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.