Morphine is the most abundant alkaloid found in opium, the dried sap (latex) derived from shallowly slicing the unripe seedpods of the opium, or common or edible, poppy, Papaver somniferum. Morphine was the first active principle purified from a plant source and is one of at least 50 alkaloids of several different types present in opium, Poppy Straw Concentrate, and other poppy derivatives. Morphine is generally 8 to 17 per cent of the dry weight of opium, although specially-designed cultivars reach 26 per cent or produce little morphine at all, under 1 per cent, perhaps down to 0.04 per cent. The latter varieties, including the Przemko and Norman strains 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. Morphine can be found in industrially useful concentrations in some crops of the Iranian poppy (P. bracteatum), oriental poppy (P. orientale), and white poppy (P. album) while lower concentrations may be found in a handful of the other 200+ members of the poppy family—as well as in some species of hops and mulberry trees. Morphine is produced most predominantly early in the life cycle of the plant and past the optimum point for extraction, various processes in the plant produce codeine, thebaine, and in some cases low quantities of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydrothebaine, and hydrocodone. The human body also produces small amounts of morphine and metabolises it into a number of other active opiates.
In clinical medicine, morphine is regarded as the gold standard, or benchmark, of analgesics used to relieve severe or agonizing pain and suffering. Like other opioids, e.g. oxycodone (OxyContin, Percocet, Percodan), hydromorphone (Dilaudid, Palladone), and diacetylmorphine (heroin), morphine acts directly on the central nervous system (CNS) to relieve pain. Morphine has a high potential for addiction; tolerance and psychological dependence develop rapidly, although physical addiction may take several months to develop.
Morphine is marketed under many different brand names in various parts of the world:
|Morphine brand names|
An opium-based elixir has been ascribed to alchemists of Byzantine times, but the specific formula was supposedly lost during the Ottoman conquest of Constantinople. Around 1522, Paracelsus made reference to an opium-based elixir which he called, laudanum from the Latin word laudare meaning "to praise." He described it as a potent pain killer, but recommended that it be used sparingly. In the late eighteenth century, when the East India Company gained a direct interest in the opium trade through India, another opiate recipe called 'laudanum' became very popular among physicians and their patients.
Morphine was discovered as the first active alkaloid extracted from the opium poppy plant in December 1804 in Paderborn, Germany by Friedrich Sertürner. The drug was first marketed to the general public by Sertürner and Company in 1817 as an analgesic, and also as a treatment for opium and alcohol addiction. 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 sufferers from the "soldier's disease" of morphine addiction. This idea has been a subject of controversy, as there have been suggestions that such a disease was in fact a fabrication; the first documented use of the phrase "soldier's disease" was in 1915.Diacetylmorphine (better known as heroin) was synthesized from morphine in 1874 and brought to market by Bayer in 1898. Heroin is approximately 1.5–2 times more potent than morphine on a milligram-for-milligram basis. Using a variety of subjective and objective measures, one study estimated the relative potency of heroin to morphine administered intravenously to post-addicts to be 1.80–2.66 mg of morphine sulfate to 1 mg of diamorphine hydrochloride (heroin).Morphine became a controlled substance in the US 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. Until the synthesis of dihydromorphine (ca. 1900), the dihydromorphinone class of opioids (1920s), and oxycodone (1916) and similar drugs, there generally were no other drugs in the same efficacy range as opium, morphine, and heroin, with synthetics still several years away (pethidine was invented in Germany in 1937) and opioid agonists amongst 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. 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. Still, the vast majority of morphine is derived from the opium poppy by either the traditional method of gathering latex from the scored, unripe pods of the poppy, or processes using poppy straw, the dried pods and stems of the plant, the most widespread of which was invented in Hungary in 1925 and announced in 1930 by the chemist János Kábay.In 2003, there was discovery of endogenous morphine occurring naturally in the human body. Thirty years of speculation were made on this subject because there was a receptor that apparently only reacted to morphine: the mu3 opiate receptor in human tissue. Human cells that form in reaction to cancerous neuroblastoma cells have been found to contain trace amounts of endogenous morphine.
Morphine can be used as an analgesic to relieve:
- pain in myocardial infarction
- pain in sickle cell crisis
- pain associated with surgical conditions, pre- and postoperatively
- pain associated with trauma
- severe chronic pain, e.g., cancer
- pain from kidney stones (renal colic, ureterolithiasis)
- severe back pain
Morphine can also be used:
- as an adjunct to general anesthesia
- in epidural anesthesia or intrathecal analgesia
- for palliative care (i.e., to alleviate pain without curing the underlying reason for it, usually because the latter is found impossible)
- as an antitussive for severe cough
- in nebulized form, for treatment of dyspnea, although the evidence for efficacy is slim. Evidence is better for other routes.
- as an antidiarrheal in chronic conditions (e.g., for diarrhea associated with AIDS, although loperamide (a non-absorbed opioid acting only on the gut) is the most commonly used opioid for diarrhea).
- for remarkable relief of acute pulmonary edema through an unknown mechanism
- To lower and stabilise blood glucose in diabetics and combat other diabetic effects including diabetic neuropathy -- morphine and whole opium preparations were used for this purpose well into the 1960s in North America and Europe and in much curtailed fashion now and in other countries. Morphine will also impact hypertension, levels of lipids like cholesterol in blood, and improve laboratory indices in certain types of anaemia, although whole opium preparations are preferred for these purposes if allowed. Most often, chronic pain patients with one or more of the four above conditions are treated with morphine rather than synthetics like pethidine.
