These findings reveal a marked increase in insular, midbrain, thalamic, cingulate, and striatal rCBF following the administration of lidocaine. Generally, lidocaine infusion increased rCBF more than either the same dose or a higher dose of procaine. In contrast, the mood and sensory effects of lidocaine were minimal and significantly less than those experienced following the procaine administration. These findings suggest that sodium channel inactivation by lidocaine has profound and regionally specific effects upon CNS rCBF despite minimal sensory effects. These findings were unexpected and difficult to interpret. Differences between lidocaine and procaine that may explain these findings are discussed below.
As procaine has relatively greater effects on the DAT relative to lidocaine (Ritz et al., 1987
), it is presumed that the greater neural alterations induced by lidocaine are due to its effects on the sodium channel. However, there are several other factors that could account for the observed differences in rCBF. Both procaine and lidocaine exhibit affinity for the 5HT3 receptor, procaine more so than lidocaine (Barann et al., 1993
). Interestingly, procaine (and cocaine) have equal affinity at both the sodium channel and 5HT3 receptor, whereas lidocaine has 4-fold the affinity for the sodium channel relative to the 5HT3 receptor (Barann et al., 1993
). Procaine also has affinity for nicotinic (Swanson and Albuquerque, 1987
; Niu et al., 1995
) and muscarinic (Karpen and Hess, 1986
; Sharkey et al., 1988
; Flynn et al., 1992
) acetylcholine receptors at pharmacologically relevant concentrations; the affinity of lidocaine at these receptors is not known.
There are also both pharmacokinetic and other pharmacodynamic differences in procaine and lidocaine that may account for the differences observed, including assumptions regarding the relative doses administered and their potency at the voltage-dependent sodium channel. Usubiaga et al. (Usubiaga et al., 1967
) observed higher mean cerebrospinal fluid concentrations (CSF) concentrations of lidocaine relative to procaine following intravenous infusion, suggesting either increased CSF penetration or less metabolism of lidocaine. Reports of the relative potencies of lidocaine and procaine at the sodium channel also differ (Agin et al., 1965
; Barann et al., 1993
). In our laboratory, we have found lidocaine has approximately 1.5 times the potency of procaine in activating prefrontal cortical field excitatory post-synaptic potential (EPSP) in rodents (unpublished).
There are few studies assessing the CNS effects of both lidocaine and procaine in humans. To our knowledge, only Foldes et al. (1960)
and Usubiaga et al. (1966)
also directly compared these two medications. Foldes et al. (1960)
utilized dramatically higher doses than those given in the present study, administering lidocaine (0.5 mg/kg/min) and procaine (1.0 mg/kg/min) for up to 25 minutes or until severe CNS symptoms became evident (i.e. seizures, loss of consciousness). Clinical symptoms of CNS toxicity showed a similar time onset following both drugs, although the infusion was tolerated significantly less time following lidocaine relative to procaine. These findings were similar to those of Usubiaga et al. (1966)
, which compared even higher doses of lidocaine (1.5 to 3.0 mg/kg/min) and procaine (3.0 to 9.0 mg/kg/min) and used only seizures as their clinical endpoint. The increased therapeutic index of procaine over lidocaine may be a result of procaine’s more rapid clearance through hydroxylation or its effect on sodium channels. Detsch et al. (1997)
measured spectral EEG in eleven healthy volunteers following lidocaine (2 minute bolus of 100mg followed by 40 ug/kg-min for 15 minutes) or placebo. Both frontotemporal and occipital EEG changes were observed in both delta and beta spectral power during lidocaine relative to placebo. Other investigators have described significant sensory disturbances following lidocaine (Attal et al., 2000
), although concurrent neural measures have not been obtained. Plewnia et al. (2007)
recently reported an association between the transient suppression of verbal auditory hallucinations in a 74-year-old woman following intravenous lidocaine administration (100mg) and rCBF reductions (as measured by PET) in the right angular and supramarginal gyrus, right inferior frontal gyrus, orbitofrontal cortex and cingulate cortex. It is likely that the relatively low dose of lidocaine administered in the present study (0.5 mg/kg) accounted for the near absence of sensory effect of lidocaine. The lidocaine in our study was also administered as bolus over one minute as opposed to the more extended dosing (5-90 minutes) used in other studies (Usubiaga et al., 1967
; Galer et al., 1993
; Detsch et al., 1997
; Attal et al., 2000
) and clinical practice (Roden, 2001
Procaine induces activation of the anterior limbic region, including the anterior cingulate, anteromesial temporal cortex, and anterior/middle insula (Ketter et al., 1996
; Servan-Schreiber et al., 1998
; Adinoff et al., 2001
; Adinoff et al., 2003a
) and significant sensory and anxiogenic effects (Stark-Adamec et al., 1982
; Kellner et al., 1987
; Ketter et al., 1996
; Servan-Schreiber et al., 1998
; Adinoff et al., 2001
; Adinoff et al., 2003a
). Although sensory disturbances were observed following procaine in the present study, particularly at the higher dose (1.0 mg/kg), limbic rCBF was limited compared to increases in rCBF observed at the somewhat higher procaine dose of 1.38 mg/kg (Adinoff et al., 2001
; Adinoff et al., 2003b
). It should be noted that the findings in the present study differed from our previous report of these data (Adinoff et al., 2002
) following a more detailed analysis using a smaller smoothing kernel (10 mm vs. 14 mm), a more rigorous statistical threshold (p<0.005 vs p<0.01), and a larger cluster extent threshold (100 vs. 50 voxels).
Methodologic strengths of our study include a carefully selected population of healthy volunteers and the inclusion of one gender (females). Although our study design (4 scans over 10 days) did not allow menstrual phase to be controlled, the within-subject design and randomized order of medication administration make menstrual phase an unlikely confound. Limits of spatial resolution and the ability to only determine relative measures of limbic rCBF are inherent in our SPECT methodology and camera. It should also be noted that the SPECT utilized assessed relative (to whole brain), not absolute, rCBF differences between groups. However, Ketter et al. (1996)
found that procaine induced significant regional changes in limbic regions using both absolute and normalized measures of cerebral blood flow. Thus, direct vascular effects, typically removed by normalization, appear not to play a major role in procaine regional responses. Dormehl et al. (1993)
has reported that baboons administered lidocaine (6 mg/kg) intravenously exhibited an increased in rCBF (with SPECT) that was associated with changes in PaCO2
, suggesting that changes in cerebrovascular autoregulation may have contributed to lidocaine-induced neural activation. In addition, Usubiaga et al. (Usubiaga et al., 1967
) observed a marked fall in systolic and diastolic blood pressure following lidocaine infusion (5-10mg) but not following procaine (10-20mg). However, our findings demonstrate that neither drug induced a significant change in blood pressure or heart rate at the doses administered. Although this does not rule-out a cerebrovascular effect of lidocaine, the specific regional distribution of rCBF findings argues against this explanation of our findings.
These findings reveal that lidocaine, a medication essentially devoid of activity at monoamine transporters, induces marked increases in striatal, thalamic, insular, cingulate, and brainstem rCBF with minimal changes in mood, sensory, or autonomic activity. Lidocaine may serve as a useful tool for neuroimaging studies to probe the specific neural circuits most sensitive to sodium channel blockade.