Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive and dose-dependent complication which can lead to limit the standard chemotherapy treatment. In addition, CIPN affects the patients quality of life during and after treatment [1].
The aim of this study is the evaluation of memantine efficacy, an uncompetitive NMDA receptor antagonist, in the prevention of docetaxel induced neuropathy in patients with breast cancer. According to the scores of DN4 and CTCAE questionnaires in the baseline and three follow-up stages, a significant difference was observed between control and intervention groups, which could be a reason for the positive efficacy of memantine in reducing the severity of neuropathy caused by docetaxel in patients participating in intervention group. According to the score of the questionnaires, it can be said that in intervention group, neuropathy has developed with less severity.
Data showed a significant difference between the control and intervention groups in terms of the time onset of neuropathy (p-value: 0.001). Subsequently, after the first cycle of docetaxel, 11 (55%) in the control group and 1 (5%) in the memantine group and after the second cycle, 6 (30%) in the control group and 8 (40%) in the memantine group experienced neuropathy. In addition, after the third cycle, (0%) in the control group and 3 (15%) in the memantine group and finally at the end of chemotherapy, 1 (5%) in the control group and 0 (0%) in the memantine showed neuropathy (the severity is mentioned in Table 1). Our data showed that fewer people in intervention group (12 patients out of 20) had neuropathy than in control group (18 patients out of 20). Moreover, in intervention group neuropathy started with a delay. In addition, the duration of neuropathy between the control and intervention groups was as follows: in the control group, 10(50%) patients with transient neuropathy, 2(10%) patients with continuous neuropathy and 6(30%) patients with transient and then continuous neuropathy were reported. However, in the intervention group, 10(50%) patients with transient neuropathy, 0(0%) patients with continuous neuropathy and 2(10%) patients with transient and then continuous neuropathy were reported.
Although based on these data, memantine does not reduce the risk of acute neuropathy (TAPS), but according to the results, the severity of neuropathy decreased. The data also showed that memantine was able to reduce both the incidence and severity of chronic neuropathy, which is due to the neuroprotective effect of memantine and due to the pathophysiology of both neuropathies, which is the result of nerve damage.
In a study by Loprinzi et al., which performed on 94 patients receiving paclitaxel, there was a significant association between the severity of transient acute neuropathy and long-term subacute neuropathy[13]. Taxane induced acute pain syndrome (TAPS) is most commonly seen in high doses and is characterized by severe arthralgia and myalgia with numbness and tingling, which usually occurs within one to three days after administration of taxane and usually lasts for 5 to 7 days. Although, TAPS is clinically distinct from CIPN, it has some clinical features in common with chemotherapy-induced peripheral neuropathy (CIPN). Prevention of acute neuropathy can reduce the severity of persistent neuropathy [14].
The related guidelines have not suggested any agent for the prevention of CIPN [5]. Due to the previous studies, duloxetine can be effective in treatment of CIPN. Although, there are strong evidences for duloxetine efficacy in treatment of CIPN, due to its side effects and interactions, it is prescribed only in cases of severe neuropathy [15, 16]. For example, one of the major interactions of duloxetine is the inhibition of the tamoxifen conversion to the active metabolite of endoxifen by inhibiting the enzyme Cyp450 2D6 [5, 17].
NMDA receptor is one of the most important channel receptors that mediates rapid excitatory neurotransmission in the central nervous system and plays an important role in the phenomenon of central sensitization [18].
Recent animal data has shown that high concentrations of glutamate can cause cell death by activating NMDA receptors. So that in animal studies, high levels of glutamate have been observed in cellular expenditure during ischemia and trauma [18].
One hypothesis that explains the role of glutamate in slow and persistent neuronal destruction of nerve cells is the " slow excitotoxicity" hypothesis. This hypothesis states that if factors such as ion channel dysfunction, changes in cell ion homeostasis, or lack of energy cause depolarization of the postsynaptic membrane. In such a case, the cell may also be destroyed by physiological concentrations of glutamate [19].
Although high concentrations of glutamate cause cell damage, physiological concentrations are essential for long-term improvement in learning and memory. On the other hand, if NMDA receptors are completely blocked by its antagonists, it can lead to serious complications such as coma, drowsiness and hallucinations. Consequently, maintaining the normal physiological activity of NMDA receptors is very important in order to maintain normal neuronal functions and prevent clinical side effects [9].
Due to the vital role of glutamate, its toxicity should be blocked without interfering with its physiological function. Measurements of extracellular glutamate in rodents immediately after brain injury have shown that although the concentration increases rapidly, this concentration is not stable and remains high for only 10–30 minutes after injury. Unfortunately, the concentration of extracellular glutamate in humans is immeasurable immediately after brain injury. But general analysis shows a stable low concentration of glutamate that may last for days and weeks [20]. This long-term increase in glutamate concentration after nerve injury has made NMDA antagonists a viable treatment option for neuropathic pain. However, Ikonomidou et al. Stated that a slight increase in glutamate concentration after injury may be due to the brain's self-defense mechanism, which maintains neuronal survival and repairs nerve tissue [19]. Therefore, NMDA antagonist administration in a few hours after brain injury can prevent the protective effect of glutamate and damage nerve cells [20]. Therefore, according to studies by Ikonomidou et al., NMDA antagonists can have a protective effect if used in a prophylactic protocol [19].
