Heroin, or diacetylmorphine (INN), also known as diamorphine (BAN), is a semi-synthetic opioid drug synthesized from morphine, a derivative of the opium poppy. It is the 3,6-diacetyl ester of morphine (di(two)-acetyl-morphine). The white crystalline form is commonly the hydrochloride salt diacetylmorphine hydrochloride, though often adulterated thus dulling the sheen and consistency from that to a matte white powder, which heroin freebase typically is.

As with other opioids, heroin is used as both a pain-killer and a recreational drug and has an extremely high potential for abuse. Frequent and regular administration is associated with tolerance, moderate physical dependence, and severe psychological dependence.

Internationally, heroin is controlled under Schedules I and IV of the Single Convention on Narcotic Drugs. It is illegal to manufacture, possess, or sell diacetylmorphine without a license in Belgium, Denmark, Germany, Iran, India, the Netherlands, the United States, Australia, Canada, Ireland, Pakistan, the United Kingdom and Swaziland.

Under the name diamorphine, it is a legally prescribed controlled drug in the United Kingdom. It is available for prescription to long-term users in the Netherlands, United Kingdom, Switzerland, Germany and Denmark alongside psycho-social care, and a similar program is being campaigned for by liberal political parties in Norway. (Via Wikipedia)

Etymology

The German drug company Bayer named its new over the counter drug "Heroin" in 1895.The name was derived from the German word "heroisch" (heroic) due to its perceived "heroic" effects upon a user. However it was chiefly developed as a morphine substitute for cough suppressants that did not have morphine's addictive side-effects; morphine at the time was a popular recreational drug so Bayer wanted 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 of dependence amongst its users.

History

The opium poppy was cultivated in lower Mesopotamia as long ago as 3400 BCE. The chemical analysis of opium in the 19th century revealed that most of its activity could be ascribed to two alkaloids, codeine and morphine.

Diacetylmorphine was first synthesized in 1874 by C. R. Alder Wright, an English chemist working at St. Mary's Hospital Medical School in London. He had been experimenting with combining morphine with various acids. He boiled anhydrous morphine alkaloid with acetic anhydride for several hours and produced a more potent, acetylated form of morphine, now called diacetylmorphine. The compound was sent to F. M. Pierce of Owens College in Manchester for analysis. Pierce told Wright:

“Doses ... were subcutaneously injected into young dogs and rabbits ... 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 slight tendency to vomiting in some cases, but no actual emesis. 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°.”

Wright's invention did not lead to any further developments, and diacetylmorphine only became popular after it was independently re-synthesized 23 years later by another chemist, Felix Hoffmann. Hoffmann, working at the Aktiengesellschaft Farbenfabriken (today the Bayer pharmaceutical company) in Elberfeld, Germany, was instructed by his supervisor Heinrich Dreser to acetylate morphine with the objective of producing codeine, a constituent of the opium poppy, 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.

From 1898 through to 1910 diacetylmorphine was marketed under the name heroin as a non-addictive morphine substitute and cough suppressant. Bayer marketed heroin as a cure for morphine addiction before it was discovered that it rapidly metabolizes into morphine. As such, heroin is essentially a quicker acting form of morphine. The company was embarrassed by the new finding, which became a historic blunder for Bayer.

In the U.S.A. the Harrison Narcotics Tax Act was passed in 1914 to control the sale and distribution of "heroin" 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 a Schedule I substance, which makes it illegal for non-medical use in signatory nations of the Single Convention on Narcotic Drugs treaty, including the United States.

Later, as with Aspirin, Bayer lost some of its trademark rights to "heroin" under the 1919 Treaty of Versailles following the German defeat in World War I.

Pharmacology

When taken orally, diacetylmorphine undergoes extensive first-pass metabolism via deacetylation, making it a prodrug for the systemic delivery of morphine. When the drug is injected, however, it avoids this first-pass effect, very rapidly crossing the blood-brain barrier due to the presence of the acetyl groups, which render it much more lipid-soluble than morphine itself. Once in the brain, it then is deacetylated into 6-monoacetylmorphine (6-MAM) and morphine which bind to μ-opioid receptors, resulting in the drug's euphoric, analgesic (pain relief), and anxiolytic (anti-anxiety) effects; diacetylmorphine itself exhibits relatively low affinity for the μ receptor. Unlike hydromorphone and oxymorphone, however, administered intravenously, diacetylmorphine creates a larger histamine release, similar to morphine, resulting in the feeling of a greater subjective "body high" to some, but also instances of pruritus (itching) when they first start using.

