Why inject morphine. Morphine (Morphine): description, action, consequences

1 ml of solution contains 10 mg of the active substance according to INN - morphine hydrochloride .

1 capsule of prolonged action contains 10 mg of Morphine.
Morphine formula: C17-H19-N-O3.

Release form

The solution is available in 1 ml ampoules. The carton pack contains 1 blister pack (for 5 ampoules) and instructions from the manufacturer.

Prolonged capsules are available in packs of cardboard (10 pieces per pack).

pharmachologic effect

What is Morphine?

Morphine is opioid pain reliever , drug . According to the mechanism of action, the drug belongs to opioid receptor agonists. The drug has antishock action , reduces the excitability of pain centers. The hypnotic effect is manifested when prescribing high dosages.

The active substance increases the tone of the sphincters, smooth muscle muscles of the bronchi and internal organs, reduces the excitability of the cough center, inhibits conditioned reflexes, causes bradycardia . The drug tones the sphincters of the bladder, biliary tract; depresses the respiratory center, lowers body temperature, slows down metabolism, inhibits the secretory activity of the digestive system, stimulates the production of ADH.

Effect on the brain

Excitation of trigger chemoreceptor zones in the medulla oblongata leads to activation of the gag reflex. After subcutaneous injection, the drug begins its action after 10-15 minutes. The effective action of prolonged capsules is recorded after 20-30 minutes.

Pharmacodynamics and pharmacokinetics

After subcutaneous administration and oral administration of capsules, the drug is rapidly absorbed and enters the systemic circulation. When taken orally, the absorption rate reaches 80%. For the drug, the nature of the effect is "first pass" through the hepatic system. Due to conjugation with glucuronides, it is fully-fledged in the liver.

The half-life is 2-3 hours. The main route of excretion of metabolites is through the renal system (90%). A small part (about 10%) is derived from. Elderly patients are characterized by an increase in T1 / 2 (similarly in the pathology of the renal system and liver).

Indications for use

Morphine - what is it? This is a narcotic analgesic prescribed for the relief of severe pain in:

• traumatic injuries;
• malignant neoplasms;
• surgical interventions;

The drug can be prescribed for severe shortness of breath, provoked by insufficiency of the cardiovascular system; with a cough that cannot be stopped with antitussive medicines.

Contraindications

• traumatic brain injury;
• respiratory failure due to depression of the respiratory center;
• severe general exhaustion of the body;
• severe pain in the epigastric region of unknown origin;
• delirium;
• epistatus;
• hepatocellular insufficiency;
• treatment with MAO inhibitors;
• age limit - up to 2 years.

Side effects

Urinary tract:

Violation of the urine flow with urethral stenosis,.

The cardiovascular system:

Rare pulse, bradycardia.

Digestive tract:

• cholestasis of the main bile duct;
• vomit;
• nausea;

Nervous system:

• increased intracranial pressure with a high risk of development;
• exciting effect;
• sedative effect;
• development ;
• delirium.

Morphine, instructions for use (Method and dosage)

Instructions for use Morphine hydrochloride

Individual dosing regimen. Subcutaneously injected once 1 mg. Further selection of the dose is carried out on the basis of the severity of the pain syndrome.

Taking capsules

Every 12 hours, 10-100 mg, depending on the desired therapeutic effect. For children from 2 years old, a single dosage is 1-5 mg.

Overdose

Poisoning is manifested by a peculiar clinical picture (acute and chronic overdose):

• clammy, cold sweat;
• fatigue;
• the fall ;
• confusion;
• difficult, slow breathing;
• bradycardia;
• miosis;
• expressed;
• bradycardia;
• delirious psychosis;
• dry mouth;
• anxiety;
• intracranial hypertension;
• stop breathing;
• muscle rigidity;
• coma.

Treatment

A specific antagonist is urgently injected intravenously - at a dose of 0.2-0.4 mg. After 2-3 minutes, the injection is repeated until the total amount of the administered medication is 10 mg.

In pediatrics, the initial dosage of Naloxone is 0.01 mg / kg. Measures are being taken to stabilize blood pressure, restore the functioning of the respiratory system, and the heart.

Interaction

Enhances the sedative, hypnotic effect of anxiolytics and anesthesia (general, local). The simultaneous administration of narcotic painkillers and barbiturates can lead to a pronounced suppression of the active brain, the development arterial hypotension , respiratory depression.

The effect of opioid analgesics is reduced with the systematic use of other barbiturates (cross-tolerance is typical). Therapy with MAO inhibitors can adversely affect the functioning of the cardiovascular system. Possible development myoclonus in cancer patients during treatment.

The need for analgesics arises in all areas of medicine. But the problem of anesthesia is especially acute in oncology. When the possibilities of traditional analgesics have been exhausted, one has to resort to narcotic drugs. The strongest 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 in its use? What should be done in case of poisoning and overdose? Is there an antidote for morphine? Below we will answer all these questions.

Description of morphine

Morphine has been known to people 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. Morphine has been used since its discovery to the present 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 made from? - the alkaloid of this substance is extracted exclusively from the frozen milky juice (opium), which is released during the incision of immature opium poppy heads. 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, okotea. But they contain alkaloid in smaller quantities. The industry also uses threshed straw and oil poppy heads.

Attention! In relation to morphine, there is a legal restriction for 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 a selective ability to suppress the feeling of pain through its influence on the central nervous system.

How does morphine work?

1. Violates the transmission of sensitive and pain impulses through neurons by activating the endogenous antinociceptive system.
2. Changes the perception of pain, affecting the centers of the brain.

Morphine acts as a stimulant of opioid receptors, which are located in the myocardium, vagus nerve, in the nerve plexus of the stomach. But the highest density of receptors is found in the gray matter of the brain and spinal ganglia. Activation of alkaloid receptors leads to a change 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 by the kidneys unchanged. After subcutaneous administration of the drug, its action begins after 15, and after 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 in case of injury, thereby preventing the development of shock.
2. Application for myocardial infarction relieves pain and prevents cardiogenic shock, which threatens the life of the patient.
3. The most common use of morphine is in cancer patients with unbearable pain that is not amenable to other drugs.
4. With a severe attack of angina pectoris.
5. It is used in the period of preparation for surgery, as well as pain relief after surgery.

And also it is used as an additional remedy 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.

Morphine is contraindicated for:

• kidney failure;
• abdominal pain of unknown etiology;
• traumatic brain injury;
• epilepsy attack;
• increased intracranial pressure;
• coma;
• children's age up to 2 years.

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

Given 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 those with cholelithiasis.
3. Operations on the urinary organs.
4. Inflammatory bowel disease.
5. Urinary canal strictures.
6. Alcoholism.
7. Hyperplasia of the prostate.
8. Suicidal tendencies.
9. emotional lability.

In asthenic condition, as well as in elderly patients and in childhood, the potential harm is commensurate with the expected benefit. Morphine is not used together with other narcotic analgesics. During the period of treatment, care should be taken when driving transport or work that requires concentration.

Use in cancer patients

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

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

Medicinal substances that are used in oncology:

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

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

Preparations

In medicine, alkaloid derivatives are used - morphine hydrochloride and sulfate. Most commonly used for subcutaneous injection. For each patient, the doctor selects an individual dose depending on the clinical symptoms. Adults use 1% ml (10 mg) subcutaneously with a frequency of 2 times in 12 hours. The maximum effect is reached 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 is available in ampoules of 1% solution for subcutaneous use.

Preparations containing this alkaloid are available in various dosage forms - granules for solution, capsules and tablets of prolonged action, 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, which differ from it in chemical structure, but are similar to it in pharmacological action.

All drugs are issued strictly by prescription, as drug addicts abuse morphine and its derivatives.

Morphine poisoning

Morphine poisoning in the home or in a medical setting can occur accidentally or intentionally with the intent to commit suicide. In adults, it occurs after ingestion of more than 0.1 grams 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.

pupillary constriction

Signs of poisoning are as follows.

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

An overdose of morphine is accompanied by loss of consciousness. In a severe case, oppressed breathing is observed, blood pressure decreases, and body temperature drops. A hallmark of an overdose of the drug 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 wash the stomach with a solution of potassium permanganate. After taking any sorbent. In addition, the patient needs to be warmed. If after these measures, the symptoms do not decrease, the patient is subject to hospitalization.

