WO2007105929A1 - Composition pharmaceutique synergique à base de tramadol et de clonixinate de lysine - Google Patents

Composition pharmaceutique synergique à base de tramadol et de clonixinate de lysine Download PDF

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WO2007105929A1
WO2007105929A1 PCT/MX2006/000018 MX2006000018W WO2007105929A1 WO 2007105929 A1 WO2007105929 A1 WO 2007105929A1 MX 2006000018 W MX2006000018 W MX 2006000018W WO 2007105929 A1 WO2007105929 A1 WO 2007105929A1
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pain
tramadol
composition according
analgesic
combination
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PCT/MX2006/000018
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Spanish (es)
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Graciela de los Ángeles AGUILERA SUÁREZ
Martha Rosaura JUÁREZ LORA
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Farmacéuticos Rayere, S.A.
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Priority to PCT/MX2006/000018 priority Critical patent/WO2007105929A1/fr
Priority to ARP070101074A priority patent/AR057508A1/es
Publication of WO2007105929A1 publication Critical patent/WO2007105929A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to pharmaceutical compositions containing two active ingredients, one being a weak opioid receptor agonist, known as tramadol, and the other a non-steroidal anti-inflammatory analgesic known as Usin clonixinate.
  • the tramadol to which the present invention refers can be any of the following compounds: ( ⁇ ) cis -2 - [(dimethylamino) methyl] -l- (3- methoxyphenyl) cyclohexanol (tramadol), its N-oxide derivative (" tramadol N-oxide "), or its derivative O-desmethyl tramadol” or mixtures thereof.
  • This also includes the individual stereoisomers, mixtures of stereoisomers, including racemates, pharmaceutically acceptable salts such as the hydrochloride salt, solvates and polymorphs of the material tramadol.
  • the combination produces analgesic pharmacological effects that indicate super-additivity (synergy). Due to the characteristics of the drugs that compose it, the CLT combination is designed for the treatment of moderate to severe pain of acute origin of the musculoskeletal system, for the treatment of postoperative pain in the treatment of dental pain, in migraine and headache, and in the treatment of neuropathic and cancer pain.
  • the combination of two or more painkillers is a resource for the effective treatment of pain in which, similar to what occurs during the administration of general anesthesia, two or more drugs are combined, sometimes administered at different levels (peripheral, spinal) that act by different mechanisms.
  • the goal of combining pain relievers with different mechanisms of action is to use low doses of each of the drugs in the combination, improving the level of analgesia, while reducing adverse effects (Barkin, 2001).
  • Opioid drugs have been used for many years as analgesics to treat severe pain, however, opioids, especially at high doses, show very severe side effects, and as a result cannot be administered repeatedly or in high doses. These side effects are well documented (Gustein and Akil, 2001). Among the undesirable effects common to all of them are: nausea and vomiting, dullness, confusion, vertigo and instability, constipation, increased intracranial pressure, increased bile duct pressure, urinary retention, delirium and hallucinations in the elderly, dysphoria, respiratory depression, miosis and drug dependence. Rare are rash, contact dermatitis, bronchial spasm in asthmatics.
  • non-steroidal anti-inflammatory pain relievers are frequently not effective enough for the treatment of severe pain such as postoperative or cancer pain (Hanses et al., 1996). Therefore, combinations of NSAIDs and opioids can be beneficial in the treatment of these types of pain because the drugs of these two families act by different mechanisms and can produce a synergism in the analgesic effect. Clinical studies have shown an increase in analgesic efficacy when these types of drugs are combined (Sunshine et al., 1997). Furthermore, there are clinical reports that show that the combination of NSAIDs and opioids in the treatment of postoperative pain allows a reduction of 20 to 50% in the dose of opioids (Dahl and Kehlet, 1991). .
  • compositions including combinations of opioid analgesics with non-analgesic drugs have been reported to exhibit a variety of effects, whether subadditive (inhibitory), additive, or superadditive (Takemori, 1976).
  • subadditive inhibitor
  • superadditive Takemori, 1976
  • morphine and methadone another analgesic opioid
  • exhibits an additive analgesic effect (Taber et al., 1969).
