A concise review of the basic biology and pharmacology of local analgesia

S Subramaniam,* M Tennant

Abstract Local analgesics are the most commonly used group drugs in dental practice. However, due to their frequent use and high margin of safety, often dental practitioners neglect to properly understand the biology and pharmacology of these drugs. This article reviews the basic concepts of pain, pain pathways, the mode of action of local analgesics and factors which affect their usage. Specific details and properties of some currently available solutions are also outlined. A greater understanding of the biology and pharmacology of local anaesthetics will ultimately lead to safer and more effective use in everyday clinical practice.
Key words: Local analgesia, drugs in dentistry, pain. Aust Dent J 2005;50 Suppl 2:S23-S30

INTRODUCTION Local analgesic drugs are the most commonly used drug group in dentistry. Some 9000 practitioners in Australia conservatively give 10 or more local analgesic doses per day which equates to between 15 and 20 million doses per annum. Against this backdrop of common usage an in-depth understanding of the biology and pharmacology of local analgesia is often lost in the volumes of other information required for quality dental practice. Importantly, local analgesia has a very good safety record, with the incidence of significant side effects very low.1,2 This safety margin is also increasing as the list of drug interactions diminishes and a better understanding developed of the pharmacological dynamics of local analgesics.3 Increased safety often changes a clinicians perspective on the importance of understanding the pharmacology of the drug interactions and complications that can arise from local analgesic usage. It is difficult to remove the innovations in delivery modes from a discussion of local analgesic biology and pharmacology. It is acknowledged that the invention of hypodermic syringes in the mid 1800s significantly improved the delivery of local analgesia, reducing the risk to patients.4,5 This review will not focus on delivery modes or the technological advancements in this area, but will limit itself to a review of the biology and pharmacology of local analgesia.

