Abstract
Introduction
Postherpetic neuralgia (PHN) is a chronic neuropathic pain condition that disproportionally affects older adults. First-line oral treatments often yield suboptimal relief and may cause systemic side effects and drug–drug interactions. Effective topical treatments offer the potential to address this significant unmet medical need in PHN. This CASPAR analysis evaluated real-world effectiveness and safety of the high-concentration capsaicin patch (HCCP) in patients with PHN.
Methods
Real-world data were evaluated for a large PHN cohort extracted from the German Pain e-Registry as part of the retrospective, noninterventional, multicohort CASPAR study. Patients received one to four HCCP treatments over 12 months. Patient-reported outcomes included average pain intensity (API), quality of life (QoL), sleep impairment, mood, concurrent pain medications, and safety.
Results
This analysis included 961 patients with PHN (mean age: 63.8 years, female: 69.7%; mean pain duration: 3.3 years) receiving one (n = 187), two (n = 209), three (n = 207), or four HCCP treatments (n = 358). Mean 24-h API decreased from 61.8 at baseline to 46.8 by month 3 (P < 0.001), and to 31.8 at month 12 (P < 0.001). Patients receiving four treatments had the greatest API reductions (63.7 at baseline versus 19.6 at month 12; P < 0.001), whereas improvements were lost in those who discontinued treatment. While ≥ 30% API response rates were similar across treatment groups at month 3 (25.6–30.7% of patients), those receiving additional treatments showed continued improvement, peaking at 99.7% by month 12 after four HCCP treatments. Trends were similar for other patient-reported outcomes, including QoL, sleep, and mood. Concomitant pain medication use decreased over time. Most adverse drug reactions were mild and application site-specific.
Conclusions
HCCP is an effective and well-tolerated topical treatment for patients with PHN, including older adults. After one treatment, improvements were noted in API, QoL, sleep, and mood outcomes, alongside decreased concomitant pain medication use, with progressive improvements following additional treatments.
A Graphical Abstract is available for this article.
Graphical Abstract
Supplementary Information
The online version contains supplementary material available at 10.1007/s13555-025-01624-7.
Keywords: Postherpetic neuralgia, Real-world evidence, Capsaicin, Topical treatment, Quality of life, Registries
Plain Language Summary
Postherpetic neuralgia (PHN) is a long-lasting pain condition that can develop after a shingles infection and often affects older adults. The pain from PHN is debilitating and can significantly reduce patients’ quality of life. Many people with PHN do not experience adequate pain relief from oral medications and often experience side effects. The CASPAR study in Germany looked back at routine clinical records of patients with neuropathic pain. They were treated with a patch that delivers a high concentration (8%) of capsaicin (a naturally occurring compound found in hot chili peppers) directly into the skin. Capsaicin acts directly on the nerve endings that cause pain to help reduce symptoms. We investigated the effectiveness and safety of this treatment in patients with PHN who had between one and four capsaicin patch treatments over 1 year. In a total of 961 patients, pain reduced significantly, and additional improvements in sleep, mood, and quality of life were noted after just one treatment with the capsaicin patch. These improvements continued to increase with additional treatments. Patients who stopped treatment lost these effects over time. Side effects from treatment with the capsaicin patch were mostly short term and mild, typically on the area where the patch was applied, including sensations such as burning and itching. In conclusion, our study supports the use of the high-concentration capsaicin patch for managing PHN. The capsaicin patch can effectively reduce pain and showed further improvements in pain and overall wellbeing and reductions in the use of other pain medications with repeated treatments.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13555-025-01624-7.
Key Summary Points
| Why carry out this study? |
| Postherpetic neuralgia (PHN) is a debilitating, chronic pain complication of the herpes zoster virus that disproportionately impacts elderly patients and is often undertreated, leading to a reduced quality of life (QoL) for many individuals. |
| This study was undertaken because although the high-concentration capsaicin patch (HCCP) is an approved topical treatment for PHN in Europe and the USA, long-term real-world effectiveness and safety data are limited. |
| What was learned from this study? |
| This analysis utilized real-world data for patient-reported outcomes from the German Pain e-Registry for a large PHN cohort (N = 961) who received one to four HCCP treatments over 12 months, finding that HCCP significantly reduced average pain intensity, enhanced sleep, improved QoL, alleviated emotional distress, reduced the need for concurrent pain medications, and had no unexpected tolerability events, with progressive improvements observed with repeat treatments and loss of benefits seen in patients who discontinued HCCP. |
| This study builds on existing evidence that HCCP is an effective and well-tolerated treatment for patients with PHN, with benefits that extend beyond one treatment and increase with ongoing treatment. |
| The implications for disease understanding and clinical care indicate that effective topical treatments such as HCCP have the potential to transform the treatment landscape for patients with PHN, including in patients who may be unable to tolerate oral medications owing to systemic side effects, comorbidities, polypharmacy, or drug–drug interactions. |
Digital Features
This article is published with digital features, including a Graphical Abstract, to facilitate understanding of the article. To view digital features for this article, go to 10.6084/m9.figshare.30800156
Introduction
Herpes zoster (HZ), an infection caused by the varicella zoster virus, affects ~20–30% of the general population [1, 2]. The European incidence rate in the general population is ~2.0–4.6 per 1000 person-years [3]. HZ is associated with a painful, blistering rash that can develop into postherpetic neuralgia (PHN)—a common and debilitating complication occurring in ~18% of patients with HZ [1, 2]. Risk factors for HZ and PHN include older age, where risk of infection and complications increase sharply > 50 years [1, 2, 4], and reduced cell-mediated immunity, such as in patients treated with biologics [4, 5].
