In the European Union, the high-concentration capsaicin patch is licensed for the management of neuropathic pain conditions in nondiabetic patients, including postherpetic neuralgia (PHN) and HIV-associated distal sensory polyneuropathy (HIV-DSP). However, in the USA, the Food and Drug Administration approved its use only in PHN patients. Capsaicin is a transient receptor potential vanilloid-1 agonist, which increases the intracellular calcium ion concentration. This triggers calcium-dependent protease enzymes causing cytoskeletal breakdown and leads to the loss of cellular integrity and ‘defunctionalization’ of nociceptor fibres. Efficacy and therapeutic effect has been shown in several clinical studies of PHN and HIV-DSP. The high-concentration capsaicin patch and its practical application are different from low-concentration creams; one application can help for up to 3 months. The process of setting up of a service to use the capsaicin 8% patch is also discussed.
Capsaicin; high concentration patch; neuropathic pain; post herpetic neauralgia; HIV; efficacy
In ancient times, physicians had a limited number of therapies to provide pain relief. Not surprisingly, plant extracts applied topically often served as the primary analgesic plan. With the discovery of the capsaicin receptor (TRPV1), the search for ‘new’ analgesics has returned to compounds used by physicians thousands of years ago. One such compound, capsaicin, couples the paradoxical action of nociceptor activation (burning pain) with subsequent analgesia following repeat or high-dose application. Investigating this ‘paradoxical’ action of capsaicin has revealed several overlapping and complementary mechanisms to achieve analgesia including receptor desensitization, nociceptor dysfunction, neuropeptide depletion and nerve terminal destruction. Moreover, the realization that TRPV1 is both sensitized and activated by endogenous products of inflammation including bradykinin, H+, ATP, fatty acid derivatives, NGF and trypsins, has renewed interest in TRPV1 as an important site of analgesia. Building on this foundation, a new series of preclinical and clinical studies targeting TRPV1 have been reported. These include trials using brief exposure to high-dose topical capsaicin in conjunction with prior application of a local anesthetic. Clinical use of resiniferatoxin (RTX), another ancient but potent TRPV1 agonist, is also being explored as a therapy for refractory pain. The development of orally-administered high affinity TRPV1 antagonists hold promise for pioneering a new generation of analgesics capable of blocking painful sensations at the site of inflammation and tissue injury. With the isolation of other members of the TRP channel family such as TRPA1, additional opportunities are emerging in the development of safe and effective analgesics.
Analgesics; Non-Narcotic; Pain; Sensory Receptors; transient receptor potential cation channel; TRP channels; TRPV1; capsaicin receptor
Topical creams with capsaicin are used to treat pain from a wide range of chronic conditions including neuropathic pain. Following application to the skin capsaicin causes enhanced sensitivity to noxious stimuli, followed by a period with reduced sensitivity and, after repeated applications, persistent desensitisation. There is uncertainty about the efficacy and tolerability of capsaicin for treating painful chronic neuropathies.
To review the evidence from controlled trials on the efficacy and tolerability of topically applied capsaicin in chronic neuropathic pain in adults.
Cochrane CENTRAL, MEDLINE, EMBASE and Oxford Pain Relief Database, searched in May 2009.
Randomised, double blind, placebo controlled studies of at least six weeks’ duration, using topical capsaicin to treat neuropathic pain.
Data collection and analysis
Two review authors independently assessed trial quality and validity, and extracted data. Information was extracted on numbers of participants with pain relief (clinical improvement) after at least six weeks, and with local skin reactions, and used to calculate relative risk and numbers needed to treat to benefit (NNT) and harm (NNH). Details of definition of pain relief and specific adverse events were sought.
Six studies (389 participants in total) compared regular application of low dose (0.075%) capsaicin cream with placebo cream; the NNT for any pain relief over six to eight weeks was 6.6 (4.1 to 17). Two studies (709 participants in total) compared a single application of high dose (8%) capsaicin patch with placebo patch; the NNT for ≥ 30% pain relief over twelve weeks was 12 (6.4 to 70). Local skin reactions were more common with capsaicin, usually tolerable, and attenuated with time; the NNH for repeated low dose application was 2.5 (2.1 to 3.1). There were insufficient data to analyse either data set by condition or outcome definition. All studies satisfied minimum criteria for quality and validity, but maintenance of blinding remains a potential problem.
Capsaicin, either as repeated application of a low dose (0.075%) cream, or a single application of a high dose (8%) patch may provide a degree of pain relief to some patients with painful neuropathic conditions. Local skin irritation, which is often mild and transient but may lead to withdrawal, is common. Systemic adverse effects are rare. Estimates of benefit and harm are not robust due to limited amounts of data for different neuropathic conditions and inconsistent outcome definition.