Definitions Two often confused words are analgesia and anaesthesia.6 Analgesia is the removal of pain sensation whilst anaesthesia is the loss of sensation in general (including pain). This separation is important and often lost in dentistry with many people (and publications) using the terminology local anaesthesia, which is not a precise definition of what dental practitioners aim to achieve with the use of the drugs in their armamentarium. For consistency this review will use the term local analgesia to describe the effects that dental practitioners aim to achieve in normal clinical activity. Injection is the common mode of delivery for local analgesia in dentistry. The technique of injection depends on many factors but can be summarized into two fundamental groups. An infiltration implies that the location of injection is the location of effect, whilst a regional block is given at a site distant from the effect. Regional block analgesia is achieved by injecting the drug to a site adjacent to nerve fibres as they pass towards the site of innervation. This grouping is not limited to dental practice and the definitions of infiltration and regional block are used throughout medicine. Psychology of pain To understand the biological processes of local analgesia it is necessary to review the basic biology and psychology of pain perception. Practising clinicians in a field where painful stimuli are common are acutely aware of the day-to-day application of this biology. However, consideration and coalescence of an understanding of pain and its perception is an important structural prelude to understanding the action of local analgesia. Different people, and individuals at different times, react differently to painful stimuli.7 The modalities available to modify someones threshold for pain are important to acknowledge and are often valuable adjuncts to interventional strategies (e.g., local analgesia). A list of pain threshold modifiers includes but is not limited to: time of day; other medical treatment; previous history; understanding of the procedure; sleep deprivation; and age and sex. The biological theory behind a persons ability to modify their pain threshold is based on nerve pathways from the higher areas of the central nervous system (e.g., cortex) sending action potentials downward to block the inward pain stimuli. Similarly, some lower
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*Dental Officer, Centre for Rural and Remote Oral Health, The University of Western Australia. Associate Professor and Director, Centre for Rural and Remote Oral Health, The University of Western Australia.
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centres (e.g., brain stem) can also modulate the flow of action potentials related to pain.7 This central modulation is most evident in people who manage extraordinary feats whilst suffering from major trauma (e.g., rescuing survivors of plane crashes whilst suffering from multiple fractures). Pain pathways Receptors Pain stimuli receptors are distributed throughout the tissues of the body. They are fundamentally naked nerve endings with no specialist receptor and these nerve endings are stimulated to initiate a train of action potentials.6 The stimulation is through direct mechanical stimuli. A number of biologically active molecules released from adjacent tissues can also be the trigger (e.g., prostaglandins during inflammation). The action potential travels back to the central nervous system through neuron processes where processing of the sensory input (afferent) is completed. Processes and action potential promulgation For local analgesia the most important part of the structure of the pathway for pain sensory information is the transmission of action potentials along the neuron process. Neuron processes (both axons and dendrites) are extensions of neurons and contain cytoplasmic elements like other cells. These processes (and in fact the entire neuron) have some fundamental specializations associated with the cell membrane that gives rise to their primary feature of being able to transmit electrical impulses (action potentials) along their surface. The intracellular components of a neuron are consistent with other cells. The cell membrane consists of a lipid bi-layer with numerous embedded proteins. The lipid bi-layer separates the two water-based environments: intercellular fluid from the cytoplasm. Along the length of the process is a complex array of microtubule apparatus involved in the transportation of vesicles (mainly containing neurotransmitters) from the neuron cell body to the synapses at the distant ends of neuron processes. Within the neuron is a mixture of ions including potassium (K+), sodium (Na+), calcium (Ca2+) and chloride (Cl-). These ions are also found in the intercellular fluid that bathes the outside of all neurons. Critically, the balance of ions between the cytoplasm of the neuron and the intercellular fluid that bathe them is managed within a very tight range. Most importantly is the management of Na+ and K+, which are kept in a state of imbalance. Comparing the intercellular fluid concentration of K+ and Na+ with that of the cytoplasm of the neuron finds K+ is about 25 times higher in the cytoplasm whilst Na+ is 15 times higher in the intercellular fluid. This imbalance is maintained through a complex electro-chemical pathway that is beyond the scope of this discussion. However, critical to the process is the presence of specific protein
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channels that at rest do not allow Na+ ions to pass and active Na+ pumps that facilitate the maintenance of the imbalance. This ionic imbalance results in the resting membrane potential of 60 to 90 mV across the neuron cell membrane.6 The promulgation of an action potential down the length of a neuron process happens in a manner analogous to the childrens game pass-the-parcel. Starting from the receptor end of the process and continuing away from the receptor, a rapid change in ionic concentration, resulting from sodium flux across the cell membrane, moves down the process. An action potential is the outcome of this rapid ionic flux, which results in sodium ions rapidly entering the neuron (following the concentration gradient) through the opening of the specific sodium channels. The net effect of this sodium influx into the neuron is a reversing of the membrane potential to +40mV for a short period of time (about 0.3 milliseconds). To terminate the action potential requires energy, as the Na+ pump (a specific protein) in the cell membrane finally restores the ionic equilibrium to the resting state equivalent to that before the rapid sodium influx induced depolarization. The critical part of the promulgation of the action potential is the opening of the sodium channels and it is this that is targeted by local analgesics.8-11 Myelination Most clinicians are well aware there are different types of neuron processes; some having a relatively thick layer of insulation (myelin) and some being naked of insulation (unmyelinated).6 This difference has a significant impact on the rate of action potential promulgation. In the peripheral nervous system myelin is produced by Schwann cells and is an extension of the Schwann cell membrane that wraps multiple times around the neuron process. Between each Schwann cell wrapping is a gap known as the Nodes of Ranvier. The myelin makes significant improvements in the speed of action potential travelling down the neuron processes and is found predominantly on processes requiring rapid promulgation of information (e.g., motor fibres). Lack of myelin has two effects. Firstly, it reduces the rate of promulgation. Secondly, it allows action potentials to be triggered in adjacent processes. Neuron processes associated with the promulgation of pain are predominantly unmyelinated fibres and this accounts for the relatively slow transmission of pain information back to the central nervous system. Diseases that damage myelin (e.g., multiple sclerosis) result in a significant increase in anomalous recruitment of processes causing significant impairment of function (i.e., misfiring of action potentials). Mode of action of local analgesics The primary mode of action of local analgesic compounds is to impede the permeability of neuron cell membrane to sodium.8,11 This action prevents the rapid
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influx of sodium during the depolarization phase of an action potential development and prevents its onward transmission. For local analgesic compounds to affect the sodium channel they must bind to specific receptors on the channel. These specific binding sites are found on the intracellular side of the channels. This has significant implications for the molecular structures of local analgesic compounds and has clinical implications for the failure to gain local analgesia under some conditions that will be discussed later. The cell membrane (of all cells including neurons) is made of lipid molecules. A local analgesic needs to bind to the intracellular receptor on the sodium channel to be effective; the local analgesic needs to be lipid soluble (i.e., uncharged) to diffuse through the cell membrane (unless there is a protein transport mechanism, which is not the case for local analgesics). Once inside the neuron the local analgesic molecule needs to be charged to bind to the receptor, which is opposite to the lipid soluble state required for entry. To resolve the need to be both uncharged and charged the local analgesic molecule, as it is exists in its available preparations, is a mixture of charged and unchanged states. The balance between the two states is determined by two factors; firstly the pH of the carrier solution and secondly a chemical constant (i.e., dissociation constant) of the molecule called the pKa.6,12 If the solution in the intercellular environment is a mixture of 50 charged and 50 uncharged molecules of local analgesic the 50 uncharged will be able to pass through the lipid cell membrane of the neuron into the cytoplasm. Once in the cytoplasm those 50 uncharged molecules will reach a steady state of 25 charged and 25 uncharged (this assumes the same pH in the intercellular and cytoplasmic environments). The 25 charged molecules are then available to bind to the receptor on the sodium channel and thus block the action potential promulgation. The two key variables (pKa and pH) in the movement of local analgesic molecules into the neuron and subsequent binding to its receptor can be influenced by the clinician and/or pharmacologist. Changing these variables clinically affects the rate of onset of analgesia because it affects the rate of receptor binding. For example, the lower the pH (i.e., the more acidic) the further the balance is shifted to the charged state. Clinically inflamed tissues have a lower pH (i.e., more acidic). Injecting local analgesic into inflamed intercellular fluid results in more molecules existing in the charged state and therefore less local analgesic able to cross the cell membrane. This leads to fewer molecules being available to bind to the receptors resulting in a reduced effectiveness of the local anaesthetic. Similarly, different local analgesic molecules have different pKa (dissociation) values. A high pKa value indicates that more molecules in the solution exist in a charged state and fewer molecules are uncharged. This
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Table 1. Ideal properties of a local analgesic drug

