Capsaicinoids in the treatment of neuropathic pain: a review

Abstract

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.

Keywords

capsaicin capsaicinoids neuropathic pain TRPV1

Introduction

The treatment of chronic neuropathic pain has been a challenge to physicians for millennia. Despite the multiple approaches used, e.g. topical, pharmaceutical, behavioral and interventional, our current treatment methods still provide only modest efficacy in this difficult pain condition. In general, treatment is very complex and single agents are rarely adequately effective.

Capsaicinoids, the hot spicy ingredients in chilies, were described in ancient writings and documents for topical analgesic use. The mechanism of action is unique. There has been renewed interest in the development of capsaicinoids for the treatment of neuropathic pain over the last few decades and new products are either on the market or in development. Low-concentration (LC), i.e. <1.0%, and over-the-counter (OTC) capsaicin preparations have been available for decades, although these products have suffered from problems of efficacy and patient compliance, due to the fact that the application has to be performed multiple times a day for multiple days and months. However, higher concentrations have been shown to circumvent some of these problems. A much higher concentration capsaicin product, such as the capsaicin 8% patch (C8P), is a fairly new therapy that produces relief after a single topical application. Other newer capsaicinoid therapies are being developed, e.g. the high-concentration (HC; 10% and 20%) liquid capsaicin and resiniferotoxin, a natural substance present in a Moroccan cactus-like plant. This article is a review of capsaicinoids in the treatment of neuropathic and chronic pain.

Transient receptor potential channels

The generation of the pain signal in small nerve fibers, i.e. the nociceptors, can be envisioned in three phases: transduction, propagation and transmission. Previously research efforts have focused on propagation and transmission. However, with the discovery of the transient receptor potential (TRP) family of ion channels, transduction can now be a focus of treatment. These channels share homology and have a six-transmembrane loop through the cell membrane [Spicarová and Palecek, 2008].

TRP channels are selective for calcium and magnesium over sodium ions and can be activated by a variety of mechanisms. For example, the group of TRP channels called vanilloid (TRPV) is activated by high temperatures and low pH [Knotkova et al. 2008]. Among these, the TRPV1 channel was the first to be cloned and has been the most studied of the 28 or more currently know TRP channels. Both morphine and cannabinoids have been proposed to interact with the TRPV1 receptor as well [Knotkova et al. 2008]. TRPV1 expressing C-fibers can be activated by exogenous substances such as capsaicin and resiniferatoxin and naturally by tissue burns, noxious heat and spider toxins. In addition, certain enzymes and inflammatory mediators will modulate the TRPV1 receptor [Szallasi et al. 2007]. All of these stimuli, through the activation of the TRPV1 channels, can cause burning pain [Knotkova et al. 2008]. These channels normally open between 37 and 45°C, but when bound, the threshold decreases below 37°C or physiologic body temperature [Spicarová and Palecek, 2008]. Binding stimulates the exocytosis of substance P (SP) from nociceptors, leading to mast cell degranulation of histamine and serotonin release from platelets. Further, TRPV1s are expressed throughout the central nervous system in areas that process pain signals, and also appear to be upregulated in the setting of neuropathic pain [Giordano et al. 2012]. Further, with nerve damage there are posttranslational changes, trafficking and expression of TRPV1s, as well upregulation of TRPV1s in the bystander uninjured nociceptors [Kim et al. 2008; Szallasi and Blumberg, 1989]. Nociceptors send signals into the dorsal horn of the spinal cord. Signals are then transmitted to higher central nervous system (CNS) centers where pain is perceived. The signal is transduced and with the lowered threshold this results in propagation and transmission to central brain areas where the signal is interpreted as pain. TRPV1 has also a number of other functions besides pain, e.g. thermoregulation, which are beyond the scope of the current paper, but discussed elsewhere [Alawi and Keeble, 2010].

