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Wednesday, August 1, 2018

Recreational drug use

From Wikipedia, the free encyclopedia
 
Adriaen Brouwer, The Smokers (1636)
Edgar Degas, L’Absinthe (1873)
















Recreational drug use is the use of a psychoactive drug to induce an altered state of consciousness for pleasure, by modifying the perceptions, feelings, and emotions of the user. When a psychoactive drug enters the user's body, it induces an intoxicating effect. Generally, recreational drugs are in three categories: depressants (drugs that induce a feeling of relaxation and calm); stimulants (drugs that induce a sense of energy and alertness); and hallucinogens (drugs that induce perceptual distortions such as hallucination). In popular practice, recreational drug use generally is a tolerated social behaviour, rather than perceived as the serious medical condition of self-medication. However, heavy use of some drugs is socially stigmatized.

Recreational drugs include alcohol (as found in beer, wine, and distilled spirits); cannabis and hashish; nicotine (tobacco); caffeine (coffee and tea); and the controlled substances listed as illegal drugs in the Single Convention on Narcotic Drugs (1961) and the Convention on Psychotropic Substances (1971) of the United Nations. What controlled substances are considered illegal drugs varies by country, but usually includes methamphetamines, heroin, cocaine, and club drugs. In 2015, it was estimated that about 5% of people aged 15 to 65 had used illegal drugs at least once (158 million to 351 million).[1]

Reasons for use

Hadzabe tribe members smoking.

Many researchers have explored the etiology of recreational drug use. Some of the most common theories are: genetics, personality type, psychological problems, self-medication, gender, age, instant gratification, basic human need, curiosity, rebelliousness, a sense of belonging to a group, family and attachment issues, history of trauma, failure at school or work, socioeconomic stressors, peer pressure, juvenile delinquency, availability, historical factors, or sociocultural influences.[2] There has not been agreement around any one single cause. Instead, experts tend to apply the biopsychosocial model. Any number of these factors are likely to influence an individual’s drug use as they are not mutually exclusive.[2][3] Regardless of genetics, mental health or traumatic experiences, social factors play a large role in exposure to and availability of certain types of drugs and patterns of drug use.[2]

According to addiction researcher Martin A. Plant, many people go through a period of self-redefinition before initiating recreational drug use. They tend to view using drugs as part of a general lifestyle that involves belonging to a subculture that they associate with heightened status and the challenging of social norms. Plant says, “From the user's point of view there are many positive reasons to become part of the milieu of drug taking. The reasons for drug use appear to have as much to do with needs for friendship, pleasure and status as they do with unhappiness or poverty. Becoming a drug taker, to many people, is a positive affirmation rather than a negative experience.”[2]

Evolution

Anthropological research has suggested that humans "may have evolved to counter-exploit plant neurotoxins". The ability to use botanical chemicals to serve the function of endogenous neurotransmitters may have improved survival rates, conferring an evolutionary advantage. A typically restrictive prehistoric diet may have emphasised the apparent benefit of consuming psychoactive drugs, which had themselves evolved to imitate neurotransmitters.[4] Chemical–ecological adaptations, and the genetics of hepatic enzymes, particularly cytochrome P450, have led researchers to propose that "humans have shared a co-evolutionary relationship with psychotropic plant substances that is millions of years old."[5]

Risks

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis and ranked 20 popular recreational drugs by their dependence liability and physical and social harms.[6]
 
This 1914 photo shows intoxicated men at a sobering-up room.

Severity and type of risks that come with recreational drug use vary widely with the drug in question and the amount being used. There are many factors in the environment and within the user that interact with each drug differently. Overall, some studies suggest that alcohol is one of the most dangerous of all recreational drugs; only heroin, crack cocaine, and methamphetamines are judged to be more harmful. However, studies which focus on a moderate level of alcohol consumption have concluded that there can be substantial health benefits from its use, such as decreased risk of cardiac disease, stroke and cognitive decline.[7][8][9][10] This claim has been disputed. Researcher David Nutt stated that these studies showing benefits for "moderate" alcohol consumption lacked control for the variable of what the subjects were drinking, beforehand.[11] Experts in the UK have suggested that some drugs that may be causing less harm, to fewer users (although they are also used less frequently in the first place), include cannabis, psilocybin mushrooms, LSD, and ecstasy. These drugs are not without their own particular risks.[12]

Responsible use

The concept of "responsible drug use" is that a person can use drugs recreationally or otherwise with reduced or eliminated risk of negatively affecting other aspects of one's life or other people's lives. Advocates of this philosophy point to the many well-known artists and intellectuals who have used drugs, experimentally or otherwise, with few detrimental effects on their lives. Responsible drug use becomes problematic only when the use of the substance significantly interferes with the user's daily life.

Responsible drug use advocates that users should not take drugs at the same time as activities such as driving, swimming, operating machinery, or other activities that are unsafe without a sober state. Responsible drug use is emphasized as a primary prevention technique in harm-reduction drug policies. Harm-reduction policies were popularized in the late 1980s, although they began in the 1970s counter-culture, when cartoons explaining responsible drug use and the consequences of irresponsible drug use were distributed to users.[13] Another issue is that the illegality of drugs in itself also causes social and economic consequences for those using them—the drugs may be "cut" with adulterants and the purity varies wildly, making overdoses more likely—and legalization of drug production and distribution would reduce these and other dangers of illegal drug use.[14] Harm reduction seeks to minimize the harm that can occur through the use of various drugs, whether legal (e.g., alcohol and nicotine), or illegal (e.g., heroin and cocaine). For example, people who inject illicit drugs can minimize harm to both themselves and members of the community through proper injecting technique, using new needles and syringes each time, and proper disposal of all injecting equipment.