In case of morphine poisoning, the antidote is Naloxone and Nalorfin. They are administered intravenously 1-2 ml of solution. Help for the patient consists in artificial ventilation of the lungs and intravenous administration of any morphine antagonist - "Naloxone" or "Nalorphine". They eliminate euphoria, dizziness, restore breathing. The introduction of drugs is repeated until the symptoms of overdose disappear. In the hospital, bladder catheterization is also done due to spasm of the excretory urinary tract.

Morphinism

As a result of the frequent use of a narcotic drug as an anesthetic for somatic diseases, morphinism develops - an addiction. When used, the drug improves mood, causes euphoria. This is the reason why it needs to be reused.

It is known that during the American Civil War, addiction to this painkiller turned into an army disease that affected about 400,000 soldiers. And at the end of the 19th century, half of the German soldiers who returned from the Franco-Prussian war were drug addicts.

Habituation develops quickly, which requires an increase in dose. People who are addicted to morphine cannot do without it - if they stop taking it, an abstinence syndrome develops. This condition is expressed by increased breathing and heart rate, decreased pressure, diarrhea, dry cough. To get a dose, drug addicts resort to all available and inaccessible methods, 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 risk of side effects and overdose. Long-term use leads to addiction, so the circulation of the substance is regulated by law - morphine belongs to the list II of the list of narcotic drugs subject to control in Russia.

Morphine is a substance that is a crystal white color with a bitter taste, is the main alkaloid of opium, and is used in medicine as a very strong analgesic. Instructions for use for Morphine must be followed very carefully, because even a slight deviation from the dosage can lead to drug dependence and severe side effects. That is why Morphine and its derivatives are included in list 1 of narcotic drugs, the circulation of which is prohibited in the territory Russian Federation. However, nevertheless, there are diseases and conditions in which this drug is indicated for use. This is what we will talk about today.

Release form

1. Morphine is available in tablets (capsules 30, 60 and 100 mg). The tablets are hard gelatin capsules with a transparent body, on which dosage information is printed.
2. Morphine is also available in ampoules and syringe tubes with a volume of 1 ml (10 mg per 1 ml) with an injection solution. The solution is clear, colorless or slightly yellowish.

Compound

Morphine, intended for injection, and medicine in tablets have different composition. The active ingredient for each dosage form is also different.

Tablets

• Active ingredient - Morphine sulfate pentahydrate (the amount of ADV - depending on the dosage)
• Aqueous dispersion of ethyl cellulose
• macrogol
• sucrose
• Corn starch
• Dibutylsebacate
• Talc
• Gelatin (body)

Solution

Pharmacokinetics

1. The action of the drug begins after 10-20 minutes, reaches a maximum after 1-2 hours and lasts about 8-12 hours
2. Plasma protein binding - 30-35%
3. Distribution volume - 4 l / kg
4. 10% of the active ingredient is excreted through the kidneys unchanged within 24 hours
5. 80% - in the form of glucuronide metabolites
6. The rest is excreted with bile (through the intestines with feces)
7. Penetrates through the placental and blood-brain barrier, found in breast milk

Indications

• Parestensions
• Insomnia
• Cerebral circulation disorders
• Muscle stiffness
• restless sleep

Digestive system

• Nausea
• Vomit
• Constipation
• stomach cramps
• Anorexia
• Gastralgia
• Spasm of the bile ducts
• Dry mouth
• cholestasis
• Hepotoxicity
• Intestinal obstruction
• Intestinal atony
• Toxic megacolon

Respiratory system

• Respiratory depression
• Atelectasis
• Bronchospasms

genitourinary system

• Decreased total urine volume
• Frequent urge to urinate and pain
• Spasm of the sphincter of the bladder
• Decreased potency and libido
• Urine outflow obstruction

Allergic and local reactions

• Hyperemia of the face
• Skin rash
• laryngospasm
• Tracheal edema
• swelling of the face
• Chills
• Swelling, burning and redness at the injection site

Instructions for use

Tablets

The initial dose of Morphine tablets is 30 mg every 12 hours. The daily dose is 60 mg, respectively.

When taking this drug, a daily dosage assessment is carried out. If the dose becomes insufficient, a revision is recommended. If necessary, the amount of the drug is increased by 25-50%. At the same time, the interval of 12 hours between doses remains unchanged.

For children weighing more than 20 kg, the required amount of the drug is calculated based on the ratio of 1 mg per kilogram of body weight.

Injections

Morphine is administered either intravenously or subcutaneously, as intramuscular injection can cause severe pain to the patient.

Here are the instructions for use for Morphine in ampoules:

Adults:

• Standard dose - 1 ml solution (10 mg / ml)
• The maximum single dose is 20 mg
• The maximum daily dose is 50 mg

Children:

• For children from 2 years old, a single dose is calculated as follows: 0.1-0.2 mg per kilogram, administered every 4-6 hours, but not more than 1.5 ml per kilogram per day

• Children under 2 years old are also prescribed 0.1-0.2 mg per kilogram, but no more than 15 mg per day

Overdose

Symptoms

• Confusion
• Dizziness
• Drowsiness
• Cold clammy sweat
• Nervousness
• Fatigue
• Lowering blood pressure
• Respiratory center depression
• Bradycardia
• Increase in body temperature
• Dry mouth
• Delirious psychosis
• Increased intracranial pressure
• Violation of cerebral circulation
• hallucinations
• convulsions
• Muscle stiffness
• Loss of consciousness
• Respiratory arrest

Treatment

• • Gastric lavage
  • Artificial lung ventilation
  • Maintaining normal blood pressure
  • Maintenance of cardiac activity
  • Administration of Nolaxone (opioid analgesic antagonist)
  • Symptomatic therapy

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Morphine or, in other words, Morphine in its pure form is presented in the form of a white powder. In addition to a sedative and hypnotic effect on the body, morphine is used in cancer for pain relief. How to use the medicine correctly and what are the features of its use?

General characteristics of oncological pain and features of the use of drugs in cancer

Malignant tumors are one of the most dangerous pathologies in modern medicine. Dangerous consequences are expressed not only in a possible fatal outcome, but also in the occurrence of severe intractable pain, which brings a lot of suffering to a person. Every person suffering from a malignant neoplasm of any localization, at each stage of its development, is faced with a pain syndrome.

Often, severe pain occurs with stage 4 cancer, when metastases are observed, radiating from the primary focus to other organs and systems. At this time, the doctor takes all measures to alleviate the intensity of pain and the general well-being of the patient. According to studies, almost half of all cancer patients do not have complete control over the symptom, and a quarter of them die not from the most malignant lesion of the body, but from an unbearable pain syndrome.

Before understanding how Morphine works in the anesthetization of a malignant tumor, it is worth considering what is the mechanism of pain in this case and how it occurs. So, in order to determine the necessary method for managing a symptom in cancer, first of all, find out the type of pain:

1. Nociceptive. Pain impulses from nociceptors to the brain are transmitted via peripheral nerves. Nociceptive pain, in turn, is divided into somatic (acute or dull), visceral (not clearly defined) and associated with previous invasive surgery.
2. neuropathic. The pain syndrome in this case is caused by damage to the nervous system. If a person is diagnosed with advanced cancer of any location, neuropathic pain may be caused by nerve root infiltration, exposure to a chemotherapy drug, or exposure to radiation from radiation therapy.

Over time, the progression of oncological disease, the pain syndrome only intensifies in its intensity, reaching maximum levels when the disease reaches stage 4. The most effective is the use of Morphine for cancer, which began to be used for such purposes back in the 1950s. Later, the World Health Organization decided to take this drug every 4 hours to achieve the desired pain relief.

In those years, Morphine in the development of cancer was used only in tablet form. To date, there are also injections (shots) of the drug. Excretion from the body of different forms of release of Morphine occurs over a different period of time. The injectable form of the drug has an immediate release and rapid absorption. For this reason Morphine injections can be taken several times a day. If we talk about the tablet form of the drug, its excretion from the body is rather slow, which allows Morphine to be used only 1 time per day.

The internal use of Morphine helps to relieve pain of a moderate or severe nature. If used correctly, the medicine is quite safe and effective. Otherwise, especially if the drug is abused, addiction and respiratory depression can be caused.

The use of Morphine in cancer has its own characteristics:

1. Individual determination of the dosage of the drug, taking into account the intensity and nature of the pain.
2. The exact time of taking Morphine in the development of cancer, which is determined by the attending physician based on the individual characteristics of the development of the pathology.
3. "Upward" use of the drug, namely, from the maximum dosage of low-potency opiates to the minimum dosage of Morphine.
4. Tablets are considered the most gentle and effective forms of medication, but when used correctly, in order to avoid dependence.

