Local analgesic drugs can be defined as those drugs that have little or no irritating effect when injected into the tissues and that will temporary interrupt conduction when absorbed into the nerve. Blockage of nerve fibers which transmit pain sensation
will result in regional analgesia.
These local analgesic agents are all synthetic compounds, with exception of cocaine which is seldom used today. The modification of the cocaine molecule has been responsible for the production of a large number of
local analgesic agents that have a definite relationship between their chemical structure and their analgesic properties.
Properties Of An Ideal Analgesic Agent
- It should have a reversible action.
- When injected
it should be nonirritating to the tissue and produce no secondary local reaction
- Produce no systemic toxicity.
- Have rapid onset and sufficient duration.
- Potent enough to allow the use of non toxic concentration.
- Have sufficient
penetrating properties to be used as topical analgesic.
- Stable in solution and undergo biotransformation readily in the body.
- Produce no allergic reaction.
- Can be sterilized without deterioration.
of the available agents fulfill all these properties, particularly as regard duration, toxicity and potency.
Common Properties Of The Injectable Local Analgesic Agents
- All are synthetic compounds that contain amine group.
- All form salts with strong acids which is water soluble.
- Alkali will hydrolyze the salt to free the alkaloid base which is soluble in lipids.
- When injected in the body they are either hydrolyzed by plasma proteins or undergo biotransformation
in the liver.
- All affect the nerve conduction in a similar manner and have a reversible action.
- All are compatible with epinephrine and other vasoconstrictors.
- All are not or slightly irritant to the tissue in the concentration used.
- All are capable of producing toxic effect when sufficient high plasma concentration is reached.
Table 1. Injectable local analgesics.
I. Ester Group
- Piperocaine (Metycaine)
- Meprylcaine (Oracaine)
- Isubocaine (Kincaine)
B. Para-Amino Benzoic Acid Esters
- Procaine (Novocaine)
- Tetracine (Pontocaine)
- Butethamine (Monocaine)
- Chloroprocaine (Nesacine)
C. Meta-Amino Benzoic Acid Esters
- Metabutethamine (Unacaine)
D- Paraethoxybenzoic Acid Esters
- Paraethoxcaine (Intracaine)
E- Cyclohexylamino-2 Propyl-Benzoate
II. Non-Ester Group
- Lidocaine (Xylocaine)
- Mepivacaine (Carbocaine)
- Pyrrocaine ( Dynacaine)
- Prilocaine (Citanest
Classification Of Local
The local analgesic drugs used in dentistry are divided into three groups, the ester group, the amide group and the hydroxy group.
I. Ester Group
It is composed of an aromatic group, an intermediate chain containing an ester linkage and a hydrophilic secondary or tertiary amino group which forms water soluble salts when combined with acids.
II. Amide Group
It is composed of an aromatic lipophilic group, an intermediate chain containing amide linkage and a hydrophilic secondary or tertiary amino group which forms water soluble salts when combined with acids.
III. Hydroxy Group
They are almost
insoluble in water as they lack the hydrophilic portion. They are used as topical analgesics.
The local analgesics can be grouped according to their chemical structures. This is important as regard their biotransformation as well as the possibility
of allergic reaction. Patient who is allergic to any one drug is usually allergic to any other drug of the same or closely related chemical structures. Table I shows a list for the available injectable local analgesics.
It should be mentioned here that
the injectable synthetic local analgesics are so balanced chemically that they have both lipophilic and hydrophilic properties. If the hydrophilic property predominates the free base will not be radially precipitated after injection and the ability oft he
drug to diffuse through the lipid rich nerves decrease. On the other hand, if the lipophilic property predominates the drug will be insoluble in water and unable to diffuse through the interstitial tissues.
Mode Of Action Of Local Analgesics
The local analgesic drugs, by an unknown action on the minute openings in the nerve membrane, prevents the passage of Na+ into the cell and the passage of K+ out of the nerve cell. Thus the polarized nerve is unable to depolarize and conduct an impulse.
The prevention of depolarization must take place over a length of two or three nodes of Ranvier as the drug reaches the myelinated nerve at these sites. Figure 2 shows a scheme which summarize the mode of action of the local analgesic agents.
