EP1523307A1

EP1523307A1 - Use of neurotoxic substances for the production of a means for the treatment of joint pain and method for application of said means

Info

Publication number: EP1523307A1
Application number: EP02745031A
Authority: EP
Inventors: Dominik Meyer
Original assignee: Mestex AG
Current assignee: Mestex AG
Priority date: 2002-07-19
Filing date: 2002-07-19
Publication date: 2005-04-20
Also published as: WO2004009064A1; CA2493041A1; AU2002317127A1; US20050215633A1; WO2004009064A8; US7964644B2; JP2005538983A; CA2493041C

Abstract

The invention relates to the use of neurotoxic substances which have a toxic effect, particularly for the axons and nociceptive nerve endings and to the production of a means for the treatment of joint pain.

Description

Use of neurotoxic substances for the preparation of an agent for the treatment of joint pain and method of application of this composition.

The invention relates to the use of neurotoxic substances for the preparation of an agent for the treatment of joint pain according to the preamble of patent claim 1 and a method for the application of this agent in the intracapsular space or in the joint lubricating bag of joints according to the preamble of claim 40.

Pains originating from joints often originate in the area of the joint capsule or in the area of the joint close to the joint. Many etiologies may be considered, e.g. Arthrotic or arthritic forms of disease, mechanical or other irritation of the joint surface near the bone, irritation or injury of the joint ligament structures, infections, autoimmune processes, etc. In all cases, which are of interest in the context of this invention, the resulting pain of nociceptive nerve fibers in the joint area go out , Nociceptive nerve fibers are also referred to as C-fibers and A-delta fibers. If an analgesic substance (for example, local anesthetics or morphine) is injected into such a diseased joint, it alleviates the patient's discomfort. However, the substances used today have a limited duration of action, which is why the complaints usually return.

For the treatment of painful diseased joints the following procedures are generally used today:

• Physiotherapy / exercise therapy

• Systemic analgesic / anti-inflammatory therapy (etc.)

• Local analgesic / anti-inflammatory procedures (etc.)

• Operational procedures:

• Arthroscopic: debridement, joint toilet, etc.

• Open / Mini-open: joint replacement, joint reinforcement, etc. A number of known substances for the therapy of painful, inflammatory joints have also been proposed in the literature, in particular:

Osmic acid or radioactive substances such as technetium 99, which lead to synoviorthesis;

• injection of local anesthetics, hyaluronic acid preparations (etc.)

• Injection of anti-inflammatory drugs

• Injection of contrast agents for joint diagnostics

• Joint flushing to the joint toilet

• Chemical, thermal, electrical or surgical ablation of the nerves supplying the joints.

All substances and procedures used so far only lead to a relatively short-term or incomplete absence of pain or cause lasting damage to the joint.

For example, in the known method of synoviorthesis there is the disadvantage of the destruction of the molecular structures, in particular denaturation of the proteins, which in the process of arthritis and z.T. Also osteoarthritis development act as a trigger for inflammation. This creates a fibrous joint capsule which is less inflammatory and thus less painful. At the same time, the fibrosis of the joint, which occurs during the synovi orthesis, reduces the hyperemia that is usually present and likewise to be treated, which also results in therapeutic benefits. However, the fibrotic scarring after synoviorthesis can lead to a reduced mobility of the joint, as well as to a reduced production of synovial fluid and to the destruction of the articular cartilage. This unwanted fibrous joint capsule should be avoided and only the sensitive innervation of the joint should be eliminated.

The invention aims to remedy this situation. The invention has for its object to look for suitable substances and to develop a method for injecting such substances, which are responsible for the Nociception nerve endings for permanently damaging prolonged analgesia without jeopardizing the structures distant from the joints.

The invention solves the stated problem with the use of neurotoxic substances according to claim 1 and a method according to the features of claim 40.

