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
] 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
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
]. 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
], brain-derived neurotrophic factor (BDNF) [51
], 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
] 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 , we summarized the acupuncture mechanisms and mediators in CIPN based on what we know from animal studies of diabetic neuropathy [59
] and from human studies of brain imaging during acupuncture [62
Figure 1 Possible targets of acupuncture treatment in CIPN. On the left side are the nervous system areas which are activated by acupuncture; on the right side are some possible beneficial effects of acupuncture in CIPN patients. CIPN = chemotherapy-induced peripheral (more ...)
It is interesting to note that all the studies which used somatic acupuncture and described their protocol [24
] 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.