Figure 1. Figure 1: L‘arc de reflex émétique: ACh = Acétylcholine, H1R = récepteurs histaminiques,
D2R = récépteurs dopaminérgiques, 5HT3R = récepteurs sérotoninériques
2.2. Emésis dans divers contextes cliniques
Les nausées et vomissements sont des symptômes qui se rencontrent dans de
multiples pathologies cliniques. Parmi les situations cliniques relativement bien
investiguées, on trouve l'émésis dû à des médicaments cytotoxiques
(chimiothérapie), l'émésis après chirurgie ou anesthésie générale (NVPO) et l'émésis
en relation avec des maladies gastro-intestinales. Le mal du voyage, l'émésis lié à la
grossesse (émésis gravidarum, en anglais early morning sickness), l'émésis dû a des
changements métaboliques (par exemple lors d'urémie) ainsi que l'émésis en relation
avec le SIDA et la radiothérapie sont d'autres conditions cliniques qui sont associées
à des nausées et des vomissements.
2.2.1. Emésis et chirurgie
Les nausées et les vomissements postopératoires (NVPO, en anglais PONV) sont
parmi les effets indésirables les plus fréquents après la chirurgie et l'anesthésie
générale. Bien que les produits anesthésiques modernes aient diminués
significativement leur incidence, les NVPO sont une complication fréquente et
stressante. Du point de vue des patients, les douleurs, les nausées et les
vomissements sont perçus comme étant leurs préoccupations les plus importantes
pendant la période post-opératoire 13. Actuellement, on estime que l'incidence
moyenne des NVPO se situe entre 25% à 30%, avec des NVPO sévères et intraitables
dans environ 0.2% des cas 14. Dans une revue systématique, des études randomisées
et contrôlées s'intéressant à la chirurgie pédiatrique du strabisme (une intervention
chirurgicale connue pour son taux de NVPO élevé), l'incidence moyenne était
d'environ 50% pour les vomissements dans les six premières heures et d'environ 60%
pour les vomissements dans les 48 premières heures après l'intervention, sans
prophylaxie préopératoire 15. La volonté actuelle de traiter les patients en ambulatoire
plutôt qu'à l'hôpital pourrait se voir remise en question par cette incidence élévée de
NVPO, qui prolongent le récupération post-opératoire et peuvent amener à des
L'étiologie des NVPO est complexe et plurifactorielle. Les facteurs déterminant les
NVPO sont en relation avec l'état du patient, son anamnèse médicale et chirurgicale
16. En l'absence de modèle animal des NVPO, les expériences tentant d'établir les
facteurs de risques et sur l'efficacité des traitements sont uniquement basées sur les
études cliniques 17. Dans une étude, trois facteurs de risques majeurs ont été
identifiés: l'analgésie postopératoire avec des opioïdes, une anamnèse d'émésis après
chirurgie et le sexe féminin 18.
2.2.2. Emesis et gastro-entérologie
Diverses pathologies gastro-intestinales peuvent aboutir à des nausées et
vomissements, dont les ulcères peptiques, les problèmes de motilité gastro-
intestinale (vagotomie, gastroparésie diabétique ou idiopathique), et les dysrythmies
gastriques résultant d'une fonction myogénique ou neurogénique altérée de
l'intestin. Typiquement, les obstructions intestinales d'origines diverses, comme par
exemple les adhésions, les malignités, les hernies ou les volvulus, aboutissent à des
vomissements. Les pathologies du foie, du pancréas ou des voies biliaires quant à
elles, peuvent également produire des vomissements. Les nausées et vomissements
peuvent accompagner l'aérophagie. Les infections virales, bactériennes et parasitaires
du tractus gastro-intestinal sont associées à des nausées et des vomissements sévères
ainsi qu'à des diarrhées. Chez les enfants, les nausées et vomissements peuvent
accompagner un état fébrile dû à des infections systémiques sévères. Les altérations
métaboliques comme l'urémie ou le diabète peuvent s'exprimer par des
vomissements, probablement par une stimulation de la zone gâchette chimio-
réceptrive par des toxines ou des métabolites 19.
Dans la muqueuse gastrique ont trouve des chimiorécepteurs, qui peuvent être
stimulés par la sulfure de cuivre, l'émétine (Ipeca®), les tétracyclines, les
analgésiques ou les entérotoxines des staphylocoques. Cette stimulation conduit à
une libération de la sérotonine périphérique avec une grande affinité pour les
récepteurs de la 5-HT3. La dépolarisation des récepteurs 5-HT3 périphériques
conduit à un signal émétogène.
La musculature du tractus gastro-intestinal est munie de détecteurs qui réagissent à
une distension active ou passive de la paroi intestinale. Le duodénum et l'antre
gastrique ne sont habituellement pas soumises à une telle distension et y sont donc
plus sensibles 19. Lors d'une lésion du tractus gastro-intestinal haut, il résulte une
perte de motilité augmentant le volume intra-luminal et conduisant à une
stimulation des mécanorécepteurs. La stimulation viscérale mécanique inclut
également la tension du mésentère, la dilatation du col utérin, ou l'irritation du
2.2.3. Emésis et cancer
Chez les patients qui souffrent d'un cancer, les facteurs étiologiques des nausées et
vomissements sont nombreux (Box 1). L'émésis est une complication principale de la
chimiothérapie 20. La physiopathologie exacte de l'émésis liée à la chimiothérapie
n'est toujours pas entièrement explorée. L'âge du patient, le sexe et l'alcoolisme sont
des facteurs associés à une réponse émétique plus marquée. La plus grande partie
des médicaments cytotoxiques agissent sur la zone gâchette. Pourtant, la stimulation
des récepteurs périphériques, des mécanismes vestibulaires ainsi qu'une altération
du goût et de l'odorat peuvent influencer la réaction.