Factors Affecting The Action Of Local Analgesics
Alkalinity of the tissues
will affect the ionization of the drug and the rate of liberation of the free base. The local analgesic drug is present in the tissue in two forms, the ionized and unionized forms. Ionization depends on the ionization constant of the drug and the pH of the
tissues. The higher is the ionization constant of the drug, the less is ionization and the less is the pH of the tissue (more acidic) the less is ionized form.
Pus has an acidic pH and it interfere with the development of potent analgesia preventing
the release of the free base and retardation of ionization of the free base.
2. Lipid solubility
As the diffusion of the free base into the nerve fibers depends on its lipid solubility, the
potency of the local analgesic drug is in direct proportion to its lipid solubility.
3. Type and size of the nerve
The myelinated nerves require more concentration and time to be blocked than
the unmyelinated nerves. This is because they are protected by an insulating barrier which is the myelin sheath. They are accessible to the drug only at the nodes of Ranvier.
On the other hand, the larger the diameter of the nerve the greater is the
concentration required to block it. Pain and temperature fibers being smaller in diameter are blocked before the touch, proprioceptive and motor fibers.
4. Concentration of the drug
local analgesia certain minimal concentration of the free base must be absorbed into the nerve fiber. The degree of analgesia depends not on the concentration of the drug injected but on the concentration of the free base which come in contact with the nerve
fibers. There are many factors that may interfere with the development of adequate concentration of the free base in the nerve fibers, these are:
- Excessive alkalinity: Increased alkalinity causes precipitation of the
free base before the solution, which is water soluble, diffuse toward the nerve. Thus absorption takes place before the free base, which is lipid soluble, comes in contact with the nerve fiber.
- Excessive dilution with blood or tissue fluids:
Once the solution is injected the intercellular fluids immediately begins to dilute it. The molecules diffuse in all directions with the concentration decreasing as the solution leaves the original site of injection. Accordingly the greater the distance of
the injection from the target nerve the lower is the concentration that reach the nerve.
- Too rapid absorption: An analgesic solution injected in a highly vascular area will be rapidly absorbed into the systemic circulation.
The effective concentration outside the nerve will reduced. Also rapid absorption increases the possibility of development of systemic toxicity. Since most of the analgesic drugs are vasodilators the addition of a vasoconstrictor is advisable not only to prolong
the duration of analgesia but also to decrease the possibility of development of systemic toxicity.
- Low alkalinity: As in cases of infection the alkalinity of the tissue is decreased to such an extent that the liberation
of the free base and its ionization is inhibited.
Biotransformation Of The Local Analgesic Drugs
Injectable local analgesics undergo biotransformation according to their intermediate linkage group in the liver and the
plasma. Ester group undergo biotransformation in the liver and the plasma while Amid group undergo biotransformation mainly in the liver. The enzymes responsible for biotransformation are the esterase enzyme in the liver and cholinesterase enzyme in the plasma.
Injectable Local Analgesic Drugs
I. Procaine (Novocaine)
Procaine is a
relatively weak analgesic agent which have a low degree of toxicity. However, it is potent enough to produce safe and sure analgesia under almost all circumstances.
The drug is vasodilator so it is rapidly absorbed into the systemic circulation. Accordingly,
addition of a vasoconstrictor is advisable. The drug is used in dentistry in 2% solution which has a sufficient potency and low systemic toxicity.
- On central nervous system: It
is capable of both stimulation and depression. The stimulation is usually an early response and may be manifested by excitement, tremors, ataxia (failure to regulate body poutsure and direction of limb movements) and even convulsion. Stimulation is usually
followed by depression. It appears the initial excitatory effect is produced by inhibition of the cortical inhibitory neurons thus the facilatory pathway acts unopposed. With the increase of the drug dose inhibition of both the inhibitory and facilatory??
neurons occur resulting in generalized CNS depression. On the peripheral nerves the effect of all esters compound is always depression.
- On cardiovascular system: In the small doses used in dentistry the drug has no effect
other than the vasodilatation of the vessels in the area. Systemically the drug cause depression of cardiac muscle, as well as smooth and skeletal muscles. In large doses the drug may produce hypotension by relaxation of the smooth muscles which result in
- On respiratory system: Large doses may severely depress respiration. In most instances of toxic over dose respiratory arrest occur before cardiac arrest.
