Newer local anesthetic drugs in dentistry

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1 Review Article Newer local anesthetic drugs in dentistry B. Poojashree, M. P. Santhosh Kumar* ABSTRACT Local anesthetics (LAs) are the safest and most effective drugs in medicine for the control and management of pain. They also represent the most important drugs in dentistry. LAs work by blocking the entry of sodium ions into their channels, thereby preventing the transient increase in permeability of the nerve membrane to sodium that is required for an action potential to occur. Even though there are LA drugs which are useful in clinics, some newer drugs have been developed with additional features and brought in clinical practice. The purpose of this review article is to enumerate the uses and mechanism of action of the newer LA drugs that are used in dentistry. KEY WORDS: Articaine, Centbucridine, Levobupivacaine, Local anesthesia, Phentolamine, Ropivacaine INTRODUCTION Local anesthetic (LA) solutions have been utilized in clinical dentistry to alleviate or eliminate pain associated with invasive procedures as early as the 19 th century. [1] An important requirement before initiating endodontic or operative dental treatment is the ability to achieve and maintain profound anesthesia. LAs are considered to be the most important drugs used in clinical dentistry. Progress in the treatment of dental disease had to await the development of methods of pain control. Pain control is the foundation of successful dental patient management. The patient who responds better to local anesthesia is basically relaxed and is a confident type of patient. An anxious or phobic dental patient may require some type of intervention strategy to relieve the stress before administering anesthesia. Local anesthesia has been defined as a loss of sensation in an area of the body caused by a depression of excitation in nerve endings or an inhibition of the conduction process in peripheral nerves. [2] The constituents of LA drugs are LA agent, vasoconstrictor, reducing agent, preservatives, vehicle, and distilled water. LA agent interrupts the propagated nerve impulse, preventing it from reaching the brain. Access this article online Website: jprsolutions.info ISSN: The purpose of the vasoconstrictor is to increase the safety, duration, and depth of action of LA. The use of the reducing agent is, it is an antioxidant and it prevents the oxidation of the vasopressor by oxygen which might be trapped in the cartridge during manufacturing or may diffuse through the semipermeable diaphragm after filling. The preservative acts as a bacteriostatic agent and the isotonic vehicle minimizes discomfort during injection. Distilled water is added as the diluent to provide the volume of the solution in the cartridge. Local anesthesia is classified into amide group, ester group, and quinolone group. [3] The criteria for selection of LA drugs are based on American Academy of Pediatric Dentistry (AAPD) guidelines. According to AAPD guidelines, the LA drugs are selected based on the patient s medical history and mental developmental status, the anticipated duration of the procedure, etc. [4] Two theories are proposed for the action of LAs. These are the membrane expansion theory and the specific binding theory. The former is a non-specific mechanism that occurs by swelling of the nerve cell membrane as the lipophilic LA is absorbed into the membrane. This perturbation influences the configuration of the sodium channel and inhibits entry of sodium into the cell, which prevents nerve cell depolarization and thus firing. Although this mechanism may play some role in the action of LA drugs, it is now accepted that the specific binding theory is a more accurate explanation of the mechanism of action of LAs. [5] Department of Oral and Maxillofacial Surgery, Saveetha Dental College, Saveetha Institute of Technical and Medical Sciences, Saveetha University, Chennai, Tamil Nadu, India *Corresponding author: Dr. M. P. Santhosh Kumar, Department of Oral and Maxillofacial Surgery, Saveetha Dental College, Saveetha Institute of Technical and Medical Sciences, Saveetha University, 162, Poonamalle High Road, Velappanchavadi, Chennai , Tamil Nadu, India. Phone: santhoshsurgeon@gmail.com Received on: ; Revised on: ; Accepted on:

