1. Introduction
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect after patient exposure to chemotherapy agents such as vinca alkaloids, platinum derivatives, and taxanes and to newer agents such as bortezomib and thalidomide. CIPN is the second most important side effect in frequency after hematologic toxicity and can limit or delay the dose of chemotherapy that can be administered [ 1 ]. Sensory, motor, and/or autonomic neurotoxicity can be very disabling and/or painful, creating a major impact on patients' quality of life and adherence to treatment.
Conventionally, CIPN is prevented with the use of intravenous calcium and magnesium, without reducing treatment response. Pharmacological treatment of other CIPN symptoms like numbness or palsies is not usually effective, but there are some other options for treatment of neuropathic pain such as the use of antiepileptic and tricyclic antidepressant drugs (e.g., carbamazepine, lamotrigine, gabapentine or pregabalin, and venflaxine). There is no established pharmacological treatment for neuroregeneration [ 2 , 3 ].
The mechanism of neurotoxicity of the antineoplastic agents is unclear. CIPN generally arises as a consequence of the disruption of axoplasmic microtubule mediated transport, distal axonal degeneration, and direct damage to the sensory nerve cell bodies of the dorsal root ganglia (DRG). Mitochondrial damage in the DRG neuron has been described as well [ 4 ]. The DRG neurons lack a vascular barrier, in contrast to those in the central nervous system, and are more exposed to the neurotoxic effects of the antineoplastic agents. Both central and peripheral mechanisms seem to be involved.
Acupuncture stimulates areas of the skin using different methods including the insertion of thin needles that are then manipulated manually or electrically. In animal models acupuncture has been shown to reduce neuropathic pain in a variety of experimental conditions. Cold allodynia has been reduced in rats treated with electroacupuncture through the mediation of spinal alfa2-adrenergic receptors [ 5 ], while in mechanical allodynia electroacupuncture has been shown to act through mu and delta but not kappa opioid receptors [ 6 ]. Another possible effect of electroacupuncture in an experimental model of neuropathy may be the inhibition of COX2 expression [ 7 ]. It has been shown that electroacupuncture at the acupoint Zusanli (ST36) reduced the mechanical allodynia in a neuropathic model, normalising the expression profile of hypothalamic proteins, that have been mainly identified as being involved in inflammatory processes, metabolism and signal transduction [ 8 ]. Ko and colleagues [ 9 ] examined the mechanism of neuropathic pain and the analgesic effects of acupuncture at the molecular level by cDNA microarray analysis. They observed that the expression of 68 genes had more than doubled in a model of neuropathic pain in the rat but returned to normal after treatment with electroacupuncture. The genes were involved in biological processes such as signal translation, gene expression, and nociceptive pathways [ 9 ]. Also the expression of the sigma opioid receptor was decreased by 50% in the neuropathic pain model and was returned to normal after acupuncture. This could explain the poor response of neuropathic pain to the treatment with opioids, since the opioid receptor is downregulated in this condition, and could partially explain the analgesic action of acupuncture in neuropathic pain, because acupuncture normalises the opioid receptor expression and also increases the release of endogenous opioid peptides.
Cancer patients often seek additional help for their disease or for treatment-related side effects. A European survey in 13 countries [ 10 ] showed a prevalence of 35.9% of complementary therapy use (range among countries 14.8% to 73.1%). Acupuncture was used by 3.9% patients before cancer diagnosis and by 3% patients after cancer diagnosis. Acupuncture has also been shown to be effective for chemotherapy induced nausea and vomiting [ 11 ], xerostomia induced by radiation therapy [ 12 , 13 ], fatigue [ 14 ], anxiety, depression, and insomnia [ 15 ]. Furthermore, acupuncture has been used encouragingly to treat peripheral neuropathy associated with diabetes and HIV [ 16 – 22 ].
In this paper the existing evidence of acupuncture effectiveness and/or efficacy for CIPN has been systematically reviewed.