- Experimentally for refractory depression. Morphine, hydromorphone, opium products and the like were used on-label for depression from antiquity or prehistoric time up into the middle 1950s.
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 increases in 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. This effect was shown in animals when a nitric oxide precursor, L-Arginine, reversed morphine-induced changes in gut motility.Addiction
In controlled studies comparing the physiological and subjective effects of injected heroin and morphine in iniduals formerly addicted to opiates, subjects showed no preference for one drug over the other. Equipotent, injected doses had comparable action courses, with no difference in subjects' self-rated feelings of euphoria, ambition, nervousness, relaxation, drowsiness, or sleepiness. Short-term addiction studies by the same researchers demonstrated that tolerance developed at a similar rate to both heroin and morphine. When compared to the opioids hydromorphone, fentanyl, oxycodone, and pethidine/meperidine, former addicts showed a strong preference for heroin and morphine, suggesting that heroin and morphine are particularly susceptible to abuse and addiction. Morphine and heroin were also much more likely to produce euphoria and other positive subjective effects when compared to these other opioids.
The "rush" of injecting morphine is the reason some people become addicted, all by itself. Morphine, heroin, and related drugs produce a "rush" and "bang" when injected intravenously, or via other routes if a blood vessel is entered and the injector does not aspirate to see if the needle is in a blood vessel (or does so on purpose when injecting IM in particular, finally pushing the plunger when they get a "register" i.e. blood steadily flowing into the syringe). The rush and bang are produced by mu and perhaps delta opioid receptors being activated in huge numbers in a very short time span; the rush is the physical sensation which is helped along by vasodilation and histamine release and the bang is the very rapid onset and increase in euphoria and some related sensations of physical origin—other methods and weaker agents like codeine can sometimes produce a (delayed) bang even when swallowed on an empty stomach with or after a potentiator, but the rush is a unique property of intravenous injection and can also be produced by drugs in other categories. Antihistamines like cyclizine and tripelennamine are sometimes mixed with morphine to increase both, a potentially dangerous practise via unsupervised injection but one used medically with oral opioid administration and under direct supervision of a doctor and nurse via the IV and SC routes in particular.
Other studies, such as the Rat Park experiments, suggest that morphine is less physically addictive than others suggest, and most studies on morphine addiction merely show that "severely distressed animals, like severely distressed people, will relieve their distress pharmacologically if they can." In these studies, rats with a morphine "addiction" overcome their addiction themselves when placed in decent living environments with enough space, good food, companionship, areas for exercise, and areas for privacy. More recent research has shown that an enriched environment may decrease morphine addiction in mice.
Morphine is a potentially highly addictive substance. It can cause psychological dependence and physical dependence as well as tolerance, with an addiction potential identical to that of heroin. When used illicitly, a very serious narcotic habit can develop in a matter of weeks, whereas iatrogenic morphine addiction rates have, according to a number of studies, remained nearly constant at one case in 150 to 200 for at least two centuries. In the presence of pain and the other disorders for which morphine is indicated, a combination of psychological and physiological factors tend to prevent true addiction from developing, although physical dependence and tolerance will develop with protracted opioid therapy. These two factors do not add up to addiction without psychological dependence which manifests primarily as a morbid seek orientation for the drug.
Tolerance to the analgesic effects of morphine is fairly rapid. There are several hypotheses 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), mu-opioid receptor internalization and/or receptor down-regulation (reducing the number of available receptors for morphine to act on), and upregulation of the cAMP pathway (a counterregulatory mechanism to opioid effects) (For a review of these processes, see Koch and Hollt.) 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.
Cessation of dosing with morphine creates the prototypical opioid withdrawal syndrome, which unlike that of barbiturates, benzodiazepines, alcohol, or sedative-hypnotics, is not fatal by itself in neurologically healthy patients without heart or lung problems; it is in theory self-limiting in length and overall impact in that a rapid increase in metabolism and other bodily processes takes place, including shedding and replacement of the cells of many organs.
Nonetheless, suicide, heart attacks, strokes, seizures proceeding to status epilepticus, and effects of extreme dehydration do lead to fatal outcomes in a small fraction of cases.
Acute morphine and other opioid withdrawal proceeds through a number of stages. Other opioids differ in the intensity and length of each, and weak opioids and mixed agonist-antagonists may have acute withdrawal syndromes which do not reach the highest level. As commonly cited, they are:
- Stage I: Six to fourteen hours after last dose: Drug craving, anxiety
- Stage II: Fourteen to eighteen hours after last dose: Yawning, perspiration, lacrimation, crying, running nose, dysphoria, "yen sleep"
- Stage III: Sixteen to twenty-four hours after last dose: Nose running like faucet and increase in other of the above, dilated pupils, piloerection (gooseflesh), muscle twitches, hot flashes, cold flashes, aching bones & muscles, loss of appetite and the beginning of intestinal cramping.