PHN pain is typically chronic (≥ 90 days following HZ rash resolution) [6], localized, and unilateral, and may present with itching, burning, stabbing, or throbbing qualities [7]. Patients may experience dysesthesia, including allodynia (touch sensitivity), thermal hyperalgesia, and numbness [7]. PHN has an extensive burden on patients beyond chronic pain, negatively impacting quality of life (QoL) [8, 9]. Disruptions to physical, social, and emotional well-being can interfere with patients’ ability to perform basic tasks, causing loss of autonomy, social isolation, and further psychosocial impact, with the elderly particularly vulnerable [8].
PHN is typically localized to a single dermatome, and primarily affects thoracic (53%), cervical/neck (20%), and trigeminal/face (15%) dermatomes [10]. Quantitative sensory testing and screening instruments (e.g., Neuropathic Pain in 4 Questions [DN4] and painDETECT) can provide insights into the sensory characteristics and clinical presentation of PHN [11–13].
HZ prevention through vaccination can effectively reduce the burden of illness and the risk of PHN, including in older adults [6, 14]. However, only ~50% of eligible individuals show vaccine willingness [15], highlighting the ongoing need for effective neuropathic pain management in patients with PHN. Despite the availability of therapeutics with different mechanisms of action, PHN-related pain often remains treatment-refractory, with many patients requiring multiple medications to achieve adequate pain relief [16, 17]. Oral treatments (antiepileptics and antidepressants) are usually administered daily and are absorbed systemically, which can cause drug–drug interactions and side effects [18]. This is particularly concerning for elderly individuals, who have a high risk of serious side effects owing to comorbidities, polypharmacy, and age-related metabolic changes [16, 19]. Additionally, many oral medications require careful titration that may be difficult for older patients, leading to suboptimal dosing and early treatment discontinuation [18]. Thus, topical formulations offer a valuable treatment option for patients with PHN.
The high-concentration capsaicin patch (HCCP), a topical formulation containing 179 mg of capsaicin (8% weight per weight), is approved for the treatment of PHN in the European Union (EU) and USA [20, 21]. Capsaicin is a highly-selective potent agonist for transient receptor potential vanilloid 1 (TRPV1) receptors on nociceptive neurons in the skin [22]. HCCP utilizes patented matrix technology to deliver high local concentrations of capsaicin into the epidermis and dermis, acting directly on TRPV1-expressing nerve fiber terminals and leading to analgesic effects in the treated area [20, 22–24]. This mode of action overcomes limitations of low-concentration capsaicin creams/lotions, which require frequent applications [22, 23], while resulting in negligible diffusion of capsaicin into the bloodstream, limiting systemic effects [20, 23]. HCCP is applied to dry, intact skin of the affected area by trained healthcare professionals for 60 min; pretreatment with topical anesthetics or oral analgesics may be considered prior to application [20]. Treatment can be repeated every 90 days as warranted by the persistence or return of pain (60-day minimum interval between treatments, based on physician assessment).
This cohort study evaluates data from the German Pain e-Registry (GPeR), which includes a large PHN cohort, as a robust platform for studying the real-world application of HCCP. This manuscript presents results for pain intensity, pain-related disability, sleep, mood, QoL, concomitant pain medication use, and tolerability in patients with PHN receiving one to four HCCP treatments over 12 months.
Methods
The retrospective, noninterventional, multicohort CASPAR study (EUPAS1000000106) used data from the web-based GPeR, which facilitates information exchange between patients and physicians for individual pain treatment and patient care using an online documentation service. GPeR methodology has been described previously [25] and is detailed in the Supplementary Methods. The study design is shown in Fig. 1. Data were extracted from the GPeR for eligible patients with a confirmed diagnosis of PHN in the claims database (≥ 18 years, received first HCCP between 1 January 2015 and 31 December 2021, with ≥ 12 months’ follow-up), who recorded ≥ 1 post-baseline/post-HCCP measurement within the evaluation period (at 12 ± 2-week intervals).
Fig. 1.
