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Capsaicin 8% Patch Repeat Treatment in Nondiabetic Peripheral Neuropathic Pain: A 52-Week, Open-Label, Single-Arm, Safety Study

Gálvez, Rafael MD, PhD*; Navez, Marie-Louise MD; Moyle, Graeme MD; Maihöfner, Christian MD§; Stoker, Malcolm PhD; Ernault, Etienne MSc; Nurmikko, Turo J. MD, PhD; Attal, Nadine MD, PhD#

doi: 10.1097/AJP.0000000000000473
Original Articles

Objectives: To investigate the long-term safety and tolerability of capsaicin 8% patch repeat treatment in nondiabetic patients with peripheral neuropathic pain.

Methods: A prospective, open-label, observational study in patients with postherpetic neuralgia, posttraumatic or postsurgical nerve injury, HIV-associated distal sensory polyneuropathy, or other peripheral neuropathic pain, and average daily pain score ≥4, who received ≤6 capsaicin 8% patch treatments over 52 weeks according to clinical need (retreatment at 9 to 12 wk intervals). Sensory testing and analgesic effectiveness were assessed using “bedside tests” and Brief Pain Inventory (question 5).

Results: Overall, 306 patients received treatment. Treatment-emergent adverse events (TEAEs) and drug-related TEAEs were reported by 252 (82.4%) and 207 (67.6%) patients. Application site pain was the most common drug-related TEAE (n=112, 36.6%); no drug-related serious TEAEs were reported. Sensory category shift analyses from baseline to end of study (EoS) in patients attending at least 2 sensory visits (n=278 for all tests except warm, n=277) found sensory deterioration/loss in at least 1 modality in 50.4% (n=140); deterioration/loss in 1, 2, 3, 4, or 5 modalities occurred in 26.6% (n=74), 14.0% (n=39), 5.8% (n=16), 2.5% (n=7), and 1.4% (n=4) cases. Newly emergent hyperesthesia or allodynia was apparent in 1.1% to 3.6% of the cases (depending on modality) by EoS. Between 25.2% and 32.0% of patients reported improvement in a sensory modality by EoS. Average daily pain was 6.6 and 4.7 at baseline and month 12.

Conclusions: Generally, capsaicin 8% patch repeat treatment over 52 weeks was well tolerated, with variable alteration in sensory function and minimal chance of complete sensory loss.

*Pain and Palliative Care Unit, Hospital Universitario Virgen de las Nieves, Granada, Spain

Center for Pain Evaluation and Treatment, Saint Etienne Hospital, Saint Etienne, France

#Center for the Treatment and Evaluation of Pain and INSERM U 987, Hôpital Ambroise Paré, Boulogne-Billancourt, France

Chelsea & Westminster NHS Foundation Trust, London

The Walton Centre NHS Foundation Trust, University of Liverpool, Clinical Sciences Centre, Liverpool, UK

§Department of Neurology, General Hospital Fürth, Fürth, Germany

Astellas Pharma Europe B.V., Leiden, The Netherlands

Supported by Astellas Pharma Europe B.V., Leiden, the Netherlands. Astellas Pharma Europe B.V. developed the protocol in conjunction with the clinical investigators and provided the study drug. The STRIDE study was initiated and funded by Astellas Pharma Europe B.V. The authors received editorial support for manuscript preparation from Vicky Hinstridge, Quercus Medical Communications Ltd, and this assistance was supported by Astellas Pharma Europe Ltd.

T.J.N. has acted as a consultant to Astellas Pharma. N.A. has received honoraria from Pfizer, Lilly, Grünenthal, Astellas Pharma, Johnson and Johnson, Sanofi Pasteur Mérieux, and Adir for advisory boards, scientific advice, or speakers bureau. C.M. has received honoraria as a consultant for Astellas, Bionorica, and Mundipharma and has participated in speakers bureaus of Allergan, Astellas Pharma, Grünenthal, Janssen, and Pfizer. G.M. M.-L.N. have no disclosures. R.G. has received honoraria from Grünenthal, Mundipharma, and Eisai Co, Ltd. for speakers’ bureau. R.G. was the Coordinating Investigator of this study. M.S. and E.E. are employed by Astellas Pharma Europe B.V.

