Re:Local Injection of Methylcobalamin Combined with Lidocaine for Acute Herpetic Neuralgia

[문형철]

beyond reason

Local methylcobalamin combined with lidocaine, optimally administered within 4–7 days of onset, may be an effective therapeutic option for acute herpetic neuralgia.

All subjects had received antiviral agents (300 mg of valaciclovir, twice daily) within 72 hours after the onset of rash, for a total of 7 days. Those in the treatment group received a combination of MeB₁₂ (1,000 µg in 2 mL, Eisai Co. Ltd, Tokyo, Japan) and 20 mg lidocaine (total 3.0 mL, Fuda Co. Ltd, Shanghai, China) by local injections; those in the control group received intramuscular MeB₁₂ (1,000 µg daily), plus once daily 20 mg lidocaine (2.0 mL) by local injection. The drugs were injected into the subcutaneous regions of crusted lesions where the subjects experienced the worst pain (0.5 mL of liquid injected per region) using 25 G needles and sterile hypodermic syringes. The dosing frequency was once daily, six times a week for 2 weeks. The subjects were observed for 1 hour after the first administration, and they were subsequently discharged without any symptoms of discomfort.

Local Injection of Methylcobalamin Combined with Lidocaine for Acute Herpetic Neuralgia 

Gang Xǔ, MD, Site Xu, BSc, Wei-Zhen Tang, BSc, Gang Xú, BSc, Chao Cheng, BSc, Jie Xu, BSc

Pain Medicine, Volume 17, Issue 3, March 2016, Pages 572–581, https://doi.org/10.1093/pm/pnv005

Published:

 

11 November 2015

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Abstract

Objective. To determine the efficacy of methylcobalamin combined with lidocaine for acute herpetic neuralgia.

Design. Randomized controlled trial with longitudinal analysis.

Subjects. The authors recruited 204 patients (>50 years) with T5-10 dermatomal acute herpetic neuralgia with rash onset within 7 days. Patients were divided into two groups based on the time of onset: immediate-early (IE, 1–3 days) and early stage (ES, 4–7 days) groups and then subdivided randomly into control (IE-Ctl, ES-Ctl) and treatment (IE-Tr, ES-Tr) groups.

Methods. Control groups received intramuscular methylcobalamin in addition to local lidocaine injection, while treatment groups received local methylcobalamin combined with lidocaine injection for 14 days. Treatment efficacy was assessed based on rash healing time, alteration in pain intensity, and interference with quality of life. Multilevel mixed modeling and survival analysis were employed to examine treatment responses.

Results. There was no significant difference in the rash healing time between IE and ES. The mean pain scores in IE-Tr (2.4 ± 0.7) and ES-Tr (1.3 ± 0.7) decreased significantly compared with those in the control groups. The median satisfactory response time was 6 days in ES-Tr and 11 days in IE-Tr. The benefit ratio for ES-Tr versus IE-Tr was 14.94. The subjects in IE-Tr and ES-Tr had higher quality of life scores (81.2 ± 6.9 vs 88.3 ± 8.6, respectively) than those in the control groups. The incidence of postherpetic neuralgia was 1.1% at 3 months.

Conclusions. Local methylcobalamin combined with lidocaine, optimally administered within 4–7 days of onset, may be an effective therapeutic option for acute herpetic neuralgia.

Herpes Zoster, Acute Herpetic Neuralgia, Methylcobalamin, Subcutaneous Injection, Randomized Clinical Trial

Topic:

 

• lidocaine
• exanthema
• intramuscular injections
• neuralgia
• pain
• reaction time
• quality of life
• post-herpetic neuralgia
• methylcobalamin
• pain score
• symptom onset
• treatment effectiveness
• fifth thoracic vertebra

Issue Section:

 Brief Research Report

Introduction

A significant proportion of patients with herpes zoster (HZ) experience intense neuritic pain and neuralgia under skin innervated by the affected neural segments prior to and during the rash [1, 2]. Acute herpetic neuralgia (AHN) is defined as the intense pain in the affected nerve during acute zoster infection within 30 days [3]. Local inflammation and tissue damage stimulate the primary afferent neurons of the skin and subcutaneous tissue, which manifest neurologically as pain. Patients with AHN who are at least 50 years old are more likely to have severe pain and to develop postherpetic neuralgia (PHN) [4], which may severely impact their quality of life (QoL). Neuritic pain should be controlled in the acute phase and antiviral therapy significantly reduces the severity of infection [5]. However, this therapy does not completely alleviate AHN [6, 7]. Therefore, identification of the optimal time and treatment option to intervene in neuritic pain during the acute phase of HZ has clinical significance.

Cobalamin (Cbl, vitamin B₁₂), known as a neurotrophic agent [8], has a special affinity for neural tissues [9]. High-dose Cbl therapy may have salutary pharmacologic effects on neurologic function in a variety of disorders. Clinical experience has shown that local methylcobalamin (MeB₁₂) injection is an effective treatment modality for subacute herpetic neuralgia (SHN) [10] and PHN [11]. MeB₁₂, a Cbl analogue, might be potentially relevant for AHN in the eruptive phase and local administration may have a more significant neurotrophic effect on affected fibers than systemic administration. Topical 5% lidocaine medicated plasters are recommended as the first-line therapy for PHN [12,13]. Multiple randomized clinical trials have demonstrated the efficacy of lidocaine patch application in patients with PHN; therefore, we hypothesized that lidocaine can effectively relieve the pain associated with AHN. In this study, a single center, randomized, observer-blind clinical trial was conducted in patients with AHN to explore the efficacy of local MeB₁₂ administered in combination with lidocaine.

Methods

Design and Ethics

This prospective study was a randomized, four-group, parallel clinical trial. The study protocol was reviewed and approved by the Tongji University Institutional Review Board, and conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Participants

From January 2012 to March 2013, consecutive immunocompetent adult patients (n = 204) with rash associated with simultaneous pain were recruited. Inclusion criteria were AHN from the fifth to tenth intercostal nerve within 7 days after onset of the rash, defined as vesicles accompanied simultaneously with continuous pain; rash severity >25 lesions; aged more than 50 years; and willingness to comply with the allocated treatment and follow-up measurements. Subjects had to experience cutaneous and/or subcutaneous pain on the unilateral T5-10 dermatome associated with their rash and a worst pain score of 6 or higher on an 11-point pain intensity numerical rating scale (NRS) in the past 24 hours. Subjects with the following conditions were excluded: unilateral dermatome pain in the vesicular region with no simultaneous onset or more than 7 days after onset of rash; diffusely distributed neuropathic pain or significant pain outside the target regions; use of steroid, analgesics, or capsaicin within 4 weeks of study entry; any clinically significant medical condition or laboratory abnormality; and cognitive impairment.

Randomization

An independent physician eval‎uated the eligibility of subjects. Written informed consent was obtained only from the eligible subjects, who agreed to enroll for the trial. Demographic and baseline characteristics of all the enrolled subjects were recorded at baseline. Based on the days since rash onset, subjects were allocated to the immediate-early stage (IE) group (≤3 days) and the early stage (ES) group (4–7 days). Subjects were then randomly assigned by computer-generated randomization in a 1:1 ratio to the treatment group (IE-Tr and ES-Tr) and control group (IE-Ctl and ES-Ctl).

Another independent clinician, who did not participate in the clinical management and was blinded to the subjects’ treatment allocation, carried out the follow-up visits of the treatment to assess the pain intensity and QoL. Given the nature and color of the injection, it was impossible to blind the physician and subjects as to the randomization assignments. However, they were informed that these treatment approaches were valid interventions that had a realistic chance of being beneficial and that no approach was known to be more effective than the other. The clinicians were also instructed to treat subjects in all four groups with the same degree of rigor, enthusiasm, and optimism.

