For citation: Isakova M.E. A new promising centrally acting analgesic "Zaldiar" in oncology // BC. 2004. No. 19. S. 1097

The fight against pain of oncological genesis is one of the priorities of the WHO program. Unfortunately, the number of cancer patients is growing all over the world - about 9 million new cases of cancer are diagnosed annually. Of these, approximately 4 million patients currently suffer from pain of varying intensity every year (40% of patients with intermediate stages of the process, 60-80% with a generalized form of the disease). Untreated and mistreated pain occurs in 25% of cases in this group of patients who die without adequate care. Pain is one of the terrible consequences for a cancer patient. For clinicians, this is one of the most difficult problems of diagnosis and treatment in oncology. Pain by its nature can be classified as either acute or chronic. The very fact of the existence of pain can be transformed from a simple symptom (pain is an alarm) into a complex syndrome (pain is a disease). The phenomenon of pain is realized through a specialized system and is a multifaceted process in which many neurotransmitters and receptors of both the peripheral and central nervous systems are involved. Pathophysiological mechanisms of pain are divided into 2 types: nociceptive, due to tissue damage (skin, bones, joints, muscles, etc.) and neuropathic, due to damage or involvement of nerve structures at various levels of the nervous system (plexus roots, trunks, etc.). Acute pain is a normal response to tissue damage and is of great importance as an acute symptom, an alarm signal. It requires a whole range of diagnostic procedures to determine its cause. Chronic pain is caused by constant irritation of nociceptors in the area of ​​existing tissue damage; its protective role is no less obvious. Pain that has a pathogenic effect, causing maladaptation, is called pathological pain [G.N. Kryzhanovsky, 1997]. The term "chronic pain" is used in two distinct cases: cancer pain and chronic non-cancer pain. Cancer pain is more like persistent "acute" pain. The intensity of oncological pain does not directly depend on the type or extent of tissue damage, but depends on the mechanism of maintaining the pain symptom. In the case of an oncological disease, one should speak of a real pain syndrome, in which the symptoms are the result of the sum of episodes of acute pain that have turned into chronic ones. Pain almost always accompanies the advanced stages of the disease, and is also the result of anticancer therapy, a consequence of the continued growth of the tumor, its germination into the surrounding tissues, metastasis, infection, the use of diagnostic and therapeutic procedures. Pain due to the progression of the underlying disease affects the entire body, but it is necessary to highlight several important symptoms depending on the predominant lesion. The pain may be constant or intensify, disappear or appear over time, change localization. Considering the versatility of the manifestations of chronic pain, the cause and mechanism of development, it is necessary to use an integrated approach in each case to select adequate pain relief. The simplest and most accessible for both patients and doctors is the method of pharmacotherapy. Knowledge of the pharmacology of analgesics can make effective therapy for cancer pain. Currently, non-narcotic and narcotic analgesics are used in pain therapy according to a three-stage scheme, consisting of the sequential use of analgesics with increasing potency in combination with adjuvant therapy as pain intensity increases. Significant progress in the treatment of pain, which has been observed in the last decade, on the one hand, is the result of the unconditional achievements of the pharmaceutical industry, and on the other hand, the study of the mechanisms of pain and the selection of drugs with a certain profile of action. Since central regulation is recognized as the most specific and reliable option for pain management, centrally acting analgesics are most often included in the complex preparation. There are many clinical studies that confirm the benefits of combinations of analgesics, primarily opioids with non-steroidal anti-inflammatory drugs and paracetamol, such as codeine-paracetamol, codeine-ibuprofen, etc. One of the ways to improve pain management and adherence to treatment is to use a combination of painkillers that have complementary mechanisms and temporal characteristics of action. The main goal of this approach to the treatment of pain is to provide a stronger analgesic activity compared to each of the drugs included in the combination. This therapeutic advantage is often achieved with lower doses of each of the active ingredients, potentially improving the tolerability and performance of the safe analgesics used. Such combined drugs have the advantages of an anti-inflammatory and analgesic drug, the combination of which leads to a mutually enhanced pharmacological effect. Abroad, combinations of paracetamol with opioids are the best-selling combined painkillers and are recommended by WHO for the treatment of moderate to severe pain. There are practically no such medicines in Russia. Recently, the list of combined analgesics has been replenished with a new drug, which is a combination of tramadol and paracetamol called "Zaldiar" (Zaldiar). One tablet contains 37.5 mg of tramadol hydrochloride and 325 mg of paracetamol. The choice of dose ratio (1:8.67) was made on the basis of the analysis of pharmacological properties and has been proven in a number of in vitro studies. In this ratio, the drugs provide adequate analgesia. The components of Zaldiar - tramadol and paracetamol - are two analgesics that have long been proven effective in monotherapy for acute and chronic pain of various origins. Tramadol is a recognized centrally acting synthetic pain reliever. Two complementary mechanisms of its action are known: - binding of the parent compound and its metabolite M1 to µ-opiate pain receptors, which leads to their activation; - inhibition of the reuptake of norepinephrine and serotonin in nerve synapses (due to this, nociceptive impulses are blocked at the spinal level). The effect of each mechanism of action is rather weak, but in general, not just summation occurs, but a multiple increase in the overall analgesic effect. It is the synergism of the two mechanisms of action of tramadol that determines its high efficiency. The affinity of tramadol and its M1 metabolite for μ receptors is much weaker than that of morphine and other true