Haloperidol for the treatment of nausea and vomiting in palliative care patients Stable (no update expected for reasons given in 'What's new')

Abstract

Abstract
Background

Nausea and vomiting are common symptoms in patients with terminal, incurable illnesses. Both nausea and vomiting can be distressing. Haloperidol is commonly prescribed to relieve these symptoms. This is an updated version of the original Cochrane review published in Issue 2, 2009, of Haloperidol for the treatment of nausea and vomiting in palliative care patients.

Objectives

To evaluate the efficacy and adverse events associated with the use of haloperidol for the treatment of nausea and vomiting in palliative care patients.

Search methods

For this updated review, we performed updated searches of CENTRAL, EMBASE and MEDLINE in November 2013 and in November 2014. We searched controlled trials registers in March 2015 to identify any ongoing or unpublished trials. We imposed no language restrictions. For the original review, we performed database searching in August 2007, including CENTRAL, MEDLINE, EMBASE, CINAHL and AMED, using relevant search terms and synonyms. Handsearching complemented the electronic searches (using reference lists of included studies, relevant chapters and review articles) for the original review.

Selection criteria

We considered randomised controlled trials (RCTs) of haloperidol for the treatment of nausea or vomiting, or both, in any setting, for inclusion. The studies had to be conducted with adults receiving palliative care or suffering from an incurable progressive medical condition. We excluded studies where nausea or vomiting, or both, were thought to be secondary to pregnancy or surgery.

Data collection and analysis

We imported records from each of the electronic databases into a bibliographic package and merged them into a core database where we inspected titles, keywords and abstracts for relevance. If it was not possible to accept or reject an abstract with certainty, we obtained the full text of the article for further evaluation. The two review authors independently assessed studies in accordance with the inclusion criteria. There were no differences in opinion between the authors with regard to the assessment of studies.

Main results

We considered 27 studies from the 2007 search. In this update we considered a further 38 studies from the 2013 search, and two in the 2014 search. We identified one RCT of moderate quality with low risk of bias overall which met the inclusion criteria for this update, comparing ABH (Ativan®, Benadryl®, Haldol®) gel, applied to the wrist, with placebo for the relief of nausea in 22 participants. ABH gel includes haloperidol as well as diphenhydramine and lorazepam. The gel was not significantly better than placebo in this small study; however haloperidol is reported not to be absorbed significantly when applied topically, therefore the trial does not address the issue of whether haloperidol is effective or well‐tolerated when administered by other routes (e.g. by mouth, subcutaneously or intravenously). We identified one ongoing trial of haloperidol for the management of nausea and vomiting in patients with cancer, with initial results published in a conference abstract suggesting that haloperidol is effective for 65% of patients. The trial had not been fully published at the time of our review. A further trial has opened, comparing oral haloperidol with oral methotrimeprazine (levomepromazine) for patients with cancer and nausea unrelated to their treatment, which we aim to include in the next review update.

Authors' conclusions

Since the last version of this review, we found one new study for inclusion but the conclusion remains unchanged. There is incomplete evidence from published RCTs to determine the effectiveness of haloperidol for nausea and vomiting in palliative care. Other than the trial of ABH gel vs placebo, we did not identify any fully published RCTs exploring the effectiveness of haloperidol for nausea and vomiting in palliative care patients for this update, but two trials are underway.

Author(s)

Fay Murray‐Brown, Saskie Dorman

Abstract

Plain language summary

 Haloperidol for the treatment of nausea and vomiting in palliative care patients 

Haloperidol is often used to help control nausea (feeling sick) or vomiting (being sick), both of which are common problems for patients with serious life‐threatening illnesses. Haloperidol can be given by mouth or by injection. There has been some research looking at how this drug works in nausea and vomiting caused by surgery and when trying to prevent nausea and vomiting caused by anti‐cancer treatments.

This is an update of the original review published in 2009 for which no studies met the inclusion criteria. For this update, in a search of the published literature in November 2014 we found one moderate quality randomised controlled trial which compared ABH (Ativan®, Benadryl®, Haldol®) gel, containing haloperidol and two other medications, to placebo.

The trial showed no difference between ABH gel and placebo. However it has previously been shown that haloperidol is not absorbed after applying ABH gel, so this result is not surprising. We identified a trial of haloperidol for nausea and vomiting in patients with cancer, with initial results presented at a conference. This suggests that haloperidol is effective in 65% of patients, but the results were not fully published at the time of our review. A further trial has opened in Australia, comparing haloperidol with another medication used for nausea, methotrimeprazine (levomepromazine).

