For Patients Who are Having Significant Post Herpetic Neuralgia: Alternative Treatments for Post Herpetic Neuralgia

For Patients Who are Having Significant Post Herpetic Neuralgia:

Local Administration of Methylcobalamin and Lidocaine for Acute Ophthalmic 


A Single-Center Randomized Controlled Trial

The below study may help patients understand alternative treatments for chronic Poster Herpetic Neuralgia (PHN) in the area of the Ophthalmic Nerve (around the eye area).

When looking for good studies, doctors usually take into account the Impact Factor of a particular Journal: how well respected is that journal and how likely is the data and information in that journal likely to represent the truth (unbiased by pharmaceutical drug money, desires for tenure by authors, etc).  The higher the Impact Factor, the better the journal, in general with exceptions.

Pain Practice Impact Factor, to 2.361.


  • herpes zoster;
  • acute ophthalmic herpetic neuralgia;
  • methylcobalamin;
  • subcutaneous injection;
  • randomized clinical trial



To determine the therapeutic efficacy of combined methylcobalamin and lidocaine for acute ophthalmic herpetic neuralgia (AOHN).


Based on the onset, patients with AOHN (n = 98) were randomly allocated into groups A (≤ 3 days) and B (4 to 7 days) and then subdivided into control (A0, B0; received intramuscular methylcobalamin in addition to local lidocaine injection) and treatment (A1, B1; received local injection of the methylcobalamin and lidocaine combination for 14 days) groups. Treatment efficacy was assessed based on rash healing time, alteration of pain intensity, and interference with quality of life. Multilevel modeling and survival analysis were performed.


The time (hours) to start and full opening of the affected eye and the time (hours) to start and full crusting were significantly reduced in both treatment groups (P < 0.05 vs. controls). The mean pain scores in A1 (2.6 ± 0.7) and B1 (1.2 ± 0.8) decreased significantly compared with those in A0 (7.0 ± 1.7) and B0 (5.6 ± 1.9), and the difference between the two therapeutic strategies significantly increased over time. The median minimum intervention time was 6 days in B1 and 11 days in A1. The incidence of postherpetic neuralgia (PHN) was 2.04% at 3 months.


Methylcobalamin combined with lidocaine mediated detumescence and improved cutaneous healing of the affected area, as well as a significant and sustained analgesic effect on AOHN. The incidence of PHN was also significantly decreased. Local methylcobalamin intervention within 4 to 7 days of onset may be an effective therapeutic option for AOHN.


Herpes zoster ophthalmicus (HZO) is caused by reactivation of varicella zoster virus (VZV), causing pathognomonic vesicular eruption in the distribution of the ophthalmic division of the trigeminal nerve; it is often accompanied by severe neuritic pain and neuralgia.[1] VZV infection may affect the trigeminal nerve in 10% to 20% of cases, and the ophthalmic branch (V1) is the most frequently involved site for herpes zoster (HZ),[2-4] followed by thoracic dermatomes. Consequently, the ophthalmic branch is one of the most common sites of postherpetic neuralgia (PHN) in the elderly,[2, 5] and this condition can severely impact the quality of life (QoL) in these patients.[6-8] Acute herpetic neuralgia (AHN) is defined as intense pain in the affected nerve within 30 days of acute zoster infection,[6] while PHN is defined as pain that persists for 90 days or more after rash onset.[9] Acute ophthalmic herpetic neuralgia (AOHN), which is a severe complication that is difficult to manage,[3, 10, 11] is likely to be due to an immediate nociceptive response. Local inflammation and tissue damage stimulate the afferent and subcutaneous fibers of V1, which are manifested neurologically as pain.[12] Neuritic pain should be controlled in the acute phase, and antiviral therapy significantly reduces the severity of infection, duration of the eruptive phase, and intensity of acute pain.[13] However, this therapy does not completely alleviate AHN.[14, 15] Therefore, knowledge of the optimal time and treatment option to control severe neuritic pain and neuralgia in the acute phase of HZO may be of clinical significance, not only in terms of improved QoL but also in preventing the development of PHN.[12, 16]
Some strategies for controlling local neuritis and preventing nerve damage might have potential for the treatment of AOHN. Cobalamin (Cbl, vitamin B12), which is a neurotrophic agent,[17, 18] has a specific affinity for neural tissues.[17, 19, 20] Vitamin B12 is not directly active in humans, but is converted into activate forms such as methylcobalamin (MeB12) or adenosylcobalamin. Compared with other analogs, MeB12is the most effective in terms of uptake by the subcellular organelles of neurons. Therefore, MeB12 may be a better treatment for neuronal disorders through effective systemic or local delivery.[21, 22] MeB12 therapy may have beneficial pharmacologic effects on neurologic function in a variety of disorders, such as diabetic neuropathy, glossopharyngeal neuralgia, autistic disorder, and Alzheimer’s disease-related cognitive decline.[23-29] In China, vitamin B1 and MeB12 are the most common treatments for herpes zoster.[30] Clinical experience has shown that local MeB12 injection is an effective treatment modality for subacute herpetic neuralgia[31] and PHN.[32] MeB12 might be potentially relevant for AOHN in the eruptive phase, and local administration may have more significant neurotrophic effects than systemic administration on affected fibers and epidermal nerve endings. Topical lidocaine (5%) medicated plasters are recommended as a first-line therapy for PHN.[33, 34] On the basis of multiple randomized clinical trials that demonstrated the efficacy of lidocaine patches in patients with PHN, we hypothesized that lidocaine could be efficacious in relieving pain associated with AOHN.
A single-center, randomized, observer-blind clinical trial was conducted in patients with AOHN to explore the efficacy of local MeB12administered in combination with lidocaine. The primary objective of the trial was to explore whether local MeB12 in combination with lidocaine injection administered in the early stages of the onset of HZO could reduce the intensity and duration of AOHN and whether it had the potential to prevent or reduce the incidence and/or severity of PHN. The secondary objective was to evaluate the time-dependent effect on the pain relief and to ascertain the optimal therapeutic window to achieve alteration in disease progression toward recovery.



