Chapter 5 Ganesan Baranidharan*; Arun K. Bhaskar Consultant in Pain Medicine, Leeds Teaching Hospitals NHS trust: D Ward, Seacroft Hospital, Leeds, LS14 6UH Capsaicin is a transient receptor potential vanilloid agonist. The pharmacology of capsaicin and its use in managing neuropathic pain will be discussed in this chapter. It is available as a low- and a high-concentration form for clinical use. Their mechanism of action varies, and their clinical use is also different. We will also endeavor to explain practical aspects of using the high-concentration capsaicin patch in clinical settings. Capsaicin is an extract from chili peppers found in native America. They were used to spice the cuisines in Mexico and America and were then passed on to Asia by Africa by Europeans [1]. The hotness of chili peppers is measured in Scoville heat units, which are the number of times a chili extract must be diluted in water for it to lose its heat. Capsaicin scores about 16,000,000 in comparison to jalapeños, which measure about 4500 units. Turnbull described the use of chili as a hot alcoholic pepper extract to treat burning or itching extremities [2]. The pure crystalline form was isolated by Thresh in 1876 [3]. Capsaicin has been available for a long time as creams, lotions, or patches in low concentration. Capsaicin 0.025% and 0.075% could be purchased over the counter to treat neuropathic and nociceptive musculoskeletal pain, such as postherpetic neuralgia (PHN), diabetic neuropathy, postsurgical pain, osteoarthritis, and rheumatic arthritis. Chili extracts were also used to treat itching, psoriasis, cluster headaches, and migraines [4]. A Cochrane review on the use of low-concentration capsaicin concluded that there was insufficient evidence to recommend for routine clinical use. Capsaicin suffered two major disadvantages: (1) burning sensation and skin reactions not tolerated by many and (2) the need to apply multiple times in a day for 4-6 weeks. Studies also suggest that the effect is not more than placebo [5]. High-concentration capsaicin 8% patch, also known as NGX-4010 (Astellas Pharma/NeurogesX, Inc.), provides rapid and longer lasting pain relief following a single application in different neuropathic pain states. In 2009, the Food and Drug Administration (FDA) and European Union (EU) approved the use of the 8% capsaicin patch after four-phase III clinical trials. The patch is currently approved for use in peripheral neuropathy in nondiabetic patients in the EU, whereas the FDA approved its use in the United States only to treat PHN. PHN [6] and HIV-associated distal sensory polyneuropathy (HIV-DSP) [7] were the two neuropathic pain models used for early clinical trials. There are also several case-series on the use of the capsaicin 8% patch in neuropathic pain states like scar pain, postsurgical pain, chemotherapy-induced neuropathy, and other localized peripheral states. Capsaicin comes from plants of the genus Capsicum, which belong to the Solanaceae family. Capsaicin is the main pungent chemical, the others being dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin [8]. The main site of action of capsaicin is the transient receptor potential vanilloid (TRPV1) channel. Although many endogenous and exogenous agonists nonselectively activate the channel, capsaicin is highly selective and highly potent at this channel. Capsaicin desensitizes nociceptive neurons. There are two distinct phenomena reported. The first is a classic pharmacological desensitization, where a prolonged and repeated application leads to progressive reduction in the size of subsequent response to capsaicin. The second phenomenon is a “functional desensitization,” where capsaicin leads to a reduction or loss of responsiveness of neurons to other stimuli. High-concentration capsaicin produces the functional desensitization [9]. Capsaicin increases the calcium:sodium permeability from a baseline of 8:1 to 25:1. There is a massive influx of calcium ions down the electrochemical gradient. In addition, there is also release of calcium through the TRPV1 channels activated on intracellular organelles like the endoplasmic reticulum. The excess intracellular calcium triggers calcium-dependent protease enzymes causing cytoskeletal breakdown. Microtubule depolymerization causes a halt in fast axonal transport [10,11]. Osmotic swelling is caused by the chloride influx. A TRPV1-independent mechanism also exists by causing direct inhibition of electron