Enno Freye

Cardiovascular Effects of High Dosages of Fentanyl, Meperdine, and Naloxone in Dogs

The purpose of this study was to determine cardiovascular reactions after the administration of a potent narcotic analgesic, such as fentanyl, in increasing dosages of 0.0025 to 0.16 mg./kg. In addition, comparison was made with meperidine in dosages from 2.5 to 20 mg./kg. The action of a narcotic antagonist (0.4 mg./kg. of naloxone) given in sequence to the analgesic was ascertained also.The data obtained indicate:1. Increase in LV dP/dt max* was directly proportional to the dose of fentanyl over a low concentration range (0.0025 to 0.03 mg./kg.).2. Increasing dosages of fentanyl caused a decrease in myocardial oxygen consumption (maximum 30 percent), pressure time index (TTI), and coronary sinus blood flow.3. High dosages of fentanyl (0.03 to 0.16 mg./kg.) did not affect LV dP/dt max, left ventricular pressure, left ventricular end-diastolic pressure, and central aortic blood pressure.4. Increasing dosages of fentanyl produced a proportionately greater decrease in mean peripheral blood pressure (maximum 40 percent) and heart rate (maximum 50 percent). Succeeding injection of the same doses had little effect on the two physiologic values, however, suggesting the development of tachyphylaxis.5. Naloxone given after fentanyl increased all measured values.6. Meperidine, even in low doses of 2.5 mg./kg., had a depressant effect on the cardiovascular system, particularly in regard to left ventricular pressure.7. Naloxone alone, up to 5.6 mg./kg., had no effect on the cardiovascular system.The results suggest that sequential analgesia, using in sequence high doses of fentanyl as the sole anesthetic agent and naloxone as the antagonist at the end of the operation, has no depressant effect on the cardiovascular system.

Opioid Rotation from High-Dose Morphine to Transdermal Buprenorphine (Transtec ® ) in Chronic Pain Patients

Abstract:  Opioid rotation is increasingly becoming an option to improve pain management especially in long‐term treatment. Because of insufficient analgesia and intolerable side effects, a total of 42 patients (23 male, 19 female; mean age 64.1 years) suffering from severe musculoskeletal (64%), cancer (21%) or neuropathic (19%) pain were converted from high‐dose morphine (120 to >240 mg/day) to transdermal buprenorphine. The dose of buprenorphine necessary for conversion (at least 52.5 µg/h) was titrated individually by the treating physician. No conversion recommendations were given and the treating physician used his or her own judgment for dose adjustment. Pain relief, overall satisfaction and quality of sleep (very good, good, satisfactory, poor, or very poor), and the incidence and severity of adverse drug reactions over a period of at least 10 weeks and up to 1 year was assessed. Following rotation, patients experiencing good/very good pain relief increased from 5% to 76% (P < 0.001). Only 5% reported insufficient relief. Relief was achieved with buprenorphine alone in 77.4%, while 17% needed an additional opioid for breakthrough pain. Sleep quality (good/very good) increased from 14% to 74% (P < 0.005). Adverse effects were reported in 11.9%, mostly because of local irritation, did not result in termination of therapy. Neither tolerance nor refractory effect following rotation from morphine to buprenorphine was noted. Conversion tables with a fixed conversion ratio are of limited value in patients treated with high‐dose morphine.

Cerebral Monitoring in the Operating Room and the Intensive Care Unit — An Introductory for the Clinician and a Guide for the Novice Wanting to Open a Window to the Brain

While there is an increasing body of knowledge in regard to central nervous system function and/or the mode of action of centrally active agents on neuronal function, little is done to develop new techniques on how to measure such changes. Also, monitoring of the cardiovascular system in the past has made extensive progress especially when it comes to evaluate the failing heart. In contrast monitoring of the central nervous system is only done in rare cases where operative procedures likely impede nervous function integrity. Since in the past decade the aging population undergoing operation has rise considerably, the risk of cerebral malperfusion or minute signs of degradation of the aging central nervous system (CNS) to anesthetics and agents being used in the operation room (OR) or the intensive care unit (ICU), needs continuous monitoring of an organ which presents the highest vulnerability and is likely to deteriorate faster than the cardiovascular system. In spite the rapid improvement in technology regarding the electroencephalogram (EEG) and evoked potential monitoring, physicians still are reluctant to use a technology on a routine base, which will give them insight information into brain function and activity. Such “windows to the brain” now not just are reserved to specialists working in the area of neurology and/or psychiatry. More so, cerebral monitoring is getting an integrated part in the overall therapy in patients undergoing operation or who need ventilatory support in the ICU as it effects the well-being and the outcome. The present book therefore, is intended for the practitioners who work with the patient, guide the clinician in his decision making and outlining those situations where cerebral monitoring presents an integrated part in the diagnosis and therapy of patient care. Without going too much into the technical details, representative cases underline the potential use of cerebral monitoring in the underlying clinical situation where either the patient presents borderline perfusion of the CNS, undergoes vascular surgery, or where monitoring of cerebral function in the intensive care in a head trauma patients is an integrated part in therapy.

