Topical capsaicin for treating sleep disturbance and / or neuropathic pain

Abstract

The invention relates to (i) the prevention or treatment of a sleep disturbance, preferably in a patient having neuropathic pain; and / or (ii) the prevention or treatment of neuropathic pain in a patient having a sleep disturbance; and / or (iii) the prevention or treatment of neuropathic pain in a patient having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance; in either cases by means of one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably pharmaceutical patches, comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, relative to the total weight of dose unit.

Description

1 GRA 4178-foreign filingTopical capsaicin for treating sleep disturbance and / or neuropathic pain

[0001] Priority is claimed of European patent application no. 25159055.0 filed on 20 February 2025 FIELD OF THE INVENTION

[0002] The invention relates to (i) the prevention or treatment of a sleep disturbance, preferably in a patient having neuropathic pain; and / or (ii) the prevention or treatment of neuropathic pain in a patient having a sleep disturbance; and / or (iii) the prevention or treatment of neuropathic pain in a patient having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance; in either cases by means of one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably pharmaceutical patches, comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, relative to the total weight of dose unit. BACKGROUND ART

[0003] Capsaicin is a highly selective agonist for the transient receptor potential vanilloid 1 receptor (TRPV1). The initial effect of capsaicin is the activation of TRPV1 -expressing cutaneous nociceptors, which results in pungency and erythema due to the release of vasoactive neuropeptides. Following capsaicin exposure, cutaneous nociceptors become less sensitive to a variety of stimuli. These later-stage effects of capsaicin are frequently referred to as "desensitization" and are thought to underlie the pain relief. Sensations from non TRPV1 -expressing cutaneous nerves are expected to remain unaltered, including the ability to detect mechanical and vibratory stimuli. Capsaicin-induced alterations in cutaneous nociceptors are reversible and it has been reported and observed that normal function (the detection of noxious sensations) returns within weeks in healthy volunteers. F. Peppin et al., Ther Adv Neurol Disord (2014) 7(1) 22-32 review the use of capsaicinoids in the treatment of neuropathic pain.

[0004] Low-concentration capsaicin creams, lotions, and patches (capsaicin concentrations of 0.025 wt.-% to 0.1% wt.-%) intended for daily topical application have been available in most countries since the early 1980s. These topical formulations are usually self-administered medications and often without the requirement of a prescription. Clinical studies have revealed that three to five topical skin applications per day for periods of two to six weeks have modest beneficial pain relieving effects against various pain syndromes, including post-herpetic neuralgia, diabetic neuropathy, and chronic musculoskeletal pain (see V. Fattori et al., Molecules 2016, 21, 844, 1-33).

[0005] Medium-concentration capsaicin patches have been tested in clinical trials. For example, J.-Y. Moon et al., Pain Physician 2017, 20:27-35 report about efficacy and safety of 0.625% (50 μg / cm2) and 1.25% (100 μg / cm2) capsaicin patch in peripheral neuropathic pain.2 GRA 4178-foreign filing

[0006] High-concentration capsaicin topical dosage forms such as liquids, creams or oils are known from e.g. WO 2004 / 091521, WO 2005 / 117981, WO 2013 / 036961, WO 2015 / 160941, US 6,248,788, US 7,771,760, US 8,367,733, US 8,802,736.

[0007] W. R. Robbins et al., Anesth Analg 1998 86 579-83 report about treatment of intractable pain with topical large-dose capsaicin. Webster et al., Journal of Pain, 3(4) S722012 and M. Wallace et al., PainWeek 2014 report about clinical trials with a topical liquid formulation of capsaicin in patients with postherpetic neuralgia.

[0008] High-concentration capsaicin topical cream (8%) has been developed and suggested for the treatment of myofascial pain syndrome. In a placebo-controlled study, patients were asked to point out the most painful trigger point during the physical examination. This trigger was demarcated by a 24 mm diameter circular mold with a stylus for use on the skin. Capsaicin 8% cream was applied in an amount of 10 g for 30 minutes on the demarcated skin area. The authors concluded that capsaicin 8%, as topically applied in patients with myofascial pain syndrome, showed significant analgesic effect. This analgesia persisted for almost two months after a single application without producing significant adverse effects (V. Romero et al., Rev Bras Anestesiol. 2019, 69(5), 432-438).

[0009] High-concentration capsaicin patches are known from e.g. US 2001 00002406, US 6,248,788, US 20040202707 and US 20140335150.

[0010] High-concentration capsaicin patch (179 mg or 8 wt.-%) is commercially available (Qutenza®) with a capsaicin concentration about 100 times greater than conventional creams (see e.g. US 6,239,180). Each 280 cm2cutaneous patch contains a total of 179 mg of capsaicin or 640 micrograms of capsaicin per cm2of patch. Each patch is 14 cm x 20 cm and consists of an adhesive side containing the active substance and an outer surface backing layer. The adhesive side is covered with a removable, clear, unprinted, diagonally cut, release liner. The cutaneous patch is applied to the most painful skin areas (using up to a maximum of 4 patches).

[0011] High-concentration capsaicin patch is indicated for the treatment of peripheral neuropathic pain in the EU and for the treatment of post herpetic neuralgia in the US, in adults either alone or in combination with other medicinal products for their treatment of pain. The efficacy of a single application of high-concentration capsaicin patch has been shown to be maintained for up to 12 weeks in multiple randomized controlled clinical trials. High-concentration capsaicin patch treatment can be repeated approximately every 3 months.

[0012] The 8% capsaicin patch in the management of neuropathic pain has been reviewed by several authors. G. Baranidharan et al., Ther Adv Neurol Disord 2013 6(5) 287-297 review the high-concentration capsaicin patch and experience in its use in the management of neuropathic pain. T. Wagner et al., Pain Medicine 2013 14 1202-1211 provide a retrospective analysis of the capsaicin 8% patch for neuropathic pain in clinical practice. H. A. Blair, Drugs 2018 78 1489-1500 reviews capsaicin 8% dermal patch in the treatment of peripheral neuropathic pain. R. Freynhagen et al., PAIN Reports 10(2):p e1235,3 GRA 4178-foreign filingApril 2025 did a narrative review of the efficacy and safety of the high-concentration (179mg) capsaicin patch in peripheral neuropathic pain with recommendations for clinical practice and future research. C. B. Bumess et al., Drugs (2016) 76: 123-134 is a review about capsaicin 8% patch in peripheral neuropathic pain.

[0013] A. Papagianni et al., PAIN Reports 2018 3 e644 1-9 report that capsaicin 8% patch reversibly reduces A-delta fiber evoked potential amplitudes. P. Anand et al. Journal of Pain Research 2019 12 2039-2052 relates to pain relief and disease modification in rational treatment of chemotherapy-induced peripheral neuropathy with capsaicin 8% patch.

[0014] The 8% capsaicin patch has been subject to various clinical trials. For example, M. Miroslav et al., Pain Medicine 2010 11 600-608 report about a randomized double-blind controlled study with open label extension regarding NGX-4010, a high-concentration capsaicin patch. L. R. Webster et al., Diab Res Clin Pract 2011 93 187-197 report about efficacy, safety and tolerability of NGX-4010 capsaicin 8% patch in an open-label study of patients with peripheral neuropathic pain. D. B. Clifford et al., J Acquir Immune Defic Syndr 2012 59(2) 126-133 report about a randomized double-blind controlled study of NGX-4010, a capsaicin 8% dermal patch for the treatment of painful HIV -associated distal sensory polyneuropathy. S. Brown et al., AIDS Res Ther. 2013 10( 1): 5 report about NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV -associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials. J. M. Raber et al., Acta Neurol Belg (2015) 115:335-343 report about the analgesic effect of capsaicin 8% as a cutaneous patch (Qutenza™) on patients with peripheral neuropathic pain.

[0015] Several clinical trials were focused on the treatment of postherpetic neuralgia. L. R. Webster et al., BMC Neurology 2010 10 92 1-11 report about the effect of duration of postherpetic neuralgia on efficacy analyses in a multicenter randomized controlled study of NGX-4010, an 8% capsaicin patch evaluated for the treatment of postherpetic neuralgia. L. R. Webster et al., The Journal of Pain, 2010 11(10) 972-982 report about a multicenter randomized double-blind controlled dose finding study of NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. G. A. Irving et al., Pain Medicine 2011 12 99-109 relates to a multicenter randomized double-blind controlled study of NGX-4010, a high-concentration capsaicin patch for the treatment of postherpetic neuralgia. L. R. Webster et al., BMC Anesthesiology 2011 11 25 1-8 report about tolerability of NGX-410, a capsaicin 8% dermal patch, following pretreatment with lidocaine 2.5% / prilocaine 2.5% cream in patients with postherpetic neuralgia. M. M. Backonjaetal., Pain Med. 2010 11(4):600-8 report about NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomized, doubleblind, controlled study with an open-label extension.

[0016] C. Maihöfner et al., CMRO 2013 29(6) 673-683 report about the first results of a prospective non-interventional study on the tolerability and analgesic effectiveness over 12 weeks after a single application of capsaicin 8% cutaneous patch in 1044 patients with peripheral neuropathic pain (QUEPP4 GRA 4178-foreign filingstudy). C. Maihöfner et al., Eur J Pain 2014 18 671-679 relates to the impact of pre-existing pain in the QUEPP-study on treatment of peripheral neuropathic pain by topical capsaicin.

[0017] C. Mankowski et al., BMC neurology 2017 17 80 2-11 report about the effectiveness of the capsaicin 8% patch in the management of peripheral neuropathic pain in European clinical practice (ASCEND study).

[0018] It has been reported that the 8% capsaicin patch is particularly useful in the treatment of refractory neuropathic pain syndromes. M. Giménez-Millà et al. BMC Anesthesiology 2014 14 120 1-7 report about the assessment of the feasibility of high-concentration capsaicin patches in the pain unit of a tertiary hospital for a population of mixed refractory peripheral neuropathic pain syndromes in non-diabetic patients. P. Bardo-Brouard et al., Curr Med Res Opin 2018 34(5) 887-891 report about a case series regarding high-concentration topical capsaicin in the management of refractory neuropathic pain in patients with neurofibromatosis type 1. R. Privitera et al., Journal of Pain Research, 2017:10 1623-1634 relates to a clinical and functional MRI study regarding capsaicin 8% patch treatment for amputation stum and phantom limb pain.

[0019] Long-term treatment with high-concentration capsaicin patches have been investigated in open label extension trials to the randomized controlled clinical trials and in two larger stand-alone clinical trials. D. M. Simpson et al., J Pain Sympt Manag 201039(6) 1053-1064 report about long-term safety of NGX-4010, a high-concentration capsaicin patch, in patients with peripheral neuropathic pain. A previous investigation of repeated applications of high-concentration capsaicin patches in a randomized controlled clinical trial of 52 weeks duration in patients with painful diabetic peripheral neuropathy has shown that high-concentration capsaicin patch on top of standard of care treatment demonstrated greater efficacy than standard of care alone (PACE study, A. I. Vinik et al., BMC Neurology 2016 16251 1-14). Likewise in a 52 week trial in non-diabetic peripheral neuropathic pain patients in the subset of patients who received 4 consecutive capsaicin 8% patch treatments (n=100), a reduction in average daily pain was observed after each successive capsaicin and / or capsaicinoid treatment, and pain relief was sustained between treatments (STRIDE study, R. Gálvez et al. Clin J Pain 201733(10) 921-931).

[0020] A problem of conventional treatment of neuropathic pain by topical application of high-concen-tration capsaicin patches has been that a considerable number of patients do not respond. N. P. Katz et al., Clin J Pain 2015 31(10) 859-866 report about predictors of response in patients with postherpetic neuralgia and HIV-associated neuropathy treated with the 8% capsaicin patch (Qutenza®). Ch. Martini et al., Journal of Pain Research 2012 5 51-59 report that treatment of chronic pain is associated with high variability in the response to pharmacological interventions. A mathematical pharmacodynamic model was developed to quantify the magnitude and onset / offset times of effect of a single capsaicin 8% patch application in the treatment of painful diabetic peripheral neuropathy in 91 patients. The model identified four distinct subgroups that responded differently to treatment: 3.3% of patients (subgroup 1) showed worsening of pain; 31% (subgroup 2) showed no change; 32% (subgroup 3) showed a quick5 GRA 4178-foreign filingreduction in pain that reached a nadir in week 3, followed by a slow return towards baseline (16% ± 6% pain reduction in week 12); 34% (subgroup 4) showed a quick reduction in pain that persisted (70% ± 5% reduction in week 12). The analysis allowed separation of a heterogeneous neuropathic pain population into four homogenous subgroups with distinct behaviors in response to treatment with capsaicin.

[0021] Thus, there is a considerable number of patients who do not properly respond to topical treatment with high-concentration capsaicin (e.g. 8% capsaicin patch or cream) such that treatment is terminated.

[0022] R. Freynhagen et al., Pain Medicine, 0(0), 2021,1-3 relates to a comprehensive new analysis and clinical implications regarding progressive response to repeat application of capsaicin 179 mg (8% w / w) cutaneous patch in peripheral neuropathic pain.

[0023] E. Viel et al., Pain Physician 2021; 24:453-463 relates to a comparison of single intervention with topical high-concentration capsaicin to daily oral pregabalin regarding treatment impact on patient-reported outcomes in peripheral neuropathic pain.

[0024] WO 2021 185887 Al relates to treatment, preferably repeated treatment of neuropathic pain by application of one or more high-concentration capsaicin and / or capsaicinoid topical dose units to patients who previously did not respond or insufficiently responded to a previous application of one or more high-concentration capsaicin and / or capsaicinoid topical dose units.

[0025] WO 2021 198524 Al relates to a regimen for treatment, preferably repeated treatment of neuropathic pain comprising a first application of one or more high-concentration capsaicin and / or capsaicinoid topical dose units followed by a second application of one or more high-concentration capsaicin and / or capsaicinoid topical dose units, wherein the time period between the first application and the second application is preferably shortened in order to increase the responder rate.

[0026] WO 2022234064 relates to one or more high-concentration capsaicinoid topical dose units for use in the treatment of a neuropathic condition, preferably neuropathic pain, in a patient who is or who was previously infected with a coronavirus, wherein each of said one or more high-concentration capsaicinoid topical dose units contains capsaicinoid, preferably capsaicin, at a concentration of at least 5 wt.-%, relative to the total weight of the dose unit.

[0027] Another problem of neuropathic pain has been that a considerable number of patients (more than 2 of 3) report sleep disturbances.

[0028] L. Ferini-Strambi, Pain Ther. 2017 Dec;6(Suppl 1): 19-23 reviews neuropathic pain and sleep. It is explained that the relationship between neuropathic pain and sleep disturbances is bidirectional. Patients with neuropathic pain are more likely to develop sleep disorders and in turn pain is exacerbated by the lack and / or poor quality of sleep. A positive association between pain sensitivity and the fre-quency / severity of insomnia and a synergistic reduction of pain tolerance in patients with both chronic pain and insomnia have been reported. A clinical evaluation of neuropathic pain following spinal cord6 GRA 4178-foreign filinginjury should include a sleep assessment. It is also discussed why current treatments are not necessarily helping with the sleep disorders or have significant draw backs.

[0029] H. Antila et al., Pain 165 (2024) 1664-1673 is a topical review on the effects of commonly used analgesics on sleep architecture. It is explained that disturbed sleep is increasingly recognized as a key factor in the development and maintenance of chronic pain and is considered an important target for treatment. Sleep problems and pain share several comorbidities such as anxiety, stress, and depression, resulting in a vicious circle where independent factors may reinforce each other. Evaluated treatments did not include topicals. Regarding the oral treatments, the authors conclude that opioids have a deleterious effect on sleep. Tricyclic antidepressants and gabapentinoids are considered to have beneficial effects on both sleep and pain.

[0030] Administration of a locally active treatment for neuropathic pain with intervals may result in pain relief but not necessarily in sleep improvement. For example, it is known that treating neuropathic pain with Botulinum Toxin A achieves pain relief without significant and consistent reduction of sleep disturbances compared to placebo (see e.g. A. D. Gupta et al., Toxins 2022, 14, 36, 1-14; M. Bayat et al., Anesth Pain Med. 2023 October; 13(5):e 136260).

[0031] US 2021 0386365A1 is related to methods of objectively detecting and measuring neuropathic pain in a subject.

[0032] US 2024 0207205A1 relates compositions in the form of a thermoformed extrudate in any suitable form allowing administration to an animal or a human being, comprising at least one natural or synthetic N-alkylamide as active substance and at least one support of natural origin chosen from the group consisting of amino acids, peptides, polypeptides, proteins, saccharides, lipids, their derivatives and their mixtures.

