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Positive Effects of Uyakujunkisan Therapy
(Kampo Medicine) for Postherpetic Neuralgia
With Concomitant Pregabalin: Two Case
Reports With a Literature Review
Toshiaki Kogure, MD, PhD; Naoyuki Harada, MD; Kanoko Yamamoto, MD; Takeshi Tatsumi, MD, PhD
Context • The hallmark of herpes zoster (HZ) is a painful,
blistering rash, but neuropathic pain can persist beyond
the clearing of the rash and is diagnosed as postherpetic
neuralgia (PHN), a chronic pain syndrome. However, the
pain in PHN is often refractory to treatment.
Objective • The study investigated the ability of
Uyakujunkisan (UJS), or Kampo medicine, a traditional
herbal medicine, to treat PHN successfully.
Design • The study was observational, with discussion of
Setting • The study took place in the Department of
Japanese Oriental Medicine at Gunma Central and
General Hospital (Maebashi, Gunma, Japan).
Participants • The participants in cases 1 and 2 were a
70-y-old male and a 70-y-old female, respectively. The
Toshiaki Kogure, MD, PhD, is the head of department.
Naoyuki Harada, MD, is a clinical fellow. Kanoko
Yamamoto, MD, is a clinical fellow. Takeshi Tatsumi, MD,
PhD, is a clinical fellow. All are located at Japanese Oriental
medicine, Gunma Central & General Hospital.
Corresponding author: Toshiaki Kogure, MD, PhD
E-mail address: firstname.lastname@example.org
ostherpetic neuralgia (PHN) is a chronic pain
syndrome that can develop following an episode of
herpes zoster (HZ). HZ results from the reactivation
of the varicella zoster virus (VZV), which the patient could
have contracted years earlier, and the lifetime risk of
developing the disease is approximately 30%. The hallmark
of HZ is a painful, blistering rash that is localized to
1 or 2 dermatomes unilaterally. The blisters typically scab in
40 ALTERNATIVE THERAPIES, NOV/DEC 2016 VOL. 22 NO. 6
woman in case 2 also had rheumatoid arthritis. Both had
been treated for HZ with antiviral drugs but continued to
experience pain and were diagnosed with PHN.
Intervention • Both participants were treated with a
decoction of UJS that was administered 3 ×/d before meals.
Outcome Measures • The patients completed a visual
Results • In case 1, the patient’s pain had almost
disappeared after 8 wk of treatment. In case 2, the patient’s
pain had disappeared by 4 mo after starting the UJS
Conclusions • Treatment with UJS may be a useful option
as a therapeutic strategy for refractory PHN, especially in
older adults. (Altern Ther Health Med. 2016;22(6):40-44.)
7 to 10 days, and the lesions clear within 2 to 4 weeks. The
condition in which neuropathic pain persists beyond the
clearing of the rash is diagnosed as PHN.1
The efficacy of first-line therapeutic agents for the
treatment of PHN has been established by randomized,
controlled clinical trials. Anticonvulsant drugs2,3,4 and
tricyclic antidepressants (TCAs)5 have been established
clinically for the treatment of PHN. A multicenter trial has
provided clinical evidence of pregabalin’s efficacy for
peripheral neuropathic pain conditions.4 However, pain in
PHN is often refractory to treatment, especially in patients
who are older adults.6,7 The clinical use of opioids in patients
with PHN is still controversial. The long-term risks of
sedation, mental clouding, and abuse limits their use, even
though they are considered safe in the context of systemic,
cardiac, renal, and hepatic adverse effects.8,9
Traditional herbal medicine, or Kampo medicine, which
is covered by the national health insurance in Japan, is often
used in the field of primary healthcare and is also applied as
an alternative remedy for refractory neuralgia, such as
PHN.10 The current research team has previously reported
that patients with idiopathic trigeminal neuralgia (TN) were
Case 2: In 2013. In the initial examination at the research team’s department. To prepare the UJS. showing vesicular eruptions on the anterior surface of the outside of his right thigh. please visit copyright. is a common herbal formula that is administered to patients with cerebral ischemia. autoimmune diseases. called a decoction. the pain had persisted despite an 8-week treatment. which are risk factors for HZ.14 Participants’ pain intensity was measured on the VAS at baseline and ongoing on a monthly basis. Her serum levels of C-reactive protein (CRP) and rheumatoid factor were 0. Ltd (Osaka. He had not experienced any cold sensations either in his limbs or elsewhere on his body. Vesicular eruptions had appeared on the anterior surface of her left thigh after 8 weeks of treatment with etanercept. according to a traditional diagnostic system. the patient visited the research team’s department using a stick to walk due to neuralgia in her left thigh. which was sometimes stabbing and was evoked with a light touch. Ltd. Byakkyosan 2.11 UJS. On February 22. but not by a cold stimulation. Table 1.12 In the current article. His condition was diagnosed as HZ. Therefore. Japan. The 10 herbs were purchased from Tochimoto Tenkaido Co.13 She noted that she had had no cold sensations in her limbs or other parts of her body. 6 41 .5 Batrytis bassiana bals.This article is protected by copyright. 