opiates, therefore, although tramadol exhibits an opioid effect, it belongs to moderately strong analgesics. The low affinity of tramadol for opiate receptors explains the fact that, at recommended doses, tramadol does not cause respiratory and circulatory depression, gastrointestinal motility (constipation) and urinary tract disorders, and long-term use does not lead to the development of drug dependence. With a low addictive potential, tramadol has shown a very low "abuse" rate in a wide variety of clinical studies conducted to date. The second component of Zaldiar - paracetamol belongs to the well-known centrally acting analgesics and antipyretics. Its mechanism of action has not been precisely established. It is believed that analgesia is caused by an increase in the pain threshold, inhibition of the release of spinal prostaglandin E2 and inhibition of nitric oxide synthesis mediated by neurotransmitter receptors (NMDA and substance P). Pharmacological and pharmacodynamic characteristics of tramadol (peak activity after 2-3 hours, half-life and duration of analgesia about 6 hours) indicated the promise of its combination with an analgesic that has a rapid onset and short-term analgesic effect. Paracetamol was well suited for the role of such a second additional agent. The action of paracetamol begins quickly (after 0.5 hours and the peak of activity - after 30-36 minutes), but the duration of its action is relatively short (about 2 hours). Comparison of the pharmacokinetic parameters of tramadol and paracetamol confirms the satisfactory qualities of their combination. It is essential that both drugs are metabolized in the liver, but each component is converted in its own way. Paracetamol undergoes N-hydroxyoxidation through cytochrome P450, which leads to the formation of a highly active metabolite (N - acetyl - benzoquinone - imine). High doses of paracetamol in excess of the recommended daily allowance may exceed the liver's ability to metabolize and bind glutathione conjugates. The accumulation of metabolites can lead to their binding to liver proteins, accompanied by necrosis of the latter. The absorption of tramadol is slower than that of paracetamol. 11 metabolites were identified, of which mono-o-desmethyltramadol has pharmacological activity. The mean half-life for the tramadol metabolite was 4.7-5.1 hours, for paracetamol it was 2-3 hours. Its maximum plasma concentration is reached within 1 hour and does not change when used together with tramadol. The bioavailability of tramadol is? 75%, with repeated use increases to 90%. Plasma protein binding? 20%. The volume of distribution is about 0.9 l/kg. Relatively small part? 20% of paracetamol binds to plasma proteins. Tramadol and its metabolites are excreted from the body mainly through the kidneys. Paracetamol is predominantly metabolized in the liver and its metabolites are excreted by the kidneys. Thus, the combination of tramadol and paracetamol represents a rational pain-relieving combination of complementary agents with a long clinical rationale. Zaldiar exhibits a pronounced analgesic effect due to a combination of three different mechanisms of action, each of which contributes to the reduction of pain. The tramadol/paracetamol complex is recommended for the treatment of moderate to severe pain at a dosage adjusted to the need in cases where a combination of rapid onset and long duration of analgesic action is desirable. Such situations can occur with acute pain in patients with chronic diseases characterized by periodic exacerbations of pain. In the WHO "analgesic ladder" Zaldiar can be defined as a second-line agent for patients who require more efficacy than first-line agents (paracetamol alone, non-steroidal anti-inflammatory drugs (NSAIDs)), but do not yet require stronger opiates. Such patients often have chronic pain that is episodically aggravated or characterized by a significant variability in intensity. Adverse events observed during treatment most often manifested in the gastrointestinal tract, CNS or in the form of mental disorders and consisted of nausea, drowsiness, dizziness and headache. The severity of adverse events was usually mild to moderate. There was not a single case with anaphylactoid reactions, although allergic reactions such as itching, rash, contact dermatitis, urticaria, etc. were noted. Symptomatic therapy of pain syndrome retains its importance in complex pharmacotherapy in cases where pain cannot be adequately controlled, used in already developed treatment regimens. The use of combined analgesics will complement the range of symptomatic drugs in the complex therapy of chronic pain in cancer patients. Given the indications, the drug Zaldiar can alleviate the suffering of the patient and provide him with a decent quality of life. Based on literature data confirming the high efficiency of Zaldiar, we used the drug on an outpatient basis in 16 patients aged 32 to 70 years with different localization of the tumor process (9 women and 7 men). According to the localization of the disease, the patients were distributed as follows: mammary gland - 6, chest - 4, plexitis - 3, rectum - 2, head and neck - 1. In all patients, the source of pain was relapses of the disease, metastases to the bones of the skeleton, involvement of nervous structures into the tumor process. Basically, these were patients after surgical interventions, repeated courses of chemo-radiation treatment. The duration of the pain syndrome remained within 2 weeks - 1 month. Pain intensity was determined on a scale of verbal assessments and ranged from 2.6 to 3.0 points. All patients were taking oral NSAIDs as well as weak opioids before the new Zaldiara was prescribed for pain relief. Efficacy was evaluated subjectively on a scale of points (0 - no pain, 1 - moderate, 2 - weak, 3 - strong, 4 - very strong). A good analgesic effect was noted mainly in patients with moderate and mild pain intensity - 9 people, satisfactory - in 4 patients with severe pain, when it was necessary to increase the dose of the drug to 10 tablets per day, as well as in 2 patients treated with tramadol (injections at night 200 mg). An unsatisfactory effect was noted in 3 patients who stopped taking the drug after 3 days of its administration due to the development of adverse reactions, which manifested themselves in the form of drowsiness, dizziness, headache, dry mouth. Thus, the combined drug Zaldiar, in terms of its analgesic potential, can be classified as a weak opioid of the WHO regimen, which expands the possibility of pharmacotherapy of chronic pain in cancer patients.

