Transcranial electrical stimulation with high frequency intermittent current (Limoge's) potentiates opiate-induced analgesia: blind studies.

Transcutaneous cranial electrical stimulation (TCES) with high frequency (166 kHz) intermittent current (100 Hz: Limoge current) has been used for several years in cardiac, thoracic, abdominal, urological and micro-surgery. The main benefits are a reduced requirement for analgesic drugs, especially opiates, and a long-lasting postoperative analgesia. We have confirmed these clinical observations in rats using the tail-flick latency (TFL) test to measure pain threshold. TCES was not found to modify the pain threshold in drug-free rats, but it potentiated morphine-induced analgesia (systemic injection). To obtain a maximal effect, the stimulation must be initiated 3 h before the drug injection and be maintained throughout the duration of its pharmacological action. TCES potentitation was found to depend on the dose of the drug, the intensity of the current and the polarity of electrodes. These findings were confirmed by blind tests of the efficiency of TCES on several opiate analgesic drugs currently used in human surgery (morphine, fentanyl, alfentanil and dextromoramide). The analgesic effect of these 4 opiates (TFL as % of baseline without or with TCES) were respectively: 174%, 306%; 176%, 336%; 160%, 215%; and 267%, 392%. The results were obtained not only after systemic opiate treatment, but also after intracerebroventricular injection of morphine (10 micrograms; analgesic effect 152%, 207% with TCES) suggesting that TCES potentiation of opiate-induced analgesia is centrally mediated.

Blockade by verapamil of cholinergic effects on atrial specialised tissue in the anaesthetised dog.

The effects of verapamil were studied in anaesthetised dogs administered dextromoramide intrathecally to provide background vagal tone. Measurements were made of spontaneous heart rate, and, in paced hearts, of conduction times in atrial muscle, the atrioventricular node (A-V node) and His-Purkinje system by means of His bundle potential recording. The effective refractory period (ERP) of A-V node was measured by the extrastimulus method. In atropinised and vagotomised animals, verapamil reduced sinus rate and increased A-V nodal conduction time. In dogs high vagal tone after dextromoramide, however, verapamil increased sinus rate and reduced A-V nodal ERP. After dextromoramide alone, A-V block was observed at an atrial pacing rate of 150 beats X min-1, but after verapamil 1:1 A-V conduction was restored. The decrease in conduction velocity in the A-V node due to ACh was neither attenuated nor enhanced by verapamil.

Influence of the restoration of vagal tone by intracisternal injection of dextromoramide on the cardiac effects of the antiarrhythmic drugs.

The effects of four antiarrhythmic drugs, quinidine, procainamide, amiodarone and verapamil were studied on sinus rate, conduction time and, when possible, effective refractory period (ERP) in atrioventricular node (AV node), and finally atrial muscle ERP. This study was made under two types of conditions, vagal tone being absent or present after restoration in the anesthetized dog by a new technique, the intracisternal injection of dextromoramide. Quinidine and procainamide which tend to slow down sinus rate and conduction in the former case accelerate them considerably in the latter by opposing the effects of acetylcholine released by vagal endings. The prolongation of atrial ERP also induced by these drugs results from both this process and their own capacity. Amiodarone and verapamil, usually responsible for bradycardia, notable delay in AV node conduction and lengthening of AV node ERP are, however, liable to elicit opposite effects, especially amiodarone when vagal tone is very high. The reduction of vagal influence is, in the case of these drugs, the only factor in the prolongation of atrial ERP. In any case, the response of both specialized and common tissue of the heart to antiarrhythmic drugs should not be interpreted unless the degree of vagal tone is known.

[Modification, by lithium, of catalepsy induced by central cholinergic stimulants and morphine-like drugs]. / Modifications par le lithium de la catalepsie induite par des stimulants cholinergiques centraux et des drogues morphiniques.

