Translational pain biomarkers in the early development of new neurotherapeutics for pain management

Abstract

Translation of the analgesic efficacy of investigational neurotherapeutics from pre-clinical pain models into clinical trial phases is associated with a high risk of failure. Application of human pain biomarkers in early stages of clinical trials can potentially enhance the rate of successful translation, which would eventually reduce both length and costs of drug development after the pre-clinical stage. Human pain biomarkers are based on the standardized activation of pain pathways followed by the assessment of ongoing and paroxysmal pain, plus evoked responses which can be applied to healthy individuals and patients prior to and after pharmacological interventions. This review discusses the rationality and feasibility of advanced human pain biomarkers in early phases of drug development for pain management which is still an unmet medical need.

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

“…The latter suggests that a repeated laser application to normal skin – interstimulus sites are changed after each laser shot – does not induce any sensitization per se . Such a phenomenon, known as cutaneous hyperalgesia, has been shown to develop following acute thermal injuries, UV irradiation and local administration of chemicals such as menthol, camphor, mustard oil or capsaicin .…”

“…In order to assess the analgesic potential of a new drug candidate in early clinical development (ECD), to inform subsequent clinical study designs and to support decision making before entering into large and costly phase II and III studies, several translational experimental human pain models have been proposed. In general, these models build on the standardized activation of nociceptive pathways in healthy volunteers or patients, combined with quantitative and objective recordings of the evoked pain responses . For example, it has been shown that specific CO 2 laser stimulations can be repeatedly applied to normal and hyperalgesic (ultraviolet (UV)‐irradiated/inflamed‐ and capsaicin‐irritated skin) skin types in healthy volunteers to generate laser‐evoked potentials (LEPs), recorded from the vertex electroencephalogram (EEG) by filtering and averaging triggered responses.…”

Cold and L-menthol-induced sensitization in healthy volunteers—a cold hypersensitivity analogue to the heat/capsaicin model

“…37 These models have also proven useful in early phases of drug development of new analgesic compounds. 4 One of the surrogate pain models that mimic aspects of cold allodynia in patients with neuropathic pain 6 is the topical high-concentration L-menthol model. 3 It is well known that low concentrations of topical L-menthol create an innocuous cooling sensation 19 ; however, when high concentrations are used, 11,47 cold hypersensitivity develops.…”

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations

“…QST has been used for decades in a variety of settings, often for the purpose of diagnosing and monitoring sensory neuropathies and pain disorders, elucidating pain mechanisms, and characterizing individual differences in pain sensitivity and pain modulation [10, 50, 147]. It has been most widely utilized for testing of cutaneous sensations, in order to quantify positive sensory symptoms (e.g., allodynia and hyperalgesia) or negative sensory deficits (e.g., hypoesthesia and hypoalgesia), but it has also been adapted to test sensations from deep tissue and viscera, allowing broad application to an array of pain conditions (e.g., [5, 56, 194]).…”