Study design. *12-week (± 2) intervals (months 3, 6, 9, and 12), either immediately before next HCCP treatment or, in patients who discontinued treatment, within ± 2 weeks of the anticipated time of treatment based on average intervals. ADR adverse drug reaction, DASS-21 21-Item Depression, Anxiety, and Stress Symptom Scale, GPeR German Pain e-Registry, HCCP high-concentration capsaicin patch, HCP healthcare professional, MCS mental component summary, mPDI modified Pain Disability Index, PCS physical component summary, PDQ7 7-Item painDETECT Questionnaire, PHN postherpetic neuralgia, QoL quality of life, VAS visual analogue scale, VR-12 Veterans RAND 12-Item Health Survey
Standardized and validated patient questionnaires were completed by patients shortly before each visit, and data were verified by their physicians. Outcomes assessed by patient questionnaires included pain intensity, pain severity, pain-related impairments of daily life, QoL, well-being, mood (depression, anxiety, stress, and suicidal ideation), as well as concomitant pain medication use and adverse drug reactions (ADRs). Briefly, average pain intensity (API) over 24 h was measured using the visual analog scale (VAS) [26], and neuropathic symptoms were graded on the 7-Item painDETECT Questionnaire (PDQ7) [12]. QoL was measured via the Veterans RAND 12-Item Health Survey (VR-12) using both mental and physical components, and impact of PHN on patients’ daily activities was assessed using the Von Korff scale [27, 28]. The modified Pain Disability Index (mPDI) was used to measure pain disability and sleep impairment [29]. The proportion of patients experiencing moderate–extremely severe emotional distress was assessed via the 21-Item Depression, Anxiety, and Stress Symptom Scale (DASS-21) [30], and a questionnaire on suicidal ideation frequency. Further details of each patient assessment can be found in Fig. 1.
Statistical Analysis
Anonymized GPeR data were analyzed for eligible patients who received ≥ 1 HCCP and had ≥ 12 months of follow-up data. Results were stratified by total number of HCCP treatments received (one to four) over 12 months. Outcomes were evaluated at baseline and at months 3, 6, 9, and 12 (Fig. 1). Chi-squared tests were used for categorical variables. Comparative analyses versus baseline used Student’s t-tests for ordinally scaled data. Effect size estimates were calculated where appropriate, including odds ratios, relative risks, standard deviations, numbers needed to treat or harm, Cohen’s d, and phi correlation coefficient. Statistical tests were performed versus baseline data, using a two-sided significance level of 0.05. The study employed an observed case analysis; missing data were not imputed. No formal sample size calculations or preplanned comparisons were performed. Variables were summarized using descriptive and inferential statistics, including the mean, 95% confidence intervals (CIs), frequency, and percentage. Further details have been previously described [25].
Ethical Approval
This noninterventional cohort study was conducted in accordance with the Declaration of Helsinki and relevant national and regulatory requirements. All participants (physicians and patients) provided their written informed consent prior to participation in the GPeR, authorizing the use of their anonymized data for healthcare research purposes. The study concept and evaluation of anonymized data from the GPeR were reviewed and approved by the steering committees of the German Pain Association and the German Pain League, with the latter paying particular attention to ensuring that patients’ rights are upheld within the framework of this study. Since this retrospective study only refers to depersonalized data (i.e., of patients, physicians, and treatment facilities) from routine care, no approval from an ethics committee was required. The study concept has been registered in the European Medicines Agency registry for noninterventional/epidemiological studies (European post‐authorization study [EU PAS] identifier: 1000000106) to make this evaluation public. CASPAR is registered with the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance in the European Union Electronic Registry of Post-Authorization Studies. All analyses were performed using only anonymized data to comply with German guidelines on protection of data privacy and with the European Union General Data Protection Regulation.
Results
Participants
Of 2574 eligible patients in the GPeR for the CASPAR study, 961 had a confirmed diagnosis of PHN. Patients received one (n = 187), two (n = 209), three (n = 207), or four (n = 358) HCCP treatments and were included in the stratified analysis. Baseline demographic data are summarized in Table 1. The mean age was 63.8 years, and 69.7% were female. On average, patients had experienced pain symptoms for 3.3 years and had a mean 24-h API score of 61.8. The PDQ7 sensory symptoms most often reported as experienced “strongly” or “very strongly” were burning (69.8%), allodynia (61.8%), and pressure sensitivity (57.4%). Most patients had truncal PHN (chest frontside [35.0%], chest backside [16.5%], abdomen [10.4%], lower back [5.9%]), and 6.8% had PHN of the face/head (off-label use). Moderate-to-extremely severe depression, anxiety, and stress were reported in up to half of patients (48.2%, 36.9%, and 47.9%, respectively). All patients at baseline were receiving concomitant pain medications (mean number of medications = 4.0 [95% CI 3.9–4.2]).
Table 1.
