Littérature scientifique sur le sujet « Oxaliplatin-induced neuropathic pain »

The antineoplastic agent oxaliplatin induces an acute hypersensitivity evoked by cold that has been suggested to be due to sensitized central and peripheral neurons. Rodent-based preclinical studies have suggested numerous treatments for the alleviation of oxaliplatin-induced neuropathic pain, but few have demonstrated robust clinical efficacy. One issue is that current understanding of the pathophysiology of oxaliplatin-induced neuropathic pain is primarily based on rodent models, which might not entirely recapitulate the clinical pathophysiology. In addition, there is currently no objective physiological marker for pain that could be utilized to objectively indicate treatment efficacy. Nonhuman primates are phylogenetically and neuroanatomically similar to humans; thus, disease mechanism in nonhuman primates could reflect that of clinical oxaliplatin-induced neuropathy. Cold-activated pain-related brain areas in oxaliplatin-treated macaques were attenuated with duloxetine, the only drug that has demonstrated clinical efficacy for chemotherapy-induced neuropathic pain. By contrast, drugs that have not demonstrated clinical efficacy in oxaliplatin-induced neuropathic pain did not reduce brain activation. Thus, a nonhuman primate model could greatly enhance understanding of clinical pathophysiology beyond what has been obtained with rodent models and, furthermore, brain activation could serve as an objective marker of pain and therapeutic efficacy.

Chemotherapy-induced peripheral neuropathy is a common factor in limiting therapy which can result in therapy cessation or dose reduction. Gabapentin, a calcium channel inhibitor, and duloxetine, a serotonin noradrenaline reuptake inhibitor, are used to treat a variety of pain conditions such as chronic low back pain, postherpetic neuralgia, and diabetic neuropathy. It has been reported that administration of gabapentin suppressed oxaliplatin- and paclitaxel-induced mechanical hyperalgesia in rats. Moreover, duloxetine has been shown to suppress oxaliplatin-induced cold allodynia in rats. However, the mechanisms by which these drugs prevent oxaliplatin- and paclitaxel-induced neuropathy remain unknown. Behavioral assays were performed using cold plate and the von Frey test. The expression levels of proteins were examined using western blot analysis. In this study, we investigated the mechanisms by which gabapentin and duloxetine prevent oxaliplatin- and paclitaxel-induced neuropathy in mice. We found that gabapentin and duloxetine prevented the development of oxaliplatin- and paclitaxel-induced cold and mechanical allodynia. In addition, our results revealed that gabapentin and duloxetine suppressed extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation in the spinal cord of mice. Moreover, PD0325901 prevented the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 activation in the spinal cord of mice. In summary, our findings suggest that gabapentin, duloxetine, and PD0325901 prevent the development of oxaliplatin- and paclitaxel-induced neuropathic-like pain behavior by inhibiting ERK1/2 phosphorylation in mice. Therefore, inhibiting ERK1/2 phosphorylation could be an effective preventive strategy against oxaliplatin- and paclitaxel-induced neuropathy.

Oxaliplatin is a chemotherapeutic agent widely used against colorectal and breast cancers; however, it can also induce peripheral neuropathy that can rapidly occur even after a single infusion in up to 80–90% of treated patients. Numerous efforts have been made to understand the underlying mechanism and find an effective therapeutic agent that could diminish pain without damaging its anti-tumor effect. However, its mechanism is not yet clearly understood. The serotonergic system, as part of the descending pain inhibitory system, has been reported to be involved in different types of pain. The malfunction of serotonin (5-hydroxytryptamine; 5-HT) or its receptors has been associated with the development and maintenance of pain. However, its role in oxaliplatin-induced neuropathy has not been clearly elucidated. In this review, 16 in vivo studies focused on the role of the serotonergic system in oxaliplatin-induced neuropathic pain were analyzed. Five studies analyzed the involvement of 5-HT, while fourteen studies observed the role of its receptors in oxaliplatin-induced allodynia. The results show that 5-HT is not involved in the development of oxaliplatin-induced allodynia, but increasing the activity of the 5-HT1A, 5-HT2A, and 5-HT3 receptors and decreasing the action of 5-HT2C and 5-HT6 receptors may help inhibit pain.

