Phase III, International, Multicentre, Double-blind, Dose Increment, Parallel-arm, Randomised Controlled Trial of Duloxetine Versus Pregabalin for Opioid-unresponsive Neuropathic Cancer Pain: a JORTC-PAL16 Trial Protocol

Introduction: Management of neuropathic cancer pain (NCP) refractory to regular opioids remains an important challenge. The efficacy of pregabalin for NCP except chemotherapy-induced peripheral neuropathy (CIPN) has already been confirmed in two randomised controlled trials (RCTs) compared with placebo. Duloxetine offers the potential of analgesia in opioid refractory NCP. However, there are no RCT of duloxetine for the management of opioid-refractory NCP as a first line treatment. Both classes of drugs have the potential to reduce NCP, but there has been no head-to-head comparison for the efficacy and safety, especially given differing side effect profiles.

Methods And Analysis: An international, multicentre, double-blind, dose increment, parallel-arm, RCT is planned. Inclusion criteria include: adults with cancer experiencing NCP refractory to opioids; Brief Pain Inventory (BPI)-item 3 (worst pain) of ≥4; Neuropathic Pain on the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale of ≥12 despite of an adequate trial of regular opioid medication (≥60 mg/day oral morphine equivalent dose). Patients with CIPN are excluded.The study will recruit from palliative care teams (both inpatients and outpatients) in Japan and Australia. Participants will be randomised (1:1 allocation ratio) to duloxetine or pregabalin arm. Dose escalation is until day 14 and from day 14 to 21 is a dose de-escalation period to avoid withdrawal effects. The primary endpoint is defined as the mean difference in BPI item 3 for worst pain intensity over the previous 24 hours at day 14 between groups. A sample size of 160 patients will be enrolled between February 2020 and March 2023.

Ethics And Dissemination: Ethics approval was obtained at Osaka City University Hospital Certified Review Board and South Western Sydney Local Health District Human Research Ethics Committee. The results of this study will be submitted for publication in international journals and the key findings presented at international conferences. TRIAL REGISTRATION NUMBERS: jRCTs051190097, ACTRN12620000656932.