The method according to the invention comprises injecting a neurotoxic, neurolytic, neuroparalytic or long-term analgesic substance (hereinafter referred to collectively as "neurotoxic" substance in particular in the patent claims) into a painful or diseased joint of the human or animal body. The substance can either be left there or, after a certain exposure time, completely or partially removed again. The therapeutic substance now diffuses to the sensory nerve endings, which directly or indirectly innervate the area of the joint, inhibiting or damaging these predominantly and thus leads to a reduced perception of joint pain. That local anesthetics have a short-term local anesthetic effect is known. However, the fact that highly concentrated solutions when deployed into the joint cavity can exert selective neurolytic (neurotoxic) action has surprisingly been revealed. Another novelty of this method is that the joint capsule or joint lubricating bag is used to concentrate the action of the therapeutic substance on the site of pain and thereby locally allow a higher concentration of the therapeutic substance than would be required without the protective joint capsule or joint lubricating bag The same concentration and tolerability would be possible and at the same time to protect the vascular / nerve structures and other structures in the vicinity of the joint relatively. Thus, a long-term relief of pain from the diseased ligament-capsule-joint complex is obtained by inhibiting or eliminating the conduction of the stimulus. This method can be used both preventatively or therapeutically. At the same time, the disinfectant effect of the neurotoxic substance kills potential infectious agents, a circumstance that can also be used therapeutically. The advantages of the use according to the invention of the neurotoxic substances and of the method according to the invention for their injection into the joint capsule or into the joint lubricating bag are the following:

• The intra-articular injection of selectively neurotoxic substances for the analgesic therapy of joints leads to a considerable protection of the capsular ligament structures, the synovium and the cartilage bone structures and thus to the maintenance of physiological conditions.

• The use of the joint capsule as the natural limit of the distribution of a neurotoxic substance.

• The efficacy of the neurotoxic substances is not dependent on specific neuronal epitopes.

• The procedure is feasible by non-specialists.

• The procedure can be performed with a thin, non-arthroscopic needle.

• The method is not harmful to infection, in contrast to the popular method of cortisone injection, which is highly locally infection-promoting, since cortisone locally inhibits the immune system.

The method leads to a sensitive denervation, i. an elimination of painful nerves.

• Expansion of joint mobility by eliminating the painful restriction of movement in contrast to synoviorthosis, in which by the resulting capsular contracture limited movement.

• Positive preparation for later arthroplasty. Due to the skierotisierende effect of the neurotoxic substance (on the one hand as a result of a chemical biological reaction on the other hand by the mechanical stress in the pain-free joint use) the joint near the bone receives a more advantageous for the future support of a prosthesis structure.

• no local fat tissue absorption (lipolysis)

No weakening of collagen tendon / ligament / capsule structures.

The invention is described below for use in humans, in particular, the indicated dosages refer to the human application. The invention is also suitable for the veterinary field, with adjustments there in the dosage must be made depending on the body weight of each animal.

As a particular suitable substances for the preparation of an agent for the treatment of joint pain, the local anesthetics have been found. Highly efficient but normally dosed local anesthetics have proven to be particularly effective (alone or preferably in combination), e.g.

Lidocaine, preferably in a concentration of more than 6%, max. Dose of 500 mg;

Prilocaine, preferably in a concentration of more than 3%, max. Dose of 600 mg;

Mepivacaine, preferably in a concentration of more than 5%, max. Dose of 500 mg; Bupivacaine, preferably in a concentration of more than 1, 5%, max. Dose of

150 mg;

Levobupivacaine, preferably in a concentration of over 5%;

Ropivacaine at a concentration of over 2%;

Etidocaine, preferably in a concentration of more than 2%, max. Dose of 300 mg;

Procaine, preferably in a concentration of more than 3%, max. Dose of 600 mg;

Chloroprocaine, preferably in a concentration of more than 3%, max. Dose of 800 mg. Levobupivacaine, preferably in a concentration of over 5%;

Ropivacaine at a concentration of over 2%;

Etidocaine, preferably in a concentration of more than 2%, max. Dose of 300 mg;

Procaine, preferably in a concentration of more than 3%, max. Dose of 600 mg;

Chloroprocaine, preferably in a concentration of more than 3%, max. Dose of 800 mg.

Tetracaine, preferably in a concentration of more than 4%, max. Dose of 100 mg.

Furthermore, the lidocaine compounds, e.g. Lidocaine (8%) and its

High concentration compounds.