Sample Size

Previous studies showed that 60% to 90% of immunocompetent subjects with zoster experience local neuritic pain in association with the acute herpetic rash; whereas 43.6%, 27.0%, 11.7%, 8.7%, 7.4%, and 6.0% of those with zoster in the general population had pain on day 15, and at months 1, 3, 6, 9, and 12, respectively [6,14]. Based on the analysis using mixed-effects modeling, sample sizes were calculated for repeated measurements. The expected proportion of NRS pain intensity of 3 or lower for the 14-day treatment was 80%. An intra-subject correlation coefficient between two consecutive measurements was 0.7. Assuming an error of 0.05 with a power of 80%, a minimum of 38 subjects per group is needed to detect differences between the two groups over the same period, with a two-sided 5% significance level. Considering a dropout rate of 15% during follow-up, at least 176 subjects in total were needed for the present study.

Intervention

All subjects had received antiviral agents (300 mg of valaciclovir, twice daily) within 72 hours after the onset of rash, for a total of 7 days. Those in the treatment group received a combination of MeB₁₂ (1,000 µg in 2 mL, Eisai Co. Ltd, Tokyo, Japan) and 20 mg lidocaine (total 3.0 mL, Fuda Co. Ltd, Shanghai, China) by local injections; those in the control group received intramuscular MeB₁₂ (1,000 µg daily), plus once daily 20 mg lidocaine (2.0 mL) by local injection. The drugs were injected into the subcutaneous regions of crusted lesions where the subjects experienced the worst pain (0.5 mL of liquid injected per region) using 25 G needles and sterile hypodermic syringes. The dosing frequency was once daily, six times a week for 2 weeks. The subjects were observed for 1 hour after the first administration, and they were subsequently discharged without any symptoms of discomfort.

Measurements

Subjects rated their worst pain since rash onset at the baseline visit and their worst pain during the past 24 hours each day using a 0–10 NRS. Zoster-related sensory symptoms are generally described as continuous spontaneous pain, paroxysmal pain, tactile allodynia, tingling, numbness, and intense itching [3]. Changes in various characteristics of the pain and discomfort related to AHN were also measured using NRS.

Subjects were assessed for cutaneous healing including time to start of crusting, full crusting, and complete healing of zoster-associated rash. The principal outcome variables were the worst pain intensity ratings calculated from baseline to the 14-day treatment termination. There were four follow-up visits assessed in telephone conversations at 1, 3, 6, and 12 months after rash onsets.

Using EuroQoL visual analogue scale (VAS), participants were asked to rate their current health state on a scale of zero (worst imaginable health state) to 100 (best imaginable health state) before and after the14-day treatment.

Statistical Analysis

The primary efficacy analysis was performed using all study subjects. The longitudinal data of repeated measurement of pain scores were used in multilevel mixed modeling, with the measurement time points (level-1, Time) nested within subjects (level-2, Group). A multilevel model was fitted for outcome variable to examine changes in pain scores over time and to compare the difference between the effects of the two treatment modalities on patients in the same rash onset group.

Longitudinal data during treatment were used in Kaplan-Meier (KM) survival analysis to explore treatment responses and optimal intervention time and to test the hypothesis that the effects in the IE-Tr group were, on average, superior with respect to therapeutic window to those in the ES-Tr groups within 21days. Previous studies among subjects with zoster pain demonstrated that pain scores ≤ 3 recorded more than 30 days after rash onset were associated with minimal interference with QoL [15], thus the satisfactory response point (terminal event) was defined as a sustainable pain score ≤3, and the minimum satisfactory response times was defined as the first day that reached the satisfactory response point for consecutive 3 days. The number of subjects with pain score ≤3 and median satisfactory response (median survival) times (50% subjects with pain score ≤3) within 21 days during local therapy was calculated by KM analysis. The model assumes that the treatment benefit is the same in each group at baseline and possibly diverges with increasing duration of therapy. The association between the proportion of subjects having pain score ≤3 and median satisfactory response times was estimated using benefit (hazard) ratios. Time zero for the KM analysis was the time of rash and pain onset, which was used to discriminate between those who reached and did not reach the satisfactory response point within 21 days.

