MXPA98001222A - Quecontain composition mefenamic acid in association with code - Google Patents

Abstract

The invention relates to a paracetamol-free composition, which contains a phenamic acid derivative in association with codeine. The invention also relates to the use of said composition in the manufacture of a medicament having analgesic activity in the center.

Description

Composition containing ephemeral acid in association with codeine.

The present invention relates to a composition free of paracetamol containing fenamic acid derivative in association with codeine, this composition has analgesic activity. Many analgesic or analgesic drugs have been developed. These are usually classified as a function of the pain that is going to be treated. This classification, which originates in the World Health, it is as follows: level 1 is that of antalgics that have peripheral action, such as paracetamol and anti-inflammatory drugs without steroids (DAISE), which are effective for mild to moderate pain; level 2 is that of antalgic associations that have the peripheral action of level 1, of the paracetamol type, with light morphine drugs such as dextropropoxyphene or codeine, for the purpose of treating moderate to severe pain; level 3 is that of analgesics that have central action, strong morphine drugs with which it is intended to treat strong to very strong pains.

The associations are already known for obtaining level 2 drugs; The paracetamol / codeine association can be given as an example of a derivative of ferric acids. In addition, derivatives of phenamic acids are known and are disclosed, for example, in "The Pharmacological Basis of Therapeutics" 8a. Edition, Goodman and Gilman, pages 662-663, Perga on press 1990. Mefenamic acid, which is an analgesic that has essentially peripheral activity, but also central activity, is already known. Mefenamic acid is used to treat mild to moderate pain, taking 1 to 3 daily doses of 250 to 500 mg. each. A pharmaceutical composition comprising mefermic acid as the sole active ingredient is available under the trademark PONSTAN® from Warner-Lambert. The composition possesses anti-inflammatory, analgesic and anti-pyretic activity, and serves to mitigate the symptoms associated with rheumatic fever, arthritis and other inflammatory or painful conditions. Codeine is also known; This is a light morphine drug that has central analgesic activity, taken in doses of 20 to 60 mg. Codeine is already used in association with paracetamol, as indicated above. The use of a composition containing a combination of analgesic agents for the treatment of pain caused by excessive prostaglandin activity is disclosed in the South African patent application no. 893274. This application discloses more in particular a tertiary composition containing paracetamol, codeine and naproxen or mefenamic acid.

In PCT 85/00596 a pharmaceutical composition is disclosed comprising non-steroidal anti-inflammatory drugs in combination with at least one other component selected from an antihistamine, decongestant, expectorant or repressive against cough and its use for the relief of cough, cold or symptoms similar to the cold. The only example given describes a composition comprising ibuprofen and diphenhydramine. None of the prior art documents discloses or suggests the surprising effects obtained with the binary composition according to the present invention, and its use in the manufacture of a medicament having central analgesic activity. Thus, this invention provides a paracetamol-free composition, which contains: (a) a phenamic acid (b) codeine derivative at a codeine / phenamic acid derivative weight index comprised between 3/1 and 30/1. In a preferred embodiment, the fenamic acid derivative is mefenamic acid. In a preferred embodiment, the codeine / phenamic acid derivative weight index is comprised between 5/1 and 20/1; the index preferably comprised between 8/1 and 12. 5/1. The codeine / phenamic acid derivative ratio is advantageously about 10/1. In a preferred embodiment, the fenamic acid derivative is present in an amount of 50 to 1000 mg. In a preferred embodiment, codeine is present in an amount of 10 to 100 mg. According to a preferred feature, the composition additionally contains pharmaceutically acceptable additives. The invention also relates to the present composition used as a medicament, and notably a medicament having central analgesic activity. Similarly, the invention relates to the use of the present composition for manufacturing a medicament having central analgesic activity. Now, the invention will be described in more detail.