Capsaicin

Capsaicinoids first recorded use, in the form of chilies, for the treatment of pain dates back to 4000 BC [Schumacher, 2010]. Columbus brought back the chili to Europe in the 1400s for both its culinary and medicinal properties [Schumacher, 2010]. The first formal report of the pain-reducing properties of topical chili extract in the West appeared in 1850 as a recommendation for burning or itching extremities [Turnbull, 1850]. Chilies are not true ‘peppers’; rather, they belong to the genus Capsicum and are a fruit [Wikipedia, 2004a]. The ‘hotness’ of peppers is due to a different set of chemicals, piperines, rather than capsaicin and they belong to a different family, Piperaceae [Wikipedia, 2004b; Vriens et al. 2008]. The major nonendogenous capsaicinoids are capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin and homocapsaicin. Capsaicin and dihydrocapsaicin account for approximately 90% of the naturally occurring capsaicinoids [Reyes-Escogido et al. 2011]. There are more than 20 known capsaicinoids and all are amides [Reyes-Escogido et al. 2011]. Research in the use of capsaicinoids for obesity, as antioxidants, anticarcinogens and analgesics is still ongoing [Reyes-Escogido et al. 2011]. Capsaicin, 8-methyl-N-vanillyl-6-nonenamide is the active ingredient in chilies that provokes burning and a flare and weal response. This response occurs rapidly while a poorly localized, protracted dull pain lingers from slow conducting C nerve fibers, all as a result of TRPV stimulation. Capsaicin will also cause a release of SP and calcitonin gene-related peptide from peripheral and central nerve terminals, contributing to the local flare (neurogenic inflammation) [Winter et al. 1995]. Heat hyperalgesia is the result to the reduction of heat pain thresholds in peripheral nociceptors. Neighboring areas of mechanical allodynia occur due to central sensitization of the dorsal horn sensory neurons.

The single application of capsaicin causes pain, however repeated applications causes analgesia through a defunctionalization or desensitization state of the C-fibers [Knotkova et al. 2008]. This has been called ‘a paradox’ and multiple mechanisms have been proposed. Defunctionalization or desensitization of nociceptors appears to be caused by localized nociceptor dysfunction and terminal axons destruction [Anand and Bley, 2011].

Capsaicin is poorly absorbed from the skin therefore LC OTC preparations do not develop adequate desensitization. HC capsaicin topicals, the C8P, HC liquids and injectable capsaicinoids are attempts to dose dependently hasten the desensitization/defunctionalization state and therefore pain relief. When capsaicin is compounded in a topical preparation at HC and administered as a single application, the analgesic benefit appears to last for several weeks. Since capsaicin does not affect the large nerve fibers involved in motor and sensory function (e.g. touch, vibration), and since systematic levels of capsaicin are very low when used topically, the regional approach represents a potential dramatic improvement in the treatment of neuropathic pain (and potentially other types of pain, vide infra).

LC capsaicin

LC capsaicin has been in use for decades and is available OTC in the United States. Unfortunately this treatment approach has poor to moderate efficacy and poor patient compliance [Derry and Moore, 2012]. Even though there has been interest in using capsaicin in a number of neuropathic pain disorders such as diabetic peripheral polyneuropathy (DPPN), human immunodeficiency virus neuropathy (HIVN) and post-herpetic neuralgia (PHN), many of the older studies yielded disappointing results perhaps due in part to weakness in tolerability, efficacy and adherence, of past available strengths of capsaicin, 0.025% and 0.075% [Rains and Bryson, 1995]. For example, 0.025% capsaicin cream was determined to be no better than the vehicle (not active) cream in a randomized, double-blind study of 30 patients with temporomandibular joint pain [Gallachia and Marcolongo, 1993].

As with PHN, other neuropathic pain conditions do not respond to low-dose topical capsaicin. A recent study, using OTC 0.025% capsaicin in a gel formulation, did not provide any significant pain relief in DPPN [Kulkantrokorn et al. 2012]. Substantially fewer studies examining the use of capsaicinoids for low back pain or myofascial pain have been published. In one such study, a randomized, double-blind, placebo-controlled study, compared the use of a topical capsaicin ‘plaster’, containing 11 mg of capsaicin per patch, with placebo in 154 chronic low back pain patients. A total of 60.8% of capsaicin-treated patients experienced 30% pain relief after 3 weeks of treatment (p < 0.02) versus 42.1% with placebo [Keitel et al. 2001]. A 0.1% capsaicin jelly has been tested in a pilot study for the treatment of migraine with positive results [Cianchetti, 2010].

