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An α-2 adrenoceptor agonist, combined with a local anesthetic, has been found to extend the duration of the peripheral nerve block. At first, clonidine has been found to extend the duration of local anesthetic action. The action of clonidine was suggested to be due to local vasoconstriction [1]. But, clonidine is not particularly specific for α-2 adrenoceptors and acts via α-1 adrenoceptors at comparatively high concentrations. Thus, it is unclear whether it acts via α-2 adrenoceptors. And despite substantial study, it is not clear which doses of clonidine are optimal for prolongation of analgesia after peripheral nerve blocks. The use of perineural clonidine is not currently recommended for clinical use [2].

Another α-2 adrenoceptor agonist, dexmedetomidine, acts more specifically against α-2 adrenoceptors and has more than 7 times the affinity for α-2 adrenoceptors of clonidine. Dexmedetomidine, which produce sympatholytic, sedative, analgesic, antihypertensive and bradycardiac effects when combined with a local anesthetic agent, have been found to extend the duration of local anesthesia effect by causing local vasoconstriction. Dexmedetomidine is a selective α-2 adrenoceptor agonist. α-2 adrenoceptors are subdivided into four subtypes: α-2A, α-2B, α-2C and α-2D. Among them, α-2A, α-2B and α-2C adrenoceptors have been well identified pharmacologically and have been shown to cause vasoconstriction [3-5]. The other possible mechanism for enhancement and prolongation of local anesthetic action by dexmedetomidine is its direct effect on peripheral nerve activity. A direct action of dexmedetomidine has been reported on exposure of isolated sciatic nerve fibers to dexmedetomidine [6]. However, in concentration for similar adrenaline effect, direct effect of dexmedetomidine on peripheral nerve activity was not observed in vivo [7]. In epidural anesthesia for rat, administration of dexmedetomidine alone at the concentration that was shown to enhance local anesthetic action produced no local anesthesia effects [7]. A possible explanation for this discrepancy is that epidural anesthesia involves injection of the local anesthetic solution into the epidural space, which includes loose connective tissue. In conduction anesthesia involving penetration of a nerve fiber in connective tissue, dexmedetomidine enhances the local anesthetic action of lidocaine by vasoconstriction via α-2A, α-2B and α-2C adrenoceptors around the site of injection. Based on the mechanism that the local anesthesia reinforcement action of dexmedetomidine depends on local vasoconstriction, using a sedated tail-flick and epidural animal model, we previously reported that prolongation of the local anesthetic effect by dexmedetomidine was concentration-dependent [7,8]. In humans, dexmedetomidine dose-dependently enhances the local anesthetic action of lidocaine in inferior alveolar nerve block (IANB, conduction anesthesia in dentistry). Furthermore, addition of dexmedetomidine at a concentration of 2.5 ppm produces similar enhancement of local anesthesia effect as addition of 1:80,000 adrenaline [9]. In children, dexmedetomidine with bupivacaine in greater palatine nerve block increased the duration of analgesia after repair of a cleft palate by 50% with no clinically relevant side effects [10]. In epidural anesthesia, dexmedetomidine is an effective adjuvant to ropivacaine [11].

In the 5.0 ppm and 7.5 ppm dexmedetomidine, blood pressure decreased, clinically insignificant degree from baseline, moreover, heart rate did not change; on the other hand, 2.5 ppm dexmedetomidine did not change both blood pressure and heart rate [9]. In 2.5 - 7.5 ppm dexmedetomidine, deep sedation was not observed with any of the concentrations of dexmedetomidine used [9]. These findings suggest that dexmedetomidine can be safely administered as an additive to local anesthetics without the risk of excessive sedation.

Moreover, sciatic nerve block with the addition of dexmedetomidine to bupivacaine resulted in a lower incidence of perineural inflammation [12]. Also, locally injected dexmedetomidine exerts anti-inflammatory effects against local acute inflammatory responses [13]. The local injection of dexmedetomidine is useful for relieving local acute inflammatory nociception that was induced by an intra plantar injection of 1% carrageenan, in rats [14]. These effects of dexmedetomidine employ a mechanism other than local α-2 adrenoceptor mediation [14].

In the current status, application of dexmedetomidine to local anesthesia has not been approved by the U.S. food and drug administration (FDA). In a word, application of dexmedetomidine to local anesthetic action is considered off-label usage. We need to pay attention to that justifiable noncompliance with the rule in individual countries.

New additive agent, dexmedetomidine, may be recommended for the safe enhancement of local anesthesia effect in patients.

References

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2. Kirksey MA, Haskins SC, Cheng J, Liu SS (2015) Local Anesthetic Peripheral Nerve Block Adjuvants for Prolongation of Analgesia: A Systematic Qualitative Review. PLoS One10: e0137312. [Crossref]
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4. Snapir A, Koskenvuo J, Toikka J, Orho-Melander M, Hinkka S, et al. (2003) Effects of common polymorphisms in the alpha1A-, alpha2B-, beta1- and beta2-adrenoreceptors on haemodynamic responses to adrenaline. ClinSci104:509-520. [Crossref]
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7. OuchiK, Koga Y, Nakao S, Sugiyama K (2014) Dexmedetomidine dose-dependently enhances local anesthetic action of lidocaine. Joral  maxillofacialsurg72:474-480. [Crossref]
8. Ouchi K, SekineJ, Koga Y, Nakao S, Sugiyama K (2013) Establishment of an animal model of sedation using epidural anesthesia that uses the tail-flick test for evaluating local anesthetic effects in rats. ExpAnim62:137-44. [Crossref]
9. Ouchi K, Sugiyama K (2016) Dexmedetomidine Dose-dependently Enhances the Local Anesthetic Action of Lidocaine in Inferior Alveolar Nerve Block: a randomized double blind study. RegAnesth PainMed 41:in press.
10. Obayah GM, Refaie A, Aboushanab O, Ibraheem N, Abdelazees M (2010) Addition of dexmedetomidine to bupivacaine for greater palatine nerve block prolongs postoperative analgesia after cleft palate repair. Eur J Anaesthesiol27:280-284. [Crossref]
11. Arunkumar S, Hemanth Kumar VR, Krishnaveni N, Ravishankar M, Jaya V, et al. (2015) Comparison of dexmedetomidine and clonidine as an adjuvant to ropivacaine for epidural anesthesia in lower abdominal and lower limb surgeries. Saudi J Anaesth9:404-408. [Crossref]
12. Brummett CM, Norat MA, Palmisano JM, Lydic R (2008) Perineural administration of dexmedetomidine in combination with bupivacaine enhances sensory and motor blockade in sciatic nerve block without inducing neurotoxicity in rat. Anesthesiol109:502-511. [Crossref]
13. Sukegawa S, Higuchi H, Inoue M, Nagatsuka H, Maeda S, et al. (2014) Locally injected dexmedetomidine inhibits carrageenin-induced inflammatory responses in the injected region. Anesthesanalges118:473-80. [Crossref]
14. Honda Y, Higuchi H, Matsuoka Y, Yabuki-Kawase A, Ishii-Maruhama M, et al. (2015) The inhibitory effect of locally injected dexmedetomidine on carrageenan-induced nociception in rats. Eur J Pharmacol764:215-219.[Crossref]