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• W2020973886 abstract "“As we learn from our errors, our errors become increasingly valuable” —Sir Karl Popper (1902–1994) This issue of Anesthesia & Analgesia contains reports of three studies that are excellent examples of, in contemporary parlance, “thinking outside the box.” Two of the studies, one by Ismail and Mowafi1 and the other by Gögenur et al.,2 examined the utility of the neurohormone melatonin as an anesthetic adjunct in the perioperative setting, and the third article, by White et al.,3 examined the use of the γ-amino butyric acid analog pregabalin as a preoperative anxiolytic. All three studies are noteworthy in that they examined whether old (melatonin) or new (pregabalin) pharmacologically active agents can be used in novel ways. In addition, the studies by Gögenur et al.2 and White et al.3 are striking in that they are essentially “negative” studies, to wit, the authors were unable to confirm their primary hypotheses that the compounds in question had clinically meaningful effects. In the past, such articles would have been unlikely to see the light of day or typesetters’ sorts. So, first to melatonin: melatonin is synthesized in the pineal gland and is released in a diurnal fashion into the bloodstream, with peak plasma levels occurring during the evening.4,5 It has a wide range of effects, key among them being synchronization of the circadian clock.6 It has long been thought that exogenously administered melatonin has hypnotic properties and, indeed, such an effect has been demonstrated in a number of studies.7,8 We have previously reviewed the use of melatonin as an anesthetic adjunct,9 and we will briefly summarize the key points of our review here. Antón-Tay et al.10 were the first to demonstrate that exogenously administered melatonin had hypnotic properties in human subjects; in a parallel fashion, the loss of consciousness seen in animals after administration of anesthetic doses of melatonin was accompanied by a pattern of electroencephalogram activity similar to that seen during loss of consciousness induced by IV and volatile anesthetics.11,12 Subsequent work demonstrated that exogenously administered melatonin markedly decreased the mean latency of sleep onset time in young13 and elderly subjects.14In vivo, both melatonin and 2-bromomelatonin, a potent melatonin receptor agonist,15 possess hypnotic and analgesic properties in rats.16,17 Those observations raised the question whether melatonin might have utility in the perioperative setting. Indeed, studies showed that exogenously administered melatonin produces anxiolysis and sedation, but not amnesia or motor impairment, in the preoperative period in both children18 and adults.19,20 In their study reported in this issue of the journal, Ismail and Mowafi1 examined the effects of preoperative administration of melatonin on the subjective experience of patients older than 60 yr of age undergoing cataract surgery under topical anesthesia, and on intraocular pressure (IOP) and surgeons’ reports of operative conditions. As might be expected from the preceding discussion, the authors found that 10 mg of melatonin given orally 90 min before surgery (n = 20) produced anxiolysis and enhanced analgesia compared with placebo (n = 20). Subjects in the melatonin group required approximately 60% less fentanyl (P = 0.007) than those in the control group. In addition, subjects in the melatonin group had significantly lower IOP than those given placebo, and surgeons reported better operating conditions in patients in the melatonin group. One can reasonably argue that analgesic drugs that lack respiratory depressant effects are valuable and have a place in our pharmacologic armamentarium; whether the anxiolysis provided by melatonin is any better than that provided by currently available short-acting benzodiazepines, such as midazolam, is unknown. Ismail and Mowafi’s report of a mean decrease in pain and anxiety scores (assessed using a simple visual analog scale [VAS]) of 1 U (of 10 U) between the melatonin and control groups1 is difficult to interpret. Although the surgeons assessing IOP and operating conditions were blinded to patient assignment, the investigators assessing pain and anxiety were not blinded to patient assignment, and the authors studied only one dose of melatonin. The value of the final observation concerning IOP and operating conditions is limited as no mention is made of whether “better quality of operative conditions” translated into shorter operating room times or fewer complications. It is also not clear whether the reduction in IOP could be attributed to the observed reduction in mean arterial blood pressure. In the study by Ismail and Mowafi,1 the 10-mg oral dose of melatonin produced significant and prolonged reductions in mean arterial blood pressure. In a randomized, double-blind study, prolonged administration of melatonin (a 3-wk course of a daily slow-release 3-mg melatonin pill) did not influence diurnal blood pressure but did significantly decrease nocturnal blood pressure without modifying heart rate in women.21 The hemodynamic