On distingue différents syndromes émétiques liés à la chimiothérapie : Les nausées et
les vomissements aigus se rencontrant dans les premières 24 heures, les nausées et
les vomissements tardifs se rencontrant après les premières 24 heures, un syndrome
émétique réfractaire et les vomissements anticipés. Les divers produits cytotoxiques
entraînent différents syndromes émétiques 21. Le cisplatine, les moutardes à l'azote, la
streptomycine, la dacarbazine, la carmustine et la dactinomycine sont hautement
émétogènes 22. Le cisplatine est particulièrement connu pour les nausées et
vomissements tardifs. Le pouvoir émétogène dépend également de la dose et de la
forme d'application.
Il n'existe pas de traitement antiémétique particulier considéré comme traitement de
choix pour tous les types d'émésis liés à la chimiothérapie. Les médicaments agissant
sur les récepteurs 5-HT3 sont considérés comme la base principale du traitement
actuel 22. Des régimes plurimédicamenteux et l'utilisation séquentielle de plusieurs
classes de médicaments sont cependant recommandés 23. Ainsi, le contrôle de
l'émésis en chimiothérapie n'est toujours pas entièrement résolu et les médicaments
anti-dopaminergiques ont gardé leur place, notamment dans le traitement des
nausées et vomissements retardés ou refractaires.
Anormalités de l'eau et des électrolytes Hypercalcémie Déplétion de l'eau Intoxication à l'eau Insuffisance surrénale Obstruction de l'intestin, péritonite Métastases au niveau du système nerveux central Cerveau Méninges Métastases hépatiques Urémie Infections locales Médicaments Thérapie cytotoxique Chimiothérapie Autres médicaments (par exemple, les opioïdes) Irradiation Psychogénique
Tableau 1. Etiologies des nausées et vomissements chez les patients souffrant d'un cancer
2.2.4 Emésis et hypertension intracrânienne
Selon l'hypothèse de Monro-Kellie modifiée, la pression intracrânienne augmente
quand un des trois composants de la cavité crânienne (le sang, les tissus du cerveau,
le liquide céphalo-rachidien) augmente en volume sans diminution compensatoire
d'un autre composant. Diverses conditions cliniques sont associées à une
augmentation de la tension intracrânienne. On peut citer les tumeurs, les lésions de la
voûte crânienne, les lésions secondaires (l'œdème cérébral et les hémorragies), les
infections (par exemple les méningites et les encéphalites) ou la pseudotumeur
cérébrale. Les vomissements, avec ou sans nausées, peuvent accompagner ces
conditions une fois qu'une valeur critique de volume intracrânienne dépassée. Les
vomissements sont corrélés directement avec la pression au niveau du plancher du
quatrième ventricule, où se trouve le centre du vomissement. De plus, une
augmentation rapide de la pression intracrânienne inhibe la fonction motrice de
l'estomac et du duodénum chez les lapins conscients 24. Il est intéressant de noter,
que dans le cas où la pression intracrânienne est induite expérimentalement chez les
chiens, le traitement avec de la prazosine (un antagoniste des récepteurs alpha) ainsi
qu'avec du propranolol (un antagoniste des récepteur bêta) est efficace, tandis que
l'ondansétron (un antagoniste des récepteurs 5-HT3) n'a pas d'effet 25.
2.3. Halopéridol
2.3.1. Histoire de l'halopéridol
L'halopéridol est synthétisé pour la première fois en février 1958 par Bert Hermans
dans les laboratoires Jannsen suite à des essais destinés à trouver une nouvelle
molécule similaire à la mépéridine (pethidine). Seulement trois mois plus tard, son
efficacité potentielle comme neuroleptique est testé chez des patients psychiatriques
belges. A l'époque, la psychopharmacologie ainsi que la neurobiochimie sont des
domaines relativement peu connus. En 1976, 2'213 articles scientifiques concernant
l'halopéridol sont publiés. Cent trente-neuf articles traitent de sa biochimie, 633
articles de sa pharmacologie et 1'441 articles décrivent son utilisation clinique.
L'halopéridol a beaucoup contribué au développement de la psychopharmacologie
et de la neurobiochimie et s'est avéré un outil important dans le développement de la
psychiatrie moderne 26.
Dès les années soixante, on a découvert chez les animaux, l'action protectrice de
l'halopéridol contre les vomissements induits par l'apomorphine (un agoniste
dopaminergique) 27, effet confirné en clinique sur l'émésis induit par les opioïdes.
Depuis, l'halopepéridol est largement utilisé comme antiémétique.
2.3.2. Les propriétés chimiques et physiques
L'halopéridol est une butyrophénone. C'est un cristal ou une poudre cristalline de
couleur blanche à jaunâtre ayant comme formule chimique 4-[4-(p-chlorophenyl)-4-
hydroxypiperidino]-4'-fluorobutyrophenone. Il s'agit d'une base avec un pKa de 8.3.
Son poids moléculaire est 37'587 Da.
2.3.3. Cinétique
L'halopéridol est bien absorbé par voie entérale. En forme de solution, sa
biodisponibilité est d'environ 75% chez l'être humain. En forme de comprimé sa
biodisponibilité est d'environ 65% 28. A cause de sa liposolubilité, l'halopéridol est
rapidement distribué dans les compartiments extravasculaires et disséminé dans le
système nerveux central, le foie et dans la plupart des autres tissus. La concentration
hépatique est environ 1'000 fois plus grande que la concentration sérique. La
concentration dans le liquide céphalo-rachidien est environ 10 fois plus importante
que la concentration sérique. Après une administration orale, on note deux pics de
concentration dans le plasma: après trois à six heures et après 12 à 20 heures. Le
deuxième pic de concentration s'explique par un cycle entero-hépatique 29.