- Stage IV: Twenty-four to thirty-six hours after last dose: Increase in all of the above including severe cramping and involuntary leg movements ("kicking the habit"), loose stool, insomnia, elevation of blood pressure, moderate elevation in body temperature, increase in frequency of breathing and tidal volume, increased pulse, restlessness, nausea
- Stage V: Thirty-six to seventy-two hours after last dose: Increase in the above, fetal position, vomiting, free and frequent liquid diarrhoea which sometimes can accelerate the time of passage of food from mouth to out of system to an hour or less, involuntary urination and ejaculation which is often painful, saturation of bedding materials with bodily fluids, weight loss of two to five kilos per 24 hours, increased WBC and other blood changes.
- Stage VI: After completion of above: Recovery of appetite ("the chucks"), and normal bowel function, beginning of transition to post-acute and chronic symptoms which are mainly psychological but which may also include increased sensitivity to pain, hypertension, colitis or other gastrointestinal afflictions related to motility, and problems with weight control in either direction.
Some authorities give the above as grades zero to four, and others add chronic withdrawal as a seventh stage. Some separate post-acute and chronic withdrawal, others do not. For an example of the use of the above system, methadone clinics require, in the absence of a direct and documented referral from a doctor, Stage II withdrawal symptoms and/or recent needle marks and/or surrender of injecting equipment and/or unused drug at the intake appointment to begin the methadone maintenance or withdrawal process; two urine tests positive for opioids must then be collected shortly thereafter.
The withdrawal symptoms associated with morphine addiction are usually experienced shortly before the time of the next scheduled dose, sometimes within as early as a few hours (usually between 6–12 hours) after the last administration. Early symptoms include watery eyes, insomnia, diarrhea, runny nose, yawning, dysphoria, sweating and in some cases a strong drug craving. Severe headache, restlessness, irritability, loss of appetite, body aches, severe abdominal pain, nausea and vomiting, tremors, and even stronger and more intense drug craving appear as the syndrome progresses. Severe depression and vomiting are very common. During the acute withdrawal period systolic and diastolic blood pressure increase, usually beyond pre-morphine levels, and heart rate increases, which could potentially cause a heart attack, blood clot, or stroke.
Chills or cold flashes with goose bumps ("cold turkey") alternating with flushing (hot flashes), kicking movements of the legs ("kicking the habit") and excessive sweating are also characteristic symptoms. Severe pains in the bones and muscles of the back and extremities occur, as do muscle spasms. At any point during this process, a suitable narcotic can be administered that will dramatically reverse the withdrawal symptoms. Major withdrawal symptoms peak between 48 and 96 hours after the last dose and subside after about 8 to 12 days. Sudden withdrawal by heavily dependent users who are in poor health is very rarely fatal. Morphine withdrawal is considered less dangerous than alcohol, barbiturate, or benzodiazepine withdrawal.
The psychological dependence associated with morphine addiction is complex and protracted. Long after the physical need for morphine has passed, the addict will usually continue to think and talk about the use of morphine (or other drugs) and feel strange or overwhelmed coping with daily activities without being under the influence of morphine. Psychological withdrawal from morphine is a very long and painful process. Addicts often suffer severe depression, anxiety, insomnia, mood swings, amnesia (forgetfulness), low self-esteem, confusion, paranoia, and other psychological disorders. The psychological dependence on morphine can, and usually does, last a lifetime. There is a high probability that relapse will occur after morphine withdrawal when neither the physical environment nor the behavioral motivators that contributed to the abuse have been altered. Testimony to morphine's addictive and reinforcing nature is its relapse rate. Abusers of morphine (and heroin) have one of the highest relapse rates among all drug users.
Researchers at the University of Pennsylvania have demonstrated that morphine withdrawal complicates hepatitis C by suppressing IFN-alpha-mediated immunity and enhancing virus replication. Hepatitis C virus (HCV) is common among intravenous drug users. This high association has piqued interest in determining the effects of drug abuse, specifically morphine and heroin, on progression of the disease. The discovery of such an association would impact treatment of both HCV infection and drug abuse.
A morphine overdose occurs by intentionally or accidentally taking too much of it. A large overdose can cause asphyxia and death by respiratory depression if the person does not get medical attention or an antidote (Naloxone) immediately.
Treatments include administration of activated charcoal, intravenous fluids, laxatives and naloxone. The latter completely reverses morphine's effects, but precipitates immediate onset of withdrawal in opiate-addicted subjects. Multiple doses of it may be needed.
The minimum lethal dose is 200 mg but in case of hypersensitivity 60 mg can bring sudden death. In case of drug addiction, 2-3 g/day can be tolerated. See L. Macchiarelli P. Arbarello G. Cave Bondi N.M. Di Luca T.Feola Medicina Legale (compendio) II edition ; Minerva Medica Publications, Italy, Turin 2002Effects on other systems and processes
It has been said by various sources for at least 200 years that under ideal circumstances, use of opium and its derivatives and synthetic analogues may promote longevity and slow or switch off the aging process. In practice, any such effect would have to compete with whatever comorbid conditions the medical patient has and the health problems the unsupervised user may have as the result of the illegality, cutting agents, purity, and other properties of the drugs he or she actually ingest and otherwise. However, the fact that opioids slow metabolism, lower blood pressure, moderate blood sugar levels, and have the above-listed acute and chronic effects on the endocrine system, blood, heart, and lungs (all other things being equal) may be a reason for this supposition, as examples of opioid-use careers from 50 to 100 years in length are uncommon but certainly in existence, even in the 19th century, when the life expectancy was lower. Some users of opioids both under medical care and unsupervised may look younger after several years of use on account of hormonal effects and skin changes related to opioid effects.