effects of oral melatonin in different age groups need to be further studied. Another significant limitation of the study is the lack of measurement of plasma concentrations of melatonin. Orally administered melatonin undergoes significant first-pass hepatic metabolism and shows pronounced variability in blood plasma levels22–24; thus, additional work is needed to relate the dose administered to the actual dose required. Although plasma melatonin concentrations were not reported in earlier studies,8,19,20 we need to move a step forward to gain a better understanding of the pharmacokinetic/pharmacodynamic behavior of oral melatonin. Those concerns notwithstanding the results of this study are interesting and should provide impetus for further studies examining the use of melatonin in the perioperative setting. In contrast to the positive findings for melatonin reported by Ismail and Mowafi,1 Gögenur et al.2 were unable to demonstrate a significant effect of melatonin on self-reported sleep quality in 61 subjects after laparoscopic cholecystectomy. Several studies have demonstrated that anesthesia and surgery impair the rhythm of melatonin secretion and the circadian clock,25,26 and melatonin administration is effective in treating postoperative delirium.27 The rationale for the study conducted by Gögenur et al.2 was that sleep disturbances are frequently observed after minimally invasive and ambulatory surgery and, as noted above, exogenous melatonin appears to have hypnotic properties. In this prospective, randomized, double-blind study, 136 subjects with an ASA physical status classification of 1–3 scheduled for elective outpatient laparoscopic cholecystectomy were randomly assigned to receive either placebo or melatonin 5 mg orally on each of the first 3 nights after surgery. Each subject was required to complete a sleep questionnaire and sleep diary. Patients documented how they had slept the preceding night (evaluated using a 100-mm VAS with 0 mm indicating best conceivable sleep and 100 mm indicating worst conceivable sleep); in addition, they were asked to record “the time they went to bed, the time they tried to sleep, how many minutes it took before they slept, the number and duration of night time awakenings, the time they woke up, and the time they got out of bed,” and the “time and duration of daytime naps.” The only significant finding was that subjects in the melatonin group reported a significantly shorter time to fall asleep (sleep latency [mean ± sd], 14 ± 18 min vs 28 ± 41 min) on the first postoperative night. Was the number of patients sufficient to demonstrate a difference in sleep quality, given the large sds reported for the individual sleep-diary variables measured (Table 2, Ref. 2)? One might argue that the number of patients was not adequate from the start to detect any significant differences in sleep quality between the groups. In addition, the authors studied patients ranging in age from 18 to 80 yr. Elderly patients are known to suffer from sleep disturbance for a variety of reasons.28,29 In addition, patients in the placebo group seem to have received more opioids (6.9 ± 8.0 mg vs 4.6 ± 7.0 mg—mean 50% higher dosage) more often (35 of 61 [57.4%] subjects vs 28 of 60 [46.7%] subjects). A multivariate statistical approach to examine the effects of age and opioid consumption, among other factors, should have been considered. There are other issues with this study that could account for its essentially negative findings. How reliable is self-reporting? Various sleep tests, including the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test, are sensitive in measuring the effects of sleep deprivation within subjects but are less sensitive in confirming sleepiness and response to treatment in groups of patients with different sleep disorders.30 Compared with objective measurement (such as actigraphy), self-reporting of sleep habits may introduce sufficient error31 to mask small but significant effects. In addition, it could very well be that melatonin has notable hypnotic properties but that the 5-mg dose used by Gögenur et al. was insufficient to achieve a notable effect. Another important question, at least for readers in the United States, relates to the specific formulation of melatonin given. The authors obtained melatonin capsules from Penn Pharmaceutical Services (Tredegar, Gwent, Wales, UK), a commercial enterprise that provides pharmaceutical development and custom manufacturing services. We do not know whether melatonin is regulated as a drug in the United Kingdom. In the United States, however, melatonin is not classified by the Food and Drug Administration as a drug; rather, it is classified in the “dietary supplement” category, and so its production is not regulated and the biological activity of any given sample cannot be guaranteed. Finally, the lack of measurement of plasma melatonin levels in this study leaves the reader in a quandary: do we assume that melatonin is truly no different than placebo, or are we left wondering whether the absence of effect reflects an absence of the requisite serum levels necessary to produce a clinically detectable