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an alkaloid narcotic drug extracted from opium; a powerful, habit-forming narcotic used to relieve pain (同)morphia
a complex consisting of an organic base in association with hydrogen chloride

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モルヒネ(鎮痛・麻酔剤)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/11/17 19:39:37」(JST)

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Morphine (INN) (/ˈmɔrfiːn/) (sold under nearly a hundred trade names) is an opioid analgesic drug, and the main psychoactive chemical in opium. In clinical medicine, morphine is regarded as the gold standard of analgesics used to relieve intense pain. Like other opioids, such as oxycodone, hydromorphone, and diacetylmorphine (heroin), morphine acts directly on the central nervous system (CNS) to relieve pain.

Morphine has a high potential for addiction; tolerance and psychological dependence develop rapidly, although physiological dependence may take several months to develop. Tolerance to respiratory depression and euphoria develops more rapidly than tolerance to analgesia, and many chronic pain patients are therefore maintained on a stable dose for years. However, its effects can also reverse fairly rapidly, worsening pain through hyperalgesia.

Morphine is the most abundant opiate found in opium, the dried latex from unripe seedpods of Papaver somniferum (the opium poppy). Morphine was the first active ingredient purified from a plant source. It is one of at least 50 alkaloids of several different types present in opium, poppy straw concentrate, and other poppy derivatives. The primary source of morphine is chemical extraction from opium.

Morphine was first isolated in 1804 by Friedrich Sertürner, which is generally believed to be the first ever isolation of a natural plant alkaloid in history. Sertürner began distributing it in 1817, and Merck began marketing it commercially in 1827. At the time, Merck was a single small chemists' shop. Morphine was more widely used after the invention of the hypodermic syringe in 1857. Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus (Greek: Μορφεύς), for its tendency to cause sleep.^[2] It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.^[3]

1 Medical uses
2 Side effects
- 2.1 Constipation
- 2.2 Addiction
- 2.3 Tolerance
- 2.4 Withdrawal
- 2.5 Hormone imbalance
- 2.6 Overdose
3 Contraindications
4 Pharmacodynamics
- 4.1 Gene expression
- 4.2 Effects on the immune system
5 Pharmacokinetics
- 5.1 Absorption and metabolism
- 5.2 Detection in biological fluids
6 Effects on human performance
7 Natural sources
8 Chemistry
- 8.1 Biosynthesis
- 8.2 Synthesis
- 8.3 Production
9 Precursor to other opioids
- 9.1 Pharmaceutical
- 9.2 Illicit
10 History
11 Society and culture
- 11.1 Legal classification
- 11.2 Illicit use
- 11.3 Slang terms
- 11.4 Trade names
- 11.5 Access in developing countries
12 See also
13 References
14 External links

Medical uses

Morphine is primarily used to treat both acute and chronic severe pain. It is also used for pain due to myocardial infarction and for labor pains.^[4] However, concerns exist that morphine may increase mortality in the setting of non ST elevation myocardial infarction.^[5] Morphine has also traditionally been used in the treatment of acute pulmonary edema.^[4] A 2006 review, though, found little evidence to support this practice.^[6]

Immediate-release morphine is beneficial in reducing the symptom of acute shortness of breath due to both cancer and noncancer causes.^[7]^[8] In the setting of breathlessness at rest or on minimal exertion from conditions such as advanced cancer or end-stage cardiorespiratory diseases, regular, low-dose sustained-release morphine significantly reduces breathlessness safely, with its benefits maintained over time.^[9]^[10]

Its duration of analgesia is about 3–4 hours when administered via the intravenous, subcutaneous, or intramuscular routes and 3–6 hours when given by mouth.^[11] 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.^[12]

Side effects

A localized reaction to intravenous morphine caused by histamine release in the veins

Constipation

Like loperamide 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 receptors in the bowel. By inhibiting gastric emptying and reducing propulsive peristalsis 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 generation.^[13] This effect was shown in animals when a nitric oxide precursor, L-Arginine, reversed morphine-induced changes in gut motility.^[14]

Addiction

Morphine is a potentially highly addictive substance. It can cause psychological dependence and physical dependence as well as tolerance. 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.

In controlled studies comparing the physiological and subjective effects of 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.^[15] 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, fentanyl, oxycodone, and pethidine/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.^[15] The choice of heroin and morphine over other opioids by former drug addicts may also be because heroin (also known as morphine diacetate, diamorphine, or diacetyl morphine) is an ester of morphine and a morphine prodrug, essentially meaning they are identical drugs in vivo. Heroin is converted to morphine before binding to the opioid receptors in the brain and spinal cord, where morphine causes the subjective effects, which is what the addicted individuals are seeking.^[16]

Other studies, such as the Rat Park experiments, suggest that morphine is less physically addictive than others suggest, and most studies on morphine addiction show that "severely distressed animals, like severely distressed people, will relieve their distress pharmacologically if they can."^[17] In these studies, rats with a morphine "addiction" overcome their addiction 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 may decrease morphine addiction in mice.^[18]

Tolerance

Tolerance to the analgesic effects of morphine is fairly rapid.^{[citation needed]} Several hypotheses are given about how tolerance develops, including opioid receptor phosphorylation (which would change the receptor conformation), functional decoupling of receptors from G-proteins (leading to receptor desensitization),^[19] 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 pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.^[20]) CCK might mediate some counter-regulatory pathways responsible for opioid tolerance. CCK-antagonist drugs, specifically proglumide, 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, or sedative-hypnotics, is not fatal by itself in neurologically healthy patients without heart or lung problems.

Acute morphine withdrawal, along with that of any other opioid, 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^{[by whom?]}, they are:

Stage I, 6 to 14 hours after last dose: Drug craving, anxiety, irritability, perspiration, and mild to moderate dysphoria
Stage II, 14 to 18 hours after last dose: Yawning, heavy perspiration, mild depression, lacrimation, crying, runny nose, dysphoria, also intensification of the above symptoms, "yen sleep" (a waking trance-like state) ^{[clarification needed]}
Stage III, 16 to 24 hours after last dose: Rhinorrhea (runny nose) and increase in other of the above, dilated pupils, piloerection (goose bumps - giving the name 'cold turkey'), muscle twitches, hot flashes, cold flashes, aching bones and muscles, loss of appetite, and the beginning of intestinal cramping
Stage IV, 24 to 36 hours after last dose: Increase in all of the above including severe cramping and involuntary leg movements ("kicking the habit" also called restless leg syndrome), loose stool, insomnia, elevation of blood pressure, moderate elevation in body temperature, increase in frequency of breathing and tidal volume, tachycardia (elevated pulse), restlessness, nausea
Stage V, 36 to 72 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, weight loss of 2 to 5 kg per 24 hours, increased white cell count, and other blood changes
Stage VI, after completion of above: Recovery of appetite and normal bowel function, beginning of transition to postacute and chronic symptoms that are mainly psychological, but may also include increased sensitivity to pain, hypertension, colitis or other gastrointestinal afflictions related to motility, and problems with weight control in either direction

In advanced stages of withdrawal, ultrasonographic evidence of pancreatitis has been demonstrated in some patients and is presumably attributed to spasm of the pancreatic sphincter of Oddi.^[21]

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 6–12 hours) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning, dysphoria, 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 ome progresses. Severe depression and vomiting are very common. During the acute withdrawal period, systolic and diastolic blood pressures increase, usually beyond premorphine levels, and heart rate increases,^[22] 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"^[16]) and excessive sweating are also characteristic symptoms.^[23] 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.^[24]^[25]

The psychological dependence associated with morphine addiction 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 usually a very long and painful process.^[26]^{[unreliable medical source]} 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. A high probability of relapse exists 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% in the estimation of some medical experts.^[27]

Hormone imbalance

Clinical studies consistently conclude, like other opioids, morphine often causes hypogonadism and hormone imbalances in chronic users of both genders. This side effect is dose-dependent and occurs in both therapeutic and recreational users. Morphine can interfere with menstruation in women by suppressing levels of luteinizing hormone. Many studies suggest the majority (perhaps as much as 90%) of chronic opioid users have opioid-induced hypogonadism. This effect may cause the increased likelihood of osteoporosis and bone fracture observed in chronic morphine users. Studies suggest the effect is temporary. As of 2013^[update], the effect of low-dose or acute use of morphine on the endocrine system is unclear.^[28]^[29]

Overdose

A large overdose can cause asphyxia and death by respiratory depression if the person does not receive medical attention immediately.^[30] Overdose treatment includes the administration of naloxone. The latter completely reverses morphine's effects, but precipitates immediate onset of withdrawal in opiate-addicted subjects. Multiple doses may be needed.^[30]

The minimum lethal dose is 200 mg, but in case of hypersensitivity, 60 mg can bring sudden death. In serious drug dependency (high tolerance), 2000–3000 mg per day can be tolerated.^[31]

Contraindications

These conditions are relative contraindications for morphine:

acute respiratory depression
renal failure (due to accumulation of the metabolites morphine-3-glucuronide and morphine-6-glucuronide)
chemical toxicity (potentially lethal in low-tolerance subjects)
raised intracranial pressure, including head injury (risk of worsening respiratory depression)
Biliary colic.^[32]

Although it has previously been thought that morphine was contraindicated in acute pancreatitis, a review of the literature shows no evidence for this.^[33]

Pharmacodynamics

Endogenous opioids include endorphins, enkephalins, dynorphins, 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–δ-opioid receptor heteromer.^[34]^[35] The μ-binding sites are discretely distributed in the human brain, with high densities in the posterior amygdala, hypothalamus, thalamus, nucleus caudatus, putamen, and certain cortical areas. They are also found on the terminal axons of primary afferents within laminae I and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of the trigeminal nerve.^[36]

Morphine is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the μ-opioid receptors in the central nervous system. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Activation of the μ-opioid receptors is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is a rapid-acting narcotic, and it is known to bind very strongly to the μ-opioid 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 and δ-opioid receptor agonist, κ-opioid's action is associated with spinal analgesia, miosis (pinpoint pupils) and psychotomimetic effects. δ-opioid is thought to play a role in analgesia.^[36] Although morphine does not bind to the σ-receptor, it has been shown that σ-agonists, such as (+)-pentazocine, inhibit morphine analgesia, and σ-antagonists enhance morphine analgesia,^[37] suggesting some interaction between morphine and the σ-opioid receptor.

The effects of morphine can be countered with opioid antagonists such as naloxone and naltrexone; the development of tolerance to morphine may be inhibited by NMDA antagonists such as ketamine or dextromethorphan.^[38] 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, ketobemidone, piritramide, and methadone 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.

Gene expression

Studies have shown that morphine can alter the expression of a number of genes. 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-related proteins.^[39]

Effects on the immune system

Morphine has long been known to act on receptors expressed on cells of the central nervous system 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, tuberculosis, and HIV) led scientists to believe that morphine may also affect the immune system. 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 cytokines, 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).^[40]

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 (toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide). This causes the p38 MAPK to be phosphorylated. This phosphorylation activates the p38 MAPK 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.

