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Wikipedia

Morphine

March 18, 2023

"Morphia" redirects here. For other uses, see Morphia (disambiguation) and Morphine (disambiguation).
Not to be confused with Morpheein.

Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (Papaver somniferum). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. There are numerous methods used to administer morphine: oral; sublingual; via inhalation; injection into a muscle; by injection under the skin; intravenously; injection into the space around the spinal cord; transdermal; or via rectal suppository.[7][9] It acts directly on the central nervous system (CNS) to induce analgesia and alter perception and emotional response to pain. Physical and psychological dependence and tolerance may develop with repeated administration.[7] It can be taken for both acute pain and chronic pain and is frequently used for pain from myocardial infarction, kidney stones, and during labor.[7] 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.[7][8] Long-acting formulations of morphine are available as MS-Contin, Kadian, and other brand names as well as generically.[7]

Morphine
Clinical data
Pronunciation/ˈmɔːrfiːn/
Trade namesStatex, MS Contin, MST Continus, Oramorph, Sevredol, and others[1]
AHFS/Drugs.comMonograph
Pregnancy
category
Dependence
liability		High
Addiction
liability		High[3]
Routes of
administration		Inhalation (smoking), insufflation (snorting), by mouth (PO), rectal, subcutaneous (SC), intramuscular (IM), intravenous (IV), epidural, and intrathecal (IT)
Drug classopioid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability20–40% (by mouth), 36–71% (rectally),[4] 100% (IV/IM)
Protein binding30–40%
MetabolismLiver 90%
Onset of action5 minutes (IV), 15 minutes (IM),[5] 20 minutes (PO)[6]
Elimination half-life2–3 hours
Duration of action3–7 hours[7][8]
ExcretionKidney 90%, bile duct 10%
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
  • 57-27-2 Y
    64-31-3 (neutral sulfate),
    52-26-6 (hydrochloride)
PubChem CID
  • 5288826
IUPHAR/BPS
  • 1627
DrugBank
  • DB00295 Y
ChemSpider
  • 4450907 Y
UNII
  • 76I7G6D29C
KEGG
  • D08233 Y
ChEBI
  • CHEBI:17303 Y
ChEMBL
  • ChEMBL70 Y
PDB ligand
  • MOI (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID9023336
ECHA InfoCard100.000.291
Chemical and physical data
FormulaC17H19NO3
Molar mass285.343 g·mol−1
3D model (JSmol)
  • Interactive image
Solubility in waterHCl & sulf.: 60 mg/mL (20 °C)
  • 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/s1 Y
  • Key:BQJCRHHNABKAKU-KBQPJGBKSA-N Y
  (verify)

Potentially serious side effects of morphine include decreased respiratory effort, vomiting, nausea, and low blood pressure.[7] Morphine is addictive and prone to abuse.[7] If one's dose is reduced after long-term use, opioid withdrawal symptoms may occur.[7] Common side effects of morphine include drowsiness, vomiting, and constipation.[7] Caution is advised for use of morphine during pregnancy or breast feeding, as it may affect the health of the baby.[7][2]

Morphine was first isolated between 1804 by German pharmacist Friedrich Sertürner.[10] This is generally believed to be the first isolation of an active ingredient from a plant.[11] Merck began marketing it commercially in 1827.[10] Morphine was more widely used after the invention of the hypodermic syringe in 1853–1855.[10][12] Sertürner originally named the substance morphium, after the Greek god of dreams, Morpheus, as it has a tendency to cause sleep.[12][13]

The primary source of morphine is isolation from poppy straw of the opium poppy.[14] In 2013, approximately 523 tons of morphine were produced.[15] Approximately 45 tons were used directly for pain, an increase of 400% over the last twenty years.[15] Most use for this purpose was in the developed world.[15] About 70 percent of morphine is used to make other opioids such as hydromorphone, oxymorphone, and heroin.[15][16][17] It is a Schedule II drug in the United States,[16] Class A in the United Kingdom,[18] and Schedule I in Canada.[19] It is on the World Health Organization's List of Essential Medicines.[20] Morphine is sold under many brand names.[1] In 2020, it was the 140th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[21][22]

Medical uses

Pain

Morphine is used primarily to treat both acute and chronic severe pain. Its duration of analgesia is about three to seven hours.[7][8] Side-effects of nausea and constipation are rarely severe enough to warrant stopping treatment.

It is used for pain due to myocardial infarction and for labor pains.[23] However, concerns exist that morphine may increase mortality in the event of non ST elevation myocardial infarction.[24]

Morphine has also traditionally been used in the treatment of acute pulmonary edema.[23] However, a 2006 review found little evidence to support this practice.[25]

A 2016 Cochrane review concluded that morphine is effective in relieving cancer pain.[26]

Shortness of breath

Morphine is beneficial in reducing the symptom of shortness of breath due to both cancer and noncancer causes.[27][28] 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.[29][30]

Opioid use disorder

Morphine is also available as a slow-release formulation for opiate substitution therapy (OST) in Austria, Germany, Bulgaria, Slovenia, and Canada for persons with opioid addiction who cannot tolerate either methadone or buprenorphine.[31]

  •  

    Two capsules (5 mg & 10 mg) of morphine sulfate extended- release

  •  

    1 milliliter ampoule containing 10 mg of morphine

Contraindications

Relative contraindications to morphine include:

Adverse effects

Adverse effects of opioids
Common and short term
Other
 
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.[34] This effect was shown in animals when a nitric oxide precursor, L-arginine, reversed morphine-induced changes in gut motility.[35]

Hormone imbalance

See also: Opioid § Hormone imbalance

Clinical studies consistently conclude that morphine, like other opioids, often causes hypogonadism and hormone imbalances in chronic users of both sexes. 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 many 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, the effect of low-dose or acute use of morphine on the endocrine system is unclear.[36][37]

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 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 of isometric force (i.e. fine motor control is impaired),[38] 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,[39] 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 2000 study[40] 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 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.

