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All about pain

One of nonspecific signs of trouble in work of bodies and human body systems is pain occurrence. The pain by the nature can be classified as sharp and chronic. The fact of existence of a pain can be transformed from a simple symptom (a pain – an alarm signal) to a difficult syndrome (a pain – illness). The pain phenomenon is realized through specialized system and represents many-sided process in which the set neurotransmitters and receptors both peripheral, and the central nervous system is involved. Pathophysiological mechanisms of a pain are divided into 2 types: nociceptive – owing to damage of fabrics (a skin, bones, joints, muscles, etc.) and neurotic, caused by defeat or involving of nervous structures at various levels of nervous system (texture backs, trunks, etc.). The acute pain is normal reaction to damage of a fabric and has huge value, as a sharp symptom, an alarm signal. She demands all complex of diagnostic procedures for definition of the reason. The chronic pain is caused by constant irritation nociceptors in the field of available damage of fabrics, its protective role isn't less obvious.

For representation formation about epidemiology and frequency of localization of a painful syndrome interest is represented by results of some researches. So, von Korf surveyed randomized sample of 1500 persons at the age from 18 till 75 years living in one of areas of Seattle (USA). Prevalence of the pains which duration made 1 day and more, and the pains arising some times within 1 year was studied. Prevalence of pains within previous 6 months was following: back pains – 41%, a headache – 26%, belly-aches – 17%, obverse pains – 12%, pains in a thorax – 12%. In New Zealand F. James an interview method surveyed sample of 1498 city dwellers. The majority of the interrogated have answered that at least 1 time in their life was disturbed by any pains. Most often there were articulate pains, back pains, a headache (25.3%), belly-aches (22.5%). Studying of prevalence of a pain, its characteristic and influence consequences on daily activity is spent A. Bassols in Catalonia (northern area of Spain). By a randomization method have been chosen 1964 adult inhabitants stratified on age, sex and area of residing. Prevalence of pains has made 78.6%, statistically above it was among women. On pain localization were distributed as follows: back pains – 50.9% (in regular intervals in all age groups), a headache – 40.2% (mainly at young women), pains in shins – 36.8% (mainly at elderly), pains in hips – 21.9% (young men).

Thus, according to the majority of researchers, prevalence of a pain in the general population makes from 7 to 64%, and prevalence of a chronic pain — from 7.6 to 45%. The basic localization of pains, undoubtedly, the back and a neck are, the headache and sustavno-muscular pains prevail also.

Considering many-sided nature of displays of a pain, the reason of occurrence and the development mechanism, it is necessary to use the complex approach in each specific case for a choice of adequate anesthesia. The most simple and accessible both for patients, and for doctors is the pharmacotherapy method. Now in pain therapy apply not narcotic and narcotic analgetics under the three-stage scheme consisting of consecutive application of analgetics with increasing force of action in a combination with adjuvant by therapy in process of increase of intensity of a pain.

The greatest distribution to treatment of a painful syndrome was received by preparations from group of nonsteroid resolvents (NAID) and paracetamol.

Nonsteroid resolvents (NAID) – one of most widely applied pharmacological groups in pain therapy. So, in the USA annually write out more than 70 million recipes on these preparations, 14-20 million patients accept NAID long time. Into these figures don't enter more than 26 billion tablets a year, which consumers buy without the recipe. In Italy in 2002 it has been sold more than 58.5 million packings NAID. In the developed countries these preparations receive 20–30% of persons of advanced age. Application NAID constantly increases.

Big "popularity" NAID speaks that they possess anti-inflammatory, analgesic and febrifugal effects and bring simplification the patient with corresponding symptoms (an inflammation, a pain, a fever) which are marked at many diseases.

For last 30 years quantity NAID has considerably increased, and today the given group totals a great number of the preparations different on features of action and application.

Now there is a big arsenal NAID (more than 25 names), and in applied medicine is used for treatment more than 1000 medical products created on their basis. Feature modern NAID is the variety of medicinal forms, including for local application in the form of ointments, gels, sprays, and also candles and preparations for parenteral introduction.