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), 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 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.^[41]

Pharmacokinetics

Absorption and metabolism

Morphine can be taken orally, sublingually, bucally, rectally, subcutaneously, intranasally, intravenously, intrathecally or epidurally and inhaled via a nebulizer. 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.^[42] Morphine is metabolised primarily in the liver and approximately 87% of a dose of morphine is excreted in the urine within 72 hours of administration. Morphine is metabolized primarily into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)^[43] via glucuronidation by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7). About 60% of morphine is converted to M3G, and 6–10% is converted to M6G.^[44] 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 an analgesic as morphine in humans.^[44] Morphine may also be metabolized into small amounts of normorphine, codeine, and hydromorphone. Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any), and use of other medications. The elimination half-life 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 can cross the blood–brain barrier, 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.^[45]

There are also slow-release formulations of orally administered morphine whose effect last substantially longer than bare morphine, availing for e.g. one administration per day.

Detection in biological fluids

Morphine and its major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, can be detected in blood, plasma, hair, and urine using an immunoassay. Chromatography can be used to test for each of these substances individually. Some testing procedures hydrolyze metabolic products into morphine before the immunoassay, which must be considered when comparing morphine levels in separately published results. Morphine can also be isolated from whole blood samples by solid phase extraction (SPE) and detected using liquid chromatography-mass spectrometry (LC-MS).

Ingestion of codeine or food containing poppy seeds can cause false positives.^[46]

A 1999 review estimated that relatively low doses of heroin (which metabolizes immediately into morphine) are detectable by standard urine tests for 1-1.5 days after use.^[47] A 2009 review determined that, when the analyte is morphine and the limit of detection is 1 ng/ml, a 20 mg intravenous (IV) dose of morphine is detectable for 12–24 hours. A limit of detection of 0.6 ng/ml had similar results.^[48]

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 depressant. 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 (i.e. fine motor control is impaired),^[49] 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 and retrograde memory,^[50] but these effects are minimal and 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 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, behavioural testing has shown normal functioning on perception, cognition, coordination and behaviour in most cases. One recent study^[51] analysed COAT patients 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 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, 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.

Natural sources

A freshly-scored opium poppy seedpod bleeding latex.

Morphine is the most abundant opiate found in opium, the dried latex extracted by shallowly scoring the unripe seedpods of the Papaver somniferum poppy. 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, and other poppy derivatives. Morphine is generally 8-14% of the dry weight of opium,^[52] although specially bred cultivars reach 26% or produce little morphine at all (under 1%, perhaps down to 0.04%). The latter varieties, including the 'Przemko' and 'Norman' cultivars of the opium poppy, are used to produce two other alkaloids, thebaine and oripavine, which are used in the manufacture of semi-synthetic and synthetic opioids like oxycodone and etorphine and some other types of drugs. P. bracteatum does not contain morphine or codeine, or other narcotic phenanthrene-type, alkaloids. This species is rather a source of thebaine.^[53] Occurrence of morphine in other Papaverales and Papaveraceae, as well as in some species of hops and mulberry 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, thebaine, and in some cases negligible amounts of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydro-thebaine, and hydrocodone (these compounds are rather synthesized from thebaine and oripavine). The human body produces endorphins,^[54] which are endogenous opioid peptides that function as neurotransmitters and have similar effects.^[55]

Chemistry

Chemical structure of morphine. The benzylisoquinoline backbone is shown in green.

Same structure with correct 3D configuration; backbone in blue.

Morphine is a benzylisoquinoline alkaloid with two additional ring closures. It has:

A rigid pentacyclic structure consisting of a benzene ring (A), two partially unsaturatedcyclohexane rings (B and C), a piperidine ring (D) and a tetrahydrofuran ring (E). Rings A, B and C are the phenanthrene ring system. This ring system has little conformational flexibility.
Two hydroxyl functional groups: a C3-phenolic OH (pKa 9.9) and a C6-allylic OH
An ether linkage between C4 and C5,
Unsaturation between C7 and C8,
A basic, 3o-amine function at position 17,
5 centers of chirality (C5, C6, C9, C13 and C14) with morphine exhibiting a high degree of stereoselectivity of analgesic action.^[56]

Most of the licit morphine produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone); many morphine derivatives can also be manufactured using thebaine and/or codeine as a starting material. 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 with a 6-methylene group produces a compound some 1,443 times more potent than morphine, stronger than the Bentley compounds such as etorphine (M99, the Immobilon® tranquilliser dart) by some measures.

The structure-activity relationship of morphine has been extensively studied. As a result of the extensive study and use of this molecule, more than 250 morphine derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th century. These drugs range from 25% the analgesic strength of codeine (or slightly more than 2% of the strength of morphine) to several thousand times the strength of morphine, to powerful opioid antagonists, including naloxone (Narcan®), naltrexone (Trexan®), diprenorphine (M5050, the reversing agent for the Immobilon® dart) and nalorphine (Nalline®). Some opioid agonist-antagonists, partial agonists, and inverse agonists are also derived from morphine. The receptor-activation profile of the semi-synthetic morphine derivatives varies widely and some, like apomorphine are devoid of narcotic effects.

Morphine and most of its derivatives do not exhibit optical isomerism, although some more distant relatives like the morphinan series (levorphanol, dextorphan and the racemic parent chemical dromoran) do, and as noted above stereoselectivity in vivo is an important issue.

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 family (levorphanol, dextromethorphan 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 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; 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, 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.

Structure and properties

Molar Mass^[57]

285.338 g/mol

Index of refraction, n_D

?

Acidity (pKa)^[57]

Step 1: 8.21	at 25 °C
Step 2: 9.85	at 20 °C

Solubility^[57]

0.15 g/L at 20 °C

Melting Point^[57]

255 °C

Boiling Point^[57]

190 °C sublimes

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.^[58]

A number of salts of morphine are used, with the most common in current clinical use being the hydrochloride, sulfate, tartrate, and citrate; less commonly methobromide, hydrobromide, hydroiodide, lactate, chloride, and bitartrate and the others listed below. Morphine diacetate, which is another name for heroin, is a Schedule I controlled substance, so it is not used clinically in the United States; it is a sanctioned medication in the United Kingdom and in Canada and some countries in Continental Europe, its use being particularly common (nearly to the degree of the hydrochloride salt) in the United Kingdom. Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate, sulphate, 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 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. Calcium morphenate is the intermediate in various latex and poppy-straw methods of morphine production, more rarely sodium morphenate takes its place. 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 current, unrelated herbal preparation of the same name), which also included the valerates of caffeine and cocaine, 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:

Select forms of morphine as 'morphiniums' or N-protonated cations of morphine, i.e. ionic salts & chemical form with freebase conversion ratios: Click to

Salt or drug	CSA schedule	ACSCN	Free base conversion ratio
Morphine (base)	II	9300	1
Morphine citrate	II	9300	0.81
Morphine bitartrate	II	9300	0.66
Morphine stearate	II	9300	0.51
Morphine phthalate	II	9300	0.89
Morphine hydrobromide	II	9300	0.78
Morphine hydrobromide (2 H₂O)	II	9300	0.71
Morphine hydrochloride	II	9300	0.89
Morphine hydrochloride (3 H₂O)	II	9300	0.76
Morphine acetate	II	9300	0.71
Morphine hydriodide (2 H₂O)	II	9300	0.64
Morphine lactate	II	9300	0.76
Morphine monohydrate	II	9300	0.94
Morphine meconate (5 H₂O)	II	9300	0.66
Morphine mucate	II	9300	0.57
Morphine nitrate	II	9300	0.82
Morphine phosphate (1/2 H₂O)	II	9300	0.73
Morphine phosphate (7 H₂O)	II	9300	0.73
Morphine salicylate	II	9300
Morphine phenylpropionate	II	9300	0.65
Morphine methyliodide	II	9300	0.67
Morphine isobutyrate	II	9300	0.76
Morphine hypophosphite	II	9300	0.81
Morphine sulfate (5 H₂O)	II	9300	0.75
Morphine tannate	II	9300
Morphine tartrate (3 H₂O)	II	9300	0.74
Morphine valerate	II	9300	0.74
Morphine diacetate	I	9200	0.74
Morphine methylbromide	I	9305	0.75
Morphine methylsulfonate	I	9306	0.75
Morphine-N-oxide	I	9307	1
Morphine-N-oxide quinate	I	9307	0.60
Pseudomorphine	I	not mentioned

Biosynthesis

The morphine is biosynthesized from the tetrahydroisoquinoline reticuline. It is converted into salutaridine, thebaine, and oripavine. The involucrated enzymes in this process are the salutaridine synthase, salutaridine:NADPH 7-oxidoreductase and the codeinone reductase.^[59]

Synthesis

The first morphine total synthesis, devised by Marshall D. Gates, Jr. in 1952, remains a widely used example of total synthesis.^[60] Several other syntheses were reported, notably by the research groups of Rice,^[61] Evans,^[62] Fuchs,^[63] Parker,^[64] Overman,^[65] Mulzer-Trauner,^[66] White,^[67] Taber,^[68] Trost,^[69] Fukuyama,^[70] Guillou,^[71] and Stork.^[72]

Production

In the opium poppy the alkaloids are bound to meconic acid. 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 is performed in many steps (one amount of crushed plant is extracted at least six to ten times, so practically every alkaloid 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.^{[citation needed]} Other methods of processing "poppy straw" (i.e., dried pods and stalks) 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 latex 24 to 48 hours later.^{[citation needed]}

In India, opium harvested by licensed poppy farmers is dehydrated to uniform levels of hydration at government processing centers, and then sold to pharmaceutical companies that extract morphine from the opium. However, in Turkey and Tasmania, morphine is obtained by harvesting and processing the fully mature dry seed pods with attached stalks, called poppy straw. In Turkey, a water extraction process is used, while in Tasmania, a solvent extraction process is used.^{[citation needed]}

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 by dry weight (depending on growing conditions).^[45] Some purpose-developed strains of poppy now produce opium that is up to 26% morphine by weight.^{[citation needed]} 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.^{[citation needed]} The Norman strain of P. Somniferum, also developed in Tasmania, produces down to 0.04% morphine but with much higher amounts of thebaine and oripavine, which can be used to synthesise semi-synthetic opioids as well as other drugs like stimulants, emetics, opioid antagonists, anticholinergics, and smooth-muscle agents.^{[citation needed]}

In the 1950s and 1960s, Hungary 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 (8,100 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, 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.

