Abstract
BACKGROUND:The main symptoms of herpes zoster (HZ) manifest as pain and skin eruption and the pain, when treated inadequately, may proceed to become post herpetic neuralgia (PHN) which has progressively increasing incidence with age.
OBJECTIVE: To observe the effect of combined therapy of super laser and Durogesic patch (transdermal fentanyl) in the treatment of elderly patients with herpes zoster and diabetes.

DESIGN: Randomized controlled observation.

SETTING: The First Affiliated Hospital of Jinan University.

PARTICIPANTS: Thirty (14 males and 16 females) elderly patients of age 62－83 years with concurrent herpes zoster (duration 6－14 days) and diabetes who had received the conventional dermatological and medication treatment but still had persistent pain were selected form the First Affiliated Hospital of Jinan University from 2003 to 2006. All elderly patients were randomly divided into 3 groups with 10 in each group.

METHODS: ① Super Lizer group (SL Group): Patients were received Super Lizer (linear polarized near-infrared light) therapy once a day for 15 days. ② Durogesic patch group (DR Group): Patients were received 2.5 mg Durogesic patch once for every 3 days. ③ Combined group (SL+ DR Group): Patients were received both the Super Lizer therapy and the Durogesic patch for 15 days.

MAIN OUTCOME MASURES: All patients received the assigned treatment for 3 days and VAS was evaluated before and at the 3rd, 15th day during treatment, also at 7th day after termination of treatment. Visual analogue scales were used to assess the degree of pain and global evaluation were done with pain relief more than 70% rated as excellent, pain relief between 30%－70% rated as effective and pain relief less than 30% rated as ineffective. Adverse effects were also recorded.

RESULTS: Thirty patients were all involved in the final analysis. VAS scores of all three groups were significantly decreased after 15-day treatment (P < 0.05); after 3-day treatment, VAS scores of DR group (2.35±1.43) and SL+DR group (2.41±1.54) were significantly lower than their respective baselines and that of the SL group (7.00±0.82) (P < 0.05) which showed no significant change from the baseline value. SL+DR group showed significantly higher excellent rating than that of the SL group and DR group (80%, 60%, 70%, P < 0.05) at the end of the 15-day treatment. At 7th days after treatment, VAS scores of SL group (3.01±1.20) and SL+DR group (2.41±1.54) were still significantly lower than that of DR group (6.70±0.67) (P < 0.05) which had returned to the pretreatment level. No serious adverse effects such as respiratory depression were observed in any of the patients. Mild side effects such as dizziness, nausea and vomiting, constipation were observed in the DR and SL+DR groups which usually subsided after a week.

CONCLUSION: Combined therapy of SL and DR shows a better pain relief in the elderly patients with herpes zoster and diabetes without significant adverse effects. It provides the advantage of fast onset of effect with the Durogesic patch and the long-term effect of Super Lizer.

INTRODUCTION

Herpes zoster is a common disease seen in dermatology and pain clinics and its incidence increases with age [1-3]. The treatment of acute herpes zoster includes antiviral agents, nerve blocks, steroid, non-steroidal anti-inflammatory drugs, opioids and tricyclic antidepressants, etc[4-10]. Due to nerve invasion and destruction by the virus, most of the herpetic patients in the acute phase experienced pain and 9%－34% of patients with herpes zoster develop PHZ. However the incidence of post herpetic neuralgia (PHN) is proportional to the advanced age with reported incidence of 50% in the elderly (those 60 years or older), especially those with concurrent herpes and diabetes who are often found to be refractory to many of the standard treatments. Recently Super Lizer therapy has been regarded as a non-invasive, non-painful, simple and easily means of treatment for various chronic pains without risk of infection. This study evaluated the clinical effect of combining the use of Super Lizer (linear directed high wavelength infrared light emission device) and Durogesic patch in the elderly patients afflicted with both herpes zoster and diabetes.

SUBJECTS AND METHODS

Subjects
This study was carried out in the First Affiliated Hospital of Jinan University from 2003 to 2006. After signing informed consents, thirty patients, 62－83 years of age, with diabetes and herpes zoster diagnosed within 2 weeks (6－15 days) from the onset of the zoster who had been treated with the usual medications but still suffered pain were referred to our pain service. There were 14 males and 16 females, and inclusion criteria into the study were shown as follows: 60 years old or older, VAS score more than 7, non-responsiveness to oral pain medications, no significant cardiopulmonary, renal or cerebral diseases, no history of allergy to opioids, being cooperative with compliance. All the patients were randomly divided into three equal groups of 10 each with group SL receiving Super Lizer treatment, group DR receiving Durogesic patch and group SL+DR receiving both treatments.

