Painful Chemotherapy-induced Peripheral Neuropathy Research Articles

Paclitaxel alters the microvascular network in the central and peripheral nervous system of rats with chemotherapy-induced painful peripheral neuropathy.

Chemotherapy-induced peripheral neurotoxicity (CIPN), with paraesthesia, numbness, dysesthesia and neuropathic pain ranks among the most common dose-limiting toxicity of several widely used anticancer drugs. Recent studies revealed the microvascular angiogenesis as a new important actor, beside peripheral neurons, in the neurotoxicity and neuropathic pain development and chronicisation. The aim of this work is to elucidate the role of vascular alterations in CIPN. We evaluated the severity of CIPN with neurophysiological, behavioural and neuropathological analysis together with the microvascular network in central and peripheral nervous systems of rats in order to correlate the features of the CIPN and the vascular abnormalities. The vascular network was quantitatively evaluated through synchrotron radiation-based X-ray phase-contrast micro-tomography imaging, measuring four specific parameters: vascular density, vessel diameter, vessel tortuosity and branching. Rats exposed to paclitaxel and affected by a severe painful sensory axonopathy showed an increased vascular density (putative sprouting angiogenesis) in the crucial districts of the central (somatosensory cortex and lumbar spinal cord) and peripheral nervous system (lumbar dorsal root ganglia). In addition, the complexity of the vascular network and the size of neo-formed vessels were significantly decreased in specific regions. On the other hand, less significant changes were observed in rats exposed to cisplatin, affected by a painless peripheral neuropathy, suggesting a specific involvement of neo-angiogenesis in the development of severe neurotoxicity and neuropathic pain. These new ground-breaking results can shed light on new pathogenetic mechanisms and potential novel therapeutic approaches for painful-CIPN.

Acupuncture-related interventions improve chemotherapy-induced peripheral neuropathy: A systematic review and network meta-analysis

BackgroundThe previous effects of acupuncture-related interventions in improving chemotherapy-induced peripheral neuropathy (CIPN) symptoms and quality of life (QoL) remain unclear in terms of pairwise comparisons.AimsThis systematic review and network meta-analysis aimed to determine the hierarchical effects of acupuncture-related interventions on symptoms, pain, and QoL associated with CIPN in cancer patients undergoing chemotherapy.MethodsNine electronic databases were searched, including PubMed, Embase, Cochrane Library, EBSCO, Medline Ovid, Airiti Library, China National Knowledge Infrastructure (CNKI), China Journal full-text database (CJFD), and Wanfang. Medical subject heading terms and text words were used to search for eligible randomized controlled trials published from database inception to May 2023.ResultsA total of 33 studies involving 2,027 participants were included. Pairwise meta-analysis revealed that acupuncture-related interventions were superior to usual care, medication, or dietary supplements in improving CIPN symptoms, CIPN pain, and QoL. Furthermore, network meta-analysis indicated that acupuncture plus electrical stimulation (acupuncture-E) had the greatest overall effect among the various interventions. The surface under the cumulative ranking curve (SUCRA) revealed that acupuncture-E ranked the highest in improving CINP symptoms. Acupuncture alone was most effective in reducing CIPN pain, and acupuncture plus moxibustion (acupuncture-M) ranked highest in enhancing QoL.ConclusionThis finding suggests that acupuncture-related interventions can provide patients with benefits in improving CIPN symptoms, pain, and QoL. In particular, acupuncture-E could be the most effective approach in which the provided evidence offers diverse options for cancer patients and healthcare professionals.Implication for the profession and/or patient careThese findings provide valuable insights into the potential benefits of acupuncture-related interventions for managing symptoms, pain, and QoL associated with CIPN in patients undergoing chemotherapy. Among the various interventions studied, overall, acupuncture-E had the most significant impact and was effective for a minimum duration of 3 weeks. On the other hand, transcutaneous electrical acupoint/nerve stimulation (TEAS) was identified as a noninvasive and feasible alternative for patients who had concerns about needles or the risk of bleeding. It is recommended that TEAS interventions should be carried out for a longer period, preferably lasting 4 weeks, to achieve optimal outcomes.Trial registrationThe study protocol was registered in the International Prospective Register of Systematic Reviews. Registration Number: CRD42022319871.

Methadone for Pain Management in Chemotherapy-Induced Peripheral Neuropathy: A Retrospective Review

Chemotherapy-Induced Peripheral Neuropathy (CIPN) refers to damage of peripheral nerve fibers due to the use of neurotoxic chemotherapy to treat various cancers. It occurs in more than 30% of patients and only duloxetine has currently been identified to show limited efficacy in symptomatic treatment of CIPN. Opioids have traditionally been used to treat cancer pain, and there is evidence for their use in treatment of peripheral neuropathic pain from other causes. With a similar mechanism of action to duloxetine, methadone has rationale for treating neuropathic pain. This study is a retrospective chart review to evaluate the outcomes of using methadone for CIPN pain. Out of 31 patients, 65% felt that methadone was an effective treatment, 19% felt that it was ineffective, and 16% felt that it was partially or temporarily effective. These results suggest that analgesic response to methadone varies between patients, but that it has a potential role in painful CIPN. Its advantages for long-term use include low cost and lack of metabolites. Potential risks include a long half-life, drug interactions, and potential for QT prolongation at high doses. Prospective studies should be conducted to evaluate the role of methadone in CIPN pain management more comprehensively.

