The main method of treatment of acute and chronic pain syndromes in modern medicine is systemic pharmacotherapy. The latter can be carried out with the help of various methods of administering the analgesic to the body (oral, rectal, sublingual, transdermal, injection), but in any case the drug is absorbed into the systemic bloodstream, and then to its site (in contrast to the regional a method of administering an analgesic, for example, perineurally, epidurally).
For the treatment of low intensity pain, according to WHO recommendations, different non-opioid analgesics are used, and for pain of moderate and high intensity, opioid analgesics are used. Non-opioid analgesics have a predominantly peripheral effect at the level of the focus of pain, have a small analgesic potential and are therefore only suitable for the elimination of mild pain. Opioids belong to the analgesics of the central action, realized through the endogenous opioid system of the organism at the level of the spinal cord and brain by inhibiting the ascending flow of painful impulses. They differ from each other in their analgesic potential and the ability to moderate or severe pain. Due to their good analgesic properties, opioids are widely used in various areas of medicine dealing with intense pain, especially in oncology and surgery.
Common to all opioids is the non-selective nature of their action, i.e., along with analgesia, they cause a number of other side effects and, at the same time, differ in the degree of severity of these or other properties, which is associated with individual features of their interaction with opioid receptors . An important condition for correct operation with opioids is knowledge of the mechanism of their action.
Mechanism of action and classification of opioids
All known opioids are divided into four main classes, depending on the nature of the interaction with the receptors.
The main class consists of opioid agonists or agonists of opioid m (mu) receptors, including substances and preparations of different analgesic potency, including a potent narcotic heroin, traditional strong opioid analgesics – morphine, fentanyl, pyrithramide, and less strong – promedol, prosidol, tramadol, codeine. This group of opioids has such side effects associated with depression of stem structures and centers of the medulla oblongata, such as sedation (less often euphoria), general weakness, oppression of the cough reflex, in large doses – respiratory depression (bradypnoea, apnea) and blood circulation (hypotension, bradycardia) . Along with these inhibitory influences, opioid agonists have an activating effect on the emetic centers with the possible development of nausea (vomiting), as well as smooth muscle of the hollow organs, resulting in motor disorders of the latter (constipation, retention of urine and bile, tendency to bronchospasm). All these serious side effects are most pronounced in the most potent opioid analgesics (fentanyl, morphine) and are less frequent in drugs with less analgesic potential.
All opioid agonists, apart from tramadol, have a specific ability to cause dependence – physical and mental, and therefore they are included in the International Convention on Drugs as narcotic drugs under control, and they are subject to special rules of appointment, discharge, accounting, storage, transportation, reporting , determined by the relevant orders of the Ministry of Health of the Russian Federation. The exemption of tramadol does not apply to drugs, because according to extensive world and domestic experience, no clear data are available for the development of dependence on tramadol. This drug is considered to be a potent agent and is prescribed on a prescription form for potent substances. A characteristic property of strong opioids is also tolerance, that is, a reduction in the analgesic effect with an increase in the duration of opioid administration, which requires prolonged therapy of a gradual dose increase to maintain anesthesia. So, the dose of morphine can increase tens of times compared to the initial one during treatment for several months, reaching or even exceeding 1000 mg / day.
The next class of opioids – partial agonists of opioid m-receptors – is buprenorphine, similar in properties to morphine, but with a longer and slightly less analgesic and other side effects.
In comparison with other classical opioid agonists, buprenorphine has a lower drug potential, but in Russia it is also classified as a drug section.
In contrast to morphine, buprenorphine has a “ceiling” of analgesic dose, over which the analgesic effect ceases to increase. This limit is determined by different authors in the range of 2.4-5 mg / day, which can limit the continuation of buprenorphine therapy in chronic pain syndrome and is a signal for the transition to a more potent opioid, morphine, which does not have a “ceiling” of the analgesic dose.
