocket. In the complex structure of N71S/F124W and nicotinamide (NIA), stacking sandwich attractions of W124-FMN-NIA were also found, implying the importance of W124 in substrate accessibility. Consequently, N71S/F124W exhibited increased 7AFZ production in vitro with nearly no toxicity and reduced 50% sleeping time (hypnosis) in vivo. Taken together, we demonstrate for the first time that N71S/F124W can serve as an effective antidote for NBDZ-induced hypnosis and provide the molecular basis for designing NfsB and the like in the future.

Club drugs: review of the 'rave' with a note of concern for the Indian scenario.

'Club drugs' which include Ecstasy, gamma-hydroxybutyrate (GHB), ketamine, and Rohypnol (flunitrazepam) have become popular with participants in 'raves', because they are perceived to enhance energy, endurance, sociability and sexual arousal. These drugs vary in their pharmacologic properties, physiological and psychological effects, and potential consequences. The use of club drugs by young people has increased in the last decade, and continue to get modified and evolve, making them very difficult to monitor. Further, these drugs are not picked up by routine drugs screening procedures, thereby making these popular with the criminals. India, which is in a phase of social transition, also faces this rising menace. Despite the nature and extent of this problem, this area has been under-researched. Data from India are sparse barring a few newspaper and police reports. Keeping abreast of current trends in club drug use prepares the clinician to recognize the clinical effects of club drug use, to manage club drug related emergencies, and to generate social awareness.

Successful thrombolysis and spasmolysis of acute leg ischemia after accidental intra-arterial injection of dissolved flunitrazepam tablets.

A 37-year-old man with known intravenous drug abuse presented in the surgical ambulatory care unit with acute leg ischemia after accidental intra-arterial injection of dissolved flunitrazepam tablets into the right femoral artery. A combination of anticoagulation, vasodilatation, and local selective and superselective thrombolysis with urokinase was performed to salvage the leg. As a result of the severe ischemia-induced pain, the patient had to be monitored over the complete therapy period on the intensive care unit with permanent administration of intravenous fluid and analgetics. We describe the presenting symptoms and the interventional technique, and we discuss the recent literature regarding the management of accidental intra-arterial injection of dissolved flunitrazepam tablets.

Evidence of clonazepam abuse liability: results of the tools developed by the French Centers for Evaluation and Information on Pharmacodependence (CEIP) network.

Recent observations suggest the existence of clonazepam abuse. To determine its importance in France, a quantitative and systematic synthesis of all clonazepam data of several epidemiological tools of the Centers for Evaluation and Information on Pharmacodependence (CEIP) network has been performed in comparison with data on others benzodiazepines (BZD). Data on clonazepam and other BZD have been analysed from different epidemiological tools: OSIAP survey that identifies drugs obtained by means of falsified prescriptions, Observation of Illegal Drugs and Misuse of Psychotropic Medications (OPPIDUM) survey that describes modalities of use and data from regional French health reimbursement system. In OSIAP survey, the proportion of clonazepam falsified prescriptions among all BZD falsified prescriptions increased. During the 2006 OPPIDUM survey, the analysis of the BZD modalities of use highlights clonazepam abuse liability (for example 23% of illegal acquisition), in second rank after flunitrazepam. Studies based on data from the French health reimbursed system show that 1.5% of subjects with clonazepam dispensing had a deviant behaviour. Among BZD, clonazepam has the second most important doctor-shopping indicator (3%) after flunitrazepam. All these data provide some arguments in favour of clonazepam abuse liability in real life and the necessity to reinforce its monitoring.

[Club drugs]. / Club drugs: Um Novo Perfil de Abuso de Substâncias em Adolescentes e Jovens Adultos.

Club drugs are the following substances: Methylenedioxymethamphetamine (MDMA); Methamphetamine; Lysergic Acid Diethylamide (LSD); Ketamine; Gamma-hydroxybutyrate (GHB) and Flunitrazepam. These substances are mainly used by adolescents and young adults, mostly in recreational settings like dance clubs and rave parties. These drugs have diverse psychotropic effects, are associated with several degrees of toxicity, dependence and long term adverse effects. Some have been used for several decades, while others are relatively recent substances of abuse. They have distinct pharmacodynamic and pharmacokinetic properties, are not easy to detect and, many times, the use of club drugs is under diagnosed. Although the use of these drugs is increasingly common, few health professionals feel comfortable with the diagnosis and treatment. The authors performed a systematic literature review, with the goal of synthesising the existing knowledge about club drugs, namely epidemiology, mechanism of action, detection, adverse reactions and treatment. The purpose of this article is creating in Portuguese language a knowledge data base on club drugs, that health professionals of various specialties can use as a reference when dealing with individual with this kind of drug abuse.