chain transport and subsequent mitochondrial dysfunction [12]. Thus, multiple mechanisms ultimately lead to loss of cellular integrity and defunctionalization of the nociceptor fibers. The nerve fibers retract to a depth at which mitochondrial function is preserved. Immunohistochemical studies have shown that capsaicin produces highly localized loss of nerve fibers in the epidermis and dermis [13]. This replaces the hypothesis in the mid-1980s about substance P depletion being responsible for capsaicin-induced pain relief. It is now known that substance P is one of the many neurotransmitters expressed by nociceptor fibers. Thus, nerve terminal defunctionalization and retraction, as caused by capsaicin, leads to decrease in all the neuropeptides released by the nerve terminals, and substance P is one among them [14]. Capsaicin 8% patch (Qutenza—Astellas Pharma Ltd.) contains 179 mg of capsaicin on a 280 cm2 patch (640 mg/cm2) and works locally in the skin and with little systemic absorption. Capsaicin is very lipophilic with little affinity for the aqueous blood phase and is readily absorbed into the epidermal and dermal layers. The amount of drug absorbed depends on the duration of exposure and also the surface area of application. Blood samples from 173 patients from the trials, at varying intervals after patch removal (0, 1, 3, 6, 24 h), had quantifiable levels of capsaicin in only 34 (20%) patients, and quantifiable plasma capsaicin above the lower limit (0.5 mg/ml) was identified in only 6% of them [15]. The mean maximum plasma concentration (Cmax) after a 60-min application was 1.38 ng/ml and the Tmax to reach these levels was 1.46 h [15] as compared to 47 min after oral ingestion of 26.6 mg of capsaicin with a Cmax of 2.47 ng/ml [16]. Capsaicin is rapidly metabolized in the liver by the cytochrome enzymes. It has a high mean apparent clearance of 54,598 L/h and is therefore eliminated with a half-life of 1.64 h compared to an elimination t1/2 of 24.9 min for oral capsaicin [17]. Capsaicin is metabolized very slowly in the skin as shown by in vitro studies [6], and it has the clinical advantage of lasting longer on its site of application in the skin. So, there is no need for dose adjustments in hepatic or renal failure as there is rapidly clearance of any systemically absorbed drug. A randomized double-blind pilot study (n = 44) comparing the high-concentration 8% patch with a low-concentration 0.04% patch as active control [18] had an initial 4-week study period followed by an open-label extension phase up to 48 weeks (n = 24), during which patients got three further applications of the study medication. The study population was comprised of adult patients with PHN of at least 6 months duration and having average numerical pain rating scores (NPRS) between 3 and 8/10. Patients using concomitant pain medications had to be on stable doses for at least 21 days prior to treatment, and patients using more than 60 mg/day of morphine did not meet the inclusion criteria. After pretreatment with 4% lidocaine cream for 1 h, the investigational capsaicin patch was applied for 60 min to a maximum surface area of 1000 cm2. Immediate treatment-related pain was managed by local cooling methods and oral oxycodone (1 mg/ml), and hydrocodone bitartarate/acetaminophen (5 mg/500 mg) were allowed as rescue medication up to day 5 only. Reduction in NPRS scores, percentage of patients with 30% pain relief, and use of questionnaires such as BPI, Short form, SAT (self assessment to treatment) questionnaire, and patients ‘global impression of change (PGIC) were measured, but the scores from the first week were discarded to avoid any confounding effect from the rescue medications. There was a 32.7% reduction in baseline NPRS scores in the NGX4010 study group compared to a mere 4.4% reduction in the control group (p = 0.003) [18]. This reduction was seen as early as the first week, and the effect seemed to be maintained through the study period (4-12 weeks), whereas in the control group pain scores returned to baseline in 2-4 weeks [18]. Fifty-three percent of patients had at least a 33% reduction in pain scores from weeks 2 to 4 with 8% capsaicin vs. none in the control group, and this was increased to 78% from weeks 9 to 12 with no patients again from the control group. Higher pain relief was seen in those patients not taking concomitant medications; this finding may suggest that patients on previous neuropathic medication may have