Both morphine and 6-MAM are μ-opioid agonists which bind to receptors present throughout the brain, spinal cord and gut of all mammals. The μ-opioid receptor also binds endogenous opioid peptides such as β-endorphin, Leu-enkephalin, and Met-enkephalin. Repeated use of diacetylmorphine results in a number of physiological changes, including decreases in the number of μ-opioid receptors. These physiological alterations lead to tolerance and dependence, so that cessation of diacetylmorphine use results in a set of extremely uncomfortable symptoms including pain, anxiety, muscle spasms, and insomnia called the opioid withdrawal syndrome. Depending on usage it has an onset 4 to 24 hours after the last dose of diacetylmorphine. Morphine also binds to δ- and κ-opioid receptors.

There is also evidence that 6-MAM binds to a subtype of μ-opioid receptors which are also activated by the morphine metabolite morphine-6β-glucuronide but not morphine itself. 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 analgesics nicomorphine (Vilan), and dipropanoylmorphine; there is also the latter's dihydromorphine analogue, diacetyldihydromorphine (Paralaudin).

Usage

Worldwide, the UN estimates there are more than 50 million regular users of heroin, cocaine and synthetic drugs. Global users of heroin are estimated at between 15.16 million and 21.13 million people aged 15–64.

Medical use

Under the name diamorphine, heroin is prescribed as a strong analgesic in the United Kingdom, where it is given via subcutaneous, intramuscular, intrathecal or intravenous route. Its use includes treatment for acute pain, such as in severe physical trauma, myocardial infarction, post-surgical pain, and chronic pain, including end-stage cancer and other terminal illnesses. In other countries it is more common to use morphine or other strong opioids in these situations.

In 2005, there was a shortage of diamorphine in the UK, due to a problem at the main UK manufacturers. Due to this, many hospitals changed to using morphine instead of diamorphine. Although there is no longer a problem with the manufacturing of heroin in the UK, many hospitals there have continued to use morphine.

Diamorphine continues to be widely used in palliative care in the United Kingdom, where it is commonly given by the subcutaneous route, often via a syringe driver, if patients could not easily swallow oral morphine solution. The advantage of diamorphine over morphine is that diamorphine is more soluble and smaller volumes of diamorphine are needed for the same analgesic effect. Both of these factors are advantageous if giving high doses of opioids via the subcutaneous route, which is often necessary in palliative care.

The medical use of diamorphine (in common with other strong opioids such as morphine, fentanyl and oxycodone) is controlled in the United Kingdom by the Misuse of Drugs Act 1971. In the UK, it is a class A controlled drug. Registers of its use are required to be kept in hospitals.

Heroin is also used as a maintenance drug in the treatment of heroin addicts. Though this is somewhat controversial among proponents of a zero tolerance drug policy it has proven superior to methadone in improving the social and health situation of addicts.

Recreational use

Diacetylmorphine is used as a recreational drug for the transcendent relaxation and intense euphoria it induces. Anthropologist Michael Agar once described heroin as "the perfect whatever drug." Tolerance quickly develops, and users need more of the drug to achieve the same effects. Its popularity with recreational drug users, compared to morphine, reportedly stems from its perceived different effects. In particular, users report an intense rush that occurs while the diacetylmorphine is being metabolized into 6-monoacetylmorphine (6-MAM) and morphine in the brain.

Diacetylmorphine produces more euphoria than other opioids upon injection. One possible explanation is the presence of 6-monoacetylmorphine, a metabolite unique to diacetylmorphine. While other opioids of recreational use, such as codeine, 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 diacetylmorphine 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. Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both diacetylmorphine and morphine. When compared to the opioids hydromorphone, fentanyl, oxycodone, and pethidine/meperidine, former addicts showed a strong preference for diacetylmorphine and morphine, suggesting that diacetylmorphine and morphine are particularly susceptible to abuse and addiction. Morphine and diacetylmorphine were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids.

One of the most common methods of illicit heroin use is via intravenous injection (colloquially termed "slamming" or "shooting up"). Heroin base (commonly found in the UK and 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 the US is most commonly its hydrochloride salt, requiring just water to dissolve. Users tend to initially inject in the easily accessible veins in the arm, but as these veins collapse over time through damage caused by the acid, the user will often resort to injecting in other veins.