2 The continuous improvement in LA agents has contributed more than any other factor to the control of pain during and especially after dental surgery. LAs directly block transmission of pain from nociceptive afferents. LA agents are applied directly, and their efficacy results from action on the nerve where the inward Na+ current is blocked at the sodium ionophore during depolarization. LAs not only block Na+ channels but also Ca2+ and K+ channels, transient receptor potential vanilloid-1 receptors, and other ligand-gated receptors as well. LAs also disrupt the coupling between certain G proteins and their associated receptors. Through this action, LA agents exert potent anti-inflammatory effects, particularly on neutrophil priming reactions. LAs inhibit local inflammatory response to injury that can sensitize nociceptive receptors and contribute to pain and hyperalgesia. [6] Among the several commercially available anesthetic solutions, lidocaine is the one most frequently used in dentistry and is the benchmark for any comparison. Mepivacaine, an amide anesthetic, is as effective as lidocaine at the same concentration and with the same vasoconstrictor agent. However, none of these agents have been proved to be effective for prolonged procedures. NEWER LA DRUGS A number of developments have occurred recently both in terms of the drugs used for local anesthesia and in relation to the equipment used to deliver these drugs. Some of the newer LA drugs are levobupivacaine, ropivacaine, articaine, centbucridine, and phentolamine. [7] Most of these drugs have the advantage of providing longer duration of anesthesia which is the most important criteria for several dental and oral surgical procedures. LEVOBUPIVACAINE Levobupivacaine is an enantiomer of the long-acting local anesthetic bupivacaine, which although currently the most widely used agent in surgery and obstetrics, is associated with potentially fatal cardiotoxicity [Figure 1]. Levobupivacaine is the levorotatory, S( ) enantiomer of bupivacaine and produces a longer nerve block duration and has a lower toxicity to both the central nervous and cardiovascular systems than R(+) bupivacaine. Levobupivacaine is an amide LA, with a mechanism of action and pharmacodynamic properties that are similar to those of bupivacaine. LAs exert their anesthetic and analgesic effects through reversible blockade of neuronal sodium channels. As myelinated nerves can be blocked by exposure to LA at the nodes of Ranvier, they are more readily blocked than unmyelinated nerves. Similarly, small nerves are more easily blocked than large nerves. Levobupivacaine is lipid soluble, highly protein Figure 1: Chemical structure of levobupivacaine bound and has a dissociation constant of, similar to that of bupivacaine and ropivacaine, but higher than that of lidocaine. Levobupivacaine is a high potency, long-acting LA due to vasodilatation properties, with a relatively slower onset of action. The absorption of levobupivacaine depends on the route of administration and tissue vascularity at the site of administration. Levobupivacaine is a single isomer of bupivacaine. A number of studies have demonstrated similar efficacies of levobupivacaine and bupivacaine. [8-10] The advantage of the former drug is that it is less toxic compared with the latter. They appear equally effective in obtaining pulpal anesthesia after inferior alveolar nerve blocks, and levobupivacaine has been shown to reduce analgesic consumption and decreases post-operative pain compared with placebo and injection of lidocaine with adrenaline following oral surgical procedures. [11] As with other LAs, levobupivacaine inhibits impulse transmission and conduction in cardiovascular and other tissues, effects that are important to the development of adverse reactions. The clinical use of levobupivacaine is that it is indicated for infiltration, nerve block, ophthalmic, epidural, and intrathecal anesthesia in adults and also for infiltration analgesia in children. Levobupivacaine is contraindicated for IV regional anesthesia. The adverse effects of levobupivacaine are nervousness, dizziness, depression, blurred vision, bradycardia, hypotension, and arrhythmia. Levobupivacaine is considered as a new alternative to analgesia, which is associated with low toxicity when applied in the dental area and with minor vasoconstriction. Thus, it is a satisfactory option for subjects in whom the use of vasoconstrictors is contraindicated. Thus, levobupivacaine, an LA with properties similar to those of bupivacaine but with less central and cardiac toxicity, is very useful in dentistry. It is available as 497