[0033] J. Elijah et al., Journal of Pain & Palliative Care Pharmacotherapy, 2022, 36(2), 112-116 relates to the efficacy of capsaicin on sleep quality and fatigue in fibromyalgia. Two studies were analyzed that met criteria and included 175 patients that received either capsaicin or placebo for an average total treatment length of 5weeks. Both studies demonstrate no changes in sleep quality. The authors conclude that existing evidence is insufficient to warrant recommending capsaicin as adjunctive therapy for improvement in sleep quality and fatigue.

[0034] V. M. Kumar et al., Sleep and Vigilance (2022) 6:41-49 relates to the role of capsaicin receptors in sleep regulation.

[0035] M. Fu et al., Neuroscience 565 (2025) 589-593 review the roles of TRPV1 receptors in nervous systems with a special emphasis on sleep and memory.

[0036] There is a demand for medicaments that are useful for treating neuropathic pain and that reduce sleep disturbances.7 GRA 4178-foreign filing

[0037] It is known that sleep and pain are interlinked. It has been shown previously that sleep can improve with oral administration of centrally active medicaments. But also because of their central activity, these medicaments often have side effects.

[0038] It has been reported that daily treatment with topical analgesics (without systemic absorption) may also improve sleep (see A. Binder et al., Pain Manag. 2016;6(3):229-39).

[0039] It is an object of the invention to provide medicaments that have advantages compared to the prior art. The medicaments should preferably be useful for treating sleep disturbances in patients having neuropathic pain. The medicaments should preferably be useful for treating neuropathic pain in patients having sleep disturbances. The medicaments should preferably be useful for treating both, neuropathic pain and sleep disturbances.

[0040] This object has been achieved by the subject-matter of the patent claims.SUMMARY OF THE INVENTION

[0041] A first aspect of the invention relates to one or more high-concentration capsaicin and / or capsa-icinoid topical dose units comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, preferably at least 5 wt.-%, relative to the total weight of dose unit; preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, preferably at least 5 wt.-%, relative to the total weight of the patch without release liner; for use(i) in the prevention or treatment of a sleep disturbance, preferably in a patient having neuropathic pain; and / or(ii) in the prevention or treatment of neuropathic pain in a patient having a sleep disturbance; and / or (iii) in the prevention or treatment of neuropathic pain in a patient having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance.

[0042] A study unexpectedly showed that patients receiving treatment according to the invention had improvement of sleep disability based on the modified pain disability index (mPDI and mPDI subscale #6).

[0043] It has been unexpectedly found for the first time for a topical treatment (i.e. treatment with limited systemic absorption) used intermittently (i.e. used with intervals of at least 60 days) that (a) sleep can be durably improved, (b) sleep improves independent from improvement in pain, (c) sleep deteriorates when the treatment is not continued, (d) sleep can be improved by using a topical product that is used intermittently, and (e) concomitant analgesic treatments with central activity including sleep can be decreased. This effect is independent of the etiology (pDPN, PHN, PNI).8 GRA 4178-foreign filing

[0044] Clinical data demonstrate that pain and sleep parameters improve to the same extent with a high concentration capsaicin patch. Moreover when treatment is discontinued, a worsening of sleep parameters as well as pain ratings occurred. The clinical data also show that in patients with neuropathic pain across several etiologies (pDPN, PHN, PNI), concomitant medication use is decreased when high concentration capsaicin patch is used regularly with intervals of minimum 60 days, and is increased when high concentration capsaicin patch is stopped. Clinical data show that with topical high concentration capsaicin patch treatment both sleep and pain improve at the same time demonstrating that sleep improvement is not a result of pain improvement. This independence is reinforced by the finding that both deteriorate when treatment is stopped.

[0045] In preferred embodiments, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are for use in the treatment of a sleep disturbance, preferably in a patient having neuropathic pain.

[0046] In other preferred embodiments, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are for use in the treatment of neuropathic pain in a patient having a sleep disturbance.

[0047] In further preferred embodiments, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are for use in the treatment of neuropathic pain in a patient having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance.

[0048] In still further preferred embodiments, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are for use in the treatment of both, a sleep disturbance and neuropathic pain, in a patient having a sleep disturbance and neuropathic pain.

[0049] In yet further preferred embodiments, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are for use in the treatment of both, a sleep disturbance and neuropathic pain, in a patient having a sleep disturbance and neuropathic pain and having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics.

[0050] In other further preferred embodiments, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are for use in the treatment of neuropathic pain, in a patient having a sleep disturbance and neuropathic pain, and having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics.

[0051] In preferred embodiments, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are for use in the treatment of both, a sleep disturbance and neuropathic pain, in a9 GRA 4178-foreign filingpatient having a sleep disturbance and neuropathic pain, wherein said patient has been treated previously and / or is treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics.DETAILED DESCRIPTION OF THE INVENTION

[0052] Preferably, the treatment is for preventing or treating (i) a sleep disturbance.

[0053] Sleep disturbances are a group of conditions that disturb normal sleep patterns. For the purpose of the specification, a "sleep disturbance" is synonymous to a "sleep disorder", a "sleep disability" according to the modified pain disability index (mPDI and mPDI subscale #6), and to a "sleep-wake disorder" according to WHO ICD-11. Other indices that are suitable to characterize a "sleep disturbance" according to the invention include but are not limited to the Pittsburgh Sleep Quality Index, the Athens Insomnia Scale, the Insomnia Severity Index, the Mini-Sleep Questionnaire, the Jenkins Sleep Scale, the Leeds Sleep Evaluation Questionnaire, the SLEEP-50 Questionnaire, and the Epworth Sleepiness Scale (see e.g. M. Fabbri et al., Int. J. Environ. Res. Public Health 2021, 18, 1082).

[0054] A "sleep disturbance" according to the invention encompasses any condition, disorder or disease that is characterized by difficulty initiating or maintaining sleep (insomnia disorders), excessive sleepiness (hypersomnolence disorders), respiratory disturbance during sleep (sleep-related breathing disorders), disorders of the sleep–wake schedule (circadian rhythm sleep-wake disorders), abnormal movements during sleep (sleep-related movement disorders), or problematic behavioral or physiological events that occur while falling asleep, during sleep, or upon arousal from sleep (parasomnia disorders).

[0055] In preferred embodiments, the sleep disturbance is associated with the neuropathic pain.

[0056] In other preferred embodiments, the sleep disturbance is not associated with the neuropathic pain.

[0057] Preferably, the sleep disturbance is selected from disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence, disorders of sleep–wake schedule, and dysfunctions associated with sleep, sleep stages, or partial arousals (parasomnia).

[0058] Preferably, the sleep disturbance is selected from dyssomnia, insomnia, parasomnia and hypersomnia; preferably dyssomnia, insomnia; more preferably dyssomnia.

[0059] Preferably, the sleep disturbance includes impaired initiation of sleep.

[0060] Preferably, the sleep disturbance includes impaired quantity of sleep.

[0061] Preferably, the sleep disturbance includes impaired maintenance of sleep.

[0062] Preferably, the sleep disturbance includes respiratory problems; preferably shortness of breath.

[0063] Preferably, the sleep disturbance includes impaired perceived adequacy of sleep.

[0064] Preferably, the sleep disturbance includes daytime somnolence.10 GRA 4178-foreign filing

[0065] Preferably, the patient has a baseline modified pain disability index (mPDI-6, mPDI subscale #6) sleep score (mm VAS) of at least 25, preferably at least 30, more preferably at least 35, still more preferably at least 40, yet more preferably at least 45, even more preferably at least 50, most preferably at least 55, and in particular at least 60.

[0066] Preferably, the treatment is for preventing or treating (ii) neuropathic pain, preferably peripheral neuropathic pain.

[0067] Preferably, the neuropathic pain includes painful diabetic neuropathy.

[0068] Preferably, the neuropathic pain includes postherpetic neuralgia.

[0069] Preferably, the neuropathic pain includes peripheral nerve injury.

[0070] Preferably, the neuropathic pain includes chemotherapy-induced neuropathic pain.

[0071] Preferably, the neuropathic pain includes HIV-associated neuropathy.

[0072] Preferably, the neuropathic pain includes small-fiber neuropathy.

[0073] Preferably, the neuropathic pain includes chronic idiopathic axonal polyneuropathy.

[0074] Preferably, the neuropathic pain includes post-traumatic neuropathic pain.

[0075] Preferably, the neuropathic pain includes post-surgical neuropathic pain.

[0076] Preferably, the neuropathic pain is moderate to severe.

[0077] Preferably, the neuropathic pain is chronic.

[0078] Preferably, the treatment of the neuropathic pain is for regenerating and / or restoring sensory nerve fibers.

[0079] Preferably, the treatment of the neuropathic pain is for increasing pain relief to more than 30% versus baseline, preferably at least 60% versus baseline, preferably on the NRS pain rating scale.

[0080] Preferably, the patient to be treated is a human.

[0081] In preferred embodiments, the patient is a female patient.

[0082] In other preferred embodiments, the patient is a male patient.

[0083] Preferably, the patient is an adult.

[0084] Preferably, the patient is a geriatric patient.

[0085] Preferably, the age of the patient is at least 60 years.

[0086] Preferably, the patient has previously been treated with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance.11 GRA 4178-foreign filing

[0087] Preferably, the patient is concomitantly being treated with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance.

[0088] Preferably, the analgesic medication for relief of neuropathic pain has been or is administered systemically, preferably orally or transdermally.

[0089] Preferably, the analgesic medication for relief of neuropathic pain has been or is administered at least once daily.

[0090] Preferably, the analgesic medication for relief of neuropathic pain is an antiepileptic. For the purpose of the specification, "antiepileptics" include but are not limited to carbamazepine, clonazepam, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, and valproate; preferably gabapentin and pregabalin.

[0091] Preferably, the analgesic medication for relief of neuropathic pain is an antidepressant. For the purpose of the specification, "antidepressants" include but are not limited to amitriptyline, clomipramine, desipramine, doxepin, duloxetine, imipramine, nortriptyline, venlafaxine, mirtazapine, and protriptyline; preferably amitriptyline and duloxetine.

[0092] Preferably, the analgesic medication for relief of neuropathic pain is an opioid analgesic. For the purpose of the specification, "opioid analgesics" include but are not limited to buprenorphine, fentanyl, hydromorphone, hydrocodone, methadone, morphine, oxycodone, oxymorphone, tapentadol, and tramadol; preferably tapentadol and fentanyl.

[0093] Preferably, the treatment of the neuropathic pain is for converting a non-responder with respect to previous topical administration of capsaicin and / or capsaicinoid into a responder.

[0094] In preferred embodiments, the invention relates to the treatment of a patient who upon previous topical administration of capsaicin and / or capsaicinoid, preferably by means of one or more high-con-centration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, preferably at least 5 wt.-%, relative to the total weight of dose unit; preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, preferably at least 5 wt.-%, relative to the total weight of the patch without release liner; did not perceive pain relief by at least 30% versus baseline, preferably on the NRS pain rating scale.

[0095] By continued (e.g. repeated) topical administration of capsaicin to patients who did not or did not sufficiently respond to initial topical administration of capsaicin (initial non-responders), these patients become responsive to capsaicin treatment overtime, i.e. are converted from initial non-responders to responders.

[0096] Repeat application also to initial non-responders provides additional benefit to patients. Across trials, more than one third of initial non-responders converted into responders upon treatment, preferably12 GRA 4178-foreign filingrepeated treatment with high-concentration capsaicin dose units (patches). Although at month 12, the responder rates in patients who initially did not or did not sufficiently respond to high-concentration capsaicin and / or capsaicinoid dose units (patches) were approximately 10% lower than in the overall population, the substantial increase in responder rates in those who initially did not respond, justifies a repeat treatment.

[0097] Furthermore, patients who have a lower initial response and receive a second application sooner (i.e. with a treatment interval < 84 days), will proportionally benefit more from a 2nd application than those who had a better initial response and were re-treated later.

[0098] In order for capsaicin to exert its effect, it is assumed that the TRPV1 receptor is functioning. If nerves are not expressing functional TRPV1 receptors logically capsaicin cannot exert its effect. It can therefore be reasonably assumed that in a subset of patients that is not responding to capsaicin this receptor is not functioning sufficiently well to generate a response. As a result it is surprising that nerves not expressing sufficiently functioning TRPV1 receptors, can turn into nerves sufficiently expressing functioning TRPV 1 receptors after a first or second application of capsaicin even if this application was not successful during a first or second administration to activate the receptors in such a way that a clinical response could be obtained.

[0099] The one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention contain capsaicin {i.e. (E)-8-methyl-N-vanillyl-6-nonenamide, trans-8-methyl-N-vanillyl-6-nonen-amide, 6-nonenamide, (E)-N-[(4-hydroxy-3-methoxyphenyl) methyl]-8-methyl} and / or one or more capsaicinoids. Capsaicin itself is sometimes regarded as a capsaicinoid. For the purpose of the specification, however, capsaicin is no capsaicinoid.

[0100] For the purpose of the specification "capsaicin and / or capsaicinoid" means either (i) capsaicin or (ii) capsaicinoid or (iii) capsaicin and capsaicinoid, whereas in each case capsaicinoid may be a single capsaicinoid or any combination of capsaicinoids with one another. Unless expressly stated otherwise, all weights and percentages refer to the total amount of all capsaicin and / or capsaicinoid that is present.

[0101] Capsaicinoids are known to the skilled person and commercially available. Preferred capsaicinoids according to the invention include but are not limited to zucapsaicin (cis-capsaicin, Civamide), (6,7-)dihydrocapsaicin, norcapsaicin, nordihydrocapsaicin I, nordihydrocapsaicin II, homocapsaicin I, homocapsaicin II, homodihydrocapsaicin I, homodihydrocapsaicin II, nomorcapsaicin, nomordihydro-capsaicin, octanoyl vanillylamide, nonanoyl vanillylamide (Nonivamide), decanoyl vanillylamide, and mixtures thereof.

[0102] Capsaicin and capsaicinoids are N-acyl derivatives of vanillylamine having different acyl chains R, as shown here below:13 GRA 4178-foreign filingTrivial names R =Capsaicin (trans) -(E)-(CH2)4-CH=CH-CH(CH3)2Zucapsaicin, cis-capsaicin, Civamide -(Z)-(CH2)4-CH=CH-CH(CH3)2(6,7-)Dihydrocapsaicin -(CH2)6-CH(CH3)2Norcapsaicin -(CH2)3-CH=CH-CH(CH3)2Nordihydrocapsaicin I -(CH2)5-CH(CH3)2Nordihydrocapsaicin II (ante iso) -(CH2)4-CH(CH3)-CH2CH3Homocapsaicin I -(CH2)4-CH=CH-CH2CH(CH3)2Homocapsaicin II (ante iso) -(CH2)4-CH=CH-CH(CH3)-CH2CH3Homodihydrocapsaicin I -(CH2)7-CH(CH3)2Homodihydrocapsaicin II (anteiso) -(CH2)6-CH(CH3)-CH2CH3Nomorcapsaicin -(CH2)2-CH=CH-CH(CH3)2Nomordihydrocapsaicin -(CH2)4-CH(CH3)2Octanoyl vanillylamide -(CH2)6-CH3Nonanoyl vanillylamide, Nonivamide -(CH2)7-CH3Decanoyl vanillylamide -(CH2)8-CH3

[0103] In a preferred embodiment, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention contain capsaicin but essentially no capsaicinoid.

[0104] For the purpose of the specification, a "dose unit" is defined as a predetermined quantity of a pharmaceutical formulation containing a high-concentration of capsaicin and / or capsaicinoid for topical application to the skin of a patient.

[0105] For example, when the pharmaceutical formulation is a cream provided in a dispensing device (e.g. tube), a dose unit according to the invention may be e.g. a strand of cream of predetermined length taken from the dispensing device. Said strand of cream of predetermined length contains a predetermined dose of capsaicin and / or capsaicinoid which, when the strand of cream is applied to and spread over the painful skin of the patient, is partially administered to the patient. A skilled person recognizes that various topical systems such as creams, gels, ointments and other liquid or semisolid formulations may be applied to the skin at various thicknesses so that the applied dose per area of skin, e.g. expressed in terms of μg / cm2, may vary. However, as the dose unit is typically applied to the skin for a comparatively short application period of time before it is removed, e.g. 15 to 90 minutes, preferably 30 to 60 minutes, these potential variations in thickness will typically not significantly alter the administered dose of capsaicin and / or capsaicinoid. Typically, within such comparatively short application periods, less than 100% of the capsaicin and / or capsaicinoid that was originally contained in the dose units will14 GRA 4178-foreign filingbe administered, whereas a significant quantity of capsaicin and / or capsaicinoid will be removed along with the remainder of the dose unit at the end of the application period.