Demographics and baseline characteristics of patients with PHN treated with HCCP
| Baseline characteristic | Patients with PHN (N = 961) |
|---|---|
| Sex, female, n (%) | 670 (69.7) |
| Sex, male, n (%) | 291 (30.3) |
| Age, years, mean (95% CI) | 63.8 (62.8–64.9) |
| Body mass index, kg/m2, mean (95% CI) | 26.9 (26.4–27.3) |
| Comorbidities, mean (95% CI) | 3.4 (3.2–3.5) |
| Pain duration, years, mean (95% CI) | 3.3 (3.1–3.6) |
| Number of different specialists visited for treatment of PHN, mean (95% CI) | 6.8 (6.7–6.9) |
| Pain localization, n (%) | |
| Face/head | 65 (6.8) |
| Shoulder | 63 (6.6) |
| Chest frontside | 336 (35.0) |
| Chest backside | 159 (16.5) |
| Lower back | 57 (5.9) |
| Abdomen | 100 (10.4) |
| Arms | 33 (3.4) |
| Hands | 12 (1.2) |
| Pelvic area | 60 (6.2) |
| Legs | 48 (5.0) |
| Feet | 28 (2.9) |
| Average 24-h pain intensity, mm VAS, mean (95% CI) | 61.8 (60.5–63.1) |
| PDQ7 sensory symptom item scores (strongly/very strongly), n (%) | |
| Burning sensation | 671 (69.8) |
| Prickling | 488 (50.8) |
| Allodynia | 594 (61.8) |
| Pain attacks | 540 (56.2) |
| Thermal sensitivity | 325 (33.8) |
| Numbness | 179 (18.6) |
| Pressure sensitivity | 552 (57.4) |
| VR-12 PCS global score, mean (95% CI) | 31.3 (30.6–31.9) |
| VR-12 MCS global score, mean (95% CI) | 42.5 (41.7–43.4) |
| Von Korff, number of days usual activities could not be performed owing to neuropathic pain in the last 3 months, mean (95% CI) | 44.7 (42.4–47.1) |
| mPDI sum score, mm VAS, mean (95% CI) | 57.6 (56.2–59.0) |
| mPDI-6 sleep score, mm VAS, mean (95% CI) | 54.0 (52.2–55.7) |
| DASS-21-D (depression), moderate-to-extremely severe, n (%) | 463 (48.2) |
| DASS-21-A (anxiety), moderate-to-extremely severe, n (%) | 355 (36.9) |
| DASS-21-S (stress), moderate-to-extremely severe, n (%) | 461 (47.9) |
| Suicidal ideation, “sometimes” or “frequent,” n (%) | 196 (20.4) |
| Current systemic neuropathic pain medications, mean (95% CI) | 4.0 (3.9–4.2) |
| Previous systemic neuropathic pain medications, mean (95% CI) | 7.7 (7.6–7.9) |
| Patients with previous neuropathic pain or adjuvant medications, n (%) | |
| Mild opioid analgesic | 744 (77.6) |
| Strong opioid analgesic | 692 (72.0) |
| Antiepileptic drugs | 664 (69.1) |
| Antidepressant drugs | 883 (91.9) |
The VAS is a scale from 0 (absence of pain) to 100 (worst possible pain)
CI confidence interval, DASS-21 21-Item Depression, Anxiety, and Stress Symptom Scale, HCCP high-concentration capsaicin patch, MCS mental component summary, mPDI modified Pain Disability Index, PCS physical component summary, PDQ7 7-Item painDETECT Questionnaire, PHN postherpetic neuralgia, VAS visual analogue scale (0–100 mm), VR-12 Veterans RAND 12-Item Health Survey
Average Pain Intensity (VAS and Responder Rate)
Mean 24-h API decreased from 61.8 at baseline to 46.8 at month 3 (P < 0.001) across all patients, with further reductions seen with successive treatments (31.8 at month 12; P < 0.001 versus baseline). Patients receiving four HCCP treatments had the greatest mean reductions at month 12, from 63.7 at baseline to 19.6 (P < 0.001). Patients who discontinued HCCP treatment during the study period subsequently lost the initial improvements seen at month 3, with gradual increased pain intensity over time (Fig. 2a).
Fig. 2.
Average pain intensity over 12 months by number of HCCP treatments. a Mean 24-h API (mm VAS); b ≥ 30% responders; c ≥ 50% responders. In panel a, P-values measure significance from baseline to timepoint. Error bars show 95% CI. Solid lines represent when patients were on HCCP treatment; dashed lines represent when patients had discontinued HCCP treatment. API average pain intensity, CI confidence interval, HCCP high-concentration capsaicin patch, VAS visual analogue scale
At month 3, after the first treatment with HCCP, 29% of patients achieved ≥ 30% API response rate. Further improvements were seen in patients receiving additional HCCP treatments, whereas improvements were gradually lost in patients who discontinued. At month 12, 99.7% of patients who received four HCCP treatments reported ≥ 30% reductions in API versus 17.6% of patients who received one HCCP treatment (Fig. 2b). Similar trends were observed for API ≥ 50% response rates (month 3: 0–0.5%; month 12: 92.7% for four HCCP treatments versus 1.6% for one HCCP treatment; Fig. 2c).
Symptoms (PDQ7)
All neuropathic pain symptoms numerically decreased from baseline to month 12 for patients receiving four HCCP treatments, with the most notable reductions observed for pain attacks, numbness, and burning sensations (all P < 0.001; Fig. 3). All reductions at month 12 were statistically significant versus baseline (P < 0.01) except for prickling (P = 0.067).
Fig. 3.