Methods
Treatments
Super Lizer Group (SL group) 10 patients in the SL group received Super Lizer treatment (Linear polarized near-infrared light emission machine: Super Lizer HA-550, Tokyo Ken Medical Research Co., Japan) once a day for 7 minutes with 2 seconds on and 5 seconds off cycle, for herpes involving the head and face the C cone was used with continuous mode at 70%－100% energy output directed at the area of lesion and used the SG cone directed at the stellate ganglion. For herpes involving arm, back and leg the B cone were used directed at the area of lesion.
Durogesic group (DR group): Ten patients received Durogesic patch 2.5 mg (Transdermal fentanyl, Janssen Pharmaceutical Co., Xi'an, China) which was applied on clean, dry and hairless skin of the body such as chest, upper back or the thigh and the patch was changed every 3 days for the study period of 15 days.
Combined Super Lizer and Durogesic patch group (SL+ DR group): Ten patients received both the Durogesic patch and the Super Lizer treatment as described above.

Evaluation
Patient's pain was evaluated with Visual Analog Scale (VAS) at baseline (before treatment), 3 and 15 days after treatment, also at 7 days after the completion of the treatment. Changes of VAS > 70%, between 30%－70% and < 30 % were rated as excellent, effective and ineffective respectively.

Observation of adverse effects
Adverse effects reported by the patient on questioning, specifically dizziness, somnolence, nausea/vomiting, constipation, urinary dysfunction or skin reactions, were recorded throughout the study period.

Statistical analysis
All values are expressed as Mean ± SD using SPSS 11.0 soft ware performed by the authors. Between group comparison was done by t-test and P < 0.05 was considered statistically significant.

RESULTS

Quantitative analysis of the participants
All 30 patients were involved in the final analysis.

Comparison of demographic data
There was no significant difference in age, gender, duration of herpes zoster among the 3 groups (P > 0.05), as was shown in Table 1.

VAS scores before and at different time point after treatment (Table 2)

All three groups of patients completed the 15-day treatment and their VAS at the end of the treatment were all significantly better than the baseline values (P < 0.05). After 3 days of treatment, VAS scores of DR group and SL+DR group were significantly lower than their respective baselines and that of the SL group (P < 0.05), which showed no significant change from the baseline value. Seven days after treatment, VAS scores of the SL group and the SL+DR group were still significantly lower than that of the DR group (P < 0.05), which had returned to the pretreatment level (Table 2).

Global evaluation of treatment effects among the three groups
Both SL group and SL+DR groups showed significantly higher rating of "excellent" than that of the DR group (P < 0.05) at the end of the 15-day treatment (Table3).

Adverse effects
There were 11 patients in the 20 patients receiving DR and SL+DR treatment reporting adverse effects, which including dizziness in 3, somnolence in 2, nausea/vomiting in 3, constipation in 2 and difficulty in urination in 1, all of which were mild and subsided spontaneously in 4－7 days without therapeutic intervention. No serious adverse effects such as respiratory depression or drug withdrawal were observed in any of the patients

