Haloperidol in palliative care

Pal iative Medicine 2004; 18: 195¡/201
Haloperidol in palliative care
Jane Vella-Brincat and AD (Sandy) Macleod Nurse Maude Hospice, Christchurch
Haloperidol is one of 20 'essential‘ medications in palliative care. Its use is widespread in
palliative care patients. The pharmacology of haloperidol is complex and the extent and
severity of some of its adverse effects, particularly extrapyramidal adverse effects (EPS),
may be related to the route of administration. Indications for the use of haloperidol in
palliative care are nausea and vomiting and delirium. Adverse effects include EPS and QT
prolongation. Sedation is not a common adverse effect of haloperidol. It is important that
palliative care practitioners have a comprehensive understanding of the indications, doses,
adverse effects and pharmacology of haloperidol. This review is intended to address these
issues. Pal iative Medicine 2004; 18: 195¡/201
Key words: cytochrome P450; extrapyramidal adverse effects; haloperidol; QT interval prolongation
review summarizes the established literature on haloper-idol and suggests the rationale for its safe and effective Haloperidol, a butyrophenone antipsychotic (neurolep- use in palliative care.
tic, major tranquillizer) was first used in 1957.1 It wascreated by Dr Paul Janssen who was looking forcompounds with morphine-like activity. He first discov- ered the analgesic dextromoramide, then a compoundwith morphine and phenothiazine-like properties which, In the 1950s haloperidol was believed to be quickly after further modification yielded compounds with deactivated by hepatic enzymes, to have no active neuroleptic properties, including haloperidol (Figure 1).
metabolites, and to induce its own metabolism.1 It is Dr Paul Janssen (Figure 2) revolutionized psychiatric now known that haloperidol is extensively metabolized care and is credited with the creation of five WHO by hepatic enzymes (partially by members of the CYP450 family) and that there are active and toxic metabolites1,3 Haloperidol has been used predominately in the (Figure 3). Only 1% is excreted unchanged in the urine.3 treatment of schizophrenia and related psychoses (mania, Haloperidol's metabolism is complex although some delirium). Indications for use in palliative care are nausea consider it to be the least complicated of the antipsycho- and vomiting, and delirium. It is considered internation- tics with fewer metabolites than most.4 Its metabolism ally to be one of 20 essential medications in palliative consists of glucuronidation to an inactive metabolite (50¡/60%), reduction (and back oxidation) to reduced- Haloperidol can be administered orally, intramuscu- haloperidol (an active metabolite) (23%) and N-deal- larly, subcutaneously or intravenously. Its use by the kylation to a pyridium metabolite (a toxic metabolite) intravenous route is unlicensed in many countries.
(20¡/30%).3 Other metabolites of haloperidol are prob- Haloperidol has complex pharmacology, which has not ably not of clinical relevance.
as yet been fully elucidated. The pharmacokinetics and Although in vitro studies suggest that the cytochrome pharmacodynamics of haloperidol following administra- P450 2D6 enzyme (CYP2D6) is only minimally involved tion by different routes are important considerations in haloperidol's metabolism, in vivo studies suggest when it is used in palliative care patients as the side-effect otherwise. CYP2D6 is genetically polymorphic with 5¡/ profile of haloperidol is significantly determined by its 10% of Caucasians and 1¡/2% of Asians/Polynesians route of administration.
being slow metabolizers of CYP2D6 substrates.4 It is Because of the ‘age' of this medication and its ‘out of noninducible.4 Nonslow metabolizers of CYP2D6 sub- patent' status, relatively few good clinical trials have been strates can be rendered slow metabolizers by the admin- performed, yet its clinical use is widespread. Its optimal istration of CYP2D6 inhibitors e.g., paroxetine.4 Slowmetabolizers of CYP2D6 substrates have 30% higher usefulness in clinical practice has been diminished haloperidol, 80% higher reduced-haloperidol plasma because of its poor evidence base. This pharmacological concentrations and 70% higher ratios of reduced-halo-peridol to haloperidol than non-slow metabolizers.3 The Address for correspondence: Jane Vella-Brincat, Nurse Maude Hospice, 35 Mansfield Avenue, Christchurch, New Zealand.
effect of CYP2D6 metabolizer status is more pronounced on reduced-haloperidol concentrations than on concen-

196 J. Vella-Brincat and A.D. (Sandy) Macleod variable pattern.3 Haloperidol concentrations reachsteady state after around one week while reduced-haloperidol concentrations take around four weeks.3 Insome cases the concentrations of reduced-haloperidolmay exceed that of the parent.4 Reduced-haloperidol isnot detected after intravenous haloperidol administrationfor even longer than after oral administration whichsuggests that first pass metabolism, at least initially, isresponsible for increased reduced-haloperidol concentra-tions.9 Haloperidol's main mechanism of action is via dopa- mine receptor antagonism in the central nervous system.
