Botulinum toxin for the treatment of peripheral neuropathic pain

Abstract

This invention relates to the use of botulinum toxin for the treatment of peripheral neuropathic pain (PNP) by topical administration of botulinum toxin. This administration involves subcutaneously injecting an effective amount of botulinum toxin into the painful skin area of ​​the patient according to a specific administration regimen. Peripheral neuropathic pain may be, for example, postherpetic neuralgia, peripheral nerve injury (e.g., due to surgery or trauma), trigeminal neuralgia, painful polyneuropathy (e.g., diabetic neuropathy), and painful radiculopathy.

Description

Technical Field

[0001] The present invention relates to the use of botulinum toxin for the treatment of peripheral neuropathic pain (PNP) by local administration of botulinum toxin. This administration involves subcutaneous injection of an effective amount of botulinum toxin into the painful affected skin area of the patient according to a specific dosing regimen. Peripheral neuropathic pain can be, for example, postherpetic neuralgia, peripheral nerve injury (e.g., due to surgery or trauma), trigeminal neuralgia, painful polyneuropathy (e.g., painful diabetic neuropathy), and painful radiculopathy.

Background Art

[0002] Currently, pain is defined by the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage" (Raja et al., Pain, 2020, 161(9):1976 - 1982). Among various pain types, neuropathic pain (NP) is characterized by hyperalgesia and / or spontaneous pain and is defined by the IASP as "pain caused by a lesion or disease of the somatosensory nervous system" (Scholz et al., Pain, 2019, 160(1):53 - 59). Neuropathic pain may be felt at a site distant from the lesion or disease of the nervous system (Raja et al, supra). Neuropathic pain can result from various disorders, and the underlying pathophysiological mechanisms are complex and poorly understood (Scholz, supra). Approximately 6 - 10% of adults suffer from chronic pain with neuropathic features (Kamerman et al., 2015, Pain, 156(5):793 - 797), resulting in harmful consequences in terms of psychosocial well - being and health - related quality of life.

[0003] Depending on the location of the lesion or disease, neuropathic pain can be classified into peripheral neuropathic pain (PNP) and central neuropathic pain (CNP). PNP is defined as pain caused by lesions or diseases of the peripheral somatic sensory nervous system, while CNP is defined as pain caused by lesions or diseases of the central somatic sensory nervous system. The most common conditions of PNP include trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy (e.g., diabetic neuropathy), postherpetic neuralgia, and painful radiculopathy. Conditions of central neuropathic pain include pain caused by spinal cord or brain injury, post-stroke pain, and pain associated with multiple sclerosis (Scholz et al., cited above).

[0004] Neuropathic pain is difficult to treat due to its chronic course and the existing limitations of both non-pharmacological and pharmacological approaches. The unmet medical need for new treatment options for neuropathic pain, particularly PNP, stems strongly from the current limitations of first-line and second-line drug therapies, which are mostly oral. Many patients do not achieve adequate analgesia with approved medications, or they cannot tolerate systemic medications due to common side effects such as dry mouth, nausea, or drowsiness, often leading to discontinuation of treatment (Finnerup et al., Lancet Neurol., 2015, 14(2):162-173). Furthermore, given the growing public health challenges of opioid misuse and addiction, there is a need for effective and safe non-opioid drug options for pain management (Coussens et al., J. Pharmacol. Exp. Ther., 2019, 371(2):396-408).

[0005] Local injection therapy with botulinum toxin (botulinum neurotoxin or BoNT) is a newly emerging treatment option. BoNT is a potent neurotoxin produced by Clostridium botulinum, and the presumed mechanism of action of BoNT in neuropathic pain may involve inhibition of the release of neurotransmitters and pain mediators (e.g., substance P, glutamate, and calcitonin gene-related protein (CGRP)), as well as a decrease in the activity of transient receptor potential (TRP) ion channels involved in the transmission of noxious stimuli (Go et al., Front. Mol. Neurosci., 2021, 14:772719, doi: 10.3389 / fnmol.2021.772719; JH Park and HJ Park, Toxins, 2017, 9(9):260). Over the past few years, several clinical trials using BoNT have been conducted to treat peripheral neuropathic pain, and BoNT treatment has shown promise in terms of efficacy and safety in several PNP conditions.

[0006] A randomized, double-blind, two-group, single-dose, placebo-controlled clinical trial conducted by Apalla et al. (Clin. J. Pain., 2013, 29(10):857-64) evaluated the efficacy and safety of BoNT type A Botox® in patients with postherpetic neuralgia. Each patient received 40 injections, each containing 5 U of Botox®, for a total maximum dose of 200 U. Injections were administered subcutaneously in a checkerboard pattern with a minimum injection site distance of 1 cm. BoNT type A was concluded to be a promising therapeutic modality for postherpetic neuralgia. Furthermore, Attal et al. (Lancet Neurol., 2016, 15(6):555-65) investigated the efficacy and safety of BoNT type A Botox® in patients with peripheral neuropathic pain (including various PNP conditions) in a randomized, double-blind, two-group, two-dose, placebo-controlled trial. The total dose of BoNT type A Botox® was determined by the size of the pain area, not exceeding 60 injection sites (i.e., not exceeding a total dose of 300 U). Injections were administered subcutaneously at a dose of 0.2 mL (5 U) per injection site, with each injection site 1.5-2 cm apart. In conclusion, two doses of BoNT type A provided sustained analgesic effect for peripheral neuropathic pain.

[0007] Another PNP trial using botulinum toxin is the randomized, double-blind, placebo-controlled, single-dose trial by Ghasemi et al. (J. Res. Med. Sci., 2014, 19(2):106-111), in which 40 participants with diabetic PNP in both feet received intradermal injections of BoNT type A (Dysport®) at 12 injection points (3x4 injection points) in a grid pattern on the top of one foot. These authors concluded that BoNT type A has a significant effect on diabetic peripheral neuropathic pain. Ranoux et al. (Ann. Neurol., 2008, 64(3):274-283) reported a double-blind, placebo-controlled, parallel-group study investigating the use of BoNT type A Botox® in 29 patients with focal painful neuropathy with mechanical allodynia (e.g., post-traumatic / postoperative pain or postherpetic neuralgia). Botox® or placebo was administered intradermally to 1.5 cm apart skin sites, not exceeding a predetermined maximum number of sites fixed at 40 (equivalent to a maximum dose of 200 units). The authors concluded that intradermal injection of BoNT type A has a direct analgesic effect in patients with focal chronic neuropathic pain with allodynia.