Prevention

In efforts to curtail recreational drug use, governments worldwide introduced several laws prohibiting the possession of almost all varieties of recreational drugs during the 20th century. The West's "War on Drugs" however, is now facing increasing criticism. Evidence is insufficient to tell if behavioral interventions help prevent recreational drug use in children.[15]

Demographics

Smoking any tobacco product, %, Males[16] 
 
Total recorded alcohol per capita consumption (15+), in liters of pure alcohol[17]

Australia

Alcohol is the most widely used drug in Australia, tried one or more times in their lives by 86.2% of Australians aged 12 years and over, while 34.8% of Australians aged 12 years and over have used cannabis one or more times in their lives.[18]

United States

In the 1960s, the number of Americans who had tried cannabis at least once increased over twentyfold.[citation needed] In 1969, the FBI reported that between the years 1966 and 1968, the number of arrests for marijuana possession, which had been outlawed throughout the United States under Marijuana Tax Act of 1937, had increased by 98%.[19] Despite acknowledgement that drug use was greatly growing among America's youth during the late 1960s, surveys have suggested that only as much as 4% of the American population had ever smoked marijuana by 1969.[20] By 1972, however, that number would increase to 12%.[20] That number would then double by 1977.[20]

The Controlled Substances Act of 1970 classified marijuana along with heroin and LSD as a Schedule I drug, i.e., having the relatively highest abuse potential and no accepted medical use.[21] Most marijuana at that time came from Mexico, but in 1975 the Mexican government agreed to eradicate the crop by spraying it with the herbicide paraquat, raising fears of toxic side effects.[21] Colombia then became the main supplier.[21] The "zero tolerance" climate of the Reagan and Bush administrations (1981–93) resulted in passage of strict laws and mandatory sentences for possession of marijuana and in heightened vigilance against smuggling at the southern borders.[citation needed] The "war on drugs" thus brought with it a shift from reliance on imported supplies to domestic cultivation (particularly in Hawaii and California).[21] Beginning in 1982 the Drug Enforcement Administration turned increased attention to marijuana farms in the United States,[21] and there was a shift to the indoor growing of plants specially developed for small size and high yield.[21] After over a decade of decreasing use, marijuana smoking began an upward trend once more in the early 1990s,[21] especially among teenagers,[21] but by the end of the decade this upswing had leveled off well below former peaks of use.[21]

Society and culture

Many movements and organizations are advocating for or against the liberalization of the use of recreational drugs, notably cannabis legalization. Subcultures have emerged among users of recreational drugs, as well as among those who abstain from them, such as teetotalism and "straight edge".
The prevalence of recreational drugs in human societies is widely reflected in fiction, entertainment, and the arts, subject to prevailing laws and social conventions. In video games, for example, enemies are often drug dealers, a narrative device that justifies the player killing them. Other games portray drugs as a kind of "power-up"; their effect is often unrealistically conveyed by making the screen wobble and blur.[22]

Common recreational drugs

The following substances are used recreationally:[23]

Routes of administration

Insufflation of caffeine powder.
 
Injection of heroin.
 
Drugs often associated with a particular route of administration. Many drugs can be consumed in more than one way. For example, marijuana can be swallowed like food or smoked, and cocaine can be "sniffed" in the nostrils, injected, or, with various modifications, smoked.
  • inhalation: all intoxicative inhalants (see below) that are gases or solvent vapours that are inhaled through the trachea, as the name suggests
  • insufflation: also known as "sniffing", or "snorting", this method involves the user placing a powder in the nostrils and breathing in through the nose, so that the drug is absorbed by the mucous membranes. Drugs that are "sniffed", or "snorted", include powdered amphetamines, cocaine, heroin, ketamine and MDMA. Additionally, snuff tobacco
  • intravenous injection (see also the article Drug injection): the user injects a solution of water and the drug into a vein, or less commonly, into the tissue. Drugs that are injected include morphine and heroin, less commonly other opioids. Stimulants like cocaine or methamphetamine may also be injected. In rare cases, users inject other drugs.
  • oral intake: caffeine, ethanol, cannabis edibles, psilocybin mushrooms, coca tea, poppy tea, laudanum, GHB, ecstasy pills with MDMA or various other substances (mainly stimulants and psychedelics), prescription and over-the-counter drugs (ADHD and narcolepsy medications, benzodiazapines, anxiolytics, sedatives, cough suppressants, morphine, codeine, opioids and others)
  • sublingual: substances diffuse into the blood through tissues under the tongue. Many psychoactive drugs can be or have been specifically designed for sublingual administration, including barbiturates, benzodiazepines,[37] opioid analgesics with poor gastrointestinal bioavailability, LSD blotters, coca leaves, some hallucinogens. This route of administration is activated when chewing some forms of smokeless tobacco (e.g. dipping tobacco, snus).
  • intrarectal: administering into the rectum, most water-soluble drugs can be used this way
  • smoking (see also the section below): tobacco, cannabis, opium, crystal meth, phencyclidine, crack cocaine and heroin (diamorphine as freebase) known as chasing the dragon
  • transdermal patches with prescription drugs: e.g. methylphenidate (Daytrana) and fentanyl
Many drugs are taken through various routes. Intravenous route is the most efficient, but also one of the most dangerous. Nasal, rectal, inhalation and smoking are safer. The oral route is one of the safest and most comfortable, but of little bioavailability.

Types

Depressants

Depressants are psychoactive drugs that temporarily diminish the function or activity of a specific part of the body or mind.[38] Colloquially, depressants are known as "downers", and users generally take them to feel more relaxed and less tense. Examples of these kinds of effects may include anxiolysis, sedation, and hypotension. Depressants are widely used throughout the world as prescription medicines and as illicit substances. When these are used, effects may include anxiolysis (reduction of anxiety), analgesia (pain relief), sedation, somnolence, cognitive/memory impairment, dissociation, muscle relaxation, lowered blood pressure/heart rate, respiratory depression, anesthesia, and anticonvulsant effects. Depressants exert their effects through a number of different pharmacological mechanisms, the most prominent of which include facilitation of GABA or opioid activity, and inhibition of adrenergic, histamine or acetylcholine activity. Some are also capable of inducing feelings of euphoria (a happy sensation). The most widely used depressant by far is alcohol.

Stimulants or "uppers", such as amphetamines or cocaine, which increase mental or physical function, have an opposite effect to depressants.

