Biomedicine & Pharmacotherapy 132 (2020) 110772

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Haloperidol in palliative care: Indications and risks

Iwona Zaporowska-Stachowiak a, b, *, Katarzyna Stachowiak-Szymczak c, Mary-Tiffany Oduah d,
Maciej Sopata b, e
a
Department of Pharmacology, Poznan University of Medical Sciences, Rokietnicka 5A Street, Poznań, Poland
b
Palliative Medicine In-patient Unit, Hospital of Lord’s Transfiguration of Poznan University of Medical Sciences, Os. Rusa 55, Poznan, Poland
c
Department of Interpreting Studies and Audiovisual Translation, University of Warsaw, Dobra 55, Warsaw, Poland
d
Poznań University of Medical Sciences, Center for Medical Education in English, Poland
e
Department of Palliative Medicine, Poznan University of Medical Sciences, Os. Rusa 55, Poznań, Poland

A R T I C L E I N F O A B S T R A C T

Keywords: Individual response to medication depends on several factors (age, gender, body weight, general clinical con­
Haloperidol dition, genetics, diet, hydration status, comorbidities, co-administered drugs and their mode of administration,
Palliative care smoking, alcohol overuse, environmental factors, e.g. sunlight) that may contribute to adverse drug reactions
Cardiotoxicity
even at therapeutic doses. Patients in palliative care are at increased risk of these reactions. Unwanted drug
Adverse effect
Neurotoxicity
effects diminish the quality of life and may lead to a suboptimal dying process. Haloperidol is one of the three
most commonly used drugs in palliative care and the most commonly employed typical antipsychotic. It has also
been recommended for inclusion into the palliative care emergency kit of home care teams. As such, it is
important to be fully conversant with the indications, benefits, and risks of haloperidol, especially in the context
of palliative care.

1. Introduction 2. Methods

Morphine, midazolam, and haloperidol (aka Haldol) are one the
most frequently used drugs in palliative care [1]. Haloperidol is most
commonly prescribed for the relief of agitated delirium [2,3] and for the
prevention/treatment of nausea/vomiting (including the
opioid-induced ones) [1]. It is widely used in acute and chronic disor­
ders such as intractable hiccups, hallucinations, restlessness and agita­
tion, psychosis [4–7], and alcohol withdrawal [8–10]. Despite the risk
associated with its use and the availability of newer antipsychotics,
haloperidol is still commonly used. Patients under palliative care are
especially susceptible to adverse and toxic effects of haloperidol (and
other drugs) due to the primary disease process, comorbid diseases,
multiorgan failure, polytherapy, cytochrome P450 (e.g.CYP 2D6) poly­
morphism [11], common cachexia, hypoproteinemia, and advanced
age. The paper will consider the safe use of haloperidol in this patient
population and related risks, with an overarching aim to improve the
quality of pharmacological treatment for these patients.
We conducted a semi-systematic review [12,122,123]. This type of
review was selected, as we investigated studies and papers displaying
different, pragmatic approaches towards haloperidol use and safety in
palliative care. Haloperidol is a 1 st generation neuroleptic introduced in
1958 by Jansen [13], and well described. At the same time, it has taken
time for palliative care to develop state-of-the-art research on drug safe
use, partially due to patient wellbeing always outshining research needs.
By the same token, there is a paucity of high-quality multi-center,
double-blind historical papers on haloperidol in palliative care. Data
from these studies are also frequently not directly parallel and compa­
rable. Therefore, we decided to conduct a review instead of a traditional
meta-analysis.
We searched the PubMed and Cochrane databases as well as insti­
tutional and personal resources to find papers investigating treatment
with haloperidol, with a special focus on palliative care. We selected
peer-reviewed papers of the last 20 years, that examined haloperidol use
in different clinical conditions in palliative care. The study window was
2019-2020. Website material has been accessible in 2020. Inclusion

* Corresponding author at: Palliative Medicine In-patient Unit, Hospital of Lord’s Transfiguration of Poznań University of Medical Sciences, Os. Rusa 55, Poznań,
Poland.