Precursor to other opioids

Pharmaceutical

Morphine is a precursor in the manufacture in a large number of opioids such as dihydromorphine, hydromorphone, nicomorphine, and heroin as well as codeine, which itself has a large family of semi-synthetic derivatives. Morphine is commonly treated with acetic anhydride and ignited to yield heroin.^[73] 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 not able to 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 groups increase the lipid solubility of the heroin molecule, causing heroin to cross the blood–brain barrier and enter the brain 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.^[74]

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.^[75]

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.^[76] As an alternative, 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, dihydrocodeine, buprenorphine, dihydroetorphine, piritramide, levo-alpha-acetylmethadol (LAAM), and special 24-hour formulations of hydromorphone 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.

Since heroin is one of a series of 3,6 diesters of morphine, it is possible to convert morphine to nicomorphine (Vilan) using nicotinic anhydride, dipropanoylmorphine with propionic anhydride, dibutanoylmorphine and disalicyloylmorphine with the respective acid anhydrides. Glacial acetic acid can be used to obtain a mixture high in 6-monoacetylmorphine, niacin (vitamin B₃) in some form would be precursor to 6-nicotinylmorphine, salicylic acid may yield the salicyoyl analogue of 6-MAM, and so on.

The clandestine conversion of morphine to ketones of the hydromorphone class or other derivatives like dihydromorphine (Paramorfan), desomorphine (Permonid), metopon, etc. and codeine to hydrocodone (Dicodid), dihydrocodeine (Paracodin), etc. 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 (Paralaudin), and hydrocodone into thebacon.

History

An opium-based elixir has been ascribed to alchemists of Byzantine times, but the specific formula was lost during the Ottoman conquest of Constantinople (Istanbul).^[77] Around 1522, Paracelsus 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 became very popular among physicians and their patients.

Friedrich Sertürner

Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn, Germany, by Friedrich Sertürner.^[78]^[79] The drug was first marketed to the general public by Sertürner and Company in 1817 as an analgesic, 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.^{[citation needed]}

Later it was found that morphine was more addictive than either alcohol or opium, and its extensive use during the American Civil War allegedly resulted in over 400,000^[80] sufferers from the "soldier's disease" of morphine addiction.^[81] 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.^[82]^[83]

Diacetylmorphine (better known as heroin) was synthesized from morphine in 1874 and brought to market by Bayer 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 can cross the blood–brain barrier faster than morphine, subsequently increasing the reinforcing component of addiction.^[84] 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).^[15]

Advertisement for curing morphine addiction, ca. 1900^[85]

An ampoule of morphine with integral needle for immediate use. From WWII. On display at the Army Medical Services Museum.

Morphine became a controlled substance in the US under the Harrison Narcotics Tax Act 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. In general, until the synthesis of dihydromorphine (ca. 1900), the dihydromorphinone class of opioids (1920s), and oxycodone (1916) and similar drugs, there were no other drugs in the same efficacy range as opium, morphine, and heroin, with synthetics still several years away (pethidine was invented in Germany in 1937) and opioid agonists among the semi-synthetics were analogues and derivatives of codeine such as dihydrocodeine (Paracodin), ethylmorphine (Dionine), and benzylmorphine (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, oxymorphone, high-dose oxycodone, or methadone as well as dextromoramide 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, poppy straw derivatives like poppy pod and poppy seed tea, propoxyphene, and tramadol.

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. at the University of Rochester.^[86] 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 Kabay.

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, it appeared, reacted only to morphine: the μ₃-opioid receptor in human tissue.^[87] Human cells that form in reaction to cancerous neuroblastoma cells have been found to contain trace amounts of endogenous morphine.^[88]

Society and culture

Legal classification

In the United Kingdom, morphine is listed as a Class A drug under the Misuse of Drugs Act 1971 and a Schedule 2 Controlled Drug under The Misuse of Drugs Regulations 2001.
In the United States, morphine is classified as a Schedule II drug under the Controlled Substances Act, with a main ACSCN 9300 (see table under Chemistry for different salts) and morphine is classified for the purpose of annual aggregate manufacturing quotas as being for sale as pharmaceuticals, which are also generally Schedule II with the exception of extremely dilute formulations which may be Schedule III, and as a precursor for conversion into other drugs. The morphine for conversion 2013 quota was 103 750 kilos, up from 91 250 kilos in 2012. The morphine-for-sale quota was unchanged from the prior year at 60 250 kilos.

In Canada, morphine is classified as a Schedule I drug under the Controlled Drugs and Substances Act.
In Australia, morphine is classified as a Schedule 8 drug under the variously titled State and Territory Poisons Acts.
In the Netherlands, morphine is classified as a List 1 drug under the Opium Law.
In Japan, morphine is classified as a narcotic under the Narcotics and Psychotropics Control Act (麻薬及び向精神薬取締法).
In Germany it is a verkehrsfähiges und verschreibungsfähiges Betäubungsmittel listed under Anlage III (the equivalent of CSA Schedule II) of the Betäubungsmittelgesetz;^[89] it is similarly scheduled under the Austrian and Swiss equivalents thereof, statuses inherited from the German Opium Law of 1929 and the Austrian Suchtgiftverordnung of 1931 and the Swiss equivalent. The Austrian Suchtmittelgesetz (1998) harmonised its regulations with that of the European Union after its accession. Austria and Switzerland (whose BetmG is very similar to the aforementioned regulations) are the home of MS-Contin type drugs being used as methadone replacements for those who cannot tblerate methadone, beginning in Vienna in the mid 1980s. The three aforementioned laws also classify morphine as a Suchtgift, an addictive substance.
It is a narcotic in the highest legal schedule of the 31. December 1970 French controlled substances law. The Austrian and Swiss schools of thought on narcotics are
Internationally, morphine is a Schedule I drug under the Single Convention on Narcotic Drugs.^[90]

Illicit use

Example of different morphine tablets

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, hydromorphone (Dilaudid, Hydal), and oxymorphone (Numorphan, Opana), as well as the latter three's methylated equivalents dihydrocodeine, hydrocodone, and oxycodone, respectively; in addition to heroin, there are dipropanoylmorphine, diacetyldihydromorphine, and other members of the 3,6 morphine diester category like nicomorphine and other similar semi-synthetic opiates like desomorphine, hydromorphinol, etc. used clinically in many countries of the world but in many cases also produced illicitly in rare instances.

In general, misuse of morphine 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 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 that 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 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, sister morphine, Vitamin M, morpho, etc.

MS Contin tablets are known as misties, and the 100 mg extended-release tablets as greys and blockbusters. The "speedball" can use morphine as the narcotic component, which is combined with cocaine, amphetamines, methylphenidate, or similar drugs. "Blue Velvet" is a combination of morphine with the antihistamine tripelennamine (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 that 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 diacetylmorphine (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, or the linctus known as Blue Morphine or Blue Morphone, or the Blue Velvet mixture described above).

Trade names

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

Morphine brand names
A:	Actiskenan, Algedol, Amidiaz, Analmorph, Anafil, Analfin, Anamorph, Astramorph, Avinza
C:	Capros, Cloruro Morfico Braun, Compensan, Continue, Contalgin
D:	DepoDur, Depolan, Dimorf, Dolcontin, Dolo Moff, Doloral, DOLQ, Doltard, Dulcontin, Duralgin, Duralmor, Duramorph
E:	Embeda, Epidural, Epimorph
F:	Filnarine
G:	GNO, Graten, G-Morphine
I:	Infumorph (morphine for intrathecal micro-infusion by implanted device)
K:	Kadian, Kapabloc, Kapanol
L:	LA Morph, Loceptin, Longphine
M:	M-Beta, M-Dolor, M-Eslon, M-Long, M-Retard, M-Stada, Malfin, Maxidon, MCR, Meconium, Meslon, Micro-Morphine, MIR, Mogetic, Morapid, Moraxen, Morcap, Moretal, Morfenil, Morficontin, Morfin, Morfin Meda, Morfina, Morin, Morph, Morphanton, Morphex, Morphgesic, Morphin, Morphini, Morphinum, Morphiphar, Morphitec, Morphium, Morstel, MOS, Moscontin, Morstel, Mortificontin, MS Contin, MS Direct, MS Long, MS Mono, MS/L, MS/S, MSI, MSIR, MSP, MSR, MST Continus, MST Unicontinus, Mundidol, MXL
N:	Neocalmans, Nepenthe, Noceptin, Novo-Morphine
O:	Oblioser, Oglos, OMS Concentrate, Onkomorphin, Opitard, Opsalvina, Oramorph, Ordine
P:	Painbreak, PMS-Morphine
Q:	Q-Med Morphine
R:	RA Morph, Ratio-Morphine, Relimal, Relipain, Repriadol, Rescudose, RMS, Roxanol
S:	S-Morphine, Sevre-Long, Sevredol, Skenan, Slo-Morph, Slovalgin, SRM-Rhotard, Statex, Stellaphine, Stellorphinad, Stellorphine, Substitol
U:	Uni Mist
V:	Vendal
Z:	Zomorph

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, six countries (Australia, Canada, France, Germany, the United Kingdom, and the United States) consume 79% of the world’s morphine. The less affluent countries, accounting for 80% of the world's population, consumed only about 6% 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.^[91]