The class of mixed opioid agonist-antagonists includes three drugs (pentazocine, butorphanol, nalbuphine), which are k (kappa) -receptor agonists and m-receptor antagonists. As k-receptor agonists, these opioids cause less pronounced analgesia than morphine, and have a slightly different spectrum of side effects (sedation predominates, nausea, dizziness, and respiratory depression are less common). Being antagonists of m-receptors, opioids of this class can weaken or eliminate the effects of classical opioid agonists, including analgesia. In this regard, the combined use of opioid agonist-antagonists and morphine analgesics is inexpedient.
Drugs of this class, like buprenorphine, have a Ceiling effect. Agonists-antagonists of the last generation butorphanol and nalbuphine (as opposed to pentazocine) are not included in the register of narcotic drugs and refer to potent substances. They have an auxiliary role in the treatment of pain syndromes due to their antagonistic relationship with opioids of the main class of agonists.
The properties of the s (sigma) -receptor agonist are ketamine, which has a moderate analgesic effect and a whole complex of side-activating influences (tachycardia, hypertension, psychomotor agitation).
An antagonist of opioids of all groups is naloxone, which quickly neutralizes all of their effects, including analgesia.
Existing opioid analgesics differ not only in the nature of the interaction with certain opioid receptors, but also in the characteristics of binding them to strength and duration. The higher the affinity of the opioid to the receptor, the stronger the analgesia, the longer the bond with the receptor, the longer the analgesia.
The choice of opioid for the treatment of moderate and high intensity pain
An important consequence of the above analysis of the mechanism of action of opioids is the generally accepted provision on the main role in the opioid therapy of pain in analgesics belonging to the class of opioid agonists, since the preparations of all other groups have certain limitations (the effect of the “ceiling” of the analgesic dose, antagonism in relation to the most powerful analgesic group of morphine, undesirable side effects). This situation is especially important to consider in the treatment of chronic pain syndrome, in order to obtain the optimal result of anesthesia and to avoid possible failures.
The spectrum of existing opioid agonists is quite wide and includes, as mentioned above, analgesics of different potencies, capable of eliminating moderate and severe pain, and indications for the treatment of such pain exist in different fields of medicine.
In what cases is the appointment of an opioid analgesic for analgesia and how to choose the right opioid? For this, first of all, it is necessary to be guided by certain general rules.
- Indications for the appointment of an opioid arise when treatment with non-opioid analgesics does not lead to the elimination of pain, that is, the pain exceeds the degree of weakness. In the treatment of chronic pain syndrome in oncological patients, opioid agonists should be preferred.
- In determining the intensity of pain should be guided by a simple scale of verbal pain assessments (SHVO): 0 – no pain, 1 point – weak, 2 points – moderate, 3 points – strong, 4 points – the strongest pain. For the treatment of moderate and high intensity pain in Russia, the instructions of the RF Ministry of Health recommend: tramadol, prosidol for moderate pain, buprenorphine for severe pain and morphine or fentanyl (including in transdermal form) for the most severe pain.
- The right to prescribe opioid analgesics related to narcotic drugs is available to doctors authorized to work with drugs (most often in oncology and surgery).
- Opioids – non-narcotics classified as potent agents (tramadol, butorphanol, nalbuphine), can be prescribed on prescription form for strong remedies by any doctor in consultation with the department head if it is necessary to stop pain in the patient, not eliminated by non-opioid analgesics (articular, neurogenic and other non-oncological pain). Among opioid agonists, the only non-narcotic drug is tramadol.
Clinical pharmacology of tramadol
Tramadol (Tramal) is an opioid agonist, standing alone among all representatives of opioids of this class, primarily because, unlike them, it does not belong to narcotic drugs. This is confirmed by extensive clinical experience of its use throughout the world and special scientific research of its narcotic potential.
