Morphine was first isolated in 1804 by German pharmacistFriedrich Sertürner.[16][17] This is believed to be the first isolation of a medicinal alkaloid from a plant.[18]Merck began marketing it commercially in 1827.[17] Morphine was more widely used after the invention of thehypodermic syringe in 1853–1855.[17][19] Sertürner originally named the substancemorphium, after the Greek god of dreams,Morpheus, as it has a tendency to cause sleep.[19][20]
Morphine is used primarily to treat both acute andchronic severepain. Its duration of analgesia is about three to seven hours.[13][14] Side effects of nausea and constipation are rarely severe enough to warrant stopping treatment.
Morphine has also traditionally been used in the treatment ofacute pulmonary edema.[13] However, a 2006 review found little evidence to support this practice.[31]
A 2016 Cochrane review concluded that morphine is effective in relievingcancer pain.[32]
Morphine is beneficial in reducing the symptom ofshortness of breath due to bothcancer and non-cancer causes.[33][34] 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.[35][36]
Although it has previously been thought that morphine was contraindicated inacute pancreatitis, a review of the literature shows no evidence for this.[38]
Likeloperamide and other opioids, morphine acts on themyenteric plexus in the intestinal tract, reducing gut motility, and causing constipation. The gastrointestinal effects of morphine are mediated primarily byμ-opioid receptors in the bowel. By inhibiting gastric emptying and reducing propulsiveperistalsis 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 ofnitric oxide generation.[40] This effect was shown in animals when a nitric oxide precursor,L-arginine, reversed morphine-induced changes in gut motility.[41]
Clinical studies consistently conclude that morphine, like other opioids, often causeshypogonadism andhormone imbalances in chronic users of both sexes. This side effect isdose-dependent and occurs in both therapeutic and recreational users. Morphine can interfere with menstruation by suppressing levels ofluteinizing hormone. Multiple studies suggest the majority (perhaps as many as 90%) of chronic opioid users have opioid-induced hypogonadism. This effect may cause the increased likelihood ofosteoporosis andbone 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.[42][43]
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 systemdepressant. Morphine has resulted in impaired functioning on critical flicker frequency (a measure of overall CNS arousal) and impaired performance on theMaddox 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 ofisometric force (i.e. fine motor control is impaired),[44] though no studies have shown a correlation between morphine and gross motor abilities.
In terms ofcognitive abilities, one study has shown that morphine may negatively impactanterograde andretrograde memory,[45] 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 inattention and cognition. The effects of morphine will likely be more pronounced in opioid-naive subjects than in 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[46] 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 theWAIS-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 onpsychomotor,cognitive, orneuropsychological functioning.
Morphine is a highlyaddictive substance. Multiple studies, including one byThe Lancet, ranked morphine/heroin as the #1 most addictive substance, followed bycocaine at #2,nicotine #3,barbiturates at #4, andethanol at #5. In controlled studies comparing the physiological and subjective effects ofheroin 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 heroin crossing theblood–brain barrier slightly quicker. No difference in subjects' self-rated feelings ofeuphoria, ambition, nervousness, relaxation, or drowsiness.[47] 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, andpethidine, 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.[47] The choice of heroin and morphine over other opioids by former drug addicts may also be because heroin is an ester of morphine and morphineprodrug, essentially meaning they are identical drugsin vivo. Heroin is converted to morphine before binding to theopioid receptors in the brain and spinal cord, where morphine causes subjective effects, which is what the addicted individuals are seeking.[48]
Several hypotheses are given about how tolerance develops, including opioid receptorphosphorylation (which would change the receptor conformation), functional decoupling of receptors fromG-proteins (leading to receptor desensitization),[49] μ-opioid receptor internalization or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of thecAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt[50]).
Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which, unlike that ofbarbiturates,benzodiazepines,alcohol, orsedative-hypnotics, is not fatal by itself in otherwise healthy people.