  • tramadol may produce certain characteristic side effects such as hot flashes and sweating. Beyond these adverse effects, the combination of opioid and non-opioid activities of tramadol makes tramadol a unique drug. In this sense, there are clinical reports for the case of the combination of diclofenac with tramadol in which no increase in adverse reactions is observed (Wilder-Smith et al., 2003).
  • tramadol and NSAIDs Some of the commercially available combinations between tramadol and NSAIDs are: paracetamol / tramadol, and ketorolac / tramadol for the treatment of pain syndromes ranging from moderate to severe pain and for various types of pain from inflammatory to neuropathic.
  • the present invention relates to the combination of tramadol and Usina clonixinate for the treatment of pain localized in the musculoskeletal system and others. This combination has a high analgesic potency, so it can be formulated orally or injectable with lower doses of Tramadol and Usina clonixinate than those usually prescribed for the drugs administered individually to have the same analgesic potency.
  • Tramadol hydrochloride has the chemical name of hydrochloride of: ( ⁇ ) cis -2- [(dimethylamino) methyl] -l- (3-methoxyphenyl) cyclohexanol, and its formula is: C 16 H 2 sNO 2 .HCl.
  • the structural formula of tramadol and its active metabolite O-desmethyltramadol are represented in figure 1.
  • Tramadol is a centrally acting pain reliever. Its efficacy is between that of codeine and that of morphine in humans and rodents. It is a safe and effective pain reliever that acts centrally and is used to treat moderate to severe pain, of acute or chronic origin. It can also be used as a preoperative analgesic, as a complement to surgical anesthesia, in the postoperative period and in diagnostic examination procedures that are in pain.
  • Tramadol's mechanism of action is dual, since on the one hand it binds to ⁇ -opioid receptors and on the other hand it inhibits the reuptake of norepinephrine and serotonin. Its analgesic action is only partially reversed by naloxone blockage of ⁇ opioid receptors. This indicates that the effect of tramadol is not governed mainly through ⁇ opioid receptors, but depends on the combination of its 2 mechanisms of action (Mehlisch, 2002). The racemic mixture of ( ⁇ ) tramadol decreases the synaptosomal recapture of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) with equivalent potencies, but the enantiomers differ in their selectivity.
  • NE norepinephrine
  • 5-HT 5-hydroxytryptamine
  • (+) - Tramadol is 5 times more potent in inhibiting 5-HT reuptake than NE.
  • (-) - Tramadol is approximately 5 to 10 times more potent than (+) - enantiomer in disabling NE recapture (Frink et. Al., 1996 and Driessen et. Al., 1993). Tramadol's ability to inhibit neural monoamine reuptake at the same concentration with which it binds to ⁇ opioid receptors, makes it very different from morphine and codeine, making tramadol an "atypical" opioid (Miranda and Pinardi, 1998 ).
  • peripheral (local) action of the analgesic In this sense, it has been shown that there are ⁇ , ⁇ and K opioid receptors in peripheral terminals of both myelinated and unmyelinated sensory nerve fibers. These receptors are generally negatively coupled to the adenylate-cyclase-cAMP pathway. It has been suggested that after the opioid agonist binds to its receptor, the excitability of the nociceptive terminal or the spread of action potentials is attenuated and that the peripheral release of excitatory neuropeptides such as substance p (SP), is inhibited.
  • SP substance p
  • opioid agonists open ATP-sensitive K + channels at both the spinal and peripheral levels, and thus possibly hyperpolarize postsynaptic neurons.
  • the peripheral analgesic effect of opioids seems to be favored when inflammation conditions exist (Stein et al., 1989).
  • tramadol has been described as being able to inhibit inflammatory edema and subsequent hyperalgesia in the yeast inflammation model, without affecting immunological mechanisms such as macrophage migration (Bianchi et al., 1999).