It exhibits partial selectivity for dopamine 2 receptorsparticularly in the corpus striatum where it is thought toexert its antipsychotic activity.10 It also acts on somealpha adrenoreceptors (a-1), opioid (sigma), muscariniccholinergic, histamine and serotonin receptors. Its ac-tions on 5-HT2 receptors occur at high doses. Long termtreatment with haloperidol in animals results in upregu-lation of dopamine receptors. Actions at sigma-opioidreceptors may add to dopamine blockade in producingdystonic reactions to haloperidol.10 There is a linear relationship between the dose of Figure 1 Dr Paul Janssen, 1926 ¡/2003.
haloperidol administered and plasma concentrations,although as mentioned earlier there is large interindivi- trations of other metabolites, suggesting that CYP2D6 is involved in the back oxidation of reduced-haloperidol to Reduced-haloperidol has low affinity for dopamine 2 and dopamine 3 receptors but equal affinity for sigma- A correlation between steady state haloperidol con- opioid receptors to the parent drug.3,9 It has a clinical centrations and CYP2D6 substrate metabolizer status is, effect and exhibits 10¡/20% of the activity of haloperidol however, only seen at doses of less than 20 mg as are in animals.4 A correlation between reduced-haloperidol routinely used in palliative care.3 At higher doses no concentrations and clinical outcome has been demon- correlation is seen, perhaps due to cytochrome P450 3A4 strated in humans. The interconversion between reduced- (CYP3A4) involvement in reduction/back oxidation to haloperidol and haloperidol is subject to large interindi- reduced-haloperidol at doses greater than 20 mg.3 vidual variation which may explain the curvilinear As a result of this variable metabolism, haloperidol has response between haloperidol and clinical effect seen in a variable half-life (12¡/35 hours).5 The pharmacokinetic some patients.4 The exact clinical significance of reduced- parameters are outlined in Table 1. Orally administered haloperidol however remains unclear.
haloperidol is subject to first pass metabolism and theoral to parenteral conversion most commonly used is ahalf to two thirds.5 ¡ 8 Reduced-haloperidol is not detected in plasma until several hours after oral haloperidol administration.9 Theratio of reduced-haloperidol to haloperidol concentra- The indications for haloperidol in a study of hospitalized tions over the range 0¡/300 mcg/L follows a sigmoid but patients were those of delirium (69%), psychosis (11%), Figure 2 Discovery of haloperidol.
Haloperidol in palliative care 197 Figure 3 Metabolism of haloperidol and reduced-haloperidol.
affective disorders/dementia (11%) and nausea/vomiting (9%).11 This suggests that its main indication in the The incidence of delirium is 25¡/85% in hospitalized general hospital population is in the management of cancer/AIDS patients,6,16,17 and 65¡/85% in terminally ill delirium and other psychiatric disorders. However, in the patients.18,19 It is associated with high morbidity and palliative care setting the more common indication is mortality, and therapy is often suboptimal.6,20 It is nausea and vomiting. Delirium, despite its high preva- proposed that causative factors induce a failure of high lence in the dying and the fact that haloperidol is the energy metabolism at an inter- and intraneuronal level drug of first choice, is a less common indication.2 resulting in a cholinergic/dopaminergic imbalance.20Haloperidol, as a dopamine antagonist of dopamine 2 Nausea and vomiting
receptors in the basal ganglia and of the limbic parts of The emetogenic process involves two distinct areas of the the forebrain, corrects the acetylcholine/dopamine sys- brain ¡/ the chemoreceptor trigger zone (CTZ) and the tems imbalance.20 vomiting centre (VC). Various neurotransmitters are In palliative care the aetiology of delirium is usually found in these areas including dopamine, acetylcholine, multifactorial. Organ failure18,20 and delirium-inducing gamma aminobutyric acid (GABA) and serotonin.12 The medications such as opioids22 are frequently implicated.
