Is morphine used now? Use of morphine in cancer patients. Detection of morphine in biological material

Dosage form:  injection Compound:

1 ml of solution contains:

Active substance:

morphine hydrochloride trihydrate - 10.00 mg, equivalent to 8.56 mg morphine hydrochloride

Excipients:

disodium edetate (disodium salt of ethylenediaminetetraacetic acid) - 200 mcg,

hydrochloric acid solution 0.1 M - to pH from 3.0 to 4.0,

water for injection - up to 1 ml.

Description: Transparent colorless or slightly colored liquid. Pharmacotherapeutic group:Analgesic drug. Refers to Schedule II of the List of Narcotic Drugs, psychotropic substances and their precursors subject to control in Russian Federation ATX:  

N.02.A.A.01 Morphine

Pharmacodynamics:

Morphine is a phenanthrene alkaloid from the opium poppy (Papaver somniferum), an opioid receptor agonist. It has a high affinity for μ-opioid receptors.

Central action

Morphine has analgesic, antitussive, sedative, tranquilizing, respiratory depressant, miotic, antidiuretic, emetic and antiemetic (late action), as well as hypotensive and depressant. heartbeat actions.

Peripheral action

Constipation, contraction of biliary sphincters, increased muscle tone Bladder and sphincter of the bladder, slowing of gastric emptying due to contraction of the pylorus, erythema; urticaria, pruritus and asthmatic bronchospasm due to the release of histamine, as well as effects on the hypothalamic-pituitary axis, leading to disruption of the action or production of hormones such as corticosteroids, sex hormones, prolactin and antidiuretic hormone. In connection with the above hormonal disorders the corresponding symptoms may appear.

The onset of action after oral administration begins after 30 - 90 minutes. The duration of action is 4-6 hours and increases significantly when using extended-release forms. After intramuscular and subcutaneous administration the onset of action appears after 15-30 minutes, with intravenous administration - after a few minutes. The duration of action does not depend on the route of administration and is 4-6 hours. After epidural and intrathecal administration, the focal analgesic effect is detected after a few minutes. The duration of action after epidural administration is 12 hours, and with intrathecal administration it exceeds this value.

With epidural and intrathecal administration, the analgesic effect is achieved at a plasma concentration not exceeding 10 ng/ml.

In in vitro and laboratory animal studies, natural opioids such as different action per links immune system. Clinical relevance these phenomena are not known.

Pharmacokinetics:

Suction

After intramuscular injection Absorption of morphine occurs quickly and completely; after 20 minutes the concentration (Cmax) of the drug reaches its peak.

Distribution

Morphine binds to approximately 20 - 35% of blood plasma proteins, mainly to the albumin fraction. The volume of distribution is 1 - 4.7 l/kg after a single dose intravenous administration 4 - 10 mg of the drug. High concentrations morphine is found in liver tissue, kidneys, gastrointestinal tract and muscles. Penetrates the blood-brain barrier.

Metabolism

Morphine is metabolized primarily in the liver, as well as in the intestinal epithelium. An important step is glucuronidation of the phenol hydroxyl group via hepatic uridine phosphate glucuronyl transferase and N-demethylation. The main metabolites are morphine-3-glucuronide (mainly) and morphine-6-glucuronide (to a lesser extent). In addition, sulfate conjugates and oxidized metabolites are formed, such as normorphine, morphine-N-oxide and hydroxylated at position 2. The half-life of glucuronides is much longer than that of free morphine. Morphine-6-glucuronide is biologically active. Possibility of prolonged action in patients with renal failure may be due to this metabolite.

Removal

After parenteral use morphine in the urine reveals 80% of the administered dose: 10% unchanged, 4% in the form of normorphine and 65% in the form of glucuronides: morphine-3-glucuronide and morphine-6-glucuronide (in a ratio of 10:1). The terminal half-life of morphine is subject to large intra-individual variations. After parenteral administration, the average half-life is 1.7 - 4.5 hours, sometimes reaching 9 hours. Approximately 10% of morphine glucuronides are excreted in the bile into the feces.

Indications: Relief of severe pain. Contraindications:

Hypersensitivity to active substance and auxiliary substances;

Paralytic ileus;

Respiratory depression;

Severe obstructive pulmonary disease;

Acute abdomen syndrome;

Bleeding disorders and infectious lesions at the injection site for epidural administration.

Pregnancy and lactation:

Pregnancy

Data about medical use insufficient to assess potential teratogenic risk. A potential association with an increased incidence of hernias has been reported. penetrates the placental barrier. Animal studies indicate potential problems in the offspring when used during pregnancy: abnormalities in the development of the central nervous system, growth retardation, testicular atrophy, disorders in neurotransmitter systems. In addition, in some animal species it influenced the sexual behavior of males and the fertility of females. In this regard, it is allowed to use during pregnancy if the benefit to the mother clearly outweighs the risk to the fetus. Unambiguous data have been obtained on the mutagenicity of morphine: it is a clastogen, this effect is also manifested in generative cell lines. Due to the mutagenic properties of morphine, it should be administered to both men and women of childbearing potential using effective methods contraception.

At long-term use During pregnancy, the development of withdrawal syndrome in newborns has been reported.

Childbirth

Morphine can both lengthen and shorten the duration of contractions. Infants whose mothers were given narcotic analgesics during labor should be monitored for respiratory depression and withdrawal symptoms and given opioid antagonists as needed.

Lactation

Morphine penetrates breast milk, its concentration in it exceeds the plasma concentration in the mother. Since clinically significant concentrations may be achieved in neonates, breast-feeding Not recommended.

Directions for use and dosage:

Dose medicinal product should be selected individually depending on the severity pain syndrome and individual sensitivity of the patient.

Intramuscular or subcutaneous

Adults

Children

0.05 - 0.2 mg/kg body weight; a single dose should not exceed 15 mg.

Intravenously

Only if it is necessary to quickly achieve analgesic effect.

Adults

5 - 10 mg slowly (10 mg per minute, if necessary, diluted in isotonic sodium chloride solution).

Children

Epidural

Adults

1 - 4 mg (diluted in 10-15 ml of isotonic sodium chloride solution).

Children

For intramuscular, subcutaneous and intravenous routes, single doses can be administered every 4-6 hours, with a gradual reduction in the frequency of administration. Due to the longer action during epidural administration, the drug is usually administered once a day.

Patients with liver and kidney failure, as well as patients with slow peristalsis gastrointestinal tract the dose of morphine should be adjusted with caution.

Elderly

Patients over 75 years of age and physically debilitated patients tend to be more sensitive to the effects of morphine. In this regard, it is necessary to select the dose more carefully and (or) administer the drug less frequently. If necessary, you should switch to lower dosages.

Special instructions for dose adjustment

The dose should be high enough, but at the same time you should strive to administer the minimum effective dose. During treatment chronic pain the drug is preferably administered on a regular basis according to a fixed schedule.

If analgesia is adjuvant (eg, surgery, plexus block), after the procedure the dose must be adjusted.

Route and method of administration

The drug is administered intramuscularly or subcutaneously, intravenously and epidurally.

The drug should not be used for longer than required. When treating chronic pain, it is necessary to regularly check the need for its extension (if necessary, through short-term breaks in administration), and also review the dose. If necessary, you should switch to other dosage forms. Since the risk of withdrawal symptoms is higher if treatment is abruptly discontinued, the dose should be gradually reduced when discontinuing therapy.

Side effects:

The frequency of occurrence of adverse reactions was assessed according to the following gradation: very often (≥ 1/10), often (≥1/100,<1/10), нечасто (≥1/1000, <1/100), редко (≥1/10 000, <1/1000), очень редко (<1/10 000), частота не известна (невозможно оценить на основании представленных данных).

Heart disorders

Uncommon: clinically significant decrease and increase in heart rate.

Frequency unknown: palpitations, heart failure.

Nervous system disorders

Morphine is a dose-dependent respiratory depressant and causes varying degrees of sedation from mild weakness to severe stupor.

Common: headache, dizziness, taste disturbance.

Very rare: tremor, convulsions - especially with epidural administration. Not known: hyperalgesia and allodynia (especially with high doses), resistant to further dose increases (dose reduction or change in opioid analgesic may be required). General weakness up to loss of consciousness.

With epidural administration, the following undesirable reactions are also possible:

Very rare: serious neurological disorders such as paralysis (for example, due to the formation of a granuloma at the tip of the catheter (see also section "Special instructions"). Prolonged respiratory depression (up to 24 hours).

Visual disorders

Very rare: blurred vision, diplopia and nystagmus.

A typical adverse reaction is pupil constriction.

Respiratory, thoracic and mediastinal disorders

Rarely: bronchospasm.

Very rare: shortness of breath.

Non-cardiogenic pulmonary edema has been reported in patients in intensive care units.

Gastrointestinal disorders

Common: vomiting (especially at the beginning of therapy), dyspepsia.

Rarely: increased activity of pancreatic enzymes, pancreatitis. Dental damage has been noted, but a causal relationship with morphine use has not been established.

Frequency unknown: Depending on the dose, may cause nausea and dry mouth. With prolonged use, constipation is often observed.

Renal and urinary tract disorders

Common: urinary problems.

Rarely: renal colic.

Skin and subcutaneous tissue disorders

Common: sweating, hypersensitivity reactions such as urticaria, itching.

