Is the Capsaicin 179 mg (8% w/w) Cutaneous Patch an Appropriate Treatment Option for Older Patients with Peripheral Neuropathic Pain?

Introduction

Neuropathic pain, a type of chronic pain that arises as a direct consequence of a lesion or disease affecting the somatosensory system,¹ may affect ~30% of older adults (aged >60 years).² This compares to a prevalence of 3–18% in the general population in Western countries.³ Most commonly, localized neuropathic pain has a peripheral presentation characterized by a consistent and circumscribed area of maximum pain.⁴ Neuropathic pain impairs quality of life and can exacerbate functional decline with age.⁵ Persistent pain (of any type) in older adults has also been associated with an increased risk of frailty.⁵

Pharmacotherapy is the recommended first-line treatment for localized neuropathic pain.⁶ However, neuropathic pain can be difficult to treat, and oral systemic treatment options (such as antidepressants, antiepileptic drugs, and/or opioids) often provide incomplete pain relief, with side effects and drug─drug interactions that can limit long-term use.^6–8 Locally applied treatments that target the allodynic or hyperalgesic area with very limited systemic effects may be preferred, particularly in older patients with multiple comorbidities and polypharmacy.^6–8

The 5% lidocaine plaster and capsaicin 179 mg (8% weight per weight) cutaneous patch (hereafter referred to as the capsaicin patch) are both recommended as first-line treatment options for localized neuropathic pain,^6,9 with some guidelines positioning the capsaicin patch as second line.¹⁰ Of these, the capsaicin patch typically has the broader indication: for peripheral neuropathic pain (PNP) in Europe, and for pain associated with post-herpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (pDPN) in the US.^11,12 Up to four patches are applied by a physician (or a healthcare professional under physician supervision) to the most painful skin areas for a duration of 30 or 60 minutes, depending on the PNP condition and/or pain site. Treatment may be repeated every 3 months.

In a head-to-head trial, the capsaicin patch provided more rapid onset of pain relief and greater satisfaction than pregabalin in patients with PNP,¹³ while a network meta-analysis suggested similar efficacy and fewer side effects when compared with oral systemic agents (pregabalin, duloxetine, and gabapentin) in pDPN.¹⁴ Other topical or locally acting therapies have been evaluated or are in development for neuropathic pain, including phenytoin cream,¹⁵ botulinum toxin,¹⁶ topical cannabinoids,¹⁷ ketamine, muscle relaxants and α2-adrenergic agents, and locally applied μ-opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) agonists. Currently, there is insufficient evidence to recommend these.^6–8

Although clinical trials of topical cutaneous therapies (including the capsaicin patch) have included older patients, efficacy and safety data in this population have up to now not been reported separately.⁷ In the authors’ experience, clinicians’ concerns over the benefit–risk profile of the capsaicin 179 mg patch in the elderly (particularly regarding local tolerability) have sometimes limited its clinical use in this population. To address these concerns, analyses were conducted on pooled data from clinical trials of the capsaicin patch to evaluate its efficacy and safety in pooled subpopulations of older and other adult patients.

Methods

Selection of Studies for Pooled Analysis

The studies included in this analysis were identified from the clinical development program for the capsaicin patch. This program comprised a series of interventional Phase 2, 3, and 4 trials, specifically aimed at assessing the efficacy and safety of the capsaicin 179 mg patch in treating various neuropathic pain conditions. All trials were supported by companies with direct involvement in the development of the capsaicin patch. An additional search of the literature resulted in the identification of clinical trials that included adult and older patients but lacked specific information regarding older patients. Therefore these trials were not considered in this analysis. For the pooled analysis of efficacy according to participant age, only randomized, double-blind, 12-week efficacy studies with similar trial design, and that included patients older than the median age in the pooled dataset (ie aged ≥73 years), were selected. Four Phase 2/3 studies (C108, C110, C116, and C117) were identified (pooled n=1,272), each of which compared the efficacy of a single treatment with the capsaicin patch with that of a low-concentration capsaicin (0.04%) control patch in patients with moderate-to-severe neuropathic pain resulting from PHN (Table 1). Excluded single-treatment randomized controlled trials included STEP (comparator, placebo) and trials C107, C109, C112, and C119 that did not include patients ≥73 years old. Duration of patch application was 60 minutes, except for trial C108 in which some patients were treated for 30 minutes or 60 minutes. Only patients who were treated for 60 minutes in the double-blind phase were included in the pooled capsaicin patch treatment group, whereas the pooled control group contained all patients treated with the control patch for any duration across the four studies. All treated patients received pretreatment of their painful areas with a topical local anesthetic cream (lidocaine 4%) before study patch application, to offset potential treatment-related discomfort or pain resulting from capsaicin. Patients used a diary to record numeric pain rating scale (NPRS) scores (from 0 to 10, with 0 indicating no pain and 10 indicating worst possible pain) from the evening of the treatment day (day 0) through to the evening before the week 12 visit. Baseline NPRS scores were recorded during the screening period (starting 7 days before randomization for trials C108 and C110, and 14 days before randomization for C116 and C117, and ending prior to randomization). The primary efficacy endpoint for each individual trial was the mean percent change from baseline to weeks 2–8 for “average pain for the past 24 hours” using the NPRS. However, as the trials were of 12 weeks’ duration, the predefined analysis of the mean percent change from baseline to weeks 2–12 for “average pain for the past 24 hours” was considered for the current analyses, to ensure that the full duration of the trial was reflected.