In equal concentration tetracaine is at least 10 times more potent and toxic than procaine. It is used in 0.15% solution which make it of equal toxicity to procaine. It is a potent topical analgesic which have
a slow onset due to its slow rate of absorption. The drug cause no vasodilatation and has a duration of about 30-45 minutes.
This drug is 1.5 - 2 times more potent than procaine
and only slightly more toxic. Onset is more rapid than procaine and has more diffusible rate. It used in dentistry in 1.5% and 2% concentrations. Duration, when used with adrenaline is 60-70 minutes for 1.5 concentration and 90-120 minutes for 2% concentration.
The drug has systemic toxicity similar to that of procaine and posses no vasodilatation property.
The drug is a satisfactory short acting analgesic of low toxicity an extremely
rapid onset. It is hydrolyzed in the plasma 4-5 times faster than procaine and less toxic. It is used in 2% solution and due to its short duration addition of vasoconstrictor is a must.
It is a rapid acting local analgesic agent that is twice as potent as procaine and is less toxic. It is non irritant when injected into the tissue and diffuse rapidly into the lipid rich nerves and has a mild vasodilator property. It is used in a concentration
VI. Oxylocaine (Lidocaine)
This drug has a rapid onset and diffuses radially through the tissue and the lipid rich nerves. The drug has an excellent topical analgesic property when
used in 4% or 10% concentrations.
- Effect on the central nervous system: The drug depresses the CNS both centrally and peripherally. Convulsions may occur but it is believed to be due
to depression of some areas in the brain rather than direct stimulation.
- Effect on cardiovascular system: Like all other local analgesic agents the drug produces an increase in the excitability threshold and the refractory
period of the heart.
- Effect on respiratory system: Small doses of the drug has no effect on the respiratory system, but large doses may cause respiratory arrest and apnea which is the most common cause of death in case of
Unlike ester group, anilide group undergo biotransformation in the liver rather than in the plasma. Accordingly this drug is to be used in cases of plasma cholinesterase deficiency
and is contraindicated in cases of sever liver diseases. The by-products are excreted in kidneys.
VII. Citanest (Prilocaine)
The drug is used in 4% concentration either alone or with adrenaline.
It is less toxic than oxylocaine and undergo biotransformation more rapidly.
Dosage suggested for different local analgesic agents are always in the conservative side. This is to offer the dentist a wide range of safety taking into consideration that the office patients are
ambulatory patients and expected to leave the clinic unassisted and have no side effects.
When deciding the dose the following should be taken into consideration:
- Age and general condition of the patients: The
dosage mentioned on the pamphlet of the drug is usually for healthy adult patients. The age and any present systemic disease may alter the dosage.
- The vasoconstrictors: The vasoconstrictors used are in most cases the deciding
factor when calculating the dosage. In most case the limit of the local analgesic volume that can be injected is guided by the vasoconstrictor dosage.
The local analgesic agents can be grouped according to their duration into:
- Short acting: Which have a duration of 45 - 75 minutes.
- Medium acting: Which have a duration of 90 - 150 minutes.
- Long acting: Which have a duration longer than 150 minutes.
Of The Local Analgesic Carpoule
The analgesic Carpoule contain substances other than the local analgesic drug. These substances are added to potentiate and to preserve the constituents of the Carpoule. It contains the following
- The analgesic drug.
- A vasoconstrictor.
- Preservative substance.
- Vehicle to make the solution isotonic.
I. The analgesic drug
This is the main substance contained in the
II. The Vasoconstrictor
Adrenaline or other synthetic vasoconstrictors are added to the analgesic Carpoule to potentiate their action and prolong their duration. The vasoconstrictors cause local vasoconstriction
of the vessels in the injected area, thus decrease the rate of absorption of the drug into the systemic circulation. (See Page ---)
Sodium meta bisulfite is added, in a concentration of 0.5 mg/ml, to prevent
oxidation of the vasoconstrictor and hence deterioration of the solution. Other preservative substance that may be used is methylparaben. It should be known that some individuals are sensitive to the preservative substance. Those patients should not take local
analgesic solution that contain this substance.
IV. Vehicle to make the solution isotonic
Physiologic salt solution in the form of 0.9% sodium choleroid or Ringer’s solution which contain sodium chloride, calcium
chloride and potassium chloride, are used as a vehicle to dissolve the analgesic drugs and other constituents of the solution.
