acupuncture for cancer patients

RESEARCH

THE CLINIC OF THE COLLEGE OF CHINESE MEDICINE

ACUPUNCTURE FOR CANCER PATIENTS

Kirsten Dhar – The Clinic of the College of Chinese Medicine,

26-28 Finchley Rd, St John’s Wood, London, NW8 6ES

Kirsten Dhar - The College of Chinese Medicine, Research and Development

ACUPUNCTURE FOR CANCER PATIENTS

A COLLECTION OF ABSTRACTS, STUDIES AND ARTICLES ON THE USE OF

ACUPUNCTURE FOR SYMPTOM CONTROL IN THE TREATMENT OF CANCER PATIENTS

1. Neurological Mechanisms of Acupuncture

2. Abstracts – Nausea and Other Symptoms

3. Studies – Two Articles with Protocol

4. Pain management with Acupuncture


1. Neurological Mechanisms of Acupuncture

Acupuncture was originally thought of as being simply a modality which can alter the body’s perception of pain. Research into the exact neurological mechanisms behind this have led to new theories and understanding of the extend to which acupuncture can regulate the body’s function in dealing with disease, rather than just pain. A great deal of neurophysiological research has been conducted in this field and evidence-based scientific work has been published, predominantly in Germany and the USA, by Zieglgansberger, Takeshige, Pomeranz, Han and many others. According to these findings, acupuncture appears to be effective in influencing neuro-endocinological functions to rebalance the system and reinstate homeostasis.

The mechanisms behind acupuncture in the treatment of diseases and pain control lie in prompting the brain to initiate physiological processes aimed to re-establish the body’s homeostasis. In this context, connections between higher, intermediate and lower brain are most relevant, with the limbic system, in particular the amygdala, and the hypothalamus playing an important role.

The amygdala is, in simple terms, the mediator between prefrontal cortex (the decision making part of the brain) and the diencephalon, namely the hypothalamus. It is also the major intermediary between sensory and motor hierarchy. Sensory input signals derive from the sensory cortex and are passed back, via the entorhinal cortex, to the amygdala (limbic) where input information is combined with previous experience (physical and emotional) and transmitted to the prefrontal cortex for decision making. Decisions are passed back to the amygdala and from there to the hypothalamus for execution. The hypothalamus, being the most important control center for the body’s homeostasis, and thus survival, executes all decisions via endocrine functions, autonomic functions and diffuse modulatory functions of neurotransmitters and modulators (i.e. amines and monoamines –


acetylcholine, dopamine, norepinephrine and serotonin – in the brainstem). In this way, acupuncture influences electro-chemical activity on a presynaptic level, triggering synapses all the way from sensory nerves to the spinal cord, brain stem, mid-brain and finally to the prefrontal cortex of the higher brain.

Recent MRI mapping of meridians (energy transmitting channels) and various studies suggest that acupuncture points are part of the peripheral nervous system and overlap nerve receptor endings. On the basis of this assumption, it can now be understood how acupuncture signal inputs project to the brain. Sensory neurons translate stimuli (mechanical, thermal, pressure, vibrations, etc.) into neural signals via depolarization.

The insertion of an acupuncture needle irritates or damages cells in the area causing them to release chemicals (bradikinin, substance P, prostaglandins, etc.), which then activate the cell’s membrane potentials. The signaling process occurs by receiving sufficient stimuli to initiate sensitization by alteration of cell membrane potential which will result in an action potential transmitted to the CNS. There are several synapses involved, after the peripheral synapse involving sensory neurons, before a signal reaches the CNS and the higher brain. The major pathway of acupuncture-induced signaling is the spinothalamic tract, the spinoreticular tract and the spinomesencephalic tract.

An important discovery is the activation of the cortex by acupuncture stimulation. This led to the hypothesis that the acupuncture stimulus projected to the higher brain contains survival information picked up by passing through the limbic system. This allows the higher brain to issue appropriate commands to be passed back to the limbic system and on to the hypothalamus for execution via endocrine, autonomic and neuro-chemical functions. Thus, pain control is only a small part of acupuncture and research into acupuncture as disease treatment is a growing area.


Never the less, pain control is an important aspect for the cancer patient. By understanding the biomolecular mechanisms behind pain and acupuncture, we could potentially create therapeutic ways to alter pain memory imprints in the brain, pain perception and the body’s functions of responding to pain. Furthermore, acupuncture is a safe and cheap tool for oncology nurses and other therapists working in cancer care, reducing the need for pharmaceutical intervention and sustaining the patient throughout treatments such as chemo- and radiotherapy and after operations.


2. Abstracts – Nausea and Other Symptoms

Acupuncture and self-acupuncture for long-term treatment of vasomotor symptoms in cancer patients – audit and treatment algorithm. Filshie J, Bolton T, Browne D, Ashley S; Royal Marsden Hospital, London and Surrey, UK; Acupunct. Med. 2006 Jun;24(2):92-6; PMID: 16430125 [PubMed - indexed for MEDLINE]

INTRODUCTION: Since hormone replacement therapy given for long periods is now recognised to produce serious side effects, patients with troublesome vasomotor symptoms are increasingly using non-hormonal treatment including acupuncture. Several randomised controlled trials have shown that acupuncture reduces menopausal symptoms in patients experiencing the normal climacteric. It may have this effect by raising serotonin levels which alter the temperature set point in the hypothalamus. Vasomotor symptoms can be extreme in breast cancer patients and patients with prostate cancer who are undergoing anticancer therapy. The safety of some herbal medicines and phytoestrogens has been questioned, as they could potentially interfere adversely with the bioavailability of tumouricidal drugs. A previous study reports short term benefit from acupuncture and the aim of this report is to describe our approach to long term treatment. ACUPUNCTURE APPROACH: After piloting several approaches, six weekly treatments were given initially at LI4, TE5, LR3 and SP6 and two upper sternal points, but avoiding any limb with existing lymphoedema or prone to developing it. If there were no contraindications, patients were given clear instructions on how to perform self acupuncture using either semi-permanent needles or conventional needling at SP6, weekly for up to six years, for long term maintenance. AUDIT METHODS AND RESULTS: A retrospective audit of electronic records was carried out by a doctor not involved in treatment. A total of 194 patients were treated, predominantly with breast and prostate cancer. One hundred and eighty two patients were female. The number of pre-treatment hot flushes per day was estimated by the patient: in the 159 cases providing adequate records, the mean was 16 flushes per day. Following treatment, 114 (79%) gained a 50% or greater reduction in hot flushes and 30 (21%) a less than 50% reduction. Treatment was abandoned in those who responded poorly or not at all. The duration of treatment varied from one month to over six years with a mean duration of nine months. Seventeen patients (9%) experienced minor side effects over the six year period, mostly minor rashes; one patient described leg swelling but this was likely to be due to a concurrent fracture. CONCLUSION: Acupuncture including self acupuncture is associated with long-term relief of vasomotor symptoms in cancer


patients. Treatment is safe and costs appear to be low. An algorithm is presented to guide clinical use. We recommend the use of self acupuncture with needles at SP6 in preference to semi-permanent needles in the first instance, but poor responders use indwelling studs if they fail to respond adequately to self acupuncture with regular needles. Point location may be of less importance than the overall 'dose', and an appropriate minimum dose may be required to initiate the effect.


Electro-acupuncture for control of myeloablative chemotherapy-induced emesis: A randomized trial. Shen J, Wenger N, Glaspy J, Hays RD, Albert PS, Choi C, Shekelle PG; National Institutes of Health, Laboratory of Clinical Studies, Bethesda MD, USA; JAMA 2001 Feb 28; 285(8):1016;PMID: 11105182 [PubMed - indexed for MEDLINE]

CONTEXT: High-dose chemotherapy poses considerable challenges to emesis management. Although prior studies suggest that acupuncture may reduce nausea and emesis, it is unclear whether such benefit comes from the non-specific effects of attention and clinician-patient interaction. OBJECTIVE: To compare the effectiveness of electro-acupuncture vs minimal needling and mock electrical stimulation or anti-emetic medications alone in controlling emesis among patients undergoing a highly emetogenic chemotherapy regimen. DESIGN: Three-arm, parallel-group, randomized controlled trial conducted from March 1996 to December 1997, with a 5-day study period and a 9-day follow-up. SETTING: Oncology centre at a university medical centre. PATIENTS: One hundred four women (mean age, 46 years) with high-risk breast cancer. INTERVENTIONS: Patients were randomly assigned to receive low-frequency electro-acupuncture at classic anti-emetic acupuncture points once daily for 5 days (n = 37); minimal needling at control points with mock electro-stimulation on the same schedule (n = 33); or no adjunct needling (n = 34). All patients received concurrent triple anti-emetic pharmacotherapy and high-dose chemotherapy (cyclophosphamide, cisplatin, and carmustine). MAIN OUTCOME MEASURES: Total number of emesis episodes occurring during the 5-day study period and the proportion of emesis-free days, compared among the 3 groups. RESULTS: The number of emesis episodes occurring during the 5 days was lower for patients receiving electro-acupuncture compared with those receiving minimal needling or pharmacotherapy alone (median number of episodes, 5, 10, and 15, respectively; P<.001). The electro-acupuncture group had fewer episodes of emesis than the minimal needling group (P<.001), whereas the minimal needling group had fewer episodes of emesis than the anti-emetic pharmacotherapy alone group (P =.01). The differences among groups were not significant during the 9-day follow-up period (P =.18). CONCLUSIONS: In this study of patients with breast cancer receiving high-dose chemotherapy, adjunct electro-acupuncture was more effective in controlling emesis than minimal needling or anti-emetic pharmacotherapy alone.


Acupuncture for side effects of chemo-radiation therapy in cancer patients. Lu W; Leonard P Zakim Center for Integrated Therapies, Dand Faber Cancer Institute, Boston, USA; Semin. Oncol. Nurs. 2005 Aug; 21(3):190-5; PMID: 16092807 [PubMed - indexed for MEDLINE]

OBJECTIVE: To review strategies and recommendations to improve utilization of acupuncture treatment for side effects of chemo-radiation therapy in cancer centres. DATA SOURCES: Research studies and articles, government reports, and author experience. CONCLUSION: Recent evidence in clinical research indicates that acupuncture is beneficial for chemotherapy-induced nausea, vomiting, and cancer pain. Other preliminary data also suggests acupuncture might be effective for chemotherapy-induced leukopenia, post-chemotherapy fatigue, radiation therapy-induced xerostomia, insomnia, and anxiety. However, the utilization rate of acupuncture remains low despite the wide use of other complementary and alternative medical therapies among cancer patients. This low usage of acupuncture in cancer patients indicates a health care quality issue. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses need to increase their awareness of the available evidence in the use of acupuncture in the supportive care of cancer patients.