more treatment-resistant pain. Overall effect of the 8% capsaicin patch was positive regardless of any concomitant medication used [19]. The two 12-week phase III trials had also significantly higher responders for 30% pain reduction in the capsaicin 8% patch group (44% vs. 33%; p = 0.05 and 47% vs. 35%; p = 0.021) [19,20] and were also significantly greater in the capsaicin group (30% vs. 21%; p = 0.035) for 50% pain reduction [20]. During weeks 2-12, 55% patients in the capsaicin group reported an improvement on the PGIC scale (− 3 to + 3 scale from very much worse to very much improved) compared to 43% in the control group [18] and similar results (41% vs. 26%; p = 0.001) were seen in other trials [19,20]. Integrated analysis of four trials in patients with PHN (n = 1079 total; n = 597 for capsaicin 8%; n = 482 for controls) showed significantly higher reductions in baseline pain scores in the capsaicin 8% group from weeks 2-12 (31.2% vs. 23.9%; p = 0.0002), and more patients achieved at least 30% pain reduction (45% vs. 36%; p = 0.0035) [21]. The capsaicin 8% patch was found to be significantly better than the 0.04% control patch in a Cochrane review of four studies (n = 1272) using capsaicin patches for managing PHN [22]. PGIC was regarded as first-tier evidence. The calculated NNT for “much” or “very much improvement” was 8.8 at 8 weeks (95% confidence interval 5.3-26) and NNT of 7.0 at 12 weeks (95% confidence interval of 4.6-15) [22]. Long-term efficacy for similar endpoints were studied in open-label extension studies, and patients received capsaicin 8% patch treatment at intervals of no less than 12 weeks and were followed up until 40 and 48 weeks in the two studies [18,23]. The mean percentage reduction in baseline NPRS scores after the first, second, and third treatments were − 31.4%, − 30.0%, and − 34.1%, respectively [18], and the median duration of response was found to be 22 weeks; 14% maintained the response for 40 weeks [21,24]. HIV patients may develop distal sensory neuropathy due to the viral load or as a complication of the antiretroviral therapy; this can occur in 29-62% of HIV patients [25]. The efficacy of the capsaicin 8% patch has been studied in two-phase III trials [25,26] and an open-label study up to 48 weeks [27]. Patients who had moderate to severe pain for more than 2 months from HIV neuropathy were included in the study. If patients were on antiretroviral therapy, doses should have been stable for at least 8 weeks to fulfill the inclusion criteria. The capsaicin 8% patch was compared with a low-concentration capsaicin 0.04% patch as active control; as in the PHN studies, the durations of application were 30, 60, or 90 min. The mean reduction in NPRS scores at weeks 2-12 was much higher (22.7%) with the capsaicin 8% patch as compared to the control group (10.7%) (p = 0.0026) [25]. Mean reduction of pain of at least 30% was seen in 42%, 24%, and 36% patients in the 30-, 60-, and 90-min application groups, respectively, and improvement in PGIC scores was seen in a higher proportion of patients in the capsaicin 8% group (33%) compared to the control group (14%). The mean pain reduction scores in the capsaicin group were observed regardless of whether patients were on concomitant neuropathic drugs or on neurotoxic antiretroviral therapy [25]. An integrated pooled analysis of the two-phase II trials (n = 239 for capsaicin; n = 100 for controls) showed significantly greater reduction in NPRS scores from weeks 2 to 12 in the capsaicin group (27.0% vs. 15.7%; p = 0.0020) [28]. A larger proportion of patients also achieved greater than 30% reduction in pain (39% vs. 23%; p = 0.0051) in the active group [28]. The Cochrane review of two studies in HIV-AN patients (n = 801) treated with the high-concentration patch reported reduction in pain intensity, and the NNT for 30% pain intensity reduction from baseline was 11 [22]. PGIC was used as a reported outcome in only one study: based on this, the NNT for “much” or “very much improved” at 12 weeks was estimated to be 5.8 (95% confidence interval 3.8-12) [22]. A 48-week open-label study included 52 HIV-AN patients who had successful response to the capsaicin patch, and three to four further 60- or 90-min applications were allowed with an interval of at least 12 weeks between subsequent applications. The capsaicin 8% group showed 12.4% reduction in the baseline NPRS scores by week 48, and about 80% of the patients reported an improvement in