Administration, Topical; Analgesics [*administration & dosage; adverse effects]; Capsaicin [*administration & dosage; adverse effects]; Chronic Disease; Diabetic Neuropathies [drug therapy]; HIV Infections [complications]; Neuralgia [*drug therapy]; Neuralgia, Postherpetic [drug therapy]; Ointments; Pain, Postoperative [drug therapy]; Adult; Humans
Dilute capsaicin produces a differential effect on incision-related pain behaviors depending upon the test; it reduces heat hyperalgesia and guarding pain but not mechanical hyperalgesia. This suggests that common mechanisms for heat hyperalgesia and guarding pain occur, and distinct mechanisms exist for mechanical hyperalgesia. The purpose of the present study was to evaluate the effect of capsaicin treatment on the activity of cutaneous nociceptors sensitized by incision to understand the mechanisms for the selective action of dilute capsaicin on incisional pain. We compared the effect of 0.05% capsaicin versus vehicle treatment on pain behaviors after incision and on the activity of nociceptors from these same rats using the in vitro glabrous skin nerve preparation. Immunohistochemical expression of protein gene product 9.5 (PGP9.5), neurofilament 200, calcitonin gene related peptide (CGRP) and isolectin B4 (IB4) in skin was also evaluated 1 week after 0.05% capsaicin infiltration. Infiltration of 0.05% capsaicin decreased CGRP and IB4/PGP9.5-immunoreactivity of nociceptors in skin. The same dose of capsaicin that inhibited heat hyperalgesia and guarding behavior interfered with chemo- and heat sensitivity of C-fibers. Neither mechanical hyperalgesia nor mechanosensitivity of nociceptors was affected by capsaicin, suggesting that the concentration of capsaicin used in this study did not cause fiber degeneration. These results demonstrate that nociceptors desensitized by capsaicin contribute to heat hyperalgesia and guarding pain after plantar incision. These putative TRPV1-expressing C-fibers are sensitized to heat and acid after incision, and the transduction of heat and chemical stimuli after plantar incision is impaired by dilute capsaicin.
Application of the capsaicin 8% patch is associated with treatment-related discomfort. Consequently, pretreatment for 60 min with anaesthetic cream is recommended; however, this may be uncomfortable and time consuming.
We conducted a multicentre, randomized (1:1), assessor-blinded study in patients with peripheral neuropathic pain to assess tolerability of the capsaicin patch following topical lidocaine (4%) or oral tramadol (50 mg) pretreatment. The primary endpoint was the proportion of patients tolerating capsaicin patch application (ability to receive ≥90% of a 60-min application). Numeric Pain Rating Scale (NPRS) scores were assessed before, during and after treatment.
Overall, 122 patients were included (61 per arm). The capsaicin patch was tolerated by 121 patients. Tolerability of the capsaicin patch was similar following pretreatment with lidocaine and tramadol. Following patch application, pain levels increased up to 55 min (change from baseline of 1.3 for lidocaine and 1.4 for tramadol). After patch removal, tramadol-treated patients experienced greater pain relief up to the end of day 1; in the evening, mean changes in NPRS scores from baseline were 0 for lidocaine and −1 for tramadol. Proportions of patients reporting increases of ≥2 NPRS points or >33% from baseline at one or more time point(s) on the day of treatment were similar between arms. Adverse event incidence was comparable between arms.
Capsaicin 8% patch tolerability was similar in the two arms, with comparable results for most secondary endpoints. Tramadol given 30 min before patch application should be considered as an alternative pretreatment option in patients receiving capsaicin patch treatment.
What's already known about this topic?
Application of topical capsaicin, a treatment for peripheral neuropathic pain conditions associated with allodynia, can cause painful discomfort.
Therefore, a 60-min application of local anaesthetic cream before capsaicin 8% patch treatment was originally recommended.
What does this study add?
Oral analgesic pretreatment may reduce overall capsaicin patch treatment time and potential unpleasantness associated with applying a topical agent to an allodynic area.
Based on LIFT data showing similar tolerability to capsaicin patch regardless of pretreatment method, the European Medicines Agency has issued a type II variation stating: treatment area may be pretreated with a topical anaesthetic or an oral analgesic may be given prior to patch application.
Capsaicin, the pungent ingredient in hot pepper, activates nociceptors to produce pain and inflammation. However, prolonged exposures of capsaicin will cause desensitization to nociceptive stimuli. Hyperpolarization-activated cation currents (Ih) contribute to the maintenance of the resting membrane potential and excitability of neurons. In the cultured dorsal root ganglion (DRG) neurons, we investigated mechanisms underlying capsaicin-mediated modulation of Ih using patch clamp recordings. Capsaicin (1 µM) inhibited Ih only in the capsaicin-sensitive neurons. The capsaicin-induced inhibition of Ih was prevented by preexposing the TRPV1 antagonist, capsazepine (CPZ). Capsaicin-induced inhibition of Ih was dose dependent (IC50= 0.68 µM) and partially abolished by intracellular BAPTA and cyclosporin A, specific calcineurin inhibitor. In summary, the inhibitory effects of capsaicin on Ih are mediated by activation of TRPV1 and Ca2+-triggered cellular responses. Analgesic effects of capsaicin have been thought to be related to desensitization of nociceptive neurons due to depletion of pain-related substances. In addition, capsaicin-induced inhibition of Ih is likely to be important in understanding the analgesic mechanism of capsaicin.
