Multiple myeloma (MM) is a common hematologic malignancy and the incidence rate increases every year worldwide. Proteasome inhibitors such as bortezomib are commonly used for the initial treatment, as well as consolidation and maintenance therapies [
]. However, chemotherapy-induced peripheral neuropathy (CIPN) during MM treatments is a dose-limiting side effect and the incidence rate of bortezomib-related neuropathy has been reported to be 30–60% [
]. Common peripheral neuropathy symptoms in the distal limbs are symmetric sensory dysfunctions, with a variety of sensory losses such as glove or sock-shaped distribution, possibly associated with paresthesia and excessive pain. Other symptoms are movement disorders such as muscle weakness, muscle atrophy, diminished or disappeared limb and tendon reflexes, inability to fasten buttons as well as walking difficulties. In addition, autonomic nervous system disorders such as orthostatic hypotension, arrhythmia, bradycardia and other symptoms may occur.
Peripheral neuropathy is a key factor for drug dose and application duration restrictions, because patients often cannot tolerate symptoms, leading to a reduced drug dose and number of therapy cycles or even discontinuation of therapy. Therefore, reducing CIPN in MM treatments is a critical point for improving a patient’s quality of life and treatment outcome.
The therapy choices for CIPN treatments in MM patients are very limited but include neurotrophic drug treatment with methylcobalamin administered orally or as an intramuscular injection. The methylation of a functional group in methylcobalamin, a coenzyme of vitamin b12, enables drug availability and thereby promotes the metabolism of nucleic acids, proteins and lipids in nerve tissues. In addition, methylcobalamin stimulates cell lecithin synthesis, repairs damaged myelin and thereby improves nerve conduction velocity. First line treatments of neuropathic pain includes gabapentin, 5% lidocaine patches and opioid analgesics such as tramadol hydrochloride. Second line drugs include lamotrigine, carbamazepine and amitriptyline, as well as other antidepressants [
]. These drugs have various side effects, such as sedation, ataxia, dizziness, double vision, nausea and indigestion. The commonly used analgesics against neuropathic pain may work, but viable treatment options often do not completely relieve the symptoms.
However, when grades III-IV neurotoxicity occurs, the neurological symptoms will be partially relieved once the chemotherapy drug doses or therapy cycles are reduced, but inevitably the therapeutic effect on MM is also diminished.
Acupuncture, first mentioned in the 5th century BC, is part of traditional Chinese medicine and its effects, especially in pain control, have been confirmed in clinical trials, which led to the usage of acupuncture also in many other countries. A questionnaire of 180 patients with peripheral neuropathy showed that 30% of them choose acupuncture as an alternative method of pain control [
Studies on humans and animals have identified the neurochemical basis of acupuncture effects on brain functions. Acupuncture can stimulate receptors or cause the regular discharge of nerve fibers, leading to peripheral and central nervous system activation, resulting in the release of a variety of neurotransmitters [
]. The specific effect of acupuncture depends on the acupuncture point choice, the form of stimulation and the duration of the therapy [
]. Chinese acupuncture, an adjunct therapy, has gained increased attention in the medical field at home and abroad in recent years. Prospective clinical trials have demonstrated that acupuncture was effective in treating pain caused by diabetes as well as HIV virus infections [
], and various clinical trials have shown the effect of acupuncture in alleviating neuropathic pain in cancer patients [
]. In addition, a case series has proven the efficacy of body acupuncture in treating patients with CIPN [
], and a pilot study demonstrated that acupuncture improved nerve conduction in peripheral neuropathy [
]. In recent studies, statistically and clinically significant reductions in subjective measurements of bortezomib-induced peripheral neuropathy (BIPN) were observed after acupuncture treatment [
]. However, to date, there have been no randomized controlled clinical research to analyze the effectiveness of acupuncture in treating CIPN of MM patients.
Since previous research showed that acupuncture had good treatment effects on peripheral neuropathy of diabetes and HIV/AIDS patients, we hypothesized that acupuncture treatment of MM CIPN will also have positive therapeutic effects.
To the best of our knowledge, this is the first randomized, controlled, prospective study on the use of acupuncture in the treatment of multiple myeloma patients with CIPN grades II–IV [
]. After 84 days (three cycles) of therapy, although methylcobalamin treatment alone was helpful in relieving pain and improving the quality of life, the study showed that acupuncture combined with methylcobalamin for the treatment of CIPN was significantly superior in providing pain relief (VAS pain scores) and life quality improvement (FACT/GOG-Ntx questionnaire scores). Our results are in agreement with previous reports that acupuncture has a beneficial effect on peripheral neuropathy and are consistent with the study of Schroder et al [
]; nerve conduction in the sural nerve was improved best in our study [
]. The SCV of the median nerve did not change after a Met + Acu therapy, which might reflect the choice of acupuncture points, indicating that they have a major impact on the therapeutic effects [
According to traditional Chinese medicine (TCM) theory, the symptoms of CIPN are caused by the body’s failure to direct Qi (vital energy) and blood to the four limbs, resulting in sensory symptoms and impaired limb function while acupuncture restores body Qi and blood, and directs their flow to the extremities [
], which is supported by a studies which demonstrated that acupuncture led to vasodilation and enhanced blood perfusion [
It has been suggested, that bortezomib mainly affects the dorsal root ganglia (DRG) of the primary sensory neurons leading to disturbed transcription, nuclear processing and transport, as well as cytoplasmic translation of mRNAs and histopathological changes in the DRG neurons. In addition, neural survival is compromised due to inhibition of nerve growth factor (NGF) transcription [
] and a highly significant correlation between the decrease in circulating levels of NGF and the severity of CIPN has been reported (
< 0.001) [
Previous animal studies noted that both protein and mRNA levels of glial cell line-derived neurotrophic factor (GDNF) and GDNF family receptor alpha-1 (GFRalpha-1) were upregulated in the DRGs after acupuncture [
However, another recent study found that acupuncture significantly changed the expression of 17 hypothalamic proteins in a rat neuropathic pain model [
]. Taken together, though enhanced blood perfusion as result of acupuncture has been proven in humans, other mechanisms of specific gene expression changes have so far only been investigated in animal models. It is also unclear whether acupuncture leads to histological changes, which might be evaluated in future studies with biopsy-analyses [
]. In addition, since the acupoints were established in TCM several centuries ago, analysis of acupoints with advanced techniques like MRI may lead to improved results.
There were no obvious unexpected side effects during the treatments of both groups, and puncture site infections or bleeding did not occur during the acupuncture process, suggesting that acupuncture is a safe treatment for CIPN in MM patients.
The study was financially supported by grants from the Administration of Traditional Chinese Medicine Science and Technology Program of Zhejiang Province, Program Number: 2010ZA057, 2014ZB060; the Science and Technology Project of the Health Department of Zhejiang Province, Program Number: 2013KYA071; and the National Natural Science Foundation of China, Program Number: 81471532, 81402353.
Availability of data and materials
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
XYH and ZC designed the study. XYH performed the study and statistical analysis, XYH and LJW assessed the efficacy and wrote the manuscript, HFS was responsible for acupuncture, GFZ, JSH, WJW, GQW, JMS, WYZ, JS, HH and ZC recruited and managed the patients. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The study was approved by the ethical committee of the First Affiliated Hospital, School of Medicine, Zhejiang University and informed written consent was obtained from all of the patients before their participation in the study.