CN117982493A - Application of pharmaceutical composition in preparation of medicines for treating and/or preventing pain - Google Patents
Application of pharmaceutical composition in preparation of medicines for treating and/or preventing pain Download PDFInfo
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- CN117982493A CN117982493A CN202310583707.9A CN202310583707A CN117982493A CN 117982493 A CN117982493 A CN 117982493A CN 202310583707 A CN202310583707 A CN 202310583707A CN 117982493 A CN117982493 A CN 117982493A
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a composition of (S) -3-aminomethyl-5-methylhexanoic acid or pharmaceutically acceptable salts thereof and riluzole, which has great application value in the field of treating and/or preventing pain.
Description
Technical Field
The invention belongs to the field of pharmacy, and relates to application of a composition of (S) -3-aminomethyl-5-methylhexanoic acid and riluzole in preparing medicines for treating and/or preventing pain.
Background
The international pain research association (International Association for the Study of Pain, IASP) redefines pain as "a perceived unpleasant sensory and emotional experience associated with actual or potential tissue damage, or the like" 2020. Acute pain is a normal balance and protection mechanism of the body after external injury stimulus, and can reduce or avoid injury to the body. Acute pain is generally localized to the site of injury and gradually disappears as the wound heals. In some cases, such as arthritis, nerve injury, cancer and chemotherapy, changes in the pain transmission pathways also lead to the continued presence of acute pain, which translates into a disease state of the nervous system, i.e., chronic pain. Chronic pain, which is relatively persistent, can persist for a considerable period of time after the initial injury, and still maintain a pain-responsive state even after the pathological symptoms have disappeared. Chronic pain has become a significant cause of confusion worldwide for humans, particularly due to the lack of effective, specific and safe therapeutic agents. Chronic pain is largely divided into inflammatory pain and neuropathic pain and can be manifested in three pain states: 1. touch-induced pain (allodynia), or hyperalgesia, refers to pain caused by a stimulus that does not cause pain under normal conditions at the site of injury or outside the injury, and is an excessive response of the body to a non-nociceptive stimulus; 2. hyperalgesia (HYPERALGESIA), which is the stronger pain caused by a certain pain stimulus intensity on the threshold at the injury site or the site outside the injury under normal conditions, is the over-strong reaction of the body to the nociceptive stimulus; 3. persistent spontaneous pain: (spontaneous pain) means pain which persists after the stimulus has disappeared and which does not persist under any external stimulus. Because the existing medicines for treating drug addiction or low curative effect have serious problems, the development of novel analgesic medicines becomes urgent.
(S) -3-aminomethyl-5-methylhexanoic acid (pregabalin) is clinically useful for the treatment of diabetic peripheral neuralgia, postherpetic neuralgia, neuralgia after spinal cord injury, and fibromyalgia in adults, and is recommended by a number of international guidelines as a first-line drug for the treatment of neuralgia. The mechanism of action of pregabalin is thought to regulate the voltage-gated calcium channel α2δ subunit, reducing glutamate, norepinephrine and substance P release. Pregabalin causes adverse reactions such as dizziness and somnolence, and the adverse reactions limit clinical application to a certain extent.
The structural formula of (S) -3-aminomethyl-5-methylhexanoic acid (pregabalin) is as follows:
(molecular formula is C 8H17NO2, molecular weight 159.23).
Riluzole (Riluzole, chemical name 2-amino-6-trifluoromethoxybenzothiazole), a drug developed by the Sainophenanthrene company for treating Amyotrophic Lateral Sclerosis (ALS), was approved by the United states FDA in 1995, and has very important roles in prolonging survival time of ALS patients, relieving symptoms and improving quality of life. The mechanism of action is thought to be related to inhibition of glutamate release, stabilization of the inactive state of voltage-dependent sodium channels, and the interference of intracellular events following neurotransmitter binding to excitatory amino acid receptors. Riluzole has a wide range of pharmacological effects including regulation of glutamate and its transporters, antidepressant, anxiolytic, antiepileptic, analgesic, neuroprotective, etc.
The structural formula of riluzole is as follows:
(molecular formula is C 8H5F3N2 OS, molecular weight 234.20).
Disclosure of Invention
The technical problems to be solved are as follows: the invention provides application of a pharmaceutical composition in preparing medicines for treating and/or preventing non-neuralgia pain, wherein the composition comprises (S) -3-aminomethyl-5-methylhexanoic acid and riluzole, and the pharmaceutical composition can generate synergistic effect when being used and can enhance the analgesic effect.
The technical scheme is as follows: use of a pharmaceutical composition comprising (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof and riluzole or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of non-neuropathic pain.
The composition is characterized in that the (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: riluzole or a pharmaceutically acceptable salt thereof, and the mass ratio of the riluzole or the pharmaceutically acceptable salt thereof is 20:1-1:4 in terms of free acid or alkali form.
Preferably, the (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: riluzole or a pharmaceutically acceptable salt thereof, and the mass ratio of the riluzole or the pharmaceutically acceptable salt thereof is 10:1-1:4 in terms of free acid or alkali form.
Preferably, the (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: riluzole or a pharmaceutically acceptable salt thereof, and the mass ratio of the riluzole or the pharmaceutically acceptable salt thereof is 6:1-1:4 in terms of free acid or alkali.
Preferably, the (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: riluzole or a pharmaceutically acceptable salt thereof, and the mass ratio of the riluzole or the pharmaceutically acceptable salt thereof is 3:1-1:2 in terms of free acid or alkali form.
The pharmaceutical composition of the present invention can be used for preparing a medicament for treating and/or preventing non-neuropathic pain type pain, characterized in that the non-neuropathic pain type pain comprises: acute pain, chronic non-neuropathic pain, migraine pain, pain associated with osteoarthritis or articular rheumatism, lower back pain, dental pain, pain associated with burns, non-neuropathic pain associated with cancers, acute or chronic tension headache, postoperative pain, fibromyalgia, pain associated with soft tissue injury or peripheral injury, central pain, pain associated with bruises, sprains or wounds, spinal pain, pain associated with spinal or brain stem injury, myofascial pain syndrome, vulvotomy pain, gouty pain, cardiac pain, muscle pain, eye pain, ear pain, inflammatory pain, orofacial pain, abdominal pain, pain associated with dysmenorrhoea, childbirth pain or endometriosis pain, somatic pain, pain associated with amputation, neuroma or vasculitis pain, hyperalgesia, sudden pain, pain caused by chemotherapy, cardiac pain, pain associated with gall stones, functional abdominal pain, headache, sinus headache, cluster headache, temporomandibular joint pain, maxillary sinus pain, pain caused by ankylosis, pain associated with ankylosis, local pain of the limb, fulness, pain of the limb, and complex pain.
