Drug Evaluation
Zucapsaicin for the treatment of neuropathic pain
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Kinga Sałat, Anna Jakubowska & Katarzyna Kulig† †
Jagiellonian University, Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Krako´w, Poland
1.
Introduction
2.
Chemistry
3.
Mechanism of action
4.
Preclinical pharmacology of zucapsaicin
5.
Clinical pharmacology of zucapsaicin
6.
Expert opinion
Introduction: Neuropathic pain (NP) is a chronic disease that stems from a primary lesion or dysfunction of the central or peripheral nervous system. Zucapsaicin is a synthetic cis isomer of natural capsaicin that has shown therapeutic efficacy in pain accompanying osteoarthritis of the knee. It is also currently under investigation for the relief of severe pain in adults suffering from NP. Areas covered: The authors provide an overview of the pharmacological properties of zucapsaicin based on available data from both preclinical and clinical trials. They also discuss its mechanism of action. Expert opinion: The mechanism of action and clinical indications of zucapsaicin are similar to that of its naturally occurring isomer, capsaicin. However, in contrast to capsaicin, zucapsaicin is better tolerated. In the future, zucapsaicin could become a valuable drug for treating pain relief. Indeed, it is possible, in addition to providing NP relief, that it may have a use in treating osteoarthritic pain, headaches and pain that accompany intestinal diseases. Keywords: neuropathic pain, topical analgesics, TRPV1 agonist, zucapsaicin Expert Opin. Investig. Drugs (2014) 23(10):1433-1440
1.
Introduction
Neuropathic pain: a challenge for contemporary medicine Neuropathic pain (NP) is a chronic disease that results from the dysfunction to the central or peripheral nervous system [1]. It is estimated that NP affects between 3 and 8% of the world’s population, worsening patients’ quality of life, general mood and occupational functioning. This relatively frequent condition with an annual incidence of almost 1% of the general population particularly often affects women and middle-aged persons [2,3]. Available analgesics, including opioids and analgesic adjuvants (such as antidepressants and anticonvulsant drugs), provide sufficient efficacy in many pain syndromes. However, opioids have proven relatively weaker effect in the alleviation of NP than in cancer pain [4,5], whereas the use of analgesic adjuvants, although effective for some types of NP, is often limited by their adverse effects and poor patients’ compliance. In view of this, NP often remains intractable and its treatment is a challenging endeavor [6]. It is estimated that the resistance to conventional analgesic pharmacotherapy is present in ~ 40% of neuropathic patients [7,8]. In view of this, there is a strong need to explore novel drug targets and search for new, analgesically active compounds with an acceptable safety profile to treat NP of various origins [4]. Currently used drugs for the treatment of NP have undesirable adverse effects causing patients’ discomfort. Moreover, they might demonstrate serious drug--drug interactions, which make the treatment of NP even more complicated [9]. In the recent years, new areas of research on the mechanisms of NP have been explored. To date, antagonists of voltage-gated ion channels selectively permeable for sodium, calcium or potassium ions; ligands of transient receptor potential 1.1
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Box 1. Drug summary. Drug name (generic) Indication Phase Route of administration Pharmacological description Chemical structure
Zucapsaicin Neuropathic pain II Topical cream TRPV1 receptor agonist O O
N H
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HO
Pivotal trials
[51,52]
channel (TRP channel) family; antagonists of ionotropic receptors (NMDA, GABAergic A receptors); ligands of histaminergic H3 receptors or angiotensin II AT2 receptor blockers proved their analgesic efficacy in numerous preclinical models and clinical trials. Additionally, compounds targeting at sigma-1 receptors, GABA, serotonin, dopamine or noradrenaline reuptake inhibitors, endocannabinoid signaling system ligands, antagonists of proinflammatory cytokines (TNF-a, IL-1b, IL-6, IL-17, IFN-g) or agents modulating the biological activity of neurotrophins (nerve growth factor [NGF] and brain-derived neurotrophic factor) are being thoroughly investigated as potential future analgesics [10-13]. Overexpressed TRPV1 channels: a target for neuropathic pain treatment
1.2
TRP channels play a pivotal role in diverse afferent physiological functions (transduction of chemical, mechanical and thermal stimuli) and efferent biological processes (e.g., cellular differentiation, thermoregulation or vasoregulation). Importantly, some of them are involved in pain transduction. Of 28 TRP channels discovered so far, 7 sense hot or high temperatures (TRPV1, V2, V3, V4, TRPM2, TRPM4, TRPM5), whereas two other (TRPA1 and TRPM8) are activated by cold. In view of this, these molecules are frequently referred to as ‘thermoTRPs’ as they comprise a wide temperature range: below 10 C (TRPA1) and above 53 C (TRPV2) [1,4,11]. Molecular cloning of the vanilloid receptor 1 (VR1, ‘capsaicin receptor’, TRPV1 -- TRP channel vanilloid subfamily member 1) in 1997 by Caterina and Julius [14] not only initiated studies on its biological function, but it also identified TRPV1 as a novel therapeutic target for analgesics and explained the mechanism of action of plant-derived analgesics, such as capsaicin. TRPV1 is present in sensory neurons, mainly in C nerve fibers and, to a lesser extent, in Ad fibers. These so called ‘capsaicin-sensitive’ neurons, and their nerve fibers can transmit both pain and itch [15]. The peripheral neuronal distribution of TRPV1 is related to its key role in the transduction of pain [1], both inflammatory and neuropathic [16,17], although the discovery of central 1434