To eliminate the pain caused by the development of a malignant tumor, tablets are taken at a rate of 0.2-0.8 mg / kg every 12 hours. The granules of the drug, which are intended for suspension and internal use, are prepared as follows: 20, 30 or 60 mg of granules in 10 ml of water, 100 mg in 20 ml, 200 mg in 30 ml. The suspension must be mixed well and drunk immediately after preparation. The dose for one injection of Morphine is 1 mg. The drug in this case is administered subcutaneously. You can inject the drug into a vein or muscle, but in a different dosage - 10 mg.

Under what circumstances is it forbidden to use the medicine

In addition to such a high efficiency of Morphine used in malignant neoplasms, there are also contraindications, which are absolute and relative. The first type includes:

• the course of pathologies in the body that cause depression of the central nervous system or respiration;
• development of intestinal obstruction;
• systematic convulsions;
• frequent increase in intracranial pressure;
• trauma to the skull in the past;
• psychosis due to alcohol dependence or other acute alcoholic pathology;
• development of bronchial asthma, cardiac arrhythmias, heart failure caused by chronic pulmonary disease;
• severe general condition, which is observed after surgery on the biliary tract;
• development of pathologies of the abdominal organs requiring surgical intervention;
• concomitant use of monoamine oxidase inhibitors (a ban on the use of Morphine within two weeks after the end of their intake);
• individual intolerance to Morphine components.

Relative contraindications to taking the drug for cancer are:

• the course of chronic obstructive pulmonary disease;
• suicidal tendencies in the patient;
• alcohol addiction;
• development of gallstone disease;
• epilepsy;
• operations that were previously performed on the organs of the gastrointestinal tract or urinary tract;
• development of renal or hepatic insufficiency;
• development of hypothyroidism;
• in men - the course of prostatic hyperplasia;
• the course of severe inflammatory bowel disease.

It is also worth carefully taking Morphine to the elderly and children. In such cases, the medicine is prescribed only by a specialist and taking into account the peculiarities of the course of oncological pathology. During pregnancy and lactation, the drug is used in case of emergency.

Adverse symptoms and overdose

Adverse symptoms can occur from many organs and systems in the body. If you take Morphine incorrectly, without the consent of your doctor or in violation of his recommendations, you can cause the following negative manifestations:

• on the part of the central nervous system and sensory organs: headaches, dizziness, a feeling of constant anxiety, apathy towards other people, nightmares that occur at night, paresthesia, increased intracranial pressure, muscle twitching, inability to coordinate movement, convulsive syndrome, impaired visual system (clouding before the eyes), a violation of taste sensations, the appearance of ear ringing;
• on the part of the cardiovascular system: the development of bradycardia, tachycardia, cardiac arrhythmias, low or high blood pressure, fainting;
• from the respiratory system: bronchospasm, development of atelectasis;
• from the digestive system: nausea, constipation or diarrhea, gagging, development of gastralgia, anorexia, cholestasis, spasms;
• from the urinary tract: a decrease in the volume of daily diuresis, spasms of the ureters, a disturbed process of excretion of urine from the body;
• allergies: redness of the skin of the face, swelling of the face or trachea, general malaise, skin rashes, itchy syndrome.

Exceeding the dosage of the drug can cause such signs of an overdose:

• increased cold sweating;
• clouding of consciousness;
• general malaise;
• increased nervous excitement;
• violation of the heart rhythm;
• anxiety syndrome;
• signs of psychosis;
• increased intracranial pressure;
• muscle weakness;
• convulsions;
• coma.

If such symptoms of an overdose occur, the necessary resuscitation measures are carried out.

Special instructions while taking medication

Special instructions that should be followed when prescribing and during the period of direct use of the drug include:

1. If there is a risk of developing intestinal obstruction, the medication should be stopped.
2. If it is necessary to carry out surgery on the heart or otherwise with severe pain, Morphine is finished taking the day before it.
3. If nausea or vomiting occurs while taking the drug, the combined use of phenothiazine is allowed.
4. To reduce the side effect of the drug on the intestines, the use of laxatives is recommended.
5. Driving vehicles during the period of treatment with Morphine must be carried out carefully, as well as engaging in activities that require increased attention.
6. The joint use of antihistamines, hypnotics and psychotropic drugs, that is, those that affect the central nervous system, is recommended to be discussed with your doctor.

No doctor will tell you exactly how long a person suffering from a malignant neoplasm of any localization will live. It all depends not so much on the individual characteristics of the organism, but on the timeliness of the appointment of appropriate treatment. For this reason, in order to avoid the use of such a strong drug as Morphine, it is recommended to consult a doctor at the first symptoms of the disease, when it occurs at the initial stage.

Systematic (IUPAC) name: (5α,6α)-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol

Trade names: MScontin, Oramorph, Sevredol, etc.

Application during pregnancy

Legality

Australia: controlled substance (S8)

Canada: List I

New Zealand: Class B

UK: Class A

USA: List II

UN: Controlled Drug Schedules I and III

℞ (prescription only)

Addiction risk:

Physical: high

Psychological: medium-high

Habituation risk: High

Application Inhalation (inhalation, smoking), inhalation (through the nose), orally, rectally, subcutaneously, intramuscularly, intravenously, epidurally and intrathecally

Bioavailability 20-40% (oral), 36-71% (rectal), 100% (IV/IM)

Protein binding 30–40%

Metabolism hepatic, 90%

Half life 2–3 h

Excretion renal 90%, bile 10%

Morphine (international nonproprietary name) is an opioid analgesic sold under hundreds of trade names. It is the main psychoactive substance found in opium. The analgesic action of morphine and other opioids (such as oxycodone, hydromorphone, and heroin) is based on their direct action on the central nervous system. Morphine use is associated with rapid development of addiction, tolerance, and psychological dependence, but physical dependence requires several months of continuous use to develop. Tolerance to such effects as respiratory depression and euphoria develops faster than to the analgesic effect. Many patients suffering from chronic pain can be maintained on the prescribed dose for years. However, the effects can reverse quite quickly, resulting in an increase in pain threshold. Morphine is an opiate found in abundance in opium, the dried milk of the immature pods of the Papaver somniferum (opium poppy) plant. Morphine was the first active ingredient isolated from a plant source. It is one of (at least) 50 alkaloids from several groups found in opium, poppy straw concentrate, and other derivatives. The primary source of morphine is a chemical extraction from opium. Morphine is Schedule II in the US, Class A in the UK, and Schedule I in Canada. Morphine was first isolated in 1804 by Friedrich Sertürner. It is believed that morphine was the first alkaloid isolated from a plant in the history of mankind. In 1027, the Merck company began commercial sales of morphine. In those days, Merck was just one small pharmacy. Morphine became more widely used after the invention of the syringe in 1857. Serturner named the substance "morphium" after the Greek god of sleep, Morpheus, as the substance had the property of inducing sleep. Morphine is on the WHO Model List of Essential Medicines (a list of the most important medicines).

Use in medicine

Morphine is used primarily for the relief of severe pain of a short-term or prolonged nature, as well as pain associated with myocardial infarction and labor pains. However, there is an increased risk of mortality when using morphine in the event of myocardial infarction without ST-segment elevation. Traditionally, morphine has also been used to treat acute pulmonary edema. However, a 2006 report showed little evidence to support this practice. Immediate-release morphine is used to relieve symptoms of short-term shortness of breath (due to cancer or a variety of other causes). In respiratory failure at rest or with minimal effort in advanced cancer or advanced cardiorespiratory disease, sustained release morphine significantly reduces respiratory failure when used consistently at low doses, while its beneficial effects continue to be observed over time. The duration of the analgesic effect of morphine is about 3–4 hours (when administered intravenously, subcutaneously, or intramuscularly) and 3–6 hours when taken orally. In Austria, Bulgaria and Slovenia, sustained release morphine is also used in opiate substitution therapy (for addicts who cannot tolerate the side effects of methadone or buprenorphine or for whom these drugs are not suitable).

Contraindications

Morphine should not be used in the following conditions:

Acute respiratory depression

Renal failure (due to accumulation of morphine-3-glucuronide and morphine-6-glucuronide metabolites)

Chemical poisoning (may be fatal for those with low tolerance)

Increased intracranial pressure, including with head trauma (risk of worsening respiratory depression)

Hepatic colic.

Although it was previously thought that morphine should not be used in acute pancreatitis, a review of the literature found no evidence to support this claim.