Low rate of allergic reactions Sterilizable Compatible with other drugs Potent Reversible Fixed working time Vasoconstrictive Long shelf life Water soluble Non-addictive Fast acting

means that there are less uncharged molecules to pass through the cell membrane to facilitate the local analgesic effect, thus slowing the rate of onset. Ideal properties of a local analgesic A local analgesic is designed to block the promulgation of action potentials from the receptor back to the central nervous system. However, the drug used must also fulfil a number of important criteria to make it clinically useful. Table 1 outlines some of these ideal properties. Since the first local analgesic compounds were used in the late 1800s attempts continue to make a single compound that fits all these ideal properties.13 Although the modern molecules are close, they do not perfectly fill all the properties and as such the solutions available today are mixtures of various compounds attempting to bring together a blend that meets all the criteria. Type of local analgesics The molecular structures of most local analgesics are similar, having a lipophilic and a hydrophilic part I joined together by a linkage component. The classification of the different molecules into either an ester or the amide group is defined by the linkage part of the molecules.2 There are differences in properties between the two groups. For example the ester group of molecules (including Procaine) are much more watersoluble than the amide group (e.g., Lignocaine). The ester group is metabolized rapidly in the plasma by pseudocholinesterases whilst the amides are transported to the liver for metabolism. It is often noted that a common hereditary condition (affecting 1:3000 people) results in molecular differences in the pseudocholinesterases resulting in the poor metabolism of the ester molecules and increasing the risk of adverse outcomes (e.g., methemoglobinemia). Historical perspective of local analgesia Although far from comprehensive a short dissertation on the historical molecules used as local analgesics provides an important basis for understanding the properties, indications and contraindications of currently employed local analgesic molecules.1,13,14 Cocaine In the mid to late 1800s cocaine was the first local analgesic molecule used. It had some advantages, being a good vasoconstrictor, and provided profound analgesic effects. However, there were a number of
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Table 2. Calculation of maximum dosages for local analgesics

