Effectiveness of Opioid Titration for Terminal Dyspnea in Opioid-Naïve and -Tolerant Patients with Advanced Cancer: A Multicenter Prospective Cohort Study

Background: Terminal dyspnea is a distressing symptom in advanced cancer patients. Although opioids are standard treatment, their effectiveness may differ between opioid-naïve and -tolerant patients. Objectives: To evaluate responses to opioid titration for terminal dyspnea and assess differences in palliative care physicians' perceptions of opioid effectiveness between opioid-naïve and -tolerant patients. Design: A pre-planned secondary analysis of a multicenter prospective cohort study. Setting/Subjects: Advanced cancer patients (n = 108) with moderate to severe terminal dyspnea and an Eastern Cooperative Oncology Group performance status of 3-4, receiving continuous parenteral opioid infusions, were included and categorized as opioid-naïve (n = 48) or opioid-tolerant (n = 60). Measurements: Opioid doses were titrated in four predefined levels within 48 hours, with effectiveness assessed 6 hours post-titration using the Clinician Global Impression-Improvement scale. Opioid ineffectiveness was defined as the need for continuous sedatives or death without dyspnea relief, with doses recorded as the parenteral morphine-equivalent daily dose. Results: The mean age was 72 years, and lung cancer was present in 43 patients (40%). Opioid-naïve patients showed a 100% response after 12 titrations, while opioid-tolerant patients exhibited a 68% response after 34 titrations. At death or one month after treatment, opioids were determined to be ineffective in 8.3% of opioid-naïve and 38% of opioid-tolerant patients (p < 0.001). Median doses at ineffectiveness were 15 mg (IQR = 7.5-23) and 36 mg (IQR = 14-200), respectively. Conclusions: Opioid-tolerant patients showed a lower-level response and were more likely to experience ineffectiveness than opioid-naïve patients. Larger studies are needed to confirm these findings and improve terminal dyspnea management.