Authors: Gang Xuˇ, MD Gang Xu´, BSc Yan Feng, BSc Wei Zhen Tang, BSc Zhong Wei Lv, MD, PhD
Affiliations:
Pain
ORIGINAL RESEARCH ARTICLE
From the Department of Rehabilitation Medicine (GX, GX, YF, WZT) and Department of Nuclear Medicine (ZWL), Tenth People’s Hospital Affiliated Tongji University, Shanghai, China.
Correspondence: All correspondence and requests for reprints should be addressed to: Zhong Wei Lv, MD, PhD, Department of Nuclear Medicine, Tenth People’s Hospital Affiliated Tongji University, 301 Middle Yanchang Rd, Shanghai, 200072, China.
Disclosures: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.
0894-9115/14/9304-0287 American Journal of Physical Medicine & Rehabilitation Copyright * 2013 by Lippincott Williams & Wilkins
Transcutaneous Electrical Nerve Stimulation in Combination with Cobalamin Injection for Postherpetic Neuralgia A Single-Center Randomized Controlled Trial ABSTRACT Xuˇ G, Xu´ G, Feng Y, Tang WZ, Lv ZW: Transcutaneous electrical nerve stimulation in combination with cobalamin injection for postherpetic neuralgia: a single-center randomized controlled trial. Am J Phys Med Rehabil 2014;93:287Y298.
Objective: The aim of this study was to explore the efficacy of transcutaneous electrical nerve stimulation (TENS) with locally injected cobalamin in relieving pain and improving activities of daily living in patients with postherpetic neuralgia.
Design: Ninety patients (Q50 yrs old) with postherpetic neuralgia with a pain score of 4 or greater were randomized to receive TENS and local injections of cobalamin or lidocaine or a combination of cobalamin and lidocaine for 8 wks. Treatment efficacy was assessed on the basis of worst pain severity, global impression of change, activities of daily living, and quality-of-life.
DOI: 10.1097/PHM.0000000000000002
Results: Time group interaction, group differences, and time effect on worst pain at each follow-up point were statistically significant (P G 0.05) among the groups. In the group receiving TENS and local injection of cobalamin and in the group receiving TENS with a combination of cobalamin and lidocaine, the mean T SD pain scores were 4.0 T 1.4 and 4.1 T 1.2 at endpoint, 28 and 26 patients achieved pain reduction of 30% or greater, and 14 and 10 perceived worst pain of 3 or less, respectively. The activities of daily living and quality-of-life data at the study endpoint showed significant benefits in the group receiving TENS and local injection of cobalamin and in the group receiving TENS and a combination of cobalamin and lidocaine (P G 0.05). In the group receiving TENS and local injection of lidocaine, the mean T SD pain score was 6.1 T 1.2 at the endpoint relative to baseline (P G 0.05), and only six patients achieved pain reduction of 30% or greater.
Conclusions: TENS in combination with local cobalamin injection has a significant analgesic effect. Key Words: Postherpetic Neuralgia, Transcutaneous Electrical Nerve Stimulation, Cobalamin, Randomized Clinical Trial
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P
ostherpetic neuralgia (PHN) is defined as pain that persists 120 days or more after rash onset.1 Patients with herpes zoster (HZ) who are older than 50 yrs are more likely to have severe pain and develop PHN. Existing analgesic therapies do not completely prevent all cases of PHN. Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacologic analgesic technique that has shown efficacy in transiently relieving neuropathic pain.2,3 The persistence of pain after the onset of vesicles implies that damage to afferent fibers and nerve endings play important roles in PHN pathogenesis.4 It is speculated that some strategies, such as neurotrophic medication that promotes damaged fiber repair or regeneration, might be potentially relevant to fibers and epidermal nerve endings affected by PHN. Cobalamin is a neurotrophic agent that has a special affinity for neural tissues. It promotes myelination and axonal cytoskeletal transport and can help maintain the nervous system and regenerate peripheral nerves.5 Clinical experience has shown that cobalamin therapy improves symptoms of both peripheral neuropathy and autonomic dysfunction.6 Recent studies have suggested that oral administration of cobalamin is more effective than parenteral supplementation.7 However, reaching the same level effectiveness as that achieved with intramuscular administration in obtaining short-term neurologic responses in patients with cobalamin deficiency requires long-term, high daily doses of oral cobalamin.8 Because delays in effective therapy can lead to irreversible neurologic dysfunction, parenteral cobalamin therapy should be strongly considered.9 Although varicella vesicles can develop in any dermatome, HZ and mononeuritis are characterized by axonal damage and myelin disruption, resulting in PHN that is often confined to a single dermatome, even if there may be cutaneous spread beyond the originally affected dermatome.10 Because TENS may only transiently relieve pain2,3 and neurotrophic cobalamin alone will not quickly achieve analgesia,11 TENS in combination with local high concentrations of cobalamin might have more significant analgesic and neurotrophic effects on HZ-affected nerve fibers. The objective of this study was to determine the effectiveness of TENS in combination with local methylcobalamin injection in controlling PHN.
METHODS Study Design and Ethics The study protocol was reviewed and approved by Tongji University institutional review board. This
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single-center randomized controlled trial was conducted at the Department of Rehabilitation Medicine. All study procedures were conducted in accordance with Good Clinical Practices and the Declaration of Helsinki. Written informed consent was obtained from all subjects before study enrollment, and they were followed for 8 wks after their participation (time from randomization to the study completion). This study was conducted from November 2011 to October 2012.
Rationale Behind Sample Size Determination Previous studies reported that PHN persisting at 3 mos may occur in 10%Y20% of HZ patients older than 50 yrs.12 A long-term study demonstrated that 9% (11 of 12 of whom were aged 951 yrs) still had pain at 1 yr after resolution of the rash.13 Therefore, the expected proportion of pain intensity numerical rating scale (NRS) scores of 3 or lower for the 56-day treatment was 80%, with a two-sided 5% significance level. With an assumption of > error of 0.05 and an anticipated dropout rate of 10%, a minimum of 29 patients per group were required for 90% statistical power. Thus, a total of 87 patients were needed for this study.
Patient Recruitment A total of 112 outpatients (58 men and 54 women) were recruited, primarily through the Good Doctor Online Website (www.HaoDF.com). The patients belonged to the Asian/Chinese race and ranged between 55 and 92 yrs old. Before study enrollment, the patients underwent a clinical examination and were asked to complete baseline questionnaires.
Inclusion Criteria Patients were included in this study on the basis of the following criteria: a confirmed diagnosis of PHN lasting for at least 120 days, older than 50 yrs, experienced cutaneous and/or subcutaneous pain of the dermatomal T6YT10 levels or adjacent cutaneous dermatomes temporally and spatially associated with their HZ rash, and a worst pain score of 4 or greater on an 11-point NRS in the past 24 hrs.
Exclusion Criteria Subjects who met the following criteria were excluded from this study: unilateral dermatomal pain in the vesicular region for less than 120 days with diffusely distributed neuropathic pain or significant pain outside the target regions; any clinically significant medical condition or laboratory abnormality; any cognitive impairment; and cardiac
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pacemakers, severe general diseases, hypersensitivity to cobalamin, or use of any topical analgesic or nerve blocker within 10 days before the baseline visit. Although the use of topical analgesics was considered an exclusion criterion, patients were allowed to continue oral analgesics that they had previously taken for pain control at the same dose. No change of medications was permitted, but dose reduction or complete discontinuation of analgesics was allowed during the course of the study.
