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Morphine

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"Morphia" redirects here. For other uses, seeMorphia (disambiguation)andMorphine (disambiguation).
Not to be confused withMorpheeinorMorpheme.

Morphine
Clinical data
Pronunciation/ˈmɔːrfiːn/
Trade namesStatex, MS Contin, Oramorph, others[1]
AHFS/DrugsMonograph
MedlinePlusa682133
License data
Pregnancy
category
Dependence
liability		High
Addiction
liability		High[3]
Routes of
administration		Inhalation(smoking),insufflation(snorting),by mouth,rectal,subcutaneous,intramuscular,intravenous,epidural,intrathecal
Drug classOpiate
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability20–40% (by mouth), 36–71% (rectally),[9]100% (IV/IM)
Protein binding30–40%
MetabolismLiver:UGT2B7
Metabolites•Morphine-3-glucuronide(90%)
•Morphine-6-glucuronide(10%)
Onset of action5 minutes (IV), 15 minutes (IM),[10]20 minutes (PO)[11]
Eliminationhalf-life2–3 hours
Duration of action3–7 hours[12][13]
ExcretionKidney90%,bile duct10%
Identifiers
  • (4R,4aR,7S,7aR,12bS)-3-Methyl-2,3,4,4a,7,7a-hexahydro-1H-4,12-methano[1]benzofuro[3,2-e]isoquinoline-7,9-diol
CAS Number
  • 57-27-2checkY
    64-31-3 (neutral sulfate),
    52-26-6 (hydrochloride)
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.000.291Edit this at Wikidata
Chemical and physical data
FormulaC17H19NO3
Molar mass285.343g·mol−1
3D model (JSmol)
Solubility in waterHCl & sulf.: 60
  • CN1CC[C@]23C4=C5C=CC(O)=C4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
  • 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/s1checkY
  • Key:BQJCRHHNABKAKU-KBQPJGBKSA-NcheckY
(verify)

Morphine,formerly also calledmorphia,[14]is a strongopiatethat is found naturally inopium,a dark brown resin produced by drying the latex of opium poppies (Papaver somniferum). It is mainly used as ananalgesic(pain medication). There are numerous methods used to administer morphine: oral;sublingual;via inhalation;injection into a muscle,injection under the skin,or injection into thespinal cordarea;transdermal;or viarectalsuppository.[12][15]It acts directly on thecentral nervous system(CNS) to induceanalgesiaand alter perception and emotional response to pain. Physical and psychological dependence and tolerance may develop with repeated administration.[12]It can be taken for bothacute painandchronic painand is frequently used for pain frommyocardial infarction,kidney stones,and duringlabor.[12]Its maximum effect is reached after about 20 minutes when administered intravenously and 60 minutes when administered by mouth, while the duration of its effect is 3–7 hours.[12][13]Long-acting formulations of morphine are available asMS-Contin,Kadian, and other brand names as well as generically.[12]

Potentially seriousside effectsof morphine include decreased respiratory effort,vomiting,nausea,andlow blood pressure.[12]Morphine isaddictiveand prone toabuse.[12]If one's dose is reduced after long-term use,opioid withdrawalsymptoms may occur.[12]Common side effects of morphine include drowsiness, vomiting, and constipation.[12]Caution is advised for use of morphine duringpregnancyorbreast feeding,as it may affect the health of the baby.[12][2]

Morphine was first isolated between 1803 and 1805 by German pharmacistFriedrich Sertürner.[16]This is believed to be the first isolation of a medicinal alkaloid from a plant.[17]Merckbegan marketing it commercially in 1827.[16]Morphine was more widely used after the invention of thehypodermic syringein 1853–1855.[16][18]Sertürner originally named the substancemorphium,after the Greek god of dreams,Morpheus,as it has a tendency to cause sleep.[18][19]

The primary source of morphine is isolation frompoppy strawof theopium poppy.[20]In 2013, approximately 523 tons of morphine were produced.[21]Approximately 45 tons were used directly for pain, an increase of 400% over the last twenty years.[21]Most use for this purpose was in thedeveloped world.[21]About 70 percent of morphine is used to make otheropioidssuch ashydromorphone,oxymorphone,andheroin.[21][22][23]It is aSchedule II drugin the United States,[22]Class Ain the United Kingdom,[5]andSchedule Iin Canada.[24]It is on theWorld Health Organization's List of Essential Medicines.[25]Morphine is sold under many brand names.[1]In 2021, it was the 156th most commonly prescribed medication in the United States, with more than 3million prescriptions.[26][27]It is available as ageneric medication.[28]

Medical uses[edit]

Pain[edit]

Morphine is used primarily to treat both acute andchronicseverepain.Its duration of analgesia is about three to seven hours.[12][13]Side-effects of nausea and constipation are rarely severe enough to warrant stopping treatment.

It is used for pain due tomyocardial infarctionand for labor pains.[12]However, concerns exist that morphine may increase mortality in the event ofnon ST elevation myocardial infarction.[29]

Morphine has also traditionally been used in the treatment ofacute pulmonary edema.[12]However, a 2006 review found little evidence to support this practice.[30]

A 2016 Cochrane review concluded that morphine is effective in relievingcancer pain.[31]

Shortness of breath[edit]

Morphine is beneficial in reducing the symptom ofshortness of breathdue to bothcancerand noncancer causes.[32][33]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.[34][35]

Opioid use disorder[edit]

Morphine is also available as a slow-release formulation foropiate substitution therapy(OST) in Austria, Germany, Bulgaria, Slovenia, and Canada for persons with opioid addiction who cannot tolerate either methadone orbuprenorphine.[36]

  • Two capsules (5 mg & 10 mg) of morphine sulfate extended-release
    Two capsules (5 mg & 10 mg) of morphine sulfate extended-release
  • 1 milliliter ampoule containing 10 mg of morphine
    1 milliliter ampoule containing 10 mg of morphine

Contraindications[edit]

Relativecontraindicationsto morphine include:

Adverse effects[edit]

Adverse effects of opioids
Common and short term
Other
A localized reaction to intravenous morphine caused by histamine release in the veins

Constipation[edit]

Likeloperamideand other opioids, morphine acts on themyenteric plexusin the intestinal tract, reducing gut motility, causing constipation. The gastrointestinal effects of morphine are mediated primarily byμ-opioid receptorsin the bowel. By inhibiting gastric emptying and reducing propulsiveperistalsisof 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 ofnitric oxidegeneration.[39]This effect was shown in animals when a nitric oxide precursor,L-arginine,reversed morphine-induced changes in gut motility.[40]

Hormone imbalance[edit]

See also:Opioid § Hormone imbalance

Clinical studies consistently conclude that morphine, like other opioids, often causeshypogonadismandhormone imbalancesin chronic users of both sexes. This side effect isdose-dependentand occurs in both therapeutic and recreational users. Morphine can interfere with menstruation by suppressing levels ofluteinizing hormone.Many studies suggest the majority (perhaps as many as 90%) of chronic opioid users have opioid-induced hypogonadism. This effect may cause the increased likelihood ofosteoporosisandbone fractureobserved in chronic morphine users. Studies suggest the effect is temporary. As of 2013,the effect of low-dose or acute use of morphine on the endocrine system is unclear.[41][42]

Effects on human performance[edit]

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 acentral nervous systemdepressant.Morphine has resulted in impaired functioning on critical flicker frequency (a measure of overall CNS arousal) and impaired performance on theMaddox wingtest (a measure of the 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 ofisometric force(i.e. fine motor control is impaired),[43]though no studies have shown a correlation between morphine and gross motor abilities.

In terms ofcognitiveabilities, one study has shown that morphine may have a negative impact onanterogradeandretrograde memory,[44]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 inattentionand 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 2000 study[45]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 the speed of responding for successful performance (e.g.,Rey Complex FigureTest) but made more errors than controls. COAT patients showed no deficits in visual-spatial perception and organization (as shown in theWAIS-RBlock 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 onpsychomotor,cognitive,orneuropsychologicalfunctioning.