The volunteers who received the maximum dose of tramadol (Tramala, hereafter referred to as “T”), and oncological patients, long treated with this drug for pain, conducted a drug dependence test using an antagonist of naloxone opioids. It is known that the introduction of naloxone in the body of heroin and other addicts immediately causes the development of the withdrawal syndrome (withdrawal syndrome), manifested by severe mental and physical symptoms: a sharp psychomotor agitation, fear of death, panic, acute cramping in the abdomen, vomiting, chills, trembling , tachycardia, etc. In the studied people, as in the experiment on animals, against the background of long-term “T” reception, naloxone did not cause these symptoms or their manifestations were indistinct and did not reach the gradation of “sind th cancellation mild. ” The probability of mental dependence on “T” is minimal; in these studies, the drug has not revealed a euphoric or dysphoric effect. It has been established that in patients with opiate addiction “T”, as with placebo, does not lead to elimination of subjective discomfort against abstinence, that is, it does not have a drug substituting action (unlike other opioids, promedola, butorphanol, nalbuphine, buprenorphine) .
Unlike other opioid agonists, “T” has a double mechanism of action. It is established that analgesia caused by “T” is not completely eliminated by the opioid antagonist naloxone and along with the opioid mechanism is realized by additional inhibition of painful impulse with the participation of serotonin and adrenergic systems. That is, by the mechanism of analgesic action “T” is not completely identical to other opioid agonists.
Recently, Russian media reported on the use of “T” drug addicts as a substitute for heroin and other strong drugs. As a professional, I consider it necessary to give explanations in connection with the erroneous interpretation by journalists of the properties of “T”. On television, in detail, a video camera recorded a case of death of a drug addict after intravenous injection of retarded “T” tablets intended for ingestion. Such a mixture could contain any toxic substances for the body when injected into the bloodstream, so it is unlikely that the root cause in this case can be considered “T”.
In an article published by the Moskovsky Komsomolets newspaper on August 28, 2002, “T” is characterized as “a potent narcotic drug from a group of heroin synthetics, very similar in effect to methadone.” This characteristic is absolutely untrue, therefore, experts consider this publication as “unprofessional and tendentious.” Neither the heroin nor the methadone “T” has anything to do with both pharmacological properties and clinical effect. It is fundamentally different from them and from other narcotic analgesics by a milder action and a minimal narcotic potential, which is described in detail above. However, uncontrolled use of “T”, as well as any other medicinal product, can lead to serious consequences, since all medicines without exceeding the therapeutic doses, without exception, cause a variety of side effects and exhibit toxic properties. This also applies to a wide range of non-prescription drugs, including analgesics. “T” according to the order of the Ministry of Health of the Russian Federation of 23.08.1999 No. 328 “On the rational prescribing of medicines, the rules for prescribing prescriptions for them and the order of their dispensing by pharmacy institutions” should be issued on the prescription of a doctor written out on a form for potent means.
Below is a description of the main clinical effects of “T”, which in their nature are similar to those of other opioid agonists, but are much less pronounced. This applies to both analgesia and side effects.
Analgesic potential “T” according to different authors, is from 0.1 to 0.2 of the morphine potential, it is equal to or slightly higher than the potential of codeine; the effectiveness of 50 mg of “T” is equivalent to 1000 mg of metamizole, that is, “T” belongs to analgesics intended for pain of moderate intensity.
The most important criterion for the safety of any opioid is the severity of its central depressive effect on respiration and circulation. Numerous studies have not established significant respiratory depression in post-operative patients under the influence of “T” in the range of therapeutic doses from 0.5 to 2 mg per 1 kg of body weight, even with intravenous bolus administration, whereas morphine at a therapeutic dose of 0.14 mg / kg statistically significant and significantly reduces the respiratory rate and increases the stress of CO2 in the exhaled air. That is, in recommended doses “T” does not cause depression of respiration, but it can not be excluded that it is possible when these doses are exceeded. The “T” does not exert an oppressive effect on the circulation. On the contrary, with intravenous administration of 0.75-1.5 mg / kg, it can increase systolic and diastolic blood pressure by 10-15 mm Hg. and slightly increase the heart rate with a rapid return to the original values, which is explained by the sympathomimetic component of its action. There was no effect of “T” on the level of histamine in the blood and on mental functions. “T” is metabolized in the liver. Only one of its metabolites is active. The half-life of “T” with oral or intravenous administration is 5-6 hours, it can increase in patients with impaired liver function, kidney function. About 90% of the oral dose of “T” is excreted by the kidneys. “T” has beneficial pharmacokinetic characteristics. Its absolute availability with intramuscular injection approaches 100%, with rectal – 78%, with oral – 68% (with a subsequent increase with the continuation of therapy). These indicators are significantly higher than morphine and pethidine. The peak concentration of “T” in plasma during oral administration is reached in 1.6-2 hours.