Symptoms of neuropathic pain (PDQ7) over 12 months in patients receiving four HCCP treatments. P-values measure significance from baseline to timepoint. CI confidence interval, HCCP high-concentration capsaicin patch, PDQ7 7-Item painDETECT Questionnaire, PHN postherpetic neuralgia
QoL and Daily Activities (VR-12 and Von Korff)
Significant improvements in QoL were seen with progressive HCCP treatments over 12 months across physical and mental health domains (Fig. 4a, b). The greatest improvements were seen in patients receiving four treatments, whereas improvements were gradually lost following discontinuation. On average, patients receiving three or four HCCP treatments surpassed a mean mental component score of 50 (which is indicative of “normal functioning” within the general population).
Fig. 4.
QoL impact over 12 months by number of HCCP treatments. a VR-12 physical component summary score; b VR-12 mental component summary score; c Von Korff analysis of the number of days over the past 3 months that usual activities were affected owing to pain. P-values measure significance from baseline to timepoint. Error bars show 95% CI. Solid lines represent when patients were on HCCP treatment; dashed lines represent when patients had discontinued HCCP treatment. CI confidence interval, HCCP high-concentration capsaicin patch, MCS mental component summary, PCS physical component summary, PHN postherpetic neuralgia, QoL quality of life, VR-12 Veteran RAND 12-Item Health Survey
There were also significant improvements in number of days of usual activities lost over the previous 3 months due to PHN (Fig. 4c), with the most notable improvements in patients receiving four HCCP treatments. Benefits were gradually lost in patients who discontinued treatment.
Pain Disability and Sleep Impairment (mPDI)
Overall impact of pain disability on daily living decreased from baseline to month 3; subsequent treatments did not transfer to further reductions over time (Supplementary Fig. S1a). Conversely, the sleep impairment subscale showed continued improvements over 12 months with progressive treatments, with the greatest benefits seen in patients receiving four HCCP treatments (Supplementary Fig. S1b). These benefits were gradually lost on average in patients who discontinued treatment.
Emotional Distress and Suicidal Ideation (DASS-21)
The proportion of patients experiencing moderate-to-extremely severe depression, anxiety, or stress decreased from baseline to month 3, with further reductions by month 12 (Supplementary Fig. S2a–c). Patients receiving four HCCP treatments showed the greatest benefits, whereas benefits were gradually lost on average in those who discontinued treatment.
Likewise, the proportion of patients experiencing “sometimes” or “frequent” suicidal ideation decreased from baseline by month 3 after one HCCP treatment; this trend continued with progressive treatments but was gradually lost in those who discontinued treatment (Supplementary Fig. S2d).
Concomitant Pain Medication Use
All patients were receiving concomitant pain medications at baseline. In patients receiving four HCCP treatments, the mean number of concomitant pain medications reduced from 4.1 at baseline to 1.4 at month 12. The proportion of patients not taking any concomitant pain medications increased over time with progressive HCCP treatments (Fig. 5a), with 32.7% of patients receiving four HCCP treatments not taking any concomitant pain medications by month 12. Pain medication reductions were seen across several drug classes, including antiepileptics, antidepressants, and strong opioids, and were greatest in patients receiving four HCCP treatments (Fig. 5b–d).
Fig. 5.
Use of selected concomitant pain medications over 12 months by number of HCCP treatments. a No concomitant pain medications; b strong opioids*; c antiepileptics; d antidepressants. *Strong opioids included morphine, hydromorphone, oxycodone, buprenorphine, fentanyl, tapentadol, methadone, and others. HCCP high-concentration capsaicin patch
Safety and Tolerability
Safety and tolerability findings were consistent with the known safety profile of HCCP (Table 2). ADRs were primarily associated with the application site and mostly occurred on the day or day after treatment application. Mean number of ADRs per HCCP treatment decreased with each subsequent application (1.5 to 0.8 from first to fourth treatment), as did the proportion of patients who experienced ≥ 1 ADR (56.3% to 38.8%) or ≥ 2 ADRs (49.8% to 27.7%). A mean of 3.6 ADRs was reported per patient (maximum of 15); the most common ADRs were pain, erythema, burning sensation, and pruritus, each at the application site. While ADRs were fairly frequent, symptoms were typically mild to moderate, and most patients fully recovered. Countermeasures such as local cooling, systemic analgesics, and antihistamines were only required for 0.7–3.2% of patients with ADRs, across all treatment applications.
Table 2.