Randomization An independent physician carried out the randomization procedure, and the patients were categorized into three different groups: TENS and local injections of cobalamin (T-MB group) or lidocaine (T-LD group) or a combination of cobalamin and lidocaine (T-BL group). Randomization was computer generated, and the allocation was centrally generated and concealed. A research physician (the second author) evaluated patient eligibility and obtained written informed consent, and only eligible patients who agreed to enroll in the trial were given the envelope containing the details of the allocated treatment. The demographic and baseline characteristics of all enrolled patients were recorded at the baseline. Because of the nature and the color of the injections, blinding the physician, the therapists, and the patients was not possible. However, they were informed that these treatment approaches were valid interventions that had a realistic chance of being beneficial and that neither approach was known to be more effective than the other. An independent rehabilitation physician (the fourth author) did not participate in clinical management and was kept blinded to the treatment allocation, and she carried out the follow-up visits on days 14, 28, 42, and 56 of the treatment and conducted the pain assessments.
Intervention The treatment programs were performed once daily every morning, between 8 and 11 a.m., six times a week for 8 wks. TENS prescription for PHN was selected from the EN-Stim program (EnrafNonius B.V., Rotterdam, the Netherlands) and was administered for 30 mins daily over the path of the affected dermatome. A patch measuring 6 8 cm was applied to the painful cutaneous area of the proximal affected region, and the other was applied distal to the affected region to complete the circuit. The stimulator produces asymmetrical www.ajpmr.com
75-microsecond square wave pulses at 100 Hz. Stimulation intensity was modulated up to the patient’s tolerance level for each patient to produce a prickling tingling sensation sustained for the whole 30 mins of treatment; the typical intensities were 40Y60 mA. After TENS treatment, the patients received local injections of methylcobalamin (T-MB group; 1000 Kg, Eisai Co. Ltd, Tokyo, Japan), 1.0% lidocaine (T-LD group; 40 mg, Fuda Co. Ltd, Shanghai, China), or a combination of both drugs (T-BL group). All drugs were diluted in sterilized water to yield 4.0 ml of subcutaneous injections, which were administered with 25-gauge needles and sterile hypodermic syringes. The drugs were injected into the most painful area reported by the patients, with 1.00 ml of liquid injected per region in up to four regions. The patients were observed for 1 hr after the first administration and were subsequently discharged without any symptoms of discomfort.
Outcome Measurements Outcome measures were consistent with the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials guidelines.14 All patients underwent a structured interview to assess the clinical and phenomenological characteristics of their pain sensations: location, descriptive characteristics, intensity, and changes in pain scores using the Zoster Brief Pain Inventory (ZBPI) and the Patients’ Global Impression of Change scale and the proportion of patients with pain of 3 or less, the proportion of patients using analgesics, and interference with activities of daily living (ADLs) and health-related quality-of-life (QoL) using the ZBPI and the EuroQoL visual analog scale (EQ-VAS). The primary outcome measures included the intensity of worst pain from baseline to days 14, 28, 42, and 56 of the treatment. The patients rated their worst perceived pain during the previous day using an 11-point Likert-type pain intensity NRS by indicating the number that best described their worst pain during the previous 24 hrs.15,16 Such ratings of daily worst pain intensity provided the basis for the primary efficacy analysis.17 Zoster-related pain is generally described as continuous pain, paroxysmal pain,18 allodynia (pain induced by lightly touching the skin),4 and paresthesia (numbness). The first item of the ZBPI describing the pain at its worst in the last 24 hrs was evaluated from 0 (no pain) to 10 (worst pain imaginable). The added sections consisted of four items that estimated patients’ continuous pain, paroxysmal pain, allodynia, and paresthesia during the previous day, using an 11-point Likert scale. On Treatment of Postherpetic Neuralgia
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the basis of the previous studies,16 clinically meaningful PHN was defined as the presence of a worst pain score of 3 or greater on the ZBPI at 3 mos or more after rash onset. All patients rated their perceived overall change since baseline with the Patients’ Global Impression of Change scale. The Patients’ Global Impression of Change scale was patient reported and asked the patient to Bindicate how you feel now, compared to how you felt before receiving treatment in this study[ on a 7-point scale of Bvery much improved,[ Bmuch improved,[ Bslightly improved,[ Bno change,[ Bslightly worsened,[ Bmuch worsened,[ or Bvastly worsened.[17,19 A rating of Bmuch improved[ was considered equal to a reduction of two units or approximately 30% in the NRS, whereas Bvery much improved[ equaled four units or a reduction of approximately 50%.17 Pain reduction rates of 30% or higher and 50% or higher from baseline have been demonstrated to be clinically important in acute and chronic pain clinical trials.19 This rating scale permitted a global evaluation of the patients’ impression of change in their condition since admission to this study. The secondary efficacy measures included the ADL and QoL scores according to the ZBPI and the EQ-VAS after the 8-wk treatments. The ZBPI ADL and QoL scores were used to measure selected ADLs and aspects of health,16 which included the interference of HZ-related pain with seven ADL and QoL components: general activity, mood, walking ability, normal work, relationship with others, sleep, and enjoyment of life. These items measured pain-related interference over seven health status domains using an 11-point Likert scale, with scores ranging from 0 (does not interfere) to 10 (completely interferes). The EQ-VAS20,21 is a validated measure of healthrelated QoL, and it helps to rate the patients’ current health state on a scale of 0 (worst imaginable health state) to 100 (best imaginable health state).
Adverse Events Adverse events were monitored and recorded in all three groups according to two methods. The first involved active monitoring during the treatment period by a treating physician who immediately reported to a researcher. The researcher then recorded the data on standardized clinical notes for each participant. The second method involved the administration of follow-up questionnaires that included an open question to record any adverse, harmful, or unpleasant effects that the patients attributed to the intervention.
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Participant Compliance The numbers of treatment sessions attended and the numbers of missed or cancelled appointments were recorded by the treating physician.
Statistical Analysis The primary measure variables were the mean score of the worst pain intensity ratings (calculated as the pain score of the previous 24 hrs) from the baseline visit to days 14, 28, 42, and 56 of treatment. Repeated-measures analyses of variance (ANOVAs) were used to evaluate the effect of time, group, and time group interaction for pain scores after treatment. The Bonferroni method was used to make pairwise comparisons of repeatedly measured data at different time points for each treated group. Least significant difference tests were used for pairwise comparisons of data in the different treated groups for each time point. For treated group comparisons of the proportions of patients who achieved 30% or 50% perceived overall change (equal to two or four units of pain reduction) from their baseline pain scores, W2 tests were performed. The ZBPI and EQ-VAS scores were analyzed using ANOVAs. All data were analyzed on an intention-totreat basis, with the missing data imputed by carrying forward the last available observed value, and two-tailed P values of less than 0.05 were considered statistically significant. All analyses were carried out using R software.
RESULTS Patient Disposition A total of 112 patients with PHN consecutively enrolled throughout the 12-mo recruitment period. Twenty-two patients were excluded from this study, and only 90 patients who met the inclusion/exclusion criteria were eligible for the trial. Reasons for exclusion were severe chronic diseases, cognitive impairment, cardiac pacemakers, dermatitis, psoriasis granulomatous reactions, or lichen planus near the zoster-affected dermatomes (n = 10); declined to participate because of personal reasons (n = 6); use of any topical analgesic or nerve blocker within 10 days before the baseline visit; or inability to adhere to treatment (n = 6). The patients’ disposition is presented in Figure 1, and their baseline characteristics are presented in Table 1. All 90 patients and their data were included in the therapeutic response analysis. In the intention-to-treat population, pain severity did not significantly differ among the groups at baseline.
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FIGURE 1 Patient flow chart. The time from randomization to the study endpoint was 56 days.
Dropouts In all, 13 patients dropped out of this study, including 4 from the T-MB group, 5 from the T-LD group, and 4 from the T-BL group. In the T-MB
group, two were discontinued from the trial because of noncompliance after receiving 28 and 40 days of treatment. The other two patients dropped out after receiving 10 and 20 days of treatment.
