Tramadol (Tramal) in the treatment of acute and chronic pain syndromes | Osipova N.A. | “Breast Cancer” №4 from 02.26.2003
Moscow Research Institute of Oncology. P.A. Herzen
The main method of treatment of acute and chronic pain syndromes in modern medicine is systemic pharmacotherapy. The latter can be carried out using different methods of administering the analgesic into the body (oral, rectal, sublingual, transdermal, by injection), but in any case, the drug is absorbed into the systemic circulation, and then to the site of its action (unlike regional the method of administration of the analgesic, for example, perineural, epidural).
For the treatment of low-intensity pain, according to WHO recommendations , various non-opioid analgesics are used, and for moderate and high-intensity pain, opioid analgesics are used. Non-opioid anesthetics have a predominantly peripheral effect at the level of the focus of pain, have a small analgesic potential and therefore are only suitable for the treatment of mild pain. Opioids are analgesics of central action, implemented through the endogenous opioid system of the body at the level of the spinal cord and brain by inhibiting the upward flow of pain impulses. They differ from each other in their analgesic potential and ability to arrest moderate or severe pain. Due to its good analgesic properties, opioids are widely used in various fields of medicine dealing with intense pain, especially in oncology and surgery [3, 7].
A common feature of all opioids is the non-selective nature of their action, i.e., along with analgesia, they cause a number of other side effects and differ from each other in the severity of certain properties, which is associated with the individual characteristics of their interaction with opioid receptors. . An important condition for proper operation with an opioid is the 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 interaction with receptors.
The main class consists of opioid agonists or agonists of opioid m (mu) receptors, including substances and drugs of different analgesic power, including the powerful drug heroin, traditional strong opioid analgesics – morphine, fentanyl, pyritramide, and also less powerful – promedol, prosidol, tramadol, codeine. This group of opioids has side effects associated with depression of the stem structures and centers of the medulla oblongata, such as sedation (less euphoria), general weakness, inhibition of the cough reflex, and in large doses – respiratory depression (bradypnea, apnea) and blood circulation (hypotension, bradycardia) . Along with these inhibitory effects, opioid agonists have an activating effect on vomiting centers with possible development of nausea (vomiting), as well as on the smooth muscle of hollow organs, which can result in impaired motility of the latter (constipation, urinary retention and bile, a tendency to bronchospasm). All of these serious side effects are most pronounced in the most potent opioid analgesics (fentanyl, morphine) and less common in drugs with lower analgesic potentials [3, 7].
All opioid agonists, except tramadol, have a specific ability to cause physical and mental dependence, so they are included in the International Convention on Drugs into the category of drugs under control , and they are subject to special rules for prescription, discharge, accounting, storage, transportation, reporting, defined by the relevant orders of the Ministry of Health of the Russian Federation . Tramadol, which represents an exception, does not refer to drugs, since, according to extensive world and domestic experience, no clear data has been obtained for the development of tramadol dependence. This drug is listed as a potent drug and is written on a prescription form for potent substances [1,9]. A characteristic feature of strong opioids is also tolerance, i.e., a decrease in the analgesic effect with an increase in the duration of opioid injection into the body, which requires, during long-term therapy, a gradual increase in dose to maintain pain relief [4,7]. Thus, the dose of morphine can increase tenfold compared with the initial treatment during several months, reaching or even exceeding 1000 mg / day.
The next class of opioids, partial opioid m – receptor agonists, is represented by buprenorphine, similar in its properties to morphine, but with longer and somewhat less pronounced analgesic and other side effects.
Compared with other classic opioid agonists, buprenorphine has a lower narcotic potential, but in Russia it is also counted as a drug.
Unlike morphine, buprenorphine has a “ceiling” of an analgesic dose, over which the analgesic effect ceases to increase. Different authors define this limit in the range of 2.4–5 mg / day [7,17], which can limit the continuation of therapy with buprenorphine in chronic pain syndrome and is a signal to switch to a more powerful opioid, morphine, which does not have an analgesic dose “ceiling” .
