A data science approach to the selection of most informative readouts of the human intradermal capsaicin pain model to assess pregabalin effects

Abstract

Persistent and, in particular, neuropathic pain is a major healthcare problem with still insufficient pharmacological treatment options. This triggered research activities aimed at finding analgesics with a novel mechanism of action. Results of these efforts will need to pass through the phases of drug development, in which experimental human pain models are established components e.g. implemented as chemical hyperalgesia induced by capsaicin. We aimed at ranking the various readouts of a human capsaicin–based pain model with respect to the most relevant information about the effects of a potential reference analgesic. In a placebo‐controlled, randomized cross‐over study, seven different pain‐related readouts were acquired in 16 healthy individuals before and after oral administration of 300 mg pregabalin. The sizes of the effect on pain induced by intradermal injection of capsaicin were quantified by calculating Cohen's d. While in four of the seven pain‐related parameters, pregabalin provided a small effect judged by values of Cohen's d exceeding 0.2, an item categorization technique implemented as computed ABC analysis identified the pain intensities in the area of secondary hyperalgesia and of allodynia as the most suitable parameters to quantify the analgesic effects of pregabalin. Results of this study provide further support for the ability of the intradermal capsaicin pain model to show analgesic effects of pregabalin. Results can serve as a basis for the designs of studies where the inclusion of this particular pain model and pregabalin is planned.

Human surrogate models of central sensitization: A critical review and practical guide

“…Areas of hyperalgesia/allodynia have been the most frequently used readouts, and are often correlated with the evoked pain within the hyperalgesic region. However, these two variables can also be dissociated (Ando et al., 2000 ; Schifftner et al., 2017 ; Zheng et al., 2009 ), and pain within the hyperalgesic region has been reported as more reliable than area size to tag clinically useful analgesia (Ando et al., 2000 ; Lötsch et al., 2020 ). Quantifying pain intensity is more subjective and prone to bias than measuring the area of hyperalgesia, which is performed without visual control from subjects (Jensen & Petersen, 2006 ).…”

Machine-Learning Analysis of Serum Proteomics in Neuropathic Pain after Nerve Injury in Breast Cancer Surgery Points at Chemokine Signaling via SIRT2 Regulation

“…On the other hand, potential drugs resulting from the present findings may also need to be tested in patients, giving preference to experimental pain models in healthy subjects. That is, although systematic analyses have shown that experimental human pain models predict the clinical analgesic effects of drug candidates quite well when the right model for the clinical target is selected from a wide range of human experimental pain models [ 84 , 85 , 86 ], including models that appear to be predictive even for neuropathic pain drugs such as pregabalin [ 87 ], the complexity of the current clinical setting, including nerve injury and cancer treatment, may limit the utility of studies in healthy volunteers. However, depending on the particular characteristics and effects of a future new drug, it is difficult to predict the exact steps of drug development.…”

The Effect of Low-Level Light Therapy on Capsaicin-Induced Peripheral and Central Sensitization in Healthy Volunteers: A Double-Blinded, Randomized, Sham-Controlled Trial

“…We used a human pain model capable of inducing the central and peripheral mechanisms. Capsaicin application rapidly produces local neurogenic inflammation (characterized by edema and erythema) when locally administered to human skin by stimulating the TRPV1 receptors on dermal sensory nerve endings [5,[16][17][18][19][20]. In this pain model, heat hyperalgesia (i.e., the increased sensitivity to heat stimulation at the site of application of capsaicin) has been found to be due to peripheral sensitization, whereas mechanical hyperalgesia (i.e., increased sensitivity to mechanical stimulation beyond the area of capsaicin) is due to central sensitization [21].…”