Table 1 Overview of Phase 2, 3, and 4 Trials (N=18) in Peripheral Neuropathic Pain Conditions in the Capsaicin Patch Database

For analysis of safety and tolerability, data were pooled from all 18 interventional Phase 2, 3, and 4 studies, regardless of PNP indication (N=4,099 treated patients) (Table 1). Overall, 1,924 patients had received a single application of the capsaicin patch, and 924 patients had received multiple (up to nine) capsaicin patch treatments. Of the 1,251 patients overall who received only control or standard of care (SoC) treatment, 819 patients received a control (low-dose capsaicin or placebo) patch, and 432 received SoC treatment. Capsaicin and control patches were applied for 30, 60, or 90 minutes. Adverse event (AE) data for the individual studies have been previously reported.^{13,18,20–33}

All trials had been approved by an institutional review board and conducted in accordance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable regulatory requirements. All patients enrolled in the trials provided their written informed consent.

Pooled Dataset Analyses

Efficacy in the pooled efficacy population was evaluated in two patient subpopulations defined by median age at baseline: <73 years and ≥73 years. The cut-off of 73 years was chosen as it represents the median age of participants in the included trials, providing a balanced perspective on the treatment’s impact across the study population. The following outcomes, all based on the NPRS score for patients’ average pain intensity experienced in the previous 24 hours, were evaluated in the capsaicin patch and low-dose capsaicin control patch groups: mean change and mean percent change from baseline to week 2–12; and responder status defined as mean decrease in NPRS score from baseline to week 2–12 of i) ≥30%; ii) ≥50%; and iii) ≥2 points. The cut-off values for the definition of responders have been based on the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations.³⁴

In the pooled safety population, treatment-emergent adverse events (TEAEs) were also evaluated in two patient subpopulations, <75 years and ≥75 years, according to treatment received (capsaicin patch or control/SoC). The age threshold was set at 75 years in line with regulatory guidelines that emphasize the importance of evaluating treatment effects in patients aged 75 years and above, a demographic often underrepresented in clinical research.³⁵ Overall, 1,924 patients had received a single application of the capsaicin patch, and 924 patients had received multiple (up to nine) capsaicin patch treatments. Some patients were offered the option to enter long-term open-label extension trials and receive capsaicin patch treatments after having completed a randomized single-application trial. As a result, of the 924 patients with multiple capsaicin patch treatments, 153 patients had already received a prior control treatment.

The cut-off of 75 years for the elderly subpopulation was selected to encompass the upper two of the three life stages that the older adult population is commonly divided into (“young-old” [65–74 years], “middle-old” [75–84 years], and “old-old” [≥85 years]).³⁶ AEs were considered treatment-emergent if onset was on or after the first topical local anesthetic application or if a pre-existing medical condition worsened on or after the first day of treatment. All AEs for the pooled analysis were coded to the Medical Dictionary for Regulatory Activities version 13.1.

