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Local Anesthesia

An Overview 

 THEORIES OF PAIN

Specificity Theory

One of the first theories of pain that was postulated is the specificity theory whereby it is thought that peripheral pain receptors in body tissue project to a centralized pain center in the brain via A-delta and C fibers. In addition, receptors in the lateral spinothalamic tract of the spinal cord carry the nerve signals throughout the central nervous system (CNS) to a pain center in the thalamus1.

Pattern Theory

The pattern theory was first proposed by Weddell2 and Sinclair3 and is based upon the premise that all nerve endings are alike, except those providing innervation to hair cells, and pain is produced by intense stimulation of nonspecific receptors. Their theory is contradictory to the aforementioned Specificity Theory and has been shown to be false with later studies.

Gate Control Theory of Pain

The gate control theory of pain sought to explain why thoughts and emotions can influence the intensity of pain perception. First proposed by Melzack and Wall in 1965, they assert that a stimulus evokes nerve impulses which relay signals to the cells of the substantia gelatinosa (SG) in the dorsal horn of the spinal cord, the dorsal-column fibers that project to the brain, and the first central transmission cells in the dorsal horn. Further, they state the SG functions as the gate which modulates the afferent patterns before influencing the transmission cells. The afferent signals in the dorsal column system act as a central activator of brain processes and the transmission cells activate neural mechanisms responsible for pain and perception of stimuli. In other words, the individual's perception of pain is a function of his/her emotional state and past experiences and not solely dependent upon the type or intensity of the stimulus.

When no input comes in to the SG, there is no subsequent transmission to the brain. Normal somatosensory input happens when a majority of large fibers are stimulated as opposed to small (pain receptor) fibers. The small-fiber stimulation is inhibited by the gate providing negative feedback. When small fibers are preferentially stimulated, there is no inhibitory feedback from the large fibers and the signal is transmitted to the brain and perceived as a painful stimulus4. (Figure 1.) 

DRUGS

Neurophysiology

The neuron is the most basic cellular unit of the central and peripheral nervous systems. Afferent nerves conduct sensory impulses to the CNS while efferent, or motor, neurons conduct impulses from the CNS to the periphery. The sensation of pain is initiated at the skin, tissue, or mucosal level where the dendritic zone (free nerve endings) starts the impulse which travels along an axon until it reaches the brain for interpretation. The axon is covered by a nerve membrane known as the axolemma which contains a gelatinous substance, axoplasm, that encases the axon. Surrounding the membrane or axolemma, there may or may not be a myelin sheath which can help speed up the transmission of nerve impulses along the associated axon.

In a resting nerve, electrical resistance keeps sodium, potassium, and chloride ions from flowing into the axoplasm.  Upon stimulation, the electrical potential is slightly decreased (known as slow polarization). This changes the conductivity and the membrane now allows sodium and potassium ions to pass into the axoplasm. The transfer of ions across the membrane provides the energy source allowing the impulse to propagate along the axon until reaching the CNS. If there is enough polarization to reach the threshold potential, a rapid depolarization of the membrane occurs. The electrical potential is then reversed which results in an external negatively charged environment and an internal positively charged environment. After the depolarization is complete, the membrane gradually returns to the normal resting potential5.  

Pharmacology of local anesthetics and vasoconstrictors

Local anesthetics block the conductivity of neurons by inhibiting the influx of sodium ions through ion channels in the nerve membrane. Receptors within the sodium channels house the binding sites for most local anesthetic compounds. The affinity of the compounds is significantly greater during either the activated or inactivated states, as opposed to minimal receptor affinity in the resting state. This property leads to the conclusion that the neural fibers having more rapid firing rates are most susceptible to local anesthetic action. Clinically, this explains why the trigeminal nerve branches V1, V2and V3 which contain only small, rapid-firing sensory fibers respond well to anesthesia. The diameter of a nerve fibercorrelates to its firing rate thus the reason that pain fibers are more sensitive than pressure or proprioceptive fibers and this explains why a patient may still feel pressure during a routine dental extraction in the absence of any pain transmission5,6.

