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Heroin

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For other uses, seeHeroin (disambiguation).
Not to be confused withHeroine.

Heroin
Clinical data
PronunciationHeroin:/ˈhɛroʊɪn/
Other namesDiacetylmorphine, acetomorphine, (dual) acetylated morphine, morphine diacetate, Diamorphine[1](BANUK)
AHFS/Drugsheroin
Dependence
liability		Very high[2]
Addiction
liability		Very high[3]
Routes of
administration		Intravenous, inhalation, transmucosal, by mouth, intranasal, rectal, intramuscular, subcutaneous, intrathecal
Drug classOpioid
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability<35% (by mouth), 44–61% (inhaled)[4]
Protein binding0% (morphinemetabolite 35%)
MetabolismLiver
Onset of actionWithin minutes[5]
Eliminationhalf-life2–3 minutes[6]
Duration of action4 to 5 hours[7]
Excretion90%kidneyasglucuronides,restbiliary
Identifiers
  • (5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol diacetate
CAS Number
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.008.380Edit this at Wikidata
Chemical and physical data
FormulaC21H23NO5
Molar mass369.417g·mol−1
3D model (JSmol)
  • CC(OC1=C(O[C@@H]2[C@]34CCN(C)[C@@H]([C@@H]4C=C[C@@H]2OC(C)=O)C5)C3=C5C=C1)=O
  • InChI=1S/C21H23NO5/c1-11(23)25-16-6-4-13-10-15-14-5-7-17(26-12(2)24)20-21(14,8-9-22(15)3)18(13)19(16)27-20/h4-7,14-15,17,20H,8-10H2,1-3H3/t14-,15+,17-,20-,21-/m0/s1checkY
  • Key:GVGLGOZIDCSQPN-PVHGPHFFSA-NcheckY
(verify)

Heroin,also known asdiacetylmorphineanddiamorphineamong other names,[1]is amorphinanopioidsubstance synthesized from thedried latexof thePapaver somniferumplant; it is mainly used as arecreational drugfor itseuphoriceffects.Medical-gradediamorphine is used as a purehydrochloride salt.Various white and brown powders sold illegally around the world as heroin are routinely diluted withcutting agents.Black tar heroinis a variable admixture ofmorphinederivatives—predominantly6-MAM(6-monoacetylmorphine), which is the result of crudeacetylationduring clandestine production of street heroin.[3]Heroin is used medically in several countries to relieve pain, such as during childbirth or aheart attack,as well as inopioid replacement therapy.[8][9][10]

It is typicallyinjected,usually into avein,but it can also be snorted, smoked, or inhaled. In a clinical context, the route of administration is most commonly intravenous injection; it may also be given by intramuscular or subcutaneous injection, as well as orally in the form of tablets.[11][3][12][13]The onset of effects is usually rapid and lasts for a few hours.[3]

Common side effects includerespiratory depression(decreased breathing), dry mouth, drowsiness, impaired mental function, constipation, andaddiction.[12]Use by injection can also result inabscesses,infected heart valves,blood-borne infections,andpneumonia.[12]After a history of long-term use,opioid withdrawalsymptoms can begin within hours of the last use.[12]When given by injection into a vein, heroin has two to three times the effect of a similar dose ofmorphine.[3]It typically appears in the form of a white or brown powder.[12]

Treatment ofheroin addictionoften includesbehavioral therapyand medications.[12]Medications can includebuprenorphine,methadone,ornaltrexone.[12]A heroin overdose may be treated withnaloxone.[12]An estimated 17 million people as of 2015use opiates, of which heroin is the most common,[14][15]and opioid use resulted in 122,000 deaths.[16]The total number of heroin users worldwide as of 2015 is believed to have increased in Africa, the Americas, and Asia since 2000.[17]In the United States, approximately 1.6 percent of people have used heroin at some point.[12][18]When people die from overdosing on a drug, the drug is usually an opioid and often heroin.[14][19]

Heroin was first made byC. R. Alder Wrightin 1874 from morphine, a natural product of theopium poppy.[20]Internationally, heroin is controlled under Schedules I and IV of theSingle Convention on Narcotic Drugs,[21]and it is generally illegal to make, possess, or sell without a license.[22]About 448 tons of heroin were made in 2016.[17]In 2015, Afghanistan produced about 66% of the world's opium.[14]Illegal heroin is often mixed with other substances such as sugar,starch,caffeine,quinine,or other opioids likefentanyl.[3][23]

Uses

Recreational

Bayer's original trade name of heroin is typically used in non-medical settings. It is used as a recreational drug for theeuphoriait induces.AnthropologistMichael Agar once described heroin as "the perfect whatever drug."[24]Tolerancedevelops quickly, and increased doses are needed in order to achieve the same effects. Its popularity with recreational drug users, compared tomorphine,reportedly stems from its perceived different effects.[25]

Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both heroin and morphine. When compared to the opioidshydromorphone,fentanyl,oxycodone,andpethidine(meperidine), former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to misuse and causing dependence. Morphine and heroin were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids.[26]

Medical uses

In theUnited States,heroin is not accepted as medically useful.[3]

Advertising sign from Bayer for use in US drug stores, dating from before thefederal prohibitionof heroin in 1924