This prospective study was a randomized, 4-group, parallel clinical trial. Outcome measurements were recorded on the days before and after treatment and also in regular follow-up conversations conducted by telephone at 1, 3, 6, and 12 months. The study protocol was reviewed and approved by the Tongji University Institutional Review Board and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.


From January 2012 to December 2013, consecutive immunocompetent adult patients (n = 106) with unilateral HZO associated with simultaneous pain were recruited. Inclusion criteria were as follows: AOHN within 7 days after onset of the rash (defined as vesicles) accompanied simultaneously with pain, rash severity > 5 lesions, swelling around the forehead and periocular area, aged ˃ 50 years, and willingness to comply with the allocated treatment and follow-up measurements. Subjects had to experience severe pain on the unilateral forehead, vertex, eyebrow, side of the nose or in the immediately adjacent region (temporally and spatially) associated with their rash, and a worse pain score ≥ 6 on an 11-point pain intensity numerical rating scale (NRS) in the previous 24 hours. Subjects with one or more of the following conditions were excluded: unilateral pain in the vesicular region with no simultaneous onset or with more than 7 days after rash onset, diffusely distributed neuropathic pain or significant pain outside the V1 regions, any clinically significant medical condition or laboratory abnormality, and cognitive impairment.


Only the eligible subjects, who agreed to enroll for the trial and provided written informed consent, were evaluated by an independent research physician. The demographic and baseline characteristics of all the enrolled subjects were recorded at the baseline visit. Based on the days from rash onset, subjects were allocated to group A (≤ 3 days) and group B (4 to 7 days). Subjects were then randomly assigned by computer-generated randomization in a 1:1 ratio to treatment groups (A1 and B1) and control groups (A0 and B0).
Another independent clinician, who did not participate in clinical management and was kept 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 the four groups with the same degree of rigor, enthusiasm, and optimism. The subjects were advised not to inform the observer about the treatment they received.

Sample Size

Postherpetic neuralgia is common following HZO.[2, 5] Previous studies showed that more than 60% to 90% of immunocompetent subjects with zoster experience local neuritic pain and hypersensitivity in association with the acute herpetic rash,[11, 35-37] whereas 43.6%, 27.0%, 11.7%, 8.7%, 7.4%, and 6.0% of those with zoster in the general population reported pain on day 15, and at 1, 3, 6, 9, and 12 months, respectively.[15] Based on the analysis by a mixed-effects modeling, sample sizes were calculated for repeated measurements. The expected proportion of pain intensity NRS of ≤ 3 for the 14-day treatment was 90%. A correlation coefficient of intrasubjects between two consecutive measurements was 0.7. Assuming an error of 0.05 with a power of 80%, a minimum of 20 subjects per group was needed to detect a difference between the two groups in the same period, with a two-sided 5% significance level. Considering a dropout rate of 15% during follow-up, at least 92 subjects in total were needed for this study.


All subjects had received antiviral agents (300 mg of valacyclovir, twice daily) within 72 hours after the onset of rash as prescribed by their dermatologist for a total of 10 days. The ocular involvement from HZO was treated by their ophthalmologist, but MeB12 or lidocaine drugs were not used. The subjects in the treatment groups 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) local injections; those in the control groups received intramuscular MeB12(1,000 μg daily), plus once-daily 20 mg lidocaine (2.0 mL) local injections. The drugs were injected into the subcutaneous regions of the affected innervations of V1 where the subjects experienced worst pain (0.3 mL of liquid injected per point, up to 10 points to cover the whole area of pain) using 25-G needles and sterile hypodermic syringes. The dosing frequency was once daily (every morning between 8 and 11 AM), 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.


The outcome measures were consistent with the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials guidelines.[38]The subjects enrolled in the study were given instructions on how to use the 11-point pain intensity NRS (in which 0 represented no pain and 10 represented the worst imaginable pain). 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 to 10 NRS. Zoster-related sensory symptoms are generally described as continuous spontaneous pain, paroxysmal pain, tactile allodynia, tingling, numbness, and itching.[6] Changes in various characteristics of the pain and discomfort related to AOHN were also measured using an 11-point Likert scale.
Subjects were assessed for cutaneous healing including time to start of opening and full opening of the affected eye and time to crusting and full crusting of zoster-associated rash. The principal outcome variables were the worst pain intensity ratings calculated from baseline to termination of the 14-day treatment. Patients were assessed in follow-up conversations conducted by telephone at 1, 3, 6, and 12 months after rash onset.
Using EuroQoL visual analog scale (VAS), participants were asked to rate their current health state on a scale of zero (worst imaginable health) to 100 (best imaginable health) before and after the 14-day treatment.

