Within the field of pain but especially neuropathic pain there is still much to be gained, as illustrated by the unmet medical need and limitedly efficacious drug treatments currently available. A... Show moreWithin the field of pain but especially neuropathic pain there is still much to be gained, as illustrated by the unmet medical need and limitedly efficacious drug treatments currently available. A key contributor to chronification of neuropathic pain is central sensitization, which may manifest clinically as hyperalgesia, a symptom non-existent in healthy individuals. Models that can induce hyperalgesia and tools that can appropriately assess altered nociceptive functioning in early-phase drug studies are sought-after, as they may aid in examining the potential of drugs as (neuropathic) pain treatment. Continuing efforts are made to expand and improve our knowledge in this field. This thesis describes our contribution, and was based on two main objectives. One was to develop and validate methods for early-phase clinical drug studies with improved accuracy or resemblance to clinical pathophysiology, to improve the evaluation of a drug’s mechanism of action and analgesic potential. The other objective was to actually test novel drugs that are proposed to have superior clinical utility, using methods we believed to be appropriate for evaluating those drugs’ analgesic effects. Show less
Berg, B. van den; Hijma, H.J.; Koopmans, I.; Doll, R.J.; Zuiker, R.G.J.A.; Groeneveld, G.J.; Buitenweg, J.R. 2022
Sleep deprivation has been shown to increase pain intensity and decrease pain thresholds in healthy subjects. In chronic pain patients, sleep impairment often worsens the perceived pain intensity.... Show moreSleep deprivation has been shown to increase pain intensity and decrease pain thresholds in healthy subjects. In chronic pain patients, sleep impairment often worsens the perceived pain intensity. This increased pain perception is the result of altered nociceptive processing. We recently developed a method to quantify and monitor altered nociceptive processing by simultaneous tracking of psychophysical detection thresholds and recording of evoked cortical potentials during intra-epidermal electric stimulation. In this study, we assessed the sensitivity of nociceptive detection thresholds and evoked potentials to altered nociceptive processing after sleep deprivation in an exploratory study with 24 healthy male and 24 healthy female subjects. In each subject, we tracked nociceptive detection thresholds and recorded central evoked potentials in response to 180 single- and 180 double-pulse intra-epidermal electric stimuli. Results showed that the detection thresholds for single- and double-pulse stimuli and the average central evoked potential for single-pulse stimuli were significantly decreased after sleep deprivation. When analyzed separated by sex, these effects were only significant in the male population. Multivariate analysis showed that the decrease of central evoked potential was associated with a decrease of task-related evoked activity. Measurement repetition led to a decrease of the detection threshold to double-pulse stimuli in the mixed and the female population, but did not significantly affect any other outcome measures. These results suggest that simultaneous tracking of psychophysical detection thresholds and evoked potentials is a useful method to observe altered nociceptive processing after sleep deprivation, but is also sensitive to sex differences and measurement repetition. Show less
Selective inhibition of certain voltage-gated sodium channels (Na(v)s), such as Na(v)1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due... Show moreSelective inhibition of certain voltage-gated sodium channels (Na(v)s), such as Na(v)1.8, is of primary interest for pharmacological pain research and widely studied as a pharmacological target due to its contribution to repetitive firing, neuronal excitability, and pain chronification. VX-128 is a highly potent and selective Na(v)1.8 inhibitor that was being developed as a treatment for pain. We evaluated the safety, tolerability, and pharmacokinetics of VX-128 in healthy subjects in a single-and multiple-ascending dose (MAD) first-in-human study. Pharmacodynamics were evaluated in the MAD part using a battery of evoked pain tests. Overall, single doses of VX-128 up to 300 mg were well-tolerated, although adverse effect (AE) incidence was higher in subjects receiving VX-128 (41.7%) compared with placebo (25.0%). After multiple dosing of up to 10 days, skin rash events were observed at all dose levels (up to 100 mg once daily [q.d.]), in five of 26 (19.2%) subjects, including one subject receiving VX-128 (100 mg q.d.) who had a serious AE of angioedema. A trend in pain tolerance were observed for cold pressor-and pressure pain, which was dose-dependent for the latter. VX-128 was rapidly absorbed (median time to maximum plasma concentration between 1 and 2 h) with a half-life of similar to 80 h at 10 mg q.d., and approximately two-fold accumulation ratio after 10 and 30 mg q.d. Although VX-128, when given in a multiple dose fashion, resulted in early study termination due to tolerability issues, effects were observed on multiple pain tests that may support further investigation of Na(v)1.8 inhibitors as pain treatments. Show less
Background and aims: Following an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the... Show moreBackground and aims: Following an infection, cytokines not only regulate the acute immune response, but also contribute to symptoms such as inflammatory hyperalgesia. We aimed to characterize the acute inflammatory response induced by a human endotoxemia model, and its effect on pain perception using evoked pain tests in two different dose levels. We also attempted to determine whether combining a human endotoxemia challenge with measurement of pain thresholds in healthy subjects could serve as a model to study drug effects on inflammatory pain.Methods and results: This was a placebo-controlled, randomized, cross-over study in 24 healthy males. Twelve subjects were administered a bolus of 1 ng/kg LPS intravenously, and twelve 2 ng/kg LPS. Before days of placebo/LPS administration, subjects completed a full study day without study drug administration, but with identical pain threshold testing. Blood sampling and evoked pain tests (electrical burst and -stair, heat, pressure, and cold pressor test) were performed pre-dose and at frequent intervals up to 10hr post-dose. Data were analysed with a repeated-measures ANCOVA. For both dose levels, LPS induced an evident acute inflammatory response, but did not significantly affect any of the pain modalities. In a post-hoc analysis, lowering of pain thresholds was observed in the first 3 h after dosing, corresponding with the peak of the acute inflammatory response around 1-3 h post-dose.Conclusion: Mild acute systemic inflammation, as induced by 1 ng/kg and 2 ng/kg LPS intravenous administration, did not significantly change pain thresholds in this study. The endotoxemia model in combination with evoked pain tests is not suitable to study acute inflammatory hyperalgesia in healthy males. Show less
