Department of Psychiatry, University of Newcastle, Newcastle upon Tyne, UK
Correspondence: Dr R. H. McAllister-Williams, Department of Psychiatry, Leazes Wing, Royal Victoria Infirmary, Newcastle upon Tyne NEI 4LP, UK. Tel: +44 (0) 191 232 5131 ext. 24336; fax: +44 (0) 191 227 5108; e-mail:r.h.mcallister-williams{at}ncl.ac.uk
Declaration of interest Sponsorship and speaker's fees received from a number of pharmaceutical companies, including AstraZeneca, Eli Lilly, GlaxoSmith Kline, Janssen, Lundbeck, Organon, Pfizer, Pharmacia & Upjohn, Sanofi-Synthelabo and Wyeth.
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ABSTRACT |
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Aims To ascertain what alternatives can be recommended to replace intramuscular droperidol.
Method Selective review of current guidelines and the literature pertaining to rapid parenteral tranquillisation.
Results Current guidelines recommend haloperidol as an alternative to droperidol. There is evidence of cardiotoxicity with haloperidol and it has a propensity to cause extrapyramidal side-effects that may exacerbate disturbed behaviour and reduce longer-term compliance. The rapid-acting intramuscular formulations of atypical antipsychotic agents show promise.
Conclusions It is recommended that the mainstay of pharmacological rapid tranquillisation should be parenteral benzodiazepines used with due care.
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INTRODUCTION |
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PAST PRACTICE |
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These treatments are not without side-effects. A survey of around 100 incidents of rapid tranquillisation conducted by Pilowski et al (1992) found few adverse events, but those reported were potentially serious, including cardiorespiratory problems, with cardiac arrests in 2% and cardiovascular complications in 3%. Although not reported in this study, dystonic reactions are not uncommon in patients administered an intramuscular antipsychotic. These reactions can be severe, and extremely unpleasant; they may exacerbate disturbed behaviour (Royal College of Psychiatrists Psychopharmacology Sub-group, 1997) and in newly diagnosed cases of schizophrenia may have long-term consequences due to lack of compliance with treatment (van Harten et al, 1999).
There has been little research into the effectiveness of rapid tranquillisation treatments. However, what work has been conducted confirms the effectiveness of antipsychotics (usually haloperidol or droperidol) and benzodiazepines (usually lorazepam or diazepam) alone and especially in combination (Garza-Trevino et al, 1989). This led to the development of a number of guidelines (Atakan & Davies, 1997; Kerr & Taylor, 1997; Royal College of Psychiatrists Psychopharmacology Sub-Group, 1977). These recommend non-pharmacological and oral therapy (when liquid and rapidly dissolving formulations may be particularly useful) before embarking on parenteral treatment. However, if the latter proves necessary, two options intramuscular droperidol and lorazepam, or intravenous haloperidol and diazepam are recommended in the first instance, with a repeat treatment 10 minutes after intravenous treatment and 30 minutes after intramuscular treatment in the event of non-response. Intravenous administration to acutely behaviourally disturbed patients is no mean undertaking, though it can be highly effective when administered in appropriate circumstances by well-trained staff. The more rapid absorption of droperidol compared with haloperidol when given intramuscularly (Atakan & Davies, 1997) has led to droperidol becoming the antipsychotic of choice of many psychiatrists. This practice is supported by a randomised, controlled trial comparing haloperidol with droperidol showing a benefit of the latter drug in acutely agitated patients (Resnick & Burton, 1984).
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RECENT PROBLEMS |
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CURRENT OPTIONS |
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Chlorpromazine
Chlorpromazine has many disadvantages because its intramuscular injection
is painful and it has a propensity for causing hypotension, particularly in
the elderly (Swett et al,
1977; Musey et al,
1986). In addition, an association between high-dose
chlorpromazine and sudden death has been mooted
(Jusic & Lader, 1994).
Consequently, chlorpromazine is not recommended for intramuscular use
(Royal College of Psychiatrists
Psychopharmacology Sub-group, 1997). It also carries a risk of
prolonged unconsciousness with intravenous administration
(Quenstedt et al,
1992).