Statistical Analysis

The primary efficacy analysis was performed using data from all study subjects. The longitudinal data of repeated measurement of pain scores were used in multilevel modeling, with the measurement time points (level 1, Time) nested within subjects (level 2, Group). A multilevel mixed model was fitted for outcome variables to examine changes in pain scores over time to compare the difference between the two treatments modalities used in the same period from rash onset.
Kaplan–Meier (KM) survival analysis of longitudinal data during treatment was conducted to explore treatment responses and optimal intervention time and to test the hypothesis that the A1 group, on average, was superior with respect to therapeutic window to the B1 group within the 21-day course. This model was chosen because it best reflects the continuous nature of the occurrence of the underlying pain relief. Previous studies among subjects with zoster-related pain demonstrated that pain scores ≤ 3 more than 30 days after rash onset were associated with minimal interference with QoL;[39] thus, the satisfied response point (terminal event) was defined as a sustainable pain score ≤ 3, and the minimum intervention (survival) time was defined as the first day on which the satisfied response point was reached for consecutive 3 days. The number of subjects with pain scores ≤ 3 and median minimum intervention times (50% subjects with pain score ≤ 3) within 21 days of local therapy were evaluated by KM analysis. This model assumes that the treatment benefit is the same in each group at baseline and possibly diverges overtime with increasing duration of therapy. The association between the proportion of subjects having pain scores ≤ 3 and minimum intervention time was estimated using benefit (hazard) ratios. Time zero for the KM analysis was the time of rash and pain onsets, which was used to discriminate between those who had and had not reached the satisfied response point within the 21-day course.
The group comparisons for detumescence and rash healing time and degree, alteration of pain intensity, proportion of subjects with pain scores ≤ 3, and EuroQoL VAS scores were analyzed using analysis of variance or chi-square tests.
The actual pain scores were assessed at 1, 3, 6, and 12 months of follow-up 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 < 0.05 were considered to indicate statistical significance. All analyses were performed using R software (R 2.15.0 version developed by Peter Dalgaard of the R Core Development team, Copenhagen, Denmark).


Patient Disposition

The total number of subjects with AOHN consecutively enrolled throughout the 24-month recruitment period was 106. Eight subjects were excluded from the study for various reasons, and only 98 subjects (48 men and 50 women) who met the inclusion criteria were eligible for the trial. Their mean age at the time of study enrollment was 63.6 years. The subject disposition is presented in Figure 1, and baseline characteristics of the eligible subjects are presented in Table 1. Data of all 98 subjects were included for analysis of therapeutic response within 21 days using the same research design and procedures, and follow-ups were continued for 12 months after rash onset in the treatment group.
Table 1. Demographic and Clinical Characteristics of Subjects at Baseline
Measures A Group (1 to 3 days) B Group (4 to 7 days)
A0 (n = 24) A1 (n = 25) B0 (n = 25) B1 (n = 24)
  1. Data presented are means (SD) or numbers (%).
  2. SD: standard deviation;
  3. NRS: numerical rating scale (pain intensity measured on 0 to 10);
  4. ‘0’ group: intramuscular methylcobalamin in addition to local lidocaine injection group;
  5. ‘1’ group: local methylcobalamin combination with lidocaine injection group.
Age at rash onset (SD) 64.4 (8.2) 64.4 (8.2) 63.0 (7.4) 63.1 (8.2)
Female, n (%) 11 (45.83) 13 (52.00) 14 (56.00) 12 (50.00)
Elementary education or less, n (%) 1 (4.16) 1 (4.00) 2 (8.00) 0 (0.00)
Times since rash and pain onset, hour (SD) 49.0 (18.0) 47.0 (20.2) 133.9 (20.7) 132.5 (20.8)
Description of rash:
Limited rash, n (%) 10 (41.67) 11 (44.00) 10 (40.00) 9 (37.50)
Extensive rash, n (%) 14 (58.33) 14 (56.00) 15 (60.00) 15 (62.50)
Severity of lesions-
Simple rash, n (%) 18 (75.00) 19 (76.00) 5 (20.00) 5 (20.83)
Pustules, n (%) 6 (25.00) 6 (24.00) 12 (48.00) 13 (54.17)
Necrotic appearance, n (%)     8 (32.00) 6 (25.00)
Periocular area, n (%) 15 (62.50) 15 (60.00) 9 (36.00) 9 (37.50)
Forehead+periocular area, n (%) 9 (37.50) 10 (40.00) 16 (64.00) 15 (62.50)
Pain NRS at baseline (SD) 8.5 (1.1) 8.6 (1.0) 8.0 (1.2) 8.0 (1.0)
EuroQoL (SD) 15.5 (6.8) 15.4 (4.5) 16.8 (7.7) 17.4 (9.2)

Figure 1. Patient flow diagram.


Only one patient from the B0 group did not complete the 14-day treatment due to lack of improvement after receiving 8 days of treatment.
At the end of treatment, subjects who completed the 14-day treatment but had the worst pain intensity score (> 4) were considered inadequate responders and assigned to another local treatment sequence. Less than 15% of the participants were lost to the 12-month follow-up in the treatment group, and their attrition was associated with neither gender nor education.

