CN114404409A

CN114404409A - Pharmaceutical composition capable of treating pain and application thereof

Info

Publication number: CN114404409A
Application number: CN202210166899.9A
Authority: CN
Inventors: 庄涛; 马玉蓉; 张桂森
Original assignee: Jiangsu Ocean University
Current assignee: Jiangsu Ocean University
Priority date: 2022-02-23
Filing date: 2022-02-23
Publication date: 2022-04-29

Abstract

The invention discloses a pharmaceutical composition capable of treating pain and application thereof, and relates to a pharmaceutical composition of an anti-inflammatory drug and a 5-hydroxytryptamine and norepinephrine reuptake inhibitor, wherein the anti-inflammatory drug is indomethacin and meloxicam, and the 5-hydroxytryptamine and norepinephrine reuptake inhibitor is duloxetine. The invention also relates to the use of said pharmaceutical combination for the prevention and/or treatment of pain caused by different tissue damages or by a neuropathic etiology. Experiments prove that the combination of two medicaments, namely indomethacin and duloxetine, meloxicam and duloxetine, has synergistic or additive synergistic effect in the treatment of neuropathic pain induced by paclitaxel and inflammatory pain induced by carrageenan, shows better analgesic effect compared with single medicament, has better effect than single medicament, and has good clinical application value and application prospect.

Description

Pharmaceutical composition capable of treating pain and application thereof

Technical Field

The invention relates to the field of medicines, in particular to a pharmaceutical composition capable of treating pain and application thereof.

Background

Pain is an unpleasant sensory and emotional experience that occurs when the body is injured, and is a complex clinical manifestation of pathological and physiological changes. Pain may be localized or reflected by systemic diseases, and diseases having the above "pain" as a main symptom are collectively referred to as "pain". At present, opioid analgesics and non-steroidal anti-inflammatory drugs are classical clinical analgesics, and have a long history of being used for treating pain, but the clinical application of the drugs also has a plurality of defects and deficiencies, and adverse reactions are daunting. For example, some strong opioid analgesics clinically used for severe pain caused by postoperative, trauma, cancer, etc. are easy to generate dependence in clinical application, and can generate certain tolerance, once the mental dependence occurs, new and larger problems are brought to clinical medication, so that the research road of human beings on pain treatment is long-term.

For the treatment of neuropathic pain, the first or second choice is that anticonvulsants, such as gabapentin, have proven effective in treating painful diabetic neuropathy and postherpetic neuralgia, in addition to which Duloxetine (Duloxetine, DUL) was the first approved agent in 2004 for the treatment of Diabetic Peripheral Neuropathy (DPN), it has been shown according to some studies that the effects of Duloxetine on 5-hydroxytryptamine and noradrenergic in the central nervous system may be associated with the relief of neuropathic pain and as an inhibitor of 5-hydroxytryptamine and noradrenaline reuptake, Duloxetine is commonly used in the treatment of painful diabetic neuropathy, osteoarthritic pain and chronic low back pain.

The structural feature of the NSAIAs is common to all steroid rings, and the inhibition of prostaglandins and their anti-inflammatory action are achieved by acetylation of the active center of cyclooxygenase (COX-1, COX-2) or by covalent bonding to it. Indomethacin (Indomethacin, IN), also known as Indomethacin, is an artificially synthesized indoleacetic acid derivative, belonging to the nonsteroidal anti-inflammatory drugs. The indometacin has effects of resisting inflammation, relieving pain and fever, inhibiting leukocyte chemotactic factor, antagonizing inflammatory factor, and relieving immunoreaction. In 1971, Vane demonstrated that indomethacin can inhibit the synthesis of Prostaglandin (PG), so that the application of indomethacin in clinical development is continuously developed in recent years, mainly for treating diseases such as rheumatoid arthritis, osteoarthritis and ankylosing spondylitis, and also for treating genitourinary system diseases, digestive system diseases, nervous system diseases, ophthalmic diseases and the like.