Side effects

Constipation

Morphine, like other opioids such as loperamide, acts on the myenteric plexus (a plexus of nerve cells that regulates intestinal motility) in the gastrointestinal tract, decreasing intestinal motility and causing constipation. The gastrointestinal effects of morphine are mediated primarily by its action on the mu-opioid receptors in the intestine. By inhibiting gastric emptying and reducing intestinal peristalsis, morphine reduces intestinal transit. This is also facilitated by a decrease in intestinal secretion and an increase in intestinal absorption of fluids. Opioids can also indirectly affect the intestines, causing tonic spasms of the intestines as a result of inhibition of nitric oxide production. This effect has been demonstrated in animal studies where a nitric oxide precursor reversed the motility-related side effects of morphine.

Hormonal imbalance

Clinical studies show that morphine, like other opioids, often provokes hypogonadism (a syndrome caused by decreased hormonal activity of the sex glands; functional testicular failure, accompanied by a decrease in blood testosterone levels and characteristic clinical manifestations) and hormonal imbalance in regular users of both sexes. This side effect is dose dependent and has been observed in both therapeutic and recreational users of morphine. Morphine can affect menstruation in women because it suppresses luteinizing hormone levels. Many studies show that the majority (about 90%) of regular opioid users have hypogonadism caused by them. This may increase the risk of osteoporosis and bone fracture in chronic morphine users. Studies show that this effect is temporary. As of 2013, it is unclear what effect morphine has on the endocrine system at low doses or when taken short term.

Impact on test scores

Most evidence shows that opioids have minimal impact on performance on tests that measure sensory, motor, and attention. However, recent evidence has shown that morphine does affect performance, which is not surprising given that it is a central nervous system depressant. Morphine violates the critical flicker frequency (the critical flicker frequency is the minimum frequency of flashes of light at which there is a feeling of continuous glow), which is an indicator of general CNS excitation, and also worsens the performance of the Maddox test (a method for determining the nature and degree of heterophoria, in which one eye of the subject a Maddox stick is placed and the deviation of the strip of light visible to this eye from zero on the Maddox scale is evaluated, which is an indicator of the deviation of the optical axis of the eyes. There have been several studies on the effects of morphine on motor abilities; high doses of morphine can cause deterioration in the performance of the finger tapping test (the finger tapping test is a test of motor control. The patient is asked to press 4 buttons on the keyboard (usually numbers) in a certain sequence for a while, for example, 4-3-1-2 -4, then count the number of errors made), as well as the ability to maintain a constant low level of isometric strength (i.e. impaired fine motor skills), but there have been no studies on the effects of morphine on gross motor skills. Regarding the effects of morphine on cognition, one study found that morphine may contribute to anterograde and retrograde amnesia, however these effects are minimal and temporary. In addition, short-term use of opioids in opioid-intolerant individuals has been associated with slight deterioration in some sensory and motor abilities, and possibly also with deterioration in measures of attention and cognition. It is very likely that such effects can only be observed in users who have not developed tolerance to morphine (so-called "naive" users). In regular morphine users (eg, those on chronic analgesic opioid therapy), behavioral testing results in most cases demonstrated normal functioning in relation to measures such as perception, cognition, coordination, and behavior. In one of the latest studies of such patients, scientists tried to establish whether regular morphine users can safely administer vehicle. The data from this study showed that chronic morphine users did not experience a significant deterioration in the abilities required to drive a car (including physical, cognitive and perceptual). Patients performed relatively quickly on tasks that required speed or reaction (for example, the Ray Complex Figure Test, in which the subject is asked to redraw a complex figure and then draw it from memory), but the number of mistakes they made was higher than that of the control group. Patients on chronic analgesic opioid therapy do not show deficits in visual-spatial perception and organization (as shown in the Wechsler test), but they have worse immediate and short-term visual memory (as shown in the Ray test, where you had to draw a complex figure from memory ). These patients did not have impairments in higher order cognitive abilities (eg planning ability). Patients experienced difficulty following instructions and showed a tendency to impulsive behavior, although this indicator did not reach statistical significance. Importantly, this study demonstrates that patients on opioid therapy are not deficient in any particular area, suggesting that opioid therapy has only minor effects on psychomotor, cognitive, or neuropsychological function. It is difficult to study the effects of morphine on performance without knowing why a person uses it. Opioid-naive subjects are volunteers who experience no pain, unlike most regular morphine users. Pain is a stressor, so it can interfere with performance tests, especially tests that require high degree concentration. Pain can also vary, changing over time and varying from person to person. It is not clear to what extent the stress caused by pain can provoke disorders, as well as what effect morphine has on these disorders.

addictive

Morphine is potentially a substance with a high risk of addiction. It is possible to develop both psychological and physical dependence, as well as tolerance. If a person is using morphine for severe pain, a combination of psychological and physical factors may be used to prevent the development of tolerance, but with long-term therapy, physical dependence and tolerance will inevitably develop. In controlled studies comparing the physiological and subjective effects of heroin and morphine in opiate addicts, patients showed no preference for either drug. Equally effective injectable doses of these drugs have similar mechanisms of action, with no difference in subjectively perceived effects such as euphoria, ambition, nervousness, relaxation, lethargy and drowsiness. Short-term studies focusing on addiction have shown that tolerance to heroin and morphine develop at about the same rate. Compared to opioids such as hydromorphone, fentanyl, oxycodone and pethidine/meperidine, former addicts showed a clear preference for heroin and morphine. Heroin and morphine are thought to be associated with a particularly high risk of abuse and dependence. These substances are also more associated with effects such as euphoria and other positive subjective effects than other opioids. The choice of these two drugs by ex-addicts may be due to the fact that heroin (also known as morphine diacetate, diamorphine, or diacetyl morphine) is an ester of morphine and is the inactive form of morphine (which is converted to the active form in the body). Therefore, these substances are identical in vivo. Heroin is converted to morphine before it binds to opioid receptors in the brain and spinal cord, after which morphine exerts its subjective effects that addicts are so drawn to. Other studies, such as an experiment called Rat Park (“Rat Park.” The essence of the experiment was that mice, having all the conditions for a full life, namely, a large cage, an abundance of food and games, did not show a tendency to self-eat morphine, as opposed to mice that were kept under more severe conditions) show that morphine has a lower potential for developing physical dependence than is commonly believed. Most studies on morphine addiction show that "highly stressed animals, like humans, will seek solace in the drug." That is, mice placed in favorable environments with plenty of living space, enough food and entertainment, company, exercise areas, and personal space are less likely to become addicted to morphine. More recent studies have also shown that improved living conditions are associated with reduced morphine cravings in mice.

Tolerance

Tolerance to the analgesic effects of morphine develops fairly rapidly. There are several hypotheses regarding the mechanisms for the development of tolerance, including: phosphorylation (inclusion of an orthophosphoric acid (H2PO3-) residue of the opioid receptor into the molecule (which will change the structure of the receptor), functional detachment of receptors from G-proteins (which leads to loss of receptor sensitivity) internalization of mu- opioid receptors (after ligand binding, many receptors are retracted into the cell by endocytosis) and/or receptor depletion (reduction in the number of available receptors that morphine can act on). For a detailed discussion of these processes, see Koch and Holt's article Cholecystokinin (a neuropeptide hormone produced by mucosal I-cells duodenum and proximal jejunum) may mediate several antagonistic pathways by affecting opioid tolerance. Antagonists of cholecystokinin (namely, Proglumide) can slow down the development of tolerance to morphine.

