Core Outcome Measures in Preclinical Assessment of Candidate Analgesics

Abstract

All preclinical procedures for analgesic drug discovery involve two components: 1) a “pain stimulus” (the principal independent variable), which is delivered to an experimental subject with the intention of producing a pain state; and 2) a “pain behavior” (the principal dependent variable), which is measured as evidence of that pain state. Candidate analgesics are then evaluated for their effectiveness to reduce the pain behavior, and results are used to prioritize drugs for advancement to clinical testing. This review describes a taxonomy of preclinical procedures organized into an “antinociception matrix” by reference to their types of pain stimulus (noxious, inflammatory, neuropathic, disease related) and pain behavior (unconditioned, classically conditioned, operant conditioned). Particular emphasis is devoted to pain behaviors and the behavioral principals that govern their expression, pharmacological modulation, and preclinical-to-clinical translation. Strengths and weaknesses are compared and contrasted for procedures using each type of behavioral outcome measure, and the following four recommendations are offered to promote strategic use of these procedures for preclinical-to-clinical analgesic drug testing. First, attend to the degree of homology between preclinical and clinical outcome measures, and use preclinical procedures with behavioral outcome measures homologous to clinically relevant outcomes in humans. Second, use combinations of preclinical procedures with complementary strengths and weaknesses to optimize both sensitivity and selectivity of preclinical testing. Third, take advantage of failed clinical translation to identify drugs that can be back-translated preclinically as active negative controls. Finally, increase precision of procedure labels by indicating both the pain stimulus and the pain behavior in naming preclinical procedures.

Evaluation of Biased and Balanced Salvinorin A Analogs in Preclinical Models of Pain

“…However, it would be worth further exploring the effects of these compounds in pain-depressed behavioral models, such as models that measure a decrease in the level of feeding or locomotor activity when animals are in a pain-like state (Negus et al, 2010). These models avoid the false positive outcomes that can occur in pain-stimulated behavioral models when drugs have sedative effects (Negus, 2019).…”

Preclinical assessment of tramadol abuse potential: Effects of acute and repeated tramadol on intracranial self-stimulation in rats

“…We have shown previously that many MOR agonists produce little or no evidence of abuse-related ICSS facilitation in opioid-naïve adult male Sprague–Dawley rats, and instead produce primarily only an efficacy-dependent ICSS depression. However, repeated MOR agonist treatment for as little as a few days is sufficient to produce both tolerance to ICSS depression and an increase or emergence of ICSS facilitation both by the repeatedly administered opioid and by other MOR agonists (Negus, 2019). In the present study with tramadol, there were three main findings.…”

Strategies for DevelopingκOpioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects

“…behaviour (Negus, 2019). In Sprague Dawley rats, two peripherally restricted KOPr agonists, ICI 204,448 and the tetrapeptide ffir, had weak and no antinociceptive effect, respectively, in a lactic-acid depressed intracranial self-stimulation assay (Negus et al, 2012).…”