Maximum dose (carpules of LA) = Body weight x maximum dose (mg/kg) Total amount of local analgesic (mg) E.g., Lingnospan Special used on a Healthy (ASA I) male weighing 65kgs Contains: each 2.2ml carpule is 2% lignocaine w/v. Maximum dosage: 7mg/kg (absolute 500mg)

Thus: To calculate the total amount of lignocaine in one carpule: 0.02 x 2.2 = 0.044g (44mg) the maximum dosage in carpules is calculated by: 65(kg) x 7(mg/kg) 44 = 10.3 carpules (rounded to 10)

*for calculations of maximum doses for multiple drugs, the above formula is used for each drug separately, however the total dose for both the local analgesics should not exceed the maximum total dose for the drug with the lower maximum total dose. For example if Lignocaine (absolute maximum dose: 500mg) and Prilocaine (absolute maximum dose: 400mg) are used together, then 400mg is the total absolute maximum dose when the total doses of both drugs are combined.

reasons for its removal as a local analgesic of choice for dentistry, primarily its addictive properties. Procaine Developed in the very early 1900s, procaine was the local analgesic of choice until the late 1940s. Procaine is remembered as a less toxic, less potent and vasodilative local analgesic compared to cocaine. In addition, procaine did have a high level of sensitivity, resulting in allergic reactions in many people. Lignocaine This amide group local analgesic was developed in the mid to late 1940s and is still in use today. Its key Table 3. Lignocaine hydrochloride
Lignocaine hydrochloride Proprietary names Concentration of LA Vasoconstrictor Approximate duration of action (mins) Methods of use Indications for use Contraindications

improvements on procaine were that it had a faster speed of onset, a longer duration of action and allergic reactions were less likely.15,16 Plain lignocaine has a vasodilating effect. It has a vasconstrictor added to its clinical preparations. Effects beyond the local effects The key non-local effects of local analgesic molecules are related to their ability to block Na+ channels and thus stabilize membranes. After crossing the blood brain barrier these molecules can, and at toxic levels will, lead to convulsions and seizures. Early signs include slurred speech, muscle twitching, visual disturbances and disorientation, while later with increased dose

Xylocaine 2% None Pulpal 5-10 Soft tissue 60-120 Infiltration and regional nerve blocks Very short acting drug with limited applications Absolute: Relative: Allergy to the Liver or renal analgesic or any of dysfunction its constituents (ASA III-IV)

Maximum dosage Summary of adverse effects

Summary of toxic effects

Alternatives *note: these drugs are alternatives NOT direct substitutes, thus pharmacology of each alternative must be assessed prior to its appropriate administration.
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4.4mg/kg (absolute max 300mg in adults) More common: Nervousness, dizziness, blurred vision, tremors, drowsiness, tinnitus, numbness, disorientation, nausea and vomiting Less common: Convulsions, unconsciousness, respiratory depression or arrest, cardiac arrest Allergy: Cutaneous lesions, urticaria, oedema, or anaphylactoid reactions CNS effects: Nervousness, dizziness, burred vision, tremors, drowsiness, convulsions and unconsciousness Respiratory effects: Respiratory arrest CVS effects: Peripheral vasodilatation, hypotension, myocardial depression, bradycardia and possible cardiac arrest Prilocaine and Mepivacaine (without Articaine, Prilocaine, Mepivacaine (with vasoconstrictors) vasoconstrictors) *Prilocaine with Octapressin can be used if an alternative drug without adrenaline is needed.