capsaicin; DRG neuron; hyperpolarization-activated cation current; rat
The treatment of neuropathic pain is difficult. Oral pharmaceuticals have significant side effects, and treatment efficacy tends to be modest. The use of topical analgesics reduces the potential for systemic side effects and allows direct application of medications to the area of pain. The natural spicy substance, capsaicin, has historically been known for its topical use. Capsaicin, once applied to the skin, causes a brief initial sensitization followed by a prolonged desensitization of the local pain nerves. This occurs through stimulation of the transient receptor potential vanilloid-1 (TRPV1) expressing pain nerve fibers. While low-dose capsaicin has not resulted in good efficacy, the larger dose 8% topical capsaicin has had some of the best data currently available in the treatment of post-herpetic neuralgia (PHN) and other neuropathic conditions. This paper discusses the data currently existing for capsaicin 8% in the treatment of PHN. It further reviews data for the low-dose capsaicin products and the current status in the development of other capsaicinoids, e.g. resiniferotoxin, and high-concentration liquid capsaicin.
capsaicin; capsaicinoids; neuropathic pain; TRPV1
Capsaicin opens the TRPV1 channel, a cation channel that depolarizes and activates nociceptive neurons. Following this initial activation, neurons become desensitized to subsequent applications of capsaicin as well as to other noxious stimuli, a phenomenon attributed primarily to the entry of Ca2+ ions through the open TRPV1 channel. This ability of capsaicin to desensitize nociceptors has led to its use as an analgesic in the treatment of a variety of chronic pain states. Because treatment with capsaicin is initially quite painful, local anesthetics are sometimes used to block axonal conduction in nociceptive neurons and thus minimize pain. However, local anesthetics might also block TRPV1 and prevent the Ca2+ entry required for capsaicin-induced desensitization. We have studied the direct effect of local anesthetics on currents induced by capsaicin (1 μM) in acutely isolated rat dorsal root ganglion neurons using the whole cell patch clamp technique. At the highest concentration tested (1 mM), bupivacaine only moderately inhibited the capsaicin-induced current to 55 ± 27% of control (mean ± S.D.; n = 12, p < 0.01). Tetracaine (1 mM), on the other hand, enhanced the capsaicin-induced current to 151 ± 34% of control (mean ± S.D.; n = 7, p < 0.01). These results show that local anesthetics can be used to prevent the initial pain induced by application of capsaicin without abolishing, and perhaps even enhancing, its desensitizing actions.
Capsaicin; TRPV1; VR1; Ionic currents; Dorsal root ganglion neuron; Sensory neuron; Local anesthetics
Neuropathic pain is common and difficult to treat. Recently a technique was developed to selectively inhibit nociceptive inputs by simultaneously applying two drugs: capsaicin, a transient receptor potential vanilloid receptor 1 channel activator and QX-314, a lidocaine derivative that intracellularly blocks sodium channels. We used this technique to investigate whether transient receptor potential vanilloid receptor 1-expressing nociceptors contribute to neuropathic pain.
The rat chronic constriction injury model was used to induce neuropathic pain in order to test the analgesic effects of both peripheral (perisciatic) and central (intrathecal) administration of the QX-314/capsaicin combination. The Hargreaves and von Frey tests were used to monitor evoked pain-like behaviors and visual observations were used to rank spontaneous pain-like behaviors.
Perisciatic injections of the QX-314/capsaicin combination transiently increased the withdrawal thresholds by ~3 fold for mechanical and thermal stimuli in rats (n = 6/group) with nerve injuries suggesting that peripheral transient receptor potential vanilloid receptor 1-expressing nociceptors contribute to neuropathic pain. In contrast, intrathecal administration of the QX-314/capsaicin combination did not alleviate pain-like behaviors (n = 5/group). Surprisingly, intrathecal QX-314 alone (n = 9) or in combination with capsaicin (n = 8) evoked spontaneous pain-like behaviors.
Data from the perisciatic injections suggested that a component of neuropathic pain was mediated by peripheral nociceptive inputs. The role of central nociceptive terminals could not be determined because of the severe side effects of the intrathecal drug combination. We concluded that only peripheral blockade of transient receptor potential vanilloid receptor 1-expressing nociceptive afferents by the QX-314/capsaicin combination was effective at reducing neuropathic allodynia and hyperalgesia.
Neuropathic pain is a frequent and disabling condition with diverse underlying etiologies and is often difficult to treat. Systemic drug treatment is often limited in efficacy. Furthermore, adverse effects may be a limiting factor when trying to reach the necessary dose. Analgesics that can be applied topically have the potential to largely overcome this problem. They may be of particular advantage in localized neuropathic pain syndromes such as postherpetic neuralgia or small fiber neuropathy. Capsaicin, the pungent component of chili peppers, is a natural ligand of the transient receptor potential vanilloid 1 channel and has long been used as topically applicable cream with concentrations of 0.025 to 0.075%. In 2009, a high-concentration transdermal capsaicin 8% patch (Qutenza®; Acorda Therapeutics, Inc., Ardsley, NY, USA; Astellas Pharma Europe Ltd., Chertsey, Surrey, UK) was introduced for the treatment of peripheral neuropathic pain syndromes other than of diabetic origin in adults. It has since been widely used in diverse neuropathic pain disorders. In this review article, we summarize current knowledge on Qutenza, its advantages and problems, and expose unmet needs.
Electronic supplementary material
The online version of this article (doi:10.1007/s40122-014-0027-1) contains supplementary material, which is available to authorized users.
