**2. Intravenous lidocaine therapy**

#### **2.1. Lidocaine pharmacology**

Local anaesthetics are primarily used for local infiltration, nerve blocks and regional anaesthesia. Analgesia results from blockade of voltage-gated Na+ channels that prevent action potential initiation and propagation. Local anaesthetics impede sodium ion access to the axon interior, probably by physically occluding the trans-membrane sodium channels. This is a reversible process, which does not damage the nerve. Depolarization cannot take place when the sodium channel is blocked, so the axon remains polarized. A local anaesthetic regional or nerve block is, therefore, a reversible, non-depolarization block. In contrast, systemically administered local anaesthetics produce analgesia at plasma levels well below that required to block an action potential. Systemic administration of local anaesthetic is most recognized with lidocaine due to its widespread use for anti-arrhythmic treatment [113–115].

Lidocaine is an amide local anaesthetic and a Class Ib cardiac anti-dysrhythmic agent [116]. Therapeutic plasma levels and duration of IVLT for acute pain management are not well defined, although the optimal therapeutic range for acute pain treatment appears to be between 1 and 5 μg/ml [6, 24, 117–120]. Only preservative free formulations should be given intravenously. Bolus administration of 2 mg/kg and a continuous infusion of 2–5 mg/kg/h have shown to reach plasma levels of 1–4 μg/ml [121]. After a bolus injection or continuous administration for up to 12 h, the half-life of lidocaine is about 100 minutes and shows linear pharmacokinetics [122].

Lidocaine metabolism occurs rapidly in the liver by cytochrome P450 isoforms CYP1A2 and 3A4, as outlined in **Figure 3**. Lidocaine undergoes oxidative N-dealkylation, to a number of metabolites that include monoethylglycinexylidide (MEGX) and glycinexylidide (GX), and N-ethylglycine (NEG), all of which have a glycine-like moiety. Less than 10% of lidocaine is excreted unchanged by the kidneys. MEGX is an active metabolite and has 80% potency of lidocaine at VGSC's. GX is also active but NEG is inactive. Following intravenous administration, MEGX concentrations in serum range from 11 to 36% of the lidocaine concentration. All lidocaine metabolites are excreted by the kidneys. The half-life of lidocaine elimination from the plasma following IV administration is 81–149 min (mean 107 ± 22 SD, *n* = 15). The systemic clearance is 0.33–0.90 l/min (mean 0.64 ± 0.18 SD, *n* = 15). Children older than 6–7 months of age distribute and eliminate intravenous lidocaine in the same manner as adults [123].

In infants less than 6–7 months of age liver metabolism is immature so metabolism of drugs is delayed, and plasma protein levels are lower [124]. There are low levels of plasma alpha-1-acid glycoprotein, which increases the free fraction of circulating lidocaine and therefore increases the risk of toxicity [125]. IVLT in high doses (6–8mg/kg/h without a bolus dose) has used to treat neonatal seizures but the risk-benefit indication is considerably different than for pain management [126]. For these reasons, IVLT for pain management cannot be recommended in infants until more evidence of efficacy and safety in this population are available.

## **2.2. Safety of IVLT for pain management**

A major advantage with IVLT is that appropriate use in adults is not associated with a significant side-effect profile [7, 127, 128]. In adults, a 100 mg bolus followed by an infusion at 1 mg/ min, which approximates to 1mg/kg/h, produces a plasma level of just over 1 μg/ml in normal individuals with no co-morbidities [129]. IVLT doses used to manage pain are usually in the range of 1–2 mg/kg/h. Plasma levels at this rate of infusion are generally less than 3–5 μg/ml, but awake patients may complain of light-headedness, perioral numbness, dizziness and or sedation. Toxic plasma lidocaine levels are considered to be in the >6 μg/ml range [130]. Early signs of local anaesthetic systemic toxicity (LAST) will present as perioral numbness, metallic taste, tinnitus, visual and auditory disturbances, paresthesias, nausea, dizziness and drowsiness [7, 131–133]. Due to the short half-life of lidocaine, the symptoms of LAST are easily reversible by lowering or discontinuing the infusion. To provide some perspective, lidocaine effects at higher plasma levels are more serious; at 8 μg/ml, patients experience visual or auditory disturbances, dissociation, muscle twitching, and decreased blood pressure. At 12 μg/ml, convulsions can occur; at 16 μg/ml, coma may develop, and at levels above 20 μg/ml respiratory arrest and cardiovascular collapse ensue [132]. Physicians administering IVLT must be aware of algorithms of care to prevent, recognise and treat LAST when it occurs [134].