Meloxicam (melexicam, MEL), a novel acidic enolamide nonsteroidal anti-inflammatory drug, is a cyclooxygenase-2 (COX-2) inhibitor, and may be effective in treating neuropathic pain because it regulates the inflammatory component that causes the disease. In addition, meloxicam is used in a large number of pain conditions and preclinical studies have shown it to be useful in reducing the pain sensation in neuropathic pain models.

Two or more medicaments are often used in combination for treating certain diseases clinically, and the compatibility of the two medicaments can cause various conditions, wherein one medicament plays the role of the medicament, and the medicaments are not interfered with each other; one is the interference of the drug effect between the drugs, the drug effect is reduced, and in addition, the side effect is enhanced after the drug combination is possibly generated, so that two drugs which cannot be taken or combined for use are frequently used in clinic. Therefore, the optimal situation is the compatibility of the medicines, the complementation and the synergistic action of the medicines are fully exerted, the medicine effect is improved, and the toxic and side effect is reduced.

In medical practice, the combination of drugs with significantly similar therapeutic effects is common, and prominent examples include analgesics, antihypertensives, antiemetics, and the like. The general purpose of multiple drug use is to treat complex conditions with drugs having different mechanisms of action. The combined use is particularly reasonable since pain involves multiple mechanisms and, in addition, the use of two drugs almost always means that the dose of each drug is low, thereby minimizing adverse effects that may be associated with higher doses of a single drug. The evaluation of drug synergy is usually performed experimentallyThe method used in this type of experiment is isoradiometric analysis, which is the gold standard for demonstrating pharmacological interactions between drugs. The core criteria of the method is to select an effect level, and experimentally determine the doses of the drug A alone, the drug B alone and the combination (a, B) which produces the same effect, wherein the line connecting the doses which produce the same effect is called an equivalent line, and the combined drug effect can be expressed as a/A + B/B ═ gamma, and when the gamma is 1, the interaction between the drugs is additive; when gamma is<1, the interaction between the drugs is synergistic; when gamma is>1, the interaction between the drugs is antagonistic. In particular, Z_t＝a+b，a＝p_AZ_t，b＝p_BZ_t，Z_t＝γA/(P_A+Rp_B)，R＝A/B，Z_add＝A/(P_A+Rp_B) Therefore, Z is_t＝γZ_add(Z_add,additive total for a specified effect；Z_t,total dose for a specified effect)。

At present, a lot of medicines for treating pain exist, but due to the problems of adverse reaction, addiction and the like, a lot of defects and deficiencies appear in clinical application, and the clinical requirement cannot be well met; aiming at the pharmacological performances of indomethacin, meloxicam and duloxetine, the invention adopts a large number of tests to screen combination and dosage, and explores two combined medicaments which have quick response, strong and durable analgesic effect and avoid or reduce adverse reactions and dosage combination thereof. Therefore, the invention provides a new medicine combination selection for clinic and has great significance.

Disclosure of Invention

The present invention aims at overcoming the demerits of available technology, and provides one kind of pain treating medicine composition and its application.

In order to achieve the purpose, the invention provides the following technical scheme: a pharmaceutical combination for the treatment of pain, for use in the prevention and/or treatment of pain arising from different tissue damage or a neuropathic etiology, said pharmaceutical combination comprising an analgesically effective amount of a first compound selected from one or more of an anti-inflammatory agent or a pharmaceutically acceptable salt thereof; the second compound is a 5-hydroxytryptamine and norepinephrine reuptake inhibitor; optionally, one or more pharmaceutically acceptable carriers are also included.

In a preferred embodiment of the present invention, the anti-inflammatory agent is selected from indomethacin, meloxicam; the 5-hydroxytryptamine and norepinephrine reuptake inhibitor is duloxetine.

In a preferred embodiment of the present invention, the pharmaceutical composition is two types of compositions, which are indomethacin and duloxetine, meloxicam and duloxetine, respectively.

Use of a pharmaceutical combination for the treatment of pain, for the prevention and/or treatment of pain caused by different tissue damages or by neuropathic etiologies, of an analgesically effective amount of a pharmaceutical combination according to claim 3, administered orally, intramuscularly, intravenously, intraperitoneally or parenterally to a patient;

administering indomethacin to the patient in a dose of 0.1-50 mg/kg; the dose of the meloxicam is 0.1-60 mg/kg; the dosage of duloxetine is 0.1-100 mg/kg.

