We have read with great interest the manuscript entitled “Propofol anesthesia significantly alters plasma blood levels of melatonin in rats,”1and we would like to comment on this interesting and provocative study. Previous studies have suggested that circadian variation in drug metabolism may be linked to anesthetic drug efficacy. It remains unclear, however, whether anesthetics themselves can directly influence the regulation of the circadian clock.

In the present study, the authors injected rats intraperitoneally with either propofol or intralipid (control) and measured subsequent melatonin secretion. The authors observed an acute suppressive effect of propofol on plasma melatonin concentration, which normalized within 24 h. On the basis of these findings, the authors concluded that these results established “disturbing effects of propofol anesthesia on the circadian rhythm of plasma melatonin” and that these results “parallel the desynchronization of the circadian rhythms of locomotor activity observed after propofol.”

Although we would like to commend the authors for performing this interesting and important investigation, we remain concerned that the conclusions drawn are premature and not fully supported by the data.

First, the study design does not allow the authors to determine definitively whether the effects of intraperitoneal injection of propofol are linked, in full or in part, with propofol-induced anesthesia. Depth of anesthesia was not measured by the authors, making it is unclear to what extent the consciousness of the individual rats was impaired. It is also interesting to consider the established ability of propofol to induce a pleasant affective state in rats at subanesthetic doses (as well as during recovery from an anesthetic dose).2Perhaps, then, the effects of propofol injections parallel those of opioids, which themselves have been shown to affect melatonin secretion indirectly.3 

Second, contrary to the suggestion in the section “What This Article Tells Us That Is New,” neither a visually nor a statistically significant phase advance of melatonin secretion was shown by the present study. In fact, the authors report only a “trend” towards this putative phase advance, and we wonder if this could be just as reasonably explained by the cocinar methodology, which is sensitive to artifacts such as changes in the waveform used in the analysis (in this case, driven by the acute suppression of melatonin at the first two Zeitgeber times after injection). Furthermore, the magnitude of the putative phase advance is slight. Given then the small magnitude and the transient nature of the “circadian” response, it does not seem prudent to link postsurgical fatigue, drowsiness, sleep disorders, and mood alterations to anesthetic-induced changes in the circadian clock. In fact, the definitive studies to provide the necessary data to support this conclusion have not yet, to our knowledge, been performed.

Third, the authors conclude that the effects of propofol on melatonin injection “parallel the desynchronization of the circadian rhythms of locomotor activity previously observed after propofol.” However, the cited study4was not performed in constant darkness, which is necessary to establish a direct linkage between anesthetic administration and circadian clock disruption. Interestingly, previous work in humans has shown that even 3 h of anesthetic exposure in humans does not affect the circadian phase of the body temperature rhythm.5In summary, it must be stressed that the ability to distinguish between effects occurring directly on the circadian pacemaker and those occurring “downstream” from the pacemaker on other physiologic control systems requires extremely rigorous experimental conditions. These conditions have yet to be met, and so for now, it is more prudent to interpret the effects of propofol on the melatonin rhythm as “masking.” In other words, the data more strongly support the concept that the “hands ” of the clock, rather than the “gears ” of the clock, have been influenced by the propofol stimulus.

*Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. meikermann@partners.org

Dispersyn G, Pain L, Touitou Y: Propofol anesthesia significantly alters plasma blood levels of melatonin in rats. Anesthesiology 2010; 112:333–7
Pain L, Oberling P, Sandner G, Di Scala G: Effect of propofol on affective state as assessed by place conditioning paradigm in rats. Anesthesiology 1996; 85:121–8
Lewczuk B, Przybylska-Gornowicz B, Wyrzykowski Z: The effect of morphine on melatonin secretion in the domestic pig. In vivo  and in vitro  study. Neuro Endocrinol Lett 1999; 20:171–8
Dispersyn G, Pain L, Touitou Y: Circadian disruption of body core temperature and rest-activity rhythms after general (propofol) anesthesia in rats. Anesthesiology 2009; 110:1305–15
Sessler DI, Lee KA, McGuire J: Isoflurane anesthesia and circadian temperature cycles in humans. Anesthesiology 1991; 75:985–9