Acupuncture point stimulation for chemotherapy-induced nausea or vomiting. Ezzo JM, Richardson MA, Vickers A, Allen C, Dibble SL, Issell BF, Lao L, Pearl M, Ramirez G, Roscoe J, Shen J, Shivnan JC, Streitberger K, Treish I, Zhang G; James P. Swyers Enterprises, Baltimore, Maryland, USA; Cochrane Data. Syst. Rev. 2006 Apr 19; (2):CD002285; PMID: 16625560 [PubMed - indexed for MEDLINE]

BACKGROUND: There have been recent advances in chemotherapy-induced nausea and vomiting using 5-HT(3) inhibitors and dexamethasone. However, many still experience these symptoms, and expert panels encourage additional methods to reduce these symptoms. OBJECTIVES: The objective was to assess the effectiveness of acupuncture-point stimulation on acute and delayed chemotherapy-induced nausea and vomiting in cancer patients. SEARCH STRATEGY: We searched MEDLINE, EMBASE, PsycLIT, MANTIS, Science Citation Index, CCTR (Cochrane Controlled Trials Registry), Cochrane Complementary Medicine Field Trials Register, Cochrane Pain, Palliative Care and Supportive Care Specialized Register, Cochrane Cancer Specialized Register, and conference abstracts. SELECTION CRITERIA: Randomized trials of acupuncture-point stimulation by any method (needles, electrical stimulation, magnets, or acupressure) and assessing chemotherapy-induced nausea or vomiting, or both. DATA COLLECTION AND ANALYSIS: Data were provided by investigators of the original trials and pooled using a fixed effect model. Relative risks were calculated on dichotomous data. Standardized mean differences were calculated for nausea severity. Weighted mean differences were calculated for number of emetic episodes. MAIN RESULTS: Eleven trials (N = 1247) were pooled. Overall, acupuncture-point stimulation of all methods combined reduced the incidence of acute vomiting (RR = 0.82; 95% confidence interval 0.69 to 0.99; P = 0.04), but not acute or delayed


nausea severity compared to control. By modality, stimulation with needles reduced proportion of acute vomiting (RR = 0.74; 95% confidence interval 0.58 to 0.94; P = 0.01), but not acute nausea severity. Electro-acupuncture reduced the proportion of acute vomiting (RR = 0.76; 95% confidence interval 0.60 to 0.97; P = 0.02), but manual acupuncture did not; delayed symptoms for acupuncture were not reported. Acupressure reduced mean acute nausea severity (SMD = -0.19; 95% confidence interval -0.37 to -0.01; P = 0.04) but not acute vomiting or delayed symptoms. Non-invasive electro-stimulation showed no benefit for any outcome. All trials used concomitant pharmacologic anti-emetics, and all, except electro-acupuncture trials, used state-of-the-art anti-emetics. AUTHORS' CONCLUSIONS: This review complements data on post-operative nausea and vomiting suggesting a biologic effect of acupuncture-point stimulation. Electro-acupuncture has demonstrated benefit for chemotherapy-induced acute vomiting, but studies combining electro-acupuncture with state-of-the-art anti-emetics, and in patients with refractory symptoms, are needed to determine clinical relevance. Self-administered acupressure appears to have a protective effect for acute nausea and can readily be taught to patients though studies did not involve placebo control. Non-invasive electro-stimulation appears unlikely to have a clinically relevant impact when patients are given state-of-the-art pharmacologic anti-emetic therapy .

Clinical observation on electric stimulation of Yongquan (Kl 1) for prevention of nausea and vomiting induced by Cisplatin. Fu J, Meng ZQ, Chen Z, Peng HT, Liu LM; Dept. of TCM, Cancer Hospital, Fudan University, China; Zhongguo Zhen Jiu 2006 Apr 26(4):250-2; PMID: 16642608 [PubMed - indexed for MEDLINE]

OBJECTIVE: To search for an effective method for controlling nausea and vomiting induced by chemotherapy. METHODS: Eighty-eight cases of hepatic cancer with interventional therapy of Cisplatin were randomly divided into a treatment group and a control group, 44 cases in each group. The treatment group were treated with an anti-emetic and electro-acupuncture at Yongquan (KI 1), and the control group only with the anti-emetic. The controlling rates for nausea and vomiting were compared between the two groups. RESULTS: The controlling rates for acute nausea, vomiting and delayed vomiting in the treatment group were better than those in the control group (P < 0.05). CONCLUSION: Electro-acupuncture at Yongquan (KI 1) can prevent and greatly improve the symptoms of nausea and vomiting in the patient with chemotherapy of Cisplatin.


Complementary and alternative medicine in breast cancer patients. Nahleh Z, Tabbara IA; George Washington University Medical Center, Washington, DC, USA; Palliat. Support Care 2003 Sep;1(3):267-73; PMID: 16594427 [PubMed - indexed for MEDLINE]

OBJECTIVE: Complementary and Alternative Medicine (CAM) is becoming increasingly popular among cancer patients, in particular those with breast cancer. It represents one of the fastest growing treatment modalities in the United States. Therefore, knowledge of CAM therapies is becoming necessary for physicians and other health care providers. CAM encompasses a wide range of modalities including special diet and nutrition, mind-body approaches, and traditional Chinese medicine. METHODS: We reviewed the biomedical literature on CAM use in breast cancer patients, using Medline search from 1975 until 2002. In addition, consensus reports and books on CAM and breast cancer were included in the review. We evaluated the prevalence of CAM use in breast cancer patients, the reasons cited for its use, the different available modalities, and the reported outcomes. RESULTS: Use of CAM in breast cancer patients ranges between 48% and 70% in the United States. The most commonly used CAM modalities include dietary supplements, mind-body approaches, and acupuncture. The reasons cited for using CAM were to boost the immune system, improve the quality of life, prevent recurrence of cancer, provide control over life, and treat breast cancer and the side effects of treatment. Several studies reported favourable results including improved survival, better pain control, reduced anxiety, improvement in coping strategies and significant efficacy in treating nausea and vomiting. Other less well-organized trials have reported either no benefit or negative effect of CAM and potential toxicity of some commercial products. SIGNIFICANCE OF RESULTS: CAM is a growing field in health care and particularly among breast cancer patients. Knowledge of CAM by physicians, especially oncologists, is necessary. Oncologists should be willing to discuss the role of CAM with their patients and encourage patients to participate in well-organized research about CAM.

Electro-acupuncture for refractory acute emesis caused by chemotherapy. Choo SP, Kong KH, Lim WT, Gao F, Chua K, Leong SS; Dept. of Oncology, National Cancer Center, Singapore; J. Altern. Complem. Med. 2006;12(10):963-9; PMID: 17212568 [PubMed - in process]

PURPOSE: To evaluate the efficacy of electro-acupuncture in preventing anthracycline-based chemotherapy-related nausea and emesis refractory to combination 5HT(3)-antagonist and dexamethasone. PATIENTS AND METHODS: Cancer patients with refractory emesis after their first cycle of doxorubicin-based chemotherapy were accrued into this study. Electro-acupuncture was given during the second cycle of chemotherapy. Each patient was evaluated for the number of emetic episodes and grade of nausea within the first 24 hours after chemotherapy and electro-acupuncture. RESULTS: Forty-seven of a total of 317 patients screened were eligible


for this study. Of these, 27 patients agreed to participate. Twenty-six (26; 96.3%) of them had significant reduction in both nausea grade and episodes of vomiting after electro-acupuncture. There was complete response with no emetic episodes in 37%. Subjectively, 25 (92.6%) of the total 27 patients believed that acupuncture was an acceptable procedure and was helpful in reducing emesis. Electro-acupuncture was well-tolerated with a median pain score of 3 of 10. CONCLUSION: Electro-acupuncture is well-tolerated and effective as an adjunct in reducing chemotherapy-related nausea and emesis.

Acupuncture in prevention of postoperative nausea and vomiting. Schlager A; Abteilung fur Anasthesie, Universitatsklinik fur Anasthesie und Allgemeine Intensivmedizin, Innsbruck, Austria; Wien. Med. Wochenschr. 1998;148(19):454-6; PMID: 10025044 [PubMed - indexed for MEDLINE]

In this review the effectiveness of the acupuncture point Pericard 6 (P 6) on postoperative nausea and vomiting (PONV) is described. Use of the acupuncture, acupressure as well as the laser stimulation of P 6 proved as efficient prophylaxis of PONV in numerous studies. These methods are free of side effects and represent therefore a good alternative to the pharmacological prophylaxis and treatment of PONV.

Evidence for symptom management in the child with cancer. Ladas EJ, Post-White J, Hawks R, Taromina K; Division of Pediatric Oncology, Integrative Therapies Program for Children with Cancer, Columbia University, New York, USA; J. Pediatr. Hematol. Oncol. 2006 Sep;28(9):601-15; PMID: 17006267 [PubMed - indexed for MEDLINE]

The use of complementary/alternative medicine (CAM) has been well documented among children with cancer. This report summarizes the research evidence on the role of CAM therapies for prevention and treatment of the most commonly reported cancer-related symptoms and late effects among children with cancer. Small clinical trials document evidence of effectiveness for select therapies, such as acupuncture or ginger for nausea and vomiting, TRAUMEEL S for mucositis, and hypnosis and imagery for pain and anxiety. Several relatively small clinical trials of varying quality have been conducted on these CAM therapies in children with cancer. Some herbs have demonstrated efficacy in adults, but few studies of herbs have been conducted in children. Larger randomized clinical trials are warranted for each of these promising therapies. Until the evidence is more conclusive, the providers' role is to assess and document the child's use of CAM, critically evaluate the evidence or lack of evidence, balance the potential risks with possible benefits, and assist the family in their choices and decisions regarding use of CAM for their child with cancer.


Psychological well-being improves in women with breast cancer after treatment with applied relaxation or electro-acupuncture for vasomotor symptom. Nedstrand E, Wyon Y, Hammar M, Wijma K; Division of Obstetrics and Gynecology, Faculty of Health Sciences, Linkoping University Hospital, Linkoping, Sweden; J Psychosom. Obstet. Gynaecol. 2006 Dec;27(4):193-9 PMID: 17225620 [PubMed - indexed for MEDLINE]

The aim of this study was to evaluate the effect of applied relaxation and electro-acupuncture (EA) on psychological well-being in breast cancer-treated women with vasomotor symptoms. Thirty-eight breast cancer-treated postmenopausal women with vasomotor symptoms were included in the study. They were randomized to either treatment with electro-acupuncture (EA) (n = 19, three of them with tamoxifen) or applied relaxation (AR) (n = 19, five of them with tamoxifen) over a 12-week study period with six months follow-up. Vasomotor symptoms were registered daily. A visual analogue scale was used to assess climacteric symptom, estimation of general well-being was made using the Symptom Checklist, and mood using the Mood Scale. These were applied during treatment and at follow-up. In total 31 women completed 12 weeks of treatment and six months of follow-up. Hot flushes were reduced by more than 50%. Climacteric symptoms significantly decreased during treatment and remained so six months after treatment in both groups. Psychological well-being significantly improved during therapy and at follow-up visits in both groups. Mood improved significantly in the electro-acupuncture treated group. In conclusion psychological well-being improved in women with breast cancer randomized to treatment with either AR or EA for vasomotor symptoms and we therefore suggest that further studies should be performed in order to evaluate and develop these alternative therapies.

Chemotherapy and Acupuncture in Cancer Patients Brenda Golianu,

MD, Elizabeth Sebestyen, MD

OBJECTIVE: To describe the use of electro-acupuncture as a complementary modality in combination with chemotherapy in the treatment of three types of cancer. Background: Cancer patients may benefit from complementary or alternative medical therapies. Electrical-acupuncture may be a modality that potentiates chemotherapy.

Design, Setting, and Patients: Case series between May 2002 and July 2004 at two US centers including patients with mucoepidermoid carcinoma of the parotid gland, small cell lung cancer, and metastatic ovarian cancer. Intervention: Points were chosen along meridians surrounding the cancer and metastatic sites. Positive polarity was oriented proximally and cephalad to the tumor site, while negative polarity was oriented distally, along the extremities, on the same meridian. Main Outcome Measure: Alteration of tumor growth.Results: In all three cases, the tumors had a response to chemotherapy that exceeded expectations or previous response patterns.


CONCLUSION: Electro-acupuncture may be a useful adjunct to conventional chemotherapy. Further research is needed, both in the laboratory and in randomized controlled clinical trials, to measure efficacy and explore mechanisms of action.