Reinforcement disorders[edit]

Addiction[edit]

Before the MorphinebySantiago Rusiñol

Morphine is a highlyaddictivesubstance. Numerous studies, including one byThe Lancet,ranked Morphine/Heroin as #1 most addictive substance, followed byCocaineat #2,Nicotine#3, followed byBarbituratesat #4 andethanolat #5. In controlled studies comparing the physiological and subjective effects ofheroinand 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 diacetylmorphine crossing the BBB slightly quicker. No difference in subjects' self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness.[46]Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both heroin and morphine. When compared to the opioidshydromorphone,fentanyl,oxycodone,andpethidine/meperidine,former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to abuse and addiction. Morphine and heroin also produced higher rates of euphoria and other positive subjective effects when compared to these other opioids.[46]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 morphineprodrug,essentially meaning they are identical drugsin vivo.Heroin is converted to morphine before binding to theopioid receptorsin the brain and spinal cord, where morphine causes the subjective effects, which is what the addicted individuals are seeking.[47]

Tolerance[edit]

Several hypotheses are given about how tolerance develops, including opioid receptorphosphorylation(which would change the receptor conformation), functional decoupling of receptors fromG-proteins(leading to receptor desensitization),[48]μ-opioid receptor internalization or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of thecAMPpathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.[49])

Dependence and withdrawal[edit]

See also:Opioid use disorderandOpioid withdrawal

Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which, unlike that ofbarbiturates,benzodiazepines,alcohol,orsedative-hypnotics, is not fatal by itself in otherwise healthy people.

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 h to 14 h after last dose: Drug craving, anxiety, irritability, perspiration, and mild to moderatedysphoria
  • Stage II,14 h to 18 h after last dose: Yawning, heavy perspiration, mild depression,lacrimation,crying, headaches, runny nose,dysphoria,also intensification of the above symptoms, "yen sleep" (a waking trance-like state)
  • Stage III,16 h to 24 h after last dose:Rhinorrhea(runny nose) and increase in other of the above, dilated pupils, piloerection (goose bumps – a purported origin of the phrase, 'cold turkey,' but in fact the phrase originated outside of drug treatment),[50]muscle twitches, hot flashes, cold flashes, aching bones and muscles, loss of appetite, and the beginning of intestinal cramping
  • Stage IV,24 h to 36 h after last dose: Increase in all of the above including severe cramping and involuntary leg movements ( "kicking the habit" also calledrestless 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 h to 72 h 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, weight loss of 2 kg to 5 kg per 24 h, increasedwhite cell count,and other blood changes
  • Stage VI,after completion of above: Recovery of appetite and normal bowel function, beginning of transition to post acute and chronic symptoms that are mainly psychological, but may also include increased sensitivity to pain, hypertension,colitisor 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 pancreaticsphincter of Oddi.[51]

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 h to 12 h) 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 syndrome 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,[52]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 "[47]) and excessive sweating are also characteristic symptoms.[53]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 h and 96 h 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.[54][55]

The psychological dependence associated with morphineaddictionis 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. Addicts often experience 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.[56]

Toxicity[edit]

See also:Opioid overdose
Properties of Morphine
Molar mass[57] 285.338 g/mol
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

A largeoverdosecan causeasphyxiaand death by respiratory depression if the person does not receive medical attention immediately.[58]Overdose treatment includes the administration ofnaloxone.The latter completely reverses morphine's effects, but may result in immediate onset of withdrawal in opiate-addicted subjects. Multiple doses may be needed as the duration of action of morphine is longer than that of naloxone.[59]

Pharmacology[edit]

Pharmacodynamics[edit]

Morphine at opioid receptors
Compound Affinities(KiTooltip Inhibitor constant) Ratio Ref
MORTooltip μ-Opioid receptor DORTooltip δ-Opioid receptor KORTooltip κ-Opioid receptor MOR:DOR:KOR
Morphine 1.8 nM 90 nM 317 nM 1:50:176 [60]
(−)-Morphine 1.24 nM 145 nM 23.4 nM 1:117:19 [61]
(+)-Morphine >10 μM >100 μM >300 μM ND [61]

Equianalgesic doses[62][63][64]
Compound Route Dose
Codeine PO 200 mg
Hydrocodone PO 20–30 mg
Hydromorphone PO 7.5 mg
Hydromorphone IV 1.5 mg
Morphine PO 30 mg
Morphine IV 10 mg
Oxycodone PO 20 mg
Oxycodone IV 10 mg
Oxymorphone PO 10 mg
Oxymorphone IV 1 mg

Due to its long history and established use as a pain medication, this compound has become the benchmark to which all other opioids are compared.[65]It interacts predominantly with the μ–δ-opioid (Mu-Delta)receptor heteromer.[66][67]The μ-binding sites are discretely distributed in thehuman brain,with high densities in the posterioramygdala,hypothalamus,thalamus,nucleus caudatus,putamen,and certain cortical areas. They are also found on theterminal axonsof primary afferents within laminaeIand II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of thetrigeminal nerve.[68]

Morphine is aphenanthreneopioid receptoragonist– its main effect is binding to and activating theμ-opioid receptor(MOR) in thecentral nervous system.Itsintrinsic activityat the MOR is heavily dependent on theassayand tissue being tested; in some situations it is afull agonistwhile in others it can be apartial agonistor evenantagonist.[69]In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system andgastrointestinal tract.Its primary actions of therapeutic value are analgesia and sedation. Activation of the MOR is associated with analgesia, sedation,euphoria,physicaldependence,andrespiratory depression.Morphine is also aκ-opioid receptor(KOR) andδ-opioid receptor(DOR) agonist. Activation of the KOR is associated with spinal analgesia,miosis(pinpoint pupils), andpsychotomimeticeffects. The DOR is thought to play a role in analgesia.[68][failed verification]Although morphine does not bind to theσ receptor,it has been shown that σ receptor agonists, such as(+)-pentazocine,inhibit morphine analgesia, and σ receptor antagonists enhance morphine analgesia,[70]suggesting downstream involvement of the σ receptor in the actions of morphine.

The effects of morphine can be countered withopioid receptor antagonistssuch asnaloxoneandnaltrexone;the development of tolerance to morphine may be inhibited byNMDA receptor antagonistssuch asketamine,dextromethorphan,andmemantine.[71][72]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 aslevorphanol,ketobemidone,piritramide,andmethadoneand 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[73]ordextromoramide.[citation needed]

Morphinehydrochlorideampoule forveterinary use

Gene expression[edit]

Studies have shown that morphine can alter the expression of a number ofgenes.A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved inmitochondrialrespiration and forcytoskeleton-related proteins.[74]

Effects on the immune system[edit]

Morphine has long been known to act on receptors expressed on cells of thecentral nervous systemresulting in pain relief andanalgesia.In the 1970s and '80s, evidence suggesting that opioid drug addicts show increased risk of infection (such as increasedpneumonia,tuberculosis,andHIV/AIDS) led scientists to believe that morphine may also affect theimmune system.This possibility increased interest in the effect of chronic morphine use on the immune system.[75]

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 thatdendritic cells,part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producingcytokines,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 moreinterleukin-12(IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and lessinterleukin-10(IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection).[76]

This regulation of cytokines appear to occur via thep38 MAPKs (mitogen-activated protein kinase)-dependent pathway.Usually, the p38 within the dendritic cell expressesTLR 4(toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide). This causes the p38 MAPK to bephosphorylated.This phosphorylation activates thep38 MAPKto 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 ofneutrophilsand othercytokines.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 fightinfectionand control healing (and, possibly, to control pain), but pre-incisional morphine administration (0.1 mg/kg to 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.[77]

Pharmacokinetics[edit]

Absorption and metabolism[edit]

Morphine can be takenorally,sublingually,bucally,rectally,subcutaneously,intranasally,intravenously,intrathecallyorepidurallyand inhaled via a nebulizer. As a recreational drug, 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 extensivefirst-pass metabolism(a large proportion is broken down in the liver), so, if taken orally, only 40% to 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 min, and, after oral administration, levels peak in approximately 30 min.[78]Morphine ismetabolisedprimarily in theliverand approximately 87% of a dose of morphine is excreted in theurinewithin 72 h of administration. Morphine is metabolized primarily intomorphine-3-glucuronide(M3G) andmorphine-6-glucuronide(M6G)[79]viaglucuronidationby phase II metabolism enzymeUDP-glucuronosyl transferase-2B7(UGT2B7). About 60% of morphine is converted to M3G, and 6% to 10% is converted to M6G.[80]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.[80]Morphine may also be metabolized into small amounts ofnormorphine,codeine,andhydromorphone.Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any), and use of other medications. The eliminationhalf-lifeof morphine is approximately 120 min, 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 theblood–brain barrier,but, because of poor lipid solubility, protein binding, rapid conjugation with glucuronic acid and ionization, it does not cross easily.Heroin,which is derived from morphine, crosses the blood–brain barrier more easily, making it more potent.[81]

Extended-release[edit]

Main article:Extended-release morphine

There areextended-releaseformulations of orally administered morphine whose effect last longer, which can be given once per day. Brand names for this formulation of morphine include Avinza,[82]Kadian,[82]MS Contin[82]and Dolcontin.[83]For constant pain, the relieving effect of extended-release morphine given once (for Kadian)[84]or twice (for MS Contin)[84]every 24 hours is roughly the same as multiple administrations ofimmediate release(or "regular" ) morphine.[85]Extended-release morphine can be administered together with "rescue doses" of immediate-release morphine as needed in case of breakthrough pain, each generally consisting of 5% to 15% of the 24-hour extended-release dosage.[85]

Detection in body fluids[edit]

Morphine and its major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, can be detected in blood, plasma, hair, and urine using animmunoassay.Chromatographycan be used to test for each of these substances individually. Some testing procedureshydrolyzemetabolic 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 bysolid phase extraction(SPE) and detected usingliquid chromatography-mass spectrometry(LC-MS).

