ABOUT NON-NARCOTIC ANALGESICS-ANTIPIRETICS (Part 1)

Opioid analgesics in our country remain the most problematic and odious drugs. Almost every doctor has examples from life when, due to the illegal use of drugs, prosperous families broke up and the destinies of loved ones collapsed. Perhaps that is why, when we have to prescribe a strong opioid analgesic, we internally resist to the last, fearing to make the patient drug dependent, and also do not want unnecessary red tape with the registration of a prescription. But there are conditions when we cannot do without narcotic drugs - severe pain syndrome, which cannot be controlled with more accessible drugs in oncological (and non-oncological) patients. Hesitation and sentiment are inappropriate here; it is necessary to quickly and accurately select a drug that will allow complete pain control and cause the least harm to the patient. For this purpose, many different non-invasive opioid agents have long been created. In general, about 60 dosage forms of opioid drugs are used in the EEC countries (excluding combined forms, for example, codeine + paracetamol, etc.). In Russia, only 6 non-invasive forms of opioid analgesics are currently used for the treatment of chronic pain:

- morphine sulfate - extended-release tablets (12 hours);

- morphine sulfate - extended-release capsules (12 hours);

— transdermal therapeutic systems (TTS) of fentanyl (72-hour patch);

- propioniphenylethoxyethylperidine (prosidol) - cheek tablets;

- tramadol hydrochloride in tablet form;

- tramadol hydrochloride in capsule form.

In fact, when prescribing strong opioids, there were previously only two INN drugs to choose from: extended-release morphine (MCT-Continus tablets or morphine sulfate capsules) or fentanyl TTC (Fendivia, Durogesic).

In 2021, another drug entered our country and began to be used - oxycodone + naloxone (Targin), which was registered in Russia in 2015.

To correctly choose which of the three drugs should be preferred in each clinical situation, it is necessary to study in more detail all the features, advantages and disadvantages of each of them.

Morphine

General information.

Opium and its derivatives have been used medicinally for more than 5 thousand years, and maybe much more, since poppy seeds were discovered by archaeologists during excavations of Neanderthal settlements, the age of which is estimated at 30 thousand years. The use of opium in medicine is described in the history of all outstanding ancient civilizations: Egyptians, Sumerians, Indians, Persians, Greeks, Romans. Paracelsus, who practiced in Europe in the Middle Ages, created his famous “magic elixir” - Laudanum, containing opium juice, and actively used it in adults and children: for pain, insomnia, cough, diarrhea, etc. German chemist Friedrich Serturner from Hanover in 1803 isolated a pure substance from opium juice, which he named morphine in honor of the god of dreams - Morpheus. This is where the scientific history of all opioid drugs began. Now morphine is the gold standard in pain therapy, since it is the most studied and its effect is accepted as the standard when comparing the effect of other opioid drugs. For example, hydromorphone has an equianalgesic ratio to morphine of 7-8/1, that is, hydromorphone is 7-8 times stronger than morphine; accordingly, the ratio of tramadol to morphine is 0.2-0.1/1, i.e. morphine is at least 5 times stronger than tramadol [1].

Pharmacology.

Pharmacologically, morphine is a true agonist predominantly of μ-opioid receptors, acting on both of their subtypes (μ1 receptors cause analgesia, μ2 receptors cause central respiratory depression, hypotension and constipation). Morphine is not absorbed from the oral cavity and is characterized by rather low bioavailability when taken orally. According to various sources, from 20 to 50% (on average 30%) of the drug enters the systemic circulation due to low intestinal adsorption, as well as pronounced parietal metabolism and the “first pass effect” through the liver. Morphine is characterized by a low degree of binding to blood proteins - 20-35%. Metabolism of the drug mainly occurs in the liver and kidneys with the formation of active metabolites, the main of which are: morphine-3-glucuronide and morphine-6-glucuronide. It is believed that morphine-6-glucuronide is 20-45 times more active than the main substance. In addition to these substances, codeine is produced in small quantities during metabolism.

Although the main metabolism of morphine occurs in the liver, liver failure has almost no effect on the processes of glucuronidation, and morphine is well tolerated by patients until the development of a precoma state. Metabolites of morphine are excreted mainly in the urine, no more than 7-10% of its metabolic products are excreted in bile, less than 10% are excreted unchanged by the kidneys. The elimination processes are not impaired even in patients with renal failure, however, the active metabolite of morphine (morphine-6-glucuronide) can accumulate when the excretory function of the kidneys decreases, this causes a prolongation of the action of a single dose, as well as sedation and respiratory depression. Therefore, other opioid drugs should be selected in patients with moderate to severe renal impairment.

In medical practice, only water-soluble morphine salts (sulfate and hydrochloride) are used, which poorly penetrate the blood-brain barrier. This is due to the extremely low lipophilicity of the drug, which leads to a significant difference in the concentration of morphine in the central nervous system (CNS) and in the liver, muscles, and blood, therefore, a high concentration of morphine in the blood plasma can lead to errors in forensic examination (in particular when determining the cause of death).

Drug Interactions and Cautions

Morphine enhances the effect of hypnotics, sedatives, local anesthetic drugs, drugs for general anesthesia and anxiolytics.

When used simultaneously with cimetidine, muscle relaxants, ethanol, and CNS depressants, respiratory depression is possible. Barbiturates, especially phenobarbital (when used systematically), reduce the severity of the analgesic effect of morphine due to the development of cross-tolerance. β-blockers increase the inhibitory effect of morphine on the central nervous system. Combined use with other opioid analgesics, barbiturates and phenothiazine derivatives can cause respiratory depression, central nervous system depression, and a decrease in blood pressure. Chlorpromazine enhances the miotic, sedative and analgesic effects of morphine. The antagonists are naloxone and naltrexone, which are administered in cases of morphine overdose.