Analgesia; Capsaicin; Neuropathic pain; Qutenza; Transient receptor potential vanilloid 1 (TRPV1)
Capsaicin elicits burning pain via the activation of the vanilloid receptor (TRPV1). Intriguingly, several reports showed that capsaicin also inhibits Na+ currents but the mechanisms remain unclear. To explore this non-TRPV1 action we applied capsaicin to HEK293 cells stably expressing inactivation-deficient rat skeletal muscle Na+ mutant channels (rNav1.4-WCW). Capsaicin elicited a conspicuous time-dependent block of inactivation-deficient Na+ currents. The 50% inhibitory concentration (IC50) of capsaicin for open Na+ channels at +30 mV was measured 6.8 ± 0.6 μM (n = 5), a value that is 10–30 times lower than those for resting (218 μM) and inactivated (74 μM) wild-type Na+ channels. On-rate and off-rate constants for capsaicin open-channel block at +30 mV were estimated to be 6.37 μM−1 s−1 and 34.4 s−1, respectively, with a calculated dissociation constant (KD) of 5.4 μM. Capsaicin at 30 μM produced ~70% additional use-dependent block of remaining rNav1.4-WCW Na+ currents during repetitive pulses at 1 Hz. Site-directed mutagenesis showed that the local anesthetic receptor was not responsible for the capsaicin block of the inactivation-deficient Na+ channel. Interestingly, capsaicin elicited little time-dependent block of batrachotoxin-modified rNav1.4-WCW Na+ currents, indicating that batrachotoxin prevents capsaicin binding. Finally, neuronal open Na+ channels endogenously expressed in GH3 cells were as sensitive to capsaicin block as rNav1.4 counterparts. We conclude that capsaicin preferentially blocks persistent late Na+ currents, probably via a receptor that overlaps the batrachotoxin receptor but not the local anesthetic receptor. Drugs that target such a non-TRPV1 receptor could be beneficial for patients with neuropathic pain.
Capsaicin; Voltage-gated sodium channel; Open-channel block; Analgesia; Use-dependent block
Postherpetic neuralgia (PHN) represents a potentially debilitating and often undertreated form of neuropathic pain that disproportionately affects vulnerable populations, including the elderly and the immunocompromised. Varicella zoster infection is almost universally prevalent, making prevention of acute herpes zoster (AHZ) infection and prompt diagnosis and aggressive management of PHN of critical importance. Despite the recent development of a herpes zoster vaccine, prevention of AHZ is not yet widespread or discussed in PHN treatment guidelines. Diagnosis of PHN requires consideration of recognized PHN signs and known risk factors, including advanced age, severe prodromal pain, severe rash, and AHZ location on the trigeminal dermatomes or brachial plexus. PHN pain is typically localized, unilateral and chronic, but may be constant, intermittent, spontaneous and/or evoked. PHN is likely to interfere with sleep and daily activities. First-line therapies for PHN include tricyclic antidepressants, gabapentin and pregabalin, and the lidocaine 5 % patch. Second-line therapies include strong and weak opioids and topical capsaicin cream or 8 % patch. Tricyclic antidepressants, gabapentinoids and strong opioids are effective but are also associated with systemic adverse events that may limit their use in many patients, most notably those with significant medical comorbidities or advanced age. Of the topical therapies, the topical lidocaine 5 % patch has proven more effective than capsaicin cream or 8 % patch and has a more rapid onset of action than the other first-line therapies or capsaicin. Given the low systemic drug exposure, adverse events with topical therapies are generally limited to application-site reactions, which are typically mild and transient with lidocaine 5 % patch, but may involve treatment-limiting discomfort with capsaicin cream or 8 % patch. Based on available clinical data, clinicians should consider administering the herpes zoster vaccine to all patients aged 60 years and older. Clinicians treating patients with PHN may consider a trial of lidocaine 5 % patch monotherapy before resorting to a systemic therapy, or alternatively, may consider administering the lidocaine 5 % patch in combination with a tricyclic antidepressant or a gabapentinoid to provide more rapid analgesic response and lower the dose requirement of systemic therapies.
Nitro-oleic acid (OA-NO2), an electrophilic fatty acid nitroalkene byproduct of redox reactions, activates transient receptor potential ion channels (TRPA1 and TRPV1) in primary sensory neurons. To test the possibility that signaling actions of OA-NO2 might modulate TRP channels, we examined: (1) interactions between OA-NO2 and other agonists for TRPA1 (allyl-isothiocyanate, AITC) and TRPV1 (capsaicin) in rat dissociated dorsal root ganglion cells using Ca2+ imaging and patch clamp techniques and (2) interactions between these agents on sensory nerves in the rat hindpaw. Ca2+ imaging revealed that brief application (15-30 sec) of each of the three agonists induced homologous desensitization. Heterologous desensitization also occurred when one agonist was applied prior to another agonist. OA-NO2 was more effective in desensitizing the response to AITC than the response to capsaicin. Prolonged exposure to OA-NO2 (20 min) had a similar desensitizing effect on AITC or capsaicin. Homologous and heterologous desensitization were also demonstrated with patch clamp recording. Deltamethrin, a phosphatase inhibitor, reduced the capsaicin or AITC induced desensitization of OA-NO2 but did not suppress the OA-NO2 induced desensitization of AITC or capsaicin, indicating that heterologous desensitization induced by either capsaicin or AITC occurs by a different mechanism than the desensitization produced by OA-NO2. Subcutaneous injection of OA-NO2 (2.5 mM, 35 μL) into a rat hindpaw induced delayed and prolonged nociceptive behavior. Homologous desensitization occurred with AITC and capsaicin when applied at 15 minute intervals, but did not occur with OA-NO2 when applied at a 30 min interval. Pretreatment with OA-NO2 reduced AITC-evoked nociceptive behaviors but did not alter capsaicin responses. These results raise the possibility that OA-NO2 might be useful clinically to reduce neurogenic inflammation and certain types of painful sensations by desensitizing TRPA1 expressing nociceptive afferents.
