[Implementation of the laryngeal tube for prehospital airway management: training of 1,069 emergency physicians and paramedics]. / Implementierung des Larynxtubus im präklinischen Atemwegsmanagement: Ausbildung von 1069 Notärzten und Rettungsassistenten.

OBJECTIVE: The European Resuscitation Council recommends that only rescuers experienced and well-trained in airway management should perform endotracheal intubation. Less trained rescuers should use alternative airway devices instead. Therefore, a concept to train almost 1,100 emergency physicians (EP) and emergency medical technicians (EMT) in prehospital airway management using the disposable laryngeal tube suction (LTS-D) is presented. METHODS: In five operational areas of emergency medicine services in Germany and Switzerland all EPs and EMTs were trained in the use of the LTS-D by means of a standardized curriculum in the years 2006 and 2007. The main focus of the training was on different insertion techniques and LTS-D use in children and infants. Subsequently, all prehospital LTS-D applications from 2008 to 2010'were prospectively recorded. RESULTS: None of the 762 participating EMTs and less than 20% of the EPs had previous clinical experience with the LTS-D. After the theoretical (practical) part of the training, the participants self-assessed their personal familiarity in using the LTS-D with a median value of 8 (8) and a range of 2-10 (range 1-10) of 10 points (1: worst, 10: best). Within the 3-year follow-up period the LTS-D was used in 303 prehospital cases of which 296 were successfully managed with the device. During the first year the LTS-D was used as primary airway in more than half of the cases, i.e. without previous attempts of endotracheal intubation. In the following years such cases decreased to 40% without reaching statistical significance. However, the mean number of intubation attempts which failed before the LTS-D was used as a rescue device decreased significantly during the study period (2008: 2.2 ± 0.3; 2009: 1.6 ± 0.4; 2010: 1.7 ± 0.3). CONCLUSION: A standardized training concept enabled almost 1,100 rescuers to be trained in the use of an alternative airway device and to successfully implement the LTS-D into the prehospital airway management algorithm. Because the LTS-D recently became an accepted alternative to endotracheal intubation in difficult airway scenarios, the number of intubation attempts before considering an alternative airway device is steadily decreasing.

No difference in electroencephalographic power spectra or sensory-evoked potentials in patients anaesthetized with desflurane or sevoflurane.

BACKGROUND AND OBJECTIVE: Hitherto, neither desflurane nor sevoflurane, with similar physicochemical properties, have been compared with regard to their effects on the central nervous system. We compared the effects of desflurane and sevoflurane on electrical cortical activity and sensory transmission at two anaesthetic concentrations in patients undergoing hysterectomy. METHODS: The 1 and 2 MAC in nitrous oxide/oxygen (55%/45%) of desflurane or sevoflurane were administered while electroencephalographic power spectra and the somatosensory-evoked potentials were measured and correlated with cardiovascular effects. RESULTS: Both volatile agents induced a concentration-related increase of power in the slow delta-band and a concomitant decrease of power in the fast beta-domain. There was a close correlation with regard to the decrease in beta-power and heart rate (r2 = 0.988) and systolic blood pressure (r2 = 0.952) following both agents. Desflurane and sevoflurane had little effect on the early N20-peak, but affected the late N100-peak. There was a concentration-related increase in latency and a depression of amplitude height. Changes were not significantly different between both agents. CONCLUSIONS: Both desflurane and sevoflurane possess a similar profile with regard to their hypnotic effects and a similar outline in depressing propagation within the sensory nervous system. Cortical nervous effects are mirrored closely in heart rate and systolic blood pressure.

[Postoperative routine use of physostigmine on vigilance, cardiovascular parameters and need of analgesics]. / Routinemässige Gabe von Physostigmin hat für die postoperative Phase keine Bedeutung--eine randomisierte Untersuchung zur Vigilanz, zum Kreislaufverhalten, Muskelzittern und Schmerzmittelbedarf.

