PROJECT SUMMARY/ABSTRACT The proposed project is in response to RFA-DE-22-011: HEAL Initiative: Secondary Analysis and Integration of Existing Data Related to Acute and Chronic Pain Development or Management in Humans. The HEAL Initiative is a trans-NIH project, Helping to End Addiction Long-term, was launched in 2018 as a direct response to the opioid crisis in the US. This crisis is even more complex in oncology as pain is one of the most feared symptom among cancer survivors, and opioid use is central to pain management in cancer care. While cancer survivors have a significantly increased risk of long-term use of opioid, in head and neck cancer (HNC), over 80% of patients have a history of receipt of opioid prescription during care, and up to 15% of patients continue using opioids long after active treatment, increasing their risk of long-term opioid therapy (LTOT), which is >90 days of opioid use following treatment. The need to characterize opioid use in HNC is underscored by the fact that HNC which only accounts for 3% of the total US cancer burden, might be responsible for 12% of opioid-related deaths among patients with cancer. Risk of both depression and suicide are higher among patients with HNC compared with the general US population; however, the relative contribution of long-term opioid treatment to these adverse psychosocial consequences of HNC is unknown. About 1-in-2 patients with HNC have a lifetime history of depression, which is significantly associated with chronic pain. In addition, HNC has the second highest rate of suicide of all cancer sites, also associated with chronic pain. It is unknown if LTOT is associated with risk of depression in these patients, or whether it increases risk of suicide in HNC. It is therefore critical to understand to establish the relative contribution of LTOT to adverse psychiatric sequelae in patients with HNC. Long-term, we hope to decrease depression and suicide risks in cancer, and develop and implement tailored interventions that will inform safe opioid prescribing, and provide evidence leading to alternative pain management in HNC and oncology care in general. Our long-term goals align with both the HEAL initiative, and several Healthy People 2030 objectives, such as reducing the proportion of adults who misuse prescription opioids, as well as decreasing suicide rate in the US by 25% in the next decade. However, to achieve these long-term goals, it is necessary to first quantify the role of LTOT in depression and suicide risks among patients with HNC beyond establishing correlations or associations. Using two distinct, independent large cohorts of patients with HNC, the objective of this proposed project is to establish the role of LTOT in depression and suicide among patients with HNC, using advanced analytics that allows for establishing temporality, dose-response and other causal-related inferences in observational data. Findings from this proposed research will impact clinical care in oncology related to safer opioid prescribing, and alternative pain management, which would decrease risk of depression and suicide in the HNC patient population.

PUBLIC HEALTH RELEVANCE STATEMENT Most of the response to the opioid crisis in the US has focused on non-cancer pain, yet at least 8 out of 10 patients with HNC will have received an opioid prescription during treatment. A recent Cochrane review concluded that the amount and quality of evidence available that justifies opioid use in cancer-related pain management is disappointingly low. Opioid is so central to cancer-pain management that it is critically urgent to develop evidence for safer opioid prescribing. This proposed project will make an important contribution to the evidence on opioid use in oncology by establishing the temporal link between long-term opioid use and adverse psychiatric sequelae in patients with HNC.