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*Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital;
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts
Address correspondence and reprint requests to Alla B. Khodorova, PhD, Pain Research Center, MRB 611, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. E-mail: gstrichz{at}zeus.bwh.harvard.edu
We investigated the effectiveness for cutaneous analgesia of bupivacaine (Bup) stereoisomers in male rats. As a model of infiltration anesthesia, inhibition of a nocifensive reflex by subcutaneous injection of 0.6 mL of different concentrations of R-, S-, and racemic-Bup was evaluated quantitatively by the fraction of times a pinprick failed to evoke a nocifensive motor response. R-Bup was more potent in the extent of block; however, S-Bup had a longer-lasting action at smaller doses. This significant difference was apparent when R-Bup and S-Bup were administered in equipotent doses of 0.06% and 0.075%, respectively. Co-injection of epinephrine (Epi) with these equipotent doses enhanced and prolonged the blocking effects of both Bup stereoisomers, although at dilutions of 1:100,000 to 1:1,000,000 Epi itself induced partial, transient analgesia. At 1:2,000,000 dilution, Epi alone had no analgesic effect; however, when co-injected with the shorter-acting R-Bup (0.06%), Epi prolonged its blocking effect to equal the duration of block evoked by equipotent S-Bup (0.075%). We conclude R-Bup is more potent for cutaneous analgesia and that the longer duration of block by S-Bup probably originates from vasoconstrictor activity.
Implications: Here we show that the more potent optical R-isomer of bupivacaine (Bup) can be used at a smaller dose (80%) than the S-isomer of Bup to give equal pain relief of a skin prick. Although the analgesia from R-Bup is briefer than that from equipotent S-Bup solutions, the durations become equal when a very dilute solution of the vasoconstrictor epinephrine is mixed with the R-isomer. The resulting vasoconstriction thus reduces vascular drug uptake and peak blood levels of systemic drug, reducing potential toxicity.
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