Cutaneous Healing

Table 2 shows the changes in cutaneous healing in terms of time to start of detumescence (opening of the affected eye) and time to crusting and full crusting of zoster-associated rash. Results indicated that the time between the start of detumescence and full opening of the affected eye and the time to start and full crusting shortened significantly in both A1 and B1 compared with the times recorded in A0 and B0, respectively (< 0.05).
Table 2. Comparisons of the Overall Improvement Among Groups
Measures A Group (1 to 3 days) B Group (4 to 7 days)
A0 (n = 24) A1 (n = 25) B0 (n = 25) B1 (n = 24)
  1. Data presented are means (SD) or numbers (%).
  2. Score: numerical rating scale (intensity measured on 0 to 10); SD: standard deviation; CI: confidence interval.
  3. ‘0’ group: intramuscular methylcobalamin in addition to local lidocaine injection group;
  4. ‘1’ group: local methylcobalamin combination with lidocaine injection group.
  5. a
    Compared between the same therapeutic groups, P < 0.05.
  6. b
    Compared within the same course groups, P < 0.05.
Reducing swelling
Start of opening the affected eye, hour (SD) 309.5 (61.8) 172.5 (34.3)a 231.9 (37.6) 91.2 (28.9)ab
Full opening the affected eye, hour (SD) 440.0 (67.4) 286.4 (45.3)a 338.9 (40.6) 162.0 (32.9)ab
Start of crusting, hour (SD) 340.5 (68.0) 215.5 (39.9)a 237.1 (39.4) 131.0 (31.6)ab
Full crusting, hour (SD) 540.0 (98.5) 385.7 (68.9)a 419.0 (40.2) 239.3 (39.9)ab
Pain at 14-day endpoint (SD) 7.0 (1.7) 2.6 (0.7)a 5.6 (1.9) 1.2 (0.8)ab
Subjects with pain ≤  3 at 14-day endpoint (%) 1 (4.17) 23 (92.00)a 4 (16.00) 23 (95.83)a
Number needed to treat (95% CI) 1.14 (0.99, 1.34)   1.25 (1.03, 1.58)  
Other pain or sensory symptoms
Subjects with paroxysmal pain (%) 15 (62.50) 7 (28.00)a 18 (72.00) 4 (12.50)a
Paroxysmal pain onset days from baseline (SD) 4.8 (2.3) 5.6 (1.7)a 2.9 (1.2) 4.5 (1.3)a
Paroxysmal pain score at initial point (SD) 7.0 (1.1) 6.6 (1.1)a 7.0 (0.8) 5.0 (0.8)ab
Paroxysmal pain at 14-day endpoint (SD) 6.7 (1.0) 2.4 (0.5)b 6.7 (0.9) 2.0 (0.8)
Subjects with allodynia (%) 7 (29.17) 4 (16.00)a 7 (28.00) 3 (12.50)a
Allodynia onset days from baseline (SD) 4.3 (1.1) 6.3 (1.7) 3.6 (1.5) 4.7 (0.6)a
Allodynia score at initial point (SD) 7.3 (1.5) 4.8 (1.0) 7.0 (1.2) 4.7 (1.0)a
Allodynia at 14-day endpoint (SD) 6.3 (1.7) 3.3 (0.5)b 6.3 (0.8) 3.0 (1.0)ba
Subjects with tingling (%) 2 (8.33) 3 (12.00) 2 (8.00) 2 (8.33)
Tingling onset days from baseline (SD) 9.5 (2.1) 6.7 (1.5) 6.0 (1.4) 5.5 (0.7)
Tingling score at initial point (SD) 5.5 (0.7) 3.3 (0.6) 5.5 (0.7) 2.5 (0.7)
Tingling at 14-day endpoint (SD) 3.5 (0.7) 2.3 (1.5) 4.5 (0.0) 1.5 (0.7)
Subjects with numbness (%) 2 (8.33) 4 (16.00)a 3 (12.00) 4 (16.67)a
Numbness onset days from baseline (SD) 9.5 (0.7) 6.5 (1.7)a 7.0 (1.0) 4.3 (1.0)a
Numbness score at initial point (SD) 4.5 (0.7) 3.0 (0.8) 4.0 (1.0) 3.3 (0.5)
Numbness at 14-day endpoint (SD) 4.0 (0.0) 1.5 (0.6)b 3.3 (0.6) 1.5 (0.7)b
Subjects with itching (%) 2 (8.33) 6 (24.00)a 3 (12.00) 7 (29.17)a
Itching onset days from baseline (SD) 10.0 (2.8) 4.8 (1.0)a 6.3 (0.6) 4.1 (1.3)a
Itching score at initial point (SD) 4.5 (0.7) 4.5 (0.8) 4.7 (0.6) 4.7 (0.5)
Itching at 14-day endpoint (SD) 4.5 (0.7) 2.8 (0.8)b 4.3 (0.6) 2.9 (0.4)b
EuroQoL at 14-day endpoint (SD) 31.3 (19.6) 78.6 (7.5)a 48.0 (22.3) 91.5 (9.4)a

Prospective Associations between Therapeutic Method and Subsequent Pain

For subjects in A0 and A1, the intercept-only model was estimated, and significant variance of the intercept indicated significant variation among the participants’ initial pain scores (2.04, < 0.001). The rate of change in pain score varied significantly among subjects (2.92,< 0.001) after random intercepts were specified in the model. The estimated intraclass correlation coefficient (ICC) was 2.04/(2.04 + 2.92) = 0.41, indicating that almost half of the total variation was due to intersubject heterogeneity. This implied that the measures were relatively stable and reduced the power to detect significance in within-subject associations. For the participants with acute pain during the 4- to 7-day period after rash onset, the ICC was 3.87/(3.87 ± 3.25) = 0.54 between B0 and B1; 46% of the variance in pain was accounted for by intrasubject variation. The analyzed results of the two final models indicated a significant difference in the changes in mean pain score between the two different therapeutic methods. The mean values of the tendency of repeated measurements and direct observation of the number of changes are shown in Figures 2 and 3, Tables 3 and 4.