Chemical structure

The structure of all local anesthetics have three common components, namely the lipophilic aromatic ring, and intermediate ester or amide linkage, and a tertiary amine. The rate of onset of an anesthetic is related to the proportion of molecules that exist in a lipid-soluble (rapid onset) versus a water-soluble (slower onset) state. In order to be stabilized for transport and administration, the molecule is formulated as a hydrochloride salt rendering it in a water-soluble state that must be converted at the site of injection. In an acidic environment, such as in inflamed tissue or a localized infection, this transformation is less likely to occur making it more challenging to achieve anesthesia at these sites7.

The intermediate linkage is what classifies the anesthetic as an amide-type or ester-type and is noteworthy in patients with allergies to local anesthetics. Typically, patients allergic to amide-type local anesthetics can be administered ester-type anesthetics with no complications. It also helps to determine the pattern of elimination during metabolism. The tertiary amine is what aids in binding and metabolism of the anesthetic molecule. If this amine exists in a tertiary form, with 3 chemical bonds, it is lipid-soluble and if it exists in a quaternary form, with 4 chemical bonds it will be water-soluble6.

Clinical action of specific anesthetics

In regards to the aforementioned intermediate linkages, amides are metabolized in the liver whereas esters, such as benzocaine, are hydrolyzed in the bloodstream by plasma esterases5,6. Most commonly used anesthetics such as lidocaine, mepivicaine, bupivicaine are amides, as esters have been mostly eliminated due to an incidence of allergy reports5. Articaine is the one exception as it has an amide intermediate linkage but also contains an ester side chain causing it to be metabolized in a manner consistent with ester-type anesthetics6.  Each anesthetic binds at a different site along the nerve membrane5.

Time for Onset

The time to achieve anesthesia is directly related the anesthetics lipid solubility. Other contributing factors the time for onset include the vasodilatory properties inherent in anesthetics (faster onset) as well as sequestration is adjacent adipose tissues or myelin sheaths (slower onset). Concentration of the anesthetics is also significant as the commercially-available articaine in 4% concentration has a faster onset than the equally lipid-soluble bupivicaine which comes in a 2% preparation.

Onset of anesthetic action is first and foremost determined by the proportion of molecules that exist in a lipid-soluble state versus a water-soluble state. The more molecules in the tertiary structure at physiologic pH (7.4), the faster the onset with be. This proportion is expressed and can be calculated using the Henderson-Hasselbalch equation: log (cationic form/uncharged form) = pKa – pH 

Moreover, an anesthetic with a neutral pKa of 7.4 injected into healthy tissue at pH 7.4, there would exist an equal proportion of charged and uncharged molecules. However, only the half these molecules would be able to enter the membrane and contribute to anesthesia in the patient. All anesthetic compounds have an actual pKa greater than 7.4. In sites with significant inflammation or infection, the body's pH is lowered beyond 7.4 and this an anesthetic with a lower pKa such as mepivicaine (pKa = 7.6) is a better choice than bupivicaine, which has a pKa of 8.16.

Duration of Action

The duration of action of local anesthetics is variable based upon their affinity to bind to protein. In the bloodstream, anesthetics can reversibly bind to plasma proteins. The greater this protein affinity is, the longer the time it will sustain neural blockade and result in anesthesia. This explains why bupivicaine, a long-acting local anesthetic, binds 95% of proteins whereas mepivicaine, a short-acting anesthetic, only has a 55% protein binding affinity6. (Figure 2.)  

Duration can also be affected by the time an anesthetic remains in close proximity to the nerve fibers. In order to increase this time, and slow the absorption to the bloodstream, vasoconstrictors or vasopressors are added to many formulations of anesthetics. Most common is epinephrine is 1:50,000 (for best hemostasis), 1:100,000 or 1:200,000 concentrations. Levonordefrin is also a commonly used vasoconstrictor. These additives allows the anesthetic molecules to remain at the site of injection for a longer time, thus more anesthetic crosses the neural membrane and reduces pain transmission, as opposed to being transported through the bloodstream, metabolized, and excreted5,7. The use of vasoconstrictors should be carefully balanced against the risks in patients with hypertension, cardiovascular disease, or hyperthyroidism. No more than 2 carpules of lidocaine with 1:100,000 epinephrine should be used on epinephrine-sensitive patients5

MEDICO-LEGAL CONSIDERATIONS/TOXICITY

Local anesthetics have been linked to approximately 50% of all deaths in dental offices. The proper dosage of anesthetic is the lowest dose that will produce adequate anesthesia. Toxicity can be caused by a simple overdose or miscalculation, administration to an allergic or sensitive individual, intravascular injection, or by improper drug combinations. High levels of any local anesthetic in the bloodstream can affect the cardiovascular system, the nervous system, and local tissues. Thus, aspiration before injection should be a critical step in the practitioner's technique. Negative aspiration does not guarantee that the bevel of the needle is not in a vessel at the time of injection.