E-mail address: iwozapor@ump.edu.pl (I. Zaporowska-Stachowiak).

https://doi.org/10.1016/j.biopha.2020.110772
Received 28 May 2020; Received in revised form 27 August 2020; Accepted 17 September 2020
Available online 14 October 2020
0753-3322/© 2020 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
I. Zaporowska-Stachowiak et al. Biomedicine & Pharmacotherapy 132 (2020) 110772

criteria revolved around keywords referring to haloperidol indications,
side effects/toxicity and palliative care. We analysed 32 studies and
reviews to describe the mechanism of action, formulations and dosage,
and significant side effects associated with the use of haloperidol
notably seen in palliative care. Material supplementary to the article
provides for the summary of studies analysed in this review, including
sample characteristics, purpose and/or interventions, key results related
to haloperidol use and the levels of evidence based on two different
classifications. At the same time, the body of this article itself may also
refer to other works, such as handbooks or guidelines.
3. Haloperidol-in clinical practice
Haloperidol pharmacokinetics are presented in Table 1.
well as cyclic adenosine monophosphate (cAMP) production via inhi­
bition of adenylyl cyclase in the mesolimbic system [16,17]. The
D2/5-HT2A activity ratio of haloperidol is medium [14,17]. Its receptor
affinity is as follows: D2 > alpha1 > D4 > 5-HT2A > D1 > H1 > M.
Existing data relating to the anti-muscarinic properties of haloperidol
are inconsistent. Thomas, Miller, Iwata, Dickman, and Marszałł [18–22]
confirm that antimuscarinic haloperidol activity is weak, whereas other
authors [23,24] maintain that the drug exerts no antimuscarinic effect.
Haloperidol exerts the following therapeutic effects:
- central neural: antiemetic/anti-singultus, sedating, anxiolytic, anti­
psychotic [17,25–28],
- autonomic: muscarinic blockade provides for its anti-emetic effect
[17,29].

3.2. Haloperidol-metabolism
3.1. Haloperidol-mechanism of action
Haloperidol undergoes extensive metabolism in the liver and only
Haloperidol, a butyrophenone antipsychotic, is primarily a dopa­ about 1 % is excreted with urine [68]. Metabolites are formed during its
minergic D2-antagonist, with alpha1-adrenolytic, H1- antagonistic, and complex metabolism via multiple enzymes (UGT1A4, 1A9, 2BT;
5-HT2A- inhibitory activity and weak anticholinergic activity, as well as CYP3A4, 3A5, 1A1, 2C8, 2C9, 2C19, 2D6, and CBR1 (Fig. 1). Haloper­
minor ganglionic binding ability [14,15]. Haloperidol blocks dopami­ idol is usually metabolized by CYP2D6, while CYP3A4 metabolizes
nergic activity in synapses within the central nervous system (CNS), as haloperidol in higher concentrations.
RHPH is the main metabolite in the plasma of patients treated with
Table 1 haloperidol [69]. Oxidative N-dealkylation is the main metabolic
Pharmacokinetic properties of haloperidol. pathway that occurs in liver microsomes, resulting in the generation of
T½D 21 days 3-(4-Fluorobenzoyl)propionic acid (4-FBPA) and 4-(4-Chlor­
ophenyl)-4-hydroxypiperidine (CPHP). In addition, haloperidol may be
T ½ (plasma) 13− 36 hrs [23]
12− 36 hrs; may have multiphasic reduced to RHPH (4-[4-(4-chlorophenyl)4-hydroxypiper­
elimination with much longer terminal idine-1-yl]-1-(4-fluorophenyl)butan-1-one) by ketone reductases [70,
T1/2 [30] 71].
after a single dose (p.o.): 14.5–36.7 hrs Cationic metabolites include MPP+, HPP+, and RHPP + . HPP + and
or up to 1.5 days; up to 21 days after
chronic administration; ≥ 3 days in poor
RHPP + are the products of haloperidol oxidation and HPP + reduction
CYP2D6 metabolizers [31] and RHPH oxidation, respectively (Fig. 1) [72,73].