[Sedation in palliative medicine: Guidelines for the use of sedation in palliative care : European Association for Palliative Care (EAPC)]. / Sedierung in der Palliativmedizin*: Leitlinie für den Einsatz sedierender Massnahmen in der Palliativversorgung : European Association for Palliative Care (EAPC).

The European Association for Palliative Care (EAPC) considers sedation to be an important and necessary therapy option in the care of selected palliative care patients with otherwise refractory distress. Prudent application of this approach requires due caution and good clinical practice. Inattention to potential risks and problematic practices can lead to harmful and unethical practice which may undermine the credibility and reputation of the responsible clinicians and institutions as well as the discipline of palliative medicine more generally. Procedural guidelines are helpful to educate medical providers, set standards for best practice, promote optimal care and convey the important message to staff, patients and families that palliative sedation is an accepted, ethical practice when used in appropriate situations. EAPC aims to facilitate the development of such guidelines by presenting a 10-point framework that is based on the pre-existing guidelines and literature and extensive peer review.

Residual effects of hypnotic drugs in aging drivers submitted to simulated accident scenarios: an exploratory study.

RATIONALE: The effects of hypnotic drugs on driving performance are most often evaluated on young healthy subjects by using a monotonous motorway driving test. The effects of drugs in urban driving situations have not yet been evaluated in any age group. Our objectives were to assess residual effects of the most prescribed hypnotics, zolpidem and zopiclone, on older middle-age drivers' capacities in an urban situation. MATERIALS AND METHODS: Sixteen healthy subjects aged 55 to 65 years underwent this double-blind, balanced, cross-over study. Zopiclone (7.5 mg), zolpidem (10 mg), and flunitrazepam (1 mg; used as positive control) or a placebo were administered at each subject's home at 11:00 PM: under the supervision of an investigator. The next morning, the subjects had to drive in a simulated urban environment where accident scenarios were introduced. Accident scenarios were implemented using data from real accident cases. RESULTS: Hypnotics did not significantly increase the number of collisions. However, significantly higher speeds were found with zopiclone and flunitrazepam; moreover, zolpidem and zopiclone induced modifications of the lateral position of the car on the road. CONCLUSIONS: This study did not reveal any major residual effects of the hypnotics studied on driving performance in aging drivers. However, the urban driving situations used here for the first time in the evaluation of drugs revealed some modifications in driving habits which could lead to risky behavior. It thus appears that urban driving simulations are useful for gaining knowledge about the effects of drugs on driving behavior.

Earlier warning: a multi-indicator approach to monitoring trends in the illicit use of medicines.

BACKGROUND: The availability of medicines on the illicit drug market is currently high on the international policy agenda, linked to adverse health consequences including addiction, drug related overdoses and injection related problems. Continuous surveillance of illicit use of medicines allows for earlier identification and reporting of emerging trends and increased possibilities for earlier intervention to prevent spread of use and drug related harm. This paper aims to identify data sources capable of monitoring the illicit use of medicines; present trend findings for Rohypnol and Subutex using a multi-indicator monitoring approach; and consider the relevance of such models for policy makers. METHODS: Data collection and analysis were undertaken in Bergen, Norway, using the Bergen Earlier Warning System (BEWS), a multi-indicator drug monitoring system. Data were gathered at six monthly intervals from April 2002 to September 2006. Drug indicator data from seizures, treatment, pharmacy sales, helplines, key informants and media monitoring were triangulated and an aggregated differential was used to plot trends. RESULTS: Results for the 4-year period showed a decline in the illicit use of Rohypnol and an increase in the illicit use of Subutex. CONCLUSION: Multi-indicator surveillance models can play a strategic role in the earlier identification and reporting of emerging trends in illicit use of medicines.

Behavioral pharmacological properties after recovery from the loss of righting reflex induced by benzodiazepine receptor agonists in mice.

In this study we examined the behavioral pharmacological side effects after recovery from the loss of righting reflex induced by three benzodiazepine receptor agonists - zolpidem, brotizolam and flunitrazepam - in ddY mice. All agents caused marked motor incoordination in the rotarod test and muscle flaccidity in the traction test until 15 min after recovery of righting reflex. Thereafter, the short-acting hypnotics zolpidem and brotizolam showed a faster recovery than the long-acting benzodiazepine flunitrazepam. However, head twitch responses were observed in the mice treated with flunitrazepam, but zolpidem and brotizolam had no such effect. The flunitrazepam-induced head twitch response was antagonized by ketanserin, a 5- HT(2A) receptor antagonist. These results indicate that flunitrazepam, a long-acting benzodiazepine that is nonselective for type I and II benzodiazepine receptors, induces head twitch responses with muscle flaccidity after recovery from the loss of righting reflex caused by these drugs. In addition, these findings suggest the involvement of a 5-HT(2A)-GABA(A) receptor/benzodiazepine interaction in this phenomenon.

