The sedative effect of opioids goes in hand with their capability to induce sleep (lat. hypnos). Such an effect is mostly seen with the mixed agonist/antagonists, while morphine takes a medium position (Figure II-41). The hypno-sedative effect of opioids is useful in premedication and during postoperative analgesia, where a sedated status of the patient is advantageous. In contrast to a potent sedative nature of mixed agonist/antagonists, the pure ^-type ligand fentanyl is characterized by a very low sedative potency. When in the beginning of use of neuroleptic analgesia for anesthesia, fentanyl was used together with the neuroleptic agent droperidol, often patients reported of intraoperative "awareness". Although being an obligatory part of anesthesia, sleep, was not sufficiently maintained throughout the whole procedure. Therefore in order to guarantee a sufficient level of sleep in patients receiving a fentanyl-based anesthetic technique, an additional hypnotic (propofol), a benzodiazepine (midazolam), a neuroleptic agent (i.e. dehydrobenzperidol), or a volatile anesthetic (sevoflurane, desflurane, or enflurane) has to be given on-top the opioid. Nowadays the problem of awareness again has gained much attention , since the technique of total intravenous anesthesia (TIVA) with remifentanil and
propofol, completely omitting nitrous oxide (N2O), often results in an insufficient level of sleep with awareness.
Typically pure K-ligands such as bremacozine and tifluadom (Table II-3), which in comparison to morphine have a 2-fold analgesic potency [79, 80], do not induce a respiratory depressive effect . Their lack in respiratory impairment is due to the selective binding in deep layers of the cortex [19, 82], where in comparison to the brain-stem, a more than 50% higher concentration of K-binding sites is found [3, 83]. Their predominant sedative effect is due to centripetal fibers descending down from deep layers of the cortex to the thalamus, thus decreasing the nociceptive input .
Although having the advantage of an increased sedative effect combined with the lack in respiratory impairment, clinically, the use of K-ligands had to be abandoned. This is because of their intense dysphoric side effects, which lasts for several hours. In addition, their analgesic potency, in comparison to pure ^-ligands is much lower. Therefore such agents cannot be regarded as suitable for intraoperative use, where an intense nociceptive barrage can only be blocked by a potent ^-opioid. Only the mixed agonist/antagonists (e.g. nalbuphine, butorphanol), which exert their analgesic action through binding at the K-site, currently are in clinical use mainly for postoperative analgesia [85, 86]. This is because cumulative dosages, contrary to a typical ^-ligand like morphine, result in a ceiling effect for respiratory depression (Figure II-42). In addition, because of their wide margin of safety, high dosages
have been advocated in balanced anesthesia where the opioid resulted in an up to 70% reduction in MAC (minimal alveolar concentration) of the volatile agent [87, 88].
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