Paracetamol is a also one of the most often appointed preparations of group NPVP. Since 1963 paracetamol has been included in the British pharmacopoeia, since then it is widely used in medical practice as soothing and a febrifuge. Now only in Europe and the North America it is consumed to 24 billion tablets of paracetamol annually. Unlike others NAID the preparation doesn't cause damages of a mucous membrane of a gastroenteric path, hemo dyscrasia, doesn't influence aggregation of uniform elements of blood and duration of a bleeding, quickly and is full soaked up in a stomach and not accumulates in an organism. Along with it it is established that at easy and moderate pains analgesic effect of paracetamol of 500 mg approximately equally effective 500 mg of acetilsalicylic acid or 200 mg of an ibuprofen.

Now it is proved that according to recommendations the CART absolutely safe is paracetamol application in a daily dose to 4 g at adults and 60 mg/kg at children. In a poisoning and development of hepatic insufficiency results its one-stage reception by adults in a dose more than 10 g, children – 140 mg/kg.

Despite presence huge, at first sight, an arsenal of anesthetics, treatment of a sharp and chronic painful syndrome presents certain difficulties for practical doctors. So, by results of questioning more than 200 doctors, spent to 14 cities of Russia, arising problems are connected in 37% of cases with insufficient efficiency of spent therapy, and in 31% of cases – with an unsatisfactory profile of safety of applied preparations. Arising difficulties are quite explainable, considering that fact that in overwhelming majority of cases in a primary link of public health services preparations of a choice for treatment of a painful syndrome of any degree of expressiveness remain NAID, despite recommendations of experts the CART to use this group of preparations in treatment of an easy pain.

The most studied problem at appointment NAID is them gastroduodenal toxicity. It is known that adverse collateral reactions from a gastroenteric path in a kind dyspepsia can develop at 15–20% of the patients regularly accepting NAID. At long reception ulcer defeat of a stomach can develop at 5–8% of patients, a duodenal gut – at 3–5% of patients. The bleeding, ulcer punching, infringement of passableness GIT are marked at 1–1.5% of patients. The big gastroenteric bleedings and stomach punching are observed at the persons accepting NAID, approximately in 5 times more often, than at not accepting them. The economic damage from these complications reaches in the USA 4 bln. dollars in a year.

However not less significant are cardiovascular effects NAID. Now it is established that long application of preparations of the given group for persons is more senior 60 years – independent predictor occurrence, and at patients with an arterial hypertension authentically on 29% worsens possibilities of control of level the HELL. The risk of development chronic heart failure increases in 2.2 times, every fifth aggravation at patients is connected with decompensation chronic heart failure with NAID. Occurrence of the given by-effects directly connect with their influence on synthesis prostanoids that can lead to infringement of a nephritic blood-groove and a liquid delay. Braking of activity prostaglandin-sintetazy by means of NAID can cause considerable decrease in speed of a glomerular filtration and even to lead to development of nephritic insufficiency. NAID are one of the cores exogenous the reasons of decompensation chronic heart failure demanding hospitalization (especially at patients of elderly and senile age). Besides, NAID, accepted by the patient, for example, in connection with osteoarthritis, can weaken therapeutic action diuretics which application is obligatory at treatment chronic heart failure.

In connection with the appeared data about cardiovascular effects new NAID the attention of the world medical public has been turned on a question cardiovascular safety of "old" preparations of this group.

Preparations from group "old" NAID it is reversible inhibit both isoforms, thus it is important to underline that this influence is carried out for various preparations with different degree of selectivity. In this connection it is possible to assume, as not selective inhibitors can make certain impact on risk of development of cardiovascular events.

For the purpose of profile definition cardiovascular safety of preparations from group NPVP P. McGettigan and D. Henry attempt of carrying out of the regular review and the meta-analysis supervised observational the researches devoted to the given problem has been undertaken. As a result of the conducted research it was possible to find out risk of development of cardiovascular events at application both "old", and "new" NAID. So, it is established that the given indicator for an ibuprofen, piroxicam and naproxen is close to 1 (1.07, 1.06 and 0.97 accordingly), and application diclofenac, indometacin and meloxicam associates with increase of risk of development of cardiovascular events (a total indicator the SHOUTING for indometacin – 1.3, for diclofenac – 1.4, for meloxicam – 1.25).

Thus, data available now about insecurity long application NAID lead to necessity of search and working out of new medical products with similar pharmacodynamic properties.