Symptoms of toxicity include a patient that is overly sleepy, or lethargic, after administration of the local anesthetic.  Other signs and symptoms include slurred speech, excitement, shivering, muscular twitching, and tremor of facial muscles or extremities. Some patients also feel warm, flushed skin, lightheadedness, dizziness, diminished sight, tinnitus, or disorientation. If a patient takes a CNS depressant, the combination with local anesthesia will reduce the toxic level for the patient and the dosage given should be monitored even more closely and potentially reduced.

For lidocaine, the toxic limit, according to Malamed Handbook of Local Anesthesia8 is 2 mg/lb with a maximum dosage of 300 mg. In a 2% lidocaine carpule, there is 20 mg of xylocaine per mL of the drug solution. A typical carpule is 1.8 mL in volume, so 20 mg/mL x 1.8 mL = 36 mg per carpule. Thus, for a 180 lb. patient, he/she could be safely administered up to 8 carpules to stay under the maximum recommended dose of 300 mg. In pediatric patients, a 50 lb. child  may only be given up to 2.7 carpules to safely stay under the toxic limits8.

Symptoms of epinephrine overdose include fear, anxiety, restlessness, headache, tenseness, perspiration, dizziness, tremor of limbs, heart palpitations, and weakness. The patient will experience an elevated blood pressure and heart rate. Some mild forms of these symptoms can be experienced by patients even following low dosages of epinephrine administration5.

ARMAMENTARIUM

Preparation

To prepare the armamentarium for patient injection, the syringe should be removed from the sterilization pouch, the needle should be firmly attached to the screw end. Then, the practitioner should retract the piston fully, and insert the cartridge, making sure to engage the harpoon. The colored cap on the needle should be removed just before the time of injection. To recap the needle after the injection, the scoop technique is the preferred method; needles should never be recapped by hand5.

The syringe

Syringes for local anesthesia administration come in five basic types with the most widely used being the metal aspirating syringe. Others include breech-loading, metal (self-aspirating or non-aspirating), pressure injectors, jet injectors, and plastic syringes. Pressure injectors are used mainly for intraligamentary injections to the periodontal ligament (PDL). Caution must be used as these can make it possible to bruise the tissue by rapid administration of anesthetic solution (20 seconds for 0.2 mL of solution is the recommended rate). Plastic syringes are lighter and are considered more esthetically pleasing to nervous patients5

The needle

Needles are available in a wide variety of lengths and diameters. Long, 25-gauge needles should be used for inferior alveolar nerve blocks, Gow-Gates and Akinosi mandibular blocks. Short, 25 or 27-gauge needs are recommended for use with other injections. Smaller needles tend to deflect more as they are inserted into tissue, and with the use of topical anesthetics, do not result in any less pain or trauma to the patient. After 3 or 4 injections on the same patient, the needle should be changed as it can become dull causing the patient to feel the insertion5.

The cartridge

In the United States, most anesthetic cartridges, or carpules, contain 1.8 mL of anesthetic solution. A latex or rubber stopper treated with silicone keeps the liquid contained in the syringe and allows for easy propulsion of the solution through the needle. The opposite end usually contains an aluminum cap with a semipermeable membrane. Inside the cartridge is the local anesthetic, sodium chloride, distilled water, and potentially a vasoconstrictor drug with preservative5. Each type of local anesthetic has its own color-coded ring that encircles the cartridge and is standardized across manufacturers.

Additional armamentarium

Additional armamentarium commonly used for local anesthetic administration include topical anesthetics which are strongly recommended to be applied to the anticipated injection site in advance. These come in a variety of forms including ointments, gels, pastes, and sprays. Further, applicator sticks for the topical anesthetic are often necessary along with cotton 2x2 gauze and a hemostat.