  • ( ⁇ ) -tramadol More than 90% of ( ⁇ ) -tramadol is absorbed after oral administration. Bioavailability is around 70%, although it can be increased up to 95% after intramuscular administration. Peak concentrations are reached between 0.5 and 2.0 h depending on the route of administration, and a range of effective concentrations for the treatment of postoperative pain of 100-300 ng / mL has been reported.
  • ( ⁇ ) -tramadol is distributed rapidly, binding to plasma proteins by 20%. Furthermore, this drug quickly crosses the blood-brain and placental barriers. Indeed, it has been suggested that spinal (local) administration of ( ⁇ ) -tramadol should be avoided as it diffuses very rapidly into the general circulation providing a pharmacokinetic profile similar to that of systemic administration.
  • ( ⁇ ) -tramadol is metabolized in the liver via CYP3A4 and CYP2D6, mainly by means of N- and O-demethylation and later by conjugation of the O-demethylation products with glucuronic acid. For this reason, the drugs that act on these liver enzymes can affect the pharmacokinetic properties of ( ⁇ ) -tramadol.
  • This biotransformation route of ( ⁇ ) -tramadol is qualitatively similar in humans and animals, although in the latter it is carried out with greater speed.
  • MI O-desmethyltramadol
  • Tramadol and its metabolites are almost completely excreted via the kidneys (Lintz et al., 1981).
  • the Usina clonixinate (CL) used in the present invention has the chemical name: Usina salt of 2- (2-methyl-3-chloro-anilino) -3-nicotmico acid, represented by the formula C 1 SHnClN 2 O 21 CeHi 4 TSf 2 O 2 . Its structural formula is shown in figure 2.
  • Usina clonixinate is classified as an NSAID, which belongs to the family of non-salicy analgesics and to the subgroup of anthranilic derivatives. Its chemical structure is similar to flufenamic acid, although it is a derivative of nicotinic acid. Its pharmacological efficacy is recognized for the treatment of moderate to severe pain syndromes such as headaches, muscle pain, joints, neuritis; odontalgias, otalgia, dysmenorrhea, post-traumatic or post-surgical pain and even in the treatment of migraine (Krymchantowski et al., 2001).
  • CL is rapidly absorbed through the gastrointestinal tract and its main mechanism of action is the reversible inhibition of cyclooxygenase enzymes, important catalysts of prostaglandin synthesis. It is important to note that in vitro the capacity of CL to inhibit COXi is slightly less than the capacity of ketorolac, which may give it a lower incidence of side effects (Pallapies et al., 1995).
  • Usina clonixinate has also been shown to inhibit bradykinin and prostaglandin PGF2 (X already produced, making it a direct antagonist to pain mediators.
  • Usina clonixinate has a potent analgesic effect, without altering the vital signs or the state of consciousness of the patients, since it is a non-narcotic analgesic.
  • Doses of 300 mg of Usina clonixinate are equipotent to 6 mg of morphine sulfate.
  • the pharmacological potency is 23.6 times greater than acetylsalicylic acid and 10 times higher compared to metamizole.
  • Usina clonixinate can cause mild cases of gastroduodenal ulcer, in addition, few cases of mild side reactions have been reported, such as heartburn, vomiting, vertigo, euphoria, drowsiness. the bone marrow nor does it interfere with clotting factors, for What does not alter neither the number nor the platelet function (Kramer et al., 2001).
  • Lysine clonixinate is rapidly and completely absorbed orally; the presence of lysine increases the compound's solubility and absorption. It begins its analgesic activity within the first 15 to 30 minutes after ingestion, reaching maximum serum concentrations of 5.2 to 6.2 mg / L between 34 and 46 minutes after its oral administration. Pharmacokinetic studies indicate that there are no significant differences in these concentrations, between young and old people, as well as with fasting or with food. It is not deposited in the gastric mucosa, therefore it has a minimal ulcerogenic index. . It is widely distributed in all tissues. It binds importantly to plasma proteins (96 to 98%) and is partially metabolized at the liver level, generating 4 main metabolites that are pharmacologically inactive. It is eliminated by urinary (74%) and biliary-fecal (25%).
