Quantitative and Selective Evaluation of Differential Sensory Nerve Block After Transdermal Lidocaine

Methods

After institutional approval and written informed consent, 15 healthy volunteers (13 men and 2 women) aged 25–36 yr participated in this study. Lidocaine 10% gel (7), approximately 1 g, was applied topically to the medial side of a forearm within a 8-cm diameter circle and covered with a plastic film for 60 min (ipsilateral forearm). The forearm contralateral to the topical lidocaine was also draped without topical lidocaine for control measurement to exclude the systemic effect of lidocaine. Sensory tests including CPT and SRPI were made at both the ipsilateral and contralateral forearm with the same time schedule.

Large myelinated A (Aβ), small myelinated A (Aδ), and unmyelinated C (C) fibers were evaluated with a series of 2000-, 250-, and 5-Hz stimuli using Neurometer CPT/C (Neurotron, Baltimore, MD), respectively. A pair of gold-plated surface electrodes was placed on the central space of lidocaine application. At each frequency (2000, 250, and 5 Hz) the current was slowly increased until the subject reported sensation. The stimulus then was turned off, the intensity was decreased by 0.1 mA, and the stimulus turned back on. This procedure was repeated until a range of 0.1 mA was established, at which level the patient reported feeling the high intensity but could not detect the lower intensity. Using a double-blinded methodology, the patient was then presented with 6–20 cycles of randomly selected real and false stimuli above and below the perception threshold level until the exact CPT value could be determined within a ±0.02-mA range. CPTs defined 0.01 mA as “1” and 10 mA as “1000.”

SRPI included light touch (dull hinged end of a ball-point pen), pinprick (26-gauge needle), cold (alcohol-soaked swab), and hot (500-mL of lactate Ringer’s plastic bottle heated to a constant temperature of 42°C) stimuli. Subjects reported the intensity of stimuli in the ipsilateral site as the relative intensity compared with the contralateral site using a numerical rating scale (from 0 to 10, with 0 = no sensation, 10 = same intensity as contralateral site).

Measurements were made before the topical lidocaine (baseline), 60 min after the draping (T0), and at 1-h intervals until 5 h after T0 (T1 to T5). These examinations for sensory tests took approximately 15 min each time, and were done with patients in the sitting position in an isolated room.

CPT data were converted to %MPE (maximum possible effect), calculated as (CPT at ipsilateral site − CPT at contralateral site)/(999 − CPT at contralateral site) × 100 to diminish the variance among the subjects. Intragroup comparisons in %MPE were evaluated using one-way repeated-measure analysis of variance. Friedman test was used to determine the effect of lidocaine gel on each SRPI. When significance was found, paired t-test or Wilcoxon’s signed rank test was used for post hoc testing. Significance was determined as P < 0.05.

Results

All subjects completed the study protocol. All baseline CPT values were within the normal range. One-way repeated-measure analysis of variance indicated that %MPE at all frequencies significantly increased. A significant increase in %MPE compared with baseline was observed until T2 at 5 Hz and T4 at 250 Hz, whereas the increase in %MPE at 2000 Hz continued throughout the study period (Fig. 1).

SRPIs of all stimuli were significantly decreased as assessed by Friedman test. No sensation returned to the baseline level during the study period (Fig. 2). All subjects experienced the disappearance of pinprick and cold sensations, whereas touch and warmth sensations were detectable during the study period.

Discussion

Our results show that when lidocaine is applied transdermally, CPT increases significantly at each frequency, and that the recovery of CPT begins initially at 5 Hz (unmyelinated C fiber), then at 250 Hz (small myelinated A fiber), and finally at 2000 Hz (large myelinated A fiber), and suggests that sensitivity of nerves to local anesthetics is proportional to the axon diameters. The results also indicate that transdermal lidocaine causes differential sensory nerve block in a different manner from intrathecal or epidural lidocaine. However, the results of SRPI demonstrate that cold and pinprick perceptions after transdermal lidocaine are more strongly affected than touch and warmth perceptions.