So, in particular, developing scientific researches in the field of pain pharmacotherapy, the pharmaceutical companies were focused on working out of the medical products possessing the central mechanism of anesthetizing action or creation of combinations already studied centrally acting of analgetics, considering that the central regulation admits the most specific and reliable mechanism of management of a pain.

The clinical researches confirming advantages of combinations of analgetics, first of all opioids with nonsteroid anti-inflammatory preparations and paracetamol are known many. Application of a combination of the sedatives having complementary mechanisms and time characteristics of action, allows to receive more analgesic effect in comparison with each of the medicines entering into a combination. This advantage in therapeutic action is often reached at smaller doses of each of active components, potentially improving shipping and characteristics of safety of used analgetics. Such combined medicines possess advantages of an anesthetizing preparation, their combination leads to mutual strengthening of pharmacological effect. Abroad combinations of paracetamol with opioids are the most sold combined anesthetics and are recommended the CART for treatment moderated and a severe pain.

One of last developed fixed combinations opioids and non-opioids an analgetic is the combination tramadol/paracetamol (Zaldiar, Grjunental Gmbh). One tablet of a preparation contains 37.5 mg of tramadol a hydrochloride and 325 mg of paracetamol. Such parity provides stronger analgesic effect in comparison with each of medicines entering into a combination separately.

Efficiency and safety of a preparation of Zaldiar are well studied in variety of clinical researches at a sharp and chronic painful syndrome. Results of the meta-analysis of 3 researches of efficiency of one dose of tramadola/paracetamol with participation of 1197 patients with the expressed and moderate postoperative toothache have shown that use of 2 tablets of a combination of tramadola/paracetamol (the total dose of 75/650 mg) provides faster approach analgesia and its big duration, than appointment only 75 mg of tramadol. Time of the beginning of anesthetizing effect at appointment of a combination tramadol/paracetamol, of tramadol or paracetamol has made of 650 mg of 17, 51 and 18 minutes accordingly, thus duration analgesia was 5.03, 2.03 and 3.05 hours.

Efficiency of a combination tramadol/paracetamol is studied and at short-term treatment of a chronic pain. Addition of the specified combination to NAID or selective to inhibitors allows to raise efficiency of spent therapy at an osteoarthritis. Moreover, addition of a combination tramadol/paracetamol improves efficiency analgesia at elderly patients (is more senior 65 years), and also raises quality of life of patients.

10-day course of treatment has shown to a back pain similar efficiency of a combination of tramadola/paracetamol in comparison with use only of tramadol.

As addition of therapy with use inhibitors or NAID, the combination tramadol/paracetamol has provided the best simplification of a pain, rather than placebo addition, in 91-day, randomized, double blind multicenter research. Out-patient patients (middle age 61 year) with inadequate control of a pain in a knee or coxofemoral joint, despite spent therapy rofecoxib or celecoxib, received additive therapy by a combination tramadol/paracetamol of 37.5/325 mg (n=153) or a placebo (n=153). Value of an estimation of expressiveness of a painful syndrome on a visual analog scale at the patients receiving in addition studied combination, was authentic more low, than at receiving placebos (41.5 and 48.3 mm accordingly).

The OTS-PREPARATIONS containing nonsteroid resolvents and paracetamol, are widely enough used and in treatment migraine a headache. In controllable clinical researches efficiency of these means has been established at treatment of an easy and moderate pain, however their influence on heavy migraine a painful syndrome owing to the clear reasons wasn't studied. For treatment expressed migraine application triptans, proved the efficiency and safety in variety of researches now is recommended to a headache. So, in particular, it has been established that positive dynamics in 2 hours after hypodermic introduction sumatriptan was marked at 79% of patients and at 45–68% of patients at oral introduction of preparations of the given group. However at variety of patients use triptans is impossible owing to a profile of safety of the given preparations. So, triptans are counter-indicative at patients with an uncontrollable hypertensia, with presence in the anamnesis of the transferred heart attack of a myocardium or a stroke. Besides, triptans it is possible to apply no more than 2 times a day.

