Bupivacaine versus lignocaine as the choice of locall anesthetic agent for impacted third molar surgery a review.

One of the most important goal in minor surgical procedures is to achieve proper and sufficient anesthesia and analgesia preoperatively, intraoperatively and in the immediate postoperative period. Several local anesthetic agents have been cited in the literature and studied. Bupivacaine is one of the most common long-acting anesthetic agents being used for surgical removal of impacted third molars. Lignocaine is one of the commonest short-acting anesthetic agents being used for the same procedure. In this review article, the analgesic and anesthetic abilities of the bupivacaine versus lignocaine have been reviewed while surgical removal of impacted third molars.

Local anesthesia is the temporary loss of sensation or pain in one part of the body produced by a topically applied or injected agent without depressing the level of consciousness. Dental anesthetics fall into two groups: Esters (procaine, benzocaine) and amides (lidocaine, mepivacaine, bupivacaine, prilocaine and articaine). Esters are no longer used as injectable anesthetics. However benzocaine is used as a topical anesthetic. Amides are the most commonly used injectable anesthetics. Bupivacaine is one of the most common long-acting anesthetic agents used in maxillofacial surgery for more than past 30 years mainly to reduce the pain even after a surgical procedure is over. Several studies have been conducted regarding the toxicity and clinical safety of this agent compared to other local anesthetics. Lignocaine, on the other hand, is one of the safest short-acting local anesthetic agents being most commonly used in minor surgical procedures done in the chair side managements. Impacted third molar surgeries under local anesthesia are one of the most commonly performed surgical procedure under local anesthesia. Mostly these studies measured and compared the blood concentrations of bupivacaine and lignocaine while they were injected as local anesthetic agents during impacted third molar surgeries. Nonsteroidal anti-inflammatory drugs are routinely used to minimize postoperative pain after lower third molar surgery. The analgesic effect of these drugs is mediated in part through their ability to suppress the synthesis of prostaglandins. In this review article the efficacy of long-acting anesthetic agent bupivacaine versus the short-acting lignocaine has been reviewed in achieving sufficient anesthesia and analgesia even after finishing the surgical procedure of removing the third molar surgery.

Literature Review

Lignocaine (N-diethylaminoacetyl-2,6-xylidide) was first synthesized by Lofgen a Swedish chemist in 1943 and was first introduced into clinical use in 1948. Its molecular weight is 234.3 and its empirical formula is C14H22N2O. Lignocaine comes under the amide anesthetic group of local anesthetic agents. Lignocaine hydrochloride (C14H22N2O.HCL) is most soluble in water and so this is most commonly used injectable solution as local anesthetic agents. The efficacy profile of lidocaine as a local anesthetic is characterized by a rapid onset of action and intermediate duration of efficacy. Therefore, lidocaine is suitable for infiltration, block, and surface anesthesia. Lidocaine or lignocaine along with adrenaline has the advantage of a rapid onset of action. Epinephrine (adrenaline) vasoconstricts arteries, reducing bleeding and also delays the resorption of lidocaine, almost doubling the duration of anesthesia. For surface anesthesia, several available formulations can be used, e.g. for endoscopies, before intubations, etc., Buffering the pH of lidocaine makes local freezing less painful.[1] Lidocaine drops can be used on the eyes for short ophthalmic procedures. Topical lidocaine has been shown in some patients to relieve the pain of postherpetic neuralgia (a complication of shingles), though not enough study evidence exists to recommend it as a first-line treatment.[2] Intravenous lidocaine also has uses as a temporary fix for tinnitus. Although not completely curing the disorder, it has been shown to reduce the effects by around two-thirds.[34] Lidocaine is also the most important class-1b antiarrhythmic drug; it is used intravenously for the treatment of ventricular arrhythmias (for acute myocardial infarction, digoxin poisoning, cardioversion, or cardiac catheterization) if amiodarone is not available or contraindicated. Lidocaine should be given for this indication after defibrillation, cardiopulmonary resuscitation, and vasopressors have been initiated. A routine prophylactic administration is no longer recommended for acute cardiac infarction; the overall benefit of this measure is not convincing. The onset of action of lidocaine is about 45–90 s and its duration is 10–20 min. It is about 95% metabolized (dealkylated) in the liver mainly by CYP3A4 to the pharmacologically active metabolites monoethylglycinexylidide (MEGX) and then subsequently to the inactive glycine xylidide. MEGX has a longer half-life than lidocaine but also is a less potent sodium channel blocker.[5] The volume of distribution is 1.1–2.1 l/kg. About 60–80% circulates bound to the protein alpha1 acid glycoprotein. The oral bioavailability is 35%, and the topical bioavailability is 3%. The elimination half-life of lidocaine is biphasic and around 90–120 min in most patients. This may be prolonged in patients with hepatic impairment (average 343 min) or congestive heart failure (average 136 min).[6] Lidocaine is excreted in the urine (90% as metabolites and 10% as unchanged drug).[7]

Bupivacaine (1-butyl-2’, 6’- pipecoloxylidide) was first synthesized in 1957 by Ekenstam, a Scandinavian chemist, and was first introduced into clinical use in 1963. It is the longer side chain with four methylene groups on the piperidine ring that is responsible for the different properties of bupivacaine when compared to lignocaine. It has a molecular weight of 288.4 and an empirical formula of C18H28N2O and exists as white crystalline base with a melting point of 251–258°C. The base is not soluble in water, but the acid salt, bupivacaine hydrochloride (C18H28N2O.HCL) is slightly soluble. It is this form of bupivacaine that is used for administration by injection.