OBJECTIVE: A central anticholinergic syndrome (CAS) can be related to the majority of anesthetic agents, but is often not recognized as such. Thus, most anesthesiologists seem to miss the occurrence of an anticholinergic syndrome especially when agitation and/or restlessness are the major symptoms. Therefore, the following study was undertaken to test the hypothesis that routine administration of the anticholinergic agent physostigmin is of benefit for patients in regard to vigilance, the cardiovascular system and the need of analgesics easing the time in the post anesthesia care unit (PACU). METHODS: After approval by the local ethics committee and written informed consent, 100 patients undergoing a cholecystectomy or a struma resection, were given either physostigmin (n = 51) or saline 0.9 % (n = 49) in a randomized fashion. The study was conceived to block a possible isoflurane-N2O/O2 (opioid-based plus relaxant) induced central anticholinergic syndrome and to evaluate the effects on the cardiovascular system on vigilance and on postoperative analgesic demand. Following parameters were measured: systolic and diastolic blood pressure, heart rate, respiratory rate, and arterial blood gases. In addition, vigilance was determined and typical anticholinergic symptoms (disorientation, slurred speech, agitation, nausea, emesis, cardiac arrhythmia and muscle shivering) were determined 10, 20, 40 and 60 minutes following the intravenous injection of physostigmin. Also, the need for the postoperative analgesic pethidine was evaluated among the two groups. RESULTS: Except for a significant reduction in the need of analgesics, a reduced diastolic pressure and heart rate and a lower incidence of muscle shivering there was no difference among the two groups. One major side effect following the use of physostigmin was the higher incidence of nausea in the im mediate minutes following injection. This effect may be due to the rapid injection of the anticholinergic compound. Otherwise there were no detrimental effects of physostigmin in patients. CONCLUSION: From the results it can be concluded that routine administration of an anticholinergic agent results in a short term beneficial effect in regard to vigilance, a lesser incidence of muscle shivering and a lesser demand for analgesics. However, because of the low incidence of a classical central anticholinergic syndrome, routine physostigmine is only indicated when agitation is diagnosed.

[Development of opioid tolerance -- molecular mechanisms and clinical consequences]. / Toleranzentwicklung unter Opioidgabe -- Molekulare Mechanismen und klinische Bedeutung.

INTRODUCTION: One often identified effect of opioid administration is that of the development of tolerance to the analgesic effect. While it is generally agreed that tolerance to opioid analgesia does occur, it does not appear to be a limiting factor. Dose escalation in chronic pain therapy is considered to be predominantly a consequence of increasing pain, which is a result of increasing nociceptive input as the disease progresses. The underlying cause of tolerance to opioids, however, as commonly identified in the ICU can be identified as an adaptation process. When the opioid is given continuously several causes of adaptation can be identified, all of which can be traced back to the cellular and molecular level. RECEPTOR RELATED CHANGES INVOLVED IN TOLERANCE: Initial effects of opioid administration in most individuals are analgesia, sedation, nausea/vomiting, respiratory depression, pupillary constriction, constipation and euphoria or dysphoria. However, numerous studies and clinical experience suggest that tolerance to different opioid effects develop at different rates, which has been termed selective tolerance. While tolerance to nausea, vomiting, sedation, euphoria and respiratory depression occur rapidly, there is minimal development of tolerance to constipation and miosis. Such diversity suggest receptor-related differences in the speed of development of tolerance. In the ICU other compounds such as benzodiazepines, when given together with opioids, seem to speed up the rate of development of tolerance of the latter. Such an effect very likely is due to a reduction in activity of the descending inhibitory nervous system. In addition, there is surmountable data suggesting that the higher the intrinsic activity of the opioid at only one receptor site, lesser receptors are needed in order to induce a potent analgesic effect. As a net result the incidence of tolerance is less likely to become clinically apparent when potent ligands such as fentanyl or sufentanil are administered. N-METHYL-D-ASPARTATE (NMDA) ACTIVATION, OPIOID RECEPTOR INTERNALIZATION AND DESENSITIZATION: An altered metabolism has little effect on the rate of development of tolerance. In chronic pain treatment with morphine, however, an increased ratio of the metabolite morphine-3-glucuronide, with antiopioid effects, to morphine-6-glucuronide is associated with staggering doses of the analgesic. Opioids which interact with micro - and/or kappa-binding sites, demonstrate an adaptation process called desensitization which is due to a reduced interaction with the internal second messenger system called G-protein. This is only a short-lived phenomenon following binding of the ligand. Another underlying mechanism of tolerance development is that of internalization of the opioid receptors. This short-lived phenomenon, termed endocytosis, results in lesser binding sites available for the mediation of analgesia. Another and more relevant mechanism of long-term opioid binding is that of subsequent protein kinase C (PKC), phospholipase C (PLC) translocation and activation of nitric oxide synthetase (NOS). All of this contributes to a N-methyl-D-aspartate (NMDA) receptor activation with ensuing antiopioid effect and tolerance. CLINICAL CONSEQUENCES FOLLOWING THE DEVELOPMENT OF TOLERANCE: Most likely genetic difference in opioid receptor synthesis and difference in their affinities for various ligands is the cause for the wide margin of dose variability in patients (genetic polymorphism). Once tolerance to the analgesic effect of the opioid is observed and in order to avoid unnecessary further development of tolerance, simultaneous administration of other receptor mediated analgesics is advocated. In the perioperative period strategies like the multimodal analgesic concept is fostered. It consists of the simultaneous administration of low-dose ketamine, co-administration of an alpha 2-agonist, and the administration of a selective COX-2 inhibitor (refecoxib, parecoxib) respectively. In chronic pain therapy combined administration with either dextromethorpharphane, or opioid rotation of a more potent ligand such as methadone, fentanyl TTS or oxycodone is suggested. Since conversion factors are not reliable in opioid rotation, it is best to start off with 50 % of the equivalent dose and rapidly titrate to the desired effect. With regard to tolerance development in the ICU, co-administration of an alpha 2-agonist (clonidine, dexmedetomidine), and daily intermittent cessation of benzodiazepine administration are advocated. Since continuous dosing of an opioid, commonly handled in the ICU setting is more likely to induce tolerance, intermittent administration is advocated. Taken together, there is an abundance of experimental data which suggests, that with every dose of an opioid several adaptive processes are being initiated. Due to genetic polymorphism such adaptation is seen clinically with striking individual different dosages, the degree and the time of onset of tolerance. Although tolerance development may result in staggering doses of an opioid, there is no reason to evade the use of such agents. On the contrary, the concept of multimodal analgesia consisting of the simultaneous use of analgesics with a different mode of action can counteract tolerance development.