Statistical Methods

No formal sample size calculation was conducted. The analyses for efficacy and safety were individual participant data pooled analyses. Efficacy analyses were performed in the pooled intent-to-treat population. Baseline pain scores were calculated as the mean of the NPRS scores for “average pain for the past 24 hours” obtained during the screening period. In the treatment period, NPRS scores for “average pain for the past 24 hours” were again collected on a daily basis, with missing scores imputed using a modified last observation carried forward (LOCF) approach. If NPRS scores were missing on any day, the previous non-missing score was used for imputation; if all post-treatment NPRS scores were missing, then the baseline score was used for imputation (baseline observation carried forward [BOCF]). Mean and least squares (LS) mean were calculated for average NPRS scores over weeks 2–12, and for absolute change and percent change in NPRS scores from baseline to week 2–12, for the active treatment and control group within each subpopulation (aged <73 and ≥73 years). Treatment differences were calculated as the difference of the LS mean between the active treatment and control groups using gender-stratified analysis of covariance (ANCOVA) with baseline pain as the covariate. The P-value was also computed using gender-stratified ANCOVA to test for the difference between the active treatment and pooled control groups, with baseline pain as covariate. For responder rates, the odds ratio (OR) was estimated by logistic regression with treatment as main effect, and gender and baseline pain as covariates. The P-value was also computed using logistic regression, with gender and baseline pain as covariates.

For the safety analyses, patient data were summarized based on actual treatment received. Analyses of TEAEs for the treatment and pooled control/SoC groups are presented using descriptive statistics.

Results

Analysis Populations

The clinical development program for the capsaicin patch included 18 interventional Phase 2, 3, and 4 trials comprising controlled double-blind trials, open-label repeated- and single-application trials in patients with PHN, pDPN, human immunodeficiency virus infection-related peripheral neuropathy (HIV-PN), and other PNP conditions (Table 1). These trials included 4,099 treated patients (2,848 who received capsaicin patch [QUTENZA^®] and 1,251 subjects who received only low-dose capsaicin control patches, placebo patches, or SoC treatment). Patients randomized to SoC received pharmacologic or other treatment deemed optimal for managing their pain in accordance with routine best medical practice. Methods and findings for the individual studies have been reported previously.^{13,18–33,37}

Demographic and baseline pain characteristics for both the pooled efficacy and pooled safety populations were similar across the treatment groups (Table 2); no subpopulation analyses by age were conducted. Mean age in the pooled efficacy population (70 years) was greater than in the pooled safety population (60–62 years), reflecting the older age profile of patients with PHN compared with other common PNP conditions, including patients with pDPN and HIV-PN.

Table 2 Demographic and Baseline Characteristics of the Pooled Analysis Populations

The pooled efficacy population encompassed 292 patients aged <73 years and 305 aged ≥73 years who had been randomized to the capsaicin patch, and 253 and 277 patients aged <73 and ≥73 years, respectively, who were randomized to the low-dose control patch; all patients had PHN (Table 3).

Table 3 NPRS Score for “Average Pain for the Past 24 Hours” – Change from Baseline and Responder Frequencies at Weeks 2–12 for the Capsaicin Vs Low-Dose Control Patch, by Age Category (ITT Analysis)a

The pooled safety population included 2,311 patients aged <75 years and 537 aged ≥75 years who received the capsaicin patch (Table 4). Of the 1,404 patients overall who received a control patch or SoC treatment at any time (ie as their only treatment or before receiving the capsaicin patch), 1,110 were aged <75 years, and 294 were ≥75 years. Of the 1,251 patients who received only control patch or SoC treatment (ie who never received the capsaicin patch), 991 were aged <75 years, and 260 were ≥75 years. Overall, in the pooled safety population, most patients had PHN (1,636 patients), pDPN (928 patients), or HIV-PN (899 patients). A total of 636 patients had other neuropathic pain indications. Among the 831 patients aged ≥75 years, 669 had PHN, 97 had pDPN, and 1 patient had HIV-PN.

Table 4 Overview of TEAEs by Age Category and for Selected Indications (as-Treated Analysis)a

Pooled Efficacy Analysis

Among patients aged ≥73 years, baseline NPRS scores for “average pain in the past 24 hours” were similar for the active treatment and control groups (mean [standard error (SE)] 5.8 [0.1] in each group) (Table 3). Average NPRS scores at weeks 2–12 had improved from baseline in both the capsaicin and the control patch groups. However, improvement in the capsaicin patch group was significantly greater than for control, with a treatment difference for LS mean absolute change from baseline (95% confidence interval [CI]) of ‒0.4 (‒0.7, ‒0.1) (P=0.003), and for LS mean percent change from baseline of ‒8.3 (‒13.2, ‒3.5) (P=0.0009), in the ≥73 years age group (Table 3). Patients aged ≥73 years in the capsaicin patch group were significantly more likely than those in the control group to achieve responder status defined by mean decrease in NPRS score from baseline to week 2–12: 36.1% vs 27.1% of patients achieved a mean decrease of ≥30% (OR [95% CI] for active treatment vs control group: 1.52 [1.06, 2.18]; P=0.0231); 24.6% vs 14.1% achieved a mean decrease of ≥50% (OR [95% CI] 1.99 [1.29, 3.08]; P=0.0019); and 33.1% vs 20.9% achieved a mean decrease of ≥2 points (OR [95% CI] 1.90 [1.30, 2.78]; P=0.0009) (Table 3; Figure 1).