  • the combination lysine clonixinate with tramadol (CLT), object of the present invention is designed with the purpose of obtaining a drug with a higher analgesic action and with fewer adverse effects than those observed when using any of the drugs separately. .
  • mice Male Balb / C mice, 6-8 weeks old, weighing 20-30 g, were used in the two models studied. The animals were kept in boxes with food and water ad libitum until the moment of the experiment, and with light-dark cycles of 12 x 12 h. Animals were set for at least one hour. The duration of the experiment was as short as possible, always considering that the number of animals used was the minimum necessary. Each animal was used for an experiment and was slaughtered immediately after the experiment following the ethical guidelines for the investigation of pain in experimental animals (Zimmermann, 1983).
  • the formalin model represents a model of acute inflammatory pain, which consists of the subcutaneous administration of formalin in the dorsal area of the mouse's paw and the subsequent observation of its behavior (Dubuisson and Dennis, 1977).
  • mice were removed for subcutaneous administration of 40 ⁇ L formalin (3% formaldehyde solution) in the dorsal area of the right foot.
  • the mouse was returned to the cylinder for the observation of the characteristic behavior which consists of the number of licks of the injected paw during periods of 5 minutes up to a total time of 60 minutes.
  • Different groups were used to characterize the dose-response curve of the analgesics, simultaneously administering formalin locally and the two analgesic drugs individually, administered intraperitoneally, 20 minutes before the formalin injection.
  • the doses for TMD that were used were: 3.2, 10, 25 and 50 mg / lcg and for CL: 0.5, 5.0 and 50 mg / kg.
  • a 0.9% physiological saline solution was administered intraperitoneally as control for each experimental set.
  • Intraperitoneal administration of both pain relievers 20 minutes before formalin injection decreased the biphasic behavior typical of this model of licking / nibbling the damaged limb.
  • the drugs administered by this route did not modify the motor behavior or the reflexes of the animal (pineal and corneal).
  • the percentage of antinociception was plotted according to the dose of the two analgesics individually or in combination.
  • the percentage of antinociception was obtained according to the following equation: n /,. . , lick time without drug V ⁇
  • the lick time that was used was that recorded in the times of 15 to 60 minutes after the nociceptive stimulus.
  • Figures 3 and 4 show the antinociceptive dose-response curves (transformed to percentage of antinociception) of CL and TMD respectively obtained after ip administration of Usina clonixinate and tramadol respectively individually. It can be seen that both drugs progressively decrease the nociceptive effect with increasing dose.
  • the ED 50 ( ⁇ ee) of the drugs could be estimated, obtaining: 13.9 ⁇ 2.8 mg / kg for TMD and 16.52 ⁇ 0.23 mg / kg for CL.
  • Figure 5 shows that systemic administration of the different doses of the CLT combination decreased nociceptive behavior in the formalin test.
  • the dose-effect curve of intraperitoneal administration of the CLT combinations shows the dose-dependent antinociceptive effect (Figure 6).
  • the maximum effect achieved by the highest dose of the combination is around 77%, and the experimental DE 5 O was 0.68 ⁇ 0.21 mg / kg of weight, which was significantly less (p ⁇ 0.05) than the theoretical DE50 dose. of 15.21 mg / kg of weight.
  • Figure 7 shows the difference between the theoretical SD 50 and the experimental SD 50 of the CLT combination, it can be seen that the co-administration by intraperitoneal route of TMD and CL in this nociception model produces a discrete synergistic interaction. The magnitude of the interaction was calculated based on the following formula: 006/000018
  • individual SD 50 is the dose of drug 1 that has the same effect (50% antinociception) as drug 2 in the combination, and SD 50 of the combination is the dose that has the same 50% of the effect of antinociception.
  • the interaction index describes the experimental ED50 as a fraction of theoretical DE 50; Values close to 1 indicate additive interaction, while values greater than 1 imply antagonistic interaction and values less than 1 indicate potentiation.
  • the calculated ⁇ value was 0.036 ( ⁇ 0.028), confirming the synergistic interaction between drugs after intraperitoneal administration. That is, after an IP co-administration of TMD and CL, the same level of antinociceptive effect is reached (50%), and the doses of both drugs can be reduced approximately 27.7 times.