TABLE 1 Baseline demographic and clinical patient characteristics Measures (Baseline) Age at rash onset, mean (SD), yrs Female sex, n (%) High school or higher educational level, n (%) Duration of pain after rash onset, mean (SD), days Pain NRS at baseline, mean (SD) Patients using analgesics, n Gabapentin Pregabalin amitriptyline Oxycodone Tramadol
T-MB Group (n = 30)
T-LD Group (n = 30)
T-BL Group (n = 30)
69.77 (9.20) 13 (43.33) 12 (40.00) 252.23 (175.59) 7.1 (1.5) 28 9 12 2 2 3
68.00 (8.30) 17 (56.67) 13 (43.33) 227.77 (149.73) 7.1 (1.6) 28 8 13 1 2 4
70.80 (8.11) 15 (50.00) 14 (46.67) 232.53 (150.35) 6.9 (1.6) 29 8 13 1 2 5
NRS: 0Y10 scale.
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FIGURE 2 Mean of the worst pain at each time point during the 56-day treatment period. Repeated-measures ANOVAs were used to evaluate the effect. & indicates time per group interaction; *, P G 0.05, pain score at each time point vs. baseline in the same group; &, P G 0.05, pain score in the different groups of each time compared with that in the T- LD group.
In the T-LD group, four patients did not complete this study because of lack of improvement after 10, 14, 28, or 30 days of treatment, whereas another was discontinued because of noncompliance after 20 days of treatment. In the T-BL group, three patients were dropped because of noncompliance after receiving 14, 28, or 42 days of treatment, and one was lost to follow-up after 20 days of treatment.
Primary Outcomes Worst Pain Intensity Time group interaction, treatment group effect, and time effect were statistically significant among the three groups (P G 0.05). The tendency of measurements within the groups and direct observation of the number of changes are shown in Figure 2 and Table 2.
TABLE 2 Patients’ perceived overall change since baseline Measure (Number, at the Endpoint)
T-MB vs. T-LD T-MB
T-LD
T-BL
OR
95% CI
T-BL vs. T-LD OR
95% CI
T-MB vs. T-BL OR
95% CI
Pain reduction 2 24 4 G30% Pain reduction 19 6 19 Q30% Pain reduction 9 0 7 56.00 10.33Y303.68a 26.00 6.53Y103.50a 2.15 0.36Y12.76 Q50% Patients with 14 2 10 pain e3 Pain score, 4.0 (1.4) 6.1 (1.2) 4.1 (1.2)a mean (SD) Patients using 12 26 17a analgesics Data are presented as number or mean (standard deviation). Treatment group comparisons for the proportions of subjects who achieved 30% or 50% of pain reduction were performed using the W2 test. The number of patients with pain NRS of 3 or less and using analgesics at endpoint was analyzed using the Kruskal-Wallis test. Comparison of pain intensity at endpoint was performed using ANOVA. a P G 0.05.
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FIGURE 3 Mean of continuous pain at each time point during the 56-day treatment period. Repeated-measures ANOVAs were used to evaluate the effect. & indicates time per group interaction; *, P G 0.05, pain score at each time point vs. baseline in the same group; &, P G 0.05, pain score in the different groups of each time compared with that in the T- LD group.
Other Different Categorized Pain Intensities Although 53, 41, 38, and 29 of the 90 patients complained of continuous pain, paroxysmal pain, allodynia, and paresthesia, respectively, the severities were not significantly different among the groups. The time group interaction on the three pain subtypes was statistically significant (P G 0.05), except paresthesia. The time effect of the categorized pain intensities at endpoint vs. baseline was statistically significant (P G 0.05), except paresthesia
in the T-LD group. Treatment group differences of continuous pain and paroxysmal pain and allodynia scores were statistically significant between the T-MB and T-LD groups (P G 0.05). No treatment effect difference for paresthesia was observed among the three groups at endpoints (P 9 0.05). Reduction differences of these subtypes, however, were not found in the T-MB group compared with those in the T-BL group for any of the time points. The changes in categorized pain intensities based on
FIGURE 4 Mean of paroxysmal pain at each time point during the 56-day treatment period. Repeated-measures ANOVAs were used to evaluate the effect. & indicates time per group interaction; *, P G 0.05, pain score at each time point vs. baseline in the same group; &, P G 0.05, pain score in the different groups of each time compared with that in the T- LD group. www.ajpmr.com
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FIGURE 5 Mean allodynia score at each time point during the 56-day treatment period. Repeated-measures ANOVAs were used to evaluate the effect. & indicates time per group interaction; *, P G 0.05, pain score at each time point vs. baseline in the same group; &, P G 0.05, pain score in the different groups of each time compared with that in the T- LD group.
time after different interventions are shown in Figures 3 to 6 and Table 2.
group (both P G 0.05). In contrast, these items were not significantly different between the T-MB and T-BL groups.
Secondary Outcomes The differences among the groups in the mean scores for ADLs and QoL based on the ZBPI and the EQ-VAS at the 56-day assessment are shown in Figure 7 and Table 3. After 56 days of treatment, the patients in the T-MB and T-BL groups had significantly lower ADL and QoL scores in the ZBPI and higher EQ-VAS scores than those in the T-LD
Adverse Events The injections were well tolerated by the patients. No serious side effects such as acute lidocaine intoxication, excessive sensory loss, or other serious adverse events were reported in any of the treatment groups. However, 45 patients, including 14 from the T-MB group, 16 from the T-LD group,
FIGURE 6 Mean paresthesia score at each time point during the 56-day treatment period. Repeated-measures ANOVAs were used to evaluate the effect. *, P G 0.05, pain score at each time point vs. baseline in the same group.
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FIGURE 7 Comparisons of ADL and QoL scores in the ZBPI before and after treatment. Comparisons among the groups used ANOVA. *, P G 0.05.
and 15 from the T-BL group, had bleeding and bruising at the local injection sites, but bleeding stopped after 1 min and bruising subsided within 7 days. The outcomes of all these adverse events were considered resolved, and no actions were taken in terms of medications. No substantial changes in vital sign parameters were observed in any of the treatment groups.
DISCUSSION TENS is an adjunctive therapy that is administered at a strong but nonpainful stimulation intensity that can achieve pain relief 22 and is often used in combination with conventional treatment of PHN pain relief.3 Early treatment of HZ with TENS may be better in preventing PHN23; however, approximately 30% of patients with PHN fail to respond to TENS, and among patients who respond initially, only a third continue to obtain pain relief after 2 yrs.2 It implies that TENS therapy may be too late and may not be enough for PHN. This study was designed to apply TENS in combination with a local anesthetic and/or neurotrophic agent to control PHN pain. This study results indicated that all three groups showed a significant response after 14 days of treatment, and worst pain scores reduced continuously until the end of the study. Although the results did not achieve a difference in pain reduction between the T-MB and T-BL groups, both differed from the T-LD group scores at all four time points. Varicella zoster virusYdamaged cutaneous nociceptive fibers that cause pain may be caused in part by increased sodium channel expression at the injury sites.24 On the basis of a number of randomized clinical trials, lidocaine was expected to relieve pain in PHN patients.25 However, this study showed that TENS with local 1% lidocaine injection did not provide www.ajpmr.com
greater pain relief than did TENS with cobalamin injection. The mean T SD pain score was 6.1 T 1.2; a total of 6 (20%) of 30 patients achieved pain reduction of 30% or greater, and two patients had stopped using analgesics by the study endpoint. It was difficult to distinguish between the significant benefits of TENS with local lidocaine injection, TENS alone,2 and spontaneous recovery.26 Compared with the lidocaine patch, local lidocaine injection (once a day) did not exert a sustained analgesic effect. The findings indicated that pain severity decreased significantly in both the T-MB and T-BL groups, and the mean T SD pain scores at endpoint were 4.0 T 1.4 and 4.1 T 1.2, respectively. The clinical effectiveness of the 56-day treatment with respect to pain relief was verified as the perceived overall change data, ADLs and QoL based on the ZBPI and EQ-VAS data for 8 wks, which showed significant benefits (Figs. 2, 7; Table 3). Odds ratios (ORs) of the T-MB and T-BL groups vs. the T-LD group demonstrated that overall change levels were 56.00 and 26.00 at the endpoint, respectively. The 95% confidence interval (CI) for the OR was greater than 1, both P G0.001 (Table 2). Interestingly, the OR of the T-MB group vs. the T-BL group was 2.15 at the study endpoint (95% CI, 0.36Y12.76, P 9 0.05), which implied that pain relief levels in the T-MB and T-BL groups were superior to that in the T-LD group. Clinical experience has shown that cobalamin therapy improves peripheral neuropathy symptoms for many years, and an intrathecal highdose methylcobalamin can rapidly relieve neuropathy symptoms.27 Only a small number of studies on the use of cobalamin for PHN had been reported; notably, two publications published in the 1950s negated its clinical efficacy.28,29 Recently, clinical experience has shown that local methylcobalamin therapy improves pain relief for subacute herpetic Treatment of Postherpetic Neuralgia
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Comparisons of VAS score among the groups were performed using ANOVA. Least significant difference tests were used for pairwise comparisons of data in the different treated groups for endpoint.