[0008] Furthermore, a randomized, double-blind, placebo-controlled, single-dose trial by Taheri et al. (Diabetes Metab. Syndr., 2020, 14(6):1823-1828) found that intradermal injection of BoNT using a 4x5 grid with an injection distance of 1 cm was effective in reducing neuropathic pain and improving symptoms associated with neuropathic pain in patients with painful diabetic neuropathy. Xiao et al. (Pain Med., 2010, 11(12):1827-1833) showed in a prospective, randomized, placebo-controlled, double-blind clinical trial conducted in China that subcutaneous injection of BoNT type A (Lanzhou Institute of Biological Products, China) at a volume of 1 mL within a skin radius of 1.0-2.0 cm (total dose of BoNT type A 77 ± 18.5 U) significantly reduced pain in postherpetic neuralgia. Yuan et al. (Neurology, 2009, 72(17):1473-1478) conducted a double-blind, placebo-controlled crossover trial in 18 patients to evaluate the efficacy of intradermal BoNT type A (Botox®) for diabetic neuropathic pain. In this trial, BoNT type A, Botox®, was administered intradermally to each patient's foot in a grid pattern (typically covering a total of 12 sites spaced 2-3 cm apart), with each injection containing approximately 4 U of Botox® in a volume of 0.1 mL. The authors found that BoNT type A significantly reduced diabetic neuropathic pain and transiently improved sleep quality.

[0009] Furthermore, the effects of BoNT / A on trigeminal neuralgia were investigated in four randomized, double-blind, placebo-controlled single-dose trials. BoNT / A was identified as BoNT type A, specifically Botox® (Shehata et al., J. Headache Pain, 2013, 14(1):92; Zuniga et al., Clin. Neuropharmacol., 2013, 36(5):146-150) and BoNT type A (Lanzhou Institute of Biological Products, China) (Wu et al., Cephalagia, 2012, 32(6):443-450; Zhang et al., J. Headache Pain, 2014, 15(1):65). In all trials, a statistically significant superiority of BoNT / A compared to placebo was demonstrated in pain reduction and, where reported, in pain attack frequency. However, in contrast to these positive clinical trial results, a multicenter, double-blind, placebo-controlled, parallel-group trial sponsored by Allergan and registered on ClinicalTrials.gov as NCT00168441 found no statistically significant difference between BoNT type A (Botox®) treatment with 2 to 80 intradermal injections (5 to 200 U) and placebo in patients with postherpetic neuralgia.

[0010] While the results of various clinical trials reflect the advantages of minimally invasive and non-systemic treatment with BoNT compared to established approaches for neuropathic pain relief, the optimal dose, maximum dose, dilution, number of injection sites, or distance between injection sites for any BoNT product in the treatment of neuropathic pain remains unestablished. [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] In view of the above, the object of the present invention is a method to provide an improved treatment for peripheral neuropathic pain. [Means for solving the problem]

[0012] This invention relates to the use of botulinum toxin for the treatment of peripheral neuropathic pain. It has been found that the use of a specific dosing and injection regimen for botulinum toxin administration is highly effective in reducing peripheral neuropathic pain, while also being well-tolerated and safe.

[0013] In a first aspect, the present invention relates to a botulinum toxin for use in the treatment of peripheral neuropathic pain, wherein the botulinum toxin is subcutaneously injected into the skin area of ​​the patient at a concentration of 35 U / ml to 65 U / ml, with a dose of 4.0 U to 6.0 U per injection point and a volume of 0.07 ml to 0.15 ml per injection point, with a distance between injection points of 1.5 cm to 2.5 cm.

[0014] Peripheral neuropathic pain is preferably selected from the group consisting of postherpetic neuralgia (PHN), peripheral nerve injury (e.g., due to surgery or trauma), trigeminal neuralgia, painful polyneuropathy (e.g., diabetic neuropathy (DNP)), and painful radiculopathy. In the present invention, PNP is particularly preferably postherpetic neuralgia (PHN), PNP due to peripheral nerve injury, particularly peripheral nerve injury due to surgery or trauma, or painful polyneuropathy, particularly diabetic neuropathy (DNP).

[0015] In the context of the present invention, the botulinum toxin is preferably of type A. Furthermore, the botulinum toxin may be in a form that does not contain a complex-forming protein, or in the form of a complex containing a complex-forming protein. Preferably, the botulinum toxin is of type A and in a form that does not contain a complex-forming protein, or in an alternative preferred embodiment, it is of type A and in the form of a complex containing a complex-forming protein.

[0016] In a second aspect, the present invention relates to a method for treating peripheral neuropathic pain, comprising administering an effective amount of botulinum toxin by subcutaneous injection into the skin area of ​​the patient at a concentration of 35 U / ml to 65 U / ml, a dose of 4.0 U to 6.0 U per injection point, and a volume of 0.07 ml to 0.15 ml per injection point, wherein the distance between injection points is 1.5 cm to 2.5 cm.

[0017] Preferred embodiments are described in the attached dependent claims and the following detailed description. [Modes for carrying out the invention]

[0018] This invention provides a specific administration and injection regimen that yields beneficial therapeutic effects of BoNT injection for peripheral neuropathic pain. The BoNT administration and injection regimen is not only highly efficient in reducing PNP and associated symptoms, but is also well-tolerated and safe. BoNT is administered by local injection into the painful skin area. This local injection is a minimally invasive treatment modality with minimal side effects. Compared to commonly prescribed systemic medications, BoNT local injection therapy does not have common side effects (e.g., dry mouth, nausea, and drowsiness) and does not involve the problems of opioid misuse and dependence. Therefore, from the standpoint of efficacy, safety, and tolerability, the specific BoNT local injection therapy according to this invention is a preferred therapeutic approach for the treatment of peripheral neuropathic pain.

[0019] The aforementioned advantages are the result of a specific combination of various aspects of administration, including the route of administration (subcutaneous injection), the distance between injection sites (preferably 2 cm), the BoNT dose per injection site (preferably 5 U), the concentration (preferably 50 U BoNT / 1 mL), the total number of injection sites (up to 90), and the total dose (up to 400 U). This unique topical treatment regimen makes a significant contribution to the field by establishing a new treatment option in the management of neuropathic pain. This topical therapy fills a significant gap in this burdensome chronic condition, where there is a medical need for an effective treatment option without systemic side effects in an era of opioid overuse, misuse, and dependence.