L'halopéridol est largement lié aux protéines plasmatiques ( 90%) 30, raison pour
laquelle le volume de distribution apparaît grand ( 1'000 – 1'500 litres). La
concentration plasmatique augmente de manière linéaire en fonction des doses
croissantes. Avant l'excrétion, l'halopéridol est métabolisé dans le foie par
désalkylation oxydative en deux métabolites hydrophiles qui sont ensuite conjugués
avec la glycine 31. L'halopéridol interagit avec le métabolisme de divers autres
médicaments par induction ou inhibition de cytochromes. Le principal cytochrome
impliqué est la CYP3A4, responsable pour la plus grand partie du métabolisme de
l'halopéridol 32. Après administration intraveineuse, la demi-vie plasmatique de
l'halopéridol est d'environ 24 heures. Après administration orale, la demi-vie
plasmatique de l'halopéridol est d'environ 19 heures 33. L'halopéridol est éliminé par
l'urine ( 30%) et par les selles ( 20%) 34. On ignore combien d'halopéridol traverse le
placenta, mais il est reconnu que l'halopéridol passe dans le lait maternel. La relation
entre la concentration dans le lait maternel et la concentration dans le plasma est
d'environ cinq à sept pour dix 35.
2.3.4. Les effet chez les animaux et chez les hommes
L'halopéridol est un dérivé des butyrophénones. Les butyrophénones sont des
neuroleptiques dit «classiques» comme les phénothiazines et les thioxanthines. Les
neuroleptiques, qu'on appelle en anglais aussi tranquillisants majeurs ou agents
antipsychotiques, forment un groupe chimiquement hétérogène. Tous les
neuroleptiques ont, par définition certaines actions cliniques communes, quand ils
sont administrés aux animaux 36. Chez le rat par exemple, ils bloquent les
comportements stéréotypés, induit par des agonistes de la dopamine et qui
consistent, en des mouvements en cercle 37.
Activité anti-dopaminergique
Les agonistes de la dopamine (par exemple l'apomorphine) agissent au niveau du
système striatonigral et mesolimbique, produisant un syndrome qui ressemble
cliniquement à une schizophrénie pouvant être partiellement neutralisé par des
Chez l'homme, l'halpéridol, comme tous les neuroleptiques, a des effets inhibiteurs
caractéristiques : un ralentissement psychomoteur, une indifférence affective ou un
état d'apaisement émotionnel (syndrome neuroleptique). Dans sa forme extrême, on
parle de catalepsie, se manifestant par une inhibition d'initiation du mouvement avec
une rigidité musculaire, dite « plastique ». Chez le patient schizophrénique, les effets
antipsychotiques n'apparaissent pas tout de suite mais progressivement. En
revanche, l'effet sédatif des neuroleptiques se produit immédiatement chez les
personnes saines, comme chez les personnes malades. Tous les neuroleptiques
n'agissent pas de la même manière. Pour cette raison il a été proposé de distinguer,
parmi les neuroleptiques ceux qui ont une action antipsychotique plus marquée (dite
« incisive ») de ceux qui ont un effet sédatif plus marqué 38. Dans la littérature,
l'halopéridol est considéré comme médicament antipsychotique hautement incisif
mais peu sédatif.
Effets indésirables de l'halopéridol
La majorité des effets indésirables sont lié son action antidopaminergique, notament
des effets endocrinologiques et neurologiques, les derniers étant les plus redoutés
(par exemple les dyskinésies tardives). Le syndrome neuroleptique malin peut se
rencontrer chez des patients traités avec des doses initiales élevées (le plus souvent
avec les butyrophénones). Ce syndrome comprend une akinésie, une rigidité
musculaire, une hyperthermie, ainsi qu'une instabilité végétative avec une perte de
conscience d'environ 24 à 72 heures après le début du traitement. S'il n'est pas
reconnu, ce syndrome peut être fatal. Il est également décrit chez des patients traités
par des butyrophénones ou des phénothiazines pour une agitation ou des nausées et
vomissements. Il ne faut pas le confondre avec l'hyperthermie modérée, qui peut
s'installer au début d'une traitement avec un neuroleptique 39. Une hypothermie peut
parfois être observée par interaction avec des structures hypothalamiques ou par
vasodilatation périphérique (stimulation des récepteurs alpha-1).
D'autres effets indésirables sont sont provoqués par l'action sur le système
adrénergique (effets cardio-vasculaires avec hypotension orthostatique et
tachycardie) ainsi que sur les récepteurs anticholinergiques (parasympathique) et
antihistaminiques. Les butyrophénones n'ont que peu d'action anticholinergique et
antihistaminique.
Les neuroleptiques abaissent le seuil de convulsion et induisent un risque accru de
crise épileptique, raison pour laquelle il faut les prescrire avec prudence chez des
patients épileptiques ou ayant subi récemment un sevrage d'opioïdes ou de
2.3.5. Utilisation classique de l'halopéridol
Depuis la fin des années 1950, l'halopéridol est largement utilisé pour traiter la
schizophrénie, la démence, le délire et la phase maniaque d'un trouble bipolaire. On
a aussi utilisé l'halopéridol pour les maladies suivantes: les troubles schizoaffectifs, le
ballisme, le syndrome Gilles de la Tourette et pour le traitement de retard mental ou
la maladie de Huntington.
Pour le contrôle des patients délirants et très agité, l'halopéridol est souvent utilisé
comme sédatif. Il a l'avantage de contrôler ces symptômes sans effets indésirables
importants au niveau du système respiratoire ou cardiaque. Ceci peut être utile
pendant la période post-opératoire aux soins intensifs. Dans une étude récente
l'incidence de l'agitation chez les patients aux soins intensifs s'élévait jusqu'à 71% 40.