G0.001 25.67 (18.78 G0.001 0.13(j6.75 0.969 25.53 (18.65 G0.001 to 32.55) to 7.01) to 32.41) 63.53 (10.44) 38.00 (13.43) 63.67 (15.81) 0.887 27.50 (15.33) 25.83 (13.96) 26.07 (13.37)
P Difference (95% CI) P Difference (95% CI) P T-MB (n = 30) T-LD (n = 30) T-BL (n = 30) T-MB (n = 30) T-LD (n = 30) T-BL (n = 30)
Baseline Mean (SD)
P
Endpoint Mean (SD)
P
Difference (95% CI)
T-BL vs. T-LD T-MB vs. T-BL T-MB vs. T-LD
At Endpoint
TABLE 3 Comparison of the EQ-VAS scores before and after treatment
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neuralgia,11 but neurotrophic cobalamin alone will not quickly achieve analgesia for PHN. The results of this study demonstrated that local cobalamin injection with TENS had a significant analgesic effect on painful areas with PHN, after 56 days treatment, and the TENS combination with methylcobalamin and lidocaine injection failed to produce an obvious synergistic effect. Twenty-eight (93%) of 30 patients in the T-MB group and 26 (86%) of 30 in the T-BL group achieved pain reduction of 30% or greater by the endpoint. It was significantly higher than that in the T-LD group or TENS alone.2 These results indicate that local injection can directly deliver high concentrations of cobalamin to varicella zoster virusYdamaged tissues to obtain neurologic responses, which is consistent with the conclusion made by Okada et al.5 PHN entails heterogeneous and variable painful symptoms and negative sensory signs because various mechanisms can act simultaneously in the same patient and each of them may be responsible for different manifestations. In addition, both clinical manifestations and pathophysiologic mechanisms usually change with time.30 Patients with PHN generally report various characteristics of pain and discomfort. Only a subset of the patients with PHN reported the same characteristics of pain or discomfort in this study. Reductions in continuous pain, paroxysmal pain, and allodynia scores in the T-MB and T-BL groups were statistically significant relative to the baseline (P G 0.05), which suggested that local methylcobalamin injection significantly reduced continuous pain, paroxysmal pain, and allodynia (Figs. 3Y6).
Limitations This study was limited by the fact that the authors were unable to blind the study participants and the research staff to the treatment group. An independent physician who did not participate in clinical management and who was kept blinded to treatment allocation conducted the pain assessment to minimize this shortcoming. Because most of the worst HZ-associated pain areas reported were partial lesion regions innervated by distal nerve branches rather than the entire nerve distribution area, the study drugs were administered as local subcutaneous injections rather than via nerve blockade. An optimal effect was not found, probably because the maximum dose of cobalamin injected was 1000 Hg/day, which may not be sufficient to relieve pain in relatively large areas. Although other neurotrophic agents may also be efficacious, Am. J. Phys. Med. Rehabil. & Vol. 93, No. 4, April 2014
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whether those results can be extrapolated to other neurotrophic agents (e.g., vitamin B1, nerve growth factor, or basic fibroblast growth factor) is unknown. Although the patients were informed that they could come back for treatment again if their pain symptoms returned, the return visit rate was lower than 10%. The patients were followed up only 56 days; there are no data for the long-term results.
CONCLUSIONS The findings of this 8-wk, single-center, randomized controlled trial suggest that the combination of TENS and local methylcobalamin administration had a significant analgesic effect on PHN. Because local subcutaneous injection of cobalamin is a safe technique that is minimally invasive and relatively inexpensive, it may prove to be an excellent treatment option for PHN. However, further studies are needed to confirm these findings in a larger number of patients. ACKNOWLEDGMENTS
The authors thank the patients who served as subjects for this study and Jiang jiao Chen, MD, for her advice on some of the statistical analyses. REFERENCES 1. Arani RB, Soong SJ, Weiss HL, et al: Phase specific analysis of herpes zoster associated pain data: A new statistical approach. Stat Med 2001;20:2429Y39 2. Bates JA, Nathan PW: Transcutaneous electrical nerve stimulation for chronic pain. Anaesthesia 1980;35:817Y22 3. Barbarisi M, Pace MC, Passavanti MB, et al: Pregabalin and transcutaneous electrical nerve stimulation for postherpetic neuralgia treatment. Clin J Pain 2010; 26:567Y72 4. Petersen KL, Rice FL, Farhadi M, et al: Natural history of cutaneous innervation following herpes zoster. Pain 2010;150:75Y82 5. Okada K, Tanaka H, Temporin K, et al: Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model. Exp Neurol 2010;222:191Y203 6. Mizukami H, Ogasawara S, Yamagishi S, et al: Methylcobalamin effects on diabetic neuropathy and nerve protein kinase C in rats. Eur J Clin Invest 2011;41:442Y50 7. Duyvendak M, Veldhuis GJ: Oral better than parenteral supplementation of vitamin B12. Ned Tijdschr Geneeskd 2009;153:B485 8. Sanz-Cuesta T, Gonzalez-Escobar P, Riesgo-Fuertes R, et al: Oral versus intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency: A pragmatic, randomised, multicentre, www.ajpmr.com
non-inferiority clinical trial undertaken in the primary healthcare setting (Project OB12). BMC Public Health 2012;12:394 9. Solomon LR: Oral pharmacologic doses of cobalamin may not be as effective as parenteral cobalamin therapy in reversing hyperhomocystinemia and methylmalonic acidemia in apparently normal subjects. Clin Lab Haematol 2006;28:275Y78 10. Gilden D, Mahalingam R, Nagel MA, et al: Review: The neurobiology of varicella zoster virus infection. Neuropathol Appl Neurobiol 2011;37:441Y63 11. Xu G, Lv ZW, Feng Y, et al: A single-center randomized controlled trial of local methylcobalamin injection for subacute herpetic neuralgia. Pain Med 2013;14:884Y94 12. Gauthier A, Breuer J, Carrington D, et al: Epidemiology and cost of herpes zoster and post-herpetic neuralgia in the United Kingdom. Epidemiol Infect 2009;137:38Y47 13. Scott FT, Leedham-Green ME, Barrett-Muir WY, et al: A study of shingles and the development of postherpetic neuralgia in East London. J Med Virol 2003;70(suppl):S24Y30 14. Dworkin RH, Turk DC, Farrar JT, et al: Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9Y19 15. Bouhassira D, Attal N, Fermanian J, et al: Development and validation of the Neuropathic Pain Symptom Inventory. Pain 2004;108:248Y57 16. Coplan PM, Schmader K, Nikas A, et al: Development of a measure of the burden of pain due to herpes zoster and postherpetic neuralgia for prevention trials: Adaptation of the Brief Pain Inventory. J Pain 2004;5:344Y56 17. Farrar JT, Young JP Jr, LaMoreaux L, et al: Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94:149Y58 18. Niv D, Maltsman-Tseikhin A: Postherpetic neuralgia: The never-ending challenge. Pain Pract 2005;5: 327Y40 19. Dworkin RH, Turk DC, Wyrwich KW, et al: Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain 2008;9:105Y21 20. The EuroQol Group: EuroQolVA new facility for the measurement of health-related quality of life. Health Policy 1990;16:199Y208 21. van Seventer R, Sadosky A, Lucero M, et al: A crosssectional survey of health state impairment and treatment patterns in patients with postherpetic neuralgia. Age Ageing 2006;35:132Y7 22. Aarskog R, Johnson MI, Demmink JH, et al: Is mechanical pain threshold after transcutaneous electrical nerve stimulation (TENS) increased locally and unilaterally? A randomized placebo-controlled trial in healthy subjects. Physiother Res Int 2007; 12:251Y63