CTZ in particular, is dopamine-rich. It is stimulated by Reversal of the aetiology in the terminally ill may not drugs, toxins and biochemical imbalances. Haloperidol always be possible, however palliation of the symptoms is acts at dopamine 2 and other receptors in various regions a feasible clinical goal. Medication is often a component of the brain as an antagonist. Antagonism of dopamine 2 of delirium management and haloperidol remains the receptors in the CTZ results in alleviation of nausea and drug of first choice. This may be challenged by the newer atypical antipsychotics, but to date clinical studies have The evidence of efficacy of haloperidol as an antie- yet to establish their superiority except in terms of the metic, although based on sound pharmacology, is not adverse effects profile.16 substantiated by any randomized controlled trials. The Haloperidol is considered by many to be the gold literature which does support the antiemetic properties of standard of delirium therapy in the medically ill.16,17,20,21 haloperidol consists of case series and reports.13 When It is effective and has few anticholinergic, sedative,16 used in combination with ondansetron, haloperidol has autonomic or hypotensive effects and can be given both been reported to alleviate intractable nausea and vomit- parenterally and orally.21 Double blind, randomized ing of advanced cancer (n¾/1 study).14 Clinical experi- controlled trials are, however, lacking.20 There have ence indicates that haloperidol is an effective antiemetic been no placebo controlled trials of drugs for the in the prophylaxis and treatment of opioid-induced treatment of delirium that use modern Diagnostic and nausea and vomiting.15 Statistical Manual (DSM) terminology or valid delirium Anecdotally antiemetic doses of haloperidol are gen- assessment measures.21 There are ethical problems in erally 1.5¡/3 mg orally (or parenteral equivalent) over 24 treating a life-threatening condition such as delirium with hours. Higher doses appear to result in little if any placebo and in acquiring informed consent from delirious therapeutic advantage. Haloperidol may be given in a patients, thus it is unlikely that such trials will be single night time dose (because of its long half-life), conducted. It may, however be argued that it is unethical which is often a compliance advantage in palliative care not to do such studies. There have been several uncon- trolled trials and case reports. A single double-blind Table 1 Pharmacokinetic parameters of haloperidol1,5,8
12 ¡/35 hours (average 16 hours) Oral availability 44 ¡/75% (average 60%) Volume of distribution Time to steady state Time to haloperidol measurable in plasma 1¡/1.5 hours (oral), immediate (iv), immediate (im) Time to peak plasma concentration 4¡/6 hours»/18 hours (oral), 5¡/15 mins (iv), 20¡/40 mins (im) Slow exponential (oral), steep over 1 hour then slow exponential (iv), like iv (im) 198 J. Vella-Brincat and A.D. (Sandy) Macleod comparator trial (in hospitalized AIDS patients) has sigma-opioid receptors.10 While haloperidol has been confirmed the efficacy of haloperidol and chlorproma- reported to cause a higher incidence of EPS, including zine, but not lorazepam.21 acute dystonia, pseudo-parkinsonism, akathisia and Delirium should not be treated with a benzodiazepine tardive dyskinesia, than other antipsychotics, this has unless it is as an adjunct to primary therapy with not been documented in well designed trials.1,3 This is haloperidol. If delirium is the correct diagnosis, haloper- compounded by what some researchers describe as the idol should be used and sole therapy with benzodiaze- ‘primitive state' of EPS-rating tools.25 Haloperidol is pines should be avoided. By contrast, when used as sole considered safe in the treatment of delirium but dystonic therapy benzodiazepines may aggravate rather than reactions and an initial worsening of symptoms have alleviate delirium.11,16 In combination, benzodiazepines been reported rarely.26 act synergistically with haloperidol and can result in Early evidence in acutely schizophrenic patients treated greater clinical effect than haloperidol alone. The seda- with haloperidol found no relationship between reduced- tive and anxiolytic properties of benzodiazepines are haloperidol concentrations and haloperidol-induced sometimes useful in delirious patients.19,20 Benzodiaze- EPS.9 This has been recently refuted in animal studies27 pines decrease the activity of the dopaminergic system by and in humans.3 In addition, reduced-haloperidol has their enhancing action on pre- and postsynaptic GABA- equal affinity to sigma-opioid receptors to haloperidol inhibitory systems.20 The combination results in an but a much lower affinity for dopamine receptors.10 The additive correction of the acetylcholine/dopamine system incidence and severity of haloperidol-induced adverse imbalance seen in delirium as demonstrated in a con- effects are associated with both high reduced-haloperidol trolled study comparing haloperidol alone with haloper- and high haloperidol concentrations and a high ratio idol in combination