i.v.: 14.1–26.2 hrs [32]; 10.1-19 hrs [33, CYP 3A4 expression is much greater in hepatocytes than in the CNS,
34] accounting for greater production of pyridine metabolites in peripheral
i.m.: 20.7 hrs [32]
tissues. These metabolites are transported via the bloodstream and
decanoate i.m.: 21 days [35]
p.o.: 14− 37 hrs [32,35] across the blood-brain barrier by the human organic cation transporter
T1/2 also depends on CYP2D6 types 1 and 2 (hOCT1 and hOCT2) into the CNS [74–76] where they
polymorphism damage the mitochondrial respiratory chain complex 1 [75,77,78].
poor metabolizers, single 2− 4 mg dose HPP + may also be produced in the CNS via an unknown mechanism and
p.o. : 29.4 hrs
extensive metabolizers, single 2− 4 mg
has been found in the CNS, plasma, and urine of patients with schizo­
dose p.o.: 16.3 hrs [36] phrenia and those chronically treated with haloperidol [71,79].
T ½ (CNS) 7 days The structures of haloperidol and its metabolites (HPP, RHPP) are
Onset of action • i.v.: seconds similar to MPTP - a precursor of MPP+ [80]. The toxicity of haloperidol
(sedation, anxiolysis, relief of • s.c.:10− 15 min [23,28]
metabolites is the result of the accumulation of HPP + and
agitation/aggression, anti-emetic, anti- • p.o.: >1 hr [23]
singularis) • chronic treatment of psychosis - 5.8 RHPP + within the substantia nigra, striatum, caudate nucleus, and
days (about 1 week) to first response hippocampus. Upon reaching dopaminergic neurons, they inhibit
[28] mitochondrial complex 1 leading to free radical release and neuro­
Duration of action i.v.: 4− 6 hrs degeneration [22]. In addition, the binding of pyridinium to neuro­
s.c.: up to 24 hrs, sometimes longer [23]
Vd 9.5–21.7 L/kg [32]
melanin in the substantia nigra leads to extrapyramidal symptoms [75].
1280− 2130 L [37]
Plasma protein binding 92 % [30]; free fraction = 7.5-11.6 % 3.3. Haloperidol-indications and dosage in selected clinical conditions
[32]
Cl 0.9–1.5 l/kg/h [15,38]
The daily dose of haloperidol ranges from 2 to 60 mg, given in
Bioavailability Concentration
peak divided doses. In most cases, titration is necessary to achieve an effect
i.v. 100 % 10− 20 min [38] (Fig. 2). Parenteral doses should be lower than the corresponding oral
p.o. (tablets, capsules) 65 (60–70)% [38, 4.9 hrs [35,37] dose. A 3:2 conversion ratio is recommended, e.g. 3 mg p.o. = 2 mg s.c. It
23] 0.5− 4 hrs [15] is also recommended that haloperidol is dose-titrated in the elderly and
38-86 % [39] 1.7–6.1 hrs [32]
>1 hr [23]
individuals with hepatic and/or renal impairment, as these patients may
p.o. (solution) 60-70 % [38] 1.7–6.1 hrs [32] be more susceptible to adverse effects. With advanced age, there is an
38-86 % [39] 30− 40 min [23] exaggerated risk of debilitating anticholinergic effects, cognitive
s.c. 100 % [40,41] 10− 20 min [23] decline, and dementia [21]. Owing to its potent sedative effect, halo­
Abbreviations: PRNas needed; CSCIconstant subcutaneous infusion; p.o - oral; i. peridol alone (10− 30 mg p.o. at night) or in combination with opioids
m - intramuscular; s.c. - subcutaneous; i.v. - intravenous; Cl - clearance; T ½ - half can relieve chronic overwhelming cancer pain [23]. The extent of its
life; CNS- central nervous system; Vd - Volume of distribution, D – daily. therapeutic and side effects is dependent on dosage and mode of

2
I. Zaporowska-Stachowiak et al.
Fig. 1. Metabolism of haloperidol in the liver.