Ingestion of codeine or food containing poppy seeds can cause false positives.[86]

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.[87]A 2009 review determined that, when theanalyteis morphine and thelimit of detectionis 1ng/ml, a 20mg intravenous (IV) dose of morphine is detectable for 12–24 hours. A limit of detection of 0.6ng/ml had similar results.[88]

Chirality and biological activity[edit]

Morphine is a pentacyclic 3°amine (alkaloid) with5 stereogenic centersand exists in32 stereoisomeric forms.But the desired analgesic activity resides exclusively in the natural product, the (-)-enantiomer with the configuration (5R,6S,9R,13S,14R).[89][90]

Natural occurrence[edit]

See also:Opium
Latex bleeding from a freshly-scored seed pod

Morphine is the most abundant opiate found inopium,the driedlatexextracted by shallowly scoring the unripe seedpods of thePapaver somniferumpoppy. Morphine is generally 8–14% of the dry weight of opium.[91]Przemko and Norman cultivars of the opium poppy, are used to produce two other alkaloids,thebaineandoripavine,which are used in the manufacture of semi-synthetic and synthetic opioids likeoxycodoneandetorphine.P. bracteatumdoes not contain morphine orcodeine,or other narcoticphenanthrene-type, alkaloids. This species is rather a source ofthebaine.[92]Occurrence of morphine in otherPapaveralesandPapaveraceae,as well as in some species ofhopsandmulberrytrees 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 ofhydromorphone,dihydromorphine,dihydrocodeine,tetrahydro-thebaine, andhydrocodone(these compounds are rather synthesized from thebaine and oripavine).

In the brain of mammals, morphine is detectable in trace steady-state concentrations.[15]The human body also producesendorphins,which are chemically relatedendogenous opioidpeptidesthat function asneuropeptidesand have similar effects to morphine.[93]

Human biosynthesis[edit]

Morphine is anendogenous opioidin humans. Various human cells are capable of synthesizing and releasing it, includingwhite blood cells.[15][94][95]The primary biosynthetic pathway for morphine in humans consists of:[15]

L-tyrosine→para-tyramineorL-DOPA→Dopamine
L-tyrosine → L-DOPA →3,4-dihydroxyphenylacetaldehyde(DOPAL)
Dopamine + DOPAL →(S)-norlaudanosoline→→→ (S)-reticuline→1,2-dehydroreticulinium→ (R)-reticuline →salutaridine→salutaridinol→thebaine→neopinone→codeinone→codeine→ morphine

The intermediate (S)-norlaudanosoline (also known as tetrahydropapaveroline) is synthesized through addition of DOPAL and dopamine.[15]CYP2D6,acytochrome P450isoenzyme is involved in two steps along the biosynthetic pathway, catalyzing both the biosynthesis of dopamine from tyramine and of morphine from codeine.[15][96]

Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals takingL-DOPAfor the treatment ofParkinson's disease.[15]

Biosynthesis in the opium poppy[edit]

Morphine biosynthesis in the opium poppy

Biosynthesis of morphine in theopium poppybegins with two tyrosine derivatives,dopamineand4-hydroxyphenylacetaldehyde.Condensation of these precursors yields the primary intermediatehigenamine(norcoclaurine).[97]Subsequent action of four enzymes yields the tetrahydroisoquinolinereticuline,which is converted intosalutaridine,thebaine,andoripavine.The enzymes involved in this process are thesalutaridine synthase,salutaridine:NADPH 7-oxidoreductaseand thecodeinone reductase.[98]Researchers are attempting to reproduce the biosynthetic pathway that produces morphine ingenetically engineeredyeast.[99]In June 2015 theS-reticuline could be produced from sugar andR-reticuline could be converted to morphine, but the intermediate reaction could not be performed.[100]In August 2015 the first complete synthesis of thebaine and hydrocodone in yeast was reported, but the process would need to be 100,000 times more productive to be suitable for commercial use.[101][102]

Chemistry[edit]

Elements of the morphine structure have been used to create completely synthetic drugs such as themorphinanfamily (levorphanol,dextromethorphanand others) and other groups that have many members with morphine-like qualities.[citation needed]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.[citation needed]Morphine-derivedagonist–antagonistdrugs have also been developed.[citation needed]

Structure description[edit]

Chemical structure of morphine. Thebenzylisoquinolinebackbone is shown in green.
Morphine structure showing its standard ring lettering and carbon numbering system.[citation needed]
Same structure, but in a three-dimensional perspective.

Morphine is abenzylisoquinolinealkaloid with two additional ring closures.[103]As Jack DeRuiter of the Department of Drug Discovery and Development (formerly, Pharmacal Sciences), Harrison School of Pharmacy, Auburn University stated in his Fall 2000 course notes for that earlier department's "Principles of Drug Action 2" course, "Examination of the morphine molecule reveals the following structural features important to its pharmacological profile...

  1. A rigidpentacyclicstructure consisting of abenzenering (A), two partially unsaturatedcyclohexanerings (B and C), apiperidinering (D) and atetrahydrofuranring (E). Rings A, B and C are thephenanthrenering system. This ring system has little conformational flexibility...
  2. Two hydroxyl functional groups: a C3-phenolic[hydroxyl group] (pKa9.9) and a C6-allylic[hydroxyl group],
  3. Anetherlinkage between E4 and E5,
  4. Unsaturationbetween C7 and C8,
  5. A basic, [tertiary]-amine function at position 17, [and]
  6. [Five] centers of chirality (C5, C6, C9, C13 and C14) with morphine exhibiting a high degree of stereoselectivity of analgesic action. "[104][better source needed][needs update]

Morphine and most of its derivatives do not exhibit optical isomerism, although some more distant relatives like the morphinan series (levorphanol, dextrorphan and the racemic parent chemical racemorphan) do,[105]and as noted above stereoselectivity in vivo is an important issue.[citation needed]

Uses and derivatives[edit]

Most of the licit morphine produced is used to makecodeineby methylation.[106]It is also a precursor for many drugs includingheroin(3,6-diacetylmorphine),hydromorphone(dihydromorphinone), andoxymorphone(14-hydroxydihydromorphinone).[107]Most semi-synthetic opioids, both of the morphine andcodeinesubgroups, are created by modifying one or more of the following:[citation needed]

  • Halogenating or making other modifications at positions 1 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 yieldshydromorphinol;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 or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of moving the methyl functional group from position 3 to 6, codeine becomesheterocodeine,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.

Many morphine derivatives can also be manufactured usingthebaineor codeine as a starting material.[citation needed]Replacement of theN-methyl group of morphine with anN-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency.[citation needed]Combining this modification with the replacement of the 6-hydroxylwith a 6-methylene groupproduces a compound some 1,443 times more potent than morphine, stronger than theBentley compoundssuch asetorphine(M99, the Immobilon tranquilliser dart) by some measures.[citation needed]Closely related to morphine are the opioids morphine-N-oxide (genomorphine), which is a pharmaceutical that is no longer in common use;[citation needed]and pseudomorphine, an alkaloid that exists in opium, form as degradation products of morphine.[citation needed]

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.[citation needed]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, includingnaloxone(Narcan),naltrexone(Trexan),diprenorphine(M5050, the reversing agent for the Immobilon dart) andnalorphine(Nalline).[citation needed]Some opioid agonist-antagonists, partial agonists, and inverse agonists are also derived from morphine.[citation needed]The receptor-activation profile of the semi-synthetic morphine derivatives varies widely and some, likeapomorphineare devoid of narcotic effects.[citation needed]

Chemical salts of Morphine[edit]