2. Methodology
To review the existing clinical and experimental studies of acupuncture in CIPN, the systematic literature search was performed from the databases inception up until January 2012 using MEDLINE, Google Scholar, Cochrane Database, CINHAL (Cumulative Index to Nursing and Allied Health Literature), CNKI (China National Knowledge Infrastructure), Wanfang Med Online, and ISI Proceedings for conference abstracts. The keywords searched were (acupoint* OR acupuncture OR electro-acupuncture OR electroacupuncture OR moxibustion) AND “peripheral neuropathy.” The CINHAL, CNKI, and Wanfang Med Online Databases did not allow logical searches with AND, so we used simple combinations of the search words. Historical searches of reference lists of relevant articles were also undertaken. To be included in the review, a study had to explore either the efficacy or the effectiveness of acupuncture needling for CIPN in either human or animal models irrespective of design. All papers with at least an abstract in English were included. Study selection was performed by two reviewers (Giovanna Franconi and Luigi Manni) with disagreement resolved by discussion and adjudication.
3. Results
A total of 3989 articles were retrieved from electronic searches and subsequent examination of reference lists of the clinical and review articles. After screening titles and/or abstracts, 3891 articles were excluded for the following reasons: the focus was on an intervention other than acupuncture, the neuropathy was not related to chemotherapy, the acupuncture treatment plan included additional interventions/modalities that were not acupuncture related, there were duplicated studies, or they were not relevant. From a total of 98 articles which were retrieved for detailed evaluation, 7 clinical studies and 1 experimental study were included in the review. For a summary of the clinical studies see Table 1 .
Only one study was identified that addressed the topic of electroacupuncture (EA) and its effects on CIPN in an animal model. Meng and colleagues [ 30 ] demonstrated that EA at both low (10 Hz) and high (100 Hz) frequencies was able to improve neuropathic pain in paclitaxel-treated rats. The authors reported that low-frequency EA was more effective than high-frequency EA in relieving neuropathic symptoms and that opioid receptors antagonists (all types) abolished EA effects. It is known that low-frequency (2–15 Hz) EA engages centrally mediated endorphin, enkephalin, serotonergic, and noradrenergic analgesia, while high frequency EA (100 Hz) engages segmental-spinal opioids (dynorphin, enkephalin) and nonopioid (gamma aminobutyric acid, glycine) analgesia [ 31 ]. Thus it is conceivable that central-mediated effects of acupuncture are involved in suppression of neuropathic pain in CIPN.
For a summary of the clinical studies see Table 1 .
The first published clinical study that explored the efficacy of acupuncture in cancer pain used auricular acupuncture in a population of 90 patients with neuropathic pain (despite stable medication) [ 23 ]. A small minority of patients also presented nociceptive pain. The patients were randomly divided into 3 arms: one arm with steel implants on auricular points eliciting an electrical response and 2 placebo arms with either steel implants or vaccaria seeds on auricular points not eliciting an electrical response. Patients were treated for 2 one-month cycles. After 2 months the pain VAS score was significantly decreased in the true acupuncture group, while there was no effect of placebo.
In one prospective case series 5 patients were treated with manual acupuncture for their chemotherapy-induced neuropathy [ 24 ]. Acupuncture was performed once a week according to TCM diagnosis using acupoints CV6 (Qihai), ST36 (Zusanli), LI11 (Quchi), EX-LE10 (Bafeng), and EX-UE9 (Baxie) for two 6-week cycles, separated by 4 weeks. All patients showed an improvement in pain score and on the WHO grade of neuropathy after treatment with acupuncture. There were no observed side effects, and benefits persisted for 6 months of followup in 4/5 patients.
Xu et al. [ 25 ] studied 64 patients with CIPN induced by paclitaxel or oxaliplatin. The patients were randomized to an acupuncture group or a control group treated with cobamamide. The acupuncture treatment included points such as Hegu (LI4), Taichong (LR3), Zusanli (ST36), Qihai (CV6), and Quchi (LI11) and was performed for an unspecified length of time. The outcome was an evaluation of neurotoxicity assessed by a CIPN questionnaire. The twenty patients in the acupuncture group significantly improved, compared to the 12 patients in the control group.
A case report [ 26 ] described one patient with multiple myeloma and bortezomib-induced CIPN who was treated with 6 weekly sessions of acupuncture, followed by subsequent 8 sessions over the next 5.5 months. The treatment protocol included body acupuncture at LI4 (Hegu), TE5 (Waiguan), LI11 (Quchi), ST40 (Fenglong), EX-LE10 (Bafeng), and auricular acupuncture at shenmen, point zero, and 2 additional points were stimulated electrically. The VAS pain score decreased from 8/10 to 2/10 after 6 treatments, and the pain medication with morphine sulphate and oxycodone was stopped after 14 treatments. The patient remained pain-free for at least one year. There were no observed side effects.