Key terms: HPP+ = 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium (haloperidol pyridium metabolite); RHPP+ = „reduced” HPP+; HAL –
haloperidol; RHPH =” reduced” Haloperidol; 4-FBPA = beta-(4-fluorobenzoyl) propionic acid; CPHP = 4-(4-chlorophenyl)-4-hydroxypiperidine; 4-FPAA = 4-fluo­
rophenylacetic acid; 4-PA = 4-pentenoic acid; CYP = cytochrome; UGT = uridine diphosphate-glucuronosyltransferase
administration (Table 2) [26,42].
3.4. Haloperidol-formulations
Haloperidol is available in various formulations (Table 3). In palli­
ative care, subcutaneous administration of haloperidol is preferred as it
is fast acting, relatively safe, and very little local irritation is observed.
There is no available data on rectal administration of haloperidol.
Haloperidol as a single agent stored in a syringe is stable 7 days at 25 C
degrees; the stability of the drug syringe combination lasts 7 days at
room temperature, when the syringe is protected from light [67].
3.5. Haloperidol-adverse effects
In comparison with other typical antipsychotics (e.g., chlorproma­
zine), the extrapyramidal toxicity of haloperidol is very high, clinical
potency is high, but sedative, anticholinergic and cardiotoxic (hypo­
tension and dose-related QT interval prolongation) potential is low
(Fig. 2) [17,23,28]. Haloperidol expresses 60–65 % D2-receptor occu­
pancy and above 80 % potential for developing extrapyramidal symp­
toms (EPS) [82].
Haloperidol may exert the following side effects: extrapyramidal
symptoms [83,84] (drug-induced parkinsonism, tardive dyskinesia that
occurs in 30 % of cases with chronic exposure to haloperidol), akathisia
[85], dystonias [17,23,86,87], akinesia (presenting as “pseudo-de­
pression”) [88], agitation, insomnia, tremor/muscle twitching, seizures
[89–91], impairment of consciousness progressing to coma, depression
[92], neuroleptic malignant syndrome [93], hyperprolactinemia,
amenorrhea and galactorrhea [94,95], autonomic effects: muscarinic
antagonist effects, alpha-1 blockade [17,96], cardiovascular effects (QT
interval prolongation, orthostatic hypotension, tachycardia, and cardiac
arrhythmias (ventricular fibrillation, torsade de pointes), conduction
3
Biomedicine & Pharmacotherapy 132 (2020) 110772
defects, and cardiac arrest) [97], bronchospasm and dyspnea [98,99],
sleep apnea [100], neutropenia [101,102], increased risk of venous
thromboembolism (VTE) or pulmonary embolism [103,104]; haloper­
idol increases the risk of hypoglycemia, especially in the elderly [105],
cholestatic jaundice, urticaria and photosensitivity [106–109].
Interestingly, two studies demonstrated that the use of haloperidol in
patients with delirium decreased symptoms at 6 days and 7 days [110,
111], but the effect was lower in patients of 75 years of age or older
[111]. Yet its use in palliative care patients with mild-moderate delirium
was not associated with lower severity scores at 72 h [3]. In addition, the
drug increased mortality rate, even at lower doses, compared to placebo
[3], however, the study population consisted mainly of patients of >65
years of age with mild/moderate delirium. Overall, there is low-quality
evidence to support that haloperidol may worsen symptoms of delirium
in terminally ill patients with mild-moderate delirium, while it may
result in higher risk of adverse effects compared to placebo [112] in
advanced cancer and advanced AIDS.
3.6. Haloperidol-overdose
Increased plasma concentration of haloperidol (due to overdose or
drug-drug interactions) may result in drowsiness progressing to coma,
severe breathing disturbance, deep somnolence, agitation, increased
neuromuscular excitability, uncontrolled movements, decreased deep
tendon reflexes, miosis, hypotension, hypothermia (hyperthermia - later
in the course), acute extrapyramidal symptoms [113,114].