Very rare: other types of rash, eg exanthema.

Frequency unknown: facial flushing.

Musculoskeletal and connective tissue disorders

Very rare: violent muscle twitching, muscle spasm, muscle rigidity.

Endocrine disorders

Very rare: syndrome of inappropriate production of antidiuretic hormone (SIADH, manifested by hyponatremia).

Metabolic and nutritional disorders

Common: decreased appetite.

Infections and infestations

The following adverse reactions are possible with epidural administration of morphine:

Uncommon: recurrence of herpetic lesions of the lips.

Vascular disorders

Uncommon: clinically significant decrease and increase in blood pressure.

General disorders and disorders at the injection site

Very rarely: peripheral edema, asthenia, weakness, chills.

Frequency unknown: habituation and dependence.

Immune system disorders

Frequency unknown: anaphylactic and anaphylactoid reactions.

Disorders of the liver and biliary tract

Rarely: biliary colic.

Very rare: increased activity of liver enzymes.

Disorders of the genital organs and breast Very rare: erectile dysfunction, amenorrhea.

Mental disorders

Morphine leads to a variety of mental adverse reactions, the intensity and nature of which vary from person to person (depending on the individual and duration of therapy).

Very common: mood changes, usually euphoria, sometimes dysphoria. Common: changes in attention (usually depression, sometimes increased or agitated), insomnia, and changes in cognitive and sensory abilities (eg, impaired thinking, disordered thoughts, cognitive impairment/hallucinations, confusion).

Rarely: withdrawal symptoms.

Very rare: dependence (see also section "Special Instructions"), decreased libido and potency.

Overdose:

Symptoms

Since individual sensitivity to morphine varies greatly, overdose symptoms may occur in adults even with a single subcutaneous or intravenous injection of 30 mg of morphine.

Triad of symptoms of opioid overdose: miosis, respiratory depression, coma. Initially, the size of the pupils becomes the size of a pinhead. However, against the background of severe hypoxia, the pupils dilate greatly. The respiratory rate decreases sharply (up to 2-4 breaths per minute). The patient becomes cyanotic.

An overdose of morphine leads to confusion and stupor, even to coma. Initially, blood pressure remains normal, but as intoxication increases, they gradually decrease, which can subsequently lead to shock. Tachycardia, bradycardia and rhabdomyolysis are possible. Muscle relaxation, and sometimes (especially in children) generalized seizures may occur. Death occurs primarily due to respiratory failure or complications such as pulmonary edema.

Treatment

Unconscious patients with apnea are treated with mechanical ventilation, intubation, and IV opioid antagonists (eg, naloxone 0.4 mg IV). Against the background of persistent respiratory failure, the administration of a single dose of naloxone should be repeated 1 to 3 times every 3 minutes until the respiratory rate normalizes and the patient responds to painful stimuli.

Continuous medical supervision (at least 24 hours) is required. Because the action of opioid receptor antagonists is shorter than that of morphine, the possibility of recurrent respiratory failure should be considered. A single dose of naloxone for children is 0.01 mg per 1 kg of body weight.

Additional measures to protect against hypothermia and replace lost fluids may be required.

Interaction:

The following drug interactions must be taken into account:

Concomitant use of morphine with other centrally acting drugs, such as tranquilizers, anesthetics, hypnotics and sedatives, antipsychotics, barbiturates, antidepressants, antihistamines, antiemetics, as well as other opioids and alcohol, may lead to increased adverse reactions of morphine at its standard dose. . Of particular concern is the possibility of respiratory depression, sedation, hypotension and coma.

Medicines with anticholinergic activity (eg, psychotropic drugs, antihistamines, antiemetics, antiparkinsonian drugs) may increase anticholinergic adverse reactions of opioids (eg, constipation, dry mouth, urinary problems).

Cimetidine and other inhibitors of liver microsomal enzymes may increase plasma concentrations of morphine by slowing its metabolism. may enhance the muscle relaxant effect of muscle relaxants.

During the simultaneous use of pethidine and certain antidepressants (monoamine oxidase inhibitors) during the previous 14 days, life-threatening drug interactions were observed, leading to disturbances in the central nervous, respiratory and cardiovascular systems. Similar interactions are not excluded for morphine.

Concomitant use with rifampicin may lead to a weakening of the effect of morphine. When using epidural morphine, systemic administration of opioids should be avoided (except in cases of emergency pain relief).

Morphine should not be mixed with other solutions before administration.

Special instructions:

The following conditions require close monitoring and, if necessary, reduce the dose: opioid dependence, impaired consciousness, diseases in which depression of the respiratory center and external respiratory function should be avoided, cor pulmonale, increased intracranial pressure (in the absence of ventilation), hypotension due to hypovolemia, hyperplasia prostate gland with urinary retention (risk of bladder rupture due to urinary retention), renal colic, gallbladder diseases, obstructive and inflammatory bowel diseases, pheochromocytoma, pancreatitis, hypothyroidism, epileptic seizures and increased tendency to seizures, epidural administration for concomitant diseases of the nervous system, as well as with the simultaneous administration of systemic glucocorticoids. The main danger of opioid overdose is respiratory depression.

The use of morphine can lead to the development of mental dependence. Withdrawal following repeated administration or use of opioid receptor antagonists may result in a typical withdrawal syndrome. When used correctly in patients with chronic pain, the risk of mental dependence is significantly reduced and requires a differentiated assessment.

Use with caution in children under 1 year of age due to an increased risk of adverse events from the respiratory system.

Morphine is used in the pre-, intra- and postoperative periods. Compared to non-surgical patients, it should be used with caution in patients undergoing surgery due to the increased risk of intestinal obstruction and respiratory depression.

The analgesic effect of morphine can lead to serious complications, for example, due to masking the symptoms of intestinal perforation.

To minimize the risk of potentially irreversible neurological complications, patients receiving continuous epidural morphine should be monitored for early signs of granuloma formation at the catheter tip (eg, decreased analgesic effect, unexpected worsening of pain, neurological symptoms).

In case of adrenal insufficiency (for example, Addison's disease), it is necessary to monitor the plasma concentration of cortisol and, if necessary, adjust the doses of replacement therapy.

Due to its mutagenic properties, it should be administered to men and women of childbearing potential only when using effective contraceptive measures (see section "Use during pregnancy and breastfeeding").

The use of morphine may give positive results in a doping test. The health consequences of morphine use should not be ignored, as severe consequences of its use cannot be ruled out.

Impact on the ability to drive vehicles. Wed and fur.:

Morphine can impair attention and speed of reactions, leading to the inability to drive vehicles and operate machinery.

This effect is typical at the beginning of therapy, with increasing doses and changing drugs, as well as with simultaneous use with alcohol and sedatives.

The attending physician must assess the situation on an individual basis. Against the background of stable therapy, a ban on these types of activities is not necessary.

Release form/dosage:Solution for injection 10 mg/ml in ampoules of 1 ml. Package:

5 ampoules each in a blister pack made of polyvinyl chloride film and printed varnished aluminum foil.

1 or 2 blister packs with instructions for use of the drug, a knife or an ampoule scarifier in a cardboard pack.

20, 50 or 100 blister packs with 20, 50 or 100 instructions for use of the drug, respectively, with knives or ampoule scarifiers in cardboard boxes or corrugated cardboard boxes (for hospital use).

When packaging ampoules with notches, rings or break points, do not insert knives or ampoule scarifiers.

Storage conditions:

List II of the "List of narcotic drugs, psychotropic substances and their precursors subject to control in the Russian Federation", in specially equipped premises with a license for the specified type of activity.

In a place protected from light, at a temperature not exceeding 20 ° C.

Keep out of the reach of children.

Best before date: 3 years. Do not use after the expiration date stated on the package. Conditions for dispensing from pharmacies: On prescription Registration number: P N001645/01 Registration date: 08.08.2008 / 06.12.2016 Expiration date: Indefinite Owner of the Registration Certificate:MOSCOW ENDOCRINE PLANT, FSUE Russia Manufacturer:   Information update date:   17.05.2018 Illustrated instructions

Morphine is an opiate-type pain reliever sold under various trade names. Its action is directed directly to the CNS (central nervous system) to reduce the sensation of pain. Can be used against acute pain and chronic pain. The drug can be administered orally, intramuscularly, subcutaneously, intravenously, into the space around the spinal cord, or rectally. The greatest effect is achieved after approximately 20 minutes when administered intravenously and 60 minutes when administered orally, and the duration of the effect is 3-7 hours. There are also long-acting medications.

... actions and are used as antitussives, narcotic painkillers. Codeine is an opioid analgesic that works similarly to hydrocodone. A small amount of codeine is converted into . The exact mechanism of action of this substance is unknown....

Potentially serious adverse effects include depression of respiratory effort and low blood pressure. The drug has a high potential for addiction and abuse. If the dose is reduced after long-term use, withdrawal symptoms may develop. Common side effects include drowsiness, vomiting, and constipation. Caution should be exercised when used during pregnancy or breastfeeding as the drug will affect the infant.

Morphine was first isolated by Friedrich Serturner in the period 1803-1805. He is believed to have been the first to isolate the active ingredient from plants. Merck began marketing it commercially in 1827. It was used even more widely after the invention of the hypodermic syringe in 1853-1855. Serturner named the substance morphine after Morpheus, the Greek god of dreams, due to its ability to induce drowsiness.