Oxaliplatin-induced neuropathic pain limits treatment compliance. However, the variability of neuropathic pain symptoms in each cycle for individual patients and the impacts on treatment compliance remain untested. Data from 322 adult patients who received oxaliplatin-based chemotherapy were extracted based on pattern of chemotherapy, adverse events, and patient survival. Cox regression and survival analyses were employed. Seventy-eight percent of patients developed neuropathic pain that oscillated between a complete absence and presence on a cycle-by-cycle basis. Consequently, the presence of neuropathy in one cycle did not predict the incidence of neuropathy in subsequent cycles. This implies that neuropathic pain need not be a sufficient criterion to reduce, delay, or cease chemotherapy. In the case of multiple system adverse events during combined drug treatment, the responsible cause for dose reduction was not identified. Cox regression analysis revealed that middle age (61–78 years old,P=0.003) and oxaliplatin cumulative dose <850 mg/m2(P=0.002) were associated with patient mortality. Completion of chemotherapy (8 cycles) and cumulative dose >850 mg/m2of oxaliplatin prolonged the median survival time by 8 and 5 months, respectively. As oxaliplatin-induced neuropathic pain fluctuates across cycles in a manner that varies from patient-to-patient, current assumptions on the predictive nature of the emergence of neuropathy (and its impact on treatment compliance) need to be reconsidered. Detailed patient-by-patient analysis of adverse events should be applied to future studies in order to determine the efficacy of current treatments (and future interventions) and whether neuropathic pain should be retained as a criterion to vary the treatment. Additionally, when two or more system toxicities occurred in cases of combined drug treatment, the causes for drug reduction should be separately recorded.

AbstractColorectal cancer is one of the most common oncological diseases. Chemotherapy is usually recommended as an adjuvant treatment for stage-II, -III, and -IV tumors. Approximately 10% of the patients develop neuropathic pain after chemotherapy, and they may remain refractory despite the administration of drugs that are commonly used to treat neuropathic pain. Spinal cord stimulation is a good treatment option for neuropathic pain of the lower limbs, and it should be trialed in patients with chemotherapy-induced peripheral neuropathy. We report the case of a patient with oxaliplatin-induced neuropathy and neuropathic pain refractory to oral medication who was successfully treated by spinal cord stimulation.

Purpose. Oxaliplatin is a platinum compound widely used in gastrointestinal cancer treatment but produces dose-limiting peripheral neuropathy. New insights into oxaliplatin-induced peripheral neuropathy (OIPN) assessment are needed to detect more effectively this condition. In this context, we conducted Canaloxa study, a prospective preliminary clinical trial that aimed to investigate how Electrochemical Skin Conductance (ESC), a parameter used in small fiber neuropathy assessment, could be helpful in OIPN diagnosis. Methods. Cancer patients treated for at least three months with oxaliplatin and suffering from clinically OIPN were included. Electrochemical Skin Conductance, thermal thresholds, and neuropathic pain were assessed in all included patients. Results. During one year, 36 patients were included. The main result was the correlation between ESC and Neuropathic Pain Symptom Inventory score for hands (rho value = -0.69, p < 0.0001) and feet (rho value = -0.79, p < 0.0001). ESC values were lower in neuropathic patients with painful symptoms than in ones without painful symptoms (p = 0.0003 and p < 0.0001 for hands and feet, respectively). No correlation was observed between ESC and thermal thresholds. Conclusion. These preliminary data suggest that ESC could be a useful objective marker of painful oxaliplatin-induced neuropathy and could complement the use of subjective clinical scales. This study was prospectively registered on clinicaltrials.gov (NCT02827916) before patient recruitment has begun.

Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb mixture composed of Aconitum carmichaelii, Angelica gigas, and Zingiber officinale. Its anti-tumor effect has been reported; however, the efficacy of JI017 against oxaliplatin-induced allodynia has never been explored. Single oxaliplatin injection [6 mg/kg, intraperitoneal, (i.p.)] induced both cold and mechanical allodynia, and oral administration of JI017 (500 mg/kg) alleviated cold but not mechanical allodynia in mice. Real-time polymerase chain reaction (PCR) analysis demonstrated that the upregulation of mRNA of spinal transient receptor potential vanilloid 1 (TRPV1) and astrocytes following oxaliplatin injection was downregulated after JI017 treatment. Moreover, TRPV1 expression and the activation of astrocytes were intensely increased in the superficial area of the spinal dorsal horn after oxaliplatin treatment, whereas JI017 suppressed both. The administration of TRPV1 antagonist [capsazepine, intrathecal (i.t.), 10 μg] attenuated the activation of astrocytes in the dorsal horn, demonstrating that the functions of spinal TRPV1 and astrocytes are closely related in oxaliplatin-induced neuropathic pain. Altogether, these results suggest that JI017 may be a potent candidate for the management of oxaliplatin-induced neuropathy as it decreases pain, spinal TRPV1, and astrocyte activation.