Antihistamines

Antihistamines (or "histamine antagonists") inhibit the release or action of histamine. "Antihistamine" can be used to describe any histamine antagonist, but the term is usually reserved for the classical antihistamines that act upon the H1 histamine receptor. Antihistamines are used as treatment for allergies. Allergies are caused by an excessive response of the body to allergens, such as the pollen released by grasses and trees. An allergic reaction causes release of histamine by the body. Other uses of antihistamines are to help with normal symptoms of insect stings even if there is no allergic reaction. Their recreational appeal exists mainly due to their anticholinergic properties, that induce anxiolysis and, in some cases such as diphenhydramine, chlorpheniramine, and orphenadrine, a characteristic euphoria at moderate doses. High dosages taken to induce recreational drug effects may lead to overdoses. Antihistamines are also consumed in combination with alcohol, particularly by youth who find it hard to obtain alcohol. The combination of the two drugs can cause intoxication with lower alcohol doses.

Hallucinations and possibly delirium resembling the effects of Datura stramonium can result if the drug is taken in much higher than therapeutical dosages. Antihistamines are widely available over the counter at drug stores (without a prescription), in the form of allergy medication and some cough medicines. They are sometimes used in combination with other substances such as alcohol. The most common unsupervised use of antihistamines in terms of volume and percentage of the total is perhaps in parallel to the medicinal use of some antihistamines to stretch out and intensify the effects of opioids and depressants. The most commonly used are hydroxyzine, mainly to stretch out a supply of other drugs, as in medical use, and the above-mentioned ethanolamine and alkylamine-class first-generation antihistamines, which are - once again as in the 1950s - the subject of medical research into their anti-depressant properties.

For all of the above reasons, the use of medicinal scopolamine for recreational uses is also seen.

Analgesics

Analgesics (also known as "painkillers") are used to relieve pain (achieve analgesia). The word analgesic derives from Greek "αν-" (an-, "without") and "άλγος" (álgos, "pain"). Analgesic drugs act in various ways on the peripheral and central nervous systems; they include paracetamol (para-acetylaminophenol, also known in the US as acetaminophen), the nonsteroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, and opioid drugs such as hydrocodone, codeine, heroin and oxycodone. Some further examples of the brand name prescription opiates and opioid analgesics that may be used recreationally include Vicodin, Lortab, Norco (hydrocodone), Avinza, Kapanol (morphine), Opana, Paramorphan (oxymorphone), Dilaudid, Palladone (hydromorphone), and OxyContin (oxycodone).

Tranquilizers

Tranquilizers (GABAergics):

Stimulants

Cocaine is a commonly used stimulant

Stimulants, also known as "psychostimulants",[39] induce euphoria with improvements in mental and physical function, such as enhanced alertness, wakefulness, and locomotion. Due to their effects typically having an "up" quality to them, stimulants are also occasionally referred to as "uppers". Depressants or "downers", which decrease mental or physical function, are in stark contrast to stimulants and are considered to be their functional opposites.

Stimulants enhance the activity of the central and peripheral nervous systems. Common effects may include increased alertness, awareness, wakefulness, endurance, productivity, and motivation, arousal, locomotion, heart rate, and blood pressure, and a diminished desire for food and sleep.

Use of stimulants may cause the body to reduce significantly its production of natural body chemicals that fulfill similar functions. Until the body reestablishes its normal state, once the effect of the ingested stimulant has worn off the user may feel depressed, lethargic, confused, and miserable. This is referred to as a "crash", and may provoke reuse of the stimulant.

Examples include:

Euphoriants

  • Alcohol: "Euphoria, the feeling of well-being, has been reported during the early (10–15 min) phase of alcohol consumption" (e.g., beer, wine or spirits)[40]
  • Catnip Catnip contains a sedative known as nepetalactone that activates opioid receptors. In cats it elicits sniffing, licking, chewing, head shaking, rolling, and rubbing which are indicators of pleasure. In humans, however, catnip does not act as a euphoriant.[41]
  • Cannabis Tetrahydrocannabinol, the main psychoactive ingredient in this plant can have sedative and euphoric properties.
  • Stimulants: "Psychomotor stimulants produce locomotor activity (the subject becomes hyperactive), euphoria, (often expressed by excessive talking and garrulous behaviour), and anorexia. The amphetamines are the best known drugs in this category..."[42]
  • MDMA: The "euphoriant drugs such as MDMA (‘ecstasy’) and MDEA (‘eve’)" are popular amongst young adults.[43] MDMA "users experience short-term feelings of euphoria, rushes of energy and increased tactility."[44]
  • Opium: This "drug derived from the unripe seed-pods of the opium poppy…produces drowsiness and euphoria and reduces pain. Morphine and codeine are opium derivatives."[45]

Hallucinogens

Hallucinogens can be divided into three broad categories: psychedelics, dissociatives, and deliriants. They can cause subjective changes in perception, thought, emotion and consciousness. Unlike other psychoactive drugs such as stimulants and opioids, hallucinogens do not merely amplify familiar states of mind but also induce experiences that differ from those of ordinary consciousness, often compared to non-ordinary forms of consciousness such as trance, meditation, conversion experiences, and dreams.

Psychedelics, dissociatives, and deliriants have a long worldwide history of use within medicinal and religious traditions. They are used in shamanic forms of ritual healing and divination, in initiation rites, and in the religious rituals of syncretistic movements such as União do Vegetal, Santo Daime, Temple of the True Inner Light, and the Native American Church. When used in religious practice, psychedelic drugs, as well as other substances like tobacco, are referred to as entheogens.

Starting in the mid-20th century, psychedelic drugs have been the object of extensive attention in the Western world. They have been and are being explored as potential therapeutic agents in treating depression, post-traumatic stress disorder, Obsessive-compulsive disorder, alcoholism, and opioid addiction. Yet the most popular, and at the same time most stigmatized, use of psychedelics in Western culture has been associated with the search for direct religious experience, enhanced creativity, personal development, and "mind expansion". The use of psychedelic drugs was a major element of the 1960s counterculture, where it became associated with various social movements and a general atmosphere of rebellion and strife between generations.

Inhalants

Inhalants are gases, aerosols, or solvents that are breathed in and absorbed through the lungs. While some "inhalant" drugs are used for medical purposes, as in the case of nitrous oxide, a dental anesthetic, inhalants are used as recreational drugs for their intoxicating effect. Most inhalant drugs that are used non-medically are ingredients in household or industrial chemical products that are not intended to be concentrated and inhaled, including organic solvents (found in cleaning products, fast-drying glues, and nail polish removers), fuels (gasoline (petrol) and kerosene), and propellant gases such as Freon and compressed hydrofluorocarbons that are used in aerosol cans such as hairspray, whipped cream, and non-stick cooking spray. A small number of recreational inhalant drugs are pharmaceutical products that are used illicitly, such as anesthetics (ether and nitrous oxide) and volatile anti-angina drugs (alkyl nitrites).