TECHNIQUES OF LOCAL ANESTHETIC ADMINISTRATION

Physical and Psychological Evaluation

On every patient in the dental clinic, including those who will be receiving local anesthetics, a complete and thorough medical history is required. The medical history should be reviewed for updates with the patient at each visit; if there have been any changes to their medical history, these should be noted in the chart with the date.  After discussing with the patient and based on clinical expertise, the dentist must determine whether to proceed with treatment, reschedule the patient for another day, or postpone treatment until the patient's physician is consulted to provide a medical clearance. Before treatment is commenced, and local anesthetic is injected, the patient's vital signs (blood pressure, heart rate, respiration rate) should be taken and noted in the chart5. If severe anxiety is present, it is not safe to administer local anesthesia and the patient should either be rescheduled when he/she is more relaxed or be treated under sedation in the future if the anxiety cannot otherwise be managed successfully.

 American Society of Anesthesiologist's Physical Status Classification System  

The most widely accepted assessment of peri-operative risk was adopted by the American Society of Anesthesiologists. This can be used as an aid to dental professionals in determining how to proceed with medically-compromised patients. There are currently six classifications to determine the fitness of the patient before surgery.

ASA Class I – Healthy individual, no medical conditions  

ASA Class II – Mild systemic disease

ASA Class III – Severe systemic disease  

ASA Class IV – Severe systemic disease that is a constant threat to life  

ASA Class V – A moribound individual who is not expected to survive without the operation9

ASA Class VI – A declared brain-dead individual whose organs are being removed for donor purposes

Generally, ASA classes I and II are safe to proceed in an outpatient dental clinic. Class III patients may require a medical consult before commencing treatment and Class IV patients should likely be treated in a surgical center or hospital setting that is equipped to deal with any potential complications. ASA Class V and VI patients are not candidates for dental procedures and would be handled by hospital emergency rooms or intensive care units.

Basic Injection Technique

Firstly, in order to provide the most atraumatic injection, both patient and practitioner should be as relaxed as possible. The tissue should be penetrated up to the end of the bevel. Monitor the patient for any signs of discomfort and slowly deposit a drop or two of anesthetic solution. Then advance the needle slowly to the target depth, deposition solution slowly along the way. If bone is contacted, deposit a few drops there as well, pause for a few seconds due to the significant innervation and vascularization that exists in this area. Aspirate the syringe: if aspiration is negative (no blood in the cartridge), deposit a few more drops, aspirate again and deposit more anesthetic. If aspiration produces blood in the cartridge, withdraw the needle slightly and repeat the process. After injection is complete, slowly withdraw the needle and recap it using a proper technique5,8

Anatomical Considerations

The extent of the effectiveness of a local anesthetic depends upon where the anesthetic is deposited relative to the nerve(s) innervating the tooth. Local infiltration techniques deposit anesthetic near superficial nerve endings and anesthesia is limited to that targeted area like a papilla or frenum. Field block anesthesia deposits solution near terminal nerve branches and provides pain reduction for a wider area of treatment such as injecting near the apex of a tooth, effectively numbing the tooth and the surrounding tissue. Nerve block anesthesia deposit anesthetic near the main nerve trunk providing for the broadest area of profound anesthesia as is seen in the IAN block which can numb the tongue, teeth, and soft tissue on the ipsilateral side of injection5,7,8.

Techniques of Maxillary Anesthesia

Supraperiosteal Injection

Also known as maxillary infiltration, this is the most popular injection to achieve pulpal anesthesia of the maxillary anterior teeth. It is ideal for numbing a single tooth or perhaps 2-3 teeth to be treated. A 25 or 27 gauge short needle is to be used, which is inserted at the height of the mucobuccal fold near the apex of the tooth. The bevel of the needle should be pointed towards the bone and approximately 1/3 of a cartridge deposited after negative aspiration.  

Posterior Superior Alveolar (PSA) Nerve Block  

The PSA nerve block is used for obtaining anesthesia in the maxillary molars. Again a short 25 or 27 gauge needle is to be used, inserted at the height of the mucobuccal fold by the maxillary second molar. The needle's path of insertion is up, back, and inward towards the PSA nerve. For this block, approximately ¾ to a full cartridge of anesthetic may be required. Keep in mind that sometimes, the mesiobuccal root of the maxillary first molar will not be innervated by the PSA and a supplemental injection site may be needed if working on this tooth.  

Middle Superior Alveolar (MSA) Nerve Block  

The MSA nerve is only present in about 20% of the population and should only be used in cases where the infraorbital and PSA injections do not provide adequate anesthesia to posterior teeth. The technique is the same as the PSA only the site is at the mucobuccal fold of the maxillary second premolar.  