Experience in the clinical use of Tramal
The first publications on the use of “T” in the clinic date back to the beginning of the 1980s, ie, its medical application has already been 20 years old. During this time, the indications for the treatment of “T” were determined for various acute and chronic pain syndromes, its analgesic and side effects, its optimal methods and methods of its application in different fields of medicine were clarified: oncology, surgery, traumatology, rheumatology, neurology, cardiology, etc. .
In the practice of the MNIOR them. PA Herzen “T” is widely used for treatment of both acute (postoperative – p / o BS) and chronic (CBC) pain syndrome in cancer patients. The general experience of its use in the institute exceeds 6000 observations, and the duration of therapy varied from several days to many months with CHB.
With the appointment of “T” we are guided by the general principles of drug treatment of pain syndromes. The main criterion is the intensity of pain estimated by the above scale (SHVO). Indications for the appointment of “T” for both CHD and n / a BS is pain of moderate intensity (2 points according to ShVO). There is no need to prescribe “T” for mild pain (1 point for SHVO), where anesthesia can be achieved with the help of non-opioid analgesics (different NSAIDs, paracetamol preparations). “T” is not shown, and with severe pain (3-4 points according to the ShVO), since it is insufficient to eliminate it, and in these cases more powerful opioids should be used to avoid further strengthening of the pain syndrome.
Most often, in opioid therapy, including “T”, it is advisable to combine opioids with non-opioid components in order to increase the efficacy and tolerability of anesthesia, although monotherapy is also acceptable.
Pathogenetically justified is the addition of “T” to one of the non-opioid analgesics of peripheral action that suppress the production of the mediator of prostaglandin pain in the focus of pain (ketoprofen, lornoxicam, diclofenac or others) and / or the central action that inhibits this mediator at the level of the pain structures of the spinal cord (paracetamol). This makes it possible to obtain complete anesthesia with a reduction in the need for opioids, i.e. when used in reduced doses and with less chance of side effects. Clinical confirmation of the feasibility of such a tactic of working with opioids is contained in numerous publications, including in the work of the staff of our institute.
The choice of dosage form, dose “T” and drugs for combination with it depends on the nature of the pain syndrome, its location, individual characteristics of the patient.
Medicinal forms and dosages of Tramal. Tramal is presented in a variety of forms:
Solution for injection (ampoules 1 and 2 ml), 50 mg in 1 ml.
Capsules 50 mg
Candles 100 mg
Tablets retard 100 mg, 150 mg.
Recommended single dose 50-100 mg; daily up to 400 mg. The drug is administered 4 times a day. Tramal in these forms is produced and available in Russia.
Tramal in chronic pain syndrome of different origin is widely used and successfully. In this article, we consider this using the example of chronic pain syndrome (CBC) of oncological genesis, which we constantly deal with in our work.
Taking into account the experience of the institute on the use of “T” for the treatment of CHD in more than 1000 patients, it is advisable to prescribe it for uncomplicated moderate (2 points) somatic HBSS (tumor or metastasis of the bones of the skeleton, soft tissues, muscles, skin, external lymph nodes) or visceral (damage to internal organs and / or membranes – pleura, peritoneum, internal lymph nodes) type. All incurable oncological patients pass through this phase of CHD, and the duration of moderate-intensity CHF varies widely, which is due to individual growth rates of the tumor.