Figure 2. Mean pain scores of subjects with onset 1 to 3 days at each time-point during the 14-day treatment period.

Figure 3. Mean pain scores of subjects with onset 4 to 7 days at each time-point during the 14-day treatment period.
Table 3. Assessment of Treatment Effect of 1- to 3-day Group
Effect Parameters Model 1 (Intercept-Only) Model 2 (Main Effects) Model 3 (Mixed Effects) Model 4 (Interaction) Model 5 (Factors)
  1. Parameter estimate standard errors listed in parentheses.
  2. ML: maximum likelihood used two-model comparison when two models had the same random effects, but different fixed effects.
  3. REML: restricted maximum likelihood used two-model comparison when two models had the same fixed effects, but different random effects.
  4. Δdf: the difference in −2 Log likelihood between two models was calculated for the likelihood ratio test.
  5. *P < 0.001; **P < 0.05.
Fixed effects
  Constant 6.81 (0.21)* 8.06 (0.20)* 7.79 (0.33)* 9.57 (0.22)* 9.97 (0.60)*
  Group   2.36 (0.26)* 2.92 (0.26)* −0.72 (0.32)** −0.73 (0.31)**
  Time   −0.30 (0.01)* −0.30 (0.03)* −0.49 (0.01)* −0.49 (0.01)*
  Group*time       0.39 (0.02)* 0.39 (0.02)*
Confounding Age         −0.18 (0.01)
Gender         −0.23 (0.26)
  Days of pain onset         0.001 (0.01)
Random effects
Level 2 Intercept 2.04 (0.45)* 0.77 (0.17)* 4.45 (1.72)* 1.14 (0.25)* 1.10 (0.25)*
Slope     0.04 (0.01)* 0.004 (0.001)* 0.003 (0.001)*
Covariance     −0.38 (0.11)* −0.03 (0.01)* −0.03 (0.01)**
Level 1 Residual 2.92 (0.16)* 1.09 (0.05)* 0.28 (0.01)* 0.28 (0.01)* 0.28 (0.02)*
Model evaluation
−2 Log likelihood   2992.2 (ML) 2271.3 (ML)/2281.9 (REML) 1528.8 (ML)/1537.1 (REML) 1418.6 (ML) 1417.6 (ML)
ΔLog likelihood (Δdf)     720.9* 744.8* 110.2* 1.0
Table 4. Assessment of Treatment Effect of 4- to 7-day Group
Effect Parameters Model 1 (Intercept-Only) Model 2 (Main Effects) Model 3 (Mixed Effects) Model 4 (Interaction) Model 5 (Factors)
  1. Parameter estimate standard errors listed in parentheses.
  2. ML: maximum likelihood used two-model comparison when two models had the same random effects, but different fixed effects.
  3. REML: restricted maximum likelihood used two-model comparison when two models had the same fixed effects, but different random effects.
  4. Δdf: refers to the difference in −2 Log likelihood between two models was calculated for the likelihood ratio test.
  5. *P < 0.001; **P < 0.05.
Fixed effects
  Constant 5.38 (0.29)* 6.31 (0.22)* 7.01 (0.21)* 8.39 (0.20)* 8.24 (0.91)*
  Group 3.44 (0.30)* 2.05 (0.28)* 1.32 (0.29)* 1.33 (0.27)*  
  Time   −0.34 (0.01)* −0.34 (0.02)* −0.47 (0.02)* −0.47 (0.02)*
  Group*time     0.27 (0.02)* 0.27 (0.02)*  
Confounding Age         0.54 (0.26)**
Gender         0.21 (0.27)
  Days of pain onset         −0.01 (0.01)
Random effects
Level 2 Intercept 3.87 (0.83)* 1.07 (0.23)* 0.98 (0.30)* 0.84 (0.21)* 0.74 (0.18)*
Slope     0.02 (0.005)* 0.005 (0.001)* 0.005 (0.001)*
Covariance     −0.05 (0.04)** −0.002 (0.01)** −0.01 (0.01)**
Level 1 Residual 3.25 (0.18)* 1.00 (0.05)* 0.55 (0.03)* 0.55 (0.03)* 0.55 (0.03)*
Model evaluation
−2 Log likelihood   3096.2 (ML) 2221.6 (ML)/2231.7 (REML) 1932.9 (ML)/1941.5 (REML) 1869.0 (ML) 1862.0 (ML)
ΔLog likelihood (Δdf)     874.6* 290.2* 63.9** 7.0
Table 2 shows the changes in QoL scores based on the EuroQoL VAS before and after treatment. Results indicated that mean QoL scores differed markedly between groups in the same period after the 14-day treatment. At the end of the 14-day treatment, the EuroQoL VAS, as reported by subjects in A1 and B1, were significantly higher than those in A0 and B0, respectively (< 0.001).

