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Drug therapy for symptoms associated with anxiety in adult

palliative care patients (Review)
Salt S, Mulvaney CA, Preston NJ
Salt S, Mulvaney CA, Preston NJ.

Drug therapy for symptoms associated with anxiety in adult palliative care patients.
Cochrane Database of Systematic Reviews 2017, Issue 5. Art. No.: CD004596.
DOI: 10.1002/14651858.CD004596.pub3.
www.cochranelibrary.com
Drug therapy for symptoms associated with anxiety in adult palliative care patients (Review)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
BACKGROUND.............................................................................................................................................................................................. 3
OBJECTIVES.................................................................................................................................................................................................. 4
METHODS..................................................................................................................................................................................................... 4
RESULTS........................................................................................................................................................................................................ 7
Figure 1.................................................................................................................................................................................................. 8
DISCUSSION.................................................................................................................................................................................................. 9
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 10
ACKNOWLEDGEMENTS................................................................................................................................................................................ 10
REFERENCES................................................................................................................................................................................................ 11
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 14
APPENDICES................................................................................................................................................................................................. 15
WHAT'S NEW................................................................................................................................................................................................. 32
HISTORY........................................................................................................................................................................................................ 32
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 32
DECLARATIONS OF INTEREST..................................................................................................................................................................... 33
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 33
NOTES........................................................................................................................................................................................................... 33
INDEX TERMS............................................................................................................................................................................................... 33
Drug therapy for symptoms associated with anxiety in adult palliative care patients (Review) i
Informed decisions.
[Intervention Review]
Drug therapy for symptoms associated with anxiety in adult palliative

care patients
Susan Salt1, Caroline A Mulvaney2, Nancy J Preston3
1Trinity Hospice, Blackpool, UK. 2School of Medicine, University of Nottingham, Nottingham, UK. 3International Observatory on End of
Life Care, Lancaster University, Lancaster, UK
Contact address: Caroline A Mulvaney, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK.
caroline.mulvaney@nottingham.ac.uk.
Editorial group: Cochrane Pain, Palliative and Supportive Care Group

Publication status and date: Stable (no update expected for reasons given in 'What's new'), published in Issue 6, 2019.
Citation: Salt S, Mulvaney CA, Preston NJ. Drug therapy for symptoms associated with anxiety in adult palliative care patients. Cochrane
Database of Systematic Reviews 2017, Issue 5. Art. No.: CD004596. DOI: 10.1002/14651858.CD004596.pub3.
ABSTRACT
Background
This is an update of a Cochrane Review first published in 2004 (Issue 1) and previously updated in 2012 (Issue 10). Anxiety is common in
palliative care patients. It can be a natural response to the complex uncertainty of having a life-limiting illness or impending death, but it
may represent a clinically significant issue in its own right.
Objectives
To assess the effectiveness of drug therapy for treating symptoms of anxiety in adults with a progressive life-limiting illness who are thought
to be in their last year of life.
Search methods
We ran the searches for this update to May 2016. We searched the CENTRAL, MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCO),
PsychLIT (Silver Platter) and PsycINFO (Ovid). We searched seven trials registers and seven pharmaceutical industry trials registers. We
handsearched the conference abstracts of the European Association of Palliative Care.
Selection criteria
Randomised controlled trials which examined the effect of drug therapy for the treatment of symptoms of anxiety in adult palliative care
patients, that is, people with a known progressive life-limiting illness that is no longer responsive to curative treatment, including advanced
heart, respiratory and neurological diseases (including dementia). Comparator treatments included placebo; another drug therapy or
different dose schedule; or a non-drug intervention such as counselling, cognitive behaviour therapies or relaxation therapies.
Data collection and analysis

Two review authors independently screened titles and abstracts to identify potentially relevant papers for inclusion in the review. We
sought full-text reports for all papers retained at this stage and two reviews authors independently assessed these for inclusion in the
review. We planned to assess risk of bias and extract data including information on adverse events. We planned to assess the evidence
using GRADE and to create a 'Summary of findings' table.
Main results
In this update, we identified 707 potentially relevant papers and of these we sought the full-text reports of 10 papers. On examination of
these full-text reports, we excluded eight and two are awaiting classification as we have insufficient information to make a decision. Thus,
in this update, we found no studies which met our inclusion criteria. For the original review, we identified, and then excluded, the full-text
Drug therapy for symptoms associated with anxiety in adult palliative care patients (Review) 1
Informed decisions.
reports of six potentially relevant studies. For the 2012 update, we sought, and excluded, two full-text reports. Thus, we found no studies
that assessed the effectiveness of drugs to treat symptoms of anxiety in palliative care patients.
Authors' conclusions
There is a lack of evidence to draw a conclusion about the effectiveness of drug therapy for symptoms of anxiety in adult palliative care
patients. To date, we have found no studies that meet the inclusion criteria for this review. We are awaiting further information for two
studies which may be included in a future update. Randomised controlled trials which assess management of anxiety as a primary endpoint
are required to establish the benefits and harms of drug therapy for the treatment of anxiety in palliative care.
PLAIN LANGUAGE SUMMARY
Drugs to help reduce anxiety in people nearing the end of life due to illness
Review question
We aimed to answer the question "how good are drugs at treating anxiety and worry in adults who have an illness which is getting worse
and are in the last year of their life?"
Background
Anxiety or worry is a common problem for people who have an illness which is getting worse and are in the last year of their life. People
may be anxious for many reasons. These reasons include being worried about pain and treatment, having to rely on other people to help
them and having to face death. Anxiety can make it difficult for people to cope with their illness. Anxiety can make other problems worse
and harder to manage, problems such as pain or feeling short of breath. For people who are nearing the end of their life due to illness, it
is important to reduce their worry if possible. The use of some medicines may help to reduce anxiety. However, anxiety in people who are
nearing the end of life has not be studied very much. People with anxiety often do not have their anxiety properly treated.
We searched for studies which looked at how good medicines were at reducing worry in adults nearing the end of their life. We were
interested in studies that compared use of a medicine to no medicine, another medicine or a different dose of that medicine, or treatments
such as talking to someone or relaxation therapy. We were interested in studies that measured anxiety. We were interested in trials designed
to ensure that participants had an equal chance of receiving any of the treatments being tested in each trial. This review was first done in
2004 and updated in 2012. This is the second update. We searched to May 2016 for studies to include in this review.
Key results
We found no studies to include in this review. No studies were found for the original 2004 review or for the 2012 update. There is a lack
of studies assessing the effect of drugs on reducing anxiety in adults who are nearing the end of their life. We found two relevant studies
which may be included in a future update, but we need more information before we can make a judgement. Anxiety can have a big impact
on how a person can cope with their illness, and we therefore need to know how to reduce their anxiety. Good-quality studies on how to
reduce anxiety are needed.
Informed decisions.
BACKGROUND Anxiety may be a manifestation of a change in metabolic state