References

^ Jonsson T, Christensen CB, Jordening H, Frølund C (April 1988). "The bioavailability of rectally administered morphine". Pharmacol. Toxicol. 62 (4): 203–5. doi:10.1111/j.1600-0773.1988.tb01872.x. PMID 3387374.
^ Smith W (2007). A Dictionary of Greek and Roman Biography and Mythology (1 ed.). London, United Kingdom: I. B. Tauris. ISBN 1-84511-002-1.
^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.
^ ^a ^b "Morphine Sulfate". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
^ Meine TJ, Roe MT, Chen AY, Patel MR, Washam JB, Ohman EM, Peacock WF, Pollack CV, Gibler WB, Peterson ED (June 2005). "Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative". Am. Heart J. 149 (6): 1043–9. doi:10.1016/j.ahj.2005.02.010. PMID 15976786.
^ Sosnowski MA. "BestBets: Does the application of opiates, during an attack of Acute Cardiogenic Pulmonary Oedma, reduce patients' mortality and morbidity?". BestBets. Best Evidence Topics. Retrieved 6 December 2008.
^ Schrijvers D, van Fraeyenhove F (2010). "Emergencies in palliative care". Cancer J 16 (5): 514–20. doi:10.1097/PPO.0b013e3181f28a8d. PMID 20890149.
^ Naqvi F, Cervo F, Fields S (August 2009). "Evidence-based review of interventions to improve palliation of pain, dyspnea, depression". Geriatrics 64 (8): 8–10, 12–4. PMID 20722311.
^ Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, Calverley PM, Gift AG, Harver A, Lareau SC, Mahler DA, Meek PM, O'Donnell DE (February 2012). "An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea". Am. J. Respir. Crit. Care Med. 185 (4): 435–52. doi:10.1164/rccm.201111-2042ST. PMID 22336677.
^ Mahler DA, Selecky PA, Harrod CG, Benditt JO, Carrieri-Kohlman V, Curtis JR, Manning HL, Mularski RA, Varkey B, Campbell M, Carter ER, Chiong JR, Ely EW, Hansen-Flaschen J, O'Donnell DE, Waller A (March 2010). "American College of Chest Physicians consensus statement on the management of dyspnea in patients with advanced lung or heart disease". Chest 137 (3): 674–91. doi:10.1378/chest.09-1543. PMID 20202949.
^ "Selected opioid analgesics for pain". Uptodate. Retrieved 23 September 2011.
^ Mattick RP, Digiusto E, Doran C, O’Brien S, Kimber J, Henderson N, Breen B, Shearer J, Gates J, Shakeshaft A, NEPOD Trial Investigators (2004). National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD): Report of Results and Recommendation (PDF). Monograph Series No. 52 (Australian Government). ISBN 0-642-82459-2.
^ Stefano GB, Zhu W, Cadet P, Bilfinger TV, Mantione K (March 2004). "Morphine enhances nitric oxide release in the mammalian gastrointestinal tract via the micro(3) opiate receptor subtype: a hormonal role for endogenous morphine". J. Physiol. Pharmacol. 55 (1 Pt 2): 279–88. PMID 15082884.
^ Calignano A, Moncada S, Di Rosa M (December 1991). "Endogenous nitric oxide modulates morphine-induced constipation". Biochem. Biophys. Res. Commun. 181 (2): 889–93. doi:10.1016/0006-291X(91)91274-G. PMID 1755865.
^ ^a ^b ^c Martin WR, Fraser HF (1961). "A comparative study of physiological and subjective effects of heroin and morphine administered intravenously in postaddicts". J. Pharmacol. Exp. Ther. 133: 388–99. PMID 13767429.
^ ^a ^b National Institute on Drug Abuse (NIDA) (April 2013). "Heroin". DrugFacts. U.S. National Institutes of Health.
^ Weissman DE, Haddox JD (1989). "Opioid pseudoaddiction-an iatrogenic syndrome". Pain 36 (3): 363–6. doi:10.1016/0304-3959(89)90097-3. PMID 2710565.
^ Xu Z, Hou B, Gao Y, He F, Zhang C (2007). "Effects of enriched environment on morphine-induced reward in mice". Exp. Neurol. 204 (2): 714–9. doi:10.1016/j.expneurol.2006.12.027. PMID 17331503.
^ Roshanpour M, Ghasemi M, Riazi K, Rafiei-Tabatabaei N, Ghahremani MH, Dehpour AR (2009). "Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone". Epilepsy Res. 83 (2–3): 261–4. doi:10.1016/j.eplepsyres.2008.10.011. PMID 19059761.
^ Koch T, Höllt V (2008). "Role of receptor internalization in opioid tolerance and dependence". Pharmacol. Ther. 117 (2): 199–206. doi:10.1016/j.pharmthera.2007.10.003. PMID 18076994.
^ [1]
^ Chan R, Irvine R, White J (1999). "Cardiovascular changes during morphine administration and spontaneous withdrawal in the rat". Eur. J. Pharmacol. 368 (1): 25–33. doi:10.1016/S0014-2999(98)00984-4. PMID 10096766.
^ "Morphine (and Heroin)". Drugs and Human Performance Fact Sheets. U.S. National Traffic Safety Administration.
^ "Narcotics". DEA Briefs & Background, Drugs and Drug Abuse, Drug Descriptions. U.S. Drug Enforcement Administration.
^ Dalrymple T (2006). Romancing Opiates: Pharmacological Lies and the Addiction Bureaucracy. Encounter. p. 160. ISBN 978-1-59403-087-1.
^ Anraku T, Ikegaya Y, Matsuki N, Nishiyama N (September 2001). "Withdrawal from chronic morphine administration causes prolonged enhancement of immobility in rat forced swimming test". Psychopharmacology (Berl.) 157 (2): 217–20. doi:10.1007/s002130100793. PMID 11594449.
^ O'Neil MJ (2006). The Merck index : an encyclopedia of chemicals, drugs, and biological. Whitehouse Station, N.J.: Merck. ISBN 0-911910-00-X.
^ Brennan MJ (March 2013). "The effect of opioid therapy on endocrine function". Am. J. Med. 126 (3 Suppl 1): S12–8. doi:10.1016/j.amjmed.2012.12.001. PMID 23414717.
^ Colameco S, Coren JS (January 2009). "Opioid-induced endocrinopathy". J Am Osteopath Assoc 109 (1): 20–5. PMID 19193821.
^ ^a ^b MedlinePlus – Morphine overdose Update Date: 2/3/2009. Updated by: John E. Duldner, Jr., MD
^ Macchiarelli L, Arbarello Cave Bondi P. Di Luca NM, Feola T (2002). Medicina Legale (compendio) (II ed.). Italy, Turin: Minerva Medica Publications.
^ Wu SD, Zhang ZH, Jin JZ, Kong J, Wang W, Zhang Q, Li DY, Wang MF (October 2004). "Effects of narcotic analgesic drugs on human Oddi's sphincter motility". World J. Gastroenterol. 10 (19): 2901–4. PMID 15334697.
^ Thompson DR (April 2001). "Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis". Am. J. Gastroenterol. 96 (4): 1266–72. doi:10.1111/j.1572-0241.2001.03536.x. PMID 11316181.
^ Yekkirala AS, Kalyuzhny AE, Portoghese PS (2010). "Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin as selective μ-δ agonists". ACS Chem Neurosci 1 (2): 146–54. doi:10.1021/cn9000236. PMC 3398540. PMID 22816017.
^ Yekkirala AS, Banks ML, Lunzer MM, Negus SS, Rice KC, Portoghese PS (2012). "Clinically employed opioid analgesics produce antinociception via μ-δ opioid receptor heteromers in Rhesus monkeys". ACS Chem Neurosci 3 (9): 720–7. doi:10.1021/cn300049m. PMC 3447399. PMID 23019498.
^ ^a ^b "MS-Contin (Morphine Sulfate Controlled-Release) Drug Information: Clinical Pharmacology". Prescribing Information. RxList.
^ Chien CC, Pasternak GW (1995). "Sigma antagonists potentiate opioid analgesia in rats". Neurosci. Lett. 190 (2): 137–9. doi:10.1016/0304-3940(95)11504-P. PMID 7644123.
^ Herman BH, Vocci F, Bridge P (1995). "The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal. Medication development issues for opiate addiction". Neuropsychopharmacology 13 (4): 269–93. doi:10.1016/0893-133X(95)00140-9. PMID 8747752.
^ Loguinov A, Anderson L, Crosby G, Yukhananov R (2001). "Gene expression following acute morphine administration". Physiol Genomics 6 (3): 169–81. PMID 11526201.
^ Messmer D, Hatsukari I, Hitosugi N, Schmidt-Wolf IG, Singhal PC (2006). "Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation". Mol. Med. 12 (11–12): 284–90. doi:10.2119/2006-00043.Messmer. PMC 1829197. PMID 17380193.
^ Clark JD, Shi X, Li X, Qiao Y, Liang D, Angst MS, Yeomans DC (2007). "Morphine reduces local cytokine expression and neutrophil infiltration after incision". Mol Pain 3: 28. doi:10.1186/1744-8069-3-28. PMC 2096620. PMID 17908329.
^ Trescot AM, Datta S, Lee M, Hansen H (2008). "Opioid pharmacology". Pain Physician 11 (2 Suppl): S133–53. PMID 18443637.
^ Kilpatrick G.J. and Smith T.W. (2005). "Morphine-6-glucuronide: actions and mechanisms". Med. Res. Rev. 25 (5): 521–544. doi:10.1002/med.20035. PMID 15952175.
^ ^a ^b van Dorp EL, Romberg R, Sarton E, Bovill JG, Dahan A (2006). "Morphine-6-glucuronide: morphine's successor for postoperative pain relief?". Anesthesia and Analgesia 102 (6): 1789–1797. doi:10.1213/01.ane.0000217197.96784.c3. PMID 16717327.
^ ^a ^b Jenkins AJ (2008) Pharmacokinetics of specific drugs. In Karch SB (Ed), Pharmacokinetics and pharmacodynamics of abused drugs. CRC Press: Boca Raton.
^ Baselt RC (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1057–1062. ISBN 0-9626523-7-7.
^ Vandevenne M, Vandenbussche H, Verstraete A (2000). "Detection time of drugs of abuse in urine". Acta Clin Belg 55 (6): 323–33. PMID 11484423.
^ Verstraete AG (April 2004). "Detection times of drugs of abuse in blood, urine, and oral fluid". Ther Drug Monit 26 (2): 200–5. doi:10.1097/00007691-200404000-00020. PMID 15228165.
^ Kerr B, Hill H, Coda B, Calogero M, Chapman CR, Hunt E, Buffington V, Mackie A (November 1991). "Concentration-related effects of morphine on cognition and motor control in human subjects". Neuropsychopharmacology 5 (3): 157–66. PMID 1755931.
^ Friswell J, Phillips C, Holding J, Morgan CJ, Brandner B, Curran HV (2008). "Acute effects of opioids on memory functions of healthy men and women". Psychopharmacology (Berl.) 198 (2): 243–50. doi:10.1007/s00213-008-1123-x. PMID 18379759.
^ Galski T, Williams JB, Ehle HT (2000). "Effects of opioids on driving ability". J Pain Symptom Manage 19 (3): 200–8. doi:10.1016/S0885-3924(99)00158-X. PMID 10760625.
^ Kapoor L (1995). Opium Poppy: Botany, Chemistry, and Pharmacology. United States: CRC Press. p. 164. ISBN 1-56024-923-4.
^ Vincent PG, Bare CE, Gentner WA (December 1977). "Thebaine content of selections of Papaver bracteatum Lindl. at different ages". J Pharm Sci 66 (12): 1716–9. doi:10.1002/jps.2600661215. PMID 925935.
^ Merriam-Webster Dictionary endorphin
^ Stewart O (2000). Functional Neuroscience. New York: Springer. p. 116. ISBN 0-387-98543-3.
^ DeRuiter J (Fall 2000). "Narcotic analgesics: morphine and "peripherally modified" morphine analogs" (PDF). Principles of Drug Action 2. Auburn University.
^ ^a ^b ^c ^d ^e Lide DR, ed. (2004). CRC handbook of chemistry and physics: a ready-reference book of chemical and physical data (85 ed.). Boca Ratan Florida: CRC Press. ISBN 0-8493-0485-7.
^ "Morphine". LHA Science Page. LaurenHill Academy.
^ Novak B, Hudlicky T, Reed J, Mulzer J, Trauner D (March 2000). "Morphine Synthesis and Biosynthesis-An Update". Current Organic Chemistry 4 (3): 343–362. doi:10.2174/1385272003376292.
^ Gates M, Tschudi G (April 1956). "The Synthesis of Morphine". Journal of the American Chemical Society 78 (7): 1380–1393. doi:10.1021/ja01588a033.
^ Rice KC (July 1980). "Synthetic opium alkaloids and derivatives. A short total synthesis of (+/-)-dihydrothebainone, (+/-)-dihydrocodeinone, and (+/-)-nordihydrocodeinone as an approach to a practical synthesis of morphine, codeine, and congeners". The Journal of Organic Chemistry 45 (15): 3135–3137. doi:10.1021/jo01303a045.
^ Evans DA, Mitch CH (January 1982). "Studies directed towards the total synthesis of morphine alkaloids". Tetrahedron Letters 23 (3): 285–288. doi:10.1016/S0040-4039(00)86810-0.
^ Toth JE, Hamann PR, Fuchs PL (September 1988). "Studies culminating in the total synthesis of (dl)-morphine". The Journal of Organic Chemistry 53 (20): 4694–4708. doi:10.1021/jo00255a008.
^ Parker KA, Fokas D (November 1992). "Convergent synthesis of (+/-)-dihydroisocodeine in 11 steps by the tandem radical cyclization strategy. A formal total synthesis of (+/-)-morphine". Journal of the American Chemical Society 114 (24): 9688–9689. doi:10.1021/ja00050a075.
^ Hong CY, Kado N, Overman LE (November 1993). "Asymmetric synthesis of either enantiomer of opium alkaloids and morphinans. Total synthesis of (-)- and (+)-dihydrocodeinone and (-)- and (+)-morphine". Journal of the American Chemical Society 115 (23): 11028–11029. doi:10.1021/ja00076a086.
^ Mulzer J, Dürner G, Trauner D (December 1996). "Formal Total Synthesis of(—)-Morphine by Cuprate Conjugate Addition". Angewandte Chemie International Edition in English 35 (2324): 2830–2832. doi:10.1002/anie.199628301.
^ White JD, Hrnciar P, Stappenbeck F (October 1999). "Asymmetric Total Synthesis of (+)-Codeine via Intramolecular Carbenoid Insertion". The Journal of Organic Chemistry 64 (21): 7871–7884. doi:10.1021/jo990905z.
^ Taber DF, Neubert TD, Rheingold AL (October 2002). "Synthesis of (−)-Morphine". Journal of the American Chemical Society 124 (42): 12416–12417. doi:10.1021/ja027882h. PMID 12381175.
^ Trost BM, Tang W (December 2002). "Enantioselective Synthesis of (−)-Codeine and (−)-Morphine". Journal of the American Chemical Society 124 (49): 14542–14543. doi:10.1021/ja0283394. PMID 12465957.
^ Uchida K, Yokoshima S, Kan T, Fukuyama T (November 2006). "Total Synthesis of (±)-Morphine". Organic Letters 8 (23): 5311–5313. doi:10.1021/ol062112m. PMID 17078705.
^ Varin M, Barré E, Iorga B, Guillou C (2008). "Diastereoselective Total Synthesis of (±)-Codeine". Chemistry - A European Journal 14 (22): 6606–6608. doi:10.1002/chem.200800744.
^ Stork G, Yamashita A, Adams J, Schulte GR, Chesworth R, Miyazaki Y, Farmer JJ (2009). "Regiospecific and Stereoselective Syntheses of (±) Morphine, Codeine, and Thebaine via a Highly Stereocontrolled Intramolecular 4 + 2 Cycloaddition Leading to a Phenanthrofuran System". Journal of the American Chemical Society 131 (32): 11402–11406. doi:10.1021/ja9038505. PMID 19624126.
^ Small LF, Lutz RE (1932). Chemistry of the Opium Alkaloids. Washington, D. C.: U. S. Government Printing Office. pp. 153–154. ASIN B000H4LBY8.
^ Klous MG, Van den Brink W, Van Ree JM, Beijnen JH (December 2005). "Development of pharmaceutical heroin preparations for medical co-prescription to opioid dependent patients". Drug Alcohol Depend 80 (3): 283–95. doi:10.1016/j.drugalcdep.2005.04.008. PMID 15916865.
^ Rapoport H, Lovell CH, Tolbert BM (December 1951). "The Preparation of Morphine-N-methyl-C¹⁴". Journal of the American Chemical Society 73 (12): 5900–5900. doi:10.1021/ja01156a543.
^ Crews JC, Denson DD (1990). "Recovery of morphine from a controlled-release preparation. A source of opioid abuse". Cancer 66 (12): 2642–4. doi:10.1002/1097-0142(19901215)66:12<2642::AID-CNCR2820661229>3.0.CO;2-B. PMID 2249204.
^ Ramoutsaki IA, Askitopoulou H, Konsolaki E (December 2002). "Pain relief and sedation in Roman Byzantine texts: Mandragoras officinarum, Hyoscyamos niger and Atropa belladonna". International Congress Series 1242: 43–50. doi:10.1016/S0531-5131(02)00699-4.
^ Friedrich Sertürner (1805) (Untitled letter to the editor), Journal der Pharmacie für Aerzte, Apotheker und Chemisten (Journal of Pharmacy for Physicians, Apothecaries, and Chemists), 13 : 229-243 ; see especially "III. Säure im Opium" (acid in opium), pp. 234-235, and "I. Nachtrag zur Charakteristik der Säure im Opium" (Addendum on the characteristics of the acid in opium), pp. 236-241.
^ Luch A, ed. (2009). Molecular, clinical and environmental toxicology. Springer. p. 20. ISBN 3-7643-8335-6.
^ Vassallo SA (July 2004). "Lewis H. Wright Memorial Lecture". ASA New Letter 68 (7): 9–10.
^ "Opiate Narcotics". The Report of the Canadian Government Commission of Inquiry into the Non-Medical Use of Drugs. Canadian Government Commission.
^ Mandel J. "Mythical Roots of US Drug Policy - Soldier's Disease and Addicts in the Civil War".
^ "Soldiers Disease A Historical Hoax?". iPromote Media Inc. 2006.
^ Winger G, Hursh SR, Casey KL, Woods JH (May 2002). "Relative reinforcing strength of three N-methyl-D-aspartate antagonists with different onsets of action". J. Pharmacol. Exp. Ther. 301 (2): 690–7. doi:10.1124/jpet.301.2.690. PMID 11961074.
^ "Morphine Easy Home Cure". Overland Monthly 35 (205): 14. 1900.
^ Dickman S (3 October 2003). "Marshall D. Gates, Chemist to First Synthesize Morphine, Dies". Press Release. University of Rochester.
^ Zhu W, Cadet P, Baggerman G, Mantione KJ, Stefano GB (2005). "Human white blood cells synthesize morphine: CYP2D6 modulation". J. Immunol. 175 (11): 7357–62. doi:10.4049/jimmunol.175.11.7357. PMID 16301642.
^ Poeaknapo C, Schmidt J, Brandsch M, Dräger B, Zenk MH; Schmidt; Brandsch; Dräger; Zenk (2004). "Endogenous formation of morphine in human cells". Proc. Natl. Acad. Sci. U.S.A. 101 (39): 14091–6. Bibcode:2004PNAS..10114091P. doi:10.1073/pnas.0405430101. PMC 521124. PMID 15383669.
^ Anlage III (zu § 1 Abs. 1) verkehrsfähige und verschreibungsfähige Betäubungsmittel
^ "List of narcotic drugs under international control". Yellow List (PDF) (50th ed.) (Austria: International Narcotics Control Board): 5. March 2011.
^ Donald G. McNeil Jr. (10 September 2007). "Drugs Banned, Many of World's Poor Suffer in Pain". New York Times. Retrieved 11 September 2007.