[0106] Likewise, when the pharmaceutical formulation is provided in form of a topical patch, a dose unit according to the invention may be a patch that is optionally cut to match the size and shape of the treatment area. Said patch contains a predetermined dose of capsaicin and / or capsaicinoid which, when the patch is applied to the painful skin of the patient, is partially administered to the patient.

[0107] Irrespective of the type of pharmaceutical formulation (e.g. cream, gel, ointment, or patch), the one or more topical dose units according to the invention contain a comparatively high-concentration of capsaicin and / or capsaicinoid of at least 2.5 wt.-%, preferably at least 5 wt.-%, preferably at least 6.0 wt.-%, more preferably at least 7.0 wt.-%, most preferably at least or about 8.0 wt.-%, relative to the total weight of the dose units.

[0108] For the purpose of the specification, unless expressly stated otherwise, "high-concentration capsaicin and / or capsaicinoid topical dose unit" refers to a dose unit comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, preferably at least 5 wt.-%, preferably at least or about 8 wt.-%, relative to the total weight of dose unit and relative to the total amount of capsaicin and / or capsaicinoid.

[0109] Preferably, the high-concentration capsaicin and / or capsaicinoid topical dose unit according to the invention contains capsaicin and / or capsaicinoid in an amount such that when the topical dose unit is applied to the skin of the patient in the prescribed manner, the applied area concentration is at least 400 micrograms of capsaicin and / or capsaicinoid per cm2of topical dose unit, more preferably at least 500 micrograms of capsaicin and / or capsaicinoid per cm2of topical dose unit, still more preferably at least 600 micrograms of capsaicin and / or capsaicinoid per cm2of topical dose unit, most preferably at least or about 640 micrograms of capsaicin and / or capsaicinoid per cm2of topical dose unit.

[0110] A high-concentration capsaicin and / or capsaicinoid topical dose unit according to the invention is not particularly limited and can be any topical system.

[0111] According to Annex A of FDA Guidance for Industry, Product Title and Initial U. S. Approval in the Highlights of Prescribing Information for Human Prescription Drug and Biological Products — Content and Format, January 2018, the term "system" is used for a drug -containing delivery system that controls the release rate of the drug product from the system by diffusion kinetics, active transport, or other means. The activity is defined in terms of the release rate of the active ingredient(s) from the system over a stated period of time. The rate of release and the total duration of drug release typically appear on the drug product and on the container label and carton labeling, but not on the product title line. Exemplified systems include intrauterine systems, ocular systems, oral mucosal systems, periodontal systems, topical systems, transdermal systems, iontophoretic transdermal systems, and vaginal systems. The high-concentration capsaicin and / or capsaicinoid topical dose unit according to the invention is preferably a "topical system" according to this meaning.15 GRA 4178-foreign filing

[0112] Preferred topical dose units (topical systems) according to the invention include but are not limited to patches (e.g. matrix patches, drug-in adhesive patches, iontophoresis systems), solutions, suspensions, lotions, liniments, creams, ointments, salves, pastes, gels (e.g. hydrogels, lipogels, poly(vinyl alcohol) semi-solid hydrogels), sprays, aerosols, foams, liposome formulations (e.g. liposome systems, liposphere systems, niosomal formulations, drug-in-cyclodextrin-in-deformable liposomes), nanostructured formulations (e.g. nanostructured lipid carrier (NLC)-based gels, nanoemulgels), biodegradable drug platforms (e.g. composed of chitosan and guar gum), and the like.

[0113] In preferred embodiments, the high-concentration capsaicin and / or capsaicinoid topical dose unit according to the invention is selected from aerosols (i.e. topical aerosols), creams, foams (i.e. topical foams), gels (i.e. topical gels), lotions, ointments, pastes, powders (i.e. topical powders), solutions (i.e. topical solutions), sprays (i.e. topical sprays), suspensions (i.e. topical suspensions), swabs, and systems (i.e. topical systems); preferably all in accordance with Annex A of FDA Guidance for Industry, Product Title and Initial U. S. Approval in the Highlights of Prescribing Information for Human Prescription Drug and Biological Products — Content and Format, January 2018.

[0114] The high-concentration capsaicin and / or capsaicinoid topical dose units according to the invention may be provided in form of application aids such as impregnated gauzes, impregnated wipes, impregnated sponges, impregnated fabrics (e.g. woven, non-woven, knit). The high-concentration capsaicin and / or capsaicinoid topical dose units according to the invention may be provided in form of application devices or dispensing devices such as spray dispenser, foam dispenser, sticks, roll-ons, smooth-ons, and the like. Low -concentration capsaicin roll-ons are commercially available e.g. under the trade-name arth Rx®, Reliaderm®, mintedLeaf®.

[0115] Preferred high-concentration capsaicin and / or capsaicinoid topical dose units according to the invention comprise capsaicin and / or capsaicinoid and one or more additives selected from hyaluronic acids, surfactants, penetration enhancers, alcohols. Topical dose units of this type are known from US 9,956,190, US 10,085,956, US 10,206,892, and US 10,583,100. Preferably, the hyaluronic acid is a mixture of two hyaluronic acids having different molecular weights, preferably high and low. Preferably, the surfactant is a nonionic surfactant, wherein the nonionic surfactant is preferably selected from polysorbates such as polysorbate 80, Cremophor® RH 40 (polyoxy 40 hydrogenated castor oil), sorbitan esters (Spans), poloxamers, cetyl alcohol, cetostearyl alcohol, polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, stearyl alcohol etc. Polysorbate 80 (PS 80) and polyox 40 hydrogenated castor oil are particularly preferred. Preferably, the penetration enhancer is selected from glycol monoethyl ether (DGME), propylene glycol, ethoxydiglycol, and dimethyl isosorbide. DGME and propylene glycol are particularly preferred. Preferably, the alcohol is selected from ethyl alcohol, benzyl alcohol, glycerol, propanol, isopropyl alcohol, polyethylene glycol, polyethylene glycols, etc. Ethyl alcohol (ethanol) is particularly preferred.16 GRA 4178-foreign filing

[0116] Preferably, the high-concentration capsaicin and / or capsaicinoid topical dose unit according to the invention in each case is a high-concentration capsaicin and / or capsaicinoid pharmaceutical patch comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, preferably at least 5 wt.-%, preferably at least 6.0 wt.-%, more preferably at least 7.0 wt.-%, most preferably at least or about 8.0 wt.-%, relative to the total weight of the patch without release liner.

[0117] For the purpose of the specification, unless expressly stated otherwise, "high-concentration capsaicin and / or capsaicinoid pharmaceutical patch" refers to a pharmaceutical patch comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, preferably at least 5 wt.-%, preferably at least or about 8 wt.-%, relative to the total weight of the patch without release liner.

[0118] Preferably, the one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches each comprise a backing layer, an adhesive layer, and a release liner; and wherein the content of capsaicin and / or capsaicinoid is at least 2.5 wt.-%, preferably at least 5 wt.-%, more preferably at least 6.0 wt.-%, still more preferably at least 7.0 wt.-%, most preferably at least or about 8.0 wt.-%, relative to the total weight of a pharmaceutical patch without release liner. Preferably, the capsaicin and / or capsaicinoid is contained in the adhesive layer (drug -in-adhesive).

[0119] For the purpose of the specification, a high-concentration capsaicin and / or capsaicinoid pharmaceutical patch comprising a backing layer, an adhesive layer, and a release liner; wherein the content of capsaicin and / or capsaicinoid is about 8.0 wt.-%, relative to the total weight of a pharmaceutical patch without release liner, is also referred to as "8% capsaicin and / or capsaicinoid patch".

[0120] Preferably, the one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches are cutaneous patches containing at least 400 micrograms of capsaicin and / or capsaicinoid per cm2of patch, more preferably at least 500 micrograms of capsaicin and / or capsaicinoid per cm2of patch, still more preferably at least 600 micrograms of capsaicin and / or capsaicinoid per cm2of patch, most preferably at least or about 640 micrograms of capsaicin and / or capsaicinoid per cm2of patch.

[0121] Preferably, the one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches are cutaneous patches each containing 640 micrograms of capsaicin and / or capsaicinoid per cm2of patch and having an area of 280 cm2(14 cm x 20 cm) such that each patch contains a total of 179 mg of capsaicin and / or capsaicinoid. Preferably, each high-concentration capsaicin and / or capsaicinoid pharmaceutical patch consists of an adhesive side containing the active substance and an outer surface backing layer. The adhesive side is preferably covered with a removable release liner. Preferably, the adhesive side is composed of a matrix comprising capsaicin and / or capsaicinoid, silicone adhesives, diethylene glycol monoethyl ether, silicone oil and ethylcellulose. Preferably, the surface backing layer is composed of a polyethylene terephthalate film with siliconized inner side. Preferably, the removable protective layer (release liner) is composed of a polyester film coated with a fluoropolymer. High-con-centration capsaicin pharmaceutical patches of this type (8% capsaicin patches) are commercially available under the tradename Qutenza®.17 GRA 4178-foreign filing

[0122] Preferably, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are not permanently applied to the skin of the patient but only for a comparatively short application period that is needed in order to topically administer capsaicin and / or capsaicinoid from the one or more dose units and patches, respectively, into the patient's skin. Administration is topical, penetration of capsaicin and / or capsaicinoid is intradermally and preferably not systemically.

[0123] The one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are preferably for single use.

[0124] When the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention are provided in form of one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, said patches are preferably cut to match the size and shape of the treatment area. Preferably, the one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches are cut prior to removal of the release liner. When treating feet, the one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches are preferably wrapped around the dorsal, lateral and plantar surfaces of each foot to completely cover the treatment area.

[0125] Preferably, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are applied to the skin of the patient for an application period of 15 to 90 minutes, preferably 30 to 60 minutes, and subsequently removed.

[0126] Preferably, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are applied to the most painful skin areas (using up to a maximum of 4 high-concentration capsaicin and / or capsaicinoid dose units and high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, respectively). For the purpose of the specification, applying "one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches to the skin" refers to simultaneous or essentially simultaneous use of 1, 2, 3 or 4 high-concentration capsaicin and / or capsaicinoid dose units and high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, respectively, preferably 1, 2, 3 or 4 8% capsaicin and / or capsaicinoid patches. More than a single high-con-centration capsaicin and / or capsaicinoid pharmaceutical patch may be needed because the area of the skin of the patient to be covered with a high-concentration capsaicin and / or capsaicinoid pharmaceutical patch is larger than can be covered with a single high-concentration capsaicin and / or capsaicinoid pharmaceutical patch.18 GRA 4178-foreign filing

[0127] The painful area is preferably determined by the physician and marked on the skin. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are preferably applied to intact, non-irritated, dry skin, and allowed to remain in place for an application period of 15 to 45 minutes, preferably 30 minutes for the feet (e.g. for treating HlV-associ-ated neuropathy, painful diabetic peripheral neuropathy) and for an application period of 45 to 75 minutes, preferably 60 minutes for other locations (e.g. for treating postherpetic neuralgia). In case of high-concentration pharmaceutical patches, they are preferably first cut to match the size and form of the painful area of the skin, and subsequently applied to the skin.

[0128] For the purpose of the specification, unless expressly stated otherwise, "application period" preferably refers to a period of 15 to 90 minutes, preferably 30 to 60 minutes, during which the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches are applied to the skin of the patient before they are removed.

[0129] Application periods shorter than 15 minutes and longer than 90 minutes are also contemplated according to the invention.

[0130] When the concentration of capsaicin and / or capsaicinoid in the high-concentration capsaicin and / or capsaicinoid topical dose unit (topical systems) according to the invention is particularly high, e.g. greater than 8 wt.-%, relative to the total weight of the dose unit, application periods shorter than 15 minutes may be sufficient in order to topically administer the desired dose of capsaicin and / or capsaicinoid.

[0131] When the concentration of capsaicin and / or capsaicinoid in the high-concentration capsaicin and / or capsaicinoid topical dose unit (topical systems) according to the invention is particularly low, e.g. below 8 wt.-%, relative to the total weight of the dose unit, application periods longer than 90 minutes may be required in order to topically administer the desired dose of capsaicin and / or capsaicinoid. Under these circumstances, it is also contemplated to apply several high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention having a capsaicin and / or capsaicinoid concentration below 8 wt.-%, relative to the total weight of the dose unit, repeatedly on several consecutive days, each dose unit for an application period of 15 to 90 minutes, preferably 30 to 60 minutes. For example, it is contemplated to apply assigned doses for 60 minutes on each of four consecutive days.

[0132] The capsaicin and / or capsaicinoid contained in the high-concentration topical dose unit (topical system) according to the invention is intended for delivery into the skin. For any high-concentration topical dose unit the administered dose of capsaicin and / or capsaicinoid from the high-concentration topical dose unit (topical system) is a function of the application period (application time), whereas depending upon the individual formulation, the rate of release may be linear of change over time. The19 GRA 4178-foreign filingindividual rate of release and other pharmacokinetic parameters can be determined by routine experiments that are well acknowledged in the art (active substance dissolution and skin permeation assays). For example, based on in vitro studies with Qutenza® (capsaicin concentration 8 wt.-%, 640 μg of capsaicin per cm2of patch), approximately 1% of capsaicin is estimated to be absorbed into the epidermal and dermal layers of skin during one-hour applications (i.e. about 6.4 μg·cm-2).

[0133] Preferably, the application period is adjusted such that depending upon the individual properties of the high-concentration topical dose unit (type, concentration of capsaicin and / or capsaicinoid, excipients such as penetration enhancers, rate of release, etc.) the dose of capsaicin and / or capsaicinoid per area of skin that is actually administered during the application period is at least 4.0 μg·cm-2, more preferably at least 4.5 μg·cm-2, still more preferably at least 5.0 μg·cm-2, even more preferably at least 5.5 μg·cm-2, most preferably at least 6.0 μg·cm-2.

[0134] After removal of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches from the skin, a cleansing gel is preferably applied liberally to the treatment area and left on for at least one minute. The cleansing gel is then preferably be wiped off with dry gauze to remove any remaining capsaicin and / or capsaicinoid from the skin. After the cleansing gel has been wiped off, the area of the skin is preferably gently washed with soap and water. A suitable cleansing gel may contain macrogol 300, carbomer, purified water, sodium hydroxide, disodium edetate, and butyl hydroxy anisole.

[0135] Preferably, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are applied to the skin of the patient, remain on the skin for an application period thereby topically administering capsaicin and / or capsaicinoid during the application period, and are subsequently removed. In preferred embodiments, as a consequence of topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient preferably perceives pain relief by at least 30% versus baseline, on either the VAS or the NRS pain rating scale, preferably the NRS pain rating scale. It may take between 1 to 3 weeks from the application period until onset of analgesia.

[0136] Further, it may take repeated application of one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, until an initial non-responder converts into a responder.

[0137] A single application of one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches typically results in a treatment period of 60 to 90 days20 GRA 4178-foreign filingor even longer, depending upon the duration of the therapeutic effect that is achieved by such single application.

[0138] Repeated application of one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches typically results in an extended treatment period depending upon the number of repetitions. Typically, each repetition extends the treatment period by another 60 to 90 days or even longer, depending upon the duration of the therapeutic effect that is achieved by such repeated application.

[0139] After application periods of e.g. 15 to 90 minutes, preferably 30 to 60 minutes, topical administration has been effected so that the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are preferably removed from the skin. When proceeding this way, after removal from the skin, as a consequence of the administered dose of capsaicin and / or capsaicinoid, treatment of (i) the sleep disturbance and / or (ii) the neuropathic pain may last for up to 90 days or even longer.

[0140] Preferably, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are applied to the skin of the patient, remain on the skin for an application period thereby topically administering capsaicin and / or capsaicinoid during the application period, and are subsequently removed. In preferred embodiments, as a consequence of topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient preferably perceives pain relief by at least 30% versus baseline for a period of at least 4 weeks, more preferably at least 6 weeks, still more preferably at least 8 weeks. As it may take between 1 to 3 weeks from the application period until onset of analgesia, the period of pain relief does not necessarily commence immediately after the application period.

[0141] Subsequent application of one or more another high-concentration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more another high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, may be preferably repeated after 2 to 4 months, preferably after 2 months or after 3 months, e.g. every 60 days or every 90 days.

[0142] In preferred embodiments, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are used for long term treatment.