A retrospective case series examined 18 patients affected by CIPN [ 27 ]. Patients were treated by 6 weekly acupuncture sessions, with acupoints selected on the basis of patient presentation at each session. No validated questionnaires were used, and side effects were not recorded. The most commonly used points were SP6 (Sanyinjiao) and ST36 (Zusanli), followed by LV3 (Taichong). After 6 weeks 82% ( n = 14) patients reported an improvement of their neuropathy symptoms, 18% ( n = 3) reported no change.
In a pilot controlled nonrandomised study [ 28 ], 6 patients with CIPN accepted acupuncture treatment, and 5 patients with CIPN who had refused acupuncture treatment served as controls. All patients received the best medical care, and the 6 patients in the acupuncture group were also treated with 10 weekly acupuncture treatments with a fixed protocol (ST34 Liangqiu, EX-LE12 Qiduan, and EX-LE10 Bafeng bilaterally). Nerve conduction studies (NCS) were done to confirm the presence of CIPN at baseline and 6 months later, that is, 3 months after the end of acupuncture treatment. Acupuncture significantly improved nerve conduction velocity and mean amplitude of NCS in treated patients, while there was no difference after the same time in the control group. There were no observed side effects.
The last study included in this review was a randomized controlled trial of 76 patients with gastrointestinal cancer and CIPN induced by oxaliplatin [ 29 ]. The intervention group received warm acupuncture and moxibustion, and the control group was treated with Neurotropin 4 mg given intramuscularly every day for 21 days. The intervention receiving acupuncture and moxibustion reported a significantly improved quality of life and reduction in neurotoxic symptoms.
4. Discussion
Complementary therapies in cancer care are used primarily to treat the symptoms associated with cancer and its treatments. This review suggests that although there are some indications that acupuncture may be effective in improving symptoms and neural damage associated with CIPN, the current evidence available is limited.
The positive effects of acupuncture in CIPN consist in a reduction in the pain score in most studies. Pain is the most common and the best studied indication for acupuncture, and acupuncture has been recommended as a complementary therapy for pain control or for reducing the amount of pain medicine in cancer patients. According to the evidence-based guidelines of the American College of Chest Physicians for lung cancer [ 32 ], acupuncture is recommended as a complementary therapy for lung cancer when pain is poorly controlled or when side effects such as neuropathy or xerostomia are clinically significant (grade 1A recommendation). The rationale is based on the analgesic action of acupuncture in acute and chronic pain and in cancer pain. Furthermore, studies on pain using functional magnetic resonance (fMRI) showed that acupuncture could modulate the cognitive-affective aspects of pain perception [ 33 ].
Improvement was also reported for other symptoms of CIPN in the paper by Wong and Sagar [ 24 ], where the effects of acupuncture were measured by the WHO CIPN score, which takes into account both the sensory and motor abnormalities of CIPN. One study [ 28 ] evaluated acupuncture effects with nerve conduction studies, which allowed a separate measurement of motor and sensory signals and showed a significant positive effect of acupuncture on motor and sensory parameters.
The studies included in this systematic review were very heterogeneous: 3 studies [ 23 , 25 , 29 ] were prospective randomized controlled trials, while another [ 28 ] was a retrospective analysis of a controlled study. These controlled studies showed a specific effect of acupuncture, unrelated to skin penetration. The remaining studies were uncontrolled case reports or case series. Such uncontrolled studies may present bias and lead to false positive results. The issue of choosing a control in acupuncture research is not a simple one, as placebo/sham acupuncture shares many pathways with true acupuncture (i.e., activation of opioid system as well as other pain-controlling neurotransmitters systems and activation of cerebral areas on fMRI), and the placebo/sham acupuncture used in acupuncture studies is not necessarily inert [ 34 – 37 ].
