Diabetes is one of the fastest growing global health emergencies of the 21st century; ~537 million adults worldwide had diabetes in 2021, which is projected to increase by 13% in Europe and 24% in North America and the Caribbean by 2045.1 The prevalence of diabetic peripheral neuropathy (DPN) is up to 50% in patients with diabetes.2 3 Symptomatic or painful DPN (pDPN) is a complex pain pathology that develops in approximately 30–50% of patients with DPN.4

Key symptoms of pDPN include burning, electric, and stabbing sensations that may be accompanied by paresthesia (unpleasant sensations like prickling/tingling), allodynia (painful sensations to innocuous stimuli), hyperalgesia (increased sensitivity to painful stimuli), sensory loss, and/or numbness.5 6 The pain associated with pDPN is chronic and can cause interference with daily activities, disability, and psychosocial activities.7 The condition is typically more severe at night and may interfere with normal sleep patterns, affecting ability to work, mood, and quality of life (QoL).8 9 Furthermore, people with diabetes, particularly those with complications associated with pain such as diabetic neuropathy, have a higher risk of suicidal behavior compared with the general population (as reviewed in Sher).10

pDPN of the feet is particularly debilitating due to the foot’s essential role in mobility and daily function, and pDPN significantly affects balance and increases the risk of falls.11 If left untreated, pDPN can lead to serious complications, including sensory loss, ulceration, infections, gangrene, and even amputation of the foot in severe cases.12 Consequently, pDPN can be one of the most distressing complications of diabetes,13 with patients commonly reporting feelings of frustration, worry, anxiety, and uncertainty.3

With no established disease-modifying therapies currently available, symptomatic treatments for pDPN can include both non-pharmacological and pharmacological (oral and/or topical) options.14–16 Oral treatments, such as antidepressants or antiepileptics, require daily administration to maintain efficacy.16 These treatments rely on systemic absorption, which can lead to drug–drug interactions and systemic side effects, often necessitating dosage adjustments, particularly in vulnerable populations like the elderly.15 17 Additionally, oral treatments often require lengthy titration to find the effective maximally tolerated dose; however, in practice, titration is often not done or is only partially completed.18 As a result, patients often receive suboptimal doses and stop taking the therapy; in a US study, up to 50% of patients discontinued their initial oral treatment within 3 months.18 Patients who do not find sufficient pain relief with one oral treatment frequently receive a combination of these medications; however, it can still be difficult for patients to achieve pain relief,6 and the most common concern among patients seeking treatment for pDPN is increasing their pill burden.3 Although not recommended due to well-documented risks of addiction and misuse, these patients may end up receiving opioids.19–21 Topical treatments are therefore often preferred and beneficial to patients due to their quick onset and minimal systemic side effects, and should be considered as a first-line treatment option.22–24

The capsaicin 179 mg (8% weight per weight) cutaneous topical system (high-concentration capsaicin topical system [HCCTS]) is an approved topical treatment for pain associated with DPN in Europe and the USA.25 26 HCCTS must be applied to intact, non-irritated, dry skin and remain in place for 30 min for the feet (EU and US label) and up to 60 min for other locations (EU label only).25 26 Treatments may be repeated every 3 months, as warranted by the persistence or return of pain.25 26

HCCTS incorporates a matrix technology that allows high concentrations of capsaicin to enter the epidermis.27 28 Capsaicin acts as a selective and potent agonist for transient receptor potential vanilloid 1 (TRPV1) receptors, which are upregulated and hyperactive in various neuropathic pain conditions.29–31 Capsaicin binds directly to TRPV1 receptors, triggering intracellular signaling pathways that lead to neurolysis of TRPV1-expressing nociceptors.29 32 One to 3 months after HCCTS treatment, TRPV1-expressing nerve fibers begin to regenerate; however, due to the chronic nature of the underlying condition, HCCTS-lysed nerve fibers may not all function normally as they regrow.33 34 Therefore, repeated HCCTS treatments may be required to achieve a response, as shown in a post hoc analysis of two clinical trials, PACE (NCT01478607; pDPN of the feet)35 36 and STRIDE (NCT01252160; peripheral neuropathic pain [PNP]) of various locations).37 These studies demonstrated that repeated HCCTS treatments can lead to improved outcomes, and some patients who did not achieve sufficient pain relief from the first treatment responded to ongoing treatments.38

The current study is part of a larger investigation evaluating the effectiveness and tolerability of one to four treatments with HCCTS over 12 months in patients with PNP, using real-world data from the German Pain e-Registry (GPeR). This manuscript focuses on the impact of HCCTS on pain, sleep, QoL, mood, and concomitant pain medication use in patients with pDPN of the feet. A visual summary for this manuscript is provided as online supplemental figure 1.