Both morphine and its hydrated form are sparingly soluble in water.[108]For this reason, pharmaceutical companies produce sulfate andhydrochloride saltsof the drug, both of which are over 300 times more water-soluble than their parent molecule.[clarification needed][citation needed]Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic.[citation needed]Since they derive from a strong acid but weak base, they are both at about pH = 5;[clarification needed][citation needed]as a consequence, the morphine salts are mixed with small amounts ofNaOHto make them suitable for injection.[citation needed]

A number of salts of morphine are used, with the most common in current clinical use being the hydrochloride, sulfate, tartrate, and citrate;[citation needed]less commonly methobromide, hydrobromide, hydroiodide, lactate, chloride, and bitartrate and the others listed below.[citation needed]Morphine diacetate (heroin) is not a salt, but rather a further derivative,[citation needed]see above.[109]

Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate, sulfate, and some others.[citation needed]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 theNSAID;[citation needed]multiplebarbituratesalts of morphine were also used in the past, as was/is morphine valerate, the salt of the acid being the active principle ofvalerian.[citation needed]Calcium morphenateis the intermediate in various latex and poppy-straw methods of morphine production, more rarely sodium morphenate takes its place.[citation needed]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.[citation needed][110]

The salts listed by theUnited States Drug Enforcement Administrationfor reporting purposes, in addition to a few others, are as follows:[citation needed]

Production[edit]

First generation production of alkaloids from licit latex-derived opium

In theopium poppy,the alkaloids are bound tomeconic 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. Theextractionis performed in many steps (one amount of crushed plant is extracted at least six to ten times, so practically everyalkaloidgoes 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, calledpoppy 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 roughly 8–19% ofopiumby dry weight (depending on growing conditions).[81]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 ofP. somniferum,also developed inTasmania,produces down to 0.04% morphine but with much higher amounts ofthebaineandoripavine,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,Hungarysupplied 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.

Chemical synthesis[edit]

Main article:Morphine total synthesis

The firstmorphine total synthesis,devised byMarshall D. Gates, Jr.in 1952, remains a widely used example oftotal synthesis.[111]Several other syntheses were reported, notably by the research groups of Rice,[112]Evans,[113]Fuchs,[114]Parker,[115]Overman,[116]Mulzer-Trauner,[117]White,[118]Taber,[119]Trost,[120]Fukuyama,[121]Guillou,[122]and Stork.[123]Because of the stereochemical complexity and consequent synthetic challenge presented by thispolycyclicstructure, Michael Freemantle has expressed the view that it is "highly unlikely" that a chemical synthesis will ever be cost-effective such that it could compete with the cost of producing morphine from the opium poppy.[124]

GMO synthesis[edit]

Research[edit]

Thebaine has been produced byGMOE. coli.[125]

Precursor to other opioids[edit]

Pharmaceutical[edit]

Morphine is a precursor in the manufacture in a number of opioids such asdihydromorphine,hydromorphone,hydrocodone,andoxycodoneas well ascodeine,which itself has a large family of semi-synthetic derivatives.[126]

Illicit[edit]

Illicit morphine is produced, though rarely, from codeine found in over-the-counter cough and pain medicines.[citation needed]Another illicit source is morphine extracted from extended-release morphine products.[127]Chemical reactions can then be used to convert morphine, dihydromorphine, and hydrocodone intoheroinor other opioids [e.g.,diacetyldihydromorphine(Paralaudin), andthebacon].[citation needed]Other clandestine conversions—of morphine, into ketones of the hydromorphone class, or other derivatives likedihydromorphine(Paramorfan),desomorphine(Permonid),metopon,etc., and of codeine intohydrocodone(Dicodid),dihydrocodeine(Paracodin), etc. —require greater expertise, and types and quantities of chemicals and equipment that are more difficult to source, and so are more rarely used, illicitly (but cases have been recorded).[citation needed]

History[edit]

Friedrich Sertürner

The earliest known reference to morphine can be traced back to Theophrastus in the 3rd century BC, however, possible references to morphine may go as far back as 2100 BC as Sumerian clay tablets which records lists of medical prescriptions include opium-based cures.[128]

An opium-based elixir has been ascribed toalchemistsofByzantinetimes, but the specific formula was lost during the Ottoman conquest ofConstantinople(Istanbul).[129]Around 1522,Paracelsusmade reference to an opium-based elixir that he calledlaudanumfrom the Latin wordlaudāre,meaning "to praise". He described it as a potent painkiller, but recommended that it be used sparingly. The recipe given differs substantially from that of modern-day laudanum.[130]

Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 inPaderbornby German pharmacistFriedrich Sertürner.[17][131]In 1817, Sertürner reported experiments in which he administered morphine to himself, three young boys, three dogs, and a mouse; all four people almost died.[132]Sertürner originally named the substancemorphiumafter the Greek god of dreams,Morpheus,as it has a tendency to cause sleep.[18][133]Sertürner's morphium was six times stronger than opium. He hypothesized that, because lower doses of the drug were needed, it would be less addictive. However Sertürner became addicted to the drug, warning that "I consider it my duty to attract attention to the terrible effects of this new substance I called morphium in order that calamity may be averted."[134]

The drug was first marketed to the general public by Sertürner and Company in 1817 as apain medication,and also as a treatment for opium and alcohol addiction. It was first used as a poison in 1822 whenEdme Castaingof France was convicted of murdering a patient.[135]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.[136][137]In the 1850s,Alexander Woodreported that he had injected morphine into his wife Rebecca as an experiment; the myth goes that this killed her because of respiratory depression,[132]but she outlived her husband by ten years.[138]

Later it was found that morphine was more addictive than either alcohol or opium, and its extensive use during theAmerican Civil Warallegedly resulted in over 400,000[139]people with the "soldier's disease" of morphine addiction.[140]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.[141][142]

Diacetylmorphine (better known asheroin) was synthesized from morphine in 1874 and brought to market byBayerin 1898. Heroin is approximately 1.5 to 2 times more potent than morphine weight for weight. Due to thelipid solubilityof diacetylmorphine, it can cross theblood–brain barrierfaster than morphine, subsequently increasing the reinforcing component of addiction.[143]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).[46]

Advertisement for curing morphine addiction, c. 1900[144]
An ampoule of morphine with integral needle for immediate use. Also known as a "syrette".From WWII. On display at theArmy Medical Services Museum.

Morphine became a controlled substance in the US under theHarrison Narcotics Tax Actof 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 ofdihydromorphine(c. 1900), the dihydromorphinone class of opioids (1920s), andoxycodone(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 (pethidinewas invented in Germany in 1937) and opioid agonists among the semi-synthetics were analogues and derivatives of codeine such asdihydrocodeine(Paracodin),ethylmorphine(Dionine), andbenzylmorphine(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 causehydromorphone,oxymorphone,high-dose oxycodone, ormethadoneas well asdextromoramidein 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 ofdihydrocodeine,poppy straw derivatives like poppy pod and poppy seed tea,propoxyphene,andtramadol.

The structural formula of morphine was determined by 1925 byRobert Robinson.[145]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, byMarshall D. Gates, Jr.at theUniversity of Rochester.[146]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 Hungarian pharmacologistJános Kabay.[147]

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: theμ3-opioid receptorin human tissue.[148]Human cells that form in reaction to cancerousneuroblastomacells have been found to contain trace amounts of endogenous morphine.[95]

Society and culture[edit]

Legal status[edit]

Non-medical use[edit]

Example of different morphine tablets

The euphoria, comprehensive alleviation of distress and therefore all aspects of suffering, promotion of sociability and empathy, "body high", andanxiolysisprovided 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 craving for the drug in the user.[153]As the prototype of the entire opioid class of drugs, morphine has properties that may lead to its misuse. Morphine addiction is the model upon which the current perception of addiction is based.[medical citation needed]

Animal and human studies and clinical experience back up the contention that morphine is one of the most euphoric drugs known, 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 asdihydromorphine,hydromorphone(Dilaudid, Hydal), andoxymorphone(Numorphan, Opana), as well as the latter three's methylated equivalentsdihydrocodeine,hydrocodone,and oxycodone, respectively; in addition to heroin, there aredipropanoylmorphine,diacetyldihydromorphine,and other members of the 3,6 morphine diester category likenicomorphineand other similar semi-synthetic opiates likedesomorphine,hydromorphinol,etc. used clinically in many countries of the world but also produced illicitly in rare instances.[medical citation needed]

In general, non-medical use of morphine entails taking more than prescribed or outside of medical supervision, injecting oral formulations, mi xing it with unapproved potentiators such as alcohol, cocaine, and the like, 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 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 thanoxycodonein 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.[medical citation needed]

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.[medical citation needed]

Names[edit]

Morphine ismarketedunder many different brand names in various parts of the world.[1]It was formerly called Morphia in British English.[14]

Informal names for morphine include: Cube Juice, Dope, Dreamer, Emsel, First Line, God's Drug, Hard Stuff, Hocus, Hows, Lydia, Lydic, M, Miss Emma, Mister Blue, Monkey, Morf, Morph, Morphide, Morphie, Morpho, Mother, MS, Ms. Emma, Mud, New Jack Swing (if mixed withheroin), Sister, Tab, Unkie, Unkie White, and Stuff.[154]

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 opioid component, which is combined with cocaine,amphetamines,methylphenidate,or similar drugs. "Blue Velvet" is a combination of morphine with the antihistaminetripelennamine(Pyrabenzamine, PBZ, Pelamine) taken by injection.