TRPV1 receptors suggests also their plausible role in the modulation of nociception [18]. In mice, TRPV1 channels have been identified at the CNS level in spinal and supraspinal structures participating in pain modulation and perception (rostral ventromedial medulla, periaqueductal gray, amygdala, solitary tract nucleus, somatosensory cortex, anterior cingulated cortex and insula) [16-19]. An increasing interest in the role of TRPV1 channels in NP has been shown in numerous studies [17,20-24]. An altered distribution of TRPV1 in primary afferent neurons was demonstrated in the diabetic or nerve injury-induced NP models in mice [22-24] and in nerve fibers of human diabetic neuropathy skin [21], whereas the increased TRPV1 expression in the rat dorsal root ganglion [25] and proteinase-activated receptor 2-mediated sensitization of TRPV1 [20] were proven to underlie paclitaxel-induced mechanical allodynia and thermal hyperalgesia. Moreover, it was also shown [26] that TRPV1 plays a crucial role in cisplatin-induced thermal hyperalgesia in vivo. It also was demonstrated that TRPV1 agonists and antagonists effectively attenuated thermal and mechanical hyperalgesia and mechanical allodynia in models of NP [17,27,28] and in human studies [15]. Numerous studies demonstrate that NGF plays a pivotal role in the development and maintenance of NP. It was also shown that NGF is able to upregulate TRPV1 receptors. The increased expression of TRPV1 is observed not only in C fibers but also in myelinated A fibers [18]. This indicates for a potential role of TRPV1 ligands not only in thermal hyperalgesia but also mechanical hyperalgesia [18,29] and provides further evidence that the function of TRPV1 in pain is more than being just a thermoreceptor. This upregulation of TRPV1 at the peripheral and CNS level proves hypersensitivity of the vanilloid system in NP, so TRPV1 channels are regarded to be suitable candidates for the development of analgesic drugs efficacious in NP conditions. TRPV1 plays an important role in chemical and thermal hyperalgesia in a model of diabetic neuropathy [29,30], but not in NP induced by oxaliplatin or paclitaxel. Moreover, the increased expression of TRPV1 leads to the enhanced glutamatergic neurotransmission in the spinal cord that is also involved in both chronic and acute pain [18]. TRPV1 is a protein containing 838 amino acids. The TRPV1 channel consists of six transmembrane domains that are assembled as homo- or heterotetramers [18]. It is permeable to calcium and sodium ions [15,31]. TRPV1-induced calcium influx into cells is responsible for the release of calcium from the endoplasmic reticulum. High calcium (and sodium) permeability through the channel pore results in cell membrane depolarization that stimulates the release of substance P (SP). SP excites primary sensory neurons, producing an intense burning sensation [15]. TRPV1 activation also induces the release of somatostatin, calcitonin gene-related peptide (CGRP) and other neuropeptides (neurokinin A, kassinin), leading to neurogenic inflammation. This initial hypersensitization is followed by a persistent desensitization that underlies
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Zucapsaicin
the analgesic effect of capsaicin and zucapsaicin (Box 1) (discussed below) [15]. The increased expression of TRPV1 in NP conditions, as well as its desensitization, provides a valid strategy for pain relief and might be a promising perspective for patients suffering from intractable NP whose treatment is still unsatisfactory [18]. In humans, topically administered capsaicin is rapidly and well absorbed through the skin [15,16]. Despite this, it is effective in a (modest) proportion of patients with postherpetic neuralgia (PHN), chronic distal painful polyneuropathy and in surgical NP, including postmastectomy pain syndromes [1,9,32]. Standard topical formulations containing low concentrations of capsaicin -- creams, lotions and patches -- are available as ‘over the counter’ preparations. Some of these formulations (creams, lotions) require many applications per day, whereas all of them cause irritation and pain due to the activation of sensory neurons expressing TRPV1 [9,18,32]. This adverse effect of capsaicin when used as a patch formulation often requires the pretreatment with an anesthetic. Hence, there is a strong need to develop new routes of capsaicin administration and develop analogs that relieve pain without causing unfavorable drug interactions, adverse effects or discomfort due to pungency [5]. 2.
Chemistry
Zucapsaicin (civamide) is the cis isomer of the naturally occurring capsaicin. Zucapsaicin compared with capsaicin has significantly lower pungency [33]. The synthesis of this compound was elaborated by Gannett et al. [34] and Orito et al. [35]. The crucial point of this synthesis was the elaboration of coupling vanillylamine with (Z)-8-methylnon-6-enoyl chloride. 3.
Mechanism of action
controversial) and iii) activation of calcium-dependent protein kinase C isoforms and subsequent channel phosphorylation [38]. Desensitization involves both tachyphylaxis (short-term desensitization) and long-term, persistent, desensitization [1,5,19]. It is suggested that the downregulation of proalgesic substances (such as SP) and upregulation of analgesic peptides are implicated in desensitization [4]. The exhaustion of SP reserves renders neurons desensitized and refractory. These mechanisms of desensitization are not fully understood. It is thought that the short-term desensitization is related to capsaicin’s ability to block the intra-axonal transport of NGF, SP and somatostatin [15]. The desensitization is a reversible phenomenon. It begins a few hours after capsaicin application and may last even several weeks [4]. The reversible desensitization was found useful in the treatment of pain, whereas the site-specific ablation of sensory nerves transmitting pain stimuli is a promising approach (‘molecular scalpel’) to achieve a permanent pain relief in patients suffering from bone cancer pain or HIV-induced neuropathies [1,5]. Desensitization and depletion of pronociceptive neurotransmitters induce chemical denervation with a loss of function, which is clinically used in osteoarthritis, diabetic neuropathy, psoriasis and others [18,39,40]. In dorsal root ganglia and the sciatic nerve, zucapsaicin decreases levels of SP and CGRP, indicating that it influences peptidergic afferent neurons via a desensitization mechanism [41]. When administered topically, the intended targets for zucapsaicin are the neurons that innervate the local area of application. These neurons transmit pain toward the CNS. 4.