Drugs with anticholinergic activity, drugs with antidiarrheal action (including loperamide) significantly increase the risk of developing constipation (up to intestinal obstruction), and also contribute to urinary retention. Metoclopramide, on the contrary, reduces the effectiveness of morphine [2].

Application

Morphine is produced in many countries in a wide variety of non-invasive forms: suppositories, tablets, capsules, solution or syrup for oral administration. Capsules and tablets are produced in two types: fast-acting and extended-acting (12 or 24 hours). There are rapid-release forms of drugs that allow you to more accurately prescribe (titrate) the required and safe dose for the patient (such forms have not yet been registered with us).

According to WHO recommendations, as well as national recommendations of the USA, Canada, Great Britain and some other countries, the oral route of drug administration is preferable, starting from the second stage (for moderate pain), if possible. Drugs should be administered in the most effective, convenient, and least painful manner [3–7].

In our country, extended-release morphine sulfate tablets (MCT-Continus) (up to 12 hours) and extended-release morphine sulfate capsules (for taking the drug 2 times a day) are registered and used for the treatment of chronic pain. Safety in the use of MCT-Continus is ensured by the gradual, artificially delayed release of the drug (within 12 hours) from the retard tablet, where morphine is placed on a hydroxyalkyl cellulose matrix and comes from this depot at a constant rate, regardless of food intake and the level of gastric or intestinal acidity content. This eliminates peak toxic concentrations of morphine in the blood, which are the cause of dangerous side effects of opioids. The drug is supplied to our country in doses of 10, 30, 60, 100 mg per tablet. The 200 mg dose, which is used abroad, has not yet been registered with us.

Extended-release morphine sulfate capsules have comparable characteristics and are available in the same dosages, but have benefits for patients who are unable to swallow food or are fed through a gastrostomy tube. The capsule consists of microgranules that take 12 hours to dissolve and can be mixed with liquid food for insertion into the stoma. In pediatric oncology practice, 10 mg capsules can be used in children who have a body weight of 20 kg and above, mixing the contents of the capsule with a pleasant meal.

It is generally accepted that morphine is used for severe pain. However, recent studies indicate that there is compelling evidence that low-dose morphine (less than 30 mg/day orally) is more effective in treating moderate cancer pain syndrome with low doses of morphine (less than 30 mg/day orally) compared with conventional doses of weak opioids. Moreover, patients receiving morphine had a significantly better quality of life, and the severity of adverse effects was the same [3, 8].

In what cases should low-dose morphine be prescribed for the treatment of moderate pain? If we refer to the WHO recommendations, then if non-opioid drugs (paracetamol or NSAIDs) are ineffective, a weak opioid - codeine or tramadol - should be prescribed. Since there are no medications containing codeine in the required doses for the treatment of moderate pain in Russia, the only drug is tramadol. Tramadol is 5-10 times weaker than morphine and its molecule does not have analgesic properties. Tramadol as a “prodrug” must pass through the liver, where, after its biotransformation under the control of cytochrome P4502D6, two enantomers are formed: the (+) isomer is a pure agonist of opioid receptors (mu- and kappa), and the (–) isomer inhibits the neuronal uptake of serotonin and norepinephrine , activating the central descending noradrenergic system.

However, it has long been established that tramadol (like codeine) is not effective in all patients. This is associated with a pronounced genetic polymorphism of cytochrome P4502D6: in 6% of the population (Caucasian type), who have naturally increased activity of this cytochrome system, the effect of tramadol will be significantly higher, and in 8-10% of people in whom this enzyme is weakened, pain relief will be ineffective [9].

Thus, almost one in ten patients may have insufficient response to pain relief with tramadol (or codeine), and this will be an indication for switching to low doses of strong opioid drugs.

According to the recommendations of the European Association for Palliative Care in 2012, for moderate pain it is advisable to use oral morphine at a dose of up to 40 mg per day as an alternative to weak opioid drugs [3].

In our country, tablets or capsules of extended-release morphine of 10 mg can be used for this purpose, which should be prescribed starting with 1 capsule, and if the effect is insufficient, then 2 capsules twice a day. Additionally, in the absence of contraindications, NSAIDs or other non-opioid pain therapies, including available non-pharmacological methods, can be used as a daytime analgesic.

In our own clinical practice, we have already begun to use this therapy option and can note that it is quite effective. In 5 patients with moderate pain due to metastatic bone lesions, we used only 1-2 capsules of morphine 10 mg at night, since the pain was bothersome at night, and tramadol was effective for only 4-6 hours. This dose was enough for 10-12 hours, and During the day, patients took NSAIDs. If antitumor drug therapy was effective, then the pain decreased and morphine was discontinued, and if the tumor process progressed, then the dose of morphine, on the contrary, was gradually increased. There were no significant adverse effects (requiring discontinuation of the drug). At the beginning of therapy (2 days), 2 patients had mild nausea, 1 patient had morning dizziness after a single evening dose of 20 mg of morphine. When the dose was reduced to 10 mg, the dizziness stopped. The only significant inconvenience that patients noted was the appearance or worsening of stool retention - constipation. To prevent them, lactulose or herbal laxatives were prescribed. In accordance with the order of the Ministry of Health of the Russian Federation No. 1175n dated December 20, 2012, upon discharge from the hospital, the patient, if necessary, can purchase the drug at the pharmacy with a prescription. To do this, he is issued a special prescription form, form No. 107/u-NP, for prescribing narcotic drugs. According to the INN, morphine tablets or capsules should be prescribed as follows:

Rp:Tab. Morphini 0.03 No. 40 (forty)

S: 1 table each. 2 times

Table 2. Recommended dose of TTC fentanyl depending on the daily oral dose of morphine per day
Rp: Caps. Morphini 0.03 No. 40 (forty)

S: 1 caps. 2 times a day

It is acceptable to indicate the dose of the drug in milligrams: Tabl. Morphini 30 mg. The number of tablets (capsules) must be indicated both in numbers and in words. The amount of the drug that a doctor has the right to prescribe on one form is presented in table. 1.

Table 1. Maximum permissible amount of morphine sulfate tablets and capsules per prescription* Note. * - the table is compiled in accordance with the standards set out in Appendix No. 1 of Order of the Ministry of Health of the Russian Federation No. 1175n dated 12/20/12 with amendments and additions dated 12/02/13, 06/30/15, 04/21/16; ** - the number of prescribed narcotic and psychotropic drugs of lists II and III of the List, other drugs subject to subject-quantitative recording, when providing palliative care to patients, can be increased by no more than 2 times compared to the maximum permissible amount of drugs for prescribing for one prescription, established by Appendix No. 1 to Order No. 1175n of the Ministry of Health of the Russian Federation. from 12/20/12.

It should be noted that all cancer patients, regardless of the intensity of pain (moderate or severe) and the prognosis of the disease, are afraid of being prescribed morphine. The odiousness, rumors and “evil fame” of the very name of the drug were so ingrained in the minds of patients and doctors that everyone forgot (and some did not know) about its beneficial properties. In the textbook from 1904 “Fundamentals of Pharmacology”, the author of which is the outstanding Russian pharmacologist N.P. Kravkov, there is a large section devoted to morphine and its preparations. Tincture of opium ( Tinctura opii simplex

;
Tinctura opii benzoica,
etc.) doctors used to treat diarrhea, irritability, severe shortness of breath, insomnia, cramps, uncontrollable cough, etc. Of course, at present there is no particular need for opium tincture, but for cancer pain we will be using morphine for a long time. Therefore, now at the reception we have to confidently and calmly explain to patients that morphine is poorly absorbed; out of 10 mg of the drug, only 3 mg will enter the body. As a rule, patients had previously taken similar medications, for example, Pentalgin-Neo, containing codeine (for headaches) or Terpincode for an indomitable cough. From each tablet containing 8-10 mg of codeine, about 1 mg of morphine is formed in the patient’s body after transformation in the liver, which reduces pain.

Despite this, many patients associate the prescription of morphine with imminent death and prefer pain relief with any other drug rather than receiving morphine. Taking into account patient preference, in the absence of contraindications, another strong opioid analgesic may be prescribed.

The causes of toothache are various dental diseases:

• caries - bacterial destruction of hard tooth tissues. The pain is minor, mainly occurs when brushing teeth, when exposed to cold or hot food;
• pulpitis - inflammation of the neurovascular bundle, which is accompanied by severe excruciating pain, intensifying at night;
• periostitis - purulent inflammation of the periosteum, severe, throbbing pain;
• periodontitis - suppuration of the soft tissues around the root of the tooth, intense pain;
• injuries, cracks cause damage to the crown of the tooth, which leads to nerve exposure and aching pain;
• hypersthesia - increased sensitivity of the tooth to external irritants, pain appears when the tooth comes into contact with hot, cold, sour food;
• eruption of wisdom teeth, pericoronitis - aching, pulling toothache that affects the jaw and cheeks.

Conventionally, all types of painkillers for toothache are divided into 2 groups.

TTC fentanyl

General information.

The history of fentanyl is only 57 years old. In 1959, it was synthesized by the German chemist Paul Janssen, and since 1960 it has been used for anesthesia during surgery [1].

The drug has the highest analgesic potential, it is 75-100 times superior to morphine, and has a low molecular weight, which distinguishes it favorably from morphine. When administered intravenously, it begins to act within 15 s, which is due to its high lyophilicity and immediate entry into the central nervous system. For a long time, the drug was used only in anesthesiology for neuroleptanalgesia. Low molecular weight and high lipophilicity made it possible to create a new dosage form for the treatment of chronic pain in the 90s of the last century - fentanyl TTC. The first generation of TTCs were very flawed, as they were made in a “ravioli” style and contained a gel with a high concentration of fentanyl. After application to the skin, the drug entered the subcutaneous fat through a semi-permeable membrane and then into the systemic bloodstream. If the membrane or outer wall of the TTC is defective, fentanyl gel could leak and cause an overdose or other adverse effects. Later, matrix-type TTCs (2nd generation) were created, which do not have this defect, where fentanyl is “embedded” in the polymer matrix in such a way that even if it is cut, the substance will not come out. In our country, 2 matrix-type fentanyl TTS drugs are registered and supplied: durogesic-matrix (Janssen-Cilag) and fendivia (Takeda Pharmaceuticals). TTS fendivia has some design differences. These patches (3rd generation) contain a smaller volume of the active substance - fentanyl, which is distributed in the matrix in the form of microdrops, therefore fendivium TTCs have a lower fentanyl content and smaller area than durogesic TTCs with the same pharmacokinetics.