Mixtures of two or more neurolytic substances have proved to be particularly effective. For example, the combination of two local anesthetics, a local anesthetic with a bisulfite (eg, sodium bisulfite or potassium bisulfite) or, for example, a cresol, or the combination of two local anesthetics with a bisulfite and / or a cresol, etc. When using local anesthetics as a neurotoxic substance, acidic additives have been found to enhance the effects, such as NaHSO ₃ to chloroprocaine. As a result, the pH is lowered to about 3, which enhances the inventive effect of the local anesthetic.

The above listed substance groups are characterized by the following advantageous properties:

Long-term effect

Can be used at one time

Systemically non-toxic in an effective dose

Predominant neurotoxic / -lytic for sensitive fibers, less for proprioceptive

Fibers and for motor fibers

Fast acting

Not toxic to synovia

Not toxic to bones

Not toxic to ligaments

Not toxic to cartilage

Not toxic to blood vessels

Not painful when injected

Little or reversibly harmful when exiting the joint capsule

Soluble and injectable

Miscible with the desired additives

In lesion of motor neurons recovery possible

Non-inflammatory

germicidal

In a particular embodiment of the invention, addition of phenol and phenol derivatives, including analogs and pharmacologically acceptable salts thereof, to local anesthetics has been found to be advantageous. Of the phenol derivatives, especially the cresols, especially ortho-, meta-, and para-cresols and their derivatives have been found to be effective. Of the cresol derivatives are especially the chloro-cresols, especially the 2-chloro-m-cresol, 3-chloro-p-cresol, 4-chloro-m-cresol, 3-chloro-o-cresol, 6-chloro-o-cresol, 2-chloro-p-cresol, 5-chloro-o-cresol, 6-chloro-m-cresol and 4- chloro-o-cresol.

Eugenol and thymol and their derivatives have also been shown to be effective.

In a preferred embodiment of the invention, in addition to the neurotoxic substance, an X-ray contrast agent, e.g. a barium supplement or an MRI contrast agent is used, so that an imaging control of the distribution of the neurotoxic substance in the intracapsular space is possible. Depending on the method, the following substances can be used as the contrast agent: X-ray, CT: iodine-containing substances, e.g. triiodinated benzoates or lopamidol, ideally 30 - 80g / 100ml or z. B. 5-10% of another contrast agent, e.g. Barium. MRI: e.g. Gadolinium, e.g. per 1 ml: 469.01 g Gadopentate dimeglumide,

0.99 mg of meglumine, 0.4 mg of diethylenetriamine pentaacetate.

In a further preferred embodiment of the invention, an antibiotic, disinfecting and / or sterilizing substance is added in addition to the neurotoxic substance.

In a further preferred embodiment of the invention, in addition to the neurotoxic substance, a viscous additive, e.g. Hyaluronic acid, preferably used at a concentration of 0.1-10.0 mg / ml solution for injection, which leads to a mechanical Gleitverbesserung of the joint.

In a further preferred embodiment of the invention, a vasoconstrictor is used in addition to the neurotoxic substance, preferably adrenaline, norepinephrine or other similar, preferably alpha-adrenergic vasoconstrictors. With adrenaline, the total dose of the neurotoxin (dg for the peripheral nervous system toxic substance) can be increased by a factor of about 2, as it reduces the systemic effect of the reduced absorption. The adrenaline concentration can be from 1: 10,000 to 1: 80,000 to 1: 200,000. The total adrenaline dose is <0.25 mg. A 50 ml solution of 1: 200'000 epinephrine contains 0.25 mg adrenaline. In a further preferred embodiment of the invention, an antiphlogistic substance is used in addition to the neurotoxic substance, for example non-steroidal anti-inflammatory drugs such as COX-2 inhibitors, acetylsalicylic acid, etc

In a further preferred embodiment of the invention, in addition to the neurotoxic substance, a steroid is used in order to control it in the event of an inflammatory reaction. In addition, it can be used to add a more causal treatment to painful inflammatory joint disease that supports symptomatic neurolytic therapy. Betamethasone has proven to be particularly suitable; e.g. 5 mg betamethasone as diproprionate (crystalline suspension) and 2 mg betamethasone as disodium phosphate (solution in 1 ml, may be added to the total amount to be injected). This solution is equivalent to 45/23 mg prednisone / prednisolone.