Access in developing countries[edit]

Although morphine is cheap, people in poorer countries often do not have access to it. According to a 2005 estimate by theInternational 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.[155]Some countries[which?]import virtually no morphine, and in others[which?]the drug is rarely available even for relieving severe pain while dying.[156]

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.[157]

See also[edit]

References[edit]

  1. ^abc"International listings for Morphine".Drugs.Archived fromthe originalon 14 June 2015.Retrieved2 June2015.
  2. ^ab"Morphine Use During Pregnancy".Drugs.14 October 2019.Retrieved21 August2020.
  3. ^Bonewit-West K, Hunt SA, Applegate E (2012).Today's Medical Assistant: Clinical and Administrative Procedures.Elsevier Health Sciences. p. 571.ISBN978-1-4557-0150-6.
  4. ^"Morphine Product information".Health Canada.9 August 2005.Retrieved4 April2024.
  5. ^abMacpherson G, ed. (2002).Black's Medical Dictionary.Vol. 87 (40th ed.). p. 162.Bibcode:1911Natur..87R.313..doi:10.1038/087313b0.ISBN978-0-7136-5442-4.S2CID3979058.Archivedfrom the original on 8 September 2017.{{cite book}}:|journal=ignored (help)
  6. ^"Sevredol Summary of Product Characteristics (SmPC)".(emc).13 February 2024.Retrieved20 February2024.
  7. ^"MS Contin- morphine sulfate tablet".DailyMed.27 December 2023.Retrieved20 February2024.
  8. ^"Modified-released oral opioids".European Medicines Agency.18 November 2010.Retrieved20 February2024.
  9. ^Jonsson T, Christensen CB, Jordening H, Frølund C (April 1988). "The bioavailability of rectally administered morphine".Pharmacology & Toxicology.62(4): 203–5.doi:10.1111/j.1600-0773.1988.tb01872.x.PMID3387374.
  10. ^Whimster F (1997).Cambridge textbook of accident and emergency medicine.Cambridge: Cambridge University Press. p. 191.ISBN978-0-521-43379-2.Archivedfrom the original on 8 September 2017.
  11. ^Liben S (2012).Oxford textbook of palliative care for children(2 ed.). Oxford: Oxford University Press. p. 240.ISBN978-0-19-959510-5.Archivedfrom the original on 8 September 2017.
  12. ^abcdefghijklmnop"Morphine sulfate".The American Society of Health-System Pharmacists.Archivedfrom the original on 2 May 2015.Retrieved1 June2015.
  13. ^abcRockwood CA (2009).Rockwood and Wilkins' fractures in children(7th ed.). Philadelphia, Pa.: Lippincott Williams & Wilkins. p. 54.ISBN978-1-58255-784-7.Archivedfrom the original on 8 September 2017.
  14. ^ab"Morphia".Lexico Dictionaries | English.Archived fromthe originalon 4 August 2020.Retrieved14 September2019.
  15. ^abcdefgStefano GB, Ptáček R, Kuželová H, Kream RM (2012)."Endogenous morphine: up-to-date review 2011"(PDF).Folia Biologica.58(2): 49–56.PMID22578954.Archived fromthe original(PDF)on 24 August 2016.Retrieved10 October2016.Positive evolutionary pressure has apparently preserved the ability to synthesize chemically authentic morphine, albeit in homeopathic concentrations, throughout animal phyla.
  16. ^abcCourtwright DT (2009).Forces of habit drugs and the making of the modern world(1 ed.). Cambridge, Mass.: Harvard University Press. pp. 36–37.ISBN978-0-674-02990-3.Archivedfrom the original on 8 September 2017.
  17. ^abLuch A, ed. (2009).Molecular, clinical and environmental toxicology.Springer. p. 20.ISBN978-3-7643-8335-0.
  18. ^abcMosher CJ (2013).Drugs and Drug Policy: The Control of Consciousness Alteration.SAGE Publications. p. 123.ISBN978-1-4833-2188-2.Archivedfrom the original on 8 September 2017.
  19. ^Fisher GL (2009).Encyclopedia of substance abuse prevention, treatment, & recovery.Los Angeles: SAGE. p. 564.ISBN978-1-4522-6601-5.Archivedfrom the original on 8 September 2017.
  20. ^Narcotic Drugs Estimated World Requirements for 2008, Statistics for 2006.New York: United Nations Pubns. 2008. p. 77.ISBN978-92-1-048119-9.Archivedfrom the original on 8 September 2017.
  21. ^abcdNarcotic Drugs 2014(PDF).INTERNATIONAL NARCOTICS CONTROL BOARD. 2015. pp. 21, 30.ISBN978-92-1-048157-1.Archived(PDF)from the original on 2 June 2015.
  22. ^abTriggle DJ (2006).Morphine.New York: Chelsea House Publishers. pp. 20–21.ISBN978-1-4381-0211-5.
  23. ^Karch SB (2006).Drug abuse handbook(2nd ed.). Boca Raton: CRC/Taylor & Francis. pp. 7–8.ISBN978-1-4200-0346-8.
  24. ^Davis's Canadian Drug Guide for Nurses.F.A. Davis. 2014. p. 1409.ISBN978-0-8036-4086-3.
  25. ^World Health Organization(2021).World Health Organization model list of essential medicines: 22nd list (2021).Geneva: World Health Organization.hdl:10665/345533.WHO/MHP/HPS/EML/2021.02.
  26. ^"The Top 300 of 2021".ClinCalc.Archivedfrom the original on 15 January 2024.Retrieved14 January2024.
  27. ^"Morphine - Drug Usage Statistics".ClinCalc.Retrieved14 January2024.
  28. ^"First Generic Drug Approvals 2023".U.S.Food and Drug Administration(FDA).30 May 2023.Archivedfrom the original on 30 June 2023.Retrieved30 June2023.
  29. ^Meine TJ, Roe MT, Chen AY, Patel MR, Washam JB, Ohman EM, et al. (June 2005). "Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative".American Heart Journal.149(6): 1043–9.doi:10.1016/j.ahj.2005.02.010.PMID15976786.
  30. ^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.Archivedfrom the original on 16 June 2010.Retrieved6 December2008.
  31. ^Wiffen PJ, Wee B, Moore RA (April 2016)."Oral morphine for cancer pain".The Cochrane Database of Systematic Reviews.4(3): CD003868.doi:10.1002/14651858.CD003868.pub4.PMC6540940.PMID27105021.
  32. ^Schrijvers D, van Fraeyenhove F (2010). "Emergencies in palliative care".Cancer Journal.16(5): 514–20.doi:10.1097/PPO.0b013e3181f28a8d.PMID20890149.
  33. ^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.PMID20722311.
  34. ^Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, et al. (February 2012)."An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea".American Journal of Respiratory and Critical Care Medicine.185(4): 435–52.doi:10.1164/rccm.201111-2042ST.PMC5448624.PMID22336677.
  35. ^Mahler DA, Selecky PA, Harrod CG, Benditt JO, Carrieri-Kohlman V, Curtis JR, et al. (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.PMID20202949.S2CID26739450.
  36. ^Mattick RP, Digiusto E, Doran C, O'Brien S, Kimber J, Henderson N, et al. (NEPOD Trial Investigators) (2004).National Evaluation of Pharmacotherapies for Opioid Dependence (NEPOD): Report of Results and Recommendation(PDF).Monograph Series No. 52. Australian Government.ISBN978-0-642-82459-2.Archived fromthe original(PDF)on 10 October 2012.
  37. ^Thompson DR (April 2001). "Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis".The American Journal of Gastroenterology.96(4): 1266–72.doi:10.1111/j.1572-0241.2001.03536.x.PMID11316181.S2CID13209026.
  38. ^abcdefFurlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E (May 2006)."Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects".CMAJ.174(11): 1589–94.doi:10.1503/cmaj.051528.PMC1459894.PMID16717269.
  39. ^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".Journal of Physiology and Pharmacology.55(1 Pt 2): 279–88.PMID15082884.
  40. ^Calignano A, Moncada S, Di Rosa M (December 1991). "Endogenous nitric oxide modulates morphine-induced constipation".Biochemical and Biophysical Research Communications.181(2): 889–93.doi:10.1016/0006-291X(91)91274-G.PMID1755865.
