Morphine

Morphine

Overview
Morphine (icon; MS Contin, MSIR, Avinza, Kadian, Oramorph, Roxanol, Kapanol) is a potent
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...

 opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...

 analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 and is considered to be the prototypical opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

. It was first isolated in 1804 by Friedrich Sertürner
Friedrich Sertürner
Friedrich Wilhelm Adam Sertürner was a German pharmacist, who discovered morphine in 1804.-Biography:He was born on 19 June 1783 in Neuhaus ....

, first distributed by same in 1817, and first commercially sold by Merck
Merck KGaA
Merck KGaA is a German chemical and pharmaceutical company. Merck, also known as “German Merck” and “Merck Darmstadt”, was founded in Darmstadt, Germany, in 1668, making it the world's oldest operating chemical and pharmaceutical company. The company was privately owned until going public in 1995...

 in 1827, which at the time was a single small chemists' shop. It was more widely used after the invention of the hypodermic needle
Hypodermic needle
A hypodermic needle is a hollow needle commonly used with a syringe to inject substances into the body or extract fluids from it...

 in 1857.
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Encyclopedia
Morphine (icon; MS Contin, MSIR, Avinza, Kadian, Oramorph, Roxanol, Kapanol) is a potent
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...

 opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...

 analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

 and is considered to be the prototypical opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

. It was first isolated in 1804 by Friedrich Sertürner
Friedrich Sertürner
Friedrich Wilhelm Adam Sertürner was a German pharmacist, who discovered morphine in 1804.-Biography:He was born on 19 June 1783 in Neuhaus ....

, first distributed by same in 1817, and first commercially sold by Merck
Merck KGaA
Merck KGaA is a German chemical and pharmaceutical company. Merck, also known as “German Merck” and “Merck Darmstadt”, was founded in Darmstadt, Germany, in 1668, making it the world's oldest operating chemical and pharmaceutical company. The company was privately owned until going public in 1995...

 in 1827, which at the time was a single small chemists' shop. It was more widely used after the invention of the hypodermic needle
Hypodermic needle
A hypodermic needle is a hollow needle commonly used with a syringe to inject substances into the body or extract fluids from it...

 in 1857. It took its name from the Greek god of dreams Morpheus
Morpheus (mythology)
Morpheus in Greek mythology is the god of dreams, leader of the Oneiroi. Morpheus has the ability to take any human form and appear in dreams...

 .

Morphine is the most abundant alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

 found in opium
Opium
Opium is the dried latex obtained from the opium poppy . Opium contains up to 12% morphine, an alkaloid, which is frequently processed chemically to produce heroin for the illegal drug trade. The latex also includes codeine and non-narcotic alkaloids such as papaverine, thebaine and noscapine...

, the dried sap (latex) derived from shallowly slicing the unripe seedpods of the opium, or common and/or edible, poppy, Papaver somniferum. Morphine was the first active principle purified from a plant source and is one of at least 50 alkaloids of several different types present in opium, Poppy Straw Concentrate
Poppy straw concentrate
Poppy straw is opium poppy that is harvested when fully mature and dry, minus the ripe poppy seeds...

, and other poppy derivatives. Morphine is generally 8 to 17 percent of the dry weight of opium, although specially-bred cultivar
Cultivar
A cultivar'Cultivar has two meanings as explained under Formal definition. When used in reference to a taxon, the word does not apply to an individual plant but to all those plants sharing the unique characteristics that define the cultivar. is a plant or group of plants selected for desirable...

s reach 26 percent or produce little morphine at all, under 1 percent, perhaps down to 0.04 percent. The latter varieties, including the 'Przemko' and 'Norman' cultivars of the opium poppy, are used to produce two other alkaloids, thebaine
Thebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...

 and oripavine
Oripavine
Oripavine is an opiate and the major metabolite of thebaine. It is the parent compound from which a series of semi-synthetic opioids are derived, which includes the compounds etorphine and buprenorphine...

, which are used in the manufacture of semi-synthetic and synthetic opioids like oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...

 and etorphine
Etorphine
Etorphine is a semi-synthetic opioid possessing an analgesic potency approximately 200 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather in "poppy straw" and in related plants, Papaver orientale and Papaver...

 and some other types of drugs. P. bracteatum
Papaver bracteatum
Papaver bracteatum, also known as the Iranian poppy, is a sturdy perennial poppy with large deep red flowers up to 8 inches across on stiff stalks up to 4 feet high with a prominent black spot near the base of the petals...

does not contain morphine or codeine, or other narcotic phenanthrene
Phenanthrene
Phenanthrene is a polycyclic aromatic hydrocarbon composed of three fused benzene rings. The name phenanthrene is a composite of phenyl and anthracene. In its pure form, it is found in cigarette smoke and is a known irritant, photosensitizing skin to light...

-type, alkaloids. This species is rather a source of thebaine
Thebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...

. Occurrence of morphine in other papaverales and papaveraceae
Papaveraceae
Papaveraceae, informally known as the poppy family, are an economically important family of 44 genera and approximately 770 species of flowering plants in the order Ranunculales. The family is cosmopolitan, occurring in temperate and subtropical climates, but almost unknown in the tropics...

, as well as in some species of hops
Hops
Hops are the female flower clusters , of a hop species, Humulus lupulus. They are used primarily as a flavoring and stability agent in beer, to which they impart a bitter, tangy flavor, though hops are also used for various purposes in other beverages and herbal medicine...

 and mulberry
Mulberry
Morus is a genus of flowering plants in the family Moraceae. The 10–16 species of deciduous trees it contains are commonly known as Mulberries....

 trees has not been confirmed. Morphine is produced most predominantly early in the life cycle of the plant. Past the optimum point for extraction, various processes in the plant produce codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...

, thebaine
Thebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...

, and in some cases negligible amounts of hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...

, dihydromorphine
Dihydromorphine
Dihydromorphine is a semi-synthetic opioid invented in Germany in 1900. In structure, it is very similar to morphine, the only difference being the reduction of the double bond between positions 7 and 8 in morphine to a single bond...

, dihydrocodeine
Dihydrocodeine
Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...

, tetrahydrothebaine, and hydrocodone
Hydrocodone
Hydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from either of two naturally occurring opiates: codeine and thebaine. It is an orally active narcotic analgesic and antitussive...

 (these compounds are rather synthesized from thebaine and oripavine). The human body produces endorphines, which are neuropeptides, with similar effects.

In clinical medicine, morphine is regarded as the gold standard, or benchmark, of analgesics used to relieve severe or agonizing pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

 and suffering
Suffering
Suffering, or pain in a broad sense, is an individual's basic affective experience of unpleasantness and aversion associated with harm or threat of harm. Suffering may be qualified as physical or mental. It may come in all degrees of intensity, from mild to intolerable. Factors of duration and...

. Like other opioids, such as oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...

, hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...

, and diacetylmorphine (heroin), morphine acts directly on the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 (CNS) to relieve pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

. Unlike many other opioids, morphine is an opiate and a natural product. Morphine has a high potential for addiction
Substance use disorder
Substance use disorders include substance abuse and substance dependence. In DSM-IV, the conditions are formally diagnosed as one or the other, but it has been proposed that DSM-5 combine the two into a single condition called "Substance-use disorder"....

; tolerance and psychological dependence
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...

 develop rapidly, although physiological
Physical property
A physical property is any property that is measurable whose value describes a physical system's state. The changes in the physical properties of a system can be used to describe its transformations ....

 dependence may take several months to develop.

Medical uses


Morphine is primarily used to treat both acute and chronic severe pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...

. It is also used for pain due to myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...

 and for labor pains. There are however concerns that morphine may increase mortality in the setting of non ST elevation myocardial infarction. Morphine has also traditionally been used in the treatment of the acute pulmonary edema. A 2006 review however found little evidence to support this practice. Immediate release morphine is beneficial in reducing the symptom of shortness of breath due to both cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

 and non-cancer causes. Its duration of analgesia is about 3-4 hours when administered via the intravenous, subcutaneous, or intramuscular route and 3-6 hours when given by mouth.
Morphine is also used in slow release formulations for opiate substitution therapy (OST) in Austria, Bulgaria, and Slovenia, for addicts who cannot tolerate the side effects of using either methadone or buprenorphine, or for addicts who are "not held" by buprenorphine or methadone. It is used for OST in many parts of Europe although on a limited basis.

Adverse effects



Constipation


Like loperamide
Loperamide
Loperamide , a synthetic piperidine derivative, is an opioid drug used against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor, Fortasec, and Pepto Diarrhea Control...

 and other opioids, morphine acts on the myenteric plexus in the intestinal tract, reducing gut motility, causing constipation. The gastrointestinal effects of morphine are mediated primarily by μ-opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

 receptors in the bowel. By inhibiting gastric emptying and reducing propulsive peristalsis
Peristalsis
Peristalsis is a radially symmetrical contraction and relaxation of muscles which propagates in a wave down the muscular tube, in an anterograde fashion. In humans, peristalsis is found in the contraction of smooth muscles to propel contents through the digestive tract. Earthworms use a similar...

 of the intestine, morphine decreases the rate of intestinal transit. Reduction in gut secretion and increased intestinal fluid absorption also contribute to the constipating effect. Opioids also may act on the gut indirectly through tonic gut spasms after inhibition of nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

 generation. This effect was shown in animals when a nitric oxide precursor, L-Arginine, reversed morphine-induced changes in gut motility.

Addiction


In controlled studies comparing the physiological and subjective effects of injected heroin and morphine in individuals formerly addicted to opiates, 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 heroin and morphine. When compared to the opioids hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...

, fentanyl, oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...

, and pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...

/meperidine, former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to abuse and addiction. Morphine and heroin were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids. The choice of heroin and morphine over other opioids by former-drug addicts may also be the result of the fact that heroin (also known as morphine diacetate, diamorphine or di-acetyl-morphine) is an ester salt of morphine and a morphine prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...