DISCUSSION

Herpes zoster is caused by varizella zoster virus (VZV), which stayed dormant in the satellite cells of the dorsal root ganglion after the initial infection. When the host's immune defense mechanism is depressed or damaged, the VZV will be reactivated and replicated in the nerve root ganglion and cause an acute viral infection of the nervous tissue with inflammation, hemorrhage and even necrosis. The activated viral infection can affect one to several segmental nerves with peripheral cutaneous eruption in the form of blisters, named zoster which is frequently accompanied by pain[1]. There is a frequently quoted incidence that 10% of the patients with acute herpes zoster will have postherpetic neuralgia (PHN) [11]; however when it comes to the the elderly, the data are misleading and the actual incidence is a lot higher. For instance, Acland et al reported that the incidence of PHN in those over 70 years old was 50%[12]. PHN pain can be long and intractable, which lasts 1－2 years or even over 10 years. It is one of the disabling pain problems in the elderly. PHN pain could be very severe and unrelenting causing much disability or even suicide in those affected. Unfortunately there is no cure to this painful affliction. Recent report indicated that nerve blocks performed during the acute phase of herpes zoster would shorten the duration of the herpes zoster and reduce the incidence of PHN[9]. However the elderly patients with diabetes frequently have cardiovascular disease as well. These co-morbidities sometimes limits the use of nerve block and corticosteroids.
Super Lizer is a light emission device with light generated by iodine lamp. The light passes through a filtering system to provide linear light beams at wavelength of 600－1 600 nm. Energy output is 1.8 W with a penetration depth of 5 cm. It can cause photo-electrical, photo-chemical activation of the tissue with cell stimulation and neural modulation effect in human tissue, which provide an anti-inflammatory, analgesic, and restorative effects to the tissue. There is an acute inflammatory neuropathy in herpes zoster due to viral infection. Super Lizer treatment can improve the circulation, reduce inflammation and edema in the nerve tissue involved thus decreasing pain and enhancing tissue healing.
Linear polarized near-infrared light produced by this type of therapeutic equipments has been used for the treatment of various painful disorders[13?熏14]. Repeated SL therapy to stellate ganglion had been shown to have stellate ganglion block effect which can improve the immune function via modulating effect on the hypothalamus. Yokohama et al reported that after series of stellate ganglion block patients with chronic pain would show an increase in the cell immunity and plasma immunity as evidenced by the increase of B cell and T cell counts, increased T cell activity, increased CD-4 cell number and decreased CD-8 cell number, and suppressed activity of the natural killer cells, all of which indicate the modulating effect of stellate ganglion in immuno-activity [15]. Using Super Lizer to effect stellate ganglion block has the advantages of being non-invasive, simple, safe, convenient and well accepted by the patients, especially in the elderly with diabetes.
Our study showed that after 15-day treatment the VAS in the SL group was significantly improved, but not for the first 3 days compared with pre-treatment. This indicates that the pain relieving effect of SL is slow and progressive which might cause poor compliance of the patients, who are in severe pain and intend to seek more immediate relief. On the other hand, SL, once takes effect, appears to provide prolonged relief, as is shown 7 days after the treatment, which may be due to its neural modulation effect.
Durogesic patch is the transdermal formulation of fentanyl, a potent opioid analgesic. After dermal application, fentanyl diffuses through the skin, enters the blood stream, produces analgesic effect in 6－12 hours. The steady state reaches at 12－24 hours and lasts for 72 hours. Due to this prolonged steady plasma level Durogesic patch is very suitable for patients with severe chronic pain[16-20]. There was no serious adverse effects such as respiratory depression in any of the patients in all three groups which indicates the safety of Durogesic and the combined use of DP plus SL in the elderly patients. Mild side effects such as dizziness, nausea and vomiting, constipation were observed in the DR and SL+DR groups which usually subsided after a week. The mild side effects observed in the DR and the DR+SL groups were primarily related to Durogesic since these side effects were not observed in the SL group. Transdermal fentanyl appears to have good pain relief effect in the HZ patients throughout the 15-day treatment, but its pain relieving effect seems be a pure opioid effect since once terminated there was no long term effect in the DR group.
Herpes zoster pain is one of the most severe pathological pain. Due to its unrelenting nature, it seriously interferes with daily activity including sleep and life quality of the patient, which frequently leads to depression, disability or even suicide. The treatment for zoster pain is limited and it primarily consists of oral analgesics and nerve blocks. Patients with diabetes and its complications who are inflicted with herpes zoster, nerve block might not be a feasible treatment. In this case Durogesic patch undoubtedly is an ideal therapeutic relief, which affects within 12 hour, much faster than that of the SL, just as demonstrated in Table 3. Table 3 shows a significant reduction of the VAS in both the DR and DR+SL groups but not in the SL group after 3-day treatment. After the initiation phase, all three treatments demonstrated significant pain relief effect to the patients as shown in Table 1, but the global evaluation showed that the combination of SL+DR produced better pain relief to the patient than either treatment alone, which indicated that an additive effect of the combined therapy. More interestingly, both SL and DR+ SL groups, but not DR group showed a lingering long-term pain relief 7 days after termination of the treatment, which indicated a neuromodulating effect of the Super Lizer therapy. The mechanism might be related to the improved the neuronal dysfunction, the basic pathogenesis of neuropathic pain in herpes zoster.
In conclusion, the present study showed that combined therapy of Super Lizer and Durogesic patch produced better pain relief than either treatment alone in the elderly patients with herpes zoster and diabetes and without significant adverse effects. It provides the advantage of fast onset of pain relief with the Durogesic patch and the long-term effect of Super Lizer by neurodulation. This combined therapy is non-invasive and well tolerated by the patients.

