Investigation of the predictive validity of laser‐EPs in normal, UVB‐inflamed and capsaicin‐irritated skin with four analgesic compounds in healthy volunteers

Schaffler, K.; Nicolas, Laurent B.; Borta, Andreas; Brand, Tobias; Reitmeir, Peter; Roebling, Robert; Scholpp, Joachim

doi:10.1111/bcp.13247

Cited by 17 publications

(22 citation statements)

References 46 publications

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“…The significant difference from placebo was also observed in the VAS postlaser pain results, and both LEP and VAS pain results were sustained up to the end of the daily experimental observation period. The LEP N2-P2 PtP profile of pregabalin in this study was similar to previous data in healthy subjects that showed reductions in PtP amplitudes of LEPs starting one to two hours postadministration and maintained for more than six hours postdose [ 13 ].…”

Section: Discussionsupporting

confidence: 89%

“…Treatment with ASP9226 (30 mg or 50 mg), compared with placebo, did not produce a difference greater than the 2.5 µV criteria that was predefined as the minimal clinically meaningful reduction in LEP N2-P2 PtP. However, treatment with pregabalin 150 mg showed differences vs placebo in LEP N2-P2 PtP amplitudes well above 2.5 µV, consistent with previous findings in healthy subjects [ 13 ], and confirmed the validity of the study design and method. In keeping with LEP results, subjects treated with pregabalin reported significantly lower postlaser VAS pain ratings compared with either dose of ASP9226 or placebo.…”

Section: Discussionsupporting

confidence: 88%

“…Several LEP and VAS pain testing sessions were performed on capsaicin-treated skin during the main assessment days to assess the analgesic/antihyperalgesic effects of ASP9226 and the positive control (pregabalin). Single-dose (150 mg) pregabalin administration orally has demonstrated pharmacologic activity in the LEP model (in capsaicin, UV, and normal skin conditions) vs placebo [ 13 ]. Upon the completion of the four study periods, or after early withdrawal, subjects had their end-of-study visit (ESV).…”

Section: Methodsmentioning

confidence: 99%

“…The application of laser technology, as a relatively novel, alternative, or complimentary technique in human pain research, has resulted in a major advance in our ability to generate and interpret well-defined thermonociceptive sensations (also dependent and interacting in their mechanisms with applied skin types). The LEP model has demonstrated construct and predictive validity for neuropathic pain across numerous compounds with various mechanisms of action [ 13 , 19 ]. Therefore, the healthy volunteer LEP model of hyperalgesia and pain is a valuable tool as it can be used to make predictions to inform investigators about dose/regimen and efficacy for the purpose of de-risking a proof of concept (PoC) clinical trial in patients.…”

Section: Introductionmentioning

confidence: 99%

“…ASP9226 is a novel and state-dependent N-VDCC inhibitor. Here, the results from a phase I study, conducted in healthy male subjects, to evaluate the analgesic/antihyperalgesic effects of two different single-dose administrations (30 mg and 50 mg) of ASP9226 vs an active control (pregabalin 150 mg, which has shown single-dose efficacy in the LEP model in healthy subjects [ 13 ]), are reported.…”

Section: Introductionmentioning

confidence: 99%

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A Phase I, Randomized, Double-Blind, Laser-Evoked Potential Study to Evaluate the Analgesic/Antihyperalgesic Effect of ASP9226, a State-Dependent N-Type Voltage-Gated Calcium Channel Inhibitor, in Healthy Male Subjects

Schaffler¹,

Passier

et al. 2018

Pain Medicine

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ObjectiveEvaluate the analgesic/antihyperalgesic effects of ASP9226, a state-dependent N-type voltage-gated calcium channel inhibitor, in healthy male subjects.DesignRandomized, double-blind, double-dummy, placebo- and active comparator–controlled crossover study.SettingHPR Dr. Schaffler GmbH, Munich, Germany.SubjectHealthy male subjects aged 18–55 years.MethodsTwenty-four eligible subjects were randomly assigned to one of four treatment sequences and received single doses of ASP9226 (30 mg or 50 mg), pregabalin (150 mg), or placebo during four treatment periods. Laser-evoked potentials (LEP) and postlaser pain visual analog scales (VAS) on capsaicin-treated skin were assessed during main assessment days (the first day of each study period). Primary and secondary end points were the differences in LEP N2-P2 peak-to-peak (PtP) amplitudes and VAS score, respectively, in all subjects.ResultsOverall, treatment with pregabalin resulted in a significantly lower LEP N2-P2 PtP amplitude vs placebo (–3.30 μV, P < 0.0001). There were no clinically relevant differences in N2-P2 PtP amplitudes between placebo and either ASP9226 dose (–0.31 μV and –0.27 μV). Furthermore, subjects reported significantly lower VAS pain scores with pregabalin vs placebo (–9.90%, P < 0.0001) in contrast to ASP9226 30 mg (–2.1%) and ASP9226 50 mg (1.2%) vs placebo. Subgroup analysis of LEP and VAS pain in participants with positive prestudy capsaicin response (n = 13) were in keeping with results in all subjects.ConclusionsASP9226 was well tolerated; however, there was no improvement in LEP and VAS pain scores with ASP9226 at either dose vs placebo.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Phase I, Randomized, Double-Blind, Laser-Evoked Potential Study to Evaluate the Analgesic/Antihyperalgesic Effect of ASP9226, a State-Dependent N-Type Voltage-Gated Calcium Channel Inhibitor, in Healthy Male Subjects