Recreational users may also administer the drug through snorting, or smoking by inhaling its vapors when heated; either with tobacco in a rolled cigarette or by heating the drug on aluminium foil from underneath. When heated the heroin powder changes to a thick liquid, similar in consistency to molten wax, and it will run across the foil giving off smoke which the user inhales through a tube, usually made from foil also so that any heroin that collects on the inside of the tube can be smoked afterward. This method of administration is known as chasing the dragon (whereas smoking methamphetamine is known as "chasing the white dragon").

The onset of diacetylmorphine's effects depends upon the route of administration. Studies have shown that the subjective pleasure of drug use (the reinforcing component of addiction) is proportional to the rate at which the blood level of the drug increases. Intravenous injection provides the fastest and most intense rush within 7 to 8 seconds. Intra-muscular injection produces a relatively slow onset of 5 to 8 minutes. Snorting or smoking reaches peak effects within 10 to 15 minutes. If taken orally, the effects take approximately half an hour to set in, with an absence of a rush.

The diacetylmorphine dose used for recreational purposes is dependant on the frequency and level of use. A first-time user may ingest between 5 and 20 mg of diacetylmorphine, while an addict may require several hundred mg per day.

Large doses of heroin can cause fatal respiratory depression, and the drug has been used for suicide or as a murder weapon. The serial killer Dr Harold Shipman used it on his victims as did Dr John Bodkin Adams (see his victim, Edith Alice Morrell). 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 death was an accident, suicide or murder. Examples include the overdose deaths of Sid Vicious, Janis Joplin, Tim Buckley, Layne Staley, Bradley Nowell, Ted Binion, and River Phoenix.

Price

The European Monitoring Centre for Drugs and Drug Addiction reports 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.

The United Nations Office on Drugs and Crime claims in its 2008 World Drug Report that typical US retail prices are US$172 per gram.

Risks of use

• For intravenous users of heroin (and any other substance), the use of non-sterile needles and syringes and other related equipment leads to several serious risks:

the risk of contracting blood-borne pathogens such as HIV and hepatitis
the risk of contracting bacterial or fungal endocarditis and possibly venous sclerosis
abscesses

•    Poisoning from contaminants added to "cut" or dilute heroin
•    Chronic constipation
•    Addiction and increasing tolerance
•    Physical dependence can result from prolonged use of all opioids, resulting in withdrawal symptoms on cessation of use
•    Decreased kidney function (although it is not currently known if this is due to adulterants or infectious diseases)

Many countries and local governments have begun funding programs that supply sterile needles to people who inject illegal drugs in an attempt to reduce these contingent risks and especially the contraction and spread of blood-borne diseases. The Drug Policy Alliance reports that up to 75% of new AIDS cases among women and children are directly or indirectly a consequence of drug use by injection. The United States federal government does not operate needle exchanges, although some state and local governments do support needle exchange programs.

Anthropologists Philippe Bourgois and Jeff Schonberg, who did a decade of field work among homeless heroin and crack addicts in San Francisco, reported that the African-American addicts they observed were more inclined to "direct deposit" heroin into a vein, rather than "skin-popping" their injections. (Skin-popping was a far more widespread practice among the white addicts: "By the midpoint of our fieldwork, most of the whites had given up searching for operable veins and skin-popped. They sank their needles perfunctorily, often through their clothing, into their fatty tissue.") Bourgois and Schonberg describes how the cultural difference between the African-Americans and the whites leads to this contrasting behavior, and also points out that the two different ways to inject heroin comes with different health risks. Skin-popping more often results in abscesses, and direct injection more often leads to fatal overdose and also to hepatitis C and HIV infection.

A heroin overdose is usually treated with an opioid antagonist, such as naloxone (Narcan), or naltrexone, which has high affinity for opioid receptors but does not activate them. This reverses the effects of heroin and other opioid agonists and causes an immediate return of consciousness but may precipitate withdrawal symptoms. The half-life of naloxone is much shorter than that of most opioid agonists, so that antagonist typically has to be administered multiple times until the opioid has been metabolized by the body.

Depending on drug interactions and numerous other factors, death from overdose can take anywhere from several minutes to several hours due to anoxia because the breathing reflex is suppressed by µ-opioids. An overdose is immediately reversible with an opioid antagonist injection. Heroin overdoses can occur due to an unexpected increase in the dose or purity or due to diminished opioid tolerance. However, many fatalities reported as overdoses are probably caused by interactions with other depressant drugs like alcohol or benzodiazepines. It should also be noted that 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 victim. Some sources give a figure of between 75 and 375 mg for a 75 kg being fatal for 50% of opiate naive people. Street 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 a dangerous overdose.