[0143] Preferably, when the patient has been treated previously and / or is treated concomitantly with an analgesic medication for relief of neuropathic pain, the administered dose of said analgesic medication is decreased or terminated in the course of long term treatment.21 GRA 4178-foreign filing

[0144] In preferred embodiments, after 12 months of long term treatment according to the invention, the administered dose, preferably the average weekly dose of said analgesic medication is lower than the dose, preferably average weekly dose of said analgesic medication that was administered before long term treatment according to the invention was commenced. Preferably, after 12 months of long term treatment according to the invention, the administered dose, preferably the average weekly dose of said analgesic medication is at most 80%, preferably at most 70%, more preferably at most 60%, still more preferably at most 50%, yet more preferably at most 40%, even more preferably at most 30%, most preferably at most 20%, and in particular at most 10% of the dose, preferably average weekly dose of said analgesic medication that was administered before long term treatment according to the invention was commenced.

[0145] In other preferred embodiments, after 12 months of long term treatment according to the invention, the administered dose, preferably the average weekly dose of said analgesic medication is lower than the dose, preferably average weekly dose of said analgesic medication that was administered during the interval after initial first application of one or more high-concentration capsaicin and / or capsaicinoid dose units according to the invention and before the first subsequent application of one or more another high-concentration capsaicin and / or capsaicinoid dose units according to the invention. Preferably, after 12 months of long term treatment according to the invention, the administered dose, preferably average weekly dose of said analgesic medication is at most 80%, preferably at most 70%, more preferably at most 60%, still more preferably at most 50%, yet more preferably at most 40%, even more preferably at most 30%, most preferably at most 20%, and in particular at most 10% of the dose, preferably average weekly dose of said analgesic medication that was administered during the interval after initial first application of one or more high-concentration capsaicin and / or capsaicinoid dose units according to the invention and before the first subsequent application of one or more another high-concentration capsaicin and / or capsaicinoid dose units according to the invention.

[0146] Preferably, after 12 months of long term treatment according to the invention, said analgesic medication is not administered any longer, i.e. administration thereof is terminated at some point in time in the course of long term treatment according to the invention, i.e. after 12 months or earlier.

[0147] For the purpose of long term treatment, subsequent application of one or more another high-concentration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more another high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, is preferably repeated more than once, preferably at least three times, at least four times, at least five times, at least six times, at least seven times, at least eight times, or even more frequently, in each case independently of one another 2 to 4 months after the preceding application, preferably after 2 months or after 3 months, e.g. every 60 days or every 90 days.

[0148] For example,22 GRA 4178-foreign filing- an initial first application of one or more high-concentration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, may be performed thereby commencing a treatment period;- 2 to 4 months after the preceding first application, preferably after 2 months or after 3 months, e.g. after 60 days or after 90 days, a subsequent second application of one or more another high-concen- tration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more another high-concentration capsaicin and / or capsaicinoid pharmaceutical patches may be performed thereby continuing the treatment period;- 2 to 4 months after the preceding second application, preferably after 2 months or after 3 months, e.g. after 60 days or after 90 days, a subsequent third application of one or more another high-con- centration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more another high-concentration capsaicin and / or capsaicinoid pharmaceutical patches may be performed thereby continuing the treatment period;- optionally, 2 to 4 months after the preceding third application, preferably after 2 months or after 3 months, e.g. after 60 days or after 90 days, a subsequent fourth application of one or more another high-concentration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more another high-concentration capsaicin and / or capsaicinoid pharmaceutical patches may be performed thereby continuing the treatment period;- optionally, 2 to 4 months after the preceding fourth application, preferably after 2 months or after 3 months, e.g. after 60 days or after 90 days, a subsequent fifth application of one or more another high-concentration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more another high-concentration capsaicin and / or capsaicinoid pharmaceutical patches may be performed thereby continuing the treatment period; and- optionally, 2 to 4 months after the preceding fifth application, preferably after 2 months or after 3 months, e.g. after 60 days or after 90 days, a subsequent sixth application of one or more another high-concentration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more another high-concentration capsaicin and / or capsaicinoid pharmaceutical patches may be performed thereby continuing the treatment period.

[0149] Long term treatment preferably lasts at least 6 months, preferably at least 9 months, more preferably at least 12 months, still more preferably more than 1 year, yet more preferably at least 15 months, even more preferably at least 18 months, most preferably at least 21 months, and in particular at least 24 months.

[0150] Preferably, the last subsequent application of one or more another high-concentration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more another high-concen-tration capsaicin and / or capsaicinoid pharmaceutical patches is performed at least 6 months, preferably23 GRA 4178-foreign filingat least 9 months, more preferably at least 12 months, still more preferably more than 1 year, yet more preferably at least 15 months, even more preferably at least 18 months, most preferably at least 21 months, and in particular at least 24 months after the initial first application commencing the treatment period.

[0151] In a preferred embodiment, in each case independently of one another subsequent application of one or more another high-concentration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more another high-concentration capsaicin pharmaceutical patches, is repeated after 2 to 3 months, preferably after less than 90 days, more preferably after less than 84 days, still more preferably after 2 months, e.g. every 60 days.

[0152] It has been found that the response rate can be relatively increased when subsequent application of one or more another high-concentration capsaicin and / or capsaicinoid dose units according to the invention proceeds in shorter intervals, preferably not later than 89 days, or not later than 88 days, or not later than 87 days, or not later than 86 days, or not later than 85 days, or not later than 84 days, or not later than 83 days, or not later than 82 days, or not later than 81 days; more preferably not later than 80 days, or not later than 79 days, or not later than 78 days, or not later than 77 days, or not later than 76 days, or not later than 75 days, or not later than 74 days, or not later than 73 days, or not later than 72 days, or not later than 71 days; still more preferably not later than 70 days, or not later than 69 days, or not later than 68 days, or not later than 67 days, or not later than 66 days, or not later than 65 days, or not later than 64 days, or not later than 63 days, or not later than 62 days, or not later than 61 days, or not later than 60 days, in each case after the previous topical administration of capsaicin and / or capsaicinoid.

[0153] In a particularly preferred embodiment, treatments may be repeated by subsequent application every 90 days, as warranted by the persistence or return of pain. Re-treatment after less than 90 days is preferably considered for individual patients. A minimum interval of 60 days between treatments is preferably observed.

[0154] For the purpose of the specification, two different preferred administration regimens are distinguished:- according to a relatively fast administration regimen, hereinafter also referred to as "[f]", the time span between two consecutive application periods is less than 90 days, preferably less than 84 days, more preferably about 2 months, e.g. 60 days;- according to a relatively slow administration regimen, hereinafter also referred to as "[s]", the time span between two consecutive application periods is about 3 months, e.g. 90 days.

[0155] It is also contemplated according to the invention that the time span between two consecutive application periods may vary, especially may be increased in the course of the overall treatment period. For example, in a preferred embodiment, the time span between the first application period and the24 GRA 4178-foreign filingsecond application period is less than 90 days, preferably less than 84 days, more preferably about 2 months, e.g. 60 days, whereas the subsequent time span between the second application period and the third application period is about 3 months, e.g. 90 days.

[0156] It is also contemplated according to the invention that the time span between two consecutive application periods may be determined by the patient in view of the individual pain perception.

[0157] When application is repeated, said one or more another high-concentration capsaicin and / or capsaicinoid dose units, preferably high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are preferably applied to the same painful area of the skin of the patient where the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems), preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, were also previously applied, i.e. 2 to 4 months ago.

[0158] It is contemplated according to the invention that the treatment area of the painful skin of the patient may be pre-treated with a topical anesthetic (e.g. topical lidocaine (4%), or topical lidocaine (2.5%) / prilocaine (2.5%)) or the patient may be administered an oral analgesic (e.g. 50 mg of tramadol) prior to application of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, to reduce potential application related discomfort. The topical anesthetic is preferably applied to cover the entire treatment area and surrounding 1 to 2 cm. Topical anesthetics are preferably removed prior to applying the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches.

[0159] The one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are(i) for use in the prevention or treatment of a sleep disturbance, preferably in a patient having neuropathic pain; and / or(ii) for use in the prevention or treatment of neuropathic pain in a patient having a sleep disturbance;and / or(iii) for use in the prevention or treatment of neuropathic pain in a patient having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance.

[0160] In preferred embodiments, the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, are for use in a patient who upon previous25 GRA 4178-foreign filingtopical administration of capsaicin and / or capsaicinoid did not perceive pain relief by at least 30% versus baseline on either the VAS or the NRS pain rating scale, preferably the NRS pain rating scale.

[0161] Previous topical administration of capsaicin and / or capsaicinoid may principally have been achieved by any suitable pharmaceutical formulation that is capable of topically administering capsaicin and / or capsaicinoid.

[0162] Preferably, however, previous topical administration of capsaicin and / or capsaicinoid was achieved also by means of one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the invention as described herein, preferably 8% capsaicin and / or capsaicinoid patches. However, in preferred embodiments, previous topical administration of capsaicin and / or capsaicinoid was previously not (yet) successful so that the patient did not perceive pain relief by at least 30% versus baseline on either the VAS or the NRS pain rating scale, preferably the NRS pain rating scale.

[0163] Conventionally, in such a situation, treatment would usually be terminated due to lack of efficiency. According to the invention, however, treatment is continued by again using one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, preferably 8% capsaicin and / or capsaicinoid patches, thereby converting initial non-responders into responders.

[0164] For the purpose of the specification, "response" is always defined with respect to the relief of neuropathic pain. Thus, e.g. a "non-responder" does not (or not sufficiently) respond with respect to the relief of neuropathic pain, whereas it is possible that a beneficial effect is observed with respect to the treatment of sleep disturbances. In other words, effects on neuropathic pain and effects on sleep disturbances may be decoupled, and for the purpose of the specification, "response" always refers to the effects on neuropathic pain, but not necessarily also to the effects of sleep disturbances.

[0165] For the purpose of the specification, a patient who upon previous topical administration of capsaicin and / or capsaicinoid did not perceive pain relief by at least 30% versus baseline is also referred to as "initial non-responder".

[0166] As onset of pain relief may occur with a delay after topical administration of capsaicin and / or capsaicinoid by applying one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, preferably one or more 8% patches, e.g. after 1 to 3 weeks, pain relief versus baseline is preferably determined 4 weeks (28 days) after topical administration.

[0167] For the purpose of the specification, consistent with existing literature and guidance, "responders" are defined as those patients who have achieved a 30% decrease from baseline on a numeric pain rating scale (NRS) or a pain visual analogue scale (VAS). Conversely, "non-responders" are defined as26 GRA 4178-foreign filingthose who did not achieve a 30% decrease from baseline on such rating scale. According to the invention, the timepoint for measuring the sustained therapeutic effect of chronic pain treatments can be after 12 weeks. This time point is conventional and in accordance with EMA pain guidance (15 December 2016 EMA / CHMP / 970057 / 2011 Committee for Medicinal Products for Human Use (CHMP)). However it is common to assess the pain ratings more frequently and therefore, the time point when it is assessed whether a patient is a responder or a non-responder is preferably 8 weeks after the preceding topical administration of capsaicin and / or capsaicinoid.

[0168] Preferably, with regard to the previous topical administration of capsaicin and / or capsaicinoid, the patient is an initial non-responder selected from complete non-responders and insufficient responders.

[0169] For the purpose of the specification, a "complete non-responder" is a patient who upon previous topical administration of capsaicin and / or capsaicinoid did not perceive any pain relief or even experienced a worsening of pain, preferably on the NRS pain rating scale, preferably upon initial topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the invention as described herein.

[0170] Forthe purpose of the specification, an "insufficient responder" is apatient who upon previous topical administration of capsaicin and / or capsaicinoid perceived pain relief to some extent, but less than 30% versus baseline, preferably on the NRS pain rating scale, preferably upon initial topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the invention as described herein.

[0171] According to the EMA pain Guidance with reference to Koltzenburg M, McMahon S, Tracey I, Turk DC (ed.) Wall and Melzack’s Textbook of Pain. 6th edition, Saunders, imprint of Elsevier Ltd., ISBN 978-0-7020-4059-7, pain intensity (PI) is still the key measure of efficacy of an analgesic drug. Among the pain rating scales the Visual analogue scale (VAS), numeric rating scale (NRS) and verbal rating scale (VRS) have been extensively used and validated. The VAS is a continuous variable on a 10 cm line representing “no pain” to “worst imaginable pain”, whereas the NRS is a discrete variable describing pain level with numbers from 0 to 10 (J. T. Farrar et al. Pain 2001;94:149–58). Due to practical considerations the latter is the most commonly used scale. The VRS, consisting of a series of verbal pain descriptors, has been shown to lack sensitivity to detect changes in PI when compared with VAS or NRS.

[0172] For the purpose of the specification, a "responder" is defined as someone who reported a decrease of 30% from baseline on either the VAS or the NRS pain rating scale, preferably the NRS pain rating scale.27 GRA 4178-foreign filing

[0173] The preferred administration regimens defined hereinafter typically involve simultaneous and / or repeated application of one or more high-concentration capsaicin and / or capsaicinoid does units, typically more than a single high-concentration capsaicin and / or capsaicinoid pharmaceutical patch according to the invention. Thus, in order to put these preferred administration regimens into practice, a plurality of high-concentration capsaicin and / or capsaicinoid dose units according to the invention, preferably a plurality of high-concentration pharmaceutical patches are used, preferably a plurality of 8% capsaicin and / or capsaicinoid patches.

[0174] In a preferred embodiment, the patient to be treated according to the invention may have a treatment history where(a-i) one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, were previously applied to the skin of the patient for a first application period thereby previously topically administering capsaicin and / or capsaicinoid during the first application period, and were subsequently removed. In preferred embodiments, as a consequence of previous topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient did not perceive pain relief by at least 30% versus baseline (initial non-responder).

[0175] The previous topical administration under (a-i) is then not part of the use of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches. The previous topical administration under (a-i) merely qualifies the patient as an initial non-responder. A skilled person can easily determine in the course of anamnesis whether a patient to be treated is an initial non-responder or not.

[0176] Preferably,(b-i) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above first application period under (a-i), one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a second application period thereby topically administering capsaicin and / or capsaicinoid during the second application period, and are subsequently removed; and(b-ii) optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 328 GRA 4178-foreign filingmonths, e.g. 90 days, after the above second application period under (b-i), one or more high- concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-con- centration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a third application period thereby topically administering capsaicin and / or capsaicinoid during the third application period, and are subsequently removed; and (b-iii) optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above third application period under (b-ii), one or more high-con- centration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concen- tration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a fourth application period thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and are subsequently removed; and (b-iv)optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above fourth application period under (b-iii), one or more high- concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-con- centration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a fifth application period thereby topically administering capsaicin and / or capsaicinoid during the fifth application period, and are subsequently removed.

[0177] In a preferred embodiment, the patient to be treated according to the invention may again have a treatment history where(a-i) one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, were previously applied to the skin of the patient for a first application period thereby previously topically administering capsaicin and / or capsaicinoid during the first application period, and were subsequently removed. In preferred embodiments, as a consequence of previous topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient did not perceive pain relief by at least 30% versus baseline (initial non-responder).

[0178] The previous topical administration under (a-i) is then again not part of the use of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to29 GRA 4178-foreign filingthe invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches. The previous topical administration under (a-i) merely qualifies the patient as an initial non-responder. A skilled person can easily determine in the course of anamnesis whether a patient to be treated is an initial non-responder or not.

[0179] Preferably,(b-i) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above first application period under (a-i), one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a second application period thereby topically administering capsaicin and / or capsaicinoid during the second application period, and are subsequently removed;preferably whereby as a consequence of topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient preferably perceives pain relief by at least 30% versus baseline (responder), whereas onset of pain relief by at least 30% versus baseline may occur with a delay of 1 to 3 weeks after the second application period; and(b-ii) optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above second application period under (b-i), one or more high- concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-con- centration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a third application period thereby topically administering capsaicin and / or capsaicinoid during the third application period, and are subsequently removed; preferably whereby as a consequence of topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient preferably still perceives pain relief by at least 30% versus baseline (responder), whereas onset of pain relief by at least 30% versus baseline may occur with a delay of 1 to 3 weeks after the third application period but preferably follows immediately the pain relief by at least 30% versus baseline that was achieved by the above second application period under (b-i).30 GRA 4178-foreign filing

[0180] In a preferred embodiment, the patient to be treated according to the invention may again have a treatment history where(a-i) one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, were previously applied to the skin of the patient for a first application period thereby previously topically administering capsaicin and / or capsaicinoid during the first application period, and were subsequently removed. In preferred embodiments, as a consequence of previous topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient did not perceive pain relief by at least 30% versus baseline (initial non-responder).

[0181] The previous topical administration under (a-i) is then again not part of the use of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches. The previous topical administration under (a-i) merely qualifies the patient as an initial non-responder. A skilled person can easily determine in the course of anamnesis whether a patient to be treated is an initial non-responder or not.