As a preferred technical scheme of the invention, the paclitaxel induced neuropathic pain can be treated by combining indomethacin and duloxetine medicaments; the weight ratio of the indometacin to the duloxetine is 1: 0.1 to 100, preferably 1: 1-5;

paclitaxel-induced neuropathic pain can be treated by a combination of meloxicam and duloxetine drugs; the weight ratio of meloxicam to duloxetine is 1: 0.3 to 100, preferably 1: 0.5 to 5;

carrageenan-induced inflammatory pain can be treated by a combination of indomethacin and duloxetine drugs; the weight ratio of the indometacin to the duloxetine is 1: 0.1 to 100, preferably 1: 1-5;

carrageenan-induced inflammatory pain can be treated by a combination of meloxicam and duloxetine drugs; the weight ratio of meloxicam to duloxetine is 1: 0.3 to 100, preferably 1: 0.5-50.

In a preferred embodiment of the present invention, the patient is selected from the group consisting of human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, and non-human primate.

As a preferred technical scheme, the drug combination used by combining indometacin and duloxetine, meloxicam and duloxetine has synergistic or additive synergistic effect in the treatment of paclitaxel induced neuropathic pain and carrageenan induced inflammatory pain.

The invention aims to provide a drug combination of two combined drugs for treating paclitaxel-induced neuropathic pain and carrageenan-induced inflammatory pain and application thereof, wherein the drugs are indomethacin, duloxetine, meloxicam and duloxetine.

The invention has the advantages that the combined administration mode of the two compositions has obvious analgesic synergy or addition effect when treating the neuropathic pain induced by paclitaxel and the inflammatory pain induced by carrageenan, has strong and lasting analgesic effect and high stability, and can avoid or reduce adverse reactions such as toxic and side effects, dependence and the like of the medicament.

The invention proves that the combination type of two combinations of indomethacin and duloxetine, meloxicam and duloxetine has synergistic or additive synergistic effect in a paclitaxel-induced mouse neuropathic pain experiment and a carrageenan-induced rat inflammatory pain experiment by a 'gold standard' -isoradiometric analysis method for evaluating the interaction of the drugs.

Drawings

Figure 1 is an area under the curve (AUC) showing that gavage indomethacin or intraperitoneal injection of duloxetine reversed paclitaxel-induced neuropathic pain (P <0.05, > P <0.01, > P <0.001, > P <0.0001vs Vehicle);

fig. 2 shows that indomethacin relatively reverses paclitaxel-induced neuropathic pain 120min after administration. The analgesic effect of the combination of duloxetine and indomethacin in the same effective dose is obviously better than that of indomethacin (P <0.01, P <0.001, P <0.0001vs Vehicle);

FIG. 3 is a graph of isoradiometric analysis of the interaction of Indomethacin (IN) and Duloxetine (DUL) IN paclitaxel-induced neuropathic pain experiments IN mice;

figure 4 is the area under the curve (AUC) showing that gavage meloxicam or intraperitoneal injection of duloxetine reversed paclitaxel-induced neuropathic pain (. P <0.05,. P <0.01,. P <0.001,. P <0.0001 vs.

Figure 5 is a graph of the relative reversal of paclitaxel-induced neuropathic pain by meloxicam 120min post-administration. The analgesic effect of the duloxetine and the meloxicam which are combined with the same effective dose is obviously better than that of the meloxicam (P <0.01, P <0.0001vs Vehicle);

FIG. 6 is an isobologram of the interaction of Meloxicam (MEL) and Duloxetine (DUL) in a paclitaxel-induced neuropathic pain assay in mice;

figure 7 is an area under the curve (AUC) showing that gavage indomethacin or intraperitoneal injection of duloxetine reversed carrageenan-induced inflammatory pain (. P <0.01,. P <0.0001vs Vehicle);

figure 8 is a graph showing the relative reversal of carrageenan-induced inflammatory pain 120min after indomethacin administration. The analgesic effect of the combination of duloxetine and indometacin with the same effective dose is obviously better than that of indometacin (P <0.0001vs Vehicle);