such as hypoxia or hypoglycaemia, or in the dying phase (last
Description of the condition 48 hours of life) as part of the result of multiple organ failure.
Certain medications commonly used in caring for people near
This is the second update of the review "Drug therapy for anxiety in
the end of life may produce symptoms that can be confused
adult palliative care patients" originally published in Issue 1, 2004
with anxiety, for example, akathisia or motor restlessness. These
(Jackson 2004) of the Cochrane Library and published as a first
include phenothiazines (e.g. prochlorperazine), butyrophenones
update in Issue 10, 2012 (Candy 2012).
(e.g. haloperidol), methotrimeprazine and metoclopramide.
Anxiety can be an intractable and crippling condition. It impacts on Abrupt discontinuation of certain substances can also lead
the person's ability to cope emotionally and to function socially, to withdrawal and precipitate an anxiety state, for instance
and may make physical symptoms more difficult to manage alcohol, nicotine, anticonvulsants, benzodiazepines, clonidine,
(Spencer 2010). In the advanced stages of a progressive, life-limiting corticosteroids, opioids and sedative-hypnotics (Maguire 1993).
illness it may also manifest with concomitant depression and Numerous other medications and substances have been associated
result in the person experiencing even greater difficulties (Mitchell with anxiety symptoms and, therefore, a thorough medication
2011; Wilson 2007). The symptoms of anxiety include feelings of history should always precede changes in a drug therapy regimen
apprehension, fear, irritability and tension. Cognitively, anxiety (Jackson 2000).
manifests itself as excessive worry or difficulty concentrating.
Behavioural symptoms involve avoidant or compulsive tendencies,
Description of the intervention
and physical and somatic symptoms include diarrhoea, sweating, While there are clinical guidelines for the treatment of clinically
restlessness, fatigue, and insomnia. People may also present with significant anxiety (Baldwin 2005; NICE 2011b; NICE 2015), few
more acute symptoms including palpitations, tachycardia, and are specific to palliative care where treatments may need to be
shortness of breath (Thielking 2003). Anxiety is a term for a number different because of the added psychological and physical burden
of disorders, specifically generalised anxiety disorders (GAD), of living with a terminal disease (National Consensus Project
substance-induced anxiety, adjustment disorders, obsessive- 2009; NICE 2004; NICE 2015). Treatment in palliative care can
compulsive disorders, specific phobias such as in response to include behavioural techniques, such as cognitive behavioural
medical interventions, panic disorders and post-traumatic stress therapy (CBT) (Moorey 2009), and drug therapy. In deciding on
disorder (DSM-5 2013). GAD and panic disorder were found in treatment options, the clinician has to consider whether a person
one study to be the most common anxiety disorders in advanced has both sufficient energy to engage with non-pharmacological
disease (Wilson 2007). The importance of a holistic approach to interventions and the time needed to establish the benefit of such
managing all symptoms including anxiety has been reaffirmed interventions. In deciding whether a pharmacological approach
by frameworks around palliative and end of life care including may be useful, the severity of the person's symptoms and the
Ambitions for Palliative and End of Life Care (National Palliative degree to which they interfere with overall function and well-being
and End of Care 2015) and National Institute for Health and Care are important factors to consider. In addition, the clinician needs
Excellence (NICE) guidance on end of life care (NICE 2011a). to assess whether the person has compromised hepatic and renal
function, and must also consider the potential adverse effects of
In people with a progressive life-limiting illness, anxiety can be a the drug therapy. Short-acting benzodiazepines, such as lorazepam
natural reaction to the extraordinary psychological and physical and oxazepam, are often the drugs of choice in terminally ill
challenges to be faced including the prognostic and treatment people (Breitbart 1996; Henderson 2006; Noyes 1998; Roth 2007).
uncertainties often associated with the situation. The prevalence However, they may not be suitable for everyone because of
of symptoms of excessive anxiety is under researched, but it is adverse effects such as excessive sedation and confusion, which
one of the most common reasons for a psychiatric consultation in are associated with an increased risk of falls. Furthermore, if
this patient group (Roth 2007). Anxiety can increase because of a benzodiazepines are given for longer than a few weeks, there
broad range of concerns faced, such as how well symptoms will is the potential risk of physical dependency. The palliative care
be managed, increasing dependency on other people, increased literature lists a variety of other potentially useful agents in the
social isolation, confrontation with existential issues, and a growing management of anxiety including antidepressants, buspirone,
inability to support and be with family and friends. Anxiety may chlorpromazine, haloperidol, hydroxyzine, levomepromazine,
also occur as the result of poorly controlled symptoms, such as ketamine and atypical antipsychotic drugs (e.g. olanzapine,
pain, or the use of medications. Despite these known risks, anxiety risperidone) (Khojainova 2002; Mintzer 2001).
in terminally ill people is underdiagnosed and undertreated, and
is less extensively researched than depression (Kolva 2011; Wilson How the intervention might work
2007).
This review explores the evidence for the effectiveness of drugs to
One of the challenges in palliative care is to distinguish between treat anxiety in palliative care patients. These medications have
excessive or maladaptive anxiety, and normal distress. There are a variety of mechanisms of action, including some drugs where
numerous causes; in particular, it has been highly correlated with the exact mechanism is unknown. Drug therapy for treatment of
uncontrolled pain (Payne 1995). In addition, many studies looking anxiety can be considered to work from two distinct approaches.
at psychiatric states in people with a life-limiting diagnosis do not The first is related to the mechanism of action at the level of
clearly separate their assessments of depression and anxiety states neurotransmitters in the central nervous system. These include
or define clearly their study populations with respect to where a dopamine, gamma amino butyric acid (GABA), noradrenaline and
person is on their illness journey. This makes it more difficult to serotonin.
identify if anxiety is associated with specific stages in an illness
journey, such as the palliative phase.
Informed decisions.
The second approach is aimed at reducing the physical symptoms For the purposes of the review, we defined palliative care patients
of anxiety that result from autonomic hyperactivity, such as as people with a progressive, life-limiting illness, no longer
tremors and palpitations. In some instances, it is these physical responsive to disease-modifying treatments who were thought
manifestations that worsen the cognitive aspects of anxiety, such as to be in the last year (or so) of life and were, or would be,
an inability to concentrate or sense of foreboding. The use of drugs eligible to receive palliative care. We did not include studies in
such as beta-blockers, which slow the heart rate, may reduce or which participants were in the last 24 to 48 hours of life. At this
eliminate these physical manifestations and so reduce the overall time, symptoms of anxiety may also be in part a manifestation of
impact of anxiety. The use of agents to treat physical manifestations irreversible processes such as multiple organ failure, and treatment
may reduce or possibly eliminate the need for agents aimed at may differ from that considered in earlier phases of the disorder.
altering neurotransmitter systems.
Types of interventions
Why it is important to do this review Interventions for anxiety included any type of drug therapy,
Anxiety is a distressing condition that is particularly common for example, 5-HT3 receptor antagonists, anxiolytic agents,
and troublesome for people dealing with the advanced stages antidepressive agents, antipsychotic and atypical antipsychotic
of a life-limiting condition. Excessive anxiety can manifest itself agents, benzodiazepines, butyrophenones, phenothiazines,
as both physical and emotional symptoms and can reduce a antihistamines, barbiturates, sedative hypnotics, antiepileptic
person's ability to cope physically and mentally with the life- drugs, ketamine and beta-blockers. We did not include any non-
limiting condition. Drugs represent one way of allaying a person's conventional drugs, such as herbal medicines.
anxiety, but choosing the most appropriate drug is dependent on
the clinician having access to evidence reviewing the effectiveness Comparator treatments included placebo; another drug therapy
of drugs for anxiety in people with life-limiting conditions. To our or different dose schedule; or a non-drug intervention such as
knowledge prior to the original review in 2004 there had been counselling, CBT or relaxation therapies.
no systematic search of the international literature for evidence
Types of outcome measures
regarding the effectiveness of drug therapy for anxiety disorders in
palliative care patients. Primary outcomes
OBJECTIVES • Anxiety: studies were eligible for inclusion if they reported