A Cochrane review of the published randomized trials involving low-dose topical capsaicin concluded that ‘although topically applied capsaicin has moderate to poor efficacy in the treatment of chronic musculoskeletal or neuropathic pain, it may be useful as an adjunct […] for a small number of patients who are unresponsive to, or intolerant of, other treatments’ [Mason et al. 2004].

HC capsaicin: 8% patch and 10–20% liquid formulations

HC capsaicin preparations have demonstrated better analgesia. The use of the C8P has focused on three neuropathic conditions, DPPN, HIVN and PHN. In one study on HIVN, 7.5% topical capsaicin cream was applied. The patients experienced notable pain relief but required epidural anesthesia to tolerate the application [Robbins et al. 1998]. C8P capsaicin concentration is 100 times higher than OTC formulation. As mentioned previously, the C8P was designed to overcome some of the problems associated with delivery of OTC low-dose topical capsaicin formulations. In PHN it is applied for 60 minutes (for PHN) and then removed. The clinical trials were difficult to design, since blinding of a HC capsaicin presented a problem. These trials were not placebo-controlled, but rather a low concentration of capsaicin, 0.04% in patch form, was used as a comparator. They were randomized, double-blind, LC (0.04%) patch-controlled, parallel-assignment, multicenter, dose finding, 12 week clinical trials. There are six trials that have been listed in ClinicalTrials.gov (see Table 1). In phase II trials on C8P, a decrease of at least 33% was found in 42% of the patients compared with only 8% in the control group [De La Rue, 2003; Holdcroft, 2003]. In an open-label trial, pain relief was sustained for up to 12 months following a single application of the patch [Backonja et al. 2004]. However, not all clinical trials were positive. In a trial with 299 patients with PHN, the C8P was applied in a single application 30, 60 and 90 minutes for 12 weeks. There was a decrease in pain only in the 90 minute group, and the trial failed to meet significance. The open-label extension was terminated as well.

Table 1.

Capsaicin 8% patch and high-concentration liquid – clinical research.