Control des nausées et vomissements
Chez les chiens, l'effet le plus étonnant commun à tous les neuroleptiques est
l'antagonisme du vomissements induit par l'apomorphine 41. Le même effet a été
démontré avec l'halopéridol chez l'homme 42. Cet effet antiémétique puissant dure
jusqu'à 64 heures chez les animaux après une administration sous-cutanée ou orale et
s'explique par un blocage des récepteurs D2 au niveau de la zone gâchette
chémoréceptrice par les butyrophénones 43. La liaison à ces récepteurs s'installe
rapidement et même avant l'effet antipsychotique.
2.3.6. Indications courantes pour le traitement d'émésis avec l'halopéridol
Nausées et vomissements postopératoires
L'halopéridol était utilisé comme antiémétique en clinique pour le traitement des
NVPO, mais il a été remplacé par d'autres antagonistes de la dopamine D2: le
dropéridol et la métoclopramide. Son efficacité, sa dose-réponse ainsi que la voie
d'administration optimale pour la prévention et le traitement des NVPO n'ont jamais
été établies. Les informations retirées des textbook sont pauvres. Certains auteurs
suggèrent 5 mg d'halopéridol par voie parentérale comme dose idéale pour le
traitement des NVPO 44. D'autres proposent 2 mg 45. En comparaison avec le
dropéridol, il a été décrit que l'halopéridol début son action plus rapidement (30 min
vs 2 h) avec une durée d'action plus courte (12 h vs 24 h) 45.
En chimiothérapie, le potentiel antiémétique des butyrophénones a été décrit pour la
première fois en 1973 46. L'halopéridol fut reconnu peu après comme le plus
« important » de ce groupe de médicament mais on ne disposait que de peu d'études
contrôlées 47. Aujourd'hui, après l'avénement des anti-sérotoninergiques, les
butyrophénones sont considérées comme modérément antiémétiques en
chimiothérapie. En revanche, ils gardent toujours leur place dans certains
recommandations, notamment lors des nausées et vomissements réfractaires 48. En
tant que médicament de réserve, des doses de 1 à 3 mg par voie intraveineuse toutes
les quatres à six heures ont été décrites comme efficaces 22.
Médecine palliative
Les textbook de médecine palliative suggèrent que des doses comprises entre 0.5 à 5
mg par voie orale toutes les quatres à six heures, sont les doses optimales pour le
traitement des nausées et des vomissements par l'halopéridol 49 50.
2.4. Pourquoi un regain d'intérêt par l'halopéridol comme antiémétique?
Le dropéridol est probablement la butyrophénone la mieux étudiée pour le contrôle
des nausées et des vomissements 51. Pourtant le dropéridol peut provoquer des
prolongations de l'intervalle QT 52. Selon la FDA (U.S. Food and Drug
Administration) plus de 100 patients dans le monde ont présenté des effets cardio-
vasculaires sérieux (torsades de pointes ou arrêt cardiaque) même après des petites
doses de dropéridol 53. En décembre 2001, la FDA a joint au feuillet
d'accompagnement du dropéridol un avertissement (black-box warning) où elle attire
l'attention sur ce risque d'arythmies sévères. Outre ces avertissements et
modifications d'emballage réalisées par le fabriquant du dropéridol (Akron
Pharmaceuticals), la direction des produits thérapeutiques du Santé Canada
(l'autorité fédérale canadienne qui règule les produits pharmaceutiques), en accord
avec la FDA, a envoyé une lettre adressée à tous les professionnels de la santé les
avertissant de la toxicité cardio-vasculaire du dropéridol injectable. Selon cette lettre,
plus de 60 cas avaient présenté une prolongation du temps QT avec des arythmies
sévères avec le dropéridol injectable. Au Canada, on a rapporté huit cas de décès
suite à l'utilisation du dropéridol avec des produits d'anesthésie, des relaxants
musculaires, des analgésiques narcotiques et des anxiolytiques 54. La littérature décrit
des cas de toxicité cardio-vasculaire associée à l'administration chronique ou à
l'administration de doses élevées de butyrophénones 55 56. En mars 2001, suite à une
analyse coût-bénéfice, Janssen-Cilag Ltd, le fabriquant du dropéridol (et de
l'halopéridol) a annoncé l'interruption de la production de tout produit contenant du
dropéridol. Néanmoins, le dropéridol est considéré comme une alternative efficace et
économique aux antagonistes 5-HT3 dans le traitement de l'émésis 57.
2.4.1. L'halopéridol comme alternative
L'halopéridol appartient à la même classe de butyrophénone que le dropéridol. Il est
probable que l'halopéridol soit également efficace sur l'émésis comme le dropéridol.
Pourtant son efficacité antiémétique et la dose-réponse n'ont jamais été étudiées de
manière systématique. Un argument souvent cité en faveur des médicaments
antiémétiques plus récents (antagonistes 5-HT3) est le risque apparent augmenté
d'effets indésirables associés à des anti-émétiques plus anciens, comme par exemples
les butyrophénones. En effet, un médicament agissant sur les récepteurs
dopaminergiques, comme l'halopéridol, a le potentiel de provoquer des symptômes
extrapyramidaux.
2.5. But de l'étude
L'objectif de cette revue systématique d'études randomisées et contrôlées est
d'évaluer l'efficacité anti-émétique de l'halopéridol et ses effets indésirables dans
divers contextes cliniques.
3. Methods
This quantitative systematic review was performed following QUORUM
recommendations 58.
3.1. Search Strategy
We identified relevant articles in all languages through searches in Medline, Cinahl,
HealthSTAR, Oldmedline, Embase, Lilacs, Web of Science, Biological Abstracts, and
the Cochrane Controlled Trials Register. We used the free text key words nausea,
vomit$, emesis, antiemetic, retch$, operati$ adj (post OR peri), surgery, anaesthesia OR
anesthesia, PONV, chemotherapy, radiation, radiotherapy, gastrointestinal, gastro-intestinal,
motion-sickness, motion-induced, and swinging sickness, the drug names and generics
haloperi$, haldol, halotest$, halperon$, butyrophenone, R 1625, aloperidol, serenace,
bioperido$, buterid$, stadol$, and the truncation random$. Electronic searches were
conducted until July 2003 and were complemented by screening bibliographies of
retrieved articles, textbooks and reviews. If there was ambiguity about data we
contacted the investigators and asked for clarification. The manufacturer of
haloperidol (Janssen-Cilag AG, Baar, Switzerland) was asked for relevant studies,
including unpublished data.