Features of the pharmacology of fentanyl

Since fentanyl is a highly active opioid drug, many foreign guidelines do not recommend the use of fentanyl TTC in opioid-naive patients (those who have not previously taken opioids) [10-13].

Before using TTC fentanyl, each patient is first advised to individually select the required amount of oral immediate release morphine, which will reduce pain to an acceptable level (from 0 to 20% on the numerological scale). In accordance with the selected daily dose of morphine, the dose of TTS fentanyl is calculated using the table of equivalents. The daily dose of morphine is determined in the same way before prescribing prolonged forms of the drug [14] (Table 2).

Given that fentanyl is significantly less constipating than morphine, when switching from morphine to fentanyl, the dose of the laxative should be halved and then adjusted according to need. In some cases, when switching from oral morphine to fentanyl TTC, patients experience withdrawal symptoms (eg, diarrhea, colic, nausea, sweating, restlessness) despite adequate pain relief. This is likely due to the differential effects of drugs on peripheral and central opioid receptors. Such symptoms can be relieved with small doses of morphine over several days [15–17].

Important advantages of TTC fentanyl over enteral forms of morphine are less severe constipation, a slight effect on the sphincter of Oddi, and the absence of active metabolites, which makes it possible to use in patients with renal or hepatic insufficiency.

The bioavailability of fentanyl from TTC is highly variable. The indicated drug doses in mcg/hour usually reflect the average amount of drug delivered to the patient during the time prescribed for TTC use. Of course, different patients have individual characteristics of drug diffusion, which will determine its entry into the systemic circulation. For example, for TTC 100 mcg/h, the average (±SD) delivery is 97 (±15) mcg/h, and the amount of unused fentanyl in the patch after 3 days can vary from 30-85% of the original contents [18, 19].

In patients in a state of cachexia, the concentration of fentanyl in plasma decreases by 1/3 - 1.2, which is likely due to the depletion of subcutaneous fat, as well as a decrease in skin hydration [20, 21].

Drug interactions

Fentanyl is metabolized via CYP3A4. Therefore, with the simultaneous use of drugs that inhibit this cytochrome (fluconazole, voriconazole, cimetidine, macrolide antibiotics: erythromycin, clarithromycin, grapefruit juice), the plasma concentration of the drug increases (the breakdown of fentanyl in the liver is inhibited), and carbamazepine, phenytoin, phenobarbital, rifampicin induce CYP3A4 activity, accordingly reducing the effectiveness of fentanyl due to increased metabolism.

Cautions

Modern matrix-type patches are not recommended to be cut, although in theory this is safe and does not cause problems. After registration and the appearance of TTS in a minimum dose of 12 mcg/h, titration became quite accurate, and, according to foreign authors, there is now no need to cut them [6].

Permitted starting doses for TTC fentanyl as a strong opioid in the UK are 12-25 mcg/h depending on prior therapy, and 12 mcg/h is considered the safest starting dose for fully opioid-naive patients and for some debilitated patients receiving low doses of weak drugs. opioid for moderate pain. Adverse effects (nausea and vomiting) are more common in opioid-naive patients. To prevent side effects, it is not recommended to increase the TTC dose daily [22].

The 2012 European Association for Palliative Care guidelines specifically address the use of fentanyl TTC and buprenorphine TTC, stating that experts found no significant differences in effectiveness between transdermal products and other opioids, but that TTC was superior in terms of risk development of constipation and patient preferences. This suggests that, in some cases, opioids in the form of TTCs are convenient and effective pain relievers in patients who have not previously received 3rd step opioids [3].

The Russian national clinical guidelines “Chronic pain syndrome (CPS) in adult patients in need of palliative care” recommend the use of TTC as a treatment of choice in patients who, for various reasons, cannot be prescribed drugs orally or transmucosally (buccally or sublingually), for example , with mucositis, ulcerative or tumor lesions of the oral mucosa, dysphagia, as well as with constant pain. The exception is patients with severe cachexia, increased sweating and impaired skin integrity [23].

Since fentanyl TTS appeared in our country in 2002, in the absence of morphine in immediate-release tablets for preliminary titration of the opioid, having studied the experience of foreign colleagues, we began to use fentanyl TTS when tramadol 300-400 mg/day or propioniphenylethoxyethylpiperidine (Prosidol) tablets were insufficiently effective. 20-60 mg/day as drugs of the 2nd step of the WHO ladder [24, 25].

In our clinical practice, we used fentanyl TTS, starting with a dose of 25 mcg/h, gradually increasing it, if necessary, every 3 days by 25 mcg/h, which ensured safety and the absence of cases of drug overdose. In our opinion, the opioid analgesic propioniphenylethoxyethylpiperidine (Prosidol) in buccal tablets 20 mg or morphine hydrochloride 1% 5 mg intramuscularly or subcutaneously can be used as a subsidy drug when using fentanyl TTC. Due to its pharmacological properties, Tramadol is not recommended for use as a subsidized drug due to its poor effectiveness and drug interactions at the level of cytochrome P450. Our positive experience with the use of low doses of TTC fentanyl 12.5 mcg/h indicates the feasibility of this practice in patients with moderate pain due to oropharyngeal tumors who are unable to take oral medications, as well as with poor tolerability of tramadol (Table 3)

Table 3. Maximum permissible amount of fentanyl TTC per prescription* Note. * - the table is compiled in accordance with the standards set out in Appendix No. 1 of the order of the Ministry of Health of the Russian Federation dated December 20, 2012 No. 1175n with amendments and additions from: 12/02/13, 06/30/15, 04/21/16. [26].

