Drug Interactions between aspirin / caffeine / dihydrocodeine and toripalimab

MONITOR: Opioid analgesics may reduce the efficacy of immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 monoclonal antibodies and/or inhibitors of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1). The mechanism of this interaction has not been fully elucidated, but may involve the ability of opioids to modify cellular functions of the immune system (T-cells), potentially affecting tumor growth. Additionally, ICIs can suppress the efficacy of opioids leading to an increase in opioid use via inhibition of the PD-1/PD-L1 signaling pathway. In a meta-analysis review of 7 studies (531 studies screened), it was observed that the use of opioids in patients treated with ICIs was negatively associated with overall survival (OS) and significantly reduced progression-free survival (PFS). Similarly, an observational, retrospective study including 375 patients with recurrent or metastatic cancer treated with anti-PD-1 or anti-PD-L1 monoclonal antibodies noted that patients who were not treated with opioid analgesics had significantly longer median PFS (6.83 vs. 4.30 months) and median OS (17.05 vs 7.68 months) compared to patients who were treated with opioid analgesics. Furthermore, a retrospective, single-center, observational cohort study observed that the median amount of change in opioid dose from baseline was significantly higher in patients who were treated with ICIs as compared to patients who were treated with non-ICI anticancer therapies (22.5 vs. 15.0 morphine mg equivalents). Multiple regression analysis and propensity score matching identified ICI administration as an independent factor associated with the amount of increase in opioid dose.

MANAGEMENT: Until more information is available, caution and clinical monitoring for reduced efficacy of immune checkpoint inhibitors (ICIs) and opioid analgesics are advised if concomitant therapy is required. Opioid analgesic use should be limited to clinically appropriate indications and durations. Clinicians should consult relevant literature, local and national treatment guidelines, and package labeling for further guidance.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.