Acute morphine withdrawal, along with that of any other opioid, proceeds through a number of stages. Other opioids differ in the intensity and length of each, and weak opioids and mixed agonist-antagonists may have acute withdrawal syndromes that do not reach the highest level. As commonly cited[by whom?], they are:
Stage I, 6 h to 14 h after last dose: Drug craving, anxiety, irritability, perspiration, and mild to moderatedysphoria
Stage II, 14 h to 18 h after last dose:Yawning, heavyperspiration, milddepression,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: Increase in all of the above,dilated pupils,piloerection (goose bumps),[51] 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,restless legs syndrome, loose stool,insomnia, elevation of blood pressure,fever, 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 all of the above, fetal position, vomiting, free and frequent liquid diarrhea, weight loss of 2 kg to 5 kg per 24 h, increasedwhite cell count, and other blood changes
Stage VI, after completion of above: Recovery of appetite and normal bowel function, beginning of transition topost-acute withdrawal 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 pancreaticsphincter of Oddi.[52]
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 common. During the acute withdrawal period, systolic and diastolic blood pressures increase, usually beyond premorphine levels, and heart rate increases,[53] which have potential to cause a heart attack, blood clot, or stroke.
Chills or cold flashes with goose bumps alternating with flushing (hot flashes), kicking movements of the legs,[48] and excessive sweating are also characteristic symptoms.[54] 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 discontinuation of morphine by heavilydependent users who are in poor health is rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal.[55][56]
The psychological dependence associated with morphineaddiction is complex and protracted. Long after the physical need for morphine has passed, addicts 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 long and painful process. Addicts often experience severe depression, anxiety, insomnia, mood swings, forgetfulness, lowself-esteem,confusion,paranoia, and other psychological problems. 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 of morphine's addictive and reinforcing nature is its relapse rate. Users of morphine have one of the highest relapse rates among all drug users, ranging up to 98% in the estimation of some medical experts.[57]
A largeoverdose can causeasphyxia and death by respiratory depression if the person does not receive medical attention immediately.[59] Overdose treatment includes the administration ofnaloxone. The latter completely reverses morphine's effects but may result in the 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.[60]
Due to its long history and established use as a pain medication, this compound has become the benchmark to which all other opioids are compared.[66] It interacts predominantly with the μ–δ-opioid (Mu-Delta)receptor heteromer.[67][68] The μ-binding sites are discretely distributed in thehuman brain, with high densities in the posterioramygdala,hypothalamus,thalamus,nucleus caudatus,putamen, and certain cortical areas. They are also found on theterminal axons of primary afferents within laminaeI and II (substantia gelatinosa) of the spinal cord and in the spinal nucleus of thetrigeminal nerve.[69]
Morphine is aphenanthreneopioid receptoragonist – its main effect is binding to and activating theμ-opioid receptor (MOR) in the central nervous system. Itsintrinsic activity at the MOR is heavily dependent on theassay and tissue being tested; in some situations it is afull agonist while in others it can be apartial agonist or evenantagonist.[70] In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system andgastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Activation of the MOR is associated with analgesia, sedation,euphoria, physicaldependence, andrespiratory depression. Morphine is also aκ-opioid receptor (KOR) andδ-opioid receptor (DOR) agonist. Activation of the KOR is associated with spinal analgesia,miosis (pinpoint pupils), andpsychotomimetic effects. The DOR is thought to play a role in analgesia.[69][failed verification] Although morphine does not bind to theσ receptor, it has been shown that σ receptor agonists, such as(+)-pentazocine, inhibit morphine analgesia, and σ receptor antagonists enhance morphine analgesia,[71] suggesting downstream involvement of the σ receptor in the actions of morphine.
