Labor pain, analgesia, and chronobiology: what factor matters?

Alleviation and control of pain are of major importance in medicine. Depending on the causes and on the clinical situations, the patterns of pain may vary during the day, with peak and trough times reported at different times of day, although sometimes with contradictory results. The therapeutic effects of local anesthetics and opioid analgesics also demonstrate circadian variations. Two articles in this issue of Anesthesia & Analgesia report investigations in parturients into the relationship between time of administration of intrathecal bupivacaine, or intrathecal fentanyl versus systemic hydromorphone, and the duration of analgesia. In both studies, the duration of analgesia was defined as the time from the first administration of analgesia during labor until the second request for analgesia. The 2 groups of investigators approached the analysis of the chronobiology of analgesic requirements during labor from somewhat different perspectives. Scavone et al. addressed the problem from a clinical perspective, with their main objective being to determine whether time-related effects might have confounded the results of a previous study by the group. Shafer et al., on the other hand, used their clinical data to examine the problems that arise when developing models to analyze the often complex periodic data obtained from clinical situations. Scavone et al. compared neuraxial versus systemic opioid analgesia in 692 healthy parturients early in labor. At the first request for analgesia, patients in the neuraxial group were given intrathecal fentanyl 25 g, whereas patients in the systemic analgesia group received 1 mg IV and 1 mg IM hydromorphone. Subjects given their initial analgesia between 0701 hours and 2300 hours were considered as the daytime group; those given their first analgesic between 2301 hours and 0700 hours, the nighttime group. The authors found no difference in the median duration of either neuraxial or systemic analgesia, irrespective of the time of administration. A major advantage claimed by the authors for their study was the large number of patients investigated, considerably greater than that of previous studies of this nature. The paper by Shafer et al. represents the final product of a manuscript initially submitted to Anesthesia & Analgesia, reporting the chronobiology of the duration of analgesia following intrathecal bupivacaine. After peer review and extensive reanalysis of the original data, the manuscript has evolved into a much more interesting exploration of the methods used in chronobiological analysis to detect the influence of external factors and in particular how one can use these methods to detect possible artifacts in the data. This is an important illustration of the value of a wellconducted peer review process. Shafer et al. make the important point in their paper that very different conclusions can be drawn, depending on the statistical methods used to analyze the data. They used 3 different smoothing functions to explore circadian rhythms graphically. These revealed a bimodal pattern in the duration of analgesia, with 1 peak at around 0630 hours and a subsequent peak in the afternoon or evening. In contrast, an analysis of variance (ANOVA) did not show any significant difference in the duration of analgesia, irrespective of the timing of the intrathecal injection of bupivacaine. Fitting the data to a simple cosine function of analgesia duration versus time demonstrated a periodic waveform with a period of 8 hours, but with peaks that corresponded with only 1 of the 3 peaks identified by the smoother functions. The authors then used a bootstrap analysis to show that 2 individual points were responsible for the statistical significance in their cosine fit. Removing these points from the dataset also removed the previously observed rhythmic effect of intrathecal bupivacaine on analgesia. The authors concluded that these 2 points were likely to be artifacts, though they acknowledge this might be uncertain, corresponding to the change in nursing and anesthesia shifts. The literature contains conflicting reports on the timedependent effects of neuraxial local anesthetics and opioids. These differences may be a consequence of the wide variety of factors that need to be considered when interpreting the results from chronobiology experiments. They also emphasize the importance of a very stringent experimental protocol, including methodology and statistical methods used to analyze the potential rhythmic effects of a drug. Many factors, both internal and external, can influence the biological rhythms of a drug’s action. These include temporal variations in light–dark, rest–activity, From *Unité de Chronobiologie, Fondation Ophtalmologique A. de Rothschild, Paris, France; and †INSERM U666 (GRERCA), CHU de Strasbourg, Faculté de médecine, Strasbourg, France.