[0020] As used herein, the terms “peripheral neuropathic pain” or “PNP” refer to pain caused by lesions or diseases of the peripheral somatic sensory nervous system. This term does not include central neuropathic pain (CNP), which is defined as pain caused by lesions or diseases of the central somatic sensory nervous system. Causes of peripheral neuropathic pain include, for example, postherpetic neuralgia, peripheral nerve injury (e.g., due to surgery or trauma), trigeminal neuralgia, painful polyneuropathy (e.g., diabetic neuropathy (DNP)), and painful radiculopathy. In the present invention, PNP is preferably postherpetic neuralgia (PHN), PNP due to peripheral nerve injury (e.g., due to surgery or trauma), or painful polyneuropathy, particularly diabetic neuropathy (DNP), or caused by them.

[0021] The type of pain is not particularly limited and includes all symptoms of PNP. For example, some patients have allodynia, a symptom of PNP. Patients with allodynia experience pain from stimuli that should not cause pain (for example, patients who feel pain from the fabric of a T-shirt touching their skin, or patients who feel pain after washing their hands with lukewarm water). However, allodynia is only one of many symptoms of PNP. Other symptoms include, for example, numbness ("pins and needles"), numbness, and electric shock-like pain. As some assumptions suggest that allodynia may be a symptom that is highly sensitive to botulinum toxin treatment, any treatment of a PNP patient with allodynia should be understood as encompassing treatment of allodynia.

[0022] As used herein, the term “patient skin area” generally refers to the skin area affected by PNP, and is also referred to herein as “PNP area,” “PNP skin area,” “pain area,” “painful skin area,” or “painful affected skin area.” The location and size of the pain area to be treated are highly individual and vary from patient to patient. In particular, the location and size of the pain area depend on the damaged nerve and the cause of the PNP. However, in the case of postherpetic neuralgia, PNP can occur anywhere on the body, but it often occurs in the rib cage. Furthermore, the area associated with postherpetic neuralgia may be larger than the area with nerve damage. Diabetic PNP usually occurs first in both feet, but can also appear in the hands, and as it progresses, it can affect the legs, arms, and other parts of the body. Postoperative / post-traumatic PNP occurs wherever nerve damage occurred. Regarding the assessment of the PNP area, it is usually done by having the treating physician outline the pain area with the patient. Patients can usually indicate the pain area fairly accurately.

[0023] As used herein, the term “patient” generally refers to a person requiring pain treatment, although this is not a limitation of the term. Preferably, in the context of the present invention, “patient” is a person having PNP that is rated at least as possible by the NeuPSIG / IASP scoring system (Finnerup et al., Neuropathic pain: an updated grading system for research and clinical practice Pain, 2016, 157(8):1599-1606).

[0024] In this specification, a number without decimal places is understood to include all numbers with one or more decimal places that, when general rounding rules are applied, result in a number without decimal places. For example, the number 50 includes 49.5 or 49.50 (these are rounded up to 50), and 50.4 or 50.49 (these are rounded down to 50), as well as all numbers in between. Similarly, a number with one decimal place is understood to include all numbers with two or more decimal places that, when general rounding rules are applied, result in a number with one decimal place (for example, 3.95 and 4.04 are rounded up / down to 4.0). Furthermore, a number with two decimal places is understood to include all numbers with three or more decimal places that, when general rounding rules are applied, result in a number with two decimal places (for example, 0.085 and 0.094 are rounded up / down to 0.09). The same applies to the endpoints of ranges; for example, the range 35-65 includes the range 34.5-65.4, the range 1.5-2.5 includes the range 1.45-2.54, and the range 0.07-0.15 includes the range 0.065-0.154.

[0025] The term "comprising" is intended to mean non-exclusive inclusion, such that a process, method, process product, composition, or formulation that comprises, includes, or contains an element or list of elements does not consist only of those elements, but may also include other elements not expressly listed for use in the process, method, process product, composition, or formulation. In addition, within the framework of the present invention, the terms "comprise", "comprising", "includes", "including", "contains", "containing", and their variants are each intended to be replaceable by the term "consists" or "consisting" or their variants, which is understood to refer to exclusive inclusion of the indicated elements. Further, the terms "a" and "an", as well as "the", and similar designators used in the context of the present invention should be construed to include both the singular and the plural, and thus may also refer to "at least one" or "two or more", unless otherwise indicated herein or clearly negated by the context.

[0026] In a first aspect, the present invention relates to a botulinum toxin for use in the treatment of peripheral neuropathic pain, wherein the botulinum toxin is subcutaneously injected into a skin area of a patient at a concentration of 35 U / ml to 65 U / ml, and at a dose of 4.0 U to 6.0 U per injection point and a volume of 0.07 ml to 0.15 ml per injection point, and the distance between injection points is 1.5 cm to 2.5 cm.

[0027] According to the present invention, the injection volume per injection point is preferably 0.07 ml to 0.14 ml, more preferably 0.08 ml to 0.13 ml, even more preferably 0.08 ml to 0.12 ml, still even more preferably 0.09 ml to 0.11 ml, and most preferably 0.10 ml. More specifically, the injection volume per injection point according to the present invention may be within the range of 0.07 ml to 0.14 ml, preferably 0.07 ml to 0.13 ml, more preferably 0.07 ml to 0.12 ml, even more preferably 0.07 ml to 0.11 ml, or preferably 0.08 ml to 0.15 ml, more preferably 0.08 ml to 0.14 ml, even more preferably 0.08 ml to 0.13 ml, still even more preferably 0.08 ml to 0.12 ml, particularly preferably 0.08 ml to 0.11 ml, or preferably 0.09 ml to 0.15 ml, more preferably 0.09 ml to 0.14 ml, even more preferably 0.09 ml to 0.13 ml, still even more preferably 0.09 ml to 0.12 ml, and particularly preferably 0.09 ml to 0.11 ml.

[0028] The dosage per injection point is preferably 4.5 U to 5.5 U. Therefore, the dosage per injection point may be, for example, 4.6 U, 4.7 U, 4.8 U, 4.9 U, 5.0 U, 5.1 U, 5.2 U, 5.3 U, and 5.4 U. The particularly preferred dosage per injection point is 5.0 U.