The main source of morphine is the isolate from the poppy straw of the opium poppy. In 2013, an estimated 523,000 kg of this substance were produced. About 45,000 kg have been used directly against pain, an increase of 4 times in the last 20 years. Most of all, the product was used for this purpose in developed countries of the world. About 70% is used to produce other opioids such as hydromorphone, oxycodone, heroin and methadone. This drug is Schedule II in the US, Class A in the UK, and Schedule I in Canada. It is included in the WHO Model List of Essential Medicines, a list of the most important medicines needed in a mainstream healthcare system.

Application in medicine

Morphine is primarily used to treat acute and chronic severe pain. This substance is also often used for pain from myocardial infarction and during childbirth. However, there is concern that it may increase mortality in myocardial infarction without ST segment elevation. Morphine is also traditionally used in the treatment of acute pulmonary edema. Although a 2006 review found little evidence to support this practice.

Rapid-release morphine is useful in reducing symptoms of acute dyspnea due to cancer and non-cancerous causes. For shortness of breath at rest or with minimal exertion from conditions such as advanced cancer or end-stage cardiorespiratory disease, regular, low-dose administration of a sustained-release formulation safely reduces shortness of breath to a significant extent, and the benefits are sustained over time.

The analgesic effect lasts approximately 3-7 hours. Morphine is also available in a slow-release form for substitution treatment (OST) in Austria, Slovenia and Bulgaria for drug users unable to tolerate methadone or buprenorphine.

Video about morphine

Contraindications

Relative contraindications to the use of morphine include:

• respiratory depression when appropriate equipment is not available.

Although it was previously thought to be contraindicated in acute pancreatitis, a review of the literature shows no evidence.

Side effects of morphine

General and short-term

• dry mouth;
• drowsiness.

Other

• opioid addiction;
• decreased sex drive;
• sexual dysfunction;
• decreased testosterone levels;
• immunodeficiency;
• opioid-induced abnormal sensitivity to pain;
• irregular menstruation;
• increased risk of falls;
• slow breathing;
• constipation.

Like loperamide and other opioids, morphine acts on the myenteric plexus of the intestine, reducing intestinal motility, thereby causing constipation. The gastrointestinal effects of morphine are primarily mediated by μ-opiate receptors in the intestine. By inhibiting gastric emptying and reducing propulsive intestinal motility, the substance reduces the rate of passage of contents through the intestines. Decreased intestinal secretions and increased intestinal fluid absorption also contribute to the effect of constipation. Opioids may also act on the intestine indirectly through tonic intestinal spasms following inhibition of nitric oxide generation. This effect was shown in animals when L-arginine, a precursor of nitric oxide, reversed morphine-induced changes in intestinal motility.

Hormonal imbalance

Clinical studies have consistently concluded that morphine, like other opioids, frequently causes hypogonadism and hormonal imbalances in chronic users of both sexes. This side effect is dose dependent and occurs with medicinal and recreational use. Morphine may interfere with menstruation in women by suppressing luteinizing hormone levels. Many studies show that the majority (perhaps as many as 90%) of chronic opiate users have opioid-induced hypogonadism. This effect may lead to an increased likelihood of developing the osteoporosis and bone fractures seen in chronic morphine users. According to various researchers, the effect is temporary. In 2013, the effect of low doses or acute use of morphine on the endocrine system remained unclear.

Impact on human activity

Most reviews have concluded that opioids produce minimal impairment in human performance on tests of sensory, motor, or attention-related abilities. However, recent studies have been able to show some disturbances caused by morphine, which is not surprising given that it has a depressant effect on the central nervous system. It resulted in impaired functioning at the critical flicker frequency (a measure of general central nervous system arousal) and impaired performance on the Maddox Wing test (a measure of deviation of the visual axes of the eyes). Several studies have examined the effects of morphine on motor performance; high dosage may impair finger tapping and the ability to maintain persistently reduced levels of isometric force (i.e., impairment of fine motor skills), although studies have not shown a correlation between this substance and gross motor skills.

In terms of cognitive abilities, one study demonstrated that morphine may negatively affect anterograde and retrograde memory, but these effects are minimal and short-lived. In general, acute doses of opioids in unstable subjects are expected to produce minor effects on some sensory and motor abilities, and perhaps also on attention and cognition. It is likely that the effects of morphine will be greater in opioid-naïve patients than in chronic opioid users.

In chronic opiate users, as on chronic opioid analgesic (CTOA) therapy for the treatment of severe, chronic pain, behavioral testing has revealed normal functioning on tests of perception, cognition, coordination, and behavior in the majority of cases. A recent study analyzed patients with CTOA to determine whether they could drive safely. The results of this study suggest that chronic opioid use does not significantly impair inherent driving abilities (this includes physical, cognitive, and perceptual skills). Patients on CTOA demonstrated rapid completion of tasks requiring speed of response for successful completion (eg, the Rey Complex Figure Test) but made more errors than controls. Patients on CTOA did not demonstrate deficits in visuospatial perception and organization (as shown in the WAIS-R Block Construction Test) but did exhibit deficits in immediate and short-term visual memory (as shown in the Rey Complex Figure Reproduction Test). These patients did not demonstrate impairment in higher order cognitive abilities (ie, planning). They appeared to have difficulty following instructions and exhibited impulsive behavior, but there was no statistical significance. Importantly, this study showed that patients on CTOA do not have deficits in specific domains, supporting the view that chronic opioid use has little effect on psychomotor, cognitive, or neuropsychological function.

Reinforcing effect

Addiction

Morphine is a highly addictive substance. In controlled studies comparing the physiological and subjective effects of morphine and heroin in individuals previously dependent on opiates, subjects did not show a preference for one drug over the other. Equal doses administered had comparable courses of action, with no difference in subjects' self-reported feelings of euphoria, ambition, nervousness, relaxation, lethargy, or drowsiness. Short-term drug addiction studies by the same researchers showed that tolerance to heroin and morphine developed at a similar rate. Compared to opioids such as hydromofrone, fentanyl, pethidine/meperidine, and oxycodone, former drug users showed a clear preference for heroin and morphine, suggesting that they are particularly susceptible to abuse and addiction. Morphine and heroin are also much more likely to produce euphoria and other positive subjective effects compared to the other opioids listed. The preference of former drug addicts for morphine and heroin over other opioids may also be due to the fact that heroin (also known as morphine diacetate, morphine diacetyl, or diamorphine) is an ester and prodrug of morphine. And this essentially means that these are identical drugs in natural conditions. Heroin is converted to morphine before it binds to opioid receptors in the brain and spinal cord, where morphine produces the subjective effects that addicts crave.

Tolerance

Tolerance to the analgesic effects of morphine develops quite quickly. Various hypotheses have been put forward about how addiction develops, including phosphorylation of the opioid receptor (which would change receptor conformation), functional uncoupling of receptors and G proteins (leading to desensitization), internalization of μ-opioid receptors, and/or down-regulation of the receptor ( reducing the number of available receptors for morphine) and regulation of the cAMP pathway (a counter-regulatory mechanism for opioid effects). CCKs may mediate some of the counterregulatory pathways responsible for opioid tolerance. CCK antagonist drugs, particularly proglumide, have been shown to slow the development of morphine tolerance.

Addiction and withdrawal symptoms

Discontinuation of morphine dosing creates a prototypical opioid withdrawal syndrome, which, unlike barbiturates, alcohol, benzodiazepines, sedatives, or hypnotics, is not in itself fatal in neurologically healthy patients without heart or lung problems.

Acute withdrawal from morphine, like any other opioid, occurs through a series of stages. Other opioids vary in intensity and duration, and weak opioids and mixed agonist-antagonists may experience acute withdrawal symptoms that do not reach the highest level. This:

• Stage I, 6–14 hours after last dose: thirst for drug, anxiety, irritability, sweating, and mild to moderate dysphoria.
• Stage II, 14-18 hours after the last dose: yawning, mild depression, heavy sweating, lacrimation, crying, headaches, runny nose, dysphoria, as well as an increase in the above symptoms, “narcotic sleep” (a state similar to a waking trance).
• Stage III, 16-24 hours after the last dose: rhinorrhea (runny nose), the above symptoms become more intense, dilated pupils, piloerection (pins and needles), muscle twitching, hot flashes, chills, aching bones and muscles, loss of appetite and intestinal cramps.
• Stage IV, 24-36 after last dose: The above symptoms become more intense, including severe cramps and involuntary kicking movements of the legs (restless legs syndrome), loose stools, insomnia, mild increase in body temperature, increased blood pressure, increased breathing and respiratory rate volume, tachycardia (increased heart rate), nausea, anxiety.
• Stage V, 36 to 72 hours after the last dose: the above symptoms become more intense, fetal position, vomiting, loose and frequent loose diarrhea, which can sometimes speed up the passage of food, weight loss of 2 to 5 kg in 24 hours, increased leukocyte levels and other changes in the blood.
• Stage VI, after completion of the stages described above: appetite and normal bowel function are restored, the transition begins to post-acute and chronic symptoms, which are mainly psychological, but may also include increased sensitivity to pain, hypertension, colitis or other gastrointestinal ailments associated with contractility, and difficulty controlling weight in any direction.