As used in the present description, the term "phenamic acid derivative" comprises fenamic, mefenamic, meclofenamic, flufenamic, tolfenamic and etofenamic acids, and should be taken to refer to both the acid form and pharmaceutically acceptable salts thereof , easy as the hydrochloride, etc. All the data on the weight refer to the acid form; all data indices are given with respect to mefenamic acid. As used in the present description, the term "codeine" means both the free base form and the pharmaceutically acceptable salts, such as phosphate, camsylate, hydrochloride, hydrogen bromide, etc. All data given on the weight are based on in the form of free base. The present composition, which is the association of an antalgic having peripheral action and an antalgic having central action, exhibits analgesic synergy, in other words, a surprising improvement in central activity. This has been shown from pharmacological analgesic tests carried out on the composition. The pharmaceutical composition of the invention can be used to treat inflammation in mammals, and produces an increased analgesic effect in addition to a good anti-inflammatory and anti-pyretic effect.

The compositions according to the invention take the form of a pharmaceutical composition, designed for administration in various forms, notably by the oral route. The pharmaceutical composition contains conventional additives and is prepared in a manner known to the person skilled in the art. For greater clarity, the following description concerns only mefenamic acid, but it is clear that any other fenamic acid derivative mentioned above can be used. The pharmaceutical composition of the invention typically comprises a non-toxic pharmaceutical diluent or carrier. The composition may be in the form of tablets, pills, capsules (filled in dry or liquid), dragees, pills, powders and suspensions or aqueous or non-aqueous solutions. Some examples of the substances that can serve as non-toxic pharmaceutical carriers or as ingredients of the non-toxic pharmaceutical carriers in the compositions of the invention are the gelatin capsules; sugars such as lactose and sucrose; starches, such as corn starch and potato; cellulose derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, cellulose acetate-phthalate; jelly; talcum powder; stearic acid; magnesium stearate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil; propylene glycol; glycerin; sorbitol; polyethylene glycol; ethanol; Water; agar-agar; alginic acid; isotonic saline; and phosphate buffer solutions, as well as other non-toxic compatible substances used in pharmaceutical formulations. In addition to said active ingredients and a non-toxic pharmaceutical carrier, the composition of the invention may contain coloring agents, flavoring agents and / or preservatives. These materials are used in relatively small amounts that do not add materiality to the toxicity of the final composition. The relative amounts of the active ingredients in the compositions of the invention can be varied. However, the active ingredients must be present in sufficient concentration to ensure that an adequate dose will be obtained. Typical doses per day will be at the rate of approximately 10 to 30 mg./kg. in body weight for mefenamic acid, and approximately 0.2 to 1.5 mg./kg. in body weight for codeine. The compositions can be administered orally, however, various forms of various doses can be administered by means of different routes at about the same time. It is clear that the dose itself depends on the individual, its weight and age, seriousness of symptoms, etc. Generally speaking, the composition is taken once or several times, the respective amounts of mefenamic acid and codeine absorbed are, respectively, 50 to 1000 mg. and from 10 to 100 mg. For oral administration purposes, solid compositions such as capsules or tablets, and liquid compositions such as suspensions, which contain appropriate amounts of said two active ingredients per unit dose are preferred. Solid compositions for oral administration may contain 200 mg. to 500 mg. of mefenamic acid, and 8 mg. to. 25 mg. of codeine phosphate per dose unit. Liquid preparations for oral use are prepared in a way that each dose unit, such as a tablespoon or a given number of milliliters, e.g. 5 ml. , contain between 25 mg. to 100 mg. of mefenamic acid and 1.25 mg. to 5 mg. of codeine phosphate. The daily dose of the compositions of the invention naturally varies somewhat with the nature and severity of the inflammatory condition being treated, and the size of the patient. Single or divided doses will usually be administered per day in a dosage unit form, such as capsules or tablets, each dose containing 250 mg. of mefenamic acid and 25 mg. of codeine phosphate, or suspensions, each dose containing 50 mg. of mefenamic acid and 2.5 mg. of codeine phosphate. In preparing the compositions of the invention, conventional pharmaceutical precautions and practices are used. Ordinary care must be exercised so that there is no incompatible condition between the active ingredients and the carrier, the condom, the flavoring agent, the coloring agent or any other constituent in the compositions, as well as under the conditions employed in the preparation. of the compositions. Now the invention will be illustrated, by way of non-limiting examples, with reference to the following examples.