3.2. Study Selection
Relevant randomized trials compared haloperidol as an antiemetic (experimental
intervention) with another antiemetic, placebo or no treatment (control intervention)
and reported on dichotomous data as to the presence or absence of nausea or
vomiting or haloperidol-related adverse reactions. Reports using pseudo-
randomization or with historical controls, experimental studies in volunteers, or
animal studies were not considered. Studies that included less than 10 patients per
group were excluded 59. We included unpublished reports of valid randomized trials
when the description of methods and results was adequate.
3.3. Assessment of Validity
Retrieved reports were screened for inclusion by one of the authors (MB) who
excluded irrelevant papers at that stage. Each author then independently scored all
eligible reports, whether published or unpublished, for methodological validity
using the five-point Oxford scale that takes into account randomization, blinding,
and description of withdrawals 60. The minimum score of an included randomized
study was 1 and the maximum score was 5. As with similar previsious analyses 61,
consensus was reached by discussion.
3.4. Data Extraction
We obtained information on clinical setting, number of randomized and analyzed
patients, dose and route of administration of study drugs, efficacy endpoints, and
adverse effects from each included report. Data from different clinical settings were
analyzed separately. Nausea and vomiting were considered as different endpoints.
Retching was regarded as vomiting. For postoperative nausea and vomiting (PONV),
we distinguished between an "early" observation period (cumulative incidence to 6
hours after surgery), and a "late" period (cumulative incidence to 24 hours) 61. For
chemo- and radiotherapy, an "acute" period (cumulative incidence to 24 hours after
a cycle), was separated from a "delayed" period (beyond 24 hours) 62. Definitions on
adverse effects were taken as provided by the investigators. We only considered
dichotomous data on presence or absence of nausea or vomiting, or on presence or
absence of adverse effects. We ignored nausea scores, delay until first emesis
episodes, numbers of patients needing rescue treatment, and data on patient
satisfaction since these data were inconsistently reported. Since there is no gold-
standard antiemetic, there was a pre-hoc decision that the primary efficacy
information would come from trials with a placebo-control group.
3.5. Data Synthesis
We calculated relative benefit (RB) and relative risk (RR) with 95% confidence
interval (CI) for efficacy data and adverse effects, respectively 63. The relative benefit
(and relative risk ) is an effect size measure that is calculated as the difference in
percentages between the study drug and the comparator divided by the percentage
in the comparator group. For rare events (for instance, extrapyramidal reactions), we
used the Peto odds ratio (OR) that ignores trials with zero cells 64. We calculated the
number-needed-to-treat/harm (NNT/H) with 95%CI as an estimate of the clinical
relevance of a treatment effect. 65 NNTs were used to compare degrees of efficacy of
different doses, of the same dose during different observation periods, or of different
efficacy endpoints (anti-nausea versus anti-vomiting efficacy); however, this was
done only when control event rates of relevant subgroups were similar. We used a
fixed effect model to combine data across studies since the data appeared to be
clinical homogenous. Formal heterogeneity testing was done when data from at least
three trials were combined.
We tested for dose-responsiveness using two conservative assumptions as in
previous similar analyses 66. First, if one dose of haloperidol was not significantly
different from placebo (i.e. the 95%CI around the RB included 1), and higher doses
were consistently more effective than placebo, we regarded this as weak evidence of
dose-responsiveness. Second, if the 95%CI around the RB of a lower dose did not
overlap with the point estimate of the RB of a higher dose, we regarded this as strong
evidence of dose-responsiveness. We further assessed for consistency in the increase
in efficacy with increasing dose. If control event rates were similar, we used the NNT
for that purpose. A decrease in the NNT by more than 20% (for instance, from 5 to 4),
was regarded as a relevant improvement, and would therefore justify an increase in
the dose 66. The optimal dose of haloperidol would have an acceptable adverse effect
profile, and any further increase would not lead to a relevant improvement (i.e. a
decrease in the NNT >20%).
Analyses were performed on a Macintosh G4 using Microsoft Excel X for Mac,
and RevMan 4.2 (Cochrane Library software, Update Software, Oxford, United
Kingdom) with Virtual PC 6.
4. Results
4.1. Search Results
We screened 793 reports. Sixty-eight were potentially relevant for the purpose of this
study and of those, 48 were subsequently excluded for various reasons (Figure 1). We
eventually analyzed data from 21 randomized trials that were published in 20 full
reports 67-86; one report 78 contained data from two dose-finding studies. In these
trials, 1,397 adults received different regimens of haloperidol, 1,694 were controls.
Twelve reports (13 trials, 1,994 patients) were published between 1962 and 1988 67-78.
Eight unpublished reports (8 trials, 474 patients) were provided by the manufacturer.
The latter were phase II and III trials as part of the manufacturer's US registration
program for haloperidol as an antiemetic in the early 1980s 79-86. The registration trials
had very similar designs, and some of these studies were subsequently published in
full 78. Details on the trials can be found on
or treatment of PONV, for the treatment of emesis due to gastrointestinal diseases,
and for the control of chemo- and radiotherapy induced sickness. There were no
randomized trials on emesis in palliative care, AIDS, hyperemesis gravidarum or
motion sickness, and there were no trials in children.
4.2. Methodological Quality of the Included Studies
Median quality score was 3 (range, 1 to 4). All studies were randomized and blinded;
however in one only 67 the authors provided details on how randomization was
done, and in two only 67 75, the method of blinding was described.