Opioids (in particular, a hydrocodon) also are widely applied in treatment sharp migraine pains. In one of supervision it has been shown that 28% of appointments of opioids are connected with a headache or a migraine. However till now in clinical researches efficiency of use has been proved at a migraine only nasal forms butorphanol and a codeine-containing of the combined preparations. And, certainly, in clinical recommendations, in connection with possibility of development of dependence to the specified preparations, their application at a sharp migraine is limited on duration.

Considering the above-stated, it becomes clear that search of effective and safe preparations in treatment moderated and expressed migraine pains proceeds, in this connection properties of a combination tramadol/paracetamol in therapy of the given disease have been studied also during randomized double blind, a placebo-supervised of clinical research in parallel groups. Research is spent at the adult patients suffering migraine by a pain (migraine a pain estimated according to criteria of the International society of a headache). Patients received or a combination tramadol/paracetamol in a dose of 75/650 mg accordingly, or a placebo. Expressiveness migraine a pain and the symptoms connected with a migraine, has been estimated before reception of a preparation and in 0.5, 1, 2, 3, 4, 6 and 24 hours after prescription of medicine. In total 305 patients have been included in research, from them 154 have received a studied combination, 151 patients – a placebo. It has been as a result established that the answer to preparation reception was statistically authentically above in group of the patients accepting active substance, rather than in placebo group, in all time intervals from 30 minutes till 6 o'clock (12.3 and 6.6%; 64.9 and 37.7% accordingly). In 2 hours intensity of a headache has decreased at 55.8% of the patients who have received a combination tramadol/paracetamol, and at 33.8% of the patients who have received a placebo (p < 0.001). The painful syndrome was completely stopped statistically authentically more often in group of the patients accepting a combination tramadol/paracetamol, in comparison with a placebo in 2 hours after preparation appointment (22.1 and 9.3%), in 6 hours (42.9 and 25.2%) and in 24 hours (52.7 and 37.9%) (fig. 1). Appointment of a combination of analgetics has led to statistically authentic reduction in 2 hours of expressiveness of photophobia (it was marked at 34.6% of patients in studied group, 52.2% of sick placebos in group) and phonophobia (34.3 and 44.9% accordingly). For the sake of justice it is necessary to notice that application of a combination tramadol/paracetamol doesn't influence such symptom of a migraine as vomiting in 2 hours after appointment of a preparation it came to light at 38.5% of the patients receiving the investigated combination, and at 29.4% of sick placebos in group (in this case statistically authentic distinctions between groups it has not been revealed).

The combination tramadol/paracetamol has favorable enough profile of safety. As shown in a number of the researches, arising during preparation reception the undesirable phenomena had passing character and were easy or moderate degree of expressiveness. Frequency of their occurrence was similar to that at application only of tramadol in a dose of 75 mg. The nausea (21 and 21%), vomiting (23 and 24%) and dizziness (5 and 5% accordingly) most often came to light. Frequency of occurrence above mentioned the undesirable phenomena at paracetamol use in a dose of 650 mg has made 9, 7 and 4%, an ibuprofen – 10, 7 and 3%, a placebo – 16, 10 and 4% accordingly.

Important, till now debated, there is a question of formation of dependence at application of tramadol. The research spent Adams E.H has been devoted studying of this problem. The period of supervision over them has made 1 year, dependence formation was estimated on an integrated indicator – to the index of dependence including an estimation of use of preparations with a view of, not designated in the doctor's instruction, impossibility to stop medicine use, independent increase of a dose. As a result of the spent work it has appeared that frequency of formation of dependence to tramadol doesn't differ from similar indicator NAID (2.7 and 2.5% accordingly) and was statistically authentically above at hydrocodon use (4.9%).

In connection with the saved up data about favorable enough profile of tramadol safety experts the CART at session of Committee on medicinal dependence in March, 2006 the decision not to include the given preparation in restrictive lists of the medical products causing medicinal dependence which turn should be supervised regulatory by bodies was accepted.

Thus, the data of scientific researches available for today allows to confirm:

  1. Use of the combined analgetics with the central mechanism pain actions is one of ways of increase of efficiency and safety of pharmacotherapy of a pain;
  2. Application of the combined analgetic tramadol/paracetamol in a dose of 75/650 mg at a migraine authentically reduces expressiveness of a headache, photophobia and phonophobia.
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