Reprints: Rafael Gálvez, MD, PhD, Unidad del Dolor, Hospital Universitario Virgen de las Nieves, Avda. de las Fuerzas Armadas 2, 18014 Granada, Spain (e-mail: rafaelgalvez@hotmail.com).

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

Received May 23, 2016

Received in revised form August 26, 2016

Accepted December 12, 2016

Neuropathic pain (NP) is a common neurological condition with an estimated prevalence of 6.9% to 8.2% among the general population in Europe, imposing a significant burden on health care organizations.1,2 The condition has been associated with a lower overall health-related quality of life in patients, in particular impairment of physical, emotional, and social functioning as well as sleep quality.3 In clinical practice, the management of NP remains suboptimal and challenging, often resulting in chronic disease. A large proportion of patients with NP still receive inadequate pain relief, despite the availability of a substantial number of treatments.4,5 Frequently used treatments for NP, such as antidepressant, anticonvulsant, and opioid medications, act on the central nervous system and are associated with a number of limitations in routine clinical practice. These include lengthy dose titration, numerous drug-drug interactions, serious adverse events, reduced compliance with treatment due to adverse events, the need for multiple daily dosing, potential for abuse, and unclear responder criteria.5–10

Capsaicin is a potent, highly selective vanilloid receptor subtype 1 (TRPV1) agonist that causes depolarization of sensory afferents, inducing short-lived warming, burning, stinging, or itching sensations.11 Exogenous agonists of TRPV1, such as capsaicin, are able to prolong this depolarization, causing defunctionalization of hyperactive nociceptors in the skin, leading to pain relief. The capsaicin 8% patch delivers a high concentration of capsaicin directly into the skin to provide both acute and long-lasting pain relief.11–13 In addition, minimal significant systemic absorption limits the potential for drug-drug interactions or the need for dose adjustment in the elderly or patients with hepatic or renal impairment.14

Several prospective, double-blind studies have confirmed the safety and efficacy of the capsaicin 8% patch in postherpetic neuralgia (PHN) and painful human immunodeficiency virus-associated neuropathies (HIV-AN).15–18 Results from a large, open-label study in various localized peripheral NP etiologies also demonstrated that the capsaicin 8% patch was well tolerated.19,20 A further study demonstrated noninferior efficacy in comparison with pregabalin, a first-line treatment for NP.21 More recently, clinical studies were conducted in patients with painful diabetic peripheral neuropathy,22,23 which subsequently led to an expansion of the European indication for the capsaicin 8% patch to the treatment of peripheral NP in adults either alone or in combination with other medicinal products for pain.14

In healthy individuals, the safety of single and repeated capsaicin 8% patch treatments has been established using neurological examination, quantitative sensory testing, and skin punch biopsies.13 The primary objective of the present prospective study was to investigate for the first time the long-term safety and tolerability of the capsaicin 8% patch repeat treatment over 52 weeks in nondiabetic patients with a broad range of peripheral NP etiologies. Of particular interest in this study was the potential for any clinically relevant deficit in sensory perception or increase in hypersensitivity after repeated application of capsaicin. Analgesic effectiveness was assessed as a secondary outcome. The objective of this study was to mimic the capsaicin 8% patch treatment in clinical practice as far as possible.

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METHODS

Patients

This phase IV, open-label, single-arm, 52-week, observational study (ClinicalTrials.gov Identifier: NCT01252160) was conducted at 63 sites in Europe between October, 2010 and September, 2013.

Key inclusion criteria were as follows: age between 18 and 90 years with a diagnosis of PHN (pain persisting since shingles vesicle crusting), posttraumatic or postsurgical nerve injury (PNI), HIV-associated distal sensory polyneuropathy (HIV-DSPN) (confirmed using the Brief Peripheral Neuropathy Screen), all of a minimum duration of 3 months, or other adequately characterized peripheral NP, including idiopathic small-fiber neuropathy (based on clinical criteria or skin biopsy, with loss of pinprick and temperature sensation in both feet); an average daily pain score ≥4 on the question 5 of the Brief Pain Inventory (BPI)24,25; intact, nonirritated, dry skin over the painful area to be treated; and in good health as determined by the investigator.