, essentially meaning that they are identical drugs in vivo. Heroin is converted to morphine before binding to the opioid receptor
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...

s in the brain and spinal cord, where morphine then causes the subjective effects which is what the addicted individuals are ultimately looking for.

Other studies, such as the Rat Park
Rat Park
Rat Park was a study into drug addiction conducted in the late 1970s , by Canadian psychologist Bruce K. Alexander and his colleagues at Simon Fraser University in British Columbia, Canada....

 experiments, suggest that morphine is less physically addictive than others suggest, and most studies on morphine addiction merely show that "severely distressed animals, like severely distressed people, will relieve their distress pharmacologically
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...

 if they can." In these studies, rats with a morphine "addiction" overcome their addiction themselves when placed in decent living environments with enough space, good food, companionship, areas for exercise, and areas for privacy. More recent research has shown that an enriched environment
Environmental enrichment (neural)
Environmental enrichment concerns how the brain is affected by the stimulation of its information processing provided by its surroundings . Brains in richer, more stimulating environments, have increased numbers of synapses, and the dendrite arbors upon which they reside are more complex...

 may decrease morphine addiction in mice.

Morphine is a potentially highly addictive
Substance use disorder
Substance use disorders include substance abuse and substance dependence. In DSM-IV, the conditions are formally diagnosed as one or the other, but it has been proposed that DSM-5 combine the two into a single condition called "Substance-use disorder"....

 substance. It can cause psychological dependence
Substance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...

 and physical dependence
Physical dependence
Physical dependence refers to a state resulting from chronic use of a drug that has produced tolerance and where negative physical symptoms of withdrawal result from abrupt discontinuation or dosage reduction...

 as well as tolerance, with an addiction potential identical to that of heroin. When used illicitly, a very serious narcotic habit can develop in a matter of weeks, whereas iatrogenic
Iatrogenesis
Iatrogenesis, or an iatrogenic artifact is an inadvertent adverse effect or complication resulting from medical treatment or advice, including that of psychologists, therapists, pharmacists, nurses, physicians and dentists...

 morphine addiction rates have, according to a number of studies, remained nearly constant at one case in 150 to 200 for at least two centuries. In the presence of pain and the other disorders for which morphine is indicated, a combination of psychological and physiological factors tend to prevent true addiction from developing, although physical dependence and tolerance will develop with protracted opioid therapy.

Tolerance


Tolerance to the analgesic effects of morphine is fairly rapid. There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

 (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization), μ-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...

 pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.) CCK
CCK
CCK may refer to:*Choa Chu Kang, a suburban town in Singapore*Complementary code keying, a modulation technique used in IEEE 802.11b*Cholecystokinin, a digestive hormone...

 might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide
Proglumide
Proglumide is a drug that inhibits gastrointestinal motility and reduces gastric secretions. It acts as a cholecystokinin antagonist, which blocks both the CCKA and CCKB subtypes...

, have been shown to slow the development of tolerance to morphine.

Withdrawal



Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which unlike that of barbiturates, benzodiazepines, alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....

, or sedative-hypnotics, is not fatal by itself in neurologically healthy patients without heart or lung problems; it is in theory self-limiting in length and overall impact in that a rapid increase in metabolism and other bodily processes takes place, including shedding and replacement of the cells of many organs.

Nonetheless, suicide, heart attacks, strokes, seizures proceeding to status epilepticus, and effects of extreme dehydration do lead to fatal outcomes in a small fraction of cases.

Acute morphine along with and other opioid withdrawal proceeds through a number of stages. Other opioids differ in the intensity and length of each, and weak opioids and mixed agonist-antagonists may have acute withdrawal syndromes that do not reach the highest level. As commonly cited, they are:
  • Stage I: Six to fourteen hours after last dose: Drug craving, anxiety, irritability, perspiration, and mild to moderate dysphoria.

  • Stage II: Fourteen to eighteen hours after last dose: Yawning, heavy perspiration, mild depression lacrimation, crying, running nose, dysphoria, also intensification of the above symtoms. "yen sleep" (a waking trance-like state)

  • Stage III: Sixteen to twenty-four hours after last dose: Rhinorrhea
    Rhinorrhea
    Rhinorrhea or rhinorrhoea is a condition where the nasal cavity is filled with a significant amount of mucous fluid. The condition, commonly known as "runny nose", occurs relatively frequently and is not usually considered dangerous. Rhinorrhea is a common symptom of allergies or certain diseases,...

     (runny nose) and increase in other of the above, dilated pupils, piloerection (gooseflesh), muscle twitches, hot flashes, cold flashes, aching bones and muscles, loss of appetite and the beginning of intestinal cramping.

  • Stage IV: Twenty-four to thirty-six hours after last dose: Increase in all of the above including severe cramping and involuntary leg movements ("kicking the habit"), loose stool, insomnia, elevation of blood pressure, moderate elevation in body temperature, increase in frequency of breathing and tidal volume, tachycardia
    Tachycardia
    Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...

     (elevated pulse), restlessness, nausea

  • Stage V: Thirty-six to seventy-two hours after last dose: Increase in the above, fetal position, vomiting, free and frequent liquid diarrhea, which sometimes can accelerate the time of passage of food from mouth to out of system to an hour or less, involuntary ejaculation, which is often painful, saturation of bedding materials with bodily fluids, weight loss of two to five kilos per 24 hours, increased white cell count
    White blood cell
    White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...

     and other blood changes.

  • Stage VI: After completion of above: Recovery of appetite ("the chucks"), and normal bowel function, beginning of transition to post-acute and chronic symptoms that are mainly psychological but that may also include increased sensitivity to pain, hypertension, colitis
    Colitis
    In medicine, colitis refers to an inflammation of the colon and is often used to describe an inflammation of the large intestine .Colitides may be acute and self-limited or chronic, i.e...

     or other gastrointestinal afflictions related to motility, and problems with weight control in either direction.


Some authorities give the above as grades zero to four, and others add chronic withdrawal as a seventh stage. Some separate post-acute and chronic withdrawal, others do not. For an example of the use of the above system, methadone clinics require, in the absence of a direct and documented referral from a doctor, Stage II withdrawal symptoms and/or recent needle marks and/or surrender of injecting equipment and/or unused drug at the intake appointment to begin the methadone maintenance or withdrawal process; two urine tests positive for opioids must then be collected shortly thereafter.

The withdrawal symptoms associated with morphine addiction are usually experienced shortly before the time of the next scheduled dose, sometimes within as early as a few hours (usually between 6–12 hours) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning, dysphoria
Dysphoria
Dysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...

, sweating and in some cases a strong drug craving. Severe headache, restlessness, irritability, loss of appetite, body aches, severe abdominal pain, nausea and vomiting, tremors, and even stronger and more intense drug craving appear as the syndrome progresses. Severe depression and vomiting are very common. During the acute withdrawal period systolic and diastolic blood pressure increase, usually beyond pre-morphine levels, and heart rate increases, which have potential to cause a heart attack, blood clot, or stroke.

Chills or cold flashes with goose bumps ("cold turkey") alternating with flushing (hot flashes), kicking movements of the legs ("kicking the habit") and excessive sweating are also characteristic symptoms. Severe pains in the bones and muscles of the back and extremities occur, as do muscle spasms. At any point during this process, a suitable narcotic can be administered that will dramatically reverse the withdrawal symptoms. Major withdrawal symptoms peak between 48 and 96 hours after the last dose and subside after about 8 to 12 days. Sudden withdrawal by heavily dependent users who are in poor health is very rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal.

The psychological dependence associated with morphine addiction
Substance use disorder
Substance use disorders include substance abuse and substance dependence. In DSM-IV, the conditions are formally diagnosed as one or the other, but it has been proposed that DSM-5 combine the two into a single condition called "Substance-use disorder"....

 is complex and protracted. Long after the physical need for morphine has passed, the addict will usually continue to think and talk about the use of morphine (or other drugs) and feel strange or overwhelmed coping with daily activities without being under the influence of morphine. Psychological withdrawal from morphine is a very long and painful process. Addicts often suffer severe depression, anxiety, insomnia, mood swings, amnesia (forgetfulness), low self-esteem, confusion, paranoia, and other psychological disorders. Without intervention, the syndrome will run its course, and most of the overt physical symptoms will disappear within 7 to 10 days including psychological dependence. There is a high probability that relapse will occur after morphine withdrawal when neither the physical environment nor the behavioral motivators that contributed to the abuse have been altered. Testimony to morphine's addictive and reinforcing nature is its relapse rate. Abusers of morphine (and heroin) have one of the highest relapse rates among all drug users, ranging up to 98 per cent in the estimation of some clinicians, neuropharmacologists, mental health/AODA professionals and other medical experts.

Overdose


A large overdose can cause asphyxia
Asphyxia
Asphyxia or asphyxiation is a condition of severely deficient supply of oxygen to the body that arises from being unable to breathe normally. An example of asphyxia is choking. Asphyxia causes generalized hypoxia, which primarily affects the tissues and organs...

 and death by respiratory depression if the person does not receive medical attention immediately. Overdose treatment includes the administration of naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...

. The latter completely reverses morphine's effects, but precipitates immediate onset of withdrawal in opiate-addicted subjects. Multiple doses may be needed.

The minimum lethal dose is 200 mg but in case of hypersensitivity 60 mg can bring sudden death. In case of drug addiction, 2-3 g/day can be tolerated.

Contraindications


The following conditions are relative contraindications for morphine:
  • acute respiratory depression
    Hypoventilation
    In medicine, hypoventilation occurs when ventilation is inadequate to perform needed gas exchange...

  • renal failure
    Renal failure
    Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

     (due to accumulation of the metabolites morphine-3-glucuronide and morphine-6-glucuronide
    Morphine-6-glucuronide
    Morphine-6-glucuronide is a major active metabolite of morphine, and as such is the molecule responsible for much of the pain-relieving effects of morphine . M6G is formed from morphine by the enzyme UDP-Glucuronosyltransferase-2B7...