desensitization; nociception; nitro-oleic acid; primary sensory neuron; TRP channels
Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 μM), the neurokinin NK1 receptor antagonist L-733060 (0.5 μM), the voltage-sensitive calcium channel blocker ruthenium red (100 μM), the TRPV1 receptor antagonist capsazepine (5 μM), the nitric oxide synthetase inhibitor Nω-nitro-l-arginine methyl ester HCl (l-NAME; 100 μM), the gap junction blocker 18α-glycyrrhetinic acid (10 μM), as well as the RhoA kinase inhibitor Y-27632 (1 μM). Further, we also used the K+ channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 μM) + apamin (0.1 μM) and iberiotoxin (0.5 μM) + apamin (0.1 μM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the above-mentioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) α-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK1, NO, vanilloid receptors, voltage-sensitive calcium channels, K+ channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism.
Capsaicin; CGRP; Human coronary artery; Human meningeal artery; Porcine coronary artery
The transient receptor potential vanilloid type 1 channel (TRPV1) and nerve growth factor (NGF) are important mediators of inflammatory pain. NGF released during inflammation sensitizes TRPV1 in afferent nerve endings of peripheral nociceptors, increasing pain sensation. Cannabinoids, by activating CB1 G protein-coupled receptors, produce analgesia in a variety of pain models, though the exact mechanisms are not known. We tested the hypothesis that activation of the CB1 receptor by cannabinoids attenuates NGF-induced TRPV1 sensitization. TRPV1-mediated currents were measured in acutely isolated primary sensory neurons with the whole-cell patch clamp technique using capsaicin (100 nM) as the agonist. After the first capsaicin application, during which the baseline current was measured, cells were exposed to NGF (100 ng/mL), and the capsaicin application was repeated after 5 minutes. NGF sensitized TRPV1 in 31.0 % of cells (13 of 42), with a mean (± SE) increase in the capsaicin-induced current of 262 ± 47 % over the baseline current. When the cannabinoid agonist ACEA (arachidonoyl-2’-chloroethylamide; 10 nM) was given before NGF, only 10.8 % of cells (4 of 37) were sensitized (p < 0.05). Neither this rate, nor the magnitude of the sensitization (198 ± 63 % of baseline) were different from that seen in cells not treated with NGF (3 of 25 cells sensitized (12.0 %), 253 ± 70 % of baseline). Pretreatment with the CB1 antagonist AM-251 (100 nM) prevented the effect of ACEA on NGF-induced sensitization. These results support the hypothesis that cannabinoids, acting through CB1 receptors, may produce analgesia in part by preventing NGF-induced sensitization of TRPV1 in afferent nociceptor nerve endings.
Cannabinoids; analgesia; nociceptor; NGF; TRPV1; patch clamp
Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel widely expressed in skin tissues, and peripheral sensory nerve fibres. Activation of TRPV1 releases neuropeptides; the resulting neurogenic inflammation is believed to contribute to the development of pruritus. A TRPV1 antagonist has the potential to perform as an anti-pruritic agent. SB705498 is a TRPV1 antagonist that has demonstrated in vitro activity against cloned TRPV1 human receptors and when orally administered has demonstrated pharmacodynamic activity in animal models and clinical studies.
To select a topical dose of SB705498 using the TRPV1 agonist capsaicin; to confirm engagement of the TRPV1 antagonistic action of SB705498 and assess whether the dose selected has an effect on itch induced by two challenge agents.
A clinical study was conducted in 16 healthy volunteers to assess the effects of 3 doses of SB705498 on skin flare induced by capsaicin. Subjects with a robust capsaicin response were chosen to determine if the selected topical formulation of SB705498 had an effect on challenge agent induced itch.
Following capsaicin challenge the greatest average reduction in area of flare was seen for the 3% formulation. This dose was selected for further investigation. Itch intensity induced by two challenge agents (cowhage and histamine) was assessed on the Computerised Visual Analogue Scale. The difference in average itch intensity (Weighted Mean Over 15 Mins) between the 3% dose of SB705498 and placebo for the cowhage challenge was −0.64, whilst the histamine challenge showed on average a −4.65 point change.
The 3% topical formulation of SB705498 cream was clinically well tolerated and had target specific pharmacodynamic activity. However there were no clinically significant differences on pruritus induced by either challenge agent in comparison to placebo. SB705498 is unlikely to be of symptomatic benefit for histaminergic or non-histaminergic induced itch.