Group comparisons for rash healing time and degree, alteration in pain intensity, proportion of subjects with pain ≤3, and EuroQoL VAS scores were analyzed using analysis of variance or Chi-square test.

Pain score were assessed at the 1-, 3-, 6-, and 12-month follow-up visits to calculate PHN preval‎ence. For all subjects who were unavailable for follow-up, the last pain score was carried forward to future time points for statistical analysis.

Two-tailed P values less than 0.05 were considered to indicate statistically significant. All analyses were performed using R software (R 2.15.0 version developed by Peter Dalgaard of the R Core Development team).

Results

Sample Description

The total number of subjects with AHN consecutively enrolled throughout the 12-month recruitment period was 204. Twenty-four subjects were excluded from the study for various reasons, and only 180 subjects who met the inclusion criteria were eligible for the trial. Sample characteristics are presented in Figure 1 and Table 1. All 180 subjects and their data were included for analysis of therapeutic response within 21 days, and follow-ups visits were continued for 12 months after rash onset in the treatment group.

Figure 1

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Patient flow diagram. Time from randomization to the study end point was 12 months.

Table 1

Demographic and clinical characteristics of subjects at baseline

Measures	IE Group (1–3 days)		ES Group (4–7 days)
	IE-Ctl (n = 45)	IE-Tr (n = 46)	ES-Ctl (n = 44)	ES-Tr (n = 45)
Age at rash onset (SD)	63.5 (8.7)	63.6 (8.5)	61.9 (8.0)	63.1 (8.3)
Female, n	29	31	27	28
Elementary education or less, n	2	2	1	2
Hours since rash and pain onset, (SD)	50.0 (18.7)	51.3 (19.6)	134.8 (26.9)	125.9 (24.9)
Description of rash
Extent-
Limited rash, n	16	17	16)	17
Extensive rash, n	29	29	28	28
Severity of lesions-
Simple rash, n	43	44	8	7
Pustules, n	2	2	25	26
Necrotic appearance, n			11	12
Pain scores at baseline (SD)	8.2 (1.2)	8.2 (1.2)	8.3 (1.2)	8.4 (1.5)
Euro QoL at baseline (SD)	16.7 (7.4)	17.7 (6.7)	15.2 (7.3)	13.9 (7.1)

Data presented are means (SD).

Score: numerical rating scale (intensity measured on 0–10); SD: standard deviation.

IE: the immediate-early stage (rash onset ≤ 3 days) group; ES: the early stage (rash onset within 4–7 days) group.

Ctl: Intramuscular methylcobalamin in addition to local lidocaine injection group; Tr: Local methylcobalamin combination with lidocaine injection group.

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Dropouts

Four subjects dropped out of the study during the 14-day therapy; one subject from the IE-Ctl group, two from the ES-Ctl group, and one from the ES-Tr group. In the IE-Ctl group, one patient was released from the trial by the investigator due to noncompliance after receiving 7 days of treatment. In the ES-Ctl group, one patient did not complete the study due to lack of improvement after receiving 8 days of treatment, and the other was lost to follow-up after receiving 10 days of treatment. In the ES-Tr group, one subject withdrew after receiving 12 days of treatment because of leg fracture.

At the end of the treatment, subjects who completed the 14-day treatment but had worst pain intensity score > 4 were considered inadequate responders and assigned to other local treatment sequences. Less than 15% of the participants were lost to the 12-month follow-up in the treatment group, and their attrition was associated neither with sex nor education.

Cutaneous Healing

Table 2 showed the changes in cutaneous healing. Results indicated that there were no significant differences in cutaneous healing time of the rash between IE-Ctl with IE-Tr, and between ES-Ctl with ES-Tr (P > 0.05).