The effects of morphine can be countered withopioid receptor antagonists such asnaloxone andnaltrexone; the development of tolerance to morphine may be inhibited byNMDA receptor antagonists such asketamine,dextromethorphan, andmemantine.[72][73] The rotation of morphine with chemically dissimilar opioids in the long-term treatment of pain will slow down the growth of tolerance in the longer run, particularly agents known to have significantly incomplete cross-tolerance with morphine such aslevorphanol,ketobemidone,piritramide, andmethadone 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[74] ordextromoramide.[citation needed]
Morphine creates analgesia through the activation of a specific group of neurons in therostral ventromedial medulla, called the "morphine ensemble."[75] This ensemble includes glutamatergic neurons that project to the spinal cord, known as RVMBDNF neurons. These neurons connect to inhibitory neurons in the spinal cord, called SCGal neurons, which release the neurotransmitter GABA and the neuropeptidegalanin. The inhibition of SCGal neurons is crucial for morphine's pain-relieving effects. Additionally, the neurotrophic factorBDNF, produced within the RVMBDNF neurons, is required for morphine's action. Increasing BDNF levels enhances morphine's analgesic effects, even at lower doses.[76][75]
Studies have shown that morphine can alter the expression of severalgenes. A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved inmitochondrial respiration and forcytoskeleton-related proteins.[77]
Morphine has long been known to act on receptors expressed in cells of the central nervous system resulting in pain relief and analgesia. In the 1970s and '80s, evidence suggesting that people addicted to opioids show an increased risk of infection (such as increasedpneumonia,tuberculosis, andHIV/AIDS) led scientists to believe that morphine may also affect theimmune system. This possibility increased interest in the effect of chronic morphine use on the immune system.[78]
The first step in determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed thatdendritic cells, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producingcytokines, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produce moreinterleukin-12 (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and lessinterleukin-10 (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection).[79]
This regulation of cytokines appears to occur via thep38 MAPKs (mitogen-activated protein kinase)-dependent pathway. Usually, the p38 within the dendritic cell expressesTLR 4 (toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide). This causes the p38 MAPK to bephosphorylated. This phosphorylation activates thep38 MAPK to begin producing IL-10 and IL-12. When the dendritic cells are chronically exposed to morphine during their differentiation process and then treated with LPS, the production of cytokines is different. Once treated with morphine, the p38 MAPK does not produce IL-10, instead favoring the 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 ofneutrophils and othercytokines. Since cytokines are produced as part of the immediate immunological response (inflammation), it has been suggested that they may also influence pain. In this way, cytokines may be a logical target for analgesic development. Recently, one study has used an animal model (hind-paw incision) to observe the effects of morphine administration on the acute immunological response. Following the hind-paw incision, pain thresholds and cytokine production were measured. Normally, cytokine production in and around the wounded area increases to fightinfection 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.[80]
Morphine can be takenorally, sublingually,bucally, rectally, subcutaneously,intranasally,intravenously,intrathecally orepidurally 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 extensivefirst-pass metabolism (a large proportion is broken down in the liver), so, if taken orally, only 40% to 50% of the dose reaches the central nervous system. Resultant plasma levels after subcutaneous (SC), intramuscular (IM), and IV injection are all comparable. After IM or SC injections, morphine plasma levels peak in approximately 20 min, and, after oral administration, levels peak in approximately 30 min.[81] Morphine ismetabolised primarily in theliver and approximately 87% of a dose of morphine is excreted in theurine within 72 h of administration. Morphine is metabolized primarily intomorphine-3-glucuronide (M3G) andmorphine-6-glucuronide (M6G)[82] viaglucuronidation by phase II metabolism enzymeUDP-glucuronosyl transferase-2B7 (UGT2B7). About 60% of morphine is converted to M3G, and 6% to 10% is converted to M6G.[83] 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.[83] Morphine may also be metabolized into small amounts ofnormorphine, codeine, and hydromorphone. Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any), and use of other medications. The eliminationhalf-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 theblood–brain barrier, but, because of poor lipid solubility, protein binding, rapid conjugation with glucuronic acid, and ionization, it does not cross easily.Heroin, which is derived from morphine, crosses the blood-brain barrier more easily, making it more potent.[84]
There areextended-release formulations of orally administered morphine whose effect lasts longer, which can be given once per day. Brand names for this formulation of morphine include Avinza,[85] Kadian,[85] MS Contin,[85] Dolcontin, and DepoDur.[86] For constant pain, the relieving effect of extended-release morphine given once (for Kadian)[87] or twice (for MS Contin)[87] every 24 hours is roughly the same as multiple administrations ofimmediate release (or "regular") morphine.[88] 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.[88]
Morphine and its major metabolites, morphine-3-glucuronide, and morphine-6-glucuronide, can be detected in blood, plasma, hair, and urine using animmunoassay.Chromatography can be used to test for each of these substances individually. Some testing procedureshydrolyze 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 bysolid phase extraction (SPE) and detected usingliquid chromatography-mass spectrometry (LC-MS).