Effect of acupuncture on interleukin-2 level and NK cell-immuno-activity of peripheral blood of malignant tumour patients Wu B, Zhou RX, Zhou MS – First Affiliated Hospital, Huaxi Medical University Chendu; Zhongguo Zhong Xi Yi Jie He Za Zhi; 1994 Sep; 14(9):537-9 PMID: 7866002 [PubMed - indexed for MEDLINE]

This paper deals with the observation of acupuncture therapy affecting interleukin-2(IL-2 level and natural killer (NK) cell immuno-activity in the peripheral blood of patients with malignant tumours. In this clinical-laboratory test research, randomized double blind method was used. The patients were divided into an acupuncture treated group (n = 25) and a control group (n = 20). The former group was treated using points, ST36, LI11, RN6 and locations of symptomatic points bilaterally. They received one treatment of 30 minutes daily for 10 days. The results showed that the IL-2 level and NK cell activity were lower than normal in patients with malignant tumour, but there was an increase in the acupuncture group after 10 days of treatment. Significance was found to be remarkable (P < 0.01). The difference between the two groups was also significant (P < 0.01). This increase might be related to the mechanism of acupuncture that adjusting the body's immune function. Thus, acupuncture therapy could enhance the cellular immune function of patients with malignant tumours and providing a beneficial effect in anti-cancer treatment.

Effect of acupuncture on T-lymphocyte and its subsets from the peripheral blood of patients with malignant neoplasm. Yuan J, Zhou R, Zhen Ci Yan Jiu; 1993; 18(3):174-7 PMID: 7923712 [PubMed - indexed for MEDLINE]

Effect of acupuncture on the T-lymphocyte and its subsets from the peripheral blood of patients with malignant neoplasm has been researched in this study. 51 patients were divided into two groups: one in acupuncture treatment and the other without any treatment. 48 healthy adults were also studied as normal control group. The results showed that the percentages of OKT3+, OKT4+, OKT8+ cells in the peripheral blood of the 51 patients were lower than those of the normal adults respectively. After the acupuncture treatment, the percentages of OKT3+, OKT4+, OKT8+ cells were obviously higher than those before acupuncture; the control group of patients showed no significant variation. This result revealed that acupuncture seemed to have more effect on OKT4+ cells than on OKT8+ cells. From our study we believe that acupuncture can be used as one of the many treatments for patients with cancer.


Clinical effectiveness of electro-acupuncture in combination with invasive therapy for massive liver cancer. Xin Y, Liu D, Meng X Dept. of Thoracic Surgery, China-Japan Friendship Hospital, Beijing; Zhonghua Wai Ke Ze Zhi; 2001 Oct; 39(10):756-8; PMID: 16201187 [PubMed - indexed for MEDLINE]

OBJECTIVE: To investigate the clinical effectiveness of electro-acupuncture therapy (EAT) in combination with liver artery intubation chemotherapy for massive liver cancer. METHODS: A total of 106 patients were divided into 3 groups. In group A, patients underwent EAT in combination with invasive therapy. In group B, patients received EAT alone. In group C, patients underwent invasive therapy of liver artery intubation chemotherapy. In groups A and B, subcostal oblique incision was performed to expose liver cancer, and electrodes were inserted into the tumour under direct vision. In group A, liver artery intubation was performed during operation. After operation, chemotherapy was given from the tube. Liver artery intubation chemotherapy was performed only in group C. RESULTS: The effective rate was 73.7% (28/38), 55.6% (20/36) and 28.1% (9/32) in groups A, B and C, respectively. CONCLUSIONS: The effect of electro-acupuncture therapy in combination with liver artery intubation chemotherapy achieves the best results. Therefore, acupuncture is an effective therapy for massive liver cancer.

Effect of electro-acupuncture in treating patients with lingual hemangioma. Li JH, Xin YL Zhang W, Liu JT, Quan KH – Chinese Journal for Integrated Medicine; 2006 Jun; 12(2):146-9; PMID: 16800996 [PubMed - indexed for MEDLINE]

OBJECTIVE: To explore the clinical effect of electro-acupuncture (EA) in treating patients with lingual hemangioma (LHG). METHODS: EA therapy was applied on 36 patients by directly inserting the platinum needles into LHG through a trocar with plastic insulating cannula to protect the normal tissues and connecting the needles with the electro-chemical therapeutic apparatus of model ZAY-B. Then electricity was given until the tumour body got contracted and rigid. The result was assessed 6 months after EA was started. RESULTS: All patients were treated effectively, namely, the effective rate was 100%, with the therapeutic effect reaching grade I in 29 patients (80.6%), grade II in 7 (19.4%), and all having the function of tongue recovered to normal. CONCLUSION: EA shows special superiorities in treating LHG, proved to bring about less injury and quick recovery and being simple in operation. Especially when applied on huge LHG, it could not only remove the tumour, but also preserve the function of the tongue, so it is a brand-new approach that is likely to be accepted by patients.


Electro-acupuncture: Treatment Method for Arm Edema, Following Surgery for Breast Cancer. C. Moldovan, et al. (Institute of Oncology,

Bucharest, Romania). International Medical Acupuncture Conference, London, England, May 4-8, 1986

Upper limb edema (bloating from retention of water) occurs following surgery for breast cancer in approximately 8-30% of the cases. Existing means have relatively limited efficiency. This study presents a treatment method with electro-acupuncture (acupuncture in which weak electrical currents are sent through the needles) on a group of 21 patients with upper limb edema. Treatment response was based on objective criteria including clinical and thermoelectric measurements. Complete recovery from edemas was obtained in 33% of the cases, while partial recovery was seen in 43% of the cases. No response was seen in 24%.

3. Studies – Two Articles with Protocol

a) ACUPUNCTURE TO REDUCE NAUSEA DURING CHEMOTHERAPY TREATMENT OF RHEUMATIC DISEASES A. Josefson, M. Kreuter, Dept. of

Rheumatology and Inflammation Research, Sahlgrenska University Hospital, Goteborg, Sweden.

Published: Rheumatology 2003;42:1149-1154, 2003 British Society for Rheumatology

ABSTRACT

Objective. To study if acupuncture, combined with ondansetron treatment, reduces nausea and vomiting associated with cyclophosphamide infusion in patients with rheumatic diseases.

Methods. Thirty-nine patients were treated with acupuncture at point PC 6 and/or in the ear to decrease nausea and vomiting. The patients reported the severity of nausea and number of bouts of vomiting at the start of chemotherapy and after 4, 8, 24, 48 and 72 h.

Results. Compared with ondansetron treatment alone, the combined acupuncture–ondansetron treatment significantly decreased both the severity of nausea and the


number of bouts of vomiting 24 and 48 h after the subjects had received acupuncture at the first treatment session (nausea: P < 0.0001; vomiting: P < 0.0035). Nearly the same results were seen 48 and 72 h after the subjects had had their last treatment of acupuncture (nausea P < 0.0080). Similar results were found after 24 to 48 h, when a comparison was made between two sessions close in time (nausea: P < 0.0001 after 24 h, P < 0.0003 after 48 h; vomiting: P < 0.0007).

Conclusions. Our results clearly indicate that combined treatment with acupuncture and ondansetron reduces the severity and the duration of chemotherapy-induced nausea as well as the number of bouts of vomiting as compared with ondansetron therapy alone, in patients with rheumatic diseases.

INTRODUCTION Acupuncture is a scientifically accepted method for treating pain. It has also been shown to reduce nausea effectively in seasickness and morning sickness during pregnancy, as well as in patients pre-medicated with opioids before surgery. Nausea of varying intensity is a very common side-effect of chemotherapy. Dundee et al.

reported that 96% of their patients felt sick after the first chemotherapy treatment, that the feeling of sickness is likely to accompany any subsequent drug administration, and that tolerance did not appear to develop to the side-effects of cancer chemotherapy agents. They found that acupuncture administered at point PC 6 (‘Neiguan’) significantly improved nausea in 97% of the 130 cancer patients studied. This effect was absent when a placebo point was tested. To determine if the beneficial effect on nausea attributed to acupuncture is due to non-specific effects of attention and clinician–patient interaction, Shen et al. performed a three-arm randomized controlled trial in 104 patients with high-risk breast cancer. Studying the effects of electroacupuncture during 5 days of chemotherapy and a 9-day follow-up period, they found that electroacupuncture was more effective in controlling emesis than minimal needling or anti-emetic pharmacotherapy alone. However, the observed effect had a limited duration and the differences between the groups were not significant at 9-day follow-up. A review by Mayer showed that acupuncture as a treatment in general is useful and presented evidence that acupuncture is effective for treatment of chemotherapy-induced nausea and vomiting in cancer patients. Patients with rheumatic diseases are nowadays also often treated with immunosuppressive drugs. This includes patients with extra-articular rheumatoid


arthritis (RA), Wegener’s granulomatosis and other primary vasculitides, systemic lupus erythematosus (SLE), scleroderma and mixed connective tissue disease (MCTD). Immunomodulating treatment is used primarily to suppress the activity of the disease by down-regulation of the proliferation of immunocompetent cells and the secretion of pro-inflammatory cytokines, such as interleukin 1 and tumour necrosis factor- . The side-effects of cyclophosphamide treatment, an alkylating agent frequently used in cases of severe rheumatic disease, are dose dependent. Cells of the bone marrow and the mucous membranes of the intestines and the urinary bladder are especially sensitive to the action of cyclophosphamide. Delayed nausea and vomiting in connection with cyclophosphamide treatment are commonly observed in clinical practice. Some patients suffer from nausea just once, while the majority may have severe symptoms for several days after each treatment. To relieve this side-effect, patients are given anti-emetic drugs such as ondansetron. In spite of this anti-emetic treatment, many patients still suffer from severe nausea and vomiting. To our knowledge, no studies have investigated the effects of acupuncture on nausea and vomiting in patients with rheumatic diseases receiving chemotherapy on repeated occasions over a long period of time. Results from the cancer studies mentioned above are not necessarily directly applicable to patients with rheumatic diseases. Furthermore, in those studies patients were treated on only one occasion or during one period. Originally we intended to randomize the patients into two treatment groups, one receiving acupuncture and no ondansetron and the other both acupuncture and ondansetron. However, randomization did not succeed since almost all patients clearly expressed a wish to have a combined acupuncture and ondansetron treatment. The aim of this study was thus to investigate the effect of acupuncture in combination with ondansetron on nausea and vomiting in patients with severe rheumatic diseases treated with chemotherapy.


PATIENTS AND METHODS

PatientsAn increasing number of patients with rheumatic diseases are treated with intravenous chemotherapy throughout the world. The immuno-modulating medication, mainly cyclophosphamide, is used in lower doses than is employed for cancer treatment. The dose level is usually between 750 and 1500 mg, depending on the patient’s weight and need of immuno-suppression. The treatment, so-called intermittent pulse treatment, is mostly administered as one infusion once a month for 4 months up to 2 yr, depending on the activity of the disease/exacerbation and on the rapidity of the clinical response to the treatment. Consecutive in-patients at the department of rheumatology with the diagnosis of SLE, RA, MCTD, primary vasculitis or other rheumatic systemic diseases with pulmonary or nephritic manifestations were invited to participate in the study and offered acupuncture as an additional treatment against nausea. The inclusion criterion was a prior session with cyclophosphamide followed by experience of nausea despite simultaneous treatment with ondansetron. Exclusion criteria were severe psychiatric illness, sensitivity to needlesticks owing to hyperaesthesia or prolonged bleeding time, or lymphatic oedema in the arms. The patients who agreed to participate in the study were contacted by one of the authors and asked to fill in a study protocol at every session of chemotherapy. All patients were informed about the experiences of acupuncture as a treatment in general and its possible beneficial effect on nausea. Seventy-six patients entered the study and 39 completed it. Fifteen patients who had acupuncture treatment only once or twice were excluded from the study because cyclophosphamide treatment was terminated owing to lack of effect on the underlying illness. In addition, 16 of the patients who had tried acupuncture treatment once or twice did not consider their nausea to be troublesome enough to continue the acupuncture and were therefore excluded from the study. Six patients dropped out without providing any reason. Of the 39 patients who completed the study, 32 were women and seven men. The median age was 47 yr (range 21–72). Thirteen patients had SLE, 11 had primary vasculitis, four MCTD, six scleroderma and five persons RA with either amyloidosis or secondary necrotizing vasculitis.