    )
  • chemical toxicity
    Toxicity
    Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...

     (potentially lethal in low tolerance subjects)
  • raised intracranial pressure, including head injury (risk of worsening respiratory depression)
  • Biliary colic
    Biliary colic
    Biliary colic is pain associated with irritation of the viscera secondary to cholecystitis and gallstones. Unlike renal colic, the phrase 'biliary colic' refers to the actual cholelithiasis....

    .


Although it has previously been thought that morphine was contraindicated in acute pancreatitis
Acute pancreatitis
Acute pancreatitis or acute pancreatic necrosis is a sudden inflammation of the pancreas. It can have severe complications and high mortality despite treatment...

, a review of the literature shows no evidence for this.

Pharmacology


Endogenous opioids include endorphin
Endorphin
Endorphins are endogenous opioid peptides that function as neurotransmitters. They are produced by the pituitary gland and the hypothalamus in vertebrates during exercise, excitement, pain, consumption of spicy food, love and orgasm, and they resemble the opiates in their abilities to produce...

s, enkephalin
Enkephalin
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, or specifically endorphins, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin were revealed, one...

s, dynorphin
Dynorphin
Dynorphins are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 , multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neo-endorphin...

s, and even morphine itself. Morphine appears to mimic endorphins. Endorphins, a contraction of the term endogenous morphines, are responsible for analgesia (reducing pain), causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement.

Morphine is the prototype narcotic drug and is the standard against which all other opioids are tested. It interacts predominantly with the μ-opioid
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...

 receptor. These μ-binding sites are discretely distributed in the human brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

, with high densities in the posterior amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...

, hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

, thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...

, nucleus caudatus, putamen
Putamen
The putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...

, and certain cortical areas. They are also found on the terminal axons
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...

 of primary afferents within laminae I
Posteromarginal nucleus
The marginal nucleus of spinal cord, or posteromarginal nucleus, or Substantia Marginalis, Rexed lamina I, is located at the most dorsal aspect of the dorsal horn of the spinal cord. The neurons located here receive input primarily from Lissauer's tract and relay information related to pain and...

 and II (substantia gelatinosa
Substantia gelatinosa of Rolando
The apex of the posterior horn of the gray matter of the spinal cord is capped by a V-shaped or crescentic mass of translucent, gelatinous neuroglia, termed the substantia gelatinosa of Rolando , which contains both neuroglia cells, and small nerve cells...

) of the spinal cord and in the spinal nucleus of the trigeminal nerve
Trigeminal nerve
The trigeminal nerve contains both sensory and motor fibres. It is responsible for sensation in the face and certain motor functions such as biting, chewing, and swallowing. Sensory information from the face and body is processed by parallel pathways in the central nervous system...

.

Morphine is a phenanthrene
Phenanthrene
Phenanthrene is a polycyclic aromatic hydrocarbon composed of three fused benzene rings. The name phenanthrene is a composite of phenyl and anthracene. In its pure form, it is found in cigarette smoke and is a known irritant, photosensitizing skin to light...

 opioid receptor
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...

 agonist – its main effect is binding to and activating the μ-opioid receptors
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...

 in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

. Its primary actions of therapeutic value are analgesia and sedation. Activation of the μ-opioid
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...

 receptors is associated with analgesia, sedation, euphoria
Euphoria (emotion)
Euphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of well-being, elation, happiness, ecstasy, excitement and joy...

, physical dependence, and respiratory depression. Morphine is a rapid-acting narcotic, and it is known to bind very strongly to the μ-opioid
Mu Opioid receptor
The μ-opioid receptors are a class of opioid receptors with high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. They are also referred to as μ opioid peptide receptors. The prototypical μ receptor agonist is the opium alkaloid morphine; μ refers to morphine...

 receptors, and for this reason, it often has a higher incidence of euphoria/dysphoria, respiratory depression, sedation, pruritus, tolerance, and physical and psychological dependence when compared to other opioids at equianalgesic doses. Morphine is also a κ-opioid
Kappa Opioid receptor
The κ-opioid receptor is a protein that in humans is encoded by the OPRK1 gene. The κ-opioid receptor is one of five related receptors that bind opium-like compounds in the brain and are responsible for mediating the effects of these compounds...

 and δ-opioid
Delta Opioid receptor
The δ-opioid receptors, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has enkephalins as its endogenous ligands.-Function:...

 receptor agonist, κ-opioid's action is associated with spinal analgesia, miosis
Miosis
Miosis is the constriction of the pupil of the eye to two millimeters or less...

 (pinpoint pupils) and psychotomimetic
Psychotomimetic
A drug with psychotomimetic actions mimics the symptoms of psychosis, including delusions and/or delirium, as opposed to just hallucinations. Some drugs of the opioid class have psychotomimetic effects, such as pentazocine and butorphanol....

 effects. δ-opioid is thought to play a role in analgesia. Although morphine does not bind to the σ-receptor
Sigma receptor
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...

, it has been shown that σ-agonists, such as (+)-pentazocine
Pentazocine
Pentazocine is a synthetically prepared prototypical mixed agonist-antagonist narcotic drug of the benzomorphan class of opioids used to treat moderate to moderately severe pain...

, antagonize morphine analgesia, and σ-antagonists enhance morphine analgesia, suggesting some interaction between morphine and the σ-opioid receptor.

The effects of morphine can be countered with opioid antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

 such as naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...

 and naltrexone
Naltrexone
Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade...

; the development of tolerance to morphine may be inhibited by NMDA
NMDA
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...

 antagonists such as ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...

 or dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...

. The rotation of morphine with chemically dissimilar opioids in the long-term treatment of pain will slow down the growth of tolerance in the longer run, particularly agents known to have significantly incomplete cross-tolerance with morphine such as levorphanol
Levorphanol
Levorphanol is an opioid medication used to treat severe pain. It is the levorotatory stereoisomer of the synthetic morphinan and a pure opioid agonist, first described in Germany in 1948 as an orally active morphine-like analgesic...

, ketobemidone
Ketobemidone
Ketobemidone is a powerful opioid analgesic. Its effectiveness against pain is in the same range as morphine, and it also has some NMDA-antagonist properties imparted by it's metabolite norketobemidone. This makes it useful for some types of pain that don't respond well to other opioids...

, piritramide
Piritramide
Piritramide is a synthetic opioid analgesic with a potency 0.65 to 0.75 times that of morphine. A common starting dose is 15 mg IV, equivalent to 10 mg of morphine hydrochloride. Piritramide is commonly used for the treatment of postoperative pain...

, and methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...

 and its derivatives; all of these drugs also have NMDA antagonist properties. It is believed that the strong opioid with the most incomplete cross-tolerance with morphine is either methadone or dextromoramide
Dextromoramide
Dextromoramide is a powerful opioid analgesic approximately three times more potent than morphine but shorter acting. It is subject to drug prohibition regimes, both internationally through UN treaties, and by the criminal law of individual states...

.

Gene expression


Studies have shown that morphine can alter the expression of a number of genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...

. A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved in mitochondrial respiration and for cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...

-related proteins.

Effects on the immune system


Morphine has long been known to act on receptors expressed on cells of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 resulting in pain relief and analgesia. In the 1970s and '80s, evidence suggesting that opiate drug addicts show increased risk of infection (such as increased pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

, tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

, and HIV) led scientists to believe that morphine may also affect the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...

. This possibility increased interest in the effect of chronic morphine use on the immune system.

The first step of determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that dendritic cells, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produce more interleukin-12 (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less interleukin-10 (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection).

This regulation of cytokines appear to occur via the p38 MAPKs (mitogen-activated protein kinase)-dependent pathway. Usually, the p38 within the dendritic cell expresses TLR 4
TLR 4
Toll-like receptor 4 is a protein that in humans is encoded by the TLR4 gene. TLR 4 is a toll-like receptor. It detects lipopolysaccharide from Gram-negative bacteria and is thus important in the activation of the innate immune system...

 (toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...

). This causes the p38 MAPK to be phosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....

. This phosphorylation activates the p38 MAPK
P38 mitogen-activated protein kinases
P38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation and apoptosis....

 to begin producing IL-10 and IL-12. When the dendritic cells are chronically exposed to morphine during their differentiation process then treated with LPS, the production of cytokines is different. Once treated with morphine, the p38 MAPK does not produce IL-10, instead favoring production of IL-12. The exact mechanism through which the production of one cytokine is increased in favor over another is not known. Most likely, the morphine causes increased phosphorylation of the p38 MAPK. Transcriptional level interactions between IL-10 and IL-12 may further increase the production of IL-12 once IL-10 is not being produced. This increased production of IL-12 causes increased T-cell immune response. This response is due to the ability of IL-12 to cause T helper cells to differentiate into the Th1 cell, causing a T cell immune response.

Further studies on the effects of morphine on the immune system have shown that morphine influences the production of neutrophils and other cytokines. Since cytokines are produced as part of the immediate immunological response (inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

), it has been suggested that they may also influence pain. In this way, cytokines may be a logical target for analgesic development. Recently, one study has used an animal model (hind-paw incision) to observe the effects of morphine administration on the acute immunological response. Following hind-paw incision, pain thresholds and cytokine production were measured. Normally, cytokine production in and around the wounded area increases in order to fight infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...

 and control healing (and, possibly, to control pain), but pre-incisional morphine administration (0.1-10.0 mg/kg) reduced the number of cytokines found around the wound in a dose-dependent manner. The authors suggest that morphine administration in the acute post-injury period may reduce resistance to infection and may impair the healing of the wound.

Absorption and metabolism


Morphine can be taken orally, sublingually, bucally, rectally, subcutaneously
Subcutaneous injection
A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the...