The solution should be isotonic for maximum effect of the local analgesic agent. The use of hypotonic solution will result
in the passage of the water from the intercellular fluid into the cell, while the use of hypertonic solution will result in the passage of the water from the cell to the intercellular fluids. In both situation the diffusion of the solution into
the tissue and its effect on the nerve will be adversely affected.
The vasoconstrictor is an
integral and necessary part of the local analgesic solution used in dentistry. The vasoconstrictors used in dentistry are all sympathomimetic amines. They are unstable in solution, therefore it is a must to include a preservative in the local analgesic solution
to prevent their oxidation.
The preservative commonly used is sodium meta bisulfite which compete with the vasoconstrictor for the oxygen available in the carpoule. Being more active the sodium bisulfite is oxidized to sodium bisulfate and the vasoconstrictor
remains relatively stable.
The presence of the vasoconstrictor in the analgesic solution offers the following advantages:
- Retard the absorption of the solution into the systemic circulation which allow
the use of smaller volume of the solution, decrease the chance for development of systemic toxicity and prolong the duration of analgesia.
- It produces haemostasis in the operative field but only when infiltration analgesia is used.
- It increases
the efficiency of the local analgesic drug.
This advantages of the vasoconstrictors are so interrelated that when one is gained others automatically follow.
In dental practice most of the disadvantages
that are attributed to the vasoconstrictors are mainly due to its practical abuse. These may be in the following ways:
- Too much volume, than what is actually needed, is used.
- Repeated injections increases the volume to nearly toxic level.
- Intravascular injection which result in toxic manifestations.
Mode of action and pharmacological effect
The vasoconstrictors are sympathomimetic in nature producing their effect by stimulating the adrenergic constrictors
(alfa receptors) present in the site of injection. Most vasoconstrictors undergo rapid biotransformation in the blood stream, thus they are usually short acting. In small doses, like those used in dentistry, no other organs should be greatly affected. However,
the use of large volume, high concentration or intravascular injection of even a small amount may result in toxic manifestations.
The Vasoconstrictor In Use
I. Epinephrine (Adrenaline)
It is the most potent and efficient vasoconstrictor used in dentistry. It has a short duration as it undergo rapid biotransformation in the blood. It may produce undesirable systemic effect in the form of tachycardia, headache and hypertension in some patients.
It is used in a concentration of 1/100.000 and 1/50.000. Other concentrations are also available.
It is slimier to epinephrine but is less potent. Concentration used in dentistry is 1/30.000.
It is similar to epinephrine in almost all aspects. It is only 1/5 the potency of epinephrine. It is used in dentistry in a concentration of 1/10.000.
It is the most stable
and the weakest vasoconstrictor. It is used in a concentration of 1/2500.
Table 2 shows the relative potency and the maximum total dose of the vasoconstrictors.
Topical Analgesic Agents
The topical analgesia has many uses in dentistry which ranges from mild generalized desensitization of the oral cavity prior to impression taking to localized numbing of the mucosa
before incision of an abscess. Generally, topical analgesia may be used in dentistry for the following procedures:
- Prior to injection to decrease the pain caused by the needle puncture.
- For minor surgical procedures as removal of very
loose deciduous teeth or removal of very superficial sequestra.
- For incision of an abscess as infiltration analgesia is contraindicated because of the presence of infection.
- For deep scaling as it is sometimes quite painful.
- In mouthwashes.
- In lozenges.
- In pastes.
- In the form of spray.
- By refrigeration.
Topical analgesics can be divided into two groups:
- Topical analgesics that produce their effect by means of refrigerant action. Among this group is the topical used of ethyl chloride spray. Being volatile, ethyl chloride when sprayed on the era will evaporate. As it evaporates it causes drop in the
temperature of the sprayed area which result in surface analgesia. Ethyl chloride is highly irritant and care when using it should be taken to protect the eyes.
- Topical analgesics that produce their effect by the action of chemical compound that is
absorbed and diffuses from the surface of the skin or mucous membrane to reach the free nerve endings. This group of topical analgesics include Xylocaine 5%, Pontocaine 2% and Benzocaine 10-15%.