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23. Kolsek M: TENSVAn alternative to antiviral drugs for acute herpes zoster treatment and postherpetic neuralgia prevention. Swiss Med Wkly 2012;141:w13229 24. Oaklander AL: Mechanisms of pain and itch caused by herpes zoster (shingles). J Pain 2008;9(suppl):S10Y8 25. Wolff RF, Bala MM, Westwood M, et al: 5% lidocainemedicated plaster vs other relevant interventions and placebo for post-herpetic neuralgia (PHN): A systematic review. Acta Neurol Scand 2011;123:295Y309 26. Thyregod HG, Rowbotham MC, Peters M, et al: Natural history of pain following herpes zoster. Pain 2007;128:148Y56
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27. Ide H, Fujiya S, Asanuma Y, et al: Clinical usefulness of intrathecal injection of methylcobalamin in patients with diabetic neuropathy. Clin Ther 1987; 9:183Y92 28. Heaton JM: Vitamin B12 and herpes zoster ophthalmicus. Br J Ophthalmol 1959;43:438Y39 29. Helle J, Ohela K: Treatment of herpes zoster neuralgia with massive doses of vitamin B12. Ann Med Exp Biol Fenn 1955;33:116Y21 30. Lanz S, Maihofner C: Symptoms and pathophysiological mechanisms of neuropathic pain syndromes. Nervenarzt 2009;80:430Y44
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Affiliations:
Pain
ORIGINAL RESEARCH ARTICLE
From the Department of Rehabilitation Medicine (GX, GX, YF, WZT) and Department of Nuclear Medicine (ZWL), Tenth People’s Hospital Affiliated Tongji University, Shanghai, China.
Correspondence: All correspondence and requests for reprints should be addressed to: Zhong Wei Lv, MD, PhD, Department of Nuclear Medicine, Tenth People’s Hospital Affiliated Tongji University, 301 Middle Yanchang Rd, Shanghai, 200072, China.
Disclosures: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article.
0894-9115/14/9304-0287 American Journal of Physical Medicine & Rehabilitation Copyright * 2013 by Lippincott Williams & Wilkins
Transcutaneous Electrical Nerve Stimulation in Combination with Cobalamin Injection for Postherpetic Neuralgia A Single-Center Randomized Controlled Trial ABSTRACT Xuˇ G, Xu´ G, Feng Y, Tang WZ, Lv ZW: Transcutaneous electrical nerve stimulation in combination with cobalamin injection for postherpetic neuralgia: a single-center randomized controlled trial. Am J Phys Med Rehabil 2014;93:287Y298.
Objective: The aim of this study was to explore the efficacy of transcutaneous electrical nerve stimulation (TENS) with locally injected cobalamin in relieving pain and improving activities of daily living in patients with postherpetic neuralgia.
Design: Ninety patients (Q50 yrs old) with postherpetic neuralgia with a pain score of 4 or greater were randomized to receive TENS and local injections of cobalamin or lidocaine or a combination of cobalamin and lidocaine for 8 wks. Treatment efficacy was assessed on the basis of worst pain severity, global impression of change, activities of daily living, and quality-of-life.
DOI: 10.1097/PHM.0000000000000002
Results: Time group interaction, group differences, and time effect on worst pain at each follow-up point were statistically significant (P G 0.05) among the groups. In the group receiving TENS and local injection of cobalamin and in the group receiving TENS with a combination of cobalamin and lidocaine, the mean T SD pain scores were 4.0 T 1.4 and 4.1 T 1.2 at endpoint, 28 and 26 patients achieved pain reduction of 30% or greater, and 14 and 10 perceived worst pain of 3 or less, respectively. The activities of daily living and quality-of-life data at the study endpoint showed significant benefits in the group receiving TENS and local injection of cobalamin and in the group receiving TENS and a combination of cobalamin and lidocaine (P G 0.05). In the group receiving TENS and local injection of lidocaine, the mean T SD pain score was 6.1 T 1.2 at the endpoint relative to baseline (P G 0.05), and only six patients achieved pain reduction of 30% or greater.
Conclusions: TENS in combination with local cobalamin injection has a significant analgesic effect. Key Words: Postherpetic Neuralgia, Transcutaneous Electrical Nerve Stimulation, Cobalamin, Randomized Clinical Trial
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P
ostherpetic neuralgia (PHN) is defined as pain that persists 120 days or more after rash onset.1 Patients with herpes zoster (HZ) who are older than 50 yrs are more likely to have severe pain and develop PHN. Existing analgesic therapies do not completely prevent all cases of PHN. Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacologic analgesic technique that has shown efficacy in transiently relieving neuropathic pain.2,3 The persistence of pain after the onset of vesicles implies that damage to afferent fibers and nerve endings play important roles in PHN pathogenesis.4 It is speculated that some strategies, such as neurotrophic medication that promotes damaged fiber repair or regeneration, might be potentially relevant to fibers and epidermal nerve endings affected by PHN. Cobalamin is a neurotrophic agent that has a special affinity for neural tissues. It promotes myelination and axonal cytoskeletal transport and can help maintain the nervous system and regenerate peripheral nerves.5 Clinical experience has shown that cobalamin therapy improves symptoms of both peripheral neuropathy and autonomic dysfunction.6 Recent studies have suggested that oral administration of cobalamin is more effective than parenteral supplementation.7 However, reaching the same level effectiveness as that achieved with intramuscular administration in obtaining short-term neurologic responses in patients with cobalamin deficiency requires long-term, high daily doses of oral cobalamin.8 Because delays in effective therapy can lead to irreversible neurologic dysfunction, parenteral cobalamin therapy should be strongly considered.9 Although varicella vesicles can develop in any dermatome, HZ and mononeuritis are characterized by axonal damage and myelin disruption, resulting in PHN that is often confined to a single dermatome, even if there may be cutaneous spread beyond the originally affected dermatome.10 Because TENS may only transiently relieve pain2,3 and neurotrophic cobalamin alone will not quickly achieve analgesia,11 TENS in combination with local high concentrations of cobalamin might have more significant analgesic and neurotrophic effects on HZ-affected nerve fibers. The objective of this study was to determine the effectiveness of TENS in combination with local methylcobalamin injection in controlling PHN.