The early laboratory study supported “size principle” which meant that the sensitivity of nerves to local anesthetics was inversely proportional to axon diameter (1). However, that study was done on myelinated fibers of frog only, and the laboratory experiments in mammalian were contrary to the size principle (4,5). These experiments suggested that large myelinated axons were substantially more susceptible to lidocaine than small unmyelinated axons. Fink and Cairns (5) demonstrated that the concentration of lidocaine needed to block myelinated axons was smaller than that in unmyelinated axons. Jaffe and Rowe (4) reported that myelinated axons were significantly more susceptive to the conduction velocity slowing the effects of lidocaine than unmyelinated axons. In contrast, spinal and epidural administration of lidocaine produces differential nerve block in accordance with the size principle that the sensitivity of nerves to local anesthetics is inversely proportional to axon diameter. Liu et al. (2) and Sakura et al. (3) demonstrated differential sensory nerve block during spinal and epidural blocks by using CPT.

The discrepancy of the anesthetic effects between clinical and laboratory examinations may have been for several reasons, including the length of nerve exposed to the anesthetics (5), continuing nerve activity (6), or lidocaine-induced inhibition of C fiber-mediated nociceptive spinal cord potential (8). At least three successive nodes of Ranvier must be exposed to anesthetics for blockade of a myelinated axon (9). In spinal and epidural spaces, large myelinated nerve fibers have fewer nodes exposed to local anesthetics, and therefore might resist conduction block as compared with small unmyelinated fibers. However, transdermal lidocaine within an 8-cm-diameter circle would cover enough nodes to block myelinated axons. Thus, our results are supported by the laboratory findings, but not by epidural and spinal observations.

CPT testing can evaluate sensory nerve fibers quantitatively and selectively. CPTs at 2000-, 250-, and 5-Hz stimuli indicate the functions of large myelinated A fibers, small myelinated A fibers, and unmyelinated C fibers (2,10). Recent clinical studies have demonstrated that CPT testing is useful for evaluation of peripheral sensory function in sensory disturbance (11–13).

In our study, CPT testing demonstrated that transdermal lidocaine preferentially inhibited large myelinated fibers, whereas lidocaine was not as effective at blocking touch stimuli mediated by large myelinated A fibers (14) in SRPI. The discrepancy of the results between CPT and SRPI data could be explained by the following reason: the electrical current generated by the Neurometer stimulates nerve fibers directly and bypasses receptors (10), because receptors have higher electrical resistance than nerve fibers, whereas SRPI is evaluated by stimulating the skin surface receptors. The former reflects the function of fibers and the latter, both receptors and fibers. Therefore, our results indicate that transdermal lidocaine would affect large more strongly than small fibers at the fiber site; and that it would also affect cold and pinprick receptors more strongly than touch and warmth receptors at the site of sensory receptors; and that the intensity of blockade is stronger at the site of receptors than at the site of fibers. These results are consistent with the study by Arendt-Nielsen and Bjerring (15) who investigated the effect of topically applied anesthetics (EMLA cream) on the sensory nerves. They demonstrated that warmth and touch perception were still perceived when pain completely disappeared in the experiment using high-energy argon laser which activates receptors.

Somewhat surprising was the finding that the sensory-blocking effect of transdermal lidocaine lasted for five hours or more. A previous study demonstrated that sensory threshold returned to the baseline level 150 minutes after the end of application of EMLA cream, 2 g, for 60 minutes (15). Thus, the duration of the sensory-blocking effect induced by lidocaine 10% gel, 1 g, is longer than that induced by EMLA cream. This difference could probably occur because the content of lidocaine is different between EMLA cream and lidocaine 10% gel. EMLA cream is a eutectic mixture of 2.5% prilocaine and 2.5% lidocaine, whose content of lidocaine is smaller compared with that in our study. Bjerring and Arendt-Nielsen (16) demonstrated that the sensory threshold was significantly increased for 210 minutes after the end of application of EMLA cream, 5 g, for 60 minutes. Therefore, we speculate that the concentration and content of transdermal lidocaine may affect the duration of sensory block.

In conclusion, when lidocaine was applied transdermally, the recovery of CPTs was faster at 5 Hz (unmyelinated C fiber) than at 250 Hz (small myelinated A fiber), and was faster at 250 Hz than at 2000 Hz (large myelinated A fiber), suggesting that the sensitivity of nerves to local anesthetics is proportional to the axon diameters. SRPI data show that transdermal lidocaine would affect pinprick and cold sensations more strongly than other sensations at the site of receptors. The discrepancy of the results between CPT and SRPI data is explained by the following reasons: first, transdermal lidocaine may block more strongly at the site of receptors than at the site of fibers. Second, CPT reflects only nerve fibers, whereas SRPI reflects both receptors and fibers.