Prescribing the drug on a prescription form

The drug is prescribed on a prescription form No. 148−1/u-88, No. 148−1/u-04 (l), No. 148−1/u-06 (l).

According to the INN, fentanyl patches should be prescribed as follows:

Rp: TTS Fentanyli 25 mkg/h No. 10 (ten)

S: 1 patch for 3 days

The maximum amount of the drug prescribed on one prescription form can be increased when providing medical care to patients, but not more than 2 times.

OTC analgesics-antipyretics for oral administration: mechanism of action and safety profile

Analgesic-antipyretics (AAs) are among the most commonly used drugs in the world. The leading place in sales is occupied by over-the-counter drugs (OTC drugs, over-the-counter, OTC-AA): acetylsalicylic acid, ibuprofen, metamizole, paracetamol. These analgesics are used for the symptomatic treatment of headache, toothache, dysmenorrhea, fever, etc.

Both therapeutic and side effects of AA are associated with inhibition of a key enzyme in arachidonic acid metabolism, cyclooxygenase (COX) [1]. As a result of this metabolism, under the influence of COX, prostaglandins are formed from arachidonic acid, and under the influence of another enzyme, lipoxygenase, leukotrienes are formed (Fig.) [2]. Prostaglandins are the main mediators of inflammation, because they [3]:

• sensitize nerve endings to the action of other inflammatory mediators (histamine, bradykinin, etc.);
• increase vascular permeability and cause vasodilation, which leads to the development of local vascular reactions;
• are chemotaxis factors for a number of immunocompetent cells, which contributes to the formation of inflammatory exudates;
• increase the sensitivity of the hypothalamic thermoregulation center to the pyrogenic effect of interleukin-1, which leads to the development of a febrile reaction.

Prostaglandins are not only involved in the process of inflammation as one of its mediators, but also play an important role in the functioning of the gastrointestinal tract, cardiovascular system, kidneys and other vital organs and systems [4]. By inhibiting the biosynthesis of prostaglandins, AA not only lead to a decrease in the inflammatory or pain response, but also to the development of adverse reactions from these systems. Not so long ago, reports began to appear about another property of AA - their antitumor activity [5]. Thus, a reduction in the risk of developing carcinoma of the rectum and esophagus has been shown with regular long-term use of Aspirin [6, 7].

Currently, there are three isoforms of COX - COX-1, COX-2 and COX-3. COX-1 is constitutive, has the functional activity of a structural enzyme, is constantly present in cells, catalyzing the formation of prostaglandins that regulate physiological functions in various organs, for example, in the mucous membrane of the stomach and bronchi, in the kidneys. COX-2 is an inducible isoform because it begins to function and its content increases during inflammation. COX-2 levels are low under normal conditions and increase under the influence of cytokines and other anti-inflammatory agents. It is believed that it is COX-2 that takes part in the synthesis of “pro-inflammatory” prostaglandins, which potentiate the activity of inflammatory mediators, such as histamine, serotonin, and bradykinin [8]. In this regard, it is assumed that the anti-inflammatory effect of AA is due to the inhibition of COX-2, and the adverse reactions are due to COX-1. COX-3 functions in the structures of the central nervous system. Studies have shown that the activity of this enzyme is inhibited by antipyretic drugs, such as paracetamol, phenacetin, antipyrine, analgin. Thus, COX-3 inhibition may represent a major central mechanism by which these drugs reduce pain and possibly fever [9].

The developed selective COX-2 inhibitors have significantly fewer side effects than non-selective AA, but they are not over-the-counter drugs. Paracetamol has a fundamentally different mechanism of action than other OTC-AAs, which even in small doses selectively inhibits the COX-3 isoform in the structures of the central nervous system and does not affect COX in peripheral tissues, which distinguishes this drug from other AA in terms of its therapeutic safety profile and side effects [10]. In particular, the drug does not have an ulcerogenic effect, does not provoke the development of bronchospasm, does not provide antiplatelet or tocolytic effects, but it has virtually no anti-inflammatory effect.

Side effects of AA

AA have a number of reliably recorded side effects:

• ulcerogenic;
• hematotoxic;
• allergic;
• Reye's syndrome;
• hepatotoxic;
• influence on the cardiovascular and respiratory systems.

The relative risk of developing side effects of AA varies (Table 1). As follows from the table, paracetamol has the lowest risk of side effects. Metamizole most often causes the development of agranulocytosis, which led to a ban on its use in most countries of the world. Usually among the side effects of AA, the first place in frequency of occurrence is occupied by ulcers of the gastrointestinal tract (primarily the stomach) and bleeding from them. According to gastroscopy, the incidence of ulceration of the gastrointestinal tract after taking AA can reach 20% [12].

The development of the ulcerogenic effect of AA is associated with the suppression of the activity of COX-2, localized in the mucous membrane of the gastrointestinal tract. As a result, the biosynthesis of prostaglandins is reduced, which leads to a decrease in the production of bicarbonates and mucus and an increase in the secretion and reverse diffusion of hydrogen ions [14]. These side effects most often occur in patients at risk:

• taking AA for a long time or taking large doses of these drugs;
• having a history of peptic ulcer disease;
• over 60 years old;
• simultaneously receiving glucocorticoids or anticoagulants;
• infected with H. pylori;
• having severe concomitant diseases (for example, congestive heart failure);
• alcohol abusers.