, intravenously, intrathecal
Intrathecal
Intrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...

ly or epidural
Epidural
The term epidural is often short for epidural analgesia, a form of regional analgesia involving injection of drugs through a catheter placed into the epidural space...

ly and inhaled via a nebulliser. On the streets, it is becoming more common to inhale (“chasing the dragon”), but, for medical purposes, intravenous (IV) injection is the most common method of administration. Morphine is subject to extensive first-pass metabolism (a large proportion is broken down in the liver), so, if taken orally, only 40–50% of the dose reaches the central nervous system. Resultant plasma levels after subcutaneous (SC), intramuscular (IM), and IV injection are all comparable. After IM or SC injections, morphine plasma levels peak in approximately 20 minutes, and, after oral administration, levels peak in approximately 30 minutes. Morphine is metabolised primarily in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

 and approximately 87% of a dose of morphine is excreted in the urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

 within 72 hours of administration. Morphine is metabolized primarily into morphine-3-glucuronide
Morphine-3-glucuronide
Morphine-3-glucuronide is a metabolite of morphine produced by UGT2B7. It is not active as an opioid agonist, but does have some action as a convulsant, which does not appear to be mediated through opioid receptors; it is mediated by GABA/glycinergic system...

 (M3G) and morphine-6-glucuronide
Morphine-6-glucuronide
Morphine-6-glucuronide is a major active metabolite of morphine, and as such is the molecule responsible for much of the pain-relieving effects of morphine . M6G is formed from morphine by the enzyme UDP-Glucuronosyltransferase-2B7...

 (M6G) via glucuronidation
Glucuronidation
Glucuronidation is the addition of glucuronic acid to a substrate. Glucuronidation is often involved in xenobiotic metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids...

 by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7
UGT2B7
UGT2B7 is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain...

 (UGT2B7). About 60% of morphine is converted to M3G, and 6–10% is converted to M6G. The cytochrome P450 (CYP) family of enzymes involved in phase I metabolism plays a lesser role. Not only does the metabolism occur in the liver but it may also take place in the brain and the kidneys. M3G does not undergo opioid receptor binding and has no analgesic effect. M6G binds to μ-receptors and is half as potent of an analgesic than morphine in humans. Morphine may also be metabolized into small amounts of normorphine
Normorphine
Normorphine is an opiate analogue that is derived from the N-demethylated derivative of morphine first described in the 1950s when a large group of N-substituted morphine analogues were characterized for activity....

, codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...

, and hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...

. Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any), and use of other medications. The elimination half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

 of morphine is approximately 120 minutes, though there may be slight differences between men and women. Morphine can be stored in fat, and, thus, can be detectable even after death. Morphine is able to cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

, but, because of poor lipid solubility, protein binding, rapid conjugation with glucuronic acid and ionization, it does not cross easily. Diacetylmorphine, which is derived from morphine, crosses the blood-brain barrier more easily, making it more potent.

Detection in biological fluids


Morphine and its major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, may be quantitated in blood, plasma, or urine to monitor for abuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Most commercial opiate screening tests based on immunoassays cross-react appreciably with these metabolites. However, chromatographic techniques can easily distinguish and measure each of these substances. When interpreting the results of a test, it is important to consider the morphine usage history of the individual, since a chronic user can develop tolerance to 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 a hydrolysis step prior to quantitation that converts the metabolic products to morphine, yielding a result that may be many times larger than with a method that examines each product individually. Interpretation can be confounded by usage of codeine or ingestion of poppy seed foods, either of which leads to the presence of morphine and its conjugated metabolites in a person's biofluids.

Effects on human performance


Most reviews conclude that opioids produce minimal impairment of human performance on tests of sensory, motor, or attentional abilities. However, recent studies have been able to show some impairments caused by morphine, which is not surprising given that morphine is a central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...

 depressant
Depressant
A depressant, or central depressant, is a drug or endogenous compound that depresses the function or activity of a specific part of the brain...

. Morphine has resulted in impaired functioning on critical flicker frequency (a measure of overall CNS arousal) and impaired performance on the Maddox Wing test (a measure of deviation of the visual axes of the eyes). Few studies have investigated the effects of morphine on motor abilities; a high dose of morphine can impair finger tapping and the ability to maintain a low constant level of isometric force
Isometric exercise
Isometric exercise or isometrics are a type of strength training in which the joint angle and muscle length do not change during contraction...

 (i.e. fine motor control is impaired), though no studies have shown a correlation between morphine and gross motor abilities.

In terms of cognitive abilities, one study has shown that morphine may have a negative impact on anterograde
Anterograde amnesia
Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...

 and retrograde memory
Retrograde amnesia
Retrograde amnesia is a loss of access to events that occurred, or information that was learned, before an injury or the onset of a disease....

, but these effects are minimal and are transient. Overall, it seems that acute doses of opioids in non-tolerant subjects produce minor effects in some sensory and motor abilities, and perhaps also in attention
Attention
Attention is the cognitive process of paying attention to one aspect of the environment while ignoring others. Attention is one of the most intensely studied topics within psychology and cognitive neuroscience....

 and cognition. It is likely that the effects of morphine will be more pronounced in opioid-naive subjects than chronic opioid users.

In chronic opioid users, such as those on Chronic Opioid Analgesic Therapy (COAT) for managing severe, chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...

, behavioural testing has shown normal functioning on perception, cognition, coordination and behaviour in most cases. One recent study analysed COAT patients in order to determine whether they were able to safely operate a motor vehicle. The findings from this study suggest that stable opioid use does not significantly impair abilities inherent in driving (this includes physical, cognitive and perceptual skills). COAT patients showed rapid completion of tasks that require speed of responding for successful performance (e.g., Rey Complex Figure Test) but made more errors than controls. COAT patients showed no deficits in visual-spatial perception and organization (as shown in the WAIS-R
Wechsler Adult Intelligence Scale
The Wechsler Adult Intelligence Scale intelligence quotient tests are the primary clinical instruments used to measure adult and adolescent intelligence. The original WAIS was published in February 1955 by David Wechsler, as a revision of the Wechsler-Bellevue Intelligence Scale...

 Block Design Test) but did show impaired immediate and short-term visual memory (as shown on the Rey Complex Figure Test – Recall). These patients showed no impairments in higher order cognitive abilities (i.e., Planning). COAT patients appeared to have difficulty following instructions and showed a propensity toward impulsive behaviour, yet this did not reach statistical significance. It is important to note that this study reveals that COAT patients have no domain-specific deficits, which supports the notion that chronic opioid use has minor effects on psychomotor
Psychomotor
Psychomotor can refer to:* Psychomotor learning* Psychomotor retardation* Psychomotor agitation...

, cognitive, or neuropsychological functioning.

It is difficult to study the performance effects of morphine without considering why a person is taking morphine. Opioid-naive subjects are volunteers in a pain-free state. However, most chronic-users of morphine use it to manage pain. Pain is a stressor and so it can confound performance results, especially on tests that require a large degree of concentration. Pain is also variable, and will vary over time and from person to person. It is unclear to what extent the stress of pain may cause impairments, and it is also unclear whether morphine is potentiating or attenuating these impairments.

Chemistry


Morphine is a benzylisoquinoline
Benzylisoquinoline
1-Benzylisoquinoline is a chemical compound, and the structural backbone of many alkaloids with a wide variety of structures, including papaverine, noscapine, codeine, morphine, apomorphine, berberine, protopine and tubocurarine.-Biosynthesis:...

 alkaloid with two additional ring closures.

Most of the licit morphine produced is used to make codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...

 by methylation. It is also a precursor for many drugs including heroin (3,6-diacetylmorphine), hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...

 (dihydromorphinone), and oxymorphone
Oxymorphone
Oxymorphone or 14-Hydroxydihydromorphinone is a powerful semi-synthetic opioid analgesic first developed in Germany circa 1914, patented in the USA by Endo Pharmaceuticals in 1955 and introduced to the United States market in January 1959 and other countries around the same time...

 (14-hydroxydihydromorphinone). Replacement of the N-methyl group of morphine with an N-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency. Combining this modification with the replacement of the 6-hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...

 with a 6-methylene produces a compound some 1,443 times more potent than morphine, stronger than the Bentley compounds
Bentley compounds
Bentley compounds are a class of semi-synthetic opioids that were first synthesized from thebaine by K. W. Bentley. The compounds include: oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and etorphine. They represent the first series of more potent μ-opioid agonists, with...

 such as etorphine
Etorphine
Etorphine is a semi-synthetic opioid possessing an analgesic potency approximately 200 times that of morphine. It was first prepared in 1960 from oripavine, which does not generally occur in opium poppy extract but rather in "poppy straw" and in related plants, Papaver orientale and Papaver...

.

The structure-activity relationship of morphine has been extensively studied. As a result of the extensive study and use of this molecule, more than 200 morphine derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th century. These drugs range from 25 percent the strength of codeine (or slightly more than 2 percent of the strength of morphine) to several hundred times the strength of morphine, to powerful opioid antagonists, including naloxone
Naloxone
Naloxone is an opioid antagonist drug developed by Sankyo in the 1960s. Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory...

 (Narcan), naltrexone
Naltrexone
Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. It is marketed in generic form as its hydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia and Depade...

 (Trexan), and nalorphine
Nalorphine
Nalorphine trade names Lethidrone and Nalline. Nalorphine acts at two opioid receptors, at the mu receptor it has antagonistic effects and at the kappa receptors it exerts agonistic characteristics. It is used to reverse opioid overdose and in a challenge test to determine opioid dependence....

 (Nalline).