METHODS Study Design and Ethics The study protocol was reviewed and approved by Tongji University institutional review board. This
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single-center randomized controlled trial was conducted at the Department of Rehabilitation Medicine. All study procedures were conducted in accordance with Good Clinical Practices and the Declaration of Helsinki. Written informed consent was obtained from all subjects before study enrollment, and they were followed for 8 wks after their participation (time from randomization to the study completion). This study was conducted from November 2011 to October 2012.
Rationale Behind Sample Size Determination Previous studies reported that PHN persisting at 3 mos may occur in 10%Y20% of HZ patients older than 50 yrs.12 A long-term study demonstrated that 9% (11 of 12 of whom were aged 951 yrs) still had pain at 1 yr after resolution of the rash.13 Therefore, the expected proportion of pain intensity numerical rating scale (NRS) scores of 3 or lower for the 56-day treatment was 80%, with a two-sided 5% significance level. With an assumption of > error of 0.05 and an anticipated dropout rate of 10%, a minimum of 29 patients per group were required for 90% statistical power. Thus, a total of 87 patients were needed for this study.
Patient Recruitment A total of 112 outpatients (58 men and 54 women) were recruited, primarily through the Good Doctor Online Website (www.HaoDF.com). The patients belonged to the Asian/Chinese race and ranged between 55 and 92 yrs old. Before study enrollment, the patients underwent a clinical examination and were asked to complete baseline questionnaires.
Inclusion Criteria Patients were included in this study on the basis of the following criteria: a confirmed diagnosis of PHN lasting for at least 120 days, older than 50 yrs, experienced cutaneous and/or subcutaneous pain of the dermatomal T6YT10 levels or adjacent cutaneous dermatomes temporally and spatially associated with their HZ rash, and a worst pain score of 4 or greater on an 11-point NRS in the past 24 hrs.
Exclusion Criteria Subjects who met the following criteria were excluded from this study: unilateral dermatomal pain in the vesicular region for less than 120 days with diffusely distributed neuropathic pain or significant pain outside the target regions; any clinically significant medical condition or laboratory abnormality; any cognitive impairment; and cardiac
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pacemakers, severe general diseases, hypersensitivity to cobalamin, or use of any topical analgesic or nerve blocker within 10 days before the baseline visit. Although the use of topical analgesics was considered an exclusion criterion, patients were allowed to continue oral analgesics that they had previously taken for pain control at the same dose. No change of medications was permitted, but dose reduction or complete discontinuation of analgesics was allowed during the course of the study.
Randomization An independent physician carried out the randomization procedure, and the patients were categorized into three different groups: TENS and local injections of cobalamin (T-MB group) or lidocaine (T-LD group) or a combination of cobalamin and lidocaine (T-BL group). Randomization was computer generated, and the allocation was centrally generated and concealed. A research physician (the second author) evaluated patient eligibility and obtained written informed consent, and only eligible patients who agreed to enroll in the trial were given the envelope containing the details of the allocated treatment. The demographic and baseline characteristics of all enrolled patients were recorded at the baseline. Because of the nature and the color of the injections, blinding the physician, the therapists, and the patients was not possible. However, they were informed that these treatment approaches were valid interventions that had a realistic chance of being beneficial and that neither approach was known to be more effective than the other. An independent rehabilitation physician (the fourth author) did not participate in clinical management and was kept blinded to the treatment allocation, and she carried out the follow-up visits on days 14, 28, 42, and 56 of the treatment and conducted the pain assessments.
Intervention The treatment programs were performed once daily every morning, between 8 and 11 a.m., six times a week for 8 wks. TENS prescription for PHN was selected from the EN-Stim program (EnrafNonius B.V., Rotterdam, the Netherlands) and was administered for 30 mins daily over the path of the affected dermatome. A patch measuring 6 8 cm was applied to the painful cutaneous area of the proximal affected region, and the other was applied distal to the affected region to complete the circuit. The stimulator produces asymmetrical www.ajpmr.com
75-microsecond square wave pulses at 100 Hz. Stimulation intensity was modulated up to the patient’s tolerance level for each patient to produce a prickling tingling sensation sustained for the whole 30 mins of treatment; the typical intensities were 40Y60 mA. After TENS treatment, the patients received local injections of methylcobalamin (T-MB group; 1000 Kg, Eisai Co. Ltd, Tokyo, Japan), 1.0% lidocaine (T-LD group; 40 mg, Fuda Co. Ltd, Shanghai, China), or a combination of both drugs (T-BL group). All drugs were diluted in sterilized water to yield 4.0 ml of subcutaneous injections, which were administered with 25-gauge needles and sterile hypodermic syringes. The drugs were injected into the most painful area reported by the patients, with 1.00 ml of liquid injected per region in up to four regions. The patients were observed for 1 hr after the first administration and were subsequently discharged without any symptoms of discomfort.
Outcome Measurements Outcome measures were consistent with the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials guidelines.14 All patients underwent a structured interview to assess the clinical and phenomenological characteristics of their pain sensations: location, descriptive characteristics, intensity, and changes in pain scores using the Zoster Brief Pain Inventory (ZBPI) and the Patients’ Global Impression of Change scale and the proportion of patients with pain of 3 or less, the proportion of patients using analgesics, and interference with activities of daily living (ADLs) and health-related quality-of-life (QoL) using the ZBPI and the EuroQoL visual analog scale (EQ-VAS). The primary outcome measures included the intensity of worst pain from baseline to days 14, 28, 42, and 56 of the treatment. The patients rated their worst perceived pain during the previous day using an 11-point Likert-type pain intensity NRS by indicating the number that best described their worst pain during the previous 24 hrs.15,16 Such ratings of daily worst pain intensity provided the basis for the primary efficacy analysis.17 Zoster-related pain is generally described as continuous pain, paroxysmal pain,18 allodynia (pain induced by lightly touching the skin),4 and paresthesia (numbness). The first item of the ZBPI describing the pain at its worst in the last 24 hrs was evaluated from 0 (no pain) to 10 (worst pain imaginable). The added sections consisted of four items that estimated patients’ continuous pain, paroxysmal pain, allodynia, and paresthesia during the previous day, using an 11-point Likert scale. On Treatment of Postherpetic Neuralgia
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the basis of the previous studies,16 clinically meaningful PHN was defined as the presence of a worst pain score of 3 or greater on the ZBPI at 3 mos or more after rash onset. All patients rated their perceived overall change since baseline with the Patients’ Global Impression of Change scale. The Patients’ Global Impression of Change scale was patient reported and asked the patient to Bindicate how you feel now, compared to how you felt before receiving treatment in this study[ on a 7-point scale of Bvery much improved,[ Bmuch improved,[ Bslightly improved,[ Bno change,[ Bslightly worsened,[ Bmuch worsened,[ or Bvastly worsened.[17,19 A rating of Bmuch improved[ was considered equal to a reduction of two units or approximately 30% in the NRS, whereas Bvery much improved[ equaled four units or a reduction of approximately 50%.17 Pain reduction rates of 30% or higher and 50% or higher from baseline have been demonstrated to be clinically important in acute and chronic pain clinical trials.19 This rating scale permitted a global evaluation of the patients’ impression of change in their condition since admission to this study. The secondary efficacy measures included the ADL and QoL scores according to the ZBPI and the EQ-VAS after the 8-wk treatments. The ZBPI ADL and QoL scores were used to measure selected ADLs and aspects of health,16 which included the interference of HZ-related pain with seven ADL and QoL components: general activity, mood, walking ability, normal work, relationship with others, sleep, and enjoyment of life. These items measured pain-related interference over seven health status domains using an 11-point Likert scale, with scores ranging from 0 (does not interfere) to 10 (completely interferes). The EQ-VAS20,21 is a validated measure of healthrelated QoL, and it helps to rate the patients’ current health state on a scale of 0 (worst imaginable health state) to 100 (best imaginable health state).