Preclinical pharmacology of zucapsaicin
Animal pharmacodynamic studies on zucapsaicin The antinociceptive effects of zucapsaicin were evaluated in several in vivo tests, including chemical and thermal methods (formalin test and thermal paw withdrawal test, respectively). These experiments were carried out on adult rats after oral administration. It was found that zucapsaicin significantly attenuated nociceptive behavior in both phases of the formalin test, and this effect was observed for a long time (4 -- 7 days). These results also showed that the antinociceptive effect of zucapsaicin observed in the formalin test could be attributable to the interruption of small afferent (tachykinin/CGRP) transmission, perhaps secondary to an acute desensitization at afferent terminals [42]. In the thermal paw withdrawal test, zucapsaicin given at tolerable doses was able to produce a protracted and statistically significant increase in the thermal response latency. The effect evolved within more than an hour and < 24 h and lasted for 2 -- 3 days. Taking into consideration the fact that zucapsaicin significantly inhibits behavioral responses in the acute phase of the formalin test, it appears that this compound is able to block acute nociception, and this action is consistent with an effect upon C-polymodal nociceptors [42]. 4.1
The mechanism of pharmacological action of zucapsaicin has not been fully understood yet. It is suggested that this compound, similarly to its trans isomer, is an agonist of the vanilloid receptor VR1 (TRPV1) and a neuronal calcium channel blocker [36]. Capsaicin is able to excite and desensitize C-fibers. As such, it is not only able to cause pain, but also exhibit analgesic properties. Initially, it stimulates TRPV1, which is responsible for a burning sensation. This effect is followed by a longlasting refractory state -- ‘desensitization’ -- during which the previously excited sensory neurons become unresponsive to capsaicin and other stimuli. It was shown that desensitization and tachyphylaxis of TRPV1 channels contribute to capsaicin-induced pain relief [37]. Desensitization of TRPV1 represents the main mechanism of its inhibitory function. Three distinct pathways of capsaicin-induced desensitization have been described: i) activation of calcineurin, which results in dephosphorylation of TRPV1; ii) activation of phospholipase C with the subsequent phosphatidylinositol 4,5-biphosphate hydrolysis (rather
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The observed inhibitory effect of zucapsaicin observed in Chung (spinal nerve ligation) model of NP was moderate, but statistically significant [42]. The topical application of zucapsaicin was also tested for the treatment of primary or recurrent experimental genital herpes simplex virus infection in guinea pigs. It was shown that zucapsaicin is better tolerated than topical treatment with capsaicin. Animals displayed evidence of mild discomfort following initial treatment but became rapidly desensitized and subsequently showed no response to further application. The animals treated during the primary infection subsequently experienced a long-lasting reduction in the recurrent disease. It is also worth noting that zucapsaicin treatment during the latent infection significantly reduced the recurrent disease [43]. Cardiovascular effects of zucapsaicin were evaluated in vivo in a dermal minipig study and an oral dog study. In the 9-month chronic dermal toxicity study in minipigs, zucapsaicin cream was used at concentrations of 0.075, 0.75 and 3.75% and electrocardiographic examinations were made prior to, at week 1, then 4.5 months and 9 months later. In dog’s oral toxicity, study of zucapsaicin at doses 0, 3, 10 and 30 mg/kg lasted 4 weeks. In both studies, electrocardiographic recordings were normal [44]. Animal pharmacokinetic studies on zucapsaicin In vivo pharmacokinetics studies are available only in the patent data [45]. They performed in rats and minipigs and confirmed minimal systemic absorption of 0.075% zucapsaicin after topical administration. In rats, dose-dependent increases in exposure for creams containing concentrations higher than 0.075% were observed. In minipigs, circulation levels of zucapsaicin were generally below the limit of quantitation (2.5 ng/l). In rats, a possible first-pass metabolism after oral administration was observed. Rat studies of intravenously administered [14C]-zucapsaicin showed that the half-life for clearance of zucapsaicin and its metabolites is 7 -- 11 h. Distribution studies in rats demonstrated that tissue distribution profiles of zucapsaicin were similar after dermal and intravenous administration, but tissue distribution profiles differed after oral administration, possibly due to the first-pass effect. In rats, the majority of zucapsaicin and its metabolites were eliminated within 72 h. The metabolism of zucapsaicin in rats was extensive and depended on both sex and route of administration. In vitro studies confirmed that cytochrome P450 is involved in the metabolism of zucapsaicin. Zucapsaicin and its metabolites are mainly excreted in urine and feces. 4.2
5.
Clinical pharmacology of zucapsaicin
Clinical pharmacodynamic studies on zucapsaicin So far several clinical trials have been conducted to assess efficacy, safety, tolerability and pharmacokinetics of various 5.1
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formulations of zucapsaicin. Six of these trials have already been completed, one of them has been terminated and two are now recruiting. One trial that evaluates zucapsaicin as a 0.01% nasal solution in the prevention of cluster headaches during an episodic cluster headache period are not recruiting, yet [46]. Safety and tolerability (burning/stinging sensations and erythema) of 0.075% zucapsaicin cream at the site of topical application was investigated in 75 healthy volunteers and compared with that of 0.075% capsaicin cream in the same vehicle. These studies showed a lower incidence of burning/ stinging sensations in zucapsaicin-treated group than that of capsaicin on both days of the test; however, only during the first day of treatment the differences were statistically significant. The incidence of erythema was lower in zucapsaicintreated group than in capsaicin group, but these differences were not statistically significant. No serious photoallergic or phototoxic potential was shown for zucapsaicin in healthy adults either [47]. Enteric capsules of zucapsaicin were tested for its efficacy in Crohn’s disease and ulcerative colitis. Zucapsaicin was administrated orally as enteric capsules for 4 weeks at doses 2.5, 5 or 20 mg twice daily following eating. After that period, most patients demonstrated a significant decrease in their crampy abdominal pain and diarrhea [48]. Topical zucapsaicin cream underwent two Phase II studies and one Phase III study. These trials demonstrated that a daily use of topical zucapsaicin provides a substantial relief of osteoarthritic pain symptoms and confirmed that topical zucapsaicin is effective both as a monotherapy and as an adjunctive treatment option in conjunction with oral cyclooxygenase-2 (COX-2) inhibitors or NSAIDs for the relief of severe pain not controlled with oral COX-2 inhibitors or NSAIDs alone, for duration of no more than 3 months [49]. In a 12-week randomized-controlled clinical trial, zucapsaicin used as a 0.075% cream was an effective analgesic in patients > 18 years of age with osteoarthritis of the knee. Its efficacy was demonstrated for up to 1 year of continuous use. Zucapsaicin cream had no risk for serious systemic toxicity as it was not absorbed systemically, having no direct effects on internal organs. Importantly, it caused less burning sensations as compared to topical capsaicin [50]. A dermal patch containing zucapsaicin has been developed for the treatment of osteoarthritic pain and PHN. Phase I study results on this zucapsaicin formulation confirmed the lack of systemic absorption from the patch, pointing out its possible use either as a monotherapy or as an adjunctive therapy combined with other drugs in PHN without the risk of drug--drug interactions. Zucapsaicin patch containing 0.210 mg of zucapsaicin per patch applied once a day for 4 weeks in the treatment of PHN and postincisional neuralgia has been also evaluated in the clinical investigation in a Phase II proof-of-concept trial [51]. This study evaluated safety and efficacy of topically administered zucapsaicin patch in the treatment of moderate-to-severe daily pain associated with