Preferably, the non-neuropathic pain type pain comprises: acute pain, chronic non-neuropathic pain, migraine, pain associated with osteoarthritis or articular rheumatism, lower back pain, dental pain, ear pain, pain caused by burns, non-neuropathic pain associated with cancer, acute or chronic tension headache, fibromyalgia, erythromelalgia, complex regional pain syndrome.
Preferably, the non-neuropathic pain type pain comprises: acute pain, chronic non-neuropathic pain, migraine, pain associated with osteoarthritis or articular rheumatism, non-neuropathic pain associated with cancer, fibromyalgia, erythromelalgia, complex regional pain syndrome.
Preferably, the non-neuropathic pain is fibromyalgia, erythromelalgia, or complex regional pain syndrome.
More preferably, the non-neuropathic pain is fibromyalgia.
The beneficial effects are that:
the animal efficacy experiment result shows that the pharmaceutical composition containing (S) -3-aminomethyl-5-methylhexanoic acid and riluzole can play a synergistic role, and the treatment effect of various types of pains is enhanced.
Detailed Description
The following examples will provide those skilled in the art with a more complete understanding of the invention, but are not intended to limit the invention in any way.
EXAMPLE 1 study of the pharmacodynamic effects of pregabalin and riluzole compositions on fibromyalgia 1
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.
1.2 Test drug
| Medicine name | Manufacturer' s | Lot number |
| Pregabalin | Adamas Reagent, Ltd | P1472904 |
| Riluzole | Shanghai Ala Biochemical technology Co.Ltd | F1502089 |
1.3 Experimental method
1.3.1 Preparation of fibromyalgia animal model
The test used an acidic saline injection into the unilateral gastrocnemius induced fibromyalgia model of the animal. Animals were anesthetized with isoflurane and the left hind limb gastrocnemius was injected with acidic saline twice (4 days apart) and the screening model 7 days after the second injection induced successful animals for subsequent efficacy testing.
1.3.2 Method for measuring mechanical pain threshold
All experimental animals were tested for mechanical withdrawal threshold (MECHANICAL WITHDRAWAL threshold, MWT) using a mechanical automatic stab needle. Placing the experimental animal in a transparent organic glass box with a wire netting at the bottom, applying force to stimulate the hind limb plantar of the experimental animal at a constant speed by using a stabbing needle after the experimental animal is adapted to 30min, and recording the reflection threshold (MWT) of the rat when the rapid foot shrinkage or the foot throwing reaction occurs, namely the mechanical pain threshold of the animal.
1.3.3 Measurement and calculation of basic pain threshold of animals
Each experimental animal was measured for a 2-day basal mechanical pain threshold, which is the average of two times, prior to molding.
1.4 Animal grouping and experimental procedure
The experimental model animals were randomly divided into 7 groups, namely, a model control group, a pregabalin group (25 mg/kg), a pregabalin group (0.5 mg/kg), a riluzole group (10 mg/kg), a riluzole group (0.5 mg/kg), a pregabalin and riluzole combination 50:1 group (pregabalin 25 mg/kg+riluzole 0.5 mg/kg), and a pregabalin and riluzole combination 1:20 group (pregabalin 0.5 mg/kg+riluzole 10 mg/kg). Pregabalin and riluzole are administered by intraperitoneal injection, 11-12 animals per group, and corresponding blank vehicle is administered in a model control group.
SD rats of appropriate body weight were selected to prepare a fibromyalgia model and post-operative mechanical pain threshold measurements were initiated at least 7 days after molding. Animals with significantly reduced postoperative left hind limb pain threshold compared to preoperative left hind limb pain threshold were selected for all subsequent efficacy trials. Experimental model animals were given the corresponding drugs or vehicle and the mechanical pain threshold of the animals was measured at time points of 0.5h, 3h after administration.
1.5 Composition synergy analysis
Whether or not pregabalin and riluzole in the composition are synergistic is evaluated according to the positive mean formula q=e (a+b)/(ea+eb-ea×eb). Wherein E (a+b) is the improvement rate of the combined drug, ea and Eb are the improvement rates of the drug A (pregabalin) and the drug B (riluzole) which are used independently. E= (pain threshold after administration-model value)/(basal value-model value). If the q value is in the range of 0.85-1.15, the two medicines are combined and simply added, and the q value is more than 1.15 and is synergistic, and if the q value is less than 0.85, the two medicines are combined and have antagonism.
1.6 Data statistics
Experimental data are expressed as Mean ± standard error (Mean ± SEM). Differences between groups were analyzed using one-way variance analysis, group comparisons were tested using LSD, P <0.05 defined as significant differences.
2. Results
The experimental results are shown in Table 1. Pregabalin 25 mg/kg, riluzole 10mg/kg, composition 50:1, composition 1:20 all significantly increased the mechanical pain threshold of animals at 0.5h post-dose (p=0.0246, P <0.0001, p=0.0203, P < 0.0001), and each of these groups also significantly increased the mechanical pain threshold of animals at 3h post-dose (P <0.0001, p=0.0002, P < 0.0001). The synergy calculation results show that: the q values of composition 50:1 at 0.5h and 3h post-administration were 0.959, 1.044, respectively, and the q values of composition 1:20 at 0.5h and 3h post-administration were 0.920, 1.033, respectively.
