A d a anaesth. Scandinav. 1‘361, 5, 73-84. NEUROLEPT-ANALGESIA-AN A L T E R N A T I V E TO GENERAL ANAESTHESIA BY ERICNILSON and PAULJANSSEN In the last twelve months, physicians in France and Belgium have drawn attention to the possibility of replacing the orthodox and classic type of general anaethesia by a process in which the emphasis is on analgesia and the blocking of vegetative reflexes. Such analgesia is produced by a new type of compound which is synthetised by the Janssen Laboratory, and which is characterised by an analgesic potency many times greater than that of morphine or pethidine. This compound has been forthcoming in connexion with a research programme aiming at elucidating the relationship between chemical structure and pharmacological effect. A further result of this work was the synthesis of a new type of neuroleptic agent unrelated chemically to reserpine of phenothiazine derivatives. It has been shown that the central nervous effects of this neuroleptic are largely the same as those of the majority of the phenothiazine derivatives, except that the former are considerably more intense. However, the purely hypnotic effects are much less pronounced. When used in a suitable combination, these two compounds-haloperidol, the neuroleptic, and phenoperidol, the analgesic-can produce what has been called the “neurolept-analgesic” state. In such a state patients can undergo operation, and since a minimum of toxic substances are administered it would appear that patients emerge from such procedures with no significant metabolic upset and with very slight risk of serious complications. PHARMACOLOGY Phenoper idine Phenoperidine is the generic name of serial number R 1406, chemically dl-l-phenyl-3-(4-carbethoxy-4-phenyl)-piperidinopropanol hydrochloride. 0 \=/ Phenoperidinr (R 1406). From the Department of Anaesthesiology, University Hospital, Lund, Swcdcn, and the Research Laboratory, P. Janssen, Beerse, Belgium. Received June 16, 1961. 74 ERIC NILSSON A N D PAUL JANSSEN This basic hydroxyester is derived from pethidine (meperidine) by replacement of the N-methyl by a phenyl-propanol moiety. The structure-activity relationship in this chemical area has been discussed in a previous paper (P. JANSSEN and N. EDDY( 1960)O). Phenoperidine is a typical morphine-like analgesic, characterised by its high potency, rapid onset of action, the intensity of its peak effect and the short duration of its pharmacological effects. In mice, low doses of phenoperidine (0.1 to 1 mg/kg s.T.) produce morphinelike excitement, Straub tail reaction and mydriasis. Ataxia, loss of righting reflex and respiratory depression occur at higher dose levels. Morphine-like excitement is also observed in phenoperidine-treated cats (P. JANSSEN, A. H. M. JAGENEAU and C. J. E. NIEMEGEERS (1960)11, P. JANSSEN and A. H. M. JACENEAU ( 1956)lo). In rats, phenoperidine produces sedation, respiratory depression and “leadpipe” rigidity. In dogs, a state of morphine-like narcosis is obtained with 1 mg/kg S.C. or more. In all these animals, and also in monkeys, the induction of a state of decreased reactivity to noxious stimuli is one of the first effects of the drug. Respiratory failure is the cause of death in all species. All important phenoperidine-induced effects are rapidly antagonised by nalorphine. The complete recovery of a phenoperidine-treated apnoeic animal within a few seconds after an intravenous dose of about 1 mg/kg of nalorphine is most striking and reproducible in all circumstances. The circulation in dogs, cats and rats is not significantly affected by the drug. The results of several quantitative comparative studies on phenoperidine, morphine and pethidine are summarised in tables 1-3. TABLE 1. 1 Species ............. Mice Method Hot platr.. I Route S.C. 1 Symbols (mpk) ED,,,, ............. Mice S.C. ED,, Hot p l a t r . . . . . . . . . . . . . . . Micr S.C. ED,,,, Hot plate.. Antiaggressive activity. . . . Micc S.C. ED,, ....... Mice S.C. ED,, .............. Mice S.C. ED,, Loss of righting reflex. . . . . Micc S.C. ED,, Acute toxicity.. . . . . . . . . . . Micc S.C. LD,, Mydriatic activity. Kotarod.. 1 Phenoperidine 0.25 (1) 0.33 (1) 0.42 (1) 0.65 (1) 1.1 (1) 1.7 (1) 2.0 (1) 110 (1) 1 Morphine 1 Pethidinc 3.4 22 (88) 23 (14) 11 (33) 6.0 (69) 38 (90) 28 (43) 23 (21) 52 (31) (14) 4.9 (7.5) 15 (14) 22 (13) 50 (25) 440 (4) > 160 ~ 0 220 (2) ) 75 NEUROLEPT-ANALGESIA 1 Method TABLE 2. I species Route ............. Rats s. c. .. Rats s. c. Amphetamine antagonism Rats s. c. Loss of conditioned avoidance behaviour ........ Rats s. c. . Rats s. c. Apomorphine antagonism Rats s. c. Inhibition of faecal output Rats s. c. Acute toxicity.. .......... Rats s. c. Acute toxicity.. .......... Rats 1. v. Hot plate.. Tryptamine antagonism. Inhibition of food intake. I Method Species I 1 I zEEe 1 symbO1' (rnpk) TABLE 3. Route 1 'rg I zEEe 1 Apomorphine antagonism Dog S.C. EDKo 0.25 (1) Loss of conditioned avoidance behaviour Dog S.C. ED,, 1.6 (1) ........ 1 Morphine Morphine 1.0 (4) >5 (>3.1) 1 Pethidine Pethidine 20 (80) >40 (>25) In various species and in different experimental conditions phenoperidine appears to be up to 75 times more active than morphine and up to 275 times pore active than pethidine, the general pharmacological spectra of the three drugs being qualitatively similar, but not identical. Phenoperidine appears to be relatively much less toxic than pethidine. Haloperidol Haloperidol is the generic name of serial number R 1625, chemically 4'-fluoro-4-hydroxy-4- (4'-chloro)-phenyl-piperidinobutyrophenone. 76 ERIC NILSSON AND PAUL JANSSEN ‘Cl Haloperidol (R 1625). The compound is a typical, potent and long-acting neuroleptic agent of novel structure. After administration of low atoxic doses of haloperidol to laboratory animals the following phenomena are observed:A typical cataleptic attitude without ataxia. Spontaneous and induced motor activity is considerably reduced. Inhibition of various conditioned motor reflexes. Reduced effectiveness of amphetamine and of apomorphine. Pharmacologically, haloperidol is therefore similar to the potent neuroleptic drugs derived from chlorpromazine. It is, however, devoid of automatic activity, such as sympathetic blockade and orthostatic hypotensive effects, which are commonly observed with most phenothiazines. The pharmacology of Haloperidol has been described in detail by P. JANSSEN and C. J. E. NIEMECEERS ( 1959)12,P. JANSSEN, C. J. E. NIEMEGEERS and K. H. L. SCHELLEKENS (1960)13, W. K. A. SCHAPER, A. H. M. JAGENEAU, J. HUYGENS and P. JANSSEN ( 1960)14. Clinically, haloperidol has been widely and successfully used in the treatment of various psychoses (J. R. BOISSIER, J. PAGNY, P. M O U I Land ~ J. FOREST (1960)1, J. DELAY,P. PICHOT,T. LEMPBRIBRE and B. ELISSALDE (1960)5, B. GERLE(1960)’). The earliest descriptions of the clinical effects of phenoperidine gave an impression of an analgesic, which, when used in anaesthesia together with haloperidol, could well provide a method closely approaching the ideal. However, the dangers of excessive dosage of haloperidol in premedication were pointed out, since this can bring about the aforementioned effects through the extrapyramidal system with resulting muscular rigidity which may cause difficulties in producing relaxation during operation (J. DELAY,P. DENIKER, A. GREENand M. Y. MORDRET ( 1957)4). It was also described how the patient could be awakened or made to react at any time during the operation even though perfect analgesia was maintained. The condition was described as being like a catatonic state, in which the patient was pain-free and lacking in initiative, from which he could be temporarily aroused by suggestions from without (J. DE CASTRO and P. MUNDELEER (1959p, J. DE CASTRO and P. MUNDELEER ( 1959)3, P. D E L I C N (1960y). ~ In human subjects the effects of phenoperidine are quite slow in onset. 77 NEUROLEPT-ANALGESIA There is also a degree of dissociation in the central nervous effects, in that respiratory arrest occurs before analgesia has become complete. The analgesic effect is of relatively short duration, and it would appear thai a steady level of analgesia is best obtained by a continuous intravenous drip rather than by intermittent injections. The drug is eliminated from the body mainly by the kidneys, and 50% of the dose administered can be recovered in the urine. The remainder is broken down successively in the liver to pethidine (and pethidinic acid), of which 75% is in turn eliminated by the kidneys. Phenoperidine is thus a powerful analgesic agent with an extremely depressing effect on respiration. This naturally implies that some form of artificial respiration is mandatory when using this drug. The respiratory depression, central in origin, passes off relatively rapidly, and towards the end of an operation there may well be adequate spontaneous respiration despite the persistence of good analgesia. Ventilation is best carried out by mechanical means, and we find that a certain degree of hyperventilation is beneficial for the patient and tends to reduce the risk of complications. If