Prospective Associations between the Timing of Treatment and Subsequent Pain

Plots of the KM curves for A1 and B1 are shown in Figure 4. The KM curve for B1 was consistently higher than the KM curve for A1. The two curves appeared to separate with increased time, with the satisfied response with pain scores ≤ 3 suggesting that the treatment in B1 was more effective than that in A1. The median minimum intervention time was reported as 6 days in B1 and 11 days in group A1 (odds ratio 0.55; 95% confidence interval [CI]: −0.01 to 1.11, < 0.001). However, the KM curves appeared to converge again around 13 days, implying that the long-term effect was similar. The benefit ratio for B1 versus A1 was 8.67 (95% CI: 3.79 to 19.82); the log rank Wilcoxon test and −2 Log tests for the effect of treatment yielded chi-square values of 26.26, 32.94, and 31.57, respectively (all corresponding to < 0.001).

Figure 4. Kaplan–Meier curves for subjects regarding timing of intervention and proportions of subjects with pain scores ≤ 3.

Prospective Associations between Therapeutic Method and Other Sensory Symptoms

The results revealed that the time of occurrence of these sensory symptoms, numbers of subjects with different sensory symptoms, and severity of these sensory symptoms varied significantly among the groups during the 14-day treatment (Table 2). The results indicated a significantly lower incidence and intensity, but with delayed onset time of the paroxysmal pain and tactile allodynia in the treatment group compared with the control group. In contrast, there was significantly higher incidence and earlier onset time of itching, and lower intensity, but earlier onset time of tingling and numbness in the treatment group compared with the control group. Comparison of the results within groups before and after treatment by paired samples t-tests showed that the local injection of MeB12 and lidocaine combination relieved paroxysmal pain, tactile allodynia, and itching in A1 and B1 (< 0.05) at the end of the 14-day treatment. Groups in which subjects had different pain and sensory symptoms ˂ 3 were not included in the analysis (Table 5).
Table 5. Comparisons the Improvement of Follow-Up between the Treated Groups
Time Measures A1 Group (n = 25) B1 Group (n = 24)
Numbers (%) Score (SD) Numbers (%) Score (SD)
  1. Data presented are means (SD) or numbers (%).
  2. Score: numerical rating scale (intensity measured on 0 to 10); SD = standard deviation;
  3. A1 group: local methylcobalamin combination with lidocaine injection group within 1- to 3-day course;
  4. B1 group: local methylcobalamin combination with lidocaine injection group within 4 to 7 days.
At 1 month Pain > 0 7 (28.00) 1.6 (0.8) 6 (25.00) 1.7 (0.8)
Tingling > 0 4 (16.00) 1.3 (0.5) 4 (16.67) 1.3 (0.5)
Numbness > 0 5 (20.00) 1.6 (0.5) 5 (20.83) 1.4 (0.5)
Itching > 0 5 (20.00) 1.8 (0.8) 6 (25.00) 2.0 (0.9)
At 3 months Pain > 0 3 (12.00) 1.7 (1.1) 3 (12.50) 1.3 (0.6)
Tingling > 0 3 (12.00) 1.3 (0.6) 3 (12.50) 1.0 (0.0)
Numbness > 0 4 (16.00) 1.3 (0.5) 3 (12.50) 1.0 (0.0)
Itching > 0 3 (12.00) 1.3 (0.6) 3 (12.50) 1.7 (0.6)
At 6 months Pain > 0 2 (8.00) 1.0 (0.0) 1 (4.17) 1.0 (0.0)
Tingling > 0 2 (8.00) 1.0 (0.0) 1 (4.17) 1.0 (0.0)
Numbness > 0 4 (16.00) 1.0 (0.0) 4 (16.67) 1.0 (0.0)
Itching > 0 3 (12.00) 1.0 (0.0) 2 (8.33) 1.0 (0.0)
At 12 months Pain > 0 1 (4.00) 1.0 (0) 0 (0) 0 (0)
Tingling > 0 2 (8.00) 1.0 (0.0) 2 (8.33) 1.0 (0.0)
Numbness > 0 5 (20.00) 1.0 (0.0) 6 (25.00) 1.0 (0.0)
Itching > 0 2 (8.00) 1.0 (0.0) 2 (8.33) 1.0 (0.0)

Long-Term Efficacy of the Local MeB12 Combined with Lidocaine Injection

At the end of the 14-day treatment, 23 of the 25 subjects with the 1- to 3-day course and 23 of the 24 subjects with the 4- to 7-day course had pain scores ≤ 3; only one subject reported a pain score ˃ 3 during the 3-month period since the rash onset in the treatment group. Hence, the follow-up assessments were focused on the sensory symptoms or discomfort evaluation of the affected region. The statistically significant difference in mean pain scores between A1 and B1 at month 1 was lost when the subjects with pain were evaluated by t-test. The difference in the numbers of subjects with pain scores ˃ 0 between A1 and B1 showed no statistical significance, when the proportion of subjects with pain over the course of the study was examined using the chi-square test. The proportions of subjects with reported pain scores ˃ 0 at 1, 3, 6, and 12 months were 26.53%, 12.24%, 6.12%, and 2.04%, respectively, of the treatment group as a whole (Table 5).


