A literature review of management for opioid-refractory neuropathic cancer pain: an update and future perspectives

Background and Objective: Managing opioid-refractory neuropathic cancer pain (NCP) remains a significant challenge. The clinical characteristics are different from pure cancer nociceptive pain, chronic non-cancer neuropathic pain, and non-neoplastic neuropathic pain associated with cancer therapy (e.g., chemotherapy-induced peripheral neuropathy). Although treatment efficacy may differ, previous guidelines and reviews have not made this distinction. This review defines NCP as pain due to nerve tissue injury caused by a tumor or its metastases. This review aims to provide an in-depth review of the diagnostic process, a summary of the current treatment options for NCP, and an insight into promising new therapies. Methods: The PubMed database was searched for "neuropathic cancer pain" or "cancer-related neuropathic pain" and "management", focusing on literature published in the last two decades and limited to English. References in the retrieved literature were manually searched to identify additional literature. Key Content and Findings: The first important consideration in managing opioid-refractory NCP is to diagnose neuropathic pain correctly. Next is the use of adjuvant analgesics; analgesics are selected based on evidence for non-cancer neuropathic pain but may be less effective for cancer pain than for non- cancer pain. Importantly, World Health Organization guidelines "recommend clinical trials" and prescribe with the mindset of immediately reducing or discontinuing harmful doses. Because adjuvant analgesics are complementary to opioids, a clinician must ensure that sufficient opioids are being used and consider increasing to the maximum dose. However, this is often impossible due to opioid side effects. Anticonvulsants and antidepressants are the most well-described pharmacologic treatments for opioid-refractory NCP. Drug selection considers NCP characteristics and tolerable side effects, which vary among patients. In addition, we present other techniques, including opioid switching, the use of methadone as an adjuvant analgesic, promising new agents, and consideration of gene polymorphism. Conclusions: Many challenges remain in managing NCP. Current guidelines for NCP are based on limited evidence and often contradict each other. More robust clinical trials are needed to support future recommendations. Identifying a gold standard for diagnosing NCP is essential for good clinical practice. Preclinical research is also needed to discover new mechanisms and agents, as opioid-refractory NCP is complex.