MethodsA pre-experimental pretest–post-test design was used. Such a design enables


questions to be answered over time by performing a pretest before the independent variable is introduced. If the probands are tested both before and after the procedure, it is possible to assess a difference in the results of the dependent variable. A pilot study comprising 10 patients was first conducted to test the method and the protocol. This resulted in some changes in the protocol to make it easier for the patients to fill in. The patients filled in the number of bouts of vomiting and rated the degree of nausea on a four-step scale (0 = no nausea, 1 = slight nausea, 2 = moderate nausea and 3 = severe nausea) at the start of the infusion and after 4, 8, 24, 48 and 72 h. The three observation times of the first 24 h were chosen after other studies, but as cyclophosphamide is known to give a delayed sickness, observations of 48 and 72 h after the infusion were added. The following information was entered into the study protocol from the patients’ records: date of treatment, dose of cyclophosphamide, diagnosis and consecutive treatment number. The acupuncture points, and time and duration of acupuncture were also noted. The acupuncture points chosen were the PC 6 (‘Neiguan’) and/or two acupuncture points in the ear (‘Lung’ and ‘Liver’). These points are considered to be equal in their effect on nausea. The needles were inserted into the patients unilaterally or bilaterally at least 15–30 min before the cyclophosphamide infusion was started. The normal time for acupuncture was 30–45 min. Stimulation was made so ‘De Qi’ (the needle sensation in most cases described as a complex feeling of numbness, pressure, tenderness and warmth/cold) was achieved when inserting and removing the needles, but not in-between. An experimental design of the study is outlined in. The patients were included in all four groups, depending on the acupuncture treatment (phase 1–6). Phase 1. The patients underwent 1–3 sessions of chemotherapy without acupuncture treatment, and severity of nausea and bouts of vomiting were measured.

Phase 2. First session of chemotherapy with acupuncture and the same registrations of side-effects were measured. This could in some cases mean that the time interval between the first time of chemotherapy without acupuncture and the first time with acupuncture could vary from 4–6 weeks up to 3 months.

Phase 3. The severity of nausea and bouts of vomiting were followed during a series of chemotherapy treatments combined with acupuncture treatment, but were not included in the analysis. The number of treatments varied between 1 and 5 and was determined by practical clinical reasons.


Phase 4. One to two chemotherapy treatments without acupuncture were then provided again, as the intention was to make extra comparisons with phases 1, 2 and 3.

Phase 5. Further sessions of chemotherapy combined with acupuncture treatment then followed. The number of treatments varied between 3 and 24 and depended on how many sessions of chemotherapy the patients were undergoing (based on the response of the disease to the treatment).

Phase 6. The last session of chemotherapy treatment with acupuncture was registered.

Analysis 1. A comparison of the data of these observations (phase 1 and phase 2) was made. If more than one session was notified in phase 1, the analysis of the first one was used.

Analysis 2. A comparison between data from phase 3 and phase 4 was made. In phase 3 the last session of acupuncture was chosen and the first of no acupuncture in phase 4.

Analysis 3. Data from phase 1 were compared with data from phase 6.

Analysis 4. Data from phase 2 were compared with data from phase 6.

Every session of chemotherapy was administered once every 4–6 weeks. Study protocols were distributed each time the patients received chemotherapy treatment. The protocols were brought back at the time of the next chemotherapy session or sent by post 10 days after chemotherapy, in connection with blood tests.

Statistical methods

Wilcoxon’s signed rank sum test for paired observations was used for testing differences between different treatments of the patient group. Discrete data (degree of nausea) were presented as frequencies and the distribution of variables of continuous data (number of bouts of vomiting) was presented as means, medians and range.

Ethical considerations


It was not necessary to obtain ethical approval from the Research Ethic's Committee, as this study was an evaluation of a common clinical treatment. The patients were informed about the study and gave their consent verbally.

RESULT Acupuncture significantly reduced the severity, especially the duration, of nausea, as well as the number of bouts of vomiting following cyclophosphamide after 24 to 48 h. The number of bouts of vomiting was significantly reduced at the first session of acupuncture. The same results could also be seen when the interim between treatments (ondansetron alone vs acupuncture–ondansetron combined) was short (within 4–6 weeks) and when the patients’ health status was considered more stable. Eighteen patients had less than 5 acupuncture treatments, fourteen patients had 6–10, two patients had 12, two had 16 and three were treated 21–24 times. The median number of acupuncture sessions was 7 (range 2–24). The total number of acupuncture treatments was 294 for the 39 patients. The effects of acupuncture on the severity of nausea and number of bouts of vomiting in patients treated with chemotherapy prior to acupuncture and at the first session of acupuncture are presented in (described in the Methods section as analysis 1 comparing data from phase 1 and phase 2). At the start of chemotherapy and after 4 and 8 h there were no significant differences between treatment modalities, as most patients did not feel nausea at all after that short observation time. However, significant decreases in the severity of nausea with acupuncture were found after 24 and 48 h (P < 0.0001) and after 72 h (P < 0.0106). The mean number of bouts of vomiting was 3.3 without acupuncture compared with 0.6 when the patients were treated with acupuncture (P

< 0.0035.

After receiving chemotherapy and acupuncture a number of times, 1–3 sessions of chemotherapy without acupuncture were measured again, and compares the treatment modalities on two occasions close in time (in the Methods section described as analysis 2 comparing data from phase 3 and phase 4). There was a significant difference in the severity of nausea in the patients treated with acupuncture after 24 h (P < 0.0001), after 48 h (P < 0.0003) and after 72 h (P < 0.0254). The number of bouts of vomiting was significantly reduced when the patients were treated with acupuncture (P < 0.0007). Other comparisons—not shown in the tables—were also made. First, between chemotherapy without acupuncture


treatment and the last session of acupuncture (described in the Methods section as analysis 3, comparing data from phase 1 and phase 6). No significant differences were found in the initial period after acupuncture though differences in the severity of nausea were found after 48 h (P < 0.0151) and 72 h (P < 0.0080). There were no significant differences in the number of bouts of vomiting.

Finally, comparisons were made to evaluate if there was a cumulative effect of acupuncture on the degree of nausea and number of bouts of vomiting between the first and last sessions of acupuncture (described in the Methods section as analysis 4, comparing data from phase 2 and phase 6). Evidence of such an effect was observed. Significant differences were found in the severity of nausea after 48 h (P < 0.0059) and in the number of bouts of vomiting (P < 0.0005), but not in the rest of the observations. As a whole, the patients kept their pattern of reaction to acupuncture and we assume that each acupuncture treatment had a similar effect on nausea.

DISCUSSION Compared with an efficient pharmacological anti-emetic treatment (ondansetron), it seems that acupuncture combined with ondansetron significantly decreased both the severity and duration of nausea, as well as the number of bouts of vomiting following intravenous cyclophosphamide therapy. The details of the underlying mechanisms of acupuncture on nausea and vomiting are largely unknown. Acupuncture may affect the sympathetic system via mechanisms at the hypothalamic and brainstem levels. Indeed, the hypothalamic beta-endorphinergic system exerts inhibitory effects on the vasomotor centre. There is evidence that hypothalamic nuclei have a central role in the mediating effects of acupuncture and that afferent input of somatic nerve fibres has a significant effect on autonomic functions. Why there is a potentiating anti-emetic effect of the combination of acupuncture and anti-emetic medication cannot be answered at present. It is apparent that the usual anti-emetic medication is not effective enough for many patients. Some of our patients (not included in this study) have tried acupuncture without ondansetron on some occasions, but found acupuncture alone to be unsatisfactory and therefore resumed the combined treatment with ondansetron and acupuncture.

There are some limitations in our study that deserve comments. Several previous acupuncture studies have been criticized for lacking adequate control groups.


Although our study used the patients as their own controls, we had no placebo group. One reason for this is that placebo needles were not available when this study was initiated. On the other hand, it may be hard to ‘deceive’ patients using the currently available sham acupuncture methods. Differences in the number of acupuncture treatments that patients underwent in this study depend to a certain extent on when the patients entered into the study. Some of the patients included here are still undergoing chemotherapy and data are still being collected from them.

The inclusion criterion was a prior treatment with cyclophosphamide followed by experience of nausea despite simultaneous treatment with ondansetron. As a good many patients on the ward did not experience nausea at all or did not consider it to be troublesome, they were thus not included in the study. The 39 persons who were both included and completed the study are in our opinion a group of patients with a generally more severe nausea problem. Another limitation of the study concerns the response scale used to assess the severity of nausea. A ceiling effect may have resulted from setting the upper endpoint to 3, since judging from comments in the protocols the patients would have marked a higher score if such had been available. This may explain why some patients marked ‘3’ for nausea but still thought they were better off with acupuncture than without it. Furthermore, the follow-up period perhaps should have been extended to 5 or 7 days.

We conclude that acupuncture combined with ondansetron reduces nausea and vomiting compared with ondansetron alone and may thus be a treatment of benefit to patients with rheumatic diseases on chemotherapy. Based on the results from our study, we recommend acupuncture as a treatment to supplement anti-emetic drugs. As the method is reasonably easy to perform and carries minimal risk, its clinical use could be extended in order to make chemotherapy more endurable for patients. However, successful implementation of this treatment requires well-organized cooperation and planning among the staff.

In our ward we have developed a carefully planned schedule to accommodate this treatment. The treatment days are concentrated to 2 days a week. Blood tests are taken the day before the cyclophosphamide infusion, which makes it possible to start all infusions at the same time on each occasion. This enables us to administer acupuncture routinely despite the hectic working situation on our ward. Supported by

grants from the F.R.F.-Foundation, Sweden, the Swedish Rheumatism Association, Legitimerade


Sjukgymnasters Riksförbunds Minnesfond and the Rune and Ulla Amlöv Foundation.

b) ACUPUNCTURE FOR CANCER PATIENTS – RESEARCH AND CASE STUDIES

INTRODUCTIONComplementary therapies can be useful adjunctive modalities in the treatment of many cancers. Between 7% and 36% of cancer patients use complementary therapies while being treated for cancer, when these services are covered by their insurance.1,2 There is a need for further research into the efficacy of complementary therapies.3 Several studies have reported that acupuncture can be effective in the treatment of chemotherapy-related nausea and vomiting, post-chemotherapy fatigue, and cancer-related pain.4-6 Some recent human and animal studies have reported that adjunctive electrical acupuncture may be effective in enhancing chemotherapy.7-9 We present 3 cases in which electro-acupuncture was added to the conventional chemotherapy treatment planned for the patient and may have played a synergistic role.

METHODS

Needling technique was determined by following a protocol practiced by Dr. Jin Zhui and Dr. Qian Xin at the Guang Zhou Medical School in the People's Republic of China for the treatment of patients with metastatic cancer. The protocol is based upon the hypothesis that a positive charge surrounding the tumor destabilizes the tumor cell membranes, rendering them more susceptible to chemotherapy.

First, the meridians that pass through or around the tumor are located. Points along these meridians are selected that are 1-2 cm proximal to the known tumor sites on those meridians. They are needled using the Flying Needle insertion technique (quick insertion using wrist action), with a dispersion method (slight counterclockwise rotation). These points receive a positively charged electrical stimulus. Distal points are selected by locating major points on each meridian, preferably on the arms or legs, and are used to ground the circuit. The positive clip of the stimulator is connected to the proximal needle and the negative clip to the distal needle of the same meridian. A Chinese Multipurpose Electrical Stimulator was used (Wujin Great Wall Medical Device Co). The following specifications were used: continuous pulse duration Tao = 0.5 (±0.15) ms; repeated pulse frequency selectivity g=1-100 Hz;


output peak voltage Vp1>= 40V±10V at a 500-ohm load. The stimulator produced a low-intensity and low-frequency (0.5-2 Hz) pulsed current for 25 minutes.

