Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a
local anesthetic of the
aminoamide type. It is also used to treat
ventricular tachycardia.[7][8] When used for local anaesthesia or in nerve blocks, lidocaine typically begins working within several minutes and lasts for half an hour to three hours.[8][9] Lidocaine mixtures may also be applied directly to the skin or
mucous membranes to numb the area.[8] It is often used mixed with a small amount of
adrenaline (epinephrine) to prolong its local effects and to decrease bleeding.[8]
If injected intravenously, it may cause cerebral effects such as confusion, changes in vision, numbness, tingling, and vomiting.[7] It can cause
low blood pressure and an irregular heart rate.[7] There are concerns that injecting it into a joint can cause problems with the
cartilage.[8] It appears to be generally safe for use in
pregnancy.[7] A lower dose may be required in those with liver problems.[7] It is generally safe to use in those allergic to
tetracaine or
benzocaine.[8] Lidocaine is an
antiarrhythmic medication of the class Ib type.[7] This means it works by
blocking sodium channels and thus decreasing the rate of contractions of the heart.[7] When injected near nerves, the nerves cannot conduct signals to or from
the brain.[8]
The efficacy profile of lidocaine as a local anaesthetic is characterized by a rapid onset of action and intermediate duration of efficacy. Therefore, lidocaine is suitable for infiltration, block, and surface anaesthesia. Longer-acting substances such as
bupivacaine are sometimes given preference for spinal and
epidural anaesthesias; lidocaine, though, has the advantage of a rapid onset of action.
Adrenaline vasoconstricts arteries, reducing bleeding and also delaying the resorption of lidocaine, almost doubling the duration of anaesthesia.[citation needed]
Lidocaine is one of the most commonly used local anaesthetics in dentistry. It can be administered in multiple ways, most often as a
nerve block or
infiltration, depending on the type of treatment carried out and the area of the mouth worked on.[15]
For surface anaesthesia, several formulations can be used for
endoscopies, before
intubations, etc. Lidocaine drops can be used on the eyes for short ophthalmic procedures. There is tentative evidence for
topical lidocaine for
neuropathic pain and
skin graft donor site pain.[16][17] As a local numbing agent, it is used for the treatment of
premature ejaculation.[18]
An adhesive
transdermal patch containing a 5% concentration of lidocaine in a
hydrogel bandage, is approved by the US FDA for reducing
nerve pain caused by shingles.[19] The transdermal patch is also used for pain from other causes, such as compressed nerves and persistent nerve pain after some surgeries.
A 2013 review on treatment for
neonatal seizures recommended intravenous lidocaine as a second-line treatment, if
phenobarbital fails to stop seizures.[21]
Other
Intravenous lidocaine infusions are also used to treat
chronic pain and
acute surgical pain as an
opiate sparing technique. The quality of evidence for this use is poor so it is difficult to compare it to
placebo or an
epidural.[22]
Inhaled lidocaine can be used as a
cough suppressor acting peripherally to reduce the
cough reflex. This application can be implemented as a safety and comfort measure for patients who have to be intubated, as it reduces the incidence of coughing and any tracheal damage it might cause when emerging from anaesthesia.[23]
A 2019 systematic review of the literature found that intraurethral lidocaine reduces pain in men who undergo cystoscopic procedures.[24]
For
gastritis, drinking a viscous lidocaine formulation may help with the pain.[27]
Adverse effects
Adverse drug reactions (ADRs) are rare when lidocaine is used as a local anesthetic and is administered correctly. Most ADRs associated with lidocaine for anesthesia relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, and
allergic reactions only rarely occur.[28] Systemic exposure to excessive quantities of lidocaine mainly result in
central nervous system (CNS) and
cardiovascular effects – CNS effects usually occur at lower
blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. ADRs by system are:
CNS excitation: nervousness, agitation, anxiety, apprehension, tingling around the mouth (circumoral paraesthesia), headache,
hyperesthesia, tremor, dizziness, pupillary changes, psychosis, euphoria, hallucinations, and seizures
CNS depression with increasingly heavier exposure: drowsiness, lethargy, slurred speech,
hypoesthesia, confusion, disorientation, loss of consciousness,
respiratory depression and
apnoea.
Skin: itching, depigmentation, rash,
urticaria, edema, angioedema, bruising,
inflammation of the vein at the injection site, irritation of the skin when applied topically
ADRs associated with the use of intravenous lidocaine are similar to toxic effects from systemic exposure above. These are dose-related and more frequent at high infusion rates (≥3 mg/min). Common ADRs include: headache, dizziness, drowsiness, confusion, visual disturbances, tinnitus, tremor, and/or
paraesthesia. Infrequent ADRs associated with the use of lidocaine include:
hypotension,
bradycardia,
arrhythmias,
cardiac arrest, muscle twitching,
seizures,
coma, and/or respiratory depression.[29]
It is generally safe to use lidocaine with vasoconstrictor such as adrenaline, including in regions such as the
nose, ears,
fingers, and
toes.[30] While concerns of tissue death if used in these areas have been raised, evidence does not support these concerns.[30]
The use of lidocaine for spinal anesthesia may lead to an increased risk of transient neurological symptoms, a painful condition that is sometimes experienced immediately after surgery.[31] There is some weak evidence to suggest that the use of alternative anesthetic medications such as
prilocaine,
procaine,
bupivacaine,
ropivacaine, or
levobupivacaine may decrease the risk of a person developing transient neurological symptoms.[31] Low quality evidence suggests that 2‐
chloroprocaine and
mepivacaine when used for spinal anesthetic have a similar risk of the person developing transient neurological symptoms as lidocaine.[31]
Interactions
Any drugs that are also
ligands of
CYP3A4 and
CYP1A2 can potentially increase serum levels and potential for toxicity or decrease serum levels and the efficacy, depending on whether they induce or inhibit the enzymes, respectively. Drugs that may increase the chance of
methemoglobinemia should also be considered carefully.