EXAMPLE 1 Capsules containing mefenamic acid and codeine phosphate. Each capsule contains the ingredients below: INGREDIENT QUANTITY PER CAPSULE Mefenamic acid 200 - 500 mg. Codeine phosphate 8-25 mg. Binders / diluents 0.1 - 15% by mass Lubricant 0.1 - 2% by mass The ingredients are mixed together by means of conventional procedures, 1 or 0 capsules filled to their size. The capsules are suitable for the treatment of pain associated with inflammation, in a dose of one capsule three to four times a day.

EXAMPLE 2 The tablets contain mefenamic acid and codeine phosphate. Each tablet contains the ingredients below: INGREDIENT QUANTITY PER TABLET Mefenamic acid 200 to 500 mg. Codeine phosphate 8 to 25 mg. Binders 1 to 10% core mass Diluent 5 to 30% core mass Disintegrants 0.5 to 10% core mass Lubricants 0.1 to 2% more than core Core mass 225 to 800 mg.

Tablets are formulated by conventional methods, and can be coated using standard sugar-coated or film-coated ingredients. Tablets are suitable for the treatment of pain associated with inflammation, in a dose of one tablet three to four times a day.

EXAMPLE 3 A suspension containing mefenamic acid and codeine phosphate. Every 5 ml. It contains the ingredients below: INGREDIENT QUANTITY PER 5 ml. Mefenamic acid 25 to 100 mg. Codeine phosphate 1.25 to 5 mg. Suspension agents 1 to 5% mass / volume Condoms 0.1 to 2% mass / volume Sweeteners 0.05 to 25% mass / volume Flavorings 0.05 to 1% mass / volume Dyes 0 to 1% mass / volume Agents Stabilization 0.05 to 1% mass / volume Water up to 100% The suspension is formulated by means of conventional procedures.

The suspension is suitable for the treatment of pain associated with pyrexia and / or inflammation, in a dose of 2.5 ml. to 10 ml. (depending on body mass) three to four times a day. Next, the main characteristics of the compositions according to the invention are discussed.

ANALGESIC ACTIVITY. Commercially available mefenamic acid is available; the form used is the free acid form. Codeine is commercially available; the form used is the phosphate form. Two series of experimental tests were conducted to confirm the analgesic activity in mammals (SD = effective dose): the peripheral analgesic activity was determined by measuring the rear motor contractions induced in mice by means of a algogenic agent consisting of phenylbenzoquinone. Mefenamic acid can decrease the number of painful contortions measured in the control; the ED50 is 16 mg / kg .. the central analgesic activity was determined by means of the hot plate test, in which codeine is particularly active. Mefenamic acid remains very ineffective; its ED 50 is 108 mg / kg. After determining the ED 50 of mefenamic acid, several compositions according to the invention were tested. The amount of mefenamic acid was set at 500 mg. while the amount of codeine was varied. Next, the analgesic activity tests were repeated. Table 1 below gives the results, the ED50 dose is expressed in mg./kg ..

TABLE 1 COMPOSITION ANALGESIC ACTIVITY ANALGESIC ACTIVITY PERIPHERAL (MG / KG) CENTRAL (MG / KG) Mefenamic acid alone 16 108 Codeine alone 10 63 mefenamic acid + codeine index 10 / 1.2 22 53 Mefenamic acid + codeine index 10/1 20 58 From the results given in the table, the ED50 of the composition according to the invention, in an index of /1, it is 20 mg./kg. for peripheral analgesia, giving proof of the absence of synergy with respect to mefenamic acid.

Contrary to this, for the central analgesia, the results are completely surprising. For example, considering the composition according to the invention at an index of 10/1, the ED 50 for the central analgesia is 58 mg./kg., Which can be compared with the value of 108 mg./kg. obtained with mefenamic acid alone. The synergy obtained is of the order of 50%; the fact of adding codeine, therefore, makes it possible to observe the central analgesic activity in doses for which neither mefenamic acid alone nor codeine alone have analgesic properties. By way of comparison, a composition of paracetamol and codeine was tested at a weight index of 10 / 0.6. The ED 50 for this composition according to the prior art was, for the central analgesia, 367 mg./kg., In other words, a dose more than ten times greater than that needed with the composition according to the invention, in an index of 10/1.

TOXICOLOGY OF COMPOSITION ACCORDING TO THE INVENTION. Subchronic and acute toxicity was measured for the composition according to the invention at a codeine / mefenamic acid ratio of 10/1.