Reinforcement disorders

Addiction

 
Before the Morphine by Santiago Rusiñol

Morphine is a highly addictive substance. Numerous studies, including one by The Lancet, ranked Morphine/Heroin as #1 most addictive substance, followed by Cocaine at #2, Nicotine #3, followed by Barbiturates at 4 and ethanol at 5. 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 diacetylmorphine crossing the BBB slightly quicker. No difference in subjects' self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness.[41] 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 also produced higher rates of euphoria and other positive subjective effects when compared to these other opioids.[41] 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.[42]

Tolerance

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),[43] μ-opioid receptor internalization 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.[44]) 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.

Dependence and withdrawal

See also: Opioid use disorder and Opioid 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 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 moderate dysphoria
  • 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),[45] 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 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 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, 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.[46]

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,[47] 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"[42]) and excessive sweating are also characteristic symptoms.[48] 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.[49][50]

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. 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.[51]

Toxicity

See also: Opioid overdose
Properties of Morphine
Molar mass[52] 285.338 g/mol
Acidity (pKa)[52]
Step 1: 8.21 at 25 °C
Step 2: 9.85 at 20 °C
Solubility[52] 0.15 g/L at 20 °C
Melting point[52] 255 °C
Boiling point[52] 190 °C sublimes

A large overdose can cause asphyxia and death by respiratory depression if the person does not receive medical attention immediately.[53] Overdose treatment includes the administration of naloxone. 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.[54]

The LD50 for humans of morphine sulphate and other preparations is not known with certainty. One poor quality study on morphine overdoses among soldiers reported that the fatal dose was 0.78 mcg/ml in males (~71 mg for an average 90 kg adult man) and 0.98mcg/ml in females (~74 mg for an average 75 kg female). It was not specified whether the dose was oral, parenteral or IV.[55] Laboratory animal studies are usually cited in the literature. In serious drug dependency (high tolerance), 2000–3000 mg per day can be tolerated.[56]

Pharmacology

Pharmacodynamics

Morphine at opioid receptors
Compound Affinities (Ki) Ratio Ref
MOR DOR KOR MOR:DOR:KOR
Morphine 1.8 nM 90 nM 317 nM 1:50:176 [57]
(−)-Morphine 1.24 nM 145 nM 23.4 nM 1:117:19 [58]
(+)-Morphine >10 μM >100 μM >300 μM ND [58]

Equianalgesic doses[59][60][61]
Compound Route Dose
Codeine PO 200 mg
Hydrocodone PO 20–30 mg
Hydromorphone PO 7.5 mg
Hydromorphone IV 2 mg
Morphine PO 30 mg
Oxycodone PO 20 mg
Oxycodone IV 20 mg
Morphine IV 10 mg
Oxymorphone PO 10 mg
Oxymorphone IV 1 mg

Morphine is the prototypical opioid and is the standard agonist to which other opioids are tested.[62] It interacts predominantly with the μ–δ-opioid (Mu-Delta) receptor heteromer.[63][64] 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.[65]

Morphine is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the μ-opioid receptor (MOR) in the central nervous system. Its intrinsic activity at the MOR is heavily dependent on the assay and tissue being tested; in some situations it is a full agonist while in others it can be a partial agonist or even antagonist.[66] 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 MOR is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is also a κ-opioid receptor (KOR) and δ-opioid receptor (DOR) agonist. Activation of the KOR is associated with spinal analgesia, miosis (pinpoint pupils), and psychotomimetic effects. The DOR is thought to play a role in analgesia.[65] Although morphine does not bind to the σ receptor, it has been shown that σ receptor agonists, such as (+)-pentazocine, inhibit morphine analgesia, and σ receptor antagonists enhance morphine analgesia,[67] suggesting downstream involvement of the σ receptor in the actions of morphine.

The effects of morphine can be countered with opioid receptor antagonists such as naloxone and naltrexone; the development of tolerance to morphine may be inhibited by NMDA receptor antagonists such as ketamine, dextromethorphan, and memantine.[68][69] 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.[citation needed]

 
Morphine Hydrochloride Ampoule for Veterinary Use

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.[70]

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 opioid drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV/AIDS) 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).[71]

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 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.[72]

Pharmacokinetics

Absorption and metabolism

Morphine can be taken orally, sublingually, bucally, rectally, subcutaneously, intranasally, intravenously, intrathecally or epidurally and 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 extensive first-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.[73] Morphine is metabolised primarily in the liver and approximately 87% of a dose of morphine is excreted in the urine within 72 h of administration. Morphine is metabolized primarily into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)[74] via glucuronidation by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7). About 60% of morphine is converted to M3G, and 6% to 10% is converted to M6G.[75] 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.[75] 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 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 the blood–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.[76]