Different protocols were utilized to treat CIPN: auricular acupuncture only, and somatic acupuncture only, combined auricular and body acupuncture, each applied on different combinations of acupoints. Acupuncture protocols are usually standardized in acupuncture research, but this may not reflect what clinical acupuncturists do every day in their clinics, as acupuncture in TCM is a very individualized medicine [ 38 ]. Furthermore the choice of acupuncture points in a protocol depends on the reference system, which comprises many different schools and different approaches to acupuncture, such as acupuncture according to traditional Chinese medicine, medical acupuncture, Japanese acupuncture, French auricular acupuncture, trigger-point acupuncture, acupressure, electroacupuncture, and transcutaneous electrical nerve stimulation (TENS) of acupuncture points, among others [ 39 ], each one with a different approach to comparable problems. Future studies with sufficient number of patients should also address the issue of whether a pragmatic approach or a protocol approach should be employed.
Heterogeneity was also present when considering the outcome measurements, which ranged from subjective evaluation to pain VAS score to nerve conduction studies (NCS), which make it impossible to compare studies. More objective outcome measurements are advisable, and among them NCS which measures the number and conduction velocities of large myelinated fibers and relates to both the clinical subjective improvement and the histological nerve healing.
Neuronal damage by antineoplastic agents probably activates second messenger systems which cause hyperalgesia, allodynia, and pain, because it may be relieved by supplementation with trophic factors such as NGF, insulin growth factor 1 (IGF-1), and neurotrophin 3 (NT-3) [ 40 ]. There is a large experimental evidence base on the involvement of NGF in CIPN [ 41 – 44 ]. NGF promotes physiological maturation, survival, and expression of the specific phenotype in primary sensory neurons located in the DRG [ 45 ]. Acupuncture analgesia is an effect that has been amply demonstrated and occurs via the activation of different systems, involving nerves, hormones, cytokines, and other mediators [ 46 ]. At a neuroendocrine level acupuncture modulates various neurotrophins and growth factors including NGF [ 47 ], glial-derived neurotrophic factor (GDNF) [ 48 – 50 ], brain-derived neurotrophic factor (BDNF) [ 51 , 52 ], and insulin growth factor (IGF) [ 53 ]. It is possible that the action of acupuncture on neuropathic pain be mediated by enhancement of spinal/central GABA-ergic, serotoninergic, and adrenergic neurotransmission [ 54 – 58 ] as well as by the action of acupuncture on the NGF system, driving NGF signalling toward its downregulation with parallel decrease in sensory neurons hypersensitization [ 59 ]. Thus, acupuncture can modify the expression of different genes and the expression of genes that control transcriptional factors that are crucial for cell homeostasis [ 60 ]. In Figure 1 , we summarized the acupuncture mechanisms and mediators in CIPN based on what we know from animal studies of diabetic neuropathy [ 59 , 61 ] and from human studies of brain imaging during acupuncture [ 62 ].
It is interesting to note that all the studies which used somatic acupuncture and described their protocol [ 24 , 26 – 28 ] employed local points. EX-LE10 (Bafeng) is 4 points on the instep of each foot, proximal to the margin of the webs between each two neighbouring toes, while EX-UE9 (Baxie) is 4 points proximal to the margin of the webs between each two of the five fingers of a hand. The rationale behind the choice of points located nearby or in the same dermatome of the affected limb/region might lie in the activation of spinal response after acupuncture. Indeed the western neurophysiological hypothesis on the mechanism of acupuncture efficacy proposes that needle insertion and stimulation elicits a three-level response: local (at the site of needling) that could encompass the so called “flare reaction”; segmental, that includes all the acupuncture-induced reflex variations in spinal neurotransmission, that is, GABA-ergic one; central, that refers to the overall variation induced by needle stimulation in the activity and feedback response in the brain [ 35 ]. Thus, it is possible to link the positive outcome in such studies to the spinal/segmental activation of opioids and/or GABA signalling, in accordance with previous results on animal models [ 30 ].
The limitations of the studies reviewed include the small sample size of most studies, the presence of poor controls or no controls, poor randomization, and lack of blinding. However, the presence of some studies of good quality which suggest a positive effect of acupuncture in CIPN support the planning of more rigorous randomised controlled clinical studies evaluating the efficacy of acupuncture in CIPN. The advantages of acupuncture are its safety and low cost, and it would be very important to demonstrate its efficacy in such a disabling and potentially dangerous side effect of cancer treatment such as CIPN.
Conflict of Interests
The authors declare that they have no conflict of interests.