Key exclusion criteria were as follows: any prior use of capsaicin patches; past or current history of type I or type II diabetes mellitus; use of oral or transdermal opioids exceeding a total daily dose of morphine of 80 mg/d, or equivalent, or any parenteral opioids, regardless of dose, within 7 days preceding the first patch application visit; use of any topical pain medication within 7 days preceding the first patch application visit; unstable or poorly controlled hypertension, or a recent history of a cardiovascular event; clinically significant abnormal electrocardiogram; significant ongoing or untreated abnormalities in cardiac, renal, hepatic, or pulmonary function; significant pain of an etiology other than painful HIV-DSPN, PHN, PNI, idiopathic small-fiber neuropathy, or other adequately characterized peripheral NP; Complex Regional Pain Syndrome (type I); NP areas located only on the face, above the hairline of the scalp, and/or in proximity to mucous membranes.

The study was approved by the institutional review board at each participating site and was conducted in accordance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice, International Conference on Harmonization guidelines, and applicable laws and regulations. Written informed consent was obtained from all patients before initiating study-related procedures.

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Study Treatment

Patients received up to 6 capsaicin 640 g/cm2 (8% weight for weight) patch treatments (QUTENZA™ cutaneous patch (capsaicin 179 mg patch [8% wt/wt]), supplied by Astellas Pharma Europe Ltd., Chertsey, UK) at 9 to 12-week intervals over a 52-week period. At each application visit, a maximum of 4 patches equivalent to an area of up to 1120 cm2 were applied for 30 minutes to the feet or for 60 minutes to other body locations. Before patch application, patients received pretreatment with a topical local anesthetic, the choice of which was at the investigator’s discretion. At screening and each application visit, the treatment area was demarcated, which included assessment of the most painful area and the area of allodynia/hyperalgesia. If allodynia was present, then the most painful area plus any additional area(s) of allodynia beyond the most painful area were treated up to a maximum of 1120 cm2, with highest priority for patch use given to treating the most painful area. Capsaicin 8% patch retreatment took place depending on the investigator’s discretion and patient feedback. Patients who did not attend a further patch retreatment visit before week 26 were recalled to determine whether a further retreatment was required.

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Assessments

Safety and Tolerability

The primary objective of the study was to assess the long-term safety and tolerability, after repeated treatment, of the capsaicin 8% patch over a 52-week period. A treatment-emergent adverse event (TEAE) was defined as an adverse event observed after the start of capsaicin 8% patch application, or an adverse event that worsened in severity after patch application. A serious TEAE was any untoward medical incident that resulted in death, persistent or significant disability/incapacity, congenital anomaly or birth defect, in-patient hospitalization, prolongation of hospitalization, was life-threatening, or was considered as a medically important event.

Sensory examination was performed to identify clinically relevant deficits in sensory function at baseline and before each capsaicin 8% patch treatment. Testing was performed at the screening visit, at all patch application visits (before patch application), at week 26 (if applicable), and at the planned (weeks 52 to 65) or early termination visit, by physicians who had been given study training. Sensory perception was assessed using standardized “bedside tests” of response to light brush, pinprick, vibration, warm, and cold (for full details, please see protocol in Supplementary Text 1, Supplemental Digital Content 2, http://links.lww.com/CJP/A397). The examining physician was advised to test up to 5 locations within the affected area. For each sensory modality, except cold, a single scale was used that ranged from loss of sensation to increased sensitivity: not felt, barely felt, normally felt, increased and not paresthetic/dysesthetic, increased and paresthetic/dysesthetic, or increased and painful. For perception of cold, the categories used were as follows: not cold, slightly cold, normally cold, cold but not paresthetic/dysesthetic, cold and paresthetic/dysesthetic, and increased and painful. An unaffected mirror-image area, on the other side (PHN), or anterior thigh or upper forearm (HIV-AN), or other area, as appropriate, was used as a demonstration site. In addition, reflex testing involved assessment of the Achilles tendon reflex using the rating scale: no response, hypoactive, normal, hyperactive, or clonus. The physician then chose 1 response that they considered to be the most clinically relevant. The sensory categories reported at baseline and the study end were recorded for each patient and a category shift schema was developed to ascertain whether a patient improved, had no change, or experienced loss in sensory function during the study.