All needles were 34 gauge, 30-mm stainless steel. They were placed to elicit a De Qi sensation and subsequently rotated as described below. The treatment was performed 2-5 times per week for 30 minutes each time. The treatments continued for 4 months for the 1st patient, 2 months for the 2nd patient, and 7 months for the 3rd patient. During this time, the patients continued treatment with conventional chemotherapy as prescribed by the treating oncologist.

Calibration Techniques

Using a conventional oscilloscope, calibrated according to the manufacturer's recommendations, we measured the electrical output of the Chinese Multipurpose Electrical Stimulator. We used a frequency of 2 Hz. The waveform was a square wave with an average magnitude of 70 mV and duration of 0.5 ms.

CASE REPORTS

Case 1

A 43-year-old man was diagnosed with T3N2bM1 poorly differentiated mucoepidermoid carcinoma of the parotid gland and had undergone right parotidectomy and radical neck dissection with 2 positive nodes. It was not possible to obtain clear tumor margins. Following surgery, a positron emission tomography (PET) scan prior to initiation of chemotherapy showed hypermetabolic left submental and left jugular lymph nodes, innumerable hypermetabolic foci within thoracic vertebral bodies (C3, T12-L4), ribs, sternum, right ischium, and right acetabulum, suggesting osseous metastatic disease. An extensive uptake of glucose suggested involvement of the majority of the L4 vertebral body. The patient was advised that chemotherapy would not be effective for this tumor but was offered it nonetheless as a palliative modality. The patient underwent 3 courses of chemotherapy consisting of carboplatin and 5-fluorouracil, lasting 3 months. During this time he also underwent acupuncture treatment 5 times per week for 30 minutes (Table 1).


Table 1. Points Used in Case 1Meridian Positive Points Negative Points

Points With Electrical StimulationST 1, 2, 34 12, 11, 36GB 30 39TH 20 5SI 19 11BL 10 23LI 4 20

Hua Tuo Jia Ji Points C2, T1, T10, L3 C7, T9, L2, BL 57Points Without Electrical Stimulation*

SP 6 sedation modeKI 3,7 tonification modeLR 3 sedation modeCV 17 tonification mode

*Sedation mode refers to hand manipulation in a counterclockwise direction; tonification mode, hand manipulation in a clockwise direction.


During treatment, recurrent hyperemia was noted at the tumor site, which resolved after acupuncture treatment, but recurred after 24 hours. The treatments continued 5 times per week for 4 months. Follow-up PET scan 4 months later showed persistent hypermetabolic activity at T8 only (Figures 1 and 2). This was the only active metastatic disease. The multiple lesions seen on prior PET scan did not show any hypermetabolic activity on this follow-up study.

Case 2

A 73-year-old woman was diagnosed with stage IV small cell lung cancer, with multiple liver metastases, periportal, mesenteric, and para-aortic lymphadenopathy. The initial lung mass was 6 cm in diameter. The patient received 6 cycles of carboplatin and etoposide, resulting in decreased tumor size to 4 x 3 cm measured by computed tomography (CT). Electroacupuncture was added 2 times per week (Table 2) to the chemotherapeutic regimen. Seven months later, the patient


Fig1 Iodine-123 metaiobenzylguanidine (MIBG) scan of case 1 before treatment Note multiple areas of uptake (representing metastatic sites) including sternum, ribs, and thoracic and lumbar vertebrae.

Fig2 MIBG scan of case 1 after 4 months of chemotherapy and acupuncture. Only 1 area of active uptake at T8 is shown.

interrupted both chemotherapy and acupuncture for a trial of a dietary regimen. Eight months after diagnosis, the tumor measured 4.5 x 3.7 cm on follow-up CT. Chemotherapy was restarted with ironotecan for 4 cycles and the patient restarted acupuncture treatments 5 times per week. The acupuncture treatment protocol is shown in Table 2. Ten months after diagnosis, the central lung mass decreased to 3.0 x 1.0 cm. There was a marked improvement in the liver metastases and near complete resolution of the periportal, mesenteric, and para-aortic lymphadenopathy.



Points With Electrical Stimulation

KI 27, 21 22, 3ST 3, 19 18, 36SP 20 3LR 14 2GB 24 39LU 1 9

Points Without Electrical Stimulation*

KI 7, 10 tonification modeSP 6, 9,10 sedation modeLR 3 sedation modeLI 4 sedation modeCV 17, 18 tonification mode


Case 3

A 69-year-old woman was diagnosed with stage IV ovarian adenocarcinoma, multiple liver metastases, and periaortic and pelvic lymph node involvement bilaterally. She underwent bilateral oophorectomy and started low-dose chemotherapy with carboplatin and taxol for 7 cycles with stabilization, but no improvement of the liver lesions or lymphadenopathy.

Six months later, electroacupuncture was added 2 times per week according to the protocol shown in Table 3. Repeat PET scan 13 months later showed complete resolution of both liver metastases and lymphadenopathy.



Points With Electrical Stimulation

KI 21, 12 16, 3ST 19, 29 25, 36SP 21 3LU 9 1LR 14 2GB 24 39

Points Without Electrical Stimulation*

KI 7, 10 tonification modeSP 6, 9, 10 sedation modeLR 3 sedation modeLI 4 sedation modeCV 17, 18 tonification mode


DISCUSSION

Although these 3 cases obviously do not allow us to draw any definitive conclusions, we report these findings because the use of electroacupuncture merits further research. We cannot determine whether electroacupuncture was responsible for tumor regression. The chemotherapy itself may have been entirely responsible for the observed phenomena, although these results were significantly better than those that were expected. If acupuncture played some role in tumor regression, the mechanism is speculative.

Electrical stimulation of sympathetic nerve endings may stimulate vasoconstriction or stimulate an immune response. There is some evidence that acupuncture may be able to affect the sympathetic and parasympathetic nervous systems.10,11 Recent


interest in influencing angiogenesis and tumor blood supply12,13 suggests that using methods that create vasoconstriction may have a role in treatment. A recent animal experiment showed that electroacupuncture enhanced natural killer cell activity in rats, and that this enhancement was suppressed by anterior hypothalamic lesions in the animals.14 Electroacupuncture may also improve immune function in humans.15

Another possible mechanism might be that daily one-on-one time with the patient for 30 minutes could have elicited a powerful placebo effect.

CONCLUSIONS

Acupuncture can be a useful modality to complement conventional cancer treatment and may potentiate the effects of chemotherapy. Further research is needed to determine efficacy and the mechanisms of action. The results of these case reports are preliminary, and we are aware of the many limitations of these reports. We plan further exploration of this phenomenon in animal models, and with a larger sample of patients in a prospective, randomized controlled trial.

ACKNOWLEDGEMENTS

We wish to thank the American Academy of Medical Acupuncture (AAMA). Some of these cases were presented at the 2004 annual meeting and received 1st place for original research. We also wish to thank Drs Nancy Federspiel, Elliot Krane, Emily Ratner, and Richard Niemtzow for their energetic advice and support.

REFERENCES

Lafferty WE, Bellas A, Baden AC, et al. The use of complementary and alternative medical providers by

insured cancer patients in Washington State. Cancer. 2004;7(100):1522-1530.

Molassiotis A, Fernandez-Ortega P, Pud D, et al. Use of complementary and alternative medicine in

cancer patients: a European survey. Ann Oncol. 2005;16:655-663.

Kerr C. The issue of complimentarily. Lancet Oncol. 2004;5(5):262.

Vickers AJ, Straus DJ, Fearon B. Acupuncture for post chemotherapy fatigue: a phase II study. J Clin

Oncol. 2004;9(22):1731-1735.

Shen J, Wenger N, Glaspy J, et al. Electroacupuncture for control of myeloablative chemotherapy-

induced emesis. JAMA. 2000;284(21):2755-2761.


Alimi D, Rubino C, Pichard-Leandri E, et al. Analgesic effect of auricular acupuncture for cancer pain; a

randomized, blinded, controlled trial. J Clin Oncol. 2003;21(22):4120-4126.

Xin YL, Liu DR, Meng X. Combined electro-acupuncture with liver artery intubation in treatment of

massive liver cancer. Hepatobiliary Pancreat Dis Int. 2002;1(3):397-400.

Manabe M, Mie M, Yanagida Y, et al. Combined effect of electrical stimulation and cisplatin in HeLa cell

death. Biotechnol Bioeng. 2004;6(86):661-666.

Isobek K, Shimizu T, Nikaido T, Takaoka K. Low voltage electrochemotherapy with low-dose

methotrexate enhances survival in mice with osteosarcoma. Clin Orthop. 2004;426:226-231.

Hidetoshi M, Uchida S, Ohsawa H, et al. Electro-acupuncture stimulation to a hindpaw and a hind leg

produces different reflex responses in sympathoadrenal medullary function in anesthetized rats. J

Auton Nerv System. 2000;79:93-98.

Haker E, Egekvist H, Bjerring P. Effect of sensory stimulation (acupuncture) on sympathetic and

parasympathetic activities in healthy subject. J Auton Nerv System. 2000;79:52-59.

Sivakumar B, Harry L, Paleolog E. Modulating angiogenesis: more vs less. JAMA. 2004;292(8):972-977.

Sersa B, Krzic M, Sentjurc M, et al. Reduced blood flow and oxygenation in SA-1 tumors after

electrochemotherapy with cisplatin. Br J Cancer. 2002;9(87):1047-1054.

Hahm ET, Lee JJ, Lee WK, et al. Electroacupuncture enhancement of natural killer cell activity

suppressed by anterior hypothalamic lesions in rats. Neuroimmunomodulation. 2004;11(4):268-272.

Ye F, Chen S, Liu W. Effects of electro-acupuncture on immune function after chemotherapy in 28

cases. J Tradit Chin Med. 2002;22(1):21-23.


4. Pain Management with Acupuncture

Introduction

Patients undergoing cancer treatment will, most likely, during the course of the disease suffer from pain. Statistically, 60 to 90 percent of cancer patients require a pain-relieving therapy at some point. However, not all cancers produce pain equally, and some cancers, even when advanced, may not cause pain at all. Cancers that are more typically painful include tumors of the bone (either primary or through spread) and the organs of the abdomen.

Types of pain are: Somatic pain, from the cancer itself, may come from a bone damaged by tumor invasion or from an obstruction in the intestine or urinary tract. Neuropathic pain, from nerve involvement, is either related to direct tumor spread such as the spread of colon cancer into the pelvis where the nerves to the legs or pelvic structures reside, or is secondary to irritating substances that tumors secrete near nerves. Neuropathic pain may also result from pressure on the nerves due to tumor formation. Surgery may cause both somatic and neuropathic pain. Chemotherapeutic drugs can have a detrimental effect on sensory receptors in the peripheral nervous system. Mucositis, sometimes a side effect of these drugs, is one example of somatic pain resulting from chemotherapy. Drugs such as antiviral agents or vincristine, cisplatin, carboplatin, Taxol and Navelbine can cause peripheral neuropathy, which is often felt as a burning in the hands and feet. After radiation therapy, pain may be due to skin damage, breakdown of mucous membranes or even scarring of the nerves (fibrosis), which can produce a neuropathic pain.

Side Effects of Pain Medications: Not all patients tolerate all analgesic drugs equally well. Some people are allergic to certain medications or develop sensitivity over prolonged periods of drug treatment. Side effects vary from individual to individual and can present yet another burden on the patient undergoing cancer treatment. While 90 to 95 percent of patients receive adequate pain control (see: the WHO


guidelines for analgesics in cancer patients), there are still 5 to 10 percent of patients who do not achieve any marked relief. There are other ways, through direct intervention, to relief pain. These interventions include nerve blocks with local anesthetics or nerve-destroying agents, alternative delivery systems such as administering narcotics under the skin (subcutaneous) or into the spine, spinal local anesthetics or other therapies that destroy nerves causing the pain.