FIG. 9 is an isobologram of the interaction of Indomethacin (IN) and Duloxetine (DUL) IN carrageenan-induced inflammatory pain assay IN rats;

figure 10 is an area under the curve (AUC) showing that gavage meloxicam or intraperitoneal injections of duloxetine reversed carrageenan-induced inflammatory pain (. p.. 0.01,. p.. 0.0001 vs. Vehicle);

figure 11 is a graph of the relative reversal of carrageenan-induced inflammatory pain 120min after meloxicam administration. The analgesic effect of the duloxetine and the meloxicam which are combined with the same effective dose is obviously better than that of the meloxicam (P <0.01, P <0.0001vs Vehicle);

figure 12 is an isobologram of the interaction of Meloxicam (MEL) and Duloxetine (DUL) in carrageenan-induced inflammatory pain tests in rats.

Detailed Description

The embodiments of the present invention will be described in detail below with reference to the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, and the scope of the present invention can be more clearly and clearly defined. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

The invention provides a pharmaceutical composition capable of treating pain, which is divided into two types, namely indomethacin and duloxetine, meloxicam and duloxetine.

The application of a pharmaceutical composition for treating pain is to evaluate the analgesic effect in an experiment of paclitaxel induced neuropathic pain in mice and an experiment of carrageenan induced inflammatory pain in rats after the combined administration of different doses of the drugs.

Paclitaxel-induced neuropathic pain in mice can be treated by a combination of indomethacin and duloxetine drugs; see example 1 in particular;

paclitaxel-induced neuropathic pain in mice can be treated by a combination of meloxicam and duloxetine drugs; see example 2 in particular;

carrageenan-induced inflammatory pain can be treated by a combination of indomethacin and duloxetine drugs; see example 3 for details;

carrageenan-induced inflammatory pain can be treated by a combination of meloxicam and duloxetine drugs; see example 4 in particular.

Example 1: evaluation of efficacy of indomethacin and duloxetine on paclitaxel-induced neuropathic pain of mice

Experimental animals: adult male ICR mice, body weight (22 ± 4g), purchased from eastern firms of febrifuge, certification code: no. 202149615.

Experimental materials: indomethacin and paclitaxel were purchased from Shanghai Michelin Biotech, Inc.; duloxetine, polyoxyethylated castor oil EL, sodium carboxymethylcellulose were purchased from Shanghai Aladdin Biotech Ltd; the physiological saline is purchased from Jiangsu Huai' an double-crane pharmaceutical industry, Inc.; absolute ethanol was purchased from shanghai tatatake technologies gmbh.

The medicine dispensing method comprises the following steps: indomethacin: preparing indometacin suspension with 0.5% sodium carboxymethylcellulose solution as solvent, wherein the concentrations are 0.0625mg/mL, 0.25mg/mL, 0.5mg/mL, 1mg/mL and 2mg/mL respectively; duloxetine: preparing duloxetine solution with normal saline as solvent, wherein the concentration is 0.5mg/mL, 1mg/mL, 2mg/mL, 3mg/mL respectively; paclitaxel: dissolved in a solution consisting of 50% cremophor EL and 50% absolute ethanol at a concentration of 6mg/mL (stored at-20 ℃ C., maximum 14 days), and then diluted with physiological saline (0.9% NaCl) to a final concentration of 0.2mg/mL before administration.

The experimental method comprises the following steps: before the experiment, the mice were randomly grouped into groups of 8 mice each, were intraperitoneally injected with paclitaxel (2mg/kg) or its vehicle (administration volume was calculated as 0.1mL/10 g), 1 time daily for 5 consecutive days, baseline values of mechanical pain thresholds of the mice were measured on the day before paclitaxel injection and the day after paclitaxel injection (mice were acclimatized for 30min before the test), and then on day 7, for the individual drug groups, the mice were gavaged with indomethacin or with intraperitoneal duloxetine (administration volumes were both calculated as 0.1mL/10 g) and mechanical pain thresholds of the mice were measured at 30, 60, 90, 120, 180, 240min after the administration. When administered in combination, the dose is given as 2ED for each of the two drugs₂₅，ED₂₅，1/2ED₂₅，1/4ED₂₅，1/8ED₂₅Data at 120min from the point of measurement were administered and selected for analysis.