phenoperidine is administered uncombined with a vasodilator agent, a degree of peripheral cyanosis may appear. This is probably due to capillary or pre-capillary contraction, but the exact site and nature of the process have not so far been determined. At the University Hospital in Lund we have used the technique of neurolept-analgesia on 250 patients during the course of the last 12 months or so. Neurolept-analgesia can be produced by a variety of drug combinations, most of which were minutely described and discussed at an International Symposium recently held at Ostend. However, the method used in Lund is that described and P. MUNDELEER (1959)e in their original paper, i.e. a by J. DE CASTRO combination of haloperidol and phenoperidine. A vasodilator preparation, hydergine, is added both to the haloperidol used for premedication and to the phenoperidine solution in order to prevent the peripheral cyanosis which is otherwise often seen in association with the use of phenoperidine. The essential difference between orthodox general anaesthesia and neurolept-analgesia is that in the latter the element of hypnosis is virtually absent, and vegetative reflexes are more powerfully suppressed. However, the indications for muscle relaxants are the same as when using other techniques. Premeditation.-We have rigidly adhered to the aforementioned combination of drugs, but have varied the premedication given to different groups of patients as specified below. The first 100 patients were given haloperidol 2.5 mg theralene 25 mg hydergine 0.3 mg by intramuscular injection 1 hour before operation (table 4). Theralene is a neuroleptic drug with a weaker central effect than haloperidol, and at the dosage mentioned it is said to reduce the effect of the latter on the extrapyramidal system. With this premedication the patients were well sedated, somewhat drowsy and distinctly tractable. + + 78 ERIC NILSSON AND PAUL JANSSEN TABLE 4. Premedication 1625 2.5 rng 5 rng 10 mg 1 Theralene 25 m g - 1 Hydergine 0.3 rng 0.3 mg 0.3 rng I No. ofcases 100 50 100 T o simplify premedication, theralene was omitted in the next 50 patients, and instead 5 mg haloperidal and 0.3 m g hydergine was given. The preoperative condition of these patients was not noticeably different, but there was a marked increase in the dose of the analgesic (phenoperidine) required before intubation could be performed. Extrapyramidal effects in the form of rigidity or increased muscle tone were not seen in this group either. The last 100 patients were given 10 mg haloperidol together with 0.3 mg hydergine as premedication. These patients were also fully sedated, and when the time came for intubation and operation there were still no signs of increased muscle tone in any of them. However, postoperative complications involving the central nervous system-presumably referable to an excessive dose of haloperidol-occurred in two cases. Indudion and Maintenance We begin with a slow intravenous injection of 2 mg phenoperidine, the aim being to hasten the onset of the analgesic state. The intravenous drip is then started, the infusion fluid consisting of 500 ml 5 yo glucose solution, 20 mg phenoperidine, 2 mg haloperidol and 0.3 mg hydergine. The drip is allowed to run at maximum speed while the patient is carefully observed and verbal contact is maintained. Respiratory depression may develop, but even when this is quite severe, it is by no means invariable that complete analgesia has been achieved. It would therefore appear that analgesia is slower in onset than respiratory depression. Even when respiration has apparently ceased, the patient will still breathe if instructed to do so. In the early part of the series, it was our custom not to intubate until full analgesia had been attained. We subsequently realised that the patient could be intubated much earlier. When talking to the patient, it is possible to observe some difficulty with phonation when respiration reaches a certain degree of depression, and we now find that this is the proper time for intubation. There has been some discussion as to whether relaxants are necessary for intubation or not. If phenoperidine is pushed to the point where the patient is completely analgesic before intubation, this procedure can be performed without relaxants, especially as laryngeal and pharyngeal reflexes are reduced to a minimum at this juncture. Since it is our practice to intubate before respira- NEUROLXPT-ANALGESIA 79 tory depression is complete, we consider it mandatory that the patient be completely