Morphine-derived agonist-antagonist drugs have also been developed. Elements of the morphine structure have been used to create completely synthetic drugs such as the morphinan
Morphinan
Morphinan is the base chemical structure of a large chemical class of psychoactive drugs, consisting of opioid analgesics, cough suppressants, and dissociative hallucinogens, among others.- Chemical Derivatives :Immediate derivatives of morphinan include:...

 family (levorphanol
Levorphanol
Levorphanol is an opioid medication used to treat severe pain. It is the levorotatory stereoisomer of the synthetic morphinan and a pure opioid agonist, first described in Germany in 1948 as an orally active morphine-like analgesic...

, dextromethorphan
Dextromethorphan
Dextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...

 and others) and other groups that have many members with morphine-like qualities. The modification of morphine and the aforementioned synthetics has also given rise to non-narcotic drugs with other uses such as emetics, stimulants, antitussives, anticholinergics, muscle relaxants, local anaesthetics, general anaesthetics, and others.

Most semi-synthetic opioids, both of the morphine and codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...

 subgroups, are created by modifying one or more of the following:
  • Halogenating or making other modifications at positions 1 and/or 2 on the morphine carbon skeleton.
  • The methyl group that makes morphine into codeine can be removed or added back, or replaced with another functional group like ethyl and others to make codeine analogues of morphine-derived drugs and vice versa. Codeine analogues of morphine-based drugs often serve as prodrugs of the stronger drug, as in codeine and morphine, hydrocodone and hydromorphone, oxycodone and oxymorphone, nicocodeine and nicomorphine, dihydrocodeine and dihydromorphine, etc.
  • Saturating, opening, or other changes to the bond between positions 7 and 8, as well as adding, removing, or modifying functional groups to these positions; saturating, reducing, eliminating, or otherwise modifying the 7-8 bond and attaching a functional group at 14 yields hydromorphinol
    Hydromorphinol
    Hydromorphinol is an opiate analogue that is a derivative of morphine, where the 14-position has been hydroxylated and the 7,8- double bond saturated. It has similar effects to morphine such as sedation, analgesia and respiratory depression, but is more potent and has a steeper dose-response curve...

    ; the oxidation of the hydroxyl group to a carbonyl and changing the 7-8 bond to single from double changes codeine into oxycodone.

  • Attachment, removal or modification of functional groups to positions 3 and/or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of moving the methyl functional group from position 3 to 6, codeine becomes heterocodeine
    Heterocodeine
    Heterocodeine is an opiate derivative, the 6-methyl ether of morphine, and a structural isomer of codeine. Heterocodeine was first synthesised in 1932, and can be made from morphine by selective methylation. Codeine is the natural mono-methyl ester, so methylated where it must be metabolized to...

    , which is 72 times stronger, and therefore six times stronger than morphine
  • Attachment of functional groups or other modification at position 14 (oxymorphone, oxycodone, naloxone)
  • Modifications at positions 2, 4, 5 or 17, usually along with other changes to the molecule elsewhere on the morphine skeleton. Often this is done with drugs produced by catalytic reduction, hydrogenation, oxidation, or the like, producing strong derivatives of morphine and codeine.


Both morphine and its hydrated form, C17H19NO3H2O, are sparingly soluble in water. In five liters of water, only one gram of the hydrate will dissolve. For this reason, pharmaceutical companies produce sulfate and hydrochloride salts of the drug, both of which are over 300 times more water-soluble than their parent molecule. Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; as a consequence, the morphine salts are mixed with small amounts of NaOH to make them suitable for injection.

A number of salts of morphine are used, with the most common in current clinical use being the hydrochloride, sulphate, tartrate, and citrate; less commonly methobromide, hydrobromide, hydroiodide, lactate, chloride, and bitartrate and the others listed below. Morphine acetate, which is another name for heroin is a Schedule I controlled substance, so it is not used clinically. Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate and some others. Like codeine, dihydrocodeine and other, especially older, opiates, morphine has been used as the salicylate salt by some suppliers and can be easily compounded, imparting the therapeutic advantage of both the opioid and the NSAID; multiple barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...

 salts of morphine were also used in the past, as was/is morphine valerate, the salt of the acid being the active principle of valerian
Valerian (herb)
Valerian is a hardy perennial flowering plant, with heads of sweetly scented pink or white flowers which bloom in the summer months. Valerian flower extracts were used as a perfume in the sixteenth century....

. Calcium morphenate is the intermediate in various latex and poppy-straw methods of morphine production. Morphine ascorbate and other salts such as the tannate, citrate, and acetate, phosphate, valerate and others may be present in poppy tea depending on the method of preparation. Morphine valerate produced industrially was one ingredient of a medication available for both oral and parenteral administration popular many years ago in Europe and elsewhere called Trivalin (not to be confused with the curremt, unrelated herbal preparation of the same name), which also included the valerates of caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...

 and cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

, with a version containing codeine valerate as a fourth ingredient being distributed under the name Tetravalin.

Closely related to morphine are the opioids morphine-N-oxide (genomorphine), which is a pharmaceutical that is no longer in common use; and pseudomorphine, an alkaloid that exists in opium, form as degradation products of morphine.

The salts listed by the United States Drug Enforcement Administration for reporting purposes, in addition to a few others, are as follows:

Production



In the opium poppy
Opium poppy
Opium poppy, Papaver somniferum, is the species of plant from which opium and poppy seeds are extracted. Opium is the source of many opiates, including morphine , thebaine, codeine, papaverine, and noscapine...

 the alkaloids are bound to meconic acid
Meconic acid
Meconic acid, also known as acidum meconicum and poppy acid, is a chemical substance found in certain plants of the Papaveraceae family such as Papaver somniferum and Papaver bracteatum. Meconic acid constitutes about 5% of opium and can be used as an analytical marker for the presence of opium...

. The method is to extract from the crushed plant with diluted sulfuric acid, which is a stronger acid than meconic acid, but not so strong to react with alkaloid molecules. The extraction
Extraction (chemistry)
Extraction in chemistry is a separation process consisting in the separation of a substance from a matrix. It may refer to Liquid-liquid extraction, and Solid phase extraction....

 is performed in many steps (one amount of crushed plant is at least six to ten times extracted, so practically every alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

 goes into the solution). From the solution obtained at the last extraction step, the alkaloids are precipitated by either ammonium hydroxide or sodium carbonate. The last step is purifying and separating morphine from other opium alkaloids. The somewhat similar Gregory process was developed in the United Kingdom during the Second World War which begins with stewing the entire plant, in most cases save the roots and leaves, in plain or mildly acidified water, then proceeding through steps of concentration, extraction, and purification of alkaloids. Other methods of processing poppy straw use steam, one or more of several types of alcohol, or other organic solvents.

The poppy straw methods predominate in Continental Europe and the British Commonwealth, with the latex method in most common use in India. The latex method can involve either vertical or horizontal slicing of the unripe pods with a two-to five-bladed knife with a guard developed specifically for this purpose to the depth of a fraction of a millimetre and scoring of the pods can be done up to five times. An alternative latex method sometimes used in China in the past is to cut off the poppy heads, run a large needle through them, and collect the dried sap 24 to 48 hours later.

Opium poppy contains at least 50 different alkaloids, but most of them are of very low concentration. Morphine is the principal alkaloid in raw opium and constitutes ~8-19% of opium
Opium
Opium is the dried latex obtained from the opium poppy . Opium contains up to 12% morphine, an alkaloid, which is frequently processed chemically to produce heroin for the illegal drug trade. The latex also includes codeine and non-narcotic alkaloids such as papaverine, thebaine and noscapine...

 by dry weight (depending on growing conditions). Some purpose-developed strains of poppy now produce opium which is up to 26 per cent morphine by weight. A rough rule of thumb to determine the morphine content of pulverised dried poppy straw is to divide the percentage expected for the strain or crop via the latex method by eight or an empirically determined factor which is often in the range of 5 to 15. The Norman strain of P. Somniferum, also developed in Tasmania, produces down to 0.04 per cent morphine but with much higher amounts of thebaine
Thebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...

 and oripavine
Oripavine
Oripavine is an opiate and the major metabolite of thebaine. It is the parent compound from which a series of semi-synthetic opioids are derived, which includes the compounds etorphine and buprenorphine...

, which can be used to synthesise semi-synthetic opioids as well as other drugs like stimulants, emetics, opioid antagonists, anticholinergics and smooth-muscle agents.

In the 1950s and 1960s, Hungary
Hungary
Hungary , officially the Republic of Hungary , is a landlocked country in Central Europe. It is situated in the Carpathian Basin and is bordered by Slovakia to the north, Ukraine and Romania to the east, Serbia and Croatia to the south, Slovenia to the southwest and Austria to the west. The...

 supplied nearly 60% of Europe's total medication-purpose morphine production. To this day, poppy farming is legal in Hungary, but poppy farms are limited by law to 2 acres (8,093.7 m²). It is also legal to sell dried poppy in flower shops for use in floral arrangements.

It was announced in 1973 that a team at the National Institutes of Health in the United States had developed a method for total synthesis of morphine, codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...

, and thebaine using coal tar as a starting material. A shortage in codeine-hydrocodone class cough suppressants (all of which can be made from morphine in one or more steps, as well as from codeine or thebaine) was the initial reason for the research.

Most morphine produced for pharmaceutical use around the world is actually converted into codeine as the concentration of the latter in both raw opium and poppy straw is much lower than that of morphine; in most countries the usage of codeine (both as end-product and precursor) is at least equal or greater than that of morphine on a weight basis and codeine is by far the most commonly-used opioid in the world. While strains of poppies have been engineered to produce much higher yields of the other useful opioid pharmaceutical precursors thebaine
Thebaine
Thebaine , its name coming from the Greek Θῆβαι, Thēbai, an ancient city in Upper Egypt, is an opiate alkaloid. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects, causing convulsions similar to strychnine...

 and oripavine
Oripavine
Oripavine is an opiate and the major metabolite of thebaine. It is the parent compound from which a series of semi-synthetic opioids are derived, which includes the compounds etorphine and buprenorphine...