External links

U.S. National Library of Medicine: Drug Information Portal – Morphine
Morphine bound to proteins in the PDB
Morphine and Heroin at The Periodic Table of Videos (University of Nottingham)
Video: Intravenous morphine loading (Vimeo) (YouTube) – A short medical education video teaching health professionals the salient points about intravenous loading of analgesics, in particular morphine.

UpToDate Contents

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1. オピオイド系薬剤を用いた癌疼痛のマネージメント：至適鎮痛作用 cancer pain management with opioids optimizing analgesia
2. 脊髄麻酔：手技 spinal anesthesia technique
3. 米国外の緩和ケアとホスピス palliative care and hospice outside of the united states
4. Anesthesia for patients with acute traumatic brain injury
5. 小児における、アデノイド切除同時施行例を含む扁桃摘出に対する麻酔 anesthesia for tonsillectomy with or without adenoidectomy in children

English Journal

Efficacy of drugs with different mechanisms of action in relieving spontaneous pain at rest and during movement in a rat model of osteoarthritis.

Ishikawa G1, Nagakura Y2, Takeshita N3, Shimizu Y4.
European journal of pharmacology.Eur J Pharmacol.2014 Sep 5;738:111-7. doi: 10.1016/j.ejphar.2014.05.048. Epub 2014 Jun 2.
Patients with osteoarthritis (OA) suffer from joint pain aggravated by movement, which affect their quality of life. In the present study, a weight bearing paradigm for pain at rest and a gait paradigm for pain during movement were tested in rats with unilateral knee arthritis induced by an intra-ar
PMID 24939049

Comparison of peripheral nerve block with periarticular injection analgesia after total knee arthroplasty: a randomized, controlled study.