	Design	Objective	Findings
Study: Phase I
C101 [Malmberg et al. 2004] Sponsored by Neurogesx^a	Randomized controlled open-label (C8P, capsaicin 0.04% patch and control patch)	Compare ENFD between groups	Significant reduction in ENFD in the C8P group
C115 [Kennedy et al. 2010; ClinicalTrials.gov identifier: NCT00254449] Sponsored by Neurogesx^a	Randomized Controlled open-label 1:1	PK and PD	Significant reduction in ENFD
Study: Phase II
C102 [Backonja et al. 2010; ClinicalTrials.gov identifier: NCT00034710] Sponsored by Neurogesx^a	Randomized dose-controlled double-blind (preceded by open-label phase). C8P with 0.04% low-dose comparator control 2:1	Tolerability and efficacy in PHN	Significant reduction in pain over the control group over 4 weeks
C106 [Backonja et al. 2010] (extension of C102, see above) Sponsored by Neurogesx^a	Open-label extension of C102, with repeat (up to three) treatments	Efficacy and tolerability in PHN with repeated applications	Pain reduction from C102 for up to 12 weeks, with similar results repeated over 1 year
C109 [ClinicalTrials.gov identifier: NCT00061152] Sponsored by Neurogesx^a	Open-label study	Investigate the tolerability and feasibility in the treatment of painful HIV-associated neuropathy, and preliminary safety and efficacy data	No study results posted on ClinicalTrials.gov
C111 [Webster et al. 2012; ClinicalTrials.gov identifier: NCT00082316] Sponsored by Neurogesx^a	Open-label randomized	Safety and tolerability using 3 different topical local anesthetics in PHN, DPPN and HIVN patients	No differences in tolerability, safety and efficacy.
C112 [ClinicalTrials.gov identifier: NCT00085761] Sponsored by Neurogesx^a	Is NGX-4010 safe, tolerable and effective in treating painful HIV-associated neuropathy	HIVN	No study results posted on ClinicalTrials.gov
C114 [ClinicalTrials.gov identifier: NCT00089557] Sponsored by Neurogesx^a	Open-labeled continuation study from C111	Safety and tolerability using three different topical local anesthetics in PHN, DPPN and HIVN patients	No study results posted on ClinicalTrials.gov
C-118 [Simpson et al. 2010; ClinicalTrials.gov identifier: NCT00233155] Sponsored by Neurogesx^a	Open-label randomized repeat treatments up to four patches	Safety with repeated applications of C8P in PHN and HIVN	No study results posted on ClinicalTrials.gov
C123 [Webster et al. 2011; ClinicalTrials.gov identifier: NCT00916942] Sponsored by Neurogesx^a	Open-label	Tolerability with pre-application of lidocaine (2.5%)/prilocaine (2.5%) cream	Pretreatment allowed all patients to complete at least 90% of application time
Study: Phase II and III
C108 [Webster et al. 2010; ClinicalTrials.gov identifier: NCT00061776] Sponsored by Neurogesx^a	Randomized, blinded study to one of three doses NGX-4010 patch or low-dose comparator versus placebo, 300 subjects	Is NGX-4010 effective in treating PHN pain	No study results posted on ClinicalTrials.gov
Study: Phase III
C107 [ClinicalTrials.gov identifier: NCT00064623] Sponsored by Neurogesx^a	Randomized, double-blind, controlled dose-finding study, NGX-4010 or matching low-dose comparator	Is NGX-4010 effective in the treatment of HIV-associated neuropathy?	No study results posted on ClinicalTrials.gov
C110 [Webster et al. 2011; ClinicalTrials.gov identifier: NCT00068081] Sponsored by Neurogesx^a	Randomized, double-blind, controlled study in PHN	Purpose to assess the efficacy, safety and tolerability of NGX 4010 applied for 60 minutes for PHN treatment
C116 [Backonja et al. 2008b; ClinicalTrials.gov identifier: NCT00115310] Sponsored by Neurogesx^a	Randomized, double-blind, controlled study in PHN, 400 subjects	Assess efficacy and safety of NGX-4010 for 60 minutes PHN
C117 [Backonja et al. 2008a; ClinicalTrials.gov identifier: NCT00300222] Sponsored by Neurogesx^a	Multicenter randomized, double-blind, controlled study in PHN, 400 subjects	Assess the efficacy and safety of 60 minute NGX-4010 application for 60 minutes for treatment of PHN
C119 [ClinicalTrials.gov identifier: NCT00321672] Sponsored by Neurogesx^a	Multicenter randomized, double-blind, controlled study in HIV-associated neuropathy, 494 subjects	Purpose was to assess efficacy and safety of NGX-4010 applied for 30 or 60 minutes for the treatment of painful HIV-associated neuropathy	ClinicalTrials.gov, ‘Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterruptable data.’
Other capsaicin 8% patch studies^b
[ClinicalTrials.gov identifier: NCT01748422] Sponsored by NHS Greater Glasgow and Clyde	12 week open labeled study, 20 End-stage renal failure patients with chronic pain from AV fistulae	Arteriovenous fistulae	Not opened for enrollment
[ClinicalTrials.gov identifier: NCT01748435] Sponsored by NHS Greater Glasgow and Clyde	Pilot randomized controlled study, 30 patients	Pre-emptive analgesia preventing neuropathic pain following lower limb amputation	Not opened for enrollment
[ClinicalTrials.gov identifier: NCT01704339] Sponsored by NHS Greater Glasgow and Clyde	Treating neuropathic pain from critical ischemia in 20 end-stage renal failure patients	Ischemic neuropathic pain in end-stage renal disease	Not opened for enrollment, status questionable
[ClinicalTrials.gov identifier: NCT01737294] Sponsored by Astellas Pharmaceuticals	Evaluate efficacy, tolerability, health-related quality of life and use of health resources associated with the C8P in standard clinical practice	Standard use of Quentza in Europe	Open for enrollment
[ClinicalTrials.gov identifier: NCT01533428] Sponsored by Astellas Pharmaceuticals	Phase III, double-blind, randomized, placebo-controlled, multicenter study in 360 subjects with painful diabetic peripheral polyneuropathy	Assess pain reduction, efficacy and safety with the use of C8P in diabetic peripheral polyneuropathy compared with placebo	Active, not yet recruiting
[ClinicalTrials.gov identifier: NCT01713426] Sponsored by Astellas Pharmaceuticals	C8P versus pregabalin in phase IV, open-label, randomized, multicenter, 526 peripheral neuropathic pain	PHN, peripheral nerve injury or nondiabetic peripheral polyneuropathy. Efficacy and tolerability evaluated	Completed
[ClinicalTrials.gov identifier: NCT01478607] Sponsored by Astellas Pharmaceuticals	Phase III, randomized, controlled, long-term safety study evaluating repeated C8P applications versus standard of care alone in 450 subjects with painful diabetic peripheral neuropathy	Assess safety of repeated C8P applications in reducing pain intensity in diabetic peripheral polyneuropathy	Active, enrollment has ended.
			No results posted on ClinicalTrials.gov
[ClinicalTrials.gov identifier: NCT01523951] Sponsored by Astellas Pharmaceuticals	Comparison of topical local anesthesia and cooling to reduce C8P application burning pain	Evaluate superiority of continuous skin cooling versus topical EMLA or placebo	Study completed. No study results posted on ClinicalTrials.gov
[ClinicalTrials.gov identifier: NCT01416116] Sponsored by Astellas Pharmaceuticals	Phase IV, 122 subjects, multicenter, randomized, assessor-blinded study	Assessing a pretreatment application evaluating superiority of either lidocaine and tramadol	Ended study, no ClinicalTrials.gov results
[ClinicalTrials.gov identifier: NCT01252160] Sponsored by Astellas Pharmaceuticals	Phase IV, 300 subject multicentre, single-arm, open-label study of C8P repeated application in peripheral neuropathic pain treatment	Evaluate the safety of repeated C8P applications in peripheral neuropathy	Active, enrollment has ended
Capsaicin liquid NGX-1998
C201 [ClinicalTrials.gov identifier: NCT00528216] Sponsored by Neurogesx^a	Randomized, controlled, single-blind, single-center study, 20 subjects	ENFD and sensory function	Phase I completed
C203 [ClinicalTrials.gov identifier: NCT00912262] Sponsored by Neurogesx^a	Randomized, single-center, single-blind controlled study, 36 healthy subjects	Identify low concentration that will not reduce healthy volunteer ENFD compared with 10% liquid (NGX-1998) but still produce local application response	Phase I completed
C204 [ClinicalTrials.gov identifier: NCT01228838] Sponsored by Neurogesx^a	12-week multicenter randomized, double-blind, controlled study, 183 subjects	Evaluation of the efficacy, safety and tolerability of NGX-1998,	Phase I completed
		10%, 20% of placebo in 2:2:1.

