A literature review on the pharmacological sensitivity of human evoked hyperalgesia pain models

Abstract

AIMSHuman evoked pain models can be used to determine the efficacy of new and existing analgesics and to aid in the identification of new targets. Aspects of neuropathic pain can be simulated by inducing hyperalgesia resulting from provoked sensitization. The present literature review aimed to provide insight into the sensitivity of different hyperalgesia and allodynia models of pharmacological treatment. METHODSA literature search was performed to identify randomized, double-blind, placebo-controlled studies that included human hyperalgesia pain models and investigated the pharmacodynamic effects of different classes of drugs. RESULTSThree hyperalgesia models [ultraviolet B (UVB) irradiation, capsaicin and thermode burn] have been used extensively. Assessment of hyperalgesia/allodynia and pharmacological effect are measured using challenge tests, which generally comprise thermal (heat/cold) or mechanical stimulation (pin-prick, stroking or impact). The UVB model was sensitive to the antihyperalgesic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. The capsaicin model was partially sensitive to opioids. The burn model did not detect any antihyperalgesic effects when NSAIDs or local anaesthetics were administered but responded to the effects of N-methyl D-aspartate (NMDA) receptor antagonists by moderately reducing mechanical hyperalgesia. CONCLUSIONSBased on pharmacological sensitivity, the UVB model adequately reflects inflammatory pain and was sensitive to NSAIDs and opioids. Findings from the capsaicin and burn models raised questions about the translatability of these models to the treatment of neuropathic pain. There is a need for a reproducible and predictive model of neuropathic pain, either in healthy subjects or in patients.British Journal of Clinical Pharmacology Br J Clin Pharmacol (2016) 82 903-922 903

Reproducibility of a battery of human evoked pain models to detect pharmacological effects of analgesic drugs

“…Importantly, ibuprofen had a significant analgesic effect in all three studies that used this drug, suggesting that the UVB‐induced heat pain model is highly sensitive to this class of compounds. This finding is consistent with expected pharmacodynamic outcomes using this pain model, as the UVB model is considered a suitable model for inflammatory pain and is therefore highly sensitive to nonsteroidal anti‐inflammatory drugs (NSAIDs; van Amerongen et al, ; Bishop et al, ). The lack of an effect of ibuprofen in the other pain models was also highly consistent, supporting the high reproducibility of these models.…”

“…Over the years, a variety of pain models has been developed for measuring pain thresholds (Andersen et al, ; Bishop, Ballard, Holmes, Young, & McMahon, ; Brennum, Kjeldsen, Jensen, & Jensen, ; Dahan et al, ; Drewes, Petersen, Qvist, Nielsen, & Arendt‐Nielsen, ; Eckhardt et al, ; Hay, Okkerse, Amerongen, & Groeneveld, ; Jones, McQuay, Moore, & Hand, ; Olesen, Andresen, Staahl, & Drewes, ; Olofsen et al, ; Petersen‐Felix et al, ; Polianskis, Graven‐Nielsen, & Arendt‐Nielsen, ; Schilder, Magerl, Hoheisel, Klein, & Treede, ; Siebenga et al, ). Historically, these models have been used as a single test; however, based on studies measuring the effect of analgesic compounds on evoked pain it has become clear that some drugs can yield significant results in one pain model but can fail to have an analgesic effect when using a different pain model (van Amerongen, Boer, Groeneveld, & Hay, ; Arendt‐Nielsen, Curatolo, & Drewes, ; Brennum et al, ). This inconsistency is due—at least in part—to the wide variety of pain signalling mechanisms and pathways at the peripheral and spinal levels, which are sensitive to different analgesics.…”

Lack of Detection of the Analgesic Properties of PF‐05089771, a Selective Nav1.7 Inhibitor, Using a Battery of Pain Models in Healthy Subjects

“…Advances in the field of pain biomarkers could lead to more predictable outcomes and to a more accurate conclusion when it comes to go/no‐go decision when a compound fails to show analgesic effects in healthy subjects. From the body of literature on effects of analgesic compounds on evoked pain tests, it is clear that certain drugs may show significant results in one pain model, but not show any analgesic efficacy in another pain model . For this reason, our study utilized a battery of multimodal pain tests.…”

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

“…ultraviolet B irradiation, thermode burn) or afferent stimulation (capsaicin) are increasingly used to determine efficacy of both new and existing analgesics. Their apparent ability to demonstrate efficacy with known analgesics provides some validation of their sensitivity, 20 and to define a drug effect and corresponding side effects at the effective dose.The following commentary considers a variety of targets and comments on systemic and neuraxial routes of delivery, reflecting the fact that drug effects upon pain processing frequently reflect an action at the first order synapse. It must be stressed that these discussions do not raise issues of safety.…”

“…ultraviolet B irradiation, thermode burn) or afferent stimulation (capsaicin) are increasingly used to determine efficacy of both new and existing analgesics. Their apparent ability to demonstrate efficacy with known analgesics provides some validation of their sensitivity, 20 and to define a drug effect and corresponding side effects at the effective dose.…”