After unique injection LiCl enhances, in albino rat, catalepsy induced by arecoline and oxotremorine perhaps by adenylcyclase inhibition and/or decrease of acetylcholine synthesis. After repetitive injection of LiCl during 5 days, this phenomenon is not observable, probably owing to increase of acetylcholine synthesis. After unique injection of LiCl enhances catalepsy induced by dextromoramide, probably on account of cholinergic properties of this drug. In contrast catalepsy induced by morphine or pethidine is suppressed. This constatation would depend on opposite influence upon cerebral neuromediators : lithium diminishing cerebral serotonin and striatal acetylcholine levels and morphine increasing them. After repetitive injections these phenomenons are not observable.

Effects of morphine and related drugs on core temperature of two strains of rat.

The changes in core temperature induced by low (5 mg/kg) and high (40 mg/kg) doses of morphine were compared in Wistar and Sprague-Dawley rats. In Sprague-Dawley rats the low dose caused a hyperthermia and the high dose a hypothermia but in Wistar rats both doses caused a hyperthermia. In either case the change in core temperature was antagonized by naloxone (2 mg/kg). Tolerance to the effects of the high dose of morphine developed in both strains of rat. Dextromoramide (3.75 and 15 mg/kg) also had an effect on core temperature, but in this case the responses of the strains were opposite to those seen with morphine. Laevomoramide was relatively ineffective. Naloxone (2 mg/kg) had no effect on the ability of rats of either strain to withstand heat or cold stress, providing no evidence that endogenous morphine-like substances have a physiological role in thermoregulation.

A study of the enhanced toxicity of doxapram in rodents treated with narcotic analgesics.

It has been shown in both mice and rats that the LD50 value for doxapram is reduced in rodents treated with narcotic analgesics. In both species the site of the toxic interaction appears to be the cardiovascular system. Doxapram alone, in sub-lethal doses, appears to cause conduction defects in the heart and this action of doxapram is increased in rodents treated with morphine. The enhancement of the toxicity of doxapram by morphine appears to involve an action in the central nervous system probably not related to respiratory depression.

Differentiation of drugs acting centrally upon the cardiovascular system by means of sympathetic and vagal responses.

The response pattern of the autonomic nervous system was investigated after central administration (intra-cisternal, vertebral artery) of amphetamine, morphine, fentanyl, dextromoramide and the substance R 28935, chemically related to the neuroleptic agent pimozide. Effects on the sympathetic system were measured by recording electrical discharges of fibres of the (preganglionic) major splanchnic nerve in anaesthetized cats; those on the vagal system by recording the heart rate in anaesthetized dogs under beta-adrenoceptor blockade; the baroreceptor reflex was elicited by the blood pressure increase of i.v. injected angiotensin. All substances decreased the spontaneous discharge rate of the splanchnic nerve. Amphetamine facilitated the vagally mediated reflex bradycardia and this was antagonized by the alpha-adrenoceptor blocking agent piperoxan. Amphetamine did not affect the resting heart rate, as has already been shown for clonidine and related substances. The narcotic analgesics lowered the resting heart rate but did not facilitate the baroreceptor reflex response. R 28935 neither influenced resting heart rate nor the baroreceptor reflex response in beta-blocked dogs. On the basis of the vagal response pattern it was therefore possible to distinguish between 3 groups of central hypotensive drugs.

On the mechanism of the decrease in cerebellar cyclic GMP content elicited by opiate receptor agonists.

Morphine, dextromoramide (4 mumol/kg i.p.) and vimonol R2 (17 mumol/kg i.p.) in analgesic doses (28 to 112 mumol/kg i.p.) decreased 3',5'-cyclic guanosine monophosphate (cGMP) in rat cerebellar cortex; morphine also decreased the cGMP content in deep cerebellar nuclei. Intrastriatal but not intracerebellar injections of morphine (20 mug) decreased cerebellar cGMP content. Naltrexone, an opiate receptor antagonist, but only apomorphine, a dopaminergic receptor agonist, blocked the effect of morphine on cerebellar cGMP. Pretreatment with 3-acetylpyridine (3-AP) which destroys the climbing fibers, failed to antagonize the effect of morphine on cerebellar cGMP. These results suggest that activation of opiate receptors in striatum decreases cerebellar cGMP content presumably by reducing activity in the mossy fiber excitatory input to cerebellum.