Extended-release

Main article: Extended-release morphine

There are extended-release formulations of orally administered morphine whose effect last longer, which can be given once per day. Brand names for this formulation of morphine include Avinza,[77] Kadian,[77] MS Contin[77] and Dolcontin.[78] For constant pain, the relieving effect of extended-release morphine given once (for Kadian)[79] or twice (for MS Contin)[79] every 24 hours is roughly the same as multiple administrations of immediate release (or "regular") morphine.[80] 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.[80]

Detection in body 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.[81]

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.[82] 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.[83]

Chirality and biological activity

Morphine has a highly challenging chemical structure. It is a pentacyclic 3°amine (alkaloid) with 5 stereogenic centers and exists in 32 stereoisomeric forms. But the desired analgesic activity resides exclusively in the natural product, the (-)-enantiomer with the configuration (5R,6S,9R,13S,14R).[84][85]

Natural occurrence

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

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 is generally 8–14% of the dry weight of opium,[86] 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.[87] 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).

In the brain of mammals, morphine is detectable in trace steady-state concentrations.[9] The human body also produces endorphins, which are chemically related endogenous opioid peptides that function as neuropeptides and have similar effects to morphine.[88]

Human biosynthesis

Morphine is an endogenous opioid in humans. Various human cells are capable of synthesizing and releasing it, including white blood cells.[9][89][90] The primary biosynthetic pathway for morphine in humans consists of:[9]

L-tyrosine → para-tyramine or L-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.[9] CYP2D6, a cytochrome P450 isoenzymem is involved in two steps along the biosynthetic pathway, catalyzing both the biosynthesis of dopamine from tyramine and of morphine from codeine.[9][91]

Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals taking L-DOPA for the treatment of Parkinson's disease.[9]

Biosynthesis in the opium poppy

 
Morphine biosynthesis in the opium poppy

Morphine is biosynthesized in the opium poppy from the tetrahydroisoquinoline reticuline. It is converted into salutaridine, thebaine, and oripavine. The enzymes involved in this process are the salutaridine synthase, salutaridine:NADPH 7-oxidoreductase and the codeinone reductase.[92] Researchers are attempting to reproduce the biosynthetic pathway that produces morphine in genetically engineered yeast.[93] In June 2015 the S-reticuline could be produced from sugar and R-reticuline could be converted to morphine, but the intermediate reaction could not be performed.[94] In August 2015 the first complete synthesis of thebaine and hydrocodone in yeast were reported, but the process would need to be 100,000 times more productive to be suitable for commercial use.[95][96]

Chemistry

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.[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-derived agonist–antagonist drugs have also been developed.[citation needed]

Structure description

 
Chemical structure of morphine. The benzylisoquinoline backbone 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 a benzylisoquinoline alkaloid with two additional ring closures.[97] 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 rigid pentacyclic structure consisting of a benzene ring (A), two partially unsaturated cyclohexane 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...
  2. Two hydroxyl functional groups: a C3-phenolic [hydroxyl group] (pKa 9.9) and a C6-allylic [hydroxyl group],
  3. An ether linkage between E4 and E5,
  4. Unsaturation between 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."[98][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, dextorphan and the racemic parent chemical racemorphan) do,[99] and as noted above stereoselectivity in vivo is an important issue.[citation needed]

Uses and derivatives

Most of the licit morphine produced is used to make codeine by methylation.[100] It is also a precursor for many drugs including heroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone).[citation needed] Most semi-synthetic opioids, both of the morphine and codeine subgroups, 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 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 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.

Many morphine derivatives can also be manufactured using thebaine or codeine as a starting material.[citation needed] 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.[citation needed] 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.[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, including naloxone (Narcan), naltrexone (Trexan), diprenorphine (M5050, the reversing agent for the Immobilon dart) and nalorphine (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, like apomorphine are devoid of narcotic effects.[citation needed]

Salts

Both morphine and its hydrated form are sparingly soluble in water.[101] 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.[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 of NaOH to 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.[102]

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 the NSAID;[citation needed] 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.[citation needed] Calcium morphenate is 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][103]

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

Production

 
First generation production of alkaloids from licit latex-derived opium

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 roughly 8–19% of opium by dry weight (depending on growing conditions).[76] 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.

Chemical synthesis

Main article: Morphine total synthesis

The first morphine total synthesis, devised by Marshall D. Gates, Jr. in 1952, remains a widely used example of total synthesis.[104] Several other syntheses were reported, notably by the research groups of Rice,[105] Evans,[106] Fuchs,[107] Parker,[108] Overman,[109] Mulzer-Trauner,[110] White,[111] Taber,[112] Trost,[113] Fukuyama,[114] Guillou,[115] and Stork.[116] Because of the stereochemical complexity and consequent synthetic challenge presented by this polycyclic structure, 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.[117]

GMO synthesis

Research

Thebaine has been produced by GMO E. coli[118]

Precursor to other opioids

Pharmaceutical

Morphine is a precursor in the manufacture in a number of opioids such as dihydromorphine, hydromorphone, hydrocodone, and oxycodone as well as codeine, which itself has a large family of semi-synthetic derivatives.[119]

Illicit

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.[120] Chemical reactions can then be used to convert morphine, dihydromorphine, and hydrocodone into heroin or other opioids [e.g., diacetyldihydromorphine (Paralaudin), and thebacon].[citation needed] Other clandestine conversions—of morphine, into ketones of the hydromorphone class, or other derivatives like dihydromorphine (Paramorfan), desomorphine (Permonid), metopon, etc., and of codeine into hydrocodone (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