Adverse drug reactions reported in patients with PHN treated with HCCP
| ADRs | Treatment with first HCCP (n = 961) | Treatment with second HCCP (n = 774) | Treatment with third HCCP (n = 565) | Treatment with fourth HCCP (n = 358) |
|---|---|---|---|---|
| Number of ADRs per patient per treatment, mean (95% CI) | 1.5 (1.4–1.6) | 1.5 (1.3–1.6) | 1.2 (1.1–1.3) | 0.8 (0.7–0.9) |
| Patients with ≥ 1 ADR, n (%) | 541 (56.3) | 433 (55.9) | 283 (50.1) | 139 (38.8) |
| Patients with ≥ 2 ADRs, n (%) | 479 (49.8) | 382 (49.4) | 220 (38.9) | 99 (27.7) |
| Specific ADRs, n (%) | ||||
| Pain* | 479 (49.8) | 372 (48.1) | 222 (39.3) | 105 (29.3) |
| Severe ADR | 64 (13.4) | 25 (6.7) | 2 (0.9) | 0 |
| Erythema* | 395 (41.1) | 322 (41.6) | 174 (30.8) | 82 (22.9) |
| Severe ADR | 50 (12.7) | 22 (6.8) | 1 (0.6) | 0 |
| Burning sensation* | 102 (10.6) | 73 (9.4) | 50 (8.8) | 27 (7.5) |
| Severe ADR | 13 (12.7) | 2 (2.7) | 1 (2.0) | 0 |
| Patients with ADRs and countermeasures, n (%) | 24 (2.5) | 31 (3.2) | 17 (1.8) | 7 (0.7) |
| Local cooling | 15 (1.6) | 25 (2.6) | 17 (1.8) | 7 (0.7) |
| Systemic analgesic | 7 (0.7) | 5 (0.5) | 0 | 0 |
| Systemic antihistamines | 0 | 1 (0.1) | 0 | 0 |
| Others | 2 (0.2) | 0 | 0 | 0 |
| Fully recovered ADRs by the time of ADR report, % | 91.9 | 91.2 | 89.8 | 92.1 |
| Discontinuation owing to ADRs alone, n (%) | 36 (3.7) | 43 (5.6) | 36 (6.4) | 44 (12.3) |
| Discontinuation owing to combination of ADRs and ineffectiveness, n (%) | 30 (3.1) | 26 (3.4) | 19 (3.4) | 9 (2.5) |
*At the application site
ADR adverse drug reaction, CI confidence interval, HCCP high-concentration capsaicin patch, PHN postherpetic neuralgia
Treatment discontinuation rates were generally low and mostly owing to ineffectiveness, ADRs, or both. Discontinuation owing to ADRs alone was reported in 3.7%, 5.6%, 6.4%, and 12.3% of patients receiving one, two, three, and four HCCP treatments, respectively (Table 2).
Discussion
CASPAR is a multicohort real-world study investigating patients with neuropathic pain receiving HCCP treatment across specialized pain treatment centers in Germany, with patients with PHN constituting the largest cohort. Patients were mostly female, and 48.3% were aged ≥ 65 years. Treatment with HCCP was associated with improvements across multiple outcomes, including pain intensity and severity, QoL, mood, sleep, and key neuropathic pain symptoms, alongside reductions in concomitant pain medication use.
Importantly, these data show that repeated HCCP treatments correlate with progressively greater improvements, with the highest benefits reported in patients receiving four HCCP treatments. In contrast, patients who discontinued treatment gradually lost benefits over time. This study adds to existing evidence that HCCP is well tolerated across patient groups, with a safety profile primarily characterized by transient, mild-to-moderate application-site reactions. Notably, there were no severe ADRs reported after four HCCP treatments, whereas the proportion of treatment discontinuations owing to ADRs increased steadily from the first to fourth treatment. This discrepancy may reflect the limitations and inherent biases of registry-based data collection.
Learnings for Clinical Practice
Patients in this study received HCCP late in their disease course, after an average of 7.7 treatments for neuropathic pain. This highlights that patients with PHN may not currently be routinely offered HCCP despite clinical guideline recommendations for early intervention [31] and evidence demonstrating that HCCP is an effective and well-tolerated treatment, including in elderly populations [32]. Early and effective treatment is vital to improve patient outcomes and can help reduce the number of concomitant medications, particularly in elderly populations where comorbidities and polypharmacy are prevalent, as demonstrated in this present analysis. Furthermore, many patients with PHN continue to initiate treatment with opioids, despite their use being controversial owing to increasing concerns over side effects and their potential for misuse [33]. This could be considered an unnecessary risk when efficacious and well-tolerated treatments such as HCCP are available, particularly considering its potential for disease-modifying effects with regeneration and restoration of nerve function [22, 34].
HCCP has also been shown to be a cost-effective treatment option for PNP versus alternative oral medications [35, 36]. There is a notable economic burden associated with PHN owing to direct medical costs such as managing side effects, clinic visits, medication switches, and polypharmacy [33]. Additionally, the impact on general activities has further financial implications as this can lead to days off work and productivity loss [33]. The present study demonstrated a considerable number of days of usual activities lost owing to PHN at baseline. This was significantly reduced following HCCP treatment, particularly for patients receiving repeated treatments. Although not stratified by age, 51.7% of patients included in this study were of working age (≤ 65 years), suggesting that HCCP also has the potential to ease economic burden.
