4. Discussion
To our knowledge, this is the first randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of silymarin in the treatment of CIPN. The silymarin-treated group showed a significant reduction in pain (measured by the VAS criterion) compared with those receiving placebo. Silymarin also significantly reduced the severity of peripheral neuropathy and more people in the silymarin-treated group showed improvement in peripheral neuropathy compared to the comparison group. But despite the improvement in quality of life in the intervention group compared to the comparison group, this difference was not statistically significant.
The development of CIPN during chemotherapy adversely affects the outcome of the disease and the patient’s quality of life [19]. Cumulative doses of chemotherapy drugs, prior or concomitant administration of other neurotoxic drugs (such as cisplatin plus paclitaxel combination therapy), pre-existing neuropathy, co-morbidities and finally the short injection time of the drug are the most important risk factor for CIPN [2].
More than 40 randomized trials have evaluated a variety of pharmacologic interventions for the treatment of CIPN, only limited agents such as duloxetine and in some trials gabapentin were effective [20-22]. Due to the side effects of synthetic drugs following long-term use for painful and inflammatory conditions, many studies have tested different plant extracts and their active compounds for their analgesic and anti-inflammatory properties [23]. Oxidative stress and increased free radicals have been suggested as an important cause of CIPN. Silymarin, due to its antioxidant activity, may have protective effect against neuropathy [24]. Silymarin is a free radical scavenger that affects various stages of the arachidonic acid cascade via the cyclogenase and lipoxygenase pathways [7].
The present study showed significantly better improvement of CIPN following use of silymarin compared to placebo (82.8% vs. 48.4%). The initial evidence of efficacy of silymarin in CIPN comes from experimental studies. Mannelli et al evaluated the efficacy of silybinin, an structural component of silymarin [25], in reducing oxaliplatin-induced neuropathic pain in a rat model. They reported that repeated administration of silybinin reduces oxaliplatin-induced pain. Silybinin was introduced as a valid treatment option for chemotherapy-induced neuropathy [26].
The effects of topical administration of silymarin in prevention of capecitabine-induced Hand–Foot Syndrome (HFS) were evaluated in a randomized, double-blinded, placebo controlled clinical trial. The trial concluded that prophylactic administration of topical silymarin could significantly reduce the severity of capecitabine-induced HFS and delay its occurrence in patients with gastrointestinal cancer after 9 weeks of application [27]. Choi et al. showed that oxaliplatin-induced neuropathy was inhibited by silymarin through combined mechanisms of combating oxidative stress, p38-mediated mitogen-activated protein kinase apoptosis, and decreased brain derived neurotrophic factor expression [28].
Following exposure to platinum agents, several morphological changes in DNA including damage to cell bodies, nuclei, nucleoli, neuronal atrophy in dorsal root ganglion cells and cell death may occur. In addition to platinum agents, ROS may have a role in the pathophysiology of CIPN following other chemotherapy agents such as taxane derivatives. Paclitaxel enhances the formation of ROS through alterations in mitochondria and subsequent pain caused by neurological and inflammatory damage through transient receptor potential ankyrin 1 (TRPA1) channels. It also leads to the production of Interleukin-1 β (IL-1β) and other proinflammatory cytokines secreted from microglia [26, 28]. Vinca alkaloids, including vincristine cause inflammatory reactions in peripheral tissues and make changes in spinal afferent fiber. Increased C fiber degradation, calcium channel modulation, production of free radicals are mechanisms proposed for neuropathic pain following taxan derivatives. Also, they increase TNF-α and IL-6 in the sciatic nerve following oxidative stress [29, 30]. Based on the aforementioned evidences, it seems that oxidative stress is the main cause of neuropathic pain by nearly all types of chemotherapy agents. So the beneficial effect of silymarin in CIPN could be contributed to its proven antioxidant properties [31].
Growing evidences suggest that different immune cells and subsequently inflammation are involved in the development of neuropathic pain. Activation of mast cells and secretion of inflammatory mediators (histamine and Tumor Necrosis Factor [TNF]-α) may lead to peripheral nerve damage. Silymarin modulates the immune system by inhibiting neutrophil migration and immobilization of mast cells. It also inhibits TNF-α mediated production of reactive oxygen species, lipid peroxidation and modulates T cell function [32-34].
For an anti-neuropathic agent to be desirable in CIPN, it is necessary that the agent does not interfere with the cytotoxicity effect of the chemotherapy agent [35].
It was shown that silymarin poses a dual action as a chemopreventive agent and a chemosensitizer. Silymarin inhibits organic anion transporters (OAT) and ATP-binding cassettes (ABC) transporters which are helpful in overcoming the resistance to chemotherapy [36]. It may has a protective role against cancer in vivo and in vitro by inducing an imbalance between cell survival and apoptosis by disrupting the expression of cell cycle regulators and proteins involved in apoptosis [37]. Also anti-metastatic activity has been reported for silybinin [28].
Our study suffers from this limitation that it was not powered enough for subgroup analysis based on CIPN associated with different chemotherapeutic agents. Considering the positive findings of this trial, we recommend conducting future clinical trials to have a better understanding of usefulness of silymarin in treatment of CIPN induced by a given chemotherapeutic class.