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超激光联合芬太尼透皮贴剂治疗老年带状疱疹合并糖尿病***☆○

王小平1，莫世湟○1,2，李雅兰1，蔡继业3
暨南大学，1附属第一医院麻醉科，3生命科学技术学院，广东省广州市 510632; 2美国加利福尼亚州立大学疼痛中心，美国加利福尼亚州
王小平☆，女，1966年生，湖南省邵东人，副主任医师，博士，主要从事急慢性疼痛的机理及治疗。
通讯作者：蔡继业，暨南大学生命科学技术学院，广东省广州市 510632
国家自然科学基金资助项目( 60578025)*；广东省医学科学技术研究基金立项项目( A2006349)*；广东省科技计划项目（2006B20401022）*
摘要
背景：老年带状疱疹合并糖尿病患者易转化为带状疱疹后神经痛，且治疗效果欠佳，而超激光疼痛治疗仪已用于很多疼痛的治疗。
目的：观察超激光联合芬太尼透皮贴剂治疗老年带状疱疹合并糖尿病15 d的疗效。
设计：随机对照观察。
单位：暨南大学附属第一医院。
对象：选择暨南大学附属第一医院2003/2006收治的合并糖尿病的老年带状疱疹患者30例，均接受常规皮肤科药物治疗，年龄> 60岁，目测类比评分> 7，且经口服或肌注镇痛剂后疼痛仍非常剧烈者。将30例患者数字表法随机分为超激光组、芬太尼组及超激光+芬太尼组3组，每组10例。
方法：①超激光组：采用超激光（点式直线偏振光近红外仪SUPER LASER HA-550，日本东京医研株式会社产品）照射治疗，1次/d，疗程15 d。②芬太尼组：单用芬太尼透皮贴剂（商品名多瑞吉，美国强生公司）治疗15 d，剂量为2.5 mg，每3 d更换1次。③超激光+芬太尼组：在超激光组的基础上应用芬太尼透皮贴剂治疗15 d。
主要观察指标：①疼痛程度：治疗3，15 d及停止治疗7 d以目测类比评分法评价（得分越高疼痛越重）。②疗效：治疗15 d后评估，显效：目测类比评分改善度≥70%；有效：30%≤评分改善度< 70%；无效：评分改善度< 30%。③不良反应。
结果：30例均进入结果分析。①目测类比评分比较：治疗3 d后，芬太尼组及超激光+芬太尼组得分低于超激光组（2.35±1.43，2.23±1.35，7.00±0.82，P < 0.05）；治疗15 d后，3组得分均较治疗前明显下降（P < 0.05）；停止治疗7 d后，超激光组及超激光+芬太尼组得分低于芬太尼组（3.01±1.20，2.36±1.49，6.70±0.67，P < 0.05）。②疗效：治疗15 d后，超激光+芬太尼组显效率较超激光组高（80%，60%，70%, P < 0.05）。③不良反应：使用芬太尼透皮贴剂治疗的患者仅出现轻度头晕、嗜睡、恶心呕吐、便秘、排尿困难等不良反应，且在1周内消失；使用超激光患者未出现不良反应。
结论：超激光联合芬太尼透皮贴剂可明显提高老年带状疱疹合并糖尿病的显效率，既发挥了芬太尼透皮贴剂长效、强效快速镇痛、使用方便的长处，又发挥了超激光作用确切、不易复发及安全性高无损伤的优势，是一种短程、高效的好方法。
关键词：超激光；带状疱疹；糖尿病；芬太尼透皮贴剂
中图分类号:R752.1 文献标识码:B 文章编号:1673-8225(2007)13-02589-04
王小平，莫世湟，李雅兰，蔡继业.超激光联合芬太尼透皮贴剂治疗老年带状疱疹合并糖尿病[J].中国组织工程研究与临床康复，2007，11(13):2589-2592
[www.zglckf.com/zglckf/ejournal/upfiles/07-13/13k-2589(ps).pdf]
(Edited by Wang XM/Ji H/Wang L)