Challenges of Treating Older Patients with PHN
PHN remains a major public health concern, particularly for older patients who are disproportionally affected by this condition (~20% of patients > 65 years, and up to 30% of patients > 80 years) [2, 17]. Pain management in elderly patients can be complex and challenging owing to multimorbidity, physiological changes, and polypharmacy [37]; patients have an increased risk of serious systemic side effects with oral medications and may be unable to tolerate optimal therapeutic doses, impacting potential efficacy [37]. Furthermore, in a US survey of 385 patients with PHN aged > 65 years, > 30% were dissatisfied and only 14% were well satisfied with their medications [38]. Topical treatments such as HCCP may be preferred by older patients as they can be limited to the affected area without systemic exposure, minimizing risk to renal and hepatic organs and reducing drug–drug interactions and side effects [32, 37]. Results from a pooled meta-analysis of older patients with PHN (aged ≥ 75 years) found no increase in the severity or duration of side effects of HCCP versus patients aged < 75 years, although a higher incidence of erythema was noted, which may be attributed to decreased skin thickness in older patients [32]. The HCCP tolerability profile in older adults is further supported by the present study in which patients aged > 65 years were a substantial proportion of the cohort (n = 464; 48.3%). Notably, many patients were able to cease all concomitant pain medications over time. This is particularly beneficial to elderly patients who may become overwhelmed by a high medication burden, leading to medical nonadherence.
PHN also has a high burden and negative impact on QoL, particularly in older patients. Many patients report substantial pain levels that interfere with essential activities of daily living, such as mobility, cooking, bathing, and housework, resulting in inactivity, loss of independence, and social isolation [38, 39]. Sleep is commonly disrupted, and many patients experience increased anxiety or depression [38]. These are essential factors to consider for PHN management. This analysis found that HCCP effectively reduces pain intensity and provides improvements across various patient-reported outcomes in sleep, QoL, daily activities, and mood. Together, these results highlight that HCCP offers a wide range of benefits for patients with PHN, including for older adults.
Strengths and Limitations
As one of the largest PHN cohorts analyzed, these findings may be applicable to the wider patient population with PHN; although, given that the population is exclusive to Germany, results may not be fully applicable internationally. Real-world data reflect a diverse patient population, enabling generalizability of results in clinical practice. Data were prospectively collected, patient-reported, and physician-verified, and underwent independent quality assurance at the e-Registry level. All patients had ≥ 12 months’ follow-up, regardless of the number of HCCP treatments received. There are limitations inherent to observational retrospective studies, which have been discussed in detail previously [25]. The research is subject to inherent biases (e.g., selection bias), which may impact results, and the lack of a comparator group limits data interpretation. Nevertheless, since data were collected for 12 months irrespective of whether patients continued treatment with HCCP, the potential bias of collecting data only from responders may be mitigated.
Conclusions
This real-world analysis supports the use of HCCP as an effective and well-tolerated treatment for PHN, with improvements demonstrated across pain intensity, QoL, mood, sleep, and concomitant pain medication use. Benefits were achieved following a single HCCP treatment, and repeated treatments resulted in further progressive improvements. HCCP is an important topical treatment option for patients with PHN, particularly elderly patients for whom comorbidities and polypharmacy are commonplace.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
Medical Writing, Editorial, and Other Assistance
Medical writing and editorial support were provided by Emily Hollebon, MSc, and Meghan Betts, PhD, of NexGen Healthcare Communications and were funded by Grünenthal GmbH, Germany. This manuscript was developed in accordance with Good Publication Practice Guidelines (https://www.ismpp.org/gpp-2022). The authors had full control of the content and made the final decision on all aspects of this publication. The authors would also like to thank the participants of the study.
Author Contributions
Sonja Ständer, Manuel P. Pereira, Mariëlle Eerdekens, Lucia Garcia-Guerra, Fabienne Percot, Samuel Allen, Rita Freitas, Tamara Quandel, and Michael Überall contributed to the conceptualization, methodology, writing (original draft), and writing (review and editing) of the manuscript. Mariëlle Eerdekens and Michael Überall contributed to visualization and supervision. Mariëlle Eerdekens and Tamara Quandel were responsible for project administration. Michael Überall additionally performed data curation, formal analysis, investigation, resource management, and funding acquisition. All authors reviewed and approved the final version of the manuscript and agree to be accountable for all aspects of the work.
Funding
This work, including the Rapid Service Fee, was supported by Grünenthal GmbH, Germany, who was involved across all stages of the publication. Data extraction and statistical analysis were performed by O’Meany Medical Data & Project Management GmbH and funded by Grünenthal GmbH.
Data Availability
The data supporting the study findings are available from the German Pain e-Registry. Restrictions apply to the availability of these data, which were used under licence for the current study and are not publicly available. Data are available, upon reasonable request, from the last author.