with a benzodiazepine in medically between the two. Reduced-haloperidol concentrations, in ill delirious patients.22 particular correlate with the incidence and severity of Dosing of haloperidol in the treatment of delirium is EPS.3 In a study of acutely schizophrenic Chinese titrated to effect. In palliative care patients a useful patients given 10 mg of haloperidol it was found that regimen may be 0.5¡/1.5 mg orally (mild), 1.5¡/5 mg reduced-haloperidol concentrations were significantly orally (severe) and 10 mg subcutaneously or intrave- higher in the 30 out of 48 patients who experienced nously (very severe). These doses may be repeated every EPS than in the 18 patients who did not.2 The incidence 30¡/40 minutes until symptoms are alleviated. Once of haloperidol-induced EPS is higher in slow metaboli- control has been achieved the maintenance dose is 50% zers of CYP2D6 substrates, suggesting a link between the of the daily dose required to achieve control, and is CYP2D6 metabolizer status (either genetically deter- usually between 1.5 and 20 mg orally per day.24 mined or due to drug interaction) of the patient andthe incidence and severity of haloperidol-induced EPS.3 In some patients the emergence of haloperidol-induced The side-effect profile of haloperidol includes extrapyr- EPS may be due to patient characteristics: in Saudi- amidal side-effects (EPS), tardive dyskinesia and QT Arabian schizophrenic patients haloperidol administra- interval prolongation. When haloperidol was first used in tion resulted in EPS in all 12 patients studied within 16¡/ the treatment of schizophrenia in the late 1950s it was 50 hours of administration.28 Haloperidol concentrations thought to be almost devoid of anti-adrenergic and were 2.5¡/14 mg/L (mean 6.5 mg/L), which is within the autonomic effects,1,8 although tardive dyskinesia was a reported normal range. In terminally ill delirious AIDS recognized problem on prolonged use.1 Later, in the patients treatment with high dose intravenous haloper- 1970s when high or mega dose haloperidol was being idol (in combination with lorazepam) resulted in halo- used in the treatment of schizophrenia resistant to other peridol-induced EPS in 50% of cases, although clinical antipsychotics, it was reported to have few adverse efficacy was good.29 The effect of the AIDS virus on effects.1 When given intravenously haloperidol had subcortical structures of the brain increases sensitivity to virtually no adverse effects on neurological, cardiac, the effects of haloperidol dopamine receptor blockade respiratory, renal, hepatic or bone marrow systems.9 High dose intravenous haloperidol is generally consid- The atypical antipsychotics such as olanzapine, risper- ered safe in most patients. Doses of up to 240 mg in 24 idone and quetiapine antagonize many CNS neurotrans- hours have been administered intravenously to acutely mitter receptors. They may cause less EPS than delirious patients with good effect and minimal adverse haloperidol although this is dose dependent.16,17,19 There have been no randomized controlled studies comparingthe atypical antipsychotics with standard ones in delir- ium.16 Studies in schizophrenic patients have reported The EPS of haloperidol are caused by dopamine block- lower EPS with these newer agents.19 Clinical studies ade in the distal ganglia,1 and perhaps by blockade of comparing haloperidol with olanzapine or quetiapine in Haloperidol in palliative care 199 delirious patients resulted in EPS in five of eleven required intravenous sedation reported that 86% received patients given haloperidol in one study and two of eleven haloperidol with diazepam intravenously, 12% diazepam in another. No EPS were seen in those treated with alone and 1.5% haloperidol alone.8 The dose of haloper- idol ranged from 2 to 60 mg (mean 21 mg) over 24 hours.
In the 1970s parenteral (intramuscular or intravenous) Thirty-seven per cent of the 132 patients experienced haloperidol was reported to cause fewer EPS than oral dystonic reactions. The authors of this study recommend haloperidol even at high doses.30 In a retrospective chart that when intravenous haloperidol is used, a regular oral review of 238 patients mentioned earlier in this paper, anticholinergic should be administered.
where 69% of patients were given haloperidol for There are several theories as to why parenterally delirium, 11% for psychosis, 9% for nausea and vomiting, administered haloperidol causes less EPS than oral 6% for affective disorder and 5% for dementia, the data were subanalysed by the route of administration.11 Theincidence of haloperidol-induced EPS following intrave- . The parenteral route is used more commonly in nous haloperidol (0.5¡/90 mg over 24 hours) and oral delirium than the oral route. In delirium the dopa- haloperidol (0.5 ¡/20 mg over 24 hours) was 7.2% and mine/acetylcholine ratios are altered leading to a lower 22.6% respectively. In addition, in a pilot study of ten susceptibility to EPS11,31 (and lower acetylcholine patients given haloperidol either intravenously (4) or concentrations seen in delirium protect against EPS).