In the later stages of withdrawal syndrome, ultrasonographic evidence of pancreatitis has been demonstrated in some patients and is thought to be associated with spasm of the pancreatic sphincter of Oddi.

Withdrawal symptoms associated with morphine addiction are typically experienced shortly before the next scheduled dose, sometimes within several more hours (most often 6-12 hours) after the last administration. Early symptoms include watery eyes, diarrhea, insomnia, runny nose, dysphoria, yawning, sweating, and in some cases, severe drug cravings. Severe headache, restlessness, loss of appetite, irritability, body aches, severe abdominal pain, nausea and vomiting, tremors and increased drug cravings appear as the syndrome progresses. Severe depression and vomiting are very common. During the acute withdrawal period, systolic and diastolic blood pressure rises, typically beyond premorphine levels, and the heart rate increases, which has the potential to cause a heart attack, blood clot, or stroke.

Chills or paroxysmal cold sensations with goose bumps, alternating with flushing (hot flashes), kicking movements of the legs and excessive sweating are also characteristic symptoms. Severe pain in the bones and muscles of the back and limbs and muscle spasms occur. At any point during this process, a suitable drug can be administered to abruptly reverse withdrawal symptoms. Major withdrawal symptoms peak between 48 and 96 hours after the last dose and disappear after approximately 8 to 12 days. Sudden withdrawal in very severely addicted patients in poor health can rarely be fatal. Morphine withdrawal is considered less dangerous than alcohol, benzodiazepines, or barbiturates.

The psychological dependence associated with drug addiction is complex and long-lasting. Long after the physical need for morphine has passed, the addict typically continues to think and talk about using it (or other drugs) and feels strange or overwhelmed to cope with daily activities without the influence of the substance. Psychological withdrawal is usually a very long and painful process. Often, drug addicts suffer from anxiety, severe depression, insomnia, mood swings, amnesia (forgetfulness), low self-esteem, confusion, paranoia and other psychological disorders. Without intervention, the syndrome will run its course, and for the most part, obvious physical symptoms will disappear within 7-10 days, including psychological dependence. A greater likelihood of relapse after morphine withdrawal exists if the physical environment or behavioral motivations that stimulated the abuse have not changed. Evidence of the addictive and reinforcing effects of morphine is its relapse rate. Those who abuse morphine and heroin have one of the highest rates of all drug relapses, up to 98% according to some medical experts.

Overdose

A severe overdose can cause asphyxia and death from respiratory depression if the person does not receive immediate medical attention. Treatment includes administration of naloxone. The latter reverses the effects of morphine, but may result in immediate onset of withdrawal symptoms in opiate-dependent subjects. Multiple doses may be required.

The minimum lethal dose is 200 mg, and in case of hypersensitivity, sudden death can be caused by a dose of 60 mg. For severe drug addiction (high tolerance), a dose of 2000-3000 mg per day may be tolerable.

Pharmacology

Pharmacodynamics

Endogenous opioids include endorphins, dynorphins, enkephalins, and even morphine itself. It appears to mimic endorphins. Endorphins, short for endogenous morphines, are responsible for analgesia (pain reduction), causing drowsiness and feelings of pleasure. They can be released in response to pain, exercise, orgasm or excitement.

Morphine is the prototypical narcotic drug and the standard by which all other opioids are tested. It interacts predominantly with the μ–δ opioid receptor heteromer. μ-binding sites are distributed discretely in the human brain, with high densities in the posterior amygdala, thalamus, hypothalamus, caudate nucleus, putamen, and some cortical areas. They are also found on the terminal axons of primary afferent neurons within the lamina I and II (substantia gelatinosa) of the spinal cord, as well as in the spinal trigeminal nucleus.

Morphine is a phenanthrene opioid receptor agonist, its main effect is the binding and activation of μ-opioid receptors in the central nervous system. In clinical settings, it has the main pharmacological effect on the central nervous system and gastrointestinal tract. Its main actions of therapeutic value are analgesia and sedation. Activation of μ-opioid receptors is associated with analgesia, sedation, euphoria, respiratory depression, and physical dependence. Morphine is a fast-acting drug and is known to bind very strongly to opioid receptors and is therefore often associated with higher levels of euphoria/dysphoria, sedation, respiratory depression, pruritus, tolerance and physical and psychological dependence than other opioids in analgesic doses. It is also an agonist at the κ-opioid and δ-opioid receptors, and the effects of the κ-opioid are associated with spinal anesthesia, miosis (constriction of the pupils), and hallucinogenic effects. δ-opioid is thought to play a significant role in pain relief. Although morphine does not bind to the σ receptor, it has been demonstrated that σ agonists, such as (+)-pentazocine, inhibit the analgesic effects of morphine, while σ antagonists enhance it, suggesting a downstream involvement of σ opioid receptors in the action of morphine. .

The effects of this substance can be counteracted by opioid antagonists such as naltrexone and naloxone. The development of morphine resistance can be inhibited by NMDA antagonists such as dextromethorphan or ketamine. Alternating morphine with chemically dissimilar opioids in the long-term treatment of pain will slow the development of tolerance in the long term. In particular, this applies to drugs with known significant incomplete cross-tolerance with morphine, such as levorphanol, pyritramide, ketobemidone and methadone, and its derivatives; all of these drugs also have NMDA antagonist properties. Methadone or dextromoramide is considered to be a strong opioid with the least cross-tolerance with morphine.

Gene expression

Studies have shown that this drug can change the expression of a number of genes. Acute administration has been shown to alter the expression of two major groups of genes for proteins involved in mitochondrial respiration and for proteins associated with the cytoskeleton.

Effect 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 that opioid addicts exhibit an increased risk of infection (such as an increase in pneumonia, tuberculosis, and HIV/AIDS) has led scientists to speculate that morphine may also affect the immune system. This possibility has led to increased interest in the effect of chronic drug use on the immune system.

The first step in determining that morphine could affect the immune system was to establish that opiate receptors known to be expressed on cells of the central nervous system were also expressed on cells of the immune system. One study demonstrated that dendritic cells, part of the immune system, display opiate receptors. Dendritic cells are responsible for producing cytokines, which serve as communication tools for the immune system. The same study found that dendritic cells chronically treated with morphine produced 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) as they differentiated. and less interleukin-10 (IL-10), a cytokine responsible for developing the B cell immune response (B cells produce antibodies to fight infection).

This cytokine regulation appears to occur through a p38 MAPK (mitogen-activated protein kinase)-dependent pathway. Typically, p38 in a dendritic cell expresses TLR 4 (toll-like receptor 4), which is activated through the ligand LPS (lipopolysaccharide). This causes p38 MAPK to become phosphorylated. In this phosphorylation, p38 MAPK is activated to begin the production of IL-10 and IL-12. When dendritic cells, chronically exposed to morphine during their differentiation process, are then treated with LPS, cytokine production is altered. Following morphine treatment, p38 MAPK does not produce IL-10, instead promoting IL-12 production. The exact mechanism through which the production of one cytokine is increased in favor of another is not known. Most likely, morphine causes an increase in phosphorylation of p38 MAPK. Transcriptional level interaction between IL-10 and IL-12 may also increase IL-12 production when IL-10 is not produced. This increase in IL-12 production causes an increased immune response from T cells.

Further research into the effects of this substance on the immune system revealed that morphine affects 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 act on pain. Thus, cytokines may serve as a logical target for the development of an analgesic response. One recent study used an animal model (hind paw incision) to observe the effects of morphine administration on the acute immunological response. After incision in the hind paw, pain thresholds and cytokine production were measured. Typically, cytokine production in and around the wound area is increased to fight infection and control healing (and possibly pain), but administration of morphine prior to incision (0.1-10.0 mg/kg) decreased the amount of cytokines around the wound depending on the dose. The authors suggest that administration of morphine acutely after injury may reduce resistance to infection and may impair wound healing.

Pharmacokinetics

Absorption and Metabolism

Morphine can be taken orally, sublingually, buccally, rectally, subcutaneously, intranasally, intravenously, epidurally, or intrathecally and inhaled through a nebulizer. It is increasingly inhaled on the streets (“chasing the dragon”), but for medical purposes intravenous (IV) injection is the most common route of administration. Morphine undergoes extensive first-pass metabolism (most is broken down in the liver), so that if taken orally, only 40-50% of the dose reaches the CNS. The resulting plasma levels after subcutaneous, intramuscular and intravenous injection are comparable. Following intramuscular or subcutaneous injections, plasma morphine levels peak at approximately 20 minutes, and following oral administration, peak levels occur at approximately 30 minutes. It is primarily metabolized in the liver, and approximately 87% of a morphine dose is excreted in the urine within 72 hours of administration. The substance is metabolized to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) via glucuronidation by the second metabolic step of the enzyme UDP-glucuronyl transferase-2B7 (UGT2B7). About 60% of morphine is converted to M3G and 6-10% is converted to M6G. Metabolism occurs not only in the liver, but also in the brain and kidneys. M3G does not bind to opioid receptors and does not have analgesic effects. M6G binds to μ receptors, and its effectiveness as an analgesic is half that of morphine in humans. Morphine can also be converted to normorphine, codeine and hydromorphone in small quantities. Metabolic rate is determined by gender, age, diet, genetics, disease state (if any), and use of other medications. The half-life of morphine is approximately 120 minutes, although there may be slight differences between men and women. Morphine can be stored in fat, and thus can be detected even after death. It is capable of crossing the blood-brain barrier, but due to poor solubility, protein binding, rapid conjugation with glucuronic acid, and ionization, it does not cross it easily. Diacetylmorphine, which is a derivative of morphine, crosses the blood-brain barrier more easily, making it more potent.