anxiety measured using a validated scale which measures
To assess the effectiveness of drug therapy for treating symptoms either anxiety alone or as a subscale. Examples of validated
of anxiety in adults with a progressive life-limiting illness who are instruments include the following:
thought to be in their last year of life. • Hamilton Anxiety Rating Scale (HAM-A) (Hamilton 1959);
• Symptom Check List-90 (SCL-90) anxiety sub scale (Derogatis
METHODS 1983);
Criteria for considering studies for this review • Diagnostic Interview Schedule (DIS) (Robins 1981);
• Affects Balance Scale (ABS) (Bradburn 1969);
Types of studies
• Hospital Anxiety and Depression Scale (HADS) (Zigmond
Randomised controlled trials (RCTs). 1983);
• Edmonton Symptom Assessment System (ESAS) (Bruera
Types of participants 1991);
Adult palliative care patients (aged 18 years or older) whose • Profile of Mood States (Pollock 1979);
symptoms of anxiety were described by the trial authors as beyond • Rotterdam Symptoms Checklist (de Haes 1996);
what could be seen as normal in this patient group. This could be • Palliative care Outcome Scale (or Patient Outcome Scale)
captured as a score equivalent to clinically significant symptoms on (Hearn 1999);
a validated scale, such as the Hamilton Anxiety Rating Scale (HAM-
• Support Team Assessment Schedule (STAS) (Higginson
A) (Hamilton 1959).
1993);
We included trials where anxiety was described as a disorder • Beck Anxiety Inventory (BAI) (Beck 1988);
such as adjustment disorder, obsessive-compulsive disorder, • State-Trait Anxiety Inventory (STAI) (Spielberger 1983).
phobia, panic disorder, post-traumatic stress disorder or GAD. We
sought to verify that symptoms reported as clinically significant We reported anxiety outcomes assessed at one week.
were measured using validated scales, and if the population
was described as having an anxiety disorder (specifically GAD, Secondary outcomes
substance-induced anxiety, adjustment disorders, obsessive- • Depression measured using any validated scale either alone or
compulsive disorders, specific phobias such as in response to as a subscale. Examples of validated instruments include:
medical interventions, panic disorders and post-traumatic stress * Hospital Anxiety and Depression Scale (HADS) (Zigmond
disorder) that it was defined using the International Classification 1983);
of Disease (ICD) (ICD-10 2010) or the Diagnostic and Statistical * Beck Depression Inventory (BDI) (Beck 1961).
Manual of Mental Disorders (DSM-III 1980; DSM-R 1987; DSM-IV
1994; DSM-IV-TR 2000; DSM-5 2013). • Breathlessness measured using a validated scale. An example
includes:
* St George's Respiratory Questionnaire (Jones 1991).
Informed decisions.
• Insomnia measured using any validated scale. Examples Registry; German Clinical Trials Register; Iranian Registry of
include: Clinical Trials; Sri Lanka Clinical Trials Registry; The Netherlands
* Insomnia Severity Index (Bastien 2001); National trial Register) (www.who.int/trialsearch) (to May 2016).
* Pittsburgh Sleep Quality Index (Buysse 1989);
For the original review and the first update, we searched the ISRCTN
* Athens Insomnia Scale (Soldatos 2000). Trials Register (www.controlled-trials.com/isrctn) to 2012, but its
• Participants experiencing any adverse events, such as sedation contents are captured by the WHO Portal and so we did not search
or failure of treatment. it for this second update in 2017.
• Withdrawals due to lack of efficacy, adverse events or any cause.
Pharmaceutical industry trials registers searched
Search methods for identification of studies
• AstraZeneca Clinical Trials (www.astrazenecaclinicaltrials.com)
Electronic searches (to May 2016).
To identify studies for inclusion in this review, we developed • Daiichi Sankyo (www.daiichisankyo.com) (to May 2016).
detailed search strategies for each electronic database searched. • Eisai (www.eisai.com/) (to May 2016).
These were based on the search strategy developed for MEDLINE • GlaxoSmithKline Clinical Trial Register (www.gsk-
but revised appropriately for each database. The search strategy clinicalstudyregister.com) (to May 2016).
used in the original review run in 2003 is reported in Appendix 1 and • Lundbeck (www.lunbeck.com) (to May 2016).
the search strategies used in the first update of 2012 are presented • NovartisClinicalTrials.com (www.novartis.com/) (to May 2016).
in Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 6,
• Roche Clinical Trial Protocol Registry (www.roche-trials.com/
and Appendix 7. The search strategies used in 2016 for the second
main.action) (to May 2016).
update of this review are reported in Appendix 8. We also updated
the list of drugs included in the search and re-ran the search for Conference abstracts
these for all years to May 2016 (see Appendix 9).
For this second update of the review, we handsearched the
Databases searched following conference abstracts:
• The Cochrane Central Register of Controlled Trials (CENTRAL; • World Research Congress EAPC (2012 and 2014);
2016, Issue 4) (Cochrane Register of Studies Online) (18 May
• World Congress EAPC (2013 and 2015).
2016).
• MEDLINE (OVID) (1966 to May week 1 2016). We did not search the EAPC 2016 conference abstracts as the
• Embase (OVID) (1980 to 16 May 2016). conference was not held until June 2016.
• CINAHL (EBSCO) (1982 to 18 May 2016).
Reference lists
• PsychLIT (Silver Platter) (1974 to 2000).
• PsycINFO (OVID) (1990 to May week 2 2016). We searched the reference lists of review articles.
For the original review, the Cochrane Pain, Palliative & Supportive Unpublished data
Care Register was searched to July 2003 but its contents are now We did not seek unpublished studies.
captured by CENTRAL and so we did not search it for this update.
Language
Searching other resources
The search was not restricted by language of publication.
We searched the following trials and pharmaceutical industry trials
registers. Data collection and analysis
Trials registers searched Selection of studies
• ClinicalTrials.gov (clinicaltrials.gov/) (to May 2016). In this update, two review authors (SS and CM) independently
• metaRegister of controlled trials (www.isrctn.com/page/mrct) assessed titles and abstracts for eligibility for inclusion in the
(to May 2016). review. We sought full-text reports of all potentially relevant studies
remaining after the initial assessment and two review authors
• ISRCTN Trials Register (www.controlled-trials.com/isrctn) (to
(SS and CM) independently assessed these against our predefined
2012).
inclusion criteria. We resolved any disagreements between the
• Netherlands Trial Register (www.trialregister.nl/trialreg/ review authors by consulting a third review author (NP). Where
index.asp) (to May 2016). we identified posters or conference abstracts which we considered
• NIHR Clinical Research Portfolio Database (public.ukcrn.org.uk/ potentially relevant, we sought full-text reports of the study
search/) (to May 2016). and, if unsuccessful, we contacted study authors to seek further
• UMIN Japan Trial Register (www.umin.ac.jp/ctr) (to May 2016). information. Where English translations for studies published in
• UK Clinical Trials Gateway (www.ukctg.nihr.ac.uk/default.aspx) another language were not available at the screening stage, we
(to May 2016). obtained full-text reports and translated these initially using an
electronic translator. We reported reasons for excluding full-text
• World Health Organization (WHO) Portal (covers
reports. See Characteristics of excluded studies table.
ClinicalTrials.gov; ISRCTN; Australian and New Zealand Clinical
Trial Registry; Chinese Clinical Trial Register; India Clinical Trials
Informed decisions.
Data extraction and management We considered studies where outcome assessment was not
blinded as having a high risk of bias.
We designed a data extraction form to collect the following data:
• Selective reporting (checking for reporting bias). We aimed to
• publication details; assess whether primary and secondary outcome measures were
• study eligibility criteria; prespecified and whether these were consistent with those
reported. We aimed to assess selective reporting as: low risk of
• study details (e.g. aim, start and end date, ethics approval);
bias (studies reported primary and secondary outcomes); high
• participant characteristics (e.g. number of participants, age, sex, risk of bias (not all prespecified outcomes reported or only for
diagnosis of anxiety, study setting); certain data collection time points).
• description of intervention and comparator (e.g. duration of • Incomplete outcome data (checking for possible attrition
treatment, timing, delivery, number randomised to groups); bias due to the amount, nature and handling of incomplete
• outcome details (e.g. instrument used to evaluate anxiety, time outcome data). We planned to assess the methods used to
points when outcomes were assessed, withdrawals). deal with incomplete data as: low risk of bias (less than 10%
of participants did not complete the study or used 'baseline
Assessment of risk of bias in included studies observation carried forward' analysis), or both; unclear risk of
We planned for two review authors (SS and CM) to independently bias (used 'last observation carried forward' analysis); high risk
assess risk of bias for each study, using the criteria outlined in the of bias (used 'completer' analysis).
Cochrane Handbook for Systematic Reviews of Interventions (Higgins • Size of study (checking for possible biases confounded by small
2011), with any disagreements resolved by discussion. We planned size). We aimed to assess studies as being at low risk of bias
to complete a 'Risk of bias' table for each included study using the (200 participants or greater per treatment arm); unclear risk of
'Risk of bias' tool in Review Manager 5 (RevMan 2014). bias (50 to 199 participants per treatment arm); high risk of bias
(fewer than 50 participants per treatment arm)
We aimed to assess the following for each study.
Measures of treatment effect
• Random sequence generation (checking for possible selection
bias). We planned to assess the method used to generate the We planned to analyse dichotomous data as odds ratios and 95%
allocation sequence as: low risk of bias (any truly random confidence intervals (CI) and continuous data as mean difference
process, e.g. random number table; computer random number and 95% CI.
generator); unclear risk of bias (method used to generate
Unit of analysis issues
sequence not clearly stated). We planned to exclude studies
using a non-random process (e.g. odd or even date of birth; For any RCTs using a cross-over design, we planned to use only data
hospital or clinic record number). from the first comparative phase prior to cross-over. This decision
• Allocation concealment (checking for possible selection bias). was based on the possibility of a carry-over of treatment effect from
The method used to conceal allocation to interventions prior to the drug evaluation or a comparative treatment.
assignment determines whether intervention allocation could
have been foreseen in advance of, or during, recruitment, or Dealing with missing data
changed after assignment. We planned to assess the methods For this review, we expected a significant loss to follow-up due to
as: low risk of bias (e.g. telephone or central randomisation; participants' declining health. We planned to report trial attrition
consecutively numbered sealed opaque envelopes); unclear risk rates in the 'Risk of bias' table. This would have included, if
of bias (method not clearly stated). We aimed to exclude studies available, reasons for attrition per treatment arm. Where study data
that did not conceal allocation (e.g. open list). were missing but might have been available, we planned to contact
• Blinding of participants and personnel (checking for possible the authors to obtain missing outcome data where possible. We
performance bias). We planned to assess the methods used planned not to exclude trials on the basis of missing data.
to blind study participants and personnel from knowledge of
which intervention a participant received. We aimed to assess Assessment of heterogeneity
methods as: low risk of bias (study stated that it was blinded If meta-analysis had been possible, we planned to use the I2 statistic
and described the method used to achieve blinding, such as to assess heterogeneity among the trials in each analysis. If we
identical tablets matched in appearance or smell, or a double- identified substantial heterogeneity (i.e. I2 greater than 50%), we
dummy technique); unclear risk of bias (study stated that it aimed to report it and explore possible causes by performing
was blinded but did not provide an adequate description of prespecified subgroup analysis.
how it was achieved). Studies that were not double-blind were
considered to have high risk of bias. Assessment of reporting biases
• Blinding of outcome assessment (checking for possible
If meta-analysis had been possible using 10 or more studies, we
detection bias). We aimed to assess the methods used to blind
planned to explore publication bias using Egger's test and by
study participants and outcome assessors from knowledge of
inspection of funnel plots for symmetry.
which intervention a participant received. We planned to assess
the methods as: low risk of bias (study had a clear statement that Data synthesis
outcome assessors were unaware of treatment allocation, and
ideally described how this was achieved); unclear risk of bias We planned to combine study data to provide a pooled effect
(study stated that outcome assessors were blind to treatment estimate using a fixed-effect model. If we had found no substantial
allocation but lacked a clear statement on how it was achieved). heterogeneity, we planned to use a random-effects model to
Informed decisions.
check the robustness of the fixed-effect model. If substantial • high probability of reporting bias (-1).
statistical heterogeneity had been observed, we would have used
the random-effects model a priori. 'Summary of findings' table
We planned to include six 'Summary of findings' tables to
If we had found studies that reported a mixture of change-from-
present the main findings for the primary outcome (anxiety) and
baseline and final value scores, we would have only combined data
five secondary outcomes (depression, breathlessness, insomnia,
if the studies reported the outcome using the same measurement
adverse events and withdrawals) in a transparent and simple
scale.
tabular format. In particular, we planned to include key information
Where there were insufficient studies to undertake a meta-analysis, concerning the quality of evidence, the magnitude of effect of the
we planned to combine individual studies in a narrative review. interventions examined, and the sum of available data.
Quality of the evidence Subgroup analysis and investigation of heterogeneity
We planned that two review authors (SS and CM) would If three or more studies reported relevant data, we planned to
independently rate the quality of the outcomes. We planned to use perform the following subgroup analyses:
the GRADE system to rank the quality of the evidence using the
• men versus women;
GRADEprofiler Guideline Development Tool software (GRADEpro
GDT 2015), and the guidelines provided in Section 12.2 of the • mild or moderate anxiety versus severe anxiety;
Cochrane Handbook for Systematic Reviews of Interventions (Higgins • follow-up no greater than one month versus follow-up greater
2011). than one month.
The GRADE approach uses five considerations (study limitations, Sensitivity analysis
consistency of effect, imprecision, indirectness and publication
We planned to perform sensitivity analyses to explore the influence
bias) to assess the quality of the body of evidence for each outcome.
of the following factors:
The GRADE system uses the following criteria for assigning grade of
evidence: • excluding unpublished studies;
• high: we are very confident that the true effect lies close to that • excluding studies considered at high risk of selection bias in
of the estimate of the effect; terms of adequate allocation concealment, detection bias in
terms of blinded outcome assessment and attrition bias due to
• moderate: we are moderately confident in the effect estimate; follow-up of less than 80% of participants in each arm;
the true effect is likely to be close to the estimate of effect, but
there is a possibility that it is substantially different; • excluding studies using the following filters:
* industry funded;
• low: our confidence in the effect estimate is limited; the true
effect may be substantially different from the estimate of the * non-validated scales used for measuring effect;
effect; * non-validated diagnostic criteria.
• very low: we have very little confidence in the effect estimate;
RESULTS
the true effect is likely to be substantially different from the
estimate of effect. Description of studies
We planned to decrease the grade rating by one (-1) or two (-2) if Results of the search
we identified:
We retrieved 707 potentially relevant studies from the electronic
• serious (-1) or very serious (-2) limitation to study quality; searches and four from other sources for this second update. After
• important inconsistency (-1); removing duplicates, we screened 597 articles for inclusion in the
review. We assessed full-text reports of 10 articles. Figure 1 shows
• some (-1) or major (-2) uncertainty about directness;
the results of the search.
• imprecise or sparse data (-1);
Informed decisions.
Figure 1. Study flow diagram.
Informed decisions.
Figure 1. (Continued)
Included studies Overall completeness and applicability of evidence