3 0.5% with epinephrine (1:200,000). In a study, 0.75% levobupivacaine was used. ROPIVACAINE Ropivacaine is an amide-type LA agent structurally related to mepivacaine and bupivacaine. It is the N-propyl homolog of these drugs mepivacaine and bupivacaine [Figure 2]. Ropivacaine is prepared as the L-isomer, while the other two drugs are racemic mixtures. Ropivacaine, however, is less lipid soluble than bupivacaine, which might impair the ability of ropivacaine to penetrate through the membranes of nerves, particularly those that have thick myelin coatings. While ropivacaine has equivalent onset time to that of bupivacaine in C fibers and smaller A fibers, it may have delayed onset in the larger a fibers. Ropivacaine is less lipophilic compared to bupivacaine, so it is less cardiotoxic and has a higher threshold for central nervous system (CNS) toxicity. [12] It inhibits platelet aggregation. The plasma concentration of ropivacaine depends on the total dose administered and the route of administration, as well as the hemodynamic and circulatory condition of the patient and vascularity of the administration site. When ropivacaine was administered intravenously in subjects, its pharmacokinetics were linear and dose proportional up to 80 mg. The absorption of ropivacaine 150 mg from the epidural space is complete and biphasic. Ropivacaine is often coadministered with fentanyl for epidural analgesia in women during labor. Ropivacaine is indicated for infiltration, nerve block, epidural, and intrathecal anesthesia in adults and children over 12 years. Adverse reactions to ropivacaine are rare when it is administered correctly; however, allergic reaction can rarely occur. Ropivacaine is a well-tolerated regional anesthetic effective for surgical anesthesia as well as the relief of post-operative and labor Figure 2: Chemical structure of ropivacaine pain. The efficacy of ropivacaine is similar to that of bupivacaine and levobupivacaine for peripheral nerve blocks and although it may be slightly less potent than bupivacaine when administered epidurally. Clinically, adequate doses of ropivacaine appear to be associated with a lower incidence or grade of motor block than bupivacaine. Several studies have demonstrated that ropivacaine may be suitable for time-consuming oral procedures and/or when prolonged post-operative analgesia is desirable. [13-15] Thus, ropivacaine, with its efficacy, lower propensity for motor block, and reduced potential for CNS toxicity and cardiotoxicity, is an important option for regional anesthesia and management of post-operative and labor pain. Brachial plexus anesthesia was broadly similar to that achieved with equivalent volumes of bupivacaine 0.5%, although the time to onset of sensory block tended to be faster, and the duration of motor block was shorter with ropivacaine. Ropivacaine has been shown to be effective in obtaining dental anesthesia after intraoral injection. However, when tested during intraligamentary anesthesia, a technique that requires good vasoconstriction for acceptable efficacy, ropivacaine was not as effective as lidocaine with adrenaline in obtaining pulpal anesthesia. [15] The optimum concentration of ropivacaine in dentistry is not well-established but is in the range of 0.5 1%. It was found that 0.75% of ropivacaine with 1:200,000 adrenaline produced excellent anesthesia and postoperative analgesia. ARTICAINE Articaine is a relatively new LA used now in dentistry in many countries. Articaine originally named carticaine was first prepared by Rusching et al., in [16] It is an amide-type LA, and, instead of benzene ring, it contains a thiophene ring that increases its lipid solubility [Figure 3]. Articaine contains a sulfur molecule and this must be remembered in patients allergic to sulfurcontaining drugs. It is unique among the amide group of LAs in that it is initially metabolized in the plasma. [17] The other amides are metabolized in the liver although prilocaine does undergo some degradation in the lungs. This means that articaine has a much shorter plasma half-life compared with lidocaine. Therefore, articaine is systemically less toxic than lidocaine. Unlike other LAs, articaine is exceptional in that it contains an additional ester group that is rapidly metabolized by plasma esterase to articainic acid. In regional anesthesia, the choice of an LA is determined by matching the patient s anesthetic and analgesic requirements with its pharmacological properties. [18] Articaine has a favorable profile as a fast and shortacting LA, and there is no conclusive evidence 498

4 higher for articaine and prilocaine, mostly with the lingual nerve. Although there may be controversy regarding its safety and advantages in comparison to other LAs, there is no conclusive evidence demonstrating neurotoxicity or significantly superior anesthetic properties of articaine for dental procedures. On comparing articaine with lignocaine, articaine has a faster onset of action, longer duration of action, higher success rate, greater potency (1.5 times more potent), and lower systemic intoxication. [21,22] Figure 3: Chemical structure of articaine demonstrating above-average neurotoxicity. Local infiltration or topical administration of articaine has proved to be suitable for dental procedures requiring anesthesia with a short to intermediate duration of action and a fast onset and for ambulatory spinal anesthesia. [19] In comparative trials, its clinical effects were not generally significantly different from those of lidocaine, prilocaine, and