In a further preferred embodiment of the invention glycerol is used in addition to the neurotoxic substance as a solvent. Glycerol also has neurotoxic properties (but especially if injected intraneurally). Furthermore, glycerine has a lubricity for the joint, so that a physical effect occurs. The concentration of glycerol is preferably between 10 and 95%.

In a further preferred embodiment of the invention, in addition to the neurotoxic substance, an analgesic is used to effect a short term analgesia in case the neurolytic effect is delayed and a painful period first occurs. Highly effective, but normally dosed, local anesthetics have proven to be particularly effective, e.g. the substances listed above.

As the solution medium, instead of glycerol, water, saline, sodium bihalamate, lophendylate, ricin, poly-ethylene glycol or propylene glycol may also be used. The advantage of glycerol as a solvent is that it is hyperbaric and in itself a bit neurotoxic. Some substances have been found to enhance the neurotoxic substances, such as antioxidants, preservatives and excipients, especially sodium bisulfite (> 0.2%), NaHSO ₃ , ammonium compounds, such as ammonium sulfate (NH ₄ ) ₂ S0 _{4 ι} 2-10 (-30%), Polysorbate 80 (PS80) 0.025 mg / ml.

The neurotoxic substance is preferably dissolved in a biocompatible solvent and is expediently injected in an amount which corresponds to the available space in the joint to be treated, so that it becomes bulging. This achieves the advantage of optimal distribution of the neurolytic substance. But it is also possible to inject less fluid, but then the joint must be well moved for better distribution of the neurolytic substance. The volume of fluid to be injected into the intracapsular area may be from 0.1 to 150 ml. For a finger joint, max. 1 ml, for the shoulder joint max. 10 ml, for the knee joint about 30 - 50 ml.

The dosage of the neurolytic substance depends on its absolute solubility in the chosen solvent medium. A significant influence on the dosage has the capsule thickness of the affected joint. The thicker the capsule, the higher the concentration or amount of the neurolytic substance is necessary.

When using chlorocresol as the neurolytic substance in glycerol as a biocompatible solvent, a ratio of chlorocresol: glycerol in the range from 1: 5 to 1:70, preferably from 1:40 to 1:50 should be selected appropriately.

When using phenol in glycerol, a concentration range of 0.5-40.0%, preferably 3-12%, should be suitably selected.

An addition to the neurotoxic substance which promotes permeation, e.g. Dimethyl sulfoxide.

To better illustrate the invention, some examples of advantageous embodiments are described below. Example 1 :

The therapist placed a syringe needle into the joint space of a knee joint under facultative, simultaneous (image converter, CT, sonography, MRI, etc.) or subsequent (X-ray, CT, MRI, sonography, arthroscopy, etc.) imaging imaging and injected 40 ml of a solution of 8% tetracaine, 16% lidocaine and 1% m-chloro-cresol in glycerol in the intracapsular space. The patient already felt clear relief of his symptoms 14 hours after the procedure. This lasted for over 6 months.

Example 2:

The therapist placed a syringe needle into the joint space of a knee joint under facultative, simultaneous (image converter, CT, sonography, MRI, arthroscopy etc.) or subsequent (X-ray, CT, MRI, sonography, etc.) imaging imaging and injected 20 ml of a solution of 0.8% sodium bisulfite in the intracapsular space. The patient felt a few days after the procedure significant relief of his symptoms. This lasted for over 6 months.

Example 3:

The injected solution was similar to that of Example 1, except that 5 ml of a visible contrast agent (lopamidol at a concentration of 50 g / 100 ml) was added for the imaging procedure to be used, which spread within the joint capsule after injection and so on Position of the hypodermic needle and the distribution of the therapeutic substance within the capsule documented. The neurotoxic substance contained in the injected solution was resuspended immediately after injection. But it could also be withdrawn after a defined substance-dependent exposure time or not at all. The patient already felt significant relief of his symptoms 15 hours after the procedure. This lasted for over 8 months.

Example 4:

The therapist inserted a thin infusion catheter into the affected joint analogous to an epidural catheter and injected with a perfusor a mixture of 5% tetracaine, 12% lidocaine, 2% chlorocresol, 5% hydrocortisone, 10% contrast agent and 66% glycerol into the affected joint at a rate of 1-10 ml / h for 12 h. Optionally, he also inserted a drain catheter with an optional defined Drainage resistance (eg 20 mm Hg) to achieve fluid turnover. With this method, the therapist achieved a uniform infiltration of the painful joint, without large concentration peaks. In addition, the exposure time could be better defined.

