Safety of Intranasal Ketamine for Reducing Uncontrolled Cancer-Related Pain: Protocol of a Phase I/II Clinical Trial

Abstract

Background Approximately 12 million Americans are affected with cancer. Of these, 53% experience pain at all stages of cancer. Pain may remain uncontrolled despite high-dose opioid therapy, and opioids have many well-documented harmful side effects. Intranasal ketamine has been shown to be effective in controlling breakthrough noncancer pain in a double-blind randomized control trial (DBRCT) by Carr et al in 2003 as well as to help with depression in a DBRCT by Lapidus et al in 2014. We seek to obtain preliminary data on the safety, feasibility, and utility of this novel technique for the treatment of uncontrolled cancer pain. Objective This study aimed to obtain preliminary data via a clinical trial addressing the safety, feasibility, pharmacokinetics, and pharmacodynamics of intranasal ketamine. These initial findings will be applied to a subsequent trial to determine the effectiveness and associated toxicities of ketamine in a larger sample of cancer patients and to address the compelling need to identify new, successful management therapies for cancer pain. Methods This is an institutional review board– and investigational new drug–approved, prospective phase I/II trial to investigate the safety and use of intranasal ketamine in patients with uncontrolled pain related to cancer or cancer treatment. Informed consent will be obtained prior to all study procedures. All patients will be assigned to the same investigational treatment arm. After patient selection via inclusion/exclusion criteria, patients will be seen over 5 visits, with each visit conducted 2-7 days apart. Patients will be administered ketamine on visits 1-4 and monitored for 240 minutes with continuous pulse oximetry and regular blood pressure checks. Blood samples as well as patient-reported outcomes will be collected at set time points at baseline and after drug delivery. Patients will receive 10 mg intranasal ketamine on visit 1, 10 mg intravenous ketamine on visit 2, 30 mg intranasal ketamine on visit 3, and 50 mg intranasal ketamine on visit 4. On visit 5, an addition blood sample will be drawn. Results As of March 2019, enrollment is in progress, and a total of 7 subjects have completed the study. Enrollment is expected to be completed by April 2019. Final data analysis will commence soon after, and the results are expected to be submitted for publication in 2019. Conclusions If intranasal ketamine can be utilized for pain control in cancer patients, it could provide superior analgesia and better quality of life, without the risk of significant respiratory depression and constipation associated with opioid medications. These findings will be an important initial step toward testing the effectiveness of intranasal ketamine as a nonopioid medication for cancer pain and as potential maintenance outpatient therapy. Trial Registration ClinicalTrials.gov NCT03146806; https://clinicaltrial...

IMPORTANCE trial: a provisional study-design of a single-center, phase II, double-blinded, placebo-controlled, randomized, 4-week study to compare the efficacy and safety of intranasal esketamine in chronic opioid refractory pain

“…Cancer pain classified as chronic (persistent or recurrent pain lasting longer than 3 months) 25 , and currently refractory despite optimized analgesic therapy including an opioid. [Optimized analgesic therapy is arbitrarily defined as: oral morphine equivalent of 60 mg/d or more 11 , 26 (or another strong opioid at optimized dose) plus at least one adjuvant analgesic drug, for at least 2 weeks.]…”

“…The advantage of this enantiomer is that it induces less dissociative effects and more powerful analgesia and anesthesia 10 . As an antidepressant, esketamine was approved by the FDA 10 , and as an analgesic it is not labeled yet due to the lack of studies assessing its efficacy and safety in relieving pain 10 , 11 .…”