In the late 1990s, research into the neurological and other systemic effects of what was initially presumed to be somewhat average lower blood oxygen concentrations in chronic users of opioids which create respiratory depression led to inconclusive results.
The theory that high dose protracted opioid use may, by itself, harm the liver or kidneys does not appear to have a basis in empirically determined medical fact, however, the fluid-balance problems attendant to opioid withdrawal could eventually lead to a higher incidence of kidney stones if not treated properly, and the paracetamol content of many proprietary medications containing weak and mid-range opioids like hydrocodone can certainly be injurious to some bodily systems, as can massive and/or chronic overdoses of aspirin, salicylates, ibuprofen, and other NSAIDs.
Central hypogonadism is seen in some long-term opioid users. The effect is more commonly seen with methadone than it is with morphine or codeine. The effects of this and other changes to the body make morphine and opium a crude form of female birth control, and lower sperm counts are seen in male subjects, as well as erectile dysfunction and decrease in libido in such cases of central hypogonadism secondary to opioid use.
The following conditions are relative contraindications for morphine:
- acute respiratory depression
- renal failure (due to accumulation of the metabolites morphine-3-glucuronide and morphine-6-glucuronide)
- chemical toxicity (potentially lethal in low tolerance subjects)
- raised intracranial pressure, including head injury (risk of worsening respiratory depression)
- Biliary colic.
Although it has previously been thought that morphine was contraindicated in acute pancreatitis, a review of the literature shows no evidence for this.
Endogenous opioids include endorphins, enkephalins, dynorphins, and even morphine itself. Morphine appears to mimic endorphins. Endogenous endorphins are responsible for analgesia (reducing pain), causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement.
Morphine is the prototype narcotic drug and is the standard against which all other opioids are tested. It interacts predominantly with the µ-opioid receptor. These 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.Morphine is a phenanthrene opioid receptor agonist – its main effect is binding to and activating the µ-opioid receptors in the central nervous system. In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and gastrointestinal tract. Its primary actions of therapeutic value are analgesia and sedation. Activation of the µ-opioid receptors is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is a rapid-acting narcotic, and it is known to bind very strongly to the µ-opioid receptors, and for this reason, it often has a higher incidence of euphoria/dysphoria, respiratory depression, sedation, pruritus, tolerance, and physical and psychological dependence when compared to other opioids at equianalgesic doses. Morphine is also a ?-opioid and d-opioid receptor agonist, ?-opioid's action is associated with spinal analgesia, miosis (pinpoint pupils) and psychotomimetic effects. d-opioid is thought to play a role in analgesia. Although morphine does not bind to the s-receptor, it has been shown that s-agonists, such as (+)-pentazocine, antagonize morphine analgesia, and s-antagonists enhance morphine analgesia, suggesting some interaction between morphine and the s-opioid receptor.The effects of morphine can be countered with opioid antagonists such as naloxone and naltrexone; the development of tolerance to morphine may be inhibited by NMDA antagonists such as ketamine or dextromethorphan. 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.
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.
Effects on the immune system
Morphine has long been known to act on receptors expressed on cells of the central nervous system resulting in pain relief and analgesia. In the 1970s and '80s, evidence suggesting that opiate drug addicts show increased risk of infection (such as increased pneumonia, tuberculosis, and HIV) led scientists to believe that morphine may also affect the immune system. This possibility increased interest in the effect of chronic morphine use on the immune system.
The first step of determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that dendritic cells, part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing cytokines, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produce more interleukin-12 (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less interleukin-10 (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection).
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 cell is 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. Future research may target the exact mechanism that increases the production of IL-12 in morphine treated dendritic cells. This increased production of IL-12 causes increased T-cell immune response. This response is due to the ability of IL-12 to cause T helper cells to differentiate into the Th1 cell, causing a T cell immune response.
Further studies on the effects of morphine on the immune system have shown that morphine influences the production of neutrophils and other cytokines. Since cytokines are produced as part of the immediate immunological response (inflammation), it has been suggested that they may also influence pain. In this way, cytokines may be a logical target for analgesic development. Recently, one study has used an animal model (hind-paw incision) to observe the effects of morphine administration on the acute immunological response. Following hind-paw incision, pain thresholds and cytokine production were measured. Normally, cytokine production in and around the wounded area increases in order to fight infection and control healing (and, possibly, to control pain), but pre-incisional morphine administration (0.1-10.0 mg/kg) reduced the number of cytokines found around the wound in a dose-dependent manner. The authors suggest that morphine administration in the acute post-injury period may reduce resistance to infection and may impair the healing of the wound.