In a subsequent arthroscopy after 1, 2, 7, 14 and 28 d it could be shown that only very little inflammatory tissue was present. The patient felt already 12 hours after the procedure significant relief of his symptoms. This lasted for over 1 year.

Example 5:

After implantation of a knee joint prosthesis, the therapist injected 50 ml of a mixture of 7% tetracaine, 15% lidocaine and 5% chlorocresol in glycerol into the resealed joint capsule. This minimized postoperative pain.

Example 6:

After implantation of a hip joint prosthesis, the therapist injected 50 ml of a mixture of 8% tetracaine, 16% lidocaine and 5% chlorocresol in glycerol into the periprosthetic area without capsule. This minimized postoperative pain.

Example 7:

In a patient with painful septic loosening of a total hip endoprosthesis, the neurotoxic substance (here: 8% tetracaine, 16% lidocaine, and 5% chorcresol in glycerine) could be injected into the (neo) capsule around the prosthesis, causing the patient a lasting (over a year) relief of pain within a few (6-12) hours. In addition, the diffusion of the neurotoxic substance (which also had an antiseptic effect) around the prosthesis shaft and around the acetabulum strongly contained and in some cases even completely eliminated the infection around the prosthesis. Optionally, this treatment can be supported with systemically administered antibiotics (eg with rifampicin 450 mg, ciprofloxacin 750 mg). Radiologically a consolidation of the bone substance around the prosthesis could be shown. Example 8:

The therapist placed a syringe needle into the joint space of a knee joint under facultative, simultaneous (image converter, CT, sonography, MRI, arthroscopy, etc.) or subsequent (X-ray, CT, MRI, sonography, etc.) imaging imaging and injected 40 ml of a solution of 20% lidocaine mixed with 0.6% sodium bisulfite in physiological saline in the intracapsular space. The patient felt a few minutes after the procedure significant relief of his symptoms. This lasted for over 6 months.

Example 9:

The therapist placed a syringe needle into the joint space of a knee joint under facultative, simultaneous (image converter, CT, sonography, MRI, arthroscopy etc.) or subsequent (X-ray, CT, MRI, sonography, etc.) imaging imaging and injected 20 ml of a solution of 1% bupivacaine mixed with 6% tetracaine in physiological saline in the intracapsular space. The patient felt noticeable relief of his symptoms already minutes after the procedure. This lasted for over 6 months.

Example 10:

The therapist placed a syringe needle into the joint space of a knee joint under facultative, simultaneous (image converter, CT, sonography, MRI, arthroscopy etc.) or subsequent (X-ray, CT, MRI, sonography, etc.) imaging imaging and injected 20 ml of a solution of 15% lidocaine mixed with 1% bupivacaine and 0.6% sodium bisulfite in physiological saline in the intracapsular space. The patient felt a few minutes after the procedure significant relief of his symptoms. This lasted for over 6 months.

Example 11:

The therapist placed a syringe needle into the joint space of a knee joint under facultative, simultaneous (image converter, CT, sonography, MRI, arthroscopy etc.) or subsequent (X-ray, CT, MRI, sonography, etc.) imaging imaging and injected 20 ml of a solution of 4% tetracaine mixed with 3% chlorocresol and 0.6% sodium bisulfite in physiological saline in the intracapsular space. Of the Patient already felt a few minutes after the procedure significant relief of his symptoms. This lasted for over 8 months.

Example 12:

In a patient with painful capsulitis of the joints (eg frozen shoulder), a mixture of 8% tetracaine and 2% chloro-cresol in physiological saline was injected into the joint A few minutes after the injection, the pain persisted, so that the physiotherapist regained the mobility lost through capsulitis, sometimes with only a temporary analgesia (2 -3 weeks), which is why the concentration of the neurotoxic substance was kept rather low here

Example 13:

In a patient with painful capsulitis of joints, a mixture of 8% tetracaine and 16% lidocaine in physiological saline was injected into the joint. A few minutes after the injection, the pain persisted, so that the patient regained the mobility lost through capsulitis with physiotherapy.