There are also slow-release oral morphine preparations that have a much longer effect, resulting in one administration per day.

Detection in body fluids

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

Consuming codeine or food containing poppy seeds may cause false positives.

A 1999 review estimated that relatively low doses of heroin, which is immediately metabolized to morphine, are detectable by standard urine testing within 1 to 1.5 days of use. A 2009 review determined that when the analyte is morphine and the detection limit is 1 ng/mL, a 20 mg IV dose is detectable within 12 to 24 hours. A detection limit of 0.6 ng/mL had similar results.

In nature

Morphine is considered the most common opiate found in opium, the dried juice extracted from the shallow cuts of the immature pods of the opium poppy. Morphine was the first stimulant 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 typically makes up 8-14% of opium's dry weight, although specially bred varieties reach 26% or produce very little morphine (less than 1%, maybe as low as 0.04%). The latter varieties, including the "Przemko" and "Norman" opium poppy varieties, are used to produce two other alkaloids, thebaine and oripavine, which are used in the production of semisynthetic and synthetic opioids such as oxycodone and etorphine and several other types of drugs. P. bracteatum does not contain morphine or codeine or other narcotic alkaloids such as phenanthrene. This species is more likely to be a source of thebaine. Morphine content has not been confirmed in other species of Papaverales and Papaveraceae, as well as in some species of hops and mulberries. Morphine is produced to its greatest extent early in the plant's life cycle. After the optimal point for extraction, various processes in the plant produce codeine, thebaine, and in some cases trace amounts of hydromorphone, dihydromorphine, tetrahydro-thebaine, hydrocodone, and dihydrocodeine (these compounds are synthesized from thebaine and oripavine). The human body produces endorphins, endogenous opioid peptides that act as neurotransmitters and have similar effects.

Physical and chemical properties

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

A rigid pentacyclic structure consisting of a benzene ring (A), two partially unsaturated cyclohexane rings (B and C), a piperidine ring (D), and a tetrahydrofuran ring (E). Rings A, B and C represent the phenanthrene ring system. This ring system has little conformational flexibility.

• Two hydroxyl functional groups: C3-phenolic OH (pKa 9.9) and C6-allylic OH
• Simple ethereal connection between C4 and C5
• Unsaturation between C7 and C8
• Basic, 3o-amine function at position 17
• The 5 chirality centers (C5, C6, C9, C13 and C14) with morphine exhibit a high degree of stereoselectivity in analgesic effects.

Most licitly produced morphine is used to make codeine through methylation. It is also a precursor for many drugs, including heroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone). Many morphine derivatives can also be manufactured using thebaine and/or codeine as starting materials. Replacing the N-methyl group of morphine with an N-phenyl-ethyl group produces a product 18 times more potent than morphine in its opiate agonist potency. Combining this modification with the replacement of the 6-hydroxyl by a 6-methylene group results in a compound 1443 times more potent than morphine, stronger than Bentley compounds such as azetorphine (M99, Immobilone tranquilizer dart) by some measures.

The structure-activity relationship of morphine has been extensively studied. As a result of extensive research and use of this molecule, more than 250 derivatives (also codeine and related drugs) have been developed since the last quarter of the 19th century. These drugs range from 25% the analgesic potency of codeine (or just over 2% of the potency of morphine) to several thousand times the potency of morphine, with powerful opioid antagonists including naloxone (Narcan), naltrexone (Trexane), diprenorphine (M5050, a tranquilizer reversal agent) immobilone) and nalorphine (nallin). Some opioid agonist-antagonists, partial agonists, and inverse agonists are also derived from morphine. The receptor-activation profile of semisynthetic morphine derivatives varies widely, and some, like apomorphine, are devoid of narcotic effects.

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

Agonist-antagonists derived from morphine have also been developed. Elements of its structure have been used to create fully synthetic drugs such as the morphinan family (dextromethorphan, levorphanol, and others) and other groups that have many members with morphine-like properties. Modification of morphine and the above-mentioned synthetic drugs has also led to the emergence of non-narcotic drugs with other uses, such as emetics, stimulants, antitussives, anticholinergics, muscle relaxants, local anesthetics, general anesthetics and others.

Most semisynthetic opioids from the morphine and codeine subgroups are created by modifying one or more of the following:

Halogenation or other modifications at positions 1 and/or 2 on the morphine carbon skeleton.

The methyl group that converts morphine to codeine can be removed or added back, or replaced with another functional group like ethyl, etc., to make codeine analogues of morphine-based drugs, and vice versa. Codeine analogues of morphine-based drugs often serve as prodrugs of a stronger drug, such as codeine and morphine, hydrocodone and hydromorphone, oxycodone and oxymorphone, nicocodeine and nicomorphine, dihydrocodeine and dihydromorphine, etc.

Saturation, opening, or other changes in the connections between positions 7 and 8, as well as the addition, deletion, or change of functional groups at these positions; saturation, reduction, removal or other changes of bond 7-8 and addition of a functional group on 14 gives hydromorphinol; oxidation of the hydroxyl group to carbonyl and the change of bond 7-8 to single from double changes codeine to oxycodone.

Addition, removal or change of functional groups at position 3 and/or 6 (Dihydrocodeine and related, hydrocodone, nicomorphine); By moving the methyl functional group from position 3 to 6, codeine is converted to heterocodeine, which is 72 times stronger, and therefore 6 times stronger than morphine.

Addition of functional groups or other modifications at position 14 (oxycodone, oxymorphone, naloxone)

Changes at positions 2, 4, 5, or 17 are usually in conjunction with other changes in the molecule elsewhere on the morphine backbone. This is often done with drugs produced by catalytic reduction, hydrogenation, oxidation or similar routes, producing strong derivatives of morphine and codeine.

Both morphine and its hydrated form, C17H19NO3H2O, are moderately soluble in water. Only one gram of hydrate will dissolve in 5 liters of water. That is why pharmaceutical companies produce sulfate and hydrochloride salts of the drug, whose solubility in water is 300 times greater than that of their original molecule. While the pH of a saturated solution of morphine hydrate is 8.5, the salts are acidic. Since they come from a strong acid but a weak base, their pH is approximately 5; as a consequence, the salts are mixed with NaOH in small quantities to make them suitable for injection.

Several morphine salts are used, and the most common in current clinical practice are the hydrochloride, tartrate, sulfate, and citrate; less commonly hydrobromide, methobromide, hydroiodide, lactate, bitartrate and chloride and others listed below. Morphine diacetate, another name for heroin, is a Schedule I controlled substance, so it is not used clinically in the United States; it is an approved medicine in the United Kingdom, Canada and some countries in continental Europe. Its use is particularly common (almost to the extent of hydrochloride) in the United Kingdom. Morphine meconate is the main form of the alkaloid in maca, as are morphine pectinate, nitrate, sulfate and several others. Like codeine, dihydrocodeine and other, especially older, opiates, morphine has been used as a salicylate salt by some suppliers and can be easily mixed, giving it the therapeutic benefits of an opioid and an NSAID. Several barbiturate salts of morphine have also been used in the past, as is morphine valerate, an acid salt that is the active component of valerian. Calcium morphenate is an intermediate product in various methods of morphine production using juice and poppy straw; less commonly, sodium morphenate takes its place. Morphine ascorbate and other salts such as tannate, acetate and citrate, valerate, phosphate and others may be present in poppy tea depending on the method of preparation. Commercially produced morphine valerate was one ingredient of a drug, available for both oral and parenteral administration, popular many years ago in Europe and elsewhere, called trivaline (not to be confused with the modern unrelated herbal preparation of the same name), which also contained caffeine and cocaine valerates, and a version containing codeine valerate as the fourth ingredient was marketed as tetravaline.

Closely related to morphine are the opioids Morphine-N-oxide (genomorphine), which is a pharmaceutical drug that is no longer used; and pseudomorphine, an alkaloid that is present in opium, are formed as morphine breakdown products.

Biosynthesis

Morphine is obtained through biosynthesis from tetrahydroisoquinoline reticuline. It is converted to salutaridine, thebaine and oripavine. The enzymes involved in this process are salutaridine synthase, salutaridin:NADPH 7-oxidoreductase and codeinone reductase. Researchers are trying to replicate the biosynthetic pathway that produces morphine in genetically engineered yeast. In June 2015, S-reticuline could be produced from sugar and R-reticuline could be converted to morphine, but the intermediate reaction could not be performed. The first total synthesis of thebaine and hydrocodone in yeast was reported in August 2015, but the process would need to be 100,000 times more productive to be suitable for commercial use.

Synthesis

The first total synthesis of morphine, developed by M.D. Gates Jr. in 1952, remains an example of a total synthesis of widespread use. Several other synthesis routes have been reported, notably by the research groups of Rice, Evans, Fuchs, Parker, Overman, Mülzer-Trauner, White, Taber, Trost, Fukuyama, Guillou, and Stork. It is extremely unlikely that chemical synthesis will ever be able to compete in cost with the production of the substance from the opium poppy.