, no known strain of P. somniferum will produce more codeine than morphine under most or all possible conditions. The poppy straw process of producing opioid alkaloids generally yields more codeine but an equal or somewhat smaller thebaine yield.

Extraction and detection


Morphine can be isolated from whole blood samples by solid phase extraction
Solid phase extraction
Solid-phase extraction is a separation process by which compounds that are dissolved or suspended in a liquid mixture are separated from other compounds in the mixture according to their physical and chemical properties. Analytical laboratories use solid phase extraction to concentrate and purify...

 (SPE) and detected using liquid chromatography-mass spectrometry
Liquid chromatography-mass spectrometry
Liquid chromatography–mass spectrometry is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography with the mass analysis capabilities of mass spectrometry. LC-MS is a powerful technique used for many applications which has very high...

 (LC-MS).

History


An opium-based elixir has been ascribed to alchemists
Alchemy
Alchemy is an influential philosophical tradition whose early practitioners’ claims to profound powers were known from antiquity. The defining objectives of alchemy are varied; these include the creation of the fabled philosopher's stone possessing powers including the capability of turning base...

 of Byzantine
Byzantine Empire
The Byzantine Empire was the Eastern Roman Empire during the periods of Late Antiquity and the Middle Ages, centred on the capital of Constantinople. Known simply as the Roman Empire or Romania to its inhabitants and neighbours, the Empire was the direct continuation of the Ancient Roman State...

 times, but the specific formula was supposedly lost during the Ottoman conquest of Constantinople
Constantinople
Constantinople was the capital of the Roman, Eastern Roman, Byzantine, Latin, and Ottoman Empires. Throughout most of the Middle Ages, Constantinople was Europe's largest and wealthiest city.-Names:...

 (Istanbul
Istanbul
Istanbul , historically known as Byzantium and Constantinople , is the largest city of Turkey. Istanbul metropolitan province had 13.26 million people living in it as of December, 2010, which is 18% of Turkey's population and the 3rd largest metropolitan area in Europe after London and...

). Around 1522, Paracelsus
Paracelsus
Paracelsus was a German-Swiss Renaissance physician, botanist, alchemist, astrologer, and general occultist....

 made reference to an opium-based elixir that he called laudanum from the Latin word laudare, meaning "to praise." He described it as a potent painkiller, but recommended that it be used sparingly. In the late eighteenth century, when the East India Company gained a direct interest in the opium trade through India, another opiate recipe called laudanum
Laudanum
Laudanum , also known as Tincture of Opium, is an alcoholic herbal preparation containing approximately 10% powdered opium by weight ....

 became very popular among physicians and their patients.

Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn, Germany, by Friedrich Sertürner
Friedrich Sertürner
Friedrich Wilhelm Adam Sertürner was a German pharmacist, who discovered morphine in 1804.-Biography:He was born on 19 June 1783 in Neuhaus ....

. The drug was first marketed to the general public by Sertürner and Company in 1817 as an analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

, and also as a treatment for opium and alcohol addiction. Commercial production began in Darmstadt, Germany in 1827 by the pharmacy that became the pharmaceutical company Merck, with morphine sales being a large part of their early growth.

Later it was found that morphine was more addictive than either alcohol or opium, and its extensive use during the American Civil War
American Civil War
The American Civil War was a civil war fought in the United States of America. In response to the election of Abraham Lincoln as President of the United States, 11 southern slave states declared their secession from the United States and formed the Confederate States of America ; the other 25...

 allegedly resulted in over 400,000 sufferers from the "soldier's disease" of morphine addiction. This idea has been a subject of controversy, as there have been suggestions that such a disease was in fact a fabrication; the first documented use of the phrase "soldier's disease" was in 1915.

Diacetylmorphine (better known as heroin) was synthesized from morphine in 1874 and brought to market by Bayer
Bayer
Bayer AG is a chemical and pharmaceutical company founded in Barmen , Germany in 1863. It is headquartered in Leverkusen, North Rhine-Westphalia, Germany and well known for its original brand of aspirin.-History:...

 in 1898. Heroin is approximately 1.5 to 2 times more potent than morphine weight for weight. Due to the lipid solubility of diacetylmorphine, it is able to cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

 faster than morphine, subsequently increasing the reinforcing component of addiction. Using a variety of subjective and objective measures, one study estimated the relative potency of heroin to morphine administered intravenously to post-addicts to be 1.80–2.66 mg of morphine sulfate to 1 mg of diamorphine hydrochloride (heroin).



Morphine became a controlled substance in the US
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 under the Harrison Narcotics Tax Act
Harrison Narcotics Tax Act
The Harrison Narcotics Tax Act was a United States federal law that regulated and taxed the production, importation, and distribution of opiates...

 of 1914, and possession without a prescription in the US is a criminal offense.
Morphine was the most commonly abused narcotic analgesic in the world until heroin was synthesized and came into use. Until the synthesis of dihydromorphine
Dihydromorphine
Dihydromorphine is a semi-synthetic opioid invented in Germany in 1900. In structure, it is very similar to morphine, the only difference being the reduction of the double bond between positions 7 and 8 in morphine to a single bond...

 (ca. 1900), the dihydromorphinone class of opioids (1920s), and oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...

 (1916) and similar drugs, there generally were no other drugs in the same efficacy range as opium, morphine, and heroin, with synthetics still several years away (pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...

 was invented in Germany in 1937) and opioid agonists amongst the semi-synthetics were analogues and derivatives of codeine such as dihydrocodeine
Dihydrocodeine
Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...

 (Paracodin), ethylmorphine
Ethylmorphine
Ethylmorphine is an opiate narcotic analgesic .Ethylmorphine was invented in Germany at Merck in 1884 and was used as a weaker alternative to heroin for all indications. Chemically, ethylmorphine is a morphine molecule with a -25 group substituted for the aromatic 3- group...

 (Dionine), and benzylmorphine
Benzylmorphine
Benzylmorphine is a semi-synthetic opiate narcotic introduced to the international market in 1896 and that of the United States very shortly thereafter...

 (Peronine). Even today, morphine is the most sought after prescription narcotic by heroin addicts when heroin is scarce, all other things being equal; local conditions and user preference may cause hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...

, oxymorphone
Oxymorphone
Oxymorphone or 14-Hydroxydihydromorphinone is a powerful semi-synthetic opioid analgesic first developed in Germany circa 1914, patented in the USA by Endo Pharmaceuticals in 1955 and introduced to the United States market in January 1959 and other countries around the same time...

, high-dose oxycodone, or methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...

 as well as dextromoramide
Dextromoramide
Dextromoramide is a powerful opioid analgesic approximately three times more potent than morphine but shorter acting. It is subject to drug prohibition regimes, both internationally through UN treaties, and by the criminal law of individual states...

 in specific instances such as 1970s Australia, to top that particular list. The stop-gap drugs used by the largest absolute number of heroin addicts is probably codeine, with significant use also of dihydrocodeine
Dihydrocodeine
Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...

, poppy straw derivatives like poppy pod and poppy seed tea, propoxyphene, and tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...

.

The structural formula of morphine was determined by 1925 by Robert Robinson. At least three methods of total synthesis of morphine from starting materials such as coal tar and petroleum distillates have been patented, the first of which was announced in 1952, by Dr. Marshall D. Gates, Jr.
Marshall D. Gates, Jr.
Marshall D. Gates, Jr. was an American chemist, holding the position of C.F. Houghton Professor of Chemistry at the University of Rochester. He was an organic chemist whose research was in the field of natural product synthesis. He is noted for publishing the first total synthesis of morphine in...

 at the University of Rochester
University of Rochester
The University of Rochester is a private, nonsectarian, research university in Rochester, New York, United States. The university grants undergraduate and graduate degrees, including doctoral and professional degrees. The university has six schools and various interdisciplinary programs.The...

. Still, the vast majority of morphine is derived from the opium poppy by either the traditional method of gathering latex from the scored, unripe pods of the poppy, or processes using poppy straw, the dried pods and stems of the plant, the most widespread of which was invented in Hungary in 1925 and announced in 1930 by the chemist János Kábay.

In 2003, there was discovery of endogenous morphine occurring naturally in the human body. Thirty years of speculation were made on this subject because there was a receptor that apparently only reacted to morphine: the mu3 opiate receptor
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...

 in human tissue. Human cells that form in reaction to cancerous neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...

 cells have been found to contain trace amounts of endogenous morphine.

Illicit use



The euphoria, comprehensive alleviation of distress and therefore all aspects of suffering, promotion of sociability and empathy, "body high", and anxiolysis provided by narcotic drugs including the opioids can cause the use of high doses in the absence of pain for a protracted period, which can impart a morbid craving for the drug in the user. Being the prototype of the entire opioid class of drugs means that morphine has properties that may lend it to misuse. Morphine addiction is the model upon which the current perception of addiction is based.

Animal and human studies and clinical experience back up the contention that morphine is one of the most euphoric of drugs on earth, and via all but the IV route heroin and morphine cannot be distinguished according to studies because heroin is a prodrug for the delivery of systemic morphine. Chemical changes to the morphine molecule yield other euphorigenics such as dihydromorphine
Dihydromorphine
Dihydromorphine is a semi-synthetic opioid invented in Germany in 1900. In structure, it is very similar to morphine, the only difference being the reduction of the double bond between positions 7 and 8 in morphine to a single bond...

, hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...

 (Dilaudid, Hydal) and oxymorphone
Oxymorphone
Oxymorphone or 14-Hydroxydihydromorphinone is a powerful semi-synthetic opioid analgesic first developed in Germany circa 1914, patented in the USA by Endo Pharmaceuticals in 1955 and introduced to the United States market in January 1959 and other countries around the same time...

 (Numorphan, Opana) as well as the latter three's methylated equivalents dihydrocodeine
Dihydrocodeine
Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...