Example 14:

In a patient with painful capsulitis of joints, a mixture of 16% lidocaine and 3% chloro-cresol in saline was injected into the joint. A few minutes after the injection, the pain persisted, so that the patient regained the mobility lost through capsulitis with physiotherapy.

Example 15:

The therapist injected 5 ml of a neurotoxic substance consisting of 8% tetracaine, 8% chlorocresol, and 40 mg cortisone in glycerol as a chronic inflamed bursa (bursa trochanterica) over the greater trochanter of the hip Solvent. Within 60 minutes disappeared the complaints of the patient, who remained symptom-free for several years at this point.

Example 16:

The therapist injected 5 ml of a neurotoxic substance consisting of 12% lidocaine, 7% chlorocresol and 40 mg cortisone in glycerol as solvent into a chronically inflamed bursa (bursa trochanterica) via the greater trochanter of the hip. Within 60 minutes disappeared the complaints of the patient, who remained symptom-free for several years at this point.

Example 17:

The therapist injected 1 ml of a neurotoxic substance consisting of 15% lidocaine, adrenaline (1: 10'000 based on the total solution) and 5% contrast agent in saline as a solvent into a painful, arthritic finger joint. After about 15 minutes, the patient's symptoms disappeared for several months. The correct position of the injection needle could be documented by means of the contrast medium.

Example 18:

The therapist injected a mixture of 5% chlorocresol, 10% lidocaine and Vinkristin in an amount of 0.7 mg in glycerol as a solvent. This mixture has been shown to be particularly effective since its components injure the nerves to be damaged in various ways. The effect of chlorocresol is that it dissolves the nerve membrane, that of lidocaine, that it destroys the nerves via irreversible receptor blockage, as well as toxic intracellular Ca release, and that of Vinkristin, that it permanently prevents nerve regeneration and inhibits axonal transport.

Example 19:

The therapist injected a mixture of 5% chlorocresol, 10% lidocaine, vincristine in an amount of 0.7 mg, adrenaline (1: 15,000 based on total solution) and 10% contrast media in glycerol as a solvent. This mixture proved to be particularly effective for permanent nerve destruction.

Claims

claims

1. Use of neurotoxic substances for the preparation of an agent for the treatment of joint pain.

2. Use according to claim 1, characterized in that the neurotoxic substances are predominantly toxic to pain-conducting (nociceptive) nerve fibers.

3. Use according to claim 1 or 2, characterized in that the neurotoxic substances are selected from the group which are toxic to the axon and the nociceptive nerve endings.

Use according to any one of claims 1 to 3, characterized in that the neurotoxic substances are less neurotoxic for motor and propioceptive nerve fibers than for sensitive ones. Nerve fibers.

5. Use according to one of claims 1 to 4, characterized in that the neurotoxic substances is a local anesthetic or a mixture of several local anesthetics.

6. Use according to claim 5, characterized in that the local anesthetic is used together with an acid, the pH-lowering additive.

7. Use according to claim 6, characterized in that the additive is a bisulfite, preferably sodium bisulfite (NaHS0 ₃ ).

8. Use according to one of claims 5 to 7, characterized in that the additive in a concentration of at least 1 wt.%, Preferably at least 2 wt.% Is present.

, Use according to one of claims 5 to 8, characterized in that the pH-lowering additive lowers the pH of the agent to below 3.5, preferably below 3.2.

10. Use according to one of claims 5 to 9, characterized in that the local anesthetic is an amide.

11.Use according to one of claims 5 to 10, characterized in that the local anesthetic is lidocaine, preferably in a concentration of more than 6%.

12. Use according to one of claims 5 to 10, characterized in that the local anesthetic is prilocaine, preferably in a concentration of more than 3%.

13. Use according to one of claims 5 to 10, characterized in that the local anesthetic is mepivacaine, preferably in a concentration of more than 5%.

14. Use according to any one of claims 5 to 10, characterized in that the local anesthetic is bupivacaine, preferably in a concentration of more than 1.5%.

15. Use according to one of claims 5 to 10, characterized in that the local anesthetic is levobupivacaine, preferably in a concentration of more than 5%.

16. Use according to one of claims 5 to 10, characterized in that the local anesthetic is ropivacaine, preferably in a concentration of more than 2%.