The most serious inhalant abuse occurs among children and teens who "[...] live on the streets completely without family ties."[46] Inhalant users inhale vapor or aerosol propellant gases using plastic bags held over the mouth or by breathing from a solvent-soaked rag or an open container. The effects of inhalants range from an alcohol-like intoxication and intense euphoria to vivid hallucinations, depending on the substance and the dosage. Some inhalant users are injured due to the harmful effects of the solvents or gases, or due to other chemicals used in the products that they are inhaling. As with any recreational drug, users can be injured due to dangerous behavior while they are intoxicated, such as driving under the influence. Computer cleaning dusters are dangerous to inhale, because the gases expand and cool rapidly upon being sprayed. In some cases, users have died from hypoxia (lack of oxygen), pneumonia, cardiac failure or arrest,[47] or aspiration of vomit.

Examples include:

List of drugs which can be smoked

Plants: Substances (also not necessarily psychoactive plants soaked with them):

List of psychoactive plants, fungi and animals

Minimally psychoactive plants which contain mainly caffeine and theobromine:
  • coffee
  • tea (caffeine in tea is sometimes called theine) – also contains theanine
  • guarana (caffeine in guarana is sometimes called guaranine)
  • yerba mate (caffeine in yerba mate is sometimes called mateine)
  • cocoa
  • kola
Most known psychoactive plants:
Solanaceae plants—contain atropine, hyoscyamine and scopolamine
Cacti with mescaline:
Other plants:
Fungi:
Psychoactive animals:

Gallery

at

A single-molecule room-temperature transistor made from 14 atoms

September 1, 2017
Original link:  http://www.kurzweilai.net/a-single-molecule-room-temperature-transistor-made-from-14-atoms
Columbia researchers wired a single molecule consisting of 14 atoms connected to two gold electrodes to show that it performs as a transistor at room temperature. (credit: Bonnie Choi/Columbia University)

Columbia Engineering researchers have taken a key step toward atomically precise, reproducible transistors made from single molecules and operating at room temperature — a major goal in the field of molecular electronics.

The team created a two-terminal transistor with a diameter of about 0.5 nanometers and core consisting of just 14 atoms. The device can reliably switch from insulator to conductor when charge is added or removed, one electron at a time (known as “current blockade”).*

The research was published in the journal Nature Nanotechnology.

Controllable structure with atomic precision

“With these molecular clusters, we have complete control over their structure with atomic precision and can change the elemental composition and structure in a controllable manner to elicit certain electrical response,” says Latha Venkataraman, leader of the Columbia research team.

The researchers plan to design improved molecular cluster systems with better electrical performance (such as higher on/off current ratio and different accessible states) and increase the number of atoms in the cluster core, while maintaining the atomic precision and uniformity of the compound.

Other studies have created quantum dots to produce similar effects, but the dots are much larger and not uniform in size, and the results have not been reproducible. The ultimate size reduction would be single-atom transistors, but they require ultra-cold temperatures (minus 196 degrees Celsius in this case, for example).

The single molecule’s 14-atom core structure comprises cobalt (blue) and sulfur (yellow) atoms (left) and ethyl-4-(methylthio)phenyl phosphine atoms, used to wire the cluster into a junction (right). (credit: Bonnie Choi/Columbia University)

* The researchers used a scanning tunneling microscope technique that they pioneered to make junctions comprising a single cluster connected to the two gold electrodes, which enabled them to characterize its electrical response as they varied the applied bias voltage. The technique allows them to fabricate and measure thousands of junctions with reproducible transport characteristics. The team worked with small inorganic molecular clusters that were identical in shape and size, so they knew exactly — down to the atomic scale — what they were measuring. The team evaluated the performance of the diode by the on/off ratio — the ratio between the current flowing through the device when it is switched on and the residual current still present in its “off” state. At room temperature, they observed a high on/off ratio of about 600 in single-cluster junctions, higher than any other single-molecule devices measured to date.

Abstract of Room-temperature current blockade in atomically defined single-cluster junctions

Fabricating nanoscopic devices capable of manipulating and processing single units of charge is an essential step towards creating functional devices where quantum effects dominate transport characteristics. The archetypal single-electron transistor comprises a small conducting or semiconducting island separated from two metallic reservoirs by insulating barriers. By enabling the transfer of a well-defined number of charge carriers between the island and the reservoirs, such a device may enable discrete single-electron operations. Here, we describe a single-molecule junction comprising a redox-active, atomically precise cobalt chalcogenide cluster wired between two nanoscopic electrodes. We observe current blockade at room temperature in thousands of single-cluster junctions. Below a threshold voltage, charge transfer across the junction is suppressed. The device is turned on when the temporary occupation of the core states by a transiting carrier is energetically enabled, resulting in a sequential tunnelling process and an increase in current by a factor of ∼600. We perform in situ and ex situ cyclic voltammetry as well as density functional theory calculations to unveil a two-step process mediated by an orbital localized on the core of the cluster in which charge carriers reside before tunnelling to the collector reservoir. As the bias window of the junction is opened wide enough to include one of the cluster frontier orbitals, the current blockade is lifted and charge carriers can tunnel sequentially across the junction.