Declarations
Conflict of Interest
Sonja Ständer has received grants or contracts from Almirall S.A., Beiersdorf A.G., Galderma S.A., Sanofi Genzyme Corporation, and Trevi Therapeutics Inc.; received consulting fees from AbbVie Deutschland GmbH & Co., Amgen Inc., Bellus Health Cough Inc., Bristol Myers Squibb Company, Clexio Biosciences Ltd., Galderma S.A., Klirna Biotech Inc., Omnicuris Healthcare Private Ltd., Pfizer Inc., P.G. Unna Academy, Sanofi-Aventis Deutschland GmbH, Sanofi-Aventis R&D, Sanofi Genzyme Corporation, and Vifor Pharma Deutschland GmbH; received payment or honoraria from lectures, presentations, speakers’ bureau, and/or manuscript writing or education writing from Beiersdorf A.G., CRM GmbH, FomF GmbH, Galderma Laboratorium GmbH, Galderma S.A., L’Oréal, Novartis Pharma GmbH, Pfizer Pharma GmbH, P.G. Unna Akademie e.V., Sanofi-Aventis (Schweiz) A.G., Sanofi-Aventis Deutschland GmbH, Sanofi B.V., Sanofi Genzyme Europe B.V., Sanofi Genzyme Corporation, Sanofi Hong Kong Ltd., Sanofi OY, Streamed-Up! GmbH, TouchIME, UCB Pharma GmbH, Vifor Pharma Deutschland GmbH, and WebMD Global LLC; received support for attending meetings and/or travel from AbbVie Deutschland GmbH & Co., Attovia Therapeutics Inc., Trevi Therapeutics Inc., Galderma Laboratorium GmbH, Sanofi-Aventis Deutschland GmbH, Lilly Deutschland GmbH, Pfizer Pharma GmbH, Sanofi Genzyme Corporation, and Vifor Pharma Deutschland GmbH; and participated on a data safety monitoring board or advisory board at Amgen Europe GmbH, Focus-Insight Healthtech Group Co. Ltd., Lilly Deutschland GmbH, Almirall Hermal GmbH, AbbVie Deutschland GmbH Co. KG, Almirall S.A., Celldex Therapeutics Inc., Galderma R&D, LLC., Galderma Laboratorium GmbH, Galderma S.A., Grünenthal GmbH, Lilly Deutschland GmbH, Regeneron Pharmaceuticals Inc., Sanofi Aventis Deutschland GmbH, Sanofi Genzyme Corporation, and Vifor Pharma Deutschland GmbH. Manuel P. Pereira has received research funding from Almirall, Clinuvel, and Pfizer; worked as a consultant for AbbVie, Galderma, Incyte, and Sanofi; was a speaker for AbbVie, Beiersdorf, Doctorflix, Eli Lilly, Falk Foundation, FomF GmbH, GA2LEN, Galderma, Novartis, P.G. Unna Academy, Sanofi, StreamedUP, TouchMDT, and Zai Lab; received travel fees from AbbVie, Celltrion, CSL Behring, GA2LEN, Galderma, Pfizer, and Sanofi; was an investigator for Allakos, Amgen, Celldex Therapeutics, Escient, Incyte, Mitsubishi, and Sanofi, and participated on a data safety monitoring board or advisory board at AbbVie, Galderma, and Sanofi. Mariëlle Eerdekens, Lucia Garcia-Guerra, Fabienne Percot, Rita Freitas, and Tamara Quandel are employees of Grünenthal GmbH, Germany, or its affiliates. Samuel Allen is an employee of Averitas Pharma, USA. Michael Überall has received grants or contracts from Grünenthal GmbH, Strathmann, and Stada (all paid to institution); received consulting fees from Almirall, Grünenthal GmbH, Stada, and Dermapharm (all paid to institution); received payment or honoraria for lectures, presentations, speakers’ bureaus, and manuscript writing or educational events from Averitas Pharma GRT Therapeutics, Grünenthal GmbH, GSK, Hexal, Johnson & Johnson, Mibe Pharmaceuticals, Nestlé, Neuraxpharm, Novartis, Strathmann, Teva, Tilray, Trommsdorff, and Viatris (all paid to institution); received payment for expert testimony from Averitas Pharma GRT Therapeutics (paid to institution); received support for attending meetings and/or travel from Averitas Pharma GRT Therapeutics, Grünenthal GmbH, GSK, Teva, and Viatris (all paid to institution); participated on a data safety monitoring board or advisory board for Grünenthal GmbH and Viatris (all paid to institution); and had a leadership or fiduciary role on another board for the German Pain Association and German Pain League (all personal).
Ethical Approval
This noninterventional cohort study was conducted in accordance with the Declaration of Helsinki and relevant national and regulatory requirements. All participants (physicians and patients) provided their written informed consent prior to participation in the GPeR, authorizing the use of their anonymized data for healthcare research purposes. The study concept and evaluation of anonymized data from the GPeR were reviewed and approved by the steering committees of the German Pain Association and the German Pain League, with the latter paying particular attention to ensuring that patients’ rights are upheld within the framework of this study. Since this retrospective study only refers to depersonalized data (i.e., of patients, physicians, and treatment facilities) from routine care, no approval from an ethics committee was required. The study concept has been registered in the European Medicines Agency registry for noninterventional/epidemiological studies (European post‐authorization study [EU PAS] identifier: 1000000106) to make this evaluation public. CASPAR is registered with the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance in the European Union Electronic Registry of Post-Authorization Studies. All analyses were performed using only anonymized data to comply with German guidelines on protection of data privacy and with the European Union General Data Protection Regulation.
Footnotes
Publisher’s Note
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data supporting the study findings are available from the German Pain e-Registry. Restrictions apply to the availability of these data, which were used under licence for the current study and are not publicly available. Data are available, upon reasonable request, from the last author.