Clinical Pain Advisor: What are the main treatment implications for pain clinicians?

Dr Yaksh: Our paper reviews the extensive work we have published in this area. Out of this, we found extensive evidence for an absence of toxicity after morphine, clonidine, and bupivacaine at doses that are multiples of the intrathecal therapeutic dose. In contrast, for the molecule ketamine, we found spinal apoptosis at doses that were comparable to those minimal doses required to have effects on pain processing. 

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Clinical Pain Advisor: What are the future directions for research in this area?

Dr Yaksh: Clearly other molecules should be examined for their relative safety. These include agents such as fentanyl, other alpha-2 agonists such as dexmedetomidine, and anesthetics such as ropivacaine or 2-chloroprocaine. Also of interest is the synergy that might be expected between anesthetics and an opiate or an opiate and an alpha-2. Such combinations require specific consideration as to their safety profile.

The effects of ketamine were disappointing, as the target of this drug, the spinal N-methyl D-aspartate (NMDA) receptor, is believed to play a major role in pain processing. There is a critical need to pursue the mechanisms of this apparent toxicity to determine whether it is mechanism- or molecule-dependent.

As noted, the extensive work we have done was not supported by extramural requests, despite diligent efforts targeted at several foundations and the National Institutes of Health. Additional work would benefit from such funding.

The development of spinal drugs for neonatal anesthesia and selective pain control has great promise. Yet, it should be emphasized that the development of such drugs must be proceeded by robust assessment of safety. In spite of the apparent safety of a drug after systemic delivery, such safety does not apply to the effects of the drug after neuraxial delivery. High concentrations and direct tissue exposure pose many issues for therapeutic safety. 


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This article originally appeared on Clinical Pain Advisor