Table 1 mechanical pain threshold (unit: g) for each group of animals
| Group of | Number of animals | Basic value | Model value | Pain threshold after 0.5h of administration | Pain threshold 3h after administration |
| Model control group | 11 | 32.18±1.87 | 13.87±0.55 | 13.57±0.40 | 13.86±0.45 |
| Pregabalin group (25 mg/kg) | 11 | 30.97±1.39 | 14.30±0.38 | 17.60±0.98* | 25.41±1.09**** |
| Pregabalin (0.5 mg/kg) | 11 | 30.79±1.69 | 14.03±0.37 | 13.56±0.49 | 15.59±1.00 |
| Riluzole group (10 mg/kg) | 12 | 31.91±1.33 | 14.09±0.40 | 26.16±1.17**** | 19.63±1.41*** |
| Riluzole group (0.5 mg/kg) | 12 | 30.52±1.37 | 13.54±0.53 | 14.81±0.95 | 13.92±0.46 |
| Composition 50:1 group | 12 | 31.23±1.43 | 13.51±0.48 | 17.64±1.50* | 24.85±1.23**** |
| Composition 1:20 group | 12 | 30.57±1.00 | 13.89±0.46 | 25.17±1.97**** | 21.23±1.09**** |
Data are expressed as mean ± standard error, P <0.05, P <0.001, P <0.0001, compared to model control.
EXAMPLE 2 study of the pharmacodynamic effects of pregabalin and riluzole compositions on fibromyalgia 2
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.
1.2 Test drug
Pregabalin and riluzole were as in example 1.
1.3 Experimental method
Preparation of fibromyalgia animal model, measurement method of mechanical pain threshold and measurement and calculation of basic pain threshold of animal are the same as in example 1.
1.4 Animal grouping and experimental procedure
The experimental model animals were randomly divided into 7 groups, namely, a model control group, a pregabalin group (20 mg/kg), a pregabalin group (1 mg/kg), a riluzole group (10 mg/kg), a riluzole group (1 mg/kg), a pregabalin and riluzole composition 20:1 group (pregabalin 20 mg/kg+riluzole 1 mg/kg), and a pregabalin and riluzole composition 1:10 group (pregabalin 1 mg/kg+riluzole 10 mg/kg). Pregabalin and riluzole were administered by intraperitoneal injection, with 11 animals per group and the model control group given the corresponding blank vehicle.
SD rats of appropriate body weight were selected to prepare a fibromyalgia model and post-operative mechanical pain threshold measurements were initiated at least 7 days after molding. Animals with significantly reduced postoperative left hind limb pain threshold compared to preoperative left hind limb pain threshold were selected for subsequent efficacy testing. Experimental model animals were given the corresponding drugs or vehicle and the mechanical pain threshold of the animals was measured at time points of 0.5h, 3h after administration.
1.5 Composition synergy analysis
Composition synergy analysis was as in example 1.
1.6 Data statistics
The data statistics are the same as in example 1.
2. Results
The experimental results are shown in Table 2. Pregabalin 20 mg/kg, riluzole 10 mg/kg, composition 20:1, composition 1:10 all significantly increased the mechanical pain threshold of animals at 0.5h post-dose (p=0.0288, P <0.0001, p=0.0209, P < 0.0001) compared to vehicle control groups, which also significantly increased the mechanical pain threshold of animals at 3h post-dose (P <0.0001 ). The synergy calculation results show that: q values for composition 20:1 at 0.5h and 3h post-dose were 1.183, 1.251, respectively, and q values for composition 1:10 at 0.5h and 3h post-dose were 1.189, 1.227, respectively, indicating synergy between composition 20:1, composition 1:10 at 0.5h, 3h post-dose.
TABLE 2 mechanical pain threshold (unit: g) for animals of each group
| Group of | Number of animals | Basic value | Model value | Pain threshold after 0.5h of administration | Pain threshold 3h after administration |
| Model control group | 11 | 31.61±1.19 | 14.42±0.35 | 13.71±0.29 | 14.14±0.39 |
| Pregabalin group (20 mg/kg) | 11 | 30.48±1.29 | 14.01±0.43 | 16.95±1.28* | 22.74±1.52**** |
| Pregabalin group (1 mg/kg) | 11 | 29.90±1.32 | 13.84±0.34 | 14.33±0.54 | 15.05±0.82 |
| Riluzole group (10 mg/kg) | 11 | 31.60±1.57 | 13.38±0.39 | 22.58±1.59**** | 25.01±1.97**** |
| Riluzole group (1 mg/kg) | 11 | 30.84±1.77 | 14.17±0.37 | 13.64±0.48 | 15.39±0.64 |
| Composition 20:1 group | 11 | 29.82±1.28 | 13.95±0.43 | 17.15±1.16* | 24.28±1.50**** |
| Composition 1:10 group | 11 | 31.65±1.15 | 13.65±0.62 | 27.31±1.11**** | 27.32±1.13**** |
Data are expressed as mean ± standard error, P <0.05, P <0.0001, compared to model control.
EXAMPLE 3 study 3 of the pharmacodynamic effects of pregabalin and riluzole compositions on fibromyalgia
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.
1.2 Test drug
Pregabalin and riluzole were as in example 1.
1.3 Experimental method
Preparation of fibromyalgia animal model, measurement method of mechanical pain threshold and measurement and calculation of basic pain threshold of animal are the same as in example 1.
1.4 Animal grouping and experimental procedure
The experimental model animals were randomly divided into 9 groups, namely, a model control group, a pregabalin group (30 mg/kg), a pregabalin group (18 mg/kg), a pregabalin group (3 mg/kg), a riluzole group (12 mg/kg), a riluzole group (3 mg/kg), a pregabalin and riluzole combination 10:1 group (pregabalin 30 mg/kg+riluzole 3 mg/kg), a pregabalin and riluzole combination 1:4 group (pregabalin 3 mg/kg+riluzole 12 mg/kg), a pregabalin and riluzole combination 6:1 group (pregabalin 18 mg/kg+riluzole 3 mg/kg). Pregabalin and riluzole are administered by intraperitoneal injection, 10-12 animals per group, and corresponding blank vehicle is administered in a model control group.
SD rats of appropriate body weight were selected to prepare a fibromyalgia model and post-operative mechanical pain threshold measurements were initiated at least 7 days after molding. Animals with significantly reduced postoperative left hind limb pain threshold compared to preoperative left hind limb pain threshold were selected for subsequent efficacy testing. Experimental model animals were given the corresponding drugs or vehicle and the mechanical pain threshold of the animals was measured at time points of 0.5h, 3h after administration.
1.5 Composition synergy analysis
Composition synergy analysis was as in example 1.
1.6 Data statistics
The data statistics are the same as in example 1.