chloroprocaine. In addition to spinal anesthesia and local infiltration, articaine 0.5% might be appropriate for intravenous regional anesthesia. Advantages are low-lipid solubility, high plasma protein binding rate, fast metabolism, fast elimination halftime, and low blood levels. Articaine seems to be the LA of the first choice in tissues with suppurative inflammation, for adults, children, elderly, pregnant women, and breastfeeding women, and patients suffering from hepatic disorders and renal function impairment. [20] The severity of cardiovascular and CNS toxicity is directly related to the LA potency, dose, and rate of administration. Clinical signs are perioral and tongue paresthesia, a metallic taste, and dizziness, passing into slurred speech, diplopia, tinnitus, confusion, restlessness, and muscle twitching progressing to neuronal depression and leading to convulsions and coma. In this context, one has to distinguish acute toxicity caused by accidental intravascular administration from toxicity caused by systemically absorbed LA. Articaine solutions must not be used in persons who are allergic or hypersensitive to sulfite, due to the content of sodium metabisulfite as the vasoconstrictor s antioxidant in it. There are two contraindications to the use of articaine that must be noted. Methemoglobinemia is seen when high doses are administered. The use of articaine in patients with a history of acquired or congenital methemoglobinemia is, therefore, relatively contraindicated. Documented allergy to sulfur represents an absolute contraindication to articaine administration. Paresthesia incidence is A study was conducted to compare four different local anesthetic solutions (2% lignocaine with 1:100,000 epinephrine, 4% Articaine with 1:100,000 epinephrine, 4% Articaine with 1:200,000 epinephrine, and 3% Prilocaine with Felypressin) revealed that 4% articaine with 1:100,000 epinephrine was the most effective solution. [23] It has excellent bone and soft tissuepenetrating properties. For maxillary tooth extractions, it has been suggested that a palatal injection may not be necessary when articaine is delivered in a buccal infiltration and that most impacted maxillary third molar extractions with articaine can be performed without palatal anesthesia. [24-27] Articaine is manufactured as a 4% solution with 1:100,000 or 1:200,000 adrenaline in 2.2 ml and 1.7 ml glass dental cartridges. 4% articaine with epinephrine 1:100,000 is a safe and effective local anesthetic for use in clinical dentistry. Articaine use in children shows that it is safe and effective for clinical procedures in children of all ages. Articaine is a safe and effective LA drug to use in all aspects of clinical dentistry for patients of all ages, with properties comparable to other common LA agents. Therefore, at this time, the decision to use articaine cannot be based on any convincing evidence of superiority over other LA drugs; rather the choice will be based on the personal preference and experiences of individual clinicians. CENTBUCRIDINE Centbucridine, a non-ester, non-amide group local anesthetic agent developed in India at CDRI, Lucknow, has advantage of inherent vasoconstrictor property. Centbucridine, a quinoline derivative, is 5 times more potent than lidocaine, with an equally rapid onset of action and a longer duration of action [Figure 4]. [28] Significantly, centbucridine does not affect the central nervous or cardiovascular systems adversely except when administered in very large doses. Centbucridine has an antihistaminic activity by blocking the H1 histamine receptors which makes it an ideal LA agent in patients with known allergy to other conventional LA agents. Centbucridine produces a significantly longer duration of anesthesia. It worked just as effectively as the gold standard lignocaine, matching it in terms of 499

5 Figure 4: Chemical structure of centbucridine time of onset, depth of anesthesia, and cardiovascular effects. It produces no side effects or toxic reactions and its safety is confirmed for use. [29,30] Gupta et al. in their study concluded that centbucridine is a safe and effective LA for dental surgery. [31] A randomized double-blind study compared the efficacy and tolerability of 0.5% centbucridine with 2% lignocaine for dental extractions, and the results revealed that the dose of analgesia obtained with centbucridine compared well with that of lignocaine and it was well-tolerated without any serious side effects or significant changes in the cardiovascular parameters. It was found that centbucridine could be used successfully for dental procedures and confidently in patients who cannot tolerate lignocaine or where adrenaline is contraindicated and stated that it produced a significantly longer duration of anesthesia which may last up to 2 h. [32] In a study by Dugal