REVISTA

Relación entre la farmacodinamia y la neuroimagen (RM): implicaciones para el desarrollo de fármacos analgésicos

Descripción: La respuesta neuronal del cerebro al dolor, puede ser una herramienta viable para evaluar la efectividad de nuevos medicamentos para el dolor durante las primeras etapas del desarrollo de fármacos en humanos, proporcionando la evidencia objetiva necesaria para prevenir el descarte prematuro de terapias potencialmente beneficiosas

TITULO FUENTE ORIGINAL:

Disambiguating Pharmacodynamic Efficacy from Behavior with Neuroimaging: Implications for Analgesic Drug Development

AUTORES:

Wanigasekera V, Mezue M, Andersson J, Kong Y, Tracey I

REVISTA ABREV.:

Anesthesiology

AÑO:

2016

REFERENCIA:

124(1):159-68

DOI:

10.1097/ALN.0000000000000924

RESUMEN ORIGINAL:

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...
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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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Enlace al pdf de acceso libre: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC[...]