Oxaliplatin is a third-generation platinum drug and is widely used as a first-line therapy for the treatment of colorectal cancer (CRC). However, a large number of patients receiving oxaliplatin develop dose-limiting painful neuropathy. Here, we report that αO-conotoxin GeXIVA[1,2], a highly potent and selective antagonist of the α9α10 nicotinic acetylcholine receptor (nAChR) subtype, can relieve and reverse oxaliplatin-induced mechanical and cold allodynia after single and repeated intramuscular (IM) injections in rats. Treatments were started at 4 days post oxaliplatin injection when neuropathic pain emerged and continued for 8 and 16 days. Cold score and mechanical paw withdrawal threshold (PWT) were detected by the acetone test and von Frey test respectively. GeXIVA[1,2] significantly relieved mechanical and cold allodynia in oxaliplatin-treated rats after a single injection. After repeated treatments, GeXIVA[1,2] produced a cumulative analgesic effect without tolerance and promoted recovery from neuropathic pain. Moreover, the long lasting analgesic effect of GeXIVA[1,2] on mechanical allodynia continued until day 10 after the termination of the 16-day repeated treatment procedure. On the contrary, GeXIVA[1,2] did not affect acute mechanical and thermal pain behaviors in normal rats after repeated injections detected by the von Frey test and tail flick test. GeXIVA[1,2] had no influence on rat hind limb grip strength and body weight after repeated treatments. These results indicate that αO-conotoxin GeXIVA[1,2] could provide a novel strategy to treat chemotherapy-induced neuropathic pain.

Les neuropathies périphériques induites par la chimiothérapie (NPIC) sont un effet indésirable commun des agents anticancéreux. Les symptômes des NPIC sont principalement sensitifs : douleurs, fourmillements, sensations d’engourdissement, altérations de la sensibilité thermique et mécanique. La symptomatologie des NPIC est associée à une forte altération de la qualité de vie des patients, et peut dans certains cas conduire à une diminution des doses et des cycles de chimiothérapie, voire à un arrêt du traitement. La prise en charge actuelle des NPIC repose principalement sur l’utilisation de molécules recommandées dans le traitement des douleurs neuropathiques, et dont l’efficacité reste très modeste. L’intérêt de l’utilisation de modulateurs du système rénine-angiotensine, et plus principalement de la stimulation des récepteurs AT2 à l’angiotensine II, a été précédemment mis en évidence au sein du laboratoire, dans un modèle murin de neuropathie induite par la vincristine. Au cours du présent travail, nous avons développé un modèle de douleur neuropathique induite par l’oxaliplatine (OXP), un agent anticancéreux de la famille des sels de platine. Nous avons mis en évidence un effet bénéfique du ramipril, un inhibiteur de l’enzyme de conversion de l’angiotensine I en angiotensine II, dans la douleur neuropathique induite par l’OXP. Nous avons également mis en évidence l’effet préventif du ramipril et du candésartan, un antagoniste des récepteurs AT1 à l’angiotensine II, contre l’allodynie mécanique induite par le paclitaxel (PTX), un agent anticancéreux de la famille des taxanes. L’effet préventif du candésartan contre l’hypersensibilité mécanique induite par le PTX est médiée par la stimulation indirecte des récepteurs AT2 à l’angiotensine II. Paradoxalement, la stimulation directe ou indirecte des récepteurs AT2 n’a pas permis de prévenir la douleur neuropathique induite par l’OXP. Ces travaux mettent donc en lumière la nécessité du développement d’un traitement des NPIC adapté à la physiopathologie de chaque agent anticancéreux
Chemotherapy-induced peripheral neuropathies (CIPN) are a common side effets of chemotherapeuticagents. CIPN symptoms are mainly sensitive: pain, tingling, numbness or alterations of thermal andtactile sensitivity. CIPN symptomatology is associated to decreased patient quality of life and can leadto decreased chemotherapy doses and cycles, or even therapy cessation. Current CIPN managementconsists in the administration of medications recommended in the treatment of neuropathic pain, withvery low efficacy. The benefit of using renin-angiotensin system modulators has been previouslydemonstrated in our lab, in a murine model of vincristine-induced peripheral neuropathy. In thepresent work, we developed a new model of neuropathic pain, induced by oxaliplatin (OXP), achemotherapeutic agent belonging to the platinum family. We showed that an angiotensin-convertingenzyme inhibitor, ramipril, was able to alleviate OXP-induced neuropathic pain. We also showed thatboth ramipril and candesartan, an angiotensin II AT1 receptor antagonist, were able to prevent tactileallodynia induced by paclitaxel (PTX), a chemotherapeutic agent belonging to the taxane family. Thepreventive effect of candesartan against PTX-induced tactile allodynia is mediated by the indirectstimulation of angiotensin II AT2 receptors. Paradoxically, the direct or indirect AT2 receptorsstimulation did not prevent OXP-induced neuropathic pain, thus highlighting the necessity to adapt thepotential CIPN treatments to each chemotherapeutic agent physiopathology