relaxed. We therefore give 0.5-1 .O mg succinylcholine per kg body weight, so that intubation can be performed easily and without local trauma. It is quite striking how seldom one sees any reaction, such as coughing or ‘bucking,’ when the tube is slid into position in the trachea. Prior to intubation the drip rate is reduced to the minimum, i.e., the infusion does little more than keep the intravenous needle patent. When the succinylcholine effect has passed off, one is left with a patient who is intubated, artificially ventilated and completely analgesic. At the same time perfect mental contact can be maintained with the patient who can be induced to carry out quite highly integrated mental processes, such as choosing between the right and the wrong date, right and wrong age, correct and incorrect calculations, etc. In a small series of patients we have demonstrated electro-encephalographicallythat it is possible to have complete analgesia simultaneously with complete wakefulness (D. INGVARand E. NIISSON (1961p). When required, we produce relaxation with d-tubocurarine, the dosage being adjusted according to the type of operation. We prefer the long-lasting, even action of d-tubocurarine to that of succinylcholine, with which it is difficult to produce even relaxation either by intermittent injection or by continuous drip. It was relatively easy to adjust the dosage of curare, so that it did not confuse the picture in the event of respiratory depression persisting at the end of the operation. The phenoperidine drop is turned off 15-20 minutes before the end of the operation, and in some cases the patient begins to breathe spontaneously at this point. However, in our series, this happened only in 25% of the cases; otherwise after the completion of surgery but prior to extubation we had to give a small dose of nalorphine in order to establish adequate spontaneous respiration. The minimum dosage was 2.5 mg, and in many cases this was sufficient. The dosage varied from 2.5 to 10 mg. Occasionally nalorphine was used before the final skin suture was inserted ; such patients almost invariably complained of pain from the wound. It would thus appear that nalorphine counteracts not only the respiratory depressant effect of phenoperidine, but also its analgesic effect. All patients were awake and able to answer questions when spoken to at the end of the operation. Even when the awake patient is not immediately extubated at the end of the operation, one rarely’sees that the tube is resented in any way. Tracheal toilet and extubation do not seem to cause any discomfort. The patients co-operate willingly during transport to the recovery room, but once in bed they lapse readily into a trance-like state if allowed to do so. The physiotherapists have, however, no difficulty in securing the patients’ cooperation in the exercises and treatment which they undergo during the first postoperative day. There is only slight postoperative pain during the first few hours, and analgesics are usually not required until after 5 or 6 hours. Reduced 80 ERIC NILSSON A N D PAUL JANSSEN amounts of analgesics are required-usually ordinary anaesthesia. about half of what is needed after Postoperative Period Phenoperidine is a drug which has a frank emetic effect, and given alone it would cause vomiting in the majority of patients. However, haloperidol has a powerful antiemetic effect somewhat like that of phenothiazine preparations, although the latter are much weaker in this respect. Haloperidol must be regarded as the most powerful antiemetic which has so far appeared. In animal experiments, for example, it has been shown that when given subcutaneously the antiemetic effect of haloperidol is 50 times greater than that of chlorpromazine, and when given by mouth it is 250 times greater. These experiments were carried out on apomorphine-induced vomiting (P. JANSSEN, <:.J. I:. NIEMECEERS and K . H. L. SCHELLEKENS ( 1960)13). In our series of 250 patients, four vomited postoperatively. These four patients all received the first type of premedication mentioned above. With an increased dosage of haloperidol there has been no postoperative vomiting. Haloperidol has not been used as an antiemetic postoperatively, the protection provided by the premedication being entirely adequate. The duration of the effect of haloperidol is considerable, and a single intramuscular dose given as premedication can be relied upon to last at least 24 hours. Postoperative complications in another two patients deserve special mention. A 35-year-old man was