Special Topics in Pain: Opioids

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Inhibition of Voltage-Gated Na+ Channels by Bupivacaine Is Enhanced by the Adjuvants Buprenorphine, Ketamine, and Clonidine.

Author(s): Stoetzer C, et al.
Journal: Reg Anesth Pain Med. 2017; 42: 462-468. 25 references.
Reprint: Carsten Stoetzer, MD, Department of Anesthesiology and Intensive Care Medicine, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. E-mail: stoetzer.carsten@mh-hannover.de
Faculty Disclosure: Abstracted by N Walea, who has nothing to disclose.
Objective: Review and evaluate the latest advances and newest information in the area of Local Anesthetics; Review and evaluate the latest advances and newest information in the area of Opioids; Review and evaluate the latest advances and newest information in the area of Psychopharmacologics; Review and evaluate the latest advances and newest information in the area of Adrenergic antagonists


Editor’s Note: Adjuvants are commonly added to local anesthetics for nerve blocks to reduce the local anesthetic dose and prolong pain relief.  This in vitro study shows that, out of the three adjuvants tested, buprenorphine had the strongest blockade behind bupivacaine, but most surprisingly, results between these two agents was very similar.  Other studies have shown that buprenorphine is the strongest opioid sodium channel blocker, being more potent than meperidine, which can be used as a sole agent for spinal anesthetics due to its local anesthetic properties.

Class: Local anesthetics; Opioids-buprenorphine; Ketamine; Clonidine

Regional anesthesia includes application of local anesthetics (LAs) into the vicinity of peripheral nerves. Besides a prolongation of the desired nerve block, adjuvants also allow a dose reduction of potent but potentially toxic LAs such as bupivacaine and ropivacaine. Furthermore, adjuvants may improve postoperative pain management by producing analgesia outlasting the offset of nerve block. Voltage-gated Na+ channels are crucial for the generation of action potentials and they are regarded as the most relevant targets of LAs on peripheral nerves.

This was an in vitro study to compare the inhibitory potencies of bupivacaine, buprenorphine, clonidine, and ketamine on neuronal Na+ channels and to explore if the adjuvants potentiate inhibition by bupivacaine. Experiments on Na+ currents were performed in the neuroblastoma hybridoma cell line ND7/23 using whole-cell patch clamp. These cells express a similar subset of Na+ channel α-subunits (Nav1.2, Nav1.3, and Nav1.7) as that found in sensory neurons.

The study investigated the effects of the LA bupivacaine alone and in combination with the adjuvants buprenorphine, ketamine, and clonidine on sodium currents of voltage-gated Na+ channels. All substances are concentration-and state-dependent inhibitors of Na+ channels. Tonic block of resting channels revealed an order of potency of bupivacaine > buprenorphine > clonidine > ketamine. Furthermore, bupivacaine and buprenorphine, but not clonidine and ketamine, induced a strong use-dependent block at 10 Hz. The study data also show that adjuvants not only directly inhibit Na+ channels, but also potentiate the block efficacy of bupivacaine on Na+ channels. For this reason, blockage of Na+ channels by adjuvants may account for the additive effect of adjuvants used for regional anesthesia.

Effectively, none of the clinically used adjuvants selectively targets only 1 mechanism able to alter neuronal excitability (i.e., they seem rather to interact with several molecules expressed on sensory axons). The primary target of LAs on peripheral nerves, however, appears to be voltage-gated Na+ channels responsible for the generation and propagation of action potentials. Therefore, it seems very likely that the direct effects of adjuvants on Na+ channels, as well as their effects on LA-induced inhibition of Na+ channels, are relevant aspects for their efficacy to enhance or prolong nerve block. The data could confirm that all 3 substances indeed block Na+ channels in a more or less obvious state-dependent manner, but with clearly different potencies in the order buprenorphine >> ketamine = clonidine for both tonic and use-dependent block.

Bupivacaine is the most potent Na+ channel blocker and long-lasting LA used for regional anesthesia and it was a surprise to note that buprenorphine has similar strong potency as bupivacaine to inhibit Na+ channels. Saying this, it was previously demonstrated that buprenorphine is the most potent opioid when it comes to inhibiting Na+ channels. Furthermore, buprenorphine seems to target the same intracellular binding sites as LAs. Co-application of bupivacaine and buprenorphine resulted in an additive effect for use-dependent block but not for tonic block or fast inactivation.

When compared with buprenorphine, both ketamine and clonidine displayed considerably lower potencies for tonic block on neuronal Na+ channels. Even vey high concentrations completely failed to induce use-dependent block. When combined with bupivacaine, high concentrations of both ketamine and clonidine induced an additive tonic block. In theory, these properties might contribute to the adjuvant effects of both substances. When used as adjuvants in clinical practice, however, clonidine (<10 µM) is applied at considerably lower concentrations than those observed to inhibit Na+ channels in this study. Therefore, it seems unlikely that Na+ channels are relevant peripheral targets of clonidine as an adjuvant. In the case of ketamine, the neurotoxicity issue more or less forbids an off-label use of ketamine as an adjuvant for regional anesthesia.

Important Points:
In this study, all substances are concentration- and state-dependent inhibitors of Na+ channels. Tonic block of resting channels revealed in order of potency of bupivacaine > buprenorphine > clonidine > ketamine. The data also show that the adjuvants not only directly inhibit Na+ channels, but also potentiate the blocking efficacy of bupivacaine on Na+ channels. For this reason, block of Na+ channels by adjuvants could contribute to account for the additive effects of adjuvants used for regional anesthesia.

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