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PHN localized to the trunk and with localized postincisional NP syndromes on the trunk [51]. The primary outcome measured in this study was the change in average daily pain score from the baseline period to the average daily pain score of the last week of the treatment period. The secondary outcome measure was the average daily sleep score. The study was composed of a 1-week nontreatment baseline period during which subjects were required to complete a daily diary assessing pain and sleep interference. This period was followed by a 4-week treatment period during which subjects applied zucapsaicin patch (0.015%) daily 12 h per day and completed a daily diary assessing overall pain and sleep interference. Next, there was a 2-week post-treatment observation period. In these studies, patients of both sexes, aged 18 -- 80 with history of PHN of at least 6 months after healing of a herpes zoster skin rash, were included. They were on a stable dose of a medication for PHN pain throughout the study. A single, localized area of skin on trunk with PHN measuring ~ 10 14 cm or less was one of the inclusion criteria. The study results are not available yet [51]. A double-blind, randomized, vehicle-controlled, parallelgroup Phase II trial evaluating the efficacy of 0.01% nasal spray containing zucapsaicin is recruiting patients with PHN of the trigeminal nerve [52]. This trial started in March 2014. It compares the activity of zucapsaicin nasal spray (0.01%, 20 mcg/dose (20 mcl), 10 mcl in each nostril, twice daily, for 6 weeks) with the effect of placebo nasal spray. The study enrolls patients of both sexes, aged between 21 and 80 years who experience average, moderate-to-severe chronic PHN restricted to the distribution of the affected trigeminal nerve or its division for at least 12 months after healing of herpes zoster skin rash. In this trial, the primary outcome measure is the change in average daily pain score from the baseline period to the last week (week 6) of the treatment period, whereas the secondary outcome measure is the change in average daily pain score from the baseline period to each of weeks 1 -- 5 of this study. Average daily sleep score, skin sensitivity, subject global impression of change, investigator global impression of change and the requirement for acute medication are also compared between the baseline period and the last week and other weeks of the treatment period [52]. Intranasal zucapsaicin (50 mcg) as a metered nasal spray suppressed neuropeptides (SP, CGRP) responsible for migraine pain, cluster headaches and symptoms of PHN of the trigeminal nerve within the trigeminal neural plexus [53]. In clinical trials, it was applied intranasally at 0.01% 20 mcg twice daily for 7 days (0.1 ml to each nostril), significantly reducing episodic cluster headaches at weeks 1, 2 and 3 of the post-treatment observation period without causing serious adverse effects [53,54]. Its single dose of either 20 or 150 mcg was effective in migraine with or without aura [5,53]. Clinical pharmacokinetic studies on zucapsaicin Oral zucapsaicin is being developed for several indications, including NP. Using animal models it was previously shown 5.2
that a single oral dose of cis-capsaicin provided a week or longer analgesia [42]. Taking into account the results of available in vivo tests, soft capsules containing zucapsaicin were developed as a potential treatment for NP and/or postoperative pain, but after their oral administration to healthy human volunteers two unexpected results occurred. First of all, zucapsaicin was not absorbed (level of zucapsaicin in serum was lower than 0.01 ng/ml). Additionally, zucapsaicin given orally produced more local burning and discomfort in the gastrointestinal tract than comparable dosages of its trans isomer, capsaicin (only patent data available) [45]. These findings became a starting point for further investigations in which zucapsaicin in a form of soft gel capsules coated with an enteric coating was given to human volunteers. The performed pharmacokinetics studies showed that zucapsaicin was not systemically absorbed and the observed earlier abdominal discomfort was essentially nonexistent. It was suggested that such a formulation of zucapsaicin could be used for treatment of pain and inflammation in the small or large bowel. Conditions amenable to such a treatment include Crohn’s disease, ulcerative colitis and irritable bowel syndrome (only patent data available) [45].
6.
Expert opinion
The resistance to conventional analgesics present in ~ 40% of neuropathic patients stimulates the need to explore novel drug targets and search for new, analgesically active compounds to treat NP of various origins. Currently used drugs for the treatment of NP have undesirable adverse effects, and they might also demonstrate serious drug--drug interactions. Zucapsaicin (civamide) is the cis isomer of the naturally occurring capsaicin. It is also worth noting that in humans a topical treatment with this drug is better tolerated than the topical treatment with its trans isomer (capsaicin). The mechanism of pharmacological action of zucapsaicin has not been fully understood. It is suggested that this compound is an agonist of the vanilloid receptor VR1 (TRPV1) and a neuronal calcium channel blocker. Although the results of clinical trials providing evidence that zucapsaicin is effective in NP are not available at present and a commercial preparation is not available for patients suffering from NP. It seems that in the future this compound may become one of the therapeutic options for the treatment of NP, particularly in patients suffering from PHN. The most common adverse events observed for topical zucapsaicin 0.075% in clinical trials were, similarly to capsaicin, application site reactions: transient burning or warming sensations after application. The former was the most common adverse drug reaction leading to the withdrawal in zucapsaicin-treated subjects. This adverse effect was strongly concentration-dependent, although the percentage of patients reporting burning sensations during treatment decreased over time in the 12-week controlled study.
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Surgical intervention often results in postsurgical pain that frequently becomes independent of the condition that originally required surgery. Dermal therapies (patches) containing zucapsaicin may be considered the least invasive method to relieve postincisional pain. Dermal drug delivery offers advantages as it avoids the need for intravenous or intramuscular drug administration or is a good choice for patients who are unable to swallow oral medications. Also, dermal drug delivery avoids the first-pass metabolism in the liver. It also overcomes the problems with drugs that are poorly absorbed in the gastrointestinal tract. Possibly, but it appears inevitable that with advancing technologies, molecules derived from zucapsaicin analogues vanilloid receptor antagonist for NP will arrive in the near future. New analogs of zucapsaicin, not inducing pain themselves but having potent analgesic and antipruritic effects, may further ignite the excitement for the therapeutic potential of this medicine for the benefit of millions of patients with NP and itch. However, it is unlikely that any new pharmaceutical would be anything close to a panacea for pain. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Given the complexity and neuroplasticity of pain transmission, polypharmacy will likely be required for many chronic pain sufferers for the foreseeable future. Additionally, the majority of NP is lumped into a single disease state and treated as a single entity. Hopefully, the treatment of NP will become more nuanced than this. It is also worth noting that in the future zucapsaicin could become a valuable drug for not only alleviating NP but also for the treatment of osteoarthritic pain and headaches.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Schnitzer TJ, Pelletier JP, Haselwood DM. Civamide cream 0.075% in patients with osteoarthritis of the knee: a 12-week randomized controlled clinical trial with a longterm extension. J Rheumatol 2012;39(3):610-20 Summary of clinical trial of zucapsaicin for the treatment of osteoarthritis.