It has been speculated that an unknown portion of heroin related deaths are the result of an overdose or allergic reaction to quinine, which may sometimes be used as a cutting agent.

A final factor contributing to overdoses is place conditioning. Heroin use is a highly ritualized behavior. While the mechanism has yet to be clearly elucidated, longtime heroin users display increased tolerance to the drug in locations where they have repeatedly administered heroin. When the user injects in a different location, this environment-conditioned tolerance does not occur, resulting in a greater drug effect. The user's typical dose of the drug, in the face of decreased tolerance, becomes far too high and can be toxic, leading to overdose.

A small percentage of heroin smokers and occasionally IV users may develop symptoms of toxic leukoencephalopathy. The cause has yet to be identified, but one speculation is that the disorder is caused by an uncommon adulterant that is only active when heated. Symptoms include slurred speech and difficulty walking.

Cocaine is sometimes used in combination with heroin, and is referred to as a speedball when injected or moonrocks when smoked together. Cocaine acts as a stimulant, whereas heroin acts as a depressant. Coadministration provides an intense rush of euphoria with a high that combines both effects of the drugs, while excluding the negative effects, such as anxiety and sedation. The effects of cocaine wear off far more quickly than heroin, thus if an overdose of heroin was used to compensate for cocaine, the end result is fatal respiratory depression

Harm reduction

Proponents of the harm reduction philosophy seek to minimize the harms that arise from the recreational use of heroin. Safer means of taking the drug, such as smoking or nasal, oral and rectal insertion, are encouraged, due to injection having higher risks of overdose, infections and blood-borne viruses. Where the strength of the drug is unknown, users are encouraged to try a small amount first to gauge the strength, to minimize the risks of overdose. For the same reason, poly drug use (the use of two or more drugs at the same time) is discouraged. Users are also encouraged to not use heroin on their own, as others can assist in the event of an overdose. Heroin users who choose to inject should always use new needles, syringes, spoons/steri-cups and filters every time they inject and not share these with other users.

Governments that support a harm reduction approach usually fund Needle & Syringe exchange programs, which supply new needles and syringes on a confidential basis, as well as education on proper filtering prior to injection, safer injection techniques, safe disposal of used injecting gear and other equipment used when preparing heroin for injection may also be supplied including citric acid sachets/vitamin C sachets, steri-cups, filters, alcohol pre-injection swabs, sterile water ampules and tourniquets (to stop use of shoe laces or belts).

Another harm reduction measure employed for example in Switzerland and Germany are safe injection sites where users can inject heroin and cocaine under the supervision of medically trained staff. Those establishments also often include a cafeteria and a designated area where the sale and acquisition of small amounts of drugs among users is tolerated. Safe injection sites are low threshold and allow social services to approach problem users that would otherwise be hard to reach.

Withdrawal

The withdrawal syndrome from heroin may begin within 6 to 24 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. Symptoms may include: sweating, malaise, anxiety, depression, priapism, extra sensitivity of the genitals in females, general feeling of heaviness, cramp-like pains in the limbs, excessive yawning or sneezing, tears, rhinorrhea, sleep difficulties (insomnia), cold sweats, chills, severe muscle and bone aches; nausea and vomiting, diarrhea, cramps, and fever.

Systematic (IUPAC) name

(5α,6α)-7,8-didehydro- 4,5-epoxy- 17-methylmorphinan- 3,6-diol diacetate

Identifiers
CAS number: 561-27-3
ATC code: N02AA09
PubChem: 5462328
ChemSpider: 4575379

Chemical data
Formula: C21H23NO5
Mol. mass: 369.41 g/mol
Synonyms: Diamorphine, Diacetylmorphine, Acetomorphine, (Dual) Acetylated morphine, Morphine diacetate

Pharmacokinetic data
Bioavailability: <35% (oral), 44–61% (inhaled)
Protein binding: 0% (morphine metabolite 35%)
Metabolism: hepatic
Half life: <10 minutes
Excretion: 90% renal as glucuronides, rest biliary

Therapeutic considerations
Pregnancy cat: Category X
Legal status: Prohibited (S9) (AU) Schedule I (CA) ? (UK) Schedule I (US)
Dependence Liability: Extremely High
Routes: Inhalation, Transmucosal, Intravenous, Oral, Intranasal, Rectal, Intramuscular