Andres F Mantilla-Santamaria, Sebastian Vallejo, David L Cedeno, Michelle M Boyd, Tony L Yaksh, Ricardo Vallejo
The addition of bupivacaine to IT morphine is associated with a safety profile similar to morphine monotherapy, although with a significantly smaller frequency of cognitive impairment, and a trend toward fewer granulomas, despite higher median morphine doses. These real-world findings are consistent with the safety profile of this consensus-backed off-label practice.
BACKGROUND: Chronic intrathecal morphine infusion is a standard US Food and Drug Administration (FDA)-approved therapy for severe refractory pain. However, long-term morphine monotherapy is associated with opioid tolerance and complications like catheter-tip granulomas. Coadministration with bupivacaine is widely used off-label to mitigate these risks, yet comparative real-world safety data remain scarce.
OBJECTIVES: To systematically compare the real-world adverse event (AE) profiles of intrathecal (IT) morphine monotherapy versus binary morphine-bupivacaine therapy.
STUDY DESIGN: Retrospective analysis.
SETTING: FDA's Manufacturer and User Facility Device Experience (MAUDE) database.
METHODS: The MAUDE database was queried for reports related to the SynchroMed® and Prometra® infusion pump systems from 2016 through 2025. Reports specifying the exclusive use of morphine monotherapy or a binary morphine-bupivacaine mixture were extracted. Data on drug dosing and device- and medication-related AEs were analyzed with the Mann-Whitney U test and Fisher's exact test. This study was exempt from IRB approval.
RESULTS: Out of 41,495 total reports for the SynchroMed and Prometra pumps during the 2016 through 2025 period, 5,423 involved morphine monotherapy and 1,072 involved the binary mixture. The median morphine dose was significantly higher in the binary group (2.20 mg/day) compared to monotherapy (1.50 mg/day) (P < 0.05). Despite higher opioid doses, the binary group had a significantly lower incidence of cognitive impairment (0.56% vs 1.48%, P < 0.05). Inflammatory granulomas trended lower in the binary group (0.65% (n = 7) vs 1.33% (n = 72), P = 0.068). Opioid withdrawal was the most common medication-related AE in both regimens (17.33% mono vs 15.30% binary, P > 0.05). Significantly different bupivacaine-specific AEs in the binary group included numbness (1.77%) and paresis (1.49%).
LIMITATIONS: As a passive surveillance system, MAUDE lacks denominator data (i.e., total devices in service), precluding the calculation of true incidence rates. Unverified reporting and lack of specific patient comorbidities are inherent limitations.
CONCLUSIONS: The addition of bupivacaine to IT morphine is associated with a safety profile similar to morphine monotherapy, although with a significantly smaller frequency of cognitive impairment, and a trend toward fewer granulomas, despite higher median morphine doses. These real-world findings are consistent with the safety profile of this consensus-backed off-label practice.