2. Results
The experimental results are shown in Table 3. Pregabalin 30 mg/kg, riluzole 12 mg/kg, composition 10:1, composition 1:4, composition 6:1 all significantly increased the mechanical pain threshold of the animals 0.5h post-dose (p=0.0244, P <0.0001, p=0.0010), pregabalin 30 mg/kg, pregabalin 18 mg/kg, riluzole 12 mg/kg, composition 10:1, composition 1:4, composition 6:1 all significantly increased the mechanical pain threshold of the animals 3h post-dose (P <0.0001 ). The synergy calculation results show that: q values of composition 10:1 at 0.5h and 3h post-dose were 1.212, 1.206, respectively, q values of composition 1:4 at 0.5h and 3h post-dose were 1.222, 1.270, respectively, and q values of composition 6:1 at 0.5h and 3h post-dose were 1.354, 1.243, respectively, indicating synergy of composition 10:1, composition 1:4, composition 6:1 at 0.5h, 3h post-dose.
TABLE 3 mechanical pain threshold (unit: g) for animals of each group
| Group of | Number of animals | Basic value | Model value | Pain threshold after 0.5h of administration | Pain threshold 3h after administration |
| Model control group | 10 | 29.27±1.25 | 14.15±0.46 | 14.98±0.61 | 15.34±0.42 |
| Pregabalin group (30 mg/kg) | 11 | 29.31±1.31 | 14.10±0.59 | 18.79±1.22* | 23.57±0.89**** |
| Pregabalin group (18 mg/kg) | 11 | 28.55±1.51 | 13.93±0.43 | 16.91±1.22 | 23.02±0.94**** |
| Pregabalin group (3 mg/kg) | 11 | 28.86±1.58 | 13.72±0.37 | 14.50±0.39 | 14.44±0.39 |
| Riluzole group (12 mg/kg) | 12 | 29.51±1.45 | 14.13±0.43 | 27.44±1.44**** | 25.22±1.97**** |
| Riluzole group (3 mg/kg) | 12 | 30.29±1.00 | 13.99±0.43 | 17.08±0.77 | 15.08±0.46 |
| Composition 10:1 group | 12 | 30.79±0.89 | 14.18±0.46 | 23.22±1.51**** | 27.72±1.12**** |
| Composition 1:4 group | 12 | 28.34±1.03 | 13.11±0.33 | 28.20±0.97**** | 28.02±1.51**** |
| Composition 6:1 group | 12 | 29.34±0.86 | 13.57±0.41 | 20.51±1.24** | 27.01±1.67**** |
Data are expressed as mean ± standard error, P <0.05, P <0.01, P <0.0001, compared to model control.
EXAMPLE 4 study of the pharmacodynamic effects of pregabalin and riluzole compositions on fibromyalgia 4
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.
1.2 Test drug
Pregabalin and riluzole were as in example 1.
1.3 Experimental method
Preparation of fibromyalgia animal model, measurement method of mechanical pain threshold and measurement and calculation of basic pain threshold of animal are the same as in example 1.
1.4 Animal grouping and experimental procedure
The experimental model animals were randomly divided into 11 groups, namely, a model control group, a pregabalin group (18 mg/kg), a pregabalin group (9 mg/kg), a pregabalin group (3 mg/kg), a riluzole group (12 mg/kg), a riluzole group (6 mg/kg), a riluzole group (3 mg/kg), a pregabalin and riluzole composition 6:1 group (pregabalin 18 mg/kg+riluzole 3 mg/kg), a pregabalin and riluzole composition 3:1 group (pregabalin 9 mg/kg+riluzole 3 mg/kg), a pregabalin and riluzole composition 1:4 group (pregabalin 3 mg/kg+riluzole 12 mg/kg), a pregabalin and riluzole composition 1:2 group (pregabalin 3 mg/kg+riluzole 6 mg/kg). Pregabalin and riluzole were administered by intraperitoneal injection, with 11 animals per group and the model control group given the corresponding blank vehicle.
SD rats of appropriate body weight were selected to prepare a fibromyalgia model and post-operative mechanical pain threshold measurements were initiated at least 7 days after molding. Animals with significantly reduced postoperative left hind limb pain threshold compared to preoperative left hind limb pain threshold were selected for subsequent efficacy testing. Experimental model animals were given the corresponding drugs or vehicle and the mechanical pain threshold of the animals was measured at time points of 0.5h, 3h after administration.
1.5 Composition synergy analysis
Composition synergy analysis was as in example 1.
1.6 Data statistics
The data statistics are the same as in example 1.
2. Results
The experimental results are shown in Table 4. Riluzole 12 mg/kg, riluzole 6 mg/kg, composition 6:1, composition 3:1, composition 1:4, composition 1:2 all significantly increased the mechanical pain threshold of animals 0.5h post-dose (P <0.0001, p=0.0056, p=0.0009, p=0.0212, P < 0.0001), pregabalin 18 mg/kg, pregabalin 9 mg/kg, riluzole 12 mg/kg, riluzole 6 mg/kg, composition 6:1, composition 3:1, composition 1:4, composition 1:2 all significantly increased the mechanical pain threshold of animals 3h post-dose (P <0.0001, p=0.0384, P < 0.0001). The synergy calculation results show that: q values of composition 6:1 at 0.5h and 3h post-dose were 1.343, 1.328, respectively, q values of composition 3:1 at 0.5h and 3h post-dose were 1.350, 1.363, respectively, q values of composition 1:4 at 0.5h and 3h post-dose were 1.161, 1.278, respectively, q values of composition 1:2 at 0.5h and 3h post-dose were 1.328, 1.239, respectively, indicating that composition 6:1, composition 3:1, composition 1:4, composition 1:2 were synergistic at 0.5h, 3h post-dose.
