|Year : 2016 | Volume
| Issue : 1 | Page : 3-9
Levobupivacaine: A safer alternative
Manazir Athar, Syed Moied Ahmed, Shahna Ali, Obaid Ahmad Siddiqi
Department of Anaesthesiology and Critical Care, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
|Date of Submission||22-Apr-2016|
|Date of Acceptance||10-May-2016|
|Date of Web Publication||16-Jun-2016|
Syed Moied Ahmed
Department of Anaesthesiology and Critical Care, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh - 202 002, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
In the quest for safer and effective anesthesia and analgesia, local anesthetics such as levobupivacaine or ropivacaine have been introduced into the clinical practice. Several studies have been done to assess their efficacy and relative superiority to bupivacaine. The aim of this review is to provide the recent and comprehensive updates regarding the clinical and pharmacological utility of levobupivacaine. Using Google search for indexing databases, a search for articles published was performed using various combinations of the following search terms: (a) Pharmacology; (b) clinical; (c) profile; (d) levobupivacaine; (e) local anesthetic; (f) recent. Additional sources were also identified by exploring the primary reference list.
Keywords: Bupivacaine, levobupivacaine, local anesthetic, pharmacology
|How to cite this article:|
Athar M, Ahmed SM, Ali S, Siddiqi OA. Levobupivacaine: A safer alternative. J Curr Res Sci Med 2016;2:3-9
| Introduction|| |
Levobupivacaine is a relatively new long-acting local anesthetic that has been produced to address the issue of cardiovascular and neurological toxicity following inadvertent intravascular injections.  The three-dimensional structure of local anesthetic molecules forms two enantiomeric molecules that exist in two different spatial configurations. These enantiomers depending on the rotation of the plane of polarized light are grouped into dextrorotatory (R+) or levorotatory (S−) stereoisomers. Traditionally available bupivacaine is a racemic mixture of both the enantiomers. However, technological advancements in the recent era have allowed the production of specific enantiomer containing optically pure molecules. The two enantiomers are exactly similar in physicochemical properties, but can have different affinity for the site of action or the side effects. The differential affinity of these enantiomers for sodium, potassium, and calcium channels results in a significant reduction of neurological and cardiac toxicity of the S-enantiomer in comparison to the R-enantiomer. , Ropivacaine and levobupivacaine are available as optically pure solutions. With the increasing usage potential of levobupivacaine for anesthesia and analgesia, especially in the ultrasound-guided peripheral blocks and labor analgesia, it is required to have the latest evidence-based knowledge about pharmaco-clinical profile of this drug. This review discusses the clinical pharmacology and toxicology of levobupivacaine and its clinical application in different fields of anesthesia.
| Methods|| |
A Google search for published articles since the year 1972 in various indexing databases such as PubMed, Scopus, Embase, Science Direct, and Google Scholar was performed using various combinations of the following search terms: (a) Pharmacology; (b) clinical; (c) profile; (d) levobupivacaine; (e) local anesthetic; (f) recent. Searches were updated till May 11, 2016. Additional sources were also identified by exploring the primary reference list. Studies in which levobupivacaine was used in regional anesthesia were selected. Large well-controlled randomized trials with ≥ 30 patients per treatment group were preferred except in cases where data are lacking. The main comparators were other amide local anesthetics such as bupivacaine, ropivacaine, and lignocaine with or without opioids.
- Proper name: Levobupivacaine hydrochloride
- Chemical name: (S) -1-Butyl- 2', 6'-pipecoloxylidide [Figure 1]
- IUPAC name: (S) -1-butyl-N- (2, 6-dimethylphenyl) piperidine-2-carboxamide
- Molecular formula: C 18 H 28 N 2 O
- Molecular mass: 288.43 g/mole
Levobupivacaine is lipid-soluble, highly protein-bound local anesthetic with a dissociation constant (pKa) similar to that of bupivacaine and ropivacaine, but higher than that of lidocaine. These pharmacological characteristics determine its relatively slow onset, high potency, and long duration of action.  Similar to other local anesthetics, inhibition of impulse transmission in various tissues leads to the development of adverse reactions. 
Most of the clinical studies suggest that levobupivacaine is relatively less potent than bupivacaine, but more potent than ropivacaine.  Greater lipid solubility and formulation of levobupivacaine could partly explain its potency differences to ropivacaine.  The typical formulation of levobupivacaine underestimates the active molecules by 12.6% than its racemate.  However, in many recent studies, , > 30% difference is found in potency suggesting that levobupivacaine is actually more potent than ropivacaine. Its potency compared to ropivacaine remained inconsistent and varied from 1 to 1.67.  Hence, based on the above facts and various previous studies, ,,,, levobupivacaine is assumed to be 1.5 times more potent than ropivacaine.
