WO2001008682A2 - Use of flupirtine for alleviating pain caused by degenerative joint diseases in dogs and cats - Google Patents

Abstract

The invention relates to the use of flupirtine or the pharmaceutically acceptable salts thereof for treating pain caused by degenerative joint diseases that can be accompanied by inflammations in dogs and cats. The inventive substances are also used to prevent such pain from becoming chronic.

Description

USE OF FLUPIRTIN TO REDUCE PAIN IN DEGENERATIVE JOINT DISEASES OF DOGS AND CATS

The present invention relates to the use of flupirtine or its pharmaceutically acceptable salts for the treatment of pain and prevention of pain chronification in degenerative joint diseases of dogs and cats, which can be associated with inflammation.

Degenerative joint diseases are understood as non-inflammatory joint diseases. In English-speaking countries, these diseases are referred to as "degenerative joint diseases" (DJD). Degenerative joint diseases occur particularly in dogs and also in many old cats. The slowly progressing loss of the articular cartilage creates an increasing and pain-related restriction in the mobility of the affected joint. As a preliminary stage of these joint diseases in dogs and cats, e.g. Hip dysplasia (growth disorder), patellar dislocation (dislocation of the kneecap or kneecap prolapse). These preliminary stages of degenerative joint diseases are also painful, even if there is no damage to the cartilage. In dogs, ligament stretching, ligament tears (e.g. torn ligament rupture) or meniscus damage often occur, which on the one hand go hand in hand with pain and on the other hand promote a renewed kneecap.

The degenerative joint diseases are generally accompanied by pain. Acute inflammatory flare-ups occur occasionally. However, there are differences in this regard between humans and dogs, because these inflammatory reactions take place in dogs in a clearly softened form (e.g. swellings which are hardly detectable in dogs, very pronounced swellings in humans). There are other painful diseases in animals that are partially accompanied by degenerative changes in the joints. These include, for example, Dachshund paralyzes or Cauda equina syndrome. The latter is the so-called "horse tail syndrome", which mainly affects dogs of large breeds (such as German shepherd). The cause of the pain is the narrowing of the spinal canal due to the partial collapse of the cartilaginous spinal disc.

Pain also occurs with instability in the lumbosacral joint, the cause of which can be explained by ligament stretching.

Medicines with different mechanisms of action are used in the treatment of chronic pain.

For example, corticosteroids are also used, which, according to their mechanism of action, also trigger serious side effects in animals.

However, non-steroidal anti-inflammatory drugs (NSAIDs) and so-called cartilage protective / protective (chondroprotective) drugs are most often used.

The cartilage-protective substances include polysulfated glycosaminoglycan and the combination of chondroitin and glucosamine. polysulphated

Glycosaminoglycan is given intramuscularly or intra-articularly (directly into the joint).

The effectiveness of this mixture is controversial not only in the human medical but also in the veterinary medical literature (Deal, CL, RW Moskowitz.

Nutraceuticals as therapeutic agents in osteoarthritis. - The role of glucosamine, chondroitin sulfate, and collagen hydrolysate. Rheumatic Disease Clinics of North

America 25: 379-782, 1999; DeHaan, JJ, Goring, RL, BS Beale and in Evaluation of polysulfated glycosaminoglycan for the treatment of hip dysplasia in dogs. Vet.

Surg. 23: 177-181, 1994).

Chondroitin and glucosamine are used either as monosubstances (glucosamine) or in combination orally. To date, their effectiveness is none controlled clinical study in both humans and animals (Leffler, CT, AF Philippi, SG Leffler, JC Mosure, PD Kim. Glucosamine, chondroitin, and magnesium ascorbate for degenerative Joint disease of the knee or low back: A randomized, double -blind, placebo-controlled pilot study. Military medicine 164: 85-91, 1999).

Even if the cartilage-protective substances show therapeutic effects under in vitro conditions, these effects have not been proven under therapeutic conditions (in vivo). (Bassler, C, L Rovati, P Franchimont. Stimulation of proteoglycan production by glucosamine sulfate in chondrocytes isolated from human osteoarthritic articular cartilage in vitro. Osteoarthritis & Cartilage 6: 427-434, 1998).

