A survey on the drug therapy for delirium

Authors


Correspondence address: Toshiyuki Someya Department of Psychiatry, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata 951-8510, Japan. Email: someya@med.niigata-u.ac.jp

Abstract

Abstract Delirium, which is experienced by 10–30% of inpatients, is commonly seen in daily practice. A survey was conducted of the delirium medications, and results were obtained from 28 psychiatric departments and related facilities. Haloperidol was used in 67% cases for the treatment of delirium. Ninety-seven per cent of facilities considered haloperidol as the drug of first choice, while 57% thought this drug had few side-effects and was easy to use. However, because the use of this drug is not covered by health insurance in Japan, its use is limited. We expect that this study on medication for the treatment of delirium will be a first step in increasing the approved indications for drugs used for the treatment of delirium, and to reduce off-label use.

INTRODUCTION

Delirium is experienced by 10–30% of all inpatients1,2 and is commonly found in daily practice, especially in emergency wards (ICU syndrome), surgical wards (postoperative delirium), and in elderly patients. By complicating with existing disorders, delirium may cause accidents such as falls and the self-removal of life-support systems.3 Studies have shown that development of delirium is an indication for bad prognosis.2,4,5

The treatment of delirium has a long history and includes bloodletting and venetomy. The introduction in the 1950s of major and minor tranquilizers drastically changed its treatment.6

There are three parts in treatment of delirium that need to proceed simultaneously: (i) the identification and removal of the cause of delirium, (ii) psychosocial approaches to relieve the symptoms, and (iii) drug treatment of the symptoms.7

Although there are no approved drugs for delirium treatment in Japan, antipsychotic drugs, especially haloperidol, are often used. In internal medicine and pediatrics, off-label drugs, which have been clinically applied and proved to have certain effectiveness, have been widely studied. Many off-label drugs with sufficient evidence are also used practically in psychiatry. The Japanese Society of Clinical Neuropsychopharmacology organized ‘The Study Group of the Off-label Use of Psychotropic Drugs’ in 1999. This Group has conducted ‘the survey on delirium drug therapy’, in particular the use of haloperidol, as the first step in the official recognition of drugs used in treatment of delirium.

METHODS

The study was conducted using a questionnaire with 12 questions (Table 1). Copies were mailed to 100 psychiatric departments and related facilities to obtain information relating to the period 1 July 2000 to 31 July 2000. Twenty-eight questionnaires were returned reporting on 167 cases.

Table 1.  Survey on medications for the treatment of delirium
1.Number of delirium patients
2.Causes of delirium
3.Number of cases treated with haloperidol
4.Route of haloperidol administration
5.Daily dose of oral haloperidol
6.Daily dose of injected haloperidol
7.Number of cases treated with haloperidol combined with other drugs
8.Use of drugs other than haloperidol
9.Use of delirium rating scale
10.Impression of haloperidol for treatment of delirium
11.Suitable types of delirium for haloperidol
12.Added indications for treatment with haloperidol

RESULTS

Of the 167 cases with delirium, there were 125 cases (75%) that were referred by other departments. The number of cases found within the psychiatric department were 42 cases (25%).

The causes of delirium were general medical conditions (n = 108, 65%), direct physiological effects of substances (n = 25, 15%), withdrawal of substances (n = 16, 10%), and multiple causes (n = 13, 8%). Approximately half of the 108 cases (n = 47, 44%) caused by general medical conditions were postoperative delirium, reflecting the characteristics of University hospitals. Substances causing delirium comprised drugs used for the treatment of general medical conditions (n = 14, 56%) and for psychiatric disorders (n = 10, 40%). In all hospitals, most (88%) withdrawal of substance cases were alcohol related.

Haloperidol was used in 112 cases (67%) for the treatment of delirium. Other drugs used were mianserin (n = 23, 14%), flunitrazepam (n = 21, 13%), and levomepromazine (n = 20, 12%) (Table 2). Haloperidol was administered orally (n = 67, 60%), by intravenous (i.v.) drip (n = 42, 38%), by i.v. injection (n = 17, 15%) and by intramuscular injection (n = 13, 12%) (Fig. 1). The daily dose of oral haloperidol was below 3 mg in 47 cases (70%) (Fig. 2). The daily dose of i.v. haloperidol varied considerably: < 5 mg in 20 cases, 5–10 mg in 27 cases, and >10 mg in 19 cases (Fig. 3). Other drugs were combined with haloperidol for the treatment of delirium in 58 cases (52%); flunitrazepam was used in approximately half of these (n = 30) (Table 3).

Table 2.  Drugs other than haloperidol
DrugNo. cases
Mianserin23
Flunitrazepam21
Levomepromazine20
Tiapride13
Trazodone10
Chlorpromazine8
Risperidone5
Thioridazine3
Diazepam2
Midazolam2
Aniracetam2
Brotizolam2
Sulpiride2
Pipamperone2
Zopiclone1
Etizolam1
Figure 1.

Route of haloperidol administration.

Figure 2.

Daily dose of haloperidol (mg/day).

Figure 3.

Daily dose of injected haloperidol (mg/day).

Table 3.  Drugs combined with haloperidol
DrugNo. cases
Flunitrazepam30
Levomepromazine7
Tiapride6
Mianserin5
Brotizolam3
Midazolam3
Nitrazepam2
Chlorpromazine2
Trazodone1
Etizolam1
Diazepam1
Thioridazine1
Risperidone1
Bromperidol1

Only four facilities (14%) applied a delirium rating scale: Delirium Rating Scale (DRS)8 in three facilities and Mini-Mental State Examination (MMSE) in one facility.