orally (6) the former had significantly less severe EPS . Delirium occurs in a normal cross-section distribution than the latter.31 Lawson et al. in 1962 gave intravenous of the population, while schizophrenic patients may haloperidol to 50 obstetric patients and reported only have pre-existent subtle damage to their basal ganglia, two cases of mild EPS;23,31 Adams et al. studied 20 placing them at higher risk of EPS.
delirious patients treated with intravenous haloperidol at . Oral haloperidol undergoes first pass metabolism resulting in an increase in reduced-haloperidol peak /240 mg over 24 hours and reported no EPS at all.31 Extensive clinical experience of the use of concentrations which results in more EPS.11,31 haloperidol intravenously in seriously ill, delirious med- . EPS do not emerge until 12 to 16 hours after an ical and surgical patients supports a lack of EPS by this intravenous dose of haloperidol, reflecting either a route.11,23,31 High dose parenteral haloperidol was also gradual onset of metabolic changes in the CNS, a reported to cause less EPS than low dose parenteral delay in distribution into the CNS5 or time for haloperidol possibly related to an increase in the antic- concentrations of reduced haloperidol to reach an holinergic activity of haloperidol at high parenteral doses (thereby antagonizing EPS) or the existence of an EPS . The duration of use of haloperidol in delirium is generally brief, usually less than a week, so perhaps the an upper limit and lower threshold of haloperidol concentrations for eliciting EPS.30 The EPS exposure is too limited for the neurological side effects scales used in the above studies were based on a modified version of a scale developed by Simpson and Anguswhere 10 items (arm dropping, shoulder, elbow and wristrigidity, head dropping, glabellar tap, tremor, salivation, akinesia and akathisia) were rated on a 0¡ Haloperidol's ability to prolong the QT interval has scores were calculated by adding individual scores for prompted some authors to suggest that ECG monitoring should occur when intravenous haloperidol is used.16 In combination with benzodiazepines the incidence of Multiforme ventricular arrhythmias (torsades de pointes) haloperidol-induced EPS is so low it is almost nonexis- have been reported with the use of intravenous haloper- tent. In delirious patients treated with intravenous idol, even with continuous infusion, and are considered a haloperidol alone (4 patients) and in combination with risk of high dose haloperidol by any route.11 This risk is diazepam (10 patients), only 1 of 14 developed more than relative, with each medication accorded an adjusted odds minimal EPS.23 The average EPS ratings were 2.3 and ratio (AOR) for QT lengthening.33 The AOR of haloper- 0.125, respectively, which was statistically significant idol rates is 3.6 (0.96¡/13.6), thioridazine 5.3, risperidone 1.8 and droperidol 6.7. Other risk factors for QT /0.001). Benzodiazepines decreased the incidence of intravenously administered haloperidol-induced EPS prolongation include long QT syndrome (genetic), elec- from low to almost zero. An explanation for this trolyte abnormalities (especially hypokalaemia), cardiac protective effect may be found in the mechanism of disease, female gender and older age, thus the influence action of benzodiazepines as a clinically effective treat- of medication may or may not be of relevance.33 It is ment of acute dystonic reactions.32 difficult to determine the true risk for torsades de pointes There are studies which refute the above contentions. A and sudden cardiac death related to haloperidol. There study of 132 severely disturbed Australian patients who would appear to be a risk, but how to estimate this in the 200 J. Vella-Brincat and A.D. (Sandy) Macleod severely physically ill delirious or terminal patient is Finally the decreased incidence and severity of halo- peridol-induced EPS after parenteral compared with oralhaloperidol is fairly well established in anecdotal reportsand small studies. The mechanism for this has still to be elucidated. If EPS are a result of high reduced-haloper- Although sedation has been reported with haloperidol, idol concentrations which are to some extent a result of this is a rare adverse effect and many clinicians consider CYP2D6 and CYP3A4 metabolism (including first-pass), the drug to be nonsedating. It has, in the past, been large peaks of reduced haloperidol concentrations may termed a ‘stimulant' tranquillizer. Doses as high as occur with oral but not parenteral haloperidol adminis- 350 mg over 24 hours have been given intravenously to tration even at steady state. Certainly if the pharmaco- delirious patients without any sedation occurring.8 Any kinetics and particularly the metabolism of haloperidol haloperidol-induced sedation is at its maximum during are closely examined, sound pharmacological reasons for the first hour after intravenous administration (distribu- this can be found. The clinical importance of this in tion phase).5 After oral administration the onset of any palliative care is that parenteral administration of sedation is gradual and lasts several hours.5 When used in haloperidol may be the safest, and the preferred, route delirium, which is by definition a disorder of conscious- of administration and is certainly not to be avoided if ness, particularly in hypoactive/torporosed deliria, con- subcutaneous administration of other medications in the tainment of the symptoms with haloperidol (in the terminal phase is occurring. Prescribers using higher absence of a benzodiazepine) may actually enhance doses may be concerned about the emergence of extra- alertness and attention. To consider haloperidol as a pyramidal adverse effects and may be reassured to know sedative agent is incorrect.34 that the incidence is low when haloperidol is used by thisroute.