TABLE 4 mechanical pain threshold (unit: g) for animals of each group
| Group of | Number of animals | Basic value | Model value | Pain threshold after 0.5h of administration | Pain threshold 3h after administration |
| Model control group | 11 | 29.42±1.59 | 14.15±0.41 | 14.30±0.79 | 15.05±0.38 |
| Pregabalin group (18 mg/kg) | 11 | 30.66±0.87 | 14.05±0.64 | 16.20±0.82 | 26.04±2.27**** |
| Pregabalin group (9 mg/kg) | 11 | 30.35±1.31 | 14.05±0.65 | 16.85±0.50 | 24.71±1.75**** |
| Pregabalin group (3 mg/kg) | 11 | 30.28±1.71 | 13.94±0.68 | 17.05±1.36 | 17.63±1.07 |
| Riluzole group (12 mg/kg) | 11 | 30.14±1.51 | 13.29±0.47 | 24.44±1.40**** | 24.61±1.07**** |
| Riluzole group (6 mg/kg) | 11 | 29.67±1.48 | 14.01±0.52 | 18.57±0.98** | 19.39±1.02* |
| Riluzole group (3 mg/kg) | 11 | 28.13±1.81 | 13.57±0.62 | 15.71±0.72 | 16.52±0.90 |
| Composition 6:1 group | 11 | 28.66±1.57 | 13.89±0.50 | 19.48±1.08*** | 25.34±1.85**** |
| Composition 3:1 group | 11 | 29.36±2.07 | 14.07±0.67 | 17.84±1.26* | 26.77±1.98**** |
| Composition 1:4 group | 11 | 29.42±1.44 | 13.53±0.66 | 25.23±0.82**** | 27.87±1.47**** |
| Composition 1:2 group | 11 | 29.24±1.28 | 13.86±0.67 | 24.00±1.45**** | 23.43±1.30**** |
Data are expressed as mean ± standard error, P <0.05, P <0.01, P <0.001, P <0.0001, compared to model control.
EXAMPLE 5 study of the pharmacodynamic effects of pregabalin and riluzole compositions on fibromyalgia 5
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.
1.2 Test drug
Pregabalin and riluzole were as in example 1.
1.3 Experimental method
Preparation of fibromyalgia animal model, measurement method of mechanical pain threshold and measurement and calculation of basic pain threshold of animal are the same as in example 1.
1.4 Animal grouping and experimental procedure
The experimental model animals were randomly divided into 9 groups, namely, a model control group, a pregabalin group (9 mg/kg), a pregabalin group (6 mg/kg), a pregabalin group (3 mg/kg), a riluzole group (6 mg/kg), a riluzole group (3 mg/kg), a pregabalin and riluzole composition 3:1 group (pregabalin 9 mg/kg+riluzole 3 mg/kg), a pregabalin and riluzole composition 1:2 group (pregabalin 3 mg/kg+riluzole 6 mg/kg), a pregabalin and riluzole composition 1:1 group (pregabalin 6 mg/kg+riluzole 6 mg/kg). Pregabalin and riluzole are administered by intraperitoneal injection, 10-12 animals per group, and corresponding blank vehicle is administered in a model control group.
SD rats of appropriate body weight were selected to prepare a fibromyalgia model and post-operative mechanical pain threshold measurements were initiated at least 7 days after molding. Animals with significantly reduced postoperative right hind limb pain threshold compared to contralateral hind limb pain threshold were selected for subsequent efficacy testing. Experimental model animals were given the corresponding drugs or vehicle and the mechanical pain threshold of the animals was measured at time points of 0.5h, 3h after administration.
1.5 Composition synergy analysis
Composition synergy analysis was as in example 1.
1.6 Data statistics
The data statistics are the same as in example 1.
2. Results
The experimental results are shown in Table 5. Compared with a vehicle control group, riluzole 6 mg/kg, composition 3:1, composition 1:2 and composition 1:1 can obviously improve the mechanical pain threshold of animals at 0.5h after administration (P=0.0035, P=0.0002, P <0.0001 and P < 0.0001), pregabalin 9 mg/kg, pregabalin 6 mg/kg, riluzole 6 mg/kg, composition 3:1, composition 1:2 and composition 1:1 can obviously improve the mechanical pain threshold of animals at 3h after administration (P <0.0001, P=0.0040, P=0.0259, P <0.0001 and P < 0.0001). The synergy calculation results show that: q values of composition 3:1 at 0.5h and 3h post-dose were 1.388, 1.344, respectively, q values of composition 1:2 at 0.5h and 3h post-dose were 1.309, 1.333, respectively, and q values of composition 1:1 at 0.5h and 3h post-dose were 1.343, 1.230, respectively, indicating synergy of composition 3:1, composition 1:2, composition 1:1 at 0.5h, 3h post-dose.
TABLE 5 mechanical pain threshold (unit: g) for animals of each group
| Group of | Number of animals | Basic value | Model value | Pain threshold after 0.5h of administration | Pain threshold 3h after administration |
| Model control group | 10 | 28.20±1.27 | 13.90±0.34 | 15.04±0.68 | 15.30±0.47 |
| Pregabalin group (9 mg/kg) | 10 | 29.79±1.32 | 13.67±0.52 | 16.14±0.82 | 21.46±2.12**** |
| Pregabalin group (6 mg/kg) | 10 | 27.80±1.50 | 14.39±0.48 | 14.64±0.39 | 20.24±1.40** |
| Pregabalin group (3 mg/kg) | 10 | 29.49±1.79 | 13.67±0.40 | 15.98±1.07 | 17.18±0.82 |
| Riluzole group (6 mg/kg) | 12 | 30.07±1.23 | 13.63±0.56 | 20.23±1.06** | 18.94±1.00* |
| Riluzole group (3 mg/kg) | 12 | 29.87±1.03 | 14.11±0.48 | 16.81±0.96 | 14.50±0.69 |
| Composition 3:1 group | 12 | 31.05±0.94 | 14.61±0.43 | 21.72±1.70*** | 28.07±1.33**** |
| Composition 1:2 group | 12 | 29.56±1.15 | 13.11±0.33 | 23.94±1.79**** | 24.21±0.78**** |
| Composition 1:1 group | 12 | 29.34±0.86 | 13.57±0.41 | 23.38±1.33**** | 25.34±1.80**** |
Data are expressed as mean ± standard error, P <0.05, P <0.01, P <0.001, P <0.0001, compared to model control.
EXAMPLE 6 pharmacodynamic effects of pregabalin and riluzole compositions on fibromyalgia study 6
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, SPF grade, weighing 150-200g.
1.2 Test drug
Pregabalin and riluzole were as in example 1.
1.3 Experimental method
Preparation of fibromyalgia animal model, measurement method of mechanical pain threshold and measurement and calculation of basic pain threshold of animal are the same as in example 1.