The developed rapidly soluble or enteric forms of acetylsalicylic acid were supposed to reduce the incidence of ulcers of the gastrointestinal tract. However, clinical trials have not revealed a significant reduction in the incidence of this side effect [15]. Probably, the observed result is associated with inhibition of COX in the mucous membranes of the gastrointestinal tract, not only during the local action of AA, but during their persistence in the blood.

The most severe complication when using OTC-AA is hematotoxicity. The use of metamizole increases the risk of developing agranulocytosis by 16 times. Therefore, its use is prohibited in more than 20 countries around the world. However, the drug is still used in the Russian Federation. However, there is an opinion that the risk of developing metamizole-induced agranulocytosis is exaggerated, and the most serious side effect of this drug is its cardiotoxic effect [16].

A rare but serious side effect when using acetylsalicylic acid is Reye's syndrome. It is characterized by severe encephalopathy and fatty liver degeneration. It usually occurs in children (with a peak incidence at 6 years of age) after viral infections [17]. With the development of Reye's syndrome, there is a high mortality rate, which can reach 50%.

Effect on the cardiovascular system

Numerous studies have found that short-term use of AA does not pose a significant risk of developing hypertension or an increase in cardiovascular disease in healthy individuals. However, the use of all AA, except paracetamol, significantly increases the risk of developing heart failure in patients with arterial hypertension and the elderly [18, 19].

All OTC-AAs, except paracetamol, affect blood clotting, but this effect is variable. Aspirin is more selective for COX-1 than for COX-2, so at low doses it selectively inhibits the formation of thromboxane A2 without affecting the biosynthesis of prostaglandin I2. In addition, unlike other AA, Aspirin is more selective towards platelet COX-1. Its action in small doses is based on the selective inhibition of thromboxane synthesis, which, accordingly, reduces platelet aggregation. Thanks to this property, Aspirin significantly reduces the likelihood of sudden cardiac death, myocardial infarction and stroke among patients at risk [20].

Unlike Aspirin, other “traditional” AA inhibit both COX-1 and COX-2, i.e., the biosynthesis of both thromboxane A2 and prostaglandin I2. The effect of these drugs on the prevention of thrombosis has not been established.

By blocking the biosynthesis of prostaglandins in the kidneys, all OTC-AAs, except paracetamol, affect water and electrolyte balance and can have a hypertensive effect. In addition, due to the effect on the renal biosynthesis of prostaglandins, the likelihood of interaction of AA with β-blockers, diuretics, ACE inhibitors and other antihypertensive drugs increases sharply.

Effect on the respiratory system

The effect on the respiratory system of AA is observed in individuals with the so-called. aspirin variant of bronchial asthma [21]. The pathogenesis of the disease is associated with inhibition of bronchial COX-2 under the influence of all OTC-AAs, except paracetamol. As a result, the biosynthesis of leukotrienes increases, causing the development of attacks of expiratory dyspnea. This effect is most pronounced with acetylsalicylic acid. The disease is characterized by a triad of symptoms:

• polypous rhinosinusitis;
• attacks of suffocation;
• intolerance to non-steroidal anti-inflammatory drugs (NSAIDs).

Aspirin-induced asthma can be combined with atopic asthma, but it can also occur in isolation. This disease most often occurs between the ages of 30 and 50 years. Women get sick more often than men. The incidence of aspirin-induced asthma can reach 40% of bronchial asthma diseases.

Adverse reactions from the skin

Nonsteroidal anti-inflammatory drugs can cause or worsen psoriasis. However, there is no clear connection between the use of Aspirin and the occurrence of psoriasis and psoriatic arthritis. However, long-term use of paracetamol and other AA (except Aspirin) may increase the risk of developing psoriasis and psoriatic arthritis [22].

In addition, negative reactions when using AA in the form of urticaria/Quincke's edema are not uncommon, although these reactions to paracetamol are quite rare [23].

Use of AA during pregnancy

Classic non-selective COX inhibitors, including Aspirin, do not increase the risk of congenital malformations in humans. However, their use in the second half of pregnancy may affect pregnancy and the fetus due to the fact that prostaglandin inhibitors have vascular effects, in particular, they can cause narrowing of the fetal ductus arteriosus and a decrease in renal blood flow. Therefore, treatment with COX inhibitors should be stopped at 32 weeks of pregnancy. The ability of AA to inhibit ovulation and induce miscarriage is still under debate [24].

The safest analgesic for pregnant women is paracetamol [23].

Compared to other AA, paracetamol has the widest range of therapeutic safety and the fewest side effects. It does not cause ulcer formation, does not have a tocolytic effect, does not affect the cardiovascular system, does not inhibit bone marrow hematopoiesis, does not cause the development of bronchospasm, is well tolerated during pregnancy, allergic reactions occur rarely [23]. However, paracetamol has side effects that are not typical for other AAs. This is a hepatotoxic effect that occurs during an overdose of the drug, due to the fact that it does not have time to bind to glucuronic acid [25].

Due to the widest therapeutic safety profile of paracetamol, it is the drug of first choice in the treatment of febrile conditions in children. It is prescribed in a single dose of 10–15 mg/kg and a daily dose of up to 60 mg/kg [26].

OTS-AA interactions

In general, OTC-AA is usually characterized by the presence of a small number of drug interactions (Table 2). Paracetamol has the least number of drug interactions, and acetylsalicylic acid has the most. Its main interactions are associated with changes in urine pH, which leads to impaired elimination of many drugs.

Dosages used, drug selection algorithm

As follows from the data presented in the article, paracetamol can be considered as the drug of first choice as an antipyretic OTC-NSAID, since this drug is less likely to cause side effects than other drugs in this group, which is due to the peculiarities of its mechanism of action ( selective inhibition of COX in the CNS). In addition, the drug has the least number of drug interactions and can be used even in childhood.