Under the generic name diamorphine, heroin isprescribedas a strongpain medicationin theUnited Kingdom,where it is administered viaoral,subcutaneous,intramuscular,intrathecal,intranasalor intravenous routes. It may be prescribed for the treatment of acute pain, such as in severephysical trauma,myocardial infarction,post-surgicalpain andchronic pain,including end-stageterminal illnesses.In other countries it is more common to use morphine or other strong opioids in these situations. In 2004, theNational Institute for Health and Clinical Excellenceproduced guidance on the management ofcaesarean section,which recommended the use of intrathecal orepiduraldiamorphine for post-operativepain relief.For women who have had intrathecal opioids, there should be a minimum hourly observation of respiratory rate, sedation and pain scores for at least 12 hours for diamorphine and 24 hours for morphine. Women should be offered diamorphine (0.3–0.4 mg intrathecally) for intra- and postoperative analgesia because it reduces the need for supplemental analgesia after a caesarean section. Epidural diamorphine (2.5–5 mg) is a suitable alternative.[27]

Diamorphine continues to be widely used inpalliative carein the UK, where it is commonly given by thesubcutaneousroute, often via asyringe driverif patients cannot easily swallowmorphine solution.The advantage of diamorphine over morphine is that diamorphine is morefat solubleand therefore more potent by injection, so smaller doses of it are needed for the same effect on pain. Both of these factors are advantageous if giving high doses of opioids via the subcutaneous route, which is often necessary for palliative care.

It is also used in the palliative management ofbone fracturesand other trauma, especially in children. In the trauma context, it is primarily given by nose in hospital; although a prepared nasal spray is available.[28]It has traditionally been made by the attending physician, generally from the same "dry" ampoules as used for injection. In children, Ayendi nasal spray is available at 720 micrograms and 1600 micrograms per 50 microlitres actuation of the spray, which may be preferable as a non-invasive alternative in pediatric care, avoiding the fear of injection in children.[29]

Maintenance therapy

Main article:Heroin-assisted treatment

A number of European countries prescribe heroin for treatment ofheroin addiction.[30]The initial Swiss HAT (heroin-assisted treatment) trial ( "PROVE" study) was conducted as a prospective cohort study with some 1,000 participants in 18 treatment centers between 1994 and 1996, at the end of 2004, 1,200 patients were enrolled in HAT in 23 treatment centers across Switzerland.[31][32]Diamorphine may be used as amaintenance drugto assist the treatment of opiate addiction, normally in long-term chronic intravenous (IV) heroin users. It is only prescribed following exhaustive efforts at treatment via other means. It is sometimes thought that heroin users can walk into a clinic and walk out with a prescription, but the process takes many weeks before a prescription for diamorphine is issued. Though this is somewhat controversial among proponents of azero-tolerancedrug policy,it has proven superior tomethadonein improving the social and health situations of addicts.[33]

The UK Department of Health'sRolleston CommitteeReport[34]in 1926 established the British approach to diamorphine prescription to users, which was maintained for the next 40 years: dealers were prosecuted, but doctors could prescribe diamorphine to users when withdrawing. In 1964, theBrain Committeerecommended that only selected approved doctors working at approved specialized centres be allowed to prescribe diamorphine andcocaineto users. The law was made more restrictive in 1968. Beginning in the 1970s, the emphasis shifted to abstinence and the use of methadone; currently, only a small number of users in the UK are prescribed diamorphine.[35]

In 1994, Switzerland began a trialdiamorphine maintenanceprogram for users that had failed multiple withdrawal programs. The aim of this program was to maintain the health of the user by avoiding medical problems stemming from the illicit use of diamorphine. The first trial in 1994 involved 340 users, although enrollment was later expanded to 1000, based on the apparent success of the program. The trials proved diamorphine maintenance to be superior to other forms of treatment in improving the social and health situation for this group of patients.[33]It has also been shown to save money, despite high treatment expenses, as it significantly reduces costs incurred by trials, incarceration, health interventions anddelinquency.[36]Patients appear twice daily at a treatment center, where they inject their dose of diamorphine under the supervision of medical staff. They are required to contribute about 450 Swiss francs per month to the treatment costs.[37]Anational referendum in November 2008showed 68% of voters supported the plan,[38]introducing diamorphine prescription into federal law. The previous trials were based on time-limited executive ordinances. The success of the Swiss trials led German, Dutch,[39]and Canadian[40]cities to try out their own diamorphine prescription programs.[41]Some Australian cities (such as Sydney) have instituted legal diamorphinesupervised injecting centers,in line with other widerharm minimizationprograms.

Since January 2009, Denmark has prescribed diamorphine to a few addicts who have tried methadone andbuprenorphinewithout success.[42]Beginning in February 2010, addicts inCopenhagenandOdensebecame eligible to receive free diamorphine. Later in 2010, other cities includingÅrhusandEsbjergjoined the scheme. It was estimated that around 230 addicts would be able to receive free diamorphine.[43]

However, Danish addicts would only be able to inject heroin according to the policy set byDanish National Board of Health.[44]Of the estimated 1500 drug users who did not benefit from the then-current oral substitution treatment, approximately 900 would not be in the target group for treatment with injectable diamorphine, either because of "massive multiple drug abuse of non-opioids" or "not wanting treatment with injectable diamorphine".[45][needs update]

In July 2009, the GermanBundestagpassed a law allowing diamorphine prescription as a standard treatment for addicts; a large-scale trial of diamorphine prescription had been authorized in the country in 2002.[46]