Topical Cannabidiol for Established Chemotherapy-Induced Neuropathy: A Pilot Randomized Placebo-Controlled Trial.

Background: Patients have been known to use cannabinoids for treating established chemotherapy-induced peripheral neuropathy (CIPN) based on anecdotal information and retrospective reports suggesting that such might be beneficial. In response, a double-blinded, placebo-controlled, randomized, pilot clinical trial was developed to evaluate whether resultant data would support a phase III trial for testing whether a cannabidiol (CBD) cream might improve CIPN. Methods: Forty patients with established CIPN were randomized, in a double-blinded manner, to topical CBD or a placebo cream. The study product was applied for 2 weeks, followed by a crossover for 2 weeks. Neuropathy was evaluated using the European Organization of Research and Treatment of Cancer (EORTC)-CIPN20, the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool, and the Global Impression of Change instruments. Side effects were recorded by symptom diaries. Results: The EORTC-CIPN20 scores were similar in the patients receiving CBD versus the placebo. Likewise, the toxicity scores were similar in patients who received the CBD versus the placebo. Conclusions: This pilot trial did not support that the studied CBD isolate cream improved painful established CIPN. It was well tolerated overall. Clinical Trial Registration Number: NCT05388058.

Analgesic Effect of Auricular Vagus Nerve Stimulation on Oxaliplatin-induced Peripheral Neuropathic Pain in a Rodent Model.

Cancer chemotherapy often triggers peripheral neuropathy in patients, leading to neuropathic pain in the extremities. While previous research has explored various nerve stimulation to alleviate chemotherapy-induced peripheral neuropathy (CIPN), evidence on the effectiveness of noninvasive auricular vagus nerve stimulation (aVNS) remains uncertain. This study aimed to investigate the efficacy of non-invasive aVNS in relieving CIPN pain. To induce CIPN in experimental animals, oxaliplatin was intraperitoneally administered to rats (6 mg/kg). Mechanical and cold allodynia, the representative symptoms of neuropathic pain, were evaluated using the von Frey test and acetone test, respectively. The CIPN animals were randomly assigned to groups and treated with aVNS (5 V, square wave) at different frequencies (2, 20, or 100 Hz) for 20 minutes. Results revealed that 20 Hz aVNS exhibited the most pronounced analgesic effect, while 2 or 100 Hz aVNS exhibited weak effects. Immunohistochemistry analysis demonstrated increased c-Fos expression in the locus coeruleus (LC) in the brain of CIPN rats treated with aVNS compared to sham treatment. To elucidate the analgesic mechanisms involving the adrenergic descending pathway, α1-, α2-, or β-adrenergic receptor antagonists were administered to the spinal cord before 20 Hz aVNS. Only the β-adrenergic receptor antagonist, propranolol, blocked the analgesic effect of aVNS. These findings suggest that 20 Hz aVNS may effectively alleviate CIPN pain through β-adrenergic receptor activation.

Motor disorders related to oxaliplatin-induced peripheral neuropathy: long-term severity and impact on quality of life.

Sensory chemotherapy-induced peripheral neuropathy (CIPN) is well-recognized, but motor CIPN remains understudied. This secondary analysis focused on the long-term severity and impact of motor disorders, their relation to sensory CIPN, neuropathic pain, psychological distress, and health-related quality of life (HRQoL) after oxaliplatin-based chemotherapy in colorectal cancer (CRC) survivors. Data from a multicenter, cross-sectional study were re-analyzed to explore motor CIPN among CRC survivors up to 5years post-chemotherapy, with no longitudinal follow-up. Questionnaires assessed sensory and motor CIPN (QLQ-CIPN20), neuropathic pain (DN4), anxiety and depression (HADS), and HRQoL (QLQ-C30). Among 405 CRC survivors, 31.1% had sensory CIPN as previously described. When categorizing the 405 CRC survivors based on the years since their last oxaliplatin-based chemotherapy, the motor scores derived from the QLQ-CIPN20 showed no significant difference between years (p = 0.08). Motor CIPN scores correlated with female gender, higher oxaliplatin dose intensity, sensory CIPN, and neuropathic pain. Motor CIPN also linked to decreased HRQoL and increased psychological distress. The study underscores the detrimental impact of motor disorders on CRC survivors post-oxaliplatin-based chemotherapy. Oncologists should prioritize assessing and managing motor manifestations alongside sensory symptoms to enhance post-cancer quality of life. NCT02970526 (2016-11-22). https://classic. gov/ct2/show/NCT02970526?term=NCT02970526&draw=2&rank=1 .

Select Minor Cannabinoids from Cannabis sativa Are Cannabimimetic and Antinociceptive in a Mouse Model of Chronic Neuropathic Pain.