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).[121] Around 1522, Paracelsus made reference to an opium-based elixir that he called laudanum from the Latin word laudāre, 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.[122]

Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn by German pharmacist Friedrich Sertürner.[11][123] 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.[124] Sertürner originally named the substance morphium after the Greek god of dreams, Morpheus, as it has a tendency to cause sleep.[12] 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."[125]

The drug was first marketed to the general public by Sertürner and Company in 1817 as a pain medication, and also as a treatment for opium and alcohol addiction. It was first used as a poison in 1822 when Dr. Edme Castaing of France was convicted of murdering a patient.[126] 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.[127][128] In the 1850s, Alexander Wood reported that he had injected morphine into his wife Rebecca as an experiment; the myth goes that this killed her because of respiratory depression,[124] but she outlived her husband by ten years.[129]

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[130] people with the "soldier's disease" of morphine addiction.[131] 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.[132][133]

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.[134] 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).[41]

 
Advertisement for curing morphine addiction, c. 1900[135]
 
An ampoule of morphine with integral needle for immediate use. Also known as a "syrette". 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 (c. 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.[136] 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.[137] 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 pharmacologist János Kabay.[138]

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.[139] Human cells that form in reaction to cancerous neuroblastoma cells have been found to contain trace amounts of endogenous morphine.[90]

Society and culture

Legal status

Non-medical 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.[citation needed] 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 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 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, mixing 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 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.[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

Morphine is marketed under many different brand names in various parts of the world.[1] It was formerly called Morphia in British English.[144]

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 with heroin), Sister, Tab, Unkie, Unkie White, and Stuff.[145]

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 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 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).

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.[146] Some countries[which?] import virtually no morphine, and in others[which?] the drug is rarely available even for relieving severe pain while dying.[147]

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.[148]

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External links

 
Wikimedia Commons has media related to Morphine.
  • "Morphine". Drug Information Portal. U.S. National Library of Medicine.
  • Morphine and Heroin at The Periodic Table of Videos (University of Nottingham)
  • Video: Intravenous morphine loading (Vimeo) (YouTube) – A short education video teaching health professionals the main points about intravenous loading of analgesics, in particular morphine.