On 26 August 2016,Health Canadaissued regulations amending prior regulations it had issued under theControlled Drugs and Substances Act;the "New Classes of Practitioners Regulations", the "Narcotic Control Regulations", and the "Food and Drug Regulations", to allow doctors to prescribe diamorphine to people who have a severe opioid addiction who have not responded to other treatments.[47][48]The prescription heroin can be accessed by doctors throughHealth Canada's Special Access Programme (SAP) for "emergency access to drugs for patients with serious or life-threatening conditions when conventional treatments have failed, are unsuitable, or are unavailable."[47]

Routes of administration

Recreational uses:

Medicinal uses:

Contraindications:
Central nervous system:

Neurological:

Psychological:

Cardiovascular & Respiratory:

Gastrointestinal:

Musculoskeletal:

Skin:

  • Itching
  • Flushing/Rash

Miscellaneous:

The onset of heroin's effects depends upon theroute of administration.Smoking is the fastest route of drug administration, althoughintravenous injectionresults in a quicker rise in blood concentration.[49]These are followed bysuppository(anal or vaginal insertion),insufflation(snorting), andingestion(swallowing).

A 2002 study suggests that a fast onset of action increases the reinforcing effects of addictive drugs. Ingestion does not produce arushas a forerunner to the high experienced with the use of heroin, which is most pronounced with intravenous use. While the onset of the rush induced by injection can occur in as little as a few seconds, the oral route of administration requires approximately half an hour before the high sets in. Thus, with both higher the dosage of heroin used and faster the route of administration used, the higher the potential risk forpsychological dependence/addiction.[50]

Large doses of heroin can cause fatal respiratory depression, and the drug has been used for suicide or as a murder weapon. The serial killerHarold Shipmanused diamorphine on his victims, and the subsequentShipman Inquiryled to a tightening of the regulations surrounding the storage, prescribing and destruction of controlled drugs in the UK.

Because significant tolerance to respiratory depression develops quickly with continued use and is lost just as quickly during withdrawal, it is often difficult to determine whether a heroin lethal overdose was accidental, suicide or homicide. Examples include the overdose deaths ofSid Vicious,Janis Joplin,Tim Buckley,Hillel Slovak,Layne Staley,Bradley Nowell,Ted Binion,andRiver Phoenix.[51]

By mouth

Use of heroin by mouth is less common than other methods of administration, mainly because there is little to no "rush", and the effects are less potent.[52]Heroin is entirely converted tomorphineby means offirst-pass metabolism,resulting indeacetylationwhen ingested. Heroin's oralbioavailabilityis both dose-dependent (as is morphine's) and significantly higher than oral use of morphine itself, reaching up to 64.2% for high doses and 45.6% for low doses; opiate-naive users showed far less absorption of the drug at low doses, having bioavailabilities of only up to 22.9%. The maximum plasma concentration of morphine following oral administration of heroin was around twice as much as that of oral morphine.[53]

Injection

Injection,also known as "slamming", "banging", "shooting up", "digging" or "mainlining", is a popular method which carries relatively greater risks than other methods of administration. Heroin base (commonly found in Europe), when prepared for injection, will only dissolve in water when mixed with an acid (most commonly citric acid powder or lemon juice) and heated. Heroin in theeast-coast United Statesis most commonly found in the hydrochloride salt form, requiring just water (and no heat) to dissolve.[citation needed]Users tend to initially inject in the easily accessible arm veins, but as these veins collapse over time, users resort to more dangerous areas of the body, such as thefemoral veinin the groin. Some medical professionals have expressed concern over this route of administration, as they suspect that it can lead todeep vein thrombosis.[54]

Intravenous users can use a variable single dose range using ahypodermic needle.The dose of heroin used for recreational purposes is dependent on the frequency and level of use.

As with the injection of any drug, if a group of usersshare a common needlewithout sterilization procedures, blood-borne diseases, such asHIV/AIDSorhepatitis,can be transmitted. The use of a common dispenser for water for the use in the preparation of the injection, as well as the sharing of spoons and filters can also cause the spread of blood-borne diseases. Many countries now supply small sterile spoons and filters for single use in order to prevent the spread of disease.[55]

Smoking

Smoking heroin refers to vaporizing it to inhale the resulting fumes, rather than burning and inhaling the smoke. It is commonly smoked in glass pipes made fromglassblownPyrextubes and light bulbs. Heroin may be smoked from aluminium foil that is heated by a flame underneath it, with the resulting smoke inhaled through a tube of rolled up foil, a method also known as "chasing the dragon".[56]

Insufflation

Another popular route to intake heroin isinsufflation(snorting), where a user crushes the heroin into a fine powder and then gently inhales it (sometimes with a straw or a rolled-upbanknote,as with cocaine) into the nose, where heroin is absorbed through the soft tissue in themucous membraneof thesinus cavityand straight into the bloodstream. This method of administration redirectsfirst-pass metabolism,with a quicker onset and higher bioavailability than oral administration, though the duration of action is shortened. This method is sometimes preferred by users who do not want to prepare and administer heroin for injection or smoking but still want to experience a fast onset. Snorting heroin becomes an often unwanted route, once a user begins to inject the drug. The user may still get high on the drug from snorting, and experience a nod, but will not get a rush. A "rush" is caused by a large amount of heroin entering the body at once. When the drug is taken in through the nose, the user does not get the rush because the drug is absorbed slowly rather than instantly.