References:

at

Fentanyl

From Wikipedia, the free encyclopedia
Fentanyl
Fentanyl2DCSD.svg
Fentanyl-xtal-3D-balls.png
Clinical data
Trade namesActiq, Duragesic, Fentora, others
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Dependence
liability		Very high
Routes of
administration		Buccal, epidural, IM, IT, IV, sublingual, skin patch
Drug classOpioid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability92% (transdermal)
89% (intranasal)
50% (buccal)
33% (ingestion)
Protein binding80–85%
Metabolismhepatic, primarily by CYP3A4
Onset of action5 minutes[1]
Elimination half-lifeIV: 6 mins (T1/2 α)
1 hours (T1/2 β)
16 hours (T1/2 ɣ)
Intranasal: 6.5 hours
Transdermal: 20–27 hours[2]
Sublingual/buccal (single dose): 2.6–13.5 hours[2]
Duration of actionIV: 30–60 minutes[3][1]
ExcretionMostly urinary (metabolites, <10 class="reference" drug="" id="cite_ref-AHFS2017_2-2" sup="" unchanged="">[2]

Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard
100.006.468 Edit this at Wikidata
Chemical and physical data
Formula
C22H28N2O
Molar mass
336.471 g/mol
3D model (JSmol)
Melting point
87.5 °C (189.5 °F)

Fentanyl (also spelled fentanil) is an opioid used as a pain medication and together with other medications for anesthesia. Fentanyl is also made illegally and used as a recreational drug, often mixed with heroin or cocaine. It has a rapid onset and effects generally last less than an hour or two. Medically, fentanyl is used by injection, as a patch on the skin, as a nasal spray, or in the mouth.

Common side effects include vomiting, constipation, sedation, confusion, hallucinations, and injuries related to poor coordination.[2][5] Serious side effects may include decreased breathing (respiratory depression), serotonin syndrome, low blood pressure, addiction, or coma.[2][5] In 2016, more than 20,000 deaths occurred in the United States due to overdoses of fentanyl and fentanyl analogues, half of all reported opioid related deaths.[6][7] Fentanyl works primarily by activating μ-opioid receptors.[2] It is around 100 times stronger than morphine, and some analogues such as carfentanil are around 10,000 times stronger.[8]

Fentanyl was first made by Paul Janssen in 1960 and approved for medical use in the United States in 1968.[2][9]In 2015, 1,600 kilograms (3,500 lb) were used in healthcare globally.[10] As of 2017, fentanyl was the most widely used synthetic opioid in medicine.[11] Fentanyl patches are on the WHO List of Essential Medicines, the most effective and safe medicines needed in a health system.[12] For a 100 microgram vial, the average wholesale cost in the developing world is US$0.66 (2015)[13] while in the USA the price is US$0.49 (2017) for that amount.[14]

Medical uses

Intravenous and intrathecal

Intravenous fentanyl is often used for anaesthesia and analgesia. During anaesthesia it is often used along with a hypnotic agent like propofol. It is also administered in combination with a benzodiazepine, such as midazolam, to produce sedation for procedures such as endoscopy, cardiac catheterization, and oral surgery, or in emergency rooms.[15][16] It is also used in the management of chronic pain including cancer pain.[17]

Fentanyl is sometimes given intrathecally as part of spinal anaesthesia or epidurally for epidural anaesthesia and analgesia. Because of fentanyl's high lipid solubility, its effects are more localized than morphine, and some clinicians prefer to use morphine to get a wider spread of analgesia.[18]

Patches

A fentanyl transdermal patch with a release rate of 12 micrograms / hour, on a person's arm.

Fentanyl transdermal patches (Duragesic) are used in chronic pain management. The patches work by slowly releasing fentanyl through the skin into the bloodstream over 48 to 72 hours, allowing for long-lasting pain management.[19] Dosage is based on the size of the patch, since, in general, the transdermal absorption rate is constant at a constant skin temperature.[19] Rate of absorption is dependent on a number of factors. Body temperature, skin type, amount of body fat, and placement of the patch can have major effects. The different delivery systems used by different makers will also affect individual rates of absorption. Under normal circumstances, the patch will reach its full effect within 12 to 24 hours; thus, fentanyl patches are often prescribed with a fast-acting opioid (such as morphine or oxycodone) to handle breakthrough pain.[19]

It is unclear if fentanyl gives long-term pain relief to people with neuropathic pain.[20]

In palliative care, transdermal fentanyl has a definite, but limited, role for:
  • people already stabilized on other opioids who have persistent swallowing problems and cannot tolerate other parenteral routes such as subcutaneous administration.
  • people with moderate to severe kidney failure.
  • troublesome side effects of oral morphine, hydromorphone, or oxycodone.[citation needed]
Care must be taken to guard against the application of external heat sources (such as direct sunlight, heating pads, etc.) which in certain circumstances can trigger the release of too much medication and cause life-threatening complications.

Duragesic was first approved by the College ter Beoordeling van Geneesmiddelen, the Medicines Evaluation Board in the Netherlands, on July 17, 1995, as 25, 50, 75 and 100 µg/h formulations after a set of successful clinical trials, and on October 27, 2004, the 12 µg/h (actually 12.5 µg/h) formulation was approved as well. On January 28, 2005, the U.S. Food and Drug Administration approved first-time generic formulations of 25, 50, 75, and 100 µg/h fentanyl transdermal systems (made by Mylan Technologies, Inc.; brand name Duragesic, made by Alza Corp.) through an FTC consent agreement derailing the possibility of a monopoly in the treatment of breakthrough chronic pain by Alza Corp. In some cases, physicians instruct people to apply more than one patch at a time, giving a much wider range of possible dosages. For example, a person may be prescribed a 37.5 µg dosage by applying one 12.5 µg patch and one 25 µg patch simultaneously, or contingent on the large size of the (largest) 100 μg/h patch, multiple patches are commonly prescribed for doses exceeding 100μg/h, such as two 75 μg/h patches worn to afford a 150 μg/h dosage regimen. Although the commonly referred to dosage rates are 12/25/50/75/100 µg/h, the "12 µg" patch actually releases 12.5 µg/h.[21] It is designed to release half the dose of the 25 µg/h dose patch.

As of July 2009, construction of the Duragesic patch had been changed from the gel pouch and membrane design to "a drug-in-adhesive matrix designed formulation", as described in the prescribing information.[21] This construction makes illicit use of the fentanyl more difficult.

Storage and disposal

The fentanyl patch is one of a small number of medications that may be especially harmful, and in some cases fatal, with just one dose, if used by someone other than the person for whom the medication was prescribed.[22] Unused fentanyl patches should be kept in a secure location that is out of children’s sight and reach, such as a locked cabinet.