, hydrocodone
Hydrocodone
Hydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from either of two naturally occurring opiates: codeine and thebaine. It is an orally active narcotic analgesic and antitussive...

 and oxycodone respectively; in addition to heroin, there are dipropanoylmorphine
Dipropanoylmorphine
Dipropanoylmorphine is an opiate derivative, the 3,6-dipropanoyl ester of morphine. It was developed in 1974 as an analgesic...

, diacetyldihydromorphine
Diacetyldihydromorphine
Diacetyldihydromorphine is a potent opiate derivative developed in Germany in 1929 which is rarely used in some countries for the treatment of severe pain such as that caused by terminal cancer, as a more potent form of diamorphine...

 and other members of the 3,6 morphine diester category like nicomorphine
Nicomorphine
Nicomorphine is the 3,6-dinicotinate ester of morphine. It is a strong opioid agonist analgesic two to three times as potent as morphine with a side effect profile similar to that of dihydromorphine, morphine, and diamorphine. Nicomorphine was patented as Vilan by Lannacher Heilmittel Ges. m.b.H...

 and other similar semi-synthetic opiates like desomorphine
Desomorphine
Desomorphine is an opiate analogue invented in 1932 in the United States that is a derivative of morphine, where the 6-hydroxyl group has been removed and the 7,8 double bond has been saturated. It has sedative and analgesic effects, and is around 8-10 times more potent than morphine...

, hydromorphinol
Hydromorphinol
Hydromorphinol is an opiate analogue that is a derivative of morphine, where the 14-position has been hydroxylated and the 7,8- double bond saturated. It has similar effects to morphine such as sedation, analgesia and respiratory depression, but is more potent and has a steeper dose-response curve...

 &c. used clinically in many countries of the world but in many cases also produced illicitly in rare instances.

Misuse of morphine generally entails taking more than prescribed or outside of medical supervision, injecting oral formulations, mixing it with unapproved potentiators such as alcohol, cocaine, and the like, and/or defeating the extended-release mechanism by chewing the tablets or turning into a powder for snorting or preparing injectables. The latter method can be every bit as time-consuming and involved as traditional methods of smoking opium. This and the fact that the liver destroys a large percentage of the drug on the first pass impacts the demand side of the equation for clandestine re-sellers, as many customers are not needle users and may have been disappointed with ingesting the drug orally. As morphine is generally as hard or harder to divert than oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...

 in a lot of cases, morphine in any form is uncommon on the street, although ampoules and phials of morphine injection, pure pharmaceutical morphine powder, and soluble multi-purpose tablets are very popular where available.

Morphine is also available in a paste which is used in the production of heroin which can be smoked by itself or turned to a soluble salt and injected; the same goes for the penultimate products of the Kompot (Polish Heroin) and black tar processes. Poppy straw as well as opium can yield morphine of purity levels ranging from poppy tea to near-pharmaceutical grade morphine by itself or with all of the more than 50 other alkaloids. It also is the active narcotic ingredient in opium and all of its forms, derivatives, and analogues as well as forming from breakdown of heroin and otherwise being present in many batches of illicit heroin as the result of incomplete acetylation.

Slang Terms


Morphine is known on the street and elsewhere as M, Number 13 (13th letter of alphabet, cf. Number 8 for heroin, Number 3 for codeine or cocaine), glad stuff, happy stuff, happy powder, white nurse, Red Cross, first line, unkie, mojo, God's Own Medicine, Vitamin M, Emma. Emmy, Lady M, white lady, cube, cube juice, mo, morf, morph, morpho, Miss Emma, mofo, hard stuff, dry grog, white hop (more accurately used for pantopon
Pantopon
Pantopon is a preparation of opiates made up of all of the alkaloids present in opium in their natural proportions as hydrochloride salts. It can sometimes be tolerated by persons who are allergic to morphine....

-type drugs), white merchandise, uncle, Uncle Morphy, big M, Murphy, morphy, coby, cobics, gold dust, monkey dust, love dust (cf. "initiative" for cocaine; more commonly used for MDA
MDA
-Companies, organizations and government bodies:* Maritime Domain Awareness, part of a U.S. Government interagency and international maritime security effort* MDA , formerly the Museum Documentation Association...

 or MDMA), needle candy (cf. nose candy for cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

; heroin, Dilaudid, Numorphan and the like are also known as such) and others.

MS Contin tablets are known as misties, and the 100 mg extended-release tablets as greys and blockbusters. The "speedball
Speedball (drug)
Speedball is a term commonly referring to the hazardous intravenous use of heroin or morphine and cocaine together in the same syringe. The speedball can also be taken by insufflation. The original speedball used cocaine hydrochloride mixed with morphine sulfate, as opposed to heroin...

" can use morphine as the narcotic component, which is combined with cocaine, amphetamines, methylphenidate
Methylphenidate
Methylphenidate is a psychostimulant drug approved for treatment of attention-deficit hyperactivity disorder, postural orthostatic tachycardia syndrome and narcolepsy. It may also be prescribed for off-label use in treatment-resistant cases of lethargy, depression, neural insult and obesity...

, or similar drugs. "Blue Velvet" is a combination of morphine with the antihistamine tripelennamine
Tripelennamine
Tripelennamine is psychoactive drug and member of the pyridine and ethylenediamine classes that is used as an antipruritic and first-generation antihistamine...

 (Pyrabenzamine, PBZ, Pelamine) taken by injection, or less commonly the mixture when swallowed or used as a retention enema; the name is also known to refer to a combination of tripelennamine and dihydrocodeine or codeine tablets or syrups taken by mouth. "Morphia" is an older official term for morphine also used as a slang term. "Driving Miss Emma" is intravenous administration of morphine. Multi-purpose tablets (readily-soluble hypodermic tablets which can also be swallowed or dissolved under the tongue or betwixt the cheek and jaw) are known, as are some brands of hydromorphone, as Shake & Bake or Shake & Shoot.

Morphine can be smoked, especially morphine diacetate (heroin), the most common method being the "Chasing The Dragon" method. To perform a relatively crude acetylation to turn the morphine into heroin and related drugs immediately prior to use is known as AAing (for Acetic Anhydride) or home-bake, and the output of the procedure also known as home-bake or, Blue Heroin (not to be confused with Blue Magic heroin, nor the linctus known as Blue Morphine or Blue Morphone, nor the Blue Velvet mixture described above.

Trade names


Morphine is marketed
Marketing
Marketing is the process used to determine what products or services may be of interest to customers, and the strategy to use in sales, communications and business development. It generates the strategy that underlies sales techniques, business communication, and business developments...

 under many different brand names in various parts of the world:

Pharmaceutical


Morphine is a precursor in the manufacture in a large number of opioids such as dihydromorphine
Dihydromorphine
Dihydromorphine is a semi-synthetic opioid invented in Germany in 1900. In structure, it is very similar to morphine, the only difference being the reduction of the double bond between positions 7 and 8 in morphine to a single bond...

, hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...

, nicomorphine
Nicomorphine
Nicomorphine is the 3,6-dinicotinate ester of morphine. It is a strong opioid agonist analgesic two to three times as potent as morphine with a side effect profile similar to that of dihydromorphine, morphine, and diamorphine. Nicomorphine was patented as Vilan by Lannacher Heilmittel Ges. m.b.H...

, and heroin as well as codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...

, which itself has a large family of semi-synthetic derivatives. Morphine is commonly treated with acetic anhydride
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...

 and ignited to yield heroin.
Throughout Europe there is growing acceptance within the medical community of the use of slow release oral morphine as a substitution treatment alternative to methadone and buprenorphine for patients who cannot tolerate the side effects of buprenorphine and methadone. Slow release oral morphine has been in widespread use for opiate maintenance therapy in Austria, Bulgaria, and Slovakia for many years and it is available on a small scale in many other countries including the UK. The long acting nature of slow release morphine mimics that of buprenorphine because the sustained blood levels are relatively flat so there is no "high" per se that a patient would feel but rather a sustained feeling of wellness and avoidance of withdrawal symptoms. For patients sensitive to the side effects that in part may be a result of the unnatural pharmacological actions of buprenorphine and methadone, slow release oral morphine formulations offer a promising future for use managing opiate addiction.
The pharmacology of heroin and morphine is identical except the two acetyl
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...

 groups increase the lipid solubility of the heroin molecule, causing heroin to cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

 and enter the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

 more rapidly in injection. Once in the brain, these acetyl groups are removed to yield morphine, which causes the subjective effects of heroin. Thus, heroin may be thought of as a more rapidly acting form of morphine.

Illicit


Illicit morphine is rarely produced from codeine found in over the counter cough and pain medicines. This demethylation reaction is often performed using pyridine and hydrochloric acid.

Another source of illicit morphine comes from the extraction of morphine from extended release morphine products, such as MS-Contin. Morphine can be extracted from these products with simple extraction techniques to yield a morphine solution that can be injected. Alternatively, the tablets can be crushed and snorted, injected or swallowed, although this provides much less euphoria but retains some of the extended-release effect, and the extended-release property is why MS-Contin is used in some countries alongside methadone
Methadone
Methadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...

, dihydrocodeine
Dihydrocodeine
Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...

, buprenorphine
Buprenorphine
Buprenorphine is a semi-synthetic opioid that is used...

, dihydroetorphine
Dihydroetorphine
Dihydroetorphine was developed by K.W.Bentley at McFarlan-Smith in the 1960s and is a potent analgesic drug , which is used mainly in China...

, piritramide
Piritramide
Piritramide is a synthetic opioid analgesic with a potency 0.65 to 0.75 times that of morphine. A common starting dose is 15 mg IV, equivalent to 10 mg of morphine hydrochloride. Piritramide is commonly used for the treatment of postoperative pain...

, levo-alpha-acetylmethadol
Levacetylmethadol
Levacetylmethadol , levomethadyl acetate , Orlaam or levo-α-acetylmethadol is a synthetic opioid similar in structure to methadone. It has a long duration of action due to its active metabolites. It was approved in 1993 by the U.S. Food and Drug Administration for use in the treatment of opioid...