1.4 Animal grouping and experimental procedure
The experimental animals were randomly divided into 11 groups, namely, a model control group, a pregabalin group (30 mg/kg), a pregabalin group (20 mg/kg), a pregabalin group (6 mg/kg), a riluzole group (10 mg/kg), a riluzole group (7.5 mg/kg), a riluzole group (6 mg/kg), a pregabalin and riluzole composition 1:1 group (pregabalin 6 mg/kg+riluzole 6 mg/kg), a pregabalin and riluzole composition 2:1 group (pregabalin 20 mg/kg+riluzole 10 mg/kg), a pregabalin and riluzole composition 3:1 group (pregabalin 30 2/kg+riluzole 10 mg/kg), a pregabalin and riluzole composition 4:1 group (pregabalin 30 mg/kg+riluzole 7.5/kg), a pregabalin and riluzole composition 1:5:5 (pregabalin 20:26+licuzole). Pregabalin and riluzole were administered orally by gavage, with 10-11 animals per group, and the model control group given the corresponding blank vehicle.
SD rats of appropriate body weight were selected to prepare animal models of fibromyalgia and post-operative mechanical pain threshold measurements were initiated at least 7 days after modeling. Animals with significantly reduced postoperative left hind limb pain threshold compared to preoperative left hind limb pain threshold were selected for all subsequent efficacy trials. Experimental model animals were given the corresponding drugs or vehicle and the mechanical pain threshold of the animals was measured at time points of 0.5h, 3h, 6h, 8h after administration.
1.5 Composition synergy analysis
Whether or not pregabalin and riluzole in the composition have a synergistic effect at the time point E max (3 h) after administration was evaluated according to the positive average formula q=e (a+b)/(ea+eb-ea×eb). Wherein E (a+b) is the improvement rate of the combined drug, ea and Eb are the improvement rates of the drug A (pregabalin) and the drug B (riluzole) which are used independently. E= (pain threshold after administration-model value)/(basal value-model value). If the q value is in the range of 0.85-1.15, the two medicines are combined and simply added, and the q value is more than 1.15 and is synergistic, and if the q value is less than 0.85, the two medicines are combined and have antagonism.
The composition was analyzed for synergy of pregabalin and riluzole according to CompuSyn software for overall efficacy from 0 to 8 hours post-administration. The calculation formula of the improvement rate of the medicine group is as follows: (AUC 0-8h -model value x 8 h)/(base value x 8 h-model value x 8 h). The Combination Index (CI) of each composition group was calculated by software, and if CI <1 was synergistic, ci=1 was additive, CI >1 indicated that the combination of the two drugs had antagonistic effects.
1.6 Data statistics
The data statistics are the same as in example 1.
2. Results
The experimental results are shown in Table 6. Pregabalin 30 mg/kg, riluzole 10 mg/kg, riluzole 7.5 mg/kg, riluzole 6 mg/kg, composition 1:1, composition 2:1, composition 3:1, composition 4:1, composition 5:1 all significantly increase the mechanical pain threshold of animals at 0.5h post-dose, （P=0.0436、P<0.0001、P<0.0001、P<0.0001、P<0.0001、P<0.0001、P<0.0001、P<0.0001、P<0.0001）; pregabalin 30 mg/kg, pregabalin 20 mg/kg, pregabalin 6 mg/kg, riluzole 10 mg/kg, composition 1:1, composition 2:1, composition 3:1, composition 4:1, composition 5:1 all significantly increase the mechanical pain threshold of animals at （P<0.0001、P<0.0001、P=0.0008、P=0.0340、P<0.0001、P<0.0001、P<0.0001、P<0.0001、P<0.0001）; pregabalin 30/kg, pregabalin 20 mg/kg, pregabalin 6 mg/kg, composition 1:1, composition 2:1, composition 3:1, composition 4:1, composition 6:1 <0.0001 > p=p <0.0001,; pregabalin 30 mg/kg, pregabalin 20 mg/kg, pregabalin 6 mg/kg, composition 1:1, composition 2:1, composition 3:1, composition 4:1 composition 5:1 significantly increases the mechanical pain threshold (P < 0.0001: P <0.0001, p=0.0004, P < 0.0001). The Jin Zhengjun formula synergy calculation results show that: the q value of composition 1:1 at 3h post-dose was 1.261, the q value of composition 2:1 at 3h post-dose was 1.280, the q value of composition 3:1 at 3h post-dose was 1.395, the q value of composition 4:1 at 3h post-dose was 1.382, the q value of composition 5:1 at 3h post-dose was 1.355, indicating synergy for composition 1:1, composition 2:1, composition 3:1, composition 4:1, composition 5:1 at 3h post-dose; compuSyn software analysis showed that: the CI of the post-dose AUC for composition 1:1 was 0.650, the CI of the post-dose AUC for composition 2:1 was 0.586, the CI of the post-dose AUC for composition 3:1 was 0.539, the CI of the post-dose AUC for composition 4:1 was 0.518, and the CI of the post-dose AUC for composition 5:1 was 0.538, indicating synergy for composition 1:1, composition 2:1, composition 3:1, composition 4:1, and composition 5:1 for 0-8h post-dose.
TABLE 6 mechanical pain threshold (unit: g) for animals of each group
| Group of | Number of animals | Basic value | Model value | Pain threshold after 0.5h of administration | Pain threshold 3h after administration | Pain threshold after 6h of administration | Pain threshold 8h after administration |
| Model control group | 11 | 29.71±1.49 | 13.87±0.48 | 14.00±0.57 | 13.36±0.33 | 13.41±0.76 | 13.54±0.78 |
| Pregabalin group (30 mg/kg) | 11 | 30.99±2.01 | 14.78±0.45 | 17.89±0.94* | 25.55±0.99**** | 25.64±0.99**** | 24.78±0.78**** |
| Pregabalin group (20 mg/kg) | 10 | 30.08±1.82 | 13.83±0.68 | 15.71±0.71 | 23.22±1.23**** | 21.42±1.20**** | 22.56±1.36**** |
| Pregabalin group (6 mg/kg) | 11 | 30.37±1.64 | 14.33±0.58 | 14.97±0.48 | 19.87±1.65*** | 19.59±1.14*** | 20.39±1.69*** |
| Riluzole group (10 mg/kg) | 11 | 28.48±0.79 | 14.25±0.58 | 25.65±1.07**** | 17.44±1.22* | 15.05±0.95 | 14.01±1.08 |
| Riluzole group (7.5 mg/kg) | 10 | 30.89±1.34 | 13.89±0.46 | 25.05±1.26**** | 13.46±0.35 | 13.98±0.67 | 14.17±0.64 |
| Riluzole group (6 mg/kg) | 11 | 30.19±0.83 | 13.95±0.68 | 25.06±1.12**** | 16.75±1.29 | 14.03±0.95 | 16.45±1.17 |
| Composition 1:1 group | 11 | 29.36±0.80 | 13.53±1.18 | 24.52±0.85**** | 25.32±1.05**** | 25.27±1.70**** | 23.73±1.35**** |
| Composition 2:1 group | 10 | 31.07±1.57 | 13.58±0.68 | 23.36±1.87**** | 27.14±1.72**** | 27.92±1.25**** | 28.45±1.26**** |
| Composition 3:1 group | 11 | 31.69±0.96 | 14.12±0.55 | 22.84±1.62**** | 31.12±2.35**** | 29.42±0.87**** | 26.38±1.84**** |
| Composition 4:1 group | 10 | 29.39±1.32 | 14.06±0.59 | 22.60±2.65**** | 29.30±1.32**** | 29.07±1.58**** | 27.92±1.75**** |
| Composition 5:1 group | 10 | 29.89±1.52 | 13.63±0.47 | 24.49±2.02**** | 29.63±1.56**** | 28.25±1.65**** | 27.06±1.93**** |
Data are expressed as mean ± standard error, P <0.05, P <0.01, P <0.001, P <0.0001, compared to model control.