There is currently no drug that can prevent cartilage destruction.

In the future, the destructive processes will be treated with substances that are causally involved in the pathogenesis of osteoarthrosis and can thus halt the progress of cartilage and bone destruction. Numerous experimental studies indicate that TNFα (tumor necrosis factor α) plays a central role in the development of degenerative changes in the joints. Osteoarthritis is always accompanied by destruction of the cartilage and bone. In osteoarthritis, neutrophils increasingly migrate into the joint, releasing TNFα. Furthermore, an increased formation of new vessels takes place under the influence of TNFα. As a result, the growth of the cartilage or bone-damaging tissue is promoted (Paleolog, E. Target effector role of vascular endothelium in the inflammatory response: insights from the clinical trial of anti-TNFα antibody in rheumatoid arthritis. Mol. Pathol. 50: 225 -233, 1997). Clinical studies have clearly demonstrated that neutralization of TNFα either by monoclonal antibodies directed against TNFα (anti-TNF mABs) or by the use of soluble TNFα receptors (soluble TNF receptor fusion proteins: sTNFR-lgGs) is not only the acute one Symptoms (e.g. swelling of the joints) but also the continuously progressing cartilage and bone destruction can be suppressed (Fenner, H. Immunopharmacological profile and therapeutic perspectives of anti-TNFα therapies. Journal. Rheumatol. 57: 294-297, 1998; Moreland, LW Soluble tumor necrosis factor receptor ( p75) fusion protein (Enbrel) as a therapy for rheumatoid arthritis. Rheum Dis. Clin. NA 24: 579-591, 1998). It is therefore conceivable that the formation of destructive cartilage and bone changes could be prevented by the use of anti-TNF mABs and sTNFR-lgGs.

Veterinary medicine primarily prescribes NSAIDs for the treatment of chronic pain. The following active ingredients are currently used in particular: aspirin, carprofen, ketoprofen, piroxicam, naproxen and meclofenamic (Papich, G. M., Hardie E. M., Management of chronic pain). However, there are numerous indications that the non-steroidal anti-inflammatories can alleviate the pain, but rather promote cartilage destruction (Wang, B, Yao, YY, Chen MZ. Effects of indometacin on Joint damage in rat and rabbit. Acta Pharmacol Sinica 19: 70-73, 1998; Rainsford, KD, Ying, C, Smith FC.Effects of meloxicam, compared with other NSAIDs, on cartilage proteoglycan metabolism, synovial prostaglandin E2, and production of interleukins 1, 6 and 8, in human and porcine explants in organ culture. J. Pharm. Pharmacol. 49: 991-8, 1997; van der Berg, WB. Impact of NSAID and steroids on cartilage destruction in murine antigen induced arthritis, J. Rheumatol. 27 (Suppl.) : 122-3, 1991; Brandt, KD, Slowman-Kovacs, S. Nonsteroidal antiinflammatory drugs in treatment of osteoarthritis. Clin. Orthopedic. Relat. Dis. 213: 84-91, 1986; Palmowski, MJ, KD Brandt. Aspirin aggravates the degeneration of canine joint cartilage caused by immobilization.Arthritis rheum. 25: 1333-1342, 1982).

As is known, NSAIDs, as inhibitors of cyclooxyeganase, cause an increase in leukotrienes by shifting the arachidonic acid metabolism, which are able to promote the degenerative processes (Brune, K, Aehringhaus, U, Peskar, BA Pharmacological control of leukotriene and prostaglandin production from mouse peritoneal macrophages, Agents Actions 14: 729-34, 1984; Achterrath-Tuckermann, U., Th.Simmet, W. Luck, I. Szelenyi, BA Peskar. Inhibition of cysteinyl-leukotriene production by azelastine and its biological significance. Agents Actions 24: 217-223 (1988).