The class of mixed opioid antagonist agonists includes three drugs (pentazocine, butorphanol, what is tramadol used for: nalbuphin), which are k (kappa) receptor agonists and m-receptor antagonists. As k-receptor agonists, these what is tramadol used for: opioids cause less pronounced analgesia than morphine, and have a slightly different spectrum of side effects (sedation prevails, nausea, dizziness, and depression of respiration are less common). As m-receptor antagonists, opioids of this class can weaken or eliminate the actions of classical opioid agonists, including analgesia [3,7,17]. In this regard, the combined use of opioid agonists, antagonists and morphine analgesics is impractical.
Drugs in this class, like buprenorphine, have an inherent effect of the “ceiling” (Ceiling effect). The agonists – antagonists of the last generation butorphanol and nalbuphine (unlike pentazocine) are not listed in the register of narcotic drugs and are potent substances. They play a supporting 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 characterized by ketamine, which is distinguished by its moderate analgesic effect  and a whole complex of side activating effects (tachycardia, hypertension, psychomotor agitation).
An opioid antagonist of all groups is naloxone, which rapidly neutralizes all their effects, including analgesia.
Existing opioid analgesics differ not only in the nature of the interaction with certain opioid receptors, but also in the peculiarities of binding with them in strength and duration. The higher the affinity of the opioid for the receptor, the stronger the analgesia, the longer the connection with the receptor, the longer the analgesia [7,17].
Choosing an opioid for treating moderate to high intensity pain
An important consequence of the analysis of the mechanism of action of opioids is the generally accepted position of the main role in opioid pain therapy for analgesics belonging to the class of opioid agonists , since drugs of all other groups have certain limitations (effect of the analgesic dose “ceiling”, antagonism in relation to the most powerful analgesics of the morphine group, undesirable side properties). This provision is especially important to consider when treating chronic pain syndrome, in order to obtain an optimal result of pain relief and to avoid possible failures.
The range 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 treating such pain exist in different areas of medicine.
In which cases is indicated the appointment of an opioid analgesic for pain relief and how to choose the right opioid? To do this, you must first be guided by certain general rules.
Indications for the appointment of an opioid occur when treatment with non-opioid analgesics does not lead to the elimination of pain, that is, pain exceeds the degree of weak. In the treatment of chronic pain in cancer patients, opioid agonists should be preferred.
When determining the intensity of pain, one should be guided by a simple scale of verbal scores of pain (SHO): 0 – no pain, 1 point – weak, 2 points – moderate, 3 points – strong, 4 points – the most severe pain. For the treatment of moderate to high intensity pain in Russia, the guidelines of the Ministry of Health of the Russian Federation recommended: tramadol, prosidol for moderate pain, buprenorphine for severe pain, and morphine or fentanyl (including in the transdermal form) for the most severe pain [10.
Doctors authorized to work with drugs (most often in oncological and surgical institutions) have the right to prescribe opioid analgesics related to narcotic drugs.
How to use What Is Tramadol at home, video lesson
Opioids – non-narcotics, classified as potent drugs (tramadol, butorphanol, nalbuphine), can be written out on prescription form for potent drugs by any doctor in consultation with the head of the department if necessary to relieve pain from the patient, which cannot be eliminated by non-opioid analgesics (articular, neurogenic and other non-opioid painkillers (neuropathic and other). pain). Among opioid agonists, tramadol is the only non-narcotic drug.
Clinical pharmacology of tramadol
Tramadol (Tramal) is an opioid agonist that stands alone among all the 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 by special scientific research of its drug potential [7,12, 15,16, etc.].
In volunteers who received the maximum dose of tramadol (Tramal, hereinafter referred to as “T”), and in cancer patients who had been treated for this pain for a long time, a drug dependence test was performed using the opioid antagonist naloxone. It is known that in heroin and other drug addicts the introduction of naloxone into the body immediately causes the development of drug withdrawal syndrome (withdrawal syndrome), manifested by severe mental and physical symptoms: severe psychomotor agitation, fear of death, panic, acute cramping pain in the abdomen, vomiting, chills, tremors , tachycardia, etc. In the studied people, as in the experiment on animals, on the background of long-term administration of “T”, naloxone did not cause the indicated symptoms or their manifestations were unclear and did not reach what is tramadol used for: radatsii “withdrawal symptoms mild.” The likelihood of mental dependence on “T” is minimal; in the above studies, the drug did not reveal a euphoric or dysphoric effect. It was established that in patients with opiate addiction “T”, like placebo, does not eliminate subjective discomfort against the background of abstinence , i.e. it does not have a substitute effect of the drug (unlike other opioids studied – promedol, butorphanol, nalbuphine , buprenorphine).