[Pain and opioids in preterm and newborns]. / Schmerz und Opioide bei Neugeborenen und Säuglingen.

Despite the fact that neonates and infants are not capable of expressing their subjective pain sensations, it has become clear that they do perceive nociception, as pain correlates to hormonal, metabolic, immune, and cardiovascular changes. New findings support the notion that repetitive painful stimuli result in long term psycho-physiological effects with ensuing decreased attentiveness and orientation, poor regulation of behavioral state and motor processes, increase in irritability as well as an altered pattern of feeding and sleeping. These sequelae of repetitive painful experiences with an increase in sensitization of sensory afferent input supports the view of a sufficient analgesia during all kinds of painful procedures in the preterm and neonate. In order to sufficiently diminish nociceptive afferent input during surgery opioids are the drugs of choice aside from local anesthetics. However, the use of opioids in neonates and especially preterm infants must be considered in the light of certain pharmacokinetic and pharmacodynamic differences when compared to adults: 1. There is a longer elimination rate, which may result in post-operative overhang of respiratory depression, especially when opioids are given repetitively, resulting in an accumulation and an increased duration of action. 2. There is a reduced hepatic enzyme activity, which ultimately affects clearance rate. 3. The blood-brain-barrier is not fully developed in the preterm, which results in more access of opioids to binding sites in the CNS. 4. Differentiation of opioid-binding sites into mu, delta, and kappa has not reached its peak; thus, higher doses relative to body weight are needed to establish a sufficient deep plane of analgesia. 5. Caudal parts of the CNS, especially the pons-medullar region exhibit an earlier expression of receptors than the rostral parts. Sequelae of such differences are a more pronounced respiratory depression, often due to muscular rigidity, and bradycardia after which a full analgesic effect takes place. Despite such potential drawbacks, opioids are still the best choice as they sufficiently block nociceptive afferent input and when compared to other anesthetics, they show the least cardiovascular changes. One, however, has to bear in mind that dosing is done according to effect and not to body weight while potential side effects are most prominent in the preterm infant.

Dose-related effects of controlled release dihydrocodeine on oro-cecal transit and pupillary light reflex. A study in human volunteers.

It is well accepted that long-term administration of opioids results in a dose-related constipation. No data so far have demonstrated conclusively whether such constipation is also seen after intake of a controlled release formulation. It was therefore of interest to evaluate whether increasing doses of a controlled release formulation of dihydrocodeine (DHC, CAS 125-28-0) after oral administration also induces a dose-related increase in constipation. Additionally, it was of interest to study whether such a peripheral opioid-related side effect is also seen in another, central receptor-mediated effect, the constriction of the pupil, at clinically relevant doses. Twelve volunteers were given controlled release DHC (60 and 120 mg, respectively) or placebo orally within a randomized, double-blind cross-over study. In order to determine the degree of constipation, oro-cecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripherally and centrally mediated effects were compared to placebo. DHC at both dosages induced a significant (p < 0.01) prolongation of oro-cecal transit time when compared to placebo. However, prolongation of oro-cecal transit was not significantly longer when comparing the lower (60 mg) with the higher dose (120 mg). DHC also induced a significant (p < 0.005) depression of the pupillary light reflex from 53.9 mm (control) to 8.3 and 7.4 mm, respectively. Similar to intestinal transit, the pupillary light reflex was not significantly different among the two doses of DHC. Also, both dosages induced a similar amount of side effects. Tiredness and dry mouth were reported in 80% after both doses while vertigo was reported in 5% and 1% complained of headache. None of the volunteers reported nausea or emesis. It is concluded that opioid receptor sites, which are located in the plexus myentericus of the intestinal wall, are responsible for the delay in propulsion. Because of the controlled release of a fixed amount of DHC over time there is constant binding of the ligand followed by a constant conformational change of peripheral and central receptor sites. Thus constant release induces no dose-related increase in oro-cecal transit and inhibition of the pupillary light reflex.