The composition was administered orally to two species of rodents, the rat and the mouse, and the acute toxicity was determined (DL = lethal dose): LD50 in the rat: 896 to 1339 mg./kg .; LD50 in the mouse: 600 to 814 mg./kg .. In addition, the subchronic toxicity was determined by administering the composition according to the invention to rats for a period of four weeks. The composition had a codeine / mefenamic acid ratio of 10/1. Three types of doses were administered to three groups of rats. The low dose was equal to 3 DTH (Human Therapeutic Dosage), the average dose was 9 DTH and the strong dose equal to 18 DTH. The DTH is the therapeutic dose proposed for man, in other words, from 20 to 25 mg./kg. / day of mefenamic acid and from 2 to 2.5 mg./kg. / codeine day. No signs of major intolerance appeared in the animals treated with the first two doses, and the weight changes were comparable to those of the controls. In the strongest doses, high toxicity appeared, with a mortality from the sixth day. At the end of the trials, and taking into account the histological data, the low dose (70 mg / kg of mefenamic acid and 7 mg / kg of codeine) constituted the dose without any toxic effect. Apart from this, in the average dose, pathologies following the loss of renal functions can be observed with diuresis reduction. All these symptoms are aggravated considerably with the strongest dose, and constitute the well-known dose-dependent aggressiveness of anti-inflammatory drugs without steroids in the digestive and renal system. Having in mind the above results, a clearly sufficient margin of safe margin is left for the therapeutic use of the compositions according to the invention.

BIO-AVAILABILITY. The bioavailability of mefenamic acid and codeine, starting from a 250 mg capsule form. of mefenamic acid and 25 mg. of codeine, was compared to that of mefenamic acid alone and codeine alone. The statistical comparisons carried out did not show a significant difference in any of the bioavailability parameters studied: areas under the curves for plasma concentration as a function of time (ASC), maximum plasma concentration (Cmax), time needed to achieve these concentrations (Tmax), average residence time (TPR) and elimination half-life (Tl / 2).

The relative bioavailability of mefenamic acid, evaluated by the areas under the curves (ASC) was 1.00 +/- 0.27 (see table II).

TABLE II MECHANICAL ACID T max Cmax ASC TPR hr. mcg / ml. mcg / ml x hr. hr. Only 1.35 4.38 18.57 5.3 + codeine 1.71 4.96 19.19 4.17 The bioavailability for codeine, evaluated by means of the areas under the curves, was 1.18 +/- 0.36 (see table III).

TABLE III CODEINE T max Cmax ASC TPR hr. mcg / ml. mcg / ml x hr. hr. Only 1.15 155.08 543.32 4.16 + mefenamic acid 0.98 141.08 481.06 4.00 Thus, in the present compositions, which comprise mefenamic acid and codeine, the bio-availability is equivalent to the respective bioavailability of each of the two products administered alone.

CLINICAL TRIALS. 1- Cross-over, double-screen, randomized study of the central analgesic effects of mefenamic acid and codeine phosphate, alone or in combination, compared to those of a placebo, using the non-reflexive flexion reflex in healthy volunteers. The test was carried out on healthy volunteers who had not received medication during the 15 days preceding the test. The drug studied: (500 mg of mefenamic acid, 50 mg of codeine phosphate); 500 mg. of mefenamic acid, 50 mg. of codeine phosphate; or placebo (corresponding to a capsule of identical weight but which only consists of pharmaceutically acceptable excipients) was administered orally in a single dose. The analgesic activity was evaluated by conducting the evolution of the RUI reflex threshold and the RUI reflex value (% variation) using the statistical analysis of variation for repeated measures with one factor (treatment) and for repeated measures using two factors (treatment and time). ). The variation analysis showed a time effect in the sense of an increase in the RUI reflex threshold. The degree of increase in the threshold was higher for the present medication than for the other treatments. The nociceptive reflex evoked by constant supraliminal stimulation progressively decreased as a function of time, regardless of the treatment administered. Exactly as in the case of threshold values, the greatest decrease was observed with the present medication: in 80 to 90 minutes an inhibition of approximately 40% of the nociceptive reflex was observed, while for the other products a decrease of 6% was found (mefenamic acid), 23% (codeine) and 19% (placebo). This depressive effect of the present medication is comparable to that caused by the administration of 0.1 mg./kg. of morphine hydrochloride. The regression analysis did not show a significant difference between the four treatments. The only result that suggests a difference between the treatments related to the decline of the regression line, which is significantly different from 0 for the present drug, while it is not different for the other three treatments tested. 2- Randomized double-screen test in the three parallel groups of outpatients who have pain after the extraction of a third lower molar included, tolerance and antalgic effectiveness of a single oral dose of the present drug, mefenamic acid and placebo.