March 18, 2023
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Morphia redirects here For other uses see Morphia disambiguation and Morphine disambiguation Not to be confused with Morpheein Morphine is a strong opiate that is found naturally in opium a dark brown resin in poppies Papaver somniferum It is mainly used as a pain medication and is also commonly used recreationally or to make other illicit opioids There are numerous methods used to administer morphine oral sublingual via inhalation injection into a muscle by injection under the skin intravenously injection into the space around the spinal cord transdermal or via rectal suppository 7 9 It acts directly on the central nervous system CNS to induce analgesia and alter perception and emotional response to pain Physical and psychological dependence and tolerance may develop with repeated administration 7 It can be taken for both acute pain and chronic pain and is frequently used for pain from myocardial infarction kidney stones and during labor 7 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 7 8 Long acting formulations of morphine are available as MS Contin Kadian and other brand names as well as generically 7 MorphineClinical dataPronunciation ˈ m ɔː r f iː n Trade namesStatex MS Contin MST Continus Oramorph Sevredol and others 1 AHFS Drugs comMonographPregnancycategoryAU C 2 DependenceliabilityHighAddictionliabilityHigh 3 Routes ofadministrationInhalation smoking insufflation snorting by mouth PO rectal subcutaneous SC intramuscular IM intravenous IV epidural and intrathecal IT Drug classopioidATC codeN02AA01 WHO Legal statusLegal statusAU S8 controlled drug BR Class A1 Narcotic drugs CA Schedule I DE Anlage III Special prescription form required NZ Class B UK Class A US Schedule II Schedule III 50mg 100Ml Ref 9810 UN Narcotic Schedules I and IIIPharmacokinetic dataBioavailability20 40 by mouth 36 71 rectally 4 100 IV IM Protein binding30 40 MetabolismLiver 90 Onset of action5 minutes IV 15 minutes IM 5 20 minutes PO 6 Elimination half life2 3 hoursDuration of action3 7 hours 7 8 ExcretionKidney 90 bile duct 10 IdentifiersIUPAC name 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 diolCAS Number57 27 2 Y 64 31 3 neutral sulfate 52 26 6 hydrochloride PubChem CID5288826IUPHAR BPS1627DrugBankDB00295 YChemSpider4450907 YUNII76I7G6D29CKEGGD08233 YChEBICHEBI 17303 YChEMBLChEMBL70 YPDB ligandMOI PDBe RCSB PDB CompTox Dashboard EPA DTXSID9023336ECHA InfoCard100 000 291Chemical and physical dataFormulaC 17H 19N O 3Molar mass285 343 g mol 13D model JSmol Interactive imageSolubility in waterHCl amp sulf 60 mg mL 20 C SMILES CN1CC C 23C4 C5C CC O C4O C H 2 C H O C C C H 3 C H 1C5InChI 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 YKey BQJCRHHNABKAKU KBQPJGBKSA N Y verify Potentially serious side effects of morphine include decreased respiratory effort vomiting nausea and low blood pressure 7 Morphine is addictive and prone to abuse 7 If one s dose is reduced after long term use opioid withdrawal symptoms may occur 7 Common side effects of morphine include drowsiness vomiting and constipation 7 Caution is advised for use of morphine during pregnancy or breast feeding as it may affect the health of the baby 7 2 Morphine was first isolated between 1804 by German pharmacist Friedrich Serturner 10 This is generally believed to be the first isolation of an active ingredient from a plant 11 Merck began marketing it commercially in 1827 10 Morphine was more widely used after the invention of the hypodermic syringe in 1853 1855 10 12 Serturner originally named the substance morphium after the Greek god of dreams Morpheus as it has a tendency to cause sleep 12 13 The primary source of morphine is isolation from poppy straw of the opium poppy 14 In 2013 approximately 523 tons of morphine were produced 15 Approximately 45 tons were used directly for pain an increase of 400 over the last twenty years 15 Most use for this purpose was in the developed world 15 About 70 percent of morphine is used to make other opioids such as hydromorphone oxymorphone and heroin 15 16 17 It is a Schedule II drug in the United States 16 Class A in the United Kingdom 18 and Schedule I in Canada 19 It is on the World Health Organization s List of Essential Medicines 20 Morphine is sold under many brand names 1 In 2020 it was the 140th most commonly prescribed medication in the United States with more than 4 million prescriptions 21 22 Contents 1 Medical uses 1 1 Pain 1 2 Shortness of breath 1 3 Opioid use disorder 2 Contraindications 3 Adverse effects 3 1 Constipation 3 2 Hormone imbalance 3 3 Effects on human performance 3 4 Reinforcement disorders 3 4 1 Addiction 3 4 2 Tolerance 3 4 3 Dependence and withdrawal 4 Toxicity 5 Pharmacology 5 1 Pharmacodynamics 5 1 1 Gene expression 5 1 2 Effects on the immune system 5 2 Pharmacokinetics 5 2 1 Absorption and metabolism 5 2 2 Extended release 5 2 3 Detection in body fluids 5 3 Chirality and biological activity 6 Natural occurrence 6 1 Human biosynthesis 6 2 Biosynthesis in the opium poppy 7 Chemistry 7 1 Structure description 7 2 Uses and derivatives 7 3 Salts 8 Production 8 1 Chemical synthesis 8 2 GMO synthesis 8 2 1 Research 9 Precursor to other opioids 9 1 Pharmaceutical 9 2 Illicit 10 History 11 Society and culture 11 1 Legal status 11 2 Non medical use 11 3 Names 11 4 Access in developing countries 12 References 13 External linksMedical uses EditPain Edit Morphine is used primarily to treat both acute and chronic severe pain Its duration of analgesia is about three to seven hours 7 8 Side effects of nausea and constipation are rarely severe enough to warrant stopping treatment It is used for pain due to myocardial infarction and for labor pains 23 However concerns exist that morphine may increase mortality in the event of non ST elevation myocardial infarction 24 Morphine has also traditionally been used in the treatment of acute pulmonary edema 23 However a 2006 review found little evidence to support this practice 25 A 2016 Cochrane review concluded that morphine is effective in relieving cancer pain 26 Shortness of breath Edit Morphine is beneficial in reducing the symptom of shortness of breath due to both cancer and noncancer causes 27 28 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 29 30 Opioid use disorder Edit Morphine is also available as a slow release formulation for opiate substitution therapy OST in Austria Germany Bulgaria Slovenia and Canada for persons with opioid addiction who cannot tolerate either methadone or buprenorphine 31 Two capsules 5 mg amp 10 mg of morphine sulfate extended release 1 milliliter ampoule containing 10 mg of morphineContraindications EditRelative contraindications to morphine include respiratory depression when appropriate equipment is not available 7 Although it has previously been thought that morphine was contraindicated in acute pancreatitis a review of the literature shows no evidence for this 32 Adverse effects EditAdverse effects of opioids Common and short termItchiness 33 Nausea 33 Vomiting 33 Constipation 33 Drowsiness 33 Dry mouth 33 Respiratory depression 7 ItchingOtherOpioid dependence Dizziness Decreased sex drive Loss of appetite Impaired sexual function Decreased testosterone levels Depression Immunodeficiency Opioid induced abnormal pain sensitivity Irregular menstruation Increased risk of falls Slowed breathing Hallucinations A localized reaction to intravenous morphine caused by histamine release in the veins Constipation Edit 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 m 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 34 This effect was shown in animals when a nitric oxide precursor L arginine reversed morphine induced changes in gut motility 35 Hormone imbalance Edit See also Opioid Hormone imbalance Clinical studies consistently conclude