The areas of spontaneous pain and allodynia/hyperalgesia were also measured at each visit as part of the sensory examination. The composite term allodynia/hyperalgesia was used to describe the presence of dynamic mechanical allodynia, cold allodynia (or hyperalgesia), heat allodynia (or hyperalgesia), and pinprick hyperalgesia. The area of allodynia/hyperalgesia and the most painful area were identified by patients and mapped by the physician. Mapping of both was performed using a cotton swab to gently stroke the skin from outside the usually most painful or sensitive area(s) toward the center, from 6 to 8 directions (from above, below, left, right, etc.). The boundary was marked at the exact location where a light swab stroke became painful (if applicable), traced on a piece of tracing paper or plastic transparency film, and the area calculated.

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Analgesic Effectiveness

Assessment of analgesic effectiveness was a secondary endpoint in this study. Assessments included average daily pain (BPI question 5) and Patient Global Impression of Change (PGIC).24

The BPI Modified Short Form is a widely used and validated, patient-completed, numeric rating scale that measures severity of pain and its interference with daily function.25,26 Average daily pain was rated using a 0 to 10 numeric scale anchored at zero for “no pain” and 10 for “pain as bad as you can imagine” for severity. Average pain was recorded daily during screening and weekly from the first patch application visit until the planned or early termination visit. All responses were recorded on the same day of the week (±2 d), as chosen by the patient during the first patch application visit.

The PGIC is a patient-rated instrument that measures changes in the overall status of patients on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).27 Patients answered a PGIC questionnaire at patch application visits (except first patch application visit), 4 weeks after each patch application visit, at Week 26 (if applicable), and at the planned or early termination visit. The EQ-5D28 Visual Analog Scale (VAS) score was also assessed at baseline and at the planned or early termination visit.

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Statistical Analyses

The study was planned to enroll 300 eligible patients in the study. The sample size was based on clinical judgment to adequately assess the safety of repeated treatments of capsaicin 8% patch over 1 year. A sample size of 300 patients yielded a 95% chance of observing at least 1 patient with an event with an incidence of 1%. The safety analysis set included all patients who received at least 1 capsaicin 8% patch and was used for all analyses of safety and effectiveness.

Descriptive statistics were used to describe the absolute values and changes from baseline for “pain now” scores, PGIC, and areas of pain and allodynia. Summary statistics for change from baseline in average daily pain was also performed.

Post-hoc analyses of sensory and reflex testing were performed in patients who received 3 consecutive treatments, and post-hoc analyses of pain scores, PGIC, and EQ-5D were performed in patients who received 4 consecutive treatments. To assess variability in the change in pain scores among the diagnostic groups, a post-hoc analysis was performed to calculate 95% confidence interval (CI) for changes from baseline to month 12.

A detailed post-hoc analysis was carried out for each sensory modality to identify any shift in the sensory category from baseline. On the basis of the mode of action of the capsaicin 8% patch and previous studies,11 it was assumed that 2 types of shift in the sensation of the treated skin area could occur: deterioration/loss of sensory acuity or increased sensitivity. Deterioration/loss of sensation was considered to have occurred if the sensory category moved from increased sensitivity or normal sensation to “barely felt” (“slightly cold”) or “not felt” (“not cold”), or from “barely felt” (“slightly cold”) to “not felt” (“not cold”) after treatment (Supplementary Table 2a, Supplemental Digital Content 3, http://links.lww.com/CJP/A398). If a patient shifted to the category “increased sensitivity and pain” by study end, he/she were considered to have developed new hyperesthesia/allodynia (Supplementary Table 2b, Supplemental Digital Content 3, http://links.lww.com/CJP/A398). However, if a patient with increased or inadequate sensation moved to “normal” or another improved category according to Supplementary Table 2c, Supplemental Digital Content 3, http://links.lww.com/CJP/A398 by study end, he/she were considered to have improvement of sensation. Patients who reported the same sensory category at baseline and study end were classified into the “no change” group. A total of 4 possible category shifts did not fit into the above categories and were designated as “unclear change” (Supplementary Table 2d, Supplemental Digital Content 3, http://links.lww.com/CJP/A398).