Additionally, the frequency, nature and intensity of possible side effects were noted. The test was carried out using a randomized double-blind monocentric method of three groups of patients, one group (the present drug) of 55 patients, another group (of mefenamic acid) of 55 patients and a placebo group of 53 patients The patients studied had undergone local anesthesia less than 22 hours before the extraction of an included lower third molar that needed gingival incision and bone resection. The medication studied, consisting of 500 mg. of mefenamic acid + 50 mg. of codeine phosphate, 500 mg. of mefenamic acid, or a placebo was determined orally in a single dose. The intensity of the pain, the degree of relief, the use or non-use of supplementary antalgic, the patient's assessment of pain relief and the tolerance judgment were used as criteria for the evaluation. The effectiveness of the medication was evaluated by descriptive analysis, difference variance analysis at different times, multiple comparisons of average values and by Chi2 test of the evaluations of patients and researchers. Tolerance was evaluated by determining the frequency of side effects between the comparison groups that used the Chi2 test. Considering the patients as a whole, the activity of the present drug in the intensity or relief of pain was not significantly different from that of mefenamic acid at various times, these two products differing significantly from placebo except in the value of pain intensity in 30 minutes, where only the activity of the present drug differed from that of the placebo. The proportion of patients who used a supplemental antalgic was not significantly different in the groups that took the present drug and mefenamic acid alone, but did differ significantly in the placebo group. Tolerance was satisfactory and no difference in the incidence of side effects between the treatment groups came to light. 3- Randomized double-screen study of three parallel groups of hospitalized patients who experienced consecutive pain due to an episiotomy, for the tolerance and antalgic effectiveness of a single oral dose of the present medication, of mefenamic acid alone and placebo. Additionally, the frequency, nature and intensity of possible side effects were compared.

The effects of the drugs were studied in three groups of patients: 55 patients (with the present drug), 48 patients (with mefenamic acid) and 53 patients (with placebo) who were newborns and had received average lateral eposiotomy less than 24 hours previously, hospitalized with moderate to severe pain. The posology, the evaluation criteria and methods to statistically analyze the results were as described in point 2) above. Of 156 patients studied, 6 were excluded from the effectiveness analysis by taking an antalgic before the second hour. Considering the entire group of patients, the activity of the present drug in the intensity or relief of pain was not significantly different from that of mefenamic acid alone at various times, these two products differed significantly from placebo except for the pain intensity value in 30 patients. minutes and 1 hour, where only the activity of the present drug was different from that of the placebo. The proportion of patients who used a supplemental antalgic was not significantly different in the group of the present drug and mefenamic acid alone, but differed significantly from the placebo group. If only those patients who experienced severe pain are considered, the time needed to obtain significant or complete relief and the time needed to obtain complete relief differs significantly between groups., with an advantage in the present medicine. The tolerance was satisfactory and no difference in the incidence of unwanted side effects between the treatment groups came to light. 4- Randomized double-screen study in three parallel groups of hospitalized patients who experienced post-operative pain after the hemorrhoidectomy or cesarean section, tolerance and antalgic effectiveness to a single oral dose of the present medication, mefenamic acid and placebo . The frequency, nature and intensity of the possible undesirable side effects were also compared. The effects of the drugs were studied in three groups of patients: 46 patients (with the present drug), 49 patients (with mefenamic acid) and 51 patients (with placebo), who underwent the hemorrhoidectomy or cesarean section less than 24 hours previously, and were hospitalized with moderate to severe pain.