Figure 1 NPRS score for “average pain for the past 24 hours” – responder frequencies at weeks 2–12 for the capsaicin vs low-dose control patch in patients aged ≥73 years (ITT analysis).a,b aData pooled from studies C108, C110, C116, and C117. For study C108, only the 60-minute capsaicin patch group was included for pooled analysis of active treatment, whereas the control group contains all subjects treated with control for any duration in all four studies. bMissing NPRS scores were imputed using the baseline score if all post-treatment scores were missing, and using the previous non-missing score for scores missing after day 8. Abbreviations: ITT, intent-to-treat; NPRS, numeric pain rating scale.

Baseline pain scores in the <73 years age group (mean [SE] 5.6 [0.1] and 5.5 [0.1] in the active treatment and control group, respectively) were slightly lower than in the older age group. However, the treatment differences (for the active treatment minus control group) for absolute change and relative change from baseline in NPRS scores for “average pain in the past 24 hours” (‒0.4 [‒0.7, ‒0.1] and ‒8.8% [‒14.3%, ‒3.2%], respectively) were similar to those for the ≥73 years subpopulation. The magnitude of response and, consequently, responder rates were higher in patients aged <73 years than those aged ≥73 years. As this was the case for both the treatment and control groups, the resulting odds ratios were slightly lower for the ≥50% responder definition but still reaching statistically significant improvements for the ≥30% and ≥2-point responder definitions.

Pooled Safety and Tolerability Analysis

In the overall pooled safety population, TEAEs were reported for 78.7% of patients who received the capsaicin patch, and for 65.8% of patients who received a control patch or SoC, prior to the TEAE (Table 4; Figure 2).

Figure 2 TEAEs and application-site reactions in patients aged ≥75 years (as-treated analysis).a aData pooled from 18 interventional Phase 2, 3, and 4 studies in patients with PHN, pDPN, HIV-PN, and other PNP conditions. Abbreviations: HIV-PN, human immunodeficiency virus infection-related peripheral neuropathy; pDPN, painful diabetic peripheral neuropathy; PHN, post-herpetic neuralgia; PNP, peripheral neuropathic pain; TEAE, treatment-emergent adverse event.

Among patients ≥75 years old, 81.6% of patients after treatment with the capsaicin patch experienced TEAEs, compared with 72.4% in the control group. A similar proportion of patients in the active treatment group vs control group had serious TEAEs (8.2% vs 6.1%, respectively) and discontinued treatment due to a TEAE (0.9% vs 1.0%) (Table 4; Figure 2). The most frequently reported TEAEs in patients aged ≥75 years who received the capsaicin patch were application-site reactions (63.1% of patients vs 49.3% for control) (Table 4; Figure 2). In this age group, erythema was the most common application-site reaction with the capsaicin patch (42.3%), followed by pain (34.1%) (Table 5; Figure 2).

Other TEAEs that were reported in ≥5% of patients aged ≥75 years who received the capsaicin patch were nausea (reported for 6.0% and 3.7% of patients who received active treatment or control/SoC, respectively) and erythema reported separately from application-site reaction (5.0% and 1.0%, respectively) (Table 6).

Table 5 Selected Application-Site Reactions by Age Category (as-Treated Analysis)

Table 6 Most Common TEAEs by System Organ Class and Age Category (as-Treated Analysis)

Similar proportions of patients aged <75 and ≥75 years who were treated with the capsaicin patch experienced TEAEs (78.1% and 81.6%, respectively), serious TEAEs (7.2% and 8.2%), and TEAEs leading to discontinuation of study treatment (1.0% and 0.9%) (Table 4; Figure 2). Among patients who received control or SoC treatment, patients aged <75 years were less likely to experience TEAEs (64.1% vs 72.4%) and serious TEAEs (4.1% vs 6.1%), and more likely to experience TEAEs leading to discontinuation (2.3% vs 1.0%), than patients aged ≥75 years. There were 16 deaths in total: 13 in the <75 years age group and 3 in the ≥75 years age group. None of the deaths were considered by the investigators to be related to trial medication and were instead deemed to be consequences of underlying disease(s).