In addition, NSAIDs have serious gastrointestinal and other potentially life-threatening side effects (Forsyth, SF, Guilford, WG, Haslett, SJ, Godfrey, J. Endoscopy of the gastrduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J. Small Animal Practice 39: 421-4, 1998).

Two subtypes of cyclooxygenases (COX) have been discovered in recent years: COX-1 and COX-2. The COX-1 enzyme is a so-called "house-keeping"

Enzyme, whose job it is, among other things, to protect the gastrointestinal mucosa and to maintain the necessary renal blood flow and to maintain adequate blood circulation.

In contrast, the COX-2 enzyme is only induced by various factors and is responsible for the inflammatory processes.

Since all previously known NSAIDs have no therapeutically relevant selectivity for COX-2, but rather inhibit both enzymes to almost the same extent, it should come as no surprise that the more recently introduced ones as well

NSAIDs cause gastrointestinal side effects.

Selective COX-2 inhibitors which do not inhibit the so-called "house-keeping" enzyme COX-1 and thus the prostaglandin synthesis in the gastrointestinal tract do not lead to gastrointestinal damage.

NSAIDs such as acetylsalicylic acid, ibuprofen, ketoprofen, naproxen, carprofen,

However, diclofenac, meclofenamic acid, piroxicam, meloxicam are not selective

COX-2 inhibitors.

According to some studies, Meloxicam is said to selectively inhibit COX-2 (Churchill, L, AG Graham, CK Shih. Selective inhibition of human cyclo-oxygenase-2 by meloxicam. Inflammopharmacol. 4: 125-135, 1996). However, the clinical results speak against this selectivity, since the typical NSAID-related intolerance reactions such as gastrointestinal and renal disorders also occur when using meloxicam (Committee on Safety of Medicine / Medicines Control Agency. Meloxicam (Mobic): gastrointestinale and skin reactions. Current Problems 24:13, 1998; Gassner, G, I Stephan, I Schütt-Mast. Observations of side effects after use of nonsteroidal anti-inflammatory drugs in dogs. Veterinarian. Pax. 26 (K): 119-123, 1998).

Other NSAIDs, such as carprofen, inhibit the two subtypes of COX with the same potency (Vane, JR, RM Botting. New insights into the mode of action of anti-inflammatory drugs. Inflamm. Res. 44: 1-10, 1995).

Accordingly, gastrointestinal side effects can occur when using such NSAIDs (Forsyth, SF, WG Guilford, SJ Haslett, J Godfrey. Endoscopy of the gastroduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J. Small Animal Pract. 39: 421-424 , 1998; Tjalve, H. Adverse reactions to veterinary drugs reported in Sweden during 1991-1995. J. Vet. Pharmacol. Therap. 20: 105-10, 1997)).

In the case of carprofen, it was necessary to change the information on possible side effects to the extent that possible gastrointestinal intolerance (bleeding, ulceration) must also be pointed out. A possible impairment of renal function, which is a typical side effect of NSAIDs, had to be mentioned in the new Carprofen package insert (Veterinary reporting results in product labeling change, USP Quality Review No. 63, May 1998).

In addition to the classic gastrointestinal and renal side effects, many analgesics can also cause other undesirable reactions that cannot be explained by the inhibition of the enzyme COX. They are substance-specific and occur with certain medications. For example, liver damage has occasionally been observed with diclofenac, naproxen, nimesuli and piroxicam (Helfgott SM, et al. Diclofenac-associated hepatotoxicity. JAMA 264: 2660-2662, 1990; Andrejak, M, et al. Cross hepatotoxicity between non-steroidal anti -inflammatory drugs. Br. Med. J. 295: 180-181, 1987; McCormick, PA, et al. COX-2 inhibitor and fulminant hepatic failure, Lancet 353: 40-41, 1990; Paterson D, et al. Piroxicam induced submassive necrosis of the liver. Gut 33: 1456-1458, 1992).

Hepatotoxicity has also been reported for the arylpropionic acid derivative carprofen, whereby the causality has also been demonstrated, since after the cessation of carprofen therapy in most dogs the liver values completely normalized (MacPhail, CM, MR Lappin, DJ Meyer, SG Smith, CRL Webster, PJ Armstrong, Hepatocellular toxicosis associated with administration of carprofen in 21 dogs, JVMA 212: 1895-1901, 1998).