Xylocaine with adrenaline or Lignospan Special 2% 1:80 000 adrenaline Pulpal 60-90 Soft tissue 180-300 Infiltration and regional nerve block Suitable for use in most dental procedures Absolute: Relative: Allergy to the Liver or renal analgesic or any impairment (ASA III-IV) of its constituents *CVS disease or hyperthyroidism are relative contraindications due to adrenaline not the analgesic agent itself. 6.6mg/kg (absolute max 500mg in adults)

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Table 4. Prilocaine hydrochloride

Prilocaine hydrochloride Proprietary names Concentration of LA Vasoconstrictor Approximate duration of action (mins) Methods of use Indications for use Contraindications Citanest with Octapressin Citanest with adrenaline 3% 3% 0.03 IU/mL Octapressin 1:300 000 adrenaline Pulpal 40-90 Soft tissue 150-210 Pulpal 30-90 Soft tissue 120 Infiltration and regional nerve blocks Suitable for use in most dental procedures Absolute: Relative: Absolute: Relative: Allergy to the Atypical plasma Allergy to the Atypical plasma analgesic or any cholinesterase, analgesic or any cholinesterase, of its constituents methaemo-globinemia, of its constituents methaemo-globinemia, significant renal significant renal impairment (ASA III-IV) impairment (ASA III-IV) *Pregnancy is a relative *CVS disease or contraindication to the hyperthyroidism are Octapressin which is relative similar to oxytocin thus contraindications due thought to induce uterine to adrenaline contractions 6.0mg/kg (absolute max 400mg in adults) 6.0mg/kg (absolute max 400mg in adults) More common: Nervousness, dizziness, blurred vision, tremor, drowsiness, tinnitus, disorientation, nausea and vomiting Less common: Convulsions, respiratory depression or arrest, hypotension, cardiovascular arrest and methaemoglobinemia Allergy: Cutaneous lesions, urticaria, oedema, or anaphylactoid reactions Nervousness, dizziness, blurred vision, tremors followed by drowsiness, convulsions, unconsciousness and possible respiratory arrest Mepivacaine, Lignocaine or Citanest Plain Lignocaine, Mepivacaine or Articaine (with *if Citanest with Octapressin is being used vasoconstrictors present) because it does not contain adrenaline, any of the *Prilocaine with Octapressin can be used if an above plain preparations can be used, however alternative drug without adrenaline is needed. the duration of action will be shortened.

Maximum dosage Summary of adverse effects

Summary of toxic effects Alternatives *note: these drugs are alternatives NOT direct substitutes, thus pharmacology of each alternative must be assessed prior to its appropriate administration.

Table 5. Articaine hydrochloride

Articaine hydrochloride Proprietary names Concentration of LA Vasoconstrictor Approximate duration of action (mins) Methods of use Indications for use Contraindications Septanest 1:100 000 Septanest 1:200 000 4% 1:100 000 adrenaline 1:200 000 adrenaline Pulpal 60-75 Soft tissue 180-360 Pulpal 45-60 Soft tissue 120-300 Infiltration and regional nerve blocks Suitable for most dental procedures in patients above the age of four Absolute: Relative: Allergy to the analgesic or constituents Liver or renal impairment (ASA III-IV) *CVS disease or hyperthyroidism are relative contraindications due to adrenaline not the analgesic agent itself 7mg/kg (absolute maximum 500mg in adults) Headache, facial oedema, gingivitis, para-, hypo- and dysaesthesia (usually temp) and nausea. Large doses in susceptible patients may induce methaemoglobinemia (very rare) Allergy: Cutaneous lesions, urticaria, oedema, or anaphylactoid reactions CNS: Nervousness, shaking, yawning, trembling, apprehension, nystagmus, logorrhea, headache, nausea, buzzing in ears Respiratory: Tachypnea, bradypnea that can lead to apnea CVS: Reduction in contraction strength of myocardium, thus decreasing heart rate and blood pressure Lignocaine, Prilocaine, Mepivacaine (with vasoconstrictors) *Prilocaine with Octapressin can be used if an alternative drug without adrenaline is needed.