**Figure 3.** Lidocaine metabolism.

nels. This is a reversible process, which does not damage the nerve. Depolarization cannot take place when the sodium channel is blocked, so the axon remains polarized. A local anaesthetic regional or nerve block is, therefore, a reversible, non-depolarization block. In contrast, systemically administered local anaesthetics produce analgesia at plasma levels well below that required to block an action potential. Systemic administration of local anaesthetic is most recognized with lidocaine due to its widespread use for anti-arrhyth-

Lidocaine is an amide local anaesthetic and a Class Ib cardiac anti-dysrhythmic agent [116]. Therapeutic plasma levels and duration of IVLT for acute pain management are not well defined, although the optimal therapeutic range for acute pain treatment appears to be between 1 and 5 μg/ml [6, 24, 117–120]. Only preservative free formulations should be given intravenously. Bolus administration of 2 mg/kg and a continuous infusion of 2–5 mg/kg/h have shown to reach plasma levels of 1–4 μg/ml [121]. After a bolus injection or continuous administration for up to 12 h, the half-life of lidocaine is about 100 minutes and shows linear

Lidocaine metabolism occurs rapidly in the liver by cytochrome P450 isoforms CYP1A2 and 3A4, as outlined in **Figure 3**. Lidocaine undergoes oxidative N-dealkylation, to a number of metabolites that include monoethylglycinexylidide (MEGX) and glycinexylidide (GX), and N-ethylglycine (NEG), all of which have a glycine-like moiety. Less than 10% of lidocaine is excreted unchanged by the kidneys. MEGX is an active metabolite and has 80% potency of lidocaine at VGSC's. GX is also active but NEG is inactive. Following intravenous administration, MEGX concentrations in serum range from 11 to 36% of the lidocaine concentration. All lidocaine metabolites are excreted by the kidneys. The half-life of lidocaine elimination from the plasma following IV administration is 81–149 min (mean 107 ± 22 SD, *n* = 15). The systemic clearance is 0.33–0.90 l/min (mean 0.64 ± 0.18 SD, *n* = 15). Children older than 6–7 months of age distribute and eliminate intravenous lidocaine in the

In infants less than 6–7 months of age liver metabolism is immature so metabolism of drugs is delayed, and plasma protein levels are lower [124]. There are low levels of plasma alpha-1-acid glycoprotein, which increases the free fraction of circulating lidocaine and therefore increases the risk of toxicity [125]. IVLT in high doses (6–8mg/kg/h without a bolus dose) has used to treat neonatal seizures but the risk-benefit indication is considerably different than for pain management [126]. For these reasons, IVLT for pain management cannot be recommended in

A major advantage with IVLT is that appropriate use in adults is not associated with a significant side-effect profile [7, 127, 128]. In adults, a 100 mg bolus followed by an infusion at 1 mg/ min, which approximates to 1mg/kg/h, produces a plasma level of just over 1 μg/ml in normal individuals with no co-morbidities [129]. IVLT doses used to manage pain are usually in the range of 1–2 mg/kg/h. Plasma levels at this rate of infusion are generally less than 3–5 μg/ml, but awake patients may complain of light-headedness, perioral numbness, dizziness and or

infants until more evidence of efficacy and safety in this population are available.

mic treatment [113–115].

72 Pain Relief - From Analgesics to Alternative Therapies

pharmacokinetics [122].

same manner as adults [123].

**2.2. Safety of IVLT for pain management**

Contraindications to IVLT include allergy to amide local anaesthetics, significant cardiac disease, heart block, seizures, liver disease and/or significant renal impairment.