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RESULTS

Patients

A total of 345 patients were screened, for inconsistencies with the inclusion and exclusion criteria, and 306 patients received capsaicin 8% patch treatment, of whom 107 had a diagnosis of PHN, 99 had PNI, 80 had HIV-DSPN, and 20 other peripheral NPs.

At baseline in the total population, the mean (SD) age was 57.9 (15.0) years, average time since peripheral NP diagnosis 5.1 (5.5) years, and average daily pain score 6.6 (1.4) (Table 1). Baseline average pain scores in each diagnostic group were as follows: PHN, 6.6 (1.5); PNI, 6.8 (1.4); HIV-DSPN, 6.4 (1.5); other peripheral NP, 6.7 (1.2). Other demographic and baseline characteristics such as age, time since diagnosis, and ethnicity were similar between the pain diagnostic groups (Table 1).

Except for 1 patient in the PHN group, all patients used preapplication topical anesthetics during the study (n=305; 99.7%): amides were the most frequent chemical subgroup (n=291; 95.1%). All patients used concomitant pain therapy during the study, and the most frequent medications used for NP are summarized in Table 2 (overall, 77.8%; PHN, 79.4%; PNI, 83.8%; HIV-DSPN, 65.0%; other peripheral NP, 90.0%). Postapplication medications (administered on days 1 to 5 after patch application) were used by 37.6% of patients (PHN, 43.9%; PNI, 38.4%; HIV-DSPN, 31.3%; other peripheral NP, 25.0%).

Overall, 176 patients (57.5%) completed the study after receiving treatment (Fig. 1). In total, 130 patients (42.5%) discontinued after treatment was initiated, most commonly due to lack of effectiveness (n=54; 17.6%), withdrawal by patient (n=33; 10.8%), and loss to follow-up (n=17; 5.6%). The average interval between each capsaicin 8% patch retreatment was 107.0 days. The majority of patients received only 1 capsaicin 8% patch treatment (n=76; 24.8%) in this study, and the proportion of patients subsequently receiving further capsaicin treatments steadily decreased throughout the duration of the study (Fig. 2A). In total, 52% (159/306) of patients received 3 capsaicin 8% patch treatments and 32.7% (100/306) received 4 treatments during the study (Fig. 2B). When analyzed by study visit, the proportion of patients who discontinued treatment decreased throughout the study and the proportion of completers increased (Supplementary Figure 1, Supplemental Digital Content 4, http://links.lww.com/CJP/A399; ad-hoc analysis).

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Safety and Tolerability

TEAEs

A total of 252 patients (82.4%) reported a TEAE and the proportions were similar between the diagnostic groups (Table 3). The maximum reported severity was mild for 78 patients (25.5%), moderate for 104 patients (34.0%), and severe for 70 patients (22.9%), which corresponded to 142 reported severe TEAEs (Table 3). The most commonly reported TEAE was application site pain (36.6%). An increase in blood pressure that was considered by the study investigator to be unusual for the patient, or that required further intervention, was observed in 7 patients (2.3%). Eleven patients (3.6%) discontinued treatment due to TEAEs (reported only once): 5 from the PHN group (application site erythema, application site pain, and PHN in 1 patient, and cerebral hemorrhage, facial neuralgia, pain, and squamous-cell carcinoma in the other 4 patients), 4 from the PNI group (burning sensation, complex regional pain syndrome, neuralgia, renal colic), 1 from the HIV-DSPN group (pneumonia), and 1 from other peripheral NP group (allodynia). Three deaths occurred during the study period and none were considered to be related to the study treatment, as assessed by the study investigator. Two deaths occurred in the PHN group (cerebral hemorrhage and squamous-cell carcinoma) and 1 in the HIV-DSPN group (pneumonia).

