Phenazepam (also known in

Russia Russia (, , ), or the Russian Federation, is a transcontinental country spanning Eastern Europe and Northern Asia. It is the largest country in the world, with its internationally recognised territory covering , and encompassing one-eig ...

as bromdihydrochlorphenylbenzodiazepine) is a benzodiazepine drug, which was developed in the

Soviet Union The Soviet Union,. officially the Union of Soviet Socialist Republics. (USSR),. was a List of former transcontinental countries#Since 1700, transcontinental country that spanned much of Eurasia from 1922 to 1991. A flagship communist state, ...

in 1975, and now produced in Russia and some CIS countries. Phenazepam is used in the treatment of various mental disorders such as psychiatric schizophrenia and anxiety. It can be used as a premedication before surgery as it augments the effects of anesthetics. Recently, phenazepam has gained popularity as a recreational drug; misuse has been reported in the United Kingdom, Finland, Sweden, and the United States.

Indications

Neurosis Neurosis is a class of functional mental disorders involving chronic distress, but neither delusions nor hallucinations. The term is no longer used by the professional psychiatric community in the United States, having been eliminated from th ...

, neurosis-like,

psychopathic Psychopathy, sometimes considered synonymous with sociopathy, is characterized by persistent antisocial behavior, impaired empathy and remorse, and bold, disinhibited, and egotistical traits. Different conceptions of psychopathy have been u ...

(personality disorder), psychopathic-like and other conditions accompanied by fear, anxiety, increased irritability, and

emotional lability In medicine and psychology, emotional lability is a sign or symptom typified by exaggerated changes in mood or affect in quick succession. Sometimes the emotions expressed outwardly are very different from how the person feels on the inside. Thes ...

Brief reactive psychosis Brief psychotic disorder ⁠— according to the classifications of mental disorders DSM-IV-TR and DSM-5 ⁠— is a psychotic condition involving the sudden onset of at least one psychotic symptom (such as disorganized thought/speech, delusions ...

and

hypochondriasis Hypochondriasis or hypochondria is a condition in which a person is excessively and unduly worried about having a serious illness. An old concept, the meaning of hypochondria has repeatedly changed. It has been claimed that this debilitating cond ...

-senestopathic syndrome * Vegetative dysfunction and vegetative lability *

Insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

Alcohol withdrawal syndrome Alcohol withdrawal syndrome (AWS) is a set of symptoms that can occur following a reduction in alcohol use after a period of excessive use. Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. Mo ...

Temporal lobe epilepsy Temporal lobe epilepsy (TLE) is a chronic disorder of the nervous system which is characterized by recurrent, unprovoked focal seizures that originate in the temporal lobe of the brain and last about one or two minutes. TLE is the most common ...

and

myoclonic epilepsy Myoclonic epilepsy refers to a family of epilepsies that present with myoclonus. It starts in both sides of the body at once, and last for more than a second or two. When myoclonic jerks are occasionally associated with abnormal brain wave activit ...

(used only occasionally as better options exist) *

Hyperkinesia Hyperkinesia refers to an increase in muscular activity that can result in excessive abnormal movements, excessive normal movements, or a combination of both. Hyperkinesia is a state of excessive restlessness which is featured in a large variet ...

and

tic A tic is a sudden, repetitive, nonrhythmic motor movement or vocalization involving discrete muscle groups.American Psychiatric Association (2000)DSM-IV-TR: Tourette's Disorder.''Diagnostic and Statistical Manual of Mental Disorders'', 4th ed., ...

s * Muscle

spasticity Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles ...

Usually, a course of treatment with phenazepam should not normally exceed 2 weeks (in some cases therapy may be prolonged for up to 2 months) due to the risk of drug abuse and dependence. To prevent withdrawal syndrome, it is necessary to reduce the dose gradually.

Chemistry

Phenazepam is a drug of the benzodiazepine class. Benzodiazepine drugs contain a benzene ring fused to a diazepine ring, which is a seven membered ring with the two nitrogen constituents located at R1 and R4. The benzyl ring of phenazepam is substituted at R7 with a bromine group. Like most benzodiazepines, phenazepam has a phenyl ring in R5 which is substituted by chlorine in the R2' group. Phenazepam also contains an oxygen group double bonded to R2 of its diazepine ring to form a ketone. This oxygen substitution at R2 is shared with other benzodiazepine drugs with the suffix -azepam. Like other benzodiazepines, phenazepam (7-bromo-5-(2-chlorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one) is composed of a benzene ring fused to a seven-membered 1,4-diazepine ring. A 2-chlorophenyl ring is attached at the 5-position and a bromine is attached at the 7-position. Phenazepam has a molecular formula of C₁₅H₁₀BrClN₂O and a molecular weight of 349.6 g/mol.

