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.
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L ~ J. FOREST:
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Anesthtsie sans sommeil. “La neuroleptanalgtsie.”
2. DE CASTRO,
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J., and P. MUNDELEER:
Anesthtsie sans barbituriques: la neuroleptanalgtsie.
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~:
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84
NEUROLEPT-ANALGESIA
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