Application-site reactions, the most common TEAEs in each age group, occurred with similar frequency in patients aged ≥75 (63.1%) and <75 (62.0%) years who received the capsaicin patch (Table 5). Among patients in the control/SoC group, 49.3% and 30.7% of patients aged ≥75 and <75 years, respectively, experienced application-site reactions. Each type of application-site reaction was more common with active treatment than with a control patch in both age groups.

With the capsaicin patch, the pattern of TEAEs, TEAEs leading to discontinuation from treatment, and application-site reactions across application durations of 30, 60, or 90 minutes were similar in the ≥75 years and <75 years age groups (Figure 3).

Figure 3 TEAEs and application-site reactions by treatment duration with the capsaicin patch in patients aged <75 years and ≥75 years (as-treated analysis).a aData pooled from 18 interventional Phase 2, 3, and 4 studies in patients with PHN, pDPN, HIV-PN, and other PNP conditions. Abbreviations: HIV-PN, human immunodeficiency virus infection-related peripheral neuropathy; min, minutes; pDPN, painful diabetic peripheral neuropathy; PHN, post-herpetic neuralgia; PNP, peripheral neuropathic pain; SAE, serious adverse event; TEAE, treatment-emergent adverse event.

Discussion

The pooled analysis of data from interventional clinical studies supports the efficacy and safety of the capsaicin patch in older patients with PNP. A statistically significant treatment effect compared with a control patch was observed; additionally, improvements were reported in pain scores relative to control that were similar in patients aged ≥73 and <73 years with PHN. The analyses also support the safety and tolerability of the capsaicin patch in older patients, and the safety profile did not differ between patients aged ≥75 and <75 years in a mixed PNP pooled population. Application-site reactions were the most commonly reported AE in both the ≥75 and <75 years age groups.

There is no scientific basis for a differential effect of a topical treatment such as the capsaicin 179 mg patch based on age as its effect is not determined by systemic exposure.³⁸ Nevertheless, it is important to verify in a clinical setting that the effectiveness of the capsaicin 179 mg patch is not age-dependent. In patients aged ≥73 years, a single treatment with the capsaicin patch resulted in an absolute treatment difference vs control of ‒0.4 (95% CI ‒0.7, ‒0.1) in change in the NPRS score from baseline to week 2–12. This difference in pain relief between the capsaicin patch and control was statistically significant. Moreover, the treatment difference between the capsaicin patch and control in change in NPRS score from baseline to week 2–12 was the same as that observed in adult patients aged <73 years, namely ‒0.4 (95% CI ‒0.7, ‒0.1). The question as to whether statistically significant results in chronic pain studies are clinically relevant is still a matter of interpretation.³⁹ The IMMPACT group recommended that statistical significance is necessary but that other factors should also be considered when evaluating the clinical relevance of the difference between treatments.³⁴ Not all factors proposed by the IMMPACT group can be considered given the limitations of the current study; nevertheless, all evaluable factors support the clinical relevance of the statistical significant effect as follows: 1) the tolerability profile of the capsaicin patch is (except for a higher incidence of transient application-site reactions) similar to that of control/SoC; the treatment with capsaicin patch has 2) no requirement for titration, 3) no negative impact on pill burden, 4) ensured compliance as the application is performed by a healthcare professional, 5) a novel mechanism of action that only requires treatment of the affected areas locally, 6) no drug–drug interactions, and 7) a treatment effect that lasts for up to 12 weeks. Of note, responder rates for a 30% decrease in NPRS score from baseline in adult patients with PNP after administration of the capsaicin patch (55.7%) were non-inferior to those obtained with daily pregabalin (54.5%), and the median time to pain intensity reduction (where 50% of patients had a 30% reduction in NPRS scores over 3 consecutive days) was significantly shorter for the capsaicin patch (7.5 days [95% CI 6.0, 10.0] vs 36.0 days [95% CI 22.0, –50.0] for pregabalin) in a head-to-head trial of 8 weeks’ duration.¹³

In terms of tolerability, the most striking difference between patients aged <75 years and those aged ≥75 years is the more frequent occurrence in the latter of erythema. This may relate, in part, to the progressive decrease of thickness of the skin with increasing age.⁴⁰ In our analysis, TEAEs leading to discontinuation of the capsaicin patch were reported for ≤1% of adults in each age group, supporting the tolerability of this topical treatment. In the head-to-head comparison with daily oral pregabalin, no patient receiving the capsaicin patch, and 8.5% of patients receiving pregabalin, discontinued study medication because of TEAEs.¹³