Discussion/conclusions
Haloperidol is a useful drug in palliative care although,
as with many medications in this field of medicine, there
is a paucity of good published clinical trials. The efficacyof haloperidol in the alleviation of delirium in the 1 Settle EC, Ayd FJ. Haloperidol: a quarter century of experience. J Clin Psychiatry 1983; 44: 440 ¡
terminally ill is based on mostly observational evidence 2 Dickerson D. The 20 essential drugs in palliative care.
collected from studies of delirious critically ill patients.
Eur J Palliat Care 1999; 6: 130 ¡/35.
Likewise the adverse effects profile of haloperidol in 3 Brockmoller J, Kirchheiner J, Schmider J, Walter S, palliative care, particularly the EPS, has been based on Sachse C, Muller-Oerlinghausen B, Roots I. The impact either schizophrenic patients or those with delirium.
of the CYP2D6 polymorphism on haloperidol pharma- Delirium, an imbalance of the dopaminergic/acetylcholi- cokinetics and on the outcome of haloperidol treatment.
nergic systems, may protect against the development of Clin Pharmacol Ther 2002; 72: 438¡/52.
extrapyramidal adverse effects. Some patients may be 4 Levy RH, Thummel KE, Trager WF, Hansten PD, more susceptible to the extrapyramidal adverse effects of Eichelbaum M eds. Metabolic drug interactions. Phila- haloperidol either through disease e.g., AIDS patients, or delphia, PA: Lippincott Williams and Wilkins, 2000: enzymes which may 5 Forsman AO. Individual variability in response to (CYP2D6) or may not (CYP3A4) be polymorphically haloperidol. Proc R Soc Med 1976; 69: 9¡
expressed. The enzymes involved in the different stages of 6 Breitbart W, Sparrow B. Management of delirium in the haloperidol's metabolism have not been fully elucidated.
terminally ill. Prog Palliat Care 1998; 6: 107 ¡/13.
From studies of CYP2D6 genetically slow and nonslow 7 Chang WH, Lam YWF, Jann MW, Chen H. Pharmaco- substrate metabolizers it would appear that CYP2D6 kinetics of haloperidol and reduced haloperidol in does indeed have a role in the metabolism of haloperidol Chinese schizophrenic patients after intravenous and at least at low haloperidol concentrations. Likewise oral administration of haloperidol. Psychopharmacology CYP3A4 also appears to play a part. It would be prudent 1992; 106: 517 ¡/22.
then to consider the patient's CYP2D6 substrate meta- 8 Nielssen O, Buhrich N, Finlay-Jones R. Intravenous bolizing status and likely interactions with other drugs sedation of involuntary psychiatric patients in New when administering haloperidol. Testing for genetically South Wales. Aust NZ J Psychiatry 1997; 31: 273 ¡/78.
9 Urlich S, Neuhof S, Braun V, Meyer FP. Reduced fast and slow metabolizers of CYP2D6 substrates is haloperidol does not interfere with the antipsychotic available in some centres, using a blood sample, although activity of haloperidol in the treatment of acute schizo- this is rarely clinically indicated. Clinicians should be phrenia. Int Clin Psychopharmacol 1999; 14: 219 ¡/28.
aware of drugs which are known to inhibit CYP2D6 such 10 Dollery C, Boobis A, Rawlins M, Thomas S, Wilkins M as paroxetine and may therefore lead to higher haloper- eds. Therapeutic drugs. 2nd ed. Edinburgh: Churchill idol plasma concentrations.
Livingstone, 1999: H3¡/H9.
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