22 NO. Component (Herb) Binominal Nomenclature Japanese Name Dose (gram) Linderae radix Uyaku 2. Informed consent was obtained from the 2 participants before the treatment with Kampo medicine was initiated. Japan or Uchidawakanyaku Ltd.5 Ephedrae herba Mao 2. This patient was an older adult but did not have malignancies. The 10 Herbs Contained in Uyakujunkisan (UJS). a 70-year-old male had consulted a practitioner at his neighborhood clinic. The pain was a continuous burning type that was evoked by the application of physical stimuli. a sharp tingling sensation and pain appeared at the same location as the eruptions had. with a scale range of 0–100 mm. respectively. the pain had persisted. To share or copy this article. She had had rheumatoid arthritis (RA) for several years and was being treated with 6 mg/week of methotrexate at a neighboring general hospital.5 Zingiberis rhizoma Shokyo 1. Japan). visit alternative-therapies. the patient had complained of continuous pain. Case 1. in Osaka. To subscribe. Use ISSN#1078-6791. such as light touch. and the aqueous extract or decoction was filtered through a sieve by each patient. Her RA disease activity was low. Kogure—Uyakujunkisan Therapy and she was then diagnosed with HZ. she complained of pain on the anterior surface of her left thigh. The study was observational.0 Angelicae dahuricae radix Byakushi 1. and facial palsies. METHODS Participants The participation of the patients whose cases are discussed in this article was approved under a comprehensive agreement of the Gunma Central and General Hospital (Maebashi. He was subsequently treated with 450 mg/day of pregabalin and 1500 μg of vitamin B12.5 Aurantii fructus immaturus Kijitsu 2.5 Platycodi radix Kikyo 2. 10 herbs were mixed with 600 mL of water and boiled down to 300 mL. in Tokyo. the authors have presented the cases of 2 older adults with refractory PHN who were successfully treated with UJS. 2012. Japan) or Uchidawakanyaku Ltd (Tokyo. or metabolic diseases such as diabetes mellitus. however.com. The extract. The team also has reviewed the literature on the effectiveness of such a remedy as an option in current therapeutic trends for PHN. disturbance of perception. but the patient could not tolerate it due to the development of dizziness. ALTERNATIVE THERAPIES. his liver and renal functions were normal. In the initial examination. In the patient’s blood analysis. A previous doctor had attempted to increase the dosage of pregabalin. Gunma. and the aqueous extract was filtered through a sieve by each patient. with a disease activity score of 28 based on her levels of CRP. Japan).5 Cnidii rhizoma Senkyu 2. and she did not have thirst or hyperhidrosis. and valaciclovir hydrochloride was administered. on the anterior surface of her left thigh. a Kampo formula. On April 18.5 Glycyrrizae radix Kanzo 1. His clinical appearance was distinctive and suggestive of PHN in the right-thigh division of the femoral nerve. was administered 3 ×/d before meals. Procedures The efficacy of Kampo formula on PHN was estimated using a visual analogue scale (VAS). NOV/DEC 2016 VOL. sometimes with a burning quality. Despite 6 weeks of treatment with 50 mg/day of pregabalin as palliative care at the neighboring hospital. Although the eruptions disappeared after 2 weeks. The 10 herbs were purchased from Tochimoto Tenkaido Co. complaining of continuous pain. and an inflammatory response was not observed. he visited the research team’s department for Kampo medicine on April 23. Her clinical condition was suggestive of PHN in the left-thigh division of the femoral nerve.5 mg/dL and 1218 IU/mL. in addition to the mild arthralgia induced by RA.com successfully treated with Uyakujunkisan (UJS). which is composed of 10 herbs.5 Aurantii nobilis pericarpium Taiso 2. although no eruptions had appeared on his right thigh. a 70-year-old female had consulted the current research team’s department. The blood analysis revealed that her hepatic and renal functions were normal. She was also receiving 25 mg/week of etanercept (25 mg/week) due to the high disease activity of the RA during the 6 months before she consulted the research team’s department.0 Note: Ten herbs were mixed with 600 ml of water and boiled down to 300 ml.