Addiction development and withdrawal syndrome

The cessation of morphine use is associated with the development of the classic withdrawal syndrome with opioid withdrawal, which, unlike the withdrawal syndrome with the withdrawal of barbiturates, benzodiazepines, alcohol or sleeping pills, is not deadly in itself (if we are talking about patients with a healthy nervous system, not having heart or lung problems). The withdrawal syndrome after the withdrawal of morphine, as well as other opioids, goes through several stages. Withdrawal symptoms after withdrawal of other opioids vary in intensity and duration. Weak opioids and mixed agonist-antagonist drugs can cause short-term and mild withdrawal symptoms. So, the stages of withdrawal syndrome:

Stage I, 6-14 hours after last dose: Desire to get high again, restlessness, irritability, sweating, dysphoria

Stage II, 14-18 hours after the last dose: yawning, severe sweating, slight depression, lacrimation, crying, moaning, rhinorrhea (copious discharge of watery mucus from the nose), dysphoria, also intensification of the above symptoms, trance-like wakefulness

Stage III, 16-24 hours post-dose: rhinorrhea, worsening of the above symptoms, dilated pupils, piloerection ("goosebumps"), muscle cramps, hot flashes, cold spells, bone and muscle pain, loss of appetite, onset of lateral pain gastrointestinal tract

Stage IV, 24-36 hours post-dose: worsening of all of the above symptoms, including severe cramps and involuntary leg movements, restless leg syndrome), loose stools, insomnia, increased blood pressure, slight increase in body temperature, increased respiratory rate and inspiratory volume, tachycardia (increased heart rate), restlessness, nausea

Stage V, 36-72 hours post-dose: worsening of the above symptoms, lying in the fetal position, vomiting, frequent loose stools, weight loss (2-5 kg ​​in 24 hours), increase in white blood cells, and other blood changes

Stage VI, after the above symptoms: restoration of appetite and normalization of bowel function, the beginning of the transition to initial and chronic symptoms, which are mainly psychological, but may also include increased sensitivity to pain, increased blood pressure, colitis or other problems of the gastrointestinal tract tract associated with its mobility, as well as problems with weight control

In the late stages of the withdrawal syndrome, some patients were found to have pancreatitis, which is presumably due to spasm in the sphincter of Oddi. The withdrawal syndrome seen in morphine addicts usually lasts for a period of time between doses (6-12 hours). Early symptoms are watery eyes, insomnia, diarrhea, rhinorrhea, yawning, dysphoria, sweating, and in some cases an irresistible urge to repeat the dose. As the syndrome progresses, severe headaches, restlessness, irritability, loss of appetite, body aches, severe pain in the abdomen, nausea and vomiting, tremors, and an even stronger craving for the drug are observed. Severe depression and vomiting are common. During an acute withdrawal syndrome, systolic and diastolic blood pressure and pulse increase, which can potentially be associated with a risk of heart attack, blood clotting, or stroke. Other characteristic symptoms include chills with goosebumps, fever, uncontrolled leg movements, and excessive sweating. There may also be severe pain in the bones and muscles of the back and limbs and muscle spasms. During withdrawal symptoms, it may be rational to take some suitable drug to relieve symptoms. Withdrawal symptoms are most severe between 48 and 96 hours after the last dose, and gradually subside over 8 to 12 days. Abrupt cessation of morphine by users who have developed a strong addiction can, in very rare cases, be fatal. The abstinence syndrome after withdrawal of morphine is considered less dangerous than after the withdrawal of alcohol, barbiturates or benzodiazepines. Psychological dependence on morphine develops in a complex and gradual manner. Long after the physical need for morphine has ceased, the addict will continue to think and talk about their experience with this and other substances and feel strange while sober. Psychological withdrawal after morphine withdrawal is usually a very long and painful process. Often during it, victims experience depression, anxiety, insomnia, mood swings, amnesia, confusion, paranoia, and other symptoms. Without intervention, most severe physical symptoms, including psychological dependence, will disappear within 7-10 days. However, without changing the physical environment or behavioral factors associated with abuse, there is a high risk of relapse. An indication of the powerful additive nature of morphine is the relapse rate. Morphine (heroin) addicts have the highest relapse rates of any drug user (about 98%).

Overdose

Severe overdose, in the absence of immediate medical attention, can cause asphyxia and death as a result of respiratory depression. Overdose treatment includes the use of naloxone. This drug completely blocks the action of morphine, but provokes the immediate development of an abstinence syndrome in individuals with opiate dependence. Multiple doses may be required. The minimum lethal dose of morphine is 200 mg, but cases of hypersensitivity have been reported in which 60 mg of the substance has been associated with sudden death. With strong dependence (and tolerance), a person can tolerate even such a high dose as 2000-3000 mg per day.

Pharmacodynamics

Endogenous opioids include endorphins, enkephalins, dynorphins, and morphine itself. Morphine mimics the action of endorphins. Endorphins (full name - endogenous morphines) are responsible for such effects as analgesia (pain reduction), falling asleep and feeling of pleasure. They are released in response to stimuli such as pain, strenuous exercise, orgasm, or arousal. Morphine is the prototype drug and is the standard drug against which all other opioids are compared. It interacts mainly with the μ-δ heteromer of the opioid receptor. μ-binding sites are scattered in the human brain, with the highest density in the posterior cerebellar tonsil, hypothalamus, thalamus, caudate nucleus, putamen, and in some cortical fields. They are also found on the terminal axons of the primary afferents in the plates I and II (gelatinous substance) of the spinal cord and in the vertebral nucleus of the fifth cranial nerve. Morphine is a phenanthrene opioid receptor agonist. Its main action is to bind and activate the μ-opioid receptor in the central nervous system. In clinical studies, morphine exerts its primary pharmacological activity in the central nervous system and gastrointestinal tract. Its main beneficial therapeutic action is associated with analgesia and sedation. Mu-opioid receptor activation is associated with analgesia, sedation, euphoria, physical dependence, and respiratory depression. Morphine is a fast-acting drug that binds very strongly to mu-opioid receptors and for this reason it causes euphoria/dysphoria, respiratory depression, sedation, pruritus, tolerance, and physical and psychological dependence when compared to other opioids at equivalent doses. Morphine is also a κ-opioid and δ-opioid receptor agonist. Effects on κ-opioid receptors are associated with spinal analgesia, pupillary constriction and psychotomimetic effects. δ-opioid effects play a role in analgesia. Although morphine does not bind to the σ receptor, σ agonists such as (+)-pentazocine have been shown to inhibit morphine-induced analgesia and that σ antagonists enhance analgesia, suggesting that the σ opioid receptor is involved in the action of morphine. The effects of morphine can be inhibited by opioid antagonists such as naloxone and naltrexone; the development of morphine tolerance can be suppressed by NMDA antagonists such as ketamine or dextromethorphan. The alternating use of morphine and chemically different opioids for a long time allows for a long time to reduce the development of tolerance. This is especially true for substances that have incomplete cross-tolerance with morphine, such as levorphanol, ketobemidone, pyritramide and methadone and their derivatives; all of these substances are also NMDA antagonists. The most potent opioids with the most incomplete cross-tolerance to morphine are considered to be methadone or dextromoramide.

Gene expression

Studies have shown that morphine can alter the expression of a number of genes. A single injection of morphine alters the expression of two major groups of genes, proteins involved in mitochondrial respiration and proteins related to the cytoskeleton.

Impact on the immune system

Morphine has long been known to act on receptors expressed on cells in the CNS, leading to pain relief and analgesia. In the 1970s and 80s, evidence emerged that opioid-dependent individuals were at increased risk of developing infections (such as pneumonia, tuberculosis, and HIV/AIDS), leading to the development of the theory that morphine affects the immune system . This has led to an increase in research into the effects of long-term exposure to morphine on the immune system. The first step in this direction was the establishment that the opioid receptors expressed on the cells of the CNS are also expressed in the cells of the immune system. One study showed that dendritic cells, which are part of the innate immune system, have opioid receptors. Dendritic cells are responsible for the production of cytokines, which in turn are responsible for the message in the immune system. The same study showed that dendritic cells, which long time treated with morphine during their differentiation, produced more interleukin-12 (IL-12), a cytokine responsible for the proliferation, growth and differentiation of T cells (another cell in the adaptive immune system) and less interleukin-10 (IL-10), a cytokine, responsible for the implementation of the B-cell immune response (B cells produce antibodies to fight infections). This regulation of cytokines is mediated through the p38 MAPKs (mitogen-activated protein kinase)-dependent pathway. Normally, p38 expresses TLR 4 (toll-like receptor 4) inside dendritic cells, which is activated via the LPS (lipopolysaccharide) ligand. This induces phosphorylation of p38 MAPK. This phosphorylation activates p38 MAPK, promoting the production of IL-10 and IL-12. With prolonged exposure of dendritic cells to morphine during their differentiation and subsequent LPS treatment, cytokine production is altered. After exposure to morphine, p38 MAPK does not produce IL-10, preferring IL-12 instead. The exact mechanism by which one cytokine is favored is not known. It is more likely that morphine increases p38 MAPK phosphorylation. Interactions at the transcriptional level between IL-10 and IL-12 can cause a further increase in the production of IL-12 while IL-10 is not being produced. The increased production of IL-12 causes an increase in the immune response of T cells. Further research on the effects of morphine on the immune system showed that morphine induces the production of neutrophils and cytokines. Because cytokines are produced in part as an immediate immunological response (inflammation), it has been hypothesized that they may also cause pain. Thus, cytokines may be a logical target for analgesic development. A recent study evaluated the effect of morphine on short-term immunological response in animals. Pain threshold and cytokine production were measured after dissection of the hind paw. Normally, when wounded, cytokine production in and around the affected area is increased to suppress infection and control healing (and possibly pain), however, 0.1-10.0 mg/kg of morphine prior to hindleg incision caused a decrease in cytokines around the wound in a dose-dependent manner. . The authors hypothesized that post-injury morphine use may reduce resistance to infection and may adversely affect wound healing.