Side effects

Side effects include

hiccups A hiccup (scientific name ''singultus'', from a Latin word meaning "to catch one's breath while sobbing"; also spelled hiccough) is an involuntary contraction ( myoclonic jerk) of the diaphragm that may repeat several times per minute. The hi ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...

loss of coordination Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

and

drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

, along with

anterograde amnesia In neurology, anterograde amnesia is the inability to create new memories after the event that caused amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact ...

which can be quite pronounced at high doses. As with other benzodiazepines, in case of abrupt discontinuation following prolonged use, severe withdrawal symptoms may occur including restlessness,

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

s, convulsions and

death Death is the irreversible cessation of all biological functions that sustain an organism. For organisms with a brain, death can also be defined as the irreversible cessation of functioning of the whole brain, including brainstem, and brain ...

, though because of its intermediate half-life as well as that of its active metabolites, these withdrawal symptoms may take two or more days to manifest.

Contraindications and special caution

Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol or drug-dependent individuals and individuals with

comorbid In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...

psychiatric disorders A mental disorder, also referred to as a mental illness or psychiatric disorder, is a behavioral or mental pattern that causes significant distress or impairment of personal functioning. Such features may be persistent, relapsing and remitti ...

. Phenazepam should not be taken with alcohol or any other CNS depressants. Phenazepam should not be used therapeutically for periods of longer than one month including tapering on and off the drug as recommended for any benzodiazepine in the British national formulary. Some patients may require longer term treatment. Phenazepam was found to be a component in some herbal incense mixtures in Australia and New Zealand in 2011, namely "Kronic". The particular product variety was withdrawn shortly from the market after and replaced with a new formulation.

Synthesis

First, 2-(o-chlorobenzoylamino)-5-bromo-2-chlorobenzophenone is prepared by

acylation In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent. Because they form a strong electrophile when treated with ...

of p-bromoaniline with o-chlorobenzoic acid acyl chloride in the presence of a

zinc chloride Zinc chloride is the name of inorganic chemical compounds with the formula ZnCl2 and its hydrates. Zinc chlorides, of which nine crystalline forms are known, are colorless or white, and are highly soluble in water. This salt is hygroscopic and e ...

catalyst. This is hydrolysed with aqueous sulfuric acid to yield 2-amino-5-bromo-2'-chlorobenzophenone, which is then acylated with

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative n ...

of aminoacetic acid acyl chloride in chloroform to form 2-(aminomethylkarbonylamino)-5-bromo-2-chlorobenzophenone

, which is converted to a base with aqueous

ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous wa ...

and then thermally cyclized to bromodihydrochlorophenylbenzodiazepine (phenazepam). Hydrochloride of aminoacetic acid acyl chloride is prepared by chemical treating glycine with

phosphorus pentachloride Phosphorus pentachloride is the chemical compound with the formula PCl5. It is one of the most important phosphorus chlorides, others being PCl3 and POCl3. PCl5 finds use as a chlorinating reagent. It is a colourless, water-sensitive and moist ...

(PCl₅) in chloroform. Phenazepam sythesis (USSR)

This method of Phenazepam synthesis was developed in the 1970s at the Physico-Chemical Institute of the Academy of Sciences of the

Ukrainian SSR The Ukrainian Soviet Socialist Republic ( uk, Украї́нська Радя́нська Соціалісти́чна Респу́бліка, ; russian: Украи́нская Сове́тская Социалисти́ческая Респ ...

Detection in biological fluids

Phenazepam may be measured in blood or plasma by chromatographic methods. Blood phenazepam concentrations are typically less than 30 μg/L during therapeutic usage, but have frequently been in the 100–600 μg/L range in automotive vehicle operators arrested for impaired driving ability.

Legal status

China

As of October 2015, phenazepam is a controlled substance in China.