When patches cannot be disposed of through a medication take-back program, flushing is recommended for fentanyl patches because it is the fastest and surest way to remove them from the home so they cannot harm children, pets and others who were not intended to use them.[22][23][24]

Intranasal

The bioavailability of intranasal fentanyl is about 70–90%, but with some imprecision due to clotted nostrils, pharyngeal swallow and incorrect administration. For both emergency and palliative use, intranasal fentanyl is available in doses of 50, 100, and 200 µg. In emergency medicine, safe administration of intranasal fentanyl with a low rate of side effects and a promising pain reducing effect was demonstrated in a prospective observational study in about 900 out-of-hospital patients.[25]

In children, intranasal fentanyl is useful for the treatment of moderate and severe pain and is well tolerated.[26]

Sublingual

Abstral dissolves quickly and is absorbed through the sublingual mucosa to provide rapid analgesia.[27] Fentanyl is a highly lipophilic compound,[27][28] which is well absorbed sublingually and generally well tolerated.[27] Such forms are particularly useful for breakthrough cancer pain episodes, which are often rapid in onset, short in duration and severe in intensity.[29]

Lozenges

Package and example of fentanyl lollipop (brand: Actiq), 400 micrograms.

Fentanyl lozenges (Actiq) are a solid formulation of fentanyl citrate on a stick in the form of a lollipop that dissolves slowly in the mouth for transmucosal absorption. These lozenges are intended for opioid-tolerant individuals and are effective in treating breakthrough cancer pain.[30] It has also been used for breakthrough pain for people with not cancer related pain, but this application is controversial.[31] The unit is a berry-flavoured lozenge on a stick swabbed on the mucosal surfaces inside the mouth—inside of the cheeks, under and on the tongue and gums—to release the fentanyl quickly into the system. It is most effective when the lozenge is consumed within 15 minutes. About 25% of the medication is absorbed through the oral mucosa, resulting in a fast onset of action, and the rest is swallowed and absorbed in the small intestine, acting more slowly. The lozenge is less effective and acts more slowly if swallowed as a whole, as despite good absorbance from the small intestine there is extensive first-pass metabolism, leading to an oral bioavailability of about 33% as opposed to 50% when used correctly, (25% via the mouth mucosa and 25% via the gut).[30]
Actiq is produced by the pharmaceutical company Cephalon on a plastic stick; this provides the means by which the medication can maintain its placement while it dissolves slowly in the mouth for absorption across the buccal mucosa, in a manner similar to sublingual buprenorphine/naloxone film strips. An Actiq lozenge contains 2 grams of sugar (8 calories).[32][33] Actiq has been linked to dental decay, with some users who had no prior dental issues suffering tooth loss, and in the U.S many users have started their own Facebook pages to educate users about the severe dental issues caused by Actiq fentanyl pops as well as suing Cephalon for damages.[34]

In September 2006, a generic fentanyl lozenge was released by Barr Pharmaceuticals.[35]

USAF Pararescue combat medics in Afghanistan use fentanyl lollipops on combat casualties from IED blasts and other trauma.[36] The stick is taped to a finger and the lozenge put in the cheek of the person. When enough fentanyl has been absorbed, the (sedated) person generally let the lollipop fall from the mouth, indicating sufficient analgesia and somewhat reducing the likelihood of overdose and associated risks.[36]

Other

Some routes of administration such as nasal sprays and inhalers generally result in faster onset of high blood levels, which can provide more immediate analgesia but also more severe side effects, especially in overdose. The much higher cost of some of these appliances may not be justified by marginal benefit compared with buccal or oral options. Intranasal fentanyl appears to be equally effective as IV morphine and superior to intramuscular morphine for management of acute hospital pain.[37]

A fentanyl patient-controlled transdermal system (PCTS) is under development, which aims to allow people to control administration of fentanyl through the skin to treat postoperative pain.[38]

Adverse effects

Fentanyl's most common side effects (more than 10% of people) include diarrhea, nausea, constipation, dry mouth, somnolence, confusion, asthenia (weakness), sweating, and less frequently (3 to 10% of people) abdominal pain, headache, fatigue, anorexia and weight loss, dizziness, nervousness, hallucinations, anxiety, depression, flu-like symptoms, dyspepsia (indigestion), shortness of breath, hypoventilation, apnoea, and urinary retention. Fentanyl use has also been associated with aphasia.[39]

Despite being a more potent analgesic, fentanyl tends to induce less nausea, as well as less histamine-mediated itching, than morphine.[40]

Sustained release fentany preparations, such as patches, may produce unexpected delayed respiratory depression.[41][42][43]The duration of action of fentanyl has sometimes been underestimated, leading to harm in a medical context.[44][45][46][47] In 2006, the U.S. Food and Drug Administration (FDA) began investigating several respiratory deaths, but doctors in the United Kingdom were not warned of the risks with fentanyl until September 2008.[48] The FDA reported in April 2012 that twelve young children had died and twelve more made seriously ill from separate accidental exposures to fentanyl skin patches.[49]

The precise reason for sudden respiratory depression is unclear, but there are several hypotheses:
  • Saturation of the body fat compartment in people with rapid and profound body fat loss (people with cancer, cardiac or infection-induced cachexia can lose 80% of their body fat).
  • Early carbon dioxide retention causing cutaneous vasodilation (releasing more fentanyl), together with acidosis, which reduces protein binding of fentanyl, releasing yet more fentanyl.
  • Reduced sedation, losing a useful early warning sign of opioid toxicity and resulting in levels closer to respiratory-depressant levels.
Fentanyl has a therapeutic index of 270.[50]

Overdose

US yearly overdose deaths, and some of the drugs involved. Among the more than 64,000 deaths estimated in 2016, the sharpest increase occurred among deaths related to fentanyl and fentanyl analogs (synthetic opioids in the chart) with over 20,000 deaths.[51]
 In July 2014, the Medicines and Healthcare Products Regulatory Agency (MHRA) of the UK issued a warning about the potential for life-threatening harm from accidental exposure to transdermal fentanyl patches, particularly in children,[52] and advised that they should be folded, with the adhesive side in, before being discarded. The patches should be kept away from children, who are most at risk from fentanyl overdose.[53]

Death from fentanyl overdose was declared a public health crisis in Canada in September 2015, and it continues to be a significant public health issue.[54] In 2016, deaths from fatal fentanyl overdoses in British Columbia, Canada, averaged two persons per day.[55] In 2017 the death rate rose over 100% with 368 overdose related deaths in British Columbia between January and April 2017.[56]

