The word “morphine” (or the outdated name “morphine”) is known to almost everyone.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, so he named the substance in honor of greek god Morphea. 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 dangerous consequences the use of the substance was 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: 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

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. Withdrawal 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.

Morphine (5a,6a)-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol)- one of the main alkaloids opium. The word comes from ancient Greek god Morpheus, literally the one who produces dreams. Outdated name - morphine. Contained in soporific poppy, stephania, sinomenium, moonseed. Less common in the genera croton, cocculus, triclesia, ocotea. Practically obtained only from dried milky juice opium poppy. The morphine content in raw opium reaches 10-20%, the minimum concentration is about 3%.
It must be said that opium poppy contains only one stereoisomer, (-)-morphine. (+)-morphine was obtained by synthesis and does not have the pharmacological properties of (-)-morphine.

The chemical formula of morphine is C17H19NO3.

In its pure form, morphine is a white crystalline powder that, when long-term storage acquires a yellowish or grayish tint. Mainly available in the form of an injection solution.

Medical purpose of morphine quite wide. Morphine derivatives, particularly hydrochloride (injectable) and sulfate (oral) as an analgesic (analgesic, mild anesthetic, sedative) drug. Morphine can effectively suppress feelings of intense physical pain and pain of psychogenic origin. It also has sedative activity and suppresses the cough reflex. By reducing the excitability of pain centers, it also has an anti-shock effect in case of injuries. Used for acute myocardial infarction.
Morphine is sometimes used in x-ray practice when examining the stomach, duodenum, and gall bladder. Administration of morphine increases the tone of the stomach muscles, enhances peristalsis, accelerates its emptying and causes distension of the duodenum. contrast agent. This helps to identify stomach ulcers and tumors, duodenal ulcers. The contraction of the sphincter of Oddi muscle caused by morphine creates favorable conditions for x-ray examination of the gallbladder.

Since morphine has a narcotic effect on the human body, drug addicts are not immune to it.

The effect of the drug begins 5-10 minutes after intravenous or intramuscular administration. The peak concentration of morphine in the blood occurs after 20 minutes. The effect of the drug on the human body is accompanied by euphoria, a feeling of warmth, drowsiness and a decrease in the level of consciousness. Depending on the dosage, the effects of morphine can last from 2 to 8 hours.
Signs of Morphine use:

Severe constriction of the pupils, eyes slightly reddish and very shiny; bruises under the eyes, shallow intermittent slow breathing; itchy skin (especially nose); lethargic and sleepy appearance; slurred speech; passivity and general relaxation; apathy towards everything except oneself; euphoria and carefree; excessive “courage” and determination; nervousness; dry skin and mucous membranes (lips, tongue); superficial sleep; decreased urine output; frequent constipation; There is no cough when you have a cold; slight decrease in body temperature. Characteristic of the action of morphine is depression of the respiratory center. Toxic doses cause periodic breathing and subsequent death due to respiratory arrest.
Consequences of using Morphine: Morphine is a strong narcotic drug and quickly becomes addictive, and as a result, persistent physical dependence develops. This is due to the fact that some parts of morphine molecules are very similar to fragments of endorphins. In normal life, endorphins are produced nervous system and regulate human emotional and intellectual activity. After 2-3 weeks of regular use of the drug, a person is practically unable to get rid of addiction on his own., and constantly increasing the dose can lead to overdose and death. Withdrawal syndrome occurs 10-12 hours after the last dose of morphine. Manifests itself in the form of irritability, aggression, muscle breakdown, nausea and vomiting. The period of acute withdrawal syndrome is 5-14 days. In addition, morphine causes side effects associated with decreased motor ability intestines (constipation).

From Morfin's story:
Morphine was first isolated from opium by the German pharmacologist Friedrich Serthuner. 1804 year. It was F. Sertuner who gave morphine its name after the god of dreams in Greek mythology- Morpheus, son of Hypnos, god of sleep.

Tom de Quincey left an essay "Confessions of an English Opium Addict" ( 1822 ), in which he described in detail how morphine drug addiction develops. Morphine was the first alkaloid obtained in purified form. However, morphine became widespread after the invention of the injection needle in 1853 year. It was used to relieve pain. In addition, it was used as a “treatment” for opium and alcohol addiction. The widespread use of morphine during the American Civil War led to the emergence of "army disease" (morphine addiction) in more than 400 thousand people.

IN 1874 diacetylmorphine, better known as heroin. Before the synthesis of heroin, morphine was the most common narcotic analgesic in the world.

IN late XIX century, German soldiers and officers returning from the Franco-Prussian War of 1870-1871 turned out to be morphine addicts in almost half of the cases. During the war, many soldiers injected themselves with morphine, which at that time became an affordable and fashionable sedative. In 1879, in one of the works, a description of the disease, called “soldier’s disease,” appeared. At that time, almost any illness in the American army was treated with opium. In 1880, on international conference, it was announced that a new disease “drug addiction” had emerged, caused by drug abuse.

At the beginning of the twentieth century, many doctors became morphine addicts. Among the medical community, there was an opinion that a doctor who understands the harmfulness of morphinism is able, if necessary, to independently use morphine for himself, avoiding addiction due to awareness. Practice has shown that this opinion was erroneous.

The complete synthesis of morphine was carried out only in 1952, but its length and complexity (17 stages were initially included) make it impractical for commercial implementation. There are currently several proposed various methods synthesis, but natural morphine is still cheaper than synthetic one.

