The goal of this clinical trial is to learn if menthol works to relieve chronic neuropathic pain and chemotherapy-induced peripheral neuropathy (CIPN). The primary objectives are to evaluate the safety and clinical efficacy of menthol-containing gloves and foot-covers, specifically whether they can improve patient-reported hypoesthesia (numbness). Secondary objectives include assessing the sustained effects on pain, dysesthesia (abnormal sensations), allodynia (touch-induced pain), and overall quality of life. Additionally, this study will include an exploratory lab analysis using blood samples to investigate potential biological markers (small extracellular vesicles and microRNA) associated with treatment responses. Participants will be asked to: Wear menthol-containing gloves and foot-covers (or shams) daily for 5 minutes per session over a 14-day period. Attend clinic visits on Days 1, 14, 21, and 28 for evaluations and tests.

Our laboratory previously discovered a unique and simple-to-apply neuroprotective method involving topical menthol treatment. In an animal model, this approach demonstrated prominent anti-inflammatory effects and improved behavioral outcomes (published in the Journal of Neuroinflammation, 2022). Based on these findings, we hypothesize that topical menthol can alleviate chemotherapy-induced peripheral neuropathy (CIPN).To test this hypothesis, our team conducted a preliminary open-label clinical study (IRB: TMANH112-REC025) evaluating menthol-based gloves and foot-covers. The pilot results revealed that the 8% menthol concentration significantly improved tactile sensation sensitivity via von Frey monofilament testing. Notably, after a 14-day intervention, the therapeutic effects appeared to persist for up to 21 days.While the small sample size in the pilot stage limited the statistical power to detect significant differences in subjective symptoms like numbness (NRS) or overall quality of life, the trending improvements in physical tactile sensation warrant a rigorous validation. Therefore, this expanded, randomized, double-blind, placebo-controlled trial is scientifically designed to provide adequate statistical power to confirm the sustained clinical efficacy and safety of 8% topical menthol treatment, while exploring underlying biological mechanisms through plasma-derived small extracellular vesicle biomarker analysis in CIPN patients.

Inclusion Criteria:

• 1. All adult cancer patients (Age≧20-year-old) who received chemotherapy regimens, including adjuvant and neoadjuvant therapy.
• 2. Stage I-IV cancer patients.
• 3. Who received chemotherapy regimens, including Taxanes (paclitaxel or docetaxel), platinum (cisplatin, oxaliplatin, carboplatin).
• 4. Who have received two cycle or have completed the neurotoxic chemotherapy regimen(24).
• 5. Baseline von Frey Monofilament test (Target force at hand) ≧ 0.07gms.
• 6. Baseline von Frey Monofilament test (Target force at foot) ≧ 0.4gms.
• 7. Eastern Cooperative Oncology Group (ECOG) performance status ≦3.
• 8. Grading of peripheral sensory neuropathy in National Cancer Institute- common terminology criteria for adverse events,v5.0 (NCI-CTCAE5) ≧1.
• 9. Written patient informed consent.
• 10. Discontinue analgesics or maintain the same dosage throughout the study period. (e.g., duloxetine, or another analgesia, including Pregabalin, Venlafaxine, Minocycline, Topical gel, Oxycodone, Naloxone, Cannabinoids).

Exclusion Criteria:

• 1. Uncontrolled Diabetic Mellitus, HbA1c≧7% is inappropriate(25).
• 2. Diabetic neuropathy diagnosed before receiving chemotherapy.
• 3. Neuropathy from any type of nerve compression (e.g., carpal/tarsal tunnel syndrome, radiculopathy, spinal stenosis, brachial plexopathy).
• 4. Other diseases that cause peripheral neuropathy (e.g., Severe chronic kidney disease, hepatitis, thyroid disorders, vitamin B12 deficiency, viral infections such as HIV and syphilis, alcohol poisoning, inflammatory diseases such as chronic demyelinating polyneuropathy, heavy metal poisoning, hereditary neuropathies).
• 5. Limb trauma that has resulted in vascular and nerve damage.
• 6. Individuals with severe mental illness or cognitive impairments who are unable to provide informed consent.
• 7. Severe hemorrhagic coagulopathy or bleeding tendency.
• 8. Unstable cardiovascular disease.
• 9. Severe skin lesions around the treatment sites.
• 10. Pregnant and breastfeeding women.
• 11. Participants who are concurrently enrolled in additional clinical trials.
• 12. Individuals allergic to topical menthol.
• 13. Adults weighing less than 50 kilograms.
• 14. The researchers will exclude any participants considered to be inappropriate for the study.
• 15. Profound weight loss (>5% to 10% of body weight).