The site of action of topical capsaicin is in the skin, and pain relief is not mediated by transdermal systemic delivery. Owing to near insolubility in water, capsaicin is not readily absorbed into the microvasculature. When cutaneous nociceptors are hypersensitive and sometimes spontaneously active, localized defunctionalization of capsaicin-responsive nerve fibre terminals in the epidermis and dermis can reduce the afferent barrage which may drive pain syndromes. Inset shows how mitochondrial dysfunction leads to nerve terminal retraction.

The site of action of topical capsaicin is in the skin, and pain relief is not mediated by transdermal systemic delivery. Owing to near insolubility in water, capsaicin is not readily absorbed into the microvasculature. When cutaneous nociceptors are hypersensitive and sometimes spontaneously active, localized defunctionalization of capsaicin-responsive nerve fibre terminals in the epidermis and dermis can reduce the afferent barrage which may drive pain syndromes. Inset shows how mitochondrial dysfunction leads to nerve terminal retraction.

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Topical capsaicin formulations are used for pain management. Safety and modest efficacy of low-concentration capsaicin formulations, which require repeated daily self-administration, are supported by meta-analyses of numerous studies. A high-concentration capsaicin 8% patch (Qutenza™) was recently approved in the EU and USA. A single 60-min applica...

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... Kandungan capsaicin dalam cabai rawit (Capsicum frutescens L.) memiliki banyak khasiat berdasarkan beberapa hasil penelitian (Fattori et al., 2016). Capsaicin dapat digunakan sebagai antibiotik (Zeyrek and Oguz, 2005), analgesik (Anand and Bley, 2011), pestisida (Maliszewska and Tegowska, 2012), dan antiinflamasi (Jolayemi and Ojewole, 2013). Berdasarkan penelitian yang dilakukan oleh Jolayemi dan Ojewole (2013), capsaicin memiliki efek antiinflamasi yang sebanding dengan efek antiinflamasi diklofenak yang diujikan ke tikus. ...
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Cayenne pepper (Capsicum frutescens L.) is a plant that has many benefits, one of which is as an anti-inflammatory. The anti-inflammatory effect of cayenne pepper was tested on white rats in the form of a gel. Two gel formulas were used with different concentrations of propylene glycol as additive, 25% and 30%, respectively. White rats were grouped into 4 groups, negative control group (gel base), positive control group (Voltaren® Emulgel), gel formula 1 group (enhancer 25%), and gel formula 2 (enhancer 30%). Albumen was induced on the backs of white rats then samples were given. Skinfold thickness measurements were taken every 1 hour for 6 hours. The data obtained in the form of skin thickness values (mm). The % Inflammation Inhibition (% PI) was calculated for each sample. Formula 1 and Formula 2 gave %PI of 32.58 ± 1.80 and 40.75 ± 5.71, respectively. Both formulas had an anti-inflammatory effect against edema on the back of rats although not better than Voltaren® Emulgel. Based on One Way ANOVA test, Formula 2 has a better anti-inflammatory effect than Formula 1. LSD test results show that %PI Formula 2 is similar to %PI Voltaren® Emulgel with a significance value of 0.117 (>0.05).
... Second, a similar previous study showed no significant damage to the unmyelinated nerve fibers following the perineural application of RTX on the sciatic nerve [47,48]. Third, decreased PGP-9.5 labelling of the cutaneous nerves after intraplantar injection, cream application and patch application of capsaicin was found to be reversible [19,45,46,49]. Fourth, further support from another study showed no difference in the transport of neuroanatomical tracer wheat germ agglutinin conjugated with horse-radish-peroxidase (WGA-HRP) when injected into the contralateral sciatic nerve compared with the ipsilateral nerve perineurally treated with capsaicin [50]. ...
... Capsaicin and its analogue RTX have been extensively used to investigate the pathophysiology and their analgesic effects in acute and chronic pain. The analgesic effects of capsaicin and RTX are based on the observations of their initial activation which leads to the excitation of the sensory neurons in the DRG and the spinal cord through TRPV1, followed by a refractory state in which neurons do not respond to various stimuli by a process described as "defunctionalization" [19]. Capsaicin and RTX act through their specific receptor TRPV1 on the unmyelinated and thinly myelinated nerve fibers that originate from small-and medium-sized neurons in the DRG [57]. ...
... The topical application of capsaicin is used widely as a tool for producing, as well as treating, pain in both clinical and preclinical studies. Either a low dose of capsaicin cream (<1% applied 2-3 times per day for 6-8 weeks) or a higher dose (8% as a single application) have been used as topical treatments for neuropathic pain [19]. However, evidence for the effectiveness of topical capsaicin is equivocal. ...
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... 33 Similarly, 2-AG, 2-LG and 2-OG were reported to be synthesized in TRPV1 transfected HEK cells following heat and capsaicin stimulation, 34 indicating a role in nociception. Further, as 2-AG can elicit calcium transients in transfected CHO cells, via PLC coupled signalling, 35 it is possible that cannabinoid mediated calcium influx can contribute to neuronal desensitization, similar to the desensitizing effects of capsaicin, 12,36 ...