Table 2

Comparisons of the overall improvement among groups

Measures	IE Group (1–3 days)		ES Group (4–7 days)
	IE-Ctl (n = 45)	IE-Tr (n = 46)	ES-Ctl (n = 44)	ES-Tr (n = 45)
Start of crusting, hour (SD)	108.8 (22.7)	104.4 (26.9)	102.0 (26.9)	99.7 (22.5)
Full crusting, hour (SD)	215.5 (37.1)	204.5 (38.4)	200.7 (29.3)	199.2 (43.5)
Healing of crusts, hour (SD)	322.1 (30.1)	328.2 (35.1)	321.3 (31.6)	323.7 (41.5)
Pain scores at endpoint (SD)	6.6 (2.0)	2.4 (0.8)*	5.9 (2.0)	1.4 (0.9)*
Subjects with pain ≤ 3 at endpoint	5	43*	6	43*
Number needed to treat (95% CI)	1.21 (1.06, 1.41)		1.22 (1.06,1.43)
Other pain or sensory symptoms
Paroxysmal pain onset days from baseline (SD)	5.2 (1.3)	6.3 (1.1)*	3.7 (1.2)	5.0 (0.8)*
Subjects with paroxysmal pain	25	7*	32	4*
Paroxysmal pain score at initial point (SD)	7.2 (1.3)	6.0 (1.3)*	6.6 (1.3)	4.0 (0.8)
Paroxysmal pain at 14-day endpoint (SD)	7.1 (1.4)	2.1 (0.7)**	6.3 (1.4)	1.3 (1.3)
Allodynia onset days from baseline (SD)	9.9 (2.1)	11.2 (2.4)*	7.9 (1.3)	9.4 (1.5)*
Subjects with allodynia	14	6*	12	7*
Allodynia score at initial point (SD)	7.3 (1.3)	4.8 (1.0)	6.1 (2.3)	3.9 (1.6)*
Allodynia at 14-day endpoint (SD)	7.1 (1.4)	3.2 (0.8)**	6.0 (2.1)	2.6 (1.0)**
Tingling onset days from baseline (SD)	12.5 (0.7)	9.1 (1.3)	11.0 (1.4)	10.2 (1.5)
Subjects with tingling	2	7	2	6
Tingling score at initial point (SD)	3.5 (0.7)	3.3 (0.8)	4.5 (0.7)	2.7 (1.2)
Tingling at 14-day endpoint (SD)	3.5 (0.7)	2.0 (1.1)**	4.0 (0.0)	1.8 (0.8)**
Numbness onset days from baseline (SD)	11.5 (2.1)	8.9 (2.5)*	12.0 (1.0)	9.2 (1.6)*
Subjects with numbness	2	8*	3	6*
Numbness score at initial point (SD)	3.5 (0.7)	3.8 (0.9)	3.3 (0.6)	4.3 (0.8)
Numbness at 14-day endpoint (SD)	3.5 (0.7)	2.3 (0.9)**	3.3 (0.6)	2.0 (0.9)**
Itching onset days from baseline (SD)	12.0 (1.4)	5.9 (1.8)*	9.0 (1.0)	5.2 (1.5)*
Subjects with itching	2	11*	3	10*
Itching score at initial point (SD)	4.5 (0.7)	4.7 (0.8)	4.3 (0.6)	4.8 (0.6)
Itching at 14-day endpoint (SD)	4.5 (0.7)	4.4 (0.7)**	4.3 (0.6)	4.4 (0.7)**
Euro Qol at 14-day endpoint (SD)	37.1 (23.2)	81.2 (6.9)*	45.4 (22.8)	88.3 (8.6)*
Subjects with pain >0 at 1 month (mean score)		19 (2.6)		17 (1.6)
Subjects with pain >0 at 3 months (mean score)		11 (2.3)		10 (1.7)
Subjects with discomfort >0 at 6 months (mean score)		7 (1.7)		6 (1.5)
Subjects with discomfort >0 at 12 months (mean score)		4 (1.7)		3 (1.7)

Data presented are means (SD).

Score: numerical rating scale (intensity measured on 0–10); SD: standard deviation; CI: confidence interval.

IE: the immediate-early stage (rash onset ≤3 days) group; ES: the early stage (rash onset within 4–7 days) group.

Ctl: Intramuscular methylcobalamin in addition to local lidocaine injection group; Tr group: Local methylcobalamin combination with lidocaine injection group.

*

Compared between the same therapeutic strategy groups, P < 0.05.