that morphine like other opioids often causes hypogonadism and hormone imbalances in chronic users of both sexes 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 many 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 36 37 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 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 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 of isometric force i e fine motor control is impaired 38 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 39 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 2000 study 40 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 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 Reinforcement disorders Edit Addiction Edit Before the Morphine by Santiago Rusinol Morphine is a highly addictive substance Numerous studies including one by The Lancet ranked Morphine Heroin as 1 most addictive substance followed by Cocaine at 2 Nicotine 3 followed by Barbiturates at 4 and ethanol at 5 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 diacetylmorphine crossing the BBB slightly quicker No difference in subjects self rated feelings of euphoria ambition nervousness relaxation drowsiness or sleepiness 41 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 also produced higher rates of euphoria and other positive subjective effects when compared to these other opioids 41 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 42 Tolerance Edit 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 43 m opioid receptor internalization 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 44 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 Dependence and withdrawal Edit See also Opioid use disorder and Opioid withdrawal This section needs additional citations for verification Please help improve this article by adding citations to reliable sources Unsourced material may be challenged and removed Find sources Morphine news newspapers books scholar JSTOR November 2019 Learn how and when to remove this template message 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 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 moderate dysphoria 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 45 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 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 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 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 directionIn 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 46 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 47 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 42 and excessive sweating are also characteristic symptoms 48 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 49 50 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 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 51 Toxicity EditSee also Opioid overdose Properties of MorphineMolar mass 52 285 338 g molAcidity pKa 52 Step 1 8 21 at 25 CStep 2 9 85 at 20 CSolubility 52 0 15 g L at 20 CMelting point 52 255 CBoiling point 52 190 C sublimesA large overdose can cause asphyxia and death by respiratory depression if the person does not receive medical attention immediately 53 Overdose treatment includes the administration of naloxone 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 54 The LD50 for humans of morphine sulphate and other preparations is not known with certainty One poor quality study on morphine overdoses among soldiers reported that the fatal dose was 0 78 mcg ml in males 71 mg for an average 90 kg adult man and 0 98mcg ml in females 74 mg for an average 75 kg female It was not specified whether the dose was oral parenteral or IV 55 Laboratory animal studies are usually cited in the literature In serious drug dependency high tolerance 2000 3000 mg per day can be tolerated 56 Pharmacology EditPharmacodynamics Edit Morphine at opioid receptors Compound Affinities Ki Ratio RefMOR DOR KOR MOR DOR KORMorphine 1 8 nM 90 nM 317 nM 1 50 176 57 Morphine 1 24 nM 145 nM 23 4 nM 1 117 19 58 Morphine gt 10 mM gt 100 mM gt 300 mM ND 58 Equianalgesic doses 59 60 61 Compound Route DoseCodeine PO 200 mgHydrocodone PO 20 30 mgHydromorphone PO 7 5 mgHydromorphone IV 2 mgMorphine PO 30 mgOxycodone PO 20 mgOxycodone IV 20 mgMorphine IV 10 mgOxymorphone PO 10 mgOxymorphone IV 1 mgMorphine is the prototypical opioid and is the standard agonist to which other opioids are tested 62 It interacts predominantly with the m d opioid Mu Delta receptor heteromer 63 64 The m 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 65 Morphine is a phenanthrene opioid receptor agonist its main effect is binding to and activating the m opioid receptor MOR in the central nervous system Its intrinsic activity at the MOR is heavily dependent on the assay and tissue being tested in some situations it is a full agonist while in others it can be a partial agonist or even antagonist 66 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 MOR is associated with analgesia sedation euphoria physical dependence and respiratory depression Morphine is also a k opioid receptor KOR and d opioid receptor DOR agonist Activation of the KOR is associated with spinal analgesia miosis pinpoint pupils and psychotomimetic effects The DOR is thought to play a role in analgesia 65 Although morphine does not bind to the s receptor it has been shown that s receptor agonists such as pentazocine inhibit morphine analgesia and s receptor antagonists enhance morphine analgesia 67 suggesting downstream involvement of the s receptor in the actions of morphine The effects of morphine can be countered with opioid receptor antagonists such as naloxone and naltrexone the development of tolerance to morphine may be inhibited by NMDA receptor antagonists such as ketamine dextromethorphan and memantine 68 69 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 citation needed Morphine Hydrochloride Ampoule for Veterinary Use Gene expression Edit 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 70 Effects on the immune system Edit 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 opioid drug addicts show increased risk of infection such as increased pneumonia tuberculosis and HIV AIDS 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 71 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 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 72 Pharmacokinetics Edit Absorption and metabolism Edit Morphine can be taken orally sublingually bucally rectally subcutaneously intranasally intravenously intrathecally or epidurally and 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 extensive first 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 73 Morphine is metabolised primarily in the liver and approximately 87 of a dose of morphine is excreted in the urine within 72 h of administration Morphine is metabolized primarily into morphine 3 glucuronide M3G and morphine 6 glucuronide M6G 74 via glucuronidation by phase II metabolism enzyme UDP glucuronosyl transferase 2B7 UGT2B7 About 60 of morphine is converted to M3G and 6 to 10 is converted to M6G 75 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 m receptors and is half as potent an analgesic as morphine in humans 75 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 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 the blood 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 76 Extended release Edit Main article Extended release morphine There are extended release formulations of orally administered morphine whose effect last longer which can be given once per day Brand names for this formulation of morphine include Avinza 77 Kadian 77 MS Contin 77 and Dolcontin 78 For constant pain the relieving effect of extended release morphine given once for Kadian 79 or twice for MS Contin 79 every 24 hours is