Дроперидол для лечения тошноты и рвоты у пациентов при оказании паллиативной помощи
Abstract
Background
This is an updated version of the original Cochrane review published in Issue 10, 2010, on droperidol for the treatment of nausea and vomiting in palliative care patients. Nausea and vomiting are common symptoms in patients with terminal illness and can be very unpleasant and distressing. There are several different types of antiemetic treatments that can be used to control these symptoms. Droperidol is an antipsychotic drug and has been used and studied as an antiemetic in the management of postoperative and chemotherapy nausea and vomiting.
Objectives
To evaluate the efficacy and adverse events (both minor and serious) associated with the use of droperidol for the treatment of nausea and vomiting in palliative care patients.
Search methods
We searched electronic databases including CENTRAL, MEDLINE (1950‐), EMBASE (1980‐), CINAHL (1981‐) and AMED (1985‐), using relevant search terms and synonyms. The basic search strategy was ("droperidol" OR "butyrophenone") AND ("nausea" OR "vomiting"), modified for each database. We updated the search on 2 December 2009. We performed updated searches of MEDLINE, EMBASE, CENTRAL and AMED 2009 to 2013 on 19 November 2013 and of CINAHL on 20 November 2013. We also searched trial registers (metaRegister of controlled trials (www.controlled‐trials.com/mrct), clinicaltrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/)) on 22 November 2013, using the keyword "droperidol".
Selection criteria
Randomised controlled trials (RCTs) of droperidol for the treatment of nausea or vomiting, or both, in adults receiving palliative care or suffering from an incurable progressive medical condition.
Data collection and analysis
We judged the potential relevance of studies based on their titles and abstracts, and obtained studies that we anticipated might meet the inclusion criteria. Two review authors independently reviewed the abstracts for the initial review and four review authors reviewed the abstracts for the update to assess suitability for inclusion. We discussed discrepancies to achieve consensus.
Main results
The 2010 search strategy identified 1664 abstracts (and 827 duplicates) of which we obtained 23 studies in full as potentially meeting the inclusion criteria. On review of the full papers, we identified no studies that met the inclusion criteria.
The updated searches carried out in November 2013 identified 304 abstracts (261 excluding duplicates) of which we obtained 18 references in full as potentially meeting the inclusion criteria. On review of the full papers, we identified no studies that met the inclusion criteria, therefore there were no included studies in this review.
We found no registered trials of droperidol for the management of nausea or vomiting in palliative care.
Authors' conclusions
Since first publication of this review, no new studies were found. There is insufficient evidence to advise on the use of droperidol for the management of nausea and vomiting in palliative care. Studies of antiemetics in palliative care settings are needed to identify which agents are most effective, with minimum side effects.
PICO
Резюме на простом языке
Дроперидол для лечения тошноты и рвоты у людей с запущенным заболеванием
Тошнота (чувство тошноты) и рвота являются распространенными и неприятными симптомами у людей с запущенным раком и другими жизне‐угрожающими заболеваниями. Имеются несколько лекарств для контроля этих симптомов. Дроперидол является одним из примеров, который был использован в попытках предотвратить или лечить тошноту и рвоту у людей, получающих хирургическое лечение или химиотерапию. В процессе нашего поиска, обновленного в ноябре 2013 года, мы не обнаружили рандомизированных исследований дроперидола для лечения тошноты или рвоты у людей, получающих паллиативную помощь или страдающих от неизлечимого прогрессирующего медицинского состояния. Несколько исследований сообщили об использовании дроперидола для предотвращения тошноты и рвоты, связанных с химиотерапией. Необходимы дальнейшие исследования, чтобы выяснить, какие лекарства являются наиболее подходящими для лечения тошноты и рвоты при оказании паллиативной помощи.
Authors' conclusions
Background
This is an updated version of the original Cochrane review published in Issue 10, 2010, on droperidol for the treatment of nausea and vomiting in palliative care patients.
Nausea and vomiting are common symptoms in patients with terminal illness and can be very distressing.
