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