In recent years, there has been a revision of the commonly used doses of paracetamol. Traditionally, in adults the drug is prescribed in a dose of 500–650 mg per 1 dose per os, 3–4 doses per day. However, the results of a study conducted on 500 patients were recently reported. It has been shown that a single dose of 1 g of the drug is more effective than 650 mg. However, when the drug was prescribed 4 times a day, the incidence of side effects was the same [27]. Thus, the following paracetamol dosage regimen can be recommended: 1 g per dose, 4 doses per day.

If paracetamol is ineffective or intolerant, the next drug of choice among OTC-AAs is ibuprofen [28]. Many studies have shown that the safety and effectiveness of ibuprofen is comparable to that of newer AA (coxibs), especially when used long-term (more than 6 months). In addition, for mild to moderate pain, ibuprofen was often more effective than paracetamol as both an analgesic and an antipyretic [29]. Usually in adults the drug is used in a dose of 400–600 mg per os 3–4 times a day.

If ibuprofen is ineffective or intolerable, acetylsalicylic acid or metamizole is prescribed orally at a dose of 500–1000 mg 2–3 times a day or 250–500 mg 2–3 times a day, respectively.

Literature

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2. Vane JR Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs // Nature New Biol. 1971; 231:232–235.
3. Weissmann G. Prostaglandins as modulators rather than mediators of inflammation // J. Lipid Med. 1993; 6:275–286.
4. DuBois RN, Abramson SB, Crofford L. et al. Cyclooxygenase in biology and disease // PASEB J. 1998; 12: 1063–1073.
5. Suthar SK, Sharma N., Lee HB, Nongalleima K., Sharma M. Novel dual inhibitors of nuclear factor-kappa B (NF-κB) and cyclooxygenase-2 (COX 2): synthesis, in vitro anticancer activity and stability studies of lantadene-non steroidal anti-inflammatory drug (NSAID) conjugates // Curr Top Med Chem. 2014; 14 (8): 991-10-04.
6. Li P., Cheng R., Zhang S. Aspirin and esophageal squamous cell carcinoma: bedside to bench // Chin Med J (Engl). 2014; 127(7):1365–1369.
7. Schrör K., Rauch B. Aspirin in primary and secondary prevention of colorectal carcinomas // Med Monatsschr Pharm. 2013, Nov; 36 (11): 411–421.
8. Sturov N.V., Kuznetsov V.I. Clinical and pharmacological characteristics of NSAIDs for a general practitioner // Zemsky Vrach. 2011. No. 1. pp. 11–14.
9. Chandrasekharan NV, Dai H., Roos KL, Evanson NK, Tomsik J., Elton TS, Simmons DL COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression // Proc . Natl. Acad. Sci. USA. 2002, Oct 15; 99(21):13926–13931. Epub. 2002, Sep 19.
10. Gorchakova N. A., Gudivok Ya. S., Gunina L. M. et al. Pharmacology of sports. K.: Olympus. l-ra. 2010. 640 p.
11. Rainsford K., Willis C. Relationship of gastric mucosal damage induced in pigs by antiinflammatory drugs to their effects on prostaglandin production // Dig. Dis. Sci. 1982; 27:624–635.
12. Roth SH, Bennett RE Nonsteroidal anti-inflammatory drug gastropathy: recognition and response // Arch Int Med. 1987; 147:2093–2100.
13. Martinez C., Weidman E. 11th Int Conf Pharmacoepid. 1995.
14. Rainsford K., Willis C. Relationship of gastric mucosal damage induced in pigs by antiinflammatory drugs to their effects on prostaglandin production // Dig. Dis. Sci. 1982; 27:624–635.
15. Kukes V. G., Sychev D. A. Clinical pharmacology of non-narcotic analgesics // Klin. Pharmacol. ter. 2002. No. 5. P. 1–5.
16. Jasiecka A., Ma?lanka T., Jaroszewski JJ Pharmacological characteristics of metamizole // Pol J Vet Sci. 2014; 17(1):207–214.
17. Weissmann G. Aspirin // Sci. Am. 1991; 264:84–90.
18. Page J., Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem // Arch Int Med. 2000; 160; 777–784.
19. Khatchadourian ZD, Moreno-Hay I., de Leeuw R. Nonsteroidal anti-inflammatory drugs and antihypertensives: how do they relate? // Oral Surg Oral Med Oral Pathol Oral Radiol. 2014, Jun; 117(6):697–703.
20. Antiplatelet Trialists' Collaboration: Secondary prevention of vascular disease by prolonged antiplatelet treatment // Br Med J. 1988; 296:320–331.
21. Kowalski ML, Makowska JS Aspirin-dependent respiratory diseases. Modern approaches to diagnosis and treatment // Allergy Clin. Immunol. Int. J. World Allergy Org. Russ. Ed. 2007. V. 2. No. 1. P. 12–22.
22. Wu S., Han J., Qureshi A.A. Use of Aspirin, Nonsteroidal Anti-inflammatory Drugs, and Aceta-minophen (Paracetamol), and Risk of Psoriasis and Psoriatic Arthritis: A Cohort Study // Acta Derm Venereol. 2014, Apr 2. doi: 10.2340/00015555–1855.
23. Graham GG, Scott KF, Day RO Tolerance of paracetamol // Drug Saf. 2005; 28(3):227–240.
24. Østensen ME, Skomsvoll JF Anti-inflammatory pharmacotherapy during pregnancy // Expert Opin Pharmacother. 2004, Mar; 5(3):571–580.
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26. WHO. Pharmaceutical Newsletter, 1999, 5–6.
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29. Rainsford KD Ibuprofen: pharmacology, efficacy and safety // Inflammofarmacol. 2009.