[0029] In a preferred embodiment of the first aspect of the present invention, the concentration of botulinum toxin is within the range of 40 U / ml to 60 U / ml (for example, 45 U / ml, 50 U / ml, and 55 U / ml), the dosage is 4.0 U to 6.0 U per injection point, and the volume is 0.07 ml to 0.15 ml per injection point. The volume per injection point is preferably 0.07 ml to 0.14 ml, and the more preferred injection volume is as described above in relation to the first aspect of the present invention. As used herein, "concentration" refers to the concentration of botulinum toxin in the liquid preparation administered by subcutaneous injection.

[0030] Preferably, in the above preferred embodiments, the dose per injection point is 4.5U to 5.5U (for example, including 4.6U, 4.7U, 4.8U, 4.9U, 5.0U, 5.1U, 5.2U, 5.3U, and 5.4U), most preferably 5.0U), and the volume per injection point is 0.07ml to 0.14ml. Preferably, the volume per injection point is 0.08ml to 0.13ml, more preferably 0.08ml to 0.12ml, even more preferably 0.09ml to 0.11ml, most preferably 0.10ml. More specifically, the volume per injection point is preferably 0.07 ml to 0.13 ml, more preferably 0.07 ml to 0.12 ml, even more preferably 0.07 ml to 0.11 ml, or preferably 0.08 ml to 0.14 ml, more preferably 0.08 ml to 0.13 ml, even more preferably 0.08 ml to 0.12 ml, and even more preferably 0.08 ml to 0.11 ml, or preferably 0.09 ml to 0.14 ml, more preferably 0.09 ml to 0.13 ml, even more preferably 0.09 ml to 0.12 ml, and even more preferably 0.09 ml to 0.11 ml.

[0031] In aspects and embodiments of the present invention, the total dose of botulinum toxin is a maximum of 400 U, and / or the total number of injection points is a maximum of 90. Preferably, the total dose is 100 U to 400 U, or a maximum of 300 U, or 200 U to 300 U, or more than 300 U to 400 U. Preferably, the total number of injection points is 40 to 90, or 50 to 90, or a maximum of 80, or 50 to 80, or 60 to 80.

[0032] Regarding the injection pattern, the injection points are typically arranged such that the distance between injection points is 1.5 cm to 2.5 cm, preferably 1.6 cm to 2.4 cm, more preferably 1.7 cm to 2.3 cm, even more preferably 1.8 cm to 2.2 cm, even more preferably 1.9 cm to 2.1 cm, and most preferably 2.0 cm.

[0033] As used herein, the term "distance between injection points" means the distance between any given injection point and a nearby injection point. In particular, unless otherwise specified, the term "distance between injection points" means the distance between any given injection point and the nearest injection point to that given injection point.

[0034] In the present invention, exemplary preferred combinations of concentration, dose per injection point, volume per injection point, and distance between injection points include: (1) concentration 35 U / ml to 65 U / ml, dose per injection point 4.0 U to 6.0 U, volume per injection point 0.08 ml to 0.13 ml, distance between injection points 1.5 cm to 2.5 cm; (2) concentration 35 U / ml to 65 U / ml, dose per injection point 4.0 U to 6.0 U, volume per injection point 0.09 ml to 0.12 ml, injection point (3) Inter-injection point distance 1.5cm~2.5cm, concentration 35U / ml~65U / ml, dose per injection point 4.0U~6.0U, volume per injection point 0.09ml~0.11ml, inter-injection point distance 1.5cm~2.5cm, (4) concentration 35U / ml~65U / ml, dose per injection point 4.0U~6.0U, volume per injection point 0.07ml~0.15ml, inter-injection point distance 1.6cm~2.4cm, (5) concentration 35U / ml~65U / ml, dose per injection point 4.0U~6.0U, 1 injection point (6) Concentration 35U / ml~65U / ml, dose per injection point 4.0U~6.0U, volume per injection point 0.07ml~0.15ml, distance between injection points 1.8cm~2.2cm, (7) Concentration 35U / ml~65U / ml, dose per injection point 4.0U~6.0U, volume per injection point 0.08ml~0.13ml, distance between injection points 1.6cm~2.4cm, (8) Concentration 35U / ml~65U / ml, 1 injection point (9) Amount per injection: 4.0U~6.0U, volume per injection point: 0.09ml~0.12ml, distance between injection points: 1.7cm~2.3cm, (10) Amount per injection point: 35U / ml~65U / ml, Amount per injection point: 4.0U~6.0U, volume per injection point: 0.09ml~0.11ml, distance between injection points: 1.8cm~2.2cm, (11) Amount per injection point: 35U / ml~65U / ml, Amount per injection point: 4.5U~5.5U, volume per injection point: 0.07ml~0.15ml, distance between injection points: 1.5cm~2.5cm, (11) concentration 35U / ml~65U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.08ml~0.13ml, distance between injection points 1.5cm~2.5cm, (12) concentration 35U / ml~65U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.08ml~0.12ml, distance between injection points 1.5cm~2.5cm, (13) concentration 35U / ml~65U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.09ml~0 (14) 0.11 ml, distance between injection points 1.5 cm to 2.5 cm, concentration 40 U / ml to 60 U / ml, dose per injection point 4.5 U to 5.5 U, volume per injection point 0.07 ml to 0.15 ml, distance between injection points 1.5 cm to 2.5 cm, (15) concentration 40 U / ml to 60 U / ml, dose per injection point 4.5 U to 5.5 U, volume per injection point 0.08 ml to 0.13 ml, distance between injection points 1.5 cm to 2.5 cm, (16) concentration 40 U / ml to 60 U / ml, dose per injection point 4.5 U to 5.5 (17) U, volume per injection point 0.08 ml~0.12 ml, distance between injection points 1.5 cm~2.5 cm, (18) concentration 40 U / ml~60 U / ml, dose per injection point 4.5 U~5.5 U, volume per injection point 0.09 ml~0.11 ml, distance between injection points 1.5 cm~2.5 cm, (19) concentration 35 U / ml~65 U / ml, dose per injection point 4.5 U~5.5 U, volume per injection point 0.07 ml~0.15 ml, distance between injection points 1.7 cm~2.3 cm, (19) concentration 35 U / ml~65 U / ml l, dose per injection point 4.5U~5.5U, volume per injection point 0.08ml~0.13ml, distance between injection points 1.7cm~2.3cm, (20) concentration 35U / ml~65U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.08ml~0.12ml, distance between injection points 1.7cm~2.3cm, (21) concentration 35U / ml~65U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.09ml~0.11ml, distance between injection points 1.5cm~2.5cm, (22) concentration 35U / ml~65U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.07ml~0.15ml, distance between injection points 1.8cm~2.2cm, (23) concentration 35U / ml~65U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.08ml~0.13ml, distance between injection points 1.8cm~2.2cm, (24) concentration 35U / ml~65U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.08ml~0 (25) 0.12 ml, distance between injection points 1.8 cm ~ 2.2 cm, concentration 35 U / ml ~ 65 U / ml, dose per injection point 4.5 U ~ 5.5 U, volume per injection point 0.09 ml ~ 0.11 ml, distance between injection points 1.8 cm ~ 2.2 cm, (26) concentration 40 U / ml ~ 60 U / ml, dose per injection point 4.5 U ~ 5.5 U, volume per injection point 0.07 ml ~ 0.15 ml, distance between injection points 1.7 cm ~ 2.3 cm, (27) concentration 40 U / ml ~ 60 U / ml, dose per injection point 4.5 U ~ 5.5 (28) Concentration 40U / ml~60U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.08ml~0.12ml, distance between injection points 1.7cm~2.3cm, (29) Concentration 40U / ml~60U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.09ml~0.11ml, distance between injection points 1.7cm~2.3cm, (30) Concentration 40U / ml~60U / ml l, dose per injection point 4.5U~5.5U, volume per injection point 0.07ml~0.15ml, distance between injection points 1.8cm~2.2cm, (31) concentration 40U / ml~60U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.08ml~0.13ml, distance between injection points 1.8cm~2.2cm, (32) concentration 40U / ml~60U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.08ml~0.12ml, distance between injection points 1.8cm~2.(33) 2cm, concentration 40U / ml~60U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.09ml~0.11ml, distance between injection points 1.8cm~2.2cm, (34) concentration 50U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.09ml~0.11ml, distance between injection points 1.5cm~2.5cm, (35) concentration 50U / ml, dose per injection point 4.5U~5.5U, volume per injection point 0.09ml~0.11ml (36) Concentration 50 U / ml, dose per injection point 4.5 U~5.5 U, volume per injection point 0.09 ml~0.11 ml, distance between injection points 1.8 cm~2.2 cm, (37) Concentration 40 U / ml~60 U / ml, dose per injection point 5.0 U, volume per injection point 0.083 ml~0.125 ml, distance between injection points 1.5 cm~2.5 cm, (38) Concentration 40 U / ml~60 U / ml, dose per injection point 5.0 U, per injection point (39) Volume 0.083ml~0.125ml, distance between injection points 1.7cm~2.3cm, (39) Concentration 40U / ml~60U / ml, dose per injection point 5.0U, Volume per injection point 0.083ml~0.125ml, distance between injection points 1.8cm~2.7cm, (40) Concentration 50U / ml, dose per injection point 5.0U, Volume per injection point 0.10ml, distance between injection points 1.5cm~2.5cm, (41) Concentration 50U / ml, dose per injection point 5.0U, per injection point (42) Volume 0.10 ml, distance between injection points 1.7 cm to 2.3 cm; (43) Concentration 50 U / ml, dose per injection point 5.0 U, volume per injection point 0.10 ml, distance between injection points 1.8 cm to 2.2 cm; (44) Concentration 50 U / ml, dose per injection point 5.0 U, volume per injection point 0.10 ml, distance between injection points 1.9 cm to 2.1 cm; (45) Concentration 50 U / ml, dose per injection point 5.0 U, volume per injection point 0.10 ml, distance between injection points 2.0 cm.