#### **2.3. The rationale for IVLT in the management of pain**

Studies in animal preparations clearly indicate that systemically administered lidocaine can silence ectopic discharges without blocking nerve conduction [135, 136]. Systemic administration of local anaesthetics provides clinical analgesia in a broad range of neuropathic pain states [23, 117, 137–140]. IVLT induces global analgesia and dampens the neuro-inflammatory response in pain [126, 141–144]. Lidocaine exerts its different effects on the neuro-inflammatory response by inhibiting ion channels and receptors. The exact lidocaine plasma level and duration of infusion required to produce this effect are unknown; however, it occurs at levels below those required for action potential initiation and propagation for neural blockade. It is also not known if plasma lidocaine concentration correlates with analgesic effect in a dose dependent manner as different channels and receptors are modulated at different plasma lidocaine concentrations [145].

Intravenous lidocaine has peripherally and centrally mediated analgesic, anti-inflammatory and anti-hyperalgesic properties. Its analgesic properties reflect the variable dose, time dependent, multimodal aspect of its action on voltage-gated channels receptors and neurotransmitters that affect nociceptive transmission pathways [24, 45, 146–148]. In vitro, low dose lidocaine inhibits voltage-gated sodium channels (VGSC), some potassium channels, the glycinergic system, and G-protein coupled receptors. Higher dose lidocaine blocks voltage-gated calcium channels, other potassium channels, and NMDA receptors [145, 149, 150]. Lidocaine dosages needed for voltage-gated sodium channel blockade range from 60 to 200 μM, whereas voltage-gated calcium channel blockade occurs at higher doses in the 1–10 mM range [6, 151–153]. A number of different sodium channel isoforms exist with distinct tissue distribution and possibly distinct physiological functions. Some of these isoforms have been shown to be up-regulated in inflammatory and neuropathic pain states [28, 154–156]. Lidocaine blocks all sodium channel isoforms but differences in isoform sensitivity to lidocaine could be an explanation for efficacy in various different pain models.

Animal studies demonstrate that systemic lidocaine changes conduction in neurons of the dorsal horn, dorsal root ganglion and hyper-excitable neuromas without affecting normal nerve conduction [23, 135, 157]. Cell membranes of injured peripheral nerves express sodium channels with unusual density and produce persistent spontaneous discharges that maintain a central hyper-excitable state [20]. Ectopic discharges can be initiated along the injured nerve, in the dorsal root ganglion, and in peripheral neuromata [157–161]. Lidocaine inhibits these aberrant electrical discharges at concentrations well below those necessary to produce conduction blockade in nerves. Dorsal-horn neurons are more sensitive to lidocaine compared with peripheral neurons [135]. The high susceptibility of hyper-excitable neurons to lidocaine may be attributed to the changed expression of sodium channels during nerve injury [28].

Analgesic effects are thought to be mediated by the inhibition of Na channels, NMDA, and G-protein-coupled receptors that lead to the suppression of spontaneous impulses generated from injured nerve fibres and the proximal dorsal root ganglion [23, 117, 159, 162].

While the main mechanism of the therapeutic action of lidocaine is considered to be blockade of voltage-gated channels, lidocaine may also have a desensitizing effect on TRP channels. This may reflect the prolonged analgesic effects sometimes seen that outlast the expected presence of lidocaine in the tissue [163].

Anti-inflammatory effects are attributable to attenuation of neurogenic inflammation and subsequent blockade of neural transmission at the site of tissue injury. Lidocaine inhibits the migration of granulocytes and release of lysosomal enzymes which leads to decreased release of pro- and anti-inflammatory cytokines [146, 162, 164–167]. Animal studies demonstrate that these anti-inflammatory effects of lidocaine are mediated by inhibition of VGSC, G-proteincoupled receptors and ATP-sensitive potassium channels.

The anti-hyperalgesic effect of lidocaine is presumed to result from the suppression of peripheral and central sensitization through a combination of nocioceptor blockade, dampening of the neuro-inflammatory response to pain, NMDA receptor inhibition and modulation of the glycinergic system [25, 168–173]. Low dose lidocaine (10 μM) enhances and high dose (1 mM) inhibits glycinergic signalling [174]. The lidocaine metabolite, N-ethylglycine (NEG) is a substrate of the glycine reuptake transporter so it competes with endogenous and synaptically released glycine for reuptake leading to increased extracellular and synaptic glycine levels [172]. This would explain why NEG has been shown to induce analgesia in rodent models of neuropathic and inflammatory pain but has minor effects on Na<sup>+</sup> channels [172]. The lidocaine metabolite MEGX has been shown to inhibit the glycine transporter which will also increase glycine levels [172].