DPPN, diabetic peripheral polyneuropathy; EMLA, lidocaine/prilocaine; ENFD, epidermal nerve fiber density; HIVN, human immunodeficiency virus neuropathy; PD, pharmacodynamics; PK, pharmacokinetics; PHN, post-herpetic neuropathy

Neurogesx was purchased by Acorda in 2013. The future of the capsaicin 8% patch and the high-concentration capsaicin liquid research program, in the US, is unclear at the time of writing.

Astellas Pharmaceuticals entered into agreement with Neurogesx in 2009. They hold the license and rights to market the capsaicin 8% patch throughout the world, except the US and Canada (see http://www.astellas.com/en/corporate/).

The use of C8P, in the clinical trials, was found to be safe and generally well tolerated. The most commonly encountered side effects were dermal irritation, erythema and pain at the site of application. These were transient, but could be mild to moderate in severity. Local cooling and short-acting opioids were effective for this transient pain.

In trigeminal PHN patients, one case report suggests efficacy in the use of the C8P [Sayanlar et al. 2012]. In addition, there was a trial examining reapplication and retreatment of the C8P. The results of this trial showed that efficacy of the retreatment were similar to the initial treatment, 31%, 30% and 33% for the first, second and third retreatment cycles [Backonja et al. 2004].

A Cochrane collaboration review on ‘high concentration topical capsaicin’ (C8P) suggested that it was ‘similar to other therapies for chronic pain’ and that it is ‘likely to be used when other available therapies have failed’ [Derry et al. 2013]. The cost and need for repeated applications were part of the rationale for this statement. Of the 1272 patients treated with C8P for PHN the numbers needed to treat was 8.8 [Derry et al. 2013].