EXAMPLE 7 study of the pharmacodynamic effects of pregabalin and riluzole compositions on acute pain
1. Materials and methods
1.1 Experimental animal
C57BL/6J mice, male, SPF grade, body weight 20-25g.
1.2 Test drug
Pregabalin and riluzole were as in example 1.
1.3 Animal grouping and experimental procedure
The experimental animals were randomly divided into 10 groups, namely, normal control group, model control group, pregabalin 10 mg/kg group, pregabalin and riluzole composition 20:1 group (pregabalin 10 mg/kg+riluzole 0.5 mg/kg), pregabalin and riluzole composition 10:1 group (pregabalin 10 mg/kg+riluzole 1 mg/kg), pregabalin and riluzole composition 6:1 group (pregabalin 10 mg/kg+riluzole 1.667 mg/kg), pregabalin and riluzole composition 4:1 group (pregabalin 10 mg/kg+riluzole 2.5 mg/kg), pregabalin and riluzole composition 3:1 group (pregabalin 10 mg/kg+riluzole 3.333 mg/kg), pregabalin and riluzole composition 1:2 group (pregabalin mg/kg+riluzole 1/kg), pregabalin and riluzole composition 4:1 group (pregabalin 10:5+20/kg).
The corresponding test compound was administered orally to each group of mice and mice were injected intraperitoneally with 0.8% acetic acid (10 mL/kg) at the Emax time point (3 h) after administration. Mice were placed in separate glass boxes and the total number of animal writhing activities was counted over 20 minutes. Twist behavior is defined as abdominal extension and simultaneous extension of at least one hindlimb.
1.4 Data statistics
The data statistics are the same as in example 1.
2. Results
The experimental results are shown in Table 7. The number of twists was significantly increased in model control animals compared to normal control (P < 0.0001); compared with the model control group, pregabalin 10 mg/kg, composition 20:1, composition 10:1, composition 6:1, composition 4:1, composition 3:1, composition 1:2 and composition 1:4 can significantly reduce the number of twists of animals (p=0.0270, p=0.0016, p=0.0007, P <0.0001 and P < 0.0001), wherein the analgesic effect of the composition is also improved with the increase of the riluzole dose initially, but the analgesic effect of the composition is not further improved when the riluzole dose is more than or equal to 20 mg/kg. The results show that compositions 6:1, 4:1, 3:1, 1:2 and 1:4 all have analgesic and synergistic effects, and the analgesic effects are superior to those of pregabalin 10 mg/kg administered alone (p=0.0238, p=0.0180, p=0.0097, p=0.0073 and p=0.0106).
TABLE 7 number of times of twisting of animals in each group
| Group of | Number of animals | Number of times of twisting body |
| Normal control group | 9 | 0±0**** |
| Model control group | 9 | 24.30±2.47 |
| Pregabalin 10 mg/kg group | 10 | 17.40±2.12* |
| Composition 20:1 group | 9 | 14.07±2.23** |
| Composition 10:1 group | 9 | 13.21±2.78*** |
| Composition 6:1 group | 9 | 10.34±2.11****# |
| Composition 4:1 group | 10 | 10.20±1.82****# |
| Composition 3:1 group | 10 | 9.50±1.97****## |
| Composition 1:2 group | 10 | 9.20±2.36****## |
| Composition 1:4 group | 10 | 9.60±2.49****# |
Data are expressed as mean ± standard error, P <0.05, P <0.01, P <0.001, P <0.0001, compared to model control; #P <0.05, #P <0.01, compared to pregabalin 10 mg/kg group.
EXAMPLE 8 study of the pharmacodynamic effects of pregabalin and riluzole compositions on chronic pain in osteoarthritis
1. Materials and methods
1.1 Experimental animal
Sprague-Dawley (SD) rats, male, grade SPF, body weight 300-400 g.
1.2 Test drug
Pregabalin and riluzole were as in example 1.
1.3 Animal grouping and experimental procedure
The experimental animals were randomly divided into 10 groups, namely, normal control group, model control group, pregabalin 10 mg/kg group, pregabalin and riluzole composition 20:1 group (pregabalin 10 mg/kg+riluzole 0.5 mg/kg), pregabalin and riluzole composition 10:1 group (pregabalin 10 mg/kg+riluzole 1 mg/kg), pregabalin and riluzole composition 6:1 group (pregabalin 10 mg/kg+riluzole 1.667 mg/kg), pregabalin and riluzole composition 4:1 group (pregabalin 10 mg/kg+riluzole 2.5 mg/kg), pregabalin and riluzole composition 3:1 group (pregabalin 10 mg/kg+riluzole 3.333 mg/kg), pregabalin and riluzole composition 1:2 group (pregabalin mg/kg+riluzole 1/kg), pregabalin and riluzole composition 4:1 group (pregabalin 10:5+20/kg).