3.7. Haloperidol in hepatic or renal impairment
There is a paucity of data on the use of haloperidol in hepatic
impairment. Haloperidol was associated with acute reversible asymp­
tomatic elevation in liver enzymes, showing a mixed or cholestatic
I. Zaporowska-Stachowiak et al.
Fig. 2. Selected factors to be taken into account when prescribing Haloperidol to a patient in palliative care.
Key terms: EPS = extrapyramidal symptoms, NMS = neuroleptic malignant syndrome, TdP = torsade des pointes
pattern. It is considered by some authors to be the safest choice in pa­
tients with chronic liver disease [15,117], while others suggest dose
adjustment in this situation [21,118].
Data regarding haloperidol in renal impairment are conflicting.
Some studies show that this drug is independent of renal function [119];
other showed no adverse events in patients at risk of renal injury [120].
Yet there are recommendations of lower dosing where possible [21],
especially when GFR drops below 10 mL/min [121].
3.8. Haloperidol-withdrawal
Haloperidol should be gradually tapered whenever possible. Rapid
discontinuation of haloperidol may precipitate withdrawal symptoms,
which may appear 24− 48 hrs after withdrawal and may last up to 14
days (long-acting formulations even longer). Withdrawal symptoms
include anxiety, agitation, depression, decreased libido, diminished
concentration, insomnia, headache, tremors, nausea, vomiting, dizzi­
ness, sweating, tachycardia, gastritis [115]. After a few days – rebound
neurological symptoms may appear: akathisia (>50 % in schizophrenic
patients [17]; in palliative care smaller doses are used, so the risk is
smaller), dystonia, parkinsonism [116]. After 1–4 weeks – withdrawal
dyskinesia and hypersensitivity psychosis can occur [21].
3.9. Haloperidol-interactions
Haloperidol is metabolized by P450 isoenzymes (Fig. 1) and it is a
CYP 2D6 inhibitor. The co-administration with substrates, inducers and/
or P450 inhibitors may result in relevant PHARMACOKINETIC (with
carbamazepine, dexamethasone, rifampicin, clonazepam, diazepam,
fentanyl, finasteride, ketamine, methadone, methylphenidate,
4
Biomedicine & Pharmacotherapy 132 (2020) 110772
midazolam, omeprazole, ondansetron, oxycodone, pantoprazole, ris­
peridone, venlafaxine, fluoxetine, paroxetine, tramadol, duloxetine,
levomepromazine, fluconazole (high doses), grapefruit juice), and/or
PHARMACODYNAMIC (with adrenaline, amiodarone, anti-epileptics,
antihypertensives, loop diuretics, antiarrhythmics class IA and III, CNS
depressants, levodopa and dopamine agonists, levomepromazine,
metoclopramide, opioids, trazodone, quinine) interactions [21,32,81].
4. Therapeutic implications for haloperidol use
The main advantages and disadvantages of Haloperidol uns in clin­
ical practice are presented in Fig. 2.
1 Haloperidol increases the risk of mortality in the elderly with
dementia-related psychosis.
2 Dosage adjustment is necessary for patients with severe cardio­
vascular disease, recent myocardial infarction, diabetes, seizures,
hepatic and/or renal impairment, advanced age, poor CYP2D6
metabolizers, dyselectrolytemia (e.g. hypokalemia), co-
administration of CYP 2D6/CYP3A4 inhibitors, and neuroleptic-
naive patients. The recommended initial haloperidol dose in
elderly patients is half the lowest adult dose.
3 Haloperidol causes a reversal of the vasopressor effects of
epinephrine. This combination should be avoided.
4 The risk of venous thromboembolism should be assessed before
and during treatment with haloperidol.
5 Intravenous administration should be avoided due to a high risk
of cardiotoxicity and arrhythmias.
I. Zaporowska-Stachowiak et al.
Table 2
Indications and dosing recommendations for haloperidol.
Symptom
Prevention of opioid-
induced nausea/
vomiting [25,43–46]
Nausea/vomiting
1 medication-induced
(np. chemotherapy,
morphine, digoxin,
theophylline, iron,
potassium, antibiotics,
etc.)