Practice shows that the appointment of “T” is not indicated in severe CHD, complicated by a neuropathic component due to the involvement of nerve formations. In these cases, stronger opioid analgesics are required in combination with complex special therapy.
The “T” is prescribed when the initial non-opioid therapy (NSAIDs, paracetamol preparations) becomes inefficient, preserving this therapy, which has its own pathogenetic orientation, supplementing the action of the opioid.
The presence of different dosage forms makes it possible to choose the optimal one for a particular patient. In most cases, the usual oral forms (capsules, retard tablets) are applicable, and in the absence of such a possibility (patients with dysphagia in esophagus and stomach cancer) another non-invasive route of administration, rectal, can be used. In the form of an injection of “T” with prolonged treatment, CHD is usually not used because of invasiveness.
For long-term therapy, retard tablets are the most convenient, which should be taken twice a day: 100-150-200 mg every 12 hours. The duration of all other forms of “T” is 5-6 hours, so they are taken 4 times a day.
Selection of the optimal dose of “T” begins with a minimum single dose of 50 mg (1 capsule) in order to evaluate both the analgesic effect and the tolerability of the drug. With good analgesia and tolerability, this single dose, administered 3-4 times a day, is retained (taking into account the duration of analgesia). If insufficiency of anesthesia is not sufficient, after 40-60 minutes, a second similar dose should be taken and its effect evaluated. If after 1 hour, sufficient anesthesia is achieved, the therapy is carried out with single doses of 100 mg to 4 times per day (capsules or suppositories), but it is more advisable to recommend a long-term retard tablets 150-200 mg twice a day, which is much more convenient (first dose in the morning after a dream, the second – in the evening before a dream). Additional non-opioid analgesics are prescribed according to their own scheme.
The clinical study “T” in cancer patients with CHD showed that with initial moderate pain (2 points), the drug always causes it to be eliminated, but with more severe pain, anesthesia with the above therapeutic doses is not achieved, so if a single dose of “T” is 100 mg in non-cardiac form is not sufficient to relieve pain, it means that the intensity of pain is underestimated and it is necessary to strengthen analgesic therapy. This can be achieved either by switching from “T” to a stronger opioid while preserving the old non-opioid therapy, or by adding another non-narcotic analgesic not previously used. For example, if after the appointment of “T” against the background of previous therapy with diclofenac, ketoprofen or other NSAIDs the pain decreased but did not stop (there was a weak pain), it is advisable to connect one of the paracetamol preparations: Panadol 500-1000 mg 4 times a day or Solpadein contains, in addition to paracetamol, small doses of codeine and caffeine) at the same doses per paracetamol. Solpadein, despite the presence of codeine, is not a registration medication due to a minimal dose of codeine, which, however, well complements the “T” effect, as an opioid of the same class with it. A similar combination of “T” with non-narcotic analgesics may be effective for a more or less prolonged period, depending on the course of the oncological process.
Treatment of HBs on the basis of “T” is usually well tolerated by patients. When you achieve analgesia, the quality of life improves – night sleep, mood, physical activity. This “T” advantageously differs from more powerful opioids (morphine, buprenorphine), which, while causing analgesia, simultaneously lead to the suppression of physical and mental activity and other significant side effects. Estimating the tolerability of “T”, it should be said that the nature of its side properties is not fundamentally different from those inherent in morphine and its derivatives, however, the frequency and degree of their expression in “T” is much less. It is much more “soft” opioid than morphine, both in analgesic and in side effects.
According to the literature and own experience, side symptoms in the treatment of “T” are observed in about half of patients and are manifested most often by transient drowsiness, less often – nausea (very rarely vomiting), dry mouth. Constipation complicating the therapy with codeine or morphine is not typical for “T”, as is the retention of urine. Perhaps transient dizziness. Drowsiness and nausea, manifested at the beginning of treatment “T”, usually terminate within 1-2 weeks and in most cases do not require correction. In the presence of such symptoms, patients are recommended to lie down after taking “T” for 30-40 minutes. With persistent nausea, the appointment of an anti-emetic is indicated (metoclopramide 10-20 mg 3-4 times a day with a gradual cessation as nausea subsides). The frequency and severity of these adverse symptoms are similar when using different “T” dosage forms. When using candles, symptoms of irritation of the rectal mucosa (soreness and tenesmus) are possible. To avoid these phenomena, the candle should be injected as deep as possible – beyond the sphincter, into the cavity of the ampulla of the rectum.