Unlike other opioid agonists, “T” has a dual mechanism of action. It has been established that analgesia caused by “T” is not completely eliminated by the opioid antagonist naloxone and, along with the opioid mechanism, is implemented by additional inhibition of pain impulses involving the serotonin – adrenergic systems . That is, according to the mechanism of analgesic action, “T” is not completely identical to other opioid agonists.
Recently, there have been reports in the Russian media about the use of “T” by 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 incorrect interpretation of the properties of “T” by journalists. The television showed in detail the case of a drug addict recorded by a video camera after intravenous injection of retard “T” tablets melted on the fire and with something diluted in oral tablets. Such a mixture could contain any substances that are toxic to the body when injected into the blood, therefore it is unlikely that the “T” could be considered as the root cause in this case.
In an article published by the newspaper Moskovsky Komsomolets dated 28.08.02, “T” is characterized as “a potent narcotic drug from the group of heroin synthetics, its action is very similar to methadone.” This characteristic is absolutely untrue, so experts view this publication as “unprofessional and biased”. Neither heroin nor methadone “T” has anything to do with both pharmacological properties and clinical action. It is fundamentally different from them and from other narcotic analgesics by a milder action and minimal narcotic potential, as described in detail above. However, the uncontrolled use of “T”, like any other drug, can lead to serious consequences, because all drugs, without exception, when therapeutic doses are exceeded, cause various side effects of what is tramadol used for: and exhibit toxic properties. This also applies to a wide range of OTC, including analgesic drugs. “T” according to the order of the Ministry of Health of the Russian Federation of August 23, 1999 No. 328 “On rational prescription of medicinal products, rules for prescribing them and the procedure for dispensing them by pharmacies” should be dispensed according to a doctor’s prescription on a form for potent drugs.
The following is a description of the main clinical effects of “T”, which by their nature are similar to the effects 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 potential of morphine [4, 7], it is equal to or slightly exceeds the potential of codeine; in terms of efficacy, 50 mg of “T” is equivalent to 1000 mg of metamizole , i.e. “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 found significant respiratory depression in postoperative 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 when administered intravenously by bolus, whereas morphine at a therapeutic dose of 0.14 mg / kg statistically significantly and significantly reduces the frequency of respiration and increases the voltage of CO2 in exhaled air . That is, in the recommended doses, “T” does not cause depression of respiration, but it cannot be excluded that it is possible if these doses are exceeded. There is no inhibitory effect on the blood circulation “T”. In contrast, 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 quick return to the original values, which is explained by the sympathomimetic component of its action . No effect of “T” on the level of histamine in the blood and on mental functions was noted . “T” is metabolized in the liver. Only one metabolite of it is active. The half-life of “T” when administered orally or intravenously is 5–6 hours, it can increase in patients with impaired liver and kidney function. About 90% of the oral dose “T” is excreted by the kidneys . “T” has beneficial pharmacokinetic characteristics. Its absolute availability with intramuscular administration is close to 100%, with rectal – 78%, with oral – 68% (with a subsequent increase with continued therapy). These figures are significantly higher than those of morphine and pethidine. The peak concentration of “T” in the plasma when taken through the mouth  is achieved after 1.6-2 hours.
Clinical experience with tramal
The first publications on the use of “T” in the clinic relate to the beginning of the 80s of the twentieth century, that is, its medical use has a 20-year history. During this time, the indications for treatment of “T” in various acute and chronic pain syndromes were determined, its analgesic and side properties, optimal methods and methods of its use in various fields of medicine: in oncology, surgery, traumatology, rheumatology, neurology, cardiology, etc. .
What Is Tramadol Used For – weight loss and principle of action
In the practice of Moscow them. PA Herzen “T” is widely used to treat both acute (postoperative – p / o BS) and chronic (CBS) pain in cancer patients. The overall experience of its use at the institute exceeds 6000 observations, and the duration of therapy ranged from several days to many months with CBS.