Heroin for pain has been mixed with sterile water on site by the attending physician, and administered using a syringe with a nebulizer tip.[57]Heroin may be used for fractures, burns, finger-tip injuries, suturing, and wound re-dressing, but is inappropriate in head injuries.[57]

Suppository

Little research has been focused on thesuppository(anal insertion) orpessary(vaginal insertion) methods of administration, also known as "plugging". These methods of administration are commonly carried out using anoral syringe.Heroin can be dissolved and withdrawn into an oral syringe which may then be lubricated and inserted into the anus or vagina before the plunger is pushed. The rectum or the vaginal canal is where the majority of the drug would likely be taken up, through the membranes lining their walls.

Adverse effects

A 2010 study ranking various illegal and legal drugs based on statements by drug-harm experts. Heroin was found to be the second overall most dangerous drug.[58]

Heroin is classified as a hard drug in terms ofdrug harmfulness.Like mostopioids,unadulterated heroin may lead toadverse effects.The purity of street heroin varies greatly, leading to overdoses when the purity is higher than expected.[59]

Short-term effects

Short-term effects of usage[60]

Users report an intenserush,an acute transcendent state ofeuphoria,which occurs while diamorphine is being metabolized into6-monoacetylmorphine(6-MAM) and morphine in the brain. Some believe that heroin produces more euphoria than other opioids; one possible explanation is the presence of 6-monoacetylmorphine, a metabolite unique to heroin – although a more likely explanation is the rapidity of onset. While other opioids of recreational use produce only morphine, heroin also leaves 6-MAM, also a psycho-active metabolite.

However, this perception is not supported by the results of clinical studies comparing the physiological and subjective effects of injected heroin and morphine in individuals formerly addicted to opioids; these subjects showed no preference for one drug over the other. Equipotent injected doses had comparable action courses, with no difference in subjects' self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness.[26]

The rush is usually accompanied by a warm flushing of the skin, dry mouth, and a heavy feeling in the extremities.Nausea,vomiting,and severeitchingmay also occur. After the initial effects, users usually will be drowsy for several hours; mental function is clouded; heart function slows, and breathing is also severely slowed, sometimes enough to be life-threatening. Slowed breathing can also lead to coma and permanentbrain damage.[61]Heroin use has also been associated withmyocardial infarction.[62]

Long-term effects

Long-term effects of intravenous usage, including – and indeed primarily because of – the effects of the contaminants common in illegal heroin and contaminated needles[60]

Repeated heroin use changes the physical structure and physiology of the brain, creating long-term imbalances in neuronal and hormonal systems that are not easily reversed. Studies have shown some deterioration of the brain's white matter due to heroin use,[63]which may affect decision-making abilities, the ability to regulate behavior, and responses to stressful situations. Heroin also produces profound degrees of tolerance and physical dependence. Tolerance occurs when more and more of the drug is required to achieve the same effects. Withphysical dependence,the body adapts to the presence of thedrug,and withdrawal symptoms occur if use is reduced abruptly.[61]

Injection

Intravenoususe of heroin (and any other substance) with needles and syringes or other related equipment may lead to:

Withdrawal

Main article:Opioid withdrawal

Thewithdrawalsyndrome from heroin may begin within as little as two hours of discontinuation of the drug; however, this time frame can fluctuate with the degree of tolerance as well as the amount of the last consumed dose, and more typically begins within 6–24 hours after cessation. Symptoms may includesweating,malaise,anxiety, depression,akathisia,priapism,extra sensitivity of the genitals in females, general feeling of heaviness, excessive yawning or sneezing,rhinorrhea,insomnia,cold sweats, chills, severe muscle and bone aches, nausea, vomiting, diarrhea, cramps, watery eyes,[65]fever, cramp-like pains, and involuntary spasms in the limbs (thought to be an origin of the term "kicking the habit"[66]).[67][68]

Overdose

Further information:US drug overdose death rates and totals over time

Heroin overdoseis usually treated with theopioid antagonistnaloxone.This reverses the effects of heroin and causes an immediate return of consciousness but may result inwithdrawalsymptoms. Thehalf-lifeof naloxone is shorter than some opioids, such that it may need to be given multiple times until the opioid has been metabolized by the body.

Between 2012 and 2015, heroin was the leading cause of drug-related deaths in the United States.[69]Since then,fentanylhas been a more common cause of drug-related deaths.[69]

Depending on drug interactions and numerous other factors, death from overdose can take anywhere from several minutes to several hours. Death usually occurs due tolack of oxygenresulting from the lack of breathing caused by the opioid. Heroin overdoses can occur because of an unexpected increase in the dose or purity or because of diminished opioid tolerance. However, many fatalities reported as overdoses are probably caused by interactions with otherdepressantdrugs such as alcohol orbenzodiazepines.[70]Since heroin can cause nausea and vomiting, a significant number of deaths attributed to heroin overdose are caused by aspiration of vomit by an unconscious person. Some sources quote themedian lethal dose(for an average 75 kg opiate-naive individual) as being between 75 and 600 mg.[71][72]Illicit heroin is of widely varying and unpredictable purity. This means that the user may prepare what they consider to be a moderate dose while actually taking far more than intended. Also, tolerance typically decreases after a period of abstinence. If this occurs and the user takes a dose comparable to their previous use, the user may experience drug effects that are much greater than expected, potentially resulting in an overdose. It has been speculated that an unknown portion of heroin-related deaths are the result of an overdose or allergic reaction toquinine,which may sometimes be used as a cutting agent.[73]