Uesugi K1, Kitano N2, Kikuchi T2, Sekiguchi M2, Konno S2.
The Knee.Knee.2014 Aug;21(4):848-52. doi: 10.1016/j.knee.2014.04.008. Epub 2014 Apr 18.
BACKGROUND: Pain after total knee arthroplasty (TKA) is usually severe. Recently, the usefulness of local periarticular injection analgesia (PAI) and peripheral nerve block (PNB) has been reported. We report a prospective blinded randomized trial of PAI versus PNB in patients undergoing primary TKA,
PMID 24827696

Japanese Journal

筋萎縮性側索硬化症患者の呼吸苦に高用量の硫酸モルヒネ製剤を使用した1例

熊野文香,高橋和也,八田裕之,池田篤平,駒井清暢
神経治療学 34(4), 463-466, 2018
… 苦の緩和目的にmorphine hydrochlorideの投与が開始され，約半年間症状の緩和がみられていたが，その後呼吸苦が増悪した．高用量のmorphine hydrochloride 3時間毎投与を行い対処したが，呼吸苦（end–of–dose failure）の改善がみられなかったため，一期的に1日2回のmorphine sulfate投与の切り替えをおこなった．morphine sulfateへの切り …
NAID 130006386693

オピオイド鎮痛薬の減量に配慮を要した腕神経叢引き抜き損傷の2例

又吉宏昭,中西俊之,三宅奈苗,福田志朗,谷口真
日本ペインクリニック学会誌 24(2), 121-125, 2017
オピオイド鎮痛薬 (以下オピオイド) を長期使用していた腕神経叢引き抜き損傷患者に対して，脊髄後根進入部破壊術 (DREZ-lesion) を施行したが，術後にオピオイドの減量に苦慮した2症例を経験した．症例1は44歳の男性．6年前に右腕神経叢引き抜き損傷を受傷．数年前から塩酸モルヒネを使用していた．DREZ-lesion後はフェンタニルの持続静注を用いてオピオイドを減量する計画であったが，術後1 …
NAID 130006832068

A Clinical Study on Administration of Opioid Antagonists in Terminal Cancer Patients: 7 Patients Receiving Opioid Antagonists Following Opioids among 2443 Terminal Cancer Patients Receiving Opioids

Uekuzu Yoshihiro,Higashiguchi Takashi,Futamura Akihiko,Ito Akihiro,Mori Naoharu,Murai Miyo,Ohara Hiroshi,Awa Hiroko,Chihara Takeshi
Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ 40(3), 278-283, 2017
… In 2443 terminal cancer patients receiving opioids, 7 patients (0.3%) received opioid antagonists: 6, morphine (hydrochloride, 5; … The median dosage of opioids was 13.3 mg/d, as converted to morphine injection. … In morphine-receiving patients, renal functions were significantly worsened at the time of administration of an opioid antagonist than the day before the start of opioid administration. …
NAID 130005398513

Related Pictures

★リンクテーブル★

リンク元	「モルヒネ」「塩酸モルヒネ」「モルヒネ塩酸塩」
拡張検索	「ethylmorphine hydrochloride」
関連記事	「hydrochloride」

「モルヒネ」

Morphine
Systematic (IUPAC) name
	(5α,6α)-7,8-didehydro-; 4,5-epoxy-17-methylmorphinan-3,6-diol
Clinical data
Trade names	Mscontin, Oramorph, Sevredol (morphine as a sulfate)
AHFS/Drugs.com	sulfate.html monograph
Pregnancy cat.	AU: D; US: C;
Legal status	AU: Controlled (S8); CA: Schedule I; US: Schedule II; UN: Narcotic Schedules I and III; Prescription Medicine Only;
Dependence; liability	High
Routes	Inhalation (smoking), insufflation (snorting), oral, rectal, subcutaneous (SC), intramuscular (IM), intravenous (IV), epidural, and intrathecal (IT)
Pharmacokinetic data
Bioavailability	20–40% (oral), 36–71% (rectally), 100% (IV/IM)
Protein binding	30–40%
Metabolism	Hepatic 90%
Half-life	2–3 h
Excretion	Renal 90%, biliary 10%
Identifiers
CAS number	57-27-2 ; 64-31-3 (neutral sulfate),; 52-26-6 (hydrochloride)
ATC code	N02AA01
PubChem	CID 5288826
IUPHAR ligand	1627
DrugBank	DB00295
ChemSpider	4450907
UNII	76I7G6D29C
KEGG	D08233
ChEBI	CHEBI:17303
ChEMBL	CHEMBL70
Chemical data
Formula	C17H19NO3
Mol. mass	285.34
	SMILES CN1CC[C@]23C4=C5C=CC(O)=C4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5;
	InChI InChI=1S/C17H19NO3/c1-18-7-6-17-10-3-5-13(20)16(17)21-15-12(19)4-2-9(14(15)17)8-11(10)18/h2-5,10-11,13,16,19-20H,6-8H2,1H3/t10-,11+,13-,16-,17-/m0/s1 ; Key:BQJCRHHNABKAKU-KBQPJGBKSA-N ;
Physical data
Solubility in water	HCl & sulf.: 60 mg/mL (20 °C)
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　　[★]

英: morphine
ラ: morphinum
同: モルフィン
化: 塩酸モルヒネ morphine hydrochloride
商: MSコンチン、MSツワイスロン、アヘンチンキ、アヘンチンキ、アヘン散、アポカイン、アンペック、エチルモルヒネ塩酸塩水和物、オプソ、カディアン、ドーフル散、パシーフ、ピーガード、プレペノン、モヒアト、モルペス
関: アヘンアルカロイド、オピオイド、モルヒネ中毒; アヘンアルカロイド系麻薬

薬理作用

･鎮痛作用:経口投与では効果小(肝初回通過効果)

精神作用:痔痛患者に陶酔感euphoria,健常人に不快感dysphoria
鎮静作用:ヒト,サル,イヌ,ウサギ,ラット
Straub tail反応: morphineの脊髄興奮作用によりマウスの尾が立ちあがる｡
呼吸抑制作用:呼吸中枢のC02に対する反応性低下　う急性中毒死
催吐作用:延髄chemoreceptor trigger zone (CTZ)に作用--吐き気,噛吐
心血管作用:動静脈の緊張低下-心臓負荷減少-→肺うっ血,浮腫を軽減　　←　　肺静脈各調査用により肺うっ血を改善させるからこういう症例に良いらしい(105C031)
消化管作用:腸管神経叢のACh遊離抑制　→蠕動運動抑制

　　　　　　　腸管壁から5-HT遊離　　　→腸管平滑筋の緊張亢進

胆管内圧上昇: Oddi括約筋の収縮(だから胆石症の時には注意)
縮瞳作用:動眼神経核の刺激
反復投与-耐性,身体的･精神的依存が形成
突然の休薬・オピオイド括抗薬投与-禁断症状withdrawal symptoms
(振戦,不安,不眠,疫撃,発汗,鼻汁,流涙,発熱,血圧上昇,頻脈,
下痢,腹痛,堰吐など)

SPC.206

中枢作用

鎮痛
快感、鎮静、眠気、知的鈍麻
呼吸抑制
鎮咳
悪心・嘔吐
瞳孔縮小

末梢作用

循環器系：ほとんど影響ない
消化器系：消化管運動低下(平滑筋の緊張亢進によるらしいい)、胆管攣縮
泌尿器：平滑筋の緊張により尿管スパズム、膀胱排尿筋収縮、利尿ホルモン分泌増加、尿閉。
その他：肥満細胞からのヒスタミン遊離により発赤、熱覚、発汗、気管支収縮。

適応

術後痛(硬膜外投与,副作用に拝み,呼吸抑制)｡末期癌疼痛
心筋梗塞の疼痛
手術後の腸管揺動運動抑制
激しい下痢(ロペラミドの開発により使用は減少)、激しい咳

循環器

末梢血管を拡張し静脈還流量を減少させる。ファロー四徴症における無酸素発作の予防につかわれる(YN.C-123)、らしい

注意

膵炎の患者に対しては投与を避ける　→　オッディ括約筋を収縮させるため

禁忌

モヒアト注射液

1. 重篤な心疾患のある患者〔症状を悪化させるおそれがある。〕
2. 重篤な呼吸抑制のある患者〔呼吸抑制を増強する。〕
3. 気管支喘息発作中の患者〔気道分泌を妨げる。〕
4. 重篤な肝障害のある患者〔昏睡に陥ることがある。〕
5. 慢性肺疾患に続発する心不全の患者〔呼吸抑制や循環不全を増強する。〕
6. 痙攣状態（てんかん重積症、破傷風、ストリキニーネ中毒）にある患者〔脊髄の刺激効果があらわれる。〕
7. 急性アルコール中毒の患者〔呼吸抑制を増強する。〕
8. アヘンアルカロイド及びアトロピンに対し過敏症の既往歴のある患者
9. 緑内障の患者〔アトロピンの抗コリン作用により房水通路が狭くなり眼圧が上昇し、緑内障を悪化させるおそれがある。〕
10. 前立腺肥大による排尿障害、尿道狭窄、尿路手術術後の患者〔排尿障害を増悪することがある。〕
11. 器質的幽門狭窄、麻痺性イレウス又は最近消化管手術を行った患者〔消化管運動を抑制する。〕
12. 出血性大腸炎の患者〔腸管出血性大腸菌（O157等）や赤痢菌等の重篤な細菌性下痢のある患者では、症状の悪化、治療期間の延長をきたすおそれがある。〕

副作用

添付文書

モヒアト注射液

http://www.info.pmda.go.jp/go/pack/8119505A1050_2_01/8119505A1050_2_01?view=body

「塩酸モルヒネ」

　　[★]

英: morphine hydrochloride
関: モルヒネ、モルヒネ塩酸塩

「モルヒネ塩酸塩」

　　[★]

英: morphine hydrochloride
関: モルヒネ、塩酸モルヒネ

「ethylmorphine hydrochloride」

　　[★]

塩酸エチルモルヒネ

関: ethylmorphine

「hydrochloride」

　　[★] 塩酸塩、ハイドロクロライド　

[pmid3387374-1] Jonsson T, Christensen CB, Jordening H, Frølund C (April 1988). "The bioavailability of rectally administered morphine". Pharmacol. Toxicol. 62 (4): 203–5. doi:10.1111/j.1600-0773.1988.tb01872.x. PMID 3387374.

[2] Smith W (2007). A Dictionary of Greek and Roman Biography and Mythology (1 ed.). London, United Kingdom: I. B. Tauris. ISBN 1-84511-002-1.

[3] "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014.

[AHFS-4] "Morphine Sulfate". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.

[pmid15976786-5] Meine TJ, Roe MT, Chen AY, Patel MR, Washam JB, Ohman EM, Peacock WF, Pollack CV, Gibler WB, Peterson ED (June 2005). "Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative". Am. Heart J. 149 (6): 1043–9. doi:10.1016/j.ahj.2005.02.010. PMID 15976786.

[6] Sosnowski MA. "BestBets: Does the application of opiates, during an attack of Acute Cardiogenic Pulmonary Oedma, reduce patients' mortality and morbidity?". BestBets. Best Evidence Topics. Retrieved 6 December 2008.

[Pal2010-7] Schrijvers D, van Fraeyenhove F (2010). "Emergencies in palliative care". Cancer J 16 (5): 514–20. doi:10.1097/PPO.0b013e3181f28a8d. PMID 20890149.

[8] Naqvi F, Cervo F, Fields S (August 2009). "Evidence-based review of interventions to improve palliation of pain, dyspnea, depression". Geriatrics 64 (8): 8–10, 12–4. PMID 20722311.

[pmid22336677-9] Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, Calverley PM, Gift AG, Harver A, Lareau SC, Mahler DA, Meek PM, O'Donnell DE (February 2012). "An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea". Am. J. Respir. Crit. Care Med. 185 (4): 435–52. doi:10.1164/rccm.201111-2042ST. PMID 22336677.