4.3. Quantitative Data Synthesis
4.3.1. Prevention of PONV
Four trials published in three reports studied the efficacy of single-dose haloperidol
regimens for the prevention of PONV in 1,586 surgical patients (Table 1A) 70 72 78. Five
fixed IM doses (0.25, 0.5, 1, 2, 4 mg) and two fixed IV doses (4, 5 mg) were compared
with placebo. One report was on two dose-finding studies with an identical design
from the manufacturer's study program 78.
Data on prevention of nausea up to the sixth hour after surgery came from one large
study (1,089 patients) that tested haloperidol 5 mg IV (Figure 2A) 70. The average
incidence of early nausea with haloperidol was 16.4%, with placebo was 43.8%; RB
1.49 (95%CI, 1.37 to 1.62), NNT 3.7. Data on prevention of early vomiting came from
two studies that tested haloperidol 4 mg IV in 140 patients 72, and 5 mg IV in 1,089
patients 70 (Figure 2B). There was some evidence of dose-responsiveness.
Haloperidol's differential effect on nausea and on vomiting could be studied with the
5 mg dose (Figure 2A and 2B). The anti-nausea effect was more pronounced and the
95%CIs of the RBs did not overlap; NNT was 3.7 for anti-nausea efficacy and was 5.2
for anti-vomiting efficacy.
Three studies (2 reports, 497 patients) reported on antiemetic efficacy during 24
hours after surgery (Figure 2C and 2D). Two dose-finding studies tested haloperidol
0.25 to 4 mg IM 78. One tested haloperidol 4 mg IV 72. The lowest dose, 0.25 mg, was
not different from placebo (Figure 2C and 2D). Higher doses were more efficacious,
but there was no evidence of dose-responsiveness; RB point estimates were between
1.34 and 1.51 (NNT 3.2 to 4.5) for anti-nausea efficacy (Figure 2C), and were between
1.26 and 1.39 (NNT 3.9 to 5.1) for anti-vomiting efficacy (Figure 2D), independent of
the dose. Anti-vomiting efficacy of the 4 mg dose was tested both with the IV 72 and
the IM route 78; there was no evidence of any difference (Figure 2D).
4.3.2. Treatment of Established PONV
One published 67 and five unpublished trials 79-82 86 reported on the therapeutic
efficacy of single-dose haloperidol regimens in 408 nauseous or vomiting surgical
patients (Table 1B). Study designs were identical; tested regimens were 1 and 2 mg
IM, and observation periods were 30 minutes and two to four hours. Haloperidol 1
mg IM was not anti-nauseous during the first 30 minutes after administration, 2 mg
IM was (Figure 3A). Neither dose was efficacious against vomiting during the same
observation period (Figure 3B). However, both 1 and 2 mg IM prevented further
vomiting during two to four hours; with the 1 mg dose, RB was 1.53 (95%CI, 1.17 to
2.00), NNT 6, with the 2 mg dose was 1.73 (95%CI, 1.11 to 2.68), NNT 4 (Figure 3C).
4.3.3. Nausea and Vomiting Related to Gastrointestinal Diseases
Two published 68 75 and three unpublished trials 83 84 85 reported on the efficacy of
haloperidol 1 and 2 mg IM for the treatment of nausea and vomiting due to
gastrointestinal diseases in 261 patients (Table 1C). Inclusion criteria and patient
demographics were poorly described. However, study designs were identical; the
efficacy of two IM doses, 1 and 2 mg, was tested during four observation periods, 0-
2, 2-4, 4-8, and 8-12 hours (Figure 4A and 4B). Both regimens were efficacious during
all observation periods (with the exeption of 2mg during the 0-2 hour period), and
efficacy decreased consistently over time. For the cumulative incidence of vomiting
over 12 hours, there was some evidence of increased efficacy with the 2mg dose
4.3.4. Nausea and Vomiting Related to Chemo- and Radiotherapy
Five published trials tested the efficacy of haloperidol in 189 patients undergoing
chemotherapy, 71 73 74 76 77 and one in 24 patients undergoing radiotherapy (Table 2) 69.
None was sponsored by the manufacturer. Five had a cross-over design. The regimen
contained cisplatin in four chemotherapy trials. Six different oral and parenteral,
single- or multiple dose haloperidol regimens were tested against two different
metoclopramide regimens in two trials, against prochlorperazine, delta-9-
tetrahydrocannabinol, benzquinamide or placebo in one trial each. No comparison
was tested more than once. In one small chemotherapy trial, haloperidol was
superior to benzquinamide to prevent acute vomiting 73. In the radioherapy trial,
haloperidol was superior to placebo to prevent delayed vomiting 69. Details on the
trials can be found on ().
4.4. Adverse Effects in Placebo-Controlled Trials
Twelve placebo-controlled trials from the postoperative and gastrointestinal settings
reported on a large variety of adverse effects. All trials tested single dose haloperidol
4.4.1. Extrapyramidal Symptoms
Presence or absence of extrapyramidal symptoms was reported in two studies with
data on 1,842 surgical patients 70 78. One of those trials tested haloperidol 0.25 to 4 mg
IV 78. Of 258 patients randomized to haloperidol, one who received 4 mg had mild
puckering of the lips; the original authors considered this to be evocative for
extrapyramidal symptoms 78. There were no such events in the 99 controls. In the
other trial, there were no extrapyramidal symptoms in 548 surgical patients who had
received haloperidol 5 mg IV and in 541 controls 70. Thus, of 806 patients exposed to
a single IV 0.25 to 5 mg haloperidol dose, one (0.1%) had extrapyramidal symptoms
with 4 mg. No other trial reported on extrapyramidal symptoms.