However, NMDA receptor antagonists such as ketamine, memantine, or dextromethorphan have been shown to relieve neuropathic pain. but, some of these antagonists, such as ketamine, have severe side effects that limit their clinical use [10].
Memantine selectively prevents NMDA receptor over activity without affecting the receptor's normal function. It also separates easily from the canal at the end of its duration and does not accumulate in the canal. Therefore, synaptic activity continues uninterrupted in physiological conditions despite the presence of memantine [9]. The profile of adverse effects of the memantine is safe and well tolerated by patients [10] .Having such properties has made memantine a viable treatment option for the prevention of chronic pain associated with increased NMDA receptor activity. In a trial conducted by Ghaffary et al., On 172 patients, results shown that prescribing memantine before cardiac surgery protects patients against Post-operative cognitive dysfunction (POCD), early after cardiac surgeries. It also improves POCD, three months after surgery [9].
To the best of our knowledge, no study has been performed specifically on the effect of memantine and other NMDA receptor antagonists on taxane induced acute pain syndrome. However, several animal studies have shown the effectiveness of memantine in reducing neuropathic pain. For example, a study was conducted in 2010 which investigated the effect of memantine and morphine on vincristine-induced neuropathy in rats. Memantine at doses of 2.5, 5, 10 mg / kg intraperitoneal, morphine at doses of 2.5, 5, 10 mg / kg intraperitoneal and vehicle (saline) were received by rats. Only the highest dose of memantine was able to increase the paw removal threshold compared with placebo. It was concluded that memantine and morphine can be a treatment for this type of neuropathy [8]. A similar study was conducted in 2016 that examined the effect of memantine on paclitaxel-induced neuropathic pain in rats. It was concluded that memantine improves mechanical sensitivity and increases paw removal threshold in rats [7].
The effects of NMDA receptor antagonists in reducing the severity of neuropathic pain have also been reported in various clinical studies, especially when given before nerve damage [8]. Morel et al., in a randomized, pilot clinical trial, showed that memantine can prevent post-mastectomy pain. Patients took memantine (5 to 20 mg daily; n = 20) or placebo (n = 20) for two weeks before and two weeks after surgery [10]. In a double-blind clinical study conducted in 2017 by Rahimzadeh P et al, it was concluded that taking oral single-dose 20 mg of memantine orally, one hour before dacryocystorhinostomy (DCR), is effective in reducing postoperative pain and reduced the demand for morphine during recovery. The total number of patients was 60 who were divided into memantine and control groups. and The intensity of pain was measured through visual analogue scale (VAS) at recovery in 1, 2, and 6 hours after operation [21]. Another study was conducted in 2017 comparing the effect of dextromethorphan and memantine on the reduction of neuropathic pain after elective orthopedic surgery of the lower limbs. The number of patients was 180 who were randomly divided into three groups of 60 people. The first group received memantine (30 mg) orally, the second group received dextromethorphan (45 mg) and the third group received placebo only, two and a half hours before surgery [22]. However, a placebo-controlled clinical trial conducted by Eisenberg et al. In 1998 showed that memantine did not show significant efficacy in reducing pain intensity in patients with post herpetic neuralgia (PHN) compared with placebo. The number of patients participating in this study was 24 who were randomly divided into two groups of 12. The duration of the study was 5 weeks. Patients received memantine at a dose of 10 mg daily for the first week and at a dose of 20 mg daily for the next 4 weeks. In this study, Multidimensional Personality Questionnaire (MPQ), Net Promoter Score (NPS) and questionnaire and triage tool (QTT), were used to assess the severity of patients' pain [23]. The ineffectiveness of memantine in this study is probably due to the short duration of the study and the small sample size.
Considering the role of NMDA receptor and central sensitization due to increased activity of this receptor in various neuropathic pains and according to the findings of studies, it is expected that NMDA receptors can be effective in reducing the severity of pain due to nerve damage. However, more studies are needed on the use of these drugs, especially memantine, in the control and prevention of acute pain. According to the data of the present study, memantine has been able to prevent neuropathy and has reduced the severity of neuropathy. The duration of memantine consumption in this study was eight weeks and the last dose of memantine was before the end of the second cycle of docetaxel. Patients did not receive memantine for the next two cycles of docetaxel. While, the time onset of neuropathy in most of the intervention group was after the end of the second cycle and only 1 patient developed neuropathy in the first cycle. Nevertheless, the time onset of neuropathy in most of the patients in control group was after the first cycle. It should be mentioned that, it seems that if patients had received memantine by the end of docetaxel cycles, they would probably not have developed neuropathy. However, further studies are recommended to substantiate this hypothesis.
Data showed that memantine reduced the severity of the neuropathy and delayed the onset of neuropathy. In addition, memantine reduced the duration of neuropathy in patients. Memantine reduced the severity of acute taxane induced pain syndrome (TAPS). Because TAPS can be the cause of subsequent neuropathy, it can be concluded that memantine, as a factor that reduces the severity of TAPS, can reduce the incidence and severity of chronic neuropathy. In conclusion, memantine can be considered as an effective drug in prophylaxis of taxane-induced neuropathy. However, memantine not labeled for the use under discussion or that the product is still investigational.