Pharmacology

Black tar heroin

When taken orally, heroin undergoes extensivefirst-pass metabolismviadeacetylation,making it aprodrugfor the systemic delivery of morphine.[74]When the drug is injected, however, it avoids this first-pass effect, very rapidly crossing theblood–brain barrierbecause of the presence of the acetyl groups, which render it much morefat solublethan morphine itself.[75]Once in the brain, it then is deacetylated variously into the inactive 3-monoacetylmorphine and the active6-monoacetylmorphine(6-MAM), and then to morphine, which bind toμ-opioid receptors,resulting in the drug's euphoric,analgesic(pain relief), andanxiolytic(anti-anxiety) effects; heroin itself exhibits relatively low affinity for the μ receptor.[76]Analgesia follows from the activation of the μ receptorG-protein coupled receptor,which indirectly hyperpolarizes the neuron, reducing the release ofnociceptiveneurotransmitters, and hence, causes analgesia and increased pain tolerance.[77]

Unlikehydromorphoneandoxymorphone,however, administered intravenously, heroin creates a larger histamine release, similar to morphine, resulting in the feeling of a greater subjective "body high" to some, but also instances ofpruritus(itching) when they first start using.[78][79]

Normally,GABA,which is released from inhibitory neurones, inhibits the release of dopamine. Opiates, like heroin and morphine, decrease the inhibitory activity of such neurones. This causes increased release of dopamine in the brain which is the reason for euphoric and rewarding effects of heroin.[80]

Both morphine and 6-MAM areμ-opioidagoniststhat bind to receptors present throughout the brain,spinal cord,andgutof allmammals.The μ-opioid receptor also binds endogenousopioid peptidessuch asβ-endorphin,leu-enkephalin,andmet-enkephalin.Repeated use of heroin results in a number of physiological changes, including an increase in the production of μ-opioid receptors (upregulation).[81]These physiological alterations lead to tolerance and dependence, so that stopping heroin use results in uncomfortable symptoms including pain, anxiety, muscle spasms, and insomnia called the opioidwithdrawalsyndrome. Depending on usage it has an onset 4–24 hours after the last dose of heroin. Morphine also binds toδ- andκ-opioid receptors.

There is also evidence that 6-MAM binds to a subtype of μ-opioid receptors that are also activated by the morphine metabolite morphine-6β-glucuronide but not morphine itself.[82]The third subtype of third opioid type is the mu-3 receptor, which may be a commonality to other six-position monoesters of morphine. The contribution of these receptors to the overall pharmacology of heroin remains unknown.

A subclass of morphine derivatives, namely the 3,6 esters of morphine, with similar effects and uses, includes the clinically used strong analgesicsnicomorphine(Vilan), anddipropanoylmorphine;there is also the latter'sdihydromorphineanalogue,diacetyldihydromorphine(Paralaudin). Two other 3,6 diesters of morphine invented in 1874–75 along with diamorphine,dibenzoylmorphineandacetylpropionylmorphine,were made as substitutes after it was outlawed in 1925 and, therefore, sold as the first "designer drugs"until they were outlawed by the League of Nations in 1930.

Chemistry

Diamorphine is produced fromacetylationofmorphinederived from natural opium sources, generally usingacetic anhydride.[83]

The major metabolites of diamorphine,6-MAM,morphine,morphine-3-glucuronide,andmorphine-6-glucuronide,may be quantitated in blood, plasma or urine to monitor for use, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Most commercial opiate screening tests cross-react appreciably with these metabolites, as well as with other biotransformation products likely to be present following usage of street-grade diamorphine such as6-Monoacetylcodeineandcodeine.[84]However,chromatographictechniques can easily distinguish and measure each of these substances. When interpreting the results of a test, it is important to consider the diamorphine usage history of the individual, since a chronic user can developtoleranceto doses that would incapacitate an opiate-naive individual, and the chronic user often has high baseline values of these metabolites in his system. Furthermore, some testing procedures employ ahydrolysisstep before quantitation that converts many of the metabolic products to morphine, yielding a result that may be 2 times larger than with a method that examines each product individually.[85]

History

Advertisement forBayerHeroin
See also:History of opium in China

Theopium poppywas cultivated in lowerMesopotamiaas long ago as 3400 BC.[86]The chemical analysis ofopiumin the 19th century revealed that most of its activity could be ascribed to thealkaloidscodeineandmorphine.