In performing this experiment, rats were induced to be anesthetized with 4% isoflurane, and then anesthetized with 2.5% isoflurane. After the animals were anesthetized, arthritis was induced by injecting 50 μl of Mycobacterium butyricum inactivated by complete Freund's adjuvant [60 mg ] into the right tibiofemoral joint capsule, adding to a mixture of paraffin oil (6 mL), 9% NaCl (4 mL) and Tween 80 (1 mL), mixing well, and sterilizing with steam at 120deg.C under high pressure for 30min ]. Chronic monoarthritic animals showed significant right ankle swelling 3-4 weeks after injection. Animals with multiple arthritis and no or slight swelling of the right ankle joint were knocked out.
At week 4 of the induction of the animal arthritis model, the experimental model animals were given the corresponding drugs or vehicles and were subjected to a behavioral test at the Emax time point (3 h) after the administration. The soft towel is used for gently wrapping animals to limit the movement of the animals, and two hind limbs are exposed for the convenience of experimenters to operate. The experimenter uses pliers equipped with strain gauges to evaluate the threshold voicing pressure. An average of three consecutive values (1 minute apart) was obtained as the sounding pressure threshold for each paw by applying increasing pressure to the dorsiflexion side of the ankle with forceps.
1.4 Data statistics
The data statistics are the same as in example 1.
2. Results
The experimental results are shown in Table 8. The threshold voicing pressure was significantly reduced in model control animals compared to normal control (P < 0.0001); compared with the vehicle control group, pregabalin 10 mg/kg, composition 20:1, composition 10:1, composition 6:1, composition 4:1, composition 3:1, composition 1:2 and composition 1:4 can significantly increase the sounding pressure threshold (p=0.0165, p=0.0009, p=0.0004, P <0.0001 and P < 0.0001) of animals, wherein the analgesic effect of the composition is also improved with the increase of the riluzole dose, but the analgesic effect of the composition is not further improved when the riluzole dose is more than or equal to 20 mg/kg. The results show that compositions 6:1, 4:1, 3:1, 1:2 and 1:4 have analgesic and synergistic effects, and the analgesic effects are superior to those of pregabalin 10 mg/kg administered alone (p=0.0374, p=0.0436, p=0.0200, p=0.0369 and p=0.0272).
TABLE 8 sounding pressure threshold for animals of each group
| Group of | Number of animals | Sounding pressure threshold (N/cm 2) |
| Normal control group | 9 | 10.2±1.2**** |
| Model control group | 10 | 2.5±1.3 |
| Pregabalin 10 mg/kg group | 11 | 6.2±0.8* |
| Composition 20:1 group | 10 | 7.8±1.4*** |
| Composition 10:1 group | 10 | 8.2±0.9*** |
| Composition 6:1 group | 10 | 9.4±1.0****# |
| Composition 4:1 group | 10 | 9.3±1.2****# |
| Composition 3:1 group | 11 | 9.7±1.0****# |
| Composition 1:2 group | 9 | 9.5±1.2****# |
| Composition 1:4 group | 10 | 9.6±0.9****# |
Data are expressed as mean ± standard error, P <0.05, P <0.001, P <0.0001, compared to model control; the group #P <0.05, compared to pregabalin 10 mg/kg.
Claims (10)
1. Use of a pharmaceutical composition comprising (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof and riluzole or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prevention of non-neuropathic pain.
2. Use of any of the compositions according to claim 1, characterized in that said (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: riluzole or a pharmaceutically acceptable salt thereof, and the mass ratio of the riluzole or the pharmaceutically acceptable salt thereof is 20:1-1:4 in terms of free acid or alkali form.
3. Use of any of the compositions according to claim 1, characterized in that said (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: riluzole or a pharmaceutically acceptable salt thereof, and the mass ratio of the riluzole or the pharmaceutically acceptable salt thereof is 10:1-1:4 in terms of free acid or alkali form.
4. Use of any of the compositions according to claim 1, characterized in that said (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: riluzole or a pharmaceutically acceptable salt thereof, and the mass ratio of the riluzole or the pharmaceutically acceptable salt thereof is 6:1-1:4 in terms of free acid or alkali.
5. Use of any of the compositions according to claim 1, characterized in that said (S) -3-aminomethyl-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof: riluzole or a pharmaceutically acceptable salt thereof, and the mass ratio of the riluzole or the pharmaceutically acceptable salt thereof is 3:1-1:2 in terms of free acid or alkali form.
6. The use according to claims 1-5, wherein said non-neuropathic pain type pain comprises: acute pain, chronic non-neuropathic pain, migraine pain, pain associated with osteoarthritis or articular rheumatism, lower back pain, dental pain, pain associated with burns, non-neuropathic pain associated with cancers, acute or chronic tension headache, postoperative pain, fibromyalgia, pain associated with soft tissue injury or peripheral injury, central pain, pain associated with bruises, sprains or wounds, spinal pain, pain associated with spinal or brain stem injury, myofascial pain syndrome, vulvotomy pain, gouty pain, cardiac pain, muscle pain, eye pain, ear pain, inflammatory pain, orofacial pain, abdominal pain, pain associated with dysmenorrhoea, childbirth pain or endometriosis pain, somatic pain, pain associated with amputation, neuroma or vasculitis pain, hyperalgesia, sudden pain, pain caused by chemotherapy, cardiac pain, pain associated with gall stones, functional abdominal pain, headache, sinus headache, cluster headache, temporomandibular joint pain, maxillary sinus pain, pain caused by ankylosis, pain associated with ankylosis, local pain of the limb, fulness, pain of the limb, and complex pain.
7. The use according to claims 1-5, wherein said non-neuropathic pain type pain comprises: acute pain, chronic non-neuropathic pain, migraine, pain associated with osteoarthritis or articular rheumatism, lower back pain, dental pain, ear pain, pain caused by burns, non-neuropathic pain associated with cancer, acute or chronic tension headache, fibromyalgia, erythromelalgia, complex regional pain syndrome.
8. The use according to claims 1-5, wherein said non-neuropathic pain type pain comprises: acute pain, chronic non-neuropathic pain, migraine, pain associated with osteoarthritis or articular rheumatism, non-neuropathic pain associated with cancer, fibromyalgia, erythromelalgia, complex regional pain syndrome.
9. The use according to claims 1-5, wherein the non-neuropathic pain is fibromyalgia, erythromelalgia, regional pain syndrome of complexity.
10. The use according to claims 1-5, wherein the non-neuropathic pain is fibromyalgia.
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