Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery

Clinical Translational Sci

Hay

et al. 2019

Self Cite

Sodium channel blockers are used for the treatment of pain, but this is limited by the lack of selectivity for different sodium channel subtypes, which can result in central nervous system and cardiovascular side effects. As such, there is special interest in the Nav1.7 subtype, which is expressed predominantly in nociceptive and sympathetic neurons. The aim was to demonstrate analgesic properties of a potent selective Nav1.7 sodium channel blocker, PF‐05089771, alone and concomitantly with pregabalin in healthy subjects using a battery of human evoked pain models. This was a double‐blind, double‐dummy, randomized, placebo‐controlled, five‐period cross‐over study with PF‐05089771 alone and PF‐05089771 concomitantly with pregabalin as treatment arms with pregabalin, ibuprofen, and placebo as control arms (NCT02349607). A battery of human evoked pain models was used to investigate analgesic properties of PF‐05089771. Twenty‐five subjects were enrolled in the study of which 23 subjects completed all five periods. PF‐05089771 alone did not differ from placebo on the primary pain end points. The same holds when comparing PF‐05089771 concomitantly with pregabalin and pregabalin alone. Pregabalin showed significant effects relative to placebo on thermal pain on the normal skin and UVB skin (least squares means with 90% confidence interval: 0.63 (0.32–0.93) and 0.53 (0.11–0.96)), pressure stimulation (1.10 (1.04–1.18)), and cold pressor (1.22 (1.14–1.32)). Ibuprofen demonstrated significant effects on thermal pain UVB skin (1.26 (0.82–1.70)) and pressure stimulation assessment (1.08 (1.01–1.15)), consistent with historical results. This study did not demonstrate analgesic properties of PF‐05089771 alone or concomitantly with pregabalin in a battery of pain models.

Section: Methodssupporting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

Section: Study Highlightsmentioning

confidence: 99%

mentioning

confidence: 99%

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Lack of Detection of the Analgesic Properties of PF‐05089771, a Selective Na_v1.7 Inhibitor, Using a Battery of Pain Models in Healthy Subjects

Clinical Translational Sci

Hay

et al. 2019

Self Cite

“…Pharmacodynamics was measured using an integrated battery of pain models designed to measure various modalities of pain. These models have been described previously (Hay et al, ), and all assessments were performed by trained personnel. In all four studies, tasks were performed in order to measure the pain detection threshold (PDT) and the pain tolerance threshold (PTT).…”

Section: Methodsmentioning

confidence: 99%

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

European Journal of Pain

Okkerse

et al. 2019

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Background Although reproducibility is considered essential for any method used in scientific research, it is investigated only rarely; thus, strikingly little has been published regarding the reproducibility of evoked pain models involving human subjects. Here, we studied the reproducibility of a battery of evoked pain models for demonstrating the analgesic effects of two analgesic compounds. Methods A total of 81 healthy subjects participated in four studies involving a battery of evoked pain tests in which mechanical, thermal and electrical stimuli were used to measure pain detection and tolerance thresholds. Pharmacodynamic outcome variables were analysed using a mixed model analysis of variance, and a coefficient of variation was calculated by dividing the standard deviation by the least squares means. Results A total of 76 subjects completed the studies. After being administered pregabalin, the subjects’ pain tolerance thresholds in the cold pressor and pressure stimulation tests were significantly increased compared to the placebo group. Moreover, the heat pain detection threshold in UVB‐irradiated skin was significantly increased in subjects who were administered ibuprofen compared to the placebo group. Variation among all evoked pain tests ranged from 2.2% to 30.6%. Conclusions Four studies using a similar design showed reproducibility with respect to the included evoked pain models. The relatively high consistency and reproducibility of two analgesics at doses known to be effective in treating clinically relevant pain supports the validity of using this pain test battery to investigate the analgesic activity and determine the active dosage of putative analgesic compounds in early clinical development. Significance The consistency and reproducibility of measuring the profile of an analgesic at clinically relevant doses illustrates that this pain test battery is a valid tool for demonstrating the analgesic activity of a test compound and for determining the optimal active dose in early clinical drug development.

Effect profile of paracetamol, Δ9‐THC and promethazine using an evoked pain test battery in healthy subjects

European Journal of Pain

Kam

et al. 2018