Diamorphine was first synthesized in 1874 byC. R. Alder Wright,an English chemist working atSt. Mary's HospitalMedical School in London who had been experimenting combining morphine with various acids. He boiled anhydrous morphine alkaloid withacetic anhydridefor several hours and produced a more potent,acetylatedform of morphine which is now calleddiacetylmorphineormorphine diacetate.He sent the compound to F. M. Pierce of Owens College in Manchester for analysis. Pierce told Wright:

Doses… were subcutaneously injected into young dogs and rabbit… with the following general results… great prostration, fear, and sleepiness speedily following the administration, the eyes being sensitive, and pupils constrict, considerable salivation being produced in dogs, and a slight tendency to vomiting in some cases, but no actualemesis.Respiration was at first quickened, but subsequently reduced, and the heart's action was diminished and rendered irregular. Marked want of coordinating power over the muscular movements, and loss of power in the pelvis and hind limbs, together with a diminution of temperature in the rectum of about 4°.[87]

Bayer Heroin bottle

Wright's invention did not lead to any further developments, and diamorphine became popular only after it was independently re-synthesized 23 years later by chemistFelix Hoffmann.[88]Hoffmann was working atBayerpharmaceutical company inElberfeld,Germany, and his supervisorHeinrich Dreserinstructed him to acetylate morphine with the objective of producing codeine, a constituent of the opium poppy that is pharmacologically similar to morphine but less potent and less addictive. Instead, the experiment produced an acetylated form of morphine one and a half to two times more potent than morphine itself. Hoffmann synthesized heroin on August 21, 1897, just eleven days after he had synthesizedaspirin.[89]

The head of Bayer's research department reputedly coined the drug's new name of "heroin", based on the Germanheroischwhich means "heroic, strong" (from the ancient Greek word "heros, ήρως" ). Bayer scientists were not the first to make heroin, but their scientists discovered ways to make it, and Bayer led the commercialization of heroin.[90]

Bayer marketed diacetylmorphine as anover-the-counter drugunder the trademark name Heroin.[91]It was developed chiefly as amorphinesubstitute forcough suppressantsthat did not have morphine's addictive side-effects. Morphine at the time was a popular recreational drug, and Bayer wished to find a similar but non-addictive substitute to market. However, contrary to Bayer's advertising as a "non-addictive morphine substitute", heroin would soon have one of the highest rates ofaddictionamong its users.[92]

From 1898 through to 1910, diamorphine was marketed under the trademark name Heroin as a non-addictive morphine substitute and cough suppressant.[93]In the 11th edition ofEncyclopædia Britannica(1910), the article on morphine states: "In the cough ofphthisisminute doses [of morphine] are of service, but in this particular disease morphine is frequently better replaced by codeine or by heroin, which checks irritable coughs without the narcotism following upon the administration of morphine. "

In the US, theHarrison Narcotics Tax Actwas passed in 1914 to control the sale and distribution of diacetylmorphine and other opioids, which allowed the drug to be prescribed and sold for medical purposes. In 1924, the United States Congress banned its sale, importation, or manufacture. It is now aSchedule I substance,which makes it illegal for non-medical use in signatory nations of theSingle Convention on Narcotic Drugstreaty, including the United States.

The Health Committee of theLeague of Nationsbanned diacetylmorphine in 1925, although it took more than three years for this to be implemented. In the meantime, the firstdesigner drugs,viz. 3,6 diesters and 6 monoesters of morphine and acetylated analogues of closely related drugs likehydromorphoneanddihydromorphine,were produced in massive quantities to fill the worldwide demand for diacetylmorphine—this continued until 1930 when the Committee banned diacetylmorphine analogues with no therapeutic advantage over drugs already in use, the first major legislation of this type.[citation needed]

Bayer lost some of its trademark rights to heroin (as well asaspirin) under the 1919Treaty of Versaillesfollowing the German defeat inWorld War I.[94][95]

Use of heroin by jazz musicians in particular was prevalent in the mid-twentieth century, includingBillie Holiday,saxophonistsCharlie ParkerandArt Pepper,trumpeter and vocalistChet Baker,guitaristJoe Passand piano player/singerRay Charles;a "staggering number of jazz musicians were addicts".[96]It was also a problem with many rock musicians, particularly from the late 1960s through the 1990s.Pete Dohertyis also a self-confessed user of heroin.[97]Nirvanalead singerKurt Cobain's heroin addiction was well documented.[98]PanterafrontmanPhil Anselmoturned to heroin while touring during the 1990s to cope with his back pain.[99]James Taylor,Jimmy Page,John Lennon,Eric Clapton,Johnny Winter,Keith Richards,Shaun Ryder,Shane MacGowanandJanis Joplinalso used heroin. Many musicians have made songs referencing their heroin usage.[100][101][102][103][104]

Society and culture

Names

"Diamorphine" is theRecommended International Nonproprietary NameandBritish Approved Name.[105][106]Other synonyms for heroin include: diacetylmorphine, and morphine diacetate. Heroin is also known by many street names including dope, H, smack, junk, horse, scag, brown, and unga, among others.[107][108]

Legal status

Asia

In Hong Kong, diamorphine is regulated under Schedule 1 ofHong Kong's Chapter 134Dangerous Drugs Ordinance.It is available by prescription. Anyone supplying diamorphine without a valid prescription can be fined $5,000,000 (HKD) and imprisoned for life. The penalty for trafficking or manufacturing diamorphine is a $5,000,000 (HKD) fine and life imprisonment. Possession of diamorphine without a license from the Department of Health is illegal with a $1,000,000 (HKD) fine and 7 years of jail time.[109][110]

Europe

In the Netherlands, diamorphine is a List I drug of theOpium Law.It is available for prescription under tight regulation exclusively to long-term addicts for whommethadone maintenancetreatment has failed. It cannot be used to treat severepainor other illnesses.[111]