Maximum dosage Summary of adverse effects

Summary of toxic effects

Alternatives *note: these drugs are alternatives NOT direct substitutes, thus pharmacology of each alternative must be assessed in regards to the patient prior to administration.

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Table 6. Mepivacaine hydrochloride

Mepivacaine hydrochloride Proprietary names Concentration of LA Vasoconstrictor Approximate duration of action (mins) Methods of use Indications for use Scandonest 3% plain 3% None Pulpal 20-40 Soft tissue 120-180 Infiltration and regional nerve blocks Routine dental procedures of a short duration where the use of vasoconstrictors in contraindicated. For use in patients three years and older Absolute: Relative: Allergy to the analgesic Liver or renal or any of its dysfunction constituents (ASA III-IV) Scandonest 2% special 2% 1:200 000 Pulpal 60 Soft tissue 120-300 Suitable for use in most dental procedures for patients three years and older

Contraindications

Absolute: Allergy to the analgesic or any of its constituents

Maximum dosage Summary of adverse effects

Summary of toxic effects

Alternatives *note: these drugs are alternatives NOT direct substitutes, thus pharmacology of each alternative must be assessed prior to its appropriate administration.

6.6mg/kg (absolute max 400mg in adults) CNS: Light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, blurred or double vision, sensations of heat, cold or numbness, twitching, tremors, convulsions and unconsciousness and respiratory arrest Respiratory: Respiratory depression and/or arrest CVS: Bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiovascular arrest Allergy: Cutaneous lesions, urticaria, oedema, or anaphylactoid reactions CNS: Light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, blurred or double vision, sensations of heat, cold or numbness, twitching, tremors, convulsions and unconsciousness and respiratory arrest Respiratory: Respiratory depression and/or arrest CVS: Bradycardia, hypotension, and cardiovascular collapse which may lead to cardiovascular arrest Lignocaine and Prilocaine (without Lignocaine, Articaine and Prilocaine vasoconstrictor) (with vasoconstrictors)

Relative: Liver or renal impairment (ASA III-IV) *CVS disease or hyperthyroidism are relative contraindications due to the presence of adrenaline 6.6mg/kg (absolute max 400mg in adults)

convulsions can occur. The cardiac side effects of local analgesics (in particular lignocaine) are sometimes used clinically to treat cardiac arrhythmias. Similar to the effects on the central nervous system the cardiac effects are resultant from the membrane stabilization effects of local analgesic molecules. As such, the main clinical cardiovascular outcome is cardiac depression. Similarly there is a slight vasodilation on the arterial system but this is not normally clinically relevant as it is often overwhelmed by sympathetic induced increase in cardiac output resulting in a slight increase in blood pressure. Vasoconstrictors Plain local analgesic solutions currently used in clinical practice do not cause vasoconstriction. However, local vasoconstriction is a favourable property of local analgesics. As such a separate vasoconstrictor molecule is added to many of the available solutions.17,18 In current practice adrenaline and felypressin are the most used vasoconstrictors whilst previously noradrenalin was more commonly used, but its significant increase in blood pressure, resulting in some adverse outcomes, has seen its use
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decline. The key reasons behind the addition of a vasoconstrictor are to provide adequate working time, to reduce the rate of loss of the analgesic solution to the general circulation and to reduce the dose required to achieve effective analgesia.12,19,20 Additionally, during surgical procedures it reduces bleeding and thus improves operator vision and therefore quality of care.2 Adrenalin in dental use ranges in concentration between 1:50 000 and 1:200 000. It is a synthetic molecule but has the same structure as endogenous adrenalin from the adrenal medulla. The effect of adrenalin, particularly if accidentally given intravascularly, is widely known, as it has exactly the same effect as naturally induced increases in circulating adrenalin (vasodilation of the skeletal muscles, pupil dilation, bronchial dilation, skin vessel contraction). An alternative vasoconstrictor developed more recently is based on the pituitary hormone felypressin.3 This is used in dosages of approximately 0.03IU/mL and has a very safe record of use. It has little or no myocardial effects and acts directly on the smooth muscle cells of the vascular tree with the effect greater on the venous side. Felypressin is contraindicated
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Table 7. Bupivacaine hydrochloride