4.4.2. Sedation and Drowsiness
Sedation or drowsiness was reported in two trials, although in none, clear definitions
of these outcomes were provided. In one large surgical trial, 239 of 548 patients
(43.6%) who had received haloperidol 5 mg IV were reported to be sedated
postoperatively compared with 113 of 541 (20.9%) controls; RR 2.09 (95%CI, 1.73 to
2.52), NNH 4.4 (95%CI, 3.6 to 5.8) 70. In one gastroenterology trial, 1 of 55
patients (1.8%) who had received 1 mg intravenous haloperidol was reported to be
drowsy as compared with none of 50 controls (odds ratio, 6.75 [95% CI, 0.13-342]) 68.
4.4.3. Arterial Hypotension
Five surgical studies reported on the presence or absence of episodes of arterial
hypotension 80 82 79 86 72. Hypotension, as defined by the investigators, occurred in 17
of 224 (7.6%) patients treated with haloperidol 1 to 4 mg as compared with 16 of 205
(7.8%) controls; OR 1.05 (95%CI, 0.49 to 2.22).
4.4.4. Other Adverse Effects
Other adverse effects that were reported in placebo-controlled trials were arterial
hypertension 78 72, blurred vision 78 68, chills and shivering 78, bradycardia 78 80,
tachycardia 86 75, and nystagmus 67. None of these was significantly associated with
administration of haloperidol. There were no reports of cardiac arrhythmias.
4.5. Adverse Effects in Active-Controlled Trials
Four chemo- and radiotherapy trials reported on presence or absence of adverse
effects 71 74 76 77. There was a large variety in the rates of adverse effects with both
haloperidol and control regimens. For instance, extrapyramidal symptoms, reported
as twitching, dystonia, akathisia, or rigor happened in 4% to 100% of patients
receiving haloperidol, and in 0% to 50% of those receiving metoclopramide or
prochlorperazine 71 76. Other adverse effects that happened more frequently with
haloperidol were sedation, fatigue, and drowsiness. None was significantly
associated with administration of haloperidol. There were no reports of cardiac
5. Discussion
Haloperidol is antiemetic at doses that are considerably lower than those used for the
treatment of psychosis or the control of agitation. The available evidence from
published and unpublished randomized trials suggests that it may not even be
worthwhile to increase the dose above 1 or 2 mg to prevent PONV. With these very
low doses, the degree of haloperidol's antiemetic efficacy is markedly strong and
comparable with many other antiemetic interventions that are used for the control of
PONV 61 87. It may be inferred from the 4 mg data (the only dose administered by the
IM and IV routes), that there is little difference between these two routes of
administration. There is also strong evidence that low-dose haloperidol is effective
for the control of emesis due to various gastrointestinal diseases. For chemo- and
radiotherapy, however, the evidence was less clear. In the chemotherapy setting,
several haloperidol regimens were tested against different control regimens, placebo
controls were lacking, endpoint reporting was inconsistent, and only a limited
amount of clinically homogenous efficacy data could be extracted from the trials. No
meaningful conclusion could be drawn. In the radiotherapy setting, valid data that
supported the antiemetic efficacy of haloperidol came from only one small trial.
Until recently, droperidol was perhaps the most widely used dopamine antagonist
for the control of nausea and vomiting. Droperidol, however, has been suggested to
be cardiotoxic 55. The FDA has changed the labeling requirements for droperidol
injections, now including a Black Box Warning 53. This severe restriction included
both chronic high-dose droperidol regimens that are used to treat psychosis and
severe agitation, and single, low-dose administrations for the control of emesis.
Haloperidol is a butyrophenone similar to droperidol, and these drugs have the
potential to prolong the QT interval with the risk of subsequent torsades de pointes and
sudden cardiac death. 88 Observational studies have suggested that high-dose
haloperidol may cause lethal cardiac arrhythmias in psychiatric patients 89 90. High-
dose haloperidol has also been suggested to cause QT prolongation in critically ill
patients in the intensive care unit 56 91, or postoperatively 92. In all these uncontrolled
observations, haloperidol was administered in anti-psychotic doses that often
exceeded several hundred milligrams per day. The QT-prolonging effect of anti-
psychotic drugs is dose-dependent 89 90. There is evidence from this systematic review
that for the control of emesis, haloperidol (similar to droperidol) 51 may be useful in
much lower doses than for the control of psychosis or agitation. In contrast to
droperidol, haloperidol's use has never been restricted. This raises the question as to
whether haloperidol is any more or less cardiotoxic than droperidol, and whether
low-dose haloperidol could perhaps replace low-dose droperidol as an anti-emetic.
In this meta-analysis, 1,397 patients received different regimens of haloperidol, and
there was no reports of cardiac arrhythmias. This result has to be interpreted
cautiously. The number of analyzed patients may have been insufficient to detect
rare adverse events. However, when the antiemetic efficacy of low-dose droperidol
was reviewed systematically, there were no reports of cardiac toxicity in 5,351
patients 51. If these randomized trials reported correctly on the absence of
arrhythmias, we may be 95% confident that with low-dose haloperidol (0.25 to 5 mg
IV), cardiac arrhythmia does not occur more often than in 0.21%. 93 We cannot
exclude that in some patients that in some patients QT prolongation did occur but
was not diagnosed. We cannot exclude, that episodes of torsades de pointes and even
cardiac arrest occurred but were not reported. Most trials were relatively old, and
monitoring of cardiac function may not have been an important feature at that time.
There was no intention to include observational data on possible cardiac toxicity of
haloperidol into our analyses. Based on the available evidence from randomized
controlled trials, it is impossible to conclude whether there is any more or less risk of
cardiac arrhythmias with low-dose haloperidol versus low-dose droperidol. Finally,
it must be emphasized that many drugs that are used in anesthesia may prolong the
QT interval, for instance, thiopental, isoflurane, sevoflurane or pancuronium 94. Also,
not all QT prolongation is dangerous and will lead to torsades de pointes arrhythmia. It
is likely that other risk factors such as electrolyte abnormalities or metabolic
conditions must be simultaneously present to provoke cardiac arrhythmia.