[Cardiovascular effect of various morphine-line analgesics in rabbits anesthetized with thiopental or alphadione (Alfatesine)]. / Effets cardiovasculaires de divers analgésiques morphinomimétiques chez le lapin anesthésié à l'aide de thiopental ou d'alphadione (Alfatésine)

Alphadione (Alfatésine, Althesin, CT 1341), a steroid anaesthetic with a quick and short action, has but a very moderate analgesic activity, so it is necessary in human anaesthesian, to associate with it a morphinic analgesis systematically. Therefore it was interesting to study the response of cardiovascular system when using this type of association. Our results show that the cardiovascular depressive effects of morphinic analgesics, when they exist, are not increased by the presence of alphadione.

[Current place of neuroleptics in cardiac surgery under extracorporeal circulation. Cardiovascular effects of different combinations]. / Place actuelle des neuroleptiques en chirurgie cardiaque sous circulation extra-corporelle. Effets cardio-vasculaires des différentes associations

We have been using narconeuroleptanalgesia for anesthesia in cardiac surgery under extra-corporeal circulation since 1969, and we have carried out about 3,500 anesthetics of this type on the 1st of October 1975. For all these anesthetics, the neuroleptic used was droperidol. The other components were: - in the case of the narcotic, penthiobarbital, then more recently Alfatesine; - in the case of the analgesic, either dextromoramide or phenoperidine or Fentanyl; in the case of the curare derivative, D, tubocurarine, and above all, pancuronium dibromide. The advantages of neuroleptanalgesia for such surgery seemed to us mainly: - greater cardio-vascular stability in patients with a heart lesion; - the possibility of better control of cardiac output, i.e. by fillingor by inotropic drugs, thanks to the relative vasoplegia produced by the neuroleptic. Finally, in a recent study, we attempted to determine the hemodynamic effect of droperidol and its association on various analgesic drugs measuring in a few patients the cardiac output, the peripheral resistances the the circulating blood volume. We will report the preliminary results of this study.

[Neuroplegia and extracorporeal circulation. Comparison between combinations of droperidol-phenoperidine and chlorprothixene-dextromoramide in cardiac surgery]. / Neuroplégie et circulation extra-corporelle. Comparaison des associations dropéridol-phénopéridine et chlorprotixène-dextromoramide en chirurgie cardiaque

After a quick review of the physiopathology of extra-corporeal circulation, the value of the use of neuroplegic drugs in cardiac surgery is recalled by means of pharmacological arguments. The experimental differences existing between the combinations droperidol - phenoperidine and chlorportixene - dextromoramide, on the rate of flow and on the pressure of the perfusion, and on the esophago-rectal thermic gradients during E.C.C. is then demonstrated. Statistic calculation confirmed the superiority of chlorprotixene in the realm of tissue perfusion during E.C.C. under hypothermia.

[Comparison of the endocrine response under 2 kinds of anesthesia: neuroleptanalgesia of the chlorprothixene-dextromoramide type and venous anesthesia of the type alfadione-fentanyl]. / Comparaison de la réponse endocrinienne sous deux modes d'anesthésie: neuroleptanalgésie de type chlorprothixène-dextromoramide et anesthésie veineuse de type alfadione-fentanyl

In 14 patients anaesthetized before undergoing an orthopedic surgical intervention, the variations induced by anaesthesia in the 17 hydroxycorticosterone rate, catecholamine, somatotropic hormone (STH), insulin, glycemia, free fatty acids and thyrotropin (TSH), all these variations were studied before the surgery. The patients were divided into 2 groups of 7, the first one being anaesthestized by chlorprothixene dextromoramide Neurolept-Analgesia and the second one by Alfadione Fentanyl venous anaesthesia.