Based on these findings, this non-COX-specific side effect had to be included in the new package insert for Carprofen (Veterinary reporting results in product labeling change, USP Quality Review No. 63, May 1998).

Many NSAIDs are racemic mixtures. With the exception of naproxen, all arylpropionic acid derivatives are mixtures of this type, that is to say that in the commercially available formulations both the R- and the S-

Isomer present. However, only those are pharmacologically and therapeutically effective

S-isomers.

However, both isomers are metabolized in the organism and both isomers must be removed from the body. This additional metabolism and

Elimination of the pharmacodynamically inactive isomer represents a significant one

Strain on the organism.

In the therapeutic application of racemic mixtures the

Organism loaded with 50% fiber. Furthermore, the inactive isomers may also contribute to drug interactions (Szelenyi, I, G Geisslinger, E Polymeropoulos, W Paul, M Herbst, K Brune. The real Gordian knot: Racemic mixtures versus pure enantiomers. Drug News & Perspectives 11: 139-160, 1998).

It is also known that NSAIDs, such as diciofenac, aspirin are incomparably better tolerated in human therapy than in dogs. Studies have shown that treatment of dogs with diciofenac had to be discontinued because of malaise and vomiting (Wigger, et al., Plasma and tissue kinetics of diciofenac in the dog; Arch Pharmacol; 357; No. 4, Suppl; R5, 1998).

Pain treatment and the prevention of pain chronification in degenerative joint diseases in dogs and cats are becoming increasingly important.

In particular, in addition to good analgesic activity of the active ingredient used, the potential for side effects must be low.

The corresponding pharmaceutical preparations must be in a form that is easily ingestible for dogs and cats and that is well tolerated in terms of taste.

It has now surprisingly been found that flupirtine or its pharmaceutically acceptable salts can be used for the treatment of pain and for the prevention of pain chronification in degenerative joint diseases in dogs and cats with little potential for side effects.

Flupirtin has not yet been used in veterinary medicine. Flupirtine is a triaminopyridine derivative with the chemical name 2-amino-3-ethoxycarbonyl-amino-6- (p-fluoro-benzylamino) pyridine.

It is a centrally acting analgesic, but without addictive potential and without side effects typical of other central analgesics such as constipation, respiratory depression, development of tolerance and withdrawal symptoms. It is known from the literature that flupirtine can be used in human therapy for the treatment of various diseases.

For example, flupirtine has muscle-relaxing properties, so that flupirtine can also be used for the treatment of muscle tension or for diseases based on muscle tension (DE 40 22 442, US 5 162 346, US 5 284 861).

Furthermore, it was found in studies of the muscle-relaxing effect of flupirtine in the rat that flupirtine is also suitable for the treatment of NMDA-mediated CNS diseases, such as, for example, cerebral ischemia, neurodegenerative diseases and epilepsy (DE 43 27 516, US 5 721 258) ,

WO 97/17072 shows the use of flupirtine for the treatment of diseases of the hematopoietic cell system, such as AIDS.

It was also possible to demonstrate that flupirtine can be used for the treatment of diseases which are associated with an unphysiologically high cell death rate (WO 97/49398).

The synthesis of flupirtine and its pharmaceutically usable salts is described in the patents DE 17 95 858, DE 31 33 519 and DE 34 16 609. Regarding the mechanism of action of flupirtine, there are several mechanisms that explain its analgesic effect:

1) Flupirtin activates the noradrenergic descending pathways in the spinal cord (Nickel, B, Engel, J, Szelenyi, I. Possible involvement of noradrenergic descending pain-modulating pathways in the mode of antinociceptive action of flupirtine, a novel non-opioid analgesic. Agents Actions 23: 112-116, 1988; Szelenyi, I., Nickel, B., Borbe, HO, Brune, K. Mode of action of flupirtine in the rat. Br. J. Pharmacol. 97: 835-842, 1989).