Oxaliplatin is commonly used for the treatment of advanced and recurrent colorectal cancer (CRC). However, oxaliplatin-induced neuropathic pain remains a challenge for the healthcare systems worldwide. In chapter II, the incidence and impact of acute oxaliplatin-induced neuropathic pain on chemotherapy treatment in colorectal cancer patients in the first cycle from the published research literature was explored. In chapter III, the variability of oxaliplatin-induced neuropathic pain symptoms from the Southwestern Sydney Local Health District Hospitals (SWLHDHs) database of patients who received oxaliplatin based chemotherapy treatment (2011-2015) and the implications for the management of colorectal cancer patients was assessed. In chapter IV, it was explored whether oxaliplatin can induce behavioural hypersensitivity in healthy rats using the dosing regimen that mimics the standard clinical protocols (oxaliplatin 2.5 mg/kg i.p every two weeks). In chapter V, the effects of oxaliplatin and 56MESS(IV) on the viability, PI staining (cell death) and activation (nitrite production) of RAW264.7 (macrophages) and N11 (microglia) cell lines were explored in vitro. In summary, oxaliplatin-induced neuropathic pain remains a big problem as it affects treatment compliance in quarter of CRC patients during cycle 1 and as neuropathic pain symptoms oscillate across cycles for individual patients. This warrants further detailed patient-by-patient analysis of pain symptoms in future clinical trials. Additionally, the in vivo and in vitro data showed that minocycline pre-treatment has a potential to ameliorate oxaliplatin and 56MESS(IV) induced production of pro-inflammatory chemical mediators such as nitrite in vitro cell lines, which may be relevant to in vivo models of chemotherapy-induced neuropathic pain. However, oxaliplatin-induced neuropathic pain is more likely multifactorial and research should be continued on the mechanisms of neuropathy and potential therapeutic drugs.