Morphine production

The alkaloids in opium poppy are related to meconic acid. The method consists of extracting the crushed plant with dilute sulfuric acid, which is a stronger acid than meconic acid, but not so strong that it reacts with the alkaloid molecules. Extraction is carried out in several stages (one volume of crushed plant is subjected to extraction at least 6-10 times, so that almost every alkaloid goes into solution). Alkaloids from the solution obtained at the last stage of extraction are precipitated with ammonium hydroxide or sodium carbonate. The last stage is the purification and separation of morphine from other opium alkaloids. A somewhat similar George process was developed in Britain during the Second World War, which begins with boiling the whole plant, in most cases retaining the roots and leaves, in plain or mildly acidified water, followed by steps of concentration, extraction and purification of the alkaloids. Other methods of processing poppy straw (i.e., dried pods and stems) use steam, one or more of several types of alcohol, or other organic solvents.

Methods using poppy straw are predominant in continental Europe and the British Commonwealth, while the sap method is more common in India. This method may involve slicing the immature pods vertically or horizontally with a two- or five-blade knife with a stop specially designed for this purpose to a depth of a fraction of a millimeter, and the pods can be scored up to five times. An alternative sap method was sometimes used in China in the past to cut off the poppy heads, run a large needle through them, and collect the dried juice 24-48 hours later.

In India, opium collected by licensed poppy farmers is dehydrated to uniform hydration levels in government processing centers and then sold to pharmaceutical companies, which extract morphine from the opium. However, in Turkey and Tasmania, the substance is obtained by collecting and processing fully mature dry seed pods with stems attached, called poppy straw. In Turkey, the water extraction process is popular, but in Tasmania, the solvent extraction process is used.

The opium poppy contains at least 50 different alkaloids, but most of them are in very low concentrations. Morphine is the main alkaloid in raw opium and makes up approximately 8-19% of the dry weight of opium (depending on growing conditions). Some specially bred poppy strains now produce opium containing up to 26% morphine by weight. A rough rule of thumb for determining the morphine content of pulverized dried poppy straw is to divide the percentage expected for the straw or harvest through the juice method by 8 or this is an empirically determined factor that is often in the range of 5 to 15. Strain Norman P. Somniferum, also developed in Tasmania, produces up to 0.04% morphine, but with much higher levels of thebaine and oripavine, which can be used for the synthesis of semi-synthetic opioids, as well as other drugs such as stimulants, emetics, opioid antagonists, anticholinergics and smooth muscle agents.

In the 1950s and 1960s, Hungary supplied almost 60% of Europe's total medicinal morphine production. To this day, poppy cultivation is legal in Hungary, but it is 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.

In 1973, it was announced that a team of specialists from the National Institutes of Health in the USA had developed a method for the total synthesis of morphine, thebaine, codeine using coal tar as a starting material. The shortage of codeine-hydrocodone class antitussives (all of which can be made from morphine in one or more steps, as well as from thebaine or codeine) was the primary reason for the study.

Most of the morphine produced for pharmaceutical use worldwide is actually converted to codeine, since the concentration of the latter in raw opium and poppy straw is significantly lower than that of morphine. In most countries, the use of codeine (as end product and precursor) is at least equal to or greater than that of morphine on a weight basis.

Precursor to other opioids

Pharmaceutical

Morphine is a precursor in the production of a large number of opioids such as dihydromorphine, hydrocodone, hydromorphone, oxycodone, like codeine, which has a large family of semisynthetic derivatives. Morphine is usually treated with acetic anhydride and set on fire to create heroin. There is growing acceptance in the European medical community for the use of sustained-release morphine as an alternative treatment to methadone and buprenorphine for patients who cannot tolerate the side effects of buprenorphine and methadone. Oral sustained-release morphine has been widely used for opiate maintenance therapy in Austria, Bulgaria, Slovakia for many years, and is available on a small scale in many other countries, including the UK. The extended-release nature of morphine mimics buprenorphine in that steady-state blood levels are relatively flat, so the patient does not get a "high" per se, but has a sustained sense of well-being and no withdrawal symptoms. For patients sensitive to adverse effects that may result in part from the unnatural pharmacological actions of buprenorphine and methadone, slow-release oral morphine formulations offer a promising future for use in the treatment of opiate addiction. The pharmacology of heroin and morphine is identical except that two acetyl groups increase the lipid solubility of the heroin molecule, causing heroin to cross the blood-brain barrier and enter the brain more quickly when injected. Once in the brain, these acetyl groups are removed to form morphine, which produces the subjective effects of heroin. Thus, heroin can be considered a faster-acting form of morphine.

Illegal

Illicit morphine is rarely made from codeine, found in over-the-counter cough and pain medications. This demethylation reaction is often performed using pyridine and hydrochloric acid.

Another source of clandestine morphine is the extraction of morphine from extended-release products such as MS-Contin. Morphine can be extracted from these products using simple extraction methods to produce a solution that can be used for injection. Alternatively, the tablets can be crushed and inhaled, injected or swallowed, although this produces much less euphoria but retains some of the sustained release effect. This sustained release property is the reason why MS-Contin is used in some countries along with methadone, buprenorphine, dihydrocodeine, dihydroethorphine, levo-alpha acetylmethadol (LAAM), pyritramide, and special 24-hour hydromorphone formulas for physical maintenance and detoxification. opioid dependent.

Another method of using or misusing morphine is through chemical reactions to convert it into heroin or another powerful opioid, using a technique reported in New Zealand (the initial precursor codeine) and elsewhere known as "home baking", morphine can be converted into what is typically a mixture of morphine, heroin, 3-monoacetylmorphine, 6-monoacetylmorphine and codeine derivatives such as acetylcodeine if the process uses morphine made by demethylating codeine.

Since heroin is one of a series of 3,6 diesters of morphine, it is possible to convert morphine to nicomorphine (Vilan) using nicotinic anhydride, dopropanoylmorphine with propionic anhydride, dibutanoylmorphine and disalicylmorphine with the appropriate acid anhydrides. Glacial acetic acid can be used to produce a mixture high in 6-monoacetylmorphine, niacin (vitamin B3) in one form or another will be a precursor to 6-nicotinylmorphine, salicylic acid can produce the salicyloyl analogue 6-MAM, and so on.

Clandestine conversion of morphine into hydromorphone class ketones or other derivatives such as dihydromorphine (parmorphan), desomorphine (permonide), methopone, etc., and codeine into hydrocodone (dicodide), dihydrocodeine (paracodine), etc. more complex, requires time, laboratory equipment of various types, and, as a rule, expensive catalysts and large volumes of morphine at the beginning. Over the past 20 years or so, it is still being detected by authorities through various means, although less frequently. Dihydromorphine can be acetylated to another morphine 3,6 diester, namely diacetiohydromorphine (paralaudin), and hydrocodone to tebacone.

Story

An opium-based elixir was attributed to alchemists of Byzantine times, but the special formula was lost during the Ottoman conquest of Constantinople (Istanbul). Around 1522, Paracelsus mentioned an opium-based elixir, which he called laudanum, from the Latin word laudare, meaning “to praise.” It was described by him as a powerful pain reliever, but was recommended for rare use. In the late 18th century, when the East India Company gained a direct interest in the opium trade throughout India, another opiate recipe called tincture of opium became very popular among physicians and their patients.

Morphine was discovered by Friedrich Sertürner as the first active alkaloid, extracted from the opium poppy in 1804 in Paderborn, Germany. The drug was first introduced to the general public by Sertürner and Company in 1817 as a pain reliever and also as a treatment for opium addiction and alcoholism. It was first used as a poison in 1822, when French physician Edme Castaing was found guilty of murdering a patient. Industrial production began in the German city of Darmstadt in 1827 in a pharmacy that became the Merck Pharmaceutical Company, and morphine sales accounted for much of its early growth.

Morphine was later found to be more addictive than any alcohol or opium, and its widespread use during the American Civil War is believed to have contributed to the development of more than 400,000 morphine-stricken "soldier's disease" sufferers. This idea has been the subject of controversy, as it has been suggested that such a disease was in fact a fiction. The phrase “soldier's disease” was first recorded in 1915.

Diacetylmorphine (better known as heroin) was synthesized from morphine in 1874 and was introduced to the market by Bayer in 1898. In terms of weight, heroin is approximately 1.5-2 times more powerful than morphine. Due to the lipid solubility of diacetylmorphine, it is able to penetrate the blood-brain barrier faster than morphine, subsequently increasing the reinforcing component of drug addiction. Using a variety of subjective and objective measures, one study estimated the relative potency of heroin and morphine when administered intravenously by former drug users as 1.80–2.66 mg morphine sulfate per 1 mg diamorphine hydrochloride (heroin).

Morphine became a controlled substance in the US under the Harrison Drug Tax Act of 1914, and possession without a prescription is a criminal offense in the US. It was the most commonly abused narcotic analgesic in the world until heroin was synthesized and came into use. In general, until the synthesis of dihydromorphine (ca. 1900), the dihydromorphine class of opioids (1920), oxycodone (1916), and similar drugs had no other drugs in the same potency range as opium, morphine, and heroin. Synthetic drugs were introduced later (pethidine in Germany in 1937), and opioid agonists among the semisynthetic drugs were analogues and derivatives, such as dihydrocodeine (paracodine), benzylmorphine (Peronine), and ethylmorphine (dionine). Even today, morphine remains the most sought after prescription drug among heroin addicts when heroin is in short supply, all other things being equal. Local policies and user preferences may place hydromorphone, oxymorphone, high-dose oxycodone, methadone, and dextromoramide in specific cases at the top of this particular list. The temporary medication used by the largest absolute number of heroin addicts is probably codeine, with significant use also of dihydrocodeine, poppy straw derivatives such as poppy pod and poppy tea, propoxyphene and tramadol.