2) Flupirtin enhances the GABAergic antinociceptive mechanisms

(Weiser, T, Wienrich M, Szelenyi, I. The amplification of the GABA _A -response by flupirtine is mediated via the steroid binding site. Arch. Pharmacol. 349 (Suppl.): R 383, 1994)

3) There is numerous evidence in the literature that opening the ATP-sensitive K ⁺ channels leads to an analgesic effect (Asano, T, lida, H, Dohi, S, Masue, T, Shimonaka, H. Nicorandil, as ATP-sensitive K ⁺ Channel opener, potentiated morphine analgesia. Jap. J. Anesth. 45: 1342-1346, 1996; Robles, Ll, Barrios M, Del Pozo E, Dordal, A, Baeyens, JM. Effects of K ⁺ Channel blockers and openers on antinociception induced by agonists of 5-HT1A receptors. Eur. J. Pharmacol. 295: 181-188, 1996).

Our own studies indicate that the active ingredient flupirtine opens certain K ⁺ channels and thus has its analgesic effect.

4) According to the latest studies, flupirtine also opens the so-called voltage-independent K ⁺ channels in the central nervous system.

Because of this mechanism of action, flupirtine is also able to prevent the chronification of pain (Kornhuber, J. A pain reliever that differs from all known analgesics. Med. Week 64:10, 1999). The analgesic effect of flupirtine is most likely due to the combination of the above effects. For example, it was shown that the opening of the central ATP-dependent K ⁺ channels not only has an antinociceptive effect per se, but that it also activates the noradrenergic descending pain-modulating pathways in the spinal cord (Narita, M, Takamori, K, Kawashima, N , Funada, M, Kamei, J, Suzuki, T, Misawa, M, Nagase, H. Activation of central ATP-sensitive potassium Channels produces the antinociception and spinal noradrenaline tumover-enhancing effect in mice. Psychopharmacol. 113: 11-14, 1993).

The mechanism of action of flupirtin thus clearly differs from that of the so-called peripheral analgesics such as aspirin, ibuprofen, diciofenac, which develop their analgesic effect by inhibiting cyclooxygenase. Since flupirtine does not inhibit prostaglandin synthesis, there is no damage to the gastrointestinal mucous membranes.

Renal function is also not affected by flupirtine. In chronic toxicological studies (6-12 months), no evidence of a liver-damaging effect was found.

The analgesic effect of flupirtine on awake dogs was investigated.

Under anesthesia, a silver wire was inserted into the tooth pulp (2nd molar tooth) and fixed in place. The animals were then trained to adapt to the

Get used to staff. The animals were tested a week after the silver wire was implanted. The silver wire was made with a

Pulse generator connected, with the help of which the current levels could be regulated continuously.

Flupirtine was administered orally to the dogs in a capsule. 30 minutes later, the current was ramped up at a steady rate. At the first sign of pain sensation, the power generator was switched off immediately. The current that was observed at the first sign of pain was considered the pain threshold. Symptoms such as salivation, lip licking, and twitching of the facial muscles were considered signs of pain sensation.

When flupirtine was given intravenously, the pain threshold was measured 10 minutes after the substance was administered.

n.u.: nicht untersuchtThe results are summarized in Table 1. Table 1 :

nu: not examined

In terms of analgesic potency, flupirtine is both in dogs

Ibuprofen as well as diciofenac clearly superior.

Buprenorphine is a very potent analgesic with a very low oral bioavailability and is one of the classic morphine derivatives.

It is therefore not surprising that buprenorphine had a significantly stronger analgesic effect than flupirtine after intravenous administration.

However, the analgesic effect of flupirtine after oral administration was comparable to that of buprenorphine.

In summary, it can be said that flupirtine has a very strong analgesic potential in dogs. Due to the mechanism of action and the available toxicological results, gastrointestinal, renal or hepatic damage is not expected with acute or long-term use. Flupirtine can preferably be administered orally, parenterally or rectally to treat pain in degenerative diseases in dogs and cats. Suitable dosage forms can be: granules, pellets, capsules, microcapsules, dragees, film-coated tablets, chewable tablets, prolonged-release tablets, two-layer tablets, prolonged-release capsules, bolus, powder, suppositories or injection solutions.