Experimental dose grouping settings are as in table 1:

table 1: experimental grouping of mouse neuropathic pain model induced by indomethacin and duloxetine combined paclitaxel

p.o.: intragastric administration; i.p. intraperitoneal injection

Data are expressed as mean ± s.e.m; drug inhibition rate of 120min ═ (mechanical threshold at 120 min-0 min mechanical threshold)/(mechanical threshold at baseline-0 min) × 100%; single or multifactor analysis of variance was performed using GraphPad Prism software and checked using Dunnett's multiple complexes test.

The experimental results are as follows:

no mortality occurred in any of the groups within 5 days of paclitaxel molding. From the mechanical threshold and the time point of measurement, the dose was positively correlated with the hyperalgesia effect on paclitaxel in each individual dose group. The inhibition rates of 20mg/kg of indomethacin and 30mg/kg of duloxetine are 47.2% and 59.99%, respectively, and the ED of the indomethacin₂₅ED of duloxetine (5 mg/kg)₂₅7.12 mg/kg; in the dosage combination of the combined medicine, the highest inhibition rate can reach 61.41 percent, and the mechanical threshold value of the combined medicine group is obviously higher than that of the single medicine group when the measurement point is 120 min; data analysis shows that Z of indometacin and duloxetine_add(ED₂₅ of the combination(theoretical))＝6.6mg/kg，Z_t(ED₂₅of the combination(experimental))＝2.47mg/kg，

The interaction of the combined effects of the two medicines is a synergistic effect, which shows that the combination of the two medicines has potential research and application values, and detailed figures 1 to 3 show.

Example 2: evaluation of drug effect of meloxicam and duloxetine on paclitaxel-induced neuropathic pain in mice

Experimental animals: the same as in example 1.

Experimental materials: meloxicam was purchased from Shanghai Michelin Biochemical technology Ltd, otherwise as in example 1.

The medicine dispensing method comprises the following steps: meloxicam: using physiological saline as a solvent to prepare meloxicam suspension, adding equimolar sodium hydroxide solid to dissolve the meloxicam suspension into a bright yellow solution, wherein the concentration of the solution is 0.1mg/mL, 0.3mg/mL, 1mg/mL and 3mg/mL respectively; other drug formulation methods were the same as example 1.

The experimental method comprises the following steps: before the experiment, the mice were randomly grouped into groups of 8 mice each, and the mice were injected intraperitoneally with paclitaxel (2mg +)kg) or its vehicle (the administration volume is calculated as 0.1mL/10 g), 1 time per day for 5 consecutive days, the baseline value of the mechanical pain threshold of the mice is measured one day before paclitaxel injection and one day after paclitaxel injection (the mice are adapted to the environment for 30min before testing), then on day 7, for the single drug group, the mice are gavaged with meloxicam or with intraperitoneal duloxetine (the administration volumes are calculated as 0.1mL/10 g) and the mechanical pain threshold of the mice is measured at 30, 60, 90, 120, 180, 240min after administration. When administered in combination, the dose is given as 2ED for each of the two drugs₂₅，ED₂₅，1/2ED₂₅，1/4ED₂₅，1/8ED₂₅Data at 120min from the point of measurement were administered and selected for analysis.

