Unilateral Periganglionic Resiniferatoxin for Personalized Pain Treatment.
Unilateral Periganglionic Resiniferatoxin for Personalized Pain Treatment.
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单侧神经节周围树脂毒素用于个性化疼痛治疗。
DOI：
10.1093/pm/pnaa393
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Iadarola,MichaelJ
中科院分区：
文献类型：
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作者：
Iadarola,MichaelJ
Dear Editor, The report by Unger et al. in the January 2019 [1] issue of Pain Medicine,“Unilateral Epidural Targeting of Resiniferatoxin Induces Bilateral Neurolysis of Spinal Nociceptive Afferents,” examined the neurochemical effects of resiniferatoxin (RTX), a potent agonist at the TRPV1 heat and ligand gated ion channel when administered unilaterally, epidurally, and close to the dorsal root ganglion. As such, they partially reproduced the neurochemical effects in swine that we reported 4 years earlier [2]. Although the report by Ungar et al. appears to be an accurate account of their experiments, the two studies differ in their fundamental conclusions. The title of the Unger paper, which is so definitive, states that the effects from unilateral injection are manifested bilaterally; in other words, no anatomic selectivity was achieved by unilateral drug placement. The end point for drug response was a loss of nociceptive afferent innervation to the dorsal spinal cord, as measured by immunocytochemistry for the neuropeptide substance P. Unilateral administration of RTX, if discrete injection parameters are used, should produce a unilateral loss of nociceptive afferent substance P-containing innervation to the dorsal spinal cord. What Ungar et al. observed was loss of substance P on both sides of the spinal cord, indicating that they did not obtain a unilateral effect. In their study, the RTX injection was preceded by an injection of contrast agent, which the authors state remained unilateral. When they administered a second, separate injection of RTX given after the contrast agent, the active pharmaceutical ingredient did not remain localized. Specifically, RTX was infused at four levels, and each periganglionic injection consisted of 5 mcg of RTX in a volume of 0.5 mL. It appears that the lack of anatomic specificity can be attributed to both the RTX dose (a total of 20 mcg) and the volume administered (a total of 2 mL). It is possible that, if the authors had been cognizant of our study, which has been in the literature for 4 years and which did demonstrate a unilateral effect, they may have explored the dose–response–volume relationships in a more incisive fashion.Why is preserving laterality important? The objective of our earlier study was to develop a technique that imparted more localization than is provided in our current clinical trial of intrathecal RTX to treat intractable pain in advanced cancer, where, frequently, multiple dermatomes are involved bilaterally (see Sapio et al.[3] and NCT00804154 at ClinicalTrials. gov). Thus, we could treat pain originating from localized peripheral generators (eg, a lateralized tumor or nerve injury). For periganglionic administration, we used a total volume of 275 mcL per ganglion, containing either 0.5 or 2.0 mcg of RTX. Thus, for four ganglia injected on one side of the animal, a total volume of 1.1 mL and either 2 or 8 mcg of drug was administered. We obtained a clear, unilateral loss of immunoreactivity for the substance P peptide, the calcitonin gene–related peptide, and the TRPV1 ion channel itself in the dorsal spinal cord and a loss of immunoreactive neuronal perikarya in the dorsal root ganglion itself. Additionally, thermal analgesia was tested in our pigs, and the analgesia showed efficacy, laterality, and sensory modality specificity. Both doses produced a significant, unilateral increase in withdrawal latency to a noxious thermal stimulus delivered by a 980-nm infrared laser diode. The advantage of the laser is that it delivered a heat pulse without contact to the skin, which avoided cueing the animal to the testing event. RTX analgesia was selective, and no loss in pin-prick pain sensitivity was detected, indicating preservation of a …