Adverse Events Adverse events were monitored and recorded in all three groups according to two methods. The first involved active monitoring during the treatment period by a treating physician who immediately reported to a researcher. The researcher then recorded the data on standardized clinical notes for each participant. The second method involved the administration of follow-up questionnaires that included an open question to record any adverse, harmful, or unpleasant effects that the patients attributed to the intervention.
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Participant Compliance The numbers of treatment sessions attended and the numbers of missed or cancelled appointments were recorded by the treating physician.
Statistical Analysis The primary measure variables were the mean score of the worst pain intensity ratings (calculated as the pain score of the previous 24 hrs) from the baseline visit to days 14, 28, 42, and 56 of treatment. Repeated-measures analyses of variance (ANOVAs) were used to evaluate the effect of time, group, and time group interaction for pain scores after treatment. The Bonferroni method was used to make pairwise comparisons of repeatedly measured data at different time points for each treated group. Least significant difference tests were used for pairwise comparisons of data in the different treated groups for each time point. For treated group comparisons of the proportions of patients who achieved 30% or 50% perceived overall change (equal to two or four units of pain reduction) from their baseline pain scores, W2 tests were performed. The ZBPI and EQ-VAS scores were analyzed using ANOVAs. All data were analyzed on an intention-totreat basis, with the missing data imputed by carrying forward the last available observed value, and two-tailed P values of less than 0.05 were considered statistically significant. All analyses were carried out using R software.
RESULTS Patient Disposition A total of 112 patients with PHN consecutively enrolled throughout the 12-mo recruitment period. Twenty-two patients were excluded from this study, and only 90 patients who met the inclusion/exclusion criteria were eligible for the trial. Reasons for exclusion were severe chronic diseases, cognitive impairment, cardiac pacemakers, dermatitis, psoriasis granulomatous reactions, or lichen planus near the zoster-affected dermatomes (n = 10); declined to participate because of personal reasons (n = 6); use of any topical analgesic or nerve blocker within 10 days before the baseline visit; or inability to adhere to treatment (n = 6). The patients’ disposition is presented in Figure 1, and their baseline characteristics are presented in Table 1. All 90 patients and their data were included in the therapeutic response analysis. In the intention-to-treat population, pain severity did not significantly differ among the groups at baseline.
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FIGURE 1 Patient flow chart. The time from randomization to the study endpoint was 56 days.
Dropouts In all, 13 patients dropped out of this study, including 4 from the T-MB group, 5 from the T-LD group, and 4 from the T-BL group. In the T-MB
group, two were discontinued from the trial because of noncompliance after receiving 28 and 40 days of treatment. The other two patients dropped out after receiving 10 and 20 days of treatment.
TABLE 1 Baseline demographic and clinical patient characteristics Measures (Baseline) Age at rash onset, mean (SD), yrs Female sex, n (%) High school or higher educational level, n (%) Duration of pain after rash onset, mean (SD), days Pain NRS at baseline, mean (SD) Patients using analgesics, n Gabapentin Pregabalin amitriptyline Oxycodone Tramadol
T-MB Group (n = 30)
T-LD Group (n = 30)
T-BL Group (n = 30)
69.77 (9.20) 13 (43.33) 12 (40.00) 252.23 (175.59) 7.1 (1.5) 28 9 12 2 2 3
68.00 (8.30) 17 (56.67) 13 (43.33) 227.77 (149.73) 7.1 (1.6) 28 8 13 1 2 4
70.80 (8.11) 15 (50.00) 14 (46.67) 232.53 (150.35) 6.9 (1.6) 29 8 13 1 2 5
NRS: 0Y10 scale.
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FIGURE 2 Mean of the worst pain at each time point during the 56-day treatment period. Repeated-measures ANOVAs were used to evaluate the effect. & indicates time per group interaction; *, P G 0.05, pain score at each time point vs. baseline in the same group; &, P G 0.05, pain score in the different groups of each time compared with that in the T- LD group.
In the T-LD group, four patients did not complete this study because of lack of improvement after 10, 14, 28, or 30 days of treatment, whereas another was discontinued because of noncompliance after 20 days of treatment. In the T-BL group, three patients were dropped because of noncompliance after receiving 14, 28, or 42 days of treatment, and one was lost to follow-up after 20 days of treatment.
Primary Outcomes Worst Pain Intensity Time group interaction, treatment group effect, and time effect were statistically significant among the three groups (P G 0.05). The tendency of measurements within the groups and direct observation of the number of changes are shown in Figure 2 and Table 2.
TABLE 2 Patients’ perceived overall change since baseline Measure (Number, at the Endpoint)
T-MB vs. T-LD T-MB
T-LD
T-BL
OR
95% CI
T-BL vs. T-LD OR
95% CI
T-MB vs. T-BL OR
95% CI
Pain reduction 2 24 4 G30% Pain reduction 19 6 19 Q30% Pain reduction 9 0 7 56.00 10.33Y303.68a 26.00 6.53Y103.50a 2.15 0.36Y12.76 Q50% Patients with 14 2 10 pain e3 Pain score, 4.0 (1.4) 6.1 (1.2) 4.1 (1.2)a mean (SD) Patients using 12 26 17a analgesics Data are presented as number or mean (standard deviation). Treatment group comparisons for the proportions of subjects who achieved 30% or 50% of pain reduction were performed using the W2 test. The number of patients with pain NRS of 3 or less and using analgesics at endpoint was analyzed using the Kruskal-Wallis test. Comparison of pain intensity at endpoint was performed using ANOVA. a P G 0.05.
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FIGURE 3 Mean of continuous pain at each time point during the 56-day treatment period. Repeated-measures ANOVAs were used to evaluate the effect. & indicates time per group interaction; *, P G 0.05, pain score at each time point vs. baseline in the same group; &, P G 0.05, pain score in the different groups of each time compared with that in the T- LD group.
Other Different Categorized Pain Intensities Although 53, 41, 38, and 29 of the 90 patients complained of continuous pain, paroxysmal pain, allodynia, and paresthesia, respectively, the severities were not significantly different among the groups. The time group interaction on the three pain subtypes was statistically significant (P G 0.05), except paresthesia. The time effect of the categorized pain intensities at endpoint vs. baseline was statistically significant (P G 0.05), except paresthesia
in the T-LD group. Treatment group differences of continuous pain and paroxysmal pain and allodynia scores were statistically significant between the T-MB and T-LD groups (P G 0.05). No treatment effect difference for paresthesia was observed among the three groups at endpoints (P 9 0.05). Reduction differences of these subtypes, however, were not found in the T-MB group compared with those in the T-BL group for any of the time points. The changes in categorized pain intensities based on
FIGURE 4 Mean of paroxysmal pain at each time point during the 56-day treatment period. Repeated-measures ANOVAs were used to evaluate the effect. & indicates time per group interaction; *, P G 0.05, pain score at each time point vs. baseline in the same group; &, P G 0.05, pain score in the different groups of each time compared with that in the T- LD group. www.ajpmr.com
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FIGURE 5 Mean allodynia score at each time point during the 56-day treatment period. Repeated-measures ANOVAs were used to evaluate the effect. & indicates time per group interaction; *, P G 0.05, pain score at each time point vs. baseline in the same group; &, P G 0.05, pain score in the different groups of each time compared with that in the T- LD group.
time after different interventions are shown in Figures 3 to 6 and Table 2.
group (both P G 0.05). In contrast, these items were not significantly different between the T-MB and T-BL groups.
