Local Anesthetic Neurotoxicity Does Not Result from Blockade of Voltage-Gated Sodium Channels

Sakura, Shinichi; Bollen, Andrew W.; Ciriales, R.; Drasner, Kenneth

doi:10.1213/00000539-199508000-00023

Cited by 37 publications

(48 citation statements)

References 23 publications

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“…The presence of particles themselves enhances local anesthetic myotoxicity in vivo (3), and can cause inflammatory responses at the nerve that may considerably outlast the duration of blockade (2,3,8). In contrast, site 1 sodium-channel blockers do not cause myo-or neurotoxicity (9,10), which would make them desirable for an extended release formulation. However, these extremely potent local anesthetics (11), being very hydrophilic, are difficult to encapsulate effectively in polymeric particles, and the systemic toxicity from their initial rapid release is dose-limiting (12,13).…”

mentioning

confidence: 99%

Prolonged duration local anesthesia with minimal toxicity

Epstein-Barash

Shichor

Kwon

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

142

157

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Injectable local anesthetics that would last for many days could have a marked impact on periprocedural care and pain management. Formulations have often been limited in duration of action, or by systemic toxicity, local tissue toxicity from local anesthetics, and inflammation. To address those issues, we developed liposomal formulations of saxitoxin (STX), a compound with ultrapotent local anesthetic properties but little or no cytotoxicity. In vitro, the release of bupivacaine and STX from liposomes depended on the lipid composition and on whether dexamethasone was incorporated. In cell culture, bupivacaine, but not STX, was myotoxic (to C2C12 cells) and neurotoxic (to PC12 cells) in a concentration- and time-dependent manner. Liposomal formulations containing combinations of the above compounds produced sciatic nerve blockade lasting up to 7.5 days (with STX + dexamethasone liposomes) in male Sprague–Dawley rats. Systemic toxicity only occurred where high loadings of dexamethasone increased the release of liposomal STX. Mild myotoxicity was only seen in formulations containing bupivacaine. There was no nerve injury on Epon-embedded sections, and these liposomes did not up-regulate the expression of 4 genes associated with nerve injury in the dorsal root ganglia. These results suggest that controlled release of STX and similar compounds can provide very prolonged nerve blocks with minimal systemic and local toxicity.

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mentioning

confidence: 99%

Prolonged duration local anesthesia with minimal toxicity

Epstein-Barash

Shichor

Kwon

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

142

157

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“…The molecular mechanisms of the local anesthetic toxicity are not understood. Work with intrathecal TTX has shown that long-lasting sodium channel block itself is not associated with a specific toxicity [139]. Small local anesthetic molecules can have effects on lipid membrane components, which reflect the detergent nature of these amphiphillic molecules [140].…”

Section: Adverse Eventsmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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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.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct 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. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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“…des fibres de Purkinje au niveau du coeur. É tant plus puissante que la lidocaïne et que la bupivacaïne sans myotoxicité ou neurotoxicité in vitro ou in vivo, 17,18 son efficacité comme anesthésique local a été examinée chez l'humain par infiltration sous-cutanée chez dix volontaires sains. 19 Des résultats prometteurs ont été dépistés sans effets indésirables.…”

Section: Innover Sans Toxicitéunclassified

“…channel subtypes possessed by the cardiac Purkinje fibres. Being more potent than both lidocaine and bupivacaine without myotoxicity or neurotoxicity in vitro or in vivo, 17,18 its efficacy as a local anesthetic in humans was examined via subcutaneous infiltration on ten healthy volunteers. 19 Promising results were detected with no adverse effects.…”

mentioning

confidence: 99%

Novelty without toxicity: a quest for a safer local anesthetic

Tsui

2010

Can J Anesth/J Can Anesth

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Local Anesthetic Neurotoxicity Does Not Result from Blockade of Voltage-Gated Sodium Channels

Cited by 37 publications

References 23 publications

Prolonged duration local anesthesia with minimal toxicity

Prolonged duration local anesthesia with minimal toxicity

Current and Future Issues in the development of spinal agents for the management of pain

Novelty without toxicity: a quest for a safer local anesthetic

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