[0182] Preferably,(b-i) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above first application period under (a-i), one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a second application period thereby topically administering capsaicin and / or capsaicinoid during the second application period, and are subsequently removed; and(b-ii) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above second application period under (b-i), one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a third application period thereby topically administering capsaicin and / or capsaicinoid during the third application period, and are subsequently removed;31 GRA 4178-foreign filingpreferably whereby as a consequence of topical administration of capsaicin and / or capsai- cinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient preferably perceives pain relief by at least 30% versus baseline (responder), whereas onset of pain relief by at least 30% versus baseline may occur with a delay of 1 to 3 weeks after the second application period; and(b-iii) optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above third application period under (b-ii), one or more high-con- centration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concen- tration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a fourth application period thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and are subsequently removed; preferably whereby as a consequence of topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient preferably still perceives pain relief by at least 30% versus baseline (responder), whereas onset of pain relief by at least 30% versus baseline may occur with a delay of 1 to 3 weeks after the fourth application period but preferably follows immediately the pain relief by at least 30% versus baseline that was achieved by the above third application period under (b-ii).

[0183] In a preferred embodiment, the patient to be treated according to the invention may again have a treatment history where(a-i) one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, were previously applied to the skin of the patient for a first application period thereby previously topically administering capsaicin and / or capsaicinoid during the first application period, and were subsequently removed. In preferred embodiments, as a consequence of previous topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient did not perceive pain relief by at least 30% versus baseline (initial non-responder).

[0184] The previous topical administration under (a-i) is then again not part of the use of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to32 GRA 4178-foreign filingthe invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches. The previous topical administration under (a-i) merely qualifies the patient as an initial non-responder. A skilled person can easily determine in the course of anamnesis whether a patient to be treated is an initial non-responder or not.

[0185] Preferably,(b-i) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above first application period under (a-i), one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a second application period thereby topically administering capsaicin and / or capsaicinoid during the second application period, and are subsequently removed; and(b-ii) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above second application period under (b-i), one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a third application period thereby topically administering capsaicin and / or capsaicinoid during the third application period, and are subsequently removed; and(b-iii) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above third application period under (b-ii), one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a fourth application period thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and are subsequently removed;preferably whereby as a consequence of topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient preferably perceives pain relief by at least 30% versus baseline (responder), whereas onset of pain relief by at least 30% versus baseline may occur with a delay of 1 to 3 weeks after the fourth application period; and33 GRA 4178-foreign filing(b-iv) optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the above fourth application period under (b-iii), one or more high- concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-con- centration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a fifth application period thereby topically administering capsaicin and / or capsaicinoid during the fifth application period, and are subsequently removed; preferably whereby as a consequence of topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient preferably still perceives pain relief by at least 30% versus baseline (responder), whereas onset of pain relief by at least 30% versus baseline may occur with a delay of 1 to 3 weeks after the fifth application period but preferably follows immediately the pain relief by at least 30% versus baseline that was achieved by the above fourth application period under (b-iii).

[0186] In another preferred embodiment, the patient to be treated according to the invention did not perceive pain relief by at least 30% versus baseline upon repeated previous topical administrations of capsaicin and / or capsaicinoid, e.g. after two consecutive previous topical administrations of capsaicin and / or capsaicinoid, or after three consecutive previous topical administrations of capsaicin and / or capsaicinoid (repeated non-responder). Preferably, said repeated previous topical administrations of capsaicin and / or capsaicinoid were also achieved by means of one or more high-concentration capsaicin and / or capsaicinoid dose units according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, but not successfully so that the patient did previously not perceive pain relief by at least 30% versus baseline, preferably on the NRS pain rating scale.

[0187] According to this embodiment, the patient to be treated according to the invention may have a treatment history where(a-i) one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, were previously applied to the skin of the patient for a first application period thereby previously topically administering capsaicin and / or capsaicinoid during the first application period, and were subsequently removed. In preferred embodiments, as a consequence of previous topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin34 GRA 4178-foreign filingand / or capsaicinoid pharmaceutical patches, the patient did not perceive pain relief by at least 30% versus baseline (initial non-responder); and(a-ii) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days, or [s] 3 months, e.g.90 days after the above first application period under (a-i), one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, were previously applied to the skin of the patient for a second application period thereby previously topically administering capsaicin and / or capsaicinoid during the second application period, and were subsequently removed. In preferred embodiments, as a consequence of previous topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient still did not perceive pain relief by at least 30% versus baseline (repeated non-responder).

[0188] The above repeated previous topical administrations under (a-i) and (a-ii) are then not part of the use of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches. The repeated previous topical administrations under (a-i) and (a-ii) merely qualify the patient as a repeated non-responder. A skilled person can easily determine in the course of anamnesis whether a patient is a repeated non-responder or not.

[0189] Preferably,(b-i) 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the second application period under (a-ii), one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a third application period thereby topically administering capsaicin and / or capsaicinoid during the third application period, and are subsequently removed;preferably whereby as a consequence of topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient preferably perceives pain relief by at least 30% versus baseline35 GRA 4178-foreign filing(responder), whereas onset of pain relief by at least 30% versus baseline may occur with a delay of 1 to 3 weeks after the second application period; and(b-ii) optionally, 2 to 4 months, preferably [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days; or [s] about 3 months, e.g. 90 days, after the third application period under (b-i), one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches, are then applied to the skin of the patient, remain on the skin for a fourth application period thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and are subsequently removed;preferably whereby as a consequence of topical administration of capsaicin and / or capsaicinoid by means of the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, the patient preferably still perceives pain relief by at least 30% versus baseline (responder), whereas onset of pain relief by at least 30% versus baseline may occur with a delay of 1 to 3 weeks after the fourth application period but preferably follows immediately the pain relief by at least 30% versus baseline that was achieved by the above third application period under (b-i).

[0190] Preferred administration regimens A to I are compiled in the following table where one or more high-concentration capsaicin and / or capsaicinoid dose units according to the invention as described herein, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, were previously used but had the effect that the patient did not perceive pain relief by at least 30% versus baseline, and one or more high-concentration capsaicin and / or capsaicinoid dose units according to the invention as described herein, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, are being used in the treatment according to the invention with the effect that the patient does perceive pain relief by at least 30% versus baseline:time patient history to be detertreatment according to the invention mined by anamnesispreviously pain relief pain relief< 30% versus baseline > 30% versus baseline(a-i) (a-ii) (a-iii) (b-i) (b-ii) (b-iii) A X days - - Y days optionally, Y days optionally, Y days B X days - - Y days Y days optionally, Y days C X days - - Y days Y days Y daysD X days X days - Y days optionally, Y days optionally, Y daysE X days X days - Y days Y days optionally, Y days36 GRA 4178-foreign filingF X days X days - Y days Y days Y daysG X days X days X days Y days optionally, Y days optionally, Y days H X days X days X days Y days Y days optionally, Y daysI X days X days X days Y days Y days Y days

[0191] In preferred embodiments, when the administration regimen is relatively fast (i.e. [f]), in each case, X is independently of one another 30 to 90, preferably 40 to 80, more preferably 50 to 70, and most preferably about 60. Preferably, X is independently of one another is less than 90, more preferably less than 84, still more preferably 60 to 83. The time intervals of X days immediately follow one another without interruption. Likewise, in each case, Y is independently of one another 30 to 90, preferably 40 to 80, more preferably 50 to 70, and most preferably about 60. The time intervals of Y days immediately follow one another without interruption.

[0192] In other preferred embodiments, when the administration regimen is relatively slow (i.e. [s]), in each case, X is independently of one another 60 to 120, preferably 70 to 110, more preferably 80 to 100, and most preferably about 90. The time intervals of X days immediately follow one another without interruption. Likewise, in each case, Y is independently of one another 60 to 120, preferably 70 to 110, more preferably 80 to 100, and most preferably about 90. The time intervals of Y days immediately follow one another without interruption.

[0193] The above table provides information about the history of the patient who was previously treated with capsaicin and / or capsaicinoid and is now preferably to be treated according to the invention (patient history, left part of the table, (a-i), (a-ii), and (a-iii), respectively). Previous treatment is not part of the treatment according to the invention but qualifies the patient as initial non-responder or repeated nonresponder. With regard to previous treatment, " X days" means that one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the invention as described herein, more preferably 8% capsaicin and / or capsaicinoid patches, were previously applied to the skin of the patient at the beginning of an interval of X days and remained on the skin for an application period (15 to 90 minutes, preferably 30 to 60 minutes) before they were removed from the skin. During the remainder of the interval of X days, no dose unit or pharmaceutical patch according to the invention as described herein was applied to the skin of the patient. Such previous treatment did not have the desired effect of achieving at least 30% pain relief versus baseline (initial non-responder or repeated non-responder).

[0194] Further, the above table provides information about preferred regimens for treating a patient according to the invention (treatment, right part of the table, (b-i), (b-ii), and (b-iii), respectively). With regard to treatment according to the invention, "Y days" means that one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches according to the invention as described herein, more preferably 8% capsaicin and / or capsaicinoid patches, are to be applied to the skin of the patient in the course of the treatment according to the invention at the beginning of an interval of Y days and remain on the37 GRA 4178-foreign filingskin for an application period (15 to 90 minutes, preferably 30 to 60 minutes) before they are removed from the skin. During the remainder of the interval of Y days, no dose unit or pharmaceutical patch according to the invention as described herein is applied to the skin of the patient. Such treatment has the desired effect of achieving at least 30% pain relief versus baseline (responder). Further, with regard to treatment according to the invention, "optionally, Y days" means that after treatment under (b-i), i.e. after the 90 days, optionally another treatment by means of one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or cap-saicinoid pharmaceutical patches according to the invention as described herein, more preferably 8% capsaicin and / or capsaicinoid patches, may occur but does not have to.

[0195] Preferred regimens in accordance with the above table are selected from (a-i)-(b-i), (a-i)-(b-i)-(b-ii), (a-i)-(b-i)-(b-ii)-(b-iii); (a-i)-(a-ii)-(b-i), (a-i)-(a-ii)-(b-i)-(b-ii), (a-i)-(a-ii)-(b-i)-(b-ii)-(b-iii); (a-i)-(a-ii)-(a-iii)-(b-i), (a-i)-(a-ii)-(a-iii)-(b-i)-(b-ii), and (a-i)-(a-ii)-(a-iii)-(b-i)-(b-ii)-(b-iii).

[0196] As already mentioned above, previous topical administration of capsaicin and / or capsaicinoid was preferably achieved by applying one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, to the skin of the patient for an application period thereby previously topically administering capsaicin and / or capsaicinoid during the application period and subsequently removing said one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches from the skin. Likewise, repeated previous topical administrations were preferably achieved by repeatedly applying one or more high-concentration capsaicin and / or capsaicinoid topical dose units (topical systems) according to the invention, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches, more preferably 8% capsaicin and / or capsaicinoid patches, to the skin of the patient for an application period thereby previously repeatedly topically administering capsaicin and / or capsaicinoid during the application period and subsequently removing said one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches from the skin.

[0197] Preferably, said one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches previously used were of the same kind as the one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches for use according to the invention, more preferably 8% capsaicin and / or capsaicinoid patches.

[0198] The invention also contemplates the use of capsaicin and / or capsaicinoid for the manufacture of one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more38 GRA 4178-foreign filinghigh-concentration capsaicin and / or capsaicinoid pharmaceutical patches comprising capsaicin and / or capsaicinoid, more preferably 8% capsaicin and / or capsaicinoid patches, for (i) preventing or treating a sleep disturbance, preferably in a patient having neuropathic pain; and / or (ii) preventing or treating neuropathic pain in a patient having a sleep disturbance; and / or (iii) the prevention or treatment of neuropathic pain in a patient having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance.

[0199] Likewise the invention also contemplates a method for (i) preventing or treating a sleep disturbance, preferably in a patient having neuropathic pain; and / or (ii) preventing or treating neuropathic pain in a patient having a sleep disturbance; and / or (iii) the prevention or treatment of neuropathic pain in a patient having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance; in either case comprising the step of applying one or more high-concentration capsaicin and / or capsaicinoid topical dose units, preferably one or more high-concentration capsaicin and / or capsaicinoid pharmaceutical patches comprising capsaicin and / or capsaicinoid, more preferably 8% capsaicin and / or capsaicinoid patches, to the skin of a patient.

[0200] In preferred embodiments of the invention,(a) one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a first application period thereby topically administering capsaicin and / or capsaicinoid during the first application period, and are subsequently removed;(b) W days after the first application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a second application period thereby topically administering capsaicin and / or capsaicinoid during the second application period, and are subsequently removed;(c) optionally, X days after the second application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a third application period thereby topically administering capsaicin and / or capsaicinoid during the third application period, and are subsequently removed; (d) optionally, Y days after the third application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a fourth application period thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and are subsequently removed; and39 GRA 4178-foreign filing(e) optionally, Z days after the fourth application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a fifth application period thereby topically administering capsaicin and / or capsaicinoid during the fifth application period, and are subsequently removed; whereinW and X independently of one another are an integer within the range of from 60 to 120; andY and Z independently of one another are an integer within the range of from 60 to 120.

[0201] Preferably, W and X independently of one another are an integer within the range of from 60 to 109.

[0202] In preferred embodiments, W is an integer within the range of from 60 to 109; preferably 60 to 91, or 60 to 90, or 60 to 89, or 60 to 85, or 60 to 84, or 60 to 83, or 60 to 69, or 60 to 68, or 60 to 67, or 60 to 64, or 60 to 63, or 60 to 62; or exactly 60.

[0203] In preferred embodiments, W is an integer within the range of from 62 to 109; preferably 62 to 91, or 62 to 90, or 62 to 89, or 62 to 85, or 62 to 84, or 62 to 83, or 62 to 69, or 62 to 68, or 62 to 67, or 62 to 64, or 62 to 63.

[0204] In preferred embodiments, W is an integer within the range of from 63 to 109; preferably 63 to 91, or 63 to 90, or 63 to 89, or 63 to 85, or 63 to 84, or 63 to 83, or 63 to 69, or 63 to 68, or 63 to 67, or 63 to 64.

[0205] In preferred embodiments, W is an integer within the range of from 64 to 109; preferably 64 to 91, or 64 to 90, or 64 to 89, or 64 to 85, or 64 to 84, or 64 to 83, or 64 to 69, or 64 to 68, or 64 to 67.

[0206] In preferred embodiments, W is an integer within the range of from 67 to 109; preferably 67 to 91, or 67 to 90, or 67 to 89, or 67 to 85, or 67 to 84, or 67 to 83, or 67 to 69, or 67 to 68.

[0207] In preferred embodiments, W is an integer within the range of from 68 to 109; preferably 68 to 91, or 68 to 90, or 68 to 89, or 68 to 85, or 68 to 84, or 68 to 83, or 68 to 69.

[0208] In preferred embodiments, W is an integer within the range of from 69 to 109; preferably 69 to 91, or 69 to 90, or 69 to 89, or 69 to 85, or 69 to 84, or 69 to 83.

[0209] In preferred embodiments, W is an integer within the range of from 83 to 109; preferably 83 to 91, or 83 to 90, or 83 to 89, or 83 to 85, or 83 to 84.

[0210] In preferred embodiments, W is an integer within the range of from 84 to 109; preferably 84 to 91, or 84 to 90, or 84 to 89, or 84 to 85.

[0211] In preferred embodiments, W is an integer within the range of from 85 to 109; preferably 85 to 91, or 85 to 90, or 85 to 89.40 GRA 4178-foreign filing

[0212] In preferred embodiments, W is an integer within the range of from 89 to 109; preferably 89 to 91, or 89 to 90.

[0213] In preferred embodiments, W is an integer within the range of from 90 to 109; preferably 90 to 91.

[0214] In preferred embodiments, W is an integer within the range of from 91 to 109.

[0215] In preferred embodiments, X is an integer within the range of from 60 to 109; preferably 60 to 91, or 60 to 90, or 60 to 89, or 60 to 85, or 60 to 84, or 60 to 83, or 60 to 69, or 60 to 68, or 60 to 67, or 60 to 64, or 60 to 63, or 60 to 62; or exactly 60.

[0216] In preferred embodiments, X is an integer within the range of from 62 to 109; preferably 62 to 91, or 62 to 90, or 62 to 89, or 62 to 85, or 62 to 84, or 62 to 83, or 62 to 69, or 62 to 68, or 62 to 67, or 62 to 64, or 62 to 63.

[0217] In preferred embodiments, X is an integer within the range of from 63 to 109; preferably 63 to 91, or 63 to 90, or 63 to 89, or 63 to 85, or 63 to 84, or 63 to 83, or 63 to 69, or 63 to 68, or 63 to 67, or 63 to 64.

