Effect profile of paracetamol, 9-THC and promethazine using an evoked pain test battery in healthy subjects

Abstract

Background: A battery of evoked pain tasks (PainCart) was developedto investigate the pharmacodynamic properties of novel analgesics inearly-phase clinical research. As part of its clinical validation,compounds with different pharmacological mechanisms of actions areinvestigated. The aim was to investigate the analgesic effects of classicand nonclassic analgesics compared to a sedating negative control in arandomized placebo-controlled crossover study in 24 healthy volunteersusing the PainCart.Methods: The PainCart consisted of pain tasks eliciting electrical,pressure, heat, cold and inflammatory pain. Subjective scales forcognitive functioning and psychotomimetic effects were included.Subjects were administered each of the following oral treatments:paracetamol (1000 mg), D9-THC (10 mg), promethazine (50 mg) ormatching placebo. Pharmacodynamic measurements were performed atbaseline and repeated up to 10 h postdose.Results: Paracetamol did not show a significant reduction in painsensation or subjective cognitive functioning compared to placebo.Promethazine induced a statistically significant reduction in PTT for coldpressor and pressure stimulation. Furthermore, reduced subjectivealertness was observed. D9-THC showed a statistically significantdecrease in PTT for electrical and pressure stimulation. D9-THC alsodemonstrated subjective effects, including changes in alertness andcalmness, as well as feeling high and psychotomimetic effects.Conclusions: This study found a decreased pain tolerance due to D9-THC and promethazine, or lack thereof, using an evoked pain taskbattery. Pain thresholds following paracetamol administration remainedunchanged, which may be due to insufficient statistical power. Weshowed that pain thresholds determined using this pain test battery arenot driven by sedation.Significance: The multimodal battery of evoked pain tasks utilized inthis study may play an important role in early-phase clinical drugdevelopment. This battery of pain tasks is not sensitive to the effects ofsedation alone, and thus suitable to investigate the analgesic potential ofnovel analgesic compounds.