In all mammals, tissue inflammation leads to pain and behavioral sensitization to thermal and mechanical stimuli called hyperalgesia. We studied pain mechanisms in the African naked mole-rat, an unusual rodent species that lacks pain-related neuropeptides (e.g., substance P) in cutaneous sensory fibers. Naked mole-rats show a unique and remarkable lack of pain-related behaviors to two potent algogens, acid and capsaicin. Furthermore, when exposed to inflammatory insults or known mediators, naked mole-rats do not display thermal hyperalgesia. In contrast, naked mole-rats do display nocifensive behaviors in the formalin test and show mechanical hyperalgesia after inflammation. Using electrophysiology, we showed that primary afferent nociceptors in naked mole-rats are insensitive to acid stimuli, consistent with the animal's lack of acid-induced behavior. Acid transduction by sensory neurons is observed in birds, amphibians, and fish, which suggests that this tranduction mechanism has been selectively disabled in the naked mole-rat in the course of its evolution. In contrast, nociceptors do respond vigorously to capsaicin, and we also show that sensory neurons express a transient receptor potential vanilloid channel-1 ion channel that is capsaicin sensitive. Nevertheless, the activation of capsaicin-sensitive sensory neurons in naked mole-rats does not produce pain-related behavior. We show that capsaicin-sensitive nociceptors in the naked mole-rat are functionally connected to superficial dorsal horn neurons as in mice. However, the same nociceptors are also functionally connected to deep dorsal horn neurons, a connectivity that is rare in mice. The pain biology of the naked mole-rat is unique among mammals, thus the study of pain mechanisms in this unusual species can provide major insights into what constitutes “normal” mammalian nociception.
Chemicals such as capsaicin and acid are considered noxious because they cause irritation and pain when applied to the skin. Acid is, for example, a very noxious stimulus and can cause intense pain. Indeed, acid is both noxious and painful to all animals including amphibians and fish. Here we describe a member of the rodent family, the African naked mole-rat (Heterocephalus glaber), that is behaviorally completely oblivious to capsaicin and acid. Tissue injury and inflammation increase sensitivity to normally non painful stimuli, a phenomenon called hyperalgesia. Here we show that the naked mole-rat does not experience hyperalgesia to painful thermal stimuli after inflammation. To our knowledge, no other mammal has so far been described that is selectively insensitive to chemical pain or that lacks thermal hyperalgesia. Naked mole-rats live in very large subterranean social groups and are remarkably tolerant to low-oxygen and high–carbon dioxide conditions. We hypothesize that naked mole-rats are selectively pain insensitive partly because of selection pressure arising from the extremity of their normal habitat.
Naked but far from vulnerable, the African naked mole-rat is an unusual mammal that is unique because it is impervious to painful chemicals that cause severe pain in all other species studied.
The capsaicin 8% patch can effectively treat neuropathic pain, but application can cause discomfort or a burning sensation. Until March 2013, it was recommended that patients be pretreated with a topical anesthetic, for example lidocaine, before capsaicin patch application. However, speculation existed over the need for pretreatment and its effectiveness in alleviating treatment-associated discomfort. This article compares tolerability to and efficacy of the capsaicin patch in pretreated and non-pretreated patients. All patients received a single capsaicin patch application. Pretreated patients received a lidocaine plaster before and intravenous lidocaine and metamizole infusions during capsaicin patch application. Pain levels, assessed using a Numeric Rating Scale (NRS), were used to determine tolerability and efficacy. All patients (pretreated n = 32; non-pretreated n = 26) completed 100% of the intended capsaicin patch application duration. At the time of capsaicin patch removal, 69% of pretreated and 88% of non-pretreated patients reported an NRS score increase, which returned to baseline by 6 hours post-treatment. There was no significant difference in mean NRS score between patient groups at any time during or after capsaicin patch treatment. Response was similar between patient groups; capsaicin patch treatment provided rapid and significant pain reductions that were sustained over 12 weeks. The same proportion of pretreated and non-pretreated patients reported willingness to receive retreatment with the capsaicin patch. This analysis shows that the capsaicin 8% patch is generally tolerable, and the small discomfort associated with patch application is short-lived. Lidocaine pretreatment does not have a significant effect on tolerability, efficacy, or patient willingness to receive retreatment.
capsaicin; nerve pain; neuralgia; nociceptors; peripheral nervous system; topical; tolerability; lidocaine pretreatment
Capsaicin ion channels are highly expressed in peripheral nervous terminals and involved in pain and thermal sensations. One characteristic of the cloned VR1 receptor is its multimodal responses to various types of noxious stimuli. The channel is independently activated by capsaicin and related vanilloids at submicromolar range, by heat above 40°C, and by protons at pH below 6.5. Furthermore, simultaneous applications of two or more stimuli lead to cross sensitization of the receptor, with an apparent increase in the sensitivity to any individual stimulus when applied alone. We studied here the mechanism underlying such cross-sensitization; in particular, between capsaicin and pH, two prototypical stimuli for the channel. By analyzing single-channel currents recorded from excised-patches expressing single recombinant VR1 receptors, we examined the effect of pH on burst properties of capsaicin activation at low concentrations and the effect on gating kinetics at high concentrations. Our results indicate that pH has dual effects on both capsaicin binding and channel gating. Lowering pH enhances the apparent binding affinity of capsaicin, promotes the occurrences of long openings and short closures, and stabilizes at least one of the open conformations of the channel. Our data also demonstrate that capsaicin binding and protonation of the receptor interact allosterically, where the effect of one can be offset by the effect of the other. These results provide important basis to further understand the nature of the activation pathways of the channel evoked by different stimuli as well as the general mechanism underling the cross-sensitization of pain.
vanilloid receptor; TRP; pain; cross-sensitization; single-channel
The angiotensin II (AngII) receptor subtype 2 (AT2R) is expressed in sensory neurons and may play a role in nociception and neuronal regeneration.