Oxaliplatin therapy of colorectal cancer induces a dose-dependent neuropathic syndrome in 50% of patients. Pharmacological treatments may offer limited relief; scientific efforts are being solicited to define a new therapeutic approach. Interestingly, adult mesenchymal stem cells offer a totipotent cellular source for replacing injured neural cells and at the same time represent a source of neuroprotective and anti-inflammatory mediators, opposing the effect of nerve damage. In our hands, adipose-derived stem cells (ASCs) injection (2x106 ASCs/rat i.v.) were able to counteract mechanical hyperalgesia induced by repeated oxaliplatin administration in rats (2.4 mg kg-1 i.p. for a total of 10 administrations). This effect reached a maximum 6h after ASCs administration and lasted up to 72h. Subsequent ASCs administrations induced a reduction of hypersensitivity, with a similar efficacy trend over time. Investigating a possible mechanism of action by which ASCs exert their effect, 2x106 ASCs labeled with 1 µM of the fluorescent probe 5-(and-6-9-(((4-chloromethyl)benzoyl)amino) tetramethylrhodamine were injected in order to evaluate the localization of ASCs in the rat body. Labelled ASCs were detectable in the bloodstream 1 and 3 h after injection, the percentage gradually decreased, 24 h after administration no cells were found. At this time, ASCs were detected in the liver digested homogenate. No ASCs were found in the central nervous system and in lungs. VEGF-A, EGF and TGF-β were assayed in plasma. EGF and TGF-β were not altered by oxaliplatin or ASCs treatments. On the contrary, VEGF-A concentration significantly increased in oxaliplatin-treated rats in comparison to the control group whereas ASCs were able to counteract this alteration, suggesting both a possible implication of VEGF modulation in the development of neuropathic pain and in ASCs pain relieving mechanism. This hypothesis was strengthened by the reduction of oxaliplatin-induced hyperalgesia after an acute i.p. administration of the VEGF-antibody bevacizumab (dose-dependently, 1-15 mg kg-1). Moreover, plantar injection of the pain-related isoform VEGF165b (10-100 ng) in naïve rats, significantly decreased the pain threshold up to 3 h after administration in a bevacizumab-reverted manner (15 mg kg-1). VEGF165b (30-100 ng) dose-dependently, significantly reduced the weight tolerated on the posterior paw also after an intrathecal administration. These data led us to further investigate the role of VEGF-A in modulating pain signaling and the correlation between ASCs anti-nociceptive efficacy and VEGF-A modulation in central nervous system. As evaluated by western blot analysis, oxaliplatin repeated treatment significantly increased VEGF165b expression in spinal cord and PAG while in DRG, cortex and thalamus the protein levels were not influenced with respect to control group. ASCs i.v. injected significantly counteracted the oxaliplatin-dependent VEGF165b increase only in spinal cord. Accordingly, an intrathecal administration of ASCs (75x103/rat) was able to revert hyperalgesia induced by repeated oxaliplatin treatments starting from 1 h after the injection and up to 6 h. To further investigate the link between central VEGF-A and the modulation of pain perception, the selective neutralization of VEGF-A and VEGF165b was performed both in oxaliplatin-treated and in control rats. The specific antibody against VEGF165b, i.t. injected (7.5 μg/rat), significantly decrease oxaliplatin-induced hyperalgesia with similar efficacy to bevacizumab (45 μg/rat i.t. injected) but with higher potency. The modulation of VEGF-A is suggested as a key mechanism in the complex response orchestrated by stem cells against neuropathy and the role of ASCs “secretome” as effector of their efficacy is highlighted. For this reason, an artificial and biocompatible niche in which ASCs can be maintained was set up and the efficacy of this engineered niche in relieving oxaliplatin-induced neuropathic pain was tested. As physiologically occurs in tissues, the artificial niches should promote ASCs proliferation, ensuring the maintenance of their stemness and meanwhile permit a bidirectional flux of solutes from the inner and outer environment without a direct delivery of ASCs. For this purpose, 4x106 rASCs were encapsulated into each artificial niche (AlgiMatrix® sponge), the day after AlgiMatrix® sponges were implanted s.c. in the back of neuropathic rats (two sponges per rat). Encapsulated rASCs significantly reduced mechanical hypersensitivity induced by oxaliplatin treatment beginning 6h after the surgery. The effect on hypersensitivity remained constant for 7 days after AlgiMatrix® sponges implantation and disappeared at 8th day. Enclose ASCs in an artificial niche allows to exploit their modulatory capabilities in response to tissue injuries reducing possible side effects associated to stem cell differentiation. So, the present data suggest an alternative approach in the use of ASCs for the treatment of oxaliplatin-induced neuropathic pain.

Abstract This chapter presents the case of a man who has cold dysesthesia due to oxaliplatin-induced peripheral neuropathy. Chemotherapy-induced peripheral neuropathy is a daily challenge in cancer patients. Oxaliplatin can cause an acute neuropathy characterized by cold dysesthesia, a chronic neuropathy characterized by a “glove-and-stocking-like” distribution of symptoms (paresthesia, dysesthesia, and pain), and sensory loss. There are no established preventive treatments. In patients with oxaliplatin-induced neuropathy, treatment mainly consists of symptomatic antineuropathic drugs akin to other painful neuropathies, and it should not start with opioids. Patients with chemotherapy-induced neuropathy reporting paresthesia such as numbness or tingling but not pain should not be treated with analgesics.