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Several studies have characterized the 50% and 95% effective doses (ED50 and ED95, respectively) of intrathecal sufentanil for labor analgesia. Few have investigated these same criteria for the less expensive alternative, fentanyl. In addition, the ventilatory effects of intrathecal fentanyl at clinically relevant doses are unclear. We performed this study to establish the dose-response relationship of intrathecal fentanyl for both analgesia and ventilatory depression. Ninety parturients in active early labor (or = 5 cm dilation) received intrathecal fentanyl 5, 7.5, 10, 15, 20, or 25 micrograms in a double-blinded, randomized fashion (n = 15 patients in each group). Parturients were monitored for degree of pain (measured using a 100-mm visual analog pain scale), blood pressure, arterial oxygen saturation (SaO2), respiratory rate, ETCO2, and fetal heart rate 0, 1, 5, 10, 15, 20, 25, and 30 min after the administration of intrathecal fentanyl. An absolute visual analog pain scale scoreor = 25 mm was defined a priori as analgesic success. The percentage of parturients who achieved analgesic success was used to construct quantal dose-response curves, from which the ED50 and ED95 values were derived for the total population (mixed parity) and the nulliparous and multiparous subpopulations separately. Overall ED50 and ED95 values (95% CI) were 5.5 (3.4-7.2) and 17.4 (13.8-27.1) micrograms, respectively. Nulliparous values were lower (5.3 and 15.9 micrograms, respectively) than multiparous values (6.9 and 26.0 micrograms, respectively) but were within the 95% CIs of the total population. Pruritus incidence in parturients with analgesic success displayed a dose-response relationship identical to that seen for analgesia. ETCO2 displayed a dose-related increase, particularly at dosesor = 15 micrograms, without concomitant changes in respiratory rate or SaO2, which suggests a decrease in tidal volume. Even in the absence of overt signs or symptoms of somnolence, intrathecal fentanyl at doses within the effective analgesic range induced a change in ventilation that may last longer than the 30-min period we studied.Intrathecal fentanyl induces rapid and satisfying dose-dependent analgesia in early labor; however, it also produces dose-related decreases in ventilation in the absence of overt somnolence.

The GABA(A) receptor is an important target for a variety of general anesthetics (Franks and Lieb, 1994) and for benzodiazepines such as diazepam. Specific point mutations in the GABA(A) receptor selectively abolish regulation by benzodiazepines (Rudolph et al., 1999; McKernan et al., 2000) and by anesthetic ethers (Mihic et al., 1997; Krasowski et al., 1998; Koltchine et al., 1999), suggesting the existence of discrete binding sites on the GABA(A) receptor for these drugs. Using anesthetics of different molecular size (isoflurane > halothane > chloroform) together with complementary mutagenesis of specific amino acid side chains, we estimate the volume of a proposed anesthetic binding site as between 250 and 370 A(3). The results of the "cutoff" analysis suggest a common site of action for the anesthetics isoflurane, halothane, and chloroform on the GABA(A) receptor. Moreover, the data support a crucial role for Leu232, Ser270, and Ala291 in the alpha subunit in defining the boundaries of an amphipathic cavity, which can accommodate a variety of small general anesthetic molecules.