roughly the same as multiple administrations of immediate release or regular morphine 80 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 80 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 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 81 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 82 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 83 Chirality and biological activity Edit Morphine has a highly challenging chemical structure It is a pentacyclic 3 amine alkaloid with 5 stereogenic centers and exists in 32 stereoisomeric forms But the desired analgesic activity resides exclusively in the natural product the enantiomer with the configuration 5R 6S 9R 13S 14R 84 85 Natural occurrence EditSee also Opium Latex bleeding from a freshly scored seed pod 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 is generally 8 14 of the dry weight of opium 86 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 87 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 In the brain of mammals morphine is detectable in trace steady state concentrations 9 The human body also produces endorphins which are chemically related endogenous opioid peptides that function as neuropeptides and have similar effects to morphine 88 Human biosynthesis Edit This section needs expansion with a more standard presentation without a scheme in text and with description of key enzymes points of pathway regulation etc You can help by adding to it October 2016 Morphine is an endogenous opioid in humans Various human cells are capable of synthesizing and releasing it including white blood cells 9 89 90 The primary biosynthetic pathway for morphine in humans consists of 9 L tyrosine para tyramine or L 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 morphineThe intermediate S norlaudanosoline also known as tetrahydropapaveroline is synthesized through addition of DOPAL and dopamine 9 CYP2D6 a cytochrome P450 isoenzymem is involved in two steps along the biosynthetic pathway catalyzing both the biosynthesis of dopamine from tyramine and of morphine from codeine 9 91 Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals taking L DOPA for the treatment of Parkinson s disease 9 Biosynthesis in the opium poppy Edit Morphine biosynthesis in the opium poppy Morphine is biosynthesized in the opium poppy from the tetrahydroisoquinoline reticuline It is converted into salutaridine thebaine and oripavine The enzymes involved in this process are the salutaridine synthase salutaridine NADPH 7 oxidoreductase and the codeinone reductase 92 Researchers are attempting to reproduce the biosynthetic pathway that produces morphine in genetically engineered yeast 93 In June 2015 the S reticuline could be produced from sugar and R reticuline could be converted to morphine but the intermediate reaction could not be performed 94 In August 2015 the first complete synthesis of thebaine and hydrocodone in yeast were reported but the process would need to be 100 000 times more productive to be suitable for commercial use 95 96 Chemistry EditThis section has multiple issues Please help improve it or discuss these issues on the talk page Learn how and when to remove these template messages This section does not cite any sources Please help improve this section by adding citations to reliable sources Unsourced material may be challenged and removed February 2020 Learn how and when to remove this template message This section possibly contains original research Please improve it by verifying the claims made and adding inline citations Statements consisting only of original research should be removed February 2020 Learn how and when to remove this template message Learn how and when to remove this template message 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 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 derived agonist antagonist drugs have also been developed citation needed Structure description Edit Chemical structure of morphine The benzylisoquinoline backbone 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 a benzylisoquinoline alkaloid with two additional ring closures 97 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 A rigid pentacyclic structure consisting of a benzene ring A two partially unsaturated cyclohexane 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 hydroxyl group pKa 9 9 and a C6 allylic hydroxyl group An ether linkage between E4 and E5 Unsaturation between C7 and C8 A basic tertiary amine function at position 17 and Five centers of chirality C5 C6 C9 C13 and C14 with morphine exhibiting a high degree of stereoselectivity of analgesic action 98 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 dextorphan and the racemic parent chemical racemorphan do 99 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 make codeine by methylation 100 It is also a precursor for many drugs including heroin 3 6 diacetylmorphine hydromorphone dihydromorphinone and oxymorphone 14 hydroxydihydromorphinone citation needed Most semi synthetic opioids both of the morphine and codeine subgroups 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 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 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 Many morphine derivatives can also be manufactured using thebaine or codeine as a starting material citation needed 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 citation needed 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 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 including naloxone Narcan naltrexone Trexan diprenorphine M5050 the reversing agent for the Immobilon dart and nalorphine 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 like apomorphine are devoid of narcotic effects citation needed Salts Edit This section needs additional citations for verification Relevant discussion may be found on the talk page Please help improve this article by adding citations to reliable sources Unsourced material may be challenged and removed March 2021 Learn how and when to remove this template message Both morphine and its hydrated form are sparingly soluble in water 101 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 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 of NaOH to 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 102 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 the NSAID citation needed 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 citation needed Calcium morphenate is 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 103 The salts listed by the United States Drug Enforcement Administration for reporting purposes in addition to a few others are as follows citation needed Select salts of morphine with their Controlled Substances Act CSA schedule Administrative Controlled Substances Code Number ACSCN and free base conversion ratio clarification needed citation needed Salt or drug CSA schedule ACSCN Free base conversion ratioMorphine base II 9300 1Morphine citrate II 9300 0 81Morphine bitartrate II 9300 0 66Morphine stearate II 9300 0 51Morphine phthalate II 9300 0 89Morphine hydrobromide II 9300 0 78Morphine hydrobromide 2 H2O II 9300 0 71Morphine hydrochloride II 9300 0 89Morphine hydrochloride 3 H2O II 9300 0 76Morphine acetate II 9300 0 71Morphine hydriodide 2 H2O II 9300 0 64Morphine lactate II 9300 0 76Morphine monohydrate II 9300 0 94Morphine meconate 5 H2O II 9300 0 66Morphine mucate II 9300 0 57Morphine nitrate II 9300 0 82Morphine phosphate 1 2 H2O II 9300 0 73Morphine phosphate 7 H2O II 9300 0 73Morphine salicylate II 9300Morphine pectinate II 9300 0 778Morphine phenylpropionate II 9300 0 65Morphine methyliodide II 9300 0 67Morphine isobutyrate II 9300 0 76Morphine hypophosphite II 9300 0 81Morphine sulfate 5 H2O II 9300 0 75Morphine tannate II 9300Morphine tartrate 3 H2O II 9300 0 