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... TRPV1 receptor agonist[41]. ...
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... A double-blind randomized study on 70 osteoarthritis patients and 31 rheumatoid arthritis patients showed that the topical application of capsaicin cream (0.025%) for 4 weeks remarkably reduced the pain by 57 and 33% in osteoarthritis and rheumatoid arthritis patients, respectively (Deal et al., 1991). The substance P is responsible for the pain sensation and the initial application of topical capsaicin released substance P from sensory nerve fibers but the repeated application of capsaicin cream depleted the substance P availability (Anand & Bley, 2011;Rumsfield & West, 1991). Capsaicin depleted the substance P from various sites of the body like dorsal root ganglia, dorsal spinal cord, sites of the cell bodies, and central terminals of primary afferent neurons (Burks, Buck, & Miller, 1985). ...
... Capsaicin was also shown to decrease rheumatoid arthritis pain, inflammatory heat, and noxious chemical hyperalgesia (Fraenkel, Bogardus, Concato, & Wittink, 2004). Anand and Bley (2011) showed that the effect of capsaicin at 8% patches (a high dose) ...
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... These processes have been considered as potential mechanisms of the analgesic action of topical capsaicin treatment, but several clinical studies proved that SP receptor antagonists failed to be analgesics [22]. Anand and Bley (2011) suggested that capsaicin has limited potential for transdermal delivery across human skin and that it causes defunctionalization only of the cutaneous nociceptors [23]. ...
... These processes have been considered as potential mechanisms of the analgesic action of topical capsaicin treatment, but several clinical studies proved that SP receptor antagonists failed to be analgesics [22]. Anand and Bley (2011) suggested that capsaicin has limited potential for transdermal delivery across human skin and that it causes defunctionalization only of the cutaneous nociceptors [23]. ...
... It might be puzzling how such a small capsaicin content might exert effective analgesia. Antinociceptive effects developed in the deeper musculoskeletal and joint areas could not be explained by the desensitization of the cutaneous afferents [23]. The activation of TRPV1 ion channels and consequent elevation of intracellular Ca 2+ concentration induces neuropeptide release but does not damage the nerve endings. ...
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Transdermal therapeutic systems (TTSs) enable convenient dosing in drug therapy. Modified silicone-polymer-based patches are well-controlled and cost-effective matrix diffusion systems. In the present study, we investigated the substance release properties, skin penetration, and analgesic effect of this type of TTS loaded with low-dose capsaicin. Release properties were measured in Franz diffusion cell and continuous flow-through cell approaches. Capsaicin was detected with HPLC-UV and UV spectrophotometry. Raman spectroscopy was conducted on human skin samples exposed to the TTS. A surgical incision or carrageenan injection was performed on one hind paw of male Wistar rats. TTSs were applied to the epilated dorsal skin. Patches were kept on the animals for 6 h. The thermal hyperalgesia and mechanical pain threshold of the hind paws were detected. Patches exhibited controlled, zero-order kinetic capsaicin release. According to the Raman mapping, capsaicin penetrated into the epidermis and dermis of human skin, where the target receptors are expressed. The thermal pain threshold drop of the operated rat paws was reversed by capsaicin treatment compared to that of animals treated with control patches. It was concluded that our modified silicone-polymer-based capsaicin-containing TTS is suitable for the relief of traumatic and inflammatory pain.
... Activation of transient receptor potential vanilloid-1 expressing nociceptor on skin causes loss of function of the sensory nerve fibers by loss of membrane potential and inability to transport neurotrophic factors, leading to an altered phenotype and reversible retraction of epidermal and dermal nerve fiber terminals. 5 Advantages of CP8 include a longer-lasting effect, patient compliance, and low risk for systemic effects or drugedrug interactions, unlike treatments usually recommended for NP. 6 We report 13 patients with neuropathic CPSP after excision of a skin melanoma treated with CP8 at a single academic institution over a 40-month period. Response to treatment and adverse effects are presented. ...
... Chronic pain can be a severe clinical manifestation of diabetic peripheral neuropathy, with a prevalence ranging from 8-30% reported in several studies of long-standing DM (1). The underlying mechanisms leading to small fiber sensory polyneuropathy and the associated pain in diabetes are diverse (2)(3)(4)(5)(6). ...
... It has been used to treat peripheral neuropathic pain as licensed in the EU, including PDPN, and for treating post-herpetic neuralgia (PHN) and PDPN, as licensed in the USA. The evidence and mechanisms for pain relief by capsaicin 8% patch (Qutenza) have been reviewed (2,(10)(11)(12)(13). Interestingly, pain relief may persist for months after a single 30-min capsaicin 8% patch application in PDPN, as reported in 1/3 subjects (14). ...