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Eid SR, Cortright DN. Transient receptor potential channels on sensory nerves. Handb Exp Pharmacol 2009;194:261-81 Backonja M, Wallace MS, Blonsky ER, et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised,
Bernstein JE. Method and compositions of civamide to treat disease of the intestines. WO2011100668 A4; 2011 Clinical trials found for civamide. Available from: https://clinicaltrials.gov/ ct2/results?term=civamide&Search=Search [Last accessed 10 August 2014]
Walker KM, Urban L, Medhurst SJ, et al. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 2003;304:56-62
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Wong GY, Gavva NR. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: recent advances and setbacks. Brain Res Rev 2009;60:267-77
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Affiliation Kinga Sałat1, Anna Jakubowska2 & Katarzyna Kulig†2 † Author for correspondence 1 Chair of Pharmacodynamics, Jagiellonian University, Faculty of Pharmacy, Medyczna 9 St., 30-688 Krako´w, Poland 2 Chair of Pharmaceutical Chemistry, Jagiellonian University, Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Medyczna 9 St., 30-688 Krako´w, Poland E-mail: [email protected]
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Zucapsaicin for the treatment of neuropathic pain
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Kinga Sałat, Anna Jakubowska & Katarzyna Kulig† †
Jagiellonian University, Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Krako´w, Poland
1.
Introduction
2.
Chemistry
3.
Mechanism of action
4.
Preclinical pharmacology of zucapsaicin
5.
Clinical pharmacology of zucapsaicin
6.
Expert opinion
Introduction: Neuropathic pain (NP) is a chronic disease that stems from a primary lesion or dysfunction of the central or peripheral nervous system. Zucapsaicin is a synthetic cis isomer of natural capsaicin that has shown therapeutic efficacy in pain accompanying osteoarthritis of the knee. It is also currently under investigation for the relief of severe pain in adults suffering from NP. Areas covered: The authors provide an overview of the pharmacological properties of zucapsaicin based on available data from both preclinical and clinical trials. They also discuss its mechanism of action. Expert opinion: The mechanism of action and clinical indications of zucapsaicin are similar to that of its naturally occurring isomer, capsaicin. However, in contrast to capsaicin, zucapsaicin is better tolerated. In the future, zucapsaicin could become a valuable drug for treating pain relief. Indeed, it is possible, in addition to providing NP relief, that it may have a use in treating osteoarthritic pain, headaches and pain that accompany intestinal diseases. Keywords: neuropathic pain, topical analgesics, TRPV1 agonist, zucapsaicin Expert Opin. Investig. Drugs (2014) 23(10):1433-1440
1.
Introduction
Neuropathic pain: a challenge for contemporary medicine Neuropathic pain (NP) is a chronic disease that results from the dysfunction to the central or peripheral nervous system [1]. It is estimated that NP affects between 3 and 8% of the world’s population, worsening patients’ quality of life, general mood and occupational functioning. This relatively frequent condition with an annual incidence of almost 1% of the general population particularly often affects women and middle-aged persons [2,3]. Available analgesics, including opioids and analgesic adjuvants (such as antidepressants and anticonvulsant drugs), provide sufficient efficacy in many pain syndromes. However, opioids have proven relatively weaker effect in the alleviation of NP than in cancer pain [4,5], whereas the use of analgesic adjuvants, although effective for some types of NP, is often limited by their adverse effects and poor patients’ compliance. In view of this, NP often remains intractable and its treatment is a challenging endeavor [6]. It is estimated that the resistance to conventional analgesic pharmacotherapy is present in ~ 40% of neuropathic patients [7,8]. In view of this, there is a strong need to explore novel drug targets and search for new, analgesically active compounds with an acceptable safety profile to treat NP of various origins [4]. Currently used drugs for the treatment of NP have undesirable adverse effects causing patients’ discomfort. Moreover, they might demonstrate serious drug--drug interactions, which make the treatment of NP even more complicated [9]. In the recent years, new areas of research on the mechanisms of NP have been explored. To date, antagonists of voltage-gated ion channels selectively permeable for sodium, calcium or potassium ions; ligands of transient receptor potential 1.1
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Box 1. Drug summary. Drug name (generic) Indication Phase Route of administration Pharmacological description Chemical structure
Zucapsaicin Neuropathic pain II Topical cream TRPV1 receptor agonist O O
N H
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HO
Pivotal trials
[51,52]
channel (TRP channel) family; antagonists of ionotropic receptors (NMDA, GABAergic A receptors); ligands of histaminergic H3 receptors or angiotensin II AT2 receptor blockers proved their analgesic efficacy in numerous preclinical models and clinical trials. Additionally, compounds targeting at sigma-1 receptors, GABA, serotonin, dopamine or noradrenaline reuptake inhibitors, endocannabinoid signaling system ligands, antagonists of proinflammatory cytokines (TNF-a, IL-1b, IL-6, IL-17, IFN-g) or agents modulating the biological activity of neurotrophins (nerve growth factor [NGF] and brain-derived neurotrophic factor) are being thoroughly investigated as potential future analgesics [10-13]. Overexpressed TRPV1 channels: a target for neuropathic pain treatment
1.2
TRP channels play a pivotal role in diverse afferent physiological functions (transduction of chemical, mechanical and thermal stimuli) and efferent biological processes (e.g., cellular differentiation, thermoregulation or vasoregulation). Importantly, some of them are involved in pain transduction. Of 28 TRP channels discovered so far, 7 sense hot or high temperatures (TRPV1, V2, V3, V4, TRPM2, TRPM4, TRPM5), whereas two other (TRPA1 and TRPM8) are activated by cold. In view of this, these molecules are frequently referred to as ‘thermoTRPs’ as they comprise a wide temperature range: below 10 C (TRPA1) and above 53 C (TRPV2) [1,4,11]. Molecular cloning of the vanilloid receptor 1 (VR1, ‘capsaicin receptor’, TRPV1 -- TRP channel vanilloid subfamily member 1) in 1997 by Caterina and Julius [14] not only initiated studies on its biological function, but it also identified TRPV1 as a novel therapeutic target for analgesics and explained the mechanism of action of plant-derived analgesics, such as capsaicin. TRPV1 is present in sensory neurons, mainly in C nerve fibers and, to a lesser extent, in Ad fibers. These so called ‘capsaicin-sensitive’ neurons, and their nerve fibers can transmit both pain and itch [15]. The peripheral neuronal distribution of TRPV1 is related to its key role in the transduction of pain [1], both inflammatory and neuropathic [16,17], although the discovery of central 1434