Bupivacaine hydrochloride Proprietary names Concentration of LA Vasoconstrictor Approximate duration of action (mins) Methods of use Indications for use Contraindications Marcain with Adrenaline 0.5% 1:200 000 Pulpal 90-180 Soft tissue 240-540 (reports up to 720) Infiltration and regional nerve blocks Long surgical procedures where prolonged analgesia is required and for the management of postoperative pain. Its use should be restricted to patients 12 years and older. Absolute: Relative: Allergy to the analgesic or any of its constituents Liver or renal impairment (ASA III-IV) *CVS disease or hyperthyroidism are relative contraindications due to adrenaline not the analgesic agent itself. Young, mentally or physically disabled patients, due to the risk of post-operative self-mutilation 1.3mg/kg (absolute max 90mg in adults) CNS: Light-headedness, nervousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, blurred vision, vomiting, sensations of heat, cold or numbness, twitching, tremors, convulsions, unconsciousness, agitation, difficulty swallowing and slurred speech Respiratory: Respiratory depression and/or arrest CVS: Bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac arrest Allergy: Cutaneous lesions, urticaria, oedema, or anaphylactoid reactions CNS: Initially circumoral paraesthesia, numbness of the tongue, light-headedness, decreased tolerance to sound (hyperacusis) and tinnitus. Visual disturbances and muscle tremor are more serious and precede the onset of generalized convulsions. Unconsciousness and grand mal convulsions may follow, these may continue for seconds or minutes. Respiratory: Increased muscle activity during seizures can result in hypoxia and hypercapnia. This may be exacerbated by airway obstruction during the seizure. CVS: These effects are more severe. Bradycardia, arrhythmia and cardiac arrest may all occur. The long duration of action of Bupivacaine is not matched by other dental analgesics available. Other amide local analgesics with added vasoconstrictors may be used as an alternative however these do not match the duration of action associated with Bupivacaine. As such alterations to procedures or supplementary pain management regimes may be indicated.

Maximum dosage Summary of adverse effects

Summary of toxic effects

Alternatives *note: these drugs are alternatives NOT direct substitutes, thus pharmacology of each alternative must be assessed prior to its appropriate administration.