In appointing “T”, we are guided by the general principles of the medical treatment of pain syndromes . The main criterion is the intensity of pain, as measured by the above scale (SHVO). The indication for the appointment of “T” in both CBS and BS n / a is the pain of moderate intensity (2 points for SCR). There is no need to prescribe a “T” for mild pain (1 point on ShVO), where anesthesia can be achieved with the help of non-opioid analgesics (different NSAIDs, paracetamol preparations). “T” is not indicated even with severe pain (3-4 points for ShVO), since it is not sufficient to eliminate it, and in these cases more powerful opioids should be used to avoid further strengthening of the pain syndrome.
Most often during opioid therapy, including “T”, it is advisable to combine an opioid with non-opioid components in order to increase the effectiveness and tolerability of analgesia, although monotherapy is quite acceptable.
Pathogenetically justified is the addition of “T” to one of non-opioid analgesics of peripheral action, which suppress the production of prostaglandin pain mediator in the pain center (ketoprofen, lornoxicam, diclofenac, etc.) and / or central action inhibiting this mediator at the level of painful structures of the spinal cord (paracetamol). This allows you to get full pain relief while reducing the need for an opioid, that is, when using it in reduced doses and less likely to have side effects. Clinical confirmation of the feasibility of such a tactic of what is tramadol: with opioids is contained in numerous publications, including the work of the staff of our institute [3,5,8,10 and others].
The choice of dosage form, dose of “T” and drugs for combination with it depends on the nature of the pain syndrome, its localization, the individual characteristics of the patient.
Dosage forms and dosages of Tramal. Tramal is presented in various forms:
Injection solution (ampoules 1 and 2 ml), 50 mg in 1 ml.
Capsules 50 mg
Candles 100 mg
Retard tablets 100 mg, 150 mg.
The recommended single dose of 50-100 mg; daily up to 400 mg. The drug is administered 4 times a day. Tramal in the specified forms is produced and available in Russia.
Tramal with chronic pain syndrome of different origin is used widely and successfully. In this article, we consider this on the example of chronic pain syndrome (CSC) of oncological origin, 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 CBS in over 1000 patients, it is advisable to prescribe with uncomplicated moderate (2 points) somatic CBS (tumor damage or metastases 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 cancer patients pass through this phase of CBS, and the duration of CBS of moderate intensity varies widely, due to individual tumor growth rates.
Practice shows that the appointment of “T” is not shown in severe CBS, complicated by the neuropathic component, due to the involvement of nerve formations. In these cases, stronger opioid analgesics are necessary in combination with complex special therapy.
“T” is prescribed when the initial non-opioid therapy (NSAIDs, paracetamol preparations) becomes insufficiently effective, while maintaining this therapy, which has its own pathogenetic orientation, which complements the action of the opioid.
The presence of different dosage forms makes it possible to choose the best of them for a particular patient. In most cases, the usual oral forms of what is tramadol: (capsules, retard tablets) are applicable, and in the absence of this possibility (patients with dysphagia in cancer of the esophagus, stomach) another non-invasive route of administration can be used – rectal. In the form of what is tramadol: “T” injections for long-term treatment of CBS are usually not used due to invasiveness.
For long-term therapy, retard tablets are the most convenient, which must 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 “T” begins with a minimum single dose of 50 mg (1 capsule) in order to assess both the analgesic effect and the tolerability of the drug. With good analgesia and tolerability, they retain this single dose, administered 3-4 times per day (taking into account the duration of analgesia). If there is insufficient analgesia 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 in single doses of 100 mg up to 4 times a day (capsules or suppositories), but it is more advisable to recommend a patient to take long-term retard tablets 150-200 mg 2 times a day, which is much more convenient (the first dose in the morning after sleep, the second – in the evening before bedtime). Additional non-opioid analgesics prescribed by their own scheme.
A clinical trial of “T” in oncological patients with CBS [6,7,8] showed that with initial moderate pain (2 points) the drug always causes its elimination, but with stronger pain, anesthesia with the above therapeutic doses is not achieved, therefore if a single a dose of “T” of 100 mg in the non-retard form is not sufficient to relieve pain, which means that the intensity of the pain has been underestimated and that analgesic therapy must be strengthened. This can be achieved either by switching from “T” to a stronger opioid, while maintaining the same non-opioid therapy, or by additional prescription of another non-narcotic analgesic, not previously used. For example, if after prescribing “T” against the background of previous therapy with diclofenac, ketoprofen or other NSAIDs, the pain decreased but did not stop (weak pain remained), it is advisable to connect one of the paracetamol preparations: Panadol 500-1000 mg 4 times a day or Solpadine ( contains, in addition to paracetamol, small doses of codeine and caffeine) in the same doses per paracetamol. Solpadein, despite the presence of codeine, is not an accounting drug due to the minimum dose of codeine, which, however, well complements the effect of “T”, as an opioid of the same class with it . Such a combination of “T” with non-narcotic analgesics can be effective for a more or less long period, depending on the course of the cancer process.