Author(s)

Fay Murray‐Brown, Saskie Dorman

Reviewer's Conclusions

Authors' conclusions

Implications for practice

Since the last version of this review, we found one new study for inclusion (Fletcher 2014) but the conclusions remain unchanged.

There is a lack of published evidence for the use of haloperidol for nausea and vomiting in palliative care. A study comparing ABH gel (containing haloperidol, diphenhydramine and lorazepam) to placebo showed no significant difference (Fletcher 2014). However haloperidol is not absorbed significantly following application of the gel (Smith 2012a). No other RCTs of haloperidol in this setting have been fully published but two trials are underway (ACTRN12610000481077; ACTRN12615000177550).

Implications for people with nausea or vomiting in the context of advanced disease

Haloperidol is often used to help control nausea (feeling sick) or vomiting (being sick). The evidence to support this is largely from other settings ‐ for example, haloperidol to control sickness after surgical operations, chemotherapy or radiotherapy. There are no published randomised trials of haloperidol to control nausea and vomiting in people with advanced disease, other than a small study of a gel containing haloperidol (ABH gel) compared with placebo. No significant difference was found between ABH gel and placebo, which is not surprising as haloperidol is not absorbed by this route. Two randomised studies are underway to compare haloperidol with other medications for nausea and vomiting.

Implications for clinicians

Haloperidol may still be used as an antiemetic, though there is no evidence from RCTs in the palliative care context to quantify its effectiveness used orally or by injection. A small study of a gel containing haloperidol (ABH gel) compared with placebo found no significant difference (Fletcher 2014), which is not surprising as haloperidol is not absorbed by this route (Smith 2012a). Initial results from a trial which is underway suggest that it may be effective in 65% of patients (ACTRN12610000481077). Further results from this ACTRN12610000481077 and another ongoing study, ACTRN12615000177550, will help to inform practice which so far has been guided by clinical experience, consensus (Keeley 2007), an uncontrolled study (Hardy 2010) and research in other settings (McLean 2013).

Implications for policy makers

Haloperidol is frequently prescribed as an antiemetic (Prommer 2012; Smith 2012b; To 2014), although there is no evidence from RCTs in the palliative care context to quantify its effectiveness used orally or by injection. A small study of a topically applied gel containing haloperidol (ABH gel) compared with placebo found no significant difference (Fletcher 2014), which is not surprising as haloperidol is not absorbed by this route (Smith 2012a). Initial results from a trial which is underway suggest that it may be effective in 65% of patients (ACTRN12610000481077). Further results from ACTRN12610000481077 and another ongoing study, ACTRN12615000177550, will help to inform practice which so far has been guided by clinical experience, consensus (Keeley 2007) and research in other settings (McLean 2013).

Implications for funders

There is limited evidence for the use of haloperidol as an antiemetic in palliative care although it is commonly prescribed. Current clinical practice is guided by clinical experience, consensus and research in other settings. Some research to compare haloperidol with other antiemetics is underway, however this is a relatively under‐researched area. Nausea and vomiting are common, distressing symptoms with a profound impact on quality of life. Further studies are needed to determine the most effective strategies for managing these symptoms.

Implications for research

Much has been written about methodological challenges when conducting research in palliative medicine (Jordhoy 1999; Ewing 2004). Nevertheless, two trials of haloperidol compared with other antiemetics are underway (ACTRN12610000481077; ACTRN12615000177550).

There is scope to build on this evidence further, using variations in intervention (e.g. dose, route of administration) and variations in trial design.

For instance, a randomised controlled trial could be conducted with participants with advanced disease who have nausea or vomiting, not associated with surgery, chemotherapy, radiotherapy or pregnancy, using an intervention of haloperidol, compared with another antiemetic, for example levomepromazine. Oral or subcutaneous routes of administration could be appropriate as these are often used in palliative care settings. Suggested outcomes include relief from nausea and from vomiting, anxiety, sedation, and extrapyramidal side effects. The duration of the study would be likely to have an impact on recruitment and attrition rates, but some side effects may only be apparent after weeks or months of use.

The pros and cons of placebo‐controlled studies have been debated (Hardy 1997; Kirkham 1997; Sanderson 2013). Placebo effects are likely to be significant, particularly in the context of a therapeutic relationship and environment (Sanderson 2013). Kris et al recommended that further trials of antiemetics in the context of chemotherapy should be conducted using active agents rather than placebo as comparator (Kris 1996). However a recent study of antiemetics in the emergency department compared metoclopramide, ondansetron and placebo and found no significant difference; most participants were satisfied with the treatment of their nausea (Egerton‐Warburton 2014). The feasibility and ethical acceptability of a placebo arm may in part depend on the participants' perception of the severity of their symptoms and the urgency of the need for treatment.

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