Acute ischaemia of the leg following accidental intra-arterial injection of dissolved flunitrazepam tablets.

Accidental intra-arterial injection of drugs is a sporadic complication in i.v. drug addicts. A 22-year-old drug-abuser injected flunitrazepam tablets dissolved in tap water into her left femoral artery and presented with clinical signs of acute ischaemia of the left leg. Severe rhabdomyolysis developed within 5 hours after the injection. Selective arterial catheter angiography showed an acute occlusion of the posterior tibial artery. Combination therapy with i.a. urokinase, i.a. prostaglandines and i.v. anticoagulation resulted in re-opening of the obstructed distal artery and complete cessation of symptoms.

Road traffic accident risk related to prescriptions of the hypnotics zopiclone, zolpidem, flunitrazepam and nitrazepam.

BACKGROUND: Despite the high prescription rate of benzodiazepine-like hypnotics (z-hypnotics), there is limited information on the road traffic accident risk associated with the use of these drugs. We wanted to investigate whether filling a prescription for zopiclone or zolpidem was associated with increased risk of road traffic accidents at a national population level. Nitrazepam and flunitrazepam were used as comparator drugs. METHOD: All Norwegians 18-69 years (3.1 million) were followed-up from January 2004 until the end of September 2006. Information on prescriptions, road traffic accidents and emigration/death was obtained from three Norwegian population-based registries. The first week after the hypnotics had been dispensed was considered to be the exposure period. Standardized incidence ratios (SIRs) were calculated by comparing the incidence of accidents in the exposed person-time to the incidence of accidents in the unexposed person-time. RESULTS: During exposure, 129 accidents were registered for zopiclone, 21 for zolpidem, 27 for nitrazepam and 18 for flunitrazepam. The SIRs were (SIR for all ages and both sexes combined; 95% CI): z-hypnotics (zopiclone+zolpidem) 2.3; 2.0-2.7, nitrazepam 2.7; 1.8-3.9 and flunitrazepam 4.0; 2.4-6.4. The highest SIRs were found among the youngest users for all hypnotics. CONCLUSIONS: This study found that users of hypnotics had a clearly increased risk of road traffic accidents. The SIR for flunitrazepam was particularly high.

Efficacy, safety, and cost effectiveness of intravenous midazolam and flunitrazepam for primary insomnia in terminally ill patients with cancer: a retrospective multicenter audit study.

BACKGROUND: Although intravenous midazolam and flunitrazepam are frequently administered for primary insomnia in Japan, there is no empirical study on their efficacy and safety. DESIGN AND SUBJECTS: To compare the efficacy, safety, and cost-effectiveness of midazolam and flunitrazepam, a multicenter retrospective audit study was performed on 104 and 59 patients receiving midazolam and flunitrazepam, respectively, from 18 certified palliative care units. RESULTS: Median administration periods were 6 days and 9 days for midazolam and flunitrazepam, respectively. The median initial and maximum doses were 10 mg per night and 18 mg per night for midazolam, and 2 mg per night and 2 mg per night for flunitrazepam, respectively. There were no significant differences in the efficacy (91% in the midazolam group versus 81% in the flunitrazepam group, p = 0.084), hangover effect (34% versus 19%, p = 0.094), delirium at night (12% versus 10%, p = 1.0) and delirium next morning (11% versus 15%, p = 0.33), treatment withdrawal (4.8% versus 1.7%, p = 0.41), and treatment-related death (0% versus 0%, p = 1.0). Flunitrazepam caused respiratory depression defined as physician or nurses records such as apnea, respiratory arrest, decreased respiratory rate, and respiratory depression significantly more frequently than midazolam (17% versus 3.8%, p = 0.0073). The maximum dose was more highly correlated with the administration period in the midazolam group than in the flunitrazepam group (rho = 0.52, versus rho = 0.39), and, for patients treated for 14 days or longer, the daily escalation dose ratio required for maintaining adequate sleep was significantly higher in the midazolam group than in the flunitrazepam group (11% versus 2.6%, p = 0.015). The costs of the initial and maximum administration were significantly higher in the midazolam group than in the flunitrazepam group (p < 0.001). CONCLUSION: Intravenous midazolam and flunitrazepam appeared to be almost equal about efficacy and safety for primary insomnia, but flunitrazepam is less expensive and shows lower risk of tolerance development. A future prospective comparison study is necessary.