Mechanism of action
Levobupivacaine has a similar mechanism of action and pharmacodynamic properties as that of bupivacaine. , It reversibly blocks the sodium channels at the nodes of Ranvier in myelinated nerves leading to faster onset as compared to unmyelinated nerves. Similarly, nerves which are small in diameter are more easily blocked than large nerves. 
Central nervous system toxicity
Systemic toxicity of local anesthetics generally occurs due to overdosing or inadvertent intravascular or intrathecal injection. The neurological features of toxicity appear early followed by cardiovascular due to increased susceptibility of central nervous system (CNS) to local anesthetics. However, according to a recent review, over 40% of the presentation did not fit into this classical description of local anesthetic systemic toxicity.  Initial signs of excitation such as shivering, tremors, and muscle twitching are produced due to preferential blockade of inhibitory central pathways. With the increase of the local anesthetic plasma concentrations, the excitatory pathway of CNS toxicity is blocked and signs of generalized CNS depression with hypoventilation and respiratory arrest, and finally generalized convulsions may occur. Based on various animal , and randomized controlled studies, ,, it is concluded that uptake of bupivacaine by the central nervous cells is also enantio-selective and hence, both levobupivacaine and ropivacaine are much safer than the bupivacaine. Their convulsive threshold is found to be higher in various animal models, leading to fewer CNS symptoms after intravenous administration in human volunteers and fewer excitatory changes in the electroencephalogram than bupivacaine. 
There is potential for cardiovascular toxicity with local anesthetics because they block ion channels not only in the nerve cell membranes but also in other excitable tissues such as the heart. The risk of toxicity is greater for longer acting local anesthetics.  The cardiovascular toxic effects of local anesthetics also follow a two-stage pathway: An initial activation of the sympathetic nervous system during the CNS excitatory phase leads to tachycardia and hypertension that can mask direct myocardial depression followed by arrhythmias and profound contractile dysfunction.  With bupivacaine, cardiotoxicity generally manifests as cardiac arrhythmias (including ventricular fibrillation and tachycardia) and severe cardiac collapse that can be rapid, irreversible, and fatal.  There seems a dose-dependent prolongation of cardiac conduction with the use of all the three commonly available local anesthetics leading to an increase in the PR interval and QRS duration on the electrocardiogram. This is due to the persistent blockade of sodium channels into diastole, predisposing to re entrant arrhythmias depending on the drugs' dissociation. As bupivacaine takes 10 times more time to dissociate than that of lidocaine, its blockade can accumulate, resulting in a more marked cardiac depression. The levorotatory isomer, on the other hand, is seven fold less potent in blocking the potassium channel and hence, decreases the propensity to prolong QTc interval. Furthermore, the potency and affinity for the potassium channel are directly dependent on the length of the alkyl substitute at position "1," so is the difference between "propylic" and "butylic" chains of ropivacaine and levobupivacaine. The inhibition of contractility is also proportional to the lipid solubility and potency, suggesting a rank order of the cardiotoxic potential as ropivacaine < S (?) bupivacaine  Hence, levobupivacaine S (?) due to stereoselective binding of sodium and potassium channels demonstrated less affinity and strength of inhibitory effect than the racemic parent or dextrobupivacaine and consequently decreased the toxicity profile.
It depends on the route and vascularity of the tissue. Epidural levobupivacaine absorption is biphasic and affected by age and concentration of the drug. There is higher spread of analgesia (by three dermatomes) in older patients. Hence, it is recommended that elderly patients receive reduced doses of levobupivacaine, according to their physical status. 
Levobupivacaine is highly bound to plasma proteins,  with widespread distribution. 
Metabolism and excretion
Levobupivacaine is metabolized by hepatic cytochrome P450 (CYP) enzymes to form 3-hydroxylevobupivacaine and to form desbutyl-levobupivacaine.  The glucuronic acid and sulfate ester conjugates of 3-hydroxylevobupicaune are excreted in the urine.
Levobupivacaine use has increased drastically for the past few years because of its safer pharmacological profile.  It is increasingly being used in subarachnoid block, epidural anesthesia and analgesia, brachial plexus blocks, peripheral nerve blocks, ocular blocks as well as local infiltration. It is also used for labor analgesia, postoperative pain as well as management of acute and chronic pain.