We used immunostaining with characterized antibodies to study the localization of AT2R in cultured human and rat dorsal root ganglion (DRG) neurons and a range of human tissues. The effects of AngII and AT2R antagonist EMA401 on capsaicin responses in cultured human and rat (DRG) neurons were measured with calcium imaging, on neurite length and density with Gap43 immunostaining, and on cyclic adenosine monophosphate (cAMP) expression using immunofluorescence.
AT2R expression was localized in small-/medium-sized cultured neurons of human and rat DRG. Treatment with the AT2R antagonist EMA401 resulted in dose-related functional inhibition of capsaicin responses (IC50 = 10 nmol/L), which was reversed by 8-bromo-cAMP, and reduced neurite length and density; AngII treatment significantly enhanced capsaicin responses, cAMP levels and neurite outgrowth. The AT1R antagonist losartan had no effect on capsaicin responses. AT2R was localized in sensory neurons of human DRG, and nerve fibres in peripheral nerves, skin, urinary bladder and bowel. A majority sub-population (60%) of small-/medium-diameter neuronal cells were immunopositive in both control post-mortem and avulsion-injured human DRG; some very small neurons appeared to be intensely immunoreactive, with TRPV1 co-localization. While AT2R levels were reduced in human limb peripheral nerve segments proximal to injury, they were preserved in painful neuromas.
AT2R antagonists could be particularly useful in the treatment of chronic pain and hypersensitivity associated with abnormal nerve sprouting.
Itch evoked by cowhage or histamine is reduced or blocked by capsaicin desensitization, suggesting that pruriceptive neurons are capsaicin-sensitive. Topical capsaicin can evoke both nociceptive sensations and itch, whereas intradermal injection of capsaicin evokes only burning pain. To dissociate the pruritic and nociceptive sensory effects caused by the chemical activation of sensory neurons, chemicals were applied in a punctiform manner to the skin of the forearm using individual, heat-inactivated cowhage spicules treated with various concentrations of capsaicin (1–200 mg/ml) or histamine (0.01–100 mg/ml). Perceived intensities of itch, pricking/stinging and burning were obtained every 30s using the general version of the Labeled Magnitude Scale and compared with ratings evoked by individual native cowhage spicules. Similar to cowhage, capsaicin and histamine spicules reliably evoked sensations of itch in a dose-dependent manner that were most often accompanied by pricking/stinging and to a lesser extent burning. Spicules containing 200 mg/ml capsaicin or 10 mg/ml histamine yielded peak magnitudes and durations of sensations comparable to those elicited by cowhage. Each type of spicule also produced comparable areas of dysesthesias (enhanced mechanically evoked itch or pain) and/or skin reactions (wheal and/or flare) in surrounding skin, though inconsistently. The incidence of flare was greater in response to histamine than to capsaicin or cowhage. These results suggest the possibility that capsaicin, histamine and cowhage activate common peripheral or central neural mechanisms that mediate pruritic sensations and associated dysesthesias.
This study evaluates the impact of the duration of pre-existing peripheral neuropathic pain on the therapeutic response to the capsaicin 8% cutaneous patch.
The non-interventional QUEPP (QUTENZA – safety and effectiveness in peripheral neuropathic pain) study evaluated the effectiveness of Qutenza™ in 1044 non-diabetic patients with peripheral neuropathic pain, who received a single application. Follow-up visits were scheduled at weeks 1–2, 4, 8 and 12. A pre-defined co-analysis of changes in average pain intensity was performed based on the duration of pre-existing pain.
In patients with pre-existing pain for <6 months, the mean relative change of the numeric pain rating scale score on days 7–14 to week 12 versus baseline was −36.6% [4.6 standard error of the mean (SEM); n = 105], −25.1% (1.9 SEM; n = 311) in patients with pain duration of 6 months to 2 years, −22.3% (1.6 SEM; n = 391) in patients with pain for >2–10 years, and −19.2% (2.6 SEM; n = 99) in patients with pain for >10 years. Thirty percent and 50% responder rates were 61.7% and 39.3% in patients with pre-existing pain for <6 months, 42.3% and 23.3% in patients with pain for 6 months to 2 years, 40.9% and 21.6% in patients with pain for >2–10 years, and 32.3% and 14.1% in patients with pain for >10 years.
The highest treatment response to the capsaicin 8% cutaneous patch was observed in patients with a history of pre-existing peripheral neuropathic pain of less than 6 months, suggesting that early initiation of topical treatment might be indicated.