The rate of systemic absorption of bupivacaine and other local anesthetics is dependent upon the dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the preparation.[8] Onset of action (route and dose-dependent) is 1–17 min. Duration of action (route and dose-dependent): 2–9 h. Half-life in neonates is 8.1 h and in adults is 2.7 h. Time to peak plasma concentration (for peripheral, epidural or caudal block) is 30–45 min. Protein binding is about 95%. Metabolism is hepatic. Excretion by renal route is 6% (unchanged). The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and peak plasma concentration of Bupivacaine, permitting the use of moderately larger total doses and sometimes prolonging the duration of action. The onset of action with Bupivacaine is rapid and anesthesia is long lasting. The duration of anesthesia is significantly longer with Bupivacaine than with any other commonly used local anesthetic. It has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for strong analgesics is reduced.

Local anesthetics are bound to plasma proteins in varying degrees. In general, the lower the plasma concentration of drug the higher the percentage of drug bound to plasma proteins.

Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion are governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding because only the free, unbound drug is available for placental transfer. Bupivacaine with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2–0.4). Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Pharmacokinetic studies on the plasma profile of bupivacaine after direct intravenous injection suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The elimination of drug from tissue distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized. After injection of bupivacaine hydrochloride for caudal, epidural, or peripheral nerve block in man, peak levels of bupivacaine in the blood are reached in 30–45 min, followed by a decline to insignificant levels during the next 3–6 h. Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of bupivacaine in adults is 2.7 h and in neonates 8.1 h. In clinical studies, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger patients. Elderly patients also exhibited higher peak plasma concentrations following administration of this product. The total plasma clearance was decreased in these patients. Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Pipecoloxylidine is the major metabolite of bupivacaine. The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine. When administered in recommended doses and concentrations, bupivacaine hydrochloride does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia.

Discussion

Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed, and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine. Therefore, incremental dosing is necessary.

Following systemic absorption, local anesthetics can produce CNS stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state. In most of the studies 0.5% bupivacaine with adrenaline 1:200,000 and 2% lignocaine with adrenaline 1:200,000 were used as local anesthetic agents for third molar surgery as they are roughly equipotent.

Studies have proved that bupivacaine is superior to lidocaine plus diflunisal in controlling postoperative pain after lower third molar surgery. Surprisingly there have been records of patients with no or mild pain at 8 h after the bupivacaine procedure was almost twice as many as after the lidocaine procedure,[9] but is explained by the reason for preference being shorter duration of the anesthetic agent. In an Australian study, most of the patients preferred the long-acting anesthetic agent bupivacaine.[10] Many authors suggest that it seems reasonable that the combination of a long-acting local anesthetic with a weak analgesic is more efficient in relieving pain than the combination of a rather short-acting local anesthetic and a weak analgesic. Bupivacaine is considered to have a therapeutic ratio of 2:0 while lignocaine in combination with adrenaline has a therapeutic ratio of 2:3. Lignocaine is considered less toxic than bupivacaine. However, it has shown that the injection route alters the relative toxicity of local anesthetics. In a study by De Jong and Bonin in 1980 they found out that the bupivacaine has a greater therapeutic ratio than lignocaine when used for surgical removal of impacted third molars.[11] Studies have proved that long-acting bupivacaine can be safely administered for surgical removal of lower third molar and it does have a long period of nalgesia postoperatively compared to lidocaine, but the cardio depressant property of bupivacaine should be kept in mind and should be administered judicially.[12] Even studies have also shown that bupivacaine combined with methylprednisolone reduced the postoperative pain and swelling compared with the use of lidocaine and placebo, lidocaine and methylprednisolone, or bupivacaine and placebo.[13] Right now clinical trials are going on bupivacaine versus lidocaine anesthesia under University of British Columbia 2014 with the idea that the longer duration of anesthesia offered by Bupivacaine when administered preoperatively in elective outpatient hand surgeries, will offer more effective postoperative pain control compared to using lidocaine only.

Conclusion

It has been found that both bupivacaine and lignocaine have their merits and demerits but beyond any doubt it has been proven by the clinical trials that bupivacaine provides better and prolonged analgesia and anesthesia post operatively during minor surgical procedures done at chair side along with surgical removal of impacted third molars. Hence, bupivacaine can be regularly used as the anaesthetic solution along with adrenaline 1:200,000 for surgical removal of impacted third molars provided care being taken regarding the dosage and the cardiodepressant property of bupivacaine. Right now, further studies are going on.