Experimental dose grouping settings are as in table 2:

table 2: experimental grouping of models of mouse neuropathic pain induced by meloxicam in combination with taxol of duloxetine

p.o.: intragastric administration; i.p.: abdominal injection

The experimental results are as follows:

no mortality occurred in any of the groups within 5 days of paclitaxel molding. From the mechanical threshold and the time point of measurement, the dose was positively correlated with the hyperalgesia effect on paclitaxel in each individual dose group. The inhibition rates of 30mg/kg of meloxicam and 30mg/kg of duloxetine are 55.95% and 59.99%, respectively, and the ED of meloxicam₂₅ED of duloxetine ═ 3.03mg/kg₂₅The highest inhibition rate in the combined drug dose combination can reach 62.14 percent, and the mechanical threshold value of the combined drug group is obviously higher than that of the single drug group when the measurement point is 120 min; data analysis shows that the drug is prepared from meloxicam and duloxetineZ_add(ED₂₅ofthe combination(theoretical))＝5.08mg/kg，Z_t(ED₂₅of the combination(experimental))＝2.04mg/kg，

The interaction of the combined effects of the two medicines is a synergistic effect, which shows that the combination of the two medicines has potential research and application values, and detailed pictures in figures 4 to 6 are shown.

Example 3: evaluation of efficacy of indomethacin in combination with duloxetine on carrageenan-induced inflammatory pain in rats

Experimental animals: adult male SD rats, body weight (240 ± 30g), purchased from eastern waters of febrifuge, certification code: no. 202149615.

Experimental materials: indomethacin was purchased from Shanghai Mecline Biotech limited; duloxetine, sodium carboxymethylcellulose, carrageenan were purchased from Shanghai Aladdin Biotech limited; the physiological saline is purchased from Jiangsu Huai' an double-crane pharmaceutical industry, Inc.

The medicine dispensing method comprises the following steps: indomethacin: preparing indometacin suspension with 0.5% sodium carboxymethylcellulose solution as solvent, wherein the concentrations are 1.25mg/mL, 2.5mg/mL, 5mg/mL and 10mg/mL respectively; duloxetine: preparing duloxetine solution with physiological saline as solvent, wherein the concentrations are 5mg/mL, 10mg/mL, 15mg/mL and 30mg/mL respectively; carrageenan: physiological saline is used as a solvent to prepare a solution with the mass fraction of 2%.

The experimental method comprises the following steps: before the experiment, rats are randomly grouped, 6 rats are in each group, and 0.1mL of carrageenan solution with the mass fraction of 2% is injected into the soles of the rats subcutaneously after the rats are adapted to the environment for 30 min; after 3 hours, for the individual drug groups, rats were gavaged with indomethacin or intraperitoneally injected with duloxetine (the administration volumes were all calculated as 0.1mL/100 g) and the mechanical pain threshold of the rats was measured at 30, 60, 90, 120, 180, 240min after administration. When administered in combination, the dose is given as 2ED for each of the two drugs₂₅，ED₂₅，1/2ED₂₅，1/4ED₂₅Data at 120min from the point of measurement were administered and selected for analysis.

Experimental dose grouping settings are as in table 3:

table 3: experimental group of Indometacin in combination with duloxetine carrageenan induced inflammatory pain model in rats

p.o.: intragastric administration; i.p.: abdominal injection

The experimental results are as follows:

no mortality occurred in any of the groups within 3 hours of carrageenan molding. From the mechanical threshold and the time point of measurement, the dose was positively correlated to the hyperalgesia effect caused by carrageenan in each individual administration group. The inhibition rates of 10mg/kg of indometacin and 30mg/kg of duloxetine are 67.80% and 63.97%, respectively, and the ED of the indometacin₂₅ED of duloxetine 0.86mg/kg₂₅5.37 mg/kg. Data analysis shows that Z is generated after the meloxicam and duloxetine are administrated_add(ED₂₅ of the combination(theoretical))＝3.12mg/kg，Z_t(ED₂₅of the combination(experimental))＝3.12mg/kg，

The mutual effect of the combination effect of the two medicines is additive effect, which shows that the combination of the two medicines has potential research and application values, and detailed pictures in figures 7 to 9.

Example 4: evaluation of drug effects of meloxicam and duloxetine on carrageenan-induced inflammatory pain in rats

Experimental materials: meloxicam is available from Shanghai Michelin Biotech, Inc.; the rest is the same as example 3.