In 1925, Robert Robinson determined the structural formula of morphine. At least three methods for its total synthesis from starting materials such as coal tar and petroleum distillates have been patented, the first of which was announced in 1952 by Dr. D. M. Gates, Jr. at the University of Rochester. However, the vast majority of the substance comes from the opium poppy, either by the traditional method of collecting the juice from unripe poppy pods, which are scored, or by processes using poppy straws, dried pods and stems of the plant, the most common of which was introduced in Hungary in 1925 and introduced in 1930 by the chemist Janos Kabay.

In 2003, endogenous morphine, which occurs naturally in the human body, was discovered. 30 years ago, hypotheses were put forward on this topic because there was a receptor that seemed to respond only to morphine: the μ3-opioid receptor in human tissue. It has been revealed that human cells that are formed in response to neuroblastoma cells contain endogenous morphine in microscopic quantities.

The need for analgesics arises in all areas of medicine. But the problem of pain relief is especially acute in oncology. When the possibilities of traditional analgesics have been exhausted, one has to resort to narcotic drugs. The most powerful of them is morphine and its derivatives.

What is morphine and where is it used? What dosage forms does it come in? What effect does it have on a person? Are there any restrictions on its use? What should you do in case of poisoning and overdose? Is there an antidote to morphine? Below we will answer all these questions.

Description of morphine

People have known what morphine is since 1804, when it was first isolated from opium by the German pharmacologist Friedrich Serturner. The scientist named this substance in honor of the Greek god of dreams, Morpheus, because in large doses it caused a hypnotic effect. But the drug began to be widely used only 50 years later, when the injection needle was invented. From its discovery to the present day, morphine has been used to relieve pain.

Morphine (Morphinum) is an opioid analgesic (the main alkaloid of opium) - a drug used in medicine as a strong pain reliever.

What is morphine obtained from? - the alkaloid of this substance is extracted exclusively from the frozen milky juice (opium), which is released during the cutting of immature heads of the opium poppy. The content of morphine with opium ranges from 10 to 20%. A natural source of the alkaloid is also plants from the poppy family - moonseed, ocotea. But they contain the alkaloid in smaller quantities. The industry also uses threshed straw and oil poppy heads.

Attention! Morphine is subject to legal restrictions on use. It belongs to List II of the list of narcotic drugs, psychotropic drugs and their precursors, the circulation of which is subject to control in Russia.

Pharmacological properties

Morphine belongs to the pharmacological group “Analgesic drugs”. It has the selective ability to suppress the feeling of pain through its influence on the central nervous system.

How does morphine work?

1. It disrupts the transmission of sensory and pain impulses along neurons by activating the endogenous antinociceptive system.
2. Changes the perception of pain by affecting the centers of the brain.

Morphine acts as a stimulator of opioid receptors, which are located in the myocardium, the vagus nerve, and in the nerve plexus of the stomach. But the highest density of receptors is found in the gray matter of the brain and the spinal ganglia. Activation of receptors by an alkaloid leads to changes in the metabolism of these organs at the biochemical level.

Action of morphine

The effect of morphine on the human body is as follows.

After absorption into the blood, 90% of morphine is broken down in the liver. Only 10% is excreted unchanged by the kidneys. After subcutaneous administration of the drug, its effect begins after 15, and internal administration - 20–30 minutes and lasts 4–5 hours.

Indications

Indications for the use of morphine in medicine are due to its analgesic effect.

What is morphine used for?

1. To relieve pain during injury, thereby preventing the development of shock.
2. Use for myocardial infarction relieves pain and prevents cardiogenic shock, which threatens the patient’s life.
3. Morphine is most often used in cancer patients for unbearable pain that does not respond to other medications.
4. With a severe attack of angina.
5. It is used during preparation for surgery, as well as pain relief after surgery.

It is also used as an additional agent for epidural and spinal anesthesia.

Side effects

Morphine has a toxic effect on all organs. The main side effects are as follows.

The severity of side effects depends on the dose and duration of use.

Contraindications

An absolute contraindication is hypersensitivity to opiates.

Contraindications for the use of morphine are:

• renal failure;
• abdominal pain of unknown etiology;
• traumatic brain injury;
• epilepsy attack;
• increased intracranial pressure;
• coma;
• children under 2 years of age.

Morphine is contraindicated for pain relief during childbirth because it can cause respiratory depression.

Considering the negative impact of the alkaloid on many systems and organs, its use is limited in people with chronic diseases.

Use morphine with caution in the following patients.

1. COPD (chronic obstructive pulmonary disease), including bronchial asthma.
2. Surgical interventions on the organs of the digestive system, including cholelithiasis.
3. Operations on the urinary organs.
4. Inflammatory bowel diseases.
5. Strictures of the urinary canal.
6. Alcoholism.
7. Prostatic hyperplasia.
8. Suicidal tendencies.
9. Emotional lability.

In asthenic conditions, as well as in elderly patients and children, the potential harm is weighed against the expected benefit. Morphine is not used together with other narcotic analgesics. During the treatment period, care should be taken when driving vehicles or doing work that requires concentration.

Use in cancer patients

The Russian Ministry of Health issued Order No. 128 of July 31, 1991 on pain therapy rooms, hospices and symptomatic care departments for cancer patients. At an early stage of cancer development, mild narcotics are used.

Morphine in oncology is used in patients at the third stage of the disease with unbearable pain.

Medicinal substances used in oncology:

• "Morphine hydrochloride";
• "Morphine sulfate";
• "Morphine."

The dosage and dosage form of these substances for cancer patients is determined by the doctor. The patient must follow the rules of taking it by the hour, and not on demand. When calculating, the initial minimum dose is increased until the analgesic effect occurs. For parenteral use, the drug is administered subcutaneously. Intramuscular use is not recommended because it is unevenly absorbed. The medicine is also administered transdermally (in a patch), orally in tablets and capsules.

Drugs

Alkaloid derivatives - morphine hydrochloride and sulfate - are used in medicine. Most often used for subcutaneous administration. The doctor selects an individual dose for each patient depending on the clinical symptoms. Adults use 1% ml (10 mg) subcutaneously with a dosing frequency of 2 times every 12 hours. The maximum effect reaches after 2 hours and lasts 10–12 hours. The maximum single dose is 2 ml (20 mg), and the daily dose is 5 ml (50 mg). For children over 2 years of age, a single dose of 1–5 mg. Morphine sulfate and hydrochloride are available in ampoules of a 1% solution for subcutaneous use.

Preparations containing this alkaloid are available in various dosage forms - granules for solution, capsules and tablets of prolonged action, solution for injection and rectal suppositories.

"Omnopon" (medical opium) is a combined narcotic analgesic. It is produced only in the form of a solution for subcutaneous administration. It contains: narcotine, papaverine, codeine, thebaine and morphine. "Omnopon" has not only a strong analgesic, but also an antispasmodic effect.

There are also synthetic drugs that replace morphine, differing from it in chemical structure, but similar to it in pharmacological action.

All drugs are issued strictly according to prescription, since morphine and its derivatives are abused by drug addicts.

Morphine poisoning

In the home or medical setting, morphine poisoning can occur accidentally or intentionally for the purpose of suicide. In adults, it occurs after more than 0.1 gram enters the body and does not depend on the dosage form and route of administration. The alkaloid causes poisoning after administration of this dose in a suppository through the rectum, ingestion or injection into a vein and under the skin. After addiction, the toxic dose increases. The clinical picture of poisoning resembles an alcoholic coma.

constriction of the pupils

Signs of poisoning are as follows.

1. At the beginning of intoxication, euphoria, anxiety, and dry mouth appear.
2. As symptoms increase, the headache intensifies, nausea, vomiting with the urge to urinate frequently occurs.
3. Further, drowsiness increases. The patient falls into a stupor, which turns into a coma.
4. A significant symptom is a sharp constriction of the pupils.
5. The leading sign of morphine poisoning is difficulty breathing, which sharply slows down to 1–5 times per minute.
6. If the morphine antidote is not administered in time, death occurs due to paralysis of the respiratory center.

An overdose of morphine is accompanied by loss of consciousness. In severe cases, depressed breathing is observed, blood pressure decreases, and body temperature drops. A distinctive sign of a drug overdose is constricted pupils. However, with severe hypoxia due to respiratory depression, the pupils can, on the contrary, be greatly dilated.

The lethal dose of morphine when taken orally is 0.5–1 grams, and when administered intravenously - 0.2. But with morphinism it increases to 3–4 grams due to addiction.

First aid for poisoning with a drug taken orally is to lavage the stomach with a solution of potassium permanganate. Afterwards, take any sorbent. In addition, the patient needs to be warmed. If after these measures the symptoms do not decrease, the patient must be hospitalized.