Ingestion of codeine or food containing poppy seeds can cause false positives.[89]
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.[90] A 2009 review determined that, when theanalyte is morphine and thelimit of detection is 1ng/ml, a 20mg intravenous (IV) dose of morphine is detectable for 12–24 hours. A limit of detection of 0.6ng/ml had similar results.[91]
Morphine is a pentacyclic 3°amine (alkaloid) with5 stereogenic centers and exists in32 stereoisomeric forms. But the desired analgesic activity resides exclusively in the natural product, the (-)-enantiomer with the configuration (5R,6S,9R,13S,14R).[92][93]
Morphine is the most abundant opiate found in opium, the driedlatex extracted by shallowly scoring the unripe seedpods of thePapaver somniferum poppy. Morphine is generally 8–14% of the dry weight of opium.[94] Przemko and Norman cultivars of the opium poppy, are used to produce two other alkaloids,thebaine andoripavine, which are used in the manufacture of semi-synthetic and synthetic opioids likeoxycodone andetorphine.P. bracteatum does not contain morphine or codeine, or other narcoticphenanthrene-type, alkaloids. This species is rather a source of thebaine.[95] Occurrence of morphine in otherPapaverales andPapaveraceae, as well as in some species ofhops andmulberry trees has not been confirmed. Morphine is produced most predominantly early in the life cycle of the plant. Past the optimum point forextraction 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 brains of mammals, morphine is detectable in trace steady-state concentrations.[15] The human body also producesendorphins, which are chemically relatedendogenous opioidpeptides that function asneuropeptides and have similar effects to morphine.[96]
This sectionneeds expansion with: a more standard presentation, without a scheme-in-text, and with a description of key enzymes, points of pathway regulation, etc. You can help byadding to it.(October 2016)
Morphine is anendogenous opioid in humans. Various human cells are capable of synthesizing and releasing it, includingwhite blood cells.[15][97][98] The primary biosynthetic pathway for morphine in humans consists of[15]
The intermediate (S)-norlaudanosoline (also known as tetrahydropapaveroline) is synthesized through the addition of DOPAL and dopamine.[15]CYP2D6, acytochrome P450 isoenzyme is involved in two steps along the biosynthetic pathway, catalyzing both the biosynthesis of dopamine from tyramine and of morphine from codeine.[15][99]
Urinary concentrations of endogenous codeine and morphine have been found to significantly increase in individuals takingL-DOPA for the treatment ofParkinson's disease.[15]
Biosynthesis of morphine in the opium poppy begins with two tyrosine derivatives, dopamine and4-hydroxyphenylacetaldehyde. Condensation of these precursors yields the primary intermediatehigenamine (norcoclaurine).[100] Subsequent action of four enzymes yields the tetrahydroisoquinoline reticuline, which is converted into salutaridine, thebaine, and oripavine. The enzymes involved in this process are thesalutaridine synthase,salutaridine:NADPH 7-oxidoreductase and thecodeinone reductase.[101] Researchers are attempting to reproduce the biosynthetic pathway that produces morphine ingenetically engineeredyeast.[102] In June 2015 theS-reticuline could be produced from sugar andR-reticuline could be converted to morphine, but the intermediate reaction could not be performed.[103] In August 2015 the first complete synthesis of thebaine and hydrocodone in yeast was reported, but the process would need to be 100,000 times more productive to be suitable for commercial use.[104][105]
Elements of the morphine structure have been used to create completely synthetic drugs such as themorphinan family (levorphanol,dextromethorphan and others) and other groups that have multiple members with morphine-like qualities.[citation needed] The modification of morphine and the aforementioned synthetics has also given rise to non-narcotic drugs with other uses such as emetics, stimulants, antitussives, anticholinergics, muscle relaxants, local anaesthetics, general anaesthetics, and others.[citation needed] Morphine-derivedagonist–antagonist drugs have also been developed.[citation needed]
Chemical structure of morphine. Thebenzylisoquinoline 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 abenzylisoquinoline alkaloid with two additional ring closures.[106] 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 rigidpentacyclic structure consisting of abenzene ring (A), two partially unsaturatedcyclohexane rings (B and C), apiperidine ring (D) and atetrahydrofuran ring (E). Rings A, B, and C are thephenanthrene 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],
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."[107][better source needed][needs update]
Morphine and most of its derivatives do not exhibit optical isomerism, although some more distant relatives like the morphinan series (levorphanol, dextrorphan, and the racemic parent chemical racemorphan) do,[108] and as noted above stereoselectivity in vivo is an important issue.[citation needed]
Most of the licit morphine produced is used to make codeine by methylation.[109] It is also a precursor for a number of drugs includingheroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone).[110] 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 andnicomorphine, dihydrocodeine and dihydromorphine, etc.
