**2.4. A central effect of systemic lidocaine**

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 lido-

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

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

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

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-protein-

from injured nerve fibres and the proximal dorsal root ganglion [23, 117, 159, 162].

caine could be an explanation for efficacy in various different pain models.

injury [28].

presence of lidocaine in the tissue [163].

74 Pain Relief - From Analgesics to Alternative Therapies

coupled receptors and ATP-sensitive potassium channels.

On-going input from peripheral nociceptors which is blocked by local anaesthetics is used to explain dependence of pain syndromes on peripheral inputs [175]. However, IVLT also has a central effect reducing components of pain caused by central nervous system injuries [176]. Systemically administered lidocaine has been shown to suppress capsaicin-induced hyperalgesia by a central mode of action, whilst concurrently reducing acute chemically induced pain by a peripheral mode of action [114]. Descending facilitatory pain transmission from the rostroventromedial medulla may also be suppressed by lidocaine [177, 178].