17. Use according to one of claims 5 to 10, characterized in that the local anesthetic is etidocaine, preferably in a concentration of more than 2%.

18. Use according to any one of claims 5 to 10, characterized in that the local anesthetic is procaine, preferably in a concentration of more than 3%.

19. Use according to one of claims 5 to 10, characterized in that the local anesthetic is chloroprocaine, preferably in a concentration of more than 3%.

20. Use according to any one of claims 5 to 10, characterized in that the local anesthetic is tetracaine or a substituted tetracaine, preferably n-butyl-tetracaine.

21. Use according to claim 20, characterized in that the local anesthetic is used in a concentration of more than 4%, preferably of more than 6%.

22. Use according to claim 21, characterized in that the local anesthetic is used in a concentration of more than 6%, preferably of more than 8%.

23. Use according to one of claims 5 to 22, characterized in that a mixture of at least two different local anesthetics is used, preferably together with a bisulfite or other pH-lowering substances.

24. Use according to claim 23, characterized in that a mixture of three or four local anesthetics is used.

25. Use according to claim 23 or 24, characterized in that a mixture of tetracaine and bupivacaine is used.

26. Use according to one of claims 5 to 25, characterized in that the local anesthetic is used in a pure enantiomeric form.

27. Use according to any one of claims 1 to 26, characterized in that the neurotoxic substances belong to the following group: bisulfites, preferably alkali bisulfites.

28. Use according to any one of claims 5 to 27, characterized in that in addition to the local anesthetic a phenol or a phenol derivative including analogs and pharmacologically acceptable salts thereof is used.

29. Use according to claim 28, characterized in that the phenol derivatives belong to the group of cresols, in particular ortho, meta, and para-cresols and their derivatives.

30. Use according to claim 29, characterized in that the cresol derivatives comprise the chloro-cresols, in particular 2-chloro-m-cresol, 3-chloro-p-cresol, 4-chloro-m-cresol, 3-chloro-o- cresol, 6-chloro-o-cresol, 2-chloro-p-cresol, 5-chloro-o-cresol, 6-chloro-m-cresol and 4-chloro-o-cresol.

31. Use according to claim 28, characterized in that the phenol derivatives belong to the group of eugenols and its derivatives.

32. Use according to claim 28, characterized in that the phenol derivatives belong to the group of thymols and its derivatives.

33. Use according to one of claims 1 to 32, characterized in that in addition to the neurotoxic substances, an X-ray contrast agent is used, preferably gadoliniumhaltige, iodine-containing or barium-containing substances.

34. Use according to one of claims 1 to 33, characterized in that in addition to the neurotoxic substances glycerol is used, preferably in a concentration of 10 to 95 wt.%.

35. Use according to one of claims 1 to 34, characterized in that in addition to the neurotoxic substances steroids are used.

36. Use according to one of claims 1 to 35, characterized in that in addition to the neurotoxic substances a vasoconstrictor is used, preferably adrenaline, norepinephrine, phenylephrine or omipressin.

37. Use according to one of claims 1 to 36, characterized in that the neurotoxic substances are dissolved in a biocompatible solvent, preferably glycerol, lophendylat or propylene glycol.

38. Use according to one of claims 1 to 37, characterized in that the neurotoxic substances are used for denervation or neurolysis in the degeneratively diseased joints.

39. Use according to one of claims 1 to 38, characterized in that in addition to the neurotoxic substance, a permeation enhancer, preferably dimethyl sulfoxide is used.

40. A method for the treatment of joint pain, characterized in that a neurotoxic substance is injected into the intracapsular area or into the joint lubricating bag of the joint affected by pain.

41. A method for the treatment of joint pain according to claim 40, characterized in that the neurotoxic substance is dissolved in a biocompatible solvent and preferably a liquid volume of 0.1 to 150 ml in the intracapsular area or in the joint lubricating bag of the joint affected by pain is injected ,

42. The method according to claim 40 or 41, characterized in that the nociceptive nerve fibers are rendered insensitive to pain by the neurotoxic substance for at least 14 days, preferably at least 8 weeks.

3. The method according to any one of claims 40 to 42, characterized in that neurotoxic substance is used in such a concentration that a neurolysis occurs.