TRPV1 receptors suggests also their plausible role in the modulation of nociception [18]. In mice, TRPV1 channels have been identified at the CNS level in spinal and supraspinal structures participating in pain modulation and perception (rostral ventromedial medulla, periaqueductal gray, amygdala, solitary tract nucleus, somatosensory cortex, anterior cingulated cortex and insula) [16-19]. An increasing interest in the role of TRPV1 channels in NP has been shown in numerous studies [17,20-24]. An altered distribution of TRPV1 in primary afferent neurons was demonstrated in the diabetic or nerve injury-induced NP models in mice [22-24] and in nerve fibers of human diabetic neuropathy skin [21], whereas the increased TRPV1 expression in the rat dorsal root ganglion [25] and proteinase-activated receptor 2-mediated sensitization of TRPV1 [20] were proven to underlie paclitaxel-induced mechanical allodynia and thermal hyperalgesia. Moreover, it was also shown [26] that TRPV1 plays a crucial role in cisplatin-induced thermal hyperalgesia in vivo. It also was demonstrated that TRPV1 agonists and antagonists effectively attenuated thermal and mechanical hyperalgesia and mechanical allodynia in models of NP [17,27,28] and in human studies [15]. Numerous studies demonstrate that NGF plays a pivotal role in the development and maintenance of NP. It was also shown that NGF is able to upregulate TRPV1 receptors. The increased expression of TRPV1 is observed not only in C fibers but also in myelinated A fibers [18]. This indicates for a potential role of TRPV1 ligands not only in thermal hyperalgesia but also mechanical hyperalgesia [18,29] and provides further evidence that the function of TRPV1 in pain is more than being just a thermoreceptor. This upregulation of TRPV1 at the peripheral and CNS level proves hypersensitivity of the vanilloid system in NP, so TRPV1 channels are regarded to be suitable candidates for the development of analgesic drugs efficacious in NP conditions. TRPV1 plays an important role in chemical and thermal hyperalgesia in a model of diabetic neuropathy [29,30], but not in NP induced by oxaliplatin or paclitaxel. Moreover, the increased expression of TRPV1 leads to the enhanced glutamatergic neurotransmission in the spinal cord that is also involved in both chronic and acute pain [18]. TRPV1 is a protein containing 838 amino acids. The TRPV1 channel consists of six transmembrane domains that are assembled as homo- or heterotetramers [18]. It is permeable to calcium and sodium ions [15,31]. TRPV1-induced calcium influx into cells is responsible for the release of calcium from the endoplasmic reticulum. High calcium (and sodium) permeability through the channel pore results in cell membrane depolarization that stimulates the release of substance P (SP). SP excites primary sensory neurons, producing an intense burning sensation [15]. TRPV1 activation also induces the release of somatostatin, calcitonin gene-related peptide (CGRP) and other neuropeptides (neurokinin A, kassinin), leading to neurogenic inflammation. This initial hypersensitization is followed by a persistent desensitization that underlies
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Zucapsaicin
the analgesic effect of capsaicin and zucapsaicin (Box 1) (discussed below) [15]. The increased expression of TRPV1 in NP conditions, as well as its desensitization, provides a valid strategy for pain relief and might be a promising perspective for patients suffering from intractable NP whose treatment is still unsatisfactory [18]. In humans, topically administered capsaicin is rapidly and well absorbed through the skin [15,16]. Despite this, it is effective in a (modest) proportion of patients with postherpetic neuralgia (PHN), chronic distal painful polyneuropathy and in surgical NP, including postmastectomy pain syndromes [1,9,32]. Standard topical formulations containing low concentrations of capsaicin -- creams, lotions and patches -- are available as ‘over the counter’ preparations. Some of these formulations (creams, lotions) require many applications per day, whereas all of them cause irritation and pain due to the activation of sensory neurons expressing TRPV1 [9,18,32]. This adverse effect of capsaicin when used as a patch formulation often requires the pretreatment with an anesthetic. Hence, there is a strong need to develop new routes of capsaicin administration and develop analogs that relieve pain without causing unfavorable drug interactions, adverse effects or discomfort due to pungency [5]. 2.
Chemistry
Zucapsaicin (civamide) is the cis isomer of the naturally occurring capsaicin. Zucapsaicin compared with capsaicin has significantly lower pungency [33]. The synthesis of this compound was elaborated by Gannett et al. [34] and Orito et al. [35]. The crucial point of this synthesis was the elaboration of coupling vanillylamine with (Z)-8-methylnon-6-enoyl chloride. 3.
Mechanism of action
controversial) and iii) activation of calcium-dependent protein kinase C isoforms and subsequent channel phosphorylation [38]. Desensitization involves both tachyphylaxis (short-term desensitization) and long-term, persistent, desensitization [1,5,19]. It is suggested that the downregulation of proalgesic substances (such as SP) and upregulation of analgesic peptides are implicated in desensitization [4]. The exhaustion of SP reserves renders neurons desensitized and refractory. These mechanisms of desensitization are not fully understood. It is thought that the short-term desensitization is related to capsaicin’s ability to block the intra-axonal transport of NGF, SP and somatostatin [15]. The desensitization is a reversible phenomenon. It begins a few hours after capsaicin application and may last even several weeks [4]. The reversible desensitization was found useful in the treatment of pain, whereas the site-specific ablation of sensory nerves transmitting pain stimuli is a promising approach (‘molecular scalpel’) to achieve a permanent pain relief in patients suffering from bone cancer pain or HIV-induced neuropathies [1,5]. Desensitization and depletion of pronociceptive neurotransmitters induce chemical denervation with a loss of function, which is clinically used in osteoarthritis, diabetic neuropathy, psoriasis and others [18,39,40]. In dorsal root ganglia and the sciatic nerve, zucapsaicin decreases levels of SP and CGRP, indicating that it influences peptidergic afferent neurons via a desensitization mechanism [41]. When administered topically, the intended targets for zucapsaicin are the neurons that innervate the local area of application. These neurons transmit pain toward the CNS. 4.