response? Both this and the study by Ismail and Mowafi highlight the need for rigorously conducted double-blind, randomized, controlled trials that include measurement of serum plasma concentrations if we are to reach a consensus on the clinical utility of melatonin in the perioperative setting. Assuming that a positive effect can be observed (we believe this will be the case), there is still the question of whether melatonin has advantages over currently available drugs, so further work lies ahead of us. Finally, we come to the study by White et al.,3 who examined the effect of pregabalin on anxiety and sedation in the preoperative period. Pregabalin, although designed to resemble the inhibitory neurotransmitter γ-amino butyric acid, appears to interact with the α2δ subunit of L-type voltage-gated Ca2+ channels.32,33 The authors studied 108 subjects with an ASA physical status classification of 1–3 undergoing elective surgery as outpatients; subjects were randomly assigned in a double-blind fashion to one of four groups: placebo or pregabalin at a dose of 75, 150, or 300 mg orally. The effects of the study drug on the patients’ level of anxiety, sedation, and pain were assessed at baseline and at numerous time points before and after surgery. Pregabalin had no effect on preoperative anxiety at any dose, but the highest dose of pregabalin was associated with significantly increased levels of sedation in the postoperative period. White et al. based their rationale for the study, in part, on the claim that “pregabalin … has been alleged to possess anxiolytic, analgesic, and antiepileptic activity.” The claim is somewhat tricky in that the data indicating pregabalin has anxiolytic properties come primarily from studies examining its efficacy in treating generalized anxiety disorders. Indeed, pregabalin has shown efficacy in reducing the symptoms of generalized anxiety disorders in a number of randomized controlled trials34–38 and is approved in Europe for treatment of this disorder (http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/03-27-2006/0004327379). However, only one study appears to have examined the acute anxiolytic effects of the drug. In that study, pregabalin at a dose of 150 mg orally was compared against placebo and an active comparator, alprazolam, in healthy male and female outpatients (age ≥18 yr) undergoing a scheduled dental procedure who were anxious at baseline (Dental Anxiety Total score ≥12 at the screening visit and at baseline on the day of the dental procedure).39 Notably, “on the primary outcome, the VAS-Anxiety, treatment with pregabalin resulted in a reduction in the VAS-Anxiety score, which was not significantly different from placebo. In contrast, treatment with alprazolam resulted in significant reduction in the VAS-Anxiety score from 2.5 h postdose through 4 h postdose.” It was only on post hoc secondary analysis that a positive effect of pregabalin on anxiety could be detected. As to unwanted side effects, somnolence occurred in 11.1% (3/37) of the subjects in the pregabalin group but none (0/31) in the alprazolam or placebo-control (0/31) groups.40 White et al.’s3 testing the utility of pregabalin as a rapid-onset anxiolytic is a good example of “thinking outside the box.” If pregabalin can be used to treat chronic anxiety, then perhaps it can be used to treat acute anxiety as well. There is a certain leap of faith in this approach, although, in that it assumes that the molecular and cellular mechanisms driving acute and chronic anxiety are the same, and this is by no means certain. That being said, this is exactly why one does the experiment. It is the obligation of the researchers, although, to design the experiment appropriately. As White et al.3 note, the “relatively low baseline levels of anxiety may have limited [their] ability to detect an acute anxiolytic effect.” This issue could potentially have been minimized by including only those subjects with high anxiety at baseline (as done in the study by Nutt et al.39). Furthermore, the absence of an active comparator also limits the value of study; the question is not only just “does this work,” but also, in today’s world, “is this better than what we have?” Even if pregabalin were shown to produce acute anxiolysis, its clinical use for that indication might very well have been limited by its previously suspected sedative qualities. As stated by Allchin40 “‘Negative’ results can represent ‘positive’ knowledge when we are confident of the conclusions.” The editors of Anesthesia & Analgesia are to be commended for choosing to publish “negative” studies; the phenomenon of publication bias in favor of positive studies has been well described.41–43 In fact, Anesthesia & Analgesia has a track record of publishing such studies.44 All results count and this applies equally to negative and positive results. In publishing articles describing negative results, Anesthesia & Analgesia fulfills its obligation to the scientific community." @default.
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• W2020973886 title "All Results Count" @default.
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