2 metabolic causes (np.
renal failure, uremia,
hypercalcemia,
ketoacidosis,
hyponatremia, tumoral
peptides)
3 infection
4 radiotherapy
[48]
Gastrointestinal
obstruction [49–51]
Psychosis/ drug-
induced psychosis
(corticosteroid
psychosis) [52,53]
Concomitant anxiety,
psychotic symptoms,
and nausea [23,51]
Table 2 (continued )
Dose Practical remarks
0.5- 5 mg q3− 12 h p. □ drug of choice
o./s.c./i.m. □ in some cases bedtime
0.25-2.5 mg s.c./i.m. dosing is sufficient
PRN □ in many cases, it is
2.5− 5 mg CSCI/ effective in doses <
24 hrs 2 mg/daily
□ less sedation and fewer
anticholinergic effects
than phenothiazines
1.5- 2.5 mg s.c. PRN □ 2/3 of patients initiating
(b.i.d. usually and morphine or other opioid
nocte) [23] up to experience nausea/
10 mg/24 hrs s.c./p.o. vomiting [47] which
occurs via activation of
chemoreceptor trigger
zone receptors, delayed
gastric emptying,
constipation and/or
vestibular disturbance
[23]; if haloperidol is
ineffective in gastric
stasis, use
metoclopramide or
domperidone
(prokinetics)
□ in chemotherapy-
induced nausea/vomit­
ing D2R-blockers are
second-line medications
□ chemotherapy-induced
nausea/vomiting should
be treated based on
guidelines
□ change/discontinue the
medication, decrease its
dose, change the mode of
treatment, monitor the
therapy in narrow
therapeutic window
□ adequate hydration,
blood pressure control,
and lung auscultation
□ treat any underlying
causes
□ GCs may be also useful
□ for radiotherapy-induced
nausea/vomiting, 5-
HT3R-blockers are first-
line medications
0.5− 20 mg/24 hrs s.c. start with low doses,
/i.m. gradually increasing the
0.5− 1 mg s.c. PRN dose
dose can be increased
0.5–5 mg s.c./i.v. PRN or
0.5− 20 mg / 24 hours CSCI
Initially 1.5 mg p.o.
bd-tds
Severe cases 3 mg p.o.
bd-tds
max dose 30 mg p.o./
24 hrs
maintenance dose
5− 10 mg p.o./24 hrs
or 3− 5 mg s.c. od or
via CSCI
max dose 10 mg s.c./
24 hrs or via CSCI
initial dose 0.5− 2 mg
q45− 60 min p.o./s.c. • doses may vary: 0.5− 4 mg
q4− 6 h p.o. or 2− 20 mg
q24 h p.o. or 1− 2 mg
q2− 4 h s.c.
5
Biomedicine & Pharmacotherapy 132 (2020) 110772
Symptom Dose Practical remarks
• haloperidol is useful in
anxiety if accompanied by
psychotic symptoms
(delusions, hallucination)
if the suspected cause is
organic, and when BDZ
are ineffective or
contraindicated
Delirium 0.5− 1 mg bid p.o./s.
mild with no c. • adjust the dose as needed
underlying psychiatric 0.25-0.5 mg for • start with low doses,
illness elderly patients mg gradually increasing the
[23,54–57] bid p.o./s.c. PRN dose
5/ 24 hrs. mg CSCI • oral-parenteral dose
conversion: parental
dose = 1/4 - 2/3 of oral
dose; in some cases 1:1
ratio is acceptable
• The dose may be
increased up to 10 mg
CSCI
• a continuous parenteral
infusion may be more
effective
• if the patient does not
respond to the dose of
10 mg CSCI, consider
alternative drugs
(risperidone, olanzapine,
quetiapine; haloperidol
acts faster; quetiapine is
recommended in EPS
risky/parkinsonian
patients)
• i.v. : cardiotoxicity, ↑ EPS
symptoms
Delirium moderate/ 0.5− 2 mg q1h s.c./p.
severe with no o. PRN until symptom • once symptom relief is
underlying psychiatric relief, then q 4− 6 h observed, 50 % of the dose
illness [6,23,58,59] up to 10 mg/24 hrs. needed to achieve
0.25-0.5 mg for symptom relief should be
elderly patients used as a maintenance
dose (~ 1,5–10 (20) mg/
24 hrs.)