... The application of high dose capsaicin leads to "defunctionalisation, " a term which encompasses a number of sequential effects, that include capsaicin receptor TRPV1 desensitization, temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fiber terminals (2). The early stages are akin to deep pruning of nociceptors, which triggers nerve regeneration, and which in turn may be healthier if the milieu is conducive; the latter may explain the prolonged analgesic effect in some patients. ...
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Introduction Current oral treatments for pain in diabetic peripheral neuropathy (DPN) do not affect the progression of DPN i.e., “disease modification.” We assessed whether Capsaicin 8% patch treatment can provide pain relief and also restore nerve density and function via nerve regeneration, in both painful (PDPN) and non-painful (NPDPN) diabetic peripheral neuropathy. Methods 50 participants with PDPN were randomized to receive Capsaicin 8% patch Qutenza with Standard of Care (SOC) (PDPN Q+SOC group), or SOC alone (PDPN SOC group). Pain symptoms were assessed with a diary (Numerical Pain Rating Scale, NRPS) and questionnaires. Investigations included quantitative sensory testing (QST) and distal calf skin biopsies, at baseline and 3 months after baseline visit; subsequent options were 3-monthly visits over 1 year. 25 participants with NPDPN had tests at baseline, and 3 months after all received Capsaicin 8% patch treatment. Results At 3 months after baseline, PDPN Q+SOC group had reduction in NPRS score ( p = 0.0001), but not PDPN SOC group. Short-Form McGill Pain Questionnaire (SF-MPQ) showed significant reductions in scores for overall and other pain descriptors only in the PDPN Q+SOC group. Warm perception thresholds were significantly improved only in the PDPN Q+SOC group ( p = 0.02), and correlated with reduction in SF-MPQ overall pain score ( p = 0.04). NPDPN Q+SOC group did not report pain during the entire study. Density of intra-epidermal nerve fibers (IENF) with PGP9.5 was increased at 3 months in PDPN Q+SOC ( p = 0.0002) and NPDPN Q+SOC ( p = 0.002) groups, but not in the PDPN SOC group. Increased sub-epidermal nerve fibers (SENF) were observed with GAP43 (marker of regenerating nerve fibers) only in PDPN Q+SOC ( p = 0.003) and NPDPN Q+SOC ( p = 0.0005) groups. Pain relief in the PDPN Q+SOC group was correlated with the increased PGP9.5 IENF ( p = 0.0008) and GAP43 ( p = 0.004), whereas those with lack of pain relief showed no such increase; in some subjects pain relief and increased nerve fibers persisted over months. PGP9.5 IENF increase correlated with axon-reflex vasodilatation in a NPDPN Q+SOC subset ( p = 0.006). Conclusions Capsaicin 8% patch can provide pain relief via nerve regeneration and restoration of function in DPN (disease modification). It may thereby potentially prevent diabetic foot complications, including ulcers.
... In addition, direct pharmacological desensitization of plasma membrane and inactivation of voltage-gated Na + channels by TRPV-1 receptors can result in impromptu reduction on neuronal responsiveness and excitability. Anand and Bley [230] further added that excessive concentration of capsaicin (than required) to TRPV1 can result in antagonist effect in mitochondrial dysfunction by inhibiting openly electron chain transport. Further findings had reported that capsaicin can interact with nerve endings, which is transgerminal in nature, and release a neurotransmitter called substance P. Substance P is a neuropeptide, which follows amino acid sequence as Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met [RPKPQQFFGLM]). ...
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Worldwide, since ages and nowadays, traditional medicine is well known, owing to its biodiversity, which immensely contributed to the advancement and development of complementary and alternative medicines. There is a wide range of spices, herbs, and trees known for their medicinal uses. Chilli peppers, a vegetable cum spice crop, are bestowed with natural bioactive compounds, flavonoids, capsaicinoids, phytochemicals, phytonutrients, and pharmacologically active compounds with potential health benefits. Such compounds manifest their functionality over solo-treatment by operating in synergy and consortium. Co-action of these compounds and nutrients make them potentially effective against coagulation, obesity, diabetes, inflammation, dreadful diseases, such as cancer, and microbial diseases, alongside having good anti-oxidants with scavenging ability to free radicals and oxygen. In recent times, capsaicinoids especially capsaicin can ameliorate important viral diseases, such as SARS-CoV-2. In addition, capsaicin provides an ability to chilli peppers to ramify as topical agents in pain-relief and also benefitting man as a potential effective anesthetic agent. Such phytochemicals involved not only make them useful and a much economical substitute to wonder/artificial drugs but can be exploited as obscene drugs for the production of novel stuffs. The responsibility of the TRPV1 receptor in association with capsaicin in mitigating chronic diseases has also been justified in this study. Nonetheless, medicinal studies pertaining to consumption of chilli peppers are limited and demand confirmation of the findings from animal studies. In this artifact, an effort has been made to address in an accessible format the nutritional and biomedical perspectives of chilli pepper, which could precisely upgrade and enrich our pharmaceutical industries towards human well-being.