 (LAAM
Lââm
Lââm is a French female singer of Tunisian descent. She has sold more than 500,000 albums and more than 2 million singles.-Biography:...

) and special 24-hour formulations of hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...

 for maintenance and detoxification of those physically dependent on opioids.

Another means of using or misusing morphine is to use chemical reactions to turn it into heroin or another stronger opioid. Morphine can, using a technique reported in New Zealand (where the initial precursor is codeine) and elsewhere known as home-bake, be turned into what is usually a mixture of morphine, heroin, 3-monoacetylmorphine, 6-monoacetylmorphine, and codeine derivatives like acetylcodeine if the process is using morphine made from demethylating codeine by mixing acetic anhydride or acetyl chloride with the morphine and cooking it in an oven between 80 and 85°C for several hours.

Since heroin is one of a series of 3,6 diesters of morphine, it is possible to convert morphine to nicomorphine
Nicomorphine
Nicomorphine is the 3,6-dinicotinate ester of morphine. It is a strong opioid agonist analgesic two to three times as potent as morphine with a side effect profile similar to that of dihydromorphine, morphine, and diamorphine. Nicomorphine was patented as Vilan by Lannacher Heilmittel Ges. m.b.H...

 (Vilan) using nicotinic anhydride, dipropanoylmorphine
Dipropanoylmorphine
Dipropanoylmorphine is an opiate derivative, the 3,6-dipropanoyl ester of morphine. It was developed in 1974 as an analgesic...

 with propionic anhydride, dibutanoylmorphine and disalicyloylmorphine with the respective acid anhydrides. Glacial acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...

 can be used to obtain a mixture high in 6-monoacetylmorphine, nicotinic acid (vitamin B3) in some form would be precursor to 6-nicotinylmorphine, salicylic acid may yield the salicyoyl analogue of 6-MAM, and so on.

Homebake or other clandestinely-produced heroin produced from extended-release morphine tablets may be known as Blue Heroin because of the blue colour of some of these tablets, even though the coloured coating of the tablet is usually removed before processing, many strengths of the tablets are not blue, bluish or a related colour like purple, and the final product tends not to be blue. A writer of a 2006 description of producing heroin from 100 mg as well as some 30 and 15 mg MS-Contin type tablets coined the term Blue Heroin to distinguish his, her or their product from New Zealand-style homebake as the process was shorter and began with uncoated tablets which in the case of the 100 mg tablet was at or above 35 per cent morphine sulphate by weight, resulting in a final liquid injectable which was brown-purple and quite potent. The drugs present in the final product are limited to heroin, 6-monoacetylmorphine, 3-monoacetylmorphine, and morphine, with the 6-MAM being just as or more sought after than the heroin for reasons elucidated in the Wikipedia heroin article.

The clandestine conversion of morphine to ketones of the hydromorphone class or other derivatives like dihydromorphine
Dihydromorphine
Dihydromorphine is a semi-synthetic opioid invented in Germany in 1900. In structure, it is very similar to morphine, the only difference being the reduction of the double bond between positions 7 and 8 in morphine to a single bond...

 (Paramorfan), desomorphine
Desomorphine
Desomorphine is an opiate analogue invented in 1932 in the United States that is a derivative of morphine, where the 6-hydroxyl group has been removed and the 7,8 double bond has been saturated. It has sedative and analgesic effects, and is around 8-10 times more potent than morphine...

 (Permonid), metopon
Metopon
Metopon is an opiate analogue that is a methylated derivative of hydromorphone which was invented in 1948 as an analgesic....

 &c. and codeine to hydrocodone
Hydrocodone
Hydrocodone or dihydrocodeinone is a semi-synthetic opioid derived from either of two naturally occurring opiates: codeine and thebaine. It is an orally active narcotic analgesic and antitussive...

 (Dicodid), dihydrocodeine
Dihydrocodeine
Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...

 (Paracodin) &c. is more involved, time consuming, requires lab equipment of various types, and usually requires expensive catalysts and large amounts of morphine at the outset and is less common but still has been discovered by authorities in various ways during the last 20 years or so. Dihydromorphine can be acetylated into another 3,6 morphine diester, namely diacetyldihydromorphine
Diacetyldihydromorphine
Diacetyldihydromorphine is a potent opiate derivative developed in Germany in 1929 which is rarely used in some countries for the treatment of severe pain such as that caused by terminal cancer, as a more potent form of diamorphine...

 (Paralaudin), and hydrocodone into thebacon.

Legal classification

  • In the United Kingdom
    United Kingdom
    The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

    , morphine is listed as a Class A drug under the Misuse of Drugs Act 1971
    Misuse of Drugs Act 1971
    The Misuse of Drugs Act 1971 is an Act of Parliament which represents UK action in line with treaty commitments under the Single Convention on Narcotic Drugs, the Convention on Psychotropic Substances, and the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic...

     and a Schedule 2 Controlled Drug under The Misuse of Drugs Regulations 2001.
  • In the United States
    United States
    The United States of America is a federal constitutional republic comprising fifty states and a federal district...

    , morphine is classified as a Schedule II drug under the Controlled Substances Act
    Controlled Substances Act
    The Controlled Substances Act was enacted into law by the Congress of the United States as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the federal U.S. drug policy under which the manufacture, importation, possession, use and distribution of certain...

    .
  • In Canada
    Canada
    Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...

    , morphine is classified as a Schedule I drug under the Controlled Drugs and Substances Act
    Controlled Drugs and Substances Act
    The Controlled Drugs and Substances Act is Canada's federal drug control statute. Passed in 1996 by the Chrétien government, it repeals the Narcotic Control Act and Parts III and IV of the Food and Drug Act and establishes eight Schedules of controlled substances and two Classes of precursors...

    .
  • In Australia
    Australia
    Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...

    , morphine is classified as a Schedule 8 drug under the variously titled State and Territory Poisons Acts.
  • In the Netherlands
    Netherlands
    The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...

    , morphine is classified as a List 1 drug under the Opium Law
    Opium Law
    The Opium Law is the section of the Dutch law which covers nearly all psychotropic drugs. All non-psychotropic, but prescription-only drugs are covered by the Medicine Act.- Origin and history :...

    .
  • In Japan
    Japan
    Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...

    , morphine is classified as a narcotic under the Narcotics and Psychotropics Control Act.
  • Internationally, morphine is a Schedule I drug under the Single Convention on Narcotic Drugs
    Single Convention on Narcotic Drugs
    The Single Convention on Narcotic Drugs of 1961 is an international treaty to prohibit production and supply of specific drugs and of drugs with similar effects except under licence for specific purposes, such as medical treatment and research...

    .

Access in developing countries


Although morphine is cheap, people in poorer countries often do not have access to it. According to a 2005 estimate by the International Narcotics Control Board
International Narcotics Control Board
The International Narcotics Control Board is the independent and quasi-judicial control organ for the implementation of the United Nations drug conventions...

, six countries (Australia, Britain, Canada, France, Germany, and the United States) consume 79 percent of the world’s morphine. The less affluent countries, accounting for 80 percent of the world's population, consumed only about 6 percent of the global morphine supply. Some countries import virtually no morphine, and in others the drug is rarely available even for relieving severe pain while dying.

Experts in pain management attribute the under-distribution of morphine to an unwarranted fear of the drug's potential for addiction and abuse. While morphine is clearly addictive, Western doctors believe it is worthwhile to use the drug and then wean the patient off when the treatment is over.

See also



  • Drug addiction
  • Drug injection
    Drug injection
    In substance dependence and recreational drug use, drug injection is a method of introducing a drug into the body with a hollow needle and a syringe which is pierced through the skin into the body...

  • Illegal drug trade
    Illegal drug trade
    The illegal drug trade is a global black market, dedicated to cultivation, manufacture, distribution and sale of those substances which are subject to drug prohibition laws. Most jurisdictions prohibit trade, except under license, of many types of drugs by drug prohibition laws.A UN report said the...

  • Morphine (data page)
    Morphine (data page)
    - Structure and properties :...

  • Morphine total synthesis
    Morphine total synthesis
    Morphine total synthesis in chemistry describes the total synthesis of the alkaloid morphine. The first synthesis by Marshall D. Gates, Jr. in 1952 is considered a classic in the field....

  • Opioid
    Opioid
    An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...

  • Opium
    Opium
    Opium is the dried latex obtained from the opium poppy . Opium contains up to 12% morphine, an alkaloid, which is frequently processed chemically to produce heroin for the illegal drug trade. The latex also includes codeine and non-narcotic alkaloids such as papaverine, thebaine and noscapine...

  • Opium licensing
    Opium licensing
    Opium licensing is a policy instrument used to counter illegal drug cultivation and production. It has been used in countries such as Turkey and India to curb illegal opium production...

  • Opium poppy
    Opium poppy
    Opium poppy, Papaver somniferum, is the species of plant from which opium and poppy seeds are extracted. Opium is the source of many opiates, including morphine , thebaine, codeine, papaverine, and noscapine...

  • Polish heroin
    Polish heroin
    Polish heroin is a crude preparation of heroin made from poppy straw. Like heroin derived from opium, it is an addictive opiate psychoactive drug, used recreationally. Poppy straw and opium are both harvested from the opium poppy...

  • Psychoactive drug
    Psychoactive drug
    A psychoactive drug, psychopharmaceutical, or psychotropic is a chemical substance that crosses the blood–brain barrier and acts primarily upon the central nervous system where it affects brain function, resulting in changes in perception, mood, consciousness, cognition, and behavior...

  • Recreational drug use
    Recreational drug use
    Recreational drug use is the use of a drug, usually psychoactive, with the intention of creating or enhancing recreational experience. Such use is controversial, however, often being considered to be also drug abuse, and it is often illegal...



External links