during pregnancy as its similarity in structure to oxytocin (the hormone responsible for labour) can result in some contraction of the uterus. Its lack of effect on the central nervous system makes it useful for patients where adrenalin is often contraindicated. At higher doses felypressin does cause some coronary artery contractions.2 Local anaesthetics reference guide Tables 3-7 are a concise reference guide to some of the available local analgesic agents available in Australia. In no way are the tables intended to replace the comprehensive literature supplied by the manufacturers. Rather, they are intended to provide a simple and basic guide for some of the currently available analgesics in Australia. Specific drug interactions have been deliberately omitted due to the many medications patients may be taking. For information on drug interactions more reliable and comprehensive sources such as MIMS or manufacturers literature should be referenced prior to the administration of a local analgesic. Specific interactions to vasoconstrictors have been dealt with in an earlier
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section of this paper thus will not be repeated in the tables. CONCLUSION Local analgesia is a very safe and effective method of pain control. Its application is one of the cornerstones of modern dental practice. For a little over 100 years dental care has seen the rapid development of new drugs and better delivery mechanisms coupled with a far more enlightened knowledge of the application of local analgesia to reduce pain for dental treatment. This short review highlights many of the important biological and pharmacological advances made. Good local analgesia requires highly skilled dental professionals to apply this knowledge coupled with a detailed understanding of the anatomical complexities21,22 to provide advanced pain management for dental patients. REFERENCES
1. Hawkins JM, Moore PA. Local anesthesia: advances in agents and techniques. Dent Clin North Am 2002;46:719-732. 2. Malamed SF. Handbook of local anesthesia. 5th edn. St Louis: Mosby, 2004.
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3. Pipa-Vallejo A, Garcia-Pola-Vallejo MJ. Local anesthetics in dentistry. Med Oral Patol Oral Cir Bucal 2004;9:438-443. 4. Ramacciato JG, Meechan JG. Recent advances in local anaesthesia. Dent Update 2005;32:8-10, 12-14. 5. Palm AM, Kirkegaard U, Poulsen S. The wand versus traditional injection for mandibular nerve block in children and adolescents: perceived pain and time of onset. Pediatr Dent 2004;26:481-484. 6. Roberts DH, Sowray JH. Local analgesia in dentistry. 3rd edn. Bristol: Wright, 1987. 7. Evers H, Haegerstam G. Handbook of dental local anaesthesia. Denmark: Schultz, 1981. 8. Fozzard HA, Lee PJ, Lipkind GM. Mechanism of local anesthetic drug action on voltage-gated sodium channels. Curr Pharm Des 2005;11:2671-2686. 9. Pugsley MK, Goldin AL. Molecular analysis of the Na+ channel blocking actions of the novel class I anti-arrhythmic agent RSD 921. Br J Pharmacol 1999;127:9-18. 10. Baker MD. Selective block of late Na(+) current by local anaesthetics in rat large sensory neurones. Br J Pharmacol 2000;129:1617-1626. 11. Meechan JG. Practical dental local anaesthesia. London: Quintessence, 2002. 12. Haas DA. An update on local anesthetics in dentistry. J Can Dent Assoc 2002;68:546-551. 13. Budenz AW. Local anesthetics in dentistry: then and now. J Calif Dent Assoc 2003;31:388-396. 14. Haas DA, Carmichael FJ. Local anesthetics. In: Roschlau WHE, Kalant H, eds. Principles of medical pharmacology. 6th edn. New York: Oxford, 1998:293-302. 15. Chiu CY, Lin TY, Hsia SH, Lai SH, Wong KS. Systemic anaphylaxis following local lidocaine administration during a dental procedure. Pediatr Emerg Care 2004;20:178-180.

16. Baluga JC. Allergy to local anesthetics in dentistry. Myth or reality? Rev Alerg Mex 2003;50:176-181. 17. Wood M, Reader A, Nusstein J, Beck M, Padgett D, Weaver J. Comparison of intraosseous and infiltration injections for venous lidocaine blood concentrations and heart rate changes after injection of 2% lidocaine with 1:100,000 epinephrine. J Endod 2005;31:435-438. 18. Costa CG, Tortamano IP, Rocha RG, Francischone CE, Tortamano N. Onset and duration periods of articaine and lidocaine on maxillary infiltration. Quintessence Int 2005;36:197-201. 19. Axelsson K, Widman B. Blood concentration of lidocaine after spinal anaesthesia using lidocaine and lidocaine with adrenaline. Acta Anaesthesiol Scand 1981;25:240-245. 20. Goebel WM, Allen G, Randall F. The effect of commercial vasoconstrictor preparations on the circulating venous serum level of mepivacaine and lidocaine. J Oral Med 1980;35:91-96. 21. Meechan JG. Why does local anaesthesia not work everytime? Dent Update 2005;32:66-68, 70-72. 22. Blanton PL, Jeske AH; ADA Council on Scientific Affairs; ADA Division of Science. Avoiding complications in local anesthesia induction: anatomical considerations. J Am Dent Assoc 2003;134:888-893.

Address for correspondence/reprints: Associate Professor Marc Tennant The Centre for Rural and Remote Oral Health The University of Western Australia 35 Stirling Highway Nedlands, Western Australia 6009 Email: marc@crroh.uwa.edu.au

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