[0218] In preferred embodiments, X is an integer within the range of from 64 to 109; preferably 64 to 91, or 64 to 90, or 64 to 89, or 64 to 85, or 64 to 84, or 64 to 83, or 64 to 69, or 64 to 68, or 64 to 67.

[0219] In preferred embodiments, X is an integer within the range of from 67 to 109; preferably 67 to 91, or 67 to 90, or 67 to 89, or 67 to 85, or 67 to 84, or 67 to 83, or 67 to 69, or 67 to 68.

[0220] In preferred embodiments, X is an integer within the range of from 68 to 109; preferably 68 to 91, or 68 to 90, or 68 to 89, or 68 to 85, or 68 to 84, or 68 to 83, or 68 to 69.

[0221] In preferred embodiments, X is an integer within the range of from 69 to 109; preferably 69 to 91, or 69 to 90, or 69 to 89, or 69 to 85, or 69 to 84, or 69 to 83.

[0222] In preferred embodiments, X is an integer within the range of from 83 to 109; preferably 83 to 91, or 83 to 90, or 83 to 89, or 83 to 85, or 83 to 84.

[0223] In preferred embodiments, X is an integer within the range of from 84 to 109; preferably 84 to 91, or 84 to 90, or 84 to 89, or 84 to 85.

[0224] In preferred embodiments, X is an integer within the range of from 85 to 109; preferably 85 to 91, or 85 to 90, or 85 to 89.

[0225] In preferred embodiments, X is an integer within the range of from 89 to 109; preferably 89 to 91, or 89 to 90.

[0226] In preferred embodiments, X is an integer within the range of from 90 to 109; preferably 90 to 91.

[0227] In preferred embodiments, X is an integer within the range of from 91 to 109.41 GRA 4178-foreign filing

[0228] In preferred embodiments,W is an integer within the range of from 60 to 109, preferably 60 to 89, more preferably 60 to 83; and X is an integer within the range of from 60 to 109, preferably 60 to 89, more preferably 60 to 83.

[0229] In preferred embodiments,(i) the average over W and X is within the range of from 60.0 to 68.0, or from 69.0 to 83.0;(ii) the average over W, X, and Y is within the range of from 60.0 to 68.0, or from 69.0 to 83.0; or (iii) the average over W, X, Y and Z is within the range of from 60.0 to 68.0, or from 69.0 to 83.0.

[0230] Preferably, W < X.

[0231] Preferably, Y and Z independently of one another are an integer within the range of from 60 to 110.EXAMPLES

[0232] The following examples further illustrate the invention but are not to be construed as limiting its scope.

[0233] A retrospective study was conducted to document initial / progressive response and develop a responder profiling algorithm based on the number of treatments in a longitudinal analysis of depersonalized bio-psycho-social real -world data of the German Pain e-Registry (CASPAR) by capsaicin 179 mg cutaneous patch treatment in adult patients with peripheral localized neuropathic pain.

[0234] Primary endpoint: The proportion of responders at 3 months and after each subsequent capsaicin 179 mg cutaneous patch treatment. The primary responder criteria were defined as a >30% reduction and / or a reduction by >20 mm (VAS 0-100 mm) in average 24h pain intensity (API) from baseline.

[0235] Secondary endpoints: The absolute and relative changes from baseline to 3, 6, 9 and 12 months after the 1st treatment, stratified by the number of treatments at 3 (2nd treatment), 6 (3rd treatment), and 9 (4th treatment) months inter alia for the following pain-related variables:• lowest, average, and highest 24h pain intensity (LPI, API, HPI), and the average 24h pain intensity index (PIX); and• pain-related disability in daily life and sleep quality at night (modified pain disability index, mPDI and mPDI subscale #6).

[0236] Study treatments: Capsaicin 179 mg cutaneous patch (QUTENZA®). One treatment can consist of the application of up to 4 patches.

[0237] CASPAR was a non-interventional, retrospective, longitudinal study to assess the effectiveness and global response of capsaicin 179 mg cutaneous patches in adult patients suffering from PNP conditions, deemed to be needing such treatment as mutually agreed by the treating physician and patient.42 GRA 4178-foreign filing

[0238] The patients were treated per routine clinical practice generally following the QUTENZA® SmPC, judgement of the treating physician, and individual needs of the patients. The study used a German Pain e-Registry (GPeR) subpopulation of adult patients with PNP receiving capsaicin 179 mg cutaneous patches. Patient data were extracted as per inclusion and exclusion criteria for analysis of this retrospective study. The data were categorized into etiology groups: postherpetic neuralgia (PHN), peripheral nerve injury (PNI), painful diabetic polyneuropathy (PDPN) or other localized peripheral neuropathies (OTH) and analyzed separately as well as together. The PDPN group was split into treatment of feet, legs, or hands. The PHN group was split into treatment on face / head and other body areas. Additionally, the PDPN subgroups were further split by interval of >84 days between treatments.

[0239] Descriptive data included patient disposition (including number of treatments and reason for treatment discontinuation), demographic (age, sex) and baseline pain, biological, psychological, and sociological characteristics. Primary effectiveness assessments included changes from baseline in average 24h pain intensity (API) following each application. Secondary and tertiary effectiveness assessments included changes from baseline pain, psychological, and sociological characteristics following each application. Secondary safety and tolerability assessments included frequency, intensity and spectrum of adverse drug reactions (ADRs) and treatment discontinuations due to ADRs. The analyses evaluated assessments at baseline, 3, 6, 9 and 12 months following the first application at baseline for a maximum study observation period of 12 months per patient. Based on the evaluated response to treatment (using the effectiveness assessments), baseline characteristics including demographics, psychological, and sociological characteristics were evaluated to identify critical parameters and their predictive value for a beneficial [early (i.e., after first treatment) and lag / late (i.e., after third treatment)] response after initial or repeated treatment with capsaicin 179 mg cutaneous patch(es).

[0240] The following table summarizes the number of patients receiving up to 4 capsaicin 179 mg cutaneous patch treatments for each etiology group, i.e. postherpetic neuralgia (PHN), peripheral nerve injury (PNI), painful diabetic peripheral neuropathy (PDPN), other localized neuropathies (OTH) -complete analysis (N = 2574):Category or statistic PHN (N = 961) PNI (N = 499) PDPN (N = 826) OTH (N = 288) Total(N = 2574) n (%) n (%) n (%) n (%) n (%) 1 Treatment 961 (100.0%) 499 (100.0%) 826 (100.0%) 288 (100.0%) 2574 (100.0%) 2 Treatments 774 (80.5%) 402 (80.6%) 653 (79.1%) 187 (64.9%) 2016 (78.3%) 3 Treatments 565 (58.8%) 264 (52.9%) 464 (56.2%) 127 (44.1%) 1420 (55.2%) 4 Treatments 358 (37.3%) 135 (27.1%) 279 (33.8%) 89 (30.9%) 861 (33.4%)

[0241] The following table summarizes the number and percentage of responders 3 months after each subsequent capsaicin 179 mg cutaneous patch treatment (complete analysis (N = 2574)) in the four etiology groups, i.e.A) postherpetic neuralgia (PHN),43 GRA 4178-foreign filingB) peripheral nerve injury (PNI),C) painful diabetic peripheral neuropathy (PDPN), andD) other localized neuropathies (OTH):Category Capsaicin 179 mg cutaneous patch treatment3M 6M 9M 12M Treatment 1st2nd3rd4thn % n % n % n % All patients (N = 2574)Exposed patients 2574 100 2016 100 1420 100 861 100 Response 992 38.5 1676 83.1 1369 96.4 853 99.1 No response 1582 65.1 340 16.9 51 3.6 8 0.9 Group PHN (N = 961)Exposed patients 961 100 774 100 565 100 358 100 Response 390 40.6 663 85.7 548 97.0 357 99.7 No response 571 59.4 111 14.3 17 3.0 1 0.3 Group PNI (N = 499)Exposed patients 499 100 402 100 264 100 135 100 Response 136 27.3 285 70.9 246 93.2 133 98.5 No response 363 72.7 117 29.1 18 6.8 2 1.5 Group PDPN (N = 826)Exposed patients 826 100 653 100 464 100 279 100 Response 375 45.4 583 89.3 457 95.8 276 98.9 No response 451 54.6 70 10.7 7 1.5 3 1.1 Group OTH (N = 288)Exposed patients 288 100 187 100 127 100 89 100 Response 91 31.6 145 77.5 118 92.9 87 97.8 No response 197 68.4 42 22.5 9 7.1 2 2.2