Haloperidol
Haloperidol given intramuscularly appears to be effective for rapid
tranquillisation (Neborsky et al,
1981). While it is generally thought to be safe and is recommended
in previous guidelines (Atakan &
Davies, 1997; Kerr &
Taylor, 1997), serious adverse events have been described
including sudden death (Jusic & Lader,
1994), cardiac arrests
(Goldney et al, 1986) and neuroleptic malignant syndrome
(Konikoff et al,
1984). The study that demonstrated increases in QTc
associated with thioridazine and droperidol found an association with
haloperidol just short of significance (P=0.06;
Reilly et al, 2000), and there are case reports of torsade de pointes occurring with this
drug (Zee-Cheng et al,
1985; Haverkamp et
al, 2000). Behavioural disturbance itself may cause
QTc prolongation. Psychiatric emergency patients have been found to
have a QTc around 50 ms longer than psychiatric out-patients
(Hatta et al, 2000)
and a recent controlled study in disturbed patients found significant
increases in QTc in a small number of patients given placebo
(David et al, 2002).
Acutely behaviourally disturbed patients may be at particular risk if
QTc prolongation occurs since adrenalin may sensitise the heart
making arrhythmias more likely (Royal
College of Psychiatrists Psychopharmacology Sub-group, 1997; Haverkamp et al,
2000). Thus the administration of haloperidol to acutely disturbed
patients, particularly intravenously as recommended in some guidelines
(Kerr & Taylor, 1997), is
controversial. In addition, studies investigating the effects of intramuscular
atypical antipsychotic agents (Brook et
al, 2000; Wright et
al, 2001a; Jones
et al, 2001) have demonstrated the propensity of
haloperidol to cause dystonia and other extrapyramidal side-effects. These
side-effects can have long-term implications for compliance with treatment
(van Harten et al,
1999) and may even exacerbate disturbed behaviour in the
short-term (Royal College of Psychiatrists
Psychopharmacology Sub-group, 1997). A meta-analysis comparing
typical and atypical antipsychotic drugs
(Geddes et al, 2000)
generated a flurry of correspondence
(http://www.bmj.com/cgi/content/full/321/7273/1371
) from patient organisations and psychiatrists because it recommended the use
of typical agents in the acute phase of schizophrenia. Much of the criticism
centred on the unfavourable side-effect profile of typical drugs, especially
extrapyramidal symptoms. Such symptoms seen in schizophrenia are not solely
related to antipsychotic use. Dyskinesia has been reported in patients who
have never received antipsychotic medication, with a prevalence that increases
with age (Fenton, 2000). A
study from India of people with schizophrenia found that never-medicated
patients aged over 50 years suffered from rates of parkinsonism, akathisia and
dyskinesia over twice those seen in agematched control subjects
(McCreadie et al,
1996). This suggests that disturbance of basal ganglia function
might be an inherent factor in the pathology of schizophrenia, or at least one
that develops over time. The use of drugs that compound these problems,
particularly haloperidol (which is contraindicated in patients with
basal ganglia disease according to the British National
Formulary; British Medical Association & Royal Pharmaceutical Society
of Great Britain, (2000)),
therefore requires caution, particularly in the elderly.
Zuclopenthixol
Some psychiatrists use the short-acting depot antipsychotic zuclopenthixol
acetate for rapid tranquillisation
(Simpson & Anderson,
1996). Because of the potential dangers of injecting a previously
untreated patient with a drug that has a long half-life, this practice is
contrary to a Royal College of Psychiatrists' consensus statement that
recommends its use only when circumstances are exceptional in
antipsychoticnaive patients (Thompson,
1994). Previous guidelines recommended the use of zuclopenthixol
acetate only when initial control of disturbed behaviour had at least
partially been established with a short-acting anti-psychotic and/or a
benzodiazepine (Atakan & Davies,
1997; Kerr & Taylor,
1997). Its use is also limited by the delayed onset (around 8
hours) of its antipsychotic effects
(Chakravarti et al,
1990), maximum serum concentrations that are only reached after
around 36 hours (Clopixol Acuphase data sheet, Lundbeck), and the number of
times the drug can be administered (four injections or 400 mg;
British Medical Association & Royal
Pharmaceutical Society of Great Britain, 2000). Further, sudden
deaths and fatal cardiac events have been reported to the Medicines Control
Agency (MCA) of the UK with this antipsychotic
(Royal College of Psychiatrists
Psychopharmacology Sub-group, 1997).