The main place in the treatment of chronic pain syndrome of oncological genesis is occupied by centrally acting analgesics, since only in rare cases the pain does not increase after its onset and remains at the level of a weak, treatable non-narcotic analgesics.

In the vast majority of patients, the progression of the disease is accompanied by an increase in pain to moderate, severe or very severe, which requires the consistent use of centrally acting analgesics with increasing analgesic potential.

True opiates. The classic representative of true opiates (agonists of opioid μ-receptors) is morphine, which is called the "gold standard" by specialists.

In the traditional version, according to the recommendation of the WHO Expert Committee on Cancer Pain Management, with an increase in pain from mild to moderate (stage 2 of chronic pain syndrome therapy), they switch to the appointment of a weak opiate - codeine, and with severe pain (stage 3) prescribe powerful opiate morphine.

Morphine and its analogues are true opium derivatives.

The powerful analgesic effect of opiates is their main property and advantage, widely used in medicine, including in the treatment of chronic cancer pain. Opioids are not selective in their action. In addition to analgesia, they have numerous inhibitory and excitatory effects on the central nervous system and peripheral organs, which is encountered when using them for the treatment of pain.

The main representatives of opiate analgesics of medium and high potency are codeine and morphine. The most dangerous side effect of morphine is depression of the vital centers of the medulla oblongata, the degree of which is proportional to the dose of the drug. In case of overdose, bradypnea develops, followed by apnea, bradycardia, and hypotension. Those using morphine preparations in specialized palliative care units and hospices believe that with a carefully selected initial dose and then a careful balance of doses, the desired analgesia can be obtained without respiratory depression and other side effects.

In the home setting, where most of these patients are, a careful balance of drug doses is not possible, and the danger of a relative overdose of the opiate is quite likely.

