Current and Future Issues in the Development of Spinal Agents for the Management of Pain

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.

The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines

“…Employing the familiar nociceptive and neuropathic pain classification for medication selection as a framework, the reorganization of medication selection is based on many factors, including survival expectation, age, previous exposure to opioids, location of pain, type of pain, and catheter location. The pharmacokinetics of the IT medications employed point toward a potentially greater spread with multiple bolus delivery compared to continuous infusion.…”

Inhibition of Neuroinflammation by AIBP: Spinal Effects upon Facilitated Pain States

“…The morbidity associated with percutaneous injections is near zero when small gauge needles are employed (Corbey et al, 1997). There is an expanding development of spinally targeted drugs (Yaksh et al, 2017), particularly where the therapeutic has long lasting effects, as is suggested in the action of AIBP. While considerable work remains to be accomplished as regards safety and tolerability (Yaksh, 2011; Yaksh and Allen, 2004), the use of the intrathecal route to deliver AIBP, which, in the murine models, had no adverse events or morbidity and produced pain-ameliorating effects, which endured for many weeks, represents a rational target for development as a therapeutic in long lasting facilitated pain states.…”

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

“…This commentary is particularly relevant for neuraxial drugs where appropriate assessment of neuraxial safety must be undertaken prior to such drug implementation. 21 Finally, it is challenging to find a drug target that can alter a pain state with a favorable therapeutic ratio (e.g. little or no effects upon mentation, arousal or motor function).…”

“…This commentary is particularly relevant for neuraxial drugs where appropriate assessment of neuraxial safety must be undertaken prior to such drug implementation. 21 …”