Secondary Outcomes The differences among the groups in the mean scores for ADLs and QoL based on the ZBPI and the EQ-VAS at the 56-day assessment are shown in Figure 7 and Table 3. After 56 days of treatment, the patients in the T-MB and T-BL groups had significantly lower ADL and QoL scores in the ZBPI and higher EQ-VAS scores than those in the T-LD
Adverse Events The injections were well tolerated by the patients. No serious side effects such as acute lidocaine intoxication, excessive sensory loss, or other serious adverse events were reported in any of the treatment groups. However, 45 patients, including 14 from the T-MB group, 16 from the T-LD group,
FIGURE 6 Mean paresthesia score at each time point during the 56-day treatment period. Repeated-measures ANOVAs were used to evaluate the effect. *, P G 0.05, pain score at each time point vs. baseline in the same group.
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FIGURE 7 Comparisons of ADL and QoL scores in the ZBPI before and after treatment. Comparisons among the groups used ANOVA. *, P G 0.05.
and 15 from the T-BL group, had bleeding and bruising at the local injection sites, but bleeding stopped after 1 min and bruising subsided within 7 days. The outcomes of all these adverse events were considered resolved, and no actions were taken in terms of medications. No substantial changes in vital sign parameters were observed in any of the treatment groups.
DISCUSSION TENS is an adjunctive therapy that is administered at a strong but nonpainful stimulation intensity that can achieve pain relief 22 and is often used in combination with conventional treatment of PHN pain relief.3 Early treatment of HZ with TENS may be better in preventing PHN23; however, approximately 30% of patients with PHN fail to respond to TENS, and among patients who respond initially, only a third continue to obtain pain relief after 2 yrs.2 It implies that TENS therapy may be too late and may not be enough for PHN. This study was designed to apply TENS in combination with a local anesthetic and/or neurotrophic agent to control PHN pain. This study results indicated that all three groups showed a significant response after 14 days of treatment, and worst pain scores reduced continuously until the end of the study. Although the results did not achieve a difference in pain reduction between the T-MB and T-BL groups, both differed from the T-LD group scores at all four time points. Varicella zoster virusYdamaged cutaneous nociceptive fibers that cause pain may be caused in part by increased sodium channel expression at the injury sites.24 On the basis of a number of randomized clinical trials, lidocaine was expected to relieve pain in PHN patients.25 However, this study showed that TENS with local 1% lidocaine injection did not provide www.ajpmr.com
greater pain relief than did TENS with cobalamin injection. The mean T SD pain score was 6.1 T 1.2; a total of 6 (20%) of 30 patients achieved pain reduction of 30% or greater, and two patients had stopped using analgesics by the study endpoint. It was difficult to distinguish between the significant benefits of TENS with local lidocaine injection, TENS alone,2 and spontaneous recovery.26 Compared with the lidocaine patch, local lidocaine injection (once a day) did not exert a sustained analgesic effect. The findings indicated that pain severity decreased significantly in both the T-MB and T-BL groups, and the mean T SD pain scores at endpoint were 4.0 T 1.4 and 4.1 T 1.2, respectively. The clinical effectiveness of the 56-day treatment with respect to pain relief was verified as the perceived overall change data, ADLs and QoL based on the ZBPI and EQ-VAS data for 8 wks, which showed significant benefits (Figs. 2, 7; Table 3). Odds ratios (ORs) of the T-MB and T-BL groups vs. the T-LD group demonstrated that overall change levels were 56.00 and 26.00 at the endpoint, respectively. The 95% confidence interval (CI) for the OR was greater than 1, both P G0.001 (Table 2). Interestingly, the OR of the T-MB group vs. the T-BL group was 2.15 at the study endpoint (95% CI, 0.36Y12.76, P 9 0.05), which implied that pain relief levels in the T-MB and T-BL groups were superior to that in the T-LD group. Clinical experience has shown that cobalamin therapy improves peripheral neuropathy symptoms for many years, and an intrathecal highdose methylcobalamin can rapidly relieve neuropathy symptoms.27 Only a small number of studies on the use of cobalamin for PHN had been reported; notably, two publications published in the 1950s negated its clinical efficacy.28,29 Recently, clinical experience has shown that local methylcobalamin therapy improves pain relief for subacute herpetic Treatment of Postherpetic Neuralgia
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Comparisons of VAS score among the groups were performed using ANOVA. Least significant difference tests were used for pairwise comparisons of data in the different treated groups for endpoint.
G0.001 25.67 (18.78 G0.001 0.13(j6.75 0.969 25.53 (18.65 G0.001 to 32.55) to 7.01) to 32.41) 63.53 (10.44) 38.00 (13.43) 63.67 (15.81) 0.887 27.50 (15.33) 25.83 (13.96) 26.07 (13.37)
P Difference (95% CI) P Difference (95% CI) P T-MB (n = 30) T-LD (n = 30) T-BL (n = 30) T-MB (n = 30) T-LD (n = 30) T-BL (n = 30)
Baseline Mean (SD)
P
Endpoint Mean (SD)
P
Difference (95% CI)
T-BL vs. T-LD T-MB vs. T-BL T-MB vs. T-LD
At Endpoint
TABLE 3 Comparison of the EQ-VAS scores before and after treatment
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neuralgia,11 but neurotrophic cobalamin alone will not quickly achieve analgesia for PHN. The results of this study demonstrated that local cobalamin injection with TENS had a significant analgesic effect on painful areas with PHN, after 56 days treatment, and the TENS combination with methylcobalamin and lidocaine injection failed to produce an obvious synergistic effect. Twenty-eight (93%) of 30 patients in the T-MB group and 26 (86%) of 30 in the T-BL group achieved pain reduction of 30% or greater by the endpoint. It was significantly higher than that in the T-LD group or TENS alone.2 These results indicate that local injection can directly deliver high concentrations of cobalamin to varicella zoster virusYdamaged tissues to obtain neurologic responses, which is consistent with the conclusion made by Okada et al.5 PHN entails heterogeneous and variable painful symptoms and negative sensory signs because various mechanisms can act simultaneously in the same patient and each of them may be responsible for different manifestations. In addition, both clinical manifestations and pathophysiologic mechanisms usually change with time.30 Patients with PHN generally report various characteristics of pain and discomfort. Only a subset of the patients with PHN reported the same characteristics of pain or discomfort in this study. Reductions in continuous pain, paroxysmal pain, and allodynia scores in the T-MB and T-BL groups were statistically significant relative to the baseline (P G 0.05), which suggested that local methylcobalamin injection significantly reduced continuous pain, paroxysmal pain, and allodynia (Figs. 3Y6).
Limitations This study was limited by the fact that the authors were unable to blind the study participants and the research staff to the treatment group. An independent physician who did not participate in clinical management and who was kept blinded to treatment allocation conducted the pain assessment to minimize this shortcoming. Because most of the worst HZ-associated pain areas reported were partial lesion regions innervated by distal nerve branches rather than the entire nerve distribution area, the study drugs were administered as local subcutaneous injections rather than via nerve blockade. An optimal effect was not found, probably because the maximum dose of cobalamin injected was 1000 Hg/day, which may not be sufficient to relieve pain in relatively large areas. Although other neurotrophic agents may also be efficacious, Am. J. Phys. Med. Rehabil. & Vol. 93, No. 4, April 2014
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whether those results can be extrapolated to other neurotrophic agents (e.g., vitamin B1, nerve growth factor, or basic fibroblast growth factor) is unknown. Although the patients were informed that they could come back for treatment again if their pain symptoms returned, the return visit rate was lower than 10%. The patients were followed up only 56 days; there are no data for the long-term results.
CONCLUSIONS The findings of this 8-wk, single-center, randomized controlled trial suggest that the combination of TENS and local methylcobalamin administration had a significant analgesic effect on PHN. Because local subcutaneous injection of cobalamin is a safe technique that is minimally invasive and relatively inexpensive, it may prove to be an excellent treatment option for PHN. However, further studies are needed to confirm these findings in a larger number of patients. ACKNOWLEDGMENTS
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Am. J. Phys. Med. Rehabil. & Vol. 93, No. 4, April 2014
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