Medical examiners concluded that musician Prince died on April 21, 2016, from an accidental fentanyl overdose.[57] Fentanyl was among many substances identified in counterfeit pills recovered from his home, especially some that were mislabeled as Watson 385, a combination of hydrocodone and paracetamol.[57][58] American rapper Lil Peep also died of an accidental fentanyl overdose on November 15, 2017.[59][60] On January 19, 2018, the medical examiner-coroner for the county of Los Angeles announced that Tom Petty died from an accidental drug overdose as a result of mixing medications that included fentanyl, acetyl fentanyl and despropionyl fentanyl (among others). He was reportedly treating "many serious ailments" that included a broken hip.[61]

In the US, Fentanyl caused 20,100 deaths in 2016, a rise of 540% over the past 3 years.[62][51]

Pharmacology

Fentanyl at opioid receptors[63]
Affinities (Ki) Ratio
MOR DOR KOR MOR:DOR:KOR
0.39 nM >1,000 nM 255 nM 1:>2564:654

Fentanyl provides some of the effects typical of other opioids through its agonism of the opioid receptors. Its strong potency in relation to that of morphine is largely due to its high lipophilicity, per the Meyer-Overton correlation. Because of this, it can more easily penetrate the central nervous system.[40]

Detection in biological fluids

Fentanyl may be measured in blood or urine to monitor for abuse, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Commercially available immunoassays are often used as initial screening tests, but chromatographic techniques are generally used for confirmation and quantitation. Blood or plasma fentanyl concentrations are expected to be in a range of 0.3–3.0 μg/l in persons using the medication therapeutically, 1–10 μg/l in intoxicated people and 3-300 μg/l in victims of acute overdosage.[64] Spray-mass spectrometry (PS-MS) may be useful for initial testing of samples.[65]

History

Fentanyl was first synthesized by Paul Janssen under the label of his relatively newly formed Janssen Pharmaceutica in 1959.[66] It was developed by screening chemicals similar to pethidine (meperidine) for opioid activity.[67] The widespread use of fentanyl triggered the production of fentanyl citrate (the salt formed by combining fentanyl and citric acid in a 1:1 stoichiometric ratio).[68] Fentanyl citrate entered medical use as a general anaesthetic in 1968, manufactured by McNeil Laboratories under the trade name Sublimaze.[69]

In the mid-1990s, Janssen Pharmaceutica developed and introduced into clinical trials the Duragesic patch, which is a formation of an inert alcohol gel infused with select fentanyl doses, which are worn to provide constant administration of the opioid over a period of 48 to 72 hours. After a set of successful clinical trials, Duragesic fentanyl patches were introduced into medical practice.

Following the patch, a flavoured lollipop of fentanyl citrate mixed with inert fillers was introduced in 1998 under the brand name of Actiq, becoming the first quick-acting formation of fentanyl for use with chronic breakthrough pain.[70]

In 2009, the US Food and Drug Administration approved Onsolis (fentanyl buccal soluble film), a fentanyl drug in a new dosage form for cancer pain management in opioid-tolerant subjects.[71] It uses a medication delivery technology called BEMA (BioErodible MucoAdhesive), a small dissolvable polymer film containing various fentanyl doses applied to the inner lining of the cheek.[71]

Fentanyl has a US DEA ACSCN of 9801 and a 2013 annual aggregate manufacturing quota of 2,108.75 kg, unchanged from the prior year.

Society and culture

Brand names

Brand names include Sublimaze,[39] Actiq, Durogesic, Duragesic, Fentora, Matrifen, Haldid, Onsolis,[72] Instanyl,[73] Abstral,[74] Lazanda[75] and others.[76] Subsys is a sublingual spray of fentanyl manufactured by Insys Therapeutics.[77]

Cost

The wholesale cost in the developing world as of 2015 is between US$0.08 and US$0.81 per 100 microgram vial.[13] In the United States this amount costs about US$0.40 as of 2017.[14] In the United States the patches cost US$11.22 for a 12 µg/hr version and US$8.74 for a 100 µg/hr version.[14]

Legal status

In the UK, fentanyl is classified as a controlled Class A drug under the Misuse of Drugs Act 1971.[78]
In the Netherlands, fentanyl is a List I substance of the Opium Law.

In the U.S., fentanyl is a Schedule II controlled substance per the Controlled Substance Act. Distributors of Abstral are required to implement an FDA-approved risk evaluation and mitigation strategy (REMS) program.[79][80] In order to curb misuse, many health insurers have begun to require precertification and/or quantity limits for Actiq prescriptions.[81][82][83]

Public health advisories

The US Food and Drug Administration (FDA) has issued public health advisories related to fentanyl patch dangers. Among these, in July 2005, the FDA issued a Public Health Advisory,[84] which advised that "deaths and overdoses have occurred in patients using both the brand name product Duragesic and the generic product." In December 2007, as part of this continuing investigation, the FDA issued a second Public Health Advisory[84] stating, "The FDA has continued to receive reports of deaths and life-threatening side effects in patients who use the fentanyl patch. The reports indicate that doctors have inappropriately prescribed the fentanyl patch... In addition, the reports indicate that patients are continuing to incorrectly use the fentanyl patch..."

Recreational use

Fentanyl powder seized by a sheriff.[85]

Illicit use of pharmaceutical fentanyl and its analogues first appeared in the mid-1970s in the medical community and continues in the present. More than 12 different analogues of fentanyl, all unapproved and clandestinely-produced, have been identified in the U.S. drug traffic. The biological effects of the fentanyl analogues are similar to those of heroin, with the exception that many users report a noticeably less euphoric high associated with the drug and stronger sedative and analgesic effects.