[0242] The following tables summarize for 1 and 4 capsaicin 179 mg cutaneous patch treatments in each of the four etiology groups A) postherpetic neuralgia (PHN), B) peripheral nerve injury (PNI), C) painful diabetic peripheral neuropathy (PDPN), and D) other localized neuropathies (OTH): (a) average 24h pain intensity, (b) proportion of responders with pain relief using average 24h pain intensity, (c) modified pain disability index, and (d) modified pain disability index for sleep:A) postherpetic neuralgia (PHN):A)(a) average 24h pain intensity:Category API (mm VAS) before each capsaicin 179 mg cutaneous patch treatmentBL 3M 6M 9M 12M Group PHN (N = 961)Patients with 1 treatment 187 187 187 187 187Mean 60.6 46.0 48.3 49.9 54.7SD 17.8 15.4 17.0 18.9 20.595% CI lower 57.7 43.5 45.5 46.8 51.395% CI upper 63.5 48.5 51.1 53.0 58.1Mean absolute change from - -14.6 -12.3 -10.7 -5.9BLRelative change from BL* - -24.1 -20.3 -17.7 -9.71 Significance to BL - <0.001 <0.001 <0.001 0.003 Patients with 4 treatments 358 358 358 358 358Mean 63.7 48.3 36.0 26.8 19.6SD 17.6 15.6 15.8 16.0 16.295% CI lower 61.6 46.5 34.1 24.9 17.795% CI upper 65.8 50.2 37.9 28.7 21.5Mean absolute change from - -15.4 -27.7 -37.0 -44.1BL44 GRA 4178-foreign filingRelative change from BL* - -24.2 -43.5 -58.0 -69.2 Significance to BL - <0.001 <0.001 <0.001 <0.001 Significance to previous - <0.001 <0.001 <0.001 <0.001 time pointA)(b) proportion of responders with pain relief after 1 and 4 treatments using average 24h pain intensity:Category % Patients responding to capsaicin 179 mg cutaneous patch treatment 3M 6M 9M 12MGroup PHN (N = 961) Patients with 1 treatment (n = 187)absolute pain decrease >20 mm VAS 27.3 20.9 21.4 13.9relative pain decrease >30% 29.4 29.9 29.9 17.6relative pain decrease >50% 0.5 0.5 3.7 1.6Patients with 4 treatments (n = 358)absolute pain decrease >20 mm VAS 31.0 65.1 83.8 93.0relative pain decrease >30% 30.7 79.6 96.4 99.7relative pain decrease >50% 0.0 37.2 69.3 92.7A)(c) modified pain disability index for 1 and 4 treatments:Category mPDI (mm VAS) before each capsaicin 179 mg cutaneous patch treatmentBL 3M 6M 9M 12M Group PHN (N = 961)Patients with 1 treatment 187 187 187 187 187 Mean 57.8 42.0 44.3 51.5 63.0SD 19.6 15.4 18.1 21.9 25.095% CI lower 54.6 39.5 41.3 47.9 59.095% CI upper 61.0 44.6 47.3 55.1 67.1 Mean absolute change - -15.7 -13.5 -6.3 5.3 from BLRelative change from BL* - -27.2 -23.3 -10.9 9.2 Significance to BL - <0.001 <0.001 0.004 0.024 Patients with 4 358 358 358 358 358 treatmentsMean 58.3 42.2 40.9 40.0 39.1SD 19.6 14.9 14.6 14.5 14.495% CI lower 56.0 40.5 39.2 38.3 37.495% CI upper 60.7 44.0 42.6 41.7 40.9 Mean absolute change - -16.1 -17.5 -18.4 -19.2 from BLRelative change from BL* - -27.6 -29.9 -31.5 -32.9 Significance to BL - <0.001 <0.001 <0.001 <0.001 Significance to previous - <0.001 0.226 0.409 0.441 time pointA)(d) modified pain disability index for sleep:Category mPDI 6 sleep (mm VAS) before each capsaicin 179 mg cutaneous patch treatmentBL 3M 6M 9M 12M Group PHN (N = 961)Patients with 1 treatment 187 187 187 187 187Mean 53.5 40.8 42.3 47.4 58.1SD 24.8 20.5 22.2 24.3 26.595% CI lower 49.4 37.4 38.7 43.4 53.895% CI upper 57.6 44.1 45.9 51.4 62.5 Mean absolute change - -12.7 -11.2 -6.1 4.6 from BLRelative change from BL* - -23.8 -21.0 -11.5 8.7 Significance to BL - <0.001 <0.001 0,016 0.082 Patients with 4 358 358 358 358 358 treatmentsMean 55.3 41.2 30.5 22.4 16.0SD 24.3 18.5 15.8 14.9 14.795% CI lower 52.4 39.0 28.6 20.6 14.395% CI upper 58.2 43.4 32.4 24.2 17.845 GRA 4178-foreign filingMean absolute change -14.1 -24.8 -32.9 -39.3 from BLRelative change from BL* -25.5 -44.8 -59.5 -71.0 Significance to BL <0.001 <0.001 <0.001 <0.001 Significance to previous <0.001 <0.001 <0.001 <0.001 time pointB) peripheral nerve injury (PNI):B)(a) average 24h pain intensityCategory API (mm VAS) before each capsaicin 179 mg cutaneous patch treatment BL 3M 6M 9M 12MGroup PNI (N = 499)Patients with 1 treatment 97 97 97 97 97Mean 53.7 40.8 42.6 43.7 47.1SD 16.4 13.4 15.2 16.6 18.295% CI lower 50.0 37.7 39.1 39.9 42.995% CI upper 57.5 43.8 46.0 47.4 51.2Mean absolute change from - -13.0 -11.2 -10.1 -6.7BLRelative change from BL* - -24.1 -20.8 -18.7 -12.4 Significance to BL - <0.001 <0.001 <0.001 0.008 Patients with 4 treatments 135 135 135 135 135Mean 52.5 43.0 34.4 27.6 21.5SD 16.8 15.1 14.9 14.9 15.395% CI lower 49.3 40.1 31.5 24.7 18.695% CI upper 55.8 45.9 37.3 30.5 24.5Mean absolute change from - -9.6 -18.2 -24.9 -31.0BLRelative change from BL* - -18.2 -34.6 -47.4 -59.0 Significance to BL - <0.001 <0.001 <0.001 <0.001 Significance to previous - <0.001 <0.001 <0.001 0.001 time pointB)(b) proportion of responders with pain relief after 1 and 4 treatments using average 24h pain intensity:Category % Patients responding to capsaicin 179 mg cutaneous patch treatment 3M 6M 9M 12MGroup PNI (N = 499)Patients with 1 treatment (n = 97)absolute pain decrease >20 mm VAS 21.6 20.6 20.6 18.6 relative pain decrease >30% 22.7 28.9 32.0 25.8 relative pain decrease >50% 1.0 1.0 4.1 3.1 Patients with 4 treatments (n = 135)absolute pain decrease >20 mm VAS 11.9 37.8 57.8 74.8 relative pain decrease >30% 14.8 61.5 89.6 97.8 relative pain decrease >50% 0.0 22.2 42.2 72.6B)(c) modified pain disability index for 1 and 4 treatments:Category mPDI (mm VAS) before each capsaicin 179 mg cutaneous patch treatment BL 3M 6M 9M 12M Group PNI (N = 499)Patients with 1 treatment 97 97 97 97 97Mean 56.6 41.8 43.4 51.1 60.9SD 17.2 14.3 16.7 21.3 23.895% CI lower 52.7 38.6 39.6 46.3 55.595% CI upper 60.5 45.1 47.2 55.9 66.4 Mean absolute change - -14.8 -13.2 -5.5 4.4 from BLRelative change from BL* - -26.1 -23.3 -9.7 7.7 Significance to BL - <0.001 <0.001 0.051 0.14846 GRA 4178-foreign filingPatients with 4 135 135 135 135 135 treatmentsMean 57.3 43.8 42.7 42.1 41.7SD 17.3 15.3 15.1 15.3 15.395% CI lower 54.0 40.8 39.8 39.2 38.895% CI upper 60.7 46.7 45.7 45.1 44.7 Mean absolute change - -13.6 -14.6 -15.2 -15.6 from BLRelative change from BL* - -23.7 -25.5 -26.5 -27.2 Significance to BL - <0.001 <0.001 <0.001 <0.001 Significance to previous - <0.001 0.576 0.741 0.837 time pointB)(d) modified pain disability index for sleep:Category inl’DI 6 sleep (nun \ AS) before each capsaicin 179 mg cutaneous patch treatmentBL 3M 6M 9M 12M Group PNI (N = 499)Patients with 1 treatment 97 97 97 97 97Mean 49.2 37.5 40.0 45.3 55.8SD 23.0 17.7 20.8 24.8 28.695% CI lower 44.0 33.5 35.3 39.7 49.395% CI upper 54.5 41.5 44.7 51.0 62.3 Mean absolute change - -11.7 -9.2 -3.9 6.6 from BLRelative change from BL* - -23.8 -18.7 -8.0 13.4 Significance to BL - <0.001 0.004 0.258 0.080 Patients with 4 135 135 135 135 135 treatmentsMean 49.6 40.4 32.7 25.7 20.3SD 22.2 19.2 18.3 17.7 16.7 95% CI lower 45.4 36.7 29.2 22.3 17.095% CI upper 53.9 44.1 36.2 29.1 23.5 Mean absolute change - -9.2 -17.0 -23.9 -29.4 from BLRelative change from BL* - -18.6 -34.2 -48.2 -59.2 Significance to BL - <0.001 <0.001 <0.001 <0.001 Significance to previous - <0.001 <0.001 0.002 0.010 time pointC) painful diabetic peripheral neuropathy (PDPN):C)(a) average 24h pain intensity:Category API (mm VAS) before each capsaicin 179 mg cutaneous patch treatmentBL 3M 6M 9M 12M Group PDPN (N = 826)Patients with 1 treatment 173 173 173 173 173Mean 56.5 41.8 44.5 46.5 51.5SD 18.0 14.4 16.9 18.0 20.495% CI lower 53.4 39.4 41.6 43.4 48.195% CI upper 59.6 44.3 47.4 49.6 55.0Mean absolute change from - -14.7 -12.0 -10.0 -4.9BLRelative change from BL‘ - -26 -21.2 -17.7 -8.75 Significance to BL - <0.001 <0.001 <0.001 0.018 Patients with 4 treatments 279 279 279 279 279Mean 59.0 43.6 31.8 23.0 16.0SD 18.0 14.9 13.6 13.2 13.295% CI lower 56.6 41.6 29.9 21.2 14.295% CI upper 61.5 45.6 33.6 24.7 17.8Mean absolute change from - -15.4 -27.3 -36.1 -43.0BL47 GRA 4178-foreign filingRelative change from BL* -26.1 -46.2 -61.1 -72.9 Significance to BL <0.001 <0.001001 <0.001 Significance to previous <0.001 <0.001001 <0.001 time pointC)(b) proportion of responders with pain relief after 1 and 4 treatments using average 24h pain intensity:Category % Patients responding to capsaicin 179 mg cutaneous patch treatment 3M 6M 9M 12MGroup PDPN (N = 826)Patients with 1 treatment (n = 173)absolute pain decrease >20 mm VAS 28.3 22.0 19.7 16.8 relative pain decrease >30% 41.0 32.9 30.6 22.0 relative pain decrease >50% 3.5 4.0 4.6 1.2 Patients with 4 treatments (n = 279)absolute pain decrease >20 mm VAS 33.0 64.9 83.9 91.4 relative pain decrease >30% 38.4 85.3 98.2 98.9 relative pain decrease >50% 1.8 41.6 73.1 92.8 C)(c) modified pain disability index for 1 and 4 treatments:Category mPDI (mm VAS) before each capsaicin 179 mg cutaneous patch treatment BL 3M 6M 9M 12M Group PDPN (N = 826)Patients with 1 treatment 173 173 173 173 173 Mean 62.1 44.1 46.6 53.8 64.7SD 18.1 13.9 16.3 21.0 23.895% CI lower 59.0 41.7 43.8 50.2 60.695% CI upper 65.2 46.4 49.3 57.4 68.8 Mean absolute change - -18.0 -15.5 -8.3 2.6 from BLRelative change from BL* - -29.0 -25.0 -13.4 4.2 Significance to BL - <0.001 <0.001 <0.001 0.256 Patients with 4 279 279 279 279 279 treatmentsMean 67.2 48.6 47.0 46.0 45.3SD 18.0 14.6 14.5 14.5 14.695% CI lower 64.8 46.6 45.1 44.1 43.395% CI upper 69.7 50.5 49.0 48.0 47.2 Mean absolute change - -18.7 -20.2 -21.2 -22.0 from BLRelative change from BL* - -27.8 -30.0 -31.6 -32.7 Significance to BL - <0.001 <0.001 <0.001 <0.001 Significance to previous - <0.001 0.215 0.408 0.537 time pointC)(d) modified pain disability index for sleep:Category mPDI 6 sleep (mm VAS) before each capsaicin 179 mg cutaneous patch treatmentBL 3M 6M 9M 12M Group PDPN (N = 826)Patients with 1 treatment 173 173 173 173 173 Mean 61.3 45.2 46.6 52.1 63.3SD 23.7 18.9 20.5 23.5 26.695% CI lower 57.3 42.0 43.2 48.1 58.895% CI upper 65.4 48.4 50.1 56.1 67.9 Mean absolute change - -16.1 -14.7 -9.2 2.0 from BLRelative change from BL* - -26.3 -23.9 -15.1 3.3 Significance to BL - <0.001 <0.001 <0.001 0.459 Patients with 4 279 279 279 279 279 treatmentsMean 61.8 45.8 33.3 23.6 16.6SD 24.8 19.4 17.1 15.8 14.495% CI lower 58.5 43.2 31.0 21.5 14.795% CI upper 65.2 48.4 35.6 25.7 18.648 GRA 4178-foreign filingMean absolute change -16.0 -28.6 -38.2 -45.2 from BLRelative change from BL* -25.9 -46.2 -61.8 -73.1 Significance to BL <0.001 <0.001 <0.001 <0.001 Significance to previous <0.001 <0.001 <0.001 <0.001 time pointD) other localized neuropathies (OTH):D)(a) average 24h pain intensity:Category API (mm VAS) before each capsaicin 179 mg cutaneous patch treatmentBL 3M 6M 9M 12MGroup OTH (N = 288)Patients with 1 treatment 101 101 101 101 101Mean 56.7 43.3 45.4 47.7 52.5SD 19.2 16.6 18.1 19.7 21.795% CI lower 52.4 39.6 41.4 43.3 47.795% CI upper 61.0 47.0 49.5 52.1 57.4Mean absolute change from - -13.5 -11.3 -9.0 -4.2BLRelative change from BL* - -23.7 -19.9 -15.9 -7.37 Significance to BL - <0.001 <0.001 0.001 0.151 Patients with 4 treatments 89 89 89 89 89Mean 58.1 45.8 35.5 27.2 20.1SD 19.2 18.0 16.9 16.6 17.095% CI lower 53.6 41.5 31.5 23.3 16.095% CI upper 62.7 50.0 39.5 31.2 24.1Mean absolute change from - -12.4 -22.7 -30.9 -38.1BLRelative change from BL* - -21.3 -39.0 -53.1 -65.4 Significance to BL - <0.001 <0.001 <0.001 <0.001 Significance to previous - <0.001 <0.001 0.001 0.005 time pointD)(b) proportion of responders with pain relief after 1 and 4 treatments using average 24h pain intensity:Category % Patients responding to capsaicin 179 mg cutaneous patch treatment 3M 6M 9M 12MGroup OTH (N = 288)Patients with 1 treatment (n = 101)absolute pain decrease >20 mm VAS 22.8 20.8 22.8 18.8 relative pain decrease >30% 30.7 28.7 27.7 24.8 relative pain decrease >50% 0.0 2.0 3.0 1.0 Patients with 4 treatments (n = 89)absolute pain decrease >20 mm VAS 18.0 51.7 70.8 83.1 relative pain decrease >30% 24.7 73.0 93.3 97.8 relative pain decrease >50% 0.0 25.8 55.1 82.0D)(c) modified pain disability index for 1 and 4 treatments:Category mPDI (mm VAS) before each capsaicin 179 mg cutaneous patch treatmentBL 3M 6M 9M 12M Group OTH (N = 288)Patients with 1 treatment 101 101 101 101 101 Mean 65.6 48.2 50.3 59.0 69.8SD 17.6 14.5 16.1 21.7 23.195% CI lower 61.7 44.9 46.7 54.2 64.695% CI upper 69.5 51.4 53.9 63.9 74.9 Mean absolute change - -17.4 -15.3 -6.5 4.2 from BLRelative change from BL* - -26.6 -23.3 -10.0 6.4 Significance to BL - <0.001 <0.001 0.020 0.15049 GRA 4178-foreign filingPatients with 4 89 89 89 89 89 treatmentsMean 64.4 47.8 46.6 45.9 45.3SD 18.8 15.6 15.4 15.7 15.795% CI lower 60.0 44.1 42.9 42.2 41.595% CI upper 68.9 51.5 50.3 49.7 49.0 Mean absolute change - -16.6 -17.8 -18.5 -19.2 from BLRelative change from BL* - -25.8 -27.7 -28.7 -29.7 Significance to BL - <0.001 <0.001 <0.001 <0.001 Significance to previous - <0.001 0.601 0.782 0.776 time pointD)(d) modified pain disability index for sleep:Category mPDI 6 sleep (mm VAS) before each capsaicin 179 mg cutaneous patch treatmentBL 3M 6M 9M 12M Group OTH (N = 288)Patients with 1 101 101 101 101 101 treatment)Mean 57.6 44.2 46.6 53.9 64.4SD 22.8 19.5 21.9 26.3 26.195% CI lower 52.5 39.9 41.7 48.0 58.695% CI upper 62.7 48.6 51.5 59.7 70.2 Mean absolute change - -13.4 -11.1 -3.8 6.8 from BLRelative change from BL* - -23.2 -19.2 -6.5 11.8 Significance to BL - <0.001 <0.001 0.279 0.052 Patients with 4 89 89 89 89 89 treatmentsMean 57.9 44.7 34.5 26.7 20.5SD 23.1 18.5 17.6 17.6 17.095% CI lower 52.4 40.3 30.3 22.5 16.495% CI upper 63.4 49.0 38.7 30.8 24.5 Mean absolute change - -13.3 -23.4 -31.2 -37.4 from BLRelative change from BL* - -22.9 -40.4 -53.9 -64.6 Significance to BL - <0.001 <0.001 <0.001 <0.001 Significance to previous - <0.001 <0.001 0.003 0.018 time point

Claims

50 GRA 4178-foreign filingPatent claims:

1. One or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, relative to the total weight of dose unit, for use in the prevention or treatment of(i) a sleep disturbance, preferably in a patient having neuropathic pain; and / or(ii) neuropathic pain in a patient having a sleep disturbance; and / or(iii) neuropathic pain in a patient having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance.

2. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 1, for use in the treatment of a sleep disturbance, preferably in a patient having neuropathic pain.

3. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 1 or 2, for use in the treatment of neuropathic pain in a patient having a sleep disturbance.

4. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, for use in the treatment of neuropathic pain in a patient having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics, wherein the patient preferably has a sleep disturbance.

5. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, for use in the treatment of both, a sleep disturbance and neuropathic pain, in a patient having a sleep disturbance and neuropathic pain.

6. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, for use in the treatment of both, a sleep disturbance and neuropathic pain, in a patient having a sleep disturbance and neuropathic pain and having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics.

7. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, for use in the treatment of neuropathic pain, in a patient having a sleep disturbance and neuropathic pain, and having been treated previously and / or being51 GRA 4178-foreign filingtreated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics.

8. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, for use in the treatment of both, a sleep disturbance and neuropathic pain, in a patient having a sleep disturbance and neuropathic pain, and having been treated previously and / or being treated concomitantly with an analgesic medication for relief of neuropathic pain, preferably selected from antiepileptics, antidepressants and opioid analgesics.

9. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the sleep disturbance is associated with the neuropathic pain.

10. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 1 to 8, wherein the sleep disturbance is not associated with the neuropathic pain.

11. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the sleep disturbance is selected from disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence, disorders of sleep–wake schedule, and dysfunctions associated with sleep, sleep stages, or partial arousals (parasomnia).

12. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the sleep disturbance is selected from dyssomnia, insomnia, parasomnia and hypersomnia; preferably dyssomnia, insomnia; more preferably dyssomnia.

13. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the sleep disturbance includes impaired initiation of sleep.

14. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the sleep disturbance includes impaired quantity of sleep.

15. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the sleep disturbance includes impaired maintenance of sleep.52 GRA 4178-foreign filing16. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the sleep disturbance includes respiratory problems; preferably shortness of breath.

17. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the sleep disturbance includes impaired perceived adequacy of sleep.

18. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the sleep disturbance includes daytime somnolence.

19. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain is moderate to severe.

20. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain is chronic.

21. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain includes peripheral neuropathic pain.

22. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain includes painful diabetic neuropathy.

23. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain includes postherpetic neuralgia.

24. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain includes peripheral nerve injury.

25. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain includes chemotherapy- induced neuropathic pain.

26. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain includes HIV-associated neuropathy.53 GRA 4178-foreign filing27. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain includes small-fiber neuropathy.

28. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain includes chronic idiopathic axonal polyneuropathy.

29. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain includes post-traumatic neuropathic pain.

30. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the neuropathic pain includes post-surgical neuropathic pain.

31. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the analgesic medication for relief of neuropathic pain has been or is administered systemically, preferably orally or transdermally.

32. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the analgesic medication for relief of neuropathic pain has been or is administered at least once daily.

33. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the analgesic medication for relief of neuropathic pain is an antiepileptic such as carbamazepine, clonazepam, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, phenytoin, pregabalin, topiramate, or valproate; preferably gabapentin or pregabalin.

34. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the analgesic medication for relief of neuropathic pain is an antidepressant such as amitriptyline, clomipramine, desipramine, doxepin, duloxetine, imipramine, nortriptyline, venlafaxine, mirtazapine, or protriptyline; preferably amitriptyline or duloxetine.

35. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the analgesic medication for relief of neuropathic pain is an opioid analgesic such as buprenorphine, fentanyl, hydromorphone, hydrocodone, methadone, morphine, oxycodone, oxymorphone, tapentadol, or tramadol; preferably tapentadol or fentanyl.54 GRA 4178-foreign filing36. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims in a patient who upon previous topical administration of capsaicin and / or capsaicinoid did not perceive pain relief by at least 30% versus baseline.

37. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein with regard to previous topical administration of capsaicin and / or capsaicinoid the patient is selected from complete non-responders and insufficient responders.

38. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims in a female patient.

39. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 1 to 37 in a male patient.

40. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims in an adult patient.

41. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims in a geriatric patient.

42. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 40 or 41, wherein the age of the patient is at least 60 years.

43. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the patient has a baseline modified pain disability index (mPDI-6, mPDI subscale #6) sleep score (mm VAS) of at least 25, preferably at least 30, more preferably at least 35, still more preferably at least 40, yet more preferably at least 45, even more preferably at least 50, most preferably at least 55, and in particular at least 60.

44. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the concentration of the capsaicin and / or capsaicinoid is at least 5 wt.-%, relative to the total weight of dose unit.

45. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the concentration of the capsaicin and / or capsaicinoid is at least 8 wt.-%, relative to the total weight of dose unit.

46. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are applied to the skin of the patient, whereby the patient perceives pain relief by at least 30% versus baseline.55 GRA 4178-foreign filing47. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are applied to the skin of the patient, whereby the patient perceives pain relief by at least 30% versus baseline for at least 8 weeks.

48. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are applied to the skin of the patient for an application period of 15 to 90 minutes and subsequently removed.

49. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 48, wherein the application period is 30 to 60 minutes.

50. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are used for long term treatment.

51. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 50, wherein subsequent application of one or more another high-concentration capsaicin and / or capsaicinoid dose units is repeated at least once, preferably more than once, preferably at least three times, at least four times, at least five times, at least six times, at least seven times, at least eight times, or even more frequently, preferably in each case independently of one another 2 to 4 months after the preceding application.

52. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein (i) an initial first application of one or more high- concentration capsaicin and / or capsaicinoid dose units is performed thereby commencing a treatment period; (ii) 2 to 4 months after the preceding first application, a subsequent second application of one or more another high-concentration capsaicin and / or capsaicinoid dose units is performed thereby continuing the treatment period; (iii) 2 to 4 months after the preceding second application, a subsequent third application of one or more another high-concentration capsaicin and / or capsaicinoid dose units is performed thereby continuing the treatment period; (iv) optionally, 2 to 4 months after the preceding third application, a subsequent fourth application of one or more another high-concentration capsaicin and / or capsaicinoid dose units is performed thereby continuing the treatment period; (v) optionally, 2 to 4 months after the preceding fourth application, a subsequent fifth application of one or more another high-concentration capsaicin and / or capsaicinoid dose units is performed thereby continuing the treatment period; and (vi) optionally, 2 to 4 months after the preceding fifth application, a subsequent sixth application of one or more another high-concentration capsaicin and / or capsaicinoid dose units is performed thereby continuing the treatment period.56 GRA 4178-foreign filing53. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 50 to 52, wherein long term treatment lasts at least 6 months, preferably at least 9 months, more preferably at least 12 months, still more preferably more than 1 year, yet more preferably at least 15 months, even more preferably at least 18 months, most preferably at least 21 months, and in particular at least 24 months.

54. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 50 to 53, wherein the last subsequent application of one or more another high-concentration capsaicin and / or capsaicinoid dose units is performed at least 6 months, preferably at least 9 months, more preferably at least 12 months, still more preferably more than 1 year, yet more preferably at least 15 months, even more preferably at least 18 months, most preferably at least 21 months, and in particular at least 24 months after the initial first application commencing the treatment period.

55. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 50 to 54, wherein the patient has been treated previously and / or is treated concomitantly with an analgesic medication for relief of neuropathic pain, and wherein the administered dose of said analgesic medication is decreased or terminated in the course of long term treatment.

56. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 55, wherein after 12 months of long term treatment, the administered dose, preferably the average weekly dose of said analgesic medication is lower than the dose, preferably average weekly dose of said analgesic medication that was administered before long term treatment was commenced.

57. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 55 or 56, wherein after 12 months of long term treatment, the administered dose, preferably the average weekly dose of said analgesic medication is at most 80%, preferably at most 70%, more preferably at most 60%, still more preferably at most 50%, yet more preferably at most 40%, even more preferably at most 30%, most preferably at most 20%, and in particular at most 10% of the dose, preferably average weekly dose of said analgesic medication that was administered before long term treatment was commenced.

58. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 55 to 57, wherein after 12 months of long term treatment, the administered dose, preferably the average weekly dose of said analgesic medication is lower than the dose, preferably average weekly dose of said analgesic medication that was administered during the interval after initial first application of one or more high-concentration capsaicin and / or57 GRA 4178-foreign filingcapsaicinoid dose units and before the first subsequent application of one or more another high- concentration capsaicin and / or capsaicinoid dose units.

59. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 55 to 58, wherein after 12 months of long term treatment, the administered dose, preferably average weekly dose of said analgesic medication is at most 80%, preferably at most 70%, more preferably at most 60%, still more preferably at most 50%, yet more preferably at most 40%, even more preferably at most 30%, most preferably at most 20%, and in particular at most 10% of the dose, preferably average weekly dose of said analgesic medication that was administered during the interval after initial first application of one or more high-con- centration capsaicin and / or capsaicinoid dose units and before the first subsequent application of one or more another high-concentration capsaicin and / or capsaicinoid dose units.

60. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 55 to 59, wherein after 12 months of long term treatment, said analgesic medication is not administered any longer.

61. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are applied to the skin of the patient 2 to 4 months after previous topical administration of capsaicin and / or capsaicinoid.

62. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 61, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are applied to the skin of the patient [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days, after previous topical administration of capsaicin and / or capsaicinoid.

63. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 61, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are applied to the skin of the patient [s] about 3 months, e.g. 90 days, after previous topical administration of capsaicin and / or capsaicinoid.

64. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein the patient did not perceive pain relief by at least 30% versus baseline upon repeated previous topical administrations of capsaicin and / or capsaicinoid.

65. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 64, wherein the one or more high-concentration capsaicin and / or capsaicinoid58 GRA 4178-foreign filingtopical dose units are applied to the skin of the patient 2 to 4 months after the last topical administration of said repeated previous topical administrations.

66. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 65, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are applied to the skin of the patient [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days, after the last topical administration of said repeated previous topical administrations.

67. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 65, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are applied to the skin of the patient [s] about 3 months, e.g. 90 days, after the last topical administration of said repeated previous topical administrations.

68. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein previous topical administration of capsaicin and / or capsaicinoid was achieved or wherein repeated previous topical administrations were achieved by applying one or more high-concentration capsaicin and / or capsaicinoid topical dose units to the skin of the patient.

69. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 68, wherein said one or more high-concentration capsaicin and / or capsaicinoid topical dose units previously applied were of the same kind as the one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use.

70. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein previous topical administration of capsaicin and / or capsaicinoid was achieved by applying one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid to the skin of the patient for a first application period of 15 to 90 minutes thereby previously topically administering capsaicin and / or capsaicinoid during the first application period, and were subsequently removed; preferably whereby the patient did not perceive pain relief by at least 30% versus baseline; and wherein (b-i) 2 to 4 months after the first application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a second application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the second application period, and are subsequently removed; and (b-ii) optionally, 2 to 4 months after the second application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a third application period of 15 to 90 minutes thereby topically administering59 GRA 4178-foreign filingcapsaicin and / or capsaicinoid during the third application period, and are subsequently removed; and (b-iii) optionally, 2 to 4 months after the third application period, one or more high-concen- tration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a fourth application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and are subsequently removed; and (b-iv) optionally, 2 to 4 months after the fourth application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a fifth application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the fifth application period, and are subsequently removed.

71. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 70, wherein (b-i) [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days, after the first application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a second application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the second application period, and are subsequently removed; and (b-ii) optionally, [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days, after the second application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a third application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the third application period, and are subsequently removed; and (b-iii) optionally, [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days, after the third application period, one or more high- concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a fourth application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and are subsequently removed; and (b-iv) optionally, [f] less than 90 days, more preferably less than 84 days, still more preferably 60 to 83 days, yet more preferably about 2 months, e.g. 60 days, after the fourth application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a fifth application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the fifth application period, and are subsequently removed.60 GRA 4178-foreign filing72. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 70, wherein (b-i) [s] about 3 months, e.g. 90 days, after the first application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a second application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the second application period, and are subsequently removed; and (b-ii) optionally, [s] about 3 months, e.g. 90 days, after the second application period, one or more high- concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a third application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the third application period, and are subsequently removed; and (b-iii) optionally, [s] about 3 months, e.g.90 days, after the third application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a fourth application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and are subsequently removed; and (b-iv) optionally, [s] about 3 months, e.g. 90 days, after the fourth application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a fifth application period of 15 to 90 minutes thereby topically administering capsaicin and / or capsaicinoid during the fifth application period, and are subsequently removed.

73. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein each of said one or more high-concentration capsaicin and / or capsaicinoid topical dose units is a high-concentration capsaicin and / or capsaicinoid pharmaceutical patch comprising capsaicin and / or capsaicinoid at a concentration of at least 2.5 wt.-%, relative to the total weight of the patch without release liner.

74. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 73, wherein the concentration of the capsaicin and / or capsaicinoid is at least 5 wt.-%, relative to the total weight of the patch without release liner.

75. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 73 or 74, wherein the concentration of the capsaicin and / or capsaicinoid is at least 8 wt.-%, relative to the total weight of the patch without release liner.

76. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 73 to 75, wherein each high-concentration capsaicin and / or capsaicinoid pharmaceutical patch comprises a backing layer, an adhesive layer, and a release liner; and61 GRA 4178-foreign filingwherein the content of capsaicin and / or capsaicinoid is at least 6.0 wt.-%, relative to the total weight of the pharmaceutical patch without release liner.

77. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 76, wherein the content of capsaicin and / or capsaicinoid is about 8.0 wt.-%, relative to the total weight of the pharmaceutical patch without release liner.

78. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 73 to 77, wherein each high-concentration capsaicin and / or capsaicinoid pharmaceutical patch comprises capsaicin and / or capsaicinoid at a content of at least 400 micrograms of capsaicin and / or capsaicinoid per cm2of patch.

79. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 78, wherein the content is about 640 micrograms of capsaicin and / or capsaicinoid per cm2of patch.

80. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein each of said one or more high-concentration capsaicin and / or capsaicinoid topical dose units is a high-concentration capsaicin topical dose unit.

81. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, wherein (a) one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a first application period thereby topically administering capsaicin and / or capsaicinoid during the first application period, and are subsequently removed; (b) W days after the first application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a second application period thereby topically administering capsaicin and / or capsaicinoid during the second application period, and are subsequently removed; (c) optionally, X days after the second application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a third application period thereby topically administering capsaicin and / or capsaicinoid during the third application period, and are subsequently removed; (d) optionally, Y days after the third application period, one or more high-con- centration capsaicin and / or capsaicinoid topical dose units comprising capsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a fourth application period thereby topically administering capsaicin and / or capsaicinoid during the fourth application period, and are subsequently removed; and (e) optionally, Z days after the fourth application period, one or more high-concentration capsaicin and / or capsaicinoid topical dose units comprising62 GRA 4178-foreign filingcapsaicin and / or capsaicinoid are applied to the skin of the patient, remain on the skin for a fifth application period thereby topically administering capsaicin and / or capsaicinoid during the fifth application period, and are subsequently removed; wherein W and X independently of one another are an integer within the range of from 60 to 120; and Y and Z independently of one another are an integer within the range of from 60 to 120.

82. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 81, wherein W and X independently of one another are an integer within the range of from 60 to 109.

83. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 81 or 82, wherein W is an integer within the range of from (i) 60 to 109; preferably 60 to 91, or 60 to 90, or 60 to 89, or 60 to 85, or 60 to 84, or 60 to 83, or 60 to 69, or 60 to 68, or 60 to 67, or 60 to 64, or 60 to 63, or 60 to 62; or exactly 60; (ii) 62 to 109; preferably 62 to 91, or 62 to 90, or 62 to 89, or 62 to 85, or 62 to 84, or 62 to 83, or 62 to 69, or 62 to 68, or 62 to 67, or 62 to 64, or 62 to 63; (iii) 63 to 109; preferably 63 to 91, or 63 to 90, or 63 to 89, or 63 to 85, or 63 to 84, or 63 to 83, or 63 to 69, or 63 to 68, or 63 to 67, or 63 to 64; (iii) 64 to 109; preferably 64 to 91, or 64 to 90, or 64 to 89, or 64 to 85, or 64 to 84, or 64 to 83, or 64 to 69, or 64 to 68, or 64 to 67; (iv) 67 to 109; preferably 67 to 91, or 67 to 90, or 67 to 89, or 67 to 85, or 67 to 84, or 67 to 83, or 67 to 69, or 67 to 68; (v) 68 to 109; preferably 68 to 91, or 68 to 90, or 68 to 89, or 68 to 85, or 68 to 84, or 68 to 83, or 68 to 69; (vi) 69 to 109; preferably 69 to 91, or 69 to 90, or 69 to 89, or 69 to 85, or 69 to 84, or 69 to 83; (vii) 83 to 109; preferably 83 to 91, or 83 to 90, or 83 to 89, or 83 to 85, or 83 to 84; (viii) 84 to 109; preferably 84 to 91, or 84 to 90, or 84 to 89, or 84 to 85; (ix) 85 to 109; preferably 85 to 91, or 85 to 90, or 85 to 89; (x) 89 to 109; preferably 89 to 91, or 89 to 90; (xi) 90 to 109; preferably 90 to 91; or (xii) 91 to 109.

84. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 81 to 83, wherein X is an integer within the range of from (i) 60 to 109; preferably 60 to 91, or 60 to 90, or 60 to 89, or 60 to 85, or 60 to 84, or 60 to 83, or 60 to 69, or 60 to 68, or 60 to 67, or 60 to 64, or 60 to 63, or 60 to 62; or exactly 60; (ii) 62 to 109; preferably 62 to 91, or 62 to 90, or 62 to 89, or 62 to 85, or 62 to 84, or 62 to 83, or 62 to 69, or 62 to 68, or 62 to 67, or 62 to 64, or 62 to 63; (iii) 63 to 109; preferably 63 to 91, or 63 to 90, or 63 to 89, or 63 to 85, or 63 to 84, or 63 to 83, or 63 to 69, or 63 to 68, or 63 to 67, or 63 to 64; (iii) 64 to 109; preferably 64 to 91, or 64 to 90, or 64 to 89, or 64 to 85, or 64 to 84, or 64 to 83, or 64 to 69, or 64 to 68, or 64 to 67; (iv) 67 to 109; preferably 67 to 91, or 67 to 90, or 67 to 89, or 67 to 85, or 67 to 84, or 67 to 83, or 67 to 69, or 67 to 68; (v) 68 to 109; preferably 68 to 91, or 68 to 90, or 68 to 89, or 68 to 85, or 68 to 84, or 68 to 83, or 68 to 69; (vi) 69 to 109; preferably 69 to 91, or 69 to 90, or 69 to 89, or 69 to 85, or 69 to 84, or 69 to 83; (vii) 83 to 109; preferably 83 to 91, or 83 to 90, or 83 to 89, or 83 to 85, or 83 to 84; (viii) 84 to 109; preferably 84 to 91, or 84 to 90, or63 GRA 4178-foreign filing84 to 89, or 84 to 85; (ix) 85 to 109; preferably 85 to 91, or 85 to 90, or 85 to 89; (x) 89 to 109; preferably 89 to 91, or 89 to 90; (xi) 90 to 109; preferably 90 to 91; or (xii) 91 to 109.

85. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 81 to 84, wherein W is an integer within the range of from 60 to 109, preferably 60 to 89, more preferably 60 to 83; and X is an integer within the range of from 60 to 109, preferably 60 to 89, more preferably 60 to 83.

86. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 81 to 85, wherein (i) the average over W and X is within the range of from 60.0 to 68.0, or from 69.0 to 83.0; (ii) the average over W, X, and Y is within the range of from 60.0 to 68.0, or from 69.0 to 83.0; or (iii) the average over W, X, Y and Z is within the range of from 60.0 to 68.0, or from 69.0 to 83.0.

87. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 81 to 86, wherein W < X.

88. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 81 to 87, wherein Y and Z independently of one another are an integer within the range of from 60 to 110.

89. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, which are for use in the treatment of neuropathic pain in a patient having a sleep disturbance, wherein the patient did not perceive pain relief by at least 30% versus baseline upon a previous topical administration of one or more high-concentration capsaicin and / or capsaicinoid topical dose units, and wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use are applied to the skin of the patient 2 to 4 months after said previous topical administration.

90. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 89, wherein the concentration of the capsaicin and / or capsaicinoid is at least 5 wt.-%, relative to the total weight of the dose unit.

91. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 89 or 90, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are a pharmaceutical patch.

92. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 89 to 91, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are applied to the skin of the patient less than 90 days after the previous topical administration.64 GRA 4178-foreign filing93. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 92, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are applied to the skin of the patient about 2 months after the previous topical administration.

94. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 89 to 93, wherein the patient is selected from complete non-responders and insufficient responders with regard to the previous topical administration.

95. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 89 to 94, wherein as a consequence of the application, the patient perceives a pain relief of at least 30% versus baseline.

96. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of the preceding claims, which are for use in the treatment of neuropathic pain in a patient having a sleep disturbance, wherein the patient is treated concomitantly with an analgesic medication for relief of neuropathic pain, wherein the one or more high-concentration capsaicin and / or capsaicinoid topical dose units are used for long term treatment, and wherein the administered dose of said analgesic medication is decreased or terminated in the course of the long term treatment.

97. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 96, wherein the long term treatment comprises repeated application of one or more high-concentration capsaicin and / or capsaicinoid topical dose units, wherein each application is separated by an interval of 2 to 4 months.

98. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 96 or 97, wherein the long term treatment lasts at least 12 months.

99. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 96 to 98, wherein after 12 months of long term treatment, the average weekly dose of said analgesic medication is lower than the average weekly dose of said analgesic medication that was administered before the long term treatment was commenced.

100. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 99, wherein after 12 months of long term treatment, the average weekly dose of said analgesic medication is at most 80%, preferably at most 50%, of the average weekly dose that was administered before the long term treatment was commenced.65 GRA 4178-foreign filing101. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 96 to 100, wherein after 12 months of long term treatment, said analgesic medication is not administered any longer.

102. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 96 to 101, wherein the sleep disturbance is associated with the neuropathic pain.

103. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 96 to 102, wherein the sleep disturbance includes impaired initiation of sleep, impaired quantity of sleep, or impaired maintenance of sleep.

104. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 96 to 103, wherein the neuropathic pain includes peripheral neuropathic pain.

105. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to claim 104, wherein the peripheral neuropathic pain includes painful diabetic neuropathy, postherpetic neuralgia, or peripheral nerve injury.

106. The one or more high-concentration capsaicin and / or capsaicinoid topical dose units for use according to any of claims 96 to 105, wherein the analgesic medication is selected from antiepileptics, antidepressants, and opioid analgesics.

Images