The medicine dispensing method comprises the following steps: meloxicam: using physiological saline as a solvent to prepare meloxicam suspension, adding equimolar sodium hydroxide solid to dissolve the meloxicam suspension into a bright yellow solution, wherein the concentration is 0.3mg/mL, 3mg/mL, 10mg/mL and 30mg/mL respectively; other drug formulation methods were the same as example 3.

The experimental method comprises the following steps: rats were randomly grouped into groups of 6 rats before the experiment, the rats were injected with 0.1mL of carrageenan solution with a mass fraction of 2% subcutaneously on the soles after acclimation for 30min, and after 3 hours, for the individual drug groups, the rats were gavaged with indomethacin or with duloxetine intraperitoneally (the administration volumes were all calculated as 0.1mL/100 g) and the mechanical pain threshold of the rats was measured at 30, 60, 90, 120, 180, 240min after administration. When administered in combination, the dose is given as 2ED for each of the two drugs₂₅，ED₂₅，1/2ED₂₅，1/4ED₂₅Data at 120min from the point of measurement were administered and selected for analysis.

Experimental dose grouping settings are as in table 4:

table 4: experimental grouping of carrageenan induced inflammatory pain model in rats combining meloxicam with duloxetine

p.o.: intragastric administration; i.p.: abdominal injection

The experimental results are as follows:

no mortality occurred in any of the groups within 3 hours of carrageenan molding. Dose and carrageenan-induced in each individual administration group from the mechanical threshold and measurement time pointsHyperalgesia is positively correlated. The inhibition rates of 30mg/kg of meloxicam and 30mg/kg of duloxetine are 75.11% and 63.97%, respectively, and the ED of meloxicam₂₅0.50mg/kg, ED of duloxetine₂₅5.37 mg/kg. Data analysis shows that Z is generated after the meloxicam and duloxetine are administrated_add(ED₂₅ of the combination(theoretical))＝2.94mg/kg，Z_t(ED₂₅ of the combination(experimental))＝2.19mg/kg，

The interaction of the combined effects of the two medicines is a synergistic effect, which shows that the combination of the two medicines has potential research and application values, and detailed pictures in figures 10 to 12.

The above examples only show some embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention.

Claims

1. A pharmaceutical composition for treating pain, comprising: the pharmaceutical combination is used for preventing and/or treating pain caused by different tissue injuries or neuropathic etiologies, and comprises a first compound and a second compound with an analgesic effective amount, wherein the first compound is one or more selected from anti-inflammatory drugs or pharmaceutically acceptable salts thereof; the second compound is a 5-hydroxytryptamine and norepinephrine reuptake inhibitor; optionally, one or more pharmaceutically acceptable carriers are also included.

2. A combination according to claim 1, wherein the combination is for use in treating pain: the anti-inflammatory drug is selected from indomethacin and meloxicam; the 5-hydroxytryptamine and norepinephrine reuptake inhibitor is duloxetine.

3. A combination according to claims 1 and 2 for the treatment of pain, wherein: the drug combination is two combination types, namely indomethacin and duloxetine, meloxicam and duloxetine.

4. The application of a pharmaceutical composition for treating pain is characterized in that: the use of the pharmaceutical combination for the prevention and/or treatment of pain caused by different tissue damages or neuropathic etiologies by administering orally, intramuscularly, intravenously, intraperitoneally or parenterally to a patient an analgesically effective amount of the pharmaceutical combination according to any one of claim 3;

5. A combination according to claims 1-3 for the treatment of pain, wherein: paclitaxel-induced neuropathic pain can be treated by combination of indomethacin and duloxetine; the weight ratio of the indometacin to the duloxetine is 1: 0.1 to 100, preferably 1: 1-5;

6. The use of a combination according to claim 4 for the treatment of pain, wherein: the patient is selected from a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate.

7. A combination according to claims 1 to 6 for the treatment of pain, wherein: the drug combination of indomethacin and duloxetine, meloxicam and duloxetine used in combination has synergistic or additive synergistic effect in the treatment of paclitaxel induced neuropathic pain and carrageenan induced inflammatory pain.