Fentanyl analogues may be hundreds of times more potent than heroin. Fentanyl is used orally, smoked, snorted, or injected. Fentanyl is sometimes sold as heroin or oxycodone, sometimes leading to overdoses. Many fentanyl overdoses are initially classified as heroin overdoses.[86] The recreational use is not particularly widespread in the EU with the exception of Tallinn, Estonia, where it has largely replaced heroin. Estonia has the highest rate of 3-methylfentanyl overdose deaths in the EU, due to its high rate of recreational use.[87]

Fentanyl is sometimes sold on the black market in the form of transdermal fentanyl patches such as Duragesic, diverted from legitimate medical supplies. The gel from inside the patches may be ingested or injected.[88]

Another form of fentanyl that has appeared on the streets is the Actiq lollipop formulation. The pharmacy retail price ranges from $15 to $50 per unit based on the strength of the lozenge, with the black market cost ranging from $5 to $25, depending on the dose.[89] The attorneys general of Connecticut and Pennsylvania have launched investigations into its diversion from the legitimate pharmaceutical market, including Cephalon's "sales and promotional practices for Provigil, Actiq and Gabitril".[89]

Non-medical use of fentanyl by individuals without opiate tolerance can be very dangerous and has resulted in numerous deaths.[88] Even those with opiate tolerances are at high risk for overdoses. Like all opioids, the effects of fentanyl can be reversed with naloxone, or other opiate antagonists. Naloxone is increasingly available to the public. Long acting or sustained release opioids may require repeat dosage. Illicitly synthesized fentanyl powder has also appeared on the United States market. Because of the extremely high strength of pure fentanyl powder, it is very difficult to dilute appropriately, and often the resulting mixture may be far too strong and, therefore, very dangerous.

Some heroin dealers mix fentanyl powder with heroin to increase potency or compensate for low-quality heroin. In 2006, illegally manufactured, non-pharmaceutical fentanyl often mixed with cocaine or heroin caused an outbreak of overdose deaths in the United States and Canada, heavily concentrated in the cities of Dayton, Ohio; Chicago; Detroit; and Philadelphia.[90]

Several large quantities of illicitly produced fentanyl have been seized by U.S. law enforcement agencies. In June 2006, 945 grams (2.08 lbs) of 83%-pure fentanyl powder was seized by Border Patrol agents in California from a vehicle that had entered from Mexico.[91] Mexico is the source of much of the illicit fentanyl for sale in the U.S. However, in April 2006, there was one domestic fentanyl lab discovered by law enforcement in Azusa, California. The lab was a source of counterfeit 80 mg OxyContin tablets containing fentanyl instead of oxycodone, as well as bulk fentanyl and other drugs.[92][93] In November 2016, the DEA uncovered an operation making counterfeit oxycodone and Xanax from a home in Cottonwood Heights, Utah. They found about 70,000 pills in the appearance of oxycodone and more than 25,000 in the appearance of Xanax. The DEA reported that millions of pills could have been distributed from this location over the course of time. The accused owned a pill press and ordered fentanyl in powder form from China.[94][95]

The "China White" form of fentanyl refers to any of a number of clandestinely produced analogues, especially α-methylfentanyl (AMF).[96] This Department of Justice document lists "China White" as a synonym for a number of fentanyl analogues, including 3-methylfentanyl and α-methylfentanyl,[97] which today are classified as Schedule I drugs in the United States.[96] Part of the motivation for AMF is that, despite the extra difficulty from a synthetic standpoint, the resultant drug is relatively more resistant to metabolic degradation. This results in a drug with an increased duration.[98]

In June 2013, the United States Centers for Disease Control and Prevention (CDC) issued a health advisory[99] to emergency departments alerting to 14 overdose deaths among intravenous drug users in Rhode Island associated with acetylfentanyl, a synthetic opioid analog of fentanyl that has never been licensed for medical use. In a separate study conducted by the CDC, 82% of fentanyl overdose deaths involved illegally manufactured fentanyl, while only 4% were suspected to originate from a prescription.[100]

Beginning in 2015, Canada has seen a widespread number of fentanyl overdoses. Authorities suspect that the drug is being imported from Asia to the western coast by organized crime groups in powder form and being pressed into pseudo-OxyContin tablets.[101] Traces of the drug have also been found in other recreational drugs including cocaine, MDMA, and heroin. The drug has been implicated in multiple deaths from the homeless to young professionals, including multiple teens and young parents.[102] Because of the rising deaths across the country, especially in British Columbia where the deaths for 2016 is 668 and deaths for 2017 (January to October) is 999,[103]Health Canada is putting a rush on a review of the prescription-only status of naloxone in an effort to combat overdoses of the drug.[104]

Fentanyl has been discovered for sale in illicit markets in Australia in 2017[105] and in New Zealand in 2018.[106] In response, New Zealand experts called for wider availability of naloxone.[107]

Incapacitating agent

Russian spetsnaz security forces used a fentanyl analogue or derivative to incapacitate people rapidly in the Moscow theater hostage crisis in 2002. The siege was ended, but about 130 of the 850 hostages died from the gas. The Russian Health Minister later stated that the gas was based on fentanyl,[108] but the exact chemical agent has not been identified.

Recalls of patches

In February 2004, a leading fentanyl supplier, Janssen Pharmaceutica Products, L.P., recalled one lot, and later, additional lots of fentanyl (brand name: Duragesic) patches because of seal breaches which might have allowed the medication to leak from the patch. A series of Class II recalls was initiated in March 2004, and in February 2008 ALZA Corporation recalled their 25 µg/h Duragesic patches due to a concern that small cuts in the gel reservoir could result in accidental exposure of patients or health care providers to the fentanyl gel.[109]

In February 2011, the manufacturer suspended production of all Duragesic patches due to quality control issues involving unspecified "microscopic crystallization" detected during the manufacturing process of the 100 µg/h strength.[citation needed]

Veterinary use

Fentanyl in injectable formulation is commonly used for analgesia and as a component of balanced sedation and general anaesthesia in small animal patients. Its potency and short duration of action make it particularly useful in critically ill patients. In addition, it tends to cause less vomiting and regurgitation than other pure-opioid agonists (morphine, hydromorphone) when given as a continuous post-operative infusion. As with other pure opioids, fentanyl can be associated with dysphoria in both dogs and cats.

Transdermal fentanyl has also been used for many years in dogs and cats for post-operative analgesia. This is usually done with off-label fentanyl patches manufactured for humans with chronic pain. In 2012 a highly concentrated (50 mg/ml) transdermal solution, trade name Recuvyra, has become commercially available for dogs only. It is FDA approved to provide four days of analgesia after a single application prior to surgery. It is not approved for multiple doses or other species.[110] The drug is also approved in Europe.
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