Pharmacokinetics

Absorption and metabolism

Morphine can be used orally, sublingually (under the tongue), buccally (behind the cheek), rectally, subcutaneously, intravenously, nasally, intrathecally (into the subarachnoid space of the spinal cord), or epidurally (into the epidural space of the spine through a catheter), or inhaled through an inhaler. On the streets, the drug is most often inhaled, but in medical institutions, morphine is administered intravenously. Morphine undergoes extensive first-pass metabolism (mostly degraded in the liver), so when taken orally, only 40–50% of a dose reaches the CNS. Plasma levels observed after subcutaneous, intramuscular and intravenous administration are approximately equal. After intramuscular or subcutaneous administration, plasma levels of morphine reach peak values ​​after approximately 20 minutes, and after oral administration - after half an hour. Morphine is metabolized primarily in the liver and approximately 87% of a morphine dose is excreted in the urine within 72 hours of administration. Morphine is metabolized to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) via glucuronidation by the second phase enzyme UDP-glucuronosyl transferase -2B7 (UGT2B7). About 60% of morphine is converted to M3G and 6–10% to M6G. Metabolism takes place not only in the liver, but can also be observed in the brain and kidneys. M3G does not bind to the opioid receptor and has no analgesic effect. M6G binds to mu receptors and is half as potent an analgesic as morphine (in humans). Morphine can also be metabolized to small amounts of normorphine, codeine, and hydromorphone. The metabolic rate depends on age, diet, genetic makeup, the presence of diseases and the 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 adipose tissue, thus being detectable in the body after death. Morphine can cross the blood-brain barrier, but due to its low lipid solubility, protein binding, rapid glucuronic acid conjugation, and ionization, it is not easy for it to cross this barrier. Diacetylmorphine, a derivative of morphine, is able to cross the blood-brain barrier more easily, making it a more potent drug. There are also sustained-release oral formulas of morphine that last substantially longer than morphine, allowing them to be used only once a day.

Detection in biological fluids

Morphine and its major metabolites, morphine-2-glucuronide and morphine-6-glucuronide, can be detected in blood, plasma, hair, and urine by immunoassay. Chromatography can be used to test each substance individually. In some testing procedures, metabolites are hydrolyzed to morphine prior to immunoassay, which should be considered when comparing morphine levels in separately published results. Morphine can be isolated from whole blood using solid phase extraction and detected using liquid chromatography-mass spectrometry techniques. Ingestion of codeine or food containing poppy seeds may give false positive results. A 1999 analysis showed that relatively small doses of heroin (which are immediately metabolized to morphine) are detectable in standard urine tests within 1-1.5 days of use. A 2009 analysis showed that when the analyte is morphine and the limit of detection is 1 ng/mL, an intravenous dose of morphine of 20 mg is detectable within 12–24 hours. The limit of detection, equal to 0.6 ng/ml, has similar performance.

natural sources

Morphine is the most abundant opiate found in opium, the dried milky sap released when the immature pods of the opium poppy (Papaver somniferum) are slightly cut. Morphine was the first active narcotic found in plants and is one of at least 50 different types of alkaloids found in opium, poppy straw concentrate and other poppy derivatives. Morphine makes up 8-14% of the dry weight of opium, although some specially grown varieties contain up to 26% morphine or, conversely, minimal amounts (less than 1%, or about 0.04%). Morphine-poor varieties (Przemko and Norman) are used to produce other alkaloids such as thebaine and oripavine, which in turn are used in the production of semi-synthetic and synthetic opioids such as oxycodone and etorphine and other substances. P. bracteatum does not contain morphine or codeine or other phenanthrene-type narcotic alkaloids. This species is a good source of thebaine. Morphine content has not been confirmed in other species (Ranunculaceae and Poppy), as well as in some types of hops and mulberries. Morphine is produced mainly at the beginning of the plant's life cycle. Various processes in the plant contribute to the production of codeine, thebaine and, in some cases, small amounts of hydromorphone, dihydromorphine, dihydrocodeine, tetrahydro-thebaine, and hydrocodone (these compounds are often synthesized from thebaine and oripavine). The human body produces endorphins, which are endogenous opioid peptides that act as neurotransmitters and exhibit morphine-like effects.

Chemistry

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

Much of the illegal morphine is used to produce codeine through methylation. It is also a precursor for the manufacture of many drugs, including heroin (3,6-diacetylmorphine), hydromorphone (dihydromorphinone), and oxymorphone (14-hydroxydihydromorphinone); many morphine derivatives can be produced using thebaine and/or codeine as starting material. Replacing the N-methyl group of morphine with an N-phenylethyl group results in the production of a substance 18 times more potent than morphine (in relation to opiate agonism). Combining this modification with the replacement of the 6-hydroxyl group with a 6-methylene group creates a compound that is 1.443 times more potent than morphine and, by some measures, more potent than Bentley's opioids such as etorphine (M99, an Immobilon® tranquilizer). The structure-activity relationships of morphine have been well studied. As a result of the research and use of this molecule, over 250 morphine derivatives (including codeine) have been discovered since the late 19th century. These drugs exhibit anywhere from about 25% of the analgesic potential of codeine (or slightly more than 2% of that of morphine) to levels several thousand times that of morphine. The most powerful opioid antagonists are naloxone (Narcan®), naltrexone (Trexan®), diprenorphine (M5050, a drug that reverses the effects of Immobilon®), and nalorphine (Nalline®). Several opioid agonist-antagonists, partial agonists, and inverse agonists have also been produced from morphine. The receptor activation profile of these semi-synthetic morphine derivatives varies considerably. Some of the derivatives, such as apomorphine, do not show narcotic effects at all. Morphine and most of its derivatives do not exhibit optical isomerism, unlike some of the more distant derivatives, such as the morphine compounds (levorphanol, dextorphan, and the racemic "parent" compound dromoran). Agonist-antagonist substances have also been synthesized from morphine. The structural elements of morphine have been used to create fully synthetic drugs, such as drugs from the morphine family (levorphanol, dextromethorphan, and others). Other groups of drugs include many substances with morphine-like qualities. Modification of morphine and the synthetic substances mentioned above have allowed the synthesis of non-narcotic drugs with a different mechanism of action, such as emetics, stimulants, antitussives, cough suppressants, muscle relaxants, local anesthetics, general anesthetics and other drugs. Most semi-synthetic opioids, both morphine and codeine, are created by modifying one or more of the above elements:

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

Removal or return of the methyl group that converts morphine to codeine, or replacement of the methyl group with another functional group (ethyl or otherwise) to produce codeine analogs from morphine-derived drugs and vice versa. Morphine-based codeine analogs are often used as a prodrug 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 relationship between positions 7 and 8, as well as the addition, removal or modification of functional groups at these positions; saturation, reduction, removal or other modification of the connection 7-8 and the addition of a functional group on hydromorphinol; oxidation of the hydroxyl group to a carbonyl group and change of the 7-8 double bond to a single one converts codeine to oxycodone.

Addition, removal or modification of functional groups at positions 3 and/or 6 (dihydrocodeine and related substances, as well as hydrocodone and nicomorphine); when the methyl functional group moves from position 3 to position 6, codeine becomes heterocodeine, which is 72 times more potent, and thus 6 times more potent than morphine

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

Modifications at positions 2, 4, 5 or 17, usually along with other changes in the morphine molecule. This is usually done with drugs produced by catalytic reduction, hydrogenation, oxidation and similar reactions to produce powerful morphine and codeine derivatives.