Strengths of these analyses include the large, pooled populations of older patients, mainly from controlled studies. Limitations of the efficacy analysis include potential for bias relating to differences in the number of patients included from each source trial in the pooled datasets, and minor differences in aspects of the trial design of the included studies. Additionally, as the pooled efficacy population included only patients with PHN, the findings may not reflect the breadth of PNP conditions experienced by older patients. Further, the efficacy analyses were all based on a single assessment tool, the NPRS, and were limited to a single 60-minute treatment with the capsaicin patch. The use of LOCF may no longer be considered as a justifiable imputation method;⁴¹ however, BOCF analysis was conducted as a sensitivity analysis with similar results (data not shown). Data on the longer-term efficacy of repeated treatment in older patients would be of benefit, as would data on the impact on patients’ quality of life, including in relation to sleep.

The availability of topical treatments with negligible systemic exposure may have particular advantages in the vulnerable population of older adults.^6–8 Older patients taking oral, centrally acting treatments for neuropathic pain are at increased risk of systemic AEs as a result of age-related pharmacokinetic and pharmacodynamic changes and polypharmacy.^6,42,43 As such, a reduced incidence of systemic AEs, and limited drug─drug interactions when taken concomitantly with other pain medications, is a benefit of topical patch treatments in this population.^6,8 Somnolence and dizziness, common AEs associated with the use of oral pain medications, can be associated with falls, and have been shown to be more common in older (≥60 years) than in younger adults receiving pregabalin.⁴⁴ Reduction or withdrawal of psychotropic medications is recommended by the World Health Organization as a preventive measure for falls, the second leading global cause of accidental injury-related death.⁴⁵ In our analysis, somnolence and dizziness were reported for 0.6% and 3.0%, respectively, of older adults who received the capsaicin patch, and for 1.0% and 4.4%, respectively, of patients who received control/SoC.

Most of the trials included in our analyses were pivotal Phase 3 trials evaluating a single treatment of the capsaicin patch, in which the use of concomitant medications was kept stable over the trial duration. However, for one trial comparing multiple treatments with the capsaicin patch with SoC in a pDPN population, the use of concomitant neuropathic pain medication has been evaluated over 52 weeks. Whilst the percentage of patients using antidepressants, antiepileptics, and opioids remained fairly stable in the capsaicin patch 30-minute treatment group (10.9%, 28.2%, and 10.9% of patients at baseline, vs 11.0%, 29.5%, and 11.0% at end of trial, respectively), in the group treated with SoC the use of these medications increased considerably (from 7.7%, 32.3%, and 8.4% at baseline to 15.1%, 43.2%, and 11.6% at end of trial, respectively).^24,37 Thus, it thus appears that patients treated with the capsaicin patch do not require additional concomitant oral neuropathic pain medication over time. This could be of particular benefit in older patients as polypharmacy and a high medication burden can become overwhelming, especially for those who cannot rely on help to take their medications, sometimes resulting in medication nonadherence and suboptimal management of chronic conditions.⁴⁶

Clear instructions are available for healthcare professionals on how to administer the capsaicin patch. The treatment ensures local delivery of capsaicin to hyperactive nociceptor nerves and does not result in clinically relevant systemic exposure. Consequently, no dose adjustment is required for patients with hepatic or renal impairment.^47,48

Of note, in our safety analysis, ≤1% of patients in each age group experienced AEs that led to discontinuation of study treatment. This may reflect findings from a recent discrete choice experiment conducted in German patients with PNP (almost half of them aged ≥60 years), showing that local skin-related side effects were more acceptable to patients than systemic side effects such as dizziness, fatigue, and nausea.⁴⁹ Overall, the published literature in the wider adult population confirms the acceptable tolerability of the capsaicin patch, with transient application-site discomfort and pain as the main adverse effects.^50–52 These are generally tolerable, usually resolve without sequelae within a short period after treatment, and in almost all cases can be well managed with local cooling and/or oral analgesics.^52,53 Adherence to the full intended treatment duration of capsaicin indicated that patch application-related pain was not a barrier to use.

In conclusion, the data from these pooled analyses indicate that in older patients with PNP, the capsaicin patch is efficacious and has a tolerability profile similar to that observed in adults. The safety profile is characterized mainly by local application-site reactions, with low rates of AE-related treatment discontinuation across age populations. Therefore, this topical treatment provides a valuable alternative to systemic oral therapies in older patients, limiting the risk of systemic AEs and the risk of drug–drug interactions with concomitant medications.