Of the 10 full-text reports we assessed for inclusion in this update, We were unable to find any evidence of the effectiveness of
we did not identify any studies fulfilling our criteria. drug therapy in the treatment of adult palliative care patients
experiencing symptoms of anxiety.
Excluded studies
In this update, we excluded eight reports for the following reasons: Quality of the evidence
five did not include a patient population of interest, specifically it We did not identify any studies to include in the review and thus we
was considered that three included participants with depression are unable to assess the quality of the evidence.
and not anxiety (Centeno 2012; Dauchy 2015; Ng 2014), and two
included participants not considered at a palliative stage of disease Potential biases in the review process
(Kronish 2012; Yazici 2012); two were not an RCT (Grob 2011;
Irwin 2013), and one study was discontinued (Daubert 2014). See We undertook a comprehensive search for studies, including
Characteristics of excluded studies table. Overall, there are 16 searching trials registers and handsearching of conference
excluded studies. abstracts with no restrictions on language of study reports. One
potential problem we encountered with identifying papers for
Studies awaiting classification inclusion was that when first reading a paper the title and abstract
might suggest that the study participants were experiencing with
Two studies provided insufficient information on which to make anxiety but, on closer inspection, participants were assessed using
a decision regarding inclusion, despite attempts to contact the scales which predominantly measured depression and thus studies
authors for further information (Hart 2012; Usmani 2013). did not meet our inclusion criteria.
Ongoing studies Agreements and disagreements with other studies or
We did not identify any ongoing studies. reviews
Risk of bias in included studies One systematic review of anxiety therapy for palliative care patients
with cancer was undertaken at a similar time to the first update
We did not identify any relevant studies. of this Cochrane Review (Nübling 2012). Nübling 2012 included
four RCTs in their review but stated that they did not make
Effects of interventions recommendations for pharmacological treatments based on the
We did not identify any relevant studies. findings of these four studies because of "deficiencies in the
studies or the analyses." All four studies were excluded from
DISCUSSION the original Cochrane Review of 2004 as study participants were
not considered those of interest for this review. Traeger 2012
Summary of main results examined the evidence for treatment of anxiety in people with
cancer and identified two of the studies included in the Nübling
We found no studies assessing the effectiveness of drug therapy 2012 review. Traeger 2012 concluded that finding evidence for
for treating symptoms of anxiety in adults with a progressive life- effective treatments of anxiety in people with cancer is challenging
limiting illness and who were thought to be in their last year of as anxiety is a complex problem, thus making a diagnosis of anxiety
life. There was a lack of RCTs; while we identified five RCTs, three and assessing the effects of treatment is difficult.
studies assessed depression rather than anxiety and were thus
excluded. There are two studies awaiting classification which may
be included in a future update.
Informed decisions.
AUTHORS' CONCLUSIONS Design

Randomised controlled trials (RCTs), adequately powered and
Implications for practice
involving more than 200 participants per arm are needed.
Due to the lack of evidence on the role of drug therapy for
treating anxiety in palliative care patients, this review cannot draw Measurement (endpoints)
any conclusions specific to any medications or drug classes in Depression and anxiety are often measured using the same scale,
this patient population. To the best of our knowledge, clinical thus it is necessary that future trials specifically assess and report
guidelines from the main health organisations across the world measures of anxiety. The diagnosis of anxiety should be clearly
recommend non-drug therapy treatments for anxiety in palliative defined and be a discrete endpoint for the trial. Outcomes need to
care patients such as psychological support and intervention (NICE be assessed using validated tools.
2004), in preference to drug treatment except in the last days of life
(NICE 2015). In the case of severe anxiety, guidelines recommend Other
referral to a psychiatrist (National Consensus Project 2009). In
addition, there is evidence for the effectiveness of cognitive RCTs should follow the CONSORT Statement (Schulz 2010).
behavioural therapy as a psychological intervention (Moorey 2009).
ACKNOWLEDGEMENTS
Until there is evidence indicating harms caused by the drugs
Original review: the authors acknowledge the assistance of the
currently used in palliative care to manage anxiety, their use is
Cochrane Pain, Palliative and Supportive Care Group, specifically
likely to be continued. However, their administration should be
Phil Wiffen and Frances Fairman. We also acknowledge the
based on the severity of symptoms and an assessment of the
contribution of Arthur G Lipman as an author of the original review.
risk of increased sensitivity to drugs. As addressed in the review,
Thank you to Nathaniel Gordon for translating from Polish two trials
underlying causes for anxiety should be thoroughly evaluated
for potential inclusion.
to determine if the cause of a person's anxiety is related to
other symptom management or the use of other medications or 2012 update: the authors acknowledge the assistance of the
substances. If appropriate, treating another symptom (e.g. pain) or Cochrane Pain, Palliative and Supportive Care Group, specifically
eliminating an agent that is causing or exacerbating anxiety (e.g. Jessica Thomas and Jane Haynes. The update was funded by Marie
caffeine) may pre-empt the need for another medication to treat Curie Cancer Care.
anxiety. If drugs are started, they should be at a lower dose than
would be prescribed for physically healthy people and any increase 2017 update: the authors acknowledge the assistance of the
should be attempted cautiously and with consideration of other Cochrane Pain, Palliative and Supportive Care Group, and in
drugs the person may be taking (Roth 2007). The drug group of particular Anne Erskine, Managing Editor, and Joanne Abbott,
choice commonly stated in the literature for palliative care patients Information Specialist. We thank the authors of the original review
(prior to the final dying phase) is short-acting benzodiazepines, and the 2012 update for allowing us the opportunity to update this
such as lorazepam or midazolam (Henderson 2006; Klein 2011; Roth review. We are very grateful to Kenny Jackson for his support and
2007). contributions to this update.
Implications for research Cochrane Review Group funding acknowledgement: the National
Institute for Health Research (NIHR) is the largest single funder of
General implications
the Cochrane Pain, Palliative and Supportive Care Review Group
As there is a lack of evidence of the effectiveness of drug therapy for (PaPaS). Disclaimer: the views and opinions expressed therein are
treating anxiety in people with a life-limiting illness there is a need those of the authors and do not necessarily reflect those of the
for research in this topic. NIHR, National Health Service (NHS), or the Department of Health.
Informed decisions.
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CHARACTERISTICS OF STUDIES
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Barreto 1996 Not an RCT.
Bruera 1986 Not the patient population of interest.
Butters 1992 Not an RCT
Centeno 2012 Not the patient population of interest.
Daubert 2014 Study discontinued.
Dauchy 2015 Not the patient population of interest.
Fernandez 1987 Not an RCT.
Grob 2011 Not an RCT.
Holland 1991 Not the patient population of interest.
Irwin 2013 Not an RCT.
Koralewski 2002 Not the patient population of interest.
Kronish 2012 Not the patient population of interest.
Informed decisions.
Study Reason for exclusion
Ng 2014 Not the patient population of interest.
Wald 1993 Not the patient population of interest.
Yazici 2012 Not the patient population of interest.
Ziolko 2004 Not the patient population of interest.
RCT: randomised controlled trial.
Characteristics of studies awaiting assessment [ordered by study ID]
Hart 2012
Methods Randomised, double-blind, double-dummy placebo-controlled pilot study.
Participants 30 participants with severe respiratory disease.
Interventions Lorazepam tablets 0.5 mg twice daily with dummy nasal spray up to 4 times daily.
Midazolam 400 mg intranasal 2 sprays up to 4 times daily with placebo tablets.
Outcomes Borg score, St Georges Respiratory Questionnaire, Hospital Anxiety and Depression scores, Notting-
ham Activities of Daily Living score.
Notes Contacted author by e-mail in July and August 2016 to ask for further details but no response re-
ceived.
Usmani 2013
Methods Intervention study.
Participants People with chronic obstructive pulmonary disease.
Interventions Paroxetine 20 mg daily as oral capsule for 4 months.
Placebo pill as oral capsule for 4 months.
Capsules identical in appearance.
Outcomes Anxiety as measured by Beck Anxiety Inventory, quality of life as assessed by Chronic Respiratory
Questionnaire (CRQ).
Notes Contacted author by e-mail September 2016 to ask for further details but no response received.
APPENDICES
Appendix 1. Search strategy used in 2003