7 April 2013 June 2013 August 2013 Abbreviations: VAS. Use ISSN#1078-6791. please visit copyright. To share or copy this article. A VAS percentage change score of -33. RESULTS Case 1 The patient’s pain level decreased to approximately half after 4 weeks of treatment and had almost disappeared after 8 weeks (VAS. and patients with PHN often have burning or electrical pain. The neuralgia. approximately half of all cases occur in individuals older than 60 years. defined as pain persisting for more than 3 months after the rash of HZ has healed. No adverse effects were observed. No adverse effects were observed.com Intervention The research team treated both participants with the UJS decoction. One of the most common and debilitating complications of HZ is PHN. Effective therapy to intervene with PHN often involves multiple drugs. The neuralgia. visit alternative-therapies. and the patient’s pain had not reoccurred at 1 year after the discontinuation of the UJS (Figure 2). Oral Treatment 450 mg 225 mg Pregablin 150 mg Kampo: Uyakujunkisan 100 VAS (%) The pain at the anterior surface of the right hand 50 0 April 2012 October 2012 April 2013 Abbreviation: VAS. Case 2 The patient’s pain decreased. The risk of PHN after HZ also increases with age. lidocaine patches. disappeared after a 16-week treatment with Uyakujunkisan. The pain VAS is a single-item scale. and the patient’s RA disease activity was not changed by the treatment with UJS. Kogure—Uyakujunkisan Therapy . Figure 1. A Chart of the clinical course for case 1. Adverse effects were not observed. The 50 mg/day of pregabalin that she had been receiving was discontinued after 3 months. shown as a solid circle in the line graph. C-reactive protein. The figure shows the state of the Uyakujunkisan before the boiling of the herbal mixture. or paroxysmal types. 89 to 21). TCAs. The research team tapered the dose of pregabalin and stopped administering it 6 months after treatment with UJS. the scale is most commonly anchored by “no pain” (score of 0) and “pain as bad as it could be” or “worst imaginable pain” (score of 100 [100-mm scale]).5 1. Outcome Measures Visual Analogue Scale.This article is protected by copyright. A previous study had demonstrated that the rate of PHN increased from 5% in patients with HZ younger than 60 years to 10% in those aged 60 to 69 years and 20% in those older than 80 years.3 0. A light touch or the brush of clothing is sometimes perceived as being painful. Furthermore. The patients ingested the decoction 3 times per day before meals. It is generally considered better to begin with a medication that has the 42 ALTERNATIVE THERAPIES. such as topical agents (eg. NOV/DEC 2016 VOL. 22 NO. Adverse effects were not observed. Her pain had almost disappeared at approximately 4 months after the start of the UJS treatment. Figure 3. The treatment with UJS was discontinued after approximately 1 year. A chart of the clinical course for case 2. a phenomenon called allodynia. Etanercept 25 mg/wk Methotrexate 6 mg/wk Pregablin 50 mg Kampo: Uyakujunkisan 100 VAS (%) The pain at the anterior surface of the left theigh 50 0 CRP (mg/mL) 0. shown as the solid circle in the line graph. 6 Figure 2. and opioids). such as continuous. visual analogue scale. CRP.0% was evaluated to be effective. the recurrence of pain was not observed at more than 1 year after discontinuation of the UJS treatment (Figure 3). For pain intensity. intermittent. Mixture of 10 dry herbs contained in Uyakujunkisan. anticonvulsant drugs.com. had disappeared after an 8-week treatment with Uyakujunkisan. and she was able to walk without a stick after 2 weeks. The risk of HZ is well known to increase with age. visual analogue scale.15 The pain generally shows various clinical features. To subscribe. DISCUSSION HZ is a distinctive syndrome caused by the reactivation of VZV. and the patient’s rheumatoid arthritis disease activity was not changed by the treatment with Uyakujunkisan.