Yu. B. Belousov*, 1, Doctor of Medical Sciences, Professor, Corresponding Member of the Russian Academy of Sciences K. G. Gurevich**, Doctor of Medical Sciences, Professor S. V. Chausova*, Candidate of Medical Sciences

* GBOU VPO RNIMU im. N. I. Pirogova Ministry of Health of the Russian Federation, Moscow ** State Budgetary Educational Institution of Higher Professional Education MGMSU named after. A. I. Evdokimova Ministry of Health of the Russian Federation, Moscow

1 Contact information

Oxycodone

General information.

Oxycodone was created by German scientists at the University of Frankfurt, Freund and Speyer, in 1916, who synthesized it from thebaine. One of the goals of this project was to create a thebaine derivative that would have analgesic effects comparable to morphine and heroin, but with less addictive potential. This goal has been achieved to a certain extent, since oxycodone does not have the same immediate addictive effect as heroin or morphine and has a shorter duration of action. The first clinical use of the drug took place in 1917, and since 1928 it has released a combination drug containing oxycodone, scopolamine and ephedrine. Ephedrine was added to reduce the inhibitory effect on the circulatory and respiratory systems. Oxycodone was first used in the United States in May 1939, and extended-release oxycodone tablets have been used in the United States for the treatment of pain since 1995.

Pharmacology

Oxycodone is a strong opioid, similar in properties to morphine, but 1.5 times stronger. The bioavailability of the drug when taken orally is 75% (60-87%), the onset of action is 20-30 minutes after oral administration of the immediate-release drug, and the time to reach peak plasma concentration is 1-1.5 hours. Plasma half-life is 3. 5 hours, duration of action 4-6 hours [27].

Research on this drug is still ongoing. Since 1997, studies have been conducted showing that oxycodone also acts on κ-opioid receptors, in contrast to morphine, which acts predominantly on μ-opioid receptors [28].

Synergism between morphine and oxycodone has been shown in animal and human studies, and a drug that combines fixed doses of oxycodone and morphine in a 1:1.5 ratio is in development [28–31].

Some studies suggest that oxycodone has less immunosuppressive effects than morphine. In a retrospective study of cancer patients with chronic pain, it was shown that there were fewer infectious complications in those receiving oxycodone than in the group receiving morphine [32].

Metabolism of oxycodone and precautions for its use

Oxycodone is metabolized primarily to noroxycodone via CYP3A4, but approximately 10% of oxycodone is converted to oxymorphone via CYP2D6 [33, 34].

When taken orally, oxycodone has a high bioavailability of 75%, which is almost 2 times more than that of morphine. This partly explains why oral oxycodone is more potent than oral morphine [35, 36].

About 20% of oxycodone is excreted unchanged in the urine. In moderate hepatic impairment, the elimination half-life is increased by approximately 2 hours. In renal impairment, oxycodone plasma concentrations are increased by 50% and the half-life is extended by 1 hour. Although oxycodone is not recommended in severe renal impairment, according to some authors, it is widely used used as an alternative to morphine in mild to moderate renal failure [37].

It is the oxycodone molecule, and not its metabolites, that has a powerful analgesic effect, therefore, like fentanyl, oxycodone is the drug of choice for impaired renal function, although it is excreted primarily in the urine, and the excretory function of the kidneys directly affects the level of oxycodone in the blood [38].

Oxycodone has the same side effects as those described with morphine. However, because oxycodone acts on both types of receptors (μ and κ), it is generally accepted that it has a greater stimulant effect than morphine.

The use of oxycodone should be accompanied by prophylactic laxatives because, like morphine, oxycodone strongly inhibits intestinal motility.

In order to reduce the serious side effects of oxycodone, mainly from the gastrointestinal tract (GIT), at the end of the last century, a combination drug oxycodone with naloxone was created, where naloxone played the role of an antidote in the competitive effect of the opioid oxycodone on intestinal motility. Because naloxone has a greater affinity for opioid μ2 receptors, which are located in the intestinal wall, it blocks them and prevents oxycodone from acting on them. Thus, oxycodone is actively absorbed in the gastrointestinal tract (up to 75%) and enters the systemic circulation, after which it has the main analgesic effect, and naloxone, which is practically not absorbed in the gastrointestinal tract (3%), provides good intestinal passage when taking a strong opioid. Used in non-cancer patients with moderate to severe pain, and in cancer patients for long-term opioid therapy. The drug under the brand name Targin is widely used in America and Europe; it is also registered in Russia and will be available for use in 2021. Considering that the drug will be used for the first time in our country, the presented review provides in more detail the rules for its clinical use [38].

Combination drugs

• Ibuklin, which contains paracetamol and ibuprofen, quickly relieves pain and maintains a long-lasting effect.
• Tempalgin contains the analgesic and tranquilizer tempidone, so in addition to eliminating moderate intensity toothaches, it calms the nervous system.
• Fanigan - the active substances (diclofenac and paracetamol) included in the medicine enhance each other’s effect. The drug has a strong anti-inflammatory and analgesic effect.

If you have a toothache, before relieving it at home, you need to read in detail the instructions for the painkillers you are taking, take into account the indications, contraindications, and possible side effects.