It is known that pain is an antagonist of the central depressive action of opiates, and as long as it persists, the patient is not threatened with depression of respiration, blood circulation and mental activity, but with complete analgesia, drug-induced depression of the central nervous system can manifest itself as drowsiness and respiratory depression, which, with the introduction of repeated doses the drug can reach a dangerous level and lead to gradually increasing hypoxia and death of the patient "in a dream."

Among the side activating central effects of morphine, the activation of the vomiting center is of clinical importance. Nausea and vomiting often appear during the initial appointment of opiates to patients, therefore, it is customary to prescribe antiemetic drugs prophylactically: metoclopramide and, if necessary, haloperidol, which, as tolerance to the emetic effect of the drug develops, can be canceled after 1-2 weeks. Morphine also has a number of stimulating and inhibitory effects on peripheral organs. The main place belongs to spastic disorders of the motility of hollow smooth muscle organs, resulting in spastic constipation, urinary retention, biliary dyskinesia. With the greatest constancy in anesthesia with morphine, constipation is observed, requiring the mandatory prescription of laxatives. Antispasmodics are used to prevent and eliminate spastic disorders of urinary and bile excretion, in some cases bladder catheterization is required.

Therefore, therapy with morphine and its analogues requires the simultaneous use of additional corrective (laxative, antiemetic, antispasmodic) agents.

Specific properties of opiates are tolerance, as well as physical and mental dependence (addiction).

Tolerance (addiction) develops during long-term therapy with morphine or its analogues and concerns its central (mainly inhibitory) effects, primarily analgesia, which is manifested by a decrease in the quality and duration of analgesia and necessitates a gradual increase in the initially prescribed effective analgesic dose.

In cancer patients with chronic pain syndrome, the need to increase the initially effective dose of morphine appears after 2-3 weeks. With long-term therapy with morphine, its dose can increase tenfold compared to the initial one and reach 1–2 g per day. In this case, it is necessary to differentiate the cause of the increase in the analgesic dose: tolerance or an increase in pain due to the progression of the tumor process. Tolerance to morphine develops regardless of the route of administration. Tolerance also develops to the sedative and emetic effects of morphine, which decrease after 1-2 weeks of therapy, but may increase again with an increase in the analgesic dose. The most stable, not susceptible to tolerance, is the spasmodic effect of opiates on the smooth muscles of the gastrointestinal tract, leading to persistent disturbance of peristalsis and persistent constipation. Thus, opiate tolerance manifests itself selectively in relation to different properties of drugs.

Tolerance should be considered as one of the manifestations of the body's physical dependence on the action of opiates, and the severity of these phenomena depends not so much on the dose of the corresponding drug, but on the duration of its use.

Physical dependence on opiates is characterized by the development of a complex of physical disorders when the drug is stopped - the so-called withdrawal syndrome. The most pathognomonic signs of morphine withdrawal syndrome are goosebumps, chills, hypersalivation, nausea (vomiting), muscle pain, and spastic abdominal pain.

It is almost impossible to catch the features of dependence against the background of regular intake of maintenance doses of the drug. It must be assumed that dependence on opiates (at least physical) develops inevitably - this is the nature of drugs, especially when taking large doses of more than 2-4 weeks.

In case of elimination of chronic pain syndrome after a course of antitumor (radiation or chemotherapy), it cannot be canceled immediately, but the dose should be reduced gradually in order to avoid withdrawal syndrome. Caution should also be exercised when it is necessary to replace an opiate with another opioid drug, given the antagonistic properties of some of them, which will be discussed in more detail below.

Psychological dependence, or addiction, is a state of the body that is characterized by a pathological need to take an opiate in order to avoid mental disorders and discomfort that occur when the drug that caused the addiction is stopped. Mental dependence can develop in parallel with physical dependence or one of these types of dependence is predominantly manifested. The source of the development of mental dependence is the emotionally positive (euphoric) effect of the drug, which has been especially studied in relation to morphine. The euphoric effect of morphine is regarded by some authors as an advantage in the treatment of chronic pain in incurable patients. However, opiate euphoria is almost non-existent in these patients. More common is the state of sedation, drowsiness.