In the United Kingdom, diamorphine is available by prescription, though it is a restrictedClass A drug.According to the 50th edition of theBritish National Formulary(BNF), diamorphinehydrochloridemay be used in the treatment of acute pain,myocardial infarction,acutepulmonary oedema,andchronic pain.The treatment of chronic non-malignantpain must be supervised by a specialist. The BNF notes that all opioid analgesics cause dependence and tolerance but that this is "no deterrent in the control of pain in terminal illness". When used in thepalliative careof cancer patients, diamorphine is often injected using asyringe driver.[112]

In Switzerland, heroin is produced in injectable or tablet form under the name Diaphin by a private company under contract to the Swiss government.[113]Swiss-produced heroin has been imported into Canada with government approval.[114]

Australia

In Australia, diamorphine is listed as a schedule 9 prohibited substance under thePoisons Standard(October 2015).[115]The state ofWestern Australia,in itsPoisons Act 1964(Reprint 6: amendments as at 10 Sep 2004), described a schedule 9 drug as: "Poisons that are drugs of abuse, the manufacture, possession, sale or use of which should be prohibited by law except for amounts which may be necessary for educational, experimental or research purposes conducted with the approval of the Governor."[116]

North America

In Canada, diamorphine is a controlled substance[117]under Schedule I of theControlled Drugs and Substances Act(CDSA).[118]Any person seeking or obtaining diamorphine without disclosing authorization 30 days before obtaining another prescription from a practitioner is guilty of an indictable offense and subject to imprisonment for a term not exceeding seven years. Possession of diamorphine for the purpose of trafficking is an indictable offense and subject to imprisonment for life.

In the United States, diamorphine is a Schedule I drug according to theControlled Substances Actof 1970, making it illegal to possess without a DEA license.[119]Possession of more than 100 grams of diamorphine or a mixture containing diamorphine is punishable with a minimum mandatory sentence of 5 years of imprisonment in a federal prison.

In 2021, the US state of Oregon became the first state to decriminalize the use of heroin after voters passedBallot Measure 110in 2020.[120]This measure will allow people with small amounts to avoid arrest.[121]

Turkey

See also:Illegal drug trade in Turkey

Turkeymaintains strict laws against the use, possession ortrafficking of illegal drugs.If convicted under these offences, one could receive a heavy fine or a prison sentence of 4 to 24 years.[122]

Misuse of prescription medication

Misused prescription medicine, such as opioids, can lead to heroin use and dependence.[123]The number of death from illegal opioid overdose follows the increasing number of death caused by prescription opioid overdoses.[124]Prescription opioids are relatively easy to obtain.[125]This may ultimately lead to heroin injection because heroin is cheaper than prescribed pills.[123]

Economics

Production

Diamorphine is produced fromacetylationof morphine derived from natural opium sources. One such method of heroin production involves isolation of the water-soluble components of raw opium, including morphine, in a strongly basic aqueous solution, followed byrecrystallizationof the morphine base by addition ofammonium chloride.The solid morphine base is then filtered out. The morphine base is then reacted withacetic anhydride,which forms heroin. This highly impure brown heroin base may then undergo further purification steps, which produces a white-colored product; the final products have a different appearance depending on purity and have different names.[83]Heroin purity has been classified into four grades. No.4 is the purest form – white powder (salt) to be easily dissolved and injected. No.3 is "brown sugar" for smoking (base). No.1 and No.2 are unprocessed raw heroin (salt or base).[126]

Trafficking

International drug routes
See also:Opium § Modern production and use

Traffic is heavy worldwide, with the biggest producer beingAfghanistan.According to a U.N. sponsored survey,[127]in 2004, Afghanistan accounted for production of 87 percent of the world's diamorphine.[128]Afghan opium kills around 100,000 people annually.[129]

In 2003The Independentreported:[130][131]

The cultivation of opium [in Afghanistan] reached its peak in 1999, when 350 square miles (910 km2) of poppies were sown... The following year the Taliban banned poppy cultivation,... a move which cut production by 94 percent... By 2001 only 30 square miles (78 km2) of land were in use for growing opium poppies. A year later, after American and British troops had removed the Taliban and installed the interim government, the land under cultivation leapt back to 285 square miles (740 km2), with Afghanistan supplanting Burma to become the world's largest opium producer once more.

Opium production in that country has increased rapidly since, reaching an all-time high in 2006.War in Afghanistanonce again appeared as a facilitator of the trade.[132]Some 3.3 million Afghans are involved in producing opium.[133]

Afghanistan opium poppy cultivation,1994–2016 (hectares)

At present, opium poppies are mostly grown in Afghanistan (224,000 hectares (550,000 acres)), and in Southeast Asia, especially in the region known as theGolden TrianglestraddlingBurma(57,600 hectares (142,000 acres)),Thailand,Vietnam,Laos(6,200 hectares (15,000 acres)) andYunnanprovince in China. There is also cultivation of opium poppies in Pakistan (493 hectares (1,220 acres)), Mexico (12,000 hectares (30,000 acres)) and inColombia(378 hectares (930 acres)).[134]According to theDEA,the majority of the heroin consumed in the United States comes from Mexico (50%) and Colombia (43–45%) via Mexican criminal cartels such asSinaloa Cartel.[135]However, these statistics may be significantly unreliable, the DEA's 50/50 split between Colombia and Mexico is contradicted by the amount of hectares cultivated in each country and in 2014, the DEA claimed most of the heroin in the US came from Colombia.[136] As of 2015,the Sinaloa Cartel is the most activedrug cartelinvolved in smuggling illicit drugs such as heroin into the United States and trafficking them throughout the United States.[137]According to theRoyal Canadian Mounted Police,90% of the heroin seized in Canada (where the origin was known) came from Afghanistan.[138]Pakistan is the destination and transit point for 40 percent of the opiates produced in Afghanistan, other destinations of Afghan opiates are Russia, Europe and Iran.[139][140]