Recent studies using HC capsaicin in a liquid formulation, at 10% and 20% have been carried out (see Table 1) [Tobias et al. 2011a, 2011b]. These liquid preparations are currently in clinical trials [ClinicalTrials.gov identifiers: NCT00912262, NCT00130962]. Results from studies of the HC capsaicin liquid formulation in DPPN have not yet been published [ClinicalTrials.gov identifier: NCT01228838].

Other capsaicinoids

A much more powerful TRPV1 agonist capsaicin analog, resiniferatoxin, is currently being studied at the National Institutes of Health for intrathecal administration for intractable cancer pain in end-stage disease patients (see Table 2). This has been described as a ‘molecular scalpel’ and may achieve permanent pain relief in these patients.

Table 2.

Industry capsaicinoid pipeline (low-dose capsaicin studies not included).

Compound	Company	Study population	Current status
Agonist
Aldea, ALGRX-4975 [ClinicalTrials.gov identifiers: NCT00130949, NCT00130962, NCT00132392, NCT00133133, NCT00146198, NCT00672568, NCT00681356, NCT00683267, NCT00583180]	Anesiva	Nine studies completed, three for knee replacement, one tennis elbow, two postoperative pain, one for hip replacement, one for shoulder arthroscopy, one for Morton’s neuroma and one for intraoperative wound instillation	No active studies posted
Civamide, WN 1001 [ClinicalTrials.gov identifiers: NCT00033839, NCT00069082, NCT00077935, NCT00758433, NCT00802217, NCT00995306, NCT00845923, NCT01341548]	Winston Labs	Intranasal, patch, cream and oral. Eight studies in total, three in cluster headache, two in osteoarthritis, one in post-herpetic neuralgia, two phase I	Current study, nasal administration for cluster headaches; not yet enrolling
Qutenza, NGX 4010 See the text, vide supra.	Neurogesx (purchased by Acorda in 2013)	See Table 1	See Table 1

N-palmitoyl-vanillamide (palvanil) is a nonpungent TRPV1 agonist capsaicin analog. In a recent study palvanil was injected subcutaneously using formalin-induced nocifensive behavior and carrageenan-induced edema and thermal hyperalgesia in the mice model. Analgesia was shown in a second mouse study as well [De Petrocellis et al. 2011]. Palvanil has fewer side effects than the typical TRPV1 agonists (hypothermia and bronchoconstriction), and appears to be still effective at reducing pain and edema [Luongo et al. 2012].

Endogenous TRPV1 ligands

Endogenous ligands of the TRPV1 channels, i.e. endovanilloids, have been identified. There are three lipid classes of such ligands, N-arachidonoyldop-amine, lipoxygenase products of arachidonic acid and anandamide [Van der Stelt and Di Marzo, 2004]. Anandamide, a cannabinoid receptor and TRPV1 ligand, has peripheral antinociceptive effect [Horvath et al. 2006].

TRPV1 antagonists

Further, TRPV1 antagonists have been developed and investigated as potential options for the treatment of pain. Table 3 gives a listing of what is currently listed on ClinicalTrials.gov. There is only one trial currently enrolling. These compounds have been plagued with significant side effects. TRPV1 antagonists have been included for completeness, since they were developed with the goal of pain reduction.

Table 3.

Industry TRPV antagonist pipeline.