Acupuncture is one modality which can bring relief for patients with acute or chronic pain and, whilst it is not sufficient during episodes of very severe pain, it can provide an alternative and, importantly, effective support for other methods of pain relief, reducing the need for analgesics and other medication. Acupuncture is also effective in symptoms of fatigue which is often a direct result of pain and reported by the majority of cancer patients at some point during their illness.

A series of different studies conducted in the US have shown that 90% of patients with advanced cancer experience severe pain and that pain occurs in 30% of all cancer patients, regardless of the stage of the disease. These studies also show that 50% of patients feel they do not receive satisfactory treatment to relieve their discomfort. Pain usually increases as cancer progresses. The most common cancer pain arises from tumors that metastasize to the bone, followed by tumors infiltrating nerves and hollow viscera. Tumors near neural structures may cause the most severe pain. The third most common pain associated with cancer occurs as a result of chemotherapy, radiation or surgery. Pain can be chronic, persistent or what is termed breakthrough pain which is a brief flare-up of severe pain and can occur while the patient is on regular pain medication.

At the College of Chinese Medicine, London, we specialize in spinal acupuncture and use, together with local and distal points along the meridian pathways, points alongside the spine to influence peripheral innervations. Pain occurs when neurons the periphery get stimulated by tissue damage or by inflammatory signaling mechanisms such as prostaglandins (PGs). PGs, produced by neutrophils at the injury site,


bind to their receptors on peripheral nerve terminals and trigger a pain message to the central nervous system (CNS). Non-neuronal cells of the CNS such as astrocytes and microglia get turned on by the incoming message and produce yet more PGs and inflammatory cytokines that further amplify the pain signal.

Not only is acupuncture effective as a complementary therapy for pain but, through its anti-inflammatory properties often replaces generally accepted pharmacological intervention. The attributive effect of acupuncture has been investigated in inflammatory diseases, including asthma, rhinitis, inflammatory bowel disease, rheumatoid arthritis, epicondylitis, complex regional pain syndrome type 1 and vasculitis. Large randomised trials demonstrating the immediate and sustained effect of acupuncture are yet missing in the UK, but have been conducted for some years now in the US, Germany, Japan and China. Mechanisms underlying the ascribed immuno-stimulating actions of acupuncture have been investigated and documented. Studies and research shows that the acupuncture-controlled release of neuropeptides from nerve endings and subsequent vaso-dilative and anti-inflammatory effects through calcitonine gene-related peptide is hypothesised (see: Mediators of Inflammation, Volume 12 (2003) Issue 2). The complex interactions with substance P, the analgesic contribution of β-endorphin and the balance between cell-specific pro-inflammatory and anti-inflammatory cytokines tumor necrosis factor-α and interleukin-10 are discussed in this context. A great deal of investigations into the molecular and neuroendocinological mechanisms of acupuncture, brain mapping and others are still on the way any should bring exciting new insight and greater understanding of acute and chronic pain.

Research Extracts by Prof. W. Zieglgansberger, Max Planck Institute, Munich, Dept. of Neuropharmacology and Chronic Pain Research

THE USE OF ACUPUNCTURE IN CHRONIC PAIN AND UNDERSTANDING PAIN MECHANISMS

More and more research into the mechanisms of acupuncture and how


it works on a cellular and neurological level is being done worldwide. At the forefront of this research is the Max-Planck Institute, Munich, Germany. Professor Dr Walter Zieglgansberger, at the Department for Clinical Neuropharmacology at the Max-Planck Institute, is one of the leading figures in the field of pain mechanism research in Europe and an ardent advocate of acupuncture as an invaluable tool in the treatment of patients suffering from acute and chronic pain. Below are small extracts from some of Prof. Zieglgansbeger’s research explaining the pathways of pain and how the effects of acupuncture can be understood in the context of molecular neuroendocrinology.


What Do We Know About The State Of Chronic Pain?

Chronic pain syndromes are characterized by altered neuronal excitability in the pain matrix. The ability to rapidly acquire and store memory of aversive events is one of the basic principles of nervous systems throughout the animal kingdom. These neuroplastic changes take place e. g. in the spinal cord, in thalamic nuclei and cortical and subcortical (limbic) areas integrating pain threshold, intensity and affective components. Chronic inflammation or injury of peripheral nerves evokes the reorganization of cortical sensory maps. Neurons conveying nociceptive information are controlled by various sets of inhibitory interneurons. The discharge activity of these interneurons counteracts long-term changes in the pain matrix following nociceptor activation, i. e. it prevents the transition of acute pain signaling to chronic pain states. Our most recent research suggests that pain states may be sensitive to novel families of agents and therapeutic measures not predicted by traditional preclinical pain models as well as human pain states. The endogenous cannabinoid system plays a central role in the extinction of aversive memories. We propose that endocannabinoids facilitate extinction of aversive memories via their selective inhibitory effects on GABAergic networks in the amygdala.

Klinik fur Anasthesiologie, Schmerzambulanz, Klinikum Grosshadern, Ludwig-Maximilians-Universitat Munchen. Article in German (Zieglgansberger W, Azad SC) PMID: 14648318 [PubMed - indexed for MEDLINE]

Understanding Neuropathic Pain

Neuropathic pain is defined as a chronic pain condition that occurs or persists after a primary lesion or dysfunction of the peripheral or central nervous system.Traumatic injury of peripheral nerves also increases the excitability of nociceptors in and around nerve trunks and involves components released from nerve terminals (neurogenic inflammation) and immunological and vascular components from cells resident within or recruited into the affected area. Action potentials generated in nociceptors and injured nerve fibers release excitatory neurotransmitters at their synaptic terminals such as L-glutamate and substance P and trigger cellular events in the central nervous system that extend over different time frames. Short-term alterations of neuronal excitability, reflected for example in rapid changes of neuronal discharge activity, are sensitive to conventional analgesics,


and do not commonly involve alterations in activity-dependent gene expression. Novel compounds and new regimens for drug treatment to influence activity-dependent long-term changes in pain transducing and suppressive systems (pain matrix) are emerging.

Department of Clinical Neuropharmacology, Max Planck Institute of Psychiatry, Kraepelinstrasse 2, 80804 Munich, Germany. (Zieglgansberger W, Berthele A, Tolle TR) Published: CNS Spectrum, 2005 Apri; 10(4):298-308 PMID: 15788957 [PubMed - indexed for MEDLINE]

The Pain Matrix – Presented at ICMART 2000 International Medical Acupuncture Congress

Emerging knowledge related to the diversity of pain-related systems in the central and peripheral nervous systems suggests that besides "classical" neurotransmitters, e.g., L-glutamate, substance P, g-aminobutyric acid (GABA) and monoamines, biologically active molecules such as peptide hormones, neurosteroids, trophic factors or cytokines participate in the integration of somatosensory information in the pain matrix. These substances are released synaptically or non-synaptically from terminals, neighboring neurons, glia cells or components of the immune system or from the circulation. These neuronal and hormonal systems, which act in concert to help the individual to cope with pain, have been detailed by the modern neurosciences.

By detailing the multiplicity of transducing and suppressive systems novel compounds and new regimes for drug treatment and afferent stimulation to prevent activity-dependent long-term changes are emerging. Chronic pain states arise from a variety of pharmacologically distinct systems which offer novel targets for selective pharmacotherapy and appear sensitive to families of agents that were otherwise not predicted by traditional preclinical pain models as well as human pain states.

The activation of a nociceptor in the peripheral tissue triggers sets of neuronal events which extend over a time frame ranging from milliseconds to hours, days or weeks. Most nociceptors in the


peripheral tissue are polymodal: they respond to noxious heat, strong mechanical stimuli, and to a battery of exogenous and endogenous chemical stimuli (including prostaglandins, bradykinin, histamine, cytokines). These multimodal nociceptors can be sensitized by a number of factors released by the damaged tissue leading to primary hyperalgesia. Sensitization causes specific upregulation of expression of ion channels and receptors on these structures.

A major facilitatory effect of the central nervous system responding to noxious stimuli involves the interaction between L-glutamate and substance P, a neuropeptide long thought to have a role in pain perception. GABA is a major inhibitory neurotransmitter in the mammalian CNS and GABA binding sites and GABA containing neurons have been characterized in almost all pain-related structures. Even slight alterations in the excitability of multi-receptive dorsal horn neurones (wide-dynamic-range, WDR neurons) can dramatically influence the size of their receptive fields measured in the peripheral tissue, i.e. the area in the periphery where a stimulus will trigger action potentials in this neuron. The excitatory receptive fields are most commonly surrounded by inhibitory receptive fields. The size of the excitatory receptive field can be increased by the application of L-glutamate into the vicinity of these neurons and can be reduced in size by the application of the inhibitory neurotransmitter GABA. Repetitive electrical stimulation of the inhibitory receptive field can induce a long-lasting suppression of neuronal discharge activity of WDR neurons. While the earliest short-term responses are reflected in rapid changes of neuronal discharge activity the long-term changes most commonly require alterations in gene expression. The importance of WDR neurons in the establishment of hyperalgesia and allodynia suggests a strategic focus for drug treatment or interventions by peripheral stimulation, e.g. by acupuncture or physical therapy, on this first stage of sensory integration in the CNS. Activity-dependent modulation of gene expression is a feature of highly integrated systems and greatly expands the capacity to react in a more plastic manner to environmental stimuli. Immediate-early-genes (IEGs) are thought to participate as third messengers in the late phase of the stimulus


transcription cascade. They code for transcription factors and alter gene expression and translation into the corresponding protein products such as enzymes, receptors or neurotransmitters. The amount of several IEG-coded proteins, produced by central neurons, is proportional to the degree of synaptic excitation following somatic and visceral acute noxious.

Similar neuroplastic changes take place in other components of the pain matrix, e.g. in areas integrating pain threshold and intensity or its unpleasantness in the neocortex or subcortical limbic areas. Chronic inflammation or injury of peripheral nerves evokes the reorganization of cortical sensory maps. These recent advances in electrophysiological, molecular and cellular biological techniques have profoundly changed the face of pain research. The multitude of dynamic changes which occur during chronic pain states may also offer explanations for some of the effects observed following acupuncture and treatment with related techniques.

W. ZIEGLGANSBERGER (Germany), Max-Planck Institute, Munchen

Other Abstracts and Reports from the ICMART 2000 International Medical Acupuncture Congress. (The following original translations from German have been edited, in terms of grammar and sentence structure, with an endeavor to stay as true to the original as possible.)

Acupuncture as Post-operative and Post-traumatic Treatment Spacek A, Department of Anesthesia, General Hospital, Vienna, Austria.

Within the last 30 years, acupuncture has become increasingly accepted within orthodox medicine and has gained great popularity among patients, primarily as a therapeutic option in the treatment of various chronic diseases. Moreover, acupuncture has been used increasingly in trauma and in connection with surgery. One of the best documented areas of the efficacy of acupuncture is the treatment of postoperative nausea and vomiting. Acupuncture appears to be as


effective as specific anti-emetic medication, both in prevention and in the treatment of postoperative nausea and vomiting, but without the side effects of pharmaceutical intervention. Great efficacy of acupuncture has also been shown for its analgesic action in treating painful conditions due to surgery or trauma. Electro-acupuncture treatment provides a significant reduction of postoperative opioid requirement and seems to be a good alternative in treating headaches after spinal anesthesia in caesarean section. Acupuncture has also been reported to be superior to placebo treatment in preventing postoperative dental pain and can reduce postoperative pain after total knee replacement by more than 20%. Although acupuncture is less effective than narcotic analgesics, it helps to alleviate the severity of complications such as postoperative urinary retention, impairment of bronchial function, intestinal paresis, vomiting, nausea and pain in 40-80% of cases. It has also been found that electro-acupuncture significantly attenuates catecholamine responses in comparison to placebo treatments during postoperative recovery. The effect of ear-acupuncture (point P 29) on blood pressure regulation has also been investigated and findings that bilateral stimulation of the P 29 mitigates hypotensive effects after induction of anesthesia. This simple technique has absolutely no risks nor side effects and may be beneficial in preventing post-induction hypotension in patients. Taking all these facts into consideration, one must conclude that the use of acupuncture as part of a comprehensive treatment concept (combined with drug therapy) in the management of postoperative and post-traumatic pain seems to be desirable.