Absorption and metabolism
Morphine can be taken orally, rectally, subcutaneously, intravenously, intrathecally or epidurally. On the streets, it is becoming more common to inhale (“chasing the dragon”), but, for medicinal purposes, intravenous (IV) injection is the most common method of administration. Morphine is subject to extensive first-pass metabolism (a large proportion is broken down in the liver), so, if taken orally, only 40–50% of the dose reaches the central nervous system. Resultant plasma levels after subcutaneous (SC), intramuscular (IM), and IV injection are all comparable. After IM or SC injections, morphine plasma levels peak in approximately 20 minutes, and, after oral administration, levels peak in approximately 30 minutes. Morphine is metabolised primarily in the liver and approximately 87% of a dose of morphine is excreted in the urine within 72 hours of administration. Morphine is metabolized primarily into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) via glucuronidation by phase II metabolism enzyme UDP-glucuronosyl transferase-2B7 (UGT2B7). About 60% of morphine is converted to M3G, and 6–10% is converted to M6G. The cytochrome P450 (CYP) family of enzymes involved in phase I metabolism plays a lesser role. Not only does the metabolism occur in the liver but it may also take place in the brain and the kidneys. M3G does not undergo opioid receptor binding and has no analgesic effect. M6G binds to mu-receptors and is a more potent analgesic than morphine. Morphine may also be metabolized into small amounts of normorphine, codeine, and hydromorphone. Metabolism rate is determined by gender, age, diet, genetic makeup, disease state (if any), and use of other medications. The elimination half-life of morphine is approximately 120 minutes, though there may be slight differences between men and women. Morphine can be stored in fat, and, thus, can be detectable even after death. Morphine is able to cross the blood-brain barrier, but, because of poor lipid solubility, protein binding, rapid conjugation with glucuronic acid and ionization, it does not cross easily. Diacetylmorphine, which is derived from morphine, crosses the blood-brain barrier more easily, making it more potent.
Detection in biological fluids
Morphine and its major metabolites, morphine-3-glucuronide and morphine-6-glucuronide, may be quantitated in blood, plasma, or urine to monitor for abuse, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Most commercial opiate screening tests based on immunoassays cross-react appreciably with these metabolites. However, chromatographic techniques can easily distinguish and measure each of these substances. When interpreting the results of a test, it is important to consider the morphine usage history of the inidual, since a chronic user can develop tolerance to doses that would incapacitate an opiate-naive inidual, and the chronic user often has high baseline values of these metabolites in his system. Furthermore, some testing procedures employ a hydrolysis step prior to quantitation that converts the metabolic products to morphine, yielding a result that may be many times larger than with a method that examines each product inidually. Interpretation can be confounded by usage of codeine or ingestion of poppy seed foods, either of which leads to the presence of morphine and its conjugated metabolites in a person's biofluids.
Effects on human performance
Most reviews conclude that opioids produce minimal impairment of human performance on tests of sensory, motor, or attentional abilities. However, recent studies have been able to show some impairments caused by morphine, which is not surprising given that morphine is a central nervous system depressant. Morphine has resulted in impaired functioning on critical flicker frequency (a measure of overall CNS arousal) and impaired performance on the Maddox Wing test (a measure of deviation of the visual axes of the eyes). Few studies have investigated the effects of morphine on motor abilities; a high dose of morphine can impair finger tapping and the ability to maintain a low constant level of isometric force (i.e. fine motor control is impaired), 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, but these effects are minimal and are transient. Overall, it seems that acute doses of opioids in non-tolerant subjects produce minor effects in some sensory and motor abilities, and perhaps also in attention and cognition. It is likely that the effects of morphine will be more pronounced in opioid-naive subjects than chronic opioid users.
In chronic opioid users, such as those on Chronic Opioid Analgesic Therapy (COAT) for managing severe, chronic pain, behavioural testing has shown normal functioning on perception, cognition, coordination and behaviour in most cases. One recent study analysed COAT patients in order to determine whether they were able to safely operate a motor vehicle. The findings from this study suggest that stable opioid use does not significantly impair abilities inherent in driving (this includes physical, cognitive and perceptual skills). COAT patients showed rapid completion of tasks which require speed of responding for successful performance (e.g. Rey Complex Figure Test) but made more errors than controls. COAT patients showed no deficits in visual-spatial perception and organization (as shown in the WAIS-R Block Design Test) but did show impaired immediate and short-term visual memory (as shown on the Rey Complex Figure Test – Recall). These patients showed no impairments in higher order cognitive abilities (i.e. Planning). COAT patients appeared to have difficulty following instructions and showed a propensity towards impulsive behaviour, yet this did not reach statistical significance. Importantly, this study reveals that COAT patients have no domain-specific deficits, which supports the notion that chronic opioid use has minor effects on psychomotor, cognitive, or neuropsychological functioning.
It is difficult to study the performance effects of morphine without considering why a person is taking morphine. Opioid-naive subjects are volunteers in a pain-free state. However, most chronic-users of morphine use it to manage pain. Pain is a stressor and so it can confound performance results, especially on tests that require a large degree of concentration. Pain is also variable, and will vary over time and from person to person. It is unclear to what extent the stress of pain may cause impairments, and it is also unclear whether morphine is potentiating or attenuating these impairments.
Morphine is a benzylisoquinoline alkaloid with two additional ring closures.
Most of the licit morphine produced is used to make codeine by methylation. It is also a precursor for many drugs including heroin (diacetylmorphine), hydromorphone, and oxymorphone. Replacement of the N-methyl group of morphine with an N-phenylethyl group results in a product that is 18 times more powerful than morphine in its opiate agonist potency. Combining this modification with the replacement of the 6-hydroxyl with a 6-methylene produces a compound some 1,443 times more potent than morphine, stronger than the Bentley compounds such as etorphine.