Chronic pain conditions affect nearly 20% of the population in the United States. Current medical interventions, such as opioid drugs, are effective at relieving pain but are accompanied by many undesirable side effects. This is one reason increased numbers of chronic pain patients have been turning to Cannabis for pain management. Cannabis contains many bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids in Cannabis lacks uniformity between experimental groups and/or excludes female mice from investigation. This makes it challenging to draw conclusions between experiments done with different minor cannabinoid compounds between laboratories or parse out potential sex differences that could be present. We chose five minor cannabinoids found in lower quantities within Cannabis: cannabinol (CBN), cannabidivarin (CBDV), cannabigerol (CBG), Δ8-tetrahydrocannabinol (Δ8-THC), and Δ9-tetrahydrocannabivarin (THCV). These compounds were then tested for their cannabimimetic and pain-relieving behaviors in a cannabinoid tetrad assay and a chemotherapy-induced peripheral neuropathy (CIPN) pain model in male and female CD-1 mice. We found that the minor cannabinoids we tested differed in the cannabimimetic behaviors evoked, as well as the extent. We found that CBN, CBG, and high-dose Δ8-THC evoked some tetrad behaviors in both sexes, while THCV and low-dose Δ8-THC exhibited cannabimimetic tetrad behaviors only in females. Only CBN efficaciously relieved CIPN pain, which contrasts with reports from other researchers. Together these findings provide further clarity to the pharmacology of minor cannabinoids and suggest further investigation into their mechanism and therapeutic potential. SIGNIFICANCE STATEMENT: Minor cannabinoids are poorly studied ligands present in lower levels in Cannabis than cannabinoids like THC. In this study, we evaluated five minor cannabinoids (CBN, CBDV, CBG, THCV, and Δ8-THC) for their cannabimimetic and analgesic effects in mice. We found that four of the five minor cannabinoids showed cannabimimetic activity, while one was efficacious in relieving chronic neuropathic pain. This work is important in further evaluating the activity of these drugs, which are seeing wider public use with marijuana legalization.

A randomized phase III clinical trial of acupuncture for chemotherapy-induced peripheral neuropathy treatment (ACT).

TPS12151 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side effect of neurotoxic chemotherapy among people who experience cancer, presenting pain, numbness, tingling, and motor weakness. CIPN worsens quality of life and disrupts active treatment regimens. Currently, duloxetine is the only ASCO-recommended painful CIPN treatment after chemotherapy completion. Still, it has undesirable side effects, i.e., fatigue, sleep disturbance, and digestive symptoms, posing a pressing need for well-tolerated, evidence-based interventions. Our pilot study demonstrated the feasibility and preliminary efficacy of acupuncture in relieving CIPN pain. Based on that, we developed the ACT trial to evaluate the effect of acupuncture on improving pain and other related symptoms among cancer survivors with CIPN pain. Methods: ACT is a prospective phase III multicenter, parallel two-arm randomized clinical trial at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSK) (ClinicalTrials.gov Identifier: NCT04917796). ACT aims to determine the efficacy of an eight-week electroacupuncture (EA) treatment vs. sham acupuncture (SA) on improving CIPN symptoms severity in cancer survivors. We plan to enroll 250 participants to detect an effect size of at least 0.45 for the primary pain outcome at 12 weeks post-randomization between EA vs. SA, with 80% power and a 1% Type I error rate, assuming a 10% loss to follow-up. Major eligibility criteria include 1) adults who have no evidence of disease or stable diseases, 2) who have completed neurotoxic chemotherapy such as platinum agents, taxanes, vinca alkaloids, and bortezomib at least three months before enrollment, and 3) who have a clinical diagnosis of CIPN with moderate to severe pain, defined as a score of at least four on the Brief Pain Inventory (BPI) average pain item. We randomly allocate participants to receive ten real or sham acupuncture treatments over eight weeks at two centers and their regional clinics. Aside from patient-reported outcome measures (i.e., BPI, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, EORTC Quality of Life Questionnaire-CIPN 20), we conduct quantitative sensory testing to assess changes in sensory function. The primary study endpoint is week 12, and the secondary study endpoint is week 24. Progress: 1) We are currently transitioning this trial to a multicenter trial, with DFCI being the coordinating center and MSK a subsite; 2) As of January 18, 2024, a total of 133 of the planned 250 participants have been enrolled; 3) The DSMB last reviewed the trial in December 2023, and suggested that the trial continue as planned at MSK. We anticipate initiating participant enrollment at DFCI in February 2024. Accrual completion is expected by December 2024. Clinical trial information: NCT04917796 .

A randomized phase III clinical trial of yoga for chemotherapy-induced peripheral neuropathy treatment (YCT).