**

Compared within the same rash onset groups, P < 0.05.

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Prospective Associations Between Therapeutic Method and Subsequent Pain

For subjects in IE-Ctl and IE-Tr, the intercept-only model was applied, and significant variance in the intercept indicated significant variation in the initial pain scores among the participants (2.32). The rate of change in pain score varied significantly among subjects (2.80) after random intercepts were specified in the model. The estimated intraclass correlation coefficient (ICC) was 2.32/(2.32 + 2.80) = 0.45, indicated that almost half of the total variation was due to between-subject heterogeneity. This implied that the measures were relatively stable and reduced the power to detect significance within-subject associations. For the participants with acute pain during the 4–7 days period of rash onset, the ICC was 4.44/(4.44 + 3.63) = 0.55 between ES-Ctl and ES-Tr; 45% of the variance in pain was accounted for by within-subject variation. The analyzed results of the final models indicated significant differences in the changes in mean pain score between the two therapeutic methods. A mean diagram generated to analyze the patterns of repeated measurements and direct observations of the number of changes are shown in Figures 2 and 3.

Figure 2

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Mean of pain of subjects with immediate-early (IE) onset (1–3 days) at each time point during the 14-day treatment period. Parameter estimate standard errors listed in parentheses. *P < 0.05; **P < 0.001.

Figure 3

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Mean of pain of subjects with early stage (ES) onset (4–7 days) at each time point during the 14-day treatment period. Parameter estimate standard errors listed in parentheses. *P < 0.05; **P < 0.001.

At the end of the 14-day treatment period, the EuroQoL VAS, as reported by subjects in the IE-Tr and ES-Tr, were significantly higher than those in the IE-Ctl and ES-Ctl, respectively (P < 0.001).

Prospective Associations Between the Timing of Treatment and Subsequent Pain

Plots of the KM curves for IE-Tr and ES-Tr are shown in Figure 4. The two curves appeared to diverge with time, with the satisfactory response with pain scores ≤3 indicating more effective treatment in ES-Tr compared with that in IE-Tr. However, the KM curves appeared to converge again around 13 days, implying the long-term effect was similar. Compared with IE-Tr, ES-Tr was associated with a significantly higher incidence of pain score ≤3 within 21 days (odds ratio 0.55; 95% confidence interval (CI): −0.11 to 1.21, P < 0.001). The benefit ratio for ES-Tr versus IE-Tr was 14.94 (95% CI: 7.99 to 27.94); the log rank test, Wilcoxon test, and −2 Log test for the effect of treatment yielded Chi-square values of 71.66, 70.60, and 18.93, respectively (P < 0.001).

Figure 4

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Kaplan–Meier curves for subjects regarding timing of intervention and proportion of subjects with pain score ≤3. Censored observations are for those who still reported pain ≥ 4 at the last point they were contacted. The tick marks on the Kaplan–Meier curves represent the censored subjects. The differences between the two curves were determined by the two-sided log-rank test.

Prospective Associations Between Therapeutic Method and Other Sensory Symptoms

Significant differences in the time of occurrence of other sensory symptoms, numbers of subjects, and severity of these sensory symptoms were detected among the groups during the 14-day treatment period (Table 2). Comparisons of the results obtained before and after treatment within the groups showed that local injection relieved paroxysmal pain in IE-Tr (P < 0.05), and tactile allodynia, tingling, numbness, and itching in IE-Tr and ES-Tr (P < 0.05) at the 14-day end point. The results of subjects with different pain and sensory symptoms < 4 were not included in the analysis.

Long-Term Efficacy of Local MeB₁₂ Combination with Lidocaine Injection

None of the participants reported pain in the 6- and 12-month follow-up, while a few subjects reported some discomfort related to HZ. Chi-squared analysis showed that there was no significant difference in the numbers of participants with discomfort > 0 over the course of the study between IE-Tr with ES-Tr (Table 2).