The search strategy combined the subject search with phases 1 and 2 of the Cochrane Sensitive Search Strategy for RCTs (as published in
Appendix 5c in the Cochrane Handbook for
Informed decisions.
Systematic Reviews of Interventions).
The subject search used a combination of controlled vocabulary and free-text terms in addition to the basic Cochrane Sensitive Search
Strategy. These terms included the following:
Disease: anxiety, agitation, adjustment disorders, obsessive-compulsive disorders, phobias, panic disorders, post-traumatic stress
disorder, generalised anxiety disorders and terminal restlessness.
Individual treatments: alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, chlorazepate, diazepam, estazolam,
flunitrazepam, flurazepam, halazepam, ketazolam, lorazepam, midazolam, nitrazepam, oxazepam, prazepam, quazepam, temazepam,
triazolam, buspirone, hydroxyzine, amitriptyline, nortriptyline, desipramine, doxepin, fluoxetine, paroxetine, sertraline, citalopram,
venlafaxine, droperidol, haloperidol, chlorpromazine, olanzapine, risperidone, thioridazine, methotrimeprazine and propofol.
Drug class names: anxiolytics, antidepressants, antipsychotics, benzodiazepines, butyrophenones, phenothiazines and
thienobenzodiazepine.
Appendix 2. MEDLINE search 2012

MEDLINE Ovid
1 exp Anxiety/
2 exp Anxiety Disorders/
3 Adjustment Disorders/
4 Psychomotor Agitation/
5 (anxious* or anxiet* or agitat* or restless* or panic* or stress* or PTSD or phobia* or phobic or nervous* or obsessive compulsive disorder*
or OCD or adjustment disorder*).mp.
6 1 or 2 or 3 or 4 or 5
7 drug therapy.fs.
8 exp Anti-Anxiety Agents/
9 exp Antidepressive Agents/
10 exp Antipsychotic Agents/
11 exp Benzodiazepines/
12 exp Butyrophenones/
13 exp Phenothiazines/
14 exp Monoamine Oxidase Inhibitors/
15 exp Serotonin Agents/
16 exp Histamine Agents/
17 exp Barbiturates/
18 exp "Hypnotics and Sedatives"/
19 exp Adrenergic Agents/
20 (acebutolol or alimemazine or alprazolam or amitriptyline or atenolol or bisoprolol or bromazepam or buproprion or buspirone or

carbamazepine or carisoprodol or carvedilol or celiprolol or clomipramine or chlorazepate or chlordiazepoxide or chlorphenamine or
chlorpromazine or citalopram or clemastine or clobazam or clonazepam or co-tenidone or cyproheptadine or diazepam or desipramine
or desvenlafaxine or dexmedetomidine or dosulepin or doxepin or droperidol or duloxetin or escitalopram or esmolol or estazolam
or eszopiclone or etizolam or flunitrazepam or fluoxetine or flurazepam or fluvoxamine or gabapentin or halazepam or haloperidol
or hydroxyzine or imipramine or isocarboxazid or ketamine or ketazolam or ketotifen or labetalol or lamotrigine or levetiracetam or
levomepromaziene or lofepramine or lorazepam or meprobamate or methotrimeprazine or metoprolol or midazolam or milnacipran
or mirtazapine or moclobemide or nadolol or nebivolol or nefazodone or nitrazepam or nortriptyline or olanzapine or ondansetron or
Informed decisions.
oxazepam or oxprenolol or paroxetine or perphenazine or phenelzine or phenobarbital or phenytoin or pindolol or prazepam or pregabalin
or primidone or promethazine or propofol or propranolol or quazepam or ramelteon or risperidone or sertraline or sotalol or temazepam
or thioridazine or tiagabine or timolol or topiramate or tranylcypromine or trazodone or triazolam or trifluoperazine or trimipramine or
tropisetron or valproate or venlafaxine or vigabatrin or zaleplon or zolpidem).mp.
21 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20
22 Palliative Care/
23 exp Terminal Care/
24 Terminally Ill/
25 palliat*.mp.
26 (terminal* adj6 (care or ill* or diseas*)).mp.
27 (terminal-stage* or terminal stage* or dying or (close adj6 death)).mp.
28 (end adj3 life).mp.
29 hospice*.mp.
30 ((end-stage* or end stage*) adj6 (disease* or illness* or care)).mp.
31 (incurable adj6 (disease* or illness*)).mp.
32 (advanced adj6 disease*).mp.
33 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32
34 6 and 21 and 33
35 randomized controlled trial.pt.
36 controlled clinical trial.pt.
37 randomized.ab.
38 placebo.ab.
39 drug therapy.fs.
40 randomly.ab.
41 trial.ab.
42 groups.ab.
43 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42
44 34 and 43
key:
mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject
heading word, unique identifier
pt=publication type
ab=abstract
fs=floating subheading
Appendix 3. CENTRAL search 2012

#1 MeSH descriptor Anxiety explode all trees
#2 MeSH descriptor Anxiety Disorders explode all trees

Informed decisions.
#3 MeSH descriptor Adjustment Disorders, this term only
#4 MeSH descriptor Psychomotor Agitation, this term only
#5 (anxious* or anxiet* or agitat* or restless* or panic* or stress* or PTSD or phobia* or phobic or nervous* or obsessive compulsive disorder*
or OCD or adjustment disorder*)
#6 (#1 OR #2 OR #3 OR #4 OR #5)
#7 Any MeSH descriptor with qualifier: DT
#8 MeSH descriptor Anti-Anxiety Agents explode all trees
#9 MeSH descriptor Antidepressive Agents explode all trees
#10 MeSH descriptor Antipsychotic Agents explode all trees
#11 MeSH descriptor Benzodiazepines explode all trees
#12 MeSH descriptor Butyrophenones explode all trees
#13 MeSH descriptor Phenothiazines explode all trees
#14 MeSH descriptor Monoamine Oxidase Inhibitors explode all trees
#15 MeSH descriptor Serotonin Agents explode all trees
#16 MeSH descriptor Histamine Agents explode all trees
#17 MeSH descriptor Barbiturates explode all trees
#18 MeSH descriptor Hypnotics and Sedatives explode all trees
#19 MeSH descriptor Adrenergic Agents explode all trees
#20 acebutolol or alimemazine or alprazolam or amitriptyline or atenolol or bisprolol or bromazepam or buproprion or buspirone or
carbamezepine or carisoprodol or carvedilol or celiprolol or clomipramine or chlorazepate or chlordiazepoxide or chlorphenamine or
chlopromazine or citalopram or clemastine or clobazam or clonazepam or co-tenidone or cypropheptadine or diazepam or desipramine
or desvenlafaxine or dexmedetomidine or dosulepin or doxepin or droperidol or doloxetin
#21 escitalopram or esmolol or estazolam or eszopiclone or etizolam or flunitrazepam or fluoxetine or flurazepam or fluvoxamine or
gabapentin or halazepam or haloperidol or hydroxyzine or imipramine or isocarboxazid or ketamine or ketazolam or ketotifen or labetalol
or lamotrigine or levetiracetam or levomepromaziene or lofepramine or lorazepam or meprobamate or methotrimeprazine or metoprolol
or midazolam or milnacipran or mirtazapine or moclobemide or nadolol or nebivolol or nefazodone or nitrazepam or nortriptyline or
olanzapine or ondansetron or oxazepam or oxprenolol or paroxetine or perphenazine or phenelzine or phenobarbital or phenytoin or
pindolol or prazepam or pregabalin or primidone or promethazine or propofol or propranolol or quazepam or ramelteon or risperidone or
sertraline or sotalol or temazepam or thioridazine or tiagabine or timolol or topiramate or tranylcypromine or trazodone or triazolam or
trifluoperazine or trimipramine or tropisetron or valproate or venlafaxine or vigabatrin or zaleplon or zolpidem
#22 (#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21)
#23 MeSH descriptor Palliative Care, this term only
#24 MeSH descriptor Terminal Care explode all trees
#25 MeSH descriptor Terminally Ill, this term only
#26 palliat*
#27 terminal* near/6 (care or ill* or diseas*)
#28 end near/6 life
#29 hospice*
#30 (end -stage* or end stage*) near/6 (disease* or illness* or care)
#31 incurable near/6 (disease* or illness*)