Infraorbital Nerve Block  

Infraorbital nerve blocks will anesthetize the area from the maxillary central incisor to the premolar area. It is the preferred technique over multiple supraperiosteal injections as one can use less anesthetic and cause less trauma to the patient with fewer injection sites. The practitioner must locate the infraorbital foramen near the lower border of the orbit. Then, with a short 25 gauge needle inserted in the mucobuccal fold over the first premolar, ½ to 2/3 cartridge of anesthetic is deposited after negative aspiration. After withdrawing the needle, it is important to apply finger pressure to the patient's fact over the foramen area to help the anesthetic penetrate into the foramen.

Greater Palatine Nerve Block  

The greater palatine nerve innervates the palatal gingiva and mucosa distal to the canine on the side of the injection. Using a short 27 gauge needle, with the bevel towards the palate, palpate for the depression of the foramen is felt, typically just medial to the second molar and about ¾ of an inch below the free gingival margin of the first and second molars. Dry the site, apply topical for 2 minutes and apply pressure with the cotton applicator. Inject along the way until reaching the palatal bone, while still providing pressure with the swab, only a few drops of anesthetic is needed due to the tautness of the tissue.  

Nasopalatine Nerve Block  

The nasopalatine nerve innervates the hard palate, gingiva, and mucosa for anterior tissue lingual to the first premolar. The site of injection is just posterior to the incisive papilla. The technique should be identical to the greater palatine block, just with a different site of administration5.

Techniques of Mandibular Anesthesia  

Inferior Alveolar Nerve (IAN) Block  

A long 25 gauge needle should be used for this block to numb the mandibular teeth on the side of the injection along with the buccal mucosa and bone of the teeth anterior to the mandibular first molar. The site of injection is at the medial border of the ramus at the pterygomandibular raphe. This should be about 1.5 cm above the mandibular occlusal plane with the bevel pointed towards the bone. The barrel of the needle should be parallel with the occlusal plane of the molars and be centered over the mandibular premolars on the opposite side. Advance the needle slowly, depositing a few drops along the way until the ramus is contacted. Withdraw slightly, aspirate, and deposit ¾ to a full syringe of anesthetic If bone is not contacted, the needle is likely too far posterior and the injection should be attempted again with the barrel over the contralateral first molar5,8.  

Buccal Nerve Block  

The buccal nerve is not anesthetized with the IAN block. It innervates the tissue and periosteum buccal to the molars. A long 25 gauge needle should be used following the IAN block if working in the relevant area. The needle is to be inserted in the mucous membrane distobuccal to the last molar with the bevel facing the ramus. Tissue should be pulled taut, the needle should penetrate 2-4 mm into tissue, contracting bone. Aspirate the syringe, and if negative, slowly deposit 1/8 of the cartridge5.  

Supplemental Injection Techniques  

There are numerous other injection techniques which are used for limited applications. For example a periodontal ligament (PDL) injection can be used as a supplement for an extraction or periodontal surgery to provide more depth of anesthesia to a tooth without adversely numbing other teeth, the tongue, or lips. Intraosseous injections may allow access into the pulp chamber of an affected tooth. Intraseptal injections can be given into the papilla to control hemostasis and provide additional soft tissue or osseous anesthesia5.  

Considerations in Dental Specialties  

In endodontics, if a tooth is considered “hot” and cannot be fully numbed by means of one of the aforementioned techniques, sometimes the treating doctor will slowly inject some anesthetic directly into the pulp chamber of the tooth. Proceed with caution as this technique can be mildly unpleasant for the patient and should be used as a last resort. After a few drops are deposited into the pulp chamber, the nerve should be anesthetized and root canal therapy should be able to be completed. Intraosseous injections, as well as PDL injections may be useful in providing endodontic therapy to a patient in need5.  

COMPLICATIONS  

Local Complications  

Pain on Injection  

The most common complication associated with local anesthesia is pain on injection. This can be caused by injecting too rapidly, injecting too much solution, or having a rough or nervous dental practitioner5,8.  

Parasthesia  

Parasthesia is the feeling of unwanted, prolonged numbness and can be caused by the needle damaging the nerve or passing through it10. Most parasthesias resolve on their own within several months. However, the patient should be closely monitored for resolution and appropriate referral to a neurologist or oral surgeon may be warranted8.  