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Drug-related TEAEs

Drug-related TEAEs were reported by 207 patients (67.6%) (Table 3). The maximum reported severity was mild for 84 patients (27.5%), moderate for 82 patients (26.8%), and severe for 41 patients (13.4%). Application site pain (22/306 patients; 7.2%) was the most common severe drug-related TEAE, reported by ≥5% patients in all diagnostic groups. Three patients (1.0%) discontinued due to drug-related TEAEs: 1 patient in PHN group (application site erythema, application site pain, and PHN), 1 patient in the PNI group (neuralgia), and 1 patient in the other peripheral NP group (allodynia). The proportion of patients who experienced drug-related TEAEs did not change over the course of the study (130/230 [56.5%] patients between first and second treatment; 87/159 [54.7%] between second and third; 57/100 [57.0%] between third and fourth; 26/52 [50.0%] between fourth and fifth treatment; 7/16 [43.8%] between fifth and sixth).

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Sensory Perception and Reflex Testing

In the total population, sensory category shift analyses in patients who attended at least 2 sensory testing visits (n=278 for all tests except warm, n=277) found that 50.4% (n=140) reported sensory deterioration/loss in at least 1 modality by study end against baseline. The number of patients with deterioration/loss in 1, 2, 3, or 4 tests by study end was 26.6% (n=74), 14.0% (n=39), 5.8% (n=16), and 2.5% (n=7), respectively. A total of 4 patients had sensory deterioration/loss in all 5 sensory tests by study end against basline. The diagnostic groups and most painful areas were as follows: PHN, n=1 (torso); HIV-DSPN, n=1 (legs); PNI, n=2, (feet, arms). In these 4 patients, sensory deterioration/loss occurred at treatments 1, 2, 6, and end of study, respectively.

At study end, 40.7% to 49.3% (depending on test) of patients showed no sensory change compared with baseline, and 25.2% to 32.0% (depending on test) reported an improved sensory category by study end (Table 4). Between 1.1% and 3.6% of patients (depending on the test) reported new hyperesthesia/allodynia at study end. With regard to reflex testing, an improved response was observed in 11.3% of patients by study end compared with baseline.

Analysis of pain in patients with sensory deterioration/loss and improvement (according to scheme in Supplementary Table 2, Supplemental Digital Content 1, http://links.lww.com/CJP/A396) in the total population by study end found that mean changes in average pain from baseline to EoS ranged from −1.2 to −1.6 (depending on test) in patients who reported deterioration/loss of sensory perception, and from −1.3 to −2.2 in patients who reported an improvement in sensory perception. In addition, analysis of quality of life changes from baseline to end of study found that mean changes in the EQ-5D VAS score ranged from −2.0 to 5.4 in patients who reported a deterioration/loss of sensory perception, and −2.8 to 8.8 in patients who reported improved sensory perception.

After 3 consecutive capsaicin 8% treatments (n=100 for all tests except warm, n=99), the majority of the patients showed either no sensory change (41.0% to 48.0% depending on test) or actual improvement (28.0% to 37.0%) before the fourth treatment (Table 5). Sensory category shift analyses from baseline found that 50.0% of patients (n=50) reported sensory deterioration/loss in at least 1 modality by study end against baseline, whereas the number of patients with sensory deterioration/loss in 1, 2, 3, 4, or 5 tests was 23.0% (n=23), 20.0% (n=20), 3.0% (n=3), 2.0% (n=2), and 2.0% (n=2), respectively.

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Area of Allodynia/Hyperalgesia

In the total population, the mean (SD) area of allodynia/hyperalgesia decreased from 241.9 cm2 (259.1) (interquartile range [IQR]: 62.5 to 323.5) before first application (n=224) to 219.9 cm2 (286.7) (IQR: 36.0 to 282.0) at end of study (n=245). In patients with PHN, the area decreased from 251.1 cm2 (219.5) (IQR: 106.0 to 323.5) before first application (n=96) to 192.3 cm2 (212.8) (IQR: 37.0 to 255.0) at end of study (n=105).

In the subset of patients who received 4 consecutive capsaicin 8% patch treatments, the area of allodynia/hyperalgesia decreased from 227.4 cm2 (268.5) (IQR: 51.5 to 282.5) before first treatment (n=80) to 213.4 cm2 (254.4) (IQR: 43.0 to 299.0) before fourth treatment (n=84).