Antagonist
ABT-102 [ClinicalTrials.gov identifier: NCT00854659]	Abbott Labs	Inflammatory pain/tissue injury	One phase I completed;
		no active studies posted
AMG-334 [ClinicalTrials.gov identifiers: NCT01723514, NCT01688739]	Amgen	Subcutaneous or intravenous for migraine	Phase I, currently enrolling
AMG-517 (no studies found on ClinicalTrials.gov) [Kym et al. 2009]	Amgen	Pain
AZD-1386 [ClinicalTrials.gov identifiers: NCT00672646, NCT00832169, NCT00878501, NCT00714337, NCT00672646, NCT00690079, NCT00945178, NCT00692146, NCT00976534]	Astra Zeneca	A total of 11 studies, 6 complete, 3 terminated, 2 in gastroesophageal reflux disease (not included in this table)	No current studies posted
DWP-05195 [ClinicalTrials.gov identifiers: NCT01094834, NCT01557010, NCT00969787].	Daewoong Pharmaceuticals	One phase II study in PHN ongoing, two phase I studies
GRC-6211^a [Szallasi and Shera, 2012]	Glenmark/Lilly	Neuropathic pain, phase I and osteoarthritis phase II.
GRC-17535 [ClinicalTrials.gov identifier: NCT01556152, NCT01726413]	Glenmark	Two phase II trials in diabetic peripheral polyneuropathy neuropathy	One withdrawn, one currently enrolling patients
GRC-15300^b [Glenmark Pharmaceuticals 2013]	Glenmark	Phase I and phase II in neuropathic pain (TRPV-3 agonist)	Unknown status
MK-2295 [ClinicalTrials.gov identifier: NCT00387140]	Merck/Neurogen	One study in dental pain
PHE-377^c [Szallasi and Shera, 2012]	PharmEste	Phase I, neuropathic pain
PHE-575^c [Szallasi and Shera, 2012]	PharmEste	TRPV1 and TRPA1 antagonist, neuropathic pain	Preclinical and phase I
SB-705498 (ClinicalTrials.gov identifiers: NCT00269022, NCT00281684, NCT00907933, NCT00461682, NCT00731250, NCT01673529]	GSK	Intranasally, topically, orally: 10 studies, 1 in migraines, 1 in tooth extraction, 1 in rectal pain, 3 phase III (4 in allergic rhinitis and 1 in cough not included)	Phase I and II completed; no active studies posted
MR-1817 [ClinicalTrials.gov identifier: NCT00960180].	Mochida	Phase I	No active studies posted
JNJ-39439335 [ClinicalTrials.gov identifiers: NCT01631487, NCT01343303, NCT01454245, NCT01006304, NCT00933582]	J&J	Phase I	Phase I studies completed; no active studies posted

TRPA1, transient receptor potential cation channel, subfamily A, member 1; TRPV1, transient receptor potential vanilloid-1; PHN, post-herpetic neuropathy

Mentioned by Szallasi and Shera [2012]; not found on ClinicalTrials.gov or on the Glenmark website.

Listed on the Glenmark website, see footnote; not listed on ClinicalTrials.gov

Mentioned by Szallasi and Shera [2012] and on the PharmEste website (http://www.pharmeste.com/home.asp?op=interna&id=2&id_pag=10&tit=Pipeline); not found on ClinicalTrials.gov.

Conclusion

In the United States, and worldwide, neuropathic pain and mixed states of chronic neuropathic–inflammatory pain still represent a tremendous challenge. The treatments that currently exist are only moderately effectively. Frequently these patients need a multidisciplinary and multimodal approach to significantly influence their pain [Gidal and Billington, 2006]. However, new treatments are being developed and higher concentrations of capsaicin, as well as other capsaicinoids, are some of these. Unfortunately due to the parent company’s shortage of funds, the future in the research program for the HC capsaicin products is unclear [Leuty, 2013]. In addition, although difficult data to obtain, topical agents do not have a large market share in the treatment of chronic pain. The total market for OTC analgesics alone is estimated at US$2.38 billion [The Pharma Letter, 2013]. In 2007 the market for topical analgesics, non-OTC, was only US$40 million [Millennium Research Group, 2013]. Data suggest that these treatments are underutilized.

The ability to determine which neuropathic pain patient will respond best to a given treatment is still an eluding challenge. However, recent data suggest that there may be approaches which might allow us this ability. Martini and colleagues and Gustorff and coworkers suggest that the actually available topical treatments reduce spontaneous neuropathic pain and affect predominantly mechanical hyperalgesia [Martini et al. 2012; Gustorff et al. 2011]. This may serve as a key marker to predict outcome with the use of these products. Clinical predictors such as pain intensity and the etiology or type of pain do not seem to serve as predictors of treatment response. However, other characteristics that seem to suggest response are intriguing and research in defining predictors of efficacy of a given treatment continues [Martini et al. 2012; Gustorff et al. 2011].

The future is daunting in both the understanding of the physiology of the TRP receptors, the development of new analogs and ligands but also in developing approaches that will select patients who will respond best. This will require extensive research in all these areas.

Footnotes

Conflict of interest statement

In the last year, JP has received consulting and advising fees from Ameritox, Endo Pharmaceuticals, INSYS Therapeutics and Zogenix Pharmaceuticals. In the last year, MP has received consulting and advising fees from Grunenthal.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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