  41. ^Brennan MJ (March 2013). "The effect of opioid therapy on endocrine function".The American Journal of Medicine.126(3 Suppl 1): S12-8.doi:10.1016/j.amjmed.2012.12.001.PMID23414717.
  42. ^Colameco S, Coren JS (January 2009). "Opioid-induced endocrinopathy".The Journal of the American Osteopathic Association.109(1): 20–5.PMID19193821.
  43. ^Kerr B, Hill H, Coda B, Calogero M, Chapman CR, Hunt E, et al. (November 1991). "Concentration-related effects of morphine on cognition and motor control in human subjects".Neuropsychopharmacology.5(3): 157–66.PMID1755931.
  44. ^Friswell J, Phillips C, Holding J, Morgan CJ, Brandner B, Curran HV (June 2008). "Acute effects of opioids on memory functions of healthy men and women".Psychopharmacology.198(2): 243–50.doi:10.1007/s00213-008-1123-x.PMID18379759.S2CID2126631.
  45. ^Galski T, Williams JB, Ehle HT (March 2000)."Effects of opioids on driving ability".Journal of Pain and Symptom Management.19(3): 200–8.doi:10.1016/S0885-3924(99)00158-X.PMID10760625.
  46. ^abcMartin WR, Fraser HF (September 1961). "A comparative study of physiological and subjective effects of heroin and morphine administered intravenously in postaddicts".The Journal of Pharmacology and Experimental Therapeutics.133:388–99.PMID13767429.
  47. ^abNational Institute on Drug Abuse (NIDA) (April 2013)."Heroin".DrugFacts.U.S. National Institutes of Health. Archived fromthe originalon 30 November 2005.Retrieved29 April2008.
  48. ^Roshanpour M, Ghasemi M, Riazi K, Rafiei-Tabatabaei N, Ghahremani MH, Dehpour AR (February 2009). "Tolerance to the anticonvulsant effect of morphine in mice: blockage by ultra-low dose naltrexone".Epilepsy Research.83(2–3): 261–4.doi:10.1016/j.eplepsyres.2008.10.011.PMID19059761.S2CID21651602.
  49. ^Koch T, Höllt V (February 2008). "Role of receptor internalization in opioid tolerance and dependence".Pharmacology & Therapeutics.117(2): 199–206.doi:10.1016/j.pharmthera.2007.10.003.PMID18076994.
  50. ^"Why do We Quit 'Cold Turkey'?".Archivedfrom the original on 21 November 2016.Retrieved21 November2016.
  51. ^"Opiate Withdrawal Stages".Archivedfrom the original on 5 June 2014.Retrieved13 June2014.
  52. ^Chan R, Irvine R, White J (February 1999). "Cardiovascular changes during morphine administration and spontaneous withdrawal in the rat".European Journal of Pharmacology.368(1): 25–33.doi:10.1016/S0014-2999(98)00984-4.PMID10096766.
  53. ^"Morphine (and Heroin)".Drugs and Human Performance Fact Sheets.U.S. National Traffic Safety Administration. Archived fromthe originalon 3 October 2006.Retrieved17 May2007.
  54. ^"Narcotics".DEA Briefs & Background, Drugs and Drug Abuse, Drug Descriptions.U.S. Drug Enforcement Administration. Archived from the original on 14 January 2012.{{cite web}}:CS1 maint: unfit URL (link)
  55. ^Dalrymple T(2006).Romancing Opiates: Pharmacological Lies and the Addiction Bureaucracy.Encounter. pp.160.ISBN978-1-59403-087-1.
  56. ^O'Neil MJ (2006).The Merck index: an encyclopedia of chemicals, drugs, and biological.Whitehouse Station, N.J.: Merck.ISBN978-0-911910-00-1.
  57. ^abcdeLide 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.ISBN978-0-8493-0485-9.
  58. ^Duldner Jr JE (2 March 2009)."Morphine overdose".MedlinePlus.U.S. National Library of Medicine. Archived fromthe originalon 24 May 2016.
  59. ^Boyer EW (July 2012)."Management of opioid analgesic overdose".The New England Journal of Medicine.367(2): 146–155.doi:10.1056/NEJMra1202561.PMC3739053.PMID22784117.
  60. ^Corbett AD, Paterson SJ, Kosterlitz HW (1993). "Selectivity of Ligands for Opioid Receptors".Opioids.Handbook of Experimental Pharmacology. Vol. 104 / 1. Berlin, Heidelberg: Springer. pp. 645–679.doi:10.1007/978-3-642-77460-7_26.ISBN978-3-642-77462-1.ISSN0171-2004.
  61. ^abCodd EE, Shank RP, Schupsky JJ, Raffa RB (September 1995). "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception".The Journal of Pharmacology and Experimental Therapeutics.274(3): 1263–70.PMID7562497.
  62. ^King TL, Brucker MC (25 October 2010).Pharmacology for Women's Health.Jones & Bartlett Publishers. pp. 332–.ISBN978-1-4496-1073-9.
  63. ^Flood P, Aleshi P (28 February 2014)."Postoperative and chronic pain: systemic and regional pain techniques".In Chestnut DH, Wong CA, Tsen KC, Ngan Kee WD, Beilin Y, Mhyre J (eds.).Chestnut's Obstetric Anesthesia: Principles and Practice E-Book.Elsevier Health Sciences. pp. 611–.ISBN978-0-323-11374-8.
  64. ^Tiziani AP (1 June 2013).Havard's Nursing Guide to Drugs.Elsevier Health Sciences. pp. 933–.ISBN978-0-7295-8162-2.
  65. ^Ogura T, Egan TD (2013). "Chapter 15 – Opioid Agonists and Antagonists".Pharmacology and physiology for anesthesia: foundations and clinical application.Philadelphia, PA: Elsevier/Saunders.doi:10.1016/B978-1-4377-1679-5.00015-6.ISBN978-1-4377-1679-5.
  66. ^Yekkirala AS, Kalyuzhny AE, Portoghese PS (February 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 Chemical Neuroscience.1(2): 146–54.doi:10.1021/cn9000236.PMC3398540.PMID22816017.
  67. ^Yekkirala AS, Banks ML, Lunzer MM, Negus SS, Rice KC, Portoghese PS (September 2012)."Clinically employed opioid analgesics produce antinociception via μ-δ opioid receptor heteromers in Rhesus monkeys".ACS Chemical Neuroscience.3(9): 720–7.doi:10.1021/cn300049m.PMC3447399.PMID23019498.
  68. ^ab"MS-Contin (Morphine Sulfate Controlled-Release) Drug Information: Clinical Pharmacology".Prescribing Information.RxList. Archived fromthe originalon 15 May 2007.
  69. ^Kelly E (August 2013)."Efficacy and ligand bias at the μ-opioid receptor".British Journal of Pharmacology.169(7): 1430–46.doi:10.1111/bph.12222.PMC3724102.PMID23646826.
  70. ^Chien CC, Pasternak GW (May 1995)."Sigma antagonists potentiate opioid analgesia in rats".Neuroscience Letters.190(2): 137–9.doi:10.1016/0304-3940(95)11504-P.PMID7644123.S2CID10033780.
  71. ^Herman BH, Vocci F, Bridge P (December 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): 269–293.doi:10.1016/0893-133X(95)00140-9.PMID8747752.
  72. ^Popik P, Kozela E, Danysz W (April 2000). "Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice".Naunyn-Schmiedeberg's Archives of Pharmacology.361(4): 425–432.doi:10.1007/s002109900205.PMID10763858.S2CID18200635.
  73. ^Crews JC, Sweeney NJ, Denson DD (October 1993). "Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics".Cancer.72(7): 2266–2272.doi:10.1002/1097-0142(19931001)72:7<2266::AID-CNCR2820720734>3.0.CO;2-P.PMID7690683.S2CID19669811.
  74. ^Loguinov AV, Anderson LM, Crosby GJ, Yukhananov RY (August 2001). "Gene expression following acute morphine administration".Physiological Genomics.6(3): 169–81.doi:10.1152/physiolgenomics.2001.6.3.169.PMID11526201.S2CID9296949.
  75. ^Sacerdote P (2006). "Opioids and the immune system".Palliative Medicine.20(Suppl 1): s9-15.doi:10.1191/0269216306pm1124oa.PMID16764216.S2CID39489581.
  76. ^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".Molecular Medicine.12(11–12): 284–90.doi:10.2119/2006-00043.Messmer.PMC1829197.PMID17380193.
  77. ^Clark JD, Shi X, Li X, Qiao Y, Liang D, Angst MS, et al. (October 2007)."Morphine reduces local cytokine expression and neutrophil infiltration after incision".Molecular Pain.3:1744-8069–3-28.doi:10.1186/1744-8069-3-28.PMC2096620.PMID17908329.