Both morphine and its hydrated form, C17H19NO3H2O, are sparingly soluble in water. Only 1 gram of hydrate dissolves in five liters of water. For this reason, pharmaceutical companies produce sulfate and hydrochloride salts from this drug, which are 300 times more soluble in water than the parent molecule. The pH of saturated morphine is 8.5, while the salts are acidic. Since they are derivatives of strong acids, but weak foundation, they both have pH = 5; and as a consequence, for injectable use, morphine salts are mixed with a small amount of NaOH. A large number of morphine salts are used, the hydrochloride, sulfate, tartrate, and citrate being most commonly used clinically; less commonly used are methobromide, hydrobromide, hydroiodide, lactate, chloride and bitartrate and other substances listed below. Morphine diacetate, also known as heroin, is a Schedule I controlled substance in the US, and for this reason is not used in medicine. In the UK, Canada and some European countries, this substance is authorized. In the UK, heroin is widely used (comparable to the use of the hydrochloride salt). Morphine meconate is the main form of alkaloid found in poppy, in addition to which it contains substances such as morphine pectinate, nitrate, sulfate and others. Like codeine, dihydrocodeine, and other opioids, especially older ones, some manufacturers use morphine as a salicylic acid ester that mixes easily with other substances, allowing the therapeutic benefits of opioids and NSAIDs to be exploited; various barbyurate salts of morphine have also been used in the past, such as morphine valerate (the salt of this acid is the active ingredient in valerian). Calcium morphenate is an intermediate in the production of morphine, while sodium morphenate is less commonly used. Morphine ascorbate and other salts such as tannate, citrate and acetate, phosphate, valerate and others may be present in maca, depending on the method of preparation. Commercially produced morphine valerate was used as an ingredient in Trivaline, an oral and parenteral drug popular many years ago in Europe and other countries (not to be confused with the herbal remedy of the same name), which also included caffeine valerates and cocaine, with a version containing codeine valerate as the fourth ingredient sold under the brand name Tetravaline. Closely related to morphine are the opioids morphine-N-oxide (genomorphine), a pharmaceutical substance that is not currently in use, and pseudomorphine, an opium alkaloid that is formed as a breakdown product of morphine.

Synthesis of morphine

Biosynthesis

Morphine is biosynthesized from tetrahydroisoquinoline reticulin. It is converted to salutaridin, thebaine and opivarine. Enzymes involved in this process include salutaridin synthase, salutaridin:NADP 7-oxidoreductase, and codeinone reductase.

Chemical synthesis

The first complete synthesis of morphine, developed by Marshall D. Gates Jr. in 1952, widely used today. Several other synthesis methods were developed by the research groups of Rice, Evans, Fook, Parker, Overman, Mulser-Trauner, White, Taber, Trost, Fukiyama, Gillow, and Stork.

Production

Opium poppy alkaloids are related to meconic acid. The production method is extraction from crushed plants using dilute sulfuric acid, a stronger acid than meconic acid, but not strong enough to react with alkaloid molecules. Extraction is carried out in several stages (one part of the crushed plant is extracted 6-10 times, so almost all alkaloids are present in the solution). From the solution obtained at the last stage of extraction, alkaloids are precipitated using ammonium hydroxide or sodium carbonate. The last step is the purification and separation of morphine from other opium alkaloids. In Great Britain during World War II, a similar synthesis method called the Gregory process was developed, which begins with the stewing of the whole plant, in most cases with the roots and leaves preserved, in slightly acidified water, followed by the steps of concentration, extraction and purification of alkaloids. Other methods of processing poppy straw (i.e. raw pods and stems) use evaporation using one or more types of alcohols or other organic solvents. Poppy straw is used mainly in continental Europe and the states of the British Commonwealth, and poppy milky juice is most often used in India. When using the milky sap methods, vertical or horizontal cuts are made on immature pods with a 2-5-blade knife with a limiter specially designed for this purpose, allowing cutting to a depth of 1 mm. Incisions can be made up to 5 times. In the past, alternative methods using milky juice were used in China. These methods included cutting off the poppy heads, threading large needles through them, and collecting the dried juice after 24-48 hours. In India, opium is grown on farms by licensed farmers. In special government centers, it is dried to a certain level, and then sold to pharmaceutical companies that extract morphine from opium. In Turkey and Tasmania, morphine is produced by growing and processing whole, dried, mature stemmed pods called "opium straws". Turkey uses an aqueous extraction process, while Tasmania uses a solvent extraction process. The opium poppy contains at least 50 different alkaloids, but most of them are present in very low concentrations. Morphine is the main alkaloid found in raw opium and makes up ~8-19% of the dry weight of opium (depending on growing conditions). Some specially grown poppies contain up to 26% opium by weight. A very approximate estimate of the morphine content of crushed poppy straw can be obtained by dividing the percentage expected in the production of the milky sap method by 8 or by an empirically determined factor which is a number between 5 and 15. Norman variety P. somniferum, also developed in Tasmania , produces less than 0.04% morphine, but higher amounts of thebaine and oripavine, which can also be used to synthesize semi-synthetic opioids and other drugs such as stimulants, emetics, opioid antagonists, anticholinergics, and smooth muscle agents. In the 1950s and 1960s, Hungary supplied almost 60% of all morphine products used in medicine. Today poppy cultivation is legal in Hungary, but the size of poppy fields is limited by law to two acres (8100 m2). It is legal to sell dried poppies in flower shops for decorative purposes. In 1973, it was announced that a team at the National Institutes of Health in the United States had developed a method for the complete synthesis of morphine, codeine, and thebaine using coal tar as the starting material. The initial objective of the research was the invention of codeine-hydrocodone class cough suppressants (which can be produced in several stages from morphine, as well as from codeine or thebaine). Much of the morphine produced for pharmaceutical use worldwide can be converted to codeine, since the concentration of the latter in raw opium and poppy straw is much lower than that of morphine; in most parts of the world, the use of codeine (both as an end product and as a precursor) is as widespread as that of morphine.

Precursor for the production of other opioids

pharmaceuticals

Morphine is a precursor in the production of many opioids such as dihydromorphine, hydromorphone, hydrocodone and oxycodone, as well as codeine, which itself has a large number of semi-synthetic derivatives. Morphine is often treated with acetyl anhydride and set on fire to make heroin. Physicians in Europe are increasingly recognizing the need for the oral use of slow-release morphine as substitution therapy in place of methadone and buprenorphine for patients unable to tolerate the side effects of the latter. Slow-release oral morphine has been widely and for many years used as opiate maintenance therapy in Austria, Bulgaria and Slovakia. In other countries, including the UK, it is also used, but on a smaller scale. Extended-release morphine acts long enough to mimic the effect of buprenorphine, maintaining constant blood levels, with no peaks or perceptible highs, but no withdrawal symptoms. In addition, slow-release orally administered morphine is a promising treatment for opiate dependent patients who are sensitive to the side effects of buprenorphine and methadone due to their unnatural pharmacological action. Heroin and morphine have nearly identical pharmacology, except that the heroin molecule has two acetyl groups, which increases its lipid solubility, making it more likely to cross the blood-brain barrier and reach the brain when injected. Upon reaching the brain, these acetyl groups are removed and the substance is converted to morphine. Thus, heroin can be seen as a faster-acting form of morphine.

Illicit production and use

Morphine is illegally produced in several ways. Quite rarely, codeine, found in cough medicines and prescription pain relievers, is used in this process. This dimethylation reaction often proceeds using pyridine and hydrochloric acid. Another source of illicitly manufactured morphine is sustained release morphine, such as the formula MS-Contin. Morphine can be isolated from these products by simple extraction, resulting in a morphine solution suitable for injectable use. As an alternative to this route of administration, morphine tablets can be crushed into a powder and inhaled through the nose, or mixed with water and injected, or simply swallowed. However, with this use, the user will not experience the full degree of euphoria, but the effect will last longer. Due to its sustained release, the MS-Contin formula is used in some countries along with methadone, dihydrocodeine, buprenorphine, dihydroetorphine, pyritramide, levo-alpha-acetylmethadol (LAAM) and special hydromorphone formulas, acting for 24 hours as maintenance therapy and for detoxification of patients who are physically dependent on opioids. In addition, through various chemical reactions, morphine can be converted into heroin or another, more powerful opioid. Using special technology (where the original precursor is codeine), morphine can be converted into a mixture of morphine, heroin, 3-monoacetylmorphine, 6-monoacetylmorphine, and codeine derivatives such as acetylcodeine. Because heroin is one of a series of morphine 3,6 diesters, morphine can be converted to nicomorphine (Vilan) using nicotinic anhydride, dipropanoylmorphine with propionic anhydride, dibutanoylmorphine, and disalicyloylmorphone with the appropriate acid anhydrides. To obtain a substance containing a large amount of 6-monoacetylmorphine, niacin (vitamin B3), crystalline acetic acid can be used.