Tablet formulations with a single or double break notch can be advantageous here in order to be able to better administer the individually required amount to the animals.

To increase the acceptance of the oral dosage forms for dogs and cats, taste enhancers such as Trigarol Digest P (Haarmann & Reimer GmbH) or artificial meat flavors, for example consisting of vegetable protein and oil from soybeans and dried pork liver powder, can be added to the tablet granules in proportions of between 5 and 10%.

In the case of oral dosage forms, for example, the individual dosage for

Flupirtine maleate 0.1 to 20 mg / kg, preferably 1 to 5 mg / kg.

Capsules containing 100 mg flupirtine maleate can be administered two to three times a day.

The maximum daily dose should not exceed 600 mg.

Suppositories can contain 0.1 to 30 mg / kg, preferably 2.5 to 7.5 mg / kg, of flupirtine maleate as a single dose. For example, suppositories with one

Dosage of 100 to 300 mg of flupirtine maleate to be administered two to three times a day.

The maximum daily dose should not exceed 900 mg. Parenteral dosage forms, preferably injection solutions for intramuscular administration, preferably contain 1.5 to 5 mg / kg of flupirtine gluconate (because of the better local tolerance).

For example, ampoules containing 164.5 mg of flupirtine gluconate in 3 ml solution can be administered once a day.

Examples

Flupirtine tablet with double score:

10 kg of 2-amino-3-carbethoxyamino-6- (4-fluoro-benzylamino) pyridine mealeat are mixed with 2.5 kg of calcium hydrogen phosphate and 2.5 kg of corn starch and the mixture with a solution of 1 kg of polyvinylpyrrolidone in 4 kg demineralized water granulated in a known manner. After adding 1.3 kg of corn starch, 2 kg of microcrystalline cellulose, 0.6 kg of magnesium stearate and 0.1 kg of highly disperse silicon dioxide and 1.5 kg of flavor enhancer Trigarol Digest P, tablets with a weight of 200 mg, a diameter of 9 mm and a radius of curvature of 10 mm with double break notch.

The breaking strength of the tablets is 80 N to 100 N (Schleuniger breaking strength tester). The disintegration time according to DAB 8 is 5 minutes. Each tablet contains 100 mg of active ingredient.

Flupirtine capsules

Analogous to the previously described method of manufacturing tablets, a capsule filling is produced in hard gelatin capsules of the appropriate size is filled. Filling quantity per capsule: 200 mg. One capsule contains 100 mg of active ingredient.

Flupirtine solution for injection

The manufacturing process applies to a batch of 20 liters (= 6500 ampoules):

Production program:

1. 10.0 l of water are heated to 70 ° C. and after the addition of 1562.0 g of gluconic acid delta lactone, the solution is left at 70 ° C. for one hour. The solution is gassed with nitrogen.

2. In solution 1, 8000.0 g of polyethylene glycol molecular weight 380 to 420 are weighed in and the solution is heated to 70 ° C. while gassing with nitrogen.

3. 30.0 g of sodium disulfite are dissolved in 500.0 ml of nitrogen-gassed water.

4. Solution 3 is added to solution 2.

5. 666.6 g of flupirtine base are sieved through a sieve with a mesh size of 0.3 mm and dissolved in solution 4 with intensive nitrogen gassing.

6. Solution 5 is cooled and made up to 20 liters with nitrogen-gassed water.

7. Solution 6 is sterile filtered through a membrane filter with a pore size of 0.2 μm and a glass fiber pre-filter. 8. In-process control: Measurement of the oxygen content of solution 7 using an oxygen electrode. Measure the pH of solution 7.

Solution 7 is filled under aseptic conditions and under nitrogen gassing into colorless ampoules, content 3 ml.

One ampoule contains 164.5 mg flupirtine gluconate in 3 ml solution.