A further concern with butyrophenones is their potential to cause neurologic adverse
effects. The trials analyzed here provided some evidence that haloperidol even at
low, antiemetic doses may cause sedation and, in very rare instances, extrapyramidal
symptoms. One in four patients will be sedated with a single dose of haloperidol 5
mg. This suggests that 5 mg is too high a dose to control nausea and vomiting in, for
instance, patients undergoing ambulatory surgery. Efficacy data also suggested that
it was not worthwhile to increase doses above 2 mg to achieve a relevant antiemetic
effect. In two trials, 806 adults received a single IV dose of haloperidol 0.25 to 5 mg,
and, according to the original authors interpretation, one had symptoms that were
suggestive of an extrapyramidal reaction. Extrapyramidal reactions with low-dose
droperidol were reported only in children. 51 In the chemotherapy setting, where
much higher and repetitive doses of haloperidol were used, the risk of
extrapyramidal symptoms was increased, but these symptoms were also reported
with metoclopramide and prochlorperazine. We did not find any association of other
adverse reactions with the administration of haloperidol.
Eight trials (35% of all trials) with data from 474 patients (19% of all patients) were
unpublished. All were phase II and III trials that originated from the manufacturer's
registration program. Inclusion of this unusually large number of unpublished data
provided a methodological challenge. Advocates of the inclusion of unpublished
material into meta-analyses argue that unpublished trials are more likely to report
negative results, and therefore, every effort should be undertaken to unearth
unpublished data to challenge publication bias. We were unable to confirm this
assumption, since all unpublished trials reported on positive results. Data on the
treatment of established PONV came from five unpublished trials that included 346
patients and from one published trial that included 62 patients. Without these
unpublished valid data we would not have much knowledge about the role of
haloperidol in the treatment of nausea and vomiting in surgical patients. Surely, the
manufacturer's decision to make data available at our request may be seen as a
laudable contribution to challenge publication bias. However, it is of note that
several decades passed until these valid data were eventually unearthed and made
accessible. Critics of the inclusion of unpublished material into meta-analyses may
argue that these data have not undergone peer review and that their scientific
validity remains unproven. For the purpose of our analyses, all data, whether
published or unpublished, underwent the same rigorous process of critical appraisal.
Several unpublished (and published) studies did not satisfy our high methodological
standards, and thus were excluded from the analyses.
Our systematic review has several limitations, and they are related to weaknesses in
the original studies. First, trial design was sometimes unsatisfactory. In some studies,
data on long-term efficacy were sparse. Data on repetitive dose regimens were
sparse. These would be especially important in settings where patients are likely to
need prolonged antiemetic therapy such as in palliative care. Second, the majority of
these trials were of limited methodological quality. They did not specify the method
of randomization or of concealment of treatment allocation, and only a few reported
on the method of blinding. Often it was unclear if this was due to inadequate trial
design or inappropriate data reporting. Most trials were conducted in the early
1980s, when recommendations for reporting of study results did not exist yet. 95
Finally, most studies were of limited size and observation periods were too short to
identify with confidence adverse effects with single low-dose haloperidol regimens.
This systematic review may serve as an evidence base to define a rational research
agenda. If haloperidol is to be considered as a true alternative to droperidol, several
issues need to be addressed. There were no direct comparisons between low-dose
droperidol and low-dose haloperidol, but we may assume from indirect comparisons
51 that both drugs exert about the same degree of antiemetic efficacy. We need to
know whether haloperidol exerts the same synergistic effect with 5-HT3 receptor
antagonists as droperidol does 96. Also, as the control of opioid-induced nausea is a
particular concern in surgical patients 97, and since droperidol, when given
concomitantly with morphine in a PCA-pump, has shown consistent anti-nausea
efficacy 98, it may be worthwhile to test the role of haloperidol for the control of
opioid-induced nausea. Finally, there was a lack of valid data on the antiemetic
efficacy of haloperidol in other settings where emesis is a problem, and there was a
complete lack of relevant pediatric studies. Direct data from children are needed to
avoid extrapolation of results from adults to children.
In conclusion, data from systematically searched, valid published and unpublished
randomized trials suggest that haloperidol is antiemetic at doses much less than that
used to treat psychiatric disorders. For the prevention and the treatment of PONV,
and for the control of nausea and vomiting due to gastrointestinal diseases,
parenteral single doses between 1 and 2 mg are efficacious with minimal toxicity.
Extrapyramidal symptoms are rare, there is no sedation, and cardiac arrhythmia has
not been reported. Haloperidol is an inexpensive drug compared to the new 5-HT3
antagonists. Haloperidol may be an interesting alternative to more expensive
antiemetic drugs, especially in health care systems with scarce resources.
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7. Tables and figures
Single-dose haloperidol regimens in surgery and gastrointestinal
Haloperidol for chemo- and radiotherapy- related nausea and vomiting.
Figure 1.
Flow chart of retrieved, excluded and analyzed reports.
Figure 2.
Prevention of postoperative nausea and vomiting with parenteral
haloperidol regimens.
Figure 3.
Treatment of established postoperative nausea and vomiting with
single-dose haloperidol regimens.
Figure 4.
Treatment of nausea and vomiting related to gastrointestinal related
with intramuscular single-dose haloperidol.
Source: https://doc.rero.ch/record/4830/files/1_these-B__ttnerM.pdf
International Journal of Current Pharmaceutical Research Academic Sciences Vol 5, Issue 4, 2013 Research Article POTENTIOMETRIC CARBON PASTE ISEs FOR DETERMINATION OF FLUOXETINE HYDROCHLORIDE IN PHARMACEUTICAL PREPARATIONS EMAD M. HUSSIEN, NAHLA S. ISMAIL AND FATMA M. ABDEL-GAWAD National Organization for Drug Control and Research, Egypt. Email: [email protected]
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