Benzodiazepines
Benzodiazepines can be used for rapid tranquillisation owing to their
sedative and anxiolytic properties. In addition, these drugs enhance
gamma-aminobutyric acid activity which can inhibit dopamine-mediated
transmission, possibly providing a direct antipsychotic effect
(Stimmel, 1996). The most
serious adverse effect of benzodiazepines is respiratory depression when high
doses are given, although this can be readily reversed using the
benzodiazepine partial agonist flumazenil. Of concern when treating acute
behavioural disturbance are numerous case reports of behavioural disinhibition
with benzodiazepines (Bond,
1998). This has been argued to be a particular risk in patients
with pre-existing poor impulse control
(Van der Bijl & Roelofse,
1991; Bond, 1998)
or hostility, and when using high doses of benzodiazepines
(Rothschild, 1992).
Conversely, it has been suggested that the incidence of aggressive dyscontrol
following treatment with benzodiazepines is less than 1% with no predictive
indicators (Dietch & Jennings,
1988) and a controlled study has not shown disinhibition to be a
side-effect of benzodiazepine use
(Rothschild et al,
2000). Some of these discrepancies may relate to the difficult
task of differentiating behavioural dyscontrol from the behaviour for which
the benzodiazepine is being administered in the first place. Nevertheless, it
is prudent to exercise care and doses should be kept as low as practically
possible (Van der Bijl & Roelofse,
1991). Another practical issue relates to concern that around 20%
of psychiatric patients who are first given benzodiazepines while in hospital
are still prescribed them at discharge
(Summers & Brown, 1998). Good clinical practice always involves repeated assessment of prescribed
medication so that drugs used for rapid tranquillisation are not continued
indefinitely on an as required basis orally when no longer
indicated. This is especially important with drugs such as benzodiazepines
that carry a high risk of dependency. However, these concerns notwithstanding,
the wide therapeutic index of these drugs makes them useful alternatives to
antipsychotics for rapid tranquillisation. Diazepam emulsion is effective when
given intravenously (Lerner et
al, 1979), but is not appropriate for intramuscular use
because of its erratic absorption (Gamble
et al, 1975). Consequently, intramuscular lorazepam,
which is better absorbed (Greenblatt
et al, 1979), is the benzodiazepine of choice
(Atakan & Davies, 1997;
Kerr & Taylor, 1997).
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FUTURE POSSIBILITIES |
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Olanzapine
Two double-blind, randomised, controlled trials have now been conducted
examining the effect of intramuscular olanzapine in patients with acute
behavioural disturbance. The first trial examined, in 270 patients, doses of
2.5-10 mg compared with haloperidol 7.5 mg and placebo
(Wright et al,
2001b). All the active treatments were more effective at
reducing the behavioural disturbance than placebo, with a dose-effect
relationship for olanzapine. Dosages of 7.5 mg and 10 mg of olanzapine were
found to be as good as or better than haloperidol 7.5 mg. No significant
serious adverse event was seen with any of the treatments, but haloperidol
caused significantly more episodes of acute dystonia and tremor than
olanzapine. There was no significant increase in QTc intervals in
patients with any treatment, in line with previous data regarding oral
treatment in large numbers of patients
(Czekalla et al,
2001). The findings in acutely disturbed patients were broadly
confirmed in a second study comparing olanzapine 10 mg with haloperidol 7.5 mg
and placebo in 311 patients (Wright et
al, 2001a). This study demonstrated a more rapid
onset of action of olanzapine compared with haloperidol, with the former
producing significantly greater reductions in disturbed behaviour 30 minutes
after injection than haloperidol. In addition, olanzapine was associated with
significantly fewer extra-pyramidal side-effects, including dystonia.
Ziprasidone
Ziprasidone is an atypical antipsychotic agent that is yet to be launched
in the United Kingdom in any formulation. However, an intramuscular
formulation of the drug exists. An open-label flexible dose comparison with
haloperidol in 132 patients found ziprasidone 5-20 mg to be as good as or
better than haloperidol 2.5-10 mg in reducing agitation
(Brook et al, 2000).
This study reported that ziprasidone produced significantly fewer
extrapyramidal side-effects compared with haloperidol. The registration of
ziprasidone in the USA was delayed because of concerns that the drug led to
prolongation of the QTc interval. However, studies requested by the
Food and Drug Administration have shown the drug to cause only a modest
average increase in QTc, with durations that predispose to
torsade de pointes being rare (see FDA Approval Letter and Labelling:
http://www.fda.gov/cder/foi/label/2001/20825lbl.pdf
). As a result, the drug was registered in the USA in February 2001, though it
carries explicit warnings regarding its use in patients at risk of
QTc prolongation.
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CONCLUSION |
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Clinical Implications and Limitations |
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LIMITATIONS
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Received for publication February 19, 2001. Revision received July 23, 2001. Accepted for publication July 26, 2001.
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