A conviction for trafficking heroin carries the death penalty in mostSoutheast Asian,someEast Asianand Middle Eastern countries (seeUse of death penalty worldwidefor details), among whichMalaysia,Singapore andThailandare the strictest. The penalty applies even to citizens of countries where the penalty is not in place, sometimes causing controversy when foreign visitors are arrested for trafficking, for example, the arrest ofnine Australians in Bali,thedeath sentencegiven toNola Blakein Thailand in 1987, or the hanging of an Australian citizenVan Tuong Nguyenin Singapore.

Trafficking history

Primary worldwide producers of heroin

The origins of the present international illegal heroin trade can be traced back to laws passed in many countries in the early 1900s that closely regulated the production and sale of opium and its derivatives including heroin. At first, heroin flowed from countries where it was still legal into countries where it was no longer legal. By the mid-1920s, heroin production had been made illegal in many parts of the world. An illegal trade developed at that time between heroin labs in China (mostly in Shanghai and Tianjin) and other nations. The weakness of the government in China and conditions of civil war enabled heroin production to take root there. Chinesetriadgangs eventually came to play a major role in the illicit heroin trade. TheFrench Connectionroute started in the 1930s.

Heroin trafficking was virtually eliminated in the US duringWorld War IIbecause of temporary trade disruptions caused by the war. Japan's war with China had cut the normal distribution routes for heroin and the war had generally disrupted the movement of opium. After World War II,the Mafiatook advantage of the weakness of the postwar Italian government and set up heroin labs in Sicily which was located along the historic route opium took westward into Europe and the United States.[141]Large-scale international heroin production effectively ended in China with the victory of the communists in the civil war in the late 1940s.[citation needed]The elimination of Chinese production happened at the same time that Sicily's role in the trade developed.

Although it remained legal in some countries until after World War II, health risks, addiction, and widespread recreational use led most western countries to declare heroin a controlled substance by the latter half of the 20th century. In the late 1960s and early 1970s, theCIAsupported anti-Communist Chinese Nationalists settled near theSino-Burmese border andHmongtribesmen inLaos.This helped the development of theGolden Triangleopium production region, which supplied about one-third of heroin consumed in the US after the 1973 American withdrawal from Vietnam. In 1999, Burma, the heartland of the Golden Triangle, was the second-largest producer of heroin, afterAfghanistan.[142]

The Soviet-Afghan war led to increased production in the Pakistani-Afghan border regions, as US-backedmujaheddinmilitants raised money for arms from selling opium, contributing heavily to the modernGolden Crescentcreation. By 1980, 60 percent of the heroin sold in the US originated in Afghanistan.[142]It increased international production of heroin at lower prices in the 1980s. The trade shifted away from Sicily in the late 1970s as various criminal organizations violently fought with each other over the trade. The fighting also led to a stepped-up government law enforcement presence in Sicily.

Following the discovery at a Jordanian airport of atoner cartridgethat had been modified into animprovised explosive device,the resultant increased level of airfreight scrutiny led to a major shortage (drought) of heroin from October 2010 until April 2011. This was reported in most of mainland Europe and the UK which led to a price increase of approximately 30 percent in the cost of street heroin and increased demand for divertedmethadone.The number of addicts seeking treatment also increased significantly during this period. Other heroin droughts (shortages) have been attributed to cartels restricting supply in order to force a price increase and also to a fungus that attacked the opium crop of 2009. Many people[weasel words]thought that the American government had introduced pathogens into the Afghanistan atmosphere in order to destroy the opium crop and thus starve insurgents of income.[citation needed]

On 13 March 2012,Haji Bagcho,with ties to theTaliban,was convicted by a US District Court of conspiracy, distribution of heroin for importation into the United States andnarco-terrorism.[143][144][145][146][147]Based on heroin production statistics[148]compiled by theUnited Nations Office on Drugs and Crime,in 2006, Bagcho's activities accounted for approximately 20 percent of the world's total production for that year.[144][145][146][147]

Street price

TheEuropean Monitoring Centre for Drugs and Drug Addictionreports that the retail price of brown heroin varies from €14.5 per gram in Turkey to €110 per gram in Sweden, with most European countries reporting typical prices of €35–40 per gram. The price of white heroin is reported only by a few European countries and ranged between €27 and €110 per gram.[149]

TheUnited Nations Office on Drugs and Crimeclaims in its 2008 World Drug Report that typical US retail prices are US$172 per gram.[150]

Research

Researchers are attempting to reproduce the biosynthetic pathway that producesmorphineingenetically engineeredyeast.[151]In June 2015 theS-reticuline could be produced from sugar andR-reticuline could be converted to morphine, but the intermediate reaction could not be performed.[152]

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