Saturating, opening, or other changes to the bond between positions 7 and 8, as well as adding, removing, or modifying functional groups to these positions; saturating, reducing, eliminating, or otherwise modifying the 7–8 bond and attaching a functional group at 14 yieldshydromorphinol; the oxidation of the hydroxyl group to a carbonyl and changing the 7–8 bond to single from double changes codeine into oxycodone.
Attachment, removal, or modification of functional groups to positions 3 or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of moving the methyl functional group from position 3 to 6, codeine becomesheterocodeine, which is 72 times stronger, and therefore six times stronger than morphine
Attachment of functional groups or other modification at position 14 (oxymorphone, oxycodone, naloxone)
Modifications at positions 2, 4, 5, or 17, usually along with other changes to the molecule elsewhere on the morphine skeleton. Often this is done with drugs produced by catalytic reduction, hydrogenation, oxidation, or the like, producing strong derivatives of morphine and codeine.
Many morphine derivatives can also be manufactured using thebaine or codeine as a starting material.[citation needed] Replacement of theN-methyl group of morphine with anN-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency.[citation needed] Combining this modification with the replacement of the 6-hydroxyl with a 6-methylene group produces a compound some 1,443 times more potent than morphine, stronger than theBentley compounds such asetorphine (M99, the Immobilon tranquilliser dart) by some measures.[citation needed] Closely related to morphine are the opioids morphine-N-oxide (genomorphine), which is a pharmaceutical that is no longer in common use;[citation needed] and pseudomorphine, an alkaloid that exists in opium, form as degradation products of morphine.[citation needed]
As a result of the extensive study and use of this molecule, more than 250 morphine derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th century.[citation needed] These drugs range from 25% the analgesic strength of codeine (or slightly more than 2% of the strength of morphine) to several thousand times the strength of morphine, to powerful opioid antagonists, includingnaloxone (Narcan),naltrexone (Trexan),diprenorphine (M5050, the reversing agent for the Immobilon dart) andnalorphine (Nalline).[citation needed] Some opioid agonist-antagonists, partial agonists, and inverse agonists are also derived from morphine.[citation needed] The receptor-activation profile of the semi-synthetic morphine derivatives varies widely and some, likeapomorphine are devoid of narcotic effects.[citation needed]
Both morphine and its hydrated form are sparingly soluble in water.[111] For this reason, pharmaceutical companies produce sulfate andhydrochloride 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 ofNaOH to make them suitable for injection.[citation needed]
Many 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.[112]
Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate, sulfate, and some others.[citation needed] Like codeine, dihydrocodeine and other (especially older) opiates, morphine has been used as the salicylate salt by some suppliers and can be easily compounded, imparting the therapeutic advantage of both the opioid and theNSAID;[citation needed] multiplebarbiturate salts of morphine were also used in the past, as was/is morphine valerate, the salt of the acid being the active principle ofvalerian.[citation needed]Calcium 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][113]
First generation production of alkaloids from licit latex-derived opium
In the opium poppy, the alkaloids are bound tomeconic acid. The method is to extract from the crushed plant with diluted sulfuric acid, which is a stronger acid than meconic acid, but not so strong to react with alkaloid molecules. The extraction is performed in multiple steps (one amount of crushed plant is extracted at least six to ten times, so practically everyalkaloid 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, calledpoppy straw. In Turkey, a water extraction process is used, while in Tasmania, a solvent extraction process is used.[114]
Opium poppy contains at least 50 different alkaloids, but most of them are of low concentration. Morphine is the principal alkaloid in raw opium and constitutes roughly 8–19% of opium by dry weight (depending on growing conditions).[84] Some purpose-developed strains of poppy now produce opium that is up to 26% morphine by weight.[citation needed] A rough rule of thumb to determine the morphine content of pulverised dried poppy straw is to divide the percentage expected for the strain or crop via the latex method by eight or an empirically determined factor, which is often in the range of 5 to 15.[citation needed] The Norman strain ofP. somniferum, also developed inTasmania, produces down to 0.04% morphine but with much higher amounts 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 poppies 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 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.