• a continuous parenteral
infusion may be more
effective
• mild-to-moderately severe
delirium associated with
distress in palliative care
should not be treated with
(supplementary)
antipsychotics [3]
Restlessness and 0.5− 2 mg s.c. PRN
agitation [60–63] max 10 mg s.c./24 hrs • an antipsychotic (e.g.
or via CSCI haloperidol) is the first-
• in the elderly 0.5− 3 mg p.o. bd-tds line treatment for
up to 1.5− 30 mg p.o./ delirium (hallucinations,
24 hrs altered cognition,
• organic mental paranoia)
syndrome • in other cases BDZ are
first-line drugs
• in older patients with
• mental retardation dementia- related
psychotic reactions use of
antipsychotics may
increase the risk of
mortality
Terminal agitation 0.5-2 (4) mg p.o./s.c.
(terminal delirium/ q45− 60 min. • hydration, pain relief,
end-of-life confusion) 2− 20 mg/24 hrs p.o. relief of bladder
[2,6,23,58] 1− 2 mg q2− 4 h s.c. distension or fecal
impaction, psychological
consult should be
implemented first; if
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Table 2 (continued ) hydromorphone, tramadol, metoclopramide, ketamine, mid­

Symptom Dose Practical remarks
ineffective, introduce
pharmacological therapy
• haloperidol is the first-line
medication (monotherapy
or with BDZ)
Hiccups (persistent) [64, 2− 5 mg s.c./i.m.
65] followed by 1− 4 mg • start with small doses and
p.p. tid or increase gradually
1− 2 mg p.o. q4− 6 h • the central action is
or mediated via ↓dopamine
3− 12 mg p.o./24 hrs • parenteral treatment more
PRN: 1.5 mg p.o. prn, effective than oral
max BD-TDS/0,5- • precaution in advanced
1.5 mg s.c. age
Target 10 (12) mg s.c.
/ 24 h CSCI
Alcohol withdrawal Initial dose 2− 10 mg □ haloperidol alleviated
syndrome [8–10]. q1− 2 h i.m./s.c., max psychiatric symptoms
30 mg /24 hrs accompanying delirium
tremens (agitation,
hallucinations,
delusions)
□ in most cases co-
administered with BDZ
□ haloperidol has the
lowest potential for
convulsions among
neuroleptics
□ a continuous parenteral
infusion may be more
effective
Chorea in Huntington’s 1.5− 80 mg/day haloperidol is preferred due
disease [66] to its strong extrapyramidal
effect
azolam, cyclizine, glycopyrronium, and hyoscine butylbromide.
14 Preserving as high as possible quality of life constitutes the
overarching goal of palliative care, however, the physician may
employ the use of haloperidol for difficult symptoms while
bearing in mind all associated risks.
5. Conclusions
The safety profile as well as indications for the use of haloperidol
have been highlighted, with a special focus on patients in palliative care.
Its use in this population warrants special caution, as the drug and its
metabolites may exert notable toxic effects, especially in the context of
multi-organ failure. In light of existing FDA warnings emphasizing an
increased risk of mortality, we propose a scoring system to aid clinical
decision making for or against the use of haloperidol and for the
assessment of patient profiles to improve the safety of the use of halo­
peridol in palliative care. The use of haloperidol in these patients should
be very carefully considered and alternatives are preferred where
possible.
Patient profile at the highest risk of haloperidol toxicity:
1 History of epileptic seizures.
2 History of EPS/existing parkinsonism.
3 History of arrhythmia/existing cardiovascular problems/congenital
long QT syndrome,
4 Polypharmacy and Concomitant use of drugs which prolong the QT
interval, electrolyte balance (hypokalemia, hypomagnesemia), lower
blood pressure, or arrhythmogenic drugs.
5 Hypothyroidism.
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