Such therapy (while it is effective) is more accessible to patients than drug treatment, given the still unformed system of full supply of narcotic analgesics for cancer patients in our country.
“T” based CBS treatment is usually well tolerated by patients. When analgesia is achieved, the quality of life improves – night sleep, mood, physical activity. This “T” compares favorably with more powerful opioids (morphine, buprenorphine), which, causing analgesia, simultaneously lead to inhibition of physical and mental activity and other significant side effects. Assessing the tolerability of “T”, it should be said that the nature of its side properties is not fundamentally different from that of morphine and its derivatives, but the frequency and degree of their severity of “T” is much less. It is a much milder opioid than morphine, both for analgesic and for side effects.
According to the literature and my own experience [2,3,7,8], adverse symptoms in the treatment of “T” are observed in about half of the patients and are most often manifested by transient drowsiness, less often by nausea (very rarely vomiting), dry mouth. Constipation complicating therapy with codeine or morphine, is not typical for “T”, as well as urinary retention. Perhaps transient dizziness. Drowsiness and nausea, manifested at the beginning of treatment “T”, as a rule, stop within 1-2 weeks and in most cases do not require correction. If these symptoms are present, patients are recommended to lie down after taking “T” for 30–40 minutes. With persistent nausea, the appointment of an antiemetic agent is shown (metoclopramide, 10–20 mg 3–4 times a day, with a gradual cessation as the nausea subsides). The frequency and severity of these adverse symptoms are similar when using different dosage forms “T”. When using candles, symptoms of irritation of the rectal mucosa are possible (soreness and tenesmus). To avoid these phenomena, the candle should be inserted as far as possible – outside the sphincter, into the cavity of the rectal ampulla.
We did not observe cases of depression of respiration and blood circulation under the action of “T” in the indicated therapeutic doses, and they are also not described in the literature [2,3,5,6,7,13].
The data we obtained on the efficacy and safety of “T” in cancer patients with CBS are confirmed by the results of a multicenter study “T” in Russia with various pain syndromes in 2,000 outpatients .
In our practice, Tramal is the medium of choice for opioids of moderate analgesic potency for the treatment of moderately severe CBS. Its advantages are:
effectiveness combined with good tolerability and the absence of dangerous side effects;
the status of a non-narcotic drug, which increases its accessibility for patients, facilitates the work of medical personnel for its intended use and accounting.
Tramal in the treatment of postoperative pain. Most of the surgical interventions in various areas of surgery, including in oncology, are operations of average trauma. In oncology, these are widespread operations such 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 are quite extensive and are accompanied by significant postoperative pain syndrome requiring opioid analgesics. However, traditional opioids (morphine, promedol, etc.) are not suitable for patients after such operations, since their use, especially in the early period after general anesthesia, is dangerous for the development of central respiratory depression and requires monitoring of the patient in the conditions of the intensive care unit. Meanwhile, in their condition, patients after such operations do not need to be hospitalized in the intensive care unit, but they need good and safe pain relief.
In our institute, the optimal tactics of anesthesia for pain relief for this type of operation has been developed and has been constantly applied over the past years. It consists of a combination of “T” with peripheral analgesics from a number of NSAIDs or metamizole. We consider it preferable to use one of the NSAIDs on the principle of prophylactic analgesia, i.e., with the introduction of the first dose before the operation and with the continuation of therapy with this drug after the operation in combination with “T”. This tactic has been successfully applied in more than 5,000 patients [5,8,10].
