In a previous study by our group, postoperative delirium developed in 50 of 293 patients (17.1%) after surgery for head and neck cancer, and we did not consider the impact of sleeping medication on the development of postoperative delirium . However, other research has shown that the use of minor tranquilizers was associated with the development of postoperative delirium and that ramelteon might prevent postoperative delirium [5, 6]. In this study, we, therefore, investigated the association of sleeping medications with the development of postoperative delirium.
We showed that eight of the 24 patients (33.3%) taking minor tranquilizers after surgery developed postoperative delirium, but that only one of the 41 patients (2.4%) taking ramelteon with or without suvorexant developed postoperative delirium. In addition, there were no cases of postoperative delirium among the 16 patients taking both ramelteon and suvorexant. These results indicate three possibilities. First, that the use of minor tranquilizers caused the development of postoperative delirium. Second, that ramelteon, suvorexant, or combination therapy with both drugs decreased the development of postoperative delirium. Third, that both the first and second conclusions are correct. All patients were administered sleeping medications postoperatively and there was a lack of control group receiving placebo in this study, so we cannot comment on the frequency of postoperative delirium in those not administered sleeping medications. However, compared with our previous study , patients taking minor tranquilizers after surgery did develop postoperative delirium more often, while those taking ramelteon with or without suvorexant developed postoperative delirium less often. Thus, there is a high possibility that the third possibility is correct, and that at the very least, ramelteon with or without suvorexant was associated with a lower risk of producing delirium compared with minor tranquilizers.
Minor tranquilizers have been associated with delirium in most previous studies, with research showing reduced use after surgery and for old patients [2, 9, 10]. By contrast, a randomized, placebo-controlled trial has shown that ramelteon can help prevent delirium . In vitro studies have also demonstrated that ramelteon has 6- and 3-fold higher affinities for melatonin receptors 1 and 2, respectively, when compared with melatonin . This suggests that a reduced frequency of delirium might be associated with higher affinities for these receptors, supporting a possible pathogenic role for melatonin neurotransmission in delirium . Suvorexant is a dual orexin receptor antagonist that is used to treat insomnia characterized by difficulty achieving and/or maintaining sleep, but no report has been published on whether it can prevent delirium . Nevertheless, similar to the implicated role of melatonin, there is a possible pathogenic role for disordered orexin neurotransmission in delirium.
It cannot be derived from this study whether ramelteon or suvorexant produced a lower risk for developing postoperative delirium or whether they actually prevented the condition. If ramelteon and suvorexant were only associated with a lower risk for developing delirium, we should only recommend their use in patients suffering from insomnia. However, if ramelteon and suvorexant can actually prevent postoperative delirium, we should consider administering them to all patients at high risk of developing postoperative delirium, regardless of whether or not they suffer from insomnia. In our previous study, an age of >70 years (odds ratio 3.935) was a significant determinant for postoperative delirium .
In this study, although there was no additive effect when suvorexant was given with ramelteon to prevent postoperative delirium, it was notable that there were no cases of postoperative delirium in any of the patients taking both medications together. Moreover, ramelteon alone was not sufficient to treat insomnia and suvorexant made up for the deficiency. It is possible that combination therapy with ramelteon and suvorexant had a stronger preventive effect on postoperative delirium. To investigate whether ramelteon is sufficient alone or in combination with suvorexant to prevent postoperative delirium, a randomized controlled trial is needed.
There are two important limitations of our study. First, we used a retrospective design at a single institution, and it is possible that the diagnosis was not accurate. Second, we did not consider the length of sobriety or use of sleeping medications before surgery. Nevertheless, all patients’ charts were systemically assessed by two psychiatrists to overcome some of these biases.
In conclusion, we showed that ramelteon with or without the use of suvorexant was associated with fewer cases of postoperative delirium after pharyngolaryngectomy with esophagectomy, but minor tranquilizers were associated with the development of postoperative delirium. We recommend that treatment with ramelteon, with or without suvorexant, be used instead of minor tranquilizers for patients undergoing pharyngolaryngectomy with esophagectomy after surgery to prevent postoperative delirium.