Ninety-seven subjects completed the 14-day treatment study; only 40 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, and other serious adverse events, were reported in any of the groups. Mild adverse events were reported for subjects who had subcutaneous hemorrhage, although bleeding stopped after 1 minute.


Although the mechanism of VZV reactivation in the neurons has not been elucidated fully, the intense pain associated with HZO is considered to be related to the neuroinflammation spread from the ganglion of Gasser to the ophthalmic branch of the trigeminal nerve.[40, 41] Cbl may exert antinociceptive and anti-inflammatory effects against acute and chronic pain.[42, 43] In the present study, analysis of the longitudinal data in mixed models indicated significant differences in the changes in the mean pain score between the two different methods of treatment. In the A0 and B0 groups treated with intramuscular MeB12 in addition to local lidocaine injection, a significant response was observed up to 14 days relative to the baseline. The rate of change in pain score for the control group decreased to 0.49 and 0.47 time-point after the baseline for A0 and B0, respectively (P < 0.0001). However, only one of the 24 subjects (4.2% for A0) or four of the 25 subjects (16.0% for B0) who had received antiviral therapy had pain scores ≤ 3 at the end of the 14-day treatment. This is similar to the known natural history of pain decline in HZ, in which pain is resolved in approximately 16% of subjects within 15 to 30 days following rash onset.[15] Consequently, it is 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 no significantly improved clinical outcomes during the first week and subsequent treatment did not show superiority, while local pain point lidocaine injection produced a transient (30 to 40 minutes) reduction in acute pain in the lesional area.
There was a significant difference in the trend of the general change in the mean pain scores between the groups in the same period since rash onset (< 0.001) over time and showed an additional decrease of 0.39 (A1) and 0.27 (B1) per time-point for the local MeB12combination with lidocaine injection (Tables 3 and 4). Compared with the control group, the mean pain score in the treatment group decreased significantly over time. A1 and B1 had mean pain scores of 2.6 ± 0.7 and 1.2 ± 0.8, respectively; only two of the 25 subjects in A1 and one of the 24 in B1 group had pain scores ˃ 3 but ˂ 4 after the 14-day treatment, and the numbers needed to treat (NNT) for the significant treatment effects of local MeB12 injection on pain ≤ 3 at the 14-day endpoint were 1.14 (95% CI: 0.99 to 1.34) for the A groups (1 to 3 days) and 1.25 (95% CI: 1.03 to 1.58) for the B groups (4 to 7 days), respectively. In the treatment group, pain decreased substantially in the first week of treatment relative to the baseline, and the efficacy was continued over 12 months.
The strategy adopted in the present study was based on previously reported evidence. On the one hand, although Cbl deficiency is fairly common, particularly in elderly adults,[44-46] no single parameter can be used to diagnose this condition.[47] Some Cbl-deficient patients may have serious neurological dysfunction, even when they have no recognizable hematological abnormalities.[48, 49] Cbl has been applied mainly in the treatment of peripheral neuropathy for many years,[23, 50, 51] although the effectiveness of oral Cbl in reversing neurological abnormalities has yet to be established.[52] The traditional cornerstone of vitamin B12 therapy has been oral medication; some studies have suggested that oral Cbl administration is better than parenteral supplementation.[53] However, due to limited uptake capacity, gastrointestinal degradation, or high background uptake by healthy tissues,[54] variability in dose responses to oral Cbl among individuals, especially across aging populations, may be attributed to slowed uptake.[55] A number of studies have provided strong evidence that vitamin B12 has analgesic properties[56-60] in experimental animals. These studies have indicated a novel effect of the B vitamins on neuropathic pain and suggested the possible clinical utility of B vitamins for treating similar neuropathy at higher doses.[59-61] Clinical experience has shown that Cbl therapy improves the symptoms of both peripheral neuropathy and autonomic dysfunction,[62] while intrathecal high-dose MeB12 can relieve symptoms of neuropathy.[63] The British Columbia Medical Association and Ministry of Health of Canada recommend oral replacement of B12(1,000 to 2,000 μg/days) for most cases of vitamin B12 deficiency, including pernicious anemia. For patients with neurologic symptoms, they recommend an initial B12 injection (1,000 μg) followed by oral replacement.[64] As delayed therapy can lead to irreversible neurological dysfunction, parenteral Cbl therapy should be strongly considered.[52, 65] In clinical treatment of subacute herpetic neuralgia and PHN, the local high doses of MeB12 were injected into the skin with damaged fibers and epidermal nerve endings.[31, 32] Such an injection had a significant analgesic effect and was not associated with toxicity in general. Therefore, MeB12 can be recommended at doses much higher than the physiological level to achieve the best treatment effect.[21] The HZO usually invades one or more branches of the ophthalmic division of the trigeminal nerve, namely the supraorbital, lacrimal, and nasociliary branches,[66] resulting in zoster-associated pain often along the involved dermatome. Therefore, treatment strategies should be focused particularly on the local subcutaneous nerve fibers of the most painful area. The results of the current study demonstrate that MeB12, a neurotrophic agent, had a significant and sustained analgesic effect on AOHN. These data indicated that local treatment allowed direct delivery of MeB12 to topical HN-damaged subcutaneous and neuronal tissue to obtain rapid and effective neurological responses. Specifically, this approach was shown to have a more significant analgesic effect than systemic administration on the nerve fibers and endings affected by AOHN. These results are consistent with the conclusions of Dongre,[67] 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%. Local lidocaine could be used in combination with MeB12 and could relieve fear and pain during injection into the irritated skin.
