Comparative Effectiveness of Opioids and Opioid Substitutes on Pain and Health Related Quality of Life Among Cancer Survivors

Introduction Chronic pain is a major but modifiable contributor to poor quality of life among long‐term cancer survivors. With growing concern over opioid‐related risks, gabapentinoids have emerged as a safer alternative, though evidence comparing their effectiveness remains limited. Methods We conducted a retrospective cohort study using SEER‐MHOS linked data (1998–2021) to examine pain interference and health‐related quality of life (HRQoL) among 24,651 cancer survivors. Participants were categorized as opioid‐only (OPIOID‐only), gabapentinoid‐only (GABA‐only), both (BOTH), or no medication (NONE). Changes in pain interference and Physical and Mental Component Summary scores (PCS, MCS) were analyzed using paired t‐tests and multivariate regression, adjusting for demographic and clinical covariates. Results Over a 1 to 3 year follow‐up, all groups showed increased pain interference and declines in PCS and MCS scores. PCS declined by −1.01 in the OPIOID‐only group and −1.06 in the GABA‐only group. The BOTH group had stable PCS (+0.06) and a modest improvement in pain interference (−0.07). Multivariate models showed no significant difference between OPIOID‐only and GABA‐only for pain interference or PCS, but the BOTH group had significantly less pain worsening ( p = 0.0001) and PCS decline ( p = 0.004). Conclusion Gabapentinoids demonstrate comparable effectiveness as opioids for pain and HRQoL in cancer survivors, supporting their use as a safer alternative. Combination therapy showed better physical function and pain control, but findings may reflect higher baseline comorbidity and limited decline capacity rather than true superiority. These results underscored the need for personalized, multimodal pain management and further research on the long‐term safety of combination therapy.