the PGIC scale [27]. Capsaicin 8% patches have also been used in other peripheral neuropathic pain states. In a recently concluded open-label, randomized, multicenter study including more than 500 patients, capsaicin 8% patches showed noninferiority over pregabalin [29]. In early findings from a small group of carefully selected patients with cancer-associated neuropathic pain, 71% of patients had up to 90% pain relief [30]. Studies have also been done in patients with postamputation pain and stump-neuroma pain [31]. Another observational study, QUEPP, showed significant reduction in pain scores and functional improvement in patients diagnosed with localized neuropathic pain, including postsurgical pain, scar pain, and peripheral neuropathy in nondiabetic adults that had been unresponsive to other neuropathic agents [32]. There are also anecdotal reports of successfully treating localized neuropathic pain on the face and scalp after adequate precautions are taken to protect the eyes and nose as well as treating postherniorrhaphy neuropathic pain close to the genital mucosa. The safety and tolerability of the high-concentration capsaicin patch has been evaluated both in phase III trials and subsequent open-label extension studies [18–20,23,25–27]. Adverse events were monitored. Vital signs, physical examination (including dermal and neurological assessments), treatment-related pain, and use of rescue medication were evaluated [19]. In the open-label extension studies, which included both PHN and HIV-DSP patients, 98% of patients completed 90% of the treatment [27]. Similar results obtained in other trials suggest that treatment with capsaicin 8% patches was generally well tolerated. A total of 883 patients (67%) of the 1327 patients from various randomized controlled trials reported adverse reactions; most of these were transient minor application site-related problems. Only 0.8% patients discontinued treatment in the study group because of the adverse reactions, and this compared with 0.6% patients in the control group [6]. The pooled data suggested an overall dropout rate of 1.5% [7]. Nine deaths were reported, but none of these were related to the capsaicin treatment. Serious adverse events were uncommon, and only one, a case of accelerated hypertension possibly due to treatment-related pain, was attributed to capsaicin treatment [7,21]. The proportion of patients reporting a change in blood pressure (mild and transient, < 8 mmg in average) over the course of the phase III studies was 1.7% in the capsaicin 8% group and 0.7% in the control group [1]. Though the incidence of cardiac events was low, the risk in patients with preexisting cardiovascular disease was higher (18%) compared to those without the cardiovascular risk (10.2%) when treated with capsaicin [7]. The most common adverse events were erythema, pain, edema, and pruritus at the patch application site; indeed, 96% of PHN patients and 75% of the HIV-DSP patients had application site reactions [27]. Dermal assessment scores above 3 were very rare and were mostly < 2 (definite erythema, readily visible, minimal edema, or minimal popular response) for PHN patients and were < 1 (minimal erythema, barely perceptible) for HIV-DSP patients [27]. These reactions were more common in the active group, peaking just after patch removal and resolved by day 3. Thirty-six percent of patients in the high-concentration patch group reported a 30% increase in baseline pain scores compared to 13% in controls during the duration of patch application, and the pain increased on days 0 and 1 and started resolving from day 2 [27]. In PHN patients (depending on the number of treatments), the proportion of patients reporting pain varied from 35% to 48%, and the mean dose of rescue analgesia (oxycodone) ranged from 12.2 to 17.1 mg. Thirty-two to 46% of patients among the HIV-AN group complained of pain during the four repeat treatments, and the mean dose of oxycodone used was 12.3-31.7 mg [2]. The use of rescue medication used from day 0 to day 5 was higher in HIV patients, and this equalized with PHN patients by day 5 [27]. Clinical neurological and sensory assessments, as well as QST, were carried out, and most subjects reported no significant changes. Those who did reported an improvement or return to normal sensation [27]. Other reported adverse events were coughing and sneezing, which occurred due to aerosolization of the capsaicin. Nausea was thought to be associated with