Intrathecal sufentanil and epidural bupivacaine for labor analgesia: Dose-response of individual agents and in combination

Backgrounds and Objectives. Combinations of local anesthetics and opioids are frequently used during spinal and epidural analgesia for the relief of labor pain. This combination allows for a dose-sparing effect which may reduce potential side effects or toxicity. The precise nature of the interaction between opioids and local anesthetics in the clinical setting, i.e., additivity versus synergism, has not been established. This trial was designed to utilize a validated technique of analysis of drug interactions, isobolography, to investigate this interaction. Methods. One hundred healthy laboring patients at term receiving a combined spinal and epidural technique were divided into nine groups as follows: intrathecal sufentanil 2, 5, or 10 μg (2 mL volume) and epidural saline (10 mL); epidural bupivacaine 5, 12.5, or 25 mg and intrathecal saline (2 mL volume); or combination of 1, 2.5, and 5 μg intrathecal sufentanil plus 2.5, 6.25, or 12.5 mg epidural bupivacaine, using similar volumes, respectively. All drugs were administered in a randomized, double-blind fashion. Pain relief scores were assessed 20 minutes after drug injection, and isobolographic analysis was utilized to determine the nature of the interaction. Results. The ED₅₀ of intrathecal sufentanil alone was 2.3 μg (95% CI 1.7-3.2), and the ED₅₀ for epidural bupivacaine was 24 mg (95% CI 12-50). The combined sufentanil and bupivacaine fractional dose ED₅₀ (in fractions of the single-dose ED₅₀ values) was found to be approximately one-third and one-tenth of the single drug fractional dose, respectively: sufentanil 0.85 μg (0.36) and bupivacaine 2.2 mg (0.09). The duration of analgesia was nearly equivalent in all sufentanil-alone groups (83, 102, and 99 minutes); a dose-response effect was more apparent in the bupivacaine group (35, 42, and 74 minutes; P = .006) and the combination group (60, 79, 101 minutes; P = .028). Isobolography showed the combination dose to lie well within the area of synergism; however, the 95% confidence limits cross the line of additivity thus a pure additive interaction cannot be excluded. Conclusions. Markedly reduced doses of these drugs in combination can be used to provide adequate analgesia during labor compared with either single drug alone.