[0035] According to the present invention, a particularly preferred combination of (1) to (44) can be further combined with a total dose of up to 400 U, or 100 U to 400 U, or up to 300 U, or 200 U to 300 U, or more than 300 U to 400 U. Furthermore, a particularly preferred combination of (1) to (44) can be further combined with a total number of injection points of up to 90, or 40 to 90, or 50 to 90, or up to 80, or 50 to 80, or 60 to 80. Furthermore, any particularly preferred combination of (1) to (44) can be further combined with one of the following combinations: (I) total dose up to 400U and total injection points up to 90, (II) total dose 200U to 400U and total injection points up to 90, (III) total dose 200U to 300U and total injection points up to 90, (IV) total dose over 300U to 400U and total injection points up to 90, (V) total dose up to 400U and total injection points 40 to 90, (VI) total dose 20 (VII) Total dose 0U to 400U and total injection points 40 to 90, (VIII) Total dose over 300U to 400U and total injection points 40 to 90, (IX) Total dose up to 400U and total injection points 50 to 80, (X) Total dose 200U to 400U and total injection points 50 to 80, (XI) Total dose 200U to 300U and total injection points 50 to 80, and (XII) Total dose over 300U to 400U and total injection points 50 to 80.

[0036] The injection points are typically arranged in a grid pattern, preferably in a square grid, more preferably in a rectangular grid where each of the four injection points forming a rectangle is equally spaced from one another (i.e., there are four adjacent injection points equidistant from each other), and most preferably in a square grid.

[0037] In the present invention, peripheral neuropathic pain is preferably selected from the group consisting of postherpetic neuralgia, peripheral nerve injury, trigeminal neuralgia, painful polyneuropathy, and painful radiculopathy. Particularly preferably, peripheral neuropathic pain is painful polyneuropathy, including postherpetic neuralgia, peripheral nerve injury, or diabetic neuropathy.

[0038] The botulinum toxin used in the present invention is not particularly limited, but any serotype of botulinum toxin (BoNT / A~H) can be used, either in a form without complex-forming proteins or in the form of a complex containing complex-forming proteins. Preferably, the botulinum toxin is serotype A or B botulinum toxin (BoNT / A, BoNT / B), with serotype A (BoNT / A) being particularly preferred. More preferably, the botulinum toxin is serotype A botulinum toxin, even more preferably serotype A1 botulinum toxin (BoNT / A1), and most preferably BoNT / A1 produced by Clostridium botulinum Hall strain. Preferably, the botulinum toxin is type A botulinum toxin, either in a form without complex-forming proteins or in the form of a complex containing complex-forming proteins, and more preferably type A botulinum toxin, in a form without complex-forming proteins.