use of oxycodone as rescue analgesia. Erythema was more common in PHN patients, whereas diarrhea, weight loss, and throat infections were more common in HIV-AN patients [27]. No cumulative toxicity was reported. Initially, the licensing agreement with the Medicines and Healthcare Regulatory Agency (United Kingdom) stipulated that clinical practitioners delivering the high-concentration capsaicin patch treatment should undergo an initial training involving clinical information and a practical application workshop with placebo patches. This was followed by live training involving the use of the capsaicin 8% patches in the clinical setting under the supervision of an experienced trainer to gain competency in applying the patch and counseling patients appropriately before, during, and after administration of the patches [33,34]. This was replaced by an online training program, following which a live training or supervision of the patch application procedure may be arranged. The service was set up with one or more trained operators, mainly nurses, as a day case service in an appropriate clinical setting with adequate ventilation. The patients for the patch treatment are counseled in a clinic about what to expect, and any questions or concerns raised by the patient or their family members were addressed to their satisfaction. They are also given appropriate patient information leaflets outlining the treatment procedure and postprocedural care at home. Patients are advised not to shave or remove any body hair from the area to be treated within 48 h before treatment to prevent any breach of skin integrity at the site of application; any troublesome hair that prevents close contact of the patch to the skin are removed using scissors prior to the procedure. Patients are encouraged to bring their own rescue medication used for the flare-up of their neuropathic pain on the day of treatment and an audiovisual media to listen to music or watch an entertainment program during the treatment. The distraction provided may help to make the experience less uncomfortable. Pretreatment with EMLA (2.5% lidocaine and 2.5% prilocaine) and/or lidocaine cream is not routinely offered following the findings from the LIFT study, which showed that the use of even a low-dose analgesic like Tramadol 50 mg prior to the patch application can effectively reduce the treatment-related discomfort comparable with the application of the topical local anesthetic [35]. The capsaicin 8% patch measures 14 cm × 20 cm (280 cm2), and a maximum of four patches can be used at any given time to treat an area of 1120 cm2; it can be used to treat localized neuropathic pain in all areas of the body with the exception of the face, above the hairline on the scalp, and on or near mucous membranes of the face or perineum [34]. Most areas on the trunk or periphery require 1-2 patches, whereas treating both feet for peripheral neuropathy often requires 3-4 patches. The patch and cleansing gel are stored below 25 °C, and an unopened patch has a shelf life of 4 years. It is recommended that once opened from the sealed pack, the patch should be used within 2 h. Once the area to be treated is confirmed by the patient and the operator, the area is traced using a skin-marking pen, and a transparency sheet is used to document the area as a record to compare the size of the treatment area for subsequent treatments. The use of well-fitting nitrile gloves ensures ease of application, as capsaicin can diffuse latex gloves and can contaminate the operator’s hands [34]. The area is cleaned and dried prior to application of the patch to ensure close contact with the skin and is done in a manner to minimize aerosolization. After application, the patches are kept in place using suitable methods like wrapping the area with cling-film, bandages, or socks. Treatment of hands and feet are tedious due to the cutting the patches into little strips and wrapping around individual digits and covering the web spaces to get the best results. During the application period, the patient is fully monitored and rescue analgesia given as appropriate. Following the completion of treatment, the patch is removed by gently rolling inward to minimize aerosolization, and the area is removed of any residual capsaicin using a cleansing gel. The used patches and all the linen, gauze, and gloves are immediately disposed of safely using a sealed waste-disposal plastic bag. Patients are advised to avoid touching