TPS12152 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is common and debilitating among cancer survivors receiving neurotoxic chemotherapy, which can cause functional disabilities and significantly increase the risk of falls. There are limited approaches to managing CIPN symptoms and related functional limitations. Our pilot study demonstrated yoga therapy's feasibility and preliminary efficacy in improving CIPN pain and functional outcomes. We developed the YCT trial to assess the effect of yoga therapy on improving pain and balance symptoms among cancer survivors with CIPN pain. Methods: YCT is a prospective phase III multicenter, parallel three-arm randomized clinical trial at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering Cancer Center (MSK) (ClinicalTrials.gov Identifier: NCT05121558). YCT aims to determine the efficacy of an eight-week yoga treatment vs. education control (EC) vs. usual care (UC) in improving CIPN pain and balance in cancer survivors. We plan to enroll and randomize 268 participants (2:1:1) to yoga, EC, and UC groups to detect an effect size of at least 0.48 for the primary pain outcome at eight weeks post-randomization between yoga vs. EC, with 80% power and a 2.5% Type I error rate, assuming 12% attrition by week 8 and 20% attrition by week 24. Major eligibility criteria include 1) adults who have no evidence of disease or stable diseases, 2) who have completed neurotoxic chemotherapy such as platinum agents, taxanes, vinca alkaloids, and bortezomib at least three months before enrollment, 3) who have a clinical diagnosis of CIPN with moderate to severe pain, defined as a score of at least four on the Brief Pain Inventory (BPI) average pain item, and 4) who experience self-identified CIPN balance difficulty. Eligible subjects in the yoga arm will receive hourly gentle therapeutic yoga classes taught by protocol-trained oncology yoga instructors, twice weekly for eight weeks, and practice home-based yoga. Subjects in the EC arm will receive hourly education classes taught by protocol-trained healthcare instructors twice weekly for eight weeks. Subjects in the UC arm will continue usual care for eight weeks. We offer free yoga sessions for participants in control groups after study completion. Aside from patient-reported outcome measures (i.e., BPI, FACT/GOG-Ntx, QLQ-CIPN 20), we measured functional improvements by functional reach, timed up-and-go, and chair-to-stand tests. We also conducted quantitative sensory testing to assess changes in sensory function. Progress: 1) We are transitioning this trial to a multicenter trial, with DFCI being the coordinating center and MSK a subsite; 2) As of January 18, 2024, 104 of the planned 268 participants have been enrolled. We anticipate initiating participant enrollment at DFCI in February 2024. Anticipated accrual completion: March 2025. Clinical trial information: NCT05121558 .

Preventing chemotherapy-induced peripheral neuropathy with acupuncture, a multinational parallel randomized controlled trials project (PACT).

TPS12156 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant challenge for patients (pts) with breast cancer treated with taxanes and platinum compounds. CIPN severely affects quality of life, leading to paresthesia and pain, and often results in dose modifications and discontinuation of treatment. Although preliminary trials suggest the effectiveness of acupuncture in managing existing symptoms of CIPN, the use of acupuncture to prevent CIPN is not well studied. Prior studies provide inconclusive results, underscoring the need for more rigorous investigation. We designed an international study, PACT, to evaluate the impact of acupuncture on the prevention of CIPN in breast cancer pts who undergo adjuvant or neoadjuvant taxane-based chemotherapy. Methods: PACT is a coordinated multi-national study consisting of three parallel randomized trials in USA, China, and South Korea, using the same inclusion/exclusion criteria, randomization, interventions, and validated measures. PACT is designed to evaluate the effectiveness of acupuncture in preventing CIPN in pts undergoing taxane-based chemotherapy for early-stage breast cancer. Participants include pts with newly diagnosed stage I-III breast cancer without preexisting neuropathy, scheduled for adjuvant or neoadjuvant taxane-based chemotherapy. Target enrollment is 140 pts from three sites: Dana-Farber Cancer Institute (USA) (n=100), Jiangsu Province Hospital of Chinese Medicine (China) (n = 20) and the Daegu Catholic University Medical Center (South Korea) (n=20), randomized (1:1) to the acupuncture arm or a control. The acupuncture arm receives a standardized protocol of 1-2 sessions per week for 12 weeks (total of 14 sessions). The control arm receives relaxation exercises with nature scenery videos for 14 sessions. The follow-up period for both arms is 12 weeks. Main measures include The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-CIPN20, QLQ-30 and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) CIPN items. The primary outcome measure is the change in CIPN severity, assessed using the EORTC QLQ-CIPN20 sensory subscale, between baseline and week 12, with secondary outcomes including occurrence of CIPN and maximum CIPN scores, pain, sleep quality, and overall quality of life. A planned pooled analysis of individual patient data will be performed. The ethics review committee of each site has approved the study. Today, 89 (64%) of the planned 140 participants have been enrolled. Clinical trial information: NCT05528263 , ChiCTR2200066714, KCT0008470.

Abstract PO1-20-03: Acupuncture for Preventing Progression of Taxane-Induced PeripheralNeuropathy (ATP): A Phase II Randomized, Placebo Controlled Trial

Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) from chemotherapy drugs such as taxanes can be detrimental to cancer survival, increasing the risk of falls and worsening physical functions. However, there is no effective treatment or preventative measure for CIPN. The current management of worsening and persistent CIPN during chemotherapy is dose reduction or discontinuation of chemotherapy. Our group previously completed a single-arm phase IIA pilot trial of women who developed National Cancer Institution Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 2 CIPN during weekly paclitaxel for stage I-III breast cancer. The result suggested an acupuncture intervention for grade 2 CIPN might slow CIPN progression during chemotherapy. However, the role of acupuncture still needs to be better defined. Trial design: The ATP trial is a two-arm, parallel, randomized controlled trial comparing weekly real acupuncture (RA) versus sham acupuncture (SA) during preplanned curative intent taxane containing regimens in patients with breast cancer. The study will include two phases: screening and intervention. In the screening phase, eligible patients will consent and receive CIPN screening each week. Patients who develop grade 1 CIPN or higher based on NCI-CTCAE version 5.0 will be consented to the intervention phase and randomized to receive either weekly RA or SA using a standardized, semi-fixed protocol developed in our preliminary studies to improve CIPN pain. Eligibility criteria for the screening phase: English or Spanish-proficient; aged ≥18 years; histological diagnoses of invasive carcinoma of the breast; and plan to receive curative intent chemotherapy regimen containing paclitaxel or nab-paclitaxel weekly or biweekly as standard of care. Eligibility criteria for the intervention phase: in additional to the screening phase eligibility criteria, developed CIPN grade ≥1 based on the NCI-CTCAE version 5.0, while receiving taxane; ≥ four weeks of paclitaxel or nab-paclitaxel weekly or biweekly planned, as standard of care and at treating physician’s discretion; willing to adhere to requirement that no new pain medication or dose changes be taken throughout the first 12 weeks of the study period; and willing to adhere to all study-related procedures, including randomization to one of the two possible acupuncture treatments. Specific aims: The primary aim is to evaluate the effectiveness of RA versus SA in preventing taxane-induced peripheral neuropathy progression as measured by Neuropathic Pain Scale (NPS) in patients with early-stage breast cancer who are receiving curative intent neurotoxic chemotherapy. The secondary aim is to evaluate the effectiveness of RA versus SA on chemotherapy relative dose intensity (RDI) and CIPN-related chemotherapy discontinuation. Statistical methods: We will randomize 80 patients, 40 to each arm. All randomized patients will be evaluable in the Intent to Treat (ITT) analyses because all will have completed the baseline assessment before randomization. We will use a linear mixed model (LMM) to compare the change in NPS between the arms from baseline to week 4. Based on our pilot data, a difference in CIPN grade from 1 to 2 corresponded to a difference in NPS from 12 to 22, a difference of ten points in 27 patients. The NPS standard deviation (SD) in patients with grade 1 CIPN was 17. With 80 patients we will have 80% power to detect a difference between arms as small as 10 points on the NPS, assuming a one-sided test, type I error of 5%, correlation between baseline and follow-up measurements of 0.5, SD of 17, and 15% attrition at week 4. Present accrual and target accrual: We accrued 20 participants in the intervention phase by the end of June 2023; the target accrual is 80 participants. Contact information for people with a specific interest in the trial: W. Iris Zhi, MD, PhD, zhiw@mskcc.org. ClinicalTrails.gov Identifier: NCT05458284. Citation Format: W. Iris Zhi, Lauren Taylor, Raymond Baser, Matthew Weitzman, Qing Li, Christina Seluzicki, Ting Bao, Jun Mao. Acupuncture for Preventing Progression of Taxane-Induced PeripheralNeuropathy (ATP): A Phase II Randomized, Placebo Controlled Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-03.

Targeting dorsal root ganglia for chemotherapy-induced peripheral neuropathy: from bench to bedside.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition affecting an increasing number of cancer survivors worldwide. However, insights into its pathophysiology and availability of effective therapies remain lacking. Dorsal root ganglia (DRG) have been studied as a key component of chemotherapeutic drug toxicity and a potential therapeutic target for CIPN treatment. This comprehensive review aims to synthesize, summarize, and correlate the results of both preclinical and clinical studies relevant to the pathophysiology and management of CIPN in relation to the DRG. Design: Review. A thorough literature search was conducted using the terms 'dorsal root ganglion' and 'chemotherapy-induced peripheral neuropathy', along with appropriate variations. Searched databases included PubMed, EMBASE, Medline, Cochrane Library, Wiley Library, and Web of Science. Inclusion criteria targeted all English language, peer-reviewed original research from the inception of these databases to the present year. Review articles, book chapters, and other nonoriginal publications were excluded. Of 134 relevant studies identified, the majority were preclinical studies elucidating how various chemotherapeutic agents, especially taxanes, disrupt neurotransmission, inflammatory processes, and apoptotic pathways within sensory neurons of DRG. Not only do these effects correlate with the presentation of CIPN, but their disruption has also been shown to reduce CIPN symptoms in preclinical models. However, clinical studies addressing DRG interventions are very limited in number and scope at this time. These results reveal various pathways within DRG that may be effective targets for CIPN treatment. While limited, clinical studies do offer promise in the utility of DRG neuromodulation in managing painful CIPN. In the future, clinical trials are needed to assess interventions aimed at these neuronal and nonneuronal pathological targets to better treat this complex condition.

Topical treatment of chemotherapy-induced peripheral neuropathy (CIPN) with high-concentration (179 mg) capsaicin patch in breast cancer patients - results of the QUCIP study.