1 Windebank AJ Grisold W Chemotherapy-induced neuropathy Journal of the Peripheral Nervous System 2008 13 1 27 46 2-s2.0-40849086432 18346229 10.1111/j.1529-8027.2008.00156.x
2 Pachman DR Barton DL Watson JC Loprinzi CL Chemotherapy-induced peripheral neuropathy: prevention and treatment Clinical Pharmacology and Therapeutics 2011 90 3 377 387 2-s2.0-80052031639 21814197 10.1038/clpt.2011.115
3 Wolf S Barton D Kottschade L Grothey A Loprinzi C Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies European Journal of Cancer 2008 44 11 1507 1515 2-s2.0-45949131693 18571399 10.1016/j.ejca.2008.04.018
4 Podratz JL Knight AM Ta LE Cisplatin induced Mitochondrial DNA damage in dorsal root ganglion neurons Neurobiology of Disease 2011 41 3 661 668 2-s2.0-79151482213 21145397 10.1016/j.nbd.2010.11.017 PMC3031677
5 Kim SK Min BI Kim JH Individual differences in the sensitivity of cold allodynia to phentolamine in neuropathic rats European Journal of Pharmacology 2005 523 1–3 64 66 2-s2.0-27644589737 16226740 10.1016/j.ejphar.2005.08.030
6 Kim JH Min BI Na HS Park DS Relieving effects of electroacupuncture on mechanical allodynia in neuropathic pain model of inferior caudal trunk injury in rat: mediation by spinal opioid receptors Brain Research 2004 998 2 230 236 2-s2.0-1642575265 14751594 10.1016/j.brainres.2003.11.045
7 Lau WK Chan WK Zhang JL Yung KKL Zhang HQ Electroacupuncture inhibits cyclooxygenase-2 up-regulation in rat spinal cord after spinal nerve ligation Neuroscience 2008 155 2 463 468 2-s2.0-49349103239 18606213 10.1016/j.neuroscience.2008.06.016
8 Somers DL Clemente FR Contralateral high or a combination of high- and low-frequency transcutaneous electrical nerve stimulation reduces mechanical allodynia and alters dorsal horn neurotransmitter content in neuropathic rats Journal of Pain 2009 10 2 221 229 2-s2.0-58849097046 19010735 10.1016/j.jpain.2008.08.008
9 Ko J Na DS Lee YH cDNA microarray analysis of the differential gene expression in the neuropathic pain and electroacupuncture treatment models Journal of Biochemistry and Molecular Biology 2002 35 4 420 427 2-s2.0-0036023034 12297003 10.5483/bmbrep.2002.35.4.420
10 Molassiotis A Fernandez-Ortega P Pud D Use of complementary and alternative medicine in cancer patients: a european survey Annals of Oncology 2005 16 4 655 663 2-s2.0-20944445252 15699021 10.1093/annonc/mdi110
11 Ezzo JM Richardson MA Vickers A Acupuncture-point stimulation for chemotherapy-induced nausea or vomiting Cochrane Database of Systematic Reviews 2006 2 CD002285 2-s2.0-33745043057 10.1002/14651858.CD002285.pub2 16625560
12 Johnstone PAS Peng YP May BC Inouye WS Niemtzow RC Acupuncture for pilocarpine-resistant xerostomia following radiotherapy for head and neck malignancies International Journal of Radiation Oncology Biology Physics 2001 50 2 353 357 2-s2.0-0035370170 10.1016/s0360-3016(00)01530-3 11380221
13 Johnstone PAS Niemtzow RC Riffenburgh RH Acupuncture for xerostomia: clinical update Cancer 2002 94 4 1151 1156 2-s2.0-0037083397 11920486
14 Vickers AJ Straus DJ Fearon B Cassileth BR Acupuncture for postchemotherapy fatigue: a phase II study Journal of Clinical Oncology 2004 22 9 1731 1735 2-s2.0-2442700591 15117996 10.1200/JCO.2004.04.102
15 Dean-Clower E Doherty-Gilman AM Keshaviah A Acupuncture as palliative therapy for physical symptoms and quality of life for advanced cancer patients Integrative Cancer Therapies 2010 9 2 158 167 2-s2.0-77954205874 20483875 10.1177/1534735409360666
16 Abuaisha BB Costanzi JB Boulton AJM Acupuncture for the treatment of chronic painful peripheral diabetic neuropathy: a long-term study Diabetes Research and Clinical Practice 1998 39 2 115 121 2-s2.0-0031981625 9597381 10.1016/s0168-8227(97)00123-x