Dronedarone and
liposomalmorphine are both absolutely a
contraindication, as they may increase the serum levels, but hundreds of other drugs require monitoring for interaction.[32]
Contraindications
Absolute contraindications for the use of lidocaine include:
Heart block, second or third degree (without pacemaker)
Intra-articular infusion (this is not an approved indication and can cause
chondrolysis)
Porphyria, especially
acute intermittent porphyria; lidocaine has been classified as porphyrogenic because of the hepatic enzymes it induces,[36] although clinical evidence suggests it is not.[37]Bupivacaine is a safe alternative in this case.
Impaired liver function – people with lowered hepatic function may have an adverse reaction with repeated administration of lidocaine because the drug is metabolized by the liver. Adverse reactions may include neurological symptoms (e.g. dizziness, nausea, muscle twitches, vomiting, or seizures).[38]
Overdosage
Overdoses of lidocaine may result from excessive administration by topical or
parenteral routes, accidental oral ingestion of topical preparations by children (who are more susceptible to overdose), accidental intravenous (rather than subcutaneous,
intrathecal, or paracervical) injection, or from prolonged use of subcutaneous infiltration anesthesia during cosmetic surgery.[citation needed]
Such overdoses have often led to severe toxicity or death in both children and adults (
local anesthetic systemic toxicity).[39] Symptoms include central nervous system manifestations such as numbness of the tongue, dizziness, tinnitus, visual disturbances, convulsions, reduced consciousness progressing to coma, as well as respiratory arrest and cardiovascular disturbances.[40] Lidocaine and its two major metabolites may be quantified in blood, plasma, or serum to confirm the diagnosis in potential poisoning victims or to assist forensic investigation in a case of fatal overdose. [citation needed]
Lidocaine is often given intravenously as an antiarrhythmic agent in critical cardiac-care situations.[41] Treatment with intravenous lipid emulsions (used for
parenteral feeding) to reverse the effects of local anaesthetic toxicity is becoming more common.[42][43]
Lidocaine alters signal conduction in
neurons by prolonging the inactivation of the fast
voltage-gated Na+ channels in the neuronal cell membrane responsible for
action potential propagation.[45] With sufficient blockage, the voltage-gated sodium channels will not open and an action potential will not be generated. Careful titration allows for a high degree of selectivity in the blockage of sensory neurons, whereas higher concentrations also affect other types of neurons.[citation needed]
The same principle applies for this drug's actions in the heart. Blocking sodium channels in the conduction system, as well as the muscle cells of the heart, raises the depolarization threshold, making the heart less likely to initiate or conduct early action potentials that may cause an arrhythmia.[46]
Pharmacokinetics
When used as an injectable it typically begins working within four minutes and lasts for half an hour to three hours.[8][9] Lidocaine is about 95% metabolized (dealkylated) in the
liver mainly by CYP3A4 to the pharmacologically active
metabolitesmonoethylglycinexylidide (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.[47] The
volume of distribution is 1.1 L/kg to 2.1 L/kg, but congestive heart failure can decrease it. About 60% to 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 min to 120 min in most patients. This may be prolonged in patients with
hepatic impairment (average 343 min) or
congestive heart failure (average 136 min).[48] Lidocaine is excreted in the urine (90% as metabolites and 10% as unchanged drug).[49]
Chemistry
Molecular structure and conformational flexibility
At the heart of lidocaine's molecular structure lies a lipophilic group featuring a 1,5-dimethylbenzene core, contributing to the molecule's hydrophobic characteristics. In addition to this aromatic unit, lidocaine incorporates an aliphatic section comprising amide, carbonyl, and enyl groups. This multifaceted arrangement endows the molecule with unique properties and a capacity to interact with biological systems.
Lidocaine exhibits a remarkable degree of conformational flexibility, resulting in more than 60 probable conformers.[50] This adaptability arises from the high lability of the amide and ethyl groups within the molecule. These groups can undergo shifts in their positions, leading to significant variations in the overall molecular configuration.
Influence of temperature and pressure on conformational preference
The dynamic transformation of lidocaine conformers in supercritical carbon dioxide (scCO2) highly depends on external factors such as pressure[50] and temperature.[51] Alterations in these conditions can lead to distinct conformations, impacting the molecule's physicochemical properties. One notable consequence of these variations is the particle size of lidocaine when produced through micronization using scCO2. Changes in the position of the amide group within the molecule can trigger a redistribution of intra- and intermolecular hydrogen bonds, affecting the outcome of the micronization process and the resultant particle size.[52]
History
Lidocaine, the first
aminoamide–type local anesthetic (previous were amino esters), was first synthesized under the name 'xylocaine' by Swedish chemist
Nils Löfgren in 1943.[53][54][55] His colleague Bengt Lundqvist performed the first injection anesthesia experiments on himself.[53] It was first marketed in 1949.
Xylocaine is a brand name, referring to the major synthetic building block
2,6-xylidine. The "ligno" prefix is chosen because "xylo" means
wood in Greek while "ligno" means the same in Latin. The "lido" prefix instead refers to the fact that the drug is chemically related to
acetanilide.[55]
Lidocaine is often added to
cocaine as a
diluent.[62][63] Cocaine and lidocaine both numb the
gums when applied. This gives the user the impression of high-quality cocaine, when in actuality the user is receiving a diluted product.[64]
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