At the beginning of the 20th century, many doctors became morphine addicts. Among the medical community, there was an opinion that a doctor who understands the harmfulness of morphinism is able, if necessary, to independently use morphine for himself, avoiding addiction due to awareness. Practice has shown that this opinion was erroneous. Mikhail Bulgakov, the author of the story “Morphine,” was a morphine addict for some time, but completely recovered from drug addiction thanks to the selfless help of his first wife. Leo Tolstoy in Anna Karenina describes how the main character became addicted to morphine after it was first used on her to relieve the pain of her second childbirth. A famous morphine addict was Hermann Goering, however, he recovered from this addiction. Many creative personalities have slipped into the trap of morphinism. Thus, Edith Piaf at the end of her life was forced to resort to injections even during her performances. Among the victims of morphine is Vladimir Vysotsky.

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) - medicinal product, 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 perception pain, 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.

Effect 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. Basic side effects, the following.

Expressiveness side effects depends on the dose and duration of use.

Contraindications

An absolute contraindication is increased sensitivity 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 promptly, 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 intravenous administration- 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. Catheterization is also performed in the hospital 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 Civil War in the United States, the harmful dependence on this painkiller turned into an army disease, affecting 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, they develop withdrawal syndrome. 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.

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

1 capsule of extended release contains 10 mg of Morphine.
Morphine Formula: C17-H19-N-O3.

Release form

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

Extended-release capsules are produced in cardboard packs (10 pieces per pack).

pharmachologic effect

What is Morphine?

Morphine is opioid pain reliever , drug . According to the mechanism of action, the drug is an opioid receptor agonist. The drug has anti-shock effect , reduces the excitability of pain centers. The hypnotic effect occurs when high dosages are prescribed.

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 and biliary tract; depresses the respiratory center, reduces body temperature, slows down metabolism, suppresses the secretory activity of the digestive system, stimulates the production of ADH.

Effect on the brain

Excitation of chemoreceptor trigger zones in the medulla oblongata leads to activation of the gag reflex. After subcutaneous administration, the medication begins to act within 10-15 minutes. The effective action of extended-release capsules is registered after 20-30 minutes.

Pharmacodynamics and pharmacokinetics

After subcutaneous administration and capsules taken orally, the drug is quickly absorbed and enters the systemic circulation. When taken orally, the absorption rate reaches 80%. The drug has a “first pass” effect through the hepatic system. Thanks to conjugation with glucuronides, it is complete 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 excreted from. Elderly patients are characterized by an increase in T1/2 (similar to pathologies of the renal system and liver).

Indications for use

Morphine - what is it? This is a narcotic analgesic prescribed to relieve severe pain in:

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

The drug can be prescribed for severe shortness of breath caused by insufficiency of cardio-vascular system; for a cough that cannot be controlled with antitussive medications.

Contraindications

• traumatic brain injuries;
• 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;
• hepatic cell failure;
• treatment with MAO inhibitors;
• age limit – up to 2 years.

Side effects

Urinary tract:

Impaired urinary outflow 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;
• stimulating effect;
• sedative effect;
• development ;
• delirium.

Morphine, instructions for use (Method and dosage)

Instructions for use of Morphine hydrochloride

Individual dosage regimen. 1 mg is administered subcutaneously. Further dose selection is carried out based on the severity of the pain syndrome.

Taking capsules

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

Overdose

Poisoning manifests itself in a unique clinical picture (acute and chronic overdose):

• sticky, cold sweat;
• fatigue;
• a fall ;
• confusion;
• difficult, slow breathing;
• bradycardia;
• miosis;
• expressed;
• bradycardia;
• delirious psychosis;
• dry mouth;
• anxiety;
• intracranial hypertension;
• respiratory arrest;
• muscle rigidity;
• coma.

Treatment

A specific antagonist is urgently administered intravenously at a dose of 0.2-0.4 mg. After 2-3 minutes, the injection is repeated until the total amount of 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 and restore the functioning of the respiratory system and heart.

Interaction

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

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

Clinical treatment of alcoholism

This drug was first formed in early XIX centuries. The synthesis was carried out by a German chemist. Despite the fact that its origins were at the beginning of this century, the popularity of morphine occurred in the middle of the century by 1857. This happened when a syringe was first developed with which this drug was injected into the body. The German scientist who discovered morphine considered it a wonderful sleeping pill. That is why the substance was named after the god Morpheus. The presented remedy could easily replace opium, so it was widely used in the treatment of opium addiction. The beneficial effect of use led to the fact that the negative aspects of this drug were not immediately identified. It should be noted that the creator of this drug himself suffered from it. negative impact. Only at the end of his life did he realize that it was morphine that was causing his illness. By 1874, it was discovered that addiction to this substance was even stronger than to opium, which is why the term “morphinism” appeared, meaning addiction to this drug. In addition, it should be noted that addiction on a psychological level occurs much faster than physical cravings.

Indications

Features of alcohol addiction treatment

When it comes to morphine, it cannot be said unequivocally that it is useful or dangerous. This remedy is still widely used for medical purposes. Morphine is available in the form of tablets, ampoules or syringe tubes. The injection format is the most common. The drug can be administered different ways. The doctor decides which method to use in a particular case.

• There is severe pain that can be present in patients due to injury, cancer and heart attack.
• When there is severe shortness of breath or cough caused by heart failure.
• When a person is prepared for surgery or helped to recover after surgery.
• In case of insomnia, especially if it is caused by pain.
• When X-ray diagnostics of the intestine is performed to identify tumors and ulcers.