  78. ^Trescot AM, Datta S, Lee M, Hansen H (March 2008). "Opioid pharmacology".Pain Physician.11(2 Suppl): S133-53.doi:10.36076/ppj.2008/11/S133.PMID18443637.
  79. ^Kilpatrick GJ, Smith TW (September 2005). "Morphine-6-glucuronide: actions and mechanisms".Medicinal Research Reviews.25(5): 521–44.doi:10.1002/med.20035.PMID15952175.S2CID20887610.
  80. ^abvan Dorp EL, Romberg R, Sarton E, Bovill JG, Dahan A (June 2006)."Morphine-6-glucuronide: morphine's successor for postoperative pain relief?".Anesthesia and Analgesia.102(6): 1789–97.doi:10.1213/01.ane.0000217197.96784.c3.PMID16717327.S2CID18890026.Archivedfrom the original on 1 December 2008.
  81. ^abJenkins AJ (2008) Pharmacokinetics of specific drugs. In Karch SB (Ed),Pharmacokinetics and pharmacodynamics of abused drugs.CRC Press: Boca Raton.
  82. ^abc"Morphine, slow release (By mouth)".University of Maryland Medical Center.Archivedfrom the original on 22 December 2015.
  83. ^Pedersen L, Fredheim O (February 2015). "Opioids for chronic noncancer pain: still no evidence for superiority of sustained-release opioids".Clinical Pharmacology and Therapeutics.97(2): 114–5.doi:10.1002/cpt.26.PMID25670511.S2CID5603973.Last reviewed on 18 November 2015
  84. ^ab"Dosing & Uses".Medscape.Archivedfrom the original on 31 October 2015.Retrieved21 December2015.
  85. ^ab"EndLink: An Internet-based End of Life Care Education Program – Morphine Dosing"(PDF).Northwestern University.Archived(PDF)from the original on 4 March 2016.
  86. ^Baselt RC (2008).Disposition of Toxic Drugs and Chemicals in Man(8th ed.). Foster City, CA: Biomedical Publications. pp. 1057–1062.ISBN978-0-9626523-7-0.
  87. ^Vandevenne M, Vandenbussche H, Verstraete A (2000). "Detection time of drugs of abuse in urine".Acta Clinica Belgica.55(6): 323–33.doi:10.1080/17843286.2000.11754319.PMID11484423.S2CID43808583.
  88. ^Verstraete AG (April 2004). "Detection times of drugs of abuse in blood, urine, and oral fluid".Therapeutic Drug Monitoring.26(2): 200–5.doi:10.1097/00007691-200404000-00020.PMID15228165.S2CID385874.
  89. ^Eliel EL, Wilen SH, Mander LN (1994).Stereochemistry of organic compounds.New York: Wiley.ISBN0-471-01670-5.OCLC27642721.
  90. ^"Morphine – Chiralpedia".18 July 2022.Retrieved28 August2022.
  91. ^Kapoor L (1995).Opium Poppy: Botany, Chemistry, and Pharmacology.United States: CRC Press. p. 164.ISBN978-1-56024-923-8.
  92. ^Vincent PG, Bare CE, Gentner WA (December 1977). "Thebaine content of selections of Papaver bracteatum Lindl. at different ages".Journal of Pharmaceutical Sciences.66(12): 1716–9.doi:10.1002/jps.2600661215.PMID925935.
  93. ^Stewart O (2000).Functional Neuroscience.New York: Springer. p. 116.ISBN978-0-387-98543-5.
  94. ^"μ receptor".IUPHAR/BPS Guide to PHARMACOLOGY.International Union of Basic and Clinical Pharmacology. 15 March 2017.Archivedfrom the original on 7 November 2017.Retrieved28 December2017.Morphine occurs endogenously
  95. ^abPoeaknapo C, Schmidt J, Brandsch M, Dräger B, Zenk MH (September 2004)."Endogenous formation of morphine in human cells".Proceedings of the National Academy of Sciences of the United States of America.101(39): 14091–6.Bibcode:2004PNAS..10114091P.doi:10.1073/pnas.0405430101.PMC521124.PMID15383669.Without doubt, human cells can produce the alkaloid morphine.
  96. ^Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D".European Journal of Pharmacology.724:211–8.doi:10.1016/j.ejphar.2013.12.025.PMID24374199.Additionally, CYP2D is involved in the synthesis of endogenous morphine from various precursors, including L-3,4-dihydroxyphenylalanine (L-DOPA), reticulin, tetrahydropapaveroline (THP), and tyramine (Kulkarni, 2001; Mantione et al., 2008; Zhu, 2008).
  97. ^Onoyovwe A, Hagel JM, Chen X, Khan MF, Schriemer DC, Facchini PJ (2013)."Morphine biosynthesis in opium poppy involves two cell types: sieve elements and laticifers".Plant Cell.25(10): 4110–4122.doi:10.1105/tpc.113.115113.PMC3877807.PMID24104569.
  98. ^Novak B, Hudlicky T, Reed J, Mulzer J, Trauner D (March 2000)."Morphine Synthesis and Biosynthesis-An Update"(PDF).Current Organic Chemistry.4(3): 343–362.CiteSeerX10.1.1.515.9096.doi:10.2174/1385272003376292.Archived(PDF)from the original on 19 June 2012.
  99. ^Le Page M (18 May 2015)."Home-brew heroin: soon anyone will be able to make illegal drugs".New Scientist.Archivedfrom the original on 13 April 2016.
  100. ^Service RF (25 June 2015)."Final step in sugar-to-morphine conversion deciphered".Science.Archivedfrom the original on 21 August 2015.
  101. ^Galanie S, Thodey K, Trenchard IJ, Filsinger Interrante M, Smolke CD (September 2015)."Complete biosynthesis of opioids in yeast".Science.349(6252): 1095–100.Bibcode:2015Sci...349.1095G.doi:10.1126/science.aac9373.PMC4924617.PMID26272907.
  102. ^"Yeast-Based Opioid Production Completed".13 August 2015.Archivedfrom the original on 7 September 2015.Retrieved15 August2015.
  103. ^Olawale DO, Okoli OO, Fontenot RS, Hollerman WA (2016).Triboluminescence: Theory, Synthesis, and Application(illustrated ed.). Springer. p. 193.ISBN978-3-319-38842-7.Extract of page 193
  104. ^DeRuiter J (Fall 2000)."Narcotic analgesics: morphine and" peripherally modified "morphine analogs"(PDF).Principles of Drug Action 2.Auburn University.Archived(PDF)from the original on 11 January 2012.
  105. ^Way EL, Adler TK (1962)."The biological disposition of morphine and its surrogates".Bulletin of the World Health Organization.27(3): 359–394.PMC2555766.PMID13999272.
  106. ^"UNODC - Bulletin on Narcotics - 1958 Issue 3 - 005".United Nations: Office on Drugs and Crime.Retrieved11 February2022.
  107. ^"Opioids",LiverTox: Clinical and Research Information on Drug-Induced Liver Injury,Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, 2012,PMID31643200,retrieved14 November2023
  108. ^Loftsson T (2013).Drug Stability for Pharmaceutical Scientists.Elsevier Science & Technology. p. 82.OCLC1136560730.
  109. ^Heroin (morphine diacetate) is a Schedule I controlled substance, so it is not used clinically in the United States;[citation needed]it is a sanctioned medication in theUnited Kingdomand inCanadaand some countries in Continental Europe, its use being particularly common (nearly to the degree of the hydrochloride salt)[clarification needed]in the United Kingdom.[citation needed]
  110. ^Morphine valerate 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 ofcaffeineandcocaine.[citation needed]A version containing codeine valerate as a fourth ingredient is distributed under the name Tetravalin.[citation needed]
  111. ^Gates M, Tschudi G (April 1956). "The Synthesis of Morphine".Journal of the American Chemical Society.78(7): 1380–1393.doi:10.1021/ja01588a033.
  112. ^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.
  113. ^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.
  114. ^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.
  115. ^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.
  116. ^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.
  117. ^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.
  118. ^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.