The firstmorphine total synthesis, devised byMarshall D. Gates, Jr. in 1952, remains a widely used example oftotal synthesis.[115] Several other syntheses were reported, notably by the research groups of Rice,[116] Evans,[117] Fuchs,[118] Parker,[119] Overman,[120] Mulzer-Trauner,[121] White,[122] Taber,[123] Trost,[124] Fukuyama,[125] Guillou,[126] and Stork.[127] Because of the stereochemical complexity and consequent synthetic challenge presented by thispolycyclic 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.[128]
This sectionneeds expansion with: sourced content that briefly summarises how morphine is used, industrially and globally, to produce other compounds with utility in medicine or research. You can help byadding to it.(February 2020)
Morphine is a precursor in the manufacture of several opioids such as dihydromorphine, hydromorphone, hydrocodone, andoxycodone as well as codeine, which itself has a large family of semi-synthetic derivatives.[130]
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.[131] Chemical reactions can then be used to convert morphine, dihydromorphine, and hydrocodone intoheroin or other opioids [e.g.,diacetyldihydromorphine (Paralaudin), andthebacon].[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]
The earliest known reference to morphine can be traced back to Theophrastus in the 3rd century BC, however, possible references to morphine may go as far back as 2100 BC as Sumerian clay tablets which records lists of medical prescriptions including opium-based cures.[132]
An opium-based elixir has been ascribed toalchemists ofByzantine times, but the specific formula was lost during the Ottoman conquest ofConstantinople (Istanbul).[133] Around 1522,Paracelsus made reference to an opium-based elixir that he calledlaudanum from the Latin wordlaudāre, meaning "to praise". He described it as a potent painkiller but recommended that it be used sparingly. The recipe given differs substantially from that of modern-day laudanum.[134]
Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 inPaderborn by German pharmacistFriedrich Sertürner.[16][18][135] 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.[136] Sertürner originally named the substancemorphium after the Greek god of dreams,Morpheus, as it has a tendency to cause sleep.[19][137] 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."[138]
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 whenEdme Castaing of France was convicted of murdering a patient.[139] 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.[140][141] 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,[136] but she outlived her husband by ten years.[142]
Later it was found that morphine was more addictive than either alcohol or opium, and its extensive use during theAmerican Civil War allegedly resulted in over 400,000[143] people with the "soldier's disease" of morphine addiction.[144] 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.[145][146]
Diacetylmorphine (better known asheroin) was synthesized from morphine in 1874 and brought to market byBayer in 1898. Heroin is approximately 1.5 to 2 times more potent than morphine weight for weight. Due to thelipid solubility of diacetylmorphine, it can cross theblood–brain barrier faster than morphine, subsequently increasing the reinforcing component of addiction.[147] 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).[47]
Advertisement for curing morphine addiction, c. 1900[148]An ampoule of morphine with integral needle for immediate use. Also known as a "syrette". From WWII. On display at theArmy Medical Services Museum.
Morphine became a controlled substance in the US under theHarrison Narcotics Tax 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), andoxycodone (1916) and similar drugs, there were no other drugs in the same efficacy range as opium, morphine, and heroin, with synthetics still several years away (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), andbenzylmorphine (Peronine). Even today, morphine is the most sought-after prescription narcotic by heroin addicts when heroin is scarce, all other things being equal; local conditions and user preference may cause hydromorphone, oxymorphone, high-dose oxycodone, ormethadone as well asdextromoramide 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, andtramadol.