14-methoxymetopon, a potent opioid, induces no respiratory depression, less sedation, and less bradycardia than sufentanil in the dog.

UNLABELLED: Opioids of the mu-receptor type depress respiration and induce addiction. At 10-min intervals 14-methoxymetopon (HS-198), which is 20,000 times more potent than morphine in the acethylcholine-writhing test, was given in graded IV doses (3, 6, and 12 microg/kg) to awake, trained canines (n = 7). The following variables were derived: PaO(2), PaCO(2), heart rate (lead II of the electrocardiogram), mean arterial blood pressure, relative changes in the delta domain and the beta domain of the electroencephalogram, the somatosensory evoked potential, and the skin-twitch reflex to electrical stimuli. Thereafter, 20 microg/kg naltrexone was given for reversal. After a washout period, the same animals were exposed to similar doses of sufentanil (SUF) followed by naltrexone. Both opioids induced a dose-related bradycardia and hypotension. The maximal bradycardic effect was 19% after HS-198 and 42% after SUF (P < 0.005). The maximal hypotension was 6% after HS-198 and 20% after SUF (P < 0.01). In the electroencephalogram, power in the delta band increased by 288% after HS-198 and by 439% after SUF (P < 0.01); simultaneously, power in the beta band decreased by 71% and by 95.7%, respectively (P < 0.01). PaO(2) decreased by 41% after SUF and by 4% after HS-198, and PaCO(2) increased by 56.8% and 6.6% in SUF and HS-198, respectively (P < 0.001). Both opioids induced a dose-related depression in the somatosensory evoked potential and increased tolerance to skin-twitch. The maximal effect was 92.7% after SUF and 81.3% after HS-198 was not significant. Naltrexone reversed all changes back to control. Compared with SUF, HS-198 does not induce hypoxia and hypercarbia, induces less hypotension and bradycardia, and induces less sedative effects. IMPLICATIONS: Compared with sufentanil, 14-methoxymetopone does not induce hypoxia and hypercarbia, induces less hypotension and bradycardia, and induces less sedative effects (electroencephalogram). Antinociception is similar to sufentanil (skin-twitch method, amplitude depression in the evoked potential). All effects are reversed by naltrexone. Interaction of kappa-receptor is suggested.

Effects of tramadol and tilidine/naloxone on oral-caecal transit and pupillary light reflex.

As has been demonstrated in binding studies the two opioids tilidine (CAS 27107-79-7)/naloxone (CAS 357-08-4) and tramadol (CAS 36282-47-0) differ in regard to their affinities to the opioid receptor site. Therefore it is of interest to evaluate whether such a difference in opioid affinity is also seen in the pharmacological effects of clinically relevant doses in man. Following institutional approval by the local ethical committee and informed consent, 12 volunteers received oral doses of tramadol (100 mg), tilidine/naloxone (100 mg) and placebo, respectively, in a randomized, double-blind cross-over design. In order to determine the degree of constipation, oral-caecal transit time was measured using the H2-exhalation test. Additionally, in order to evaluate a centrally mediated effect, the response of the pupil to light was quantified using the pupillary light reflex technique. Both, peripheral and central mediated effects were compared to placebo. Tramadol as well as tilidine/naloxone induced a significant (p < 0.05) prolongation of oral-caecal transit when compared to placebo. However, prolongation of oral-caecal transit was significantly longer in the tilidine/naloxone (p < 0.05) than in the tramadol group. Compared to tramadol, the pronounced constipating effect of tilidine/naloxone is likely to be due to the 10 fold higher affinity of that drug to the peripheral opioid receptor sites in the intestinal tract, which are responsible for normal propulsion. Such difference in binding is underlined by a central effect, the pupillary light reflex response. The amount of constriction of the iris to light was reduced after both opioids. Again, tilidine/naloxone significantly reduced (p < 0.001) the pupillary light reflex when compared to tramadol. Other side effects such as tiredness, nausea, emesis and dry mouth were more often reported after tilidine/naloxone than after tramadol (40% versus 15%; p < 0.05). Vertigo and perspiration were more often reported after tramadol than after after tilidine/naloxone (58% and 78% versus 8%; p < 0.01). All these data support the findings that while tramadol is considered an opioid, it does not mediate its main clinical relevant properties via binding at the opioid receptor. More likely, due to its monoaminergic reuptake mechanism, to a lesser extent opioid-like effects are induced.

Slow EEG-power spectra correlate with haemodynamic changes during laryngoscopy and intubation following induction with fentanyl or sufentanil.