Informed decisions.
#32 advanced near/6 disease*
#33 terminal-stage* or terminal stage* or dying or (close near/6 death)
#34 (#23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33)
#35 (#6 AND #22 AND #34)
Appendix 4. Embase search 2012

Embase Ovid
1 anxiety/
2 exp anxiety disorder/
3 adjustment disorder/
4 agitation/
6 1 or 2 or 3 or 4 or 5
7 dt.fs.
8 exp anxiolytic agent/
9 exp antidepressant agent/
10 exp neuroleptic agent/
11 exp benzodiazepine derivative/
12 exp butyrophenone derivative/
13 exp phenothiazine derivative/
14 exp serotonin receptor affecting agent/
15 exp histaminergic receptor affecting agent/
16 exp barbituric acid derivative/
17 exp hypnotic sedative agent/
18 beta adrenergic receptor blocking agent/ or exp adrenergic receptor blocking agent/

20 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19
21 exp palliative therapy/
22 exp terminally ill patient/
Informed decisions.
23 exp terminal care/
24 palliat*.mp.
28 hospice*.mp.
32 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31
33 6 and 20 and 32
34 crossover procedure/
35 randomized controlled trial/
36 single blind procedure/
37 random*.mp.
38 factorial*.mp.
39 (crossover* or cross over* or cross-over).mp.
40 placebo*.mp.
41 (doubl* adj blind*).mp.
42 (singl* adj blind*).mp.
43 assign*.mp.
44 allocat*.mp.
45 volunteer*.mp.
46 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45
47 33 and 46
key:
[mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade
name, keyword]
Appendix 5. PsycINFO search 2012

PsycINFO Ovid
1 exp anxiety/
2 exp anxiety disorders/
3 adjustment disorders/
4 Agitation/
5 restlessness/
Informed decisions.
7 1 or 2 or 3 or 4 or 5 or 6
8 exp drug therapy/
9 exp tranquilizing drugs/
10 exp antidepressant drugs/
11 benzodiazepines/
12 exp monoamine oxidase inhibitors/
13 exp neurotransmitter uptake inhibitors/
14 exp antihistaminic drugs/
15 exp barbiturates/
16 exp hypnotic drugs/
17 exp sedatives/
18 exp adrenergic blocking drugs/

20 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19
21 palliative care/
22 hospice/
23 palliat*.mp.
27 hospice*.mp.
31 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30
32 7 and 20 and 31
key:
Informed decisions.
mp=title, abstract, heading word, table of contents, key concepts, original title, tests & measures
Appendix 6. CINAHL plus 2012

1. MW anxiety
2. MH exp adjustment disorders
3. MH agitation
4. (anxious* or anxiet* or agitat* or restless* or panic* or stress* or PTSD or phobia* or phobic or nervous* or obsessive compulsive disorder*
5. 1 or 2 or 3 or 4
6. MH exp drug therapy
7. MH exp tranquilizing agents
8. MH exp antidepressant agents
9. MH exp antianxiety agents
10. MH exp monoamine oxidase inhibitors
11. MH exp neurotransmitter uptake inhibitors
12. MH exp histamine agents
13. MH exp barbiturates
14. MH exp hypnotic and sedatives
15. MH exp adrenergic agents
16. MH exp antipsychotic agents
17. (acebutolol or alimemazine or alprazolam or amitriptyline or atenolol or bisoprolol or bromazepam or buproprion or buspirone or
18. 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17
19. MH palliative care
20. MH hospice
21. MH exp terminally ill patient
22. terminal care or ill* or diseas*
23. terminal disease
24. terminal stage* or terminal-stage*
25. dying
26. hospice
Informed decisions.
27. end-stage or end stage
28. incurable disease
29. advanced disease
30. incurable illness
31. 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30
32. 5 and 18 and 31
Appendix 7. Antiepileptic drugs

To enhance the completeness of this review an additional search was run in January 2012 for antiepileptic drugs. The searches were run
on MEDLINE, Embase, CINAHL, PsycINFO and CENTRAL. In these searches we used the following terms for the intervention:
exp Antiepileptic Agents/
carbamazepine or eslicarbazepine or ethosuximide or gabapentin or lacosamide or lamotrigine or levetiracetam or oxcarbazepine or

phenobarbital or pregabalin or primidone or phenytoin or retigabine or rufinamide or tiagabine or topiramate or valproate or vigabatrin
or zonisamide.
Appendix 8. Searches run in May 2016

CENTRAL (CRSO)
#1 MESH DESCRIPTOR Anxiety EXPLODE ALL TREES 5582
#2 MESH DESCRIPTOR Anxiety Disorders EXPLODE ALL TREES 4375
#3 MESH DESCRIPTOR Adjustment Disorders EXPLODE ALL TREES 192
#4 MESH DESCRIPTOR Psychomotor Agitation EXPLODE ALL TREES 602
#5 ((anxious* or anxiet* or agitat* or restless* or panic* or stress* or PTSD or phobia* or phobic or nervous* or obsessive compulsive
disorder* or OCD or adjustment disorder*)):TI,AB,KY 65130
#6 #1 OR #2 OR #3 OR #4 OR #5 65442
#7 MESH DESCRIPTOR drug therapy EXPLODE ALL TREES 117835
#8 MESH DESCRIPTOR Anti-Anxiety Agents EXPLODE ALL TREES 8799
#9 MESH DESCRIPTOR Antidepressive Agents EXPLODE ALL TREES 10354
#10 MESH DESCRIPTOR Antipsychotic Agents EXPLODE ALL TREES 7126
#11 MESH DESCRIPTOR Benzodiazepines EXPLODE ALL TREES 7745
#12 MESH DESCRIPTOR Butyrophenones EXPLODE ALL TREES 1787
#13 MESH DESCRIPTOR Phenothiazines EXPLODE ALL TREES 2181
#14 MESH DESCRIPTOR Monoamine Oxidase Inhibitors EXPLODE ALL TREES 854
#15 MESH DESCRIPTOR Serotonin Agents EXPLODE ALL TREES 11113
#16 MESH DESCRIPTOR Histamine Agents EXPLODE ALL TREES 7708
#17 MESH DESCRIPTOR Barbiturates EXPLODE ALL TREES 1837
#18 MESH DESCRIPTOR Hypnotics and Sedatives EXPLODE ALL TREES 11260
#19 MESH DESCRIPTOR Adrenergic Agents EXPLODE ALL TREES 27721
#20 ((acebutolol or alimemazine or alprazolam or amitriptyline or atenolol or bisoprolol or bromazepam or buproprion or buspirone or
Informed decisions.
or desvenlafaxine or dexmedetomidine or dosulepin or doxepin or duloxetin or escitalopram or esmolol or estazolam or eszopiclone