Chemotherapy-induced peripheral neuropathy (CIPN) following oral or intravenous chemotherapy often results in neuropathic pain, accompanied by symptoms such tingling, burning and hypersensitivity to stimuli, with a notable decline in quality of life (QoL). Effective therapies for CIPN are lacking, with a high demand for analgesics to address this issue. The QUCIP study aimed to assess the effectiveness of high concentration (179 mg) capsaicin patch (HCCP) in alleviating neuropathic pain and associated symptoms in breast cancer patients with confirmed CIPN. QUCIP is a prospective, multi-center observational study spanning 36 weeks with up to three HCCP treatments. Initial treatment (visit V0) was followed by two telephone contacts (T1, T2) and subsequent face-to-face visits every 12 weeks or upon retreatment (visits V1-V3). 73 female patients with painful CIPN post neoadjuvant/adjuvant breast cancer therapy were enrolled. Primary endpoint was the reduction of neuropathic pain symptom score (painDETECT®). Secondary endpoints included improvements in CIPN-specific QoL (QLQ-CIPN20), reductions in pain intensity (numeric pain rating scale, NPRS), and achievement of ≥ 30% and ≥ 50% pain reduction. Median age was 61 years, with 52.0% of patients experiencing peripheral neuropathic pain for > 1 year (> 2 years: 34.2%). The painDETECT® score significantly decreased from baseline (19.71 ± 4.69) to 15.80 ± 6.20 after initial treatment (p < 0.0001) and continued to decrease at follow-up visits. The NPRS indicated significant pain intensity reduction at each time point, particularly pronounced in patients receiving three HCCP treatments. Clinically significant pain relief of ≥ 30% increased from 25.0% at week 4 (T2) to 36.2%, 43.5%, and 40.0% at weeks 12 (V1), 24 (V2), and 36 (V3), respectively. The percentage of patients achieving pain relief of ≥ 50% increased from 14.7% at T2 to 15.5%, 21.7% and 32.5% at V1, V2 and V3, respectively. Patients further reported a significant improvement in their CIPN-related QoL throughout the study. Adverse drug reactions (ADRs) mainly included application site reactions. In this study, HCCP shows benefit in managing CIPN in real-world settings. The data demonstrate a sustained and progressive reduction in neuropathic pain and symptomatology, confirming the clinical benefit of repeated treatment observed in former clinical trials. HCCP treatment has also the potential to significantly improve the QoL associated with CIPN. The safety profile of HCCP was confirmed, supporting its use in clinical practice.

Efficacy of transauricular vagus nerve stimulation for the treatment of chemotherapy-induced painful peripheral neuropathy: a randomized controlled exploratory study.

Chemotherapy-induced painful peripheral neuropathy (CIPN) is a common adverse event in cancer patients, and there is still a lack of effective treatment. Transauricular vagal nerve stimulation (taVNS) is a minimally invasive treatment, but there are few reports regarding its efficacy for CIPN. To investigate the efficacy and possible mechanism of taVNS in patients with CIPN. Twenty-seven patients with CIPN were randomly divided into a taVNS group (n = 14) and a sham stimulation (SS) group (n = 13). A numerical rating scale (NRS) for pain, NCICTCAE 4.0 (neurotoxicity classification), quantitative sensory test (QST), Short-Form-Health Survey-12 (SF-12), and Athens Insomnia Scale (AIS) were administered before the intervention (D-10) and on the day after the intervention (D0), and the inflammatory cytokines in plasma were also measured. The NRS, NCI-CTCAE 4.0, SF-12, and AIS were administered again at D30 and D90. Compared with the SS group, the NRS and AIS in the taVNS group were significantly lower at D0. The impact lasted until D30. There were no statistically significant differences in the NRS and AIS between the 2 groups at D90. On D30, the mental component score of the SF-12 was significantly higher in the taVNS group than in the SS group. No adverse events were found. There was no significant difference in QST and plasma inflammatory cytokines between the 2 groups. taVNS can relieve chemotherapy-induced neuropathic pain in the short term, can improve sleep status and quality of life, and is expected to become a novel clinical treatment method for CIPN.

Is Electroacupuncture Contraindicated for Preventing and Treating Chemotherapy-Induced Peripheral Neuropathy?

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side-effect of several drugs used to combat cancer. Thus, researchers have sought better treatments for and prevention of CIPN, such as electroacupuncture (EA). Some trials show EA worsens or prolongs CIPN pain and recommend against further studies on this. This narrative review explores EA for preventing or treating CIPN, comparing positive and negative outcomes. PubMed, ScienceDirect, and Google Scholar were searched for electroacupuncture, CIPN, and peripheral neuropathy. A snowballing method was used to find systematic reviews and studies in systematic reviews. Seven English-language trials were found on using EA for preventing or treating CIPN. In 3 prevention studies, 1 had significant benefits, 1 had modest benefits, and 1 had worse pain in an EA group at follow-up, compared to sham controls. In 4 treatment studies, 2 had significant benefits, 1 had no difference from 3 controls, and 1 had sham control was superior to verum EA. Most of the studies were limited by small sample sizes, and some studies used EA protocols and treatment doses (frequency and total number of sessions) that were potentially suboptimal. The quantity and quality of the studies are insufficient to draw firm conclusions on effectiveness and safety. More studies must test optimal EA protocols and treatment dosages. It is inappropriate to say that EA is not recommended for CIPN prevention or treatment, because there is no robust evidence to justify this. Generally, research has found benefits and no harms.

Role of pattern recognition receptors in chemotherapy-induced neuropathic pain.