Safety

One hundred and eighty subjects completed the 14-day treatment study; only 91 in the treatment groups completed the follow-up. The injections were well-tolerated by these patients. No serious side-effects, such as acute lidocaine intoxication, excessive sensory loss, dysesthesias, or other serious adverse events were reported in any of the groups. Mild adverse events were reported for subjects who had subcutaneous hemorrhage, but bleeding stopped after 1 minute. No serious adverse events were reported in any of the groups.

Discussion

Although the mechanism of varicella zoster virus (VZV) reactivation in the neurons has not fully been elucidated, the intense pain associated with HZ is considered to be related to neuroinflammation in the dorsal root ganglia and nerve fibers [16]. Cbl may have anti-nociceptive and anti-inflammatory effects against acute and chronic pain [17]. The present study indicated a significant difference in the changes in mean pain score between the two different treatment modes. In the IE-Ctl and ES-Ctl groups, significant responses were observed at 14 days relative to baseline. The rate of change in pain score for the control group decreased to 0.10 in IE-Ctl and 0.20 in ES-Ctl per measurement point after the baseline (P < 0.001). However, only five of 45 in the IE-Ctl and six of 44 in the ES-Ctl subjects who had received antiviral therapy had pain score ≤3 at the 14-day treatment endpoint, which was considerably lower than the known natural history of pain decline in HZ [6], making it difficult to distinguish between the significant benefits of the intramuscular MeB₁₂ in addition to local lidocaine injection and spontaneous recovery. The present study showed that systemic MeB₁₂ administration did not significantly improve clinical outcomes during the first week and subsequent treatment did not show superior effects, while local lidocaine injection produced a transient reduction in acute pain, which only lasted for 30–40 minutes.

There was a significant difference in the trend of general changes line in the mean pain scores between the groups over the same time period (P < 0.001), representing an additional decrease of 0.38 in IE-Tr and 0.28 in ES-Tr per time point for the local MeB₁₂ combined with lidocaine injection. The mean pain score in the treatment groups decreased significantly compared with that in the control groups over time. The mean pain scores in IE-Tr and ES-Tr were 2.4 ± 0.7 and 1.3 ± 0.7, respectively; only three of 46 in the IE-Tr and two of 45 in the ES-Tr subjects had pain scores of 4 after the 14-day treatment, and the number needed-to-treat to show the significant treatment effects of local MeB₁₂ injection on pain ≤3 at the 14-day endpoint were 1.21 (95% CI: 1.06 to 1.41) for the IE groups and 1.22 (95% CI:1.06 to 1.43) for the ES groups. In the treatment group, the pain decreased substantially in the first week of treatment relative to the baseline, with continued efficacy over 12 months. Cbl has been applied mainly in the treatment of peripheral neuropathy for many years [18–20]. MeB₁₂ has been reported to be neurotrophic or growth-promoting for nerve cells [21], a property that may help regenerate central and peripheral nervous tissues damaged in disorders [22], while intrathecal high-dose MeB₁₂ can relieve the symptoms of neuropathy [23]. For patients with neurologic symptoms, an initial B₁₂ injection (1,000 µg, IM) followed by oral replacement is recommended [24]. In clinical treatment of SHN and PHN, the local high doses of MeB₁₂ were not only efficacious in relieving pain, but also appears to be safe and tolerable [10,11]. Such treatment had a significant analgesic effect, without general toxicity. Therefore, MeB₁₂ treatment can be recommended at much higher than physiological level to achieve the best treatment effect [25]. In the partial areas of the affected dermatome with AHN, there was marked neuroinflammatory pain; therefore, the strategies should particularly be focused on the local subcutaneous nerve fibers of the most painful area. The results of this study demonstrated that MeB₁₂ had a significant and sustained analgesic effect on AHN; local treatment delivers MeB₁₂ directly to topical HZ-damaged subcutaneous and neuronal tissue to obtain rapid and effective neurological responses, which has a more significant and specific analgesic effect on affected fibers with AHN than its systemic administration. These results are consistent with the conclusions of Dongre and Swami [26], who reported that the overall reduction in the mean pain score of diabetic peripheral neuropathy patients treated over 14 days by pregabalin with MeB₁₂ was 72.3%. While local lidocaine in combination with MeB₁₂, could relieve fear and pain during injection into the irritated skin.