  • the visceral pain model that was used in this study was the stretching model. 018
  • This method consists of the administration of 0.5 ml of 1% acetic acid intraperitoneally in mice that are previously set in a 20 cm transparent acrylic cylinder. diameter. Immediately after administration, the number of contortions (characterized by slight arching of the back, development of tension in the abdominal muscles, elongation of the body and extension of the extremities) observed for 30 min at 5 min intervals was quantified.
  • the vehicle and drugs were administered 20 minutes before the administration of acetic acid.
  • the doses for tramadol were: 0.05, 0.5, and 1.0 mg / kg and for Usina clonixinate of: 0.5, 5 and 50 mg / kg of weight.
  • the ratio 1:58 was calculated and different combinations of TMD and CL were designed. These combinations maintained constant proportions of each analgesic drug, that is, the ratio of the individual drug in any combination remains constant regardless of the level of total dose administered, allowing the efficacy of the combination to be the product of that ratio.
  • the total dose of the combination, as well as the dose of each drug in each combination is shown in Table 2, in all cases the proportion of TMD-CL was kept in a 1:58 ratio.
  • the highest dose of the combination produced a maximum effect close to 71.2%, which exceeds the maximum expected by the sum of the individual effects.
  • the experimental SD 40 ( ⁇ e..e.) That was obtained after administering the combinations was 0.44 ⁇ 0.05 mg / kg. Which was significantly less (p ⁇ 0.05) than the theoretical additive SD 4O (the dose of the combination that only produces a summation effect) 4.70 ⁇ 1.43 mg ⁇ cg ( Figure 13).
  • the interaction index was 0.095 ( ⁇ 0.034), confirming the synergistic interaction between the drugs after intraperitoneal administration. That is, after an intraperitoneal co-administration of TMD and CL, the same level of antinociceptive effect is reached (40%), but the doses of both drugs can be reduced approximately 10.7 times.
  • mice 5 experimental groups of 10 mice each were used, which were administered by systemic route (intraperitoneal) the highest doses of both the individual drugs and the maximum combination, comparing the observations with respect to a control administered with saline solution. This administration was done every 24 hours, twice a day for 3 days. Subsequently, a daily evaluation of the neurological profile was carried out. The results of that evaluation at the end of the third day are shown in Table 3. It could be seen that the administration of tramadol in doses as high as 50 mg / kg is capable of producing a state of sedation that reversed around 20 minutes later. of opioid administration at a rate of 3/10 individuals. However, this did not occur in any of the other treated groups.
  • mice were sacrificed by cervical dislocation and the stomach and small intestine were obtained to undergo a histological study, where they were evaluated for damage or the appearance of ulcers or bleeding.
  • mice were sacrificed by cervical dislocation and the stomach and small intestine were obtained to undergo a histological study, where they were evaluated for damage or the appearance of ulcers or bleeding. Macroscopic observation of GI tissue did not indicate the presence of abnormalities even in those treated with TMD 50 mg / kg and in the other treatments.
  • the combination of Usina clonixinate and tramadol mentioned in the present invention can be formulated in different pharmaceutical forms for use as an analgesic.
  • the pharmaceutical forms can be both solid forms such as; tablets, capsules, suspensions; semi-solid such as suppositories and as oral and injectable solutions for intramuscular and intravenous administration.
  • Usina clonixinate and tramadol can be formulated in mixtures with conventional excipients, ie, organic or inorganic substances that act as appropriate vehicles for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other modes of administration. appropriate administration that is described in the state of the art.
  • Appropriate pharmaceutically acceptable carriers include but are not limited to: water, saline solutions, alcohols, gum arabic, vegetable oils, benzyl alcohol, polyethylene glycols, carbohydrates such as lactose, annul or starch, magnesium stearate, talc, silicone acid, paraffin, scented oils, monoglyceride and diglyceride fatty acids, fatty acid esters of pentaerythritol, hydroxymethylcellulose, polyvinylpyrrolidone, etc.