The eyelids are commonly involved in HZO[66] and may develop edema and inflammation in the surrounding tissues. This study also evaluated the rash, swelling healing time, and pain interference in terms of QoL. The times for swelling reduction and rash healing were significantly shortened in both A1 (286.4 ± 45.3; 385.7 ± 68.9) and B1 (162.0 ± 32.9; 239.3 ± 39.9) compared with those in A0 (440.0 ± 67.4; 540.0 ± 98.5) and B0 (338.9 ± 40.6; 419.0 ± 40.2), which implied that MeB12 combined with lidocaine exerted anti-inflammatory and detumescence effects on the affected area. With regard to the disease course factor, there were no significant differences in the time for rash healing and swelling reduction between A0 and B0. The subjects in A1 (78.6 ± 7.5) and B1 (91.5 ± 9.4) experienced greater improvement in their QoL and better state of health than those in A0 (31.3 ± 19.6) and B0 (48.0 ± 22.3) at the end of treatment.
Although early active and aggressive management, including antiviral treatment during the acute phase of HZ promise better results,[68] this study showed that early and repeated local administration of MeB12 did not provide significant pain relief when administered immediately after pain and rash onset. The KM curve indicated that the subjects in the B1 responded better to treatment than those in A1, and the median minimum intervention time was 6 days in B1 and 11 days in A1. No immediate effects of local MeB12 injection were observed in A1, but B1 was associated with a significantly higher incidence of pain scores ≤ 3 within 21 days. The benefit ratio for B1 versus A1 was 8.67, indicating that this treatment is ineffective until the HZO reaches a certain stage in its progression. The mechanism underlying the differences in responses associated with the timing of treatment requires further investigation.
Most subjects complained of continuous neuroinflammatory pain (redness, swelling, burning, throbbing, aching, and shooting pain) in the acute phase within 7 days. A few had experienced more than one type of sensory symptoms or discomfort such as paroxysmal pain, tactile allodynia, tingling, numbness, and itching during treatment and subsequent follow-up. These results indicated that treatment by local MeB12combination with lidocaine injection alters or mediates the pathological process from neuroinflammatory pain to neuropathic pain, with the incidence and intensity of positive symptoms such as various types of pain decreasing, while the incidence of itching increased.
PHN occurs in 5% to more than 30% of patients.[69] In the ARIZONA study, the percentage of subjects with PHN ranged from 6.0% to 15.2% in the 70 to 74 years to 85+ years age groups, respectively, at month 12.[70] It has been reported that PHN lasts longer than 1 year in a greater percentage of patients after HZO than HZ overall (50% of HZO vs. 37% of HZ, aged 60 to 69; 61% of HZO vs. 47% of HZ, aged ≥ 70 years).[71] This study results showed that the incidence of PHN was 2.04% (1/49) at 3 months for the treatment group as a whole, which was considerably lower than that reported by Rabaud et al.,[15] in which 6.0% of subjects with zoster in the general population had pain at month 12. Early treatment with MeB12 not only provided an analgesic effect, but was also shown to prevent PHN. The proportion of subjects with reported pain, tingling, numbness, or itching scores ˃ 0 at month 12 ranged from 8.16% to 22.45% for the treatment group as a whole, which implied that local MeB12 combined with lidocaine therapy did not completely eliminate all symptoms.
This study has some limitations that need to be taken into account when considering the study and its results. The first limitation was the difficulty of blinding local injections. Pain assessment was conducted by an independent rehabilitation physician who did not participate in clinical management and was kept blind to treatment allocation to prevent bias due to unblinding of the treatment. The second limitation concerning the primary evaluation criteria used for assessing pain by the patient during regular phone calls; it is possible that the patients’ perception of pain may have been different during a routine monitoring visit. However, patient-reported outcomes are pertinent to gather information in a real-life situation.


The findings of this 14-day single-center, observer-blind, randomized, controlled clinical trial suggest that MeB12 has a significant analgesic effect on AOHN. MeB12 combined with lidocaine not only improved detumescence and cutaneous healing of the affected area, but also exerted a significant and sustained analgesic effect on AOHN. Furthermore, the incidence of PHN was also significantly reduced. Local treatment allows direct delivery of MeB12 to topical HN-damaged subcutaneous and neuronal tissue to obtain more rapid and effective responses innerve fibers affected by AOHN than are achieved by systemic administration. It can be speculated antineuroinflammatory, analgesic, and neuroprotective effects are involved in the mechanism of the functions of MeB12. Local MeB12 injection within 4 to 7 days may be an optimal therapeutic option, with more rapid and greater pain relief, improvement in QoL, and reduction in the incidence of PHN achieved by timely initiation of treatment. It should be stressed that first-line therapy for HN should include strategies using neurotrophic agents to protect the affected neural fibers and endings against VZV damage. Effective and long-lasting pain relief in AOHN and PHN remains a largely unmet medical need, and further studies are needed to confirm the findings of the present study.


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


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