Han CH. which is an ingredient of Citrus reticulata.67:241-251. TCAs.12 UJS has been described in a traditional text book. several further pharmacological studies will be required to clarify its action. Kampo medicines are considered to have superior safety to conventional anticonvulsant drugs or other invasive techniques and may represent an option as a therapeutic strategy for PHN in older or immunocompromised patients. Brogi F. Oxcarbazepine monotherapy in postherpetic neuralgia unresponsive to carbamazepine and gabapentin. the action of each component may be totally relevant to the analgesic effects. Such patients are more likely to be immunocompromised and often take many medicines. NOV/DEC 2016 VOL. randomized controlled trials are needed in the future to determine its efficacy for PHN. Cowles VE. Lippi S. heart disease. and paresthesia of the limbs. To share or copy this article. Clin Interven Aging. without taking a traditional diagnostic system into consideration. 6. 2012. CONCLUSIONS The current research team has described successful treatment of older patients with refractory PHN using Kampo Medicine (ie. Gilron I. 4. However. However.21 In multicomponent drugs such as UJS. Guharay T. visit alternative-therapies. Therefore. J Pharm Sci. or opioids. please visit copyright. REFERENCES 1. can reverse the neurocytotoxicity induced by the accumulation of amyloid β. PHN is very difficult to treat. 1996. An ingredient contained in Zingiberis rhizoma. Cappuzzo KA. and glutamate. continued treatment should be limited to patients who respond to UJS. The current article provides the first case report that describes the successful treatment of 2 older PHN patients with UJS. and UJS was effective for his PHN. 2005. 2011. Dworkin RH. edema. it is a calcium (Ca)-channel antagonist that decreases the release of several neurotransmitters. and facial palsies. the current research team had considered that UJS might be generally effective for neuropathic pain. such as dizziness. 2.19 and an aqueous extract of Lindera radix was able to lengthen markedly the duration of pain tolerance in mice in a hot-plate test. however. such as antitumor necrosis factor or interleukin 6. (6)-shoganol. UJS is a common herbal formula that is administered to patients with cerebral ischemia.17 The second case described in the present study was an RA patient who had developed HZ and PHN while receiving etanercept for the treatment of RA. Héjì Júfāng: Wazaikyokuho. 22 NO. Many PHN patients cannot tolerate effective doses of anticonvulsants.4:17-23. norepinephrine. hypesthesia. ALTERNATIVE THERAPIES. enriched enrollment randomized withdrawal placebocontrolled trial. hypesthesia. Criscuolo S.com fewest adverse effects. inhibits the release of substance P on terminal afferents. depression. and tolerability of a once-daily gastroretentive dosage form of gabapentin for the treatment of postherpetic neuralgia. headache. The successful treatment of idiopathic TN had been previously reported with UJS therapy. Although the mechanism of action of pregabalin is still not clear. Furthermore. paresthesia. the first patient was receiving the usual dose of pregabalin.22 The current study’s findings prompted the research team to speculate that the mechanism of action of UJS differs from blocking a Ca channel. Wajsbrot D. Brogi A. several systemic drugs cannot be administered due to adverse effects. or cerebrovascular diseases.111:229-232. disturbance of perception. Pain. Sweeney M. efficacy. Bisai S. However. which was not effective. but without poor circulation. including substance P. 2013. to RA patients with high disease activity may influence the occurrence of VZ and PHN. therefore. without binding to γ-aminobutyric acid receptors.com. 3.This article is protected by copyright. difficulties are associated with selecting a medication without adverse effects or performing topical surgical therapies for those patients. 5. without adverse effects. Therefore. The team considered that the analgesic mechanism of UJS can possibly be attributed to its multifunction effects.102:1155-1164. AUTHOR DISCLOSURE STATEMENT The research team declares that no conflicts of interest exist. Pain and its persistence in herpes zoster. it is not uncommon for the pain of PHN to interfere with sleep and recreational activities and to be associated with clinical depression. Achar A.20 A recent study has demonstrated that nobiletin. Although the traditional target group of UJS includes patients with headaches. Use ISSN#1078-6791. UJS may be a useful agent for the treatment of PHN. according to a traditional diagnostic system. UJS may be considered to be one of the options for the treatment of neuropathic pain. pregabalin occasionally causes adverse effects. Therrien F. Acta Dermatovenerol Croat. The severity of RA is associated with the development of HZ.27:185-193. Comparative study of clinical efficacy of amitriptyline and pregabalin in postherpetic neuralgia. Older patients often have hypertension. The second patient received an additional dose of UJS in combination with a low dose of pregabalin. and the target group is listed as patients having fatigue. As a result. Chakraborty PP. Clin J Pain. those effects cannot sufficiently explain the mechanism of action of UJS. Portenoy RK. 6 43 . depression. Chen C. Kogure—Uyakujunkisan Therapy The actions of UJS have not yet been elucidated in detail. Treatment of postherpetic neuralgia: Focus on pregabalin. To subscribe. Kampo medicines. Pregabalin for peripheral neuropathic pain: A multicenter.20:89-94. Biswas A. Lemay J. Thus. because UJS is a multicomponent drug. Auletta C. Cellular immunity to VZV is well known to play a role in preventing the occurrence of HZ and the complications of PHN: therefore.18 The components of UJS are shown in Table 1 and Figure 1. and numbness. especially in older patients and immunocompromised individuals. The rate of response to UJS for refractory PHN currently remains unclear.23 whereas Kampo medicine is generally superior in safety. Acta Neurol Scand. Pharmacokinetics. UJS). which are covered by national health insurance in Japan. an immunosuppressive condition is a risk factor for PHN in addition to aging. A previous observational study had revealed that the incidence of HZ was increasing in patients with RA and that the incidence has risen in recent years. 2009. are generally used in the field of primary healthcare and are also administered as an alternative remedy for refractory chronic pain such as TN. and heart failure. treatment with UJS may contribute to the control of refractory PHN. In the current study’s cases.11 After the success of the treatment in the current study.16 The clinical application of biologics. Therefore.
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