Between 40% and 70% of patients with advanced cancer are thought to suffer from nausea or vomiting (Twycross 1998), and these symptoms are also common in other terminal conditions (Edmonds 2001; Klinkenberg 2004). Antiemetic drugs can help control symptoms while the medical team undertakes an assessment of the patient and tries to treat the underlying cause. There are many such causes in patients with terminal illness, including the underlying illness (for example, bowel obstruction or metastases in the liver), biochemical disturbance (for example, renal failure or hypercalcaemia) or drugs (for example, when starting morphine). Several causes of nausea and vomiting may coexist in an individual patient. Doctors try to choose the best first choice antiemetic based on what is thought to be the underlying cause (Bentley 2001), using a second line antiemetic if the first is not effective. An antiemetic such as levomepromazine, which has effect at several receptors relevant to nausea and vomiting, is often used as a second line antiemetic.
Whilst the choice of first line antiemetic based on the likely cause of symptoms is a widespread approach, there is little evidence from randomised controlled trials for many of the drugs used for these symptoms in this patient group (for example, cyclizine, haloperidol or levomepromazine) (Davis 2010; Glare 2004).
Droperidol is one example of an antiemetic that may be used to try to reduce nausea and vomiting (Rhodes 2001). It is in the butyrophenone class of drugs and acts as a dopamine antagonist at the chemoreceptor trigger zone in the brain (Mannix 2004). Theoretically, therefore, it should be effective for biochemical causes of nausea or to reduce the emetic effect of drugs such as morphine, which is mediated through the chemoreceptor trigger zone. Haloperidol is another example of a butyrophenone and its use in this context has been systematically reviewed separately (Perkins 2009). Droperidol is used alone or together with other antiemetics orally, intravenously or intramuscularly.
In the UK, droperidol is available as an injection (2.5 mg in 1 mL), licensed for intravenous use for the prevention and treatment of postoperative nausea and vomiting (PONV) or the prevention of nausea and vomiting induced by morphine derivatives during postoperative patient‐controlled analgesia (PCA). For PONV the dose is 0.625 mg to 1.25 mg in adults (0.625 mg for the elderly or those with renal or hepatic impairment). For use with PCA in adults, the dose is 15 to 50 micrograms of droperidol per mg of morphine, up to a maximum daily dose of 5 mg of droperidol. There are no data on PCA for patients with renal or hepatic impairment in the Summary of Product Characteristics (SPC).
The United States Food and Drug Administration issued a black box warning in 2001 following concerns about QT interval prolongation and deaths due to cardiac arrhythmia with the use of droperidol (Food and Drug Administration 2001). This decision has been the focus of debate (Habib 2008; Kao 2003; Ludwin 2008; Nuttall 2007). The UK Medicines and Healthcare products Regulatory Authority (MHRA) raised concerns about the potential effect of droperidol on the QT interval and requested a risk‐benefit analysis, which led to the voluntary withdrawal of some formulations of droperidol by Jansen‐Cilag (MHRA 2001). The MHRA subsequently granted marketing authorisation for droperidol to the pharmaceutical company ProStrakan, in January 2008 (MHRA 2008).
Droperidol is also known by its trade names Droleptan (Australia, New Zealand), Inapsine (US, Canada), Xomolix (UK), Droperdal (Brazil), Dehydrobenzperidol (Belgium, Luxembourg), Droperol (India), Sintodian (Italy), Dridol (Norway, Sweden), Inapsin (South Africa), Paxical (South Africa) and Dehidrobenzperidol (Spain, Portugal) (Martindale 2009).
The medical literature regarding droperidol as an antiemetic relates primarily to its use intravenously in the prevention of postoperative nausea and vomiting or chemotherapy‐associated nausea and vomiting. We wanted to establish whether there was any evidence to support its use in the palliative care setting.
All patients with terminal illness should have access to palliative care, independent of their diagnosis, and we wish to reflect this in our review. Defining this population has been identified as a problem in previous reviews. We used the definition 'adult patients in any setting, receiving palliative care or suffering an incurable progressive medical condition', which has previously been used in a Cochrane review (Hirst 2001).