It should be emphasized that the possibility of developing addiction to a drug cannot be a reason for refusing to prescribe it to an incurable patient, if this is necessary to alleviate his suffering.

A separate ethical and psychological problem is presented by situations when even doomed patients with severe chronic pain syndrome are afraid of becoming addicted to drugs and psychologically do not accept this.

In such cases, one can choose to prescribe a potent opioid with the least dependence potential (for example, buprenorphine), and, if necessary, to prescribe morphine, find convincing arguments individually for each particular patient. As practice shows, such patients are found mainly among highly intelligent people.

Thus, when using opiates, the full range of their pharmacological effects should be taken into account.

Table: medium and high potency opiates.

An analysis of literature data and our own experience with the use of various morphine preparations indicate the need to follow certain tactics for prescribing morphine preparations in order to facilitate the selection of the optimal dose, better assess the quality of analgesia and adverse reactions of the patient to morphine. Treatment begins with the use of morphine hydrochloride preparations, the action of which is well known, more manageable and easily predictable. After that, they switch to long-acting morphine sulfate.

Morphine sulfate extended release (MCT-continus) is available in tablets of 10, 30, 60, 100, 200 mg for ease of dosing. The action of the analgesic dose of MCT continus is 2-3 times longer than morphine hydrochloride (10-12 hours versus 4).

Along with MCT-continus tablets, a longer-acting dosage form of morphine, which is more favorable in the pharmacokinetic aspect, has been developed - capsules with analgesic microgranules in a polymer shell (for example, capanol, skenan preparations).

In rare cases, when oral administration of drugs is impossible (dysphagia, stomatitis, pharyngitis, partial intestinal obstruction), there are indications for parenteral therapy with morphine hydrochloride or other morphine-like drugs. The drug is administered subcutaneously, intramuscularly or intravenously by slow infusion, including a method controlled by the patient using a dispenser. The ratio of doses of morphine in oral and parenteral therapy usually corresponds to 2-3:1. In domestic practice, along with morphine, promedol or omnopon (a complex of opium alkaloids) are often used, the analgesic potential of which is lower than that of morphine (1/6 and 1/2, respectively).

A number of foreign authors believe that it is most advisable to start therapy with oral administration of a solution of morphine hydrochloride. This solution is prepared at the rate of 1200 mg of morphine hydrochloride per 240 ml of distilled water (1 ml of the solution contains 5 mg of morphine) and is administered in an initial dose of 2-4 ml (10-20 mg) every 4 hours. The shelf life of such a solution is 28 days. The dose is gradually increased in steps with insufficient analgesia or reduced with severe side effects. The initial single dose of morphine hydrochloride is usually 30-50 mg and is administered every 4 hours. When the optimal effect of morphine hydrochloride is achieved, you can switch to therapy with tablets - morphine sulfate retard. The daily dose of the latter remains the same, and the intervals between injections increase by 2-3 times. For example, at a dose of morphine hydrochloride 40 mg every 4 hours, MCT-continus is prescribed 120 mg every 12 hours. As the duration of therapy increases and tolerance to morphine develops, its dose increases and may exceed 2 g per day. Mentions are also made of much higher doses - more than 7 g per day. In a number of observations, the daily dose of MCT-continus was increased almost 2-fold after 2 weeks of therapy, while the duration of action of each dose was also approximately halved.

The use of morphine monotherapy in massive doses at the current level of knowledge cannot be considered acceptable. The desire at all costs to achieve pain relief by increasing the dose of morphine is unjustified, since it does not give the desired effect. In such cases, a combination of morphine with special non-opioid pain relievers is necessary, which are often more effective than opiates themselves (calcium channel blockers, adrenergic receptor agonists, excitatory amino acid antagonists, etc.).

In order to remove opioid dependence, a special treatment regimen is prescribed with sequential use for 2 days of intravenous infusion of NSAIDs aspizol (3 g / day) and antikininogen trasilol (500,000 IU / day), and then oral administration of verapamil, sirdalud, amitriptyline in therapeutic doses allows already within the first week, reduce the dose of opiates by half, and after 2 weeks, reduce it to a minimum and then completely cancel it.

It should be noted that with intense somatic and visceral chronic pain syndrome of oncological genesis, combined pharmacotherapy is also almost always required, including, in addition to the opioid, certain adjuvant agents according to indications.