We studied nociception-associated arousal following laryngoscopy and intubation in patients scheduled for elective open heart surgery, using EEG power spectra and hemodynamics. Either fentanyl (7 micrograms/kg; n = 30) or sufentanil (1 microgram/kg; n = 30) were given in a randomized fashion to induce anesthesia in heavily premedicated patients, followed by pancuronium bromide (100 micrograms/kg). EEG-power spectra (delta, theta, alpha, beta) as well as mean arterial blood pressure (MAP) and heart rate (HF) were measured at the following end-points: before the induction of anesthesia (control), 1 and 10 minutes after laryngoscopy and intubation (L & I). Linear regression analysis was computed to determine which of the EEG power spectra was most sensitive to detect insufficient blockade of nociceptive-related arousal when correlated with haemodynamics. In the fentanyl group the change in HF closely correlated with the decrease of power in the slow delta- and theta-domain (r2 = 0.98 and r2 = 0.89 respectively) of the EEG. The change in MAP also closely correlated with a decrease in the slow delta- and theta-domain (r2 = 0.97 and r2 = 0.99 respectively). There was little correlation in regard to spectral edge frequency (SEF) and HF and MAP changes (r2 = 0.36 and r2 = 0.12 respectively). In the sufentanil group the change in HF correlated closely with an increase of power in the fast alpha and a decrease in the slow theta-domain (r2 = 0.91 and r2 = 0.98 respectively) of the EEG. The changes in MAP closely correlated with an increase in the fast alpha-band a decrease in the slow theta-domain (r2 = 0.98 and r2 = 0.73 respectively). Also there was little correlation of SEF with HF and MAP changes (r2 = 0.09 and r2 = 0.02 respectively). Among the EEG-spectra, reduction of power in the slow delta- and theta-bands are the most sensitive parameters to determine insufficient antinociception of opioids commonly used for the induction in cardiac anesthesia. Increase of power in the alpha-band seems to be closely correlated with cortical reactivation and reduction of hypnosis, while a reduction of power especially in the deltabut more so in the theta-band of the EEG reflects nociception related arousal.

[The opioid tramadol demonstrates excitatory properties of non-opioid character--a preclinical study using alfentanil as a comparison]. / Das Opioid Tramadol hat zentral-exzitatorische Effekte von nicht-opioidartigem Charakter.Teil 1: Präklinische Ergebnisse im Vergleich zu Alfentanil.

Tramadol, an analgesic with mean potency one tenth that of morphine is used regularly for the treatment of chronic and postoperative pain. Previous reports have indicated that tramadol may induce seizure activity when given together with a selective serotonin reuptake inhibitor (SSRI). Therefore, its major mode of action may be questioned which purportedly is due to binding with the opioid receptor and partly due to the inhibition of monoamine reuptake. We therefore set out to study its potential in inducing seizure activity and to quantify its effect on EEG-power spectra and on the central modulation of sensory afferents in awake and trained dogs (n=7). In order to demonstrate if opioid receptors mediated these effects, incremental doses of tramadol were given which was followed by naloxone for possible reversal. After a wash-out period the same animals were exposed to graded doses of alfentanil, a pure mu-receptor agonist. Again this was followed by the opioid antagonist naloxone for reversal.The electroencephalogram (EEG) and the event-related evoked potentials (SEP) were used to demonstrate possible excitatory effects. In order to derive the SEP the front paw was stimulated electrically (Digi Stim II trade mark ) while the evoked potentials were picked up contralaterally from the somatosensory cortex using stick-on electrodes. 256 sweeps were averaged (Lifescan) and the peak-to-peak amplitude was measured to demonstrate CNS excitation compared to control (%). Additionally, the raw electroencephalogram was viewed for epileptogenic changes and its power computed into the various power bands alpha, beta, delta und theta using FFT over a time epoch of 60 s. Following control, graded doses of either tramadol (2-5-10 mg/kg i.v.) or alfentanil (10-30-60 microg/kg i.v.) were given every 15 min while the EEG and the SEP were recorded. Thereafter naloxone (20 microg/kg i.v.) was injected for reversal. Tramadol did not suppress the amplitude of the SEP at any dose. High doses (>5 mg/kg i.v.) resulted in an increase (+100%) of the amplitude of the evoked potential. This was accompanied by short-term muscle fibrillations, and a short-term spike-and-wave activity in the EEG followed by a long-lasting theta-dominance. These effects could not be reversed by naloxone. In contrast to tramadol, alfentanil induced a dose-related depression of amplitude in the SEP with a maximum of 82% suggesting a depressive effect of modulation of afferents in the sensory cortex. This effect was fully naloxone reversible and was followed by a rebound in amplitude of the SEP together with an increase in fast beta-waves in the EEG. Tramadol very little mediates its central action via the mu-opioid receptor as the present effects were not naloxone reversible. Consistent with the results is the very low affinity of tramadol to the opioid receptor which is several thousand times less than that of morphine. Most likely, inhibition of central norepinephrine and serotonin reuptake as well as the reduction in 5-HT-turnover may contribute to the effects of tramadol. Due to the monoamine reuptake inhibition an increase in transmission may result, triggering off excitatory phenomena with spike-and-wave activity in the CNS. Such excitatory effects, however, may only be seen when tramadol is used in doses exceeding the therapeutic range.