Hematoma  

After the dental appointment, the patient may experience a hematoma if the needle nicks one or more blood vessels during the injection. These occur most often after a PSA block or IAN block. Advise the patient of possible soreness, but the hematoma should resolve on its own within 7-14 days and typically does not require additional treatment5,10.

Trismus  

Trismus, or difficulty in opening the mouth, is caused by trauma to muscles of blood vessels in the infratemporal fossa. Sometimes, depositing too much anesthetic solution in this area can bring about symptoms of trismus. Heat therapy and exercise of the jaw muscles are the recommended treatment and if symptoms do not resolve in 2-3 days, antibiotics or referral to a specialist may be necessary5,8,10.  

Bell's Palsy (Facial nerve paralysis)  

If the local anesthetic is injected into the parotid gland, containing branches of the facial nerve, the patient's face will droop and he/she will not be able to close their eye. This usually occurs as a complication of a failed IAN block, and is thus self-limiting, meaning symptoms will dissipate as the anesthetic is metabolized5,8.  

Systemic Complications

Systemic complications in response to local anesthetic administration are rare, but when they occur, can be severe, even life-threatening. These would include toxicity as described earlier in this review, along with seizures, coma, or death. These can manifest in healthy patients or in medically-compromised patients. Timeliness of response is key in order to minimize the long-term effects of any complications. In patients with known or unknown sensitivities to local anesthetics or the preservatives used, anaphylactic shock is also a possible outcome. By obtaining an adequate medical history, sticking to the dosage guidelines, and being astutely aware of all changes in a patient's appearance/vitals, a practitioner can hopefully intervene before a systemic complication becomes life-threatening; prevention is key8,10,11.  

TRENDS/ALTERNATIVES

TENS (Treanscutaneous electrical nerve stimulation)  

Proper electronic dental anesthesia can eliminate the need for topical and injectable local anesthetics during a procedure. The patient can control the level of the electrical impulses which relates to the level of anesthesia needed. There are many theories as to the underlying mechanism, but none have been proven definitive yet5. This alternative form of anesthesia has yet to catch on in the mainstream dental marketplace.

Lidocaine Patch

The DentiPatch is an adhesive patch containing 46.1 mg of lidocaine. Resembling a Band-Aid, it provides mild topical anesthesia for a quick procedure or prior to injection of a local anesthetic5. As with the TENS device, this has also failed to transform the marketplace.  

WaterLase (Dental Lasers)

The WaterLase laser created by Biolase, while not an alternative form of local anesthesia eliminates the need for anesthetic when performing a restorative or simple surgical procedure. Again, the mechanism is not fully understood, but a filling, including inlays/onlays may be prepared and caries removed from a tooth by use of the laser. This is marketed towards dentists who want to be on the cutting-edge of technology as well as patients whom are fearful and experience anxiety in response to the injections of local anesthetics12.  

REFERENCES  

  1. Head, H. Studies in Neurology . London: Keegan Paul; 1920
  2. Weddell, G. Annu. Rev. Psychol.1955; 6: 119.
  3. Sinclair, D.C. Brain 1955; 78: 584.
  4. Melzack, R & Wall, P.D. Science 1965; 150: 3699. 
  5. Mennito, A.S. Local Anesthetic Review. The Academy of Dental Learning & OSHA Training 2012.
  6. Becker, D.E. & Reed, K.L. Local Anesthetics: Review of Pharmacological Considerations. Anesth. Prog. 2012; 59: 90-102.
  7. Berde, C.B., Strichartz,G.R. Local Anesthetics. In: Millers, R.D., Eriksson, L.I., Fleisher, LA. Et al, eds. Miller's Anesthesia. 7th ed. Philadelphia, PA: Elsevier, Churchill Livingstone; 2009.
  8. Malamed, S.F. Handbook of Local Anesthesia. Maryland Heights, MO: Mosby; 2004.
  9. New Classification of Physical Status. Anesthesiology. 1963; 24: 111.
  10. Schatz, M. Adverse reactions to local anesthetics. Immunol Allergy Clin North Am. 1992; 12: 585-609. 
  11. Neal, J.M. et. al. ASRA Practice Advisory on Local Anesthetic Systemic Toxicity. Regional Anesthesia and Pain Medicine. 2010; 35(2): 152-161.
  12. Dental Lasers. http://www.biolase.com//products/iplus. Accessed June 12, 2014.
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