[0039] As used herein, the term “botulinum toxin” (“BT”) is used synonymously with the term “botulinum neurotoxin” (“BoNT”). These terms are intended to refer to both the form of the toxin that does not contain complex-forming proteins, i.e., the (active) neurotoxic polypeptide that ultimately inhibits acetylcholine release (also referred herein as “pure botulinum neurotoxin,” “neurotoxic component,” “150kDa neurotoxin,” or “Botulinum neurotoxin (150kD)”) and the form of the toxin that is a complex containing complex-forming proteins (i.e., a complex of the neurotoxic component and complex-forming proteins). Botulinum toxin complexes are high-molecular-weight complexes of the neurotoxic component and a series of complex-forming proteins (NAPs), including the 900kDa, 500kDa, and 300kDa Clostridium botulinum type A toxin complexes. The complex-forming protein is a non-toxic, non-hemagglutinin (NTNHA), and different hemagglutinins (HA) are used in strains of serotypes A-D. For example, a 900 kDa complex is found in onabotulinumtoxin A (Botox® / Vistabel®, Allergan, Irvine, California, USA), and abobotulinumtoxin A (Dysport® / Azzalure®, Ipsen, Paris, France), Alluzience® (Ipsen / Galderma), and Innotox® (Meditox) also contain toxin complexes as active agents. Preferably, the botulinum toxin is either pure botulinum neurotoxin contained in Xeomin®, or Xeomin®, or a toxin complex contained in Botox® or Dysport®, or Botox® or Dysport®.

[0040] In the present invention, botulinum toxin may be a natural neurotoxin obtainable from Clostridium botulinum, or any other botulinum toxin obtainable from alternative sources, including recombinant technology and genetically modified or chemically modified botulinum toxins. Chimeric or genetically modified botulinum toxins, i.e., botulinum toxins containing mutations including substitutions, deletions, and insertions, are also included in terms such as “botulinum toxin” and “neurotoxic component.” Preferably, the mutation does not impair any of the biological activity of the botulinum toxin. However, the use of mutations to modulate the biological activity of the botulinum toxin is also intended. Botulinum toxins containing chemically modified amino acids, e.g., glycosylated, acetylated, or otherwise modified one or more amino acids, which may be beneficial for toxin uptake or stability, are also included. Lipidization of the neurotoxic component is particularly preferred.

[0041] In the context of this invention, the dose is expressed in biological units because the botulinum toxin used may contain a variable proportion of inactive toxin, for example, that contributes to the total protein load without contributing to efficacy. In the context of this invention, the biological titer of the botulinum toxin is determined using a mouse bioassay (MBA). In the MBA, the mean lethal dose (LD) of the toxin / neurotoxin after intraperitoneal injection in mice is determined. 50), that is, the dose of toxin / neurotoxin capable of killing 50% of the mouse population is determined. Based on this premise, as used herein, one unit (U) of toxin / neurotoxin is defined as one mouse LD50 (1.0 LD50 = 1.0 U). The LD50 mouse bioassay is the gold standard among various biological, chemical, or immunological methods for detecting and determining the activity of botulinum toxin and is known to those skilled in the art (see, for example, Pearce, LB; Borodic, GE; First, ER; MacCallum, RD Measurement of botulinum toxin activity: Evaluation of the lethality assay. Toxicol. Appl. Pharmacol. 1994, 128, 69-77).

[0042] Another useful method for determining the biological activity (biological titer) of botulinum neurotoxin is a cell-based titer assay, such as those disclosed in International Publication No. 2009 / 114748, International Publication No. 2013 / 049508, or International Publication No. 2014 / 207109. The activity results obtained from such cell-based assays correspond to the activity values ​​obtained from mouse intraperitoneal LD50 assays, as their values ​​are calibrated using an LD50 reference standard.

[0043] Due to differences in LD50 testing used by manufacturers of commercially available botulinum toxin preparations, the unit potency indicated by manufacturers for commercially available botulinum toxin preparations is unique and cannot be easily compared. Therefore, within the framework of this invention, the conversion ratios provided below apply to incobotulinum toxin A ("INCO"; Xeomin®, Bocouture®; botulinum toxin serotype A, without complex-forming protein; Mertz Pharmaceuticals), onabotulinum toxin A ("ONA"; Botox®, Vistabel®; botulinum toxin complex of serotype A; Allergan), and avobotulinum toxin A ("ABO"; Dysport®, Az Used to establish comparative titers for zalure®; botulinum toxin complex of serotype A; Medicis Pharmaceuticals, Galderma Laboratories), rimabotulinumtoxin B ("RIM"; Myobloc®, NeuroBloc®; botulinum toxin serotype B; Solstice Neurosciences), and PurTox® ("TBD"; botulinum toxin serotype A; Mentor Worldwide). For use herein, the conversion ratio of ONA to INCO is 1:1. The conversion ratio of ONA / INCO:ABO is 1:2.5. The conversion ratio of ONA / INCO:RIM is 1:50, and the conversion ratio of ONA / INCO:TBD is 1:1.5. Furthermore, and preferably, in the context of the present invention, 1 U of INCO (Xeomin®) and 1 U of onabotulinum toxin A ("ONA"; Botox®) are considered to correspond to 1 mouse LD50 (1.0 LD50), or 1 U, as measured above.

[0044] Generally, the botulinum toxin used in the present invention is in the form of a liquid composition. The liquid composition can be formulated by various techniques known in the art, depending on the desired application. The liquid composition may be provided as a ready-to-use liquid formulation, or as a lyophilized powder that is prepared prior to use, typically in saline. Preferably, the botulinum toxin used in the present invention is in the form of an aqueous solution, more preferably in the form of saline or physiological saline, and most preferably in the form of phosphate-buffered saline. The aqueous solution may additionally contain one or more pharmaceutically acceptable substances. Suitable pharmaceutically acceptable substances include those known in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0045] In particular, aqueous botulinum toxin solutions or aqueous botulinum toxin compositions may contain other carriers or non-toxic, non-therapeutic, and non-immunogenic stabilizers. Therefore, aqueous botulinum toxin compositions may contain glycerol, protein stabilizers (HSAs), or non-protein stabilizers such as polyvinylpyrrolidone (PVP), hyaluronic acid, or free amino acids, such as methionine or histidine. Suitable non-protein stabilizers are disclosed in International Publication No. 2005 / 007185 or International Publication No. 2006 / 020208. Furthermore, aqueous botulinum toxin compositions may not contain amino acids and / or stabilizer peptides (e.g., consisting of 5-50 amino acids, 10-40 amino acids, or 15-30 amino acids). Botulinum toxin compositions may also contain nonionic or ionic surfactants, such as polysorbate or poloxamer. Suitable formulations of HSA-stabilized preparations containing botulinum toxin according to the present invention are disclosed, for example, in U.S. Patent No. 8,398,998(B2).