[Treament of morphine-induced constipation with oral naloxone]. / Aufhebung einer Morphin-induzierten Obstipation durch orales Naloxon.

INTRODUCTION: Almost all patients treated with opioids suffer from constipation. Numerous laxatives are used to overcome the problem, but none has yet been found to yield favourable results in all patients. Several studies have attempted to reverse opioid-induced constipation by the use of oral naloxone. Experiments carried out in rats showed that morphine-induced constipation is reduced by oral naloxone without impairment of antinociception [4]. However, evaluation of clinical studies reveals that there is uncertainty about the dosage regimen (the daily dose of naloxone ranged from 0.5% to about 60% that of morphine) and a lack of larger numbers of patients studied. METHODS: Fifteen patients suffering from opioid-induced constipation participated in the present study. Constipation had been present for 5 to 14 days despite the use of laxatives. According to the results obtained in the animal experiments [4], it was originally planned to administer oral naloxone at a dose ratio of 1:1 with respect to morphine on day 1 and 2; reducing it on day 3 and 4 to one-half and then to one-fourth of the initial dose on day 5 and 6. RESULTS: Twelve patients experienced a strong laxative effect with spontaneous bowel evacuation 1 to 4 h after the first intake of oral naloxone. Three patients had no laxative effects even after repeated doses. Eleven of the 15 patients reported an average loss of 10%-15% of analgesia after oral naloxone as measured by visual analogue scales. Increasing the morphine dose by about 15% restored the previous level of analgesia without reappearance of constipation. Eight of the 12 patients having a laxative effect experienced abdominal cramps, and therefore, the total dose of naloxone was reduced on day 2 to 2%-15% of that originally planned; this dose still produced a laxative effect. Four of the 15 patients had a withdrawal syndrome. A single dose of morphine equivalent to their daily morphine intake abolished the symptoms. DISCUSSION: The medical history of the 3 patients in whom naloxone failed to abolish constipation revealed neurological disturbances. Treatment of these patients included the use of neuroleptics, antiemetics, and other drugs. In this context, it should be noted that oral naloxone can be expected to abolish only opioid-induced constipation. In conclusion, it was found that the treatment of opioid-induced constipation by administration of oral naloxone produced positive results. A controlled study will show, whether the side effects can be minimized by reducing the naloxone dose.

[Interaction of S-(+)-ketamine with opiate receptors. Effects on EEG, evoked potentials and respiration in awake dogs]. / Interaktion von S-(+)-Ketamin mit Opiatrezeptoren. Effekte auf EEG, evoziertes Potential und Atmung am wachen Hund.

To check for suspected opioid-receptor mediated hypnotic and antinociceptive effects of S(+)-ketamine, highly selective antagonists were used after the anaesthetic. METHODS. To determine the hypnotic effects of increasing doses of S(+)-ketamine (2-5-10-20 mg/kg given at 10-min intervals), EEG power spectra (delta, theta, alpha, beta) were derived (Lifescan), and antinociceptive potency was evaluated using the somatosensory evoked potential (SEP, Lifescan) in awake, trained dogs (n = 10). To check for an opioid-receptor-related interaction, an antagonist of the methoxymorphinane series (HS-275, 80 micrograms/kg i.v.) with higher selectivity than naloxone for the mu-receptor was given at the end. After washout the same animals were exposed to S(+)-ketamine. This time, however, the highly selective delta-antagonist naltrindole (160 micrograms/kg i.v.) was given. To show up any respiratory depression arterial blood gases were taken after each dose. RESULTS. S(+)-Ketamine induced a dose-related increase in power in the theta band (3-8 Hz), with a ceiling effect at 10 mg/kg. The changes were reversed by both antagonists. In the beta band (13-30 Hz) and in the delta domain, power decreased or increased, respectively, in a highly significant manner (P < 0.005) at 20 mg/kg. Both effects reversed after the antagonists with an overshoot in beta (+12% and +14%, respectively) and a decrease in delta (-45% and -62%, respectively) compared with control. S(+)-Ketamine induced a dose-dependent increase in peak latency and depression of the SEP amplitude by a maximum of over 50%. Latency changes were completely reversed only by HS-275. Amplitude height was only partly restored by both antagonists. A clinical relevant decrease in PaO2 and increase in PaCO2 increase were seen at 20 mg/kg. Hypoxia was reversed by both antagonists; hypercapnia was only partially reversed. CONCLUSION. The results confirm the suspicion that S(+)-ketamine induces an opioid theta- and delta-receptor-mediated deep hypnotic effect. Blockade of nociceptive impulses in afferent sensory nervous pathways suggests an efficient analgesic effect mediated partly by the opioid mu-receptor. Other mechanisms, such as an interaction with the NMDA receptor, have to be taken into consideration to account for the full antinociceptive effect. Respiratory depression may be of clinical importance when high dosages of S(+)-ketamine are given.

