Purpose High concentration capsaicin patch (179 mg or 8% w/w) (HCCP) is indicated for the treatment of peripheral neuropathic pain (PNP) in the EU and for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN) and for neuropathic pain associated with diabetic peripheral neuropathy (DPN) of the feet in the US. HCCP can be administered in adults as a monotherapy or in combination with other medicinal products for the treatment of chronic neuropathic pain. The rapid and sustained pain relief from a single application of HCCP has been shown to be maintained for up to 12 weeks in multiple randomized controlled clinical trials. HCCP treatment can be repeated approximately every 3 months. Repeated treatments with HCCP have been investigated in open label extension trials following randomized controlled clinical trials and in two larger stand-alone clinical trials. A previous investigation of repeated applications of HCCP in a randomized controlled clinical trial with a duration of 52 weeks in patients with painful diabetic peripheral neuropathy (PDPN) has shown that HCCP demonstrated greater efficacy than standard of care, and the magnitude of the differential treatment effect increased over time from the first to the last patch application (PACE published by Vinik A. et al., 2019). Likewise, in a 52-week trial in non-diabetic PNP, the subset of patients who received 4 consecutive HCCP treatments (n=100), displayed a reduction in average daily pain scores. This observation was recorded after each successive HCCP treatment, and in addition, pain relief was sustained between treatments (STRIDE published by Gálvez R. et al., 2017). Available data and literature do not provide detailed insights regarding responder rates beyond the first application of HCCP. In particular, the question whether patients deemed as non-responders following the first application could become responders after a second or third application remains unknown. To investigate this question, we conducted a post hoc analysis of the two 52-week trials mentioned previously, considering a subset of subjects defined as initial non-responders. Safety/tolerability data of the two trials included in this analysis have been previously published (Vinik A. et al., 2016 and Gálvez R. et al., 2017). Methods In the two selected trials of 52-week duration, HCCP was applied 30 min to the feet or 60 mins to other body areas. All patients were diagnosed with PNP (i.e. PDNP in PACE and non-diabetic PNP in STRIDE) and had an average daily pain score ≥4 on the question 5 of the Brief Pain Inventory or the Brief Pain Inventory-Diabetic Neuropathy scale. In the STRIDE study repeat treatment was allowed every 9-12 weeks, whereas in PACE, repeat treatment was allowed after an interval of at least 8 weeks. Initial non-responders were defined as patients having a <30% decrease on the Numeric Pain Rating Scale (NPRS) from baseline to 3 months post-baseline. Responders were defined as patients who achieved a ≥30% decrease on the NPRS at predefined timepoints (month 6, 9 and 12). Results In the STRIDE study at month 3, 76.6% of patients having received an initial treatment with HCCP (n=306) did not meet the responder criteria. A total of 168non-responders had a repeat treatment and 115 patients (68%) were still enrolled in the trial at 12 months. In comparison, from the total trial population (responders and non-responders), 174 patients (56.9%) were still enrolled in the trial at month 12. Of the initial non-responders who were still in the trial at 12 months (n=115), 57.4% received at least 4 applications of HCCP and, 33.9% had become responders to HCCP treatment whereas of the total population 43.7% could be classified as responders. In the PACE study at month 3, 54% of patients who received an initial treatment with HCCP (n=313) did not meet the responder criteria (n= 152). Of the 152 patients, 127 (i.e. 83.5%) were still enrolled in the trial at 12 months whereas from the total population (responders and non-responders), 250 patients (78.9%) were still enrolled in the trial. Of the initial non-responders receiving repeat applications, 80.2% had received at least 4 applications at month 12. In addition, of the initial non-responders who were still in the trial at 12 months (n=127), 45.7% had become responders to HCCP treatment whereas of the total population 58% could be classified as responders. Conclusions Repeat treatment with HCCP over 52 weeks in patients with various types of peripheral neuropathic pain etiologies was well tolerated. Importantly, repeated application in initial non-responders provides additional benefit to patients. As observed across trials, more than one third of initial non-responders converted into responders with continued repeated treatment with HCCP. Although at month 12, the responder rates in patients who did not initially respond to HCCP were approximately 10% lower than in the overall population, the substantial increase in responder rates (≥30% decrease on NPRS) justifies a repeat treatment with the HCCP.