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Area of Spontaneous Pain

The majority of patients reported painful areas at the torso (41.2%) or the feet (34.6%) before first treatment, and the distribution of painful areas remained similar throughout the study. In the total population, the mean (SD) area of maximal spontaneous pain decreased from 365.0 cm2 (313.9) (IQR: 117.0 to 519.0) before first application to 322.7 cm2 (324.2) (IQR: 82.0 to 472.0) at end of study. In patients with PHN (n=107), the area of pain decreased from 327.2 cm2 (235.2) (IQR: 155.0 to 467.0) to 254.0 cm2 (225.6) (IQR: 82.0 to 331.0).

In the subset of patients who received 4 consecutive capsaicin 8% patch treatments (n=100), the area of pain decreased from 310.1 cm2 (275.4) (IQR: 97.5 to 437.5) to 268.5 cm2 (254.4) (IQR: 74.5 to 409.5).

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Analgesic Effectiveness

Average Daily Pain

For the total population and each individual diagnostic group, a sustained reduction in average daily pain intensity was observed during the study (Fig. 3A). The average daily pain (SD) was 6.6 (1.43) at baseline and 4.7 (2.27) at month 12. The overall change in mean daily pain intensity was −1.9 (SD, 1. 89; 95% CI, −2.19 to −1.59) from baseline to month 12. In patients with assessments at baseline and month 12 (n=174), no differences in average daily pain reduction were observed between the total population and any of the individual diagnostic groups (data not shown).

In the subset of patients who received 4 consecutive capsaicin 8% patch treatments (n=100), a reduction in average daily pain was observed after each successive capsaicin treatment, and pain relief was sustained between treatments (Fig. 3B). The change in average daily pain intensity was −2.1 (SD, 1.7; 95% CI, −2.46 to −1.78) from baseline to month 12 in this subset of patients.

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PGIC

The majority of patients in the total population, as well as the individual diagnostic groups, reported an improvement in their overall status during the study. Of the total population, 31.6% of patients reported themselves to be “very much improved” or “much improved” by the end of the study (Fig. 4). In patients who received 4 capsaicin 8% patch treatments (n=100), 48.1% reported themselves to be “very much improved” or “much improved” 4 weeks after their fourth treatment.

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DISCUSSION

The present study investigated for the first time the safety and tolerability of up to 6 capsaicin 8% patch treatments over 52 weeks in a large cohort of nondiabetic patients with various peripheral NP etiologies. Of note, two-thirds of the patients received chronic pain medication, suggesting a relatively refractory pain condition. Results showed that capsaicin 8% patch repeat treatment over 52 weeks was well tolerated regardless of the etiology, with variable alteration in sensory function and a minimal risk of complete sensory loss. In addition, capsaicin 8% patch repeat treatment induced substantial and sustained reductions in pain over 52 weeks, with progressive reductions in line with the periods of each consecutive retreatment.

Methodological considerations of this study that are important to highlight include the study design and safety assessment. The study was designed so that patch application was dependent on the effectiveness and safety experienced by patients, reflecting use in routine clinical practice. Safety was assessed using a standardized neurological examination, which enabled qualitative categorization of deficit and pain.

As capsaicin causes defunctionalization of hyperactive nociceptors, which leads to pain relief,11 impaired sensory perception may have been a potential effect of the patch after repeat treatment. In addition, regenerating small-diameter fibers may be sensitive29 and can therefore lead to unwanted cutaneous tenderness or frank pain. Indeed, both types of sensory changes were observed across all sensory modalities. The development of new hyperalgesia/allodynia in a minority of patients may be considered an unfortunate adverse effects, but it appears not to have had an effect on the total pain of these patients. There was no substantial difference in pain scores or EQ-5D VAS scores in patients with worsened as against improved sensory perception. In some patients, there was a surprising change in large-diameter fiber-mediated sensory function (touch, vibration), the cause of which is not entirely clear. However, improvement of such functions could lead to increased detection of applied stimuli. It is therefore important to put these findings in clinical context and it is noteworthy that complete loss of sensation after treatment was observed in only 4 patients. In 1 of these patients, the patch was applied over the feet, and in the others it is was applied over the leg, torso, and arm, where such sensory deterioration/loss would have likely had less clinical effect. A total of 74 and 39 patients had sensory deterioration/loss in 1 and 2 tests, respectively, whereas only 7 patients had sensory deterioration/loss in 4 tests. Sensory deterioration in 1 or 2 tests is of limited clinical significance in this patient setting, and clinically may be regarded as acceptable. In addition, after 3 consecutive treatments, no increase in sensory deterioration was observed in patients, contradicting any cumulative sensory alteration at the application site. In a recent exploratory study of 20 patients with peripheral NP, no significant deterioration was shown in any sensory function other than warm detection after a single application of the capsaicin 8% patch.30 This result may seem to contradict findings of the present study; however, sensory changes in the exploratory study were based on whole-group analyses, whereas in the present study the change in each sensory function in each individual was recorded. Given the main aim of safety and the greater number of patch applications in the present study, we believe that our method is better suited to identify patients who might be particularly susceptible to adverse sensory effects of high-concentration capsaicin.

