Title:Current and Future Issues in the Development of Spinal Agents for the Management of Pain
Volume: 15
Issue: 2
Author(s): Tony L. Yaksh, Casey J. Fisher, Tyler M. Hockman and Ashley J. Wiese
Affiliation:
Keywords:
Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity.
Abstract: Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious
experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or
nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the
peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic
states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the
hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive
processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following
acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of
spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium
channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii)
ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets
(cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including
gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum
toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial
drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the
preclinical evaluation of intrathecal drug safety.