United States

Under federal United States law, phenazepam is not currently classified as a controlled substance, as the

Federal Analog Act The Federal Analogue Act, , is a section of the United States Controlled Substances Act passed in 1986 which allows any chemical "substantially similar" to a controlled substance listed in Schedule I or II to be treated as if it were listed in ...

only provides for automatic assumed classification of chemicals "substantially similar" to existing Schedule I or Schedule II drugs, whereas all controlled benzodiazepines under the Controlled Substances Act are classified as Schedule IV. Although phenazepam is currently not controlled, sale for human use remains illegal in the United States. Suppliers attempt to circumvent this regulation by placing a "Not for human use" disclaimer on the product's label. Individual states in the United States often ban these analog drugs by name as they appear. Since 2012,

Louisiana Louisiana , group=pronunciation (French: ''La Louisiane'') is a state in the Deep South and South Central regions of the United States. It is the 20th-smallest by area and the 25th most populous of the 50 U.S. states. Louisiana is borde ...

has classified phenazepam as a controlled dangerous substance. This ban affects several products, some of which were sold at retail stores under the guise of air freshener or similar, containing phenazepam yet claiming not to be for human use. This legislation was introduced after one such product, branded as "Zannie" and marketed as an air freshener rapidly gained publicity as the subject of numerous media reports, attracting the attention of officials. The ensuing investigation effort, led by Senator Fred Mills and Louisiana Poison Center Director Mark Ryan, positively identified the active ingredient of "Zannie" as phenazepam. According to Ryan,

chemical analysis Analytical chemistry studies and uses instruments and methods to separate, identify, and quantify matter. In practice, separation, identification or quantification may constitute the entire analysis or be combined with another method. Separati ...

identified the active ingredient as "100 percent phenazepam". Paul Halverson, director and state health officer for the Arkansas Department of Health, approved an emergency rule to ban the sale and distribution of phenazepam shortly after the Louisiana ban.

United Kingdom

Phenazepam is a class C drug in the UK. The UK home office banned importation of phenazepam on Friday 22 July 2011 while it drafted legislation, released in January 2012 to become law at the end of March 2012. The bill was quashed following advice from the

ACMD The Advisory Council on the Misuse of Drugs (ACMD) is a British statutory non-departmental public body, advisory non-departmental public body, which was established under the Misuse of Drugs Act 1971. Mandate Its terms of reference, according to ...

as it included two non-abusable steroids. There was a new discussion about its fate on April 23, 2012, where it was decided that the bill would be rewritten and phenazepam would still be banned. It was eventually banned on June 13, 2012 as a class C, schedule II drug.

Elsewhere

Phenazepam was classified as a narcotic in Finland in July, 2014. Phenazepam is considered a narcotic in Norway, as per a March 23, 2010 Health Department addition to the Regular Narcotic List. In Russia, while the drug is considered a prescription medication (but not a controlled one, as all other benzodiazepines except tofisopam), some pharmacies sell it without prescriptions required. Since March 22, 2021 phenazepam must be a controlled substance in Russia. In Estonia, phenazepam is a Schedule IV substance under the Narcotic Drugs and Psychotropic Substances Act. Schedule IV is the lowest classification of psychoactive substances in Estonia. It includes prescribable drugs, including other benzodiazepines.

UN Single Convention on Narcotic Drugs

On 8 March 2016 at its 59th Session, the Commission on Narcotic Drugs (CND) added Phenazepam to relevant schedules of the Single Convention on Narcotic Drugs of 1961.

Trade names

RU: * «Феназепам» (Phenazepam) tablets 0.25, 0.5 and 1 mg, solution for intramuscular and intravenous injection 1 mg/mL (0.1%) * «Элзепам» (Elzepam) tablets 0.5 and 1 mg, solution for intramuscular and intravenous injection 1 mg/mL (0.1%) * «Фензитат» (Phenzitat) tablets 0.5 and 1 mg * «Фенорелаксан» (Phenorelaxan) tablets 0.5 and 1 mg, solution for intramuscular and intravenous injection 1 mg/mL (0.1%) * «Транквезипам» (Trankvezipam) tablets 0.5 and 1 mg, solution for intramuscular and intravenous injection 1 mg/mL (0.1%) * «Фезипам» (Phezipam) tablets 0.5 and 1 mg ''(not to be confused with «Фезам» (Phezam) which contains

cinnarizine Cinnarizine is an antihistamine and calcium channel blocker of the diphenylmethylpiperazine group. It is prescribed for nausea and vomiting due to motion sickness or other sources such as chemotherapy, vertigo, or Ménière's disease. Cinnariz ...

/ piracetam)'' * «Фезанеф» (Phezanef) tablets 1 mg

References

{{GABAAR PAMs Benzodiazepines Chlorobenzenes Organobromides Lactams Designer drugs Russian drugs GABAA receptor positive allosteric modulators Drugs in the Soviet Union