Levobupivacaine is a better alternative to bupivacaine for spinal anesthesia. It has similar sensory and motor characteristics and recovery time like bupivacaine [Table 1]. Minimum effective local anesthetic dose of levobupivacaine as recommended by sequential up and down study is 11.7 mg. 
|Table 1: Comparative efficacy of intrathecal ropivacaine and levobupivacaine. Randomized, double-blind trials of ropivacaine and levobupivacaine in patients undergoing anesthesia for elective cesarean section or lower limb surgery[12,25,27-29] |
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Levobupivacaine has been successfully used in providing epidural anesthesia and analgesia [Table 2].
|Table 2: Comparative efficacy of levobupivacaine in epidural nerve block|
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It provides similar sensory block, but delayed and less dense motor block. 
Epidural levobupivacaine as a continuous infusion of 15 mg/h provides effective pain relief in the postoperative period.  It has been successfully used in knee arthroscopy,  patient-controlled femoral nerve block,  caudal block in pediatrics,  epidural block and transverse abdominis plane block for colorectal surgeries. , Postincisional wound infiltration with 0.125% levobupivacaine provides an effective analgesia. In a recent study, levobupivacaine is reported to have a positive effect in the earlier period of wound healing followed by a negative effect thereafter. 
Peripheral nerve block
Levobupivacaine is a good substitute for bupivacaine [Table 3]. Compared to ropivacaine, it provides a significantly longer duration of analgesia. 
|Table 3: Comparative efficacy of levobupivacaine in peripheral nerve block|
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Subarachnoid block for cesarean section
Onset as well as the duration of sensory and the motor block is slightly higher with levobupivacaine than bupivacaine in cesarean section.  The relative potency order is bupivacaine > levobupivacaine > ropivacaine. ,
Either combined spinal-epidural (CSE) or purely epidural block can be used for providing labor analgesia. Various studies have shown the minimum local analgesic doses for intrathecal as 2.73-3.16 mg for levobupivacaine and 3.33-3.96 mg for ropivacaine.  The addition of opioids provides relative local anesthetic sparing effect with an improved sensory block and less motor block in CSE. , The use of levobupivacaine and ropivacaine has been encouraged in the epidural block because of relative safety and less motor blockade. The analgesic efficacy is dependent on its concentration, and at least 0.1% is required for satisfactory analgesia.  Levobupivacaine, ropivacaine, and bupivacaine, all provide adequate analgesia without any significant difference in labor duration and neonatal outcome. 
The decreased cardiovascular and neurological toxicity of levobupivacaine and ropivacaine has favored their use in retrobulbar and peribulbar blocks. At equipotent doses, levobupivacaine has been shown to provide more effective anesthesia as compared to ropivacaine and 2% lignocaine. ,
It may be safely used in spinal, caudal, or infiltration for postoperative analgesia.
A comparatively higher dose of 1.2 mg/kg is required in comparison to 1 mg/kg of isobaric 0.5% bupivacaine and ropivacaine in neonates. 
Levobupivacaine in a dose of 2.5 mg/kg is recommended for the caudal block. Its potency is similar to bupivacaine for lower abdominal surgery. 
Elderly patients generally have concomitant comorbidities, and safer alternatives such as levobupivacaine and ropivacaine may significantly reduce the side effects during the subarachnoid block. 
- Patients with a hypersensitivity to ropivacaine or any other local anesthetic agent of the amide type
- Intravenous regional anesthesia (bier block)
- Patients with severe hypotension such as cardiogenic or hypovolemic shock
- Obstetric paracervical block anesthesia. 
Pregnancy and lactation
Levobupivacaine is a category B drug. It is contraindicated for paracervical block in obstetrics. Based on experience with bupivacaine, fetal bradycardia may occur and therefore not to be given during early pregnancy unless clearly necessary. Levobupivacaine excretion in breast milk is unknown. It is likely to be poorly excreted in breast milk as for bupivacaine. Breastfeeding is possible after local anesthesia. 
Cytochrome P450 inhibitors
As CYP3A4 and CYP1A2 are involved in the metabolism of levobupivacaine, there is a potential for interactions with inhibitors of these enzymes, such as methylxanthines (CYP1A2 inhibitors) and ketoconazole (a CYP3A4 inhibitor).
it is recommended that caution is taken when co-administering levobupivacaine with antiarrhythmics that have local anesthetic effects, such as Class III antiarrhythmics and mexiletine, as toxic effects may be additive. 
The most commonly reported side effects are hypotension, nausea, vomiting, dizziness, headache, tachycardia or bradycardia, back pain, and fetal distress syndrome in obstetrics. Apart from this, overdosage and unintentional intravascular injection may cause reactions with amide local anesthetics. Neurological damage is rare but well-recognized consequence of neuraxial blocks. Rare reports of cauda equina syndrome and transient Horner's syndrome in association with regional anesthetic use have been obtained. ,
| Conclusion|| |
Levobupivacaine is a long-acting local anesthetic with much safer pharmaco-clinical profile in comparison to its parent compound bupivacaine.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]