  119. ^Taber DF, Neubert TD, Rheingold AL (October 2002). "Synthesis of (-)-morphine".Journal of the American Chemical Society.124(42): 12416–7.doi:10.1021/ja027882h.PMID12381175.S2CID32048193.
  120. ^Trost BM, Tang W (December 2002)."Enantioselective synthesis of (-)-codeine and (-)-morphine".Journal of the American Chemical Society.124(49): 14542–3.doi:10.1021/ja0283394.PMID12465957.
  121. ^Uchida K, Yokoshima S, Kan T, Fukuyama T (November 2006). "Total synthesis of (+/-)-morphine".Organic Letters.8(23): 5311–3.doi:10.1021/ol062112m.PMID17078705.
  122. ^Varin M, Barré E, Iorga B, Guillou C (2008). "Diastereoselective total synthesis of (+/-)-codeine".Chemistry: A European Journal.14(22): 6606–8.doi:10.1002/chem.200800744.PMID18561354.
  123. ^Stork G, Yamashita A, Adams J, Schulte GR, Chesworth R, Miyazaki Y, et al. (August 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): 11402–6.doi:10.1021/ja9038505.PMID19624126.
  124. ^Freemantle M (20 June 2005)."The Top Pharmaceuticals That Changed The World-Morphine".Chemical and Engineering News.
  125. ^"Genetically modified E. coli pump out morphine precursor: Bacteria yield 300 times more opiates than yeast".ScienceDaily.
  126. ^"Narcotics (Opioids) | DEA".dea.gov.Retrieved21 January2021.
  127. ^Crews JC, Denson DD (December 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.PMID2249204.
  128. ^Norn S, Kruse PR, Kruse E (2005)."[History of opium poppy and morphine]".Dansk Medicinhistorisk Arbog.33:171–184.PMID17152761.
  129. ^Ramoutsaki IA, Askitopoulou H, Konsolaki E (December 2002). "Pain relief and sedation in Roman Byzantine texts:Mandragoras officinarum,Hyoscyamos nigerandAtropa belladonna".International Congress Series.1242:43–50.doi:10.1016/S0531-5131(02)00699-4.
  130. ^Sigerist HE (1941)."Laudanum in the Works of Paracelsus"(PDF).Bull. Hist. Med.9:530–544.Retrieved5 September2018.
  131. ^"Friedrich Sertürner (Untitled letter to the editor)"[Journal of Pharmacy for Physicians, Apothecaries, and Chemists].Journal der Pharmacie für Aerzte, Apotheker und Chemisten(in German).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. 1805. Archived fromthe originalon 17 August 2016.
  132. ^abDahan A, Aarts L, Smith TW (January 2010)."Incidence, Reversal, and Prevention of Opioid-induced Respiratory Depression".Anesthesiology.112(1): 226–38.doi:10.1097/ALN.0b013e3181c38c25.PMID20010421.
  133. ^Sertürner coined the termmorphiumin: Sertuerner (1817)"Ueber das Morphium, eine neue salzfähige Grundlage, und die Mekonsäure, als Hauptbestandtheile des Opiums"(On morphine, a new salifiable [i.e., precipitable], fundamental substance, and meconic acid, as principal components of opium),Annalen der Physik,55:56–89. It wasGay-Lussac,a French chemist and editor ofAnnales de Chimie et de Physique,who coined the wordmorphinein a French translation of Sertuener's original German article: Sertuener (1817)"Analyse de l'opium: De la morphine et de l'acide méconique, considérés comme parties essentielles de l'opium"(Analysis of opium: On morphine and on meconic acid, considered as essential constituents of opium),Annales de Chimie et de Physique,2nd series,5:21–42. From p. 22:"... car il a pris pour cette substance, que j'appellemorphine(morphium), ce qui n'en était qu'une combinaison avecl'acide de l'opium."(... for he [i.e., French chemist and pharmacist Charles Derosne (1780–1846)] took as that substance [i.e., the active ingredient in opium], which I call "morphine" (ormorphium), what was only a compound of it withacid of opium.)
  134. ^Offit P (March–April 2017). "God's Own Medicine".Skeptical Inquirer.41(2): 44.
  135. ^Annual Register.J. Dodsley. 1824. p.1.Retrieved1 September2015.Edme.
  136. ^Kirsch DR (2016).Drug Hunters.Arcade Publishing.ISBN978-1-62872-719-7.OCLC966360188.
  137. ^Gootenberg P (1999).Cocaine global histories.London: Routledge. p. 90.ISBN92-9078-018-5.OCLC1162209949.
  138. ^Davenport-Hines R (2003).The Pursuit of Oblivion: A Global History of Narcotics.W.W. Norton. p. 68.ISBN978-0-393-32545-4.
  139. ^Vassallo SA (July 2004)."Lewis H. Wright Memorial Lecture".ASA Newsletter.68(7): 9–10. Archived fromthe originalon 2 February 2014.
  140. ^"Opiate Narcotics".The Report of the Canadian Government Commission of Inquiry into the Non-Medical Use of Drugs.Canadian Government Commission.Archivedfrom the original on 4 April 2007.
  141. ^Mandel J."Mythical Roots of US Drug Policy – Soldier's Disease and Addicts in the Civil War".Archivedfrom the original on 5 April 2007.
  142. ^"Soldiers Disease A Historical Hoax?".iPromote Media Inc. 2006. Archived fromthe originalon 27 September 2007.
  143. ^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".The Journal of Pharmacology and Experimental Therapeutics.301(2): 690–7.doi:10.1124/jpet.301.2.690.PMID11961074.S2CID17860947.
  144. ^"Morphine Easy Home Cure".Overland Monthly.35(205): 14. 1900.Archivedfrom the original on 1 February 2014.
  145. ^Gulland JM, Robinson R (1925). "Constitution of codeine and thebaine".Memoirs and Proceedings of the Literary and Philosophical Society of Manchester.69:79–86.
  146. ^Dickman S (3 October 2003)."Marshall D. Gates, Chemist to First Synthesize Morphine, Dies".Press Release.University of Rochester.Archivedfrom the original on 1 December 2010.
  147. ^Bayer I (July 1987). "[János Kabay and the poppy straw process. Commemoration on the 50th anniversary of his death]".Acta Pharmaceutica Hungarica.57(3–4): 105–10.PMID3314338.
  148. ^Zhu W, Cadet P, Baggerman G, Mantione KJ, Stefano GB (December 2005)."Human white blood cells synthesize morphine: CYP2D6 modulation".Journal of Immunology.175(11): 7357–62.doi:10.4049/jimmunol.175.11.7357.PMID16301642.
  149. ^"Anlage III (zu § 1 Abs. 1) verkehrsfähige und verschreibungsfähige Betäubungsmittel"[Appendix III (to §1 paragraph 1) marketable and prescription narcotics].Bundesamt für Justiz (Federal Office of Justice)(in German). Archived fromthe originalon 28 April 2014.
  150. ^"Misuse of Drugs Act 1975, sch 2".13 January 2022.Archivedfrom the original on 27 January 2021.
  151. ^82FR51293
  152. ^"List of narcotic drugs under international control"(PDF).Yellow List(PDF) (50th ed.): 5. March 2011.Archived(PDF)from the original on 22 December 2014.
  153. ^Moini J, Koenitzer J, LoGalbo A (1 January 2021), Moini J, Koenitzer J, LoGalbo A (eds.),"Chapter 22 - The opioid epidemic",Global Emergency of Mental Disorders,Academic Press, pp. 401–418,doi:10.1016/B978-0-323-85837-3.00019-4,ISBN978-0-323-85837-3,S2CID236695938,retrieved11 January2024
  154. ^Miller RL (1 January 2002).The Encyclopedia of Addictive Drugs.Greenwood Publishing Group.p. 306.ISBN978-0-313-31807-8.
  155. ^Milani B.Scholten(3rd ed.). Switzerland: World Health Organization. pp. 1–22. Archived fromthe originalon 5 June 2018.Retrieved17 January2018.
  156. ^Human Rights Watch (2 June 2011)."Global State of Pain Treatment; Access to Palliative Care as a Human Right".Human Rights Watch.Retrieved27 January2020.
  157. ^McNeil Jr DG (10 September 2007)."Drugs Banned, Many of World's Poor Suffer in Pain".The New York Times.Archivedfrom the original on 12 May 2023.Retrieved11 September2007.

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