Schaffler¹,

Passier

et al. 2018

Pain Medicine

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Revealing the time course of laser‐evoked potential habituation by high temporal resolution analysis

Kersebaum

Fabig

Sendel

et al. 2021

European Journal of Pain

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Background and Objectives Reduced laser‐evoked potential (LEP) habituation indicates abnormal central pain processing. But the paradigm (four stimulation blocks a 25 stimuli) is time consuming and potentially omits important information on the exact habituation time course. This study examined whether a high temporal resolution (HTR) analysis (dividing the four stimulation blocks into 12 analysis blocks) can answer the following questions: (a) After how many stimuli does LEP habituation occur? (b) Is there a difference in LEP habituation in younger versus older subjects? (c) Is HTR applicable on radiculopathy patients? Methods EEG data of 129 subjects were included. Thirty‐four young healthy and 28 advanced‐aged healthy subjects were tested with LEPs on the hand dorsum. Thirty‐seven radiculopathy patients and 30 controls were tested with LEPs on the L3 dermatome. The EEG data of the hand dorsa have been analysed conventionally and with HTR analysis. The applicability of HTR has been tested on radiculopathy patients and respective controls. Results HTR was well feasible in young healthy subjects and revealed a strong habituation effect during the first 25 stimuli (i.e. within the first 5 min). After approximately 48 stimuli, no further significant habituation was detectable. LEP amplitudes were higher in young subjects. HTR was unsuitable for elderly subjects and middle‐aged radiculopathy patients. Conclusions In young healthy subjects, HTR allows a shortening of the test protocol while providing a detailed information on the time course of LEP habituation. A shorter protocol might be useful for the applicability of the LEP paradigm for clinical and experimental settings as well as pharmacological studies. Significance The usage of high temporal resolution (HTR) analysis in young healthy subjects enables a short test protocol and provides the exact time course of laser‐evoked potential habituation. This can be useful for the examination of neurological conditions affecting younger patients and for pharmacological studies. HTR was inapplicable in advanced‐aged subjects and patients with radiculopathy.

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Topically applied novel TRPV1 receptor antagonist, ACD440 Gel, reduces evoked pain in healthy volunteers, a randomized, double‐blind, placebo‐controlled, crossover study

Segerdahl,

Rother,

Halldin

et al. 2024

European Journal of Pain

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BackgroundThe TRPV1 receptor is a key molecule in pain generation. Previous development of oral TRPV1‐antagonists was halted due to systemic heat insensitivity and body temperature alterations. The present Phase 1b study investigated the efficacy, safety and plasma exposure of a topically administered TRPV1‐antagonist (ACD440 Gel) in healthy subjects.MethodsThe study comprised two parts.In part 1, 24 healthy subjects were included in this randomized double‐blind, placebo‐controlled, crossover trial. ACD440 Gel or Placebo was applied once daily and wiped off after 1 h, for 5 consecutive days. Assessments were done in normal skin, skin optimized for penetration (by stripping and occlusive gel application) and UVB‐irradiated skin. Pain induced by thermo‐nociceptive CO2 laser impulses generated laser‐evoked potentials (LEPs), with readouts of peak‐to‐peak (PtP) amplitude in vertex‐EEG and pain assessments by VAS (0–100). Endpoints include effects at 1 hour post‐dose, AUC(Days 1–5) and AUC(0–24, Day 4). In UVB‐irradiated skin, also pain on pinprick and skin redness were assessed.Part 2 explored the plasma pharmacokinetics of ACD440.ResultsACD440 Gel reduced LEP PtP amplitude and VAS pain, p < 0.001, in all skin conditions, versus placebo. In UVB‐irradiated skin, pinprick pain was also reduced, p = 0.047. Effects were significant after 1 h, maintaining for at least 9 h. There were no adverse events or drug‐induced erythema. Plasma exposures of ACD440 were too low to establish an elimination half‐life of ACD400.ConclusionsTopical ACD440 Gel demonstrated a significant analgesic effect on LEP, VAS score and pinprick pain, with low systemic exposures, supporting further clinical development.SignificanceThis study demonstrates that the topical administration of a TRPV1‐antagonist, ACD440 Gel, has potential as a new treatment for painful conditions affecting the skin, such as chronic peripheral neuropathic pain, without any local or systemic side effects.

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Investigation of the predictive validity of laser‐EPs in normal, UVB‐inflamed and capsaicin‐irritated skin with four analgesic compounds in healthy volunteers

Abstract: LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical development.

Cited by 17 publications

References 46 publications

A Phase I, Randomized, Double-Blind, Laser-Evoked Potential Study to Evaluate the Analgesic/Antihyperalgesic Effect of ASP9226, a State-Dependent N-Type Voltage-Gated Calcium Channel Inhibitor, in Healthy Male Subjects

A Phase I, Randomized, Double-Blind, Laser-Evoked Potential Study to Evaluate the Analgesic/Antihyperalgesic Effect of ASP9226, a State-Dependent N-Type Voltage-Gated Calcium Channel Inhibitor, in Healthy Male Subjects

Revealing the time course of laser‐evoked potential habituation by high temporal resolution analysis

Topically applied novel TRPV1 receptor antagonist, ACD440 Gel, reduces evoked pain in healthy volunteers, a randomized, double‐blind, placebo‐controlled, crossover study

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