or etizolam or flunitrazepam or fluoxetine or flurazepam or fluvoxamine or gabapentin or halazepam or haloperidol or hydroxyzine or
imipramine or isocarboxazid or ketamine or ketazolam or ketotifen or labetalol or lamotrigine or levetiracetam or levomepromaziene
or lofepramine or lorazepam or meprobamate or methotrimeprazine or metoprolol or midazolam or milnacipran or mirtazapine or
moclobemide or nadolol or nebivolol or nefazodone or nitrazepam or nortriptyline or olanzapine or ondansetron or oxazepam or
oxprenolol or paroxetine or perphenazine or phenelzine or phenobarbital or phenytoin or pindolol or prazepam or pregabalin or primidone
or promethazine or propranolol or quazepam or ramelteon or risperidone or sertraline or sotalol or temazepam or thioridazine or tiagabine
or timolol or topiramate or tranylcypromine or trazodone or triazolam or trifluoperazine or trimipramine or tropisetron or valproate or
venlafaxine or vigabatrin or zaleplon or zolpidem)):TI,AB,KY 59251
#21 ((Lormetazepam or Loprazolam or Zopiclone or Chloral hydrate or Chlormethiazole or Clomethiazole or Pericyazine or Perphenazine
or Prochloperazine or Promazine or Paliperidone or Quetiapine or agomelatine or Reboxetine or Tryptophan or Acrivastine or Bilastine or
Cetirizine or Desoloratadine or Fexofenadine or Levocetirizine or loratadine or Mizolastine or Rupatadine or Trimeprazine)):TI,AB,KY 5824
#22 #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 190456
#23 MESH DESCRIPTOR Palliative Care 1215
#24 MESH DESCRIPTOR Terminal Care EXPLODE ALL TREES 315
#25 MESH DESCRIPTOR Terminally Ill 60
#26 palliat*:TI,AB,KY 3307
#27 ((terminal* near6 (care or ill* or diseas*))):TI,AB,KY 563
#28 ((terminal-stage* or terminal stage* or dying or (close adj6 death))):TI,AB,KY 510
#29 ((end adj3 life)):TI,AB,KY 352
#30 hospice*:TI,AB,KY 280
#31 (((end-stage* or end stage*) adj6 (disease* or illness* or care))):TI,AB,KY 1869
#32 ((incurable adj6 (disease* or illness*))):TI,AB,KY 51
#33 ((advanced adj6 disease*)):TI,AB,KY 2462
#34 #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 8421
#35 #6 AND #22 AND #34 90
#36 14/03/2012 TO 31/05/2016:DL 272867
#37 #35 AND #36 27
MEDLINE (Ovid)
1 exp Anxiety/ (64420)
2 exp Anxiety Disorders/ (69302)
3 Adjustment Disorders/ (4031)
4 Psychomotor Agitation/ (4308)
or OCD or adjustment disorder*).mp. (1246199)
6 or/1-5 (1260505)
7 drug therapy.fs. (1854584)
8 exp Anti-Anxiety Agents/ (60302)
9 exp Antidepressive Agents/ (128780)
10 exp Antipsychotic Agents/ (110788)

Informed decisions.
11 exp Benzodiazepines/ (60534)
12 exp Butyrophenones/ (21427)
13 exp Phenothiazines/ (48388)
14 exp Monoamine Oxidase Inhibitors/ (20566)
15 exp Serotonin Agents/ (144506)
16 exp Histamine Agents/ (88729)
17 exp Barbiturates/ (52978)
18 exp "Hypnotics and Sedatives"/ (111515)
19 exp Adrenergic Agents/ (355644)

venlafaxine or vigabatrin or zaleplon or zolpidem).mp. (304943)
21 (Lormetazepam or Loprazolam or Zopiclone or Chloral hydrate or Chlormethiazole or Clomethiazole or Pericyazine or Perphenazine

Cetirizine or Desoloratadine or Fexofenadine or Levocetirizine or loratadine or Mizolastine or Rupatadine or Trimeprazine).mp. [mp=title,
abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare
disease supplementary concept word, unique identifier] (66773)
22 or/7-21 (2507015)
23 Palliative Care/ (44411)
24 exp Terminal Care/ (43801)
25 Terminally Ill/ (5769)
26 palliat*.mp. (69308)
27 (terminal* adj6 (care or ill* or diseas*)).mp. (33751)
28 (terminal-stage* or terminal stage* or dying or (close adj6 death)).mp. (29543)
29 (end adj3 life).mp. (14084)
30 hospice*.mp. (12120)
31 ((end-stage* or end stage*) adj6 (disease* or illness* or care)).mp. (33473)
32 (incurable adj6 (disease* or illness*)).mp. (2694)
33 (advanced adj6 disease*).mp. (35405)
34 or/23-33 (202878)
35 randomized controlled trial.pt. (415460)
36 controlled clinical trial.pt. (90651)
Informed decisions.
37 randomized.ab. (312371)
38 placebo.ab. (158310)
40 randomly.ab. (220598)
41 trial.ab. (323081)
42 groups.ab. (1391694)
43 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 (3523448)
44 exp animals/ not humans.sh. (4239199)
45 43 not 44 (3001538)
46 6 and 22 and 34 and 45 (1510)
47 (2012* or 2013* or 2014* or 2015* or 2016*).ed. (3534743)
48 46 and 47 (382)
Embase (Ovid)
6 or/1-5 (2147293)
8 exp Anti-Anxiety Agents/ (172725)
9 exp Antidepressive Agents/ (349098)
10 exp Antipsychotic Agents/ (244079)
11 exp Benzodiazepines/ (162297)
12 exp Butyrophenones/ (69061)
13 exp Phenothiazines/ (98054)
14 exp Monoamine Oxidase Inhibitors/ (44772)
15 exp Serotonin Agents/ (339905)
16 exp Histamine Agents/ (229873)
17 exp Barbiturates/ (139016)
18 exp "Hypnotics and Sedatives"/ (328978)
19 exp Adrenergic Agents/ (507749)

Informed decisions.


abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] (124603)
22 or/7-21 (4380654)
26 palliat*.mp. (113733)
30 hospice*.mp. (19005)
34 or/23-33 (315911)
35 random$.tw. (1080929)
36 factorial$.tw. (27596)
37 crossover$.tw. (57278)
38 cross over$.tw. (25537)
39 cross-over$.tw. (25537)
40 placebo$.tw. (237354)
41 (doubl$ adj blind$).tw. (167979)
42 (singl$ adj blind$).tw. (17556)
43 assign$.tw. (285956)
44 allocat$.tw. (103682)
45 volunteer$.tw. (206547)
46 Crossover Procedure/ (46987)
47 double-blind procedure.tw. (235)
48 Randomized Controlled Trial/ (403142)
Informed decisions.
49 Single Blind Procedure/ (22048)
50 or/35-49 (1693538)
51 (animal/ or nonhuman/) not human/ (5029808)
52 50 not 51 (1503726)
53 6 and 22 and 34 and 52 (591)
54 (2012* or 2013* or 2014* or 2015* or 2016*).dd. (6852351)
55 53 and 54 (227)
PsycINFO (Ovid)
4 Agitation/ (1198)
5 restlessness/ (321)
7 or/1-6 (487305)
8 exp drug therapy/ (125834)
9 exp tranquilizing drugs/ (41641)
10 exp antidepressant drugs/ (34233)
11 benzodiazepines/ (4635)
12 exp monoamine oxidase inhibitors/ (2163)
13 exp neurotransmitter uptake inhibitors/ (12703)
14 exp antihistaminic drugs/ (984)
15 exp barbiturates/ (2092)
16 exp hypnotic drugs/ (5517)
17 exp sedatives/ (18535)
18 exp adrenergic blocking drugs/ (3619)

Informed decisions.

Cetirizine or Desoloratadine or Fexofenadine or Levocetirizine or loratadine or Mizolastine or Rupatadine or Trimeprazine).mp. (8915)
21 or/8-20 (180411)
22 palliative care/ (8996)
23 hospice/ (2649)
24 palliat*.mp. (11674)
28 hospice*.mp. (4266)
32 or/22-31 (48760)
33 7 and 21 and 32 (404)
34 clinical trials/ (9558)
35 (randomis* or randomiz*).tw. (60920)
36 (random$ adj3 (allocat$ or assign$)).tw. (34606)
37 ((clinic$ or control$) adj trial$).tw. (51502)
38 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw. (22211)
39 (crossover$ or "cross over$").tw. (8245)
40 random sampling/ (688)
41 Experiment Controls/ (855)
42 Placebo/ (4532)
43 placebo$.tw. (34693)
44 exp program evaluation/ (17993)
45 treatment effectiveness evaluation/ (19892)
46 ((effectiveness or evaluat$) adj3 (stud$ or research$)).tw. (69778)
47 or/34-46 (218371)
48 33 and 47 (67)
49 limit 48 to yr="2012 -Current" (25)
CINAHL (EBSCO)
S47 S45 AND S46
S46 EM 20120101-20160531
S45 S35 AND S44

Informed decisions.
S44 S36 OR S37 OR S38 OR S39 OR S40 OR S41 OR S42 OR S43
S43(allocat* random*)
S42(MH "Quantitative Studies")
S41 (MH "Placebos")
S40 placebo*
S39(random* allocat*)
S38 (MH "Random Assignment")
S37 (Randomi?ed control* trial*)
Search modes - Boolean/Phrase
S36 (singl* blind* ) or (doubl* blind* ) or (tripl* blind* ) or (trebl* blind* ) or (trebl* mask* ) or (tripl* mask* ) or (doubl* mask* ) or (singl*
mask* )
S35 S6 AND S22 AND S34
S24 S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30 OR S31 OR S32 OR S33
S33 (advanced N6 disease*)
S32 (incurable N6 (disease* or illness*))
S31 ((end-stage* or end stage*) N6 (disease* or illness* or care))
S30 hospice*
S29 (end N3 life)
S28 (terminal-stage* or terminal stage* or dying or (close N6 death))
S27 (terminal* N6 (care or ill* or diseas*))
S26 palliat*
S25 (MH "Terminally Ill Patients")
S24 (MH "Terminal Care+")
S23 (MH "Palliative Care")
S22 S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21
S21 (Lormetazepam or Loprazolam or Zopiclone or Chloral hydrate or Chlormethiazole or Clomethiazole or Pericyazine or Perphenazine
Cetirizine or Desoloratadine or Fexofenadine or Levocetirizine or loratadine or Mizolastine or Rupatadine or Trimeprazine)
S20(acebutolol or alimemazine or alprazolam or amitriptyline or atenolol or bisoprolol or bromazepam or buproprion or buspirone or

venlafaxine or vigabatrin or zaleplon or zolpidem)
S19 (MH "Adrenergic Agents+")
Informed decisions.
S18 (MH "Hypnotics and Sedatives+")
S17 (MH "Barbiturates+")
S16 (MH "Histamine Agents+")
S15 (MH "Serotonin Agents+")
S14 (MH "Monoamine Oxidase Inhibitors+")
S13 (MH "Antipsychotic Agents, Phenothiazine+")
S12 (MH "Antipsychotic Agents, Butyrophenone+")
S11 (MH "Antianxiety Agents, Benzodiazepine+")
S10 (MH "Antipsychotic Agents+")
S9 (MH "Antidepressive Agents+")
S8 (MH "Antianxiety Agents+")
S7 (MH "Drug Therapy+")
S6 S1 OR S2 OR S3 OR S4 OR S5
S5 (anxious* or anxiet* or agitat* or restless* or panic* or stress* or PTSD or phobia* or phobic or nervous* or obsessive compulsive disorder*
S4 (MH "Psychomotor Agitation")
S3 (MH "Adjustment Disorders")
S2 (MH "Anxiety Disorders+")
S1 (MH "Anxiety+")
Appendix 9. Searches run in May 2016 for additional drugs