[pmid20202949-10] Mahler DA, Selecky PA, Harrod CG, Benditt JO, Carrieri-Kohlman V, Curtis JR, Manning HL, Mularski RA, Varkey B, Campbell M, Carter ER, Chiong JR, Ely EW, Hansen-Flaschen J, O'Donnell DE, Waller A (March 2010). "American College of Chest Physicians consensus statement on the management of dyspnea in patients with advanced lung or heart disease". Chest 137 (3): 674–91. doi:10.1378/chest.09-1543. PMID 20202949.

[11] "Selected opioid analgesics for pain". Uptodate. Retrieved 23 September 2011.

[NEPOD_Report-12] Mattick RP, Digiusto E, Doran C, O’Brien S, Kimber J, Henderson N, Breen B, Shearer J, Gates J, Shakeshaft A, NEPOD Trial Investigators (2004). National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD): Report of Results and Recommendation (PDF). Monograph Series No. 52 (Australian Government). ISBN 0-642-82459-2.

[pmid15082884-13] Stefano GB, Zhu W, Cadet P, Bilfinger TV, Mantione K (March 2004). "Morphine enhances nitric oxide release in the mammalian gastrointestinal tract via the micro(3) opiate receptor subtype: a hormonal role for endogenous morphine". J. Physiol. Pharmacol. 55 (1 Pt 2): 279–88. PMID 15082884.

[Calignano.2C_Moncada_and_Di_Rosa-14] Calignano A, Moncada S, Di Rosa M (December 1991). "Endogenous nitric oxide modulates morphine-induced constipation". Biochem. Biophys. Res. Commun. 181 (2): 889–93. doi:10.1016/0006-291X(91)91274-G. PMID 1755865.

[martin_and_fraser-15] Martin WR, Fraser HF (1961). "A comparative study of physiological and subjective effects of heroin and morphine administered intravenously in postaddicts". J. Pharmacol. Exp. Ther. 133: 388–99. PMID 13767429.

[urlDrugFacts:_Heroin_.7C_National_Institute_on_Drug_Abuse_.28NIDA.29-16] National Institute on Drug Abuse (NIDA) (April 2013). "Heroin". DrugFacts. U.S. National Institutes of Health.

[17] Weissman DE, Haddox JD (1989). "Opioid pseudoaddiction-an iatrogenic syndrome". Pain 36 (3): 363–6. doi:10.1016/0304-3959(89)90097-3. PMID 2710565.

[18] Xu Z, Hou B, Gao Y, He F, Zhang C (2007). "Effects of enriched environment on morphine-induced reward in mice". Exp. Neurol. 204 (2): 714–9. doi:10.1016/j.expneurol.2006.12.027. PMID 17331503.

[19] Roshanpour M, Ghasemi M, Riazi K, Rafiei-Tabatabaei N, Ghahremani MH, Dehpour AR (2009). "Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone". Epilepsy Res. 83 (2–3): 261–4. doi:10.1016/j.eplepsyres.2008.10.011. PMID 19059761.

[20] Koch T, Höllt V (2008). "Role of receptor internalization in opioid tolerance and dependence". Pharmacol. Ther. 117 (2): 199–206. doi:10.1016/j.pharmthera.2007.10.003. PMID 18076994.

[21] [1]

[Chan.2C_Irvine.2C_and_White-22] Chan R, Irvine R, White J (1999). "Cardiovascular changes during morphine administration and spontaneous withdrawal in the rat". Eur. J. Pharmacol. 368 (1): 25–33. doi:10.1016/S0014-2999(98)00984-4. PMID 10096766.

[urlDrugs_and_Human_Performance_FACT_SHEETS_-_Morphine_.28and_Heroin.29-23] "Morphine (and Heroin)". Drugs and Human Performance Fact Sheets. U.S. National Traffic Safety Administration.

[24] "Narcotics". DEA Briefs & Background, Drugs and Drug Abuse, Drug Descriptions. U.S. Drug Enforcement Administration.

[25] Dalrymple T (2006). Romancing Opiates: Pharmacological Lies and the Addiction Bureaucracy. Encounter. p. 160. ISBN 978-1-59403-087-1.

[pmid11594449-26] Anraku T, Ikegaya Y, Matsuki N, Nishiyama N (September 2001). "Withdrawal from chronic morphine administration causes prolonged enhancement of immobility in rat forced swimming test". Psychopharmacology (Berl.) 157 (2): 217–20. doi:10.1007/s002130100793. PMID 11594449.

[27] O'Neil MJ (2006). The Merck index : an encyclopedia of chemicals, drugs, and biological. Whitehouse Station, N.J.: Merck. ISBN 0-911910-00-X.

[pmid23414717-28] Brennan MJ (March 2013). "The effect of opioid therapy on endocrine function". Am. J. Med. 126 (3 Suppl 1): S12–8. doi:10.1016/j.amjmed.2012.12.001. PMID 23414717.

[pmid19193821-29] Colameco S, Coren JS (January 2009). "Opioid-induced endocrinopathy". J Am Osteopath Assoc 109 (1): 20–5. PMID 19193821.

[Duldner-30] MedlinePlus – Morphine overdose Update Date: 2/3/2009. Updated by: John E. Duldner, Jr., MD

[31] Macchiarelli L, Arbarello Cave Bondi P. Di Luca NM, Feola T (2002). Medicina Legale (compendio) (II ed.). Italy, Turin: Minerva Medica Publications.

[pmid15334697-32] Wu SD, Zhang ZH, Jin JZ, Kong J, Wang W, Zhang Q, Li DY, Wang MF (October 2004). "Effects of narcotic analgesic drugs on human Oddi's sphincter motility". World J. Gastroenterol. 10 (19): 2901–4. PMID 15334697.

[pmid11316181-33] Thompson DR (April 2001). "Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis". Am. J. Gastroenterol. 96 (4): 1266–72. doi:10.1111/j.1572-0241.2001.03536.x. PMID 11316181.

[34] Yekkirala AS, Kalyuzhny AE, Portoghese PS (2010). "Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin as selective μ-δ agonists". ACS Chem Neurosci 1 (2): 146–54. doi:10.1021/cn9000236. PMC 3398540. PMID 22816017.

[35] Yekkirala AS, Banks ML, Lunzer MM, Negus SS, Rice KC, Portoghese PS (2012). "Clinically employed opioid analgesics produce antinociception via μ-δ opioid receptor heteromers in Rhesus monkeys". ACS Chem Neurosci 3 (9): 720–7. doi:10.1021/cn300049m. PMC 3447399. PMID 23019498.

[rxlist.com-36] "MS-Contin (Morphine Sulfate Controlled-Release) Drug Information: Clinical Pharmacology". Prescribing Information. RxList.

[37] Chien CC, Pasternak GW (1995). "Sigma antagonists potentiate opioid analgesia in rats". Neurosci. Lett. 190 (2): 137–9. doi:10.1016/0304-3940(95)11504-P. PMID 7644123.

[38] Herman BH, Vocci F, Bridge P (1995). "The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal. Medication development issues for opiate addiction". Neuropsychopharmacology 13 (4): 269–93. doi:10.1016/0893-133X(95)00140-9. PMID 8747752.

[39] Loguinov A, Anderson L, Crosby G, Yukhananov R (2001). "Gene expression following acute morphine administration". Physiol Genomics 6 (3): 169–81. PMID 11526201.

[messmer_2006-40] Messmer D, Hatsukari I, Hitosugi N, Schmidt-Wolf IG, Singhal PC (2006). "Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation". Mol. Med. 12 (11–12): 284–90. doi:10.2119/2006-00043.Messmer. PMC 1829197. PMID 17380193.

[pmid17908329-41] Clark JD, Shi X, Li X, Qiao Y, Liang D, Angst MS, Yeomans DC (2007). "Morphine reduces local cytokine expression and neutrophil infiltration after incision". Mol Pain 3: 28. doi:10.1186/1744-8069-3-28. PMC 2096620. PMID 17908329.

[42] Trescot AM, Datta S, Lee M, Hansen H (2008). "Opioid pharmacology". Pain Physician 11 (2 Suppl): S133–53. PMID 18443637.

[43] Kilpatrick G.J. and Smith T.W. (2005). "Morphine-6-glucuronide: actions and mechanisms". Med. Res. Rev. 25 (5): 521–544. doi:10.1002/med.20035. PMID 15952175.

[van_Dorp-44] van Dorp EL, Romberg R, Sarton E, Bovill JG, Dahan A (2006). "Morphine-6-glucuronide: morphine's successor for postoperative pain relief?". Anesthesia and Analgesia 102 (6): 1789–1797. doi:10.1213/01.ane.0000217197.96784.c3. PMID 16717327.

[Jenkins_AJ_2008-45] Jenkins AJ (2008) Pharmacokinetics of specific drugs. In Karch SB (Ed), Pharmacokinetics and pharmacodynamics of abused drugs. CRC Press: Boca Raton.

[46] Baselt RC (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1057–1062. ISBN 0-9626523-7-7.

[pmid11484423-47] Vandevenne M, Vandenbussche H, Verstraete A (2000). "Detection time of drugs of abuse in urine". Acta Clin Belg 55 (6): 323–33. PMID 11484423.

[pmid15228165-48] Verstraete AG (April 2004). "Detection times of drugs of abuse in blood, urine, and oral fluid". Ther Drug Monit 26 (2): 200–5. doi:10.1097/00007691-200404000-00020. PMID 15228165.

[pmid1755931-49] Kerr B, Hill H, Coda B, Calogero M, Chapman CR, Hunt E, Buffington V, Mackie A (November 1991). "Concentration-related effects of morphine on cognition and motor control in human subjects". Neuropsychopharmacology 5 (3): 157–66. PMID 1755931.

[50] Friswell J, Phillips C, Holding J, Morgan CJ, Brandner B, Curran HV (2008). "Acute effects of opioids on memory functions of healthy men and women". Psychopharmacology (Berl.) 198 (2): 243–50. doi:10.1007/s00213-008-1123-x. PMID 18379759.

[51] Galski T, Williams JB, Ehle HT (2000). "Effects of opioids on driving ability". J Pain Symptom Manage 19 (3): 200–8. doi:10.1016/S0885-3924(99)00158-X. PMID 10760625.

[Kapoor-52] Kapoor L (1995). Opium Poppy: Botany, Chemistry, and Pharmacology. United States: CRC Press. p. 164. ISBN 1-56024-923-4.

[pmid925935-53] Vincent PG, Bare CE, Gentner WA (December 1977). "Thebaine content of selections of Papaver bracteatum Lindl. at different ages". J Pharm Sci 66 (12): 1716–9. doi:10.1002/jps.2600661215. PMID 925935.

[54] Merriam-Webster Dictionary endorphin

[55] Stewart O (2000). Functional Neuroscience. New York: Springer. p. 116. ISBN 0-387-98543-3.

[urlwww.auburn.edu-56] DeRuiter J (Fall 2000). "Narcotic analgesics: morphine and "peripherally modified" morphine analogs" (PDF). Principles of Drug Action 2. Auburn University.