Opioid-induced respiratory depression and analgesia may be mediated by different subreceptors

Use of selective delta opioid antagonists provide evidence that the delta receptor within the brain seems an integrated part in the mediation of respiratory depression induced by a potent analgesic like fentanyl. Low doses of the delta antagonists RX-8008M (3–6 µg/kg) as well as ICI 174,864 (3–6 µg/kg) reversed fentanyl-related respiratory depression (arterial blood gases) in the unanesthetized canine. Opioid-induced blockade of afferent sensory nerve volleys (amplitude height of the somatosensory-evoked potential) could be reversed only by a high dose (9 µg/kg) of RX-8008M. Depression of amplitude height of the SEP could not be reversed by ICI 174,864 over the whole dose range (3–6–9 µg/kg). In comparison, naloxone (1–5–10 µg/kg) not only reversed depression of PaO2, it also reversed the blockade of afferent sensory nerve impulses in the low (5-µg/kg)-dose range. A highly selective delta antagonist may have a therapeutic value in reversing opioid-related respiratory depression, resulting in little or no attenuation of analgesia.

Ganglionäre lokale Opioidanalgesie (GLOA)

Zur Therapie atypischer Gesichtsschmerzen, postzosterischer Schmerzen und/ oder einer postoperativen posttraumatischen Neuralgie, Schmerzsyndrome die mit Allodynie und Hyperasthesie einhergehen (sog. neuropathisches Schmerzsyndrom), wird die lokale Injektion eines Opioids in das Ganglion cervikale superius (GCS) propagiert (Wulf et al. 1991; Tabelle 26.1). Das Grenzstrangganglion ist ca. 2,5 cm lang und liegt etwa 2 cm unterhalb der Schadelbasis zwischen dem M. longus capitis und dem hinteren Digastrikusbauch. Zur Punktion mit anschliesender Applikation des Opioids wird eine atraumatische 25-G-Spinalkanule uber eine spezielle Fuhrungskanule mit Abstandhalter geschoben. Die Punktion erfolgt intraoral an der Rachenmandel vorbei, unterhalb des Gaumensegels und in Hohe des zweiten Halswirbelkorpers (Abb. 26.1). Wegen der engen anatomischen Nahe zu den Nn. Vagus, glossopharyngicus, hypoglossus und laryngeus superior, aber auch zur A. carotis interna, hat eine Injektion von Lokalanasthetika an dieser Stelle mit groster Vorsicht zu erfolgen.

An open comparison of propofol and enflurane for prolonged abdominal operations

Anaesthesia in 15 patients scheduled for prolonged abdominal surgery was induced with hexobarbitone and maintained with nitrous oxide and enflurane, while in a further 15 patients propofol was used for induction and maintenance. Three patients in the latter group required additional fentanyl but cardiovascular responses were, otherwise similar in the two groups. Return of consciousness, response to verbal command, ability to answer questions and adequate spontaneous ventilation was more rapid in the propofol patients. EEG power spectra also returned to baseline more rapidly in the propofol group.

Naloxone reverses the hypnotic effect and the depressed baroreceptor reflex of halothane anaesthesia in the dog

In order to evaluate the effect of an opioid antagonist on depressed intrinsic central vaso-motor drive (carotid sinus reflex) and high voltage slow delta waves in the EEG associated with halothane, naloxone was injected intravenously in a bolus of 100 or 200 εgkg-1 on different days in the anaesthetized dog (0.64 Vol% halothane in oxygen). Only the 200 εg*kg-1 dose of naloxone reversed the halothane-induced depression of the blood pressure and heart rate response to clamping of both exteriorized common carotid arteries. The EEG changed from high voltage slow waves to low voltage fast waves, inducing a reduction of power in the delta band in spectral analysis. This effect was most pronounced during the 20th minute post naloxone injection. Naloxone did not reverse the halothane-related hypotension and bradycardia. Because of the late “cortical arousal” reaction during halothane-anaesthesia and the high dose necessary, naloxone appears to exert its action through a generalized increase in CNS excitation. An antagonisation of halothane-induced release of opiate-like peptides therefore is less likely.RésuméPour rechercher les effets d’un opiacé antagoniste sur la réduction du baroréflexe déprimé du sinus carotidien et sur la vigilance diminuée par une narcose à l’halothane (0.64 Vol% dans O2), la naloxone a été administrié deux jours de suite à la dose respective de 100 et 200 εg*kg-1 en injection intraveineuse. Seulement la dose de 200 εg*kg-1 de naloxone a permis d’antagoniser l’effet central induit par l’halothane, la régulation déficiente de la circulation du sinus carotidien et le ralentissement de londe de l’EEG. Cet effet est obtenu 20 minutes après l’injection. L’hypotension et la bradycardie caractéristiques de l’halothane peuvent ne pas être inftuencées par une injection intraveineuse de naloxone. Sur la base de la réaction de réveil induite tardivement par la naloxone ainsi que la haute dose nécessaire, l’effet ne semble pas être une antagonisation reposant sur l’endorphine libérée par l’halothane. Les bases des excitations du SNC semblent résulter d’une interaction avec d’autres neurones (peut-être zone GABA). Les recherches cliniques et pratiques de Iutilisation de hautes doses de naloxone après narcose gazeuse doivent être poursuivies.