The structure-activity relationship of morphine has been extensively studied. The structural formula of morphine was determined in 1925 and confirmed in 1952 when two methods of total synthesis were also published. As a result of the extensive study and use of this molecule, more than 200 morphine derivatives (also counting codeine and related drugs) have been developed since the last quarter of the 19th Century. These drugs range from 25 per cent the strength of codeine or a little over 2 per cent of the strength of morphine, to several hundred times the strength of morphine to several powerful opioid antagoinsts including naloxone (Narcan), naltrexone (Trexan), and nalorphine (Nalline) for human use and also among the strongest antagonists known, such as diprenorphine (M5050), the reversing agent in the Immobilon large animal tranquilliser dart kit; the tranquilliser is another ultra-potent morphine derivative/structural analogue, viz., etorphine (M99). Morphine-derived agonist-antagonist drugs have also been developed. Elements of the morphine structure have been used to create completely synthetic drugs such as the morphinan family (levorphanol, dextromethorphan and others) and other groups which have many members with morphine-like qualities. The modification of morphine and the aforementioned synthetics has also given rise to non-narcotic drugs with other uses such as emetics, stimulants, antitussives, anticholinergics, muscle relaxants, local anaesthetics, general anaesthetics, and others.
Most semi-synthetic opioids, both of the morphine and codeine subgroups, are created by modifying one or more of the following:
- Halogenating or making other modifications at positions 1 and/or 2 on the morphine carbon skeleton.
- The methyl group which makes morphine into codeine can be removed or added back, or replaced with another functional group like ethyl and others to make codeine analogues of morphine-derived drugs and vice versa. Codeine analogues of morphine-based drugs often serve as prodrugs of the stronger drug, as in codeine and morphine, hydrocodone and hydromorphone, oxycodone and oxymorphone, nicocodeine and nicomorphine, dihydrocodeine and dihydromorphine, etc.
- Saturating, opening, or other changes to the bond between positions 7 and 8, as well as adding, removing, or modifying functional groups to these positions; saturating, reducing, eliminating, or otherwise modifying the 7-8 bond and attaching a functional group at 14 yields hydromorphinol; the oxidation of the hydroxyl group to a carbonyl and changing the 7-8 bond to single from double changes codeine into oxycodone.
- Attachment, removal or modification of functional groups to positions 3 and/or 6 (dihydrocodeine and related, hydrocodone, nicomorphine); in the case of moving the methyl functional group from position 3 to 6, codeine becomes heterocodeine which is 72 times stronger, and therefore six times stronger than morphine
- Attachment of functional groups or other modification at position 14 (oxymorphone, oxycodone, naloxone)
- Modifications at positions 2, 4, 5 or 17, usually along with other changes to the molecule elsewhere on the morphine skeleton. Often this is done with drugs produced by catalytic reduction, hydrogenation, oxidation, or the like, producing strong derivatives of morphine and codeine.
Both morphine and its hydrated form, C17H19NO3H2O, are sparingly soluble in water. In five liters of water, only one gram of the hydrate will dissolve. For this reason, pharmaceutical companies produce sulfate and hydrochloride salts of the drug, both of which are over 300 times more water-soluble than their parent molecule. Whereas the pH of a saturated morphine hydrate solution is 8.5, the salts are acidic. Since they derive from a strong acid but weak base, they are both at about pH = 5; as a consequence, the morphine salts are mixed with small amounts of NaOH to make them suitable for injection.
A number of salts of morphine are used, with the most common in current clinical use being the hydrochloride, sulphate, tartrate, acetate, citrate; less commonly methobromide, hydrobromide, hydroiodide, lactate, chloride, and bitartrate and the others listed below. Morphine meconate is a major form of the alkaloid in the poppy, as is morphine pectinate, nitrate and some others. Like codeine, dihydrocodeine and other, especially older, opiates, morphine has been used as the salicylate salt by some suppliers and can be easily compounded, imparting the therapeutic advantage of both the opioid and the NSAID; multiple barbiturate salts of morphine were also used in the past, as was/is morphine valerate, the salt of the acid being the active principle of valerian. Calcium morphenate is the intermediate in various latex and poppy-straw methods of morphine production. Morphine ascorbate and other salts such as the tannate, citrate, and acetate, phosphate, valerate and others may be present in poppy tea depending on the method of preparation. Morphine valerate produced industrially was one ingredient of a medication available for both oral and parenteral administration popular many years ago in Europe and elsewhere called Trivalin (not to be confused with the curremt, unrelated herbal preparation of the same name) which also included the valerates of caffeine and cocaine, with a version containing codeine valerate as a fourth ingredient being distributed under the name Tetravalin.
Closely related to morphine are the opioids morphine-N-oxide (genomorphine) which is a pharmaceutical which is no longer in common use; and pseudomorphine, an alkaloid which exists in opium, form as degradation products of morphine.
A Hungarian chemist, János Kabay, found and internationally patented a method to extract morphine from poppy straw. 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 at least six to ten times extracted, 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. Opium poppy contains at least 40 different alkaloids, but most of them are of very low concentration. Morphine is the principal alkaloid in raw opium and constitutes ~8-19% of opium by dry weight (depending on growing conditions) . 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.
The UN Office On Drugs & Crime Bulletin On Narcotics, issue II of 1952, describes the process which led to the final determination of the structural formula of morphine in 1925 and the invention of two methods of total synthesis of morphine.