Opioid receptors-mediated respiratory effects and antinociception after S(+)-ketamine.

Until recently only the racemic mixture of ketamine was available for anesthesia. Little is known, of the central nervous effects of the pharmacological more potent S(+)-isomer. In order to evaluate the effects on respiration, the electroencephalographic activity and on the somatosensory evoked potential (SEP), increasing doses of S(+)-ketamine (2-5-10-20 mg/kg) were given to trained and awake canines (n = 10) at 10 minutes interval. To demask any opioid-receptor mediated effect, the highly selective mu-antagonist naltrexone or the highly selective delta-antagonist naltrindole (NTI) was given after S(+)-ketamine. S(+)-ketamine depressed respiration in a dose-related manner (PaO2 decrease, PaCO2 increase). Hypoxia was fully reversed by NTI and naltrexone; however hypercapnia was only partly reversed. S(+)-ketamine induced a dose-related increase of power in the theta-band (3-8 Hz) with little increase of power in the alpha-domain (8-13 Hz). Both these changes were reversed by NTI and naltrexone. Compared to control, low doses (2-5 mg/kg) increased power (p < 0.05) in the beta-(13-30 Hz) and decreased power (p < 0.05) in the delta-(0.5-3 Hz) band. These effects changed with higher doses (5-10 mg/kg). When compared to control, power in the delta-domain was significantly higher (p < 0.05), while power in the beta-band decreased significantly following 20 mg/kg of S(+)-ketamine. NTI was capable to reverse all these effects, however, naltrexone was not. In the SEP, S(+)-ketamine induced a dose-related increase in peak latency and a depression of amplitude of more than 50% when compared to control. Latency changes and amplitude height was only partly restored by both antagonists. The present results corroborate the connotation, that the central effects of the S(+)-isomer of ketamine are related to the opioid delta- and mu-receptor. The respiratory depression may be of importance when S(+)-ketamine is used (in very high doses). The S(+)-isomer induced hypersynchronisation in the EEG, suggests a deep plane of anesthesia; the pronounced blockade of nociceptive stimuli in the sensory nervous pathways suggests an analgesic effect which is partly mediated by the opioid receptor.

The delta receptor is involved in sufentanil-induced respiratory depression--opioid subreceptors mediate different effects.

It is generally accepted that analgesia induced by central analgesics is mediated through the mu-receptor. However, it still remains open to question as to whether or not the mu- and/or the delta-receptor site is mainly involved in the mediation of opioid-related respiratory impairment. Using a highly selective antagonist, naltrindole (NTI), or its benzofuran analogue naltriben (NTB), the hypothesis that competitive antagonism at the delta-receptor is able to attenuate sufentanil-related respiratory depression was tested in the dog. High dose (20 micrograms kg-1) sufentanil-induced respiratory impairment could be reversed by selective NTI-antagonism in a dose-related fashion (40-80-160 micrograms kg-1) increasing PaO2 from 57 to 81 mmHg and lowering PaCO2 from 52.1 to 49.2 mmHg. NTB-antagonism (40-80-160 micrograms kg-1) increased PaO2 from 48.4 to 91.2 mmHg and reduced PaCO2 from 46.9 to 37.6 mmHg. Simultaneously, somatosensory-evoked potentials (SEP) were used to quantify the opioid-induced attenuation and the reversal of afferent sensory input to pain modulating centres in the CNS. Sufentanil induced a significant depression (P < 0.01) of amplitude height of the SEP (13.9 to 0.9 microV in the NTI- and 8.8 microV to 1.3 microV in the NTB-group) which was only partially reversed by NTI (2.6 microV) and NTB (2.3 microV) respectively. The results suggest that delta-receptors are involved in sufentanil-related respiratory impairment. These receptors play a minor role in opioid-induced attenuation of sensory input to the brain. Highly selective delta-antagonists may be of clinical interest in reversing the respiratory depressant effect of potent opioids while maintaining analgesia.

[Pharmacodynamic effects of S-(+)-ketamine on EEG, evoked potentials and respiration. A study in the awake dog]. / Pharmakodynamische Effekte von S-(+)-Ketamin auf EEG, evoziertes Potential und Atmung. Eine Untersuchung am wachen Hund.