The posology, evaluation criteria and methods for the satisfactory analysis of the results were as described in point 2) above. Of the 146 patients studied, 11 were excluded from the effectiveness analysis, 10 for having taken an antalgic before the second hour and one for having vomited after taking the treatment. Considering all patients, the activity of the three products in pain intensity did not differ significantly except for the sum of the differences in pain intensity value, regardless of the period, where only the activity of the present medication differed of the placebo. For the relief of pain alone, the activity of the present drug differed from that of the placebo in the period from HO to H2. For the period HO to H6, the activity of the present drug and mefenamic acid differed significantly from that of the placebo. The proportion of patients who had used a supplemental antalgic did not differ significantly from one group to another. The time needed to obtain significant or complete relief differed significantly between the groups. The tolerance was completely satisfactory and no difference in the incidence of undesirable side effects between the groups under treatment emerged.

- Randomized double screen study in two groups of hospitalized patients who had severe pain after surgery of the stomach or facial maxillus, for antalgic effectiveness and tolerance of the present medication against paracetamol / codeine, during repeated doses. The antalgic activity and tolerance of the present drug were compared with those of an acetaminophen / codeine association. The test used a monocentric, double-screen analysis, at random, in two parallel groups of patients: 43 patients (with the present medication) and 44 patients (with paracetamol / codeine). The hospitalized patients studied had undergone, less than 24 hours previously and under general anesthesia, surgery for dental inclusion or cancer or post-traumatic intervention, and experienced severe and severe pain the day after the operation. The drug studied (500 g of mefenamic acid + 50 mg of codeine phosphate, 1000 mg of paracetamol + 60 mg of codeine phosphate) was administered three times a day for three days orally. Tolerance and analgesic activity were evaluated by pain intensity, use or non-use of a supplementary antalgic, occurrence of undesirable side effects, patient's appreciation in pain relief and total tolerance judgment. The descriptive analysis was carried out on the surgical and demographic data and for the treatments used together with the comparison of these data before the treatment, to verify the homogeneity of the two groups of patients. The criterion of a principle was expressed in a frequency table by random group. A Chi2 test was applied (or Fisher's exact test if conditions justify it). The supplementary analysis was carried out after successfully regrouping / failure. The secondary criteria were evaluated by the Chi2 test. In this study, the association of mefenamic acid plus codeine phosphate (the present drug) showed a greater analgesic effectiveness than an association of paracetamol / codeine phosphate, by the percentage of patients who had an average value of lower pain intensity at 50% of the base value, and by the percentage of partial or complete success. The two products were comparable with respect to all the other parameters studied. The biological and clinical tolerance of the present drug was completely satisfactory. Tolerance was judged satisfactory by 95.3% of patients treated with the present drug, and 93.2% of patients treated with paracetamol / codeine. 11.6% of the patients who received the present medication and 18.2% of those who received the paracetamol / codeine combination had undesirable clinical side effects. No significant difference was found. 6- Randomized double-screen study in two groups of hospitalized patients with severe pain after gynecological surgery, for the antalgic activity and tolerance of the present drug compared to paracetamol / dextropropoxyphene, in repeated doses. The tolerance and antalgic activity of the present drug were compared with those of an acetaminophen / dextropropoxyphene combination. The test was carried out using a bicentric double screen randomization method in two parallel groups of patients: 52 patients (with the present drug) and 52 patients (with paracetamol / dextropropoxyphene). Within the previous 24 hours, the hospitalized patients studied had undergone surgery under general anesthesia for dental or gynecological inclusion, pelvic cancer or breast surgery, and experienced severe acute pain the day after surgery. The medication studied (500 mg of mefenamic acid + 50 mg of codeine phosphate); u 800 mg. of paracetamol + 60 mg. of dextropropoxyphene) was administered three times a day for three days, orally. Tolerance and analgesic activity were studied based on the intensity of the pain, the use or non-use of a supplementary antalgic, the occurrence of undesirable clinical side effects, the patient's assessment of pain relief and the total tolerance judgment. The descriptive analysis was carried out on the demographic and surgical data, and for the treatments used together with the comparison of these data before the treatment, to check