Progress in the development of effective chemotherapy is producing a growing population of patients with acute and chronic painful chemotherapy-induced peripheral neuropathy (CIPN), a serious treatment-limiting side effect for which there is currently no US Food and Drug Administration-approved treatment. CIPNs induced by diverse classes of chemotherapy drugs have remarkably similar clinical presentations, leading to the suggestion they share underlying mechanisms. Sensory neurons share with immune cells the ability to detect damage associated molecular patterns (DAMPs), molecules produced by diverse cell types in response to cellular stress and injury, including by chemotherapy drugs. DAMPs, in turn, are ligands for pattern recognition receptors (PRRs), several of which are found on sensory neurons, as well as satellite cells, and cells of the immune system. In the present experiments, we evaluated the role of two PRRs, TLR4 and RAGE, present in dorsal root ganglion (DRG), in CIPN. Antisense (AS)-oligodeoxynucleotides (ODN) against TLR4 and RAGE mRNA were administered intrathecally before ('prevention protocol') or 3 days after ('reversal protocol') the last administration of each of three chemotherapy drugs that treat cancer by different mechanisms (oxaliplatin, paclitaxel and bortezomib). TLR4 and RAGE AS-ODN prevented the development of CIPN induced by all three chemotherapy drugs. In the reversal protocol, however, while TLR4 AS-ODN completely reversed oxaliplatin- and paclitaxel-induced CIPN, in rats with bortezomib-induced CIPN it only produced a temporary attenuation. RAGE AS-ODN, in contrast, reversed CIPN induced by all three chemotherapy drugs. When a TLR4 antagonist was administered intradermally to the peripheral nociceptor terminal, it did not affect CIPN induced by any of the chemotherapy drugs. However, when administered intrathecally, to the central terminal, it attenuated hyperalgesia induced by all three chemotherapy drugs, compatible with a role of TLR4 in neurotransmission at the central terminal but not sensory transduction at the peripheral terminal. Finally, since it has been established that cultured DRG neurons can be used to study direct effects of chemotherapy on nociceptors, we also evaluated the role of TLR4 in CIPN at the cellular level, using patch-clamp electrophysiology in DRG neurons cultured from control and chemotherapy-treated rats. We found that increased excitability of small-diameter DRG neurons induced by in vivo and in vitro exposure to oxaliplatin is TLR4-dependent. Our findings suggest that in addition to the established contribution of PRR-dependent neuroimmune mechanisms, PRRs in DRG cells also have an important role in CIPN.

Coping with and self-management of chronic painful chemotherapy-induced peripheral neuropathy: a qualitative study among cancer survivors.

Patients with chronic painful chemotherapy-induced peripheral neuropathy (CIPN) may experience a negative impact of CIPN on daily life. They can use various coping (i.e., dealing with symptoms and resulting impairments in general) and self-management (i.e., practical actions to reduce symptoms) strategies to live with their limitations. This paper aimed to examine experienced helpful coping and self-management strategies of patients with chronic painful CIPN. Semi-structured interviews were conducted with twelve patients with chronic painful CIPN. We applied a hybrid deductive-inductive coding approach. ATLAS.ti was used for coding. Generated from the data were two themes and nine codes for coping and four themes and 31 codes for self-management strategies. Coping of patients often included active strategies like planning, seeking social support, and acceptance. Additionally, patients often used passive strategies such as focusing on and venting emotions and suppressing competing activities. The most common self-management strategies were mostly passive (i.e., medication, deliberate choice of shoes, resting, sitting, and consulting healthcare professionals) but also active (i.e., exercising) strategies. Patients exhibit a great variety of coping and self-management strategies that they perceive as helpful to deal with chronic painful CIPN. However, research has shown that certain strategies are not that helpful or even come with aversive effects. More research into the effectiveness and implementation of psychosocial interventions is needed since it may help patients adopting helping strategies. In addition, healthcare professionals need to refer patients with CIPN in a timely manner to physical therapists, occupational therapists, or rehabilitation teams to reduce or prevent (further) impairments. Patients can consult one of their healthcare providers in case of problems in dealing with their symptoms, to get proper guidance and possible referral.

Topical coapplication of hyaluronan with transdermal drug delivery enhancers attenuates inflammatory and neuropathic pain.

We have previously shown that intradermal injection of high-molecular-weight hyaluronan (500-1200 kDa) produces localized antihyperalgesia in preclinical models of inflammatory and neuropathic pain. In the present experiments, we studied the therapeutic effect of topical hyaluronan, when combined with each of 3 transdermal drug delivery enhancers (dimethyl sulfoxide [DMSO], protamine or terpene), in preclinical models of inflammatory and neuropathic pain. Topical application of 500 to 1200 kDa hyaluronan (the molecular weight range used in our previous studies employing intradermal administration), dissolved in 75% DMSO in saline, markedly reduced prostaglandin E 2 (PGE 2 ) hyperalgesia, in male and female rats. Although topical 500- to 1200-kDa hyaluronan in DMSO vehicle dose dependently, also markedly, attenuated oxaliplatin chemotherapy-and paclitaxel chemotherapy-induced painful peripheral neuropathy (CIPN) in male rats, it lacked efficacy in female rats. However, following ovariectomy or intrathecal administration of an oligodeoxynucleotide antisense to G-protein-coupled estrogen receptor (GPR30) mRNA, CIPN in female rats was now attenuated by topical hyaluronan. Although topical coadministration of 150 to 300, 300 to 500, or 1500 to 1750 kDa hyaluronan with DMSO also attenuated CIPN, a slightly lower-molecular-weight hyaluronan (70-120 kDa) did not. The topical administration of a combination of hyaluronan with 2 other transdermal drug delivery enhancers, protamine and terpene, also attenuated CIPN hyperalgesia, an effect that was more prolonged than with DMSO vehicle. Repeated administration of topical hyaluronan prolonged the duration of antihyperalgesia. Our results support the use of topical hyaluronan, combined with chemically diverse nontoxic skin penetration enhancers, to induce marked antihyperalgesia in preclinical models of inflammatory and neuropathic pain.