Most morphine produced for pharmaceutical use around the world, for example a little under 50 per cent of opium licitly produced by the latex method, is actually converted into codeine as the concentration of the latter in both raw opium and poppy straw is much lower than that of morphine; in most countries the usage of codeine (both as end-product and precursor) is at least equal or greater than that of morphine on a weight basis and codeine is by far the most commonly-used opioid in the world. Whilst strains of poppies have been engineered to produce much higher yields of the other useful opioid pharmaceutical precursors thebaine and oripavine, no known strain of P. somniferum will produce more codeine than morphine under most or all possible conditions. The poppy straw process of producing licit(lawful) opioid alkaloids generally yields more codeine but an equal or somewhat smaller thebaine yield.
Extraction and detection
Morphine can be isolated from whole blood samples by solid phase extraction (SPE) and detected using liquid chromatography-mass spectrometry (LC-MS).
The euphoria, comprehensive alleviation of distress and therefore all aspects of suffering, promotion of sociability and empathy, "body high", and anxiolysis provided by narcotic drugs including the opioids can cause the use of high doses in the absence of pain for a protracted period, which can impart a morbid craving for the drug in the user. Being the prototype of the entire opioid class of drugs means that morphine has properties that may lend it to misuse. Morphine addiction is the model upon which the current perception of addiction is based.
Animal and human studies and clinical experience back up the contention that morphine is one of the most euphoric of drugs, and via all but the IV route heroin and morphine cannot be distinguished according to studies. Chemical changes to the morphine molecule yield other powerful 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 &c. used clinically in many countries of the world but in many cases also produced illicitly in rare instances.
Misuse of morphine generally entails taking more than prescribed or outside of medical supervision, injecting oral formulations, mixing it with unapproved potentiators such as alcohol, cocaine, and the like, and/or defeating the extended-release mechanism by chewing the tablets or turning into a powder for snorting or preparing injectables. The latter method can be every bit as time-consuming and involved as traditional methods of smoking opium. This and the fact that the liver destroys a large percentage of the drug on the first pass impacts the demand side of the equation for clandestine re-sellers, as many customers are not needle users and may have been disappointed with ingesting the drug orally. As morphine is generally as hard or harder to ert than oxycodone in a lot of cases, morphine in any form is uncommon on the street, although ampoules and phials of morphine injection, pure pharmaceutical morphine powder, and soluble multi-purpose tablets are very popular where available.
Morphine is also available in a paste which is used in the production of heroin which can be smoked by itself or turned to a soluble salt and injected; the same goes for the penultimate products of the Kompot (Polish Heroin) and black tar processes. Poppy straw as well as opium can yield morphine of purity levels ranging from poppy tea to near-pharmaceutical grade morphine by itself or with all of the more than 50 other alkaloids. It also is the active narcotic ingredient in opium and all of its forms, derivatives, and analogues as well as forming from breakdown of heroin and otherwise being present in many batches of illicit heroin as the result of incomplete acetylation.
Morphine is known on the street and elsewhere as M, Number 13 (13th letter of alphabet, cf. Number 8 for heroin, Number 3 for codeine or cocaine), glad stuff, happy stuff, happy powder, white nurse, Red Cross, first line, unkie, mojo, God's Own Medicine, Vitamin M, Emma. Emmy, Lady M, white lady, cube, cube juice, mo, morf, morph, morpho, Miss Emma, mofo, hard stuff, shit, dope, dry grog, white hop (more accurately used for pantopon-type drugs), white merchandise, uncle, Uncle Morphy, big M, Murphy, morphy, coby, cobics, gold dust, monkey dust, love dust (cf. "initiative" for cocaine; more commonly used for MDA or MDMA), needle candy (cf. nose candy for cocaine; heroin, Dilaudid, Numorphan and the like are also known as such) and others.
MS Contin tablets are known as misties, and the 100 mg extended-release tablets as greys and blockbusters. The "speedball" can use morphine as the narcotic component, which is combined with cocaine, amphetamines, methylphenidate, or similar drugs. "Blue Velvet" is a combination of morphine with the antihistamine tripelennamine (Pyrabenzamine, PBZ, Pelamine) taken by injection, or less commonly the mixture when swallowed or used as a retention enema; the name is also known to refer to a combination of tripelennamine and dihydrocodeine or codeine tablets or syrups taken by mouth. "Morphia" is an older official term for morphine also used as a slang term. "Driving Miss Emma" is intravenous administration of morphine. Multi-purpose tablets (readily-soluble hypodermic tablets which can also be swallowed or dissolved under the tongue or betwixt the cheek and jaw) are known, as are some brands of hydromorphone, as Shake & Bake or Shake & Shoot.Morphine can be smoked, the most common method thereof being the Chasing The Dragon method as with heroin and opium and discussed in greater detail in the articles about such things. To perform a relatively crude acetylation to turn the morphine into heroin and related drugs immediately prior to use is known as AAing (for Acetic Anhydride) or home-bake, and the output of the procedure also known as home-bake or, as explored elsewhere in this article, Blue Heroin (not to be confused with Blue Magic heroin, nor the linctus known as Blue Morphine or Blue Morphone, nor the Blue Velvet mixture described above. Morphine is rarely referred to as "hospital heroin" or "drugstore heroin" -- hydromorphone is usually the definition of this term; it can also be used for oxymorphone, nicomorphine, dihydromorphine, desomorphine, dextromoramide, and, of course, medicinal diamorphine (heroin) where it is still in medical use.