Objectives
To evaluate the efficacy and adverse events (both minor and serious) associated with the use of droperidol for the treatment of nausea and vomiting in palliative care patients.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) of droperidol for the treatment of nausea or vomiting, or both, in any setting.
Types of participants
Inclusion criteria
Adults receiving palliative care or suffering from an incurable progressive medical condition. Adults suffering from nausea or vomiting, or both.
Exclusion criteria
Nausea or vomiting, or both, thought to be secondary to pregnancy or surgery; antiemetic(s) used for the prophylaxis of nausea or vomiting associated with chemotherapy.
Types of interventions
We included studies where droperidol was used to treat nausea or vomiting (alone or in addition to other agents) including any dose of droperidol, via any route, over any duration of follow‐up.
Acceptable comparators
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Placebo
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Other drug
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Non‐pharmacological intervention
Types of outcome measures
Primary outcomes
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Nausea rating: intensity, duration (the patient's report of his or her symptoms)
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Vomiting severity rating (the patient's report of his or her symptoms)
Secondary outcomes
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Quality of life measurement
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Acceptability of treatment
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Need for rescue antiemetic medication
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Adverse events (including sedation, rigidity, tremor and cardiovascular side effects)
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Withdrawal from study because of side effects
Search methods for identification of studies
We searched electronic databases including CENTRAL, MEDLINE, EMBASE, CINAHL and AMED, using relevant search terms and synonyms. The basic search strategy was ("droperidol" OR "butyrophenone") AND ("nausea" OR "vomiting"), modified for each database. Handsearching complemented the electronic searches (using reference lists of included studies, relevant chapters and review articles). We did not impose a language restriction on studies. The MEDLINE search strategy is shown in Appendix 1. The search was undertaken on 23 November 2007 and updated 16 June 2009 and again on 2 December 2009.
We performed updated searches of MEDLINE, EMBASE, CENTRAL and AMED 2009 to 2013 on 19 November 2013 and of CINAHL on 20 November 2013.
We also searched trial registers (metaRegister of controlled trials (www.controlled-trials.com/mrct), clinicaltrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (http://apps.who.int/trialsearch/)) on 22 November 2013, using the keyword "droperidol".
Data collection and analysis
We judged the potential relevance of studies based on their titles and abstracts, and obtained studies that we anticipated might meet the inclusion criteria. Two review authors independently reviewed the abstracts for the initial review and four review authors reviewed the abstracts for the update to assess suitability for inclusion. We discussed discrepancies to achieve consensus. For the initial review, a translator enabled us to assess whether two Japanese papers identified by the search met the inclusion criteria for the review (Fujii 1987; Niijima 1986). We planned to assess the quality of included papers using the Jadad criteria (Jadad 1996).
Results
Description of studies
The search strategy run on 23 November 2007 identified 1851 abstracts (1021 excluding duplicates), of which we obtained 23 references in full as potentially meeting the inclusion criteria. On review of the full papers, we identified no studies that met the inclusion criteria. We identified a further 140 abstracts when the search was updated on 16 June 2009 and we identified 48 abstracts when the search was further updated on 2 December 2009.
From assessment of these additional abstracts, none met the inclusion criteria.
The updated searches carried out in November 2013 identified 304 abstracts (261 excluding duplicates), of which we obtained 18 references in full as potentially meeting the inclusion criteria. On review of the full papers, we identified no studies that met the inclusion criteria, therefore there were no studies included in the review.
We found no registered trials of droperidol for the management of nausea or vomiting in palliative care. The study flow diagram is shown in Figure 1.
Study flow diagram.
We excluded 41 studies (23 from the 2010 review and 18 from the updated 2013 search) and these are detailed in the Characteristics of excluded studies table.
Risk of bias in included studies
We included no studies.
Effects of interventions
It was not possible to draw conclusions about the effects of droperidol in the palliative care setting as we could find no included studies for this review.
Discussion
Evidence for the effectiveness of droperidol
Droperidol has been widely used as an antiemetic, particularly for the prophylaxis and treatment of postoperative nausea and vomiting (PONV), and it has been studied for the prophylaxis of nausea and vomiting associated with chemotherapy (e.g. cisplatin).