14-methoxymetopon, A Potent Opioid, Induces No Respiratory Depression, Less Sedation, and Less Bradycardia than Sufentanil in the Dog

Opioids of the &mgr;-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 &mgr;g/kg) to awake, trained canines (n = 7). The following variables were derived: Pao2, Paco2, heart rate (lead II of the electrocardiogram), mean arterial blood pressure, relative changes in the &dgr; domain and the &bgr; domain of the electroencephalogram, the somatosensory evoked potential, and the skin-twitch reflex to electrical stimuli. Thereafter, 20 &mgr;g/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 &dgr; band increased by 288% after HS-198 and by 439% after SUF (P < 0.01); simultaneously, power in the &bgr; band decreased by 71% and by 95.7%, respectively (P < 0.01). Pao2 decreased by 41% after SUF and by 4% after HS-198, and Paco2 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 &kgr;-receptor is suggested.

Bremazocine: An Opiate That Induces Sedation and Analgesia without Respiratory Depression

The benzomorphan analogue bremazocine has been shown to be a potent analgesic with a low dependence liability and with no respiratory depressant effects in preliminary pharmacologic screening. As this compound may prove to be of potential interest to anesthesiologists, it was tested in the conscious dog in increasing doses (1, 5, 10, 20, and 40 μg/kg) while blood pressure, heart rate, respiratory rate, arterial blood-gas tensions, electrical cortical activity, and somatosensory-evoked potentials (SS-EVP) were recorded. Bremazocine had no significant cardiovascular or respiratory effects. Power spectral analysis of the EEG showed a dose-related increase of power in the theta to delta band. SSEVP was characterized by a decrease in amplitude of the P45 and P70 waves and an increase in the latency of the P100 peak. EEG and peak latency changes could be reversed by the kappa-specific antagonist Mr 2266 (20 μg/kg), but not by the classic opiate antagonist naloxone (20 μg/kg). It is suggested that kappa receptor sites distinct from those interacting with common opioids (μ) are responsible for the observed changes associated with bremazocine.

Effervescent morphine results in faster relief of breakthrough pain in patients compared to immediate release morphine sulfate tablet.

▪ Abstract:  Morphine tablets have been formulated to produce an easily ingested effervescent solution when placed in water. It was hypothesized that an aqueous solution would result in fast gastrointestinal transit with a more rapid onset of action compared to immediate release morphine sulfate (IRMS), which would be especially beneficial in treating breakthrough pain (BTP). In an open‐label safety and efficacy study, effervescent morphine was given to 76 chronic cancer pain patients for treatment of BTP evaluating time until pain relief, global satisfaction and side effects. Results were compared to those obtained using an IRMS formulation in a preceding run‐in period. For BTP, a mean dose of 28 mg of effervescent morphine (range 10–80 mg) resulted in a highly significant reduction of pain score (mean 7.8 to mean 3.2; P < 0.001). Efficacy was not different from that observed with IRMS. However, mean time until sufficient pain relief was significantly shorter than with IRMS (13 ± 5.6 vs. 27 ± 4.4 minutes; P < 0.01). The incidence of side effects was similar with the new morphine formulation and with IRMS. There was no relationship between the previous dose of the daily opioid and the effective dose of effervescent morphine. The dose for treatment of BTP was determined by individual titration and not predicted by the dose taken with the basic pain medication. Compared to IRMS, overall satisfaction for effervescent morphine was rated “superior” by 16.7%, and “better” by 63.2% of patients. Effervescent morphine offers an alternative for management of breakthrough cancer pain compared with the commonly used IRMS. ▪