Potencies and Probabilities: One-Sided P Values Suggest a One-Sided Story!

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

In Reply— I thank Drs. Polley and Columb for their interest in our recent publication in Anesthesia & Analgesia(1) and appreciate the opportunity to respond to their concerns. First of all, Dr. Columb has co-authored several recent publications that describe the determination of the concentration of a local anesthetic necessary to produce epidural analgesia (visual analog scale for pain [VASP] <10/100 by 30 min) in 50% of laboring parturients. This body of work has raised awareness within the Obstetric Anesthesia community of the possibility that local anesthetics such as bupivacaine and ropivacaine may not be equipotent. The 50% effective concentration (EC50) ratio (%w/v) for bupivacaine:ropivacaine of 0.6 was indeed independently determined by two recent studies coauthored by Dr. Columb (2,3). Unfortunately, this research model focuses entirely on only one point on the concentration (dose) response curve (i.e., EC50). Of importance, anesthesiologists providing epidural labor analgesia do not routinely (if ever) utilize such ineffective concentrations in clinical practice. Secondly, the upper end of the concentration (dose) response curves (i.e., EC90, EC95) for these local anesthetics have yet to be determined as acknowledged by Drs. Columb and Polley. Consequently, EC90 or EC95 (%w/v) ratio comparisons are unknown, and therefore any conjecture related to the clinically relevant potencies of the two local anesthetics is premature and potentially misleading! Drs. Columb and Polley’s suggestion that the “up-down sequential allocation” method of determining the EC50 on the “straight part of the cumulative dose-response curve” allows the EC50 to be “better estimated” may be true, but certainly not clinically relevant. To overcome “potential errors at the extremes of distribution” (i.e., EC90 determinations), I suggest appropriate studies be undertaken with enrollment of large numbers of patients rather than the 30 per group used to “estimate” EC50s (2,3). “Basic mathematics” aside, proclamations that bupivacaine and ropivacaine are not equipotent based on EC50 studies have yet to be validated and are extremely premature. Our investigation compared concentrations of bupivacaine and ropivacaine (0.08%) combined with 2 μg/mL fentanyl that had not been previously described. Both medication combinations proved effective labor analgesia with mean times to VASP 0/100 of approximately 12 min in both groups. Only one study to date (coauthored by Dr. Columb) reported the EC50 of bupivacaine, combined with 2 μg/mL fentanyl, to be 0.048%(4). We acknowledged this result in our discussion to illustrate the inability of the EC50 studies to be extrapolated to the clinical relevant portions of the concentration (dose) response curves for each local anesthetic. As Drs. Columb and Polley suggest “the dose of bupivacaine (required) is 40% less than that of ropivacaine” if the goal is to provide “effective” (VASP <10/100 × 30 minutes) in only 50% of laboring women (2,3). Our study results suggest that the initiation of epidural analgesia with 0.08% ropivacaine plus 2 μg/mL fentanyl approximates at least the EC95 (if not higher) for ropivacaine. Therefore, if the concentration (dose) response curves for the two local anesthetics are truly parallel, then 40% less bupivacaine, or only 0.048% should represent the EC95 for bupivacaine. However, Dr. Columb and co-workers reported that this concentration produced effective epidural labor analgesia in only 50%, not 95%, of laboring women! Consequently, our data does not support such a large concentration (%w/v) ratio of 0.6 for bupivacaine:ropivacaine at concentrations that produce effective labor analgesia. In fact, recent investigations (5,6), including our own (1), have reported similar total requirements of bupivacaine and ropivacaine over the entire duration of labor, rather than only at the time of initiation, using patient-controlled epidural anesthesia. These reports provide preliminary evidence that the EC95s may be similar, in combination with fentanyl, at clinically relevant concentrations. I agree with Drs. Columb and Polley that this is certainly of interest and requires further investigation. I am surprised that Drs. Columb and Polley devoted so much effort criticizing the analysis of a secondary outcome of the study that we clearly stated requires further investigation. I am intrigued by the criticism of the one-sided Fisher’s exact test pertaining to the incidence of forceps deliveries between the groups. Of note, we found that “all” women in the ropivacaine group were able to ambulate compared with significantly fewer women in the bupivacaine group. Do Drs. Columb and Polley actually believe that any local anesthetic (bupivacaine) that causes significantly more motor blockade would actually have less chance of producing a forceps delivery than one that does not? Our use of the one-sided P value was based on our expected outcome that bupivacaine, which produced significantly more motor blockade, could only cause more forceps deliveries, not fewer. In summary, I thank Drs. Columb and Polley for their interest in our recent article. I am hopeful that, in our continuing attempts to improve epidural labor analgesia, the issue of relative potencies of these and newer local anesthetics (with or without fentanyl) will be addressed in future investigations using clinically relevant concentrations. David C. Campbell MD, MSc, FRCPC