Preclinical pharmacology of zucapsaicin
Animal pharmacodynamic studies on zucapsaicin The antinociceptive effects of zucapsaicin were evaluated in several in vivo tests, including chemical and thermal methods (formalin test and thermal paw withdrawal test, respectively). These experiments were carried out on adult rats after oral administration. It was found that zucapsaicin significantly attenuated nociceptive behavior in both phases of the formalin test, and this effect was observed for a long time (4 -- 7 days). These results also showed that the antinociceptive effect of zucapsaicin observed in the formalin test could be attributable to the interruption of small afferent (tachykinin/CGRP) transmission, perhaps secondary to an acute desensitization at afferent terminals [42]. In the thermal paw withdrawal test, zucapsaicin given at tolerable doses was able to produce a protracted and statistically significant increase in the thermal response latency. The effect evolved within more than an hour and < 24 h and lasted for 2 -- 3 days. Taking into consideration the fact that zucapsaicin significantly inhibits behavioral responses in the acute phase of the formalin test, it appears that this compound is able to block acute nociception, and this action is consistent with an effect upon C-polymodal nociceptors [42]. 4.1
The mechanism of pharmacological action of zucapsaicin has not been fully understood yet. It is suggested that this compound, similarly to its trans isomer, is an agonist of the vanilloid receptor VR1 (TRPV1) and a neuronal calcium channel blocker [36]. Capsaicin is able to excite and desensitize C-fibers. As such, it is not only able to cause pain, but also exhibit analgesic properties. Initially, it stimulates TRPV1, which is responsible for a burning sensation. This effect is followed by a longlasting refractory state -- ‘desensitization’ -- during which the previously excited sensory neurons become unresponsive to capsaicin and other stimuli. It was shown that desensitization and tachyphylaxis of TRPV1 channels contribute to capsaicin-induced pain relief [37]. Desensitization of TRPV1 represents the main mechanism of its inhibitory function. Three distinct pathways of capsaicin-induced desensitization have been described: i) activation of calcineurin, which results in dephosphorylation of TRPV1; ii) activation of phospholipase C with the subsequent phosphatidylinositol 4,5-biphosphate hydrolysis (rather
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The observed inhibitory effect of zucapsaicin observed in Chung (spinal nerve ligation) model of NP was moderate, but statistically significant [42]. The topical application of zucapsaicin was also tested for the treatment of primary or recurrent experimental genital herpes simplex virus infection in guinea pigs. It was shown that zucapsaicin is better tolerated than topical treatment with capsaicin. Animals displayed evidence of mild discomfort following initial treatment but became rapidly desensitized and subsequently showed no response to further application. The animals treated during the primary infection subsequently experienced a long-lasting reduction in the recurrent disease. It is also worth noting that zucapsaicin treatment during the latent infection significantly reduced the recurrent disease [43]. Cardiovascular effects of zucapsaicin were evaluated in vivo in a dermal minipig study and an oral dog study. In the 9-month chronic dermal toxicity study in minipigs, zucapsaicin cream was used at concentrations of 0.075, 0.75 and 3.75% and electrocardiographic examinations were made prior to, at week 1, then 4.5 months and 9 months later. In dog’s oral toxicity, study of zucapsaicin at doses 0, 3, 10 and 30 mg/kg lasted 4 weeks. In both studies, electrocardiographic recordings were normal [44]. Animal pharmacokinetic studies on zucapsaicin In vivo pharmacokinetics studies are available only in the patent data [45]. They performed in rats and minipigs and confirmed minimal systemic absorption of 0.075% zucapsaicin after topical administration. In rats, dose-dependent increases in exposure for creams containing concentrations higher than 0.075% were observed. In minipigs, circulation levels of zucapsaicin were generally below the limit of quantitation (2.5 ng/l). In rats, a possible first-pass metabolism after oral administration was observed. Rat studies of intravenously administered [14C]-zucapsaicin showed that the half-life for clearance of zucapsaicin and its metabolites is 7 -- 11 h. Distribution studies in rats demonstrated that tissue distribution profiles of zucapsaicin were similar after dermal and intravenous administration, but tissue distribution profiles differed after oral administration, possibly due to the first-pass effect. In rats, the majority of zucapsaicin and its metabolites were eliminated within 72 h. The metabolism of zucapsaicin in rats was extensive and depended on both sex and route of administration. In vitro studies confirmed that cytochrome P450 is involved in the metabolism of zucapsaicin. Zucapsaicin and its metabolites are mainly excreted in urine and feces. 4.2
5.
Clinical pharmacology of zucapsaicin
Clinical pharmacodynamic studies on zucapsaicin So far several clinical trials have been conducted to assess efficacy, safety, tolerability and pharmacokinetics of various 5.1
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formulations of zucapsaicin. Six of these trials have already been completed, one of them has been terminated and two are now recruiting. One trial that evaluates zucapsaicin as a 0.01% nasal solution in the prevention of cluster headaches during an episodic cluster headache period are not recruiting, yet [46]. Safety and tolerability (burning/stinging sensations and erythema) of 0.075% zucapsaicin cream at the site of topical application was investigated in 75 healthy volunteers and compared with that of 0.075% capsaicin cream in the same vehicle. These studies showed a lower incidence of burning/ stinging sensations in zucapsaicin-treated group than that of capsaicin on both days of the test; however, only during the first day of treatment the differences were statistically significant. The incidence of erythema was lower in zucapsaicintreated group than in capsaicin group, but these differences were not statistically significant. No serious photoallergic or phototoxic potential was shown for zucapsaicin in healthy adults either [47]. Enteric capsules of zucapsaicin were tested for its efficacy in Crohn’s disease and ulcerative colitis. Zucapsaicin was administrated orally as enteric capsules for 4 weeks at doses 2.5, 5 or 20 mg twice daily following eating. After that period, most patients demonstrated a significant decrease in their crampy abdominal pain and diarrhea [48]. Topical zucapsaicin cream underwent two Phase II studies and one Phase III study. These trials demonstrated that a daily use of topical zucapsaicin provides a substantial relief of osteoarthritic pain symptoms and confirmed that topical zucapsaicin is effective both as a monotherapy and as an adjunctive treatment option in conjunction with oral cyclooxygenase-2 (COX-2) inhibitors or NSAIDs for the relief of severe pain not controlled with oral COX-2 inhibitors or NSAIDs alone, for duration of no more than 3 months [49]. In a 12-week randomized-controlled clinical trial, zucapsaicin used as a 0.075% cream was an effective analgesic in patients > 18 years of age with osteoarthritis of the knee. Its efficacy was demonstrated for up to 1 year of continuous use. Zucapsaicin cream had no risk for serious systemic toxicity as it was not absorbed systemically, having no direct effects on internal organs. Importantly, it caused less burning sensations as compared to topical capsaicin [50]. A dermal patch containing zucapsaicin has been developed for the treatment of osteoarthritic pain and PHN. Phase I study results on this zucapsaicin formulation confirmed the lack of systemic absorption from the patch, pointing out its possible use either as a monotherapy or as an adjunctive therapy combined with other drugs in PHN without the risk of drug--drug interactions. Zucapsaicin patch containing 0.210 mg of zucapsaicin per patch applied once a day for 4 weeks in the treatment of PHN and postincisional neuralgia has been also evaluated in the clinical investigation in a Phase II proof-of-concept trial [51]. This study evaluated safety and efficacy of topically administered zucapsaicin patch in the treatment of moderate-to-severe daily pain associated with