Until recently, only the racemic mixture of ketamine has been used in anaesthesia. Little is known of the central nervous effects of the pharmacologically more potent S(+)-isomer. Information in regard to the putative receptor site involved in the mediation of its anaesthetic/analgesic effect is particularly sparse. METHODS. In order to evaluate the anaesthetic and antinociceptive properties of S(+)-ketamine, a dose-response relationship of the compound on the EEG, somatosensory-evoked potentials (SEP), and respiration was established. Increasing doses (2, 5, 10, 20 mg/kg) were given to trained and awake dogs (n = 10) at 10-min intervals. In order to detect a possible opioid receptor-related interaction, an antagonist of the methoxymorphinane series (cyprodime 80 g/kg i.v.) with higher selectivity than naloxone for the mu-receptor was given at the end. RESULTS. Compared to controls, S(+)-ketamine induced a dose-related increase in output in the theta-(3-8 Hz) band and an increase in output in the alpha-domain (8-13 Hz) following 20 mg/kg. Both effects were reversed completely by the opioid antagonist. At low doses (2-5 mg/kg) there was an increase in output (P less than 0.05) in the beta-(13-30 Hz) and a concomitant decrease in output (P less than 0.05) in the delta-(0.5-3 Hz) band. These effects were reversed with increasing doses (5-10 mg/kg). After 20 mg/kg, however, output in the delta-domain increased while power in the beta band decreased significantly (P less than 0.005) when compared to controls. Both effects were reversed by the opioid antagonist. Compared to controls, the reversal resulted in a 12% increase in output in the beta- and a 49% decrease in output in the delta-domain. In SEP, S(+)-ketamine induced a dose-related increase in peak latency and depression of amplitude of more than 50% when compared to controls. While latency changes were completely reversed, amplitude height was only partly restored by the antagonist. Respiration was depressed in a dose-related fashion (PaO2 decreased, PaCO2 increased). Hypoxaemia was fully reversed by the antagonist; hypercapnia was only partly reversed. CONCLUSION. The results support the presumption that the S(+)-isomer of ketamine induces opioid mu-receptor-mediated central effects. Hypersynchronisation of the EEG suggests a deep plane of anaesthesia after S(+)-ketamine. The pronounced blockade of impulses in the sensory nervous pathways suggests an efficient analgesic effect that is partly mediated by the opioid-receptor. The respiratory depression may be of importance when S(+)-ketamine is used in high dosages in man.

Antagonisation of fentanyl-induced respiratory depression by nalbuphine.

The opioid antagonistic efficacy of nalbuphine (20 mg i.v.) was determined in 11 healthy volunteers, who had received 10 micrograms/kg fentanyl ten minutes before. The mean respiratory minute volume decreased to 31.5% of baseline level after fentanyl and increased to 116.8% 2 min. after the administration of nalbuphine. PaCO2, PaO2 and pH values showed the typical clinical signs of respiratory depression and reached pre-fentanyl levels following nalbuphine. No significant hemodynamic changes were caused by the antagonisation. These results suggest that nalbuphine effectively and safely reverses the respiratory depressant effects of commonly used doses of fentanyl without causing hemodynamic side effects.

Transdermal fentanyl against postoperative pain.

60 patients (ASA class I-II) undergoing knee arthrotomy received in a double blind fashion, a transdermal drug delivery system, containing either fentanyl (delivery rate of 75 micrograms/hour)--Fentanyl TTS--or placebo. The system remained in place for 24 hours. Even when piritramid was added as escape analgesia, all respiratory and hemodynamic parameters, as well as blood gas analysis showed no statistical significant difference between both groups (fentanyl or placebo). One patient had evidence of a beginning respiratory depression, but no specific therapy was needed. No significant side effects were seen. Concerning escape medication, a highly statistically significant difference in favour of Fentanyl TTS was found (p less than 0.001).

[Problems in anesthesia of drug addicts]. / Probleme der Anaesthesie bei Drogenabhängigen.

This review attempts to provide an inside view of the current state of knowledge on the anesthetic management of the drug addict intra- and postoperatively. The summary of the numerous publications on this subject demonstrates that neither a unanimous opinion nor a uniform anesthetic procedure exists. The choice of procedure depends on the medical history as well as the physical and psychological status of the patient.

[Opiate receptors]. / Opiatrezeptoren.

In view of the basic principles of the receptor theory, one should expect all opioids to exhibit principally the same spectrum of effects, as they exert their actions by interaction with "the opiate receptor." Clinical experience shows, however, that the opioids in clinical usage in fact exhibit a variety of spectra of effects. This discrepancy is explained by introducing the "multiple receptor theory," as developed by Gilbert and Martin. This review attempts to class practical clinical consequences with those more recent pharmacological findings.

Reversal by nalbuphine of respiratory depression caused by fentanyl.

In 60 ASA class I or II patients given intravenous fentanyl for elective operations in doses large enough to produce postoperative respiratory depression, the intravenous administration of 20 mg nalbuphine resulted in prompt reversal of respiratory depression without loss of analgesia.