The structural formula of morphine was determined by 1925 byRobert Robinson.[149] At least three methods of total synthesis of morphine from starting materials such as coal tar and petroleum distillates have been patented, the first of which was announced in 1952, byMarshall D. Gates, Jr. at theUniversity of Rochester.[150] Still, the vast majority of morphine is derived from the opium poppy by either the traditional method of gathering latex from the scored, unripe pods of the poppy, or processes using poppy straw, the dried pods and stems of the plant, the most widespread of which was invented in Hungary in 1925 and announced in 1930 by Hungarian pharmacologistJános Kabay.[151]
In 2003, there was a discovery of endogenous morphine occurring naturally in the human body. Thirty years of speculation were made on this subject because there was a receptor that, it appeared, reacted only to morphine: theμ3-opioid receptor in human tissue.[152] Human cells that form in reaction to cancerousneuroblastoma cells have been found to contain trace amounts of endogenous morphine.[98]
In France, morphine is in the strictest schedule of controlled substances, based upon the December 1970 French controlled substances law.
In Germany, morphine is averkehrsfähiges und verschreibungsfähiges Betäubungsmittel listed underAnlage III (the equivalent of CSA Schedule II) of theBetäubungsmittelgesetz.[153]
In Switzerland, morphine is scheduled similarly to Germany's legal classification of the drug.
In the United States, morphine is classified as aSchedule II controlled substance under theControlled Substances Act under mainAdministrative Controlled Substances Code Number 9300. Morphine pharmaceuticals are subject to annual manufacturing quotas; in 2017 these quotas were 35.0tonnes of production for sale, and 27.3 tonnes of production as an intermediate, or chemical precursor, for conversion into other drugs.[155] Morphine produced for use in extremely dilute formulations is excluded from the manufacturing quota.[citation needed]
The euphoria, comprehensive alleviation of distress and therefore all aspects of suffering, promotion of sociability and empathy, "body high", andanxiolysis provided by narcotic drugs including opioids can cause the use of high doses in the absence of pain for a protracted period, which can impart a craving for the drug in the user.[157] 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 a number of 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 some 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 thanoxycodone 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 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 into 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 the breakdown of heroin and otherwise present in multiple batches of illicit heroin as the result of incomplete acetylation.[medical citation needed]
Morphine ismarketed under multiple different brand names in various parts of the world.[2] It was formerly called Morphia in British English.[158]
Informal names for morphine include: Cube Juice, Dope, Dreamer, Emsel, First Line, God's Drug, Hard Stuff, Hocus, Hows, Lydia, Lydic, M, Miss Emma, Mister Blue, Monkey, Morf, Morph, Morphide, Morphie, Morpho, Mother, MS, Ms. Emma, Mud, New Jack Swing (if mixed withheroin), Sister, Tab, Unkie, Unkie White, and Stuff.[159]
MS Contin tablets are known as misties, and the 100 mg extended-release tablets as greys and blockbusters. The "speedball" can use morphine as the opioid component, which is combined with cocaine,amphetamines,methylphenidate, or similar drugs. "Blue Velvet" is a combination of morphine with the antihistaminetripelennamine (Pyrabenzamine, PBZ, Pelamine) taken by injection.
Although morphine is cheap, people in poorer countries often do not have access to it. According to a 2005 estimate by theInternational Narcotics Control Board, six countries (Australia, Canada, France, Germany, the United Kingdom, and the United States) consume 79% of the world's morphine. The less affluent countries, accounting for 80% of the world's population, consumed only about 6% of the global morphine supply.[160] Some countries[which?] import virtually no morphine, and in others[which?] the drug is rarely available even for relieving severe pain while dying.[161]
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.[162][unreliable medical source?]
Morphine is a common perioperative analgesic in small animal veterinary medicine due to morphine's low cost and multiple routes of administration. Morphine has been used in cats and dogs since the late 19th century. Morphine can be used in dogs, cats, and horses. In horses usage is less common due to concerns overgastrointestinal ileus and neurological effects. Lower doses such as 0.1–0.2mg/kg given epidurally do not result in these adverse effects. Opioids in general are uncommon for livestock due to regulations around their usage. Morphine can be used for surgery in pigs, cattle, goats, and llamas.[163]
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