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PHN localized to the trunk and with localized postincisional NP syndromes on the trunk [51]. The primary outcome measured in this study was the change in average daily pain score from the baseline period to the average daily pain score of the last week of the treatment period. The secondary outcome measure was the average daily sleep score. The study was composed of a 1-week nontreatment baseline period during which subjects were required to complete a daily diary assessing pain and sleep interference. This period was followed by a 4-week treatment period during which subjects applied zucapsaicin patch (0.015%) daily 12 h per day and completed a daily diary assessing overall pain and sleep interference. Next, there was a 2-week post-treatment observation period. In these studies, patients of both sexes, aged 18 -- 80 with history of PHN of at least 6 months after healing of a herpes zoster skin rash, were included. They were on a stable dose of a medication for PHN pain throughout the study. A single, localized area of skin on trunk with PHN measuring ~ 10 14 cm or less was one of the inclusion criteria. The study results are not available yet [51]. A double-blind, randomized, vehicle-controlled, parallelgroup Phase II trial evaluating the efficacy of 0.01% nasal spray containing zucapsaicin is recruiting patients with PHN of the trigeminal nerve [52]. This trial started in March 2014. It compares the activity of zucapsaicin nasal spray (0.01%, 20 mcg/dose (20 mcl), 10 mcl in each nostril, twice daily, for 6 weeks) with the effect of placebo nasal spray. The study enrolls patients of both sexes, aged between 21 and 80 years who experience average, moderate-to-severe chronic PHN restricted to the distribution of the affected trigeminal nerve or its division for at least 12 months after healing of herpes zoster skin rash. In this trial, the primary outcome measure is the change in average daily pain score from the baseline period to the last week (week 6) of the treatment period, whereas the secondary outcome measure is the change in average daily pain score from the baseline period to each of weeks 1 -- 5 of this study. Average daily sleep score, skin sensitivity, subject global impression of change, investigator global impression of change and the requirement for acute medication are also compared between the baseline period and the last week and other weeks of the treatment period [52]. Intranasal zucapsaicin (50 mcg) as a metered nasal spray suppressed neuropeptides (SP, CGRP) responsible for migraine pain, cluster headaches and symptoms of PHN of the trigeminal nerve within the trigeminal neural plexus [53]. In clinical trials, it was applied intranasally at 0.01% 20 mcg twice daily for 7 days (0.1 ml to each nostril), significantly reducing episodic cluster headaches at weeks 1, 2 and 3 of the post-treatment observation period without causing serious adverse effects [53,54]. Its single dose of either 20 or 150 mcg was effective in migraine with or without aura [5,53]. Clinical pharmacokinetic studies on zucapsaicin Oral zucapsaicin is being developed for several indications, including NP. Using animal models it was previously shown 5.2
that a single oral dose of cis-capsaicin provided a week or longer analgesia [42]. Taking into account the results of available in vivo tests, soft capsules containing zucapsaicin were developed as a potential treatment for NP and/or postoperative pain, but after their oral administration to healthy human volunteers two unexpected results occurred. First of all, zucapsaicin was not absorbed (level of zucapsaicin in serum was lower than 0.01 ng/ml). Additionally, zucapsaicin given orally produced more local burning and discomfort in the gastrointestinal tract than comparable dosages of its trans isomer, capsaicin (only patent data available) [45]. These findings became a starting point for further investigations in which zucapsaicin in a form of soft gel capsules coated with an enteric coating was given to human volunteers. The performed pharmacokinetics studies showed that zucapsaicin was not systemically absorbed and the observed earlier abdominal discomfort was essentially nonexistent. It was suggested that such a formulation of zucapsaicin could be used for treatment of pain and inflammation in the small or large bowel. Conditions amenable to such a treatment include Crohn’s disease, ulcerative colitis and irritable bowel syndrome (only patent data available) [45].
6.
Expert opinion
The resistance to conventional analgesics present in ~ 40% of neuropathic patients stimulates the need to explore novel drug targets and search for new, analgesically active compounds to treat NP of various origins. Currently used drugs for the treatment of NP have undesirable adverse effects, and they might also demonstrate serious drug--drug interactions. Zucapsaicin (civamide) is the cis isomer of the naturally occurring capsaicin. It is also worth noting that in humans a topical treatment with this drug is better tolerated than the topical treatment with its trans isomer (capsaicin). The mechanism of pharmacological action of zucapsaicin has not been fully understood. It is suggested that this compound is an agonist of the vanilloid receptor VR1 (TRPV1) and a neuronal calcium channel blocker. Although the results of clinical trials providing evidence that zucapsaicin is effective in NP are not available at present and a commercial preparation is not available for patients suffering from NP. It seems that in the future this compound may become one of the therapeutic options for the treatment of NP, particularly in patients suffering from PHN. The most common adverse events observed for topical zucapsaicin 0.075% in clinical trials were, similarly to capsaicin, application site reactions: transient burning or warming sensations after application. The former was the most common adverse drug reaction leading to the withdrawal in zucapsaicin-treated subjects. This adverse effect was strongly concentration-dependent, although the percentage of patients reporting burning sensations during treatment decreased over time in the 12-week controlled study.
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Surgical intervention often results in postsurgical pain that frequently becomes independent of the condition that originally required surgery. Dermal therapies (patches) containing zucapsaicin may be considered the least invasive method to relieve postincisional pain. Dermal drug delivery offers advantages as it avoids the need for intravenous or intramuscular drug administration or is a good choice for patients who are unable to swallow oral medications. Also, dermal drug delivery avoids the first-pass metabolism in the liver. It also overcomes the problems with drugs that are poorly absorbed in the gastrointestinal tract. Possibly, but it appears inevitable that with advancing technologies, molecules derived from zucapsaicin analogues vanilloid receptor antagonist for NP will arrive in the near future. New analogs of zucapsaicin, not inducing pain themselves but having potent analgesic and antipruritic effects, may further ignite the excitement for the therapeutic potential of this medicine for the benefit of millions of patients with NP and itch. However, it is unlikely that any new pharmaceutical would be anything close to a panacea for pain. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Affiliation Kinga Sałat1, Anna Jakubowska2 & Katarzyna Kulig†2 † Author for correspondence 1 Chair of Pharmacodynamics, Jagiellonian University, Faculty of Pharmacy, Medyczna 9 St., 30-688 Krako´w, Poland 2 Chair of Pharmaceutical Chemistry, Jagiellonian University, Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Medyczna 9 St., 30-688 Krako´w, Poland E-mail: [email protected]
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