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.
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.