MEDLINE (Ovid)

6 or/1-5 (1261866)
7 (Lormetazepam or Loprazolam or Zopiclone or Chloral hydrate or Chlormethiazole or Clomethiazole or Pericyazine or Perphenazine or
Prochloperazine or Promazine or Paliperidone or Quetiapine or agomelatine or Reboxetine or Tryptophan or Acrivastine or Bilastine or
abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare
disease supplementary concept word, unique identifier] (66822)
11 palliat*.mp. (69375)
15 hospice*.mp. (12129)
19 or/8-18 (203067)
20 randomized controlled trial.pt. (415956)
Informed decisions.
21 controlled clinical trial.pt. (90682)

22 randomized.ab. (312879)
23 placebo.ab. (158504)
25 randomly.ab. (220900)
26 trial.ab. (323631)
27 groups.ab. (1393402)
28 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 (3527435)
29 exp animals/ not humans.sh. (4241825)
30 28 not 29 (3005030)
31 6 and 7 and 19 and 30 (11)
WHAT'S NEW
Date Event Description
30 May 2019 Review declared as stable See Published notes
HISTORY
Protocol first published: Issue 1, 2004
Review first published: Issue 1, 2004
Date Event Description
28 February 2017 New citation required but conclusions The list of drugs to search for was updated and a database
have not changed search for these rerun for all years up to May 2016. From the
searches, no new studies to include were identified. We updat-
ed the background sections with more recent references. We list-
ed primary and secondary outcomes of interest. We planned to
construct a 'Summary of findings' table and assess the quality
of the evidence using the GRADE approach. The authorship was
changed.
15 December 2016 New search has been performed This review was updated to include the results of a new search
on 17 May 2016.
29 February 2012 New search has been performed This review is an update of the original review published in Issue
1, 2004 of the Cochrane Library.
29 February 2012 New citation required but conclusions A search for new studies was conducted to January 2012 and no
have not changed new included studies were identified. Two new studies were ex-
cluded (Koralewski 2002; Ziolko 2004). As part of the update the
Background, Methods and Discussion were updated and the au-
thorship changed.
27 October 2008 Amended Converted to new review format.
CONTRIBUTIONS OF AUTHORS
2012 update:
• all authors revised the search strategy;

• LJ and BC screened studies;
Informed decisions.
• KCJ, AT, MK and LJ commented on the draft review;

• all authors agreed the final document.
2017 update:
• SS updated the drugs listed in the search strategy;

• SS and CM searched trials registers and handsearched conference abstracts;
• SS and CM undertook screening of papers with deferment to NP for points of disagreement;
• all authors commented on the draft manuscript and agreed the final version.
DECLARATIONS OF INTEREST
SS: none known; SS is a specialist in palliative care and manages patients with anxiety.
CM: none known.
NP: none known.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
2012 update
• The Background, Methods, Results and Discussion were updated and revised to conform with current Cochrane style guidelines.
2017 update
• In the first update and this second update we searched a range of trial registers that were not searched in the original Cochrane Review.
However, while the ISRCTN Trials Register (www.controlled-trials.com/isrctn) was searched in the first update, it was not searched in
this latest update as it is covered by WHO Portal.
• We did not search the Cochrane Pain, Palliative & Supportive Care Register as its contents are captured by CENTRAL.
• We added an additional 25 drugs to our search and thus database searches for these were rerun from 2012 (see Appendix 9).
• We updated the Background section to include references to more recently published work.
• We updated the Methods section to take into account changes in the search strategy. We thought that we should be searching for studies
currently in progress, in addition to published studies, and thus undertook searches of trial registers.
• We added new outcomes, and specified primary and secondary outcomes. We specified that we will report outcomes assessed at one
week.
• We changed the description of 'Types of participants' and 'Types of interventions' to reflect current terminology. We also added
comparators of interest.
• We expanded our risk of bias descriptions.
• We stated that we planned to construct a 'Summary of findings' table and to assess the quality of the evidence used the GRADE approach.
• The Results and Discussion sections were updated to take into account the fact that no studies were found to include in the review and
to include references to more recently published work.
• All sections were updated and revised to conform with current Cochrane style guidelines.
NOTES
A restricted search in March 2019 did not identify any potentially relevant studies likely to change the conclusions. Therefore, this review
has now been stabilised following discussion with the authors and editors. The review will be re-assessed for updating in two years. If
appropriate, we will update the review before this date if new evidence likely to change the conclusions is published, or if standards change
substantially which necessitates major revisions.
INDEX TERMS
Medical Subject Headings (MeSH)

*Palliative Care; Anti-Anxiety Agents [*therapeutic use]; Anxiety [*drug therapy]; Terminally Ill [*psychology]
MeSH check words

Adult; Humans

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Drug therapy for symptoms associated with anxiety in adult

Salt S, Mulvaney CA, Preston NJ

Salt S, Mulvaney CA, Preston NJ.

Drug therapy for symptoms associated with anxiety in adult palliative

Susan Salt1, Caroline A Mulvaney2, Nancy J Preston3

Editorial group: Cochrane Pain, Palliative and Supportive Care Group

Data collection and analysis

PLAIN LANGUAGE SUMMARY

BACKGROUND Anxiety may be a manifestation of a change in metabolic state

OBJECTIVES • Anxiety: studies were eligible for inclusion if they reported

Quality of the evidence Subgroup analysis and investigation of heterogeneity

Figure 1. Study flow diagram.

Included studies Overall completeness and applicability of evidence

AUTHORS' CONCLUSIONS Design

Usmani 2013 {published data only} Derogatis 1983

Jackson 2000 content/uploads/2015/09/Ambitions-for-Palliative-and-End-of-

National Consensus Project 2009 Roth 2007

National Palliative and End of Care 2015 Schulz 2010

Soldatos 2000 Journal of Clinical Oncology 2012;30:1197-205. [DOI: 10.1200/

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Barreto 1996 Not an RCT.

Bruera 1986 Not the patient population of interest.

Butters 1992 Not an RCT

Centeno 2012 Not the patient population of interest.

Daubert 2014 Study discontinued.

Dauchy 2015 Not the patient population of interest.

Fernandez 1987 Not an RCT.

Grob 2011 Not an RCT.

Holland 1991 Not the patient population of interest.

Irwin 2013 Not an RCT.

Koralewski 2002 Not the patient population of interest.

Kronish 2012 Not the patient population of interest.

Study Reason for exclusion

Ng 2014 Not the patient population of interest.

Wald 1993 Not the patient population of interest.

Yazici 2012 Not the patient population of interest.

Ziolko 2004 Not the patient population of interest.

RCT: randomised controlled trial.

Characteristics of studies awaiting assessment [ordered by study ID]

Participants 30 participants with severe respiratory disease.

Midazolam 400 mg intranasal 2 sprays up to 4 times daily with placebo tablets.

Participants People with chronic obstructive pulmonary disease.

Interventions Paroxetine 20 mg daily as oral capsule for 4 months.

Placebo pill as oral capsule for 4 months.

Capsules identical in appearance.

Appendix 1. Search strategy used in 2003

Systematic Reviews of Interventions).

Appendix 2. MEDLINE search 2012

2 exp Anxiety Disorders/

8 exp Anti-Anxiety Agents/

9 exp Antidepressive Agents/

10 exp Antipsychotic Agents/

14 exp Monoamine Oxidase Inhibitors/

15 exp Serotonin Agents/

16 exp Histamine Agents/

18 exp "Hypnotics and Sedatives"/

19 exp Adrenergic Agents/

20 (acebutolol or alimemazine or alprazolam or amitriptyline or atenolol or bisoprolol or bromazepam or buproprion or buspirone or

30 ((end-stage* or end stage) adj6 (disease or illness* or care)).mp.

#30 (end -stage* or end stage) near/6 (disease or illness* or care)

29 ((end-stage* or end stage) adj6 (disease or illness* or care)).mp.