opcrated on for a tumour of the testicle. Neurolept-analgesia was used, and both this and the operation were completely trouble-free. 0.3 mg hydergine, and during the Premedication was with 10 mg haloperidol opcration he received 12 mg phenoperidine. At the end of the operation he was still apnoric; Iic was therefore given a total of 7.5 mg of nalorphine before spontaneous respiration was adequate. For the first 48 hours everything was all right, but after that hr began to experirnce psychomotor disturbances. He wanted to get out of bed and walk about; he could not keep his hands still, and he was unable to concentrate o n anything. He could not read, for cxample, brcause he was unable to remember what he read, and the words somehow made no impression on him. This state lasted for about 2 days, and after that time it slowly passed off without any particular treatment. The patient was a doctor, and so he was able to give a very clear account of his symptoms, which he regarded as distinctly unpleasant. The other patient was a 45-year-old man with an incisional hernia; he received the 0.3 mg hydergine. During the operation which same premedication, 10 mg haloperidol lasted 1 ?L2 hours, he was given 14 mg phenoperidine. I t was noticed that he sweated profusely during the operation, but there was no reason to think that inadequate analgesia was to be blamed. The patient was ventilated mechanically, and afterwards he was given 5 mg of nalorphine which brought about a return of spontaneous respiration. During the postoperative period while he was still in hospital, and for about a month afterwards, he also experienced psychomotor symptoms which he found most upsetting. His proprioception and co-ordination were clearly affected, and he could not, or dared not, for example, drive his car. He had difficulty in co-ordinating the various foot movements in operating the prdals. He was unable to concentrate on mental work. Poor concentration, slow cerr- + + 81 NEUROLEPT-ANALGESIA bration and poor memory were the main symptoms, but these slowly faded away over the course of a month. Now, three months after the operation, the patient is completely back to normal again. Our 250 cases include cases from all risk-categories between the ages of 15 and 80 years. What has been particularly striking is the way in which the patients with poor circulatory function have survived anaesthesia and operation with little noticeable adverse effect. Five cases of recent myocardial infarction are included in this series, and none of these were any the worse for surgery or anaesthesia. The various types of operation in which neurolept-analgesia was used in this trial are listed in table 5. - TABLE 5. Types OF operation Neck and thyroid. ........... Intrathoracic ................ Radical mastectomy. ......... Biliary tract. ................ Digestive tract.. ............. Hernia. ..................... Urological ................... Extremities. ................. Neurosurgical. ............... Miscellaneous. ............... Total. . 1 No. of cases 7 5 10 112 36 10 40 4 1 25 250 There was one death in the series, due to a purely surgical complication in connexion with an operation for bleeding ulcer. Death occurred 36 hours after operation. DISCUSSION Neurolept-analgesia has been found to be a technique by means of which the patient is rendered pain-free and in a general condition suitable for operation, while at the same time sparing many central nervous structures and pathways which are blocked or put out of action in orthodox anaesthesia. The emphasis in this technique is on effective analgesia, which is feasible thanks to the extraordinary potency of phenoperidine. Furthermore, the patient’s mental state becomes such that he lies in a resting state, without initiative, virtually catatonic and offering no resistance to the surgical intervention to which his body is being subjected. This effect, produced by haloperidol and hydergine, has been called ‘disconnexion’ by J. DE CASTRO and P. MUNDELEER ( 1959)293, i. e. the patient is cut off from disturbing impressions from the outer 82 ERIC N I N O N AND PAUL JANSSEN world, and when left to his own devices he has but little contact with his surroundings. This disconnexion occurs both peripherally (hydergine) and in the brain stem (haloperidol), but the cortex and subcortical centies are unaffected. This is demonstrated by the contact that can be maintained with the patient, who by nodding or shaking his head can give adequate answers to questions. The patients are not, in