Atomic Physics and Neurophysiology on the Concept of Meridian Qi (Energy) Warnke U, University of Saarland, Germany

In modern science, the considered electromagnetic and mechanical neuron activity is, up to now, not sufficient remarked:

a) As long as resting potential is stable, electrons within the cell


membrane have a potential energy of approx. 70meV. During depolarization, this energy is set free as a coherent radiated electromagnetic oscillation with the quantum energy of 70 meV = 1,7 x 10 Hz. At the same time, the molecule dipoles fixed in their movement previously through the high electrostatic field of the resting potential of the membrane (up to 10 V/m) suddenly oscillate and, in this way, send coherent electromagnetic oscillations of different frequencies outside and inside the neurite.

b) Through the high electrostatic field force of the resting potentials, a very high compression of the membrane is caused. At depolarization, the membrane snaps back to its real expansion (electrostriction). The desultory expansion is causing the mechanical resonance of the membrane elements which thus send out a sound wave. As the sound wave runs through the tissue and the fluids it modulates, through periodic pressure fluctuation, the dielectric constant of the medium in the rhythm of the sound frequency. Thereby the membrane sends out in addition to the coherent electromagnetic oscillation an electromagnetic dispersion wave. The triggered sound wave is directly coupled with the emission of the dispersion wave. Both work in the same tissue and fluid volume and in this way they amplify one another. Through dielectric focusing, e.g. through the walls of blood vessels, this radiation can be focused again. The stream of blood works like an antenna and pulls in the electromagnetic field analogous to the warmth, then, guided forward, the field conductive and connective proteins have a habit to changing their geometric form, e.g. they twist their side chains around an anticipated angle of torsion. This happens likewise as a consequence of specific energy absorption. The electromagnetic radiation of some activated enzymes is fixed in resonance to the microwave area (10/12 - 10/13 Hz.). That is exactly the area in which membranes of neurons send out coherent oscillations in the case of depolarization.

Post-operative Pain Management with Acupuncture Grube T, Kornberg


A, Uhlemann C, Meissner W, Scheele J, Surgical Clinic, Jena, Germany

Background: Acupuncture has become very popular in several fields of pain management, especially in treatment of chronicle pain. The purpose of this study is the assessment of acupuncture in the treatment of postoperative pain.

Material and methods: After defined operations (vaginal and laparoscopic hysterectomy, laparoscopic appendectomy), all patients received patient controlled analgesia (PCA) with piritramid and we randomized in three groups;

Group 1 (n = 18) received PCA and acupuncture after a defined time table.Group 2 (n = 17) received PCA and 1 g metamizol at the same time.Group 3 (n = 17) PCA only was.

At defined points of time, patients were asked to comment on pain intensity, nausea and frequency of vomiting using visual analog scale (VAS). At the same time, blood pressure, heart frequency and skin temperature were noted. At the end of the evaluation, levels of piritramid taken were documented.

Results: The use of acupuncture (group 1) lead to a reduction of piritramid use of more than 50 percent compared to group 3. In group 2, the intake of piritramid was less than in group 3, but still higher than in group 1. We also noticed very good results of acupuncture in the treatment of nausea and vomiting.

Conclusion: Using scientific and reproducible parameters, acupuncture alone proved to be sufficient in the management of postoperative pain, nausea and vomiting. Especially multi-morbid patients at risk of suffering from surgery-related or pharmacological side effects benefit from acupuncture. We noted no effect of acupuncture regarding blood pressure and heart rate.


Mechanisms of Acupuncture Analgesia Produced by Low-FrequencyElectrical Stimulation of Acupuncture Points

By Chifuyu Takeshige

Introduction

Three noteworthy phenomena have been recognized in surgical acupuncture analgesia (AA) produced by low-frequency electrical stimulation of acupuncture points (APs): 1) Consciousness is maintained, allowing the patient to talk during surgery; 2) Stimulation of specific acupuncture points is essential to maintain analgesia; and 3) Analgesia persists long after stimulation has been terminated, allowing the patient to move without pain after surgery. The mechanisms by which AA is produced might be clarified by investigating these phenomena. This review will explore possible mechanisms based on results from animal experiments.Consciousness depends on activation of the brainstem ascending reticular activating system (RAS) that produces widespread stimulation of the cerebral cortex and non-specifically maintains consciousness through the reticular nucleus in the thalamus. The RAS is activated by collateral pathways that diverge from each specific sensory afferent pathway that projects to each sensory cortex. Neurophysiological research has shown that anesthetic drugs used during surgical operations inhibit activity of the RAS. Since consciousness is diminished under this condition, sensory information reaching the sensory cortex is not translated into perception. On the other hand, it is also commonly observed that normally painful stimuli are suppressed on the battlefield of war and on the playing field of aggressive sports such as rugby. Such analgesia is thought to be brought about by activation of the descending pain inhibitory system (DPIS) originating from the limbic system that blocks pain information as it enters the central nervous system. Consciousness can thus be maintained in such a condition. If stimulation of a specific acupuncture point activates the DPIS through a particular pathway connected to the brain system which suppresses pain, it can be assumed that AA is produced by activation of the DPIS. This assumption has been examined in our laboratories by several animal experiments.

1. Classification of acupuncture afferent and efferent pathways for producing acupuncture analgesia [11,12,13,16,22,23]


The neuronal structures comprising the AA-producing brain pathway can be identified when microelectrode stimulation induces analgesia in a manner that mimics AA and by tissue ablation that results in subsequent blockage of AA. However, the nature of the analgesia produced depends upon the brain areas stimulated and can be classified into two categories. The first category includes analgesia that 1) is naloxone-reversible, 2) disappears after hypophysectomy, 3) persists long after stimulation of the acupoint is terminated, and 4) exhibits individual variation in effectiveness. These features are similar to those of AA. In this category, brain potentials are evoked by stimulation of acupoints in the same areas that produce analgesia. Stimulation of brain areas associated with the second category produces analgesia that 1) is not naloxone-reversible, 2) is not affected by hypophysectomy, 3) is produced only during stimulation, and 4) exhibits no individual variation in effectiveness. Evoked potentials are not obtained from brain regions producing analgesia of this second category, but non-synchronized neuronal activities are obtained by stimulation of acupoints [16].Brain regions producing analgesia of the first category appear to comprise an afferent pathway for acupuncture, since the pituitary gland is involved in this analgesia and electrical potentials are evoked in these brain regions by stimulation of acupoints. Similarly, areas producing analgesia related to the second category appear to comprise an efferent pathway for acupuncture, since the pituitary gland is not involved and synchronized electrical potentials are not evoked in these regions by stimulation of acupoints [12,16,19]. All brain regions producing analgesia associated with the second category seem to be connected to the DPIS; AA is produced by activation of the DPIS that is excited by stimulation of specific acupoints through a particular pathway connected to the DPIS. This DPIS-producing analgesia related to the second category is defined as the acupuncture efferent pathway, whereas the particular pathway from specific acupoints to the DPIS is defined as the acupuncture afferent pathway.

1a. Acupuncture efferent pathway [13,16,24]

AA can be abolished by concurrent lesions of the Raphe nucleus and the reticular paragigantocellular nucleus that are known as the origins of the serotonergic and the noradrenergic descending pain-inhibitory systems. Stimulation of these nuclei respectively produces serotonergic and noradrenergic analgesia of the second category. The final production of AA is induced by activation of these descending pain-inhibitory systems. The descending pain-inhibitory pathway serves as the acupuncture efferent pathway from the hypothalamic ventromedian nucleus (HVM); it is divided into two parts that connect to the descending serotonergic and noradrenergic systems. The


posterior part of the hypothalamic arcuate nucleus (P-HARN) is anatomically connected to the HVM. Analgesia produced by stimulation of both the HVM and the P-HARN is associated with the second category. Synaptic transmission from the P-HARN to the HVM is apparently dopaminergic, since analgesia produced by stimulation of the P-HARN is blocked by lesions of the HVM or by dopamine antagonists.

1b. Acupuncture afferent pathway [11,12,23]

The acupuncture afferent pathway starts from an acupoint, ascends through the contralateral anterolateral tract to the dorsal periaqueductal central gray, and reaches the medial part of the hypothalamic arcuate nucleus (M-HARN). Brain regions belonging to the AA afferent pathway can be identified by exhibition of analgesia of the first group related to anatomically known connections. The rostral and caudal relations between these regions have been identified by the loss of stimulation-produced analgesia of the caudal region that follows lesions of the rostral region.

1c. Synaptic connections between acupuncture afferent and efferent pathways [25,28].

The final region of the acupuncture afferent pathway is found in the M-HARN, which is anatomically close to the P-HARN, the initial region of the acupuncture efferent pathway. Microinjection of the dopamine antagonist haloperidol antagonizes AA dose-dependently while microinjection of dopamine into the P-HARN induces a dose-dependent analgesia. Dopamine thus seems to serve as the neurotransmitter between the M-HARN and the P-HARN, i.e. as the neurotransmitter at the interface between the acupuncture afferent and efferent pathways. This possibility is further supported by neuronal activity in the P-HARN. Neurons in the P-HARN that respond to acupoint stimulation also respond to iontophoretically administered dopamine, whereas neurons in the M-HARN that do not respond to acupoint stimulation also do not respond to iontophoretically administered dopamine [25].A branch of the acupuncture afferent pathway ascending to the M-HARN diverges at the lateral hypothalamus (LH) to reach the pituitary gland. Lesions of brain nuclei near this pathway to the pituitary, e.g. the preoptic area (POA) or the median eminence (ME), abolish AA. Electrical potentials are evoked in these brain areas by stimulation of acupoints, but stimulation of these particular brain structures does not produce analgesia [25,28] (Fig.1, 2 and 5). Since both acupuncture analgesia and pain relief produced by stimulation of the acupuncture afferent pathway to the M-HARN -endorphin released from the pituitary glandare abolished by hypophysectomy, may play an essential role in


dopaminergic transmission in the P-HARN [25]. Microinjection of naloxone to the P-HARN antagonizes AA -endorphin or morphine producesdose-dependently and microinjection of -endorphinanalgesia dose-dependently. Analgesia produced by microinjection of disappears after denervation of the M-HARN, but analgesia produced by microinjection of dopamine to the P-HARN remains [25]. These findings -endorphin might act presynaptically at dopaminergic synapses insuggest that the P-HARN. This notion is further supported by the activity of P-HARN neurons. Neuronal activity in the P-HARN that occurs in response to acupuncture stimulation is not affected by iontophoretic administration of morphine or by -endorphin via picosprizer [22].

-ultramicroinjection Since -endorphin released from -endorphin act similarly in the P-HARN, morphine and the pituitary gland might be the neurohumoral factor acting presynaptically on axon terminals of the M-HARN neurons that innervate P-HARN neurons. Although -endorphin into the P-HARN produces analgesia, electricalmicroinjected stimulation of the POA or ME in the pathway to the pituitary gland does not; -endorphin by such stimulation is nottherefore, the released amount of sufficient to activate the P-HARN neurons without afferent impulse from the -endorphin might also act in other areas of the AAM-HARN. Morphine and afferent pathway. This possibility was explored by recording electrical potentials evoked by stimulation of the acupoint in the final station of the AA afferent pathway, the M-HARN. Such potentials are enhanced by intravenously administered morphine (0.5 mg/kg) and are abolished by hypophysectomy. The abolished evoked-potentials are temporarily restored by morphine [12]. -endorphin released from the pituitary glandTherefore, sites responsive to might be widespread in the AA afferent pathway. Opioid receptors have also been reported in many regions of the acupuncture afferent pathway [1,5,10].

