Gewandter, J.S., Mohile, S.G., Heckler, C.E., Ryan, J.L., Kirshner, J.J., Flynn, P.J., . . . Morrow, G.R. (2014). A phase III randomized, placebo-controlled study of topical amitriptyline and ketamine for chemotherapy-induced peripheral neuropathy (CIPN): A University of Rochester CCOP study of 462 cancer survivors. Supportive Care in Cancer, 22, 1807–1814.

To determine the effectiveness and safety of the topical application of a combined 2% ketamine and 4% amitriptyline (KA) cream for reduction of chemotherapy-induced peripheral neuropathy (CIPN) in patients who have completed chemotherapy

One week prior to enrollment, subjects completed a seven-day daily pain, numbness, and tingling diary over the past 24 hours. Subjects answered the question for any of the three symptoms in either their hands or feet. At enrollment, subjects were instructed to use a measuring device for application of 4 g of either KA or placebo cream twice daily to each area of hands or feet with any pain, numbness, or tingling. The seven-day daily pain, numbness, and tingling diary for pain over the past 24 hours, by numeric rating scale (NRS), was completed at three and six weeks after enrollment. A secondary analysis for pain using NRS was done at baseline, three, and six weeks.

• N = 458
• AGE = 18 years or older; range not defined
• MALES: 29%, FEMALES: 71%
• KEY DISEASE CHARACTERISTICS: 40% breast cancer, 27% gastrointestinal cancer, 9% hematologic malignancy, 3% head and neck cancer, 8% lung cancer, 7% gynecologic cancer, 5% genitourinary cancer
• OTHER KEY SAMPLE CHARACTERISTICS: 100% had previous chemotherapy, 85% had previous surgery, 48% had previous radiation therapy, and 53% had prior taxanes; no statistical difference in sample characteristics between groups
• INCLUSION: One month post-completion of chemotherapy; subjects with average seven-day pain, numbness, and tingling ratings of greater than 4; 18 years or older; KPS greater than 60; pain medications allowed if the dose was stable for two weeks prior to enrollment
• EXCLUSION: Pre-existing peripheral neuropathy resulting from something other than chemotherapy; prior neurologic procedures or topical treatment; clinical depression; medications: monoamine oxidase inhibitors, barbiturates, anticholinergic agents, sympathomimetic drugs, inhibitors CP450 2D6; open skin lesions in the region of cream application; creatinine greater than 2 mg/dL within 30 days prior to screening

• SITE: Multi-site 
• SETTING TYPE: Outpatient    
• LOCATION: University of Rochester Cancer Center Community Clinical Oncology Program

• PHASE OF CARE: Transition phase after active treatment 
• APPLICATIONS:  Elder care, palliative care

• Multi-center, phase III, double-blind, randomized, placebo-controlled clinical trial
  • Stratified into two treatment regimen groups: prior taxanes and nontaxane

• NRS (0 = not at all to 10 = as bad as you could imagine) for evaluation of any pain, numbness, and tingling in hands or feet
• Secondary analysis for pain in hands or feet was evaluated with an NRS  (0 = no pain to 10 = worst pain you can imagine) adapted from the MD Anderson Symptom Inventory.

No therapeutic effect was observed with the application of KA cream to the affected areas on hands or feet for reduction of pain, numbness, and tingling (p = 0.363). Secondary analysis for pain alone did not show a statistically significant difference between groups comparing means at 95% CI (KA cream, 4.64; placebo, 4.68). Patients in the treatment regimen group of prior taxanes, regardless of receiving study treatment with either KA or placebo, reported a reduction in pain, numbness, and tingling at six weeks (p = 0.042). No statistically significant adverse events were reported for the KA treatment group compared to the placebo group.

This study showed no therapeutic benefit for the topical application of KA cream for CIPN.

• Measurement validity/reliability questionable
• No separation for measurement of pain, numbness, or tingling in the primary analysis
• No standardized scale for symptom assessment of peripheral neuropathy was used (i.e., National Cancer Institute Common Toxicity Criteria) in the primary analysis
• Other limitations/explanation: Unknown type of prior chemotherapy for sample population other than taxanes; unknown surgical and radiation therapy anatomic sites; unknown patient sample age range and comorbidities

Further studies need to be done to investigate if any combination or separate topical compound targeting specific nociceptive pathways has a therapeutic benefit for CIPN.