For morphine poisoning, the antidote is Naloxone and Nalorphine. They are administered intravenously with 1–2 ml of solution. Help for the patient consists of artificial ventilation of the lungs and intravenous administration of any morphine antagonist - Naloxone or Nalorphine. They eliminate euphoria, dizziness, and restore breathing. The administration of the drugs is repeated until the overdose symptom disappears. In the hospital they also do catheterization of the bladder due to spasm of the excretory urinary tract.

Morphinism

As a result of frequent use of a narcotic drug as an anesthetic for somatic diseases, morphinism develops - addiction. When used, the drug improves mood and causes euphoria. This is related to the need for its reuse.

It is known that during the American Civil War, the addiction to this painkiller turned into an army disease that affected about 400 thousand soldiers. And at the end of the 19th century, half of the German soldiers who returned from the Franco-Prussian War were drug addicts.

Addiction develops quickly, which requires increasing the dose. People addicted to morphine cannot do without it; if they stop taking it, withdrawal symptoms develop. This condition is expressed by increased breathing and heart rate, decreased blood pressure, diarrhea, and dry cough. To get a dose, drug addicts resort to all available and inaccessible methods, and often commit crimes.

Analyzing the above, we recall that the alkaloid morphine is extracted from natural raw materials - opium and other varieties of poppies. In medicine, morphine derivatives of varying intensity and duration of analgesic action are used. There is a danger of side effects and overdose. Long-term use leads to addiction, so the circulation of the substance is regulated by law - morphine belongs to List II of the list of narcotic drugs subject to control in Russia.

MORPHINE

MORPHINE, MORPHINE

a colorless crystalline powder obtained from opium, bitter and poisonous; in small doses it is an analgesic and hypnotic.

A complete dictionary of foreign words that have come into use in the Russian language. - Popov M., 1907 .

MORPHINE

main compound. parts of opium, from which. extracted in the form of colorless prismatic crystal, bitter taste, difficult to dissolve. in water; poisonous.

Dictionary of foreign words included in the Russian language. - Pavlenkov F., 1907 .

MORPHINE

or morphine, Novolatinsk. morphium, from Greek. Morpheus, Morpheus. Opium alkaloid used instead of opium.

Explanation of 25,000 foreign words that have come into use in the Russian language, with the meaning of their roots. - Mikhelson A.D., 1865 .

MORPHINE or MORPHINE

(from the Greek Morpheus - Morpheus). Opium alkaloid, analgesic and narcotic poison.

Dictionary of foreign words included in the Russian language. - Chudinov A.N., 1910 .

Morphine

morphine, plural no, m. (apt.). A narcotic, painkiller extracted from the milky juice of poppy heads. [ From Morpheios - god of sleep in Greek. mythology.]

Large dictionary of foreign words. - Publishing House "IDDK", 2007 .

Morphine

Explanatory dictionary of foreign words by L. P. Krysin. - M: Russian language, 1998 .

Synonyms:

See what "MORPHINE" is in other dictionaries:

MORPHINE- MORPHINE, Morphium, s. Morphinum, C17HieN03+H20, opium alkaloid, contained in it in the form of salts of meconic (CbHOa(OH) (COOH)2], sulfuric and lactic acids in quantities from 3% to 26%, on average 8% 12%. M. isolated from opium for the first time in a mixture with another narcotic... ... Great Medical Encyclopedia

MORPHINE, a white crystalline ALKALOID obtained from OPIUM. First isolated in 1806. Morphine depresses the CENTRAL NERVOUS SYSTEM and is used as an ANALGESIC to relieve severe pain. It is an addictive drug... Scientific and technical encyclopedic dictionary

MORPHINE, morphine, many. no, husband (apt.). A narcotic, painkiller extracted from the milky juice of poppy heads. Inject morphine. (From Morpheios, the god of sleep in Greek mythology.) Ushakov’s explanatory dictionary. D.N. Ushakov. 1935 1940 … Ushakov's Explanatory Dictionary

MORPHINE, morphine man. sleeping potion, an alkali extracted from opium, name from the Greek god of sleep, Morpheus. Dahl's Explanatory Dictionary. IN AND. Dahl. 1863 1866 … Dahl's Explanatory Dictionary

MORPHINE, me (y) and MORPHINE, ah, husband. A narcotic and painkiller extracted from the milky juice of the opium poppy. Inject m. | adj. morphine, aya, oh, morphine, aya, oh and morphine, aya, oh. Ozhegov's explanatory dictionary. S.I. Ozhegov, N.Yu.... ... Ozhegov's Explanatory Dictionary

Noun, number of synonyms: 3 alkaloid (862) morphine (8) drug (78) ASIS Dictionary of Synonyms ... Synonym dictionary

morphine- and obsolete morphine... Dictionary of difficulties of pronunciation and stress in modern Russian language

A story, also called a story by some researchers of Bulgakov's work. Published: Medical Worker, M., 1927, No. No. 45 47. M. is adjacent to the series “Notes of a Young Doctor”, has, like the stories of this cycle, ... ... Bulgakov Encyclopedia

Morphine: An obsolete name for morphine. Morphine (story) work by M. A. Bulgakov. Morphine (film) film by Alexei Balabanov ... Wikipedia

From it. Morphium from lat. Morpheus (see previous). Morphine was discovered by F.W. Sertürner (1783 - 1841) in Kramer's pharmacy in Paderborn (see Kluge? Götze 399; Schulz? Basler 2, 154) ... Etymological Dictionary of the Russian Language by Max Vasmer

The word “morphine” (or the outdated name “morphine”) is known to almost everyone. But few people are familiar with the specifics of this substance and know about its properties. In the minds of most people, it is strongly associated with a drug. But is this really so?

Morphine's calling card

In medical terms, morphine is considered an alkaloid of opium. Its content was found in sleeping pill poppy, moonseed, and stephania.

Quite rarely found in varieties such as triclisia, croton, ocotea. Obtaining morphine is not difficult. The substance can be easily obtained from latex (dried juice) by first finely chopping unripe poppy pods. This alkaloid is found in opium in the form of sulfuric and lactic acids, as well as meconic salt. Its concentration can reach 26%, but on average this figure does not exceed 12%.

Origin of morphine

Morphine was first obtained at the very beginning of the 19th century. The progenitor of the substance is considered to be the German chemist Friedrich Serturner, who discovered this drug in 1804. But morphine's finest hour came much later - in 1857, when the first syringe was invented.

The German scientist considered it a good sleeping pill, and therefore named the substance in honor of the Greek god Morpheus. In addition, according to Serturner, this drug was a good substitute for opium, as a result of which it was successfully used to treat opium addiction. Positive results led to the fact that the dangerous consequences of using the substance were not immediately discovered.

No matter how paradoxical it may sound, its creator also became a victim of morphine. However, Serturner only realized towards the end of his life what was causing his illness. It turned out that morphine is even more addictive than opium. So in 1874 a new term arose - morphinism, meaning dependence on morphine. Moreover, psychological dependence arises very quickly, physical dependence a little slower.

Morphine - indications for use

However, in the case of morphine, not everything is so simple. If it is not abused, then it does not show its negative properties. This drug is still used in modern medicine. It appears as white crystals, which may become yellowish over time. The drug is available in tablets, ampoules and syringe tubes. Most often, the substance is used in the form of injections. Depending on the doctor’s prescription, it can be administered intravenously, intramuscularly, or subcutaneously.

Indications for use include:

• Severe physical pain, for example, during myocardial infarction, injuries, malignant tumors.
• With severe shortness of breath, cough, which are caused by heart failure.
• Before preparing for operations or in the postoperative period.
• For insomnia, especially if it is caused by severe pain.
• For X-ray examinations of the intestines to detect tumors or ulcers.

Morphine acts directly on the nervous system, thereby reducing pain. A physically healthy person, without lung or heart disease, can easily tolerate drug withdrawal. However, even in such cases, sometimes negative consequences appear: epileptic seizures, convulsions, suicide. Side effects of the substance can manifest themselves in the form of dizziness and increased intracranial pressure, bronchospasms and tachycardia, vomiting and nausea. Morphine should be prescribed especially carefully to children under 2 years of age. Since they are more sensitive, the effects of the drug sometimes cause unpredictable reactions

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Signs of morphinism - addiction

As often happens, the medicinal drug has attracted the attention of drug addicts, because it improves mood, causes mild euphoria, and begins to act within 10 minutes. Moreover, this state can last up to 8 hours.

It is very easy to identify a morphine addict. It will always be given out:

• Watery eyes with a reddish tint and constricted pupils.
• Scars (and if hygiene is not observed, ulcers) on the skin at the injection site.
• Relaxation, apathy, lethargy and drowsiness.
• Incorrect bowel function - diarrhea or constipation.
• Temperature drop. Quite often there are cases when chills in combination with goose bumps give way to fever.

Consequences of morphine use

Uncontrolled use of the drug cannot lead to anything good. Such a person is more susceptible to various diseases of the lungs or heart, hepatitis, decreased immunity, and the development of encelopathy, which causes the death of brain cells. may begin 10-12 hours after the last dose of the drug. Withdrawal symptoms usually last up to 2 weeks.

Psychological dependence on morphine is terrible. Even if there is no physical need to use the substance, addicts still cannot cope with daily activities and think about the drug. This is why the percentage of relapses among such people is high (up to 96%). To get rid of psychological addiction, it is advisable to change the environment and determine the motivation for quitting drugs and healthy behavior.