[CRC_85-57] Lide DR, ed. (2004). CRC handbook of chemistry and physics: a ready-reference book of chemical and physical data (85 ed.). Boca Ratan Florida: CRC Press. ISBN 0-8493-0485-7.

[urlMorphine-58] "Morphine". LHA Science Page. LaurenHill Academy.

[59] Novak B, Hudlicky T, Reed J, Mulzer J, Trauner D (March 2000). "Morphine Synthesis and Biosynthesis-An Update". Current Organic Chemistry 4 (3): 343–362. doi:10.2174/1385272003376292.

[60] Gates M, Tschudi G (April 1956). "The Synthesis of Morphine". Journal of the American Chemical Society 78 (7): 1380–1393. doi:10.1021/ja01588a033.

[61] Rice KC (July 1980). "Synthetic opium alkaloids and derivatives. A short total synthesis of (+/-)-dihydrothebainone, (+/-)-dihydrocodeinone, and (+/-)-nordihydrocodeinone as an approach to a practical synthesis of morphine, codeine, and congeners". The Journal of Organic Chemistry 45 (15): 3135–3137. doi:10.1021/jo01303a045.

[62] Evans DA, Mitch CH (January 1982). "Studies directed towards the total synthesis of morphine alkaloids". Tetrahedron Letters 23 (3): 285–288. doi:10.1016/S0040-4039(00)86810-0.

[63] Toth JE, Hamann PR, Fuchs PL (September 1988). "Studies culminating in the total synthesis of (dl)-morphine". The Journal of Organic Chemistry 53 (20): 4694–4708. doi:10.1021/jo00255a008.

[64] Parker KA, Fokas D (November 1992). "Convergent synthesis of (+/-)-dihydroisocodeine in 11 steps by the tandem radical cyclization strategy. A formal total synthesis of (+/-)-morphine". Journal of the American Chemical Society 114 (24): 9688–9689. doi:10.1021/ja00050a075.

[65] Hong CY, Kado N, Overman LE (November 1993). "Asymmetric synthesis of either enantiomer of opium alkaloids and morphinans. Total synthesis of (-)- and (+)-dihydrocodeinone and (-)- and (+)-morphine". Journal of the American Chemical Society 115 (23): 11028–11029. doi:10.1021/ja00076a086.

[66] Mulzer J, Dürner G, Trauner D (December 1996). "Formal Total Synthesis of(—)-Morphine by Cuprate Conjugate Addition". Angewandte Chemie International Edition in English 35 (2324): 2830–2832. doi:10.1002/anie.199628301.

[67] White JD, Hrnciar P, Stappenbeck F (October 1999). "Asymmetric Total Synthesis of (+)-Codeine via Intramolecular Carbenoid Insertion". The Journal of Organic Chemistry 64 (21): 7871–7884. doi:10.1021/jo990905z.

[68] Taber DF, Neubert TD, Rheingold AL (October 2002). "Synthesis of (−)-Morphine". Journal of the American Chemical Society 124 (42): 12416–12417. doi:10.1021/ja027882h. PMID 12381175.

[69] Trost BM, Tang W (December 2002). "Enantioselective Synthesis of (−)-Codeine and (−)-Morphine". Journal of the American Chemical Society 124 (49): 14542–14543. doi:10.1021/ja0283394. PMID 12465957.

[70] Uchida K, Yokoshima S, Kan T, Fukuyama T (November 2006). "Total Synthesis of (±)-Morphine". Organic Letters 8 (23): 5311–5313. doi:10.1021/ol062112m. PMID 17078705.

[71] Varin M, Barré E, Iorga B, Guillou C (2008). "Diastereoselective Total Synthesis of (±)-Codeine". Chemistry - A European Journal 14 (22): 6606–6608. doi:10.1002/chem.200800744.

[72] Stork G, Yamashita A, Adams J, Schulte GR, Chesworth R, Miyazaki Y, Farmer JJ (2009). "Regiospecific and Stereoselective Syntheses of (±) Morphine, Codeine, and Thebaine via a Highly Stereocontrolled Intramolecular 4 + 2 Cycloaddition Leading to a Phenanthrofuran System". Journal of the American Chemical Society 131 (32): 11402–11406. doi:10.1021/ja9038505. PMID 19624126.

[73] Small LF, Lutz RE (1932). Chemistry of the Opium Alkaloids. Washington, D. C.: U. S. Government Printing Office. pp. 153–154. ASIN B000H4LBY8.

[Klous_2005-74] Klous MG, Van den Brink W, Van Ree JM, Beijnen JH (December 2005). "Development of pharmaceutical heroin preparations for medical co-prescription to opioid dependent patients". Drug Alcohol Depend 80 (3): 283–95. doi:10.1016/j.drugalcdep.2005.04.008. PMID 15916865.

[75] Rapoport H, Lovell CH, Tolbert BM (December 1951). "The Preparation of Morphine-N-methyl-C¹⁴". Journal of the American Chemical Society 73 (12): 5900–5900. doi:10.1021/ja01156a543.

[76] Crews JC, Denson DD (1990). "Recovery of morphine from a controlled-release preparation. A source of opioid abuse". Cancer 66 (12): 2642–4. doi:10.1002/1097-0142(19901215)66:12<2642::AID-CNCR2820661229>3.0.CO;2-B. PMID 2249204.

[77] Ramoutsaki IA, Askitopoulou H, Konsolaki E (December 2002). "Pain relief and sedation in Roman Byzantine texts: Mandragoras officinarum, Hyoscyamos niger and Atropa belladonna". International Congress Series 1242: 43–50. doi:10.1016/S0531-5131(02)00699-4.

[78] Friedrich Sertürner (1805) (Untitled letter to the editor), Journal der Pharmacie für Aerzte, Apotheker und Chemisten (Journal of Pharmacy for Physicians, Apothecaries, and Chemists), 13 : 229-243 ; see especially "III. Säure im Opium" (acid in opium), pp. 234-235, and "I. Nachtrag zur Charakteristik der Säure im Opium" (Addendum on the characteristics of the acid in opium), pp. 236-241.

[79] Luch A, ed. (2009). Molecular, clinical and environmental toxicology. Springer. p. 20. ISBN 3-7643-8335-6.

[80] Vassallo SA (July 2004). "Lewis H. Wright Memorial Lecture". ASA New Letter 68 (7): 9–10.

[urlCanadian_Government_Commission_-_Opiate_Narcotics-81] "Opiate Narcotics". The Report of the Canadian Government Commission of Inquiry into the Non-Medical Use of Drugs. Canadian Government Commission.

[urlMythical_Roots_of_US_Drug_Policy_-_Soldiers_Disease_and_Addicts_in_the_Civil_War-82] Mandel J. "Mythical Roots of US Drug Policy - Soldier's Disease and Addicts in the Civil War".

[urlSoldiers_Disease_A_Historical_Hoax.3F-83] "Soldiers Disease A Historical Hoax?". iPromote Media Inc. 2006.

[pmid11961074-84] Winger G, Hursh SR, Casey KL, Woods JH (May 2002). "Relative reinforcing strength of three N-methyl-D-aspartate antagonists with different onsets of action". J. Pharmacol. Exp. Ther. 301 (2): 690–7. doi:10.1124/jpet.301.2.690. PMID 11961074.

[85] "Morphine Easy Home Cure". Overland Monthly 35 (205): 14. 1900.

[urlMarshall_D._Gates.2C_Chemist_to_First_Synthesize_Morphine.2C_Dies_:_Rochester_News-86] Dickman S (3 October 2003). "Marshall D. Gates, Chemist to First Synthesize Morphine, Dies". Press Release. University of Rochester.

[87] Zhu W, Cadet P, Baggerman G, Mantione KJ, Stefano GB (2005). "Human white blood cells synthesize morphine: CYP2D6 modulation". J. Immunol. 175 (11): 7357–62. doi:10.4049/jimmunol.175.11.7357. PMID 16301642.

[88] Poeaknapo C, Schmidt J, Brandsch M, Dräger B, Zenk MH; Schmidt; Brandsch; Dräger; Zenk (2004). "Endogenous formation of morphine in human cells". Proc. Natl. Acad. Sci. U.S.A. 101 (39): 14091–6. Bibcode:2004PNAS..10114091P. doi:10.1073/pnas.0405430101. PMC 521124. PMID 15383669.

[89] Anlage III (zu § 1 Abs. 1) verkehrsfähige und verschreibungsfähige Betäubungsmittel

[90] "List of narcotic drugs under international control". Yellow List (PDF) (50th ed.) (Austria: International Narcotics Control Board): 5. March 2011.

[91] Donald G. McNeil Jr. (10 September 2007). "Drugs Banned, Many of World's Poor Suffer in Pain". New York Times. Retrieved 11 September 2007.

Systematic (IUPAC) name


(5α,6α)-7,8-didehydro- 4,5-epoxy-17-methylmorphinan-3,6-diol
Clinical data
Trade names	Mscontin, Oramorph, Sevredol (morphine as a sulfate)
AHFS/Drugs.com	sulfate.html monograph
Pregnancy cat.	AU: D US: C
Legal status	AU: Controlled (S8) CA: Schedule I US: Schedule II UN: Narcotic Schedules I and III Prescription Medicine Only
Dependence liability	High
Routes	Inhalation (smoking), insufflation (snorting), oral, rectal, subcutaneous (SC), intramuscular (IM), intravenous (IV), epidural, and intrathecal (IT)
Pharmacokinetic data
Bioavailability	20–40% (oral), 36–71% (rectally),^[1] 100% (IV/IM)
Protein binding	30–40%
Metabolism	Hepatic 90%
Half-life	2–3 h
Excretion	Renal 90%, biliary 10%
Identifiers
CAS number	57-27-2^Y 64-31-3 (neutral sulfate), 52-26-6 (hydrochloride)
ATC code	N02AA01
PubChem	CID 5288826
IUPHAR ligand	1627
DrugBank	DB00295
ChemSpider	4450907^Y
UNII	76I7G6D29C^Y
KEGG	D08233^Y
ChEBI	CHEBI:17303^Y
ChEMBL	CHEMBL70^Y
Chemical data
Formula	C₁₇H₁₉NO₃
Mol. mass	285.34
SMILES CN1CC[C@]23C4=C5C=CC(O)=C4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
InChI InChI=1S/C17H19NO3/c1-18-7-6-17-10-3-5-13(20)16(17)21-15-12(19)4-2-9(14(15)17)8-11(10)18/h2-5,10-11,13,16,19-20H,6-8H2,1H3/t10-,11+,13-,16-,17-/m0/s1^Y Key:BQJCRHHNABKAKU-KBQPJGBKSA-N^Y
Physical data
Solubility in water	HCl & sulf.: 60 mg/mL (20 °C)
Y (what is this?) (verify)

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morphine hydrochloride