74Morphine valerate II 9300 0 74Morphine diethylbarbiturate II 9300 0 619Morphine cyclopentylallylbarbiturate II 9300 0 561Morphine diacetate I 9200 0 74Morphine methylbromide I 9305 0 75Morphine methylsulfonate I 9306 0 75Morphine N oxide I 9307 1Morphine N oxide quinate I 9307 0 60Morphine dinicotinate HCl Nicomorphine II 9312 0 931Production Edit First generation production of alkaloids from licit latex derived opium 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 roughly 8 19 of opium by dry weight depending on growing conditions 76 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 Chemical synthesis Edit Main article Morphine total synthesis The first morphine total synthesis devised by Marshall D Gates Jr in 1952 remains a widely used example of total synthesis 104 Several other syntheses were reported notably by the research groups of Rice 105 Evans 106 Fuchs 107 Parker 108 Overman 109 Mulzer Trauner 110 White 111 Taber 112 Trost 113 Fukuyama 114 Guillou 115 and Stork 116 Because of the stereochemical complexity and consequent synthetic challenge presented by this polycyclic structure 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 117 GMO synthesis Edit Research Edit Thebaine has been produced by GMO E coli 118 Precursor to other opioids EditPharmaceutical Edit This section needs expansion with sourced content that brielfy summarises how morphine is used industrially and globally to produce other compounds with utility in medicine or research You can help by adding to it February 2020 Morphine is a precursor in the manufacture in a number of opioids such as dihydromorphine hydromorphone hydrocodone and oxycodone as well as codeine which itself has a large family of semi synthetic derivatives 119 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 120 Chemical reactions can then be used to convert morphine dihydromorphine and hydrocodone into heroin or other opioids e g diacetyldihydromorphine Paralaudin and thebacon citation needed Other clandestine conversions of morphine into ketones of the hydromorphone class or other derivatives like dihydromorphine Paramorfan desomorphine Permonid metopon etc and of codeine into hydrocodone 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 Serturner 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 121 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 The recipe given differs substantially from that of modern day laudanum 122 Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn by German pharmacist Friedrich Serturner 11 123 In 1817 Serturner reported experiments in which he administered morphine to himself three young boys three dogs and a mouse all four people almost died 124 Serturner originally named the substance morphium after the Greek god of dreams Morpheus as it has a tendency to cause sleep 12 Serturner 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 Serturner 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 125 The drug was first marketed to the general public by Serturner and Company in 1817 as a pain medication and also as a treatment for opium and alcohol addiction It was first used as a poison in 1822 when Dr Edme Castaing of France was convicted of murdering a patient 126 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 127 128 In the 1850s Alexander Wood reported that he had injected morphine into his wife Rebecca as an experiment the myth goes that this killed her because of respiratory depression 124 but she outlived her husband by ten years 129 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 400 000 130 people with the soldier s disease of morphine addiction 131 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 132 133 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 134 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 41 Advertisement for curing morphine addiction c 1900 135 An ampoule of morphine with integral needle for immediate use Also known as a syrette 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 c 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 136 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 137 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 pharmacologist Janos Kabay 138 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 m3 opioid receptor in human tissue 139 Human cells that form in reaction to cancerous neuroblastoma cells have been found to contain trace amounts of endogenous morphine 90 Society and culture EditLegal status Edit In Australia morphine is classified as a Schedule 8 drug under the variously titled State and Territory Poisons Acts In Canada morphine is classified as a Schedule I drug under the Controlled Drugs and Substances Act In France morphine is in the strictest schedule of controlled substances based upon the December 1970 French controlled substances law In Germany morphine is a verkehrsfahiges und verschreibungsfahiges Betaubungsmittel listed under Anlage III the equivalent of CSA Schedule II of the Betaubungsmittelgesetz 140 In Switzerland morphine is scheduled similarly to Germany s legal classification of the drug 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 mayaku oyobi kōseishinyaku torishimarihō In the Netherlands morphine is classified as a List 1 drug under the Opium Law In New Zealand morphine is classified as a Class B drug under the Misuse of Drugs Act 1975 141 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 controlled substance under the Controlled Substances Act under main Administrative Controlled Substances Code Number 9300 Morphine pharmaceuticals are subject to annual manufacturing quotas in 2017 these quotas were 35 0 tonnes of production for sale and 27 3 tonnes of production as an intermediate or chemical precursor for conversion into other drugs 142 Morphine produced for use in extremely dilute formulations is excluded from the manufacturing quota citation needed Internationally UN morphine is a Schedule I drug under the Single Convention on Narcotic Drugs 143 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 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 citation needed 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 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 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 mixing 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 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 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 is marketed under many different brand names in various parts of the world 1 It was formerly called Morphia in British English 144 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 with heroin Sister Tab Unkie Unkie White and Stuff 145 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 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 amp Bake or Shake amp Shoot Morphine can be smoked especially diacetylmorphine heroin the most common method being the Chasing The Dragon method To perform 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 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 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 146 Some countries which import virtually no morphine and in others which the drug is rarely available even for relieving severe pain while dying 147 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to Morphine Morphine Drug Information Portal U S National Library of Medicine Morphine and Heroin at The Periodic Table of Videos University of Nottingham Video Intravenous morphine loading Vimeo YouTube A short education video teaching health professionals the main points about intravenous loading of analgesics in particular morphine Portal Medicine Retrieved from https en wikipedia org w index php title Morphine amp oldid 1144887040, wikipedia, wiki, book, books, library,

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