Droperidol for postoperative nausea and vomiting has been systematically reviewed (Carlisle 2006), and there is some evidence for its effectiveness in this context. Carlisle's systematic review identified 222 studies examining the effectiveness of droperidol for PONV. The relative risk (compared to placebo) was 0.65 for nausea and 0.65 for vomiting. A systematic review of antiemetics for the control of PONV for patients receiving patient‐controlled analgesia found that droperidol was significantly more effective than placebo (Tramer 1999), with numbers needed to treat of 2.7 for nausea (confidence interval 1.8 to 5.2) and 3.1 for vomiting (confidence interval 2.3 to 4.8), compared to placebo.
Of the studies reporting the effectiveness of droperidol for the prevention of nausea and vomiting associated with chemotherapy (Aapro 1991; Fujii 1987; Herrstedt 1991; Jacobs 1980; Kim 1994; Lehoczky 2001; Lennox 1985; Lewis 1984; Melsom 1982; Minegishi 2003; Muller 1989; Niijima 1986; Owens 1984; Poka 1993; Roberts 1985; Sagae 2003; Saller 1986; Stuart‐Harris 1983), one included only participants in the palliative stage of their illness. This was a cross‐over study of 32 in‐patients with advanced lung cancer receiving cisplatin chemotherapy (Fujii 1987). The addition of droperidol to dexamethasone and metoclopramide was reported to be associated with a shorter median duration of nausea (two days versus four days, P value < 0.05), but no significant difference in median vomiting duration or volume. However, randomisation, allocation concealment and blinding methods were not clear.
The use of droperidol as an antiemetic has also been studied in patients with severe non‐malignant low back pain who were treated with an epidural catheter (Aldrete 1995), and in patients attending the emergency department who received treatment of nausea or vomiting due to any cause (Braude 2006; Patanwala 2010).
It is not clear to what extent these studies can be extrapolated to the palliative care setting and other causes of nausea and vomiting.
Side effects
In 2001, the United States Food and Drug Administration issued a black box warning against the use of droperidol, in view of case reports of prolongation of the QT interval, and cardiac arrhythmia and sudden death (Food and Drug Administration 2001).
This has been an area of controversy, with several authors subsequently defending the use of droperidol (McKeage 2006; Nuttall 2007). A full review of the relevant literature is beyond the scope of this systematic review.
Other side effects reported in the literature (in the context of postoperative nausea and vomiting and chemotherapy‐associated nausea and vomiting) include drowsiness or sedation, akathisia, dystonia, anxiety or restlessness, euphoria, hypotension, flush, dry mouth or rigor (Aapro 1991; Braude 2006; Jacobs 1980; Roberts 1985; Sagae 2003; Saller 1986). Since droperidol is often given with other medication in these settings it can be difficult to establish causality. Sedation appears to be the most commonly reported side effect.
Droperidol in palliative care
Despite previous widespread use and research in anaesthesia and oncology, we did not find any published evidence from randomised controlled trials of the use of droperidol in palliative care settings. A letter by Thangathurai asserts the usefulness of droperidol for the palliation of nausea and vomiting (Thangathurai 2010). Haloperidol (like droperidol, a butyrophenone) is more commonly used in palliative care within the UK and its use for the management of nausea and vomiting in palliative care has been systematically reviewed separately (Perkins 2009).
Studies of antiemetics in palliative care settings are needed to identify which agents are most effective, with minimum side effects (Davis 2010).
Systematic reviews and the evidence base in palliative care
Previous systematic reviews in palliative care have been beset by the problem of the lack of evidence from original studies, particularly randomised controlled trials. Cochrane systematic reviews in palliative care published up to December 2007 were reviewed by Wee 2008, who concluded that "Cochrane reviews in palliative care ... fail to provide good evidence for clinical practice because the primary studies are few in number, small, clinically heterogeneous, and of poor quality and external validity". It can be difficult to carry out randomised controlled trials in palliative care (Grande 2000), and other methodological approaches may be useful in this context. However, Hadley et al note that good quality observational studies are also sparse (Hadley 2009).
Study flow diagram.