According to the present invention, flupirtine or its pharmaceutically usable salts can also be used in combination with other active substances for treating pain in degenerative joint diseases in dogs and cats.

The following combinations can advantageously be used here:

* Flupirtin in combination with anti-inflammatories, in particular with selective COX-2 inhibitors, such as Celecoxib, Rofecoxib, Valdecoxib and Parecoxib in order to achieve an efficacy potentiation.

* Flupirtin in combination with other centrally acting analgesics such as nefopam, tramadol, nalbuphin, dextropropoxyphene

* Flupirtin in combination with metamizole

* Flupirtine in combination with chloroquine, hydroxychloroquine, methotrexate, penicillamine, ademetionin, sulfasalazine, ß-sitosterol, thiamine, cyano-cobalamin, pyridoxine

* Flupirtin in combination with steroids such as prednisolone, methylprednisolone

* Flupirtin in combination with the chondroprotective substances like chondroitin, glucosamine and polysulfated glycosaminoglycan

* Flupirtin in combination with TNFα receptors

* Flupirtin in combination with plant extracts such as devil's claw root, nettle leaves, guaiac wood, willow bark, arnica

Claims

claims 1. Use of flupirtine or its therapeutically usable salts for the treatment of pain and for the prevention of pain chronification in degenerative joint diseases of dogs and cats, which can be associated with inflammation. Use of flupirtine or its therapeutically usable salts for the treatment of pain in hip dysplasia in dogs and cats. Use of flupirtine or its therapeutically usable salts for the treatment of pain in patelle dislocation of dogs and cats. 4. Use of flupirtine or its therapeutically usable salts for the treatment of pain in Dachshund paralyzes in dogs and cats. 5. Use of flupirtine or its therapeutically usable salts for the treatment of pain in the cauda equina syndrome in dogs and cats. Use of flupirtine or its therapeutically usable salts according to one of claims 1 to 5, characterized in that the preparation, in addition to flupirtine, contains customary pharmaceutical carriers and / or auxiliaries. 7. Use of flupirtine or its therapeutically usable salts according to claim 6, characterized in that the oral preparation contains taste improvers. 8. Use of flupirtine or its therapeutically usable salts according to claims 6 and 7, characterized in that the preparation in the form of granules, tablets, capsules, bolus, powder, suppository or solution for injection are administered. 9. Use of flupirtine or its therapeutically usable salts according to claim 8, characterized in that the tablets are administered in the form of film-coated tablets, chewable tablets, two-layer tablets or prolonged-release tablets. 10. Use of flupirtine or its therapeutically usable salts according to claim 8, characterized in that the tablets advantageously contain double or single notches. 11. Use of flupirtine or its therapeutically usable salts according to claim 1 in combination with anti-inflammatories, in particular with selective COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib and parecoxib. 12. Use of flupirtine or its therapeutically usable salts according to claim 1 in combination with other centrally acting analgesics, such as nefopam, tramadol, nalbuphin or dextropropoxyphene. 13. Use of flupirtine or its therapeutically usable salts according to claim 1 in combination with metamizole. 14. Use of flupirtine or its therapeutically usable salts according to claim 1 in combination with antirheumatic agents such as chloroquine, hydroxychloroquine, methotrexate, penicillamine, ademetionin, sulfasalazine or β-sitosterol 15. Use of flupirtine or its therapeutically usable salts according to claim 1 in combination with vitamin B, such as thiamine, cyanocobalamin, pyridoxine. 16. Use of flupirtine or its therapeutically usable salts according to claim 1 in combination with steroids, such as prednisolones. 17. Use of flupirtine or its therapeutically useful salts according to claim 1 in combination with chondroprotective substances such as chondroitin, glucosamine or polysulfated glycosaminoglycan. 18. Use of flupirtine or its therapeutically usable salts according to claim 1 in combination with TNFα receptors. 19. Use of flupirtine or its therapeutically usable salts according to claim 1 in combination with plant extracts such as devil's claw root, nettle leaves, guaiac wood, willow bark, arnica