Protease-Activated Receptor 2 (PAR2) Expressed in Sensory Neurons Contributes to Signs of Pain and Neuropathy in Paclitaxel Treated Mice

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting side effect of cancer therapy. Protease-activated receptor 2 (PAR2) is implicated in a variety of pathologies, including CIPN. In this study, we demonstrate the role of PAR2 expressed in sensory neurons in a paclitaxel (PTX)-induced model of CIPN in mice. PAR2 knockout/wildtype (WT) mice and mice with PAR2 ablated in sensory neurons were treated with PTX administered via intraperitoneal injection. In vivo behavioral studies were done in mice using von Frey filaments and the Mouse Grimace Scale. We then examined immunohistochemical staining of dorsal root ganglion (DRG) and hind paw skin samples from CIPN mice to measure satellite cell gliosis and intra-epidermal nerve fiber (IENF) density. The pharmacological reversal of CIPN pain was tested with the PAR2 antagonist C781. Mechanical allodynia caused by PTX treatment was alleviated in PAR2 knockout mice of both sexes. In the PAR2 sensory neuronal conditional knockout (cKO) mice, both mechanical allodynia and facial grimacing were attenuated in mice of both sexes. In the DRG of the PTX-treated PAR2 cKO mice, satellite glial cell activation was reduced compared to control mice. IENF density analysis of the skin showed that the PTX-treated control mice had a reduction in nerve fiber density while the PAR2 cKO mice had a comparable skin innervation as the vehicle-treated animals. Similar results were seen with satellite cell gliosis in the DRG, where gliosis induced by PTX was absent in PAR cKO mice. Finally, C781 was able to transiently reverse established PTX-evoked mechanical allodynia. PerspectiveOur work demonstrates that PAR2 expressed in sensory neurons plays a key role in PTX-induced mechanical allodynia, spontaneous pain, and signs of neuropathy, suggesting PAR2 as a possible therapeutic target in multiple aspects of PTX CIPN.

A randomized phase III clinical trial of acupuncture for chemotherapy-induced peripheral neuropathy in survivors of cancer.

TPS12144 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect in cancer survivors that can last long after completion of neurotoxic chemotherapy. Patients with CIPN often experience neuropathy symptoms such as pain, tingling, numbness, paresthesia, and dysesthesia, which can lead to significant functional decline and diminished quality of life. This outcome highlights the importance of developing effective CIPN treatments to improve quality of life for this population. Identifying nonpharmacological approaches to reduce CIPN symptoms and improve cancer survivors’ outcomes is urgently needed. Acupuncture is a widely used, minimally invasive Traditional Chinese Medicine technique that has shown promising evidence as an effective and safe treatment for CIPN. We hypothesize that acupuncture may reduce CIPN pain and improve overall CIPN symptoms in cancer survivors. Methods: We are conducting a two-arm, parallel randomized clinical trial comparing electroacupuncture (EA) versus sham acupuncture (SA) in cancer survivors. The EA arm includes ten sessions of EA over eight weeks using a standardized, semi-fixed protocol developed by our group. The SA arm includes a sham technique that uses a combination of non-acupuncture points and a non-insertion procedure in ten sessions over eight weeks. The primary outcome of this study is the Brief Pain Inventory-Short Form average pain item. The secondary outcomes are quantitative sensory testing measures and patient-reported outcomes that include the Neuropathic Pain Scale, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, CIPN-20, PROMIS Global Health Scale, and Patients' Global Impression of Change. The primary end point is week 12 and the secondary end point is week 24; treatment effects are assessed at baseline and at weeks 4, 8, 12, 18, and 24. The eligibility criteria includes: 1) Patients must be have no evidence of disease or have stable disease; 2) CIPN diagnosis with moderate-to-severe CIPN pain, defined by a score of 4 or greater on a scale 0-10 numerical scale rating; 3) completed neurotoxic chemotherapy at least three months prior; and 4) no changes in anti-neuropathy medications within three months of enrollment. As of February 2023, we have accrued 89 participants, with a total accrual target of 250 participants. Accrual completion is anticipated by December 2024. The demographic breakdown of our participants is as following: 71% white, 15% black or African American, 10% Asian, 3% more than one race, and 1% Native Hawaiian or Pacific Islander. 89% of the participants are non-Hispanic or Latino, 10% are Hispanic or Latino, and 1% are unknown. 71% of the participants are female and 29% are male. Clinical trial information: NCT04917796 .