the homogeneity of the two groups of patients. The main criterion was expressed in a frequency table by random group. A Chi2 test was applied (or Fischer exact test if conditions justified it). The supplementary analysis was carried out after the regrouping of success / failure. The secondary criteria were evaluated by the Chi2 test. In this study, the association of mefenamic acid / codeine phosphate (the present drug) showed a greater analgesic effectiveness than the paracetamol / dextropropoxyphene association for the average pain intensity. The two products did not differ statistically with the rest of the parameters studied, but the results were quite favorable with the present medicine. The biological and clinical tolerance of the present drug was completely satisfactory. Tolerance was judged satisfactory by 86.5% of patients treated with the present drug, and 82.7% of patients treated with paracetamol / dextropropoxyphene. 26.9% of the patients who received the present medication, and 23.1% of those who received the paracetamol / dextropropoxyphene combination had undesirable clinical side effects. No significant difference was found. 7- Randomized double-screen study of two groups of hospitalized patients who had severe pain after orthopedic or traumatological surgery, for tolerance and antalgic effectiveness of the present medication compared to paracetamol / codeine, in repeated doses. The tolerance and antalgic activity of the present drug were compared with those of an acetaminophen / codeine combination. The test was carried out using a monocentric, randomized, double-screen method of analysis in two parallel groups of hospitalized patients: 44 patients (with the present drug) and 46 patients (with acetaminophen / codeine) who had experienced, within of the previous 24 hours and under general anesthesia, orthopedic or trauma surgery, and experienced acute and severe pain the day after surgery. The drug studied (500 mg of mefenamic acid + 50 mg of codeine phosphate, or 1000 mg of paracetamol + 60 mg of codeine) was administered three times a day for three days, orally. Tolerance and analgesic activity were evaluated based on pain intensity, use or non-use of supplemental antalgic, occurrence of undesirable clinical side effects, patient's appreciation of pain relief and total tolerance judgment. The descriptive analysis was carried out on the demographic and surgical data, and for the treatments used together with the comparison of these data before the treatment, to verify the homogeneity of the two groups of patients. The criterion of a principle was expressed in a frequency table by random group. A Chi2 test was applied (or Fischer exact test if conditions justified it). The supplementary analysis was carried out after successfully regrouping / failure. The secondary criteria were evaluated by the Chi2 test. In this study, the association of mefenamic acid / codeine phosphate (the present medicine) showed a greater analgesic effectiveness than that of the paracetamol / codeine phosphate association for the average pain intensity, for the evaluation of pain intensity in the analogous visual scale, for the number of patients who had complete disappearance, or significant or complete disappearance of pain and for the time needed for significant or complete relief of pain that occurred in the patients, and for the patient's assessment of pain relief at the end of the study. The biological and clinical tolerance of the present drug was satisfactory. Tolerance was judged satisfactory by 97.7% of patients treated with the present drug, and 100.0% of patients treated with paracetamol / codeine phosphate. 18.2% of patients who received the present drug and 10.9% of those who received the paracetamol / codeine phosphate combination had undesirable clinical side effects. No significant difference was found.

Claims (11)

Claims

1. A paracetamol-free composition containing a) phenamic acid derivative b) codeine at a weight index of fenamic acid / codeine derivative comprised between 3/1 and 30/1.

2. The composition according to claim 1, wherein the fenamic acid derivative is mefenamic acid.

3. The composition according to claim 1 or 2, wherein the weight index of the fenamic acid / codeine derivative is comprised between 5/1 and 20/1.

4. The composition according to claim 3, wherein the weight index of the fenamic acid / codeine derivative is between 8/1 and 12.5 / 1.

5. The composition according to claim 4, wherein the weight index of the fenamic acid / codeine derivative is approximately 10/1.

6. The composition according to any of claims 1 to 5, wherein the phenamic acid derivative is present in an amount of 50 to 1000 mg.

7. The composition according to any of claims 1 to 6, wherein the codeine is present in an amount of 10 to 100 mg.

8. The composition according to any of claims 1 to 7, which additionally contains pharmaceutically acceptable additives.

9. The composition according to any of claims 1 to 8, for use as a medicament.

10. The composition according to claim 9, for use as a medicament having a central analgesic activity.

11. The use of the composition according to any of claims 1 to 8, for the manufacture of a medicament having central analgesic activity.