17 Zhang C Ma Y Yan Y Clinical effects of acupuncture for diabetic peripheral neuropathy Journal of Traditional Chinese Medicine 2010 30 1 13 14 2-s2.0-77951277713 20397454 10.1016/s0254-6272(10)60003-9
18 Beal MW Nield-Anderson L Acupuncture for symptom relief in HIV-positive adults: lessons learned from a pilot study Alternative Therapies in Health and Medicine 2000 6 5 33 42 2-s2.0-0033846419 10979160
19 Wu B Recent development of studies on traditional Chinese medicine in prophylaxis and treatment of AIDS Journal of Traditional Chinese Medicine 1992 12 1 10 20 2-s2.0-0026824611 1597994
20 Özsoy M Ernst E How effective are complementary therapies for HIV and AIDS? A systematic review International Journal of STD and AIDS 1999 10 10 629 635 2-s2.0-0032869498 10582628 10.1258/0956462991913088
21 Power R Gore-Felton C Vosvick M Israelski DM Spiegel D HIV: effectiveness of complementary and alternative medicine Primary Care 2002 29 2 361 378 2-s2.0-0036310353 12391716 10.1016/s0095-4543(01)00013-6
22 Head KA Peripheral neuropathy: pathogenic mechanisms and alternative therapies Alternative Medicine Review 2006 11 4 294 329 2-s2.0-33845927528 17176168
23 Alimi D Rubino C Pichard-Léandri E Fermand-Brulé S Dubreuil-Lemaire M Hill C Analgesic effect of auricular acupuncture for cancer pain: a randomized, blinded, controlled trial Journal of Clinical Oncology 2003 21 22 4120 4126 2-s2.0-0642286275 14615440 10.1200/JCO.2003.09.011
24 Wong R Sagar S Acupuncture treatment for chemotherapy-induced peripheral neuropathy—a case series Acupuncture in Medicine 2006 24 2 87 91 2-s2.0-33745891520 16783284 10.1136/aim.24.2.87
25 Xu WR Hua BJ Hou W Bao YJ Clinical randomized controlled study on acupuncture for treatment of peripheral neuropathy induced by chemotherapeutic drugs Zhongguo Zhen Jiu 2010 30 6 457 460 2-s2.0-77955911879 20578381
26 Bao T Zhang R Badros A Lao L Acupuncture treatment for bortezomib-induced peripheral neuropathy: a case report Pain Research and Treatment 2011 2011 4 pages 920807 10.1155/2011/920807 PMC3199913 22110934
27 Donald GK Tobin I Stringer J Evaluation of acupuncture in the management of chemotherapy-induced peripheral neuropathy Acupuncture in Medicine 2011 29 3 230 233 2-s2.0-80052446613 21875929 10.1136/acupmed.2011.010025
28 Schroeder S Meyer-Hamme G Epplée S Acupuncture for chemotherapy-induced peripheral neuropathy (CIPN): a pilot study using neurography Acupuncture in Medicine 2012 30 1 4 7 2-s2.0-84859712851 22146780 10.1136/acupmed-2011-010034
29 Tian YP Zhang Y Jia YJ The curative effect of warm acupuncture and moxibustion on peripheral neurotoxicity caused by oxaliplatin Tianjin Journal of Traditional Chinese Medicine 2011 3 212 213
30 Meng X Zhang Y Li A The effects of opioid receptor antagonists on electroacupuncture-produced anti-allodynia/hyperalgesia in rats with paclitaxel-evoked peripheral neuropathy Brain Research 2011 1414 58 65 2-s2.0-80052930512 21872220 10.1016/j.brainres.2011.08.004 PMC3176966
31 Ulett GA Han J Han S Traditional and evidence-based acupuncture: history, mechanisms, and present status Southern Medical Journal 1998 91 12 1115 1120 2-s2.0-0031788678 9853722 10.1097/00007611-199812000-00004
32 Cassileth BR Deng GE Gomez JE Johnstone PAS Kumar N Vickers AJ Complementary therapies and integrative oncology in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition) Chest 2007 132 3 340 354 2-s2.0-34848847242 10.1378/chest.07-1389 17873179
33 Wu MT Hsieh JC Xiong J Central nervous pathway for acupunture stimulation: localization of processing with functional MR imaging of the brain—preliminary experience Radiology 1999 212 1 133 141 2-s2.0-0033008913 10405732 10.1148/radiology.212.1.r99jl04133