et al., centbucridine was found to be an ideal LA agent with no effects on cardiovascular parameters and exhibited a sufficient degree of LA activity suitable for use in routine minor surgery cases. It proved to be advantageous in patients where adrenaline is absolutely contraindicated due to systemic problems. [33] Centbucridine has been tested successfully as a topical anesthetic in ophthalmic surgeries. Its topical anesthetic action is concentration dependent. [34] It also demonstrates a longer duration of action and analgesic properties. Centbucridine has been used in subarachnoid and extradural anesthesia and in intravenous regional anesthesia. It is available in the strength of 0.5%. PHENTOLAMINE Phentolamine mesylate, a non-selective α-adrenergic blocking drug, is the first therapeutic agent marketed for the reversal of soft tissue anesthesia and the associated functional deficits resulting from an intraoral submucosal injection of an LA containing a vasoconstrictor [Figure 5]. It inhibits the ability of sympathomimetic amines such as norepinephrine and epinephrine to cause vascular contraction. [35] Phentolamine mesylate under the trade name of oraverse is the first therapeutic agent approved and marketed for the reversal of soft tissue anesthesia and the associated functional deficits due to intraoral submucosal injection of an LA consisting of a vasoconstrictor. An injectable form of phentolamine mesylate has been developed to terminate the numbing action of local anesthesia when it is no longer desirable. Like other competitive antagonists, phentolamine shares a structural similarity with the agonist epinephrine but includes bulky side chains that are presumed to permit receptor binding yet prevent receptor activation. Phentolamine mesylate acts as a competitive inhibitor, blocking the effects of epinephrine, an active ingredient in some LAs that cause vasoconstriction. Phentolamine blocks α-adrenergic receptors, causing smooth muscle relaxation. This relaxation will lead to greater blood flow, resulting in a more rapid systemic absorption of the LA. Thus, phentolamine mesylate is not an antagonist of the LA itself but of the epinephrine added to prolong the effect of the LA. [36] Therefore, phentolamine mesylate has not been tested for efficacy following the use of LA without added vasoconstrictors. The delivery method of phentolamine mesylate is similar to that of local anesthesia. It comes in a cartridge like that of regular LAs. The main challenge to the clinician using phentolamine mesylate is the timing of the injection. Since there is a delayed onset, the clinician needs to plan ahead to ensure that the client will regain sensation of soft tissue by the end of the dental appointment. Safety measures in all of the studies included the recording of vital signs at regular intervals, periodic assessments of pain at the injection and operative sites, the need for analgesic medications, visual assessments of the oral cavity, and reports of adverse events. No serious or severe adverse effects were noted during any of the studies nor were there any significant differences in vital signs, pain, or adverse events between phentolamine and sham-treated subjects. [37,38] Recently, there has been a renewed interest in reversal of local anesthesia. This can be achieved by injecting the alpha-adrenergic antagonist phentolamine mesylate at the end of treatment to oppose the effects of the vasoconstrictor (adrenaline) in the original LA. The local injection of phentolamine has been shown to significantly shorten the time taken for return to normal sensation of the lip and tongue after dental anesthesia. Unlike local anesthesia, there are no known contraindications for phentolamine mesylate delivery. However, it is contraindicated in patients with faster heart rate, heart 500

6 Figure 5: Chemical structure of phentolamine attack, and hypersensitivity to this drug. It is available as a cartridge with a concentration of 0.4 mg/1.7 ml. Articaine, levobupivacaine, and ropivacaine seem to be a suitable alternative to lidocaine in post-operative pain control. Levobupivacaine and ropivacaine seem to be promising long-acting anesthetics. Oraqix contains 2.5% lidocaine and 2.5% prilocaine, is a topical periodontal gel which is deposited into periodontal pockets during scaling and root planning. [39,40] It is of prime importance for the dental practitioners to keep themselves updated with the newly evolving LA agents and choose them correctly based on the needs of the patients and the nature of dental procedures performed in the dental clinics. [41] CONCLUSION Local anesthesia has been the cornerstone of modern day pain-free dental practice. There are many LA drugs which have been newly developed over the years for clinical use. 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