Story

The creation of an opium-based elixir is attributed to the alchemists of Byzantine times, but during the Ottoman conquest of Constantinople (Istanbul), the exact formula was lost. Around 1522, Paracelsus wrote about an opium-based elixir which he called laudanum (from the Latin laudare, meaning "praise"). He described the remedy as a potential pain reliever, but recommended its use in moderation. In the late 18th century, when the East India Company began trading opium throughout India, another opiate called laudanum gained popularity among doctors and their patients. Friedrich Sertürner first discovered morphine as the first active alkaloid isolated from opium in December 1804 in Paderborn, Germany. In 1817, Serturner and Company marketed the drug as an analgesic and also as a treatment for alcohol and opium addiction. In 1827, commercial sales of morphine began in a pharmacy in the German city of Darmstadt. This pharmacy would later evolve into the pharmaceutical giant Merck, thanks in large part to the sale of morphine. Morphine was later found to be much more addictive than alcohol or opium. The extensive use of morphine during the American Civil War resulted in over 400,000 cases of so-called "soldier's disease", or morphine addiction. This idea became the subject of controversy, since there was an assumption that the very existence of such a disease was fabricated; the first documented mention of the phrase "soldier's illness" occurs in 1915. Diacetylmorphine (also known as heroin) was synthesized from morphine in 1874. In 1898 it was brought to market by Bayer. Heroin is approximately 1.5-2 times more potent than morphine on a weight basis. Due to the fat-soluble nature of heroin, it can cross the blood-brain barrier faster than morphine, greatly increasing the addiction potential. In one study, using various subjective and objective methods, the relative potency of heroin to morphine (when administered intravenously to ex-addicts) was 1.80–2.66 mg morphine sulfate per 1 mg diamorphine hydrochloride (heroin). In 1914, the Harrison Narcotic Tax Act was passed in the United States, making morphine a controlled substance and making it a criminal offense to possess it without a prescription. Until heroin was first synthesized, morphine was the most popular narcotic analgesic in the world. In general, until the synthesis of dihydromorphine (circa 1900), the dihydromorphinone class of opioids (1920s), as well as oxycodone (1916) and similar drugs, there were no drugs in the world that could compare in effectiveness with opium , morphine and heroin (the first synthetic opioids, such as pethidine, synthesized in Germany in 1937, would not be invented until a few years later). Codeine analogs and derivatives such as dihydrocodeine (Paracodin), ethylmorphine (Dionine) and benzylmorphine (Peronine) were semi-synthetic opioid agonists. Even today, heroin addicts prefer morphine to all other opioids (if they can't get their hands on heroin). Under certain conditions (lack of available morphine), hydromorphone, oxymorphone, high doses of oxycodone or methadone (as in the 1970s in Australia) share the palm. The most commonly used "interim measures" used by heroin addicts to ease withdrawal are codeine, as well as dihydrocodeine and poppy straw derivatives such as poppy pods and poppy seed tea, propoxyphene, and tramadol. The structural formula of morphine was determined in 1925 by Robert Robinson. At least 3 methods have been patented for the complete synthesis of morphine from materials such as coal tar and petroleum distillates, with the first method described in 1952 by Dr. Marshall D. Gates Jr. at the University of Rochester. Despite this, most morphine is still obtained from the opium poppy, either by traditional methods (collecting the milky juice from immature poppy fruits) or by processes using poppy straw, dried bolls and stems of the plant (the most popular method was invented in 1925 and described in 1930 by the Hungarian chemist Janos Kabai). In 2003, endogenous morphine produced in the human body was discovered. For this, scientists took 30 years of controversy and conjecture. It was known that there is a receptor in the human body that responds only to morphine, the μ3-opioid receptor. Trace amounts of endogenous morphine have been found in human cells that form in response to neuroblastoma cancer cells.

Society and culture

legal status

Illegal use

Euphoria, complete suppression of stress and all aspects of pain ("suffering"), increased empathy and talkativeness, pleasurable sensations in the body, and relief of anxiety symptoms (anxiolysis) are the effects that most often cause psychological dependence and are therefore the main cause of opiate overdose. , and in the absence of a dose - a severe withdrawal syndrome. As the prototype of an entire class of drugs, morphine has all of their characteristics and has a high potential for abuse. Society's attitude to drugs is largely determined by its attitude to morphine addiction. Animal and human studies and clinical data support the claim that morphine is one of the most euphoric substances on the planet, and that morphine and heroin cannot be distinguished by any route of administration (other than intravenous) because heroin is the prodrug for delivering morphine into the body . Chemical modification of the structure of the morphine molecule allows the production of other euphoric substances such as dihydromorphine, hydromorphone (Dilaudid, Hydal) and oxymorphone (Numorphan, Opana), as well as three methylated equivalents of the latter (dihydrocodeine, hydrocodone, oxycodone). In addition to heroin, the 3,6 morphine ester category includes dipropanoylmorphine, diacetyldihydromorphine, and other substances such as nicomorphine and other semi-synthetic opioids such as desomorphine, hydromorphinol, etc. In general terms, abuse of morphine includes taking more than what was prescribed by a doctor, or using morphine without a prescription and medical supervision, making and using injections from morphine tablets, mixing morphine with substances such as alcohol, cocaine and the like, to increase its effect. , and/or the use of methods that disrupt the mechanism of action of extended release morphine, such as chewing tablets or crushing them into a powder, followed by inhalation, or making injections. The latter method is very time consuming and is used alongside traditional opium smoking methods. Morphine is rarely seen as a street drug, although it is used where it is available, in the form of injectable ampoules, pure pharmaceutical powder, and dissolvable tablets. Morphine is also available as a paste, which is used in the manufacture of heroin, which can be smoked or converted into a soluble salt and injected. Poppy straw, like opium, can contain morphine, which ranges in purity from that of poppy tea to near-pharmaceutical levels (with the final substance not only containing morphine, but also the other 50 alkaloids present in opium).

Slang designations

On the streets, morphine is called "M", "sister morphine", "vitamin M", "morpho", etc. MS Contin tablets are referred to as "misties" and 100-mg sustained release tablets as "gray" or "blockbuster" tablets. "Speedball" is a mixture of substances in which some elements compensate for others, for example, morphine can be mixed with cocaine, amphetamines, methylphenidate or similar drugs. The injectable combination drug Blue Velvet is a mixture of morphine with the antihistamine Tripelennamide (Pyrabenzamine, PBZ, Pelamin), and is less commonly used as an enema; the same term refers to a mixture of tripelennamine and dihydrocodeine or codeine tablets or syrups taken orally. "Morphia" is obsolete official name morphine, which is also used as a slang term. Driving Miss Emma is morphine taken by mouth. General purpose tablets (quick-dissolving hypodermic tablets that can also be administered orally or sublingually or buccally), as well as some trade names for hydromorphone, are also called "Shake & Bake" or "Shake & Shoot". Morphine (especially diacetylmorphine, that is, heroin) can be smoked, this method is also called "Chasing The Dragon" ("chasing the dragon"). The process of relatively crude acetylation to convert morphine to heroin and related substances immediately before use is called "AAing" (Acetic Anhydride) or "home-bake" ("home-made"), and the final product is also called "home-bake" or "blue heroin" (not to be confused with "magic blue heroin" (Blue Magic - 100% pure heroin), as well as cough medicine called Blue Morphine or Blue Morphone, or with "Blue Velvet").

Availability of morphine in developing countries

Despite the cheapness of morphine, often people in poor countries cannot afford to buy it. According to 2005 data provided by the International Narcotics Control Board (established in 1964 under the 1961 Convention, composed of 13 members elected by ECOSOC for 5 years and acting in their personal capacity), 79% of morphine is consumed in 6 countries of the world - Australia, Canada, France, Germany, the United Kingdom and the USA. Less affluent countries, in which 80% of the world's population lives, consume only about 6% of morphine. In some countries, imports of morphine have effectively been banned, while in others, the substance is virtually unavailable, even to relieve severe pain if a person is dying. Experts believe that morphine's unavailability is due to its addiction potential. However, despite these characteristics of morphine, many Western doctors believe that it can be used with a subsequent gradual dose reduction at the end of treatment.

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List of used literature:

Morphine sulfate. The American Society of Health-System Pharmacists. Retrieved $1 $2. Check date values ​​in: |accessdate= (help)