34 Lund I Lundeberg T Are minimal, superficial or sham acupuncture procedures acceptable as inert placebo controls? Acupuncture in Medicine 2006 24 1 13 15 2-s2.0-33645771235 16618044 10.1136/aim.24.1.13
35 Lund I Näslund J Lundeberg T Minimal acupuncture is not a valid placebo control in randomised controlled trials of acupuncture: a physiologist’s perspective Chinese Medicine 2009 4 article 1 2-s2.0-61349187733 10.1186/1749-8546-4-1 PMC2644695 19183454
36 Lundeberg T Lund I Sing A Näslund J Is placebo acupuncture what it is intended to be? Evidence-Based Complementary and Alternative Medicine 2011 2011 5 pages 2-s2.0-80052756441 932407 10.1093/ecam/nep049 PMC3139519 19525330
37 Andersson S Lundeberg T Acupuncture—from empiricism to science functional background to acupuncture effects in pain and disease Medical Hypotheses 1995 45 3 271 281 2-s2.0-0028846878 8569551 10.1016/0306-9877(95)90117-5
38 Robinson N Lorenc A Ding W Jia J Bovey M Wang X Exploring practice characteristics and research priorities of practitioners of traditional acupuncture in China and the EU—a survey Journal of Ethnopharmacology 2012 140 3 604 613 2-s2.0-84859005950 22338645 10.1016/j.jep.2012.01.052
39 Cohen AJ Menter A Hale L Acupuncture: role in comprehensive cancer care—a primer for the oncologist and review of the literature Integrative Cancer Therapies 2005 4 2 131 143 2-s2.0-19444380544 15911926 10.1177/1534735405276419
40 Cavaletti G Marmiroli P The role of growth factors in the prevention and treatment of chemotherapy-induced peripheral neurotoxicity Current Drug Safety 2006 1 1 35 42 2-s2.0-50649089668 18690913 10.2174/157488606775252656
41 Aloe L Manni L Properzi F de Santis S Fiore M Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by Cisplatin: behavioral, structural and biochemical analysis Autonomic Neuroscience 2000 86 1-2 84 93 2-s2.0-0034727919 11269929 10.1016/S1566-0702(00)00247-2
42 Cavaletti G Bogliun G Marzorati L Early predictors of peripheral neurotoxicity in cisplatin and paclitaxel combination chemotherapy Annals of Oncology 2004 15 9 1439 1442 2-s2.0-4644282779 15319252 10.1093/annonc/mdh348
43 de Santis S Pace A Bove L Patients treated with antitumor drugs displaying neurological deficits are characterized by a low circulating level of nerve growth factor Clinical Cancer Research 2000 6 1 90 95 2-s2.0-17044460959 10656436
44 Geldof AA Nerve-growth-factor dependent neurite outgrowth assay; a research model for chemotherapy-induced neuropathy Journal of Cancer Research and Clinical Oncology 1995 121 11 657 660 2-s2.0-0028973492 7593129 10.1007/BF01218523 PMC12200421
45 Levi-Montalcini R The nerve growth factor 35 years later Science 1987 237 4819 1154 1162 2-s2.0-0023236055 3306916 10.1126/science.3306916
46 Zhang ZJ Wang XM McAlonan GM Neural acupuncture unit: a new concept for interpreting effects and mechanisms of acupuncture Evidence-Based Complementary and Alternative Medicine 2012 2012 23 pages 429412 10.1155/2012/429412 PMC3310280 22474503
47 Aloe L Manni L Low-frequency electro-acupuncture reduces the nociceptive response and the pain mediator enhancement induced by nerve growth factor Neuroscience Letters 2009 449 3 173 177 2-s2.0-57149121457 19013501 10.1016/j.neulet.2008.11.003
48 Dong ZQ Ma F Xie H Wang YQ Wu GC Changes of expression of glial cell line-derived neurotrophic factor and its receptor in dorsal root ganglions and spinal dorsal horn during electroacupuncture treatment in neuropathic pain rats Neuroscience Letters 2005 376 2 143 148 2-s2.0-13444311961 15698937 10.1016/j.neulet.2004.11.044