general, amnesic for the operative period, but their memory of this time is not positive and direct. By this we mean that they often have difficulty in giving an account of their experiences, but if their memories are jogged, and they are reminded of what happened (such as ventilation with a face mask prior to intubation, intubation itself, conversation in the operation room, etc.), they are immediately able to expand and give further details. However, there are some patients who can give a clear account of everything that happened or went on around them. This should be borne in mind by those present when indulging in conversation. A few patients have maintained that they felt pain during the operation, not in the normal unpleasant way, however, but somehow modified or different. Different is perhaps the best way of describing the subjective experiences of many patients, as compared with their impressions of previous orthodox anaesthesia with, for example, barbiturate induction. If it is desired to cut off the patient from his surroundings to a greater extent than is provided by the disconnexion obtained with haloperidolhydergine, the patient may be ventilated with equal parts of nitrous oxide and oxygen, or a 60140 mixture. None of our patients were warned pre-operatively of what to expect, nor told that anything new or different was being tried out. In this way the patient’s subsequent description of his experiences was uninfluenced by any preconceived notions or ideas. S U M MARY An account is given of the pharmacological characteristics of haloperidol and phenoperidine, as manifested in experimental animals. Neurolept-analgesia is discussed as an alternative “anaesthetic” technique for patients undergoing surgery. The neurolept-analgesic state is defined, and reactions manifested by patients so treated are discussed. A detailed account is given of a neurolept-analgesic technique as used in a series of 250 patients undergoing surgery. Complications and their treatment are discussed. The advantages of neurolept-analgesia can be summarised as follows :1. Administration of toxic agents is reduced to a minimum, and there is thus very little interference with general cell function. 2. The condition produced is easily controllable. In the event of overdosage with phenoperidine, nalorphine is an effective antidote. NEUROLEPT-ANALGESIA 83 3. The condition of the circulatory system remains remarkably stable during neurolept-analgesia. 4. Patients react well to the trauma of surgery and “anaesthesia,” and their good postoperative condition is noteworthy. Very small amounts of analgesics are required postoperatively. Z U S A M M E N FAS S U N G Die auf Grund von Tierexperimenten festgestellten pharmakologischen Eigedschaften von Haloperidol und Phenoperidin werden geschildert. Neurolept-Analgesie wird als Alternativ-“Anaesthesie”-Technikfur Patienten diskutiert, die sich chirurgischen Eingriffen unterziehen miissen. Der Zustand der Neurolept-Analgesie wird definiert und die Reaktionen der so behandelten Patienten diskutiert. Die Technik der Neurolept-Analgesie, wie sie bei einer Serie von 250 chirurgischen Patienten angewendet wurde, wird im Detail geschildert. Komplikationen und deren Behandlung werden besprochen. Die Vorteile der Neurolept-Analgesie konnen wie folgt zusammengefasst werden : 1. Die Menge des toxischen Agens wird auf ein Minimum reduziert, daher ist auch der Einfluss auf die allgemeinen Zellfunktionen gering. 2. Der erzeugte Zustand kann leicht kontrolliert werden. Im Falle der tl‘berdosierung mit Phenoperidin ist Nalorphin ein wirkungsvolles Antidot. 3. Der Kreislauf bleibt im Zustand der Neurolept-Analgesie bemerkenswert stabil. 4. Die Patienten reagieren auf das Trauma der Operation und der “Anaesthesie” giinstig und ihr guter postoperativer Zustand ist bemerkenswert. Postoperativ werden nur kleine Mengen von analgetischen Mitteln benotigt. REFERENCES 1. BOISSIER, J. R., J. PAGNY,P. M O U I L and L ~ J. FOREST: Quelques actions pharmacologiques du haloptridol (R 1625). Acta neurol. psychiat. Bclg. 1960, 60, 39. J., and P. MUNDELEER: Anesthtsie sans sommeil. “La neuroleptanalgtsie.” 2. DE CASTRO, Acta chir. Belg. 1959, 58, 689. 3. DE CASTRO, J., and P. MUNDELEER: Anesthtsie sans barbituriques: la neuroleptanalgtsie. Anesth. et analg. 1959, 16, 1022. 4. DELAY,J., P. DENIKER, A. GREENand MLLE.M. Y. MORDRET: Le syndrome excitomoteur provoqut par les mtdicaments neuroleptiques. Presse mid. 1957, 65, 1771. 5. DELAY,J. P. PICHOT, T. 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