PainCart®

PainCart is a comprehensive battery of tests used for the evaluation of analgesic properties of pharmaceutical compounds developed for the treatment of pain. The battery can test the efficacy of analgesic compounds against several types of pain (thermal, electrical, mechanical) at various sites of the pain pathway (peripheral and central).

Human pain models are an important tool for assessing the analgesic effect of drugs and providing information about a drug's pharmacology. However, no single experimental model can replicate the complex nature of clinical pain. CHDR's PainCart® provides the solution: a multi-modal, standardised, comprehensive battery of tests for studying the efficacy of analgesic compounds for several types of pain. PainCart can be implemented in both single and multiple ascending dose studies, offers high inter-subject and intra-subject consistency and repeatability and the tests can be repeated many times after drug delivery. Furthermore, PainCart has been extensively used in proof-of-concept studies in healthy volunteers and chronic pain patients.

Using PainCart, CHDR has created an extensive database of profiles describing the analgesic properties of different analgesic drugs, including acetaminophen, ibuprofen, opioids (fentanyl, morphine, buprenorphine), ketamine and various experimental compounds. The database allows for the comparison of analgesic profiles between established analgesics used in clinical practice with analgesic drugs in development. Studies performed at CHDR have demonstrated the success of this approach. In one such study, the PainCart was used to show that a compound targeting the nerve growth factor (NGF) pathway – a new class of potential analgesics – had a clear therapeutic effect and a profile similar to ibuprofen, revealing anti-inflammatory properties. Such information may be critical in defining next steps in drug development and patient selection for follow-up studies.

An overview of the PainCart tests

A thermode attached to the subject’s skin is used to induce heat pain at various temperature intensities to activate cutaneous nociceptors. The test can evaluate sensory and pain threshold levels and induce tonic heat pain.
An electrical stimulus is applied to the skin of the lower leg to activate cutaneous nociceptors. The current is increased incrementally with 0.5-mA per second. During pain stimulation the subject rates the pain using an electronic visual analogue scale (VAS) to determine the pain threshold and tolerance level.
Pressure pain induction is a model for ‘deep’ muscle pain. This test primarily assesses nociception generated within the muscles with minimal contribution from cutaneous nociceptors. An inflatable tourniquet cuff is placed over the calf, and the pneumatic pressure is increased steadily while the subject rates the pain intensity using an electronic VAS. The test is used to detect the pain threshold level.
The cold pressor test can be used to investigate both cardiovascular and analgesic responses. In this test, the subject first places an extremity (usually a hand) into a warm water bath for 2 minutes with a slightly inflated blood pressure cuff on the upper arm. After 2 minutes, the subject transfers the extremity to an ice-cold water bath. The test ends when the subject’s pain tolerance threshold is reached. The duration of hand immersion is measured to quantify the pain experience.
Pain is modulated at a central level by pain facilitatory and inhibitory pathways. Conditioned pain modulation evaluates the function of this inhibitory pain pathway and is known to be impaired in many patients with chronic pain. The pathway is evaluated using two pain stimuli applied at different parts of the body. To evaluate conditioned pain modulation the electrical pain threshold and tolerance level are determined before and after the cold pressor test (the conditioning stimulus).
UVB irradiation is used to induce localised ‘sunburn’, which is a model for inflammatory pain. Mild erythema is induced on a small part of the skin using UVB irradiation. As a result, thermal pain perception is intensified in the affected area (primary hyperalgesia) and in the surrounding (unaffected) area (secondary hyperalgesia) which is detected by the evaluation of thermal detection thresholds.
The capsaicin test is a model used to mimic central alterations observed in patients with chronic pain. Capsaicin induces chemical activation of TRPV1 receptors in the skin, which leads to activation of sensory neurons in the dorsal horn. Application of capsaicin will lead to changes of the skin such as erythema, spontaneous pain, allodynia, and hyperalgesia. Allodynia is observed in the direct treated area (primary allodynia) and in the surrounding (unaffected) area (secondary allodynia). The area of capsaicin-induced allodynia is measured and quantified using von Frey filaments, which are small filaments used to quantify mechanical detection thresholds.
Sensitivity of ascending pathways in the nociceptive system are reflected by nociceptive thresholds in human subjects. These nociceptive thresholds can be estimated using electrical stimulation of nociception specific nerve fibers. Using intra-epidermal electrical stimulation, nociceptive Aδ-fibers are stimulated using low current amplitudes to detect sensory thresholds. The effect of analgesic drugs on sensory threshold can be evaluated with this method.
Quantitative Sensory Testing (QST) is a separate test battery to detect sensory thresholds and is usually used as a diagnostic test in pain medicine to assess sensory function of different nerve fibers. It can be used to profile chronic pain patients and evaluate the functionality of sensory pathways. In research it is also used as a predictive model for treatment effect.
With the use of Virtual Reality (VR) it is possible to artificially induce pain experiences that are not possible to induce in real life. For example, VR allows for the evaluation of pain experiences upon burning. For this, participants wear a VR headset which displays images of the subject’s hands, lower leg and feet. Pain is induced by electrical stimulation applied to electrodes placed on the lower leg, which are also visualised in the VR environment. To mimic an actual burning experience, the VR environment simulates the visualisation of skin burning around the electrodes accompanied by a sizzling sound. The method allows for evaluation of pain intensity, which is rated using a visual analogue scale (VAS) and psychological factors involved in pain.
Centrally acting drugs may influence respiratory physiology by either enhancing or decreasing ventilation. For example, opioids are well-known for their respiratory depressant effects, which have the potential of being life threatening. Our state-of-the-art respiratory physiology facility allows for the evaluation of respiratory effects (both depressant or stimulatory) of analgesics or other centrally acting compounds. For this, breath-to-breath minute ventilation is measured while subjects breath into a face mask fitted over nose and mouth which is connected to a pneumothachograph and pressure transducer system. The facility is equipped to administer different compositions of inhaled gas mixtures to mimic hypoxia and hypercapnia conditions and allow for well controlled circumstances (for example dynamic end-tidal forcing) to accurately measure respiratory effects.