The mechanisms underlying trigeminal pain conditions are incompletely understood. In vitro animal studies have elucidated various targets for pharmacological intervention; however, a lack of clinical models that allow evaluation of viable innervated human tissue has impeded successful translation of many preclinical findings into clinical therapeutics. Therefore, we developed and characterized an in vitro method that evaluates the responsiveness of isolated human nociceptors by measuring basal and stimulated release of neuropeptides from collected dental pulp biopsies.
Informed consent was obtained from patients presenting for extraction of normal wisdom teeth. Patients were anesthetized using nerve block injection, teeth were extracted and bisected, and pulp was removed and superfused in vitro. Basal and capsaicin-evoked peripheral release of immunoreactive calcitonin gene-related peptide (iCGRP) was analyzed by enzyme immunoassay. The presence of nociceptive markers within neurons of the dental pulp was characterized using confocal microscopy.
Capsaicin increased the release of iCGRP from dental pulp biopsies in a concentration-dependent manner. Stimulated release was dependent on extracellular calcium, reversed by a TRPV1 receptor antagonist, and desensitized acutely (tachyphylaxis) and pharmacologically by pretreatment with capsaicin. Superfusion with phorbol 12-myristate 13-acetate (PMA) increased basal and stimulated release, whereas PGE2 augmented only basal release. Compared with vehicle treatment, pretreatment with PGE2 induced competence for DAMGO to inhibit capsaicin-stimulated iCGRP release, similar to observations in animal models where inflammatory mediators induce competence for opioid inhibition.
These results indicate the release of iCGRP from human dental pulp provides a novel tool to determine the effects of pharmacological compounds on human nociceptor sensitivity.
The potential modulation of TRPV1 nociceptive activity by the CB1 receptor was investigated here using CB1 wildtype (WT) and knock-out (KO) mice as well as selective CB1 inverse agonists. No significant differences were detected in baseline thermal thresholds of ICR, CB1WT or CB1KO mice. Intraplantar capsaicin produced dose- and time-related paw flinch responses in ICR and CB1WT mice and induced plasma extravasation yet minimal responses were seen in CB1KO animals with no apparent differences in TRPV1 channel expression. Capsaicin-evoked CGRP release from spinal cord tissue and capsaicin-evoked action potentials on isolated skin-nerve preparation were significantly decreased in CB1KO mice. Pretreatment with intraplantar galanin and bradykinin, compounds known to sensitize TRPV1 receptors, restored capsaicin-induced flinching in CB1KO mice. The possibility that constitutive activity at the CB1 receptor is required to maintain the TRPV1 receptor in a “sensitized” state was tested using CB1 inverse agonists. The CB1 inverse agonists elicited concentration-related inhibition of capsaicin-induced calcium influx in F-11 cells and produced dose-related inhibition of capsaicin-induced flinching in ICR mice. These data suggest that constitutive activity at the CB1 receptor maintains the TRPV1 channel in a sensitized state responsive to noxious chemical stimuli. Treatment with CB1 inverse agonists may promote desensitization of the channel resulting in antinociceptive actions against chemical stimulus modalities. These studies propose possible therapeutic exploitation of a novel mechanism providing pain relief by CB1 inverse agonists.
TRPV1; CB1; Capsaicin; PIP2; phospholipase C; knockout mouse
Peripheral serotonin (5HT) has been implicated in migraine and temporomandibular pain disorders in humans and animal models and yet the mechanism(s) by which 5HT evokes pain remains unclear. Trigeminal pain can be triggered by activation of the transient receptor potential V1 channel (TRPV1), expressed by a subset of nociceptive trigeminal ganglia (TG) neurons and gated by capsaicin, noxious heat, and other noxious stimuli. As 5HT is released in the periphery during inflammation and evokes thermal hyperalgesia and TRPV1 is essential for thermal hyperalgesia, we hypothesized that 5HT increases the activity of capsaicin-sensitive trigeminal neurons and that this increase can be attenuated by pharmacologically targeting peripheral 5HT receptors. TG cultures were pretreated with 5HT (10 nM–100 µM), sumatriptan (5HT1B/1D agonist), ketanserin (5HT2A antagonist), granisetron (5HT3 antagonist) or vehicle prior to capsaicin (30 nM – 50 nM). Single-cell accumulation of intracellular calcium was recorded or CGRP release was measured following each treatment. In addition, using in situ hybridization and immunohistochemistry, we detected the co-localization of 5HT1B, 5HT1D, 5HT2A and 5HT3A, but not 5HT2C, mRNA with TRPV1 in TG cells. 5HT pretreatment evoked a significant increase in calcium accumulation in capsaicin-sensitive trigeminal neurons and enhanced capsaicin-evoked CGRP release, but had no significant effect when given alone. Sumatriptan, ketanserin and granisetron treatment attenuated calcium accumulation and 5HT enhancement of capsaicin-evoked CGRP release. Together these results indicate that 5HT increases the activity of capsaicin-sensitive peripheral nociceptors, which can be attenuated by pharmacologically targeting peripheral 5HT receptors, thereby providing a mechanistic basis for peripheral craniofacial pain therapy.
calcitonin-gene related peptide; inflammation; pain; 5HT; periphery; craniofacial; orofacial