Although sensory deterioration/loss was reported by a proportion of patients, it is also noted that improvement in sensation was observed in 25.2% to 32.0% of treated patients by study end. Our putative hypothesis is that after capsaicin treatment, the phenotype of regenerated fibers may be closer to those unaffected by the disease, resulting in restoration of sensory perception; however, this hypothesis requires further study.

The secondary outcome of the present study concerned the analgesic effectiveness of repeated treatment with the capsaicin 8% patch. Repeated treatment with the capsaicin 8% patch induced a sustained reduction in average daily pain intensity for the total population, and had a similar effect on each individual diagnostic group and also the subgroup who received 4 consecutive capsaicin 8% patch treatments. The reduction in pain was consistent after each treatment, with no or minimal increase before retreatment. These results were supported by the global impression of improvement reported by about one-third of patients at the end of the study.

Although the open-label design of this study may be considered to be more reflective of clinical practice, it is a major limitation, and as patients knew as to which treatment they were receiving, the findings related to analgesic effectiveness should be interpreted with caution. There was a high rate of patient discontinuation, which is consistent with the study design, but may also be considered as a limitation. This was also a single-arm study, preventing comparison of results in patients who did not receive capsaicin. Regarding sensory testing, a single scale that allowed only the examiner to identify the most intense sensation may have masked other important sensory changes. Recovery of a patient with allodynia at baseline could have unmasked the presence of sensory deficit. The inherent inaccuracy in this methodology could have been avoided using separate scales for sensory detection and suprathreshold stimuli, and further strengthened by the application of quantitative sensory testing.31 Possible variations between investigators in the “bedside tests” of sensory function and concomitant opioid use also need to be considered. The large number of centers involved was a major reason for the present choice of methodology, even if this may have compromised the accuracy of sensory assessment. Topical anesthetics were used by all but 1 patient before capsaicin 8% patch treatment, with amides being the most common group. It is noted that lidocaine has been shown to have differential effects on sensory function.32 Detection thresholds were significantly elevated for touch, pinprick pain, and mechanically induced wind-up after lidocaine 5% patch application in a randomized, double-blind study conducted in 20 healthy volunteers.30 However, this effect was completely reversed in 2 to 3 days, probably due to clearance of lidocaine from the skin. In the present study, sensory testing was performed several weeks after the previous application of the capsaicin 8% patch, making any impact from the use of topical anesthetics on the results unlikely.

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CONCLUSIONS

Capsaicin 8% patch repeat treatment over 52 weeks in various peripheral NP etiologies was well tolerated, with mostly local adverse effects, resulting in variable sensory alteration and no increase in the area of allodynia or of maximum pain. Both improvement and worsening of sensation were observed with a minimal chance of complete sensory loss. No accumulation of any adverse effects was observed after 3 or 4 capsaicin 8% patch treatments. Sustained reductions in average pain intensity were also observed. The findings from this study demonstrate that capsaicin 8% patch repeat treatment is a well-tolerated and effective long-term treatment option in patients with peripheral NP.

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ACKNOWLEGMENTS

The authors thank all study investigators (for a full list, see Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/CJP/A396) and Faysal Riaz, PhD of Astellas Pharma Europe Ltd., Chertsey, UK, for a critical review and valuable medical writing assistance.

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Keywords:

capsaicin 8% patch; peripheral neuropathic pain; safety; sensory function; phase 3 study

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