Precursor to other opioids, in a pharmaceutical manufacturing setting
Morphine is a precursor in the manufacture in a large number of opioids such as dihydromorphine, hydromorphone, nicomorphine, and heroin as well as codeine, which itself has a large family of semi-synthetic derivatives. Morphine is commonly treated with acetic anhydride and ignited to yield heroin. The pharmacology of heroin and morphine is identical except the two acetyl groups increase the lipid solubility of the heroin molecule, causing it to cross the blood-brain barrier and enter the brain more rapidly. Once in the brain, these acetyl groups are removed to yield morphine, which causes the subjective effects of heroin. Thus, heroin may be thought of as a more rapidly acting form of morphine..
Precursor to other opioids, in an underground and illicit setting
Illicit morphine is rarely produced from codeine found in over the counter cough and pain medicines. This demethylation reaction is often performed using pyridine and hydrochloric acid.
Another source of illicit morphine comes from the extraction of morphine from extended release morphine products, such as MS-Contin. Morphine can be extracted from these products with simple extraction techniques to yield a morphine solution that can be injected. Alternatively, the tablets can be crushed and snorted, injected or swallowed, although this provides much less euphoria although retaining some of the extended-release effect and the extended-release property is why MS-Contin is used in some countries alongside methadone, dihydrocodeine, buprenorphine, dihydroetorphine, piritramide, levo-alpha-acetylmethadol (LAAM) and special 24-hour formulations of hydromorphone for maintenance and detoxification of those physically dependent on opioids.
Another means of using or misusing morphine is to use chemical reactions to turn it into heroin or another stronger opioid. Morphine can, using a technique reported in New Zealand (where the initial precursor is codeine) and elsewhere known as home-bake, be turned into what is usually a mixture of morphine, heroin, 3-monoacetylmorphine, 6-monoacetylmorphine, and codeine derivatives like acetylcodeine if the process is using morphine made from demethylating codeine by mixing acetic anhydride or acetyl chloride with the morphine and cooking it in an oven between 80 and 85°C for several hours.Since heroin is one of a series of 3,6 diesters of morphine, it is possible to convert morphine to nicomorphine (Vilan) using nicotinic anhydride, dipropanoylmorphine with propionic anhydride, dibutanoylmorphine and disalicyloylmorphine with the respective acid anhydrides. Glacial acetic acid can be used to obtain a mixture high in 6-monoacetylmorphine, nicotinic acid (vitamin B3) in some form would be precursor to 6-nicotinylmorphine, salicylic acid may yield the salicyoyl analogue of 6-MAM, and so on.
Homebake or other clandestinely-produced heroin produced from extended-release morphine tablets may be known as Blue Heroin because of the blue colour of some of these tablets, even though the coloured coating of the tablet is usually removed before processing, many strengths of the tablets are not blue, bluish or a related colour like purple, and the final product tends not to be blue. A writer of a 2006 description of producing heroin from 100 mg as well as some 30 and 15 mg MS-Contin type tablets coined the term Blue Heroin to distinguish his, her or their product from New Zealand-style homebake as the process was shorter and began with uncoated tablets which in the case of the 100 mg tablet was at or above 35 per cent morphine sulphate by weight, resulting in a final liquid injectable which was brown-purple and quite potent. The drugs present in the final product are limited to heroin, 6-monoacetylmorphine, 3-monoacetylmorphine, and morphine, with the 6-MAM being just as or more sought than the heroin for reasons elucidated in the Wikipedia heroin article.The clandestine conversion of morphine to ketones of the hydromorphone class or other derivatives like dihydromorphine (Paramorfan), desomorphine (Permonid), metopon &c. and codeine to hydrocodone (Dicodid), dihydrocodeine (Paracodin) &c. is more involved, time consuming, requires lab equipment of various types, and usually requires expensive catalysts and large amounts of morphine at the outset and is less common but still has been discovered by authorities in various ways during the last 20 years or so. Dihydromorphine can be acetylated into another 3,6 morphine diester, namely diacetyldihydromorphine (Paralaudin), and hydrocodone into thebacon.
- In the United Kingdom, morphine is listed as a Class A drug under the Misuse of Drugs Act 1971 and a Schedule 2 Controlled Drug under The Misuse of Drugs Regulations 2001.
- In the United States, morphine is classified as a Schedule II drug under the Controlled Substances Act.
- In Canada, morphine is classified as a Schedule I drug under the Controlled Drugs and Substances Act.
- In Australia, morphine is classified as a Schedule 8 drug under the variously titled State and Territory Poisons Acts.
- In the Netherlands, morphine is classified as a List 1 drug under the Opium Law.
- In Japan, morphine is classified as a narcotic under the Narcotics and Psychotropics Control Act.
- Internationally, morphine is a Schedule I drug under the Single Convention on Narcotic Drugs.
Access to morphine in poor 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, Britain, Canada, France, Germany, and the United States) consume 79 percent of the world’s morphine. The less affluent countries, accounting for 80 percent of the world's population, consumed only about 6 percent of the global morphine supply. Some countries import virtually no morphine, and in others the drug is rarely available even for relieving severe pain while dying.
Experts in pain management attribute the under-distribution of morphine to an unwarranted fear of the drug's potential for addiction and abuse. While morphine is clearly addictive, Western doctors believe it is worthwhile to use the drug and then wean the patient off when the treatment is over.