49 Liang XB Luo Y Liu XY Electro-acupuncture improves behavior and upregulates GDNF mRNA in MFB transected rats NeuroReport 2003 14 8 1177 1181 2-s2.0-0042769073 12821804 10.1097/00001756-200306110-00015
50 Wei G Huang Y Wu G Cao X Regulation of glial cell line-derived neurotrophic factor expression by electroacupuncture after transient focal cerebral ischemia Acupuncture and Electro-Therapeutics Research 2000 25 2 81 90 2-s2.0-0033837393 10968645 10.3727/036012900816356208
51 Liang XB Liu XY Li FQ Long-term high-frequency electro-acupuncture stimulation prevents neuronal degeneration and up-regulates BDNF mRNA in the substantia nigra and ventral tegmental area following medial forebrain bundle axotomy Molecular Brain Research 2002 108 1-2 51 59 2-s2.0-0037121908 12480178 10.1016/s0169-328x(02)00513-2
52 Manni L Albanesi M Guaragna M Barbaro Paparo S Aloe L Neurotrophins and acupuncture Autonomic Neuroscience 2010 157 1-2 9 17 2-s2.0-77957858905 20451467 10.1016/j.autneu.2010.03.020
53 Mannerås L Jonsdottir IH Holmäng A Lönn M Stener-Victorin E Low-frequency electro-acupuncture and physical exercise improve metabolic disturbances and modulate gene expression in adipose tissue in rats with dihydrotestosterone-induced polycystic ovary syndrome Endocrinology 2008 149 7 3559 3568 2-s2.0-46349104851 18388196 10.1210/en.2008-0053
54 Sung HJ Kim YS Kim IS Proteomic analysis of differential protein expression in neuropathic pain and electroacupuncture treatment models Proteomics 2004 4 9 2805 2813 2-s2.0-4444296075 15352254 10.1002/pmic.200300821
55 Xing GC Liu FY Qu XX Han JS Wan Y Long-term synaptic plasticity in the spinal dorsal horn and its modulation by electroacupuncture in rats with neuropathic pain Experimental Neurology 2007 208 2 323 332 17936754 10.1016/j.expneurol.2007.09.004
56 Fusumada K Yokoyama T Miki T C-Fos expression in the periaqueductal gray is induced by electroacupuncture in the rat, with possible reference to GABAergic neurons Okajimas Folia Anatomica Japonica 2007 84 1 1 10 2-s2.0-34547850658 17654838 10.2535/ofaj.84.1
57 Silva JRT Silva ML Prado WA Analgesia induced by 2- or 100-Hz electroacupuncture in the rat tail-flick test depends on the activation of different descending pain inhibitory mechanisms Journal of Pain 2011 12 1 51 60 2-s2.0-78650707308 20554480 10.1016/j.jpain.2010.04.008
58 Park JH Han JB Kim SK Go DH Sun B Min BI Spinal GABA receptors mediate the suppressive effect of electroacupuncture on cold allodynia in rats Brain Research 2010 1322 24 29 2-s2.0-77649234717 20138846 10.1016/j.brainres.2010.02.001
59 Manni L Florenzano F Aloe L Electroacupuncture counteracts the development of thermal hyperalgesia and the alteration of nerve growth factor and sensory neuromodulators induced by streptozotocin in adult rats Diabetologia 2011 54 7 1900 1908 2-s2.0-79959748470 21431457 10.1007/s00125-011-2117-5
60 Ventura C CAM and cell fate targeting: molecular and energetic insights into cell growth and differentiation Evidence-Based Complementary and Alternative Medicine 2005 2 3 277 283 2-s2.0-24344471766 16136206 10.1093/ecam/neh100 PMC1193541
61 Nori SL Rocco ML Florenzano F Ciotti MT Aloe L Manni L Increased nerve growth factor signaling in sensory neurons of early diabetic rats is corrected by electroacupuncture Evidence-Based Complementary and Alternative Medicine 2013 2013 15 pages 652735 10.1155/2013/652735 PMC3654322 23710226
62 Huang W Pach D Napadow V Characterizing acupuncture stimuli using brain imaging with fMRI—a systematic review and meta-analysis of the literature PLoS ONE 2012 7 4 2-s2.0-84859492705 e32960 10.1371/journal.pone.0032960 PMC3322129 22496739