the treated area following the treatment as well as ensuring that there is no contact with contaminated clothes/linen. The vast majority of patients tolerate the procedure very well, and interactions/reassurance from the operator, as well as distraction strategies, help in managing the symptoms. The use of rescue analgesia is encouraged but is seldom needed. Dry cooling using a linen-wrapped cold pack applied over the treated area is possibly the best way to alleviate the symptoms. Wet compresses are not recommended prior to the cessation of treatment, as it interferes with patch adhesion, and postprocedure it can cause leaching of the capsaicin from the deeper layers of the skin. Patients who have had their feet treated for peripheral neuropathy found it comforting to wrap their feet in cling-film or plastic bags and immerse in water at room temperature after 24 h posttreatment. Most of the symptoms settle down within 48-72 h, and it is very rare that the symptoms persist after 5 days. Patients are routinely contacted by telephone 24 h and 72-96 h postprocedure to ensure that they feel well, as well as to address any queries. Patients are then reviewed in the pain clinic at 4 weeks and 8 weeks. During this time, systemic analgesics, including opioid and neuropathic drugs, are down-titrated or even tapered off if the pain control is good. The authors do not advocate repeating the patch routinely every 3 months, but wait for the symptoms to recur before offering the next treatment, as the duration of effect has been shown to vary between 3 and 15 months on average, depending on the underlying pathology [36]. • Identify the area to be treated; ensure that the skin is intact and unbroken. • Using the skin-marking pen, mark the area to be treated; if any hair is to be removed, it should be clipped closely to the skin using a pair of scissors. • The area to be treated is traced onto the tracing sheet clearly labeling the cephalo-caudal and right-left orientation. • Topical anesthetic cream (EMLA or 4% lidocaine) is applied for a period of time as per manufacturers’ instruction—usually for an hour. • After the stipulated time, remove the topical anesthetic cream and dry the skin carefully; if patient has significant allodynia over the area to be treated, the use of a hair dryer is often helpful to dry and warm the area to facilitate adhesion. • Capsaicin 8% patches are cut to shape and orientation based on the tracing sheet template of the treatment area. • Apply the capsaicin patches to the treatment area, ensuring close adhesion to the skin; bandaging, cling-film, or socks may be used to facilitate the adhesion. The patch is left in place for 30 min if the feet are being treated or for 60 min for the rest of the body. • After the treatment duration has been completed, the capsaicin 8% patch is removed by carefully rolling inward to reduce the risk of aerosolization. • Clean the treated area of any residual capsaicin on the skin with the cleansing gel, and allow the area to dry spontaneously. • Counsel about avoiding contamination of clothes and towels with capsaicin at home. • Care should be taken to avoid contact of the treated area particularly with children and pets. • There may be delayed onset of burning sensation and pain a few hours after the treatment once the effect of the local anesthetic has worn off. • Discuss use of localized dry-cooling and analgesics for managing pain and discomfort. • Avoid hot baths/showers, exposure to direct sunlight to the treated area, and vigorous exercise for 24-48 h or until the acute symptoms have settled down. • Ensure not to abruptly discontinue preexisting prescribed analgesia and neuropathic pain medications without medical advice and supervision, even if there is a dramatic pain relief to avoid withdrawal effects. • Contact the treatment unit or the patient’s general practitioner if there is any concerns of adverse side effects. • Provide contact details of the treatment unit.
Use of Topical Capsaicin for Pain Relief
* Corresponding author: g.baranidharan@nhs.net
Abstract
Introduction
Pharmacodynamics
Pharmacokinetics
Efficacy and Therapeutic Uses
Postherpetic Neuralgia
HIV-Associated Distal Sensory Polyneuropathy
Other Neuropathic Pain States
Safety and Tolerability
Delivery of Treatment with Capsaicin 8% Patch—Practical Aspects
Application Procedure for the Capsaicin 8% Patch
Postprocedural Instructions for Patients
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