Microneurography: An opportunity for translational drug development in neuropathic pain

Abstract Background Attrition rates of new analgesics during drug development are high; poor assay sensitivity with reliance on subjective outcome measures being a crucial factor. Methods The authors assessed the utility of functional magnetic resonance imaging with capsaicin-induced central sensitization, a mechanism relevant in neuropathic pain, for obtaining mechanism-based objective outcome measures that can differentiate an effective analgesic (gabapentin) from an ineffective analgesic (ibuprofen) and both from placebo. The authors used a double-blind, randomized phase I study design (N = 24) with single oral doses. Results Only gabapentin suppressed the secondary mechanical hyperalgesia–evoked neural response in a region of the brainstem’s descending pain modulatory system (right nucleus cuneiformis) and left (contralateral) posterior insular cortex and secondary somatosensory cortex. Similarly, only gabapentin suppressed the resting-state functional connectivity during central sensitization between the thalamus and secondary somatosensory cortex, which was plasma gabapentin level dependent. A power analysis showed that with 12 data sets, when using neural activity from the left posterior insula and right nucleus cuneiformis, a statistically significant difference between placebo and gabapentin was detected with probability ≥ 0.8. When using subjective pain ratings, this reduced to less than or equal to 0.6. Conclusions Functional imaging with central sensitization can be used as a sensitive mechanism–based assay to guide go/no-go decisions on selecting analgesics effective in neuropathic pain in early human drug development. We also show analgesic modulation of neural activity by using resting-state functional connectivity, a less challenging paradigm that is ideally suited for patient studies because it requires no task or pain provocation.

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NS1209/SPD 502, A Novel Selective AMPA Antagonist for Stroke, Neuropathic Pain or Epilepsy? Drug Development Lessons Learned

Drug Development Research ◽

10.1002/ddr.21376 ◽

2017 ◽

Vol 78 (2) ◽

pp. 75-80 ◽

Cited By ~ 3

Author(s):

Jan M. Keppel Hesselink

Keyword(s):

Neuropathic Pain ◽

Drug Development ◽

Lessons Learned ◽

Ampa Antagonist

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Lyophilization Serves as an Effective Strategy for Drug Development of the α9α10 Nicotinic Acetylcholine Receptor Antagonist α-Conotoxin GeXIVA[1,2]

Marine Drugs ◽

10.3390/md19030121 ◽

2021 ◽

Vol 19 (3) ◽

pp. 121

Author(s):

Zhiguo Li ◽

Xiaolu Han ◽

Xiaoxuan Hong ◽

Xianfu Li ◽

Jing Gao ◽

...

Keyword(s):

Neuropathic Pain ◽

Drug Development ◽

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Analgesic Effect ◽

Tail Flick ◽

Clinical Use ◽

Effective Strategy ◽

Scanning Calorimetry ◽

Nicotinic Acetylcholine

α-Conotoxin GeXIVA[1,2] is a highly potent and selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype. It has the advantages of strong efficacy, no tolerance, and no effect on motor function, which has been expected help patients with neuropathic pain. However, drug development for clinical use is severely limited owing to its instability. Lyophilization is applied as the most preferred method to solve this problem. The prepared lyophilized powder is characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and Fourier transform infrared spectroscopy (FTIR). Molecular simulation is also used to explore the internal distribution and forces formed in the system. The analgesic effect on paclitaxel-induced neuropathic pain following single and 14-day repeated administrations are evaluated by the von Frey test and the tail-flick test. Trehalose combined with mannitol in a ratio of 1:1 is employed as the excipients in the determined formulation, where trehalose acts as the stabilizer and mannitol acts as the bulking agent, according to the results of DSC, PXRD, and FTIR. Both GeXIVA[1,2] (API) and GeXIVA[1,2] lyophilized powder (formulation) could produce stable analgesic effect. These results indicated that GeXIVA[1,2] lyophilized powder could improve the stability and provide an effective strategy to push it into clinical use as a new analgesic drug.

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