Ninety-seven per cent of facilities considered haloperidol as the drug of first choice, while 57% thought this drug had few side-effects and was easy to use. However, about one-third of facilities answered that haloperidol by itself had not given sufficient sedation and involved extrapyramidal signs (Table 4). Eighteen facilities (64%) replied that haloperidol was appropriate for relieving the symptoms of hyperactivity that accompanied hallucination, delusion and psychomotor excitement (Table 5).

Table 4.  Opinion of haloperidol for treatment of delirium
OpinionNo. cases (%)
Drug of first choice27 (97%)
Less side-effects, easy to use16 (57%)
Extrapyramidal signs are troublesome11 (39%)
Sedation is weak9 (32%)
Over sedation and hangover are
troublesome
4 (14%)
Use if there are no alternatives3 (11%)
Table 5.  Suitable types of delirium for haloperidol
Type of deliriumNo. cases
Symptoms of hyperactivity accompanying
hallucination, delusion, and
psychomotor excitement
18
Cases with physical complication5
Delirium general4
Moderate or severe delirium3
Postoperative delirium2
Non-senile or non-organic2
Delirium caused by steroid psychosis
or organic disease
1
Cases in which oral administration
is impossible
1
Withdrawal of alcohol1

Although the approved indications for haloperidol are only schizophrenia and mania, these indications were added to the prescription in only a few cases (4.8%) when giving haloperidol for the treatment of delirium. The most frequent diagnosis, as an approved indication, was hallucinatory/delusional state (n = 49, 29%), with the second most frequent being delirium (n = 23, 17%) (Table 6).

Table 6.  Added indications for treatment with haloperidol
IndicationsNo. cases
Hallucinatory/delusional state49
Delirium23
Organic psychosis10
Schizophrenia7
Delirious conditions5
Neurasthenic condition5
Organic psychosis (delirium)4
Symptomatic psychosis3
Psychomotor excitement2
Manic state1
Depression1
Acute psychosis1
Psychotic state1
Psychogenic reaction1
Insomnia1
None1

DISCUSSION

For the treatment of delirium, haloperidol, a highly potent antipsychotic drug, is the most frequently used and its efficacy is supported by sufficient evidence.6,9–15 This study provided additional evidence that haloperidol was typically used for the treatment of delirium. Another study by Tomita et al., using the same questionnaire, obtained similar results; haloperidol was chosen in more than half the cases (50.4%) of delirium.16 The indication for haloperidol is broad because it does not have anticholinergic, hypotensive and respiratory depression effects, and shows a low cardiotoxicity.6 It has been reported that i.v. administration in particular decreased the incidence and severity of side-effects in the extrapyramidal system.17 Low-dose administration has been recommended (e.g. 1–2 mg of haloperidol every 2– 4 h,18 0.25–0.50 mg every 4 h in elder patients19). In this study, low-dose administration was given in 70% of the cases. Because it is suggested that the plasma concentration of haloperidol is determined partly by CYP2D6 polymorphic activity,20 genotype data (e.g. CYP2D6*5) may provide useful information for the safer use of haloperidol in the treatment of delirium. Antipsychotic drugs with low potency, such as chlorpromazine, are not recommended as drugs of first choice for delirium treatment because of their strong hypotensive and anticholinergic effects.6,12

Risperidone does not have any anticholinergic effect,21 and studies have shown that this drug reduces the tendency to induce delirium and is effective and safe in the elderly and demented patients with delirium.22,23 In the present study, risperidone was used in only 3% of cases, while in Tomita et al.'s study risperidone was used in 13% of cases, which shows a variation in its popularity.

Benzodiazepines are recommended only for delirium related to alcohol or withdrawal of benzodiazepines as they can induce delirium;6 the effect of benzodiazepine alone is lower than that of haloperidol,15 and less evidence supports the use of benzodiazepine alone.6 For sleep disorders involved in delirium, a combination therapy of haloperidol and benzodiazepines (such as lorazepam, flunitrazepam, and midazolam, which have relatively short half-lives and a short duration of effect) is effective.11,24–26 In half of the cases in the present study, flunitrazepam was combined with haloperidol.

The present study shows that mianserin was the second most popular drug for the treatment of delirium. It is reported that mianserin, which is a tetracyclic antidepressant, is effective against sleep disorder and psychomotor excitement without severe side-effects, and is easy to use in elderly patients.27,28 The effectiveness of trazodone is also reported in delirium cases who display difficulties in morning awaking because of mianserin.29

The present study discusses the results of a study on the use of medications for delirium, a condition commonly found in inpatients of general hospitals. However, there is no approved drug in Japan, including haloperidol, for the treatment of delirium. Although the effectiveness of haloperidol and other drugs are supported by international evidence, the domestic use of these drugs in Japan is limited because they are assessed based on health insurance criteria, often criticized, and can lead to legal complications.

On 1 February 1999, the Ministry of Health and Welfare released notification titled, ‘The Off-label Use of Prescribed Drugs’. According to this notification, when relevant academic societies require use of a drug and there is sufficient evidence supporting its effectiveness, the drug can be approved without going through the typical processes of clinical trials. We expect that the present study on the medication for the treatment of delirium will be the first step to increase the approved indications for drugs used in the treatment of delirium, and to reduce off-label use.

Ancillary