The cases of depression of respiration and blood circulation under the influence of “T” in the indicated therapeutic doses, we have not observed, and in the literature they are also not described.
Our data on the efficacy and safety of “T” in cancer patients with CHD are confirmed by the results of a multicenter “T” study in Russia with different pain syndromes in 2000 outpatients.
In our practice, Tramal is a means of choosing among opioids an average analgesic potency for the treatment of moderate-intensity CBS. Its advantages:
- effectiveness combined with good tolerability and the absence of dangerous side effects;
- status of non-narcotic drug, which increases its accessibility for patients, facilitates the work of medical personnel in its appointment and accounting.
Tramal in the treatment of postoperative pain. Most of the surgical interventions in various areas of surgery, including oncology, are operations of moderate trauma. In oncology – these are such widespread operations as radical mastectomy, thyroidectomy, transvaginal amputation of the cervix, removal of soft tissue tumors, etc. Compared with radical intracavitary these operations are less traumatic, but they are quite extensive and are accompanied by a significant postoperative pain syndrome requiring the use of opioid analgesics. However, traditional opioids (morphine, promedol, etc.) for patients after such operations are of little use, since their use, especially in the early period after general anesthesia, is dangerous due to the development of central respiratory depression and requires monitoring of the patient in an intensive care setting. Meanwhile, according to their condition, patients after such operations do not need to be admitted to the intensive care unit, but they need a good and safe anesthesia.
In our institute, the optimal tactics of analgesia for operations of this type has been constantly developed and for the last few years. It consists in the combination of “T” with analgesics of peripheral action from a number of NSAIDs or metamizole. Preferably use one of the NSAIDs according to the principle of prophylactic analgesia, i.e. with the administration of the first dose before the beginning of the operation and with the continuation of therapy with this drug after surgery in combination with “T”. This tactic has been successfully used in more than 5000 patients.
Prophylactic preoperative doses of NSAIDs are 30 mg for ketorolac, 100 mg for ketoprofen, 8 mg for lornoxicam; The dose of metamizole is 1000 mg. Postoperative analgesia is maintained by the planned use of one of these peripheral analgesics in the recommended daily dosage in combination with “T”, the average analgesic daily dose of which varies, according to our data, from 345-29 mg on the 1st day after surgery to 205-16 mg (4th day). At the same time, good analgesia is achieved in the active state of the operated patients without serious side effects characteristic of morphine and promedol (drowsiness, lethargy, hypoventilation of the lungs).
The developed method of postoperative pain relief on the basis of “T” in combination with one of the analgesic agents of peripheral action is effective, safe, allows to carry out anesthesia of the patient in the general ward, without special intensive observation.
Tramadol (Tramal) occupies a special place among all opioid analgesics, which is determined by the originality of the mechanism of central action and clinical pharmacology. It differs from traditional narcotic analgesics of morphine series with less pronounced analgesic effect, but at the same time less pronounced side effects. In analgesic doses, he is deprived of the main dangerous properties of morphine and its analogues – a depressive effect on vital functions and the ability to induce opioid dependence. Therefore, it is safer than other opioids and is not counted as a narcotic, but as a potent remedy. Tramadol has advantages over traditional opioid analogous analgesic potency – codeine, belonging to a number of drugs and not having so many diverse non-invasive and injective forms.
All these features of tramadol make it possible to use it successfully and widely for the treatment of acute and chronic pain syndromes of moderate intensity in various fields of medicine, including oncology and surgery, where its role is particularly great.