The results showing that there were no significant differences in the cutaneous healing time of rash among groups indicates that MeB₁₂ and/or lidocaine has no direct effect on rash healing. The subjects in the treatment groups experienced more improvement in their QoL and reported a better state of health than those in the control group at end of the study.

Although early active and aggressive management, including antiviral treatment during the acute phase of HZ tends to yield better results [27], the results of the present study show that early and repeated local administration of MeB₁₂ does not achieve significant pain relief when administered immediately after pain and rash onset. The KM curve indicates a better response prognosis for the subjects in ES-Tr than those in IE-Tr, with a median satisfactory response time of 6 days for ES-Tr and 11 days for IE-Tr. ES-Tr was associated with a significantly higher incidence of pain score ≤3 within 21 days. The benefit (hazard) ratio ES-Tr versus IE-Tr was 14.94, indicating that this strategy is ineffective until the disease reached a certain stage in its progress. The mechanism underlying the differences in the timing of treatment requires further investigation.

Most subjects complained of continuous neuroinflammatory pain during the acute phase within 7 days. A few experienced more than one type of sensory symptom or discomfort during treatment and subsequent follow-up. The results suggest that treatment with local MeB₁₂ combined with lidocaine injection could alter or modify the pathological process from neuroinflammatory pain to neuropathic pain, with decreased incidence and intensity of positive symptoms such as various type pains, while the incidence of itching, tingling, and numbness increased.

PHN is defined as the presence of a worst pain NRS ≥3 at 3 months or more after rash onset [3]. Once PHN is established, pain can be extremely difficult to manage; therefore, prevention is the ideal approach. In the present study, 43 of 46 subjects in IE-Tr and 43 of 45 in ES-Tr had worst pain NPS ≤ 3 at the 14-day treatment endpoint. The proportion of subjects with reported pain >0 and < 4 at month 1 were 39.6% (36/91); while the proportion reporting pain greater >0 and  <3 at months 3, 6, and 12 were 23.1% (21/91), 14.3% (13/91), and 7.7% (7/91), respectively, in the treatment group as a whole (Table 2). Only one subject reported a pain score of 3 over 3 months after the rash onset in the treatment group. The incidence of PHN was 1.1% (1/91) at 3 months in the treatment group as a whole, which was considerably lower than the incidence reported by Rabaud et al. [6]. Early treatment with MeB₁₂ had not only an analgesic effect, but also prevented PHN. None of the subjects complained of pain at the 6- and 12-month follow-up, although a few subjects reported slight discomfort related to HZ.

Given the nature of the injection and color of the drugs, it was impossible to select a color matched and risks minimized drug as a placebo to the randomization assignments. The primary intent of this study is focuses on the value of local injection of MeB₁₂ for relieving pain and improving QoL of patients, the conventional therapy control group may be preferable, as both groups received local lidocaine would be nonspecific placebo benefits for patients.

Conclusions

The findings of this clinical trial suggest that MeB₁₂ has a significant analgesic effect on AHN. Local subcutaneous injection of MeB₁₂ is more effective than systemic administration for relieving zoster-related pain with AHN. Timely treatment with MeB₁₂ provides rapid relief from pain, improves QoL, and reduces the incidence of PHN. These results suggest that local MeB₁₂ injection within 4–7 days may be an optimal therapeutic option. It should be stressed that first-line therapy for HN should include strategies using neurotrophic agent such as MeB₁₂ to protect the affected neural fibers against VZV damage. Effective and long-lasting pain relief in AHN and PHN remains a largely unmet medical need. Further studies are needed to confirm‎ these findings.

Acknowledgments

We express our sincere appreciation to the patients who served as subjects for this study, and Drs Yan Feng, BSc; Chaosheng Zhou, MSc; Wen Li, BSc for data collection of the clinical trial.

Disclosure and conflicts of interest: This research did not receive any financial benefits and there is no conflict of interest.

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