2. Stimulation of specific acupoints for production of acupuncture analgesia [23]

Low-frequency (1 Hz) electrical stimulation of the first dorsal finger muscle and the anterior tibial muscle in rats [11, 23] that are the muscles underlying, respectively, the human LI 4 (Hegu) and ST 36 (Zusanli) acupoints, produces behavioral analgesia, as evaluated by tail-flick latency. The intensity of electrical stimulation must be sufficient to cause muscle contraction in order to obtain AA. In contrast to this effect, stimulation of other muscles does not produce behavioral analgesia. Hence, the Hegu and Zusanli acupoints seem uniquely able


to activate the DPIS through the particular pathway connected to the DPIS [3].

3. Differentiation of acupoints and non-acupoints by responses of central neuronal structures [11,14,15,17,18]

Potentials can be evoked specifically in the bilateral dorsal areas of the periaqueductal central gray (D-PAG) by stimulation of the muscles underlying the Hegu and Zusanli acupoints, but not by stimulation of other muscles. Lesions of the D-PAG abolish AA. Microelectrode stimulation of this region produces analgesia of the first category that can be reversed by either naloxone or hypophysectomy. Stimulation of the auricular levator muscle beneath the X 18 (Chihmo) acupoint in rabbits elicits evokes potentials in the D-PAG [11,23]. Stimulus conditions as stated above which lead to AA were confirmed by potentials in the D-PAG. Therefore, only three acupoints for producing AA have been identified: Hegu, Zunsanli, and Chihmo.Stimulation of muscles beneath Hegu and Zusanli also produces nonspecific potentials bilaterally in the lateral parts of the periaqueductal central gray (L-PAG) [17]. Potentials in the L-PAG are gradually decreased by 1 Hz repetitive stimulation of these muscles and disappear completely 10 minutes after the onset of stimulation [15,17]. Hence, potentials in the L-PAG are inhibited by such stimulation in a self-inhibiting fashion. Lesions of the L-PAG do not affect AA, but analgesia is produced by stimulation of the rostral L-PAG. This analgesia is largely reversible with dexamethasone and the dexamethasone-insensitive portion is readily blocked by naloxone or hypophysectomy. Hence, acupoints are connected via the D-PAG to the particular pathway that is not self-inhibited during the production of AA. On the other hand, acupoints as well as non-acupoints are connected to the other, self-inhibiting pathway nonspecifically, via the L-PAG. The latter brain region belongs to a pathway distinct from the AA afferent pathway, whose analgesia production is self-inhibiting. These results imply that acupoints and non-acupoints can be differentiated by their connections with different analgesia-producing central pathways [14,17].

4. Similarities between acupuncture analgesia and morphine analgesia

Analgesia produced by 0.5 mg/kg morphine is of a similar degree to that produced by low frequency electroacupuncture. In addition, both types of analgesia are abolished by hypophysectomy, by lesions of either the AA afferent or efferent pathways, by naloxone or by antagonists of transmitters involved in the AA efferent pathway. In


addition, individual variation in effectiveness between AA and morphine analgesia are highly correlated. Animals can be classified as responders or non-responders by the presence or absence of a significant increase (P < 0.05) in tail-flick latency.

5. Activation of the spinal acupuncture analgesia afferent pathway by morphine [8,11,12,14,18]

Potentials evoked in the D-PAG by stimulation of acupoints are blocked by contralateral lesions of the anterolateral tract or by intrathecal administration of the antiserum to methionine-enkephalin (Met-enkephalin). These potentials are also blocked by naloxone, but not by the administration of antisera to leucine-enkephalin or dynorphin [18] supporting the involvement of a met-enkephalin pathway that is activated by morphine. In AA-responder animals, dose-response curves of analgesia were obtained for both low and high doses of morphine, administered either intraperitoneally or intrathecally. However, in non-responder animals, only a single dose-response curve for higher doses of morphine was obtained. In AA responders, bilateral lesions of the anterolateral tract, or lesions of the D-PAG that is part of the AA afferent pathway abolished dose-dependent responses to low doses of morphine without affecting the dose-response to high doses of morphine. Therefore, morphine analgesia produced by lower doses is probably induced by activation of the AA afferent pathway through Met-enkephalin receptors in the spinal cord [18]. Such receptors in the spinal AA afferent pathway are likely to be those that are activated by intraperitoneal morphine at 0.5 mg/kg or by intrathecal morphine at 0.05 mg/kg, that produce morphine analgesia of a degree similar to that of AA [8,11]. This mechanism may explain the reason for the similarity between AA and morphine analgesia.

Summary

Acupuncture analgesia is produced by activation of the DPIS through a specific pathway connected to the acupoints while still allowing maintenance of consciousness. The AIS, in contrast, is activated by stimulation of acupoints or non-acupoints, leading to a non-specific inhibition of different interconnected pathways. Therefore, acupoints and non- acupoints can be distinguished by their anatomically distinct brain pathways. The after-effects of AA might be produced -endorphin released from the pituitary by the actions of an increased amount of gland on components of the AA-producing pathway.References


1. Atweh SF, Kuhar MJ. Autoradiographic localization of opiate receptors in rat brain: the brainstem. Brain Res 1997;129:1-12.

2. Arai T, Guo SY, Takeshige C. Cholecystokinin in the analgesia inhibitory system and its antagonists in this system. J Showa Med Assoc 1992;52:58-67.

3. Huang SF, Luo CP, Takeshige C. Identity of a central analgesia producing mechanism in Ho-ku point stimulation with that in Tsusanli point stimulation. J Showa Med Assoc 1998;48:485-492.

4. Lung CH, Sun AC, Tsao CJ, Chang,YL, Fan L. An observation of the humoral factor in acupuncture analgesia in rats. Amer J Chin Med 1974;2:203-205.

5. Malizia E, Andreucci G, Paolucci D, Grescenzi F, Fabbri A, Fraioli F. -endorphin and ACTH levels.Electroacupuncture and peripheral Lancet 1979; 535-536.

6. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science 1973;179:1011-1014.

7. Sato T, Hishida F, Luo CP, Tsuchiya M, Takeshige C. Relations of adrenal gland and sodium ions in production of acupuncture and non-acupuncture points stimulation-produced analgesia. J Showa Med Assoc 1989;49:286-294.

8. Sato T, Takeshige C, Shimizu S. Morphine analgesia mediated by activation of the acupuncture-analgesia-producing system. Acupunct Electro-Ther Res 1991;16:13-26.

9. Sjolund B, Terenius L, Erikson M. Increased cerebrospinal fluid levels of endorphins after electro-acupuncture. Acta Physiol Scand 1977;100:382-384.

*10. Snyder SH. Opiate receptor in normal and drug altered brain function. Nature 1955;257:185-189.

*11. Takeshige C. Mechanism of acupuncture analgesia based on animal experiments. In: Scientific Bases of Acupuncture, Pomeranz B, Stux G (eds) Springer-Verlag, 1990, pp..

12. Takeshige C. Mechanism of acupuncture analgesia (AA) caused by low frequency stimulation of the acupuncture point based on animal experiments, Part1: Acupuncture afferent and efferent pathways and the nature of AA. Acupunct Scient Int J 1990;1:75-88.

13. Takeshige C, Sato T, Komugi H. Role of peri-aqueductal central gray in acupuncture analgesia. Acupunct Electro-Ther Res 1980;5:323-337.

14. Takeshige C. Differentiation between acupuncture and non-acupuncture points by association with analgesia inhibitory system. Acupunct Electro-Ther Res 1985;10:195-203.

15. Takeshige C. Inhibition associated with acupuncture analgesia: inactivation of hypersensitive neurons. Charlazonits N, Gola M (eds) Alan R. Liss, Inc., 1987, pp.255-262.

16. Takeshige C, Kamada Y, Hisamatu T. Commonly responsive neurons in the periaqueductal gray matter and midbrain reticular formation of rabbits to acupuncture stimulation, inversion, pressure on body parts and morphine. Acupunct Electro-Ther Res 1981;6: 57-74.

17. Takeshige C, Kobori M, Hishida F, Luo CP, Usamai S. Analgesia inhibitory system involvement in nonacupuncture point-stimulation-produced analgesia. Brain Res Bull 1992;28:379-391.

18. Takeshige C, Luo CP, Hishida F, Igarashi O. Differentiation of acupuncture and non-acupuncture points by difference of associated opioids in the spinal cord in production of analgesia by acupuncture and non-acupuncture point stimulation, and relations between sodium and those opioids. Acupunct Electro-Ther Res 1990;15:193-209.

19. Takeshige C, Luo CP, Kamada Y, Oka K, Murai M, Hisamatu T. Relation between midbrain neurons (Periqueductal central gray and midbrain reticular formation) and acupuncture analgesia, animal hypnosis. In Bonica J et al (eds). Advances Pain Res Ther 3: 1979;615-621


20. Takeshige C, Mera H, Hisamatu T, Tanaka M, Hishida F. Inhibition of the analgesia inhibitory system by D-phenylalanine and proglumide. Brain Res Bull 1991;26:385-391.

21. Takeshige C, Murai M, Tanaka M, Hachisu M. Parallel individual variations in effectiveness of acupuncture, morphine analgesia, and dorsal PAG-SPA and their abolition by D-phenylalanine. In Bonica J et al (eds). Adv Pain Res Ther 1983;5:563-569.

22. Takeshige C, Nakanura A, Asamoto S, Arai T. Positive feedback action of -endorphin on acupuncture analgesia afferent pathway.pituitary Brain Res Bull 1992;29: 37-44.

23. Takeshige C, Oka K, Mizuno T, Hisamatu T, Luo CP, Kobori M, Mera H, Fang TQ. The acupuncture point and its connecting central pathway for producing acupuncture analgesia. Brain Res Bull 1993;30:53-67.

24. Takeshige C, Sato T, Mera T, Hisamitsu T, Fang TO. Descending pain inhibitory system involved in acupuncture analgesia. Brain Res Bull 29:1992;617-634.

25. Takeshige C, Tsutiya M, Guo SY, Sato T. Dopaminergic transmission in the hypothalamic arcuate nucleus to produce acupuncture analgesia in correlation with the pituitary gland. Brain Res Bull 1991;26:113-122.

26. Takeshige C, Tsutiya M, Zhao W, Guo S. Analgesia produced by pituitary ACTH and dopaminergic transmission in the arcuate. Brain Res Bull 1991;26:779-788.

27. Takeshige C, Tanaka M, Sato T, Hishida F. Mechanism of individual variation in effectiveness of acupuncture analgesia based on animal experiments. Eur J Pain 1990;11:109-113.

28. Takeshige C, Zhao WH, Guo SY. Convergence from the preoptic area and arcuate nucleus to the median eminence in acupuncture and non-acupuncture point stimulation analgesia. Brain Res Bull 1991;26:771-778.

29. Takeshige C, Luo CP, Kamada Y. Modulation of EGG and unit discharges of deep structure of brain during acupunctureal stimulation and by hypnosis of rabbits. In Bonica JJ, Albe-Fressard D (ed.). Adv Pain Res Ther, Raven Press 1976;1:781-785.

30. Toyoda I, Takeshige C. Changes in characteristics of analgesia produced by difference in duration of stimulation of acupuncture points. J Showa Med Assoc 1992;52:1-7.

31. Xu M, Aiuchi T, Nakaya K, Arakawa H, Maeda M, Tsuji A, Kato T, Takeshige C, Nakamura Y. Effect of low-frequency electric stimulation on in vivo release of cholecystokinin-like immunoreactivity in medial thalamus of conscious rat. Neurosci Let 1990;118: 205-207.


acupuncture for cancer patients

Documents