[0046] Preferably, the botulinum toxin used in the present invention is in the form of an aqueous solution containing sodium chloride (NaCl), preferably in the form of physiological saline (i.e., a solution containing physiologically concentrated sodium chloride, e.g., about 9 g / l NaCl), and further comprises one or more of the following (i) to (ix), or any combination of (i) to (ix): (i) without other excipients (except NaCl), (ii) human serum albumin (HSA) and sugars, especially monosaccharides or disaccharides, (iii) human serum albumin (HSA) and lactose, (iv) human serum albumin (HSA) and sucrose, (v) monosaccharides and / or disaccharides (e.g., lactose and / or sucrose), (vi) without buffer, (vii) without a single amino acid, (viii) without human serum albumin (HSA), sodium chloride, and lactose, or without HSA, sodium chloride, and sucrose, or (ix) without HSA and sodium chloride.

[0047] Particularly preferred is the botulinum toxin in the form of an aqueous formulation containing botulinum toxin, sodium chloride, and human serum albumin, or an aqueous formulation containing botulinum toxin, sodium chloride, human serum albumin, and lactose, or an aqueous formulation containing botulinum toxin, sodium chloride, human serum albumin, and sucrose. Another particularly preferred aqueous formulation contains botulinum toxin, sodium chloride, human serum albumin, and histidine. The botulinum toxin may be as defined above herein.

[0048] In a second aspect, the present invention relates to a method for treating peripheral neuropathic pain, comprising administering an effective amount of botulinum toxin by subcutaneous injection into the skin area of ​​the patient at a concentration of 35 U / ml to 65 U / ml, a dose of 4.0 U to 6.0 U per injection point, and a volume of 0.07 ml to 0.15 ml per injection point, wherein the distance between injection points is 1.5 cm to 2.5 cm.

[0049] The method according to the second aspect of the present invention is closely related to the use according to the first aspect of the present invention. Therefore, all definitions, descriptions, advantages, etc., given herein with respect to the use according to the first aspect of the present invention also apply equally to the method according to the second aspect of the present invention. [Examples]

[0050] Efficacy and safety of botulinum toxin in the treatment of peripheral neuropathic pain using the administration / injection plan according to the present invention A parallel-group, placebo-controlled, multicenter, double-blind, randomized two-group, proof-of-concept clinical trial will be conducted to investigate the efficacy and safety of subcutaneous injection of botulinum toxin (botulinum neurotoxin or "BoNT"), particularly botulinum toxin type A (BoNT / A), such as NT201 (Xeomin®), in the treatment of peripheral neuropathic pain. The medical condition being tested is moderate to severe chronic PNP due to postherpetic neuralgia (PHN) or peripheral nerve injury (postoperative / post-traumatic neuropathic pain).

[0051] In total, for example, 120 subjects (male or female) aged 18 years or older will be enrolled in the study. The main enrollment criteria include: (1) chronic PNP lasting for at least 6 months by the time of the screening visit and reasonably associated with either an episode of herpes zoster or peripheral nerve injury (caused by surgery or mechanical trauma); (2) a documented diagnosis of either chronic neuropathic pain after peripheral nerve injury (i.e., postoperative / post-traumatic neuropathic pain) or PHN, with at least probable certainty using the NeuPSIG / IASP scoring system; and (3) a score of at least 4 out of 10 on the Neuropathic Pain 4 Questions (DN4) questionnaire.

[0052] Participants were randomized in a 1:1 ratio, with approximately 60 participants assigned to the BoNT group and 60 to the placebo group. At baseline (day 1), participants received a single intervention session involving subcutaneous injection of either BoNT or placebo into the PNP skin area. The BoNT preparation used had a concentration of 50 U / ml and could be prepared, for example, by re-preparing a 100 U vial of botulinum toxin, such as NT201 (Xeomin®), with 2 ml of sterile physiological (0.9%) sodium chloride solution to a concentration of 50 U / ml. The total dose of BoNT injected may be up to 400 U, but in this embodiment it was up to 300 U, divided into up to 60 subcutaneous (SC) injections (i.e., 5 U per site). The injections were placed in a square grid pattern with a distance of 2 cm between injection points. Subjects in the placebo group are administered a placebo solution (0.9% sodium chloride) containing only the excipients of the botulinum toxin saline used (i.e., sucrose and human serum albumin in the case of NT201).

[0053] All randomized subjects are then followed up with daily self-administered clinical outcome assessments (injection session on day 1) during a double-blind follow-up period, for example, 20 weeks. To assess changes in PNP intensity, efficacy variables are determined daily or at regular intervals for the last 7 days prior to baseline (day 1) and until the end of the study. The last 7 days prior to day 1 constitute the 7-day baseline pain assessment period. In addition, safety is assessed as known to those skilled in the art, using safety parameters including adverse events (AEs), particularly noteworthy adverse events (AESIs), and serious adverse events (SAEs). At the end-of-study (EoS) visit at 20 weeks, the principal investigator performs an overall assessment of the treatment's tolerability based on a 4-point response scale (1=very good, 2=good, 3=moderate, 4=poor).

[0054] The primary efficacy variable is mean daily pain (ADP) from week 2 to week 12, established by the subjects' daily self-assessments. This item establishes evidence of the effectiveness of BoNT in treating PNP compared to placebo. Pain resulting from chronic neuropathies is a core symptom that directly impacts patients' quality of life. The secondary efficacy variable is the change from baseline in the total score of the Neuropathic Pain Symptom Questionnaire (NPSI) from week 2 to week 12, self-assessed regularly (e.g., every 7 days) by the subjects. This variable is used to estimate the reduction in the severity of PNP symptoms in PNP treatment compared to placebo. The evaluation of these primary and secondary efficacy variables, as well as other efficacy variables, is further described below.

[0055] NRS for ADP, WDP, and LDP Participants record their mean daily pain (ADP), worst daily pain (WDP), and least daily pain (LDP) PNP intensities over the past 24 hours using the Numeric Rating Scale for Neuropathic Pain (NRS). Each assessment is evaluated on an 11-point NRS scale ranging from "0 - no pain" to "10 - worst pain imaginable." NRS assessment of ADP intensity is frequently used as a primary efficacy endpoint in clinical pain trials and is recommended by the European Medicines Agency (EMA) in its guidance document "Guideline on the clinical development of medicinal products intended for the treatment of pain" (2016) and the U.S. Food and Drug Administration (FDA) in its guidance document "Guidance for Industry Analgesic Indications: Developing Drug and Biological Products (Draft Guidance)" (2014).