Preventive preoperative doses of NSAIDs are 30 mg for ketorolac, 100 mg for ketoprofen, and 8 mg for lornoxicam; Metamizole dose – 1000 mg. Postoperative analgesia is supported by the planned use of one of these peripheral analgesics in the recommended daily dose in combination with “T”, the average analgesic daily dose of which is tramadol: varies, according to our data, from 345 ± 29 mg on the 1st day after surgery up to 205 ± 16 mg (4th day). At the same time, good analgesia is achieved with the active state of operated patients without serious adverse symptoms characteristic of morphine and promedol (drowsiness, lethargy, hypoventilation of the lungs).
The developed method of postoperative anesthesia on the basis of “T” in combination with one of the peripheral analgesics is effective, safe, allows for 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 peculiarity of the mechanism of central action and clinical pharmacology. It differs from the traditional narcotic analgesics of the morphine series by a 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 cause opioid dependence. Therefore, it is safer than other opioids and counted not as narcotic, but as potent drugs. Tramadol has advantages over the traditional opioid of similar analgesic potency – codeine, which belongs to a number of drugs and does not have so many different non-invasive and injectable forms.
All these features of tramadol allow it to be successfully and widely used 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 especially great.
1. Babayan E. A., Gaevsky A. V., Bardin E. V. Legal aspects of drug trafficking, psychotropic, potent, toxic substances and precursors. M. MCFER, 2000, 438 p.
2. Bunyatyan A. A., Trekova N. A., Osipova N. A., Manukyan L. M., Folomeev M. Yu. Analgetik Tramal in the treatment of acute and chronic pain in 2,000 outpatients. New drugs. 1997, Vol. 7, pp. 3-11.
3. Lebedeva R.N., Nikoda V.V. Pharmacotherapy of acute pain. M.AIR ART, 1998, p. 7 – 39.
4. Cancer anesthesia and palliative treatment. WHO, Geneva, 1992, 76 p.
5. Osipova N. A., Petrova V. V., Dolgopolova T. V., Vetsheva M. S., Andrianova K. Yu., Beresnev V. A. Synthetic opioids of the last generation in oncosurgery. Russian Medical Journal, 1995, No. 1, p. 35 – 39.
6. Osipova N. A., Novikov G. A., Prokhorov B. M., Loseva N. A., Sokolenov A. S., Abuzarova G. R. Tramal in outpatient therapy for chronic pain in cancer patients. New drugs, 1997, Vol. 7, s. 3-11.
7. Osipova N. A., Novikov G. A., Prokhorov B. M. Chronic pain syndrome in oncology. M. Medicine, 1998, 178 p.
8. Osipova N. A., Novikov G. A. Pain syndromes in the oncological clinic. In the book. “Selected lectures on clinical oncology”, M. 2000, p. 213 – 226.
9. Osipova N. A., Abuzarova G. R. Treatment of chronic pain in incurable cancer patients at home. Doctor, 2002, № 4, p. 7 – 9.
Is Tramadol in bodybuilding: how to take, composition, reviews
10. The procedure and timing of the use of narcotic analgesics. Methodical instructions of the Ministry of Health of the Russian Federation., M. 2001, 23 p.
11. Pchelintsev M.V., Soloviev S.L., Safronov A.G., Zvartau E. E. Clinical and psychological studies of the psychotropic effect of opiate receptor agonist-antagonists. In the book. “Pharmacodynamics of painkillers in experiment and clinic”, L., 1990, p. 130 – 136.
12. Barth, H., Durra, S., Giertz, H., Goroll, D., Flohe L. Long-term administration of tramadol. Pain, 1987 b, suppl. 4, Abstract No. 439, p. 231.
13. Drugs. Reprint, (Focusion Tramadol). Aug. 1993, V. 46, No. 2, p. 313 – 340.
14. Liao S., Hill J.F., Nayak R.K. Pharmacokinetics of tramadol following single and multiple oral doses in man. Pharmaceutical. Research, 1992, 9 Suppl., P. 308, Abstract No. PPDM 8206.
15. Preston K.L., Jasinski D.R., Testa M. Abuse potential and Pharmacological comparison of Tramadol, Morphine and Pethidine. Drug and Alcohol Dependence, 1991, 27, p. 7 – 17.
16. Richter, W., Barth, H., Flohe L., Giertz, H. Clinical review of the course of oral therapy with Tramadol. Arzneimittel – Forchung / Drug Research 1985, 35, p. 1742 – 1744.
17. WHO Expert Committee on Drug Dependence: Twenty-fifth Report. Series 775. WHO, Geneva, 1989.