  • compositions can be sterilized and if required can be mixed with auxiliary agents, eg, lubricants, preservatives, stabilizers, humectants, emulsifiers, salts to modify osmolarity, pH buffers, substances to give color, flavor and / or aromatic substances and the like.
  • auxiliary agents eg, lubricants, preservatives, stabilizers, humectants, emulsifiers, salts to modify osmolarity, pH buffers, substances to give color, flavor and / or aromatic substances and the like.
  • Ketorolac potentiates morphine antinociception during visceral nociception in the rat. Anesthesiology. 80 (5): 1094-1101.
  • Pircio AW Buynisl ⁇ JP, Roebel LE. (1978) Pharmacological effects of a combination of butorphanol and acetaminophen. Arch Int Pharmacodyn Ther. Sep. 235 (1): 116-23.

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Abstract

La présente invention concerne des compositions pharmaceutiques contenant deux principes actifs dont, d'une part, un analgésique opiacé connu sous le nom générique de tramadol ou un de ses énantiomères ou un de ses sels de qualité pharmaceutique et, d'autre part, un analgésique anti-inflammatoire non stéroïdien connu sous le nom générique de clonixinate de lysine. Lorsque ces deux composants sont combinés en proportions spécifiques, la combinaison obtenue produit des effets pharmacologiques d'analgésie qui indiquent une superadditivité (synergie), ce qui signifie qu'il est possible d'utiliser une quantité des deux composants plus petite pour obtenir le même degré d'analgésie que lorsque l'on utilise chaque composant seul. Lorsque l'on réduit la quantité de chaque composant dans la combinaison, les effets secondaires associés à chacun des composants sont réduits en nombre et en intensité. Par conséquent, cette stratégie thérapeutique peut constituer un outil prometteur pour soulager la douleur aiguë modérée à sévère avec, pour avantage, moins d'effets indésirables typiques des opioïdes, tels que la prédisposition à l'abus, la tolérance, la constipation et la dépression respiratoire.
PCT/MX2006/000018 2006-03-16 2006-03-16 Composition pharmaceutique synergique à base de tramadol et de clonixinate de lysine WO2007105929A1 (fr)

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PCT/MX2006/000018 WO2007105929A1 (fr) 2006-03-16 2006-03-16 Composition pharmaceutique synergique à base de tramadol et de clonixinate de lysine
ARP070101074A AR057508A1 (es) 2006-03-16 2007-03-16 Composicion farmaceutica sinergistica de tramadol y clonixinato de lisina

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0546676A1 (fr) * 1991-10-30 1993-06-16 Mcneilab, Inc. Composition contenant du tramadol et un agent anti-inflammatoire non-stéroique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0546676A1 (fr) * 1991-10-30 1993-06-16 Mcneilab, Inc. Composition contenant du tramadol et un agent anti-inflammatoire non-stéroique

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CANOS VEREDECHOTM M. ET AL.: "Protocolos de tratamiento de dolor postoperatorio mediante AINEs", VII REUNION OF THE SOCIEDAD DEL DOLOR. VALENCIA, 2004, XP030177077 *
RADBRUCH L. ET AL.: "A Risk-Benefit Assessment of Tramadol in the Management or Pain", DRUG SAFETY, vol. 15, no. 1, 1996, pages 8 - 29 *
SANCHEZ RIVERO D. ET AL.: "Principios de Urgencias, Emergencias and Cuidados Criticos. Capitulo 12: Sedacion and Analgesia. Epigrafe 2.4.1.3.3.2", XP003017076, Retrieved from the Internet <URL:http://www.tratado.uninet.edu/c120202.html#2.4.1.3> *
TORRES L.M. ET AL.: "Tratamineto del dolor postoperatorio tras cirugia biliar con sistema PCA intravenoso", COMPARACION ENTRE CLONIXINATO DE LISINA, TRAMADOL AND KETOROLACO. REVISTA OF THE SOCIEDAD ESPANOLA DEL DOLOR, vol. 5, 1998, pages 112 - 119 *

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