[0056] NPSI Participants periodically complete the Neuropathic Pain Symptoms Questionnaire (NPSI), a 12-item questionnaire designed to assess typical neuropathic pain symptoms (Bouhassira et al., Pain, 2004, 108(3):248-57). The NPSI includes 10 items that ask participants about the mean severity of typical neuropathic pain symptoms over the past 24 hours, including spontaneous pain (items 1-3), painful attack (items 5-6), induced pain (items 8-10), or paresthesia (items 11-12). Items are rated on an 11-point scale ranging from 0, indicating no symptoms (e.g., "no pain" or "no tingling"), to 10, indicating the worst possible symptom intensity (e.g., "worst pain" or "worst tingling"). These 10 items are used to calculate the total NPSI score, as well as five subscores for various pain domains ((superficial spontaneous) burning pain, (deep spontaneous) pressure pain, paroxysmal pain, provoked pain, and paresthesia / abnormal sensation). These scores are also intended for use in sensory phenotyping. Furthermore, the NPSI includes two items: one for the duration of spontaneous pain per day (item 4) and another for the frequency of paroxysmal pain attacks per day (item 7), each with five answer choices.

[0057] PGIC In the assessment of Patient Global Impression of Change (PGIC), participants are asked to indicate their overall impression of the changes since the study treatment using a 9-point Likert scale (from "-4 - significantly worse" to "+4 - significantly improved").

[0058] EQ-5D-5L and EQ VAS The EQ-5D-5L (EuroQol 5-Dimensions 5-Levels) is a scale that records participants' health status on the assessment day across five elements: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression (Herdman M, Gudex C, Lloyd A, et al., Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L), Qual. Life Res. 2011, 20(10):1727-36). For each element, participants can choose from five response options indicating no problem, mild problem, moderate problem, severe problem, or extreme problem in each domain. Participants also rate their overall health on the evaluation day on a EuroQol Visual Analog Scale (EQ-VAS) ranging from 0 - worst possible health to 100 - best possible health.

[0059] BPI-SF Impairment Assessment Participants report how much pain interfered with their general activity, mood, walking ability, normal work, relationships with other people, sleep, and enjoyment of life over the past 24 hours using the seven impairment assessment items of the Brief Pain Inventory - Short Form - Interference (BPI-SF Interference) (Cleeland, CS and Ryan, KM, Ann. Acad. Med. Singap., 1994, 23(2):129-38). The items are assessed on an 11-point scale ranging from 0 ("no impairment") to 10 ("complete impairment"), indicating no impairment.

[0060] HADS The Hospital Anxiety & Depression Scale (HADS) is used to quantify anxiety and depression. Each of the two domains consists of seven items with four answer choices (Zigmond AS and Snaith RP, Acta Psychiatr. Scand., 1983, 67(6):361-70). The answer choices are closely related to the concept of anxiety or depression, for example, asking how often or to what extent the patient felt that way.

[0061] The above approach, involving combinations of injection dose, injection volume, number of injections, and distance between injection points, provides an effective, well-tolerated, safe, localized, and minimally invasive therapy that serves as an alternative to established PNP therapy.

Claims

1. Botulinum toxin for use in the treatment of peripheral neuropathic pain, wherein the botulinum toxin is subcutaneously injected into the skin area of ​​the patient at a concentration of 35 U / ml to 65 U / ml, at a dose of 4.0 U to 6.0 U per injection point, and at a volume of 0.07 ml to 0.15 ml per injection point, with a distance between injection points of 1.5 cm to 2.5 cm.

2. The botulinum toxin for use according to claim 1, wherein the volume per injection point is 0.08 ml to 0.13 ml.

3. Botulinum toxin for use according to claim 1 or claim 2, wherein the dose per injection point is 4.5 U to 5.5 U.

4. The botulinum toxin for use according to claim 1 or claim 2, wherein the concentration is 40 U / ml to 60 U / ml.

5. The botulinum toxin for use according to claim 4, wherein the dose per injection point is 4.5 U to 5.5 U, and the volume per injection point is 0.07 ml to 0.14 ml.

6. The botulinum toxin for use according to claim 5, wherein the volume per injection point is 0.08 ml to 0.13 ml.

7. Botulinum toxin for use according to any one of claims 1 to 6, wherein the distance between the injection points is 1.8 cm to 2.2 cm.

8. Botulinum toxin for use according to any one of claims 1 to 7, wherein the total dose is a maximum of 400 U, or the total number of injection points is a maximum of 90, or the total dose is a maximum of 400 U and the total number of injection points is a maximum of 90.

9. Botulinum toxin for use according to claim 8, wherein the total dose is 100 U to 400 U, or a maximum of 300 U, or 200 U to 300 U, or more than 300 U to 400 U, or the total number of injection points is 40 to 90, or 50 to 90, or a maximum of 80, or 50 to 80, or 60 to 80, or the total dose is 100 U to 400 U, or a maximum of 300 U, or 200 U to 300 U, or more than 300 U to 400 U, and the total number of injection points is 40 to 90, or 50 to 90, or a maximum of 80, or 50 to 80, or 60 to 80.

10. Botulinum toxin for use according to any one of claims 1 to 9, wherein the injection points are arranged in a grid pattern including a square grid, a rectangular grid where each of the four injection points forming a rectangle is equally spaced from one another, and a square grid.

11. The botulinum toxin for use according to any one of claims 1 to 10, wherein the peripheral neuropathic pain is selected from the group consisting of postherpetic neuralgia, peripheral nerve injury, trigeminal neuralgia, painful polyneuropathy, and painful radiculopathy.

12. The botulinum toxin for use according to claim 11, wherein the peripheral neuropathic pain is painful polyneuropathy including postherpetic neuralgia, peripheral nerve injury, or diabetic neuropathic pain.

13. The botulinum toxin for use according to any one